CN100413878C - Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof - Google Patents
Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof Download PDFInfo
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- CN100413878C CN100413878C CNB038244993A CN03824499A CN100413878C CN 100413878 C CN100413878 C CN 100413878C CN B038244993 A CNB038244993 A CN B038244993A CN 03824499 A CN03824499 A CN 03824499A CN 100413878 C CN100413878 C CN 100413878C
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Abstract
The present invention provides pyrazole derivatives represented by the general formula: wherein R<1> represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group represented by the general formula: or a group represented by the general formula: while the other represents an optionally substituted C1-6 alkyl group etc.; R<2> represents H, a halogen atom, OH, an optionally substituted C1-6 alkyl group etc.; X represents a single bond, O or S; Y represents an optionally substituted C1-6 alkylene group etc.; Z represents -R<B>, -COR<C> etc. in which R<B> represents an optionally substituted C1-6 alkyl group etc.; and R<C> represents an optionally substituted C1-6 alkyl group etc.,; R<4> represents H, an optionally substituted C1-6 alkyl group etc.; and R<3>, R<5> and R<6> represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase of blood galactose level such as galactosemia, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.
Description
Technical field
The present invention relates to the pyrazole derivatives of useful as drug, its pharmacy acceptable salt or its prodrug contain their pharmaceutical composition, its pharmaceutical use and be used to produce their intermediate.
More specifically, the present invention relates in people SGLT1, have the active pyrazole derivatives of inhibition, its pharmacy acceptable salt or its prodrug, their useful as drug are with prevention or treatment and hyperglycemia diseases associated (as diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication or obesity), and with blood semi-lactosi level rising diseases associated (as galactosemia).Also relate to the pharmaceutical composition that contains them, its pharmaceutical use and be used to produce their intermediate.
Background technology
Diabetes are and one of mode of life diseases associated that its background is the change of food habits and lacks motion.Therefore, in diabetic, carry out diet and kinesitherapy.In addition, when being difficult to fully control and persistent movement, pharmacological agent can be carried out simultaneously.In addition, large-scale clinical trial is verified, is necessary to carry out the strictness control of secular glucose level, so that prevent diabetic because receive treatment and take place or develop diabetic complication (document 1 and 2 of face as follows).In addition, the many epidemiological studies at impaired glucose tolerance and macroscopical vascular disease (macroangiopathy) show that impaired glucose tolerance also is the Hazard Factor of macroscopical vascular disease and diabetes as a kind of boundary types.Therefore, need improve postprandial hyperglycemia and become focus (the face document 3 as follows).
In recent years, under the background that diabetic increases fast, the exploitation of various antidiabetic medicines is underway.For example, alpha-glucosidase inhibitor (it can postpone the digestion of carbohydrate and the absorption in small intestine) is used to improve postprandial hyperglycemia.Report that also when acarbose (a kind of alpha-glucosidase inhibitor) when being used to suffer from the patient of impaired glucose tolerance, it has prevention or postpones the effect (the face document 4 as follows) of the morbidity of diabetes.Yet, form the high glucose level (the face document 5 as follows) that causes because alpha-glucosidase inhibitor can not influence because of the sugar that changes recently in ingestion of glucose monose and the meal, therefore need exploitation to have the active medicine that suppresses carbohydrate absorption more widely.
Simultaneously, know that sodium dependent glucose vehicle 1 (SGLT1) is present in the small intestine, the absorption of its control carbohydrate.Also report,, have the incomplete absorption (row document 6-8 as follows) of glucose and semi-lactosi because of congenital people SGLT1 has among the handicapped patient unusually.In addition, verified, SGLT1 relates to the absorption (row document 9 and 10 as follows) of glucose and semi-lactosi.
In addition, confirm that OLETF rat and suffering from the rat of U-9889 inductive diabetic symptom, the mRNA of SGLT1 and albumen increase, and (row document 11 and 12 as follows) accelerated in the absorption of glucose.Usually, in diabetic, the digestion and the absorption of carbohydrate increase.For example, confirm that the mRNA of SGLT1 and albumen are (the face document 13 as follows) that roll up in people's small intestine.
Therefore, blocking-up people SGLT1 activity can suppress carbohydrate such as the absorption of glucose in small intestine, can prevent the rising of glucose level subsequently.Especially, think, postpone the absorption of glucose, can make postprandial hyperglycemia normalizing effectively based on above-mentioned mechanism.In addition, because the increase of SGLT1 is considered to cause the increase of carbohydrate absorption in the small intestine,, has needed to develop as early as possible people SGLT1 has been had the active medicine of effective inhibition therefore in order to prevent or treat diabetes.
Reference 1: diabetes contrast and complication experimental study group (The Diabetes Control andComplications Trial Research Group), N.Engl.J.Med., 1993.9, Vol.329, No.14, pp.977-986;
Reference 2: the following diabetes study group (UK Prospective Diabetes Study Group) of Britain, Lancet, 1998.9, Vol.352, No.9131, pp.837-853;
Reference 3:Makoto, TOMINAGA, Endocrinology ﹠amp; Diabetology, 2001.11, Vol.13, No.5, pp.534-542;
Reference 4:Jean-Louis Chiasson and 5 people, Lancet, 2002.6, Vol.359, No.9323, pp.2072-2077;
Reference 5:Hiroyuki, 0DAKA and 3 people, Journal of Japanese Society ofNutrition and Food Science, 1992, Vol.45, No.1, pp.27-31;
Reference 6:Tadao, BABA and 1 people, Supplementary volume of Nippon Rinsho, Ryoikibet su Shokogun, 1998, No.19, pp.552-554;
Reference 7:Michihiro, KASAHARA and 2 people, Saishin Igaku, 1996.1, Vol.51, No.1, pp.84-90;
Reference 8:Tomofusa, TSUCHIYA and 1 people, Nippon Rinsho, 1997.8, Vol.55, No.8, pp.2131-2139;
Reference 9:Yoshikatsu, KANAI, Kidney and Dialysis, 1998.12, Vol.45, supplementary issue, pp.232-237;
Reference 10:E.Turk and 4 people, Nature, 1991.3, Vol.350, pp.354-356;
Reference 11:Y.Fujita and 5 people, Diabetologia, 1998, Vol.41, pp.1459-1466;
Reference 12:J.Dyer and 5 people, Biochemical Society Transactions, 1997, Vol.25, p.479S;
Reference 13:J.Dyer and 4 people, American Journal of Physio1ogy, 2002.2, Vol.282, No.2, pp.G241-G248.
Summary of the invention
The inventor studies in earnest, to seek the SGLT1 that finds the right person the active compound of inhibition is arranged.As a result, found that the pyrazole derivatives shown in some following general formula (I) has the activity that suppresses people SGLT1 in small intestine, and the inhibition activity that excellence can be arranged the glucose level rising as follows, constituted basis of the present invention thus.
The inventor studies in earnest, to seek the SGLT1 that finds the right person the active compound of inhibition is arranged.As a result, found that the pyrazole derivatives shown in some following general formula (I) has the activity that suppresses people SGLT1 in small intestine, and as follows glucose level is raise there is excellent inhibition activity, constituted basis of the present invention thus.
The invention provides novel pyrazole derivatives, this derivative is by the absorption of carbohydrate such as glucose in and the inhibition small intestine active to the inhibition of people SGLT1, thereby the activity that the excellent inhibition glucose level of performance raises, its pharmacy acceptable salt or its prodrug also are provided, also provide the pharmaceutical composition that contains them, its pharmaceutical use and be used to produce their intermediate.
So, the present invention relates to
[1] pyrazole derivatives shown in the following general formula:
In the formula
R
1Expression hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, or can on ring, have identical or different 1-3 substituent aryl C
1-6Alkyl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group;
One among Q and the T is the group shown in the following formula:
Or the group shown in the following formula:
And another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
2Be hydrogen atom, halogen atom, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Alkoxyl group or-A-R
A, in the formula A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
ABe C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, carboxyl, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
The C of Y for being replaced by hydroxyl
1-6Alkylidene group or C
2-6Alkylene group;
Z is-R
B,-COR
C,-SO
2R
C,-CON (R
D) R
E,-SO
2NH
RF or-C (=NR
G) N (R
H) R
I
R
CRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl;
R
4, R
B, R
D, R
EAnd R
FCan be identical or different, and each naturally hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl, or R
4And R
BBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1- 6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, or R
DAnd R
EBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
G, R
HAnd R
ICan be identical or different, and each hydrogen atom, cyano group, formamyl, C naturally
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, nitro, C
1-6Alkyl sulphonyl, sulfoamido, imines formyl radical (carbamimidoyl) or C
1-6Alkyl, they can have 1-5 the identical or different group that is selected from following substituting group group (i), or R
GAnd R
HBoth are in conjunction with the formation ethylidene, or R
HAnd R
IBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
3, R
5And R
6Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; And
Substituting group group (i) is made of following: hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1- 6Alkyl) urea groups, list or two (C
1-6Alkyl) sulfoamido, C
2-7Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl sulphonyl, carboxyl, C
2-7Alkoxy carbonyl ,-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt;
[2] pyrazole derivatives in [1], wherein R above a kind of being described in
4Represent hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl; R
BRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl; R
CExpression can have 1-3 the identical or different substituent aryl of the group of being selected from down: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from substituting group group (i)
1-6Alkyl; And
Substituting group group (i) is made of following: hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1- 6Alkyl) urea groups, list or two (C
1-6Alkyl) sulfoamido, C
2-7Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl sulphonyl, carboxyl, C
2-7Alkoxy carbonyl ,-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt;
[3] at the pyrazole derivatives described in above-mentioned [2], Z is-R in the formula
BR
BExpression can have 1-3 the identical or different substituent aryl of the group of being selected from down: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from substituting group group (i)
1-6Alkyl; And
Substituting group group (i) is made of following: hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1- 6Alkyl) urea groups, list or two (C
1-6Alkyl) sulfoamido, C
2-7Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl sulphonyl, carboxyl, C
2-7Alkoxy carbonyl ,-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt;
[4] at the pyrazole derivatives described in above-mentioned [3], R in the formula
4Represent hydrogen atom; R
BExpression C
1-6Alkyl, it can have 1-5 the identical or different group that is selected from substituting group group (iA); And
Substituting group group (iA) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, carboxyl, C
2-7Alkoxy carbonyl and-CON (R
JA) R
KA, R wherein
JAAnd R
KACan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino and formamyl, or R
JAAnd R
KABoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl,
Or its pharmacy acceptable salt;
[5] at pyrazole derivatives or its pharmacy acceptable salt described in above-mentioned [4], R in the formula
BExpression can have the C of formamyl
1-6Alkyl;
[6] at pyrazole derivatives or its pharmacy acceptable salt described in above-mentioned [2], Z is-CON (R in the formula
D) R
E
[7] at the pyrazole derivatives described in above-mentioned [6], R in the formula
DRepresent hydrogen atom; R
EExpression has the C of 1-5 the identical or different group that is selected from substituting group group (iB)
1-6Alkyl; And substituting group group (iB) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino and-CON (R
JB) R
KB, R wherein
JBAnd R
KBCan be identical or different, and each hydrogen atom, C naturally
1-6Alkyl, they can have the substituting group that identical or different 1-3 is selected from down group: hydroxyl, amino and singly or two (C
1-6Alkyl) amino, or its pharmacy acceptable salt;
[8] at the pyrazole derivatives described in above-mentioned [2], Z is-C (=NR in the formula
G) N (R
H) R
I, or its pharmacy acceptable salt;
[9] at the pyrazole derivatives described in above-mentioned [8], R in the formula
GRepresent hydrogen atom or C
1-6Alkyl sulphonyl; R
HRepresent hydrogen atom; R
IThe C of the 1-5 that represents hydrogen atom maybe can have to be selected from substituting group group (iC) identical or different group
1-6Alkyl; And substituting group group (iC) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, or its pharmacy acceptable salt;
[10] at the pyrazole derivatives described in above-mentioned [2], Z is-COR in the formula
CR
CExpression can have the C of the group that is selected from substituting group group (iD)
1-6Alkyl; And substituting group group (iD) is made of following: amino and-CON (R
JC) R
KC, R wherein
JCAnd R
KCBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, or its pharmacy acceptable salt;
[11] arbitrary described pyrazole derivatives in above-mentioned [1]-[10], X is singly-bound or Sauerstoffatom in the formula; And Y is ethylene or trimethylene, or its pharmacy acceptable salt;
[12] arbitrary described pyrazole derivatives in above-mentioned [1]-[11], R in the formula
1Be hydrogen atom or hydroxyl (C
2-6Alkyl) group; T represents the group shown in the following formula:
Or the group shown in the following formula:
Q is C
1-6Alkyl or halo (C
1-6Alkyl) group; And R
3, R
5And R
6Be hydrogen atom or its pharmacy acceptable salt;
[13] arbitrary described pyrazole derivatives in above-mentioned [1]-[11], one in the formula among Q and the T is the group shown in the following formula:
Another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl, or its pharmacy acceptable salt;
[14] at the pyrazole derivatives described in above-mentioned [12] or [13], T is the group shown in the following formula in the formula:
Or its pharmacy acceptable salt;
[15] at the pyrazole derivatives described in above-mentioned [12] or [14], Q is a sec.-propyl in the formula, or its pharmacy acceptable salt;
[16] prodrug of arbitrary described pyrazole derivatives in above-mentioned [1]-[15], or its pharmacy acceptable salt;
[17] at the prodrug described in above-mentioned [16], wherein T is the group shown in the following formula:
Or the group shown in the following formula:
In the formula, replaced by glucopyranosyl or galactopyranose base, perhaps, replaced by following group: glucopyranosyl (glucopyranosyl), galactopyranose base (galactopyranosyl), C at 6 hydroxyls at 4 hydroxyls
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl or C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl;
[18] pyrazole derivatives in [1] above a kind of being described in, it is to be selected from compound and the pharmacy acceptable salt thereof described in the following example numbering:
Embodiment 28, embodiment 29, embodiment 32, embodiment 33, embodiment 45, embodiment 48, embodiment 51, embodiment 52 (embodiment 111), embodiment 55, embodiment 56, embodiment 57, embodiment 59, embodiment 66, embodiment 67, embodiment 71, embodiment 77, embodiment 79, embodiment 81, embodiment 82, embodiment 83, embodiment 84, embodiment 87, embodiment 90, embodiment 94, embodiment 107, embodiment 108, embodiment 109, embodiment 114, embodiment 117, embodiment 118, embodiment 119, embodiment 121, embodiment 123, embodiment 124, embodiment 126, embodiment 127, embodiment 128, embodiment 129, embodiment 130, embodiment 134, embodiment 141, embodiment 147, embodiment 150, embodiment 151, embodiment 170, embodiment 175, embodiment 177, embodiment 178, embodiment 179, embodiment 180 and embodiment 181;
[19] a kind of pharmaceutical composition, it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[20] a kind of people SGLT1 inhibitor, it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[21] a kind of preparation that suppresses postprandial hyperglycemia, it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[22] preparation of a kind of prevention or treatment hyperglycemia relative disease, it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[23] in the above being used to described in [22] preparation that prevents or treat, wherein the hyperglycemia relative disease is the disease that is selected from down group: diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia and gout;
[24] a kind of impaired glucose tolerance in the individuality or too much obstacle of fasting plasma glucose (impairedfasting glycemia) of preventing develops into the preparation of diabetes, and it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[25] a kind of prevention or treatment and the blood semi-lactosi level preparation of relevant disease that raises, it contains in top [1]-[18] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[26] in the above being used to described in [25] preparation that prevents or treat, be galactosemia wherein with the blood semi-lactosi level relevant disease that raises;
[27] in the above the pharmaceutical composition described in [19], wherein formulation is a sustained release preparation;
[28] in the above arbitrary described preparation in [20]-[26], wherein formulation is a sustained release preparation;
[29] method of a kind of prevention or treatment hyperglycemia relative disease, it comprises arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in top [1]-[18] of using significant quantity;
[30] a kind of method that develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose that is suppressed in the individuality, it comprises arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in top [1]-[18] of using significant quantity;
[31] method of a kind of prevention or treatment and blood semi-lactosi level rising diseases associated, it comprises arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in top [1]-[18] of using significant quantity;
[32] purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in [1]-[18] above, they are used to prepare the pharmaceutical composition of prevention or treatment hyperglycemia relative disease;
[33] purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in [1]-[18] above, they are used to prepare and are suppressed in the individuality pharmaceutical composition that develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose;
[34] purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in [1]-[18] above, they are used to prepare and are used to prevent or the pharmaceutical composition of treatment and blood semi-lactosi level rising diseases associated;
[35] a kind of pharmaceutical composition; it contains arbitrary described pyrazole derivatives in (A) top [1]-[18]; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibric acid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier;
[36] a kind of prevention or treatment hyperglycemia relative disease or with the method for blood semi-lactosi level rising diseases associated, it comprises that the medicine of using being selected from of significant quantity above-mentioned group (A) and at least one are selected from member's material of above-mentioned group (B);
[37] a kind of method that develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose that is suppressed in the individuality, it comprises that the medicine of using being selected from of significant quantity above-mentioned group (A) and at least one are selected from member's material of above-mentioned group (B);
[38] a kind of medicine that is selected from above-mentioned group (A) is selected from the purposes of member's material of above-mentioned group (B) with at least one, and they are used to prepare the pharmaceutical composition of prevention or treatment hyperglycemia relative disease and blood semi-lactosi level rising diseases associated;
[39] a kind of medicine that is selected from above-mentioned group (A) and at least one are selected from the purposes of member's material of above-mentioned group (B), and they are used to prepare and are suppressed in the individuality pharmaceutical composition that develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose;
[40] pyrazole derivatives shown in the following general formula:
In the formula
R
11Represent hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, the hydroxyl C that can have protecting group
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group or can on ring, have identical or different 1-3 substituent aryl (C
1-6Alkyl), described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group;
Q
2And T
2In one be 2,3,4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base group, 2,3,4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base group, 2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base group or 2; 3; 4,6-four-O-pivaloyl group-β-D-galactopyranose oxygen base group, and another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
12Be hydrogen atom, halogen atom, the hydroxyl that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Alkoxyl group or-A-R
1AIn the formula A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
1ABe C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl, the carboxyl that can have protecting group, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
Y
1Expression C
1-6Alkylidene group (hydroxyl that can be able to be had protecting group replaces) or C
2-6Alkylene group;
Z
1Expression-R
1B,-COR
1C,-SO
2R
1C,-CON (R
1D) R
1E,-SO
2NHR1F or-C (=NR
1G) N (R
1H) R
1I
R
1CRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl;
R
14, R
1B, R
1D, R
1EAnd R
1FCan be identical or different, and each naturally hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl maybe can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl, or R
14And R
1BBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, or R
1DAnd R
1EBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
1G, R
1HAnd R
1ICan be identical or different, and each hydrogen atom, cyano group, formamyl, C naturally
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, nitro, C
1-6Alkyl sulphonyl, sulfoamido, imines formyl radical (carbamimidoyl), maybe can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl, or R
1GAnd R
1HBoth are in conjunction with the formation ethylidene, or R
1HAnd R
1IBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
3, R
5And R
6Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; And
The substituting group group (ii) is made of following: hydroxyl, the C that can have protecting group
1-6Alkoxyl group, C
1-6Alkylthio, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6Alkyl) sulfoamido, C
2-7Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl sulphonyl, the carboxyl that can have protecting group, C
2-7Alkoxy carbonyl ,-CON (R
1J) R
1K, R wherein
1JAnd R
1KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
1JAnd R
1KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkoxyl group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkylthio: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino, or its salt; Or the like.
In the present invention, for example, R
1Preferably hydrogen atom or hydroxyl C
2-6Alkyl more preferably is a hydrogen atom; T is the following formula group preferably:
Perhaps following formula group:
Q is C preferably
1-6Alkyl or halo C
1-6Alkyl more preferably is C
1-6Alkyl; C among the Q
1-6Alkyl is ethyl or sec.-propyl preferably, more preferably is sec.-propyl; X is singly-bound or Sauerstoffatom preferably; Y is C preferably
1-6Alkoxyl group or C
2-6Alkylene group more preferably is C
1-6Alkoxyl group; C among the Y
1-6Alkylidene group is ethylidene, trimethylene or tetramethylene preferably, more preferably is ethylene or trimethylene.Z preferably-R
B,-COR
C,-CON (R
D) R
EOr-C (=NR
G) N (R
H) R
I, more preferably be-R
BOr-CON (R
D) R
E, and be best-R
BR among the Z
BC preferably
1-6Alkyl, this alkyl can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (iA), more preferably are the C with formamyl
1-6Alkyl; R in Z
DHydrogen atom preferably; R
EC preferably
1-6Alkyl, this alkyl can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (iB); R among the Z
GPreferably hydrogen atom or C
1-6Alkyl sulphonyl; R
HHydrogen atom preferably; R
IPreferably hydrogen atom or C
1-6Alkyl, it can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (iC); With the R among the Z
CC preferably
1-6Alkyl, this alkyl can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (iD).R
4 is preferredIt is hydrogen atom; R
2Preferably hydrogen atom, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Group shown in alkoxyl group or the following general formula :-A-R
AA and R in the formula
AHave identical meanings as defined above, and more preferably be hydrogen atom, chlorine atom, fluorine atom or methyl; And R
3, R
5And R
6Preferably hydrogen atom or halogen atom, and all they more preferably all be hydrogen atom.
As particular compound of the present invention, be representational at the compound described in the embodiment 1-187.Particularly, following compounds or its pharmacy acceptable salt are preferred.
For example, the represented compound of general formula of the present invention (I), can be according to following flow preparation:
Wherein L1 represents leavings group, for example halogen atom, mesyloxy, tosyloxy or similar group; L
2Expression MgBr, MgCl, MgI, ZnI, ZnBr, ZnCl or lithium atom; R represents C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl; R
0Expression C
1-6Alkyl; Q
3And T
3In one be hydroxyl, another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl; And R
1, R
2, R
3, R
4, R
5, R
6, R
11, R
12, R
14, Q, Q
2, T, T
2, X, Y, Y
1, Z and Z
1Has identical meanings as defined above.
Flow process 1-1
Compound shown in the above-mentioned general formula (VI) can prepare like this: in inert solvent, in the presence of alkali such as sodium hydride or potassium tert.-butoxide, with benzyl compounds shown in the following formula (IV) and the pyruvate condensation shown in the last formula V.As the inert solvent that is used to react, for example, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-2
Can prepare like this by the benzyl pyrazole derivative shown in the following formula (III): in inert solvent; in the alkali existence or not; hydrazine compound or its monohydrate shown in compound shown in the following formula (VI) and the following formula (VII) are carried out condensation, and under some occasion, introduce hydroxyl protection as required in the usual way.As the inert solvent that is used for condensation reaction, for example, toluene, tetrahydrofuran (THF), chloroform, methyl alcohol, ethanol, its mixed solvent etc. can be used as to be enumerated, and as alkali, for example triethylamine, N, N-diisopropylethylamine, pyridine, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.Benzyl pyrazole derivative shown in the following formula (III) that obtains after changing salify suitably with ordinary method, can be used for flow process subsequently.
Flow process 1-3
The compound of following formula (X) expression can prepare like this: in inert solvent, in the presence of alkali (as sodium amide), the ketone compound shown in dithiocarbonic acid ester cpds shown in the following formula (VII) and the following formula (IX) is carried out condensation.As the inert solvent that is used to react, for example, toluene etc. can be used as to be enumerated.Temperature of reaction usually can from-20 ℃ to room temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-4
The benzyloxy pyrazole derivatives of following formula (XI) expression can prepare like this: in inert solvent; at alkali (as triethylamine or N; the N-diisopropylethylamine) exists down; hydrazine compound shown in compound shown in the following formula (X) and the following formula (VII) or its monohydrate or its salt are carried out condensation, and under some occasion, introduce hydroxyl protection as required in the usual way.As the inert solvent that is used for condensation reaction, for example, acetonitrile etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times is generally 1 hour to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-5
The pyrazoles aldehyde derivatives of following formula (XII) expression can prepare like this: in all kinds of SOLVENTS, with phosphoryl chloride and N, dinethylformamide carries out the Vilsmeier reaction to the compound shown in the following formula (XI).As the solvent that is used to react, for example, N, dinethylformamide etc. can be used as and enumerate.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-6
The compound of following formula (XIV) expression can prepare like this: in inert solvent, with the lithium reagent condensation shown in the compound shown in the following formula (XII) and Grignard reagent, Reformatsky reagent or the following formula (XIII).As the inert solvent that is used to react, for example, tetrahydrofuran (THF), ether, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from-78 ℃ to room temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-7
Can prepare like this by the benzyl pyrazole derivative shown in the following formula (III): in inert solvent, in existing or not existing under the acid (example hydrochloric acid), with the compound shown in the following formula (XIV) being carried out shortening with palladium catalyst (as palladium-carbon dust), and have under the situation of sulphur atom at the compound shown in the following formula (XIV), the compound that obtains is carried out acid treatment in the aqueous solution of trifluoroacetic acid and dimethyl thioether, usually 0 ℃ to reflux temperature reaction 30 minutes to 1 day, this can be according to actual needs.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, acetate, Virahol or its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.The benzyl pyrazole derivative of following formula (III) expression that obtains after changing salify suitably with ordinary method, can also be used for flow process subsequently.
Flow process 1-8
[1] in the benzyl pyrazole derivative of following formula (III) expression, works as Q
3And T
3In one be C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7During cycloalkyl; the present invention can be prepared like this by the respective compound of following formula (II) expression: in inert solvent; in existing under the alkali (as silver carbonate, sodium hydride etc.), with acetyl bromide-α-D-glucose, acetyl bromide-α-D-semi-lactosi, 2,3; 4; 6-four-O-pivaloyl group-α-D-glucopyranosyl bromine or 2,3,4; 6-four-O-pivaloyl group-α-D-galactopyranose base bromine, the corresponding benzyl pyrazole derivative that following formula (III) is represented carries out glycosidation.As the inert solvent that is used to react, for example, tetrahydrofuran (THF), glycol dimethyl ether, N, dinethylformamide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
[2] in the benzyl pyrazole derivative of following formula (III) expression, work as Q
3And T
3In one be halo (C
1-6Alkyl) during group; the present invention can be prepared like this by the respective compound of following formula (II) expression: in inert solvent; alkali (as salt of wormwood etc.) exist down, with acetyl bromide-α-D-glucose, acetyl bromide-α-D-semi-lactosi, 2,3; 4; 6-four-O-pivaloyl group-α-D-glucopyranosyl bromine or 2,3,4; 6-four-O-pivaloyl group-α-D-galactopyranose base bromine, the corresponding benzyl pyrazole derivative that following formula (III) is represented carries out glycosidation.As the inert solvent that is used to react, for example, tetrahydrofuran (THF), acetonitrile, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
[3] in the benzyl pyrazole derivative of following formula (III) expression, work as Q
3And T
3In one be C
2-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7During cycloalkyl; the present invention can be prepared like this by the respective compound of following formula (II) expression: in aqueous inert solvent; in alkali (as sodium hydroxide; potassium hydroxide; salt of wormwood; Deng) and phase-transfer catalyst (as zephiran chloride three (normal-butyl) ammonium; bromination benzyl three (normal-butyl) ammonium; hydrogen sulfate four (normal-butyl) ammonium; Deng) exist down; with acetyl bromide-α-D-glucose; acetyl bromide-α-D-semi-lactosi; 2; 3; 4; 6-four-O-pivaloyl group-α-D-glucopyranosyl bromine or 2; 3; 4; 6-four-O-pivaloyl group-α-D-galactopyranose base bromine, the corresponding benzyl pyrazole derivative that following formula (III) is represented carries out glycosidation.As the inert solvent that is used to react, methylene dichloride, toluene, its mixed solvent of phenylfluoroform etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
The benzyl pyrazole derivative of the glycosidation of following formula (II) expression that obtains is changing salify and after separating suitably with ordinary method, can also be used for flow process subsequently.
Flow process 1-9
The pyrazole derivatives of following formula of the present invention (I) expression can prepare like this: the compound of following formula (II) expression is carried out alkaline hydrolysis, remove blocking group then or the nitro of the compound that forms is reduced, this can according to circumstances need.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.As mentioned above, after hydrolysis compound at R
11, R
12, R
14, Y
1And/or Z
1In when having blocking group, protecting group can be removed suitably with ordinary method.In addition, after above-mentioned reaction is finished, the compound that nitro is arranged in R2 of following formula (I) expression can be derivatized to by catalytic reduction has amino compound accordingly, wherein use palladium catalyst (as palladous oxide) and in inert solvent (as ethyl acetate), according to a conventional method usually in room temperature reaction 30 minutes to 1 day to the reflux temperature.
In the compound of representing as the following formula (III) of raw material, can there be following 3 kinds of R
11 is the tautomer of hydrogen atom, and they change along with the difference of reaction conditions, and the compound of following formula (III) expression comprises all these compounds:
R wherein, R
3, R
5, R
6, R
12, R
14, X, Y
1And Z
1Has identical meanings as defined above.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1Be C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl or can on ring, have identical or different 1-3 substituent aryl C
1-6(described substituting group is selected from down group to alkyl: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group) compound, for example, according to following flow preparation:
L wherein
3Expression leavings group, for example halogen atom, mesyloxy, tosyloxy or similar group; R
21Expression C
1-6Alkyl, C
2-6Alkenyl, the hydroxyl (C that can have protecting group
2-6Alkyl) group, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, or can on ring, have identical or different 1-3 substituent aryl C
1-6(described substituting group is selected from down group to alkyl: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group); R
31Expression C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl or can on ring, have identical or different 1-3 substituent aryl C
1-6(described substituting group is selected from down group to alkyl: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group); And R
2, R
3, R
4, R
5, R
6, R
12, R
14, Q, Q
2, T, T
2, X, Y, Y
1, Z and Z
1Has identical meanings as defined above.
Flow process 2
The pyrazole derivatives of following formula of the present invention (Ia) expression can prepare like this: press and the similar approach described in the above-mentioned flow process 1-9; compound to following formula (IIa) expression is hydrolyzed; then in inert solvent; in existing under the alkali (as cesium carbonate or salt of wormwood); alkylating agent with following formula (XV) expression carries out the N-alkanisation; and and have at compound under the situation of blocking group, according to circumstances need blocking group to be removed suitably with ordinary method.As the inert solvent that is used for the N-alkanisation, for example, acetonitrile, ethanol, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 10 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1, R
4With Z be the compound of hydrogen atom, for example, also can be according to following flow preparation:
L wherein
4Expression leavings group, for example mesyloxy, tosyloxy or similar group; And R
2, R
3, R
5, R
6, R
12, Q, Q
2, T, T
2, X, Y and Y
1Has identical meanings as defined above.
Flow process 3-1
The compound of following formula (XVII) expression can prepare like this: in inert solvent, the compound of following formula (XVI) being represented with palladium catalyst (as palladium-carbon dust) carries out shortening, so that remove benzyl.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, acetate, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-2
The compound of following formula (XVIII) expression can prepare like this: in inert solvent, in alkali (as triethylamine or N, the N-diisopropylethylamine) exists down,, leavings group is introduced the compound shown in the following formula (XVII) with sour muriate (as methylsulfonyl chloride or toluene sulfonyl chloride).As the solvent that is used to introduce reaction, for example, methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to room temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-3
The compound of following formula (XIX) expression can prepare like this: in inert solvent, with azide reagent (as sodiumazide), the compound shown in the following formula (XVIII) is carried out azide.As the solvent that is used for azido reaction, for example methylene dichloride, ethyl acetate, N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone, N, N-dimethyl-imidazolinone, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-4
Compound shown in the following formula of the present invention (IIb) can prepare like this: in inert solvent, with palladium catalyst (as palladium-carbon dust) the described compound of following formula (XIX) is carried out shortening.As the solvent that is used for catalytic hydrogenation reaction, for example tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate, its mixed solvent etc. can be used as and enumerate.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-5
The compound of following formula (XX) expression can prepare like this: the compound shown in the following formula (XIX) is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12And/or Y
1Under the situation of middle protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
Flow process 3-6
The pyrazole derivatives of following formula of the present invention (Ib) expression can prepare like this: the compound to following formula (IIb) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as and enumerate.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12 Hes/ or Y
1Under the situation of middle protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
Flow process 3-7
The pyrazole derivatives of following formula of the present invention (Ib) expression can prepare like this: in inert solvent, with palladium catalyst (as palladium-carbon dust), the compound shown in the following formula (XX) is carried out shortening.As the solvent that is used for catalytic hydrogenation reaction, for example tetrahydrofuran (THF), methyl alcohol, ethanol, ethyl acetate, its mixed solvent etc. can be used as and enumerate.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1And R
4For hydrogen atom and Z are-COR
C,-SO
2R
C,-CON (R
D) R
EOr-C (=NR
2G) NHR
2HCompound, for example, according to following flow preparation:
L wherein
5Expression leavings group, for example pyrazolyl, methylthio group, benzotriazole base or similar group; R
2GAnd R
2HCan be identical or different, and each hydrogen atom, benzyloxycarbonyl or tert-butoxycarbonyl naturally; Z
2Expression-COR
1C,-SO
2R
1C,-CONHR
IDOr-C (=NR
2G) NHR
2HZ
AExpression-COR
C,-SO
2R
C,-CONHR
DOr-C (=NR
2G) NHR
2HAnd R
1C, R
1D, R
1E, R
2, R
3, R
5, R
6, R
12, R
D, R
E, Q, Q
2, T, T
2, X, Y and Y
1Has identical meanings as defined above.
Flow process 4-1
The compound of following formula (IIc) expression can prepare like this: according to following method 1-4 the compound shown in the following formula (IIb) is handled, according to circumstances needed then to remove blocking group with ordinary method.
＜method 1 〉
With the compound shown in the following formula (IIb), with with following formula (XXI) or the sour muriate (XXII), exist down (as triethylamine, N in alkali, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) and in inert solvent (as methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, acetonitrile or its mixed solvent), usually 0 ℃ to reflux temperature, reacted usually 30 minutes to 1 day.
＜method 2 〉
With the compound shown in the following formula (IIb), with isocyanic ester (or salt) compound shown in the following formula (XXIII), in existing or not existing alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene), and in inert solvent (as methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, acetonitrile, toluene or its mixed solvent), usually 0 ℃ to reflux temperature, reacted usually 30 minutes to 1 day.
＜method 3 〉
With the compound shown in the following formula (IIb), with the carboxylic acid cpd shown in the following formula (XXIV) (according to circumstances need add suitably once in a while I-hydroxybenzotriazole after), in the presence of condensing agent (as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexyl carbodiimide), and exist or do not exist alkali (as triethylamine or N, the N-diisopropylethylamine) and in inert solvent (as N, dinethylformamide, methylene dichloride or its mixed solvent), usually 0 ℃ to reflux temperature, reacted usually 1 hour to 2 days.
＜method 4 〉
With the compound shown in the following formula (IIb), with the guanidine radicals reagent shown in the following formula (XXV) (as N-benzyloxycarbonyl-1H-pyrazoles-1-acyl amidine (carboxami dine)), in inert solvent (as tetrahydrofuran (THF), methyl alcohol, ethanol, toluene, N, dinethylformamide or its mixed solvent), usually in room temperature to reflux temperature, reacted usually 1 hour to 5 days.
Flow process 4-2
The pyrazole derivatives of following formula of the present invention (Ic) expression can prepare like this: the compound to following formula (IIc) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as and enumerate.As alkali, for example sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as and enumerate.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, Y
1And/or Z
2In have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
Flow process 5-1
The Acibenzolar compound of following formula (XXVII) expression can prepare like this: with the compound shown in the following formula (IIb), with the reagent that is used to prepare Acibenzolar shown in the following formula (XXVI), in alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) exist down, and in inert solvent, react.As the solvent that is used for condensation reaction, for example methylene dichloride, tetrahydrofuran (THF), ethyl acetate, acetonitrile, pyridine, its mixed solvent etc. can be used as and enumerate.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-2
Pyrazole derivatives shown in the following formula of the present invention (IId) can prepare like this: with the compound shown in the following formula (XXVII); with amine compound or its salt shown in the following formula (XXVIII); in existing or not existing alkali (as triethylamine, N; N-diisopropylethylamine, pyridine, 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium hydride, potassium tert.-butoxide, salt of wormwood or cesium carbonate); and in inert solvent, react, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for condensation reaction, for example, methylene dichloride, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, acetonitrile, pyridine, N, dinethylformamide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-3
Pyrazole derivatives shown in the following formula of the present invention (Id) can prepare like this: the compound shown in the following formula (IId) is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, R
1D, R
1EAnd/or Y
1In have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1For hydrogen atom and Z are R
BCompound, for example, also can be according to following flow preparation:
R in the formula
14, R
1B, R
2, R
3, R
4, R
5, R
6, R
12, R
B, L
4, Q, Q
2, T, T
2, X, Y and Y
1Has identical meanings as defined above.
Flow process 6
Pyrazole derivatives shown in the following formula of the present invention (Ie) can prepare like this: (wherein according to circumstances need and can carry out after adding sodium iodide) in inert solvent; in existing or not existing alkali (as triethylamine; N; the N-diisopropylethylamine; pyridine; 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene; sodium hydride; potassium tert.-butoxide; salt of wormwood or cesium carbonate); amine compound or its salt shown in compound shown in the following formula (XVIII) and the following formula (XXIX) are carried out condensation; the compound that forms is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for condensation reaction, for example, acetonitrile, N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone, methyl alcohol, ethanol, 2-propyl alcohol, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 1 hour to 5 days, this can change according to used raw material, solvent and temperature of reaction.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, R
14, R
1BAnd/or Y
1Have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1Be hydrogen atom; R
4Be C
1-6Alkyl, it can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (i); Represent hydrogen atom, C with Z
1-6Alkyl (can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (i)) ,-COR
C,-SO
2R
C,-CONHR
DOr-C (=NR
2G) NHR
2HCompound, for example, also can be according to following flow preparation:
L wherein
6Expression leavings group, for example halogen atom, mesyloxy, tosyloxy or similar group; W represents 2-nitro, 4-nitro or 2,4-dinitrobenzene; R
24Expression C
1-6Alkyl, it can have and is selected from above-mentioned substituting group group 1-5 (ii) identical or different group; R
34After reduction, form R with adjacent carbons
24R
4BAnd R
5BBoth and adjacent carbons combine, and constitute to have side chain C after reduction
3-6The R of alkyl
24R
4AExpression C
1-6Alkyl, it can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (i); Z
3Expression C
1-6Alkyl (it can have be selected from above-mentioned substituting group group 1-5 (ii) identical or different group) ,-COR
1C,-SO
2R
1C,-CONHR
1DOr-C (=NR
2G) NHR
2HZ
BExpression C
1-6Alkyl (it can have 1-5 the identical or different group that is selected from above-mentioned substituting group group (i)) ,-COR
C,-SO
2R
C,-CONHR
DOr-C (=NR
2G) NHR
2HAnd L
5, R
1C, R
1D, R
2G, R
2H, R
2, R
3, R
5, R
6, R
12, Q, Q
2, T, T
2, X, Y and Y
1Has identical meanings as defined above.
Flow process 7-1
Compound shown in the following formula of the present invention (IIe) can be according to following method 1-3 from the compound shown in the following formula (IIb).
＜method 1 〉
1) with the compound shown in the following formula (IIb), with the sour muriate shown in the following formula (XXX), in existing alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene), and in inert solvent (as methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, acetonitrile or its mixed solvent), usually at 0 ℃ to room temperature, usually reaction is 30 minutes to 1 day, thus corresponding sulfonamide compounds.
2) sulfonamide compounds of Huo Deing, in inert solvent (as N, dinethylformamide, acetone, tetrahydrofuran (THF), acetonitrile or its mixed solvent) and can need add after the sodium iodide by situation, exist down in alkali (as salt of wormwood, cesium carbonate or sodium hydride), carry out the N-alkylation with the alkylating agent shown in the following formula (XXXI), reacted 1 hour to 2 days to reflux temperature in room temperature usually.Perhaps, the sulfonamide compounds that obtains, in inert solvent (as tetrahydrofuran (THF), ethyl acetate, acetonitrile or its mixed solvent), in the presence of azodicarboxy acid diesters (as diethylazodicarboxylate (diethyl azodicarboxylate) or diisopropyl azo-2-carboxylic acid) and triphenylphosphine, carry out the N-alkylation with the alkylol cpd shown in the following formula (XXXII), usually in room temperature to reflux temperature, usually reaction is 30 minutes to 1 day, thereby the acquisition corresponding N, the dibasic sulfonamide compounds of N-.
3-4) the N of Huo Deing; the dibasic sulfonamide compounds of N-; at inert solvent (as N; dinethylformamide, acetonitrile or its mixed solvent) in; exist down in alkali (as cesium carbonate or salt of wormwood), go protection, reacted 1 hour to 1 day usually to reflux temperature in room temperature usually with thiol reagent (as Thiovanic acid or thiophenol); thereby obtain corresponding secondary amine compound, and protecting group can need according to circumstances to remove with ordinary method.
＜method 2 〉
The ketone compound of the aldehyde cpd of following formula (XXXIII) expression or following formula (XXXIV) expression, in inert solvent (as tetrahydrofuran (THF), 1,2-ethylene dichloride, acetate or its mixed solvent), reductive agent as (cyano group sodium borohydride or triacetyl oxygen base sodium borohydride) in the presence of, carry out reductive amination with the compound shown in the following formula (IIb).Usually in room temperature to reflux temperature, reacted usually 1 hour to 1 day.
＜method 3 〉
Compound shown in the following formula (IIb), carry out N-alkylation (can by situation need after adding sodium iodide) with the alkanisation reagent shown in the following formula (XXXI), be reflected at existence or do not exist alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) under, in inert solvent (as acetonitrile, N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone, methyl alcohol, ethanol, 2-propyl alcohol or its mixed solvent), and usually in room temperature to reflux temperature, carried out 1 hour to 5 days.
Flow process 7-2
1) sulfonamide compounds shown in the following formula (XXXV) carries out the N-alkylation with the compound shown in the following formula (XVII).Being reflected at azodicarboxy acid diesters (as diethylazodicarboxylate or diisopropyl azo-2-carboxylic acid) and triphenylphosphine exists down, in inert solvent (as tetrahydrofuran (THF), ethyl acetate, acetonitrile or its mixed solvent), usually in room temperature to reflux temperature, usually carried out 30 minutes to 1 day, thereby the acquisition corresponding N, the dibasic sulfonamide compounds of N-.
2-3) the N of Huo Deing, the dibasic sulfonamide compounds of N-goes protection with thiol reagent (as Thiovanic acid or thiophenol).Being reflected at alkali (as cesium carbonate or salt of wormwood) exists down; in inert solvent (as N; dinethylformamide, acetonitrile or its mixed solvent); usually in room temperature to reflux temperature; usually carried out 1 hour to 1 day; thereby obtain corresponding secondary amine compound, and protecting group can need according to circumstances to remove with ordinary method, thereby prepare the pyrazole derivatives shown in the following formula of the present invention (IIe).
Flow process 7-3
The pyrazole derivatives of following formula of the present invention (If) expression can prepare like this: the compound shown in the following formula (IIe) is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, R
24And/or Y
1Have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
Flow process 7-4
The compounds of this invention shown in the following formula (IIf) can from the compound shown in the following formula (IIe), according to circumstances need to remove blocking group with ordinary method then according to following method 1-6.
＜method 1 〉
Sour muriate reaction with the compound shown in the following formula (IIe) and following formula (XXI) or (XXII).This reacts on alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene) exist down, and in inert solvent (as methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, acetonitrile or its mixed solvent), usually 0 ℃ to reflux temperature, carried out usually 30 minutes to 1 day.
＜method 2 〉
Isocyanic ester (or salt) compound shown in the compound following formula (XXIII) shown in the following formula (IIe) is reacted.This reacts on existence or does not exist alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene), in inert solvent (as methylene dichloride, ethyl acetate, tetrahydrofuran (THF), pyridine, acetonitrile, toluene or its mixed solvent), usually 0 ℃ to reflux temperature, carried out usually 30 minutes to 1 day.
＜method 3 〉
With the carboxylic acid cpd shown in compound shown in the following formula (IIe) and the following formula (XXIV) reaction (can after need adding I-hydroxybenzotriazole suitably) by situation.This reaction condensing agent (as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexyl carbodiimide) exists down, and exist or do not exist alkali (as triethylamine or N, the N-diisopropylethylamine), and in inert solvent (as N, dinethylformamide, methylene dichloride or its mixed solvent), usually 0 ℃ to reflux temperature, carried out usually 1 hour to 2 days.
＜method 4 〉
Guanidine radicals reagent shown in compound shown in the following formula (IIe) and the following formula (XXV) (is reacted as N-benzyloxycarbonyl-1H-pyrazoles-1-acyl amidine (carboxamidine).This is reflected in the inert solvent in (as tetrahydrofuran (THF), methyl alcohol, ethanol, toluene, N, dinethylformamide or its mixed solvent), usually in room temperature to reflux temperature, carried out usually 1 hour to 5 days.
＜method 5 〉
The ketone compound of the aldehyde cpd of following formula (XXXIII) expression or following formula (XXXIV) expression carries out reductive amination with the compound shown in the following formula (IIe).This is reflected at reductive agent (as cyano group sodium borohydride or triacetyl oxygen base sodium borohydride) and exists down, in inert solvent (as tetrahydrofuran (THF), 1,2-ethylene dichloride, acetate or its mixed solvent), usually in room temperature to reflux temperature, carried out usually 1 hour to 1 day.
＜method 6 〉
Compound shown in the following formula (IIe) carries out alkylation (can after need adding sodium iodide suitably by situation) with the alkylating agent shown in the following formula (XXXI).This is reflected at existence or does not exist alkali (as triethylamine, N, N-diisopropylethylamine, pyridine or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene), in inert solvent (as acetonitrile, N, dinethylformamide, methyl-sulphoxide, N-Methyl pyrrolidone, methyl alcohol, ethanol, 2-propyl alcohol or its mixed solvent), usually in room temperature to reflux temperature, carried out usually 1 hour to 5 days.
Flow process 7-5
Pyrazole derivatives of the present invention shown in the following formula (Ig) can prepare like this: the compound shown in the following formula (IIf) is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, R
24, Y
1And/or Z
3In have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1Be hydrogen atom; The X represention oxygen atom; Y is-CH
2CH (OH) CH
2-; With Z be R
BCompound, for example, also can be according to following flow preparation:
L wherein
7Expression leavings group, for example halogen atom, mesyloxy, tosyloxy, nosyloxy group or similar group; And R
1B, R
2, R
3, R
4, R
5, R
6, R
12, R
14, R
B, Q, Q
2, T and T
2Has identical meanings as defined above.
Flow process 8-1
The compound of following formula (XXXVIII) expression can prepare like this: the alkylating agent with shown in the following formula (XXXVII), carry out the O-alkylation to the compound shown in the following formula (XXXVI).This is reflected at and need adds phase-transfer catalyst (as bromination four (normal-butyl) ammonium etc.) suitably by situation and afterwards, exist down in alkali (as cesium carbonate, salt of wormwood, sodium hydride, sodium hydroxide, cesium fluoride etc.), carries out in inert solvent.As being used for the alkylating solvent of O-, N, dinethylformamide, acetone, tetrahydrofuran (THF), chlorobenzene, methylene dichloride, water, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 1 hour to 3 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 8-2
Pyrazole derivatives of the present invention shown in the following formula (Ih) can prepare like this: amine or its salt shown in compound shown in the following formula (XXXVIII) and the following formula (XXIX) are carried out condensation.This is reflected at and exists or do not exist under the alkali (as triethylamine, N, N-diisopropylethylamine, pyridine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium hydride, potassium tert.-butoxide, salt of wormwood or cesium carbonate), carries out in inert solvent.Again the compound that forms is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for condensation reaction, for example, acetonitrile, N, dinethylformamide, methyl alcohol, ethanol, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can be from room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
12, R
14And/or R
1BIn have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1And R
4Represent hydrogen atom; With Z-C (=NCN) N (R
7) R
8Compound, for example, also can be according to following flow preparation:
R in the formula
7And R
8Can be identical or different, and each naturally hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from above-mentioned substituting group group (i)
1-6Alkyl, or R
7And R
8Both and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The C that alkyl sulfonyl-amino replaces
1-6Alkyl; And R
1B, R
2, R
3, R
5, R
6, R
12, R
14, Q, Q
2, T, T
2, X, Y and Y
1Has identical meanings as defined above.
Flow process 9-1
The compound of following formula (XXXX) expression can prepare like this: in inert solvent, condensation is carried out in the different sulfonyl urea agent (isothioureidating reagent) shown in compound shown in the following formula (IIb) and the following formula (XXXIX).As the solvent that is used for condensation reaction, for example, methyl alcohol, ethanol, 2-propyl alcohol, tetrahydrofuran (THF), toluene, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
Flow process 9-2
The present invention can be prepared like this by the compound of following formula (II) expression: in inert solvent; in existing or not existing alkali (as triethylamine, N; N-diisopropylethylamine, pyridine, 1; 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium hydride, potassium tert.-butoxide, salt of wormwood or cesium carbonate) under; amine compound or its salt shown in compound shown in the following formula (XXXX) and the following formula (XXIX) are carried out condensation; again the compound that forms is carried out alkaline hydrolysis, according to circumstances need then to remove blocking group with ordinary method.As the solvent that is used for condensation reaction, for example, methyl alcohol, ethanol, acetonitrile, 2-propyl alcohol, N, dinethylformamide, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can be from room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate, methylamine, dimethylamine etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound after hydrolysis is at R
1B, R
12, R
14And/or Y
1In have under the situation of protecting group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In above-mentioned production technique, need to remove under the situation of blocking group, also can use the method except aforesaid method in the usual way.
With the The compounds of this invention that the following formula (I) of above-mentioned Production Flow Chart acquisition is represented, available conventional separation means is separated and purifying, as fractional recrystallization, usefulness chromatography purification, solvent extraction and Solid-Phase Extraction.
The pyrazole derivatives of following formula of the present invention (I) expression, available ordinary method changes pharmacy acceptable salt into.The example of these salt comprises and mineral acid (example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid etc.) acid salt of Xing Chenging, with organic acid (as arboxylic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, propionic acid, citric acid, succsinic acid, tartrate, fumaric acid, butyric acid, oxalic acid, propanedioic acid, toxilic acid, lactic acid, oxysuccinic acid, carbonic acid, L-glutamic acid, aspartic acid etc.) acid salt of Xing Chenging, the salt that forms with mineral alkali is (as sodium salt, sylvite etc.), and with organic bases (as N-methyl D glucosamine, N, N '-dibenzyl-ethylenediamin, the 2-monoethanolamine, three (methylol) aminomethane, arginine, Methionin etc.) salt of Xing Chenging.
The compound of following formula of the present invention (I) expression comprises the solvate that forms with pharmaceutically acceptable solvent (as the second alcohol and water).
In the pyrazole derivatives of following formula of the present invention (I) expression and prodrug thereof, have in each compound of unsaturated link(age) and have two kinds of isomer.In the present invention, can adopt cis (Z)-isomer or trans (E)-isomer.
In the pyrazole derivatives and prodrug thereof of following formula of the present invention (I) expression, in having each compound of unsymmetrical carbon, there are two kinds of rotational isomerisms of R isomer and S isomer (except pyranoglucose oxygen base section or galactopyranose oxygen base section).In the present invention, can use any one or two kinds of mixture of isomers in the isomer.
The preparation of the prodrug of the compound of following formula of the present invention (I) expression, can be according to a conventional method, use reagent corresponding, any one that organize under being selected from by compound shown in the proper group introducing following formula (I) that will form prodrug or a plurality of group: hydroxyl, amino and ring amino (as pyrazoles ring, piperazine), thereby produce prodrug (as halogenide etc.), according to circumstances need then to separate suitably and purifying with ordinary method.
As the group that is used at hydroxyl or amino formation prodrug, for example, C
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyls etc. can be used as to be enumerated.As the group that is used for forming prodrug at ring amino, for example, C
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl, (C
2-7Acyloxy) methyl, 1-(C
2-7Acyloxy) ethyl, (C
2-7Alkoxy carbonyl) oxo methyl, 1-[(C
2-7Alkoxy carbonyl) oxo] ethyl, (C
3-7Cycloalkyl) the oxo ketonic oxygen is for methyl, 1-[(C
3-7Cycloalkyl) oxo ketonic oxygen generation] ethyl etc. can be used as and enumerate.Term " C
1-6The C that alkoxyl group replaces
2-7Acyl group " refers to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
2-7Acyl group; Term " C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group " refers to by above-mentioned C
2-7The above-mentioned C that alkoxy carbonyl replaces
2-7Acyl group; Term " C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl " refers to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
2-7Alkoxy carbonyl; Term " (C
2-7Acyloxy) methyl " refer to by above-mentioned C
2-7The methylol that acyl group replaces at O-; Term " 1-(C
2-7Acyloxy) ethyl " refers to by above-mentioned C
2-7The 1-hydroxyethyl that acyl group replaces at O-; Term " (C
2-7Alkoxy carbonyl) oxo methyl " refer to by above-mentioned C
2-7The methylol that alkoxy carbonyl replaces; And term " 1-[(C
2-7Alkoxy carbonyl) oxo] ethyl " refer to by above-mentioned C
2-7The 1-hydroxyethyl that alkoxy carbonyl replaces at O-.In addition, term " (C
3-7Cycloalkyl) the oxo carbonyl " refers to have above-mentioned C
3-7The cyclo alkoxy carbonyl of cycloalkyl; Term " (C
3-7Cycloalkyl) the oxo ketonic oxygen is for methyl " refer to by above-mentioned (C
3-7Cycloalkyl) the oxo carbonyl is at the methylol of O-replacement; And term " 1-[(C
3-7Cycloalkyl) oxo ketonic oxygen generation] ethyl " refer to by above-mentioned (C
3-7Cycloalkyl) the oxo carbonyl is at the 1-hydroxyethyl of O-replacement.In addition, as the group that forms prodrug, glucopyranosyl or galactopyranose base can be used as to be enumerated.For example, these groups should be introduced in glucopyranosyl or the galactopyranose base 4 or 6 hydroxyl, more preferably are introduced in the glucopyranosyl 4 or 6 hydroxyl.
The pyrazole derivatives of following formula of the present invention (I) expression, for example, as described belowly suppress active at people SGLT1 and confirm to show in the test potent people SGLT1 and suppress active, and raise at the rat serum glucose level and to suppress the active activity that excellent inhibition blood glucose level raises that confirms to show in the test.Therefore, the pyrazole derivatives of following formula of the present invention (I) expression shows in small intestine urgees excellent SGLT1 inhibition activity, and can significantly suppress the rising of blood glucose level and/or reduce blood semi-lactosi level by the absorption that postpones glucose and semi-lactosi.Therefore, the pyrazole derivatives that contains following formula of the present invention (I) expression, its pharmacy acceptable salt or prodrug are as the pharmaceutical composition of activeconstituents, extremely be suitable for as the medicine that suppresses postprandial hyperglycemia, suppress in the individuality to develop into the medicine of diabetes from impaired glucose tolerance (IGT) or the too much obstacle of fasting plasma glucose (IFG), and the medicine of prevention or treatment hyperglycemia relative disease is [as diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication is (as retinopathy, neuropathy, ephrosis, ulcer, the macroscopic view vascular disease), obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, the lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia, gout etc., these diseases relate to the SGLT1 activity in the small intestine], and the medicine of prevention or treatment and blood semi-lactosi level rising diseases associated (as galactosemia).
In addition, The compounds of this invention is fit to and at least a drug combination except the SGLT2 inhibitor.Can comprise with the example of the medicine of The compounds of this invention coupling: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advancedglycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB (PDGF); Thr6 PDGF BB (PDGF) analogue is (as PDGF-AA; PDGF-BB; PDGF-AB); Urogastron (EGF); nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibric acid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier.
With The compounds of this invention and above-mentioned one or more drug combinations the time, the formulation that the present invention includes administration simultaneously (perhaps is single agent, perhaps for the preparation that separates of identical or different route of administration administration), and by the preparation that separates (with identical or different route of administration administration) of various dose administration pitch time.The pharmaceutical composition that contains The compounds of this invention and said medicine comprises the formulation as single agent or the preparation that separates, so that carry out coupling as mentioned above.
When with above-mentioned one or more medicines suitably during coupling, The compounds of this invention can or be treated in prevention and be obtained the effect more favourable than additive effect aspect the above-mentioned disease.In addition, compare with only using a kind of medicine, dosage can descend, and perhaps uses the adverse effect of the medicine except the SGLT1 inhibitor jointly and can be avoided or reduce.
Being used for the particular compound of coupling and preferred disease to be treated enumerates below.Yet the present invention is not limited thereto, and particular compound comprise its free cpds and they or other pharmacy acceptable salt.
The example of insulin sensitivity enhancer has, peroxisome proliferator-activated receptor-gamma agonists such as troglitazone, the hydrochloric acid U-721017E, rosiglitazone (rosiglitazone) maleate, darglitazone sodium, GI-262570, Netoglitazone (rosiglitazone), LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium and NIP-221, peroxisome proliferator-activated acceptor-alfa agonists such as GW-9578 and BM-170744, peroxisome proliferator-activated acceptor-α/gamma agonist such as GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 and DRF-MDX8, retinoids X receptor stimulant such as ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754 and hundred Sha Luoting (bexarotene), and if other insulin sensitivity enhancer lattice give birth to (reglixane), ONO-5816, MBX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929, AR-H049020 and GW-501516.Insulin sensitivity enhancer is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for diabetes, impaired glucose tolerance or hyperinsulinemia, this is because improved the disorderly situation of insulin signaling transduction in the surrounding tissue and strengthened that ingestion of glucose enters tissue from blood, thereby has reduced glucose level.
Example as glucose absorption inhibitor, compound except the SGLT1 inhibitor, alpha-glucosidase inhibitor such as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25 are arranged, 637, Camiglibose and MDL-73,945, alpha-amylase inhibitor such as AZM-127.Glucose absorption inhibitor is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity or hyperinsulinemia, more preferably be used for impaired glucose tolerance, this is because suppressed the enzymolysis of the enzyme of intestines and stomach to carbohydrate in the food, and suppresses or delayed the absorption of health to glucose.
The example of two guanidines has phenformin, hydrochloric acid buformin, hydrochloric acid metformin etc.Biguanides is preferred for diabetes, impaired glucose tolerance, diabetic complication or hyperinsulinemia, more preferably be used for diabetes, impaired glucose tolerance or hyperinsulinemia, this is because the restraining effect of liver glyconeogenesis has been reduced glucose level, has promoted the glucolytic influence of anaerobism in the tissue or has improved in the surrounding tissue effect to insulin resistance.
The example of insulin secretion enhancers has tolbutamide; P-607; first sulphur nitrogen grass urea; acetohexamide; U26452; glyburide (Glyburide); gliclazide; 1-butyl-3-metanilyl urine; invenol; glibornuride; Glipizide; gliquidone; glisoxepide; Glybuthiazole; glybuzole; glyhexamide; glymidine sodium; glypinamide; R-131; metahexamide; glimepiride; nateglinide (nateglinide); mitiglinide hydrate of calcium (mitiglinide calcium hydrate); repaglinide etc.In addition, insulin secretion enhancers comprises sugared kinase activator agent such as R0-28-1675.Insulin secretion enhancers is preferred for diabetes, impaired glucose tolerance or diabetic complication, more preferably be used for diabetes or impaired glucose tolerance, thereby this is because reduced glucose level and strengthened insulin secretion by acting on the pancreas beta cell.
The example of SGLT2 inhibitor, T-1095 is arranged and be described in compound in the following patent publications: Japanese patent application publication No.Hei10-237089 and 2001-288178, and international application publication No.WO01/16147, WO01/27128, WO01/68660, WO01/74834, WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/53573 etc.The SGLT2 inhibitor is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity or hyperinsulinemia, more preferably be used for diabetes, impaired glucose tolerance, obesity or hyperinsulinemia are because they can absorb the level that reduces blood glucose again by what suppress glucose at kidney proximal tubule place.
The example of Regular Insulin or insulin analog has the analogue of insulin human, animal insulin, human or animal's Regular Insulin etc.These preparations are preferred for diabetes, impaired glucose tolerance or diabetic complication, more preferably are used for diabetes or impaired glucose tolerance.
The example of glucagon receptor antagonist has BAY-27-9955, NNC-92-1687 etc.; The example of insulin receptor kinase stimulant has TER-17411, L-783281, KRX-613 etc.; The example of three peptidyl peptase II inhibitor has UCL-1397 etc.; The example of inhibitors of dipeptidyl IV has NVP-DPP728A, TSL-225, P-32/98 etc.; The example of Protein-tyrosine-phosphatase-1B inhibitor has PTP-112, OC-86839, PNU-177496 etc.; The example of glycogen phosphorylase inhibitors has NN-4201, CP-368296 etc.; The example of fructose-diphosphatase inhibitor has R-132917 etc.; The example of pyruvate dehydrogenase inhibitor has AZD-7545 etc.; The example of glycogen heteroplasia inhibitor has FR-225659 etc.; The example of glucagon-like-peptide-1 analogue has exendin-4, CJC-1131 etc.; The example of glucagon-like-peptide-1 agonist has AZM-134, LY-315902 etc.; The example of islet amyloid polypeptide, islet amyloid polypeptide analogue, islet amyloid polypeptide agonist has tripro-amylin acetate etc.In these medicines, G-6-Pase inhibitor, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like-peptide-1 are preferred for diabetes, impaired glucose tolerance, diabetic complication or hyperinsulinemia, more preferably are used for diabetes or impaired glucose tolerance.
The example of aldose reductase inhibitor has ascorbyl gamolenate, tolrestatin, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat (fidarestat), sorbinil, Statyl, Li Sasita (risarestat), zenarestat, minalrestat (minalrestat), Mei Suonier (methosorbini1), AL-1567, Mi Ruisita, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, Lin Duosita (lindolrestat) etc.Aldose reductase inhibitor is preferred for diabetic complication, and this is that it is present in the lasting hyperglycemia state of diabetic complication tissue because it can suppress the excessive intracellular accumulation that aldose reductase also can reduce Sorbitol Powder in the accelerating type poly-hydroxy approach.
The example that senior glycan end product forms inhibitor has Pyridoxylamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride etc.Senior glycan end product forms inhibitor and is preferred for diabetic complication, and this is because it can suppress the formation of senior glycan end product, increases under the lasting hyperglycemia state of this end product in diabetes, and can alleviate the damage of pair cell.
The example of inhibitors of protein kinase C has LY-333531, Mi Duosilin (midostaurin) etc.Inhibitors of protein kinase C is preferred for diabetic complication, but this is the activity because of its arrestin kinase c, and it continues to keep hyperglycemia state in diabetes.
The example of gamma-aminobutyric acid receptor antagonist has topiramate etc.; The example of sodium channel antagonist has mexiletine hydrochloride, O'Casey equality; The example of the transcription factor NF-KB inhibitor Pu Tan (dexlipotam) etc. that gets profit; The example of lipid peroxide enzyme inhibitors has Tiritazad (tirilazad) methylsulfonyl ester etc.; The example of the acid-Dipeptidase inhibitor of N-acetylize-α-connection has GPI-5693 etc.; The example of carnitine derivative has carnitine, hydrochloric acid L-carnitine, L-carnitine muriate, L-carnitine, ST-261 etc.In these medicines, insulin-like growth factor I, Thr6 PDGF BB, Thr6 PDGF BB analogue, Urogastron, nerve growth factor, uridine, 5-hydroxyl-1-methylhydantoi, EGB-761, ratio More, sulosemide, Y-128 are preferred for diabetic complication.
The example of anti-diarrhea agents or cathartic has polycarbophil calcium, albumin tannate, Vikaline etc.These medicines are preferred for following dysentery, the constipation and other diseases in diseases such as diabetes.
The example of methylol-glutaryl CoA reductase inhibitor has cerivastatin sodium, Pravastatin sodium, lovastatin, Simvastatin, fluvastatin sodium, the atorvastatin hydrate of calcium, SC-45355, SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987, Da Tating calcium (calcium pitavastatin), Luo Shatating calcium (calciumrosuvastatin), Colestolone, Dalvastatin, acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950, the lattice logical sequence is cut down his spit of fland, his spit of fland (carvastatin) of block-regulations, BMY-22089, Bervastatin etc.Methylol-glutaryl CoA reductase inhibitor is preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for hyperlipidaemia, hypercholesterolemia or arteriosclerosis, thereby this is to reduce blood cholesterol levels because it can suppress 3-hydroxy-3-methylglutaryl coenzyme A reductase.
The example of fiber acid derivative has bezafibrate, Sgd-24774, binifibrate, Win-35833, S-8527, chlorine Bei Te, the special aluminium of chlorine shellfish, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, Ronifibrate, simfibrate, Sai Oubeite (theofibrate), AHL-157 etc.Fiber acid derivative is preferred for hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for hyperlipidaemia, hypertriglyceridemia or arteriosclerosis, this is because it can activate the lipoprotein lipase of liver and strengthen oxidation of fatty acids, thereby has reduced the triglyceride levels of blood.
β
3The example of-adrenoceptor agonists has BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178 etc.β
3-adrenoceptor agonists is preferred for obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy, more preferably is used for obesity or hyperinsulinemia, and this is because it can stimulate β in the fatty tissue
3-adrenoceptor also strengthens oxidation of fatty acids, thereby causes consumed energy.
The example of acyl group-coenzyme A chole-sterol acyltransferase inhibitor has NTE-122; MCC-147; PD-132301-2; DUP-129; U-73482; U-76807; RP-70676; P-06139; CP-113818; RP-73163; FR-129169; FY-038; EAB-309; KY-455; LS-3115; FR-145237; T-2591; J-104127; R-755; FCE-28654; YIC-C8-434; A Wamite (avasimibe); CI-976; RP-64477; F-1394; Ai Demite (eldacimibe); CS-505; CL-283546; YM-17E; lecimibide; 447C88; YM-750; E-5324; KW-3033; HL-004; Ai Fumite (eflucimibe) etc.Acyl group-coenzyme A chole-sterol acyltransferase inhibitor is preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy; more preferably be used for hyperlipidaemia or hypercholesterolemia, thereby this is to reduce blood cholesterol levels because it can suppress acyl group-coenzyme A cholesterol acetyl transferase.
The example of thyroid hormone receptor agonists has sodium triiodothyronine, levothyroxine sodium, KB-2611 etc.; The example of cholesterol absorption inhibitor has Yi Zhami than (ezetimibe), SCH-48461 etc.; The example of esterase inhibitor has orlistat, ATL-962, AZM-131, RED-103004 etc.; The example of Carnitine palmitoyltransferase inhibitor has etomoxir etc.; The example of squalene synthase inhibitor has SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 etc.; The example of nicotinic acid derivates has that nicotinic acid, niacinamide, nicomol, pentaerythritol tetranicotinate, Yangxi are not taken charge of, Nicoril etc.; The example of bile acid chelating agent has Colestyramine, Colestilan, examines tretamine hydrochloride (colesevelamhydrochloride), GT-102-279 etc.; The example of sodium/bile acide cotransporter inhibitor has 264W94, S-8921, SD-5613 etc.; The example of cholestery ester transfer protein inhibitors has PNU-107368E, SC-795, JTT-705, CP-529414 etc.In these medicines, probucol, microsome tri-glyceride transporter inhibitors, lipoxygenase inhibitor, low density lipoprotein receptor toughener are preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy.
The example of appetite suppressant has monoamine reuptake inhibitors, thrombotonin reuptake inhibitor, thrombotonin release of irritants, combination of serotonin agonist (5HT especially
2C-agonist), norepinephrine reuptake inhibitor, norepinephrine release of irritants, α
1-adrenoceptor agonists, β
2-adrenoceptor agonists, dopamine agonist, hemp ester (cannabinoid) receptor antagonist, gamma-aminobutyric acid receptor antagonist, H
3-histamine antagonist, the L-histamine, obesity inhibin (leptin), the obesity inhibin analogue, the obesity inhibin receptor agonist, melanocortin (melanocortin) receptor stimulant (MC3-R agonist especially, the MC4-R agonist), α-melanocyte stimulates hormone, the transcript of Cocaine and Amphetamine control, redwood albumen (mahogany protein), enterostatin (enterostatin) agonist, thyrocalcitonin, the peptide relevant with calcitonin gene, sandfly toad peptide, cholecystokinin agonist (especially CCK-A agonist), corticotropin releasing hormone, the corticotropin releasing hormone analogue, the corticotropin releasing hormone agonist, Urocortin (urocortin), somatostatin, somatostatin analogs, the somatostatin receptor agonist, pituitary adenylate cyclase activation peptide, brain derived neurotrophic factor, ciliary neurotrophic factor, thyrotrophin-releasing hormone, neurotensin, sauvagine, the neuropeptide tyrosine antagonist, the opioid peptide antagonists, the galanin antagonist, the melanin concentration hormone antagonist, agouti associated protein inhibitor and orexin receptor antagonists etc.Specifically, monoamine reuptake inhibitors has Mazindol etc.; The example of thrombotonin reuptake inhibitor has Dexfenfluramine Hudrochlorid, Phenfluoramine, Sibutramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride etc.; The example of combination of serotonin agonist has Ying Nuo Qu Tan (inotriptan), (+)-go cresol fluorine Lamine etc.; The example of norepinephrine reuptake inhibitor has Bupropion, GW-320659 etc.; The example of norepinephrine release of irritants has rolipram, YM-992 etc.; β
2The example of-adrenoceptor agonists has Amphetamine, dexamphetamine, phentermine, Benzphetamine, meth, phendimetrazine, Preludin, Diethylpropion, Phenylpropanolamine, clobenzorex etc.; The example of dopamine agonist has ER-230, many Pulis new (doprexin), bromocriptine methylsulfonyl ester etc.; The favourable Mo Nata of example (rimonabant) of hemp ester receptor antagonist etc.; The example of gamma-aminobutyric acid receptor antagonist has topiramate etc.; H
3The example of-histamine antagonist has GT-2394 etc.; The example of obesity inhibin, obesity inhibin analogue or obesity inhibin receptor agonist has LY-355101 etc.; The example of cholecystokinin agonist (especially CCK-A agonist) has SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378 etc.; The example of neuropeptide tyrosine antagonist has SR-120819-A, PD-160170, NGD-95-1, BIBP-3226,1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814 etc.Appetite-inhibiting agent is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy, arteriosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia or gout, more preferably be used for obesity, this is because it can activate or suppress the active and depress appetite of the biologically active peptides in IC monoamine or the maincenter appetite Controlling System, takes in thereby reduce energy.
The example of angiotensin-convertion enzyme inhibitor has captopril, enalapril maleate, alacepril, delapril hydrochloride, Ramipril, lisinopril, hydrochloric acid imidapril, benazepril hydrochloride, SQ-29852 monohydrate, Yipingshu, fosinopril sodium, perindopril erbumine, moveltipril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, Trolapril, zofenopril calcium, hydrochloric acid not glycosides Puli, rentiapril etc.Angiotensin-convertion enzyme inhibitor is preferred for diabetic complication or hypertension.
The example of neutral endopeptidase inhibitor has Ou Puqu to draw (omapatrilat), MDL-100240, Fasidotril, Sampatrilat, GW-660511X, rice Sha pula (mixanpril), SA-7060, E-4030, SLV-306, ecadotril etc.The neutral endopeptidase inhibitor is preferred for diabetic complication or hypertension.
The example of angiotensin II receptor antagonists has Candesartan hila west to carry (cilexetil), Candesartan hila west to carry/HCTZ, Losartan Potassium, Eprosartan methylsulfonyl ester, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, Ao Mishatan (olmesartan), Tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 etc.Angiotensin II receptor antagonists is preferred for diabetic complication or hypertension.
The example of inhibitors of endothelin-converting enzyme has CGS-31447, CGS-35066, SM-19712 etc.; The example of endothelin receptor antagonists has L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sitaxsentan sodium (sodium sitaxsentan), BMS-193884, reach as giving birth to smooth (darusentan), TBC-3711, bosentan, he gives birth to smooth sodium (sodium tezosentan) by azoles, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, R0-61-1790, ABT-546, enrasentan (enlasentan), BMS-207940 etc.These medicines are preferred for diabetic complication or hypertension, more preferably are used for hypertension.
The example of diuretic(s) has chlorthalidone, metolazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, Hydroflumethiazide, the benzylic hydrogens chlorothiazide, Pentylhydroflumethiazide, Methyclothiazide, indapamide, tripamide, mefruside, azosemide, Ethacrynic, torasemide, piretanide, Furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone, triamterene, aminophylline, BN-1270, LLU-α, PNU-80873A, Isosorbide, D-N.F,USP MANNITOL, the D-Sorbitol Powder, fructose, glycerine, acetazolamide, Methalthiazide, FR-179544, OPC-31260, Li Xi cuts down smooth (lixivaptan), hydrochloric acid health Buddhist nun cuts down smooth (conivaptanhydrochloride) etc.Diuretic(s) is preferred for diabetic complication, hypertension, congestive heart failure or oedema, more preferably is used for hypertension, congestive heart failure or oedema, thereby this is to bring high blood pressure down or improve oedema because it can increase to urinate.
The example of calcium antagonist has Aranidipine, efonidipine, nicardipine hydrochloride, Bamidipine Hydrochloride, KW-3049, CV-4093, cilnidipineb, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, the amlodipine esilate, pranidipine, R-75, Isrodipine, elgodipine, Azelnidipine, Lacidipine (62, his Horizon (vatanidipine) hydrochloride of method, Lemildipine, diltiazem hydrochloride, Crane sulphur Zhuo (clentiazem) maleate, verapamil hydrochloride, the S-verapamil, Fasudil Hydrochloride, Bepridil hydrochloride, Algocor (Ravizza) etc.; The example that causes vasodilative antihypertensive drug has indapamide, hydrochloric acid todralazine, hydralazine hydrochloride, cadralazine, budralazine etc.; The example of sympathetic blocking agent has amosulalol hydrochloride, Vasocard, E-643, PRAZOSINI HYDROCHLORIDE, Doxazosin methylsulfonyl ester, propranolol hydrochloride, atenolol USP 23, metoprolol tartrate, carvedilol, nipradolol, Celiprolol Hydrochorid, nebivolol, betaxolol hydrochloride, pindolol, Tertatolol Hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride, the bisoprolol hemifumarate, the Bopindolol malonate, nipradolol, penbutolol vitriol, Acebutolol, N-696, the many Luo Er of sodium, urapidil, Indoramine etc.; Act on the favourable blood equality of example of the antihypertensive drug of nervus centralis; α
2The example of-adrenoceptor agonists has Tenso-Timelets, methyldopa, CHF-1035, guanabenz acetate, Guanfacine Hydrochloride, moxonidine, lofexidine, hydrochloric acid talipexole etc.These medicines are preferred for hypertension.
The example of anti-platelet agents has hydrochloric acid Ticlopidine, Dipyridamole, Cilostazole, ethyl Yi Sha spray ester (icosapentate), Sarpogrelatehydrochloride, Indoramine dihydrochloride, trapidil, beraprost sodium, Asprin etc.Anti-platelet agents is preferred for arteriosclerosis or congestive heart failure.
The example of uric acid synthetic inhibitor has Zyloric, oxipurinol etc.; The example of uricosuric has benzbromarone, probenecid etc.; The example of urine basifier has sodium bicarbonate, Tripotassium Citrate, Trisodium Citrate etc.These medicines are preferred for hyperuricemia or gout.
When with drug combination except the SGLT2 inhibitor, when for example being used for diabetes, be preferred with being selected from down at least a drug combination of organizing: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, islet amyloid polypeptide (amylin) agonist and appetite-inhibiting agent; With being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, islet amyloid polypeptide (amylin) analogue and islet amyloid polypeptide (amylin) agonist; With being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, biguanides, insulin secretion enhancers, SGLT2 inhibitor and Regular Insulin or insulin analog.Similarly, when being used for diabetic complication, with being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), the Glycogen Synthase kinase 3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, the islet amyloid polypeptide agonist, aldose reductase inhibitor, senior glycan end product (advanced glycation endproducts) synthetic inhibitor, inhibitors of protein kinase C, the gamma aminobutyric acid antagonist, the sodium channel antagonist, the transcription factor NF-KB inhibitor, the lipid peroxidation enzyme inhibitors, the sour Dipeptidase inhibitor of N-acetylize-α-connection, insulin like growth factor-1, Thr6 PDGF BB, the Thr6 PDGF BB analogue, Urogastron, nerve growth factor, carnitine derivative, uridine, 5-hydroxyl-1-methylhydantoi (methylhidantoin), EGB-761, than More (bimoclomol), sulosemide, Y-128, angiotensin converting enzyme inhibitor, the neutral endopeptidase inhibitor, angiotensin II receptor antagonists, the endothelin converting enzyme inhibitor, endothelin-receptor antagonists and diuretic(s); With being selected from down at least a drug combination of organizing is preferred: aldose reductase inhibitor, angiotensin converting enzyme inhibitor, nerve (neutrality) endopeptidase inhibitor and angiotensin II receptor antagonists.In addition, when being used for obesity, be preferred with being selected from down at least a drug combination of organizing: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like peptide 1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, the islet amyloid polypeptide agonist, β
3-adrenoceptor and appetite-inhibiting agent; With being selected from down at least a drug combination of organizing is preferred: SGLT2 inhibitor, β
3-adrenoceptor and appetite-inhibiting agent.
When pharmaceutical composition of the present invention is used for actual therapeutic, can use various formulations according to its purposes.The example of these formulations has pulvis, granule, micro mist agent, dry syrup, tablet, capsule, injection, solution, ointment, suppository, plaster etc., and they are oral or parenteral administration.Pharmaceutical composition of the present invention also comprises sustained release preparation, comprises intestines and stomach mucous membrane absorption preparation (for example international publication No:WO99/10010, WO99/26606, and Japanese Patent publication No:2001-2567).
These preparation of drug combination can be by with suitable medicine additives mixed or by dilution be dissolved in suitable additive, these additives have vehicle, disintegrating agent, tackiness agent, lubricant, thinner, buffer reagent, isotonic agent, antiseptic, wetting agent, emulsifying agent, dispersion agent, stablizer, solubilizing agent etc., and dispose this mixture according to ordinary method.When the drug combination beyond compound of the present invention and the SGLT1 inhibitor, can be with various activeconstituentss built in making various activeconstituentss together or respectively, thus make pharmaceutical composition.
When pharmaceutical composition of the present invention is used for actual therapeutic, can suitably determine as the compound of the above-mentioned general formula of the usefulness of activeconstituents (I) expression or the dosage of its pharmacy acceptable salt or prodrug according to the degree of each patient's age, sex, body weight and symptom and treatment, this dosage is approximately each grownup 0.1-1 every day when dosage forms for oral administration, 000mg, this dosage is approximately each grownup 0.01-300mg every day when parenteral administration, and daily dosage can be divided into once a day or several times and medication in suitable.Simultaneously, when the drug combination beyond compound of the present invention and the SGLT1 inhibitor, can reduce the dosage of The compounds of this invention, this depends on the dosage of the medicine beyond the SGLT1 inhibitor usually.
Embodiment
By following comparative example, embodiment and test case, further illustrate in greater detail the present invention.Yet the present invention is not subjected to the restriction of these examples.
The comparative example 1
2-amino-2-methyl propionic acid amide
To 2-benzyloxycarbonyl amino-2-methyl propionic acid (1g) at N, solution in the dinethylformamide (10mL), add I-hydroxybenzotriazole (0.63g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21g), triethylamine (1.76mL) and 28% ammonia soln (2mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is used 0.5mol/L hydrochloric acid, water, 1mol/L aqueous sodium hydroxide solution, water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, obtains 2-benzyloxycarbonyl amino-2-methyl propionic acid amide (0.26g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (30mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (0.11g).
1H-NMR(DMSO-d
6)δppm：
1.15(6H，s)，1.9(2H，brs)，6.83(1H，brs)，7.26(1H，brs)
The comparative example 2
2-(2-nitrobenzene sulfonyl ammonia base) ethanamide
To glycyl amide hydrochloride (0.11g) and triethylamine (0.35mL) in the suspension in methylene dichloride (3mL), add 2-nitrobenzene sulfonyl chloride (0.27g), mixture was stirring at room 1 hour then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Organic layer is water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=20/1), obtain title compound (72mg) by silica gel column chromatography then.
1H-NMR(DMSO-d
6)δppm：
3.57(2H，d，J＝5.9Hz)，7.1(1H，brs)，7.33(1H，brs)，7.8-7.9(2H，m)，7.95-8.1(2H，m)，8.16(1H，t，J＝5.9Hz)
The comparative example 3
(S)-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide
The preparation method of title compound is similar to comparative example 2, wherein uses L-alanimamides hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.33(3H，d，J＝7.1Hz)，4.03(1H，q，J＝7.1Hz)，7.75-7.85(2H，m)，7.85-7.9(1H，m)，8.05-8.15(1H，m)
The comparative example 4
2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide
The preparation method of title compound is similar to comparative example 2, wherein uses 2-amino-2-methyl propionic acid amide to replace glycyl amide hydrochloride.
1H-NMR(DMSO-d
6)δppm：
1.32(6H，s)，7.2-7.3(2H，m)，7.8-7.9(2H，m)，7.92(1H，s)，7.95-8.0(1H，m)，8.05-8.15(1H，m)
The comparative example 5
3-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide
The preparation method of title compound is similar to comparative example 2, wherein uses the amino propionic acid amide of hydrochloric acid 3-to replace glycyl amide hydrochloride.
1H-NMR(DMSO-d
6)δppm：
2.27(2H，t，J＝7.3Hz)，3.0-3.15(2H，m)，6.85(1H，brs)，7.34(1H，brs)，7.8-7.9(2H，m)，7.95-8.05(3H，m)
The comparative example 6
[4-(3-benzyloxy propoxy-) phenyl] methyl alcohol
At N, in the solution in the dinethylformamide (20mL), add the sodium iodide of cesium carbonate (7.17g), benzyl 3-bromopropyl ether (4.81g) and catalytic amount to 4-hydroxy benzaldehyde (2.44g), mixture was stirring at room 4 days then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 4-(3-benzyloxy propoxy-) phenyl aldehyde.With this substance dissolves in ethanol (20mL).Add sodium borohydride (757mg) in this solution, mixture was stirring at room 3 hours then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.Water is added residue, then the mixture extracted with diethyl ether.Organic layer washs with saturated sodium bicarbonate aqueous solution, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=5/1-2/1), obtain title compound (5.17g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.54(1H，t，J＝5.9Hz)，2.05-2.15(2H，m)，3.66(2H，t，J＝6.2Hz)，4.09(2H，t，J＝6.2Hz)，4.52(2H，s)，4.61(2H，d，J＝5.9Hz)，6.85-6.95(2H，m)，7.2-7.35(7H，m)
The comparative example 7
[4-(2-benzyloxy oxyethyl group) phenyl] methyl alcohol
The preparation method of title compound is similar to comparative example 6, wherein uses benzyl 2-bromotrifluoromethane ether to replace benzyl 3-bromopropyl ether.
1H-NMR(CDCl
3)δppm：
1.53(1H，t，J＝5.8Hz)，3.8-3.85(2H，m)，4.1-4.2(2H，m)，4.62(2H，d，J＝5.8Hz)，4.64(2H，s)，6.85-6.95(2H，m)，7.25-7.4(7H，m)
The comparative example 8
[4-(4-benzyloxy butoxy phenyl] methyl alcohol
The preparation method of title compound is similar to comparative example 6, wherein uses benzyl 4-brombutyl ether to replace benzyl 3-bromopropyl ether.
1H-NMR(CDCl
3)δppm：
1.52(1H，t，J＝5.6Hz)，1.75-1.95(4H，m)，3.54(2H，t，J＝6.1Hz)，3.98(2H，t，J＝6.3Hz)，4.52(2H，s)，4.61(2H，d，J＝5.6Hz)，6.8-6.9(2H，m)，7.2-7.4(7H，m)
The comparative example 9
[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl alcohol
At N, in the solution of dinethylformamide (10mL), add cesium carbonate (4.79g) to 4-bromo-3-methylphenol (2.5g), the sodium iodide of benzyl 3-bromopropyl ether (2.48mL) and catalytic amount, mixture was stirring at room 60 hours then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 4-(3-benzyloxy propoxy-)-1-bromo-2-toluene.This material is dissolved in tetrahydrofuran (THF) (100mL).Under-78 ℃ and argon gas atmosphere, (the 2.46mol/L hexane solution 6mL), stirred the mixture 5 minutes then to add n-Butyl Lithium in this solution.In reaction mixture, add N, dinethylformamide (2.57mL) allows mixture be warmed to 0 ℃ and stirred 1 hour then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer is water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 4-(3-benzyloxy propoxy-)-2-tolyl aldehyde.With this substance dissolves in ethanol (40mL).Add sodium borohydride (506mg) in this solution, mixture is in stirred overnight at room temperature then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.Water is added residue, then the mixture extracted with diethyl ether.Organic layer washs with saturated sodium bicarbonate aqueous solution, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=5/1-1.5/1), obtain title compound (3.33g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.37(1H，t，J＝5.7Hz)，2.0-2.15(2H，m)，2.36(3H，s)，3.66(2H，t，J＝6.2Hz)，4.08(2H，t，J＝6.3Hz)，4.52(2H，s)，4.63(2H，d，J＝5.7Hz)，6.65-6.8(2H，m)，7.15-7.4(6H，m)
The comparative example 10
[4-(2-benzyloxy oxyethyl group)-2-aminomethyl phenyl] methyl alcohol
The preparation method of title compound is similar to comparative example 9, wherein uses benzyl 2-bromotrifluoromethane ether to replace benzyl 3-bromopropyl ether.
1H-NMR(CDCl
3)δppm：
1.39(1H，t，J＝5.8Hz)，2.35(3H，s)，3.8-3.85(2H，m)，4.1-4.2(2H，m)，4.6-4.65(4H，m)，6.73(1H，dd，J＝8.2Hz，2.6Hz)，6.78(1H，d，J＝2.6Hz)，7.22(1H，d，J＝8.2Hz)，7.25-7.4(5H，m)
The comparative example 11
4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To [4-(the 3-benzyloxy propoxy-) phenyl] solution of methyl alcohol (5.17g) in tetrahydrofuran (THF) (25mL), add triethylamine (3.04mL) and methylsulfonyl chloride (1.62mL) down ice-cooled, stirred the mixture then 1 hour.Insoluble substance is removed by filtering.With methylsulfonic acid [4-(the 3-benzyloxy propoxy-) phenyl] solution of methyl esters in tetrahydrofuran (THF) that obtains, add to sodium hydride (60%, 875mg) with the 4-methyl-suspension of 3-oxopentanoic acid ethyl ester (3.3g) in tetrahydrofuran (THF) (50mL), the reflux mixture is 8 hours then.In reaction mixture, add 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression.To the solution of residue in toluene (10mL), add hydrazine monohydrate (2.76mL), mixture spends the night 100 ℃ of stirrings then.Reaction mixture carries out purifying (eluent: methylene chloride=50/1-20/1), obtain title compound (5.22g) by silica gel column chromatography.
1H-NMR(CDCl
3)δppm：
1.14(6H，d，J＝6.8Hz)，2.0-2.1(2H，m)，2.8-2.95(1H，m)，3.6-3.7(4H，m)，4.04(2H，t，J＝6.5Hz)，4.51(2H，s)，6.75-6.85(2H，m)，7.05-7.15(2H，m)，7.2-7.35(5H，m)
The comparative example 12
4-{[4-(2-benzyloxy oxyethyl group) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-(2-benzyloxy oxyethyl group) phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(CDCl
3)δppm：
1.14(6H，d，J＝7.3Hz)，2.8-2.95(1H，m)，3.66(2H，s)，3.75-3.85(2H，m)，4.05-4.15(2H，m)，4.62(2H，s)，6.75-6.85(2H，m)，7.1-7.15(2H，m)，7.25-7.4(5H，m)
The comparative example 13
4-{[4-(4-benzyloxy butoxy phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-(4-benzyloxy butoxy) phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(CDCl
3)δppm：
1.14(6H，d，J＝7.0Hz)，1.7-1.9(4H，m)，2.8-2.95(1H，m)，3.53(2H，t，J＝6.1Hz)，3.66(2H，s)，3.93(2H，t，J＝6.3Hz)，4.51(2H，s)，6.7-6.8(2H，m)，7.05-7.15(2H，m)，7.27.35(5H，m)
The comparative example 14
4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrrole
Azoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.04(6H，d，J＝7.0Hz)，1.9-2.0(2H，m)，2.24(3H，s)，2.65-2.8(1H，m)，3.44(2H，s)，3.56(2H，t，J＝6.4Hz)，3.97(2H，t，J＝6.1Hz)，4.47(2H，s)，6.6(1H，dd，J＝8.6Hz，2.6Hz)，6.69(1H，d，J＝2.6Hz)，6.78(1H，d，J＝8.6Hz)，7.2-7.35(5H，m)
The comparative example 15
4-[(4-benzyloxy phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses (4-benzyloxy phenyl) methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.06(6H，d，J＝6.8Hz)，2.75-2.9(1H，m)，3.5(2H，s)，5.03(2H，s)，6.85-6.9(2H，m)，7.0-7.1(2H，m)，7.25-7.45(5H，m)
The comparative example 16
4-{[4-(2-benzyloxy oxyethyl group)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrrole
Azoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-(2-benzyloxy oxyethyl group)-2-aminomethyl phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(CDCl
3)δppm：
1.1(6H，d，J＝6.9Hz)，2.3(3H，s)，2.75-2.9(1H，m)，3.6(2H，s)，3.75-3.85(2H，m)，4.05-4.15(2H，m)，4.62(2H，s)，6.64(1H，dd，J＝8.5Hz，2.5Hz)，6.74(1H，d，J＝2.5Hz)，6.94(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 17
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
To 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl } 1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone (5.08g), acetyl bromide-α-D-glucose (5.49g) and the solution of zephiran chloride three (normal-butyl) ammonium (2.08g) in methylene dichloride (40mL), add 5mol/L aqueous sodium hydroxide solution (8mL), mixture was stirring at room 3 hours then.Reaction mixture is purifying (eluent: n-hexane/ethyl acetate=1/1-1/3-1/5) by the column chromatography of carrying out on aminopropyl silica gel.The material of purifying further on silica gel by column chromatography purifying (eluent: n-hexane/ethyl acetate=1/1-1/2-1/4), obtain title compound (2.75g) in addition.
1H-NMR(CDCl
3)δppm：
1.15(6H，d，J＝7.1Hz)，1.87(3H，s)，1.95-2.1(11H，m)，2.85-2.95(1H，m)，3.5-3.7(4H，m)，3.8-3.9(1H，m)，4.03(2H，t，J＝6.4Hz)，4.15(1H，dd，J＝12.3Hz，2.4Hz)，4.31(1H，dd，J＝12.3Hz，4.1Hz)，4.51(2H，s)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，7.0-7.05(2H，m)，7.2-7.35(5H，m)
The comparative example 18
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxy oxyethyl group) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(2-benzyloxy oxyethyl group) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.14(6H，d，J＝6.8Hz)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.8-2.95(1H，m)，3.57(1H，d，J＝15.8Hz)，3.63(1H，d，J＝15.8Hz)，3.75-3.9(3H，m)，4.05-4.2(3H，m)，4.31(1H，dd，J＝12.4Hz，4.1Hz)，4.62(2H，s)，5.15-5.3(3H，m)，5.55-5.6(1H，m)，6.75-6.85(2H，m)，7.0-7.05(2H，m)，7.25-7.4(5H，m)
The comparative example 19
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(4-benzyloxy butoxy) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(4-benzyloxy butoxy phenyl] methyl-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.15(6H，d，J＝6.7Hz)，1.7-1.9(7H，m)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.5-3.6(3H，m)，3.62(1H，d，J＝16.3Hz)，3.8-3.9(1H，m)，3.92(2H，t，J＝6.5Hz)，4.1-4.2(1H，m)，4.31(1H，dd，J＝12.3Hz，4.1Hz)，4.51(2H，s)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，6.95-7.05(2H，m)，7.2-7.4(5H，m)
The comparative example 20
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.8(3H，s)，1.9-2.15(11H，m)，2.25(3H，s)，2.75-2.85(1H，m)，3.49(1H，d，J＝16.4Hz)，3.59(1H，d，J＝16.4Hz)，3.64(2H，t，J＝6.3Hz)，3.8-3.9(1H，m)，4.0-4.05(2H，m)，4.1-4.15(1H，m)，4.3(1H，dd，J＝12.2Hz，4.1Hz)，4.51(2H，s)，5.15-5.3(3H，m)，5.55(1H，d，J＝7.8Hz)，6.57(1H，dd，J＝8.4Hz，2.6Hz)，6.68(1H，d，J＝2.6Hz)，6.79(1H，d，J＝8.4Hz)，7.2-7.4(5H，m)
The comparative example 21
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-benzyloxy phenyl) methyl]-5-
Sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-[(4-benzyloxy phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝7.1Hz)，1.85(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.57(1H，d，J＝15.9Hz)，3.63(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，4.1-4.2(1H，m)，4.31(1H，dd，J＝12.6Hz，3.9Hz)，5.02(2H，s)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.8-6.9(2H，m)，7.0-7.1(2H，m)，7.25-7.45(5H，m)
The comparative example 22
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxy oxyethyl group)-2-
Aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(2-benzyloxy oxyethyl group)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.81(3H，s)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.25(3H，s)，2.7-2.85(1H，m)，3.5(1H，d，J＝16.6Hz)，3.59(1H，d，J＝16.6Hz)，3.75-3.9(3H，m)，4.05-4.2(3H，m)，4.3(1H，dd，J＝12.2Hz，4.1Hz)，4.62(2H，s)，5.1-5.3(3H，m)，5.55(1H，d，J＝8.0Hz)，6.6(1H，dd，J＝8.5Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.8(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 23
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (2.75g), be dissolved in the mixed solvent of methyl alcohol (20mL) and tetrahydrofuran (THF) (9mL).Add 10% palladium-carbon dust (550mg) in this solution, mixture stirred 4 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (2.4g).
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.89(3H，s)，1.95-2.1(11H，m)，2.85-2.95(1H，m)，3.58(1H，d，J＝16.3Hz)，3.63(1H，d，J＝16.3Hz)，3.8-3.9(3H，m)，4.05-4.1(2H，m)，4.13(1H，dd，J＝12.1Hz，2.1Hz)，4.3(1H，dd，J＝12.1Hz，4.1Hz)，5.15-5.3(3H，m)，5.58(1H，d，J＝7.3Hz)，6.7-6.8(2H，m)，7.0-7.05(2H，m)
The comparative example 24
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-hydroxyl-oxethyl) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-benzyloxy oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝6.8Hz)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.58(1H，d，J＝16.0Hz)，3.63(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.9-4.0(2H，m)，4.0-4.1(2H，m)，4.1-4.2(1H，m)，4.25-4.35(1H，m)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.75-6.85(2H，m)，7.0-7.1(2H，m)
The comparative example 25
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(4-hydroxyl butoxy) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(4-benzyloxy butoxy) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.65-1.8(2H，m)，1.8-1.95(5H，m)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.57(1H，d，J＝16.2Hz)，3.63(1H，d，J＝16.2Hz)，3.71(2H，t，J＝6.3Hz)，3.8-3.9(1H，m)，3.96(2H，t，J＝6.2Hz)，4.14(1H，dd，J＝12.4Hz，2.4Hz)，4.31(1H，dd，J＝12.4Hz，4.1Hz)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，7.0-7.05(2H，m)
The comparative example 26
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-first
The base phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，1.95-2.1(11H，m)，2.26(3H，s)，2.75-2.9(1H，m)，3.5(1H，d，J＝16.5Hz)，3.58(1H，d，J＝16.5Hz)，3.75-3.9(3H，m)，4.0-4.15(3H，m)，4.28(1H，dd，J＝12.3Hz，4.1Hz)，5.1-5.3(3H，m)，5.55(1H，d，J＝7.9Hz)，6.59(1H，dd，J＝8.3Hz，2.5Hz)，6.69(1H，d，J＝2.5Hz)，6.81(1H，d，J＝8.3Hz)
The comparative example 27
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-hydroxy phenyl) methyl]-5-is different
Propyl group-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-benzyloxy phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.89(3H，s)，2.0(3H，s)，2.02(3H，s)，2.06(3H，s)，2.85-3.0(1H，m)，3.57(1H，d，J＝16.2Hz)，3.61(1H，d，J＝16.2Hz)，3.8-3.9(1H，m)，4.05-4.2(1H，m)，4.29(1H，dd，J＝12.5Hz，4.0Hz)，4.91(1H，brs)，5.15-5.3(3H，m)，5.55-5.6(1H，m)，6.65-6.75(2H，m)，6.95-7.05(2H，m)
The comparative example 28
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-hydroxyl-oxethyl)-2-first
The base phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-benzyloxy oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.26(3H，s)，2.75-2.9(1H，m)，3.51(1H，d，J＝16.9Hz)，3.59(1H，d，J＝16.9Hz)，3.8-3.85(1H，m)，3.9-3.95(2H，m)，4.0-4.1(2H，m)，4.11(1H，dd，J＝12.5Hz，2.5Hz)，4.28(1H，dd，J＝12.5Hz，4.1Hz)，5.1-5.3(3H，m)，5.55(1H，d，J＝7.9Hz)，6.6(1H，dd，J＝8.3Hz，2.7Hz)，6.71(1H，d，J＝2.7Hz)，6.82(1H，d，J＝8.3Hz)
The comparative example 29
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (2.21g) in methylene dichloride (35mL); add triethylamine (0.65mL) and methylsulfonyl chloride (0.33mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-] phenyl } methyl)-1H-pyrazoles.With this substance dissolves in N, dinethylformamide (20mL).Add sodiumazide (0.46g) in this solution, mixture stirred 1.5 hours at 100 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer washes 3 times with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-1/3), obtain title compound (1.6g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.89(3H，s)，1.95-2.1(11H，m)，2.85-2.95(1H，m)，3.5(2H，t，J＝6.7Hz)，3.57(1H，d，J＝15.9Hz)，3.63(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，4.0(2H，t，J＝5.9Hz)，4.1-4.2(1H，m)，4.31(1H，dd，J＝12.2Hz，4.2Hz)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，7.0-7.1(2H，m)
The comparative example 30
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-nitrine oxyethyl group) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 29; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.5-3.7(4H，m)，3.8-3.9(1H，m)，4.11(2H，t，J＝5.1Hz)，4.14(1H，dd，J＝12.2Hz，2.2Hz)，4.31(1H，dd，J＝12.2Hz，4.0Hz)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.75-6.85(2H，m)，7.0-7.1(2H，m)
The comparative example 31
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(4-nitrine butoxy) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 29; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(4-hydroxyl butoxy) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.7-1.95(7H，m)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.35(2H，t，J＝6.8Hz)，3.57(1H，d，J＝16.0Hz)，3.63(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.94(2H，t，J＝6.0Hz)，4.14(1H，dd，J＝12.6Hz，2.5Hz)，4.31(1H，dd，J＝12.6Hz，4.1Hz)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，7.0-7.1(2H，m)
The comparative example 32
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-)-2-first
The base phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 29; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.81(3H，s)，1.95-2.1(11H，m)，2.26(3H，s)，2.75-2.9(1H，m)，3.45-3.55(3H，m)，3.59(1H，d，J＝16.5Hz)，3.8-3.9(1H，m)，3.95-4.05(2H，m)，4.05-4.15(1H，m)，4.29(1H，dd，J＝12.6Hz，4.1Hz)，5.1-5.3(3H，m)，5.55(1H，d，J＝7.9Hz)，6.57(1H，dd，J＝8.7Hz，2.6Hz)，6.68(1H，d，J＝2.6Hz)，6.8(1H，d，J＝8.7Hz)
The comparative example 33
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-nitrine oxyethyl group)-2-first
The base phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 29; wherein use 3-(2; 3; 4; 6-four-0-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.82(3H，s)，2.0(3H，s)，2.02(3H，s)，2.06(3H，s)，2.27(3H，s)，2.75-2.9(1H，m)，3.45-3.65(4H，m)，3.8-3.9(1H，m)，4.05-4.15(3H，m)，4.29(1H，dd，J＝12.2Hz，4.2Hz)，5.1-5.3(3H，m)，5.56(1H，d，J＝7.7Hz)，6.6(1H，dd，J＝8.3Hz，2.6Hz)，6.71(1H，d，J＝2.6Hz)，6.82(1H，d，J＝8.3Hz)
Embodiment 1
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-nitrine propoxy-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (1.6g) in tetrahydrofuran (THF) (25mL); add 10% palladium-carbon dust (300mg), mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (1.5g).
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.85-2.0(8H，m)，2.01(3H，s)，2.02(3H，s)，2.8-3.0(3H，m)，3.6(2H，s)，3.9-4.0(1H，m)，4.01(2H，t，J＝6.0Hz)，4.11(1H，dd，J＝12.4Hz，2.5Hz)，4.29(1H，dd，J＝12.4Hz，3.9Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝8.2Hz)，6.75-6.85(2H，m)，7.0-7.05(2H，m)
Embodiment 2
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino ethoxy) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-nitrine oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝6.9Hz)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.05(2H，t，J＝5.0Hz)，3.57(1H，d，J＝16.0Hz)，3.63(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.94(2H，t，J＝5.0Hz)，4.1-4.2(1H，m)，4.25-4.35(1H，m)，5.15-5.3(3H，m)，5.5-5.65(1H，m)，6.75-6.8(2H，m)，7.0-7.1(2H，m)
Embodiment 3
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino butoxy of 4-) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(4-nitrine butoxy) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.15(6H，d，J＝6.8Hz)，1.5-1.65(2H，m)，1.7-1.85(2H，m)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.76(2H，t，J＝7.1Hz)，2.85-2.95(1H，m)，3.56(1H，d，J＝15.7Hz)，3.62(1H，d，J＝15.7Hz)，3.8-3.9(1H，m)，3.92(2H，t，J＝6.5Hz)，4.1-4.2(1H，m)，4.31(1H，dd，J＝12.2Hz，4.1Hz)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.8(2H，m)，6.95-7.05(2H，m)
Embodiment 4
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-)-
The 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-nitrine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.82(3H，s)，1.85-1.95(2H，m)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.25(3H，s)，2.75-2.95(3H，m)，3.5(1H，d，J＝16.5Hz)，3.58(1H，d，J＝16.5Hz)，3.75-3.9(1H，m)，3.9-4.05(2H，m)，4.05-4.2(1H，m)，4.29(1H，dd，J＝12.6Hz，4.0Hz)，5.1-5.3(3H，m)，5.5-5.6(1H，m)，6.58(1H，dd，J＝8.4Hz，2.7Hz)，6.68(1H，d，J＝2.7Hz)，6.8(1H，d，J＝8.4Hz)
Embodiment 5
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino ethoxy)-
The 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-nitrine oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.82(3H，s)，2.0(3H，s)，2.02(3H，s)，2.06(3H，s)，2.26(3H，s)，2.75-2.85(1H，m)，3.0-3.1(2H，m)，3.5(1H，d，J＝16.3Hz)，3.59(1H，d，J＝16.3Hz)，3.8-3.9(1H，m)，3.9-4.0(2H，m)，4.12(1H，dd，J＝12.4Hz，2.4Hz)，4.29(1H，dd，J＝12.4Hz，4.0Hz)，5.15-5.3(3H，m)，5.55(1H，d，J＝7.9Hz)，6.59(1H，dd，J＝8.5Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.81(1H，d，J＝8.5Hz)
Embodiment 6
4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrrole
Azoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.1g) in methyl alcohol (2mL); add sodium methylate (28% methanol solution; 0.062mL), mixture was stirring at room 30 minutes then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (57mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.8-1.95(2H，m)，2.8(2H，t，J＝7.0Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，3.99(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.7-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 7
4-{[4-(2-amino ethoxy) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrrole
Azoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.8-2.95(1H，m)，2.96(2H，t，J＝5.4Hz)，3.25-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，3.95(2H，t，J-5.4Hz)，5.05-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 8
4-{[4-(the amino butoxy of 4-) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrrole
Azoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino butoxy of 4-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.55-1.7(2H，m)，1.7-1.85(2H，m)，2.67(2H，t，J＝7.1Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.7Hz)，3.8-3.9(1H，m)，3.93(2H，t，J＝6.3Hz)，5.0-5.15(1H，m)，6.7-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 9
4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-different third
Base-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.7-2.9(3H，m)，3.25-3.45(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝5.9Hz)，4.95-5.1(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 10
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(methanesulfonamido) propoxy-] and phenyl } first
Base)-the 1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.36g) in methylene dichloride (6mL); add triethylamine (0.2mL) and methylsulfonyl chloride (0.05mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/3-ethyl acetate) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(methanesulfonamido) propoxy-] and phenyl } methyl)-1H-pyrazoles (255mg).This material is dissolved in methyl alcohol (6mL).In this solution, (28% methanol solution, 0.11mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (0.16g) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.05(2H，m)，2.8-2.95(4H，m)，3.24(2H，t，J＝7.0Hz)，3.3-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，4.01(2H，t，J＝6.1Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 11
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[2-(methanesulfonamido) oxyethyl group] and phenyl } first
Base)-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 10; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.8-2.95(1H，m)，2.97(3H，s)，3.25-3.45(6H，m)，3.6-3.7(2H，m)，3.74(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，4.03(2H，t，J＝5.4Hz)，5.0-5.15(1H，m)，6.8-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 12
4-[(4-{3-[N-(carbamyl ylmethyl)-N-(methylsulfonyl) amino] propoxy-}-the 2-aminomethyl phenyl)
Methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 10; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(formamyl methylamino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.95-2.1(2H，m)，2.29(3H，s)，2.75-2.85(1H，m)，3.0(3H，s)，3.25-3.4(4H，m)，3.46(2H，t，J＝7.1Hz)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.95-4.05(4H，m)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.3Hz，2.7Hz)，6.72(1H，d，J＝2.7Hz)，6.85(1H，d，J＝8.3Hz)
Embodiment 13
4-(4-[3-(2-glycyl amino) propoxy-] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-
Sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-amino propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.1g) is at N; solution in the dinethylformamide (1mL); add 2-benzyloxycarbonyl Padil (51mg), I-hydroxybenzotriazole (33mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (93mg), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is water, saturated sodium bicarbonate aqueous solution, water and salt water washing successively, with anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue carries out purifying (eluent: ethyl acetate-methylene chloride=30/1-20/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-(benzyloxycarbonyl amino) kharophen] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (46mg).This material is dissolved in methyl alcohol (3mL).Add 10% palladium-carbon dust (20mg) in this solution, mixture stirred 1.5 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering; the solvent of filtrate is removed in decompression then, obtains 3-(2,3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(2-glycyl amino) propoxy-] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (34mg).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.01mL), mixture was stirring at room 30 minutes then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (23mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.9-2.0(2H，m)，2.85-2.95(1H，m)，3.23(2H，s)，3.25-3.45(6H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.98(2H，t，J＝6.1Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 14
4-[(4-{3-[(S)-and the amino propionamido of 2-] propoxy-} phenyl) methyl]-3-(β-D-pyranoglucose
The oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13, wherein uses (S)-2-(benzyloxycarbonyl amino) propionic acid to replace 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.24(3H，d，J＝6.9Hz)，1.9-2.0(2H，m)，2.8-2.95(1H，m)，3.25-3.45(7H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，3.98(2H，t，J＝6.0Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.0-7.15(2H，m)
Embodiment 15
4-(4-[3-(the amino propionamido of 3-) propoxy-] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen
Base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13, wherein uses 3-(benzyloxycarbonyl amino) propionic acid to replace 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-2.0(2H，m)，2.33(2H，t，J＝6.6Hz)，2.75-2.95(3H，m)，3.25-3.45(6H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.7-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 16
4-[(4-{3-[(S)-and 2-amino-3-hydroxyl propionamido] propoxy-} phenyl) methyl]-3-(β-D-pyrrole
The glucosyloxy of muttering)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13, wherein uses (S)-2-benzyloxycarbonyl amino-3-hydroxy-propionic acid to replace 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.9-2.0(2H，m)，2.8-2.95(1H，m)，3.25-3.45(7H，m)，3.55-3.7(4H，m)，3.73(1H，d，J＝15.6Hz)，3.8-3.9(1H，m)，3.99(2H，t，J＝6.2Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 17
4-[(4-{3-[(S)-and 2-amino-3-(1H-imidazol-4 yl) propionamido] propoxy-} phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13, wherein uses (S)-2-benzyloxycarbonyl amino-3-(1H-imidazol-4 yl) propionic acid to replace 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.8-1.95(2H，m)，2.7-3.0(3H，m)，3.25-3.45(6H，m)，3.5-3.55(1H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.7Hz)，3.8-3.95(3H，m)，5.0-5.15(1H，m)，6.75-6.85(3H，m)，7.05-7.15(2H，m)，7.54(1H，s)
Embodiment 18
4-[(4-{3-[2-amino-2-(methyl) propionamido] propoxy-} phenyl) methyl]-3-(β-D-pyrans
Glucosyloxy)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13, wherein uses 2-benzyloxycarbonyl amino-2-methyl propionic acid to replace 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.29(6H，s)，1.9-2.0(2H，m)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.1Hz)，3.8-3.9(1H，m)，3.98(2H，t，J＝6.1Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.2(2H，m)
Embodiment 19
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{3-[2-(morpholine-4-yl) ethyl] urea
Base } propoxy-) phenyl] methyl }-the 1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (97mg) in methylene dichloride (3mL); add triethylamine (0.035mL) and 4-chloroformate nitrophenyl ester (35mg), mixture was stirring at room 1 hour then.In reaction mixture, add 4-(2-amino-ethyl) morpholine (41mg), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is water, saturated sodium bicarbonate aqueous solution, water and salt water washing successively, with anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue carries out purifying (eluent: ethyl acetate-methylene chloride=10/1-5/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{3-[2-(morpholine-4-yl) ethyl] urea groups } propoxy-) phenyl] methyl }-1H-pyrazoles (58mg).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.03mL), mixture was stirring at room 30 minutes then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (39mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.10-1.15(6H，m)，1.85-1.95(2H，m)，2.35-2.5(6H，m)，2.85-2.95(1H，m)，3.2-3.45(8H，m)，3.6-3.7(6H，m)，3.73(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.2Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 20
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{3-[2-(dimethylamino) ethyl]
Urea groups } propoxy-) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses N, and the N-dimethyl-ethylenediamine is replaced 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.85-1.95(2H，m)，2.26(6H，s)，2.43(2H，t，J＝6.7Hz)，2.85-2.95(1H，m)，3.2-3.4(8H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 21
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1-(methylol)-1-(methyl) second
Base] urea groups } propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses 2-amino-2-methyl-1, and ammediol is replaced 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(9H，m)，1.8-1.95(2H，m)，2.8-2.95(1H，m)，3.2-3.45(6H，m)，3.5-3.8(7H，m)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.1Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 22
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1-(methylol) ethyl] urea groups } third
The oxygen base) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses 2-amino-1, and ammediol is replaced 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-1.95(2H，m)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.5-3.75(8H，m)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.2Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 23
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[3-(2-hydroxyethyl) urea groups] propoxy-} phenyl) first
Base]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses the 2-monoethanolamine to replace 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-1.95(2H，m)，2.85-2.95(1H，m)，3.21(2H，t，J＝5.6Hz)，3.25-3.45(6H，m)，3.55(2H，t，J＝5.6Hz)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.1Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.2Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 24
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1,1-two (methyl) ethyl] urea groups }
Propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses 2-amino-2-methyl-1-propanol to replace 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.1-1.5(6H，m)，1.22(6H，s)，1.85-1.95(2H，m)，2.8-2.95(1H，m)，3.24(2H，t，J＝6.6Hz)，3.25-3.45(4H，m)，3.5(2H，s)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.8Hz)，3.8-3.9(1H，m)，3.96(2H，t，J＝6.2Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 25
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{3-[2-(tetramethyleneimine-1-yl) ethyl]
Urea groups } propoxy-) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses 1-(2-amino-ethyl) tetramethyleneimine to replace 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.75-1.85(4H，m)，1.85-1.95(2H，m)，2.5-2.65(6H，m)，2.85-2.95(1H，m)，3.2-3.45(8H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.8Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 26
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1,1-two (methylol) ethyl] urea
Base } propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19, wherein uses three (methylol) aminomethane to replace 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-1.95(2H，m)，2.8-2.95(1H，m)，3.2-3.45(6H，m)，3.55-3.7(8H，m)，3.73(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.97(2H，t，J＝6.1Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 27
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonylamino }
Propoxy-)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.4-2.55(6H，m)，2.75-2.85(1H，m)，3.25-3.45(10H，m)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，3.96(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.5Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 28
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1-(methylol)-1-(methyl) second
Base] urea groups } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.19(3H，s)，1.85-1.95(2H，m)，2.29(3H，s)，2.75-2.85(1H，m)，3.2-3.4(6H，m)，3.5-3.75(7H，m)，3.75-3.85(1H，m)，3.96(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.6Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.6Hz)
Embodiment 29
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{3-[2-hydroxyl-1,1-two (methyl) ethyl] urea groups }
Propoxy-)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.23(6H，s)，1.8-1.95(2H，m)，2.29(3H，s)，2.75-2.85(1H，m)，3.24(2H，t，J＝6.8Hz)，3.25-3.4(4H，m)，3.5(2H，s)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.96(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.5Hz，2.6Hz)，6.71(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 30
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[3-(2-hydroxyethyl) urea groups] propoxy-}-the 2-methyl
Phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-monoethanolamine, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-1.95(2H，m)，2.29(3H，s)，2.75-2.85(1H，m)，3.22(2H，t，J＝5.7Hz)，3.25-3.4(6H，m)，3.55(2H，t，J＝5.7Hz)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.96(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.2Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.2Hz)
Embodiment 31
4-{[4-(2-{3-[1-formamyl-1-(methyl) ethyl] urea groups } oxyethyl group)-the 2-aminomethyl phenyl]
Methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.44(6H，s)，2.29(3H，s)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.44(2H，t，J＝5.3Hz)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.95(2H，t，J＝5.3Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.5Hz，2.6Hz)，6.72(1H，d，J＝2.6Hz)，6.86(1H，d，J＝8.5Hz)
Embodiment 32
3-(β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[2-hydroxyl-1-(methylol)-1-(methyl) second
Base] urea groups } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.2(3H，s)，2.29(3H，s)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.43(2H，t，J＝5.3Hz)，3.5-3.75(7H，m)，3.75-3.85(1H，m)，3.94(2H，t，J＝5.3Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.3Hz，2.7Hz)，6.73(1H，d，J＝2.7Hz)，6.86(1H，d，J＝8.3Hz)
Embodiment 33
3-(β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[2-hydroxyl-1,1-two (methyl) ethyl] urea groups }
Oxyethyl group)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 4-(2-amino-ethyl) morpholine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.23(6H，s)，2.29(3H，s)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.42(2H，t，J＝5.3Hz)，3.52(2H，s)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.94(2H，t，J＝5.3Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.3Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.3Hz)
Embodiment 34
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[4-(2-hydroxyethyl) piperazine
Piperazine-1-yl] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.29g) in methylene dichloride (5mL); add triethylamine (0.08mL) and methylsulfonyl chloride (0.04mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles.With this substance dissolves in N, dinethylformamide (3mL).Add 1-(2-hydroxyethyl) piperazine (0.13g) in this solution, mixture stirred 9 hours at 60 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer washes 2 times with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: ethyl acetate-methylene chloride=10/1-5/1), obtain title compound (91mg) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.81(3H，s)，1.9-2.0(5H，m)，2.02(3H，s)，2.07(3H，s)，2.26(3H，s)，2.3-2.75(12H，m)，2.75-2.9(1H，m)，3.49(1H，d，J＝16.4Hz)，3.55-3.7(3H，m)，3.8-3.9(1H，m)，3.9-4.0(2H，m)，4.1-4.2(1H，m)，4.3(1H，dd，J＝12.3Hz，3.8Hz)，5.15-5.3(3H，m)，5.55(1H，d，J＝8.3Hz)，6.57(1H，dd，J＝8.6Hz，2.7Hz)，6.68(1H，d，J＝2.7Hz)，6.79(1H，d，J＝8.6Hz)
Embodiment 35
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[4-(2-hydroxyethyl) piperazine-1-yl] propoxy-}-the 2-first
The base phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[4-(2-hydroxyethyl) piperazine-1-yl] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.28(3H，s)，2.3-2.85(13H，m)，3.25-3.4(4H，m)，3.6-3.75(5H，m)，3.75-3.85(1H，m)，3.96(2H，t，J＝6.2Hz)，4.95-5.1(1H，m)，6.6(1H，dd，J＝8.5Hz，2.4Hz)，6.69(1H，d，J＝2.4Hz)，6.84(1H，d，J＝8.5Hz)
The comparative example 34
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[N '-(cyano group)-S-
(methyl) isothioureido] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.19g) in 2-propyl alcohol (2mL); add S; S '-dimethyl-N-cyano group two sulphur iminocarbonic esters (cyanodithioiminocarbonate) (57mg), mixture was stirring at room 4 hours then.Reaction mixture carries out purifying (eluent: n-hexane/ethyl acetate=1/1-methylene chloride=20/1), obtain title compound (0.19g) by silica gel column chromatography.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.91(3H，s)，1.97(3H，s)，2.0-2.1(8H，m)，2.56(3H，s)，2.85-3.0(1H，m)，3.5-3.65(4H，m)，3.9-4.05(3H，m)，4.11(1H，dd，J＝12.4Hz，2.3Hz)，4.29(1H，dd，J＝12.4Hz，4.0Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝8.0Hz)，6.75-6.85(2H，m)，7.0-7.1(2H，m)
Embodiment 36
4-(4-[3-(2-cyano group-3-methyl guanidine radicals) propoxy-] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen
Base)-5-sec.-propyl-1H-pyrazoles
With methylamine (40% methanol solution; 2mL) add 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[N '-(cyano group)-S-(methyl) isothioureido] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (40mg), mixture is in stirred overnight at room temperature then.To the reaction mixture concentrating under reduced pressure, then residue is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.02mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (18mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.95-2.05(2H，m)2.76(3H，s)，2.85-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.2Hz)，3.8-3.9(1H，m)，4.0(2H，t，J＝5.9Hz)，5.05-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 37
4-[(4-{3-[2-cyano group-3-(2-hydroxyethyl) guanidine radicals] propoxy-} phenyl) methyl]-3-(β-D-pyrans
Glucosyloxy)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[N '-(cyano group)-S-(methyl) isothioureido] propoxy-} phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (30mg) in methyl alcohol (1mL); add 2-monoethanolamine (0.5mL), mixture spends the night 50 ℃ of stirrings then.After being cooled to room temperature, in reaction mixture, (28% methanol solution, 0.02mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (15mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.95-2.05(2H，m)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.5-3.7(6H，m)，3.73(1H，d，J＝15.8Hz)，3.8-3.9(1H，m)，4.0(2H，t，J＝5.9Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 38
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(sulfamoylamino group) propoxy-] phenyl }
Methyl)-the 1H-pyrazoles
To the solution of isocyanic acid chlorine sulfonyl ester (0.022mL) in acetonitrile (1mL), add entry (0.005mL), mixture was stirring at room 10 minutes then.Reaction mixture is added to 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (51mg) and triethylamine (0.052mL) solution in methylene dichloride (2mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=30/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(sulfamoylamino group) propoxy-] and phenyl } methyl)-1H-pyrazoles (18mg).This material is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.01mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (3mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.95-2.05(2H，m)，2.8-2.95(1H，m)，3.21(2H，t，J＝6.8Hz)，3.25-3.45(4H，m)，3.6-3.8(3H，m)，3.84(1H，d，J＝11.6Hz)，4.02(2H，t，J＝6.0Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 39
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[3-(formamyl first
Base is amino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (98mg) in tetrahydrofuran (THF) (2mL); add 2-(2-nitrobenzene sulfonyl ammonia base) ethanamide (40mg); (40% toluene solution, 0.1mL), mixture is in stirred overnight at room temperature then for triphenylphosphine (45mg) and diethylazodicarboxylate (diethyl azodicarboxylate).Reaction mixture carries out purifying (eluent: ethyl acetate-methylene chloride=10/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[N-(2-oil of mirbane alkylsulfonyl)-N-(carbamyl ylmethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1H-pyrazoles (92mg).With this substance dissolves in acetonitrile (1mL).In this solution, add cesium carbonate (0.14g) and thiophenol (0.012mL), mixture was stirring at room 1 hour then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Dried over sodium sulfate is used in organic layer salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=10/1-5/1), obtain title compound (57mg) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.83(3H，s)，1.9-2.05(11H，m)，2.26(3H，s)，2.75-2.9(3H，m)，3.28(2H，s)，3.53(1H，d，J＝16.1Hz)，3.58(1H，d，J＝16.1Hz)，3.85-3.95(1H，m)，4.01(2H，t，J＝6.3Hz)，4.06(1H，dd，J＝12.4Hz，2.3Hz)，4.27(1H，dd，J＝12.4Hz，4.2Hz)，5.0-5.15(2H，m)，5.2-5.3(1H，m)，5.43(1H，d，J＝8.0Hz)，6.61(1H，dd，J＝8.5Hz，2.6Hz)，6.71(1H，d，J＝2.6Hz)，6.77(1H，d，J＝8.5Hz)
Embodiment 40
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[3-(carbamyl ylmethyl
Amino) propoxy-] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.85-2.0(8H，m)，2.01(3H，s)，2.02(3H，s)，2.78(2H，t，J＝6.9Hz)，2.85-3.0(1H，m)，3.27(2H，s)，3.59(2H，s)，3.9-4.0(1H，m)，4.01(2H，t，J＝6.2Hz)，4.11(1H，dd，J＝12.5Hz，2.3Hz)，4.3(1H，dd，J＝12.5Hz，4.0Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.47(1H，d，J＝8.4Hz)，6.75-6.85(2H，m)，7.0-7.05(2H，m)
Embodiment 41
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-1-(amino
Formyl radical) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-(2-nitrobenzene sulfonyl ammonia base) ethanamide.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.27(3H，d，J＝6.9Hz)，1.85-2.0(8H，m)，2.01(3H，s)，2.02(3H，s)，2.65-2.8(2H，m)，2.85-3.0(1H，m)，3.59(2H，s)，3.9-4.05(3H，m)，4.11(1H，dd，J＝12.5Hz，2.2Hz)，4.3(1H，dd，J＝12.5Hz，3.9Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝7.8Hz)，6.75-6.85(2H，m)，7.0-7.05(2H，m)
Embodiment 42
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-formamyl-1-
(methyl) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-(2-nitrobenzene sulfonyl ammonia base) ethanamide.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.31(6H，s)，1.85-2.0(8H，m)，2.01(3H，s)，2.02(3H，s)，2.6-2.8(2H，m)，2.85-3.0(1H，m)，3.59(2H，s)，3.9-4.0(1H，m)，4.02(2H，t，J＝6.1Hz)，4.11(1H，dd，J＝12.5Hz，2.6Hz)，4.3(1H，dd，J＝12.5Hz，4.1Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝8.2Hz)，6.75-6.85(2H，m)，7.0-7.05(2H，m)
Embodiment 43
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[2-(formamyl first
Base is amino) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.83(3H，s)，1.96(3H，s)，2.0(3H，s)，2.02(3H，s)，2.26(3H，s)，2.75-2.9(1H，m)，2.96(2H，t，J＝5.2Hz)，3.32(2H，s)，3.53(1H，d，J＝16.6Hz)，3.59(1H，d，J＝16.6Hz)，3.85-3.95(1H，m)，4.03(2H，t，J＝5.2Hz)，4.06(1H，dd，J＝12.3Hz，2.0Hz)，4.27(1H，dd，J＝12.3Hz，4.2Hz)，5.0-5.15(2H，m)，5.2-5.35(1H，m)，5.43(1H，d，J＝8.0Hz)，6.64(1H，dd，J＝8.5Hz，2.3Hz)，6.74(1H，d，J＝2.3Hz)，6.78(1H，d，J＝8.5Hz)
Embodiment 44
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-(carbamyl
Base) ethylamino] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 3-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-(2-nitrobenzene sulfonyl ammonia base) ethanamide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.83(3H，s)，1.96(3H，s)，2.0(3H，s)，2.02(3H，s)，2.26(3H，s)，2.47(2H，t，J＝6.7Hz)，2.75-2.9(1H，m)，2.9-3.05(4H，m)，3.53(1H，d，J＝16.4Hz)，3.59(1H，d，J＝16.4Hz)，3.85-3.95(1H，m)，4.0-4.1(3H，m)，4.27(1H，dd，J＝12.5Hz，4.1Hz)，5.0-5.15(2H，m)，5.25-5.35(1H，m)，5.43(1H，d，J＝8.2Hz)，6.64(1H，dd，J＝8.3Hz，2.6Hz)，6.75(1H，d，J＝2.6Hz)，6.79(1H，d，J＝8.3Hz)
Embodiment 45
4-(4-[3-(formamyl methylamino) propoxy-]-the 2-aminomethyl phenyl } methyl)-3-(β-D-pyrrole
The glucosyloxy of muttering)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(formamyl methylamino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.28(3H，s)，2.7-2.85(3H，m)，3.24(2H，s)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 46
4-(4-[3-(formamyl methylamino) propoxy-] and phenyl } methyl)-3-(β-D-pyranoglucose
The oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(formamyl methylamino) propoxy-] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1，2(6H，m)，1.85-2.0(2H，m)，2.75(2H，t，J＝6.9Hz)，2.8-2.95(1H，m)，3.25(2H，s)，3.3-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.3Hz)，3.8-3.9(1H，m)，4.02(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 47
4-[(4-{3-[(S)-and 1-(formamyl) ethylamino] propoxy-} phenyl) methyl]-3-(β-D-pyrrole
The glucosyloxy of muttering)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-and 1-(formamyl) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.26(3H，d，J＝7.0Hz)，1.85-2.0(2H，m)，2.6-2.75(2H，m)，2.8-2.95(1H，m)，3.19(1H，q，J＝7.0Hz)，3.25-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，4.0(2H，t，J＝6.2Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 48
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-} phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.29(6H，s)，1.85-1.95(2H，m)，2.65(2H，t，J＝7.1Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，4.02(2H，t，J＝5.9Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 49
4-(4-[2-(formamyl methylamino) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-3-(β-D-pyrrole
The glucosyloxy of muttering)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[2-(formamyl methylamino) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.75-2.85(1H，m)，2.94(2H，t，J＝5.2Hz)，3.25-3.4(6H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.02(2H，t，J＝5.2Hz)，4.95-5.1(1H，m)，6.64(1H，dd，J＝8.4H-z，2.5Hz)，6.74(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 50
4-[(4-{2-[2-(formamyl) ethylamino] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[2-(formamyl) ethylamino] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.44(2H，t，J＝6.8Hz)，2.7-2.85(1H，m)，2.9(2H，t，J＝6.8Hz)，2.95(2H，t，J＝5.1Hz)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.03(2H，t，J＝5.1Hz)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.5Hz，2.4Hz)，6.74(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.5Hz)
Embodiment 51
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.25g) in tetrahydrofuran (THF) (2mL); add 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide (0.14g); (40% toluene solution, 0.26mL), mixture is in stirred overnight at room temperature then for triphenylphosphine (0.12g) and diethylazodicarboxylate (diethyl azodicarboxylate).Reaction mixture carries out purifying (eluent: n-hexane/ethyl acetate=1/4-methylene chloride=20/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{N-(2-oil of mirbane alkylsulfonyl)-N-[1-formamyl-1-(methyl) ethyl] amino } propoxy-)-the 2-aminomethyl phenyl] methyl }-1H-pyrazoles (0.32g).With this substance dissolves in acetonitrile (3mL).In this solution, add cesium carbonate (0.46g) and thiophenol (0.038mL), mixture was stirring at room 1 hour then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/5-methylene chloride=15/1-10/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (20mg).This material is dissolved in methyl alcohol (1mL).In this solution, (28% methanol solution, 0.01mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (11mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.29(6H，s)，1.85-1.95(2H，m)，2.29(3H，s)，2.65(2H，t，J＝6.9Hz)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.5Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 52
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 51, wherein uses 3-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide to replace 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.42(2H，t，J＝6.9Hz)，2.7-2.9(5H，m)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 53
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (R)-2-hydroxyl-3-[2-hydroxyl-1-(methylol)-1-
(methyl) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
With 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and the 4-[(4-hydroxy phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.55g), (R)-1-(3-oil of mirbane sulfonyloxy)-2; 3-propylene oxide (0.38g) and cesium carbonate (0.57g) are at N; mixture in the dinethylformamide (5mL) at room temperature stirred 24 hours.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=2/1) by silica gel column chromatography then; obtain 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(R) and-2,3-epoxy group(ing) propoxy-] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (0.4g).This material (43mg) is dissolved in ethanol (1.5mL).In this solution, add 2-amino-2-methyl-1, ammediol (51mg), mixture stirred 14 hours for 75 ℃ then.In reaction mixture, add 1mol/L aqueous sodium hydroxide solution (0.28mL), mixture was stirring at room 1 hour then.Reaction mixture by the reverse column chromatography direct purification of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ m,
20 * 50mm, flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90), obtain title compound (12mg).
1H-NMR(CD
3OD)δppm：
1.0(3H，s)，1.05-1.15(6H，m)，2.68(1H，dd，J＝11.6Hz，8.1Hz)，2.78(1H，dd，J＝11.6Hz，3.8Hz)，2.8-2.95(1H，m)，3.25-3.55(8H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.1Hz)，3.8-4.0(4H，m)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 54
3-(β-D-pyranoglucose oxygen base)-4-(4-[(R)-2-hydroxyl-3-(2-hydroxyethylamino) propoxy-]
Phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 53, wherein uses the 2-monoethanolamine to replace 2-amino-2-methyl-1, ammediol.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，2.65-2.95(5H，m)，3.25-3.45(4H，m)，3.6-3.8(5H，m)，3.8-3.9(1H，m)，3.91(2H，d，J＝5.4Hz)，4.0-4.1(1H，m)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 55
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-guanidine radicals propoxy-)-2-aminomethyl phenyl] methyl }-5-is different
Propyl group-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (70mg) in tetrahydrofuran (THF) (3mL); add N-benzyloxycarbonyl-1H-pyrazoles-1-acyl amidine (carboxamidine) (0.27g), mixture stirred 20 hours at 60 ℃ then.To the reaction mixture concentrating under reduced pressure; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(N '-the benzyloxycarbonyl guanidine radicals) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (50mg).This material is dissolved in methyl alcohol (1mL).In this solution, (28% methanol solution, 0.01mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water by Solid-Phase Extraction on ODS then, eluent: methyl alcohol), obtain 4-({ 4-[3-(N '-benzyloxycarbonyl guanidine radicals) propoxy-]-2-aminomethyl phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (35mg).This material is dissolved in methyl alcohol (2mL).Add 10% palladium-carbon dust (15mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (27mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.95-2.05(2H，m)，2.29(3H，s)，2.75-2.9(1H，m)，3.25-3.45(6H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝5.7Hz)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.6Hz，2.5Hz)，6.73(1H，d，J＝2.5Hz)，6.87(1H，d，J＝8.6Hz)
Embodiment 56
3-(β-D-pyranoglucose oxygen base)-4-{[4-(2-guanidine radicals oxyethyl group)-2-aminomethyl phenyl] methyl }-5-is different
Propyl group-1H-pyrazoles
The preparation method of title compound is similar to embodiment 55; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.3(3H，s)，2.75-2.9(1H，m)，3.25-3.4(4H，m)，3.55(2H，t，J＝5.0Hz)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.06(2H，t，J＝5.0Hz)，5.02(1H，d，J＝7.0Hz)，6.65(1H，dd，J＝8.5Hz，2.6Hz)，6.75(1H，d，J＝2.6Hz)，6.88(1H，d，J＝8.5Hz)
Embodiment 57
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methyl) ethylamino] third oxygen
Base }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (1g) in methylene dichloride (16mL); add triethylamine (0.29mL) and methylsulfonyl chloride (0.15mL), mixture was stirring at room 3 hours then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (1.12g).With the 3-(2 that obtains; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (0.2g) is dissolved in the mixed solvent of acetonitrile (2mL) and ethanol (2mL).In this solution, add the sodium iodide of 2-amino-2-methyl-1-propanol (0.25g) and catalytic amount, mixture stirred 2 days at 60 ℃ then.To the reaction mixture concentrating under reduced pressure, then residue is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.16mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (0.13g) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.0-1.15(12H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.65-2.85(3H，m)，3.25-3.4(6H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝5.6Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.5Hz，2.6Hz)，6.71(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 58
3-(β-D-pyranoglucose oxygen base)-4-(4-[3-(2-hydroxyethylamino) propoxy-]-the 2-aminomethyl phenyl }
Methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57, wherein uses the 2-monoethanolamine to replace 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.7-2.85(5H，m)，3.25-3.4(4H，m)，3.553.75(5H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝5.9Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.5Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 59
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1-(methylol) ethylamino] propoxy-}-
The 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57, wherein uses 2-amino-1, and ammediol is replaced 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.65-2.9(4H，m)，3.25-3.4(4H，m)，3.54(2H，dd，J＝11.1Hz，5.8Hz)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.6Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.6Hz)
Embodiment 60
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1-(methylol) ethylamino] propoxy-}
Phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.9-2.0(2H，m)，2.65-2.75(1H，m)，2.8-2.95(3H，m)，3.25-3.45(4H，m)，3.54(2H，dd，J＝11.2Hz，5.9Hz)，3.55-3.7(4H，m)，3.73(1H，d，J＝15.8Hz)，3.8-3.9(1H，m)，4.02(2H，t，J＝6.1Hz)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 61
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methyl) ethylamino] propoxy-}
Phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.15(12H，m)，1.85-2.0(2H，m)，2.65-2.8(2H，m)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，3.95-4.05(2H，m)，5.0-5.15(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 62
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1-(methylol) ethylamino] oxyethyl group }-
The 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.7-2.85(2H，m)，3.04(2H，t，J＝5.2Hz)，3.25-3.4(4H，m)，3.55(2H，dd，J＝11.2Hz，5.8Hz)，3.6-3.75(5H，m)，3.75-3.85(1H，m)，4.06(2H，t，J＝5.2Hz)，4.95-5.1(1H，m)，6.65(1H，dd，J＝8.5Hz，2.7Hz)，6.75(1H，d，J＝2.7Hz)，6.87(1H，d，J＝8.5Hz)
Embodiment 63
3-(β-D-pyranoglucose oxygen base)-4-(4-[2-(2-hydroxyethylamino) oxyethyl group]-the 2-aminomethyl phenyl }
Methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-monoethanolamine, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.75-2.85(3H，m)，2.99(2H，t，J＝5.2Hz)，3.25-3.4(4H，m)，3.6-3.75(5H，m)，3.75-3.85(1H，m)，4.05(2H，t，J＝5.2Hz)，4.95-5.1(1H，m)，6.65(1H，dd，J＝8.4Hz，2.4Hz)，6.74(1H，d，J＝2.4Hz)，6.87(1H，d，J＝8.4Hz)
Embodiment 64
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(3-pyridylmethyl amino) propoxy-]
Phenyl } methyl)-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 3-picoline amine, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.77(2H，t，J＝7.2Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.7(2H，m)，3.73(1H，d，J＝16.3Hz)，3.75-3.9(3H，m)，4.0(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.7-6.8(2H，m)，7.05-7.15(2H，m)，7.35-7.45(1H，m)，7.8-7.85(1H，m)，8.4-8.45(1H，m)，8.5-8.55(1H，m)
Embodiment 65
4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-(β-D-pyranoglucose oxygen base)-5-is different for 3-
Propyl group-1H-pyrazoles
The preparation method of title compound is similar to embodiment 6; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.7-2.85(1H，m)，2.99(2H，t，J＝5.2Hz)，3.25-3.4(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.97(2H，t，J＝5.2Hz)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.6Hz，2.7Hz)，6.74(1H，d，J＝2.7Hz)，6.86(1H，d，J＝8.6Hz)
Embodiment 66
3-(β-D-pyranoglucose oxygen base)-4-(4-[3-(3-hydroxyl third amino) propoxy-]-the 2-aminomethyl phenyl }
Methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57, wherein uses 3-amino-1-propyl alcohol to replace 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.7-1.8(2H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.65-2.85(5H，m)，3.25-3.4(4H，m)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.5Hz，2.5Hz)，6.7(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.5Hz)
Embodiment 67
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1-(methylol)-1-(methyl) ethylamino]
Propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57, wherein uses 2-amino-2-methyl-1, and ammediol is replaced 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.01(3H，s)，1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.7-2.85(3H，m)，3.25-3.4(4H，m)，3.4-3.55(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.3Hz，2.6Hz)，6.72(1H，d，J＝2.6Hz)，6.84(1H，d，J＝8.3Hz)
Embodiment 68
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1-(methylol)-1-(methyl) ethylamino]
Oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.01(3H，s)，1.05-1.15(6H，m)，2.29(3H，s)，2.7-2.85(1H，m)，2.92(2H，t，J＝5.3Hz)，3.25-3.4(4H，m)，3.4-3.55(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.02(2H，t，J＝5.3Hz)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.4Hz，2.7Hz)，6.74(1H，d，J＝2.7Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 69
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methylol) ethylamino] third oxygen
Base } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and three (methylol) aminomethane, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-2.0(2H，m)，2.75-2.95(3H，m)，3.25-3.4(4H，m)，3.56(6H，s)，3.6-3.75(3H，m)，3.8-3.9(1H，m)，4.02(2H，t，J＝6.1Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 70
3-(β-D-pyranoglucose oxygen base)-4-(4-[2-(3-hydroxyl third amino) oxyethyl group]-the 2-aminomethyl phenyl }
Methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyl-oxethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 3-amino-1-propyl alcohol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.7-1.8(2H，m)，2.29(3H，s)，2.65-2.85(3H，m)，2.94(2H，t，J＝5.2Hz)，3.25-3.4(4H，m)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，4.03(2H，t，J＝5.2Hz)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.1Hz，2.4Hz)，6.74(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.1Hz)
Embodiment 71
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methylol) ethylamino] third oxygen
Base }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 57, wherein uses three (methylol) aminomethane to replace 2-amino-2-methyl-1-propanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-1.95(2H，m)，2.28(3H，s)，2.75-2.85(3H，m)，3.25-3.4(4H，m)，3.56(6H，s)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.01(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.5Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.84(1H，d，J＝8.5Hz)
The comparative example 35
2-[2-amino-2-(methyl) propionamido] ethanol
To the solution of 2-benzyloxycarbonyl amino-2-(methyl) propionic acid (1g) in tetrahydrofuran (THF) (5mL), add 1,1 '-carbonyl diurethane-1H-imidazoles (889mg), mixture was stirring at room 1 hour then.In reaction mixture, add 2-monoethanolamine (0.38mL), mixture was stirring at room 2 hours then.Reaction mixture by silica gel column chromatography carry out purifying (eluent: methylene chloride=20/1), obtain 2-[2-benzyloxycarbonyl amino-2-(methyl) propionamido] ethanol (973mg).This material is dissolved in methyl alcohol (5mL).In this solution, add 10% palladium-carbon dust (200mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (505mg).
1H-NMR(CD
3OD)δppm：1.31(6H，s)，3.25-3.35(2H，m)，3.6(2H，t，J＝5.7Hz)
The comparative example 36
4-methyl isophthalic acid-[2-amino-2-(methyl) propionyl] piperazine
The preparation method of title compound is similar to comparative example 35, wherein uses the 1-methylpiperazine to replace the 2-monoethanolamine.
1H-NMR(DMSO-d
6)δppm：
1.24(6H，s)，1.83(2H，brs)，2.16(3H，s)，2.26(4H，t，J＝5.0Hz)，3.5-3.95(4H，br)
The comparative example 37
2-[2-amino-2-(methyl) propionamido]-2-methyl isophthalic acid-propyl alcohol
The preparation method of title compound is similar to comparative example 35, wherein uses 2-amino-2-methyl-1-propanol to replace the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.28(12H，s)，3.55(2H，s)
The comparative example 38
3-[2-amino-2-(methyl) propionamido]-the 1-propyl alcohol
The preparation method of title compound is similar to comparative example 35, wherein uses 3-amino-1-propyl alcohol to replace the 2-monoethanolamine.
1H-NMR(DMSO-d
6)δppm：
1.16(6H，s)，1.5-1.6(2H，m)，1.89(2H，brs)，3.05-3.15(2H，m)，3.35-3.45(2H，m)，4.43(1H，t，J＝5.3Hz)，7.8-7.95(1H，br)
The comparative example 39
N-[2-amino-2-(methyl) propionyl] morpholine
The preparation method of title compound is similar to comparative example 35, wherein uses morpholine to replace the 2-monoethanolamine.
1H-NMR(DMSO-d
6)δppm：
1.25(6H，s)，1.75-2.3(2H，br)，3.45-3.6(4H，m)，3.65-3.95(4H，br)
Embodiment 72
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-(2-hydroxyethylamino formyl radical)-1-(methyl)
Ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (0.77g) in methylene dichloride (5mL); add triethylamine (0.26mL) and methylsulfonyl chloride (0.12mL), mixture was stirring at room 30 minutes then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-] phenyl } methyl)-1H-pyrazoles (0.85g).3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-of obtaining ({ 4-[3-(mesyloxy) propoxy-] phenyl } methyl)-1H-pyrazoles (0.2g) is dissolved in the mixed solvent of acetonitrile (1.5mL) and ethanol (1.5mL).In this solution, add 2-[2-amino-2-(methyl) propionamido] sodium iodide of ethanol (0.25g) and catalytic amount, mixture was 60 ℃ of stirrings 4 days then.To the reaction mixture concentrating under reduced pressure; residue carries out purifying (eluent: methylene chloride=20/1-10/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.13g).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.05mL), mixture was stirring at room 3 hours then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (93mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.28(6H，s)，1.8-1.95(2H，m)，2.63(2H，t，J＝6.9Hz)，2.85-2.95(1H，m)，3.2-3.4(6H，m)，3.55(2H，t，J＝5.8Hz)，3.6-3.9(4H，m)，4.03(2H，t，J＝6.2Hz)，5.0-5.1(1H，m)，6.7-6.85(2H，m)，7.0-7.15(2H，m)
Embodiment 73
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(first
Base) ethylamino } propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72, wherein uses 4-methyl isophthalic acid-[2-amino-2-(methyl) propionyl] piperazine to replace 2-[2-amino-2-(methyl) propionamido] ethanol.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.34(6H，s)，1.8-1.95(2H，m)，2.19(3H，s)，2.3-2.4(4H，m)，2.66(2H，t，J＝6.3Hz)，2.8-2.95(1H，m)，3.3-3.4(4H，m)，3.55-4.15(10H，m)，5.0-5.15(1H，m)，6.7-6.8(2H，m)，7.05-7.15(2H，m)
Embodiment 74
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1,1-two (methyl) ethylamino first
Acyl group]-1-(methyl) ethylamino } propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72, wherein uses 2-[2-amino-2-(methyl) propionamido]-2-methyl isophthalic acid-propyl alcohol replacement 2-[2-amino-2-(methyl) propionamido] ethanol.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.24(6H，s)，1.25(6H，s)，1.85-1.95(2H，m)，2.64(2H，t，J＝6.9Hz)，2.8-2.95(1H，m)，3.3-3.45(4H，m)，3.48(2H，s)，3.6-3.9(4H，m)，4.03(2H，t，J＝6.1Hz)，5.05-5.1(1H，m)，6.75-6.8(2H，m)，7.05-7.15(2H，m)
Embodiment 75
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-(3-hydroxypropyl formamyl)-1-(methyl)
Ethylamino] propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72, wherein uses 3-[2-amino-2-(methyl) propionamido]-1-propyl alcohol replacement 2-[2-amino-2-(methyl) propionamido] ethanol.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.27(6H，s)，1.55-1.7(2H，m)，1.85-1.95(2H，m)，2.62(2H，t，J＝6.8Hz)，2.8-2.95(1H，m)，3.23(2H，t，J＝6.7Hz)，3.3-3.4(4H，m)，3.53(2H，t，J＝6.2Hz)，3.6-3.85(4H，m)，4.03(2H，t，J＝6.0Hz)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 76
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[(morpholine-4-yl) carbonyl]-1-(methyl) second ammonia
Base } propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72, wherein uses N-[2-amino-2-(methyl) propionyl] morpholine replacement 2-[2-amino-2-(methyl) propionamido] ethanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.35(6H，s)，1.8-1.95(2H，m)，2.6-2.75(2H，m)，2.8-2.95(1H，m)，3.3-3.4(4H，m)，3.45-4.15(14H，m)，5.0-5.15(1H，m)，6.7-6.8(2H，m)，7.05-7.15(2H，m)
Embodiment 77
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[3-(2-hydroxyethyl)-2-methylsulfonyl guanidine radicals] ethoxy
Base }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
Down to the solution of Dichlorophenoxy methylmethane (1g) in acetonitrile (10mL), add Toluidrin (0.39g) ice-cooled, mixture was stirring at room 48 hours then.Pour reaction mixture into saturated sodium bicarbonate aqueous solution, then the mixture ethyl acetate extraction of Xing Chenging.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 1-(N-methylsulfonyl imino-)-1,1-hexichol oxygen methylmethane (0.95g).To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1H-pyrazoles (50mg) in tetrahydrofuran (THF) (1mL); at the ice-cooled 1-(N-methylsulfonyl imino-)-1 that adds down; 1-hexichol oxygen methylmethane (26mg), mixture was stirring at room 1 hour then.In reaction mixture, add 2-monoethanolamine (49mg), mixture spends the night 60 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure, then residue is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.008mL), mixture was stirring at room 3 hours then to add sodium methylate.In reaction mixture, add acetate (0.01mL).The mixture that obtains is through concentrating under reduced pressure, and residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (38mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.28(3H，s)，2.75-2.85(1H，m)，2.9(3H，s)，3.25-3.4(6H，m)，3.6(2H，t，J＝5.3Hz)，3.6-3.75(5H，m)，3.8(1H，d，J＝12.0Hz)，4.05(2H，t，J＝5.3Hz)，4.95-5.05(1H，m)，6.65(1H，dd，J＝8.1Hz，2.4Hz)，6.76(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.1Hz)
Embodiment 78
4-[(4-{3-[(S)-and 5-benzyloxycarbonyl amino-1-(formamyl) penta amino] propoxy-}-2-
Aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-2-amino-6-(benzyloxycarbonyl amino) hexanamide; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-[2-amino-2-(methyl) propionamido] ethanol.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.3-1.45(2H，m)，1.45-1.7(4H，m)，1.85-2.0(2H，m)，2.28(3H，s)，2.6-2.85(3H，m)，3.05-3.15(3H，m)，3.25-3.4(4H，m)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.1(3H，m)，6.61(1H，dd，J＝8.4Hz，2.5Hz)，6.7(1H，d，J＝2.5Hz)，6.84(1H，d，J＝8.4Hz)，7.2-7.4(5H，m)
Embodiment 79
4-[(4-{3-[(S)-and 5-amino-1-(formamyl) penta amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 4-[(4-{3-[(S)-5-benzyloxycarbonyl amino-1-(formamyl) penta amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen the base)-5-sec.-propyl-solution of 1H-pyrazoles (0.17g) in methyl alcohol (4mL); add 10% palladium-carbon dust (30mg), mixture stirred 1 hour under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (0.13g).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.3-1.7(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.6-2.9(5H，m)，3.08(1H，t，J＝6.6Hz)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝6.1Hz)，5.01(1H，d，J＝7.0Hz)，6.61(1H，dd，J＝8.4Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 80
4-[(4-{3-[(S)-2,5-diamino valeryl amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-
D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 13; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(the amino propoxy-of 3-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-2,5-two (benzyloxycarbonyl amino) valeric acid; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.35-1.75(4H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.59(2H，t，J＝6.9Hz)，2.75-2.9(1H，m)，3.2-3.5(7H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.97(2H，t，J＝6.0Hz)，5.01(1H，d，J＝7.3Hz)，6.62(1H，dd，J＝8.5Hz，2.3Hz)，6.72(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.5Hz)
The comparative example 40
1-benzyloxycarbonyl-4-[2-carboxyl-2-(methyl) propionyl] piperazine
To the solution of dimethyl malonic ester (3g) in ethanol (5mL), add the solution of sodium hydroxide (0.64g) in water (2mL), mixture was stirring at room 5 days then.To the reaction mixture concentrating under reduced pressure, residue acidifying then by adding 2mol/L hydrochloric acid.The mixture ethyl acetate extraction that forms.Extract salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains dimethyl malonic acid one ethyl ester (2.43g).To dimethyl malonic acid one ethyl ester (1g) that obtains at N, solution in the dinethylformamide (20mL), add 1-(benzyloxycarbonyl) piperazine (1.38g), I-hydroxybenzotriazole (0.93g), triethylamine (1.31mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.4g), mixture was stirring at room 2 days then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Extract is with saturated sodium bicarbonate aqueous solution, water and salt water washing, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, then residue by silica gel column chromatography carry out purifying (eluent: n-hexane/ethyl acetate=4/1-2/1), obtain 1-benzyloxycarbonyl-4-[2-ethoxy carbonyl-2-(methyl) propionyl] piperazine (1.77g).With this substance dissolves in ethanol (5mL).Add 2mol/L aqueous sodium hydroxide solution (2.93mL) in this solution, mixture spends the night 55 ℃ of stirrings then.Reaction mixture is poured in the water, and the mixture of Xing Chenging washs with ethyl acetate then.Aqueous layer is acidifying, mixture extracted with diethyl ether then by adding 2mol/L hydrochloric acid.Extract salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (0.28g).
1H-NMR(CDCl
3)δppm：
1.48(6H，s)，3.25-3.7(8H，m)，5.14(2H，s)，7.3-7.4(5H，m)
Embodiment 81
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{2-methyl-2-[(piperazine-1-yl) carbonyl
Base] propionamido } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 13; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 1-benzyloxycarbonyl-4-[2-carboxyl-2-(methyl) propionyl] piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(the amino propoxy-of 3-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-benzyloxycarbonyl Padil.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.37(6H，s)，2.3(3H，s)，2.35-2.9(5H，m)，3.1-3.75(13H，m)，3.81(1H，d，J＝11.5Hz)，4.02(2H，t，J＝5.4Hz)，5.02(1H，d，J＝7.4Hz)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
The comparative example 41
N, N-dimethyl-N '-(2-oil of mirbane alkylsulfonyl)-1,3-diaminopropanes
To N, N-dimethyl-1,3-diaminopropanes (0.92g) and the solution of triethylamine (0.95mL) in methylene dichloride (10mL) add 2-nitrobenzene sulfonyl chloride (1g), and mixture is in stirred overnight at room temperature then.Reaction mixture carries out purifying (eluent: methylene chloride=10/1), obtain title compound (1.26g) by silica gel column chromatography.
1H-NMR(CDCl
3)δppm：
1.7-1.8(2H，m)，2.28(6H，s)，2.46(2H，t，J＝5.9Hz)，3.15-3.25(2H，m)，7.65-7.75(2H，m)，7.8-7.85(1H，m)，8.05-8.15(1H，m)
The comparative example 42
3-(2-nitrobenzene sulfonyl ammonia base) methyl propionate
The preparation method of title compound is similar to comparative example 2, wherein uses 3-alanine methyl ester hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CDCl
3)δppm：
2.61(2H，t，J＝6.2Hz)，3.37(2H，q，J＝6.2Hz)，3.69(3H，s)，5.96(1H，t，J＝6.2Hz)，7.7-7.8(2H，m)，7.85-7.9(1H，m)，8.1-8.2(1H，m)
The comparative example 43
4-methyl isophthalic acid-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine
To the solution of 3-(2-nitrobenzene sulfonyl ammonia base) methyl propionate (6.15g) in ethanol (20mL) and methyl alcohol (5mL), add 5mol/L aqueous sodium hydroxide solution (20mL), mixture is in stirred overnight at room temperature then.Reaction mixture acidifying, and the mixture ethyl acetate extraction that forms by adding 2mol/L hydrochloric acid (55mL).Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue is handled with normal hexane and ethyl acetate then.Sedimentary crystal is collected by filtering, and with normal hexane washing and drying under reduced pressure, obtains 3-(2-nitrobenzene sulfonyl ammonia base) propionic acid (5.83g).To the solution of 3-(2-nitrobenzene sulfonyl ammonia base) propionic acid (0.5g) in tetrahydrofuran (THF) (5mL) that obtains, add 1,1 '-carbonyl diurethane-1H-imidazoles (0.35g), mixture was stirring at room 2 hours then.In reaction mixture, add 1-methylpiperazine (0.46g), mixture stirred 3 days for 50 ℃ then.To the reaction mixture concentrating under reduced pressure, then residue by the column chromatography of on aminopropyl silica gel, carrying out purifying (eluent: methylene chloride=40/1), obtain title compound (0.61g).
1H-NMR(CDCl
3)δppm：
2.25-2.4(7H，m)，2.61(2H，t，J＝5.7Hz)，3.3-3.45(4H，m)，3.55-3.65(2H，m)，7.65-7.75(2H，m)，7.8-7.9(1H，m)，8.1-8.15(1H，m)
The comparative example 44
4-benzyl-1-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine
The preparation method of title compound is similar to comparative example 43, wherein uses the 1-benzyl diethylenediamine to replace the 1-methylpiperazine.
1H-NMR(CDCl
3)δppm：
2.35-2.45(4H，m)，2.59(2H，t，J＝5.8Hz)，3.3-3.45(4H，m)，3.52(2H，s)，3.55-3.65(2H，m)，7.2-7.35(5H，m)，7.65-7.75(2H，m)，7.8-7.9(1H，m)，8.05-8.15(1H，m)
The comparative example 45
4-(2-hydroxyethyl)-1-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine
The preparation method of title compound is similar to comparative example 43, wherein uses 1-(2-hydroxyethyl) piperazine to replace the 1-methylpiperazine.
1H-NMR(CDCl
3)δppm：
2.4-2.65(8H，m)，3.37(2H，t，J＝5.8Hz)，3.43(2H，t，J＝5.0Hz)，3.55-3.7(4H，m)，7.7-7.75(2H，m)，7.8-7.9(1H，m)，8.1-8.15(1H，m)
The comparative example 46
4-(2-acetoxyl group ethyl)-1-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine
To 4-(2-hydroxyethyl)-1-[3-(2-oil of mirbane sulfuryl amino) propionyl] piperazine (1.15g) and the solution of pyridine (1.47mL) in methylene dichloride (10mL), add diacetyl oxide (1.72mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2-methylene chloride=10/1), obtain title compound (0.38g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.07(3H，s)，2.4-2.55(4H，m)，2.55-2.7(4H，m)，3.3-3.45(4H，m)，3.55-3.65(2H，m)，4.05-4.15(2H，m)，6.34(1H，t，J＝6.5Hz)，7.7-7.75(2H，m)，7.8-7.9(1H，m)，8.1-8.15(1H，m)
Embodiment 82
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[3-(dimethylamino) third amino] third oxygen
Base }-the 2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 51, wherein uses N, N-dimethyl-N '-(2-oil of mirbane alkylsulfonyl)-1, and the 3-diaminopropanes is replaced 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.6-1.75(2H，m)，1.85-2.0(2H，m)，2.22(6H，s)，2.29(3H，s)，2.3-2.4(2H，m)，2.61(2H，t，J＝7.4Hz)，2.7-2.85(3H，m)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.1(1H，m)，6.61(1H，dd，J＝8.2Hz，2.5Hz)，6.7(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.2Hz)
Embodiment 83
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[2-(methoxycarbonyl) ethylamino] third
The oxygen base }-the 2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 51, wherein uses 3-(2-nitrobenzene sulfonyl ammonia base) methyl propionate to replace 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.95-2.05(2H，m)，2.29(3H，s)，2.64(2H，t，J＝6.5Hz)，2.75-2.85(1H，m)，2.9-3.1(4H，m)，3.25-3.4(4H，m)，3.6-3.7(6H，m)，3.75-3.85(1H，m)，4.03(2H，t，J＝6.0Hz)，5.0-5.05(1H，m)，6.64(1H，dd，J＝8.3Hz，2.3Hz)，6.73(1H，d，J＝2.3Hz)，6.87(1H，d，J＝8.3Hz)
Embodiment 84
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(4-methylpiperazine-1-yl) carbonyl
Base] ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 51, wherein uses 4-methyl isophthalic acid-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine to replace 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(6H，s)，2.35-2.45(4H，m)，2.6(2H，t，J＝6.6Hz)，2.75-2.9(5H，m)，3.3-3.4(4H，m)，3.5-3.7(7H，m)，3.8-3.85(1H，m)，4.0(2H，t，J＝6.0Hz)，5.0-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 85
3-(β-D-pyranoglucose oxygen base)-4-(4-[3-(2-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }
Ethylamino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 51, wherein uses 4-(2-acetoxyl group ethyl)-1-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine replacement 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.46(2H，t，J＝5.1Hz)，2.5-2.55(4H，m)，2.6(2H，t，J＝6.6Hz)，2.75-2.9(5H，m)，3.25-3.4(4H，m)，3.5-3.7(9H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.6Hz)，6.72(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 86
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(piperazine-1-yl) carbonyl] second ammonia
Base } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(4-benzyl diethylenediamine-1-yl) carbonyl] ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-preparation method of 1H-pyrazoles is similar to embodiment 51, wherein uses 4-benzyl-1-[3-(2-nitrobenzene sulfonyl ammonia base) propionyl] piperazine replaces 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.Then; the preparation method of title compound is similar to embodiment 79, wherein uses this substitution of materials 4-[(4-{3-[(S)-5-benzyloxycarbonyl amino-1-(formamyl) penta amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.59(2H，t，J＝6.6Hz)，2.7-2.9(9H，m)，3.3-3.4(4H，m)，3.45-3.55(4H，m)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.3Hz)，6.72(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 87
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-(2-hydroxyethylamino formyl radical) ethylamino] third
The oxygen base }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To the solution of 3-benzyloxycarbonyl alanine (1g) in tetrahydrofuran (THF) (10mL), add 1,1 '-carbonyl diurethane-1H-imidazoles (0.94g), mixture was stirring at room 1 hour then.In reaction mixture, add 2-monoethanolamine (0.81mL), mixture was stirring at room 1 hour then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Extract washs successively with 0.5mol/L hydrochloric acid, water and salt solution, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, and residue washs with the mixed solvent (2/1) of normal hexane and ethyl acetate then, and drying under reduced pressure, obtains 2-[3-(benzyloxycarbonyl amino) propionamido] ethanol (0.25g).With 2[3-(benzyloxycarbonyl amino) propionamido that obtains] ethanol (50mg) is dissolved in methyl alcohol (3mL).Add 10% palladium-carbon dust (20mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains 2-(the amino propionamido of 3-) ethanol (24mg).To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.81g) and the solution of triethylamine (0.21mL) in methylene dichloride (6mL); add methylsulfonyl chloride (0.11mL), mixture was stirring at room 1 hour then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (0.89g).To the 3-(2 that obtains; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(mesyloxy) propoxy-]-the 2-aminomethyl phenyl } methyl)-solution of 1H-pyrazoles (50mg) in acetonitrile (1mL)-ethanol (1mL); add described 2-(the amino propionamido of 3-) ethanol (23mg) and sodium iodide (11mg), mixture stirred 3 days at 60 ℃ then.To the reaction mixture concentrating under reduced pressure; residue carries out purifying (eluent: methylene chloride=10/1-5/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-(2-hydroxyethylamino formyl radical) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (42mg).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.03mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (18mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.41(2H，t，J＝6.7Hz)，2.7-2.9(5H，m)，3.25-3.4(6H，m)，3.57(2H，t，J＝5.7Hz)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 88
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-(3-hydroxypropyl formamyl) ethylamino] third
The oxygen base }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 87, wherein uses 3-amino-1-propyl alcohol to replace the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.65-1.75(2H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.4(2H，t，J＝6.8Hz)，2.75-2.9(5H，m)，3.24(2H，t，J＝6.9Hz)，3.25-3.4(4H，m)，3.56(2H，t，J＝6.3Hz)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 89
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{2-[2-hydroxyl-1-(methylol) ethylamino formyl
Base] ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 87, wherein uses 2-amino-1, and ammediol is replaced the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.44(2H，t，J＝6.7Hz)，2.75-2.85(3H，m)，2.88(2H，t，J＝6.71Hz)，3.25-3.4(4H，m)，3.55-3.7(7H，m)，3.75-3.85(1H，m)，3.9-3.95(1H，m)，4.0(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 90
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{2-[2-hydroxyl-1-(methylol)-1-(methyl) second
The base formamyl] ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 87, wherein uses 2-amino-2-methyl-1, and ammediol is replaced the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.22(3H，s)，1.9-2.0(2H，m)，2.29(3H，s)，2.4(2H，t，J＝6.5Hz)，2.75-2.9(5H，m)，3.25-3.4(4H，m)，3.55-3.75(7H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 91
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{2-[2-hydroxyl-1,1-two (methylol) ethylamino
Formyl radical] ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 87, wherein uses three (methylol) aminomethane to replace the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.44(2H，t，J＝6.4Hz)，2.75-2.9(5H，m)，3.25-3.4(4H，m)，3.6-3.75(9H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.2Hz)，6.71(1H，d，J＝2.2Hz)，6.85(1H，d，J＝8.4Hz)
The comparative example 47
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(3-benzyloxy third oxygen
Base)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(3-benzyloxy propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.81(3H，s)，1.98(3H，s)，2.0-2.1(5H，m)，2.22(3H，s)，2.26(3H，s)，2.75-2.85(1H，m)，3.5(1H，d，J＝16.5Hz)，3.55-3.7(3H，m)，4.0-4.1(3H，m)，4.1-4.2(2H，m)，4.52(2H，s)，5.07(1H，dd，J＝10.3Hz，3.3Hz)，5.35-5.45(2H，m)，5.52(1H，d，J＝7.8Hz)，6.58(1H，dd，J＝8.4Hz，2.7Hz)，6.69(1H，d，J＝2.7Hz)，6.79(1H，d，J＝8.4Hz)，7.2-7.35(5H，m)
The comparative example 48
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(3-hydroxyl third oxygen
Base)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-benzyloxy propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，1.95-2.05(8H，m)，2.16(3H，s)，2.27(3H，s)，2.75-2.85(1H，m)，3.51(1H，d，J＝16.6Hz)，3.61(1H，d，J＝16.6Hz)，3.8-3.9(2H，m)，4.0-4.2(5H，m)，5.07(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.51(1H，d，J＝8.2Hz)，6.6(1H，dd，J＝8.5Hz，2.7Hz)，6.7(1H，d，J＝2.7Hz)，6.81(1H，d，J＝8.5Hz)
The comparative example 49
3-benzylamino propionic acid amide
To the solution of acrylamide (32g) in ethanol (450mL), add benzene methanamine (59mL), mixture spends the night 60 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-methylene chloride=50/1), obtain title compound (73.2g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.35-2.45(2H，m)，2.9-2.95(2H，m)，3.81(2H，s)，5.15-5.6(1H，br)，7.2-7.65(6H，m)
Embodiment 92
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[N-benzyl-N-(2-
The formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.1g) and the solution of triethylamine (0.026mL) in methylene dichloride (3mL); add methylsulfonyl chloride (0.013mL), mixture was stirring at room 1 hour then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (0.11g).With this substance dissolves in the mixed solvent of acetonitrile (2mL) and methyl alcohol (2mL).In this solution, add 3-benzylamino propionic acid amide (46mg) and sodium iodide (24mg), mixture stirred 3 days at 60 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=20/1-10/1), obtain title compound (78mg) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.83(3H，s)，1.9-2.0(5H，m)，2.02(3H，s)，2.15(3H，s)，2.26(3H，s)，2.39(2H，t，J＝6.1Hz)，2.67(2H，t，J＝7.0Hz)，2.7-2.85(3H，m)，3.5(1H，d，J＝16.6Hz)，3.55-3.65(3H，m)，3.91(2H，t，J＝6.1Hz)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.07(1H，dd，J＝10.4Hz，3.5Hz)，5.21(1H，brs)，5.35-5.45(2H，m)，5.53(1H，d，J＝8.2Hz)，6.53(1H，dd，J＝8.6Hz，2.4Hz)，6.63(1H，d，J＝2.4Hz)，6.79(1H，d，J＝8.6Hz)，7.2-7.35(5H，m)，7.44(1H，brs)
Embodiment 93
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[N-benzyl-N-(2-ammonia
Base formyl radical ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 92; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.15(6H，m)，1.82(3H，s)，1.9-2.1(11H，m)，2.25(3H，s)，2.39(2H，t，J＝6.1Hz)，2.66(2H，t，J＝7.2Hz)，2.7-2.9(3H，m)，3.49(1H，d，J＝16.2Hz)，3.58(1H，d，J＝16.2Hz)，3.62(2H，s)，3.8-3.95(3H，m)，4.05-4.15(1H，m)，4.29(1H，dd，J＝12.2Hz，4.0Hz)，5.15-5.3(4H，m)，5.56(1H，d，J＝7.6Hz)，6.52(1H，dd，J＝8.2Hz，2.7Hz)，6.62(1H，d，J＝2.7Hz)，6.79(1H，d，J＝8.2Hz)，7.2-7.35(5H，m)，7.47(1H，brs)
Embodiment 94
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (75mg) in methyl alcohol (3mL); add 10% palladium-carbon dust (20mg), mixture stirred 2.5 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering; then filtrate is carried out concentrating under reduced pressure, obtains 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(2,3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles (66mg).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.03mL), mixture was stirring at room 1 hour then to add sodium methylate.In reaction mixture, add acetate (0.04mL), the mixture of Xing Chenging is through concentrating under reduced pressure then.Residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (43mg) by Solid-Phase Extraction on ODS.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.28(3H，s)，2.42(2H，t，J＝6.8Hz)，2.7-2.9(5H，m)，3.49(1H，dd，J＝9.7Hz，3.2Hz)，3.55-3.8(6H，m)，3.85(1H，d，J＝3.2Hz)，3.99(2H，t，J＝6.1Hz)，5.0-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.5Hz)，6.7(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 95
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (45.3g) in methyl alcohol (400mL); add sodium methylate (28% methanol solution; 2.2mL), mixture was stirring at room 1 hour then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: methylene chloride=5/1-4/1), obtain title compound (33.2g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-1.95(2H，m)，2.28(3H，s)，2.4(2H，t，J＝6.9Hz)，2.55-2.65(2H，m)，2.75-2.85(3H，m)，3.25-3.4(4H，m)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，3.92(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.55(1H，dd，J＝8.5Hz，2.8Hz)，6.62(1H，d，J＝2.8Hz)，6.83(1H，d，J＝8.5Hz)，7.15-7.35(5H，m)
The comparative example 50
(4-benzyloxy-2-aminomethyl phenyl) methyl alcohol
The preparation method of title compound is similar to comparative example 9, wherein uses bromotoluene to replace benzyl 3-bromopropyl ether.
1H-NMR(CDCl
3)δppm：
1.37(1H，t，J＝5.8Hz)，2.36(3H，s)，4.64(2H，d，J＝5.8Hz)，5.06(2H，s)，6.79(1H，dd，J＝8.4Hz，2.4Hz)，6.84(1H，d，J＝2.4Hz)，7.23(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 51
[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl alcohol
The solution in tetrahydrofuran (THF) (35mL) to tetrahydrochysene-4H-pyrans-4-alcohol (3.62g) and triethylamine (5.6mL), at the ice-cooled methylsulfonyl chloride (2.93mL) that adds down, mixture was stirring at room 1 hour then.Insoluble substance is removed by filtering.In this filtrate, add N, dinethylformamide (70mL), 4-benzyloxy-2-hydroxy benzaldehyde (5.39g) and cesium carbonate (23g), mixture stirred 12 hours at 80 ℃ then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=4/1-2/1), obtain 4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl aldehyde (4.58g) by silica gel column chromatography then.With this substance dissolves in ethanol (70mL).Down add sodium borohydride (0.28g) in this solution ice-cooled, mixture was stirring at room 3 hours then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.Saturated sodium bicarbonate aqueous solution is added to residue, then the mixture extracted with diethyl ether.Extract is used saturated sodium bicarbonate aqueous solution, water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=3/1-1/1), obtain title compound (4.45g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.75-1.85(2H，m)，1.95-2.05(2H，m)，2.11(1H，t，J＝6.3Hz)，3.5-3.65(2H，m)，3.9-4.0(2H，m)，4.45-4.55(1H，m)，4.63(2H，d，J＝6.3Hz)，5.05(2H，s)，6.5-6.6(2H，m)，7.19(1H，d，J＝7.7Hz)，7.3-7.45(5H，m)
The comparative example 52
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses (4-benzyloxy-2-aminomethyl phenyl) methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.04(6H，d，J＝6.8Hz)，2.24(3H，s)，2.65-2.8(1H，m)，3.44(2H，s)，5.02(2H，s)，6.69(1H，dd，J＝8.7Hz，2.4Hz)，6.75-6.85(2H，m)，7.25-7.45(5H，m)
The comparative example 53
4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-1,2-dihydro-5-is different
Propyl group-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝7.1Hz)，1.75-1.9(2H，m)，1.95-2.1(2H，m)，2.9-3.05(1H，m)，3.5-3.6(2H，m)，3.64(2H，s)，3.9-4.05(2H，m)，4.4-4.5(1H，m)，5.0(2H，s)，6.45-6.55(2H，m)，7.0(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 54
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-
D-pyranoglucose oxygen base)-the 1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein uses 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and 2,3,4,6-four-O-pivaloyl group-α-D-glucopyranosyl bromine (Kunz, H.; Harreus, A.Liebigs Ann.Chem.1982,41-48Velarde, S.; Urbina, J.; Pena, M.R.J.Org.Chem.1996,61,9541-9545), replace 4-{[4-(3-benzyloxy propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.04(9H，s)，1.05-1.2(33H，m)，2.27(3H，s)，2.7-2.85(1H，m)，3.45-3.6(2H，m)，3.8-3.9(1H，m)，4.11(1H，dd，J＝12.6Hz，4.8Hz)，4.17(1H，dd，J＝12.6Hz，1.8Hz)，5.0(2H，s)，5.15-5.3(2H，m)，5.37(1H，t，J＝9.5Hz)，5.65(1H，d，J＝7.8Hz)，6.64(1H，dd，J＝8.4Hz，2.8Hz)，6.77(1H，d，J＝2.8Hz)，6.83(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 55
4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17; wherein use 4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-1; 2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and 2; 3; 4; 6-four-O-pivaloyl group-α-D-glucopyranosyl bromine replaces 4-{[4-(3-benzyloxy propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.7-1.85(2H，m)，1.95-2.05(2H，m)，2.85-2.95(1H，m)，3.5-3.65(4H，m)，3.8-3.9(1H，m)，3.9-4.0(2H，m)，4.12(1H，dd，J＝12.4Hz，5.1Hz)，4.19(1H，dd，J＝12.4Hz，1.8Hz)，4.4-4.5(1H，m)，4.99(2H，s)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.4Hz)，5.66(1H，d，J＝8.0Hz)，6.42(1H，dd，]＝8.3Hz，2.3Hz)，6.47(1H，d，J＝2.3Hz)，6.86(1H，d，J＝8.3Hz)，7.25-7.45(5H，m)
The comparative example 56
1-(2-benzyloxy ethyl)-4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
Under ice-cooled; to 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and the solution of 1H-pyrazoles (2g) in N,N-dimethylacetamide (36mL), add sodium hydride (55%; 0.26g) and benzyl 2-bromotrifluoromethane ether (0.76mL), mixture was stirring at room 2 hours then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Extract washes 2 times with water, and uses the salt water washing, uses anhydrous magnesium sulfate drying then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=4/1), obtain title compound (0.89g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.28(3H，s)，2.95-3.05(1H，m)，3.52(1H，d，J＝17.0Hz)，3.57(1H，d，J＝17.0Hz)，3.75-3.85(3H，m)，4.0-4.2(4H，m)，4.46(1H，d，J＝12.1Hz)，4.49(1H，d，J＝12.1Hz)，4.99(2H，s)，5.1-5.2(2H，m)，5.34(1H，t，J＝9.5Hz)，5.61(1H，d，J＝8.1Hz)，6.6(1H，dd，J＝8.5Hz，2.6Hz)，6.73(1H，d，J＝8.5Hz)，6.77(1H，d，J＝2.6Hz)，7.2-7.45(10H，m)
The comparative example 57
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1-(3-benzyloxy propyl group)-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 56, wherein uses benzyl 3-bromopropyl ether to replace benzyl 2-bromotrifluoromethane ether.
1H-NMR(CDCl
3)δppm：
1.03(9H，s)，1.05-1.2(33H，m)，2.05-2.15(2H，m)，2.28(3H，s)，2.9-3.0(1H，m)，3.45-3.6(4H，m)，3.7-3.8(1H，m)，3.95-4.1(3H，m)，4.12(1H，dd，J＝12.0Hz，1.9Hz)，4.51(2H，s)，5.0(2H，s)，5.1-5.2(2H，m)，5.33(1H，t，J＝9.5Hz)，5.61(1H，d，J＝8.2Hz)，6.61(1H，dd，J＝8.3Hz，2.7Hz)，6.72(1H，d，J＝8.3Hz)，6.77(1H，d，J＝2.7Hz)，7.2-7.5(10H，m)
The comparative example 58
4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-
β-D-pyranoglucose oxygen base)-the 1H-pyrazoles
With 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (5g) is dissolved at tetrahydrofuran (THF) (18mL).Add 10% palladium-carbon dust (500mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (4.45g).
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.24(3H，s)，2.7-2.85(1H，m)，3.52(2H，s)，3.8-3.9(1H，m)，4.09(1H，dd，J＝12.4Hz，4.7Hz)，4.15(1H，dd，J＝12.4Hz，1.9Hz)，4.6(1H，s)，5.15-5.25(2H，m)，5.36(1H，t，J＝9.2Hz)，5.65(1H，d，J＝8.0Hz)，6.5(1H，dd，J＝8.3Hz，2.9Hz)，6.61(1H，d，J＝2.9Hz)，6.78(1H，d，J＝8.3Hz)
The comparative example 59
1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methyl phenyl) methyl]-(2,3,4,6-four for 5-sec.-propyl-3-
-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles
The preparation method of title compound is similar to comparative example 58; wherein use 1-(2-benzyloxy ethyl)-4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.26(3H，s)，2.9-3.0(1H，m)，3.51(1H，d，J＝17.0Hz)，3.55(1H，d，J＝17.0Hz)，3.75-3.9(2H，m)，3.9-4.0(2H，m)，4.0-4.15(4H，m)，4.61(1H，s)，5.15-5.25(2H，m)，5.35(1H，t，J＝9.4Hz)，5.53(1H，d，J＝8.1Hz)，6.48(1H，dd，J＝8.4Hz，2.7Hz)，6.61(1H，d，J＝2.7Hz)，6.67(1H，d，J＝8.4Hz)
The comparative example 60
4-[(4-hydroxy-2-methyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2,3,4,6-
Four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles
The preparation method of title compound is similar to comparative example 58; wherein use 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1-(3-benzyloxy propyl group)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.03(9H，s)，1.05-1.15(24H，m)，1.19(9H，s)，1.9-2.0(2H，m)，2.25(3H，s)，2.9-3.0(1H，m)，3.5(1H，d，J＝17.3Hz)，3.54(1H，d，J＝17.3Hz)，3.6-3.7(2H，m)，3.8-3.9(1H，m)，3.93(1H，t，J＝6.4Hz)，4.1-4.2(3H，m)，4.22(1H，dd，J＝12.6Hz，1.7Hz)，4.51(1H，s)，5.15-5.25(2H，m)，5.35(1H，t，J＝9.4Hz)，5.52(1H，d，J＝8.1Hz)，6.48(1H，dd，J＝8.3Hz，2.4Hz)，6.61(1H，d，J＝2.4Hz)，6.66(1H，d，J＝8.3Hz)
The comparative example 61
4-{[4-hydroxyl-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 58; wherein use 4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.9(2H，m)，1.95-2.1(2H，m)，2.8-2.95(1H，m)，3.52(1H，d，J＝16.5Hz)，3.55-3.65(3H，m)，3.8-3.9(1H，m)，3.9-4.05(2H，m)，4.05-4.2(2H，m)，4.4-4.5(1H，m)，5.14(1H，brs)，5.15-5.3(2H，m)，5.3-5.4(1H，m)，5.65(1H，d，J＝8.1Hz)，6.22(1H，dd，J＝8.2Hz，2.3Hz)，6.37(1H，d，J＝2.3Hz)，6.78(1H，d，J＝8.2Hz)
The comparative example 62
4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-spy penta
Acyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles
To 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (8.58g), 1-bromo-3-chloropropane (2.85mL) and the solution of bromination four (normal-butyl) ammonium (1.86g) in tetrahydrofuran (THF) (43mL); add 5mol/L aqueous sodium hydroxide solution (5.76mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Extract is used 1mol/L hydrochloric acid, water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, then under refluxad, residue is dissolved in normal hexane (15mL)-Di Iso Propyl Ether (5mL).Solution is cooled to room temperature, and (25mL) adds to solution with normal hexane.Sedimentary crystal is collected by filtering, and crystal obtains title compound (6.06g) with normal hexane washing and drying under reduced pressure then.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.15-2.25(2H，m)，2.27(3H，s)，2.7-2.85(1H，m)，3.51(1H，d，J＝16.7Hz)，3.53(1H，d，J＝16.7Hz)，3.73(2H，t，J＝6.4Hz)，3.8-3.9(1H，m)，4.05(2H，t，J＝5.9Hz)，4.11(1H，dd，J＝12.4Hz，4.7Hz)，4.17(1H，dd，J＝12.4Hz，1.9Hz)，5.15-5.3(2H，m)，5.3-5.4(1H，m)，5.65(1H，d，J＝8.1Hz)，6.57(1H，dd，J＝8.4Hz，2.7Hz)，6.68(1H，d，J＝2.7Hz)，6.83(1H，d，J＝8.4Hz)
The comparative example 63
4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-1-(2-hydroxyethyl)-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
To 1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.69g), 1-bromo-3-chloropropane (0.22mL) and the solution of bromination four (normal-butyl) ammonium (0.14g) in tetrahydrofuran (THF) (8mL); add 5mol/L aqueous sodium hydroxide solution (0.43mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Extract is water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1), obtain title compound (0.56g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.15-2.25(2H，m)，2.28(3H，s)，2.9-3.0(1H，m)，3.52(1H，d，J＝16.9Hz)，3.57(1H，d，J＝16.9Hz)，3.73(2H，t，J＝6.2Hz)，3.75-4.0(4H，m)，4.0-4.15(6H，m)，5.15-5.25(2H，m)，5.35(1H，t，J＝9.6Hz)，5.54(1H，d，J＝8.1Hz)，6.56(1H，dd，J＝8.5Hz，2.5Hz)，6.69(1H，d，J＝2.5Hz)，6.72(1H，d，J＝8.5Hz)
The comparative example 64
4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-1-(3-hydroxypropyl)-5-sec.-propyl-3-
(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 63; wherein use 4-[(4-hydroxy-2-methyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.02(9H，s)，1.05-1.15(24H，m)，1.19(9H，s)，1.9-2.0(2H，m)，2.15-2.25(2H，m)，2.28(3H，s)，2.9-3.0(1H，m)，3.51(1H，d，J＝16.9Hz)，3.55(1H，d，J＝16.9Hz)，3.6-3.7(2H，m)，3.73(2H，t，J＝6.3Hz)，3.8-3.9(1H，m)，3.96(1H，t，J＝6.4Hz)，4.05(2H，t，J＝5.9Hz)，4.1-4.2(3H，m)，4.23(1H，dd，J＝12.6Hz，1.7Hz)，5.15-5.25(2H，m)，5.35(1H，t，J＝9.4Hz)，5.52(1H，d，J＝8.1Hz)，6.55(1H，dd，J＝8.4Hz，2.6Hz)，6.69(1H，d，J＝2.6Hz)，6.71(1H，d，J＝8.4Hz)
The comparative example 65
4-{[4-(3-chlorine propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-the 5-sec.-propyl
-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 63; wherein use 4-{[4-hydroxyl-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.9(2H，m)，2.0-2.1(2H，m)，2.15-2.25(2H，m)，2.85-2.95(1H，m)，3.5-3.65(4H，m)，3.73(2H，t，J＝6.4Hz)，3.8-3.9(1H，m)，3.9-4.1(4H，m)，4.13(1H，dd，J＝12.4Hz，4.8Hz)，4.19(1H，dd，J＝12.4Hz，1.9Hz)，4.4-4.55(1H，m)，5.15-5.3(2H，m)，5.3-5.4(1H，m)，5.66(1H，d，J＝8.1Hz)，6.34(1H，dd，J＝8.4Hz，2.4Hz)，6.41(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
The comparative example 66
3-[N-benzyloxycarbonyl-N-(3-bromopropyl) amino] propionic acid amide
To the solution of acrylamide (2g) in ethanol (30mL), add 3-amino-1-propyl alcohol (3.23mL), mixture was stirring at room 3 hours then.Reaction mixture is through concentrating under reduced pressure.In residue, add tetrahydrofuran (THF) (30mL) and N-(benzyloxycarbonyloxy base) succinimide (14g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, then residue by silica gel column chromatography carry out purifying (eluent: methylene chloride=40/1-20/1-5/1), obtain 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl) amino] propionic acid amide (3.51g).To 3-[N-benzyloxycarbonyl-N-(3-hydroxypropyl) amino that obtains] propionic acid amide (0.5g) and the solution of carbon tetrabromide (0.65g) in methylene dichloride (5mL), at the ice-cooled triphenylphosphine (1.03g) of adding down, mixture was stirring at room 2 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/4-methylene chloride=10/1), obtain title compound (0.41g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
2.0-2.2(2H，m)，2.4-2.55(2H，m)，3.35-3.5(4H，m)，3.56(2H，t，J＝6.9Hz)，5.12(2H，s)，7.25-7.45(5H，m)
Embodiment 96
4-[(4-{3-[N-benzyloxycarbonyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-methyl
Phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-
Pyrazoles
To 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles (0.4g), 3-[N-benzyloxycarbonyl-N-(3-bromopropyl) amino] propionic acid amide (0.28g) and the solution of bromination four (normal-butyl) ammonium (87mg) in methylene dichloride (4mL); add 5mol/L aqueous sodium hydroxide solution (0.32mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Extract 1mol/L hydrochloric acid, water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/3-1/6), obtain title compound (0.42g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.9-2.05(2H，m)，2.25(3H，s)，2.4-2.55(2H，m)，2.75-2.85(1H，m)，3.45-3.65(6H，m)，3.85-4.0(3H，m)，4.08(1H，dd，J＝12.5Hz，1.9Hz)，4.16(1H，dd，J＝12.5Hz，4.4Hz)，4.95-5.2(4H，m)，5.35-5.45(1H，m)，5.58(1H，d，J＝7.9Hz)，6.45-6.75(2H，m)，6.8(1H，d，J＝8.4Hz)，7.25-7.4(5H，m)
Embodiment 97
4-{[4-{3-[N-benzyloxycarbonyl-N-(2-formamyl ethyl) amino] propoxy-}-2-(tetrahydrochysene
-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-
Pyranoglucose oxygen base)-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 96; wherein use 4-{[4-hydroxyl-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.7-1.85(2H，m)，1.9-2.15(4H，m)，2.4-2.55(2H，m)，2.85-2.95(1H，m)，3.35-3.65(8H，m)，3.85-4.0(5H，m)，4.11(1H，dd，J＝12.5Hz，1.9Hz)，4.18(1H，dd，J＝12.5Hz，4.4Hz)，4.45-4.6(1H，m)，5.05-5.2(4H，m)，5.35-5.4(1H，m)，5.57(1H，d，J＝8.2Hz)，6.2-6.6(2H，m)，6.8(1H，d，J＝8.4Hz)，7.2-7.45(5H，m)
Embodiment 98
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
With 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (1.34g); 3-benzylamino propionic acid amide (0.73g); sodium iodide (0.24g), the mixture of ethanol (6mL) and acetonitrile (6mL) stirred 2 days at 70 ℃.In reaction mixture, add sodium iodide (0.2g), mixture further stirred 24 hours at 75 ℃ then.Pour reaction mixture into 1mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water, saturated sodium bicarbonate aqueous solution and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/5-methylene chloride=15/1), obtain title compound (0.97g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.85-1.95(2H，m)，2.26(3H，s)，2.4(2H，t，J＝6.9Hz)，2.62(2H，t，J＝6.9Hz)，2.75-2.9(3H，m)，3.52(1H，d，J＝16.4Hz)，3.56(1H，d，J＝16.4Hz)，3.62(2H，s)，3.85-3.95(3H，m)，4.08(1H，dd，J＝12.4Hz，1.8Hz)，4.16(1H，dd，J＝12.4Hz，4.4Hz)，5.05-5.2(2H，m)，5.35-5.45(1H，m)，5.58(1H，d，J＝8.1Hz)，6.52(1H，dd，J＝8.5Hz，2.5Hz)，6.61(1H，d，J＝2.5Hz)，6.79(1H，d，J＝8.5Hz)，7.15-7.35(5H，m)
Embodiment 99
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-1-(2-hydroxyethyl)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-
The 1H-pyrazoles
The preparation method of title compound is similar to embodiment 98; wherein use 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-1-(2-hydroxyethyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.85-1.95(2H，m)，2.28(3H，s)，2.4(2H，t，J＝7.1Hz)，2.62(2H，t，J＝7.0Hz)，2.8(2H，t，J＝7.1Hz)，3.05-3.15(1H，m)，3.5-3.65(4H，m)，3.8-3.95(5H，m)，4.0-4.2(4H，m)，5.0-5.2(2H，m)，5.36(1H，t，J＝9.5Hz)，5.59(1H，d，J＝7.8Hz)，6.5(1H，dd，J＝8.5Hz，2.7Hz)，6.62(1H，d，J＝2.7Hz)，6.7(1H，d，J＝8.5Hz)，7.15-7.4(5H，m)
Embodiment 100
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-
The 1H-pyrazoles
The preparation method of title compound is similar to embodiment 98; wherein use 4-{[4-(3-chlorine propoxy-))-the 2-aminomethyl phenyl] methyl }-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.85-2.05(4H，m)，2.28(3H，s)，2.4(2H，t，J＝7.0Hz)，2.62(2H，t，J＝7.0Hz)，2.8(2H，t，J＝7.0Hz)，3.0-3.1(1H，m)，3.5-3.65(6H，m)，3.85-3.95(3H，m)，4.0-4.2(4H，m)，5.0-5.2(2H，m)，5.37(1H，t，J＝9.4Hz)，5.6(1H，d，J＝7.7Hz)，6.5(1H，dd，J＝8.4Hz，2.6Hz)，6.62(1H，d，J＝2.6Hz)，6.67(1H，d，J＝8.4Hz)，7.15-7.35(5H，m)
Embodiment 101
4-{[4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base
Oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-
Pyrazoles
The preparation method of title compound is similar to embodiment 98; wherein use 4-{[4-(3-chlorine propoxy-))-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles and 2-amino-2-methyl propionic acid amide; replace 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl respectively] methyl }-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-3-D-pyranoglucose oxygen base)-1H-pyrazoles and 3-benzylamino propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(42H，m)，1.32(6H，s)，1.7-1.85(2H，m)，1.85-2.1(4H，m)，2.69(2H，t，J＝7.0Hz)，2.85-2.95(1H，m)，3.53(1H，d，J＝16.6Hz)，3.55-3.7(3H，m)，3.85-4.05(5H，m)，4.11(1H，dd，J＝12.4Hz，1.6Hz)，4.18(1H，dd，J＝12.4Hz，4.3Hz)，4.55-4.65(1H，m)，5.05-5.2(2H，m)，5.3-5.4(1H，m)，5.56(1H，d，J＝8.2Hz)，6.38(1H，dd，J＝8.4Hz，2.2Hz)，6.53(1H，d，J＝2.2Hz)，6.81(1H，d，J＝8.4Hz)
Embodiment 102
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-different third
Base-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
To 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-solution of 1H-pyrazoles (0.96g) in tetrahydrofuran (THF) (5mL); add 10% palladium-carbon dust (0.1g), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (0.87g).
1H-NMR(CD
3OD)δppm：
1.05-1.2(42H，m)，1.9-2.0(2H，m)，2.27(3H，s)，2.43(2H，t，J＝6.8Hz)，2.75-2.9(5H，m)，3.53(1H，d，J＝16.4Hz)，3.56(1H，d，J＝16.4Hz)，3.9-4.05(3H，m)，4.08(1H，dd，J＝12.4Hz，1.8Hz)，4.16(1H，dd，J＝12.4Hz，4.4Hz)，5.05-5.2(2H，m)，5.35-5.45(1H，m)，5.58(1H，d，J＝8.1Hz)，6.59(1H，dd，J＝8.4Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.81(1H，d，J＝8.4Hz)
Embodiment 103
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(2-hydroxyl
Ethyl)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to embodiment 102; wherein use 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(2-hydroxyethyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(42H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.42(2H，t，J＝6.9Hz)，2.77(2H，t，J＝7.1Hz)，2.85(2H，t，J＝6.9Hz)，3.05-3.2(1H，m)，3.56(1H，d，J＝16.8Hz)，3.61(1H，d，J＝16.8Hz)，3.8-4.2(9H，m)，5.0-5.2(2H，m)，5.37(1H，t，J＝9.4Hz)，5.59(1H，d，J＝8.0Hz)，6.56(1H，dd，J＝8.4Hz，2.5Hz)，6.65-6.75(2H，m)
Embodiment 104
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxyl
The base propyl group)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to embodiment 102; wherein use 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.9-2.05(4H，m)，2.29(3H，s)，2.44(2H，t，J＝6.8Hz)，2.81(2H，t，J＝7.1Hz)，2.88(2H，t，J＝6.8Hz)，3.0-3.15(1H，m)，3.5-3.65(4H，m)，3.85-4.2(7H，m)，5.0-5.2(2H，m)，5.37(1H，t，J＝9.5Hz)，5.6(1H，d，J＝8.4Hz)，6.57(1H，dd，J＝8.3Hz，2.3Hz)，6.65-6.75(2H，m)
Embodiment 105
4-{[4-{3-[2-(formamyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo)
Phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-
Pyrazoles
The preparation method of title compound is similar to embodiment 102; wherein use 4-{[4-{3-[N-benzyloxycarbonyl-N-(2-formamyl ethyl) amino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.0-1.2(42H，m)，1.7-1.85(2H，m)，2.0-2.1(2H，m)，2.1-2.2(2H，m)，2.67(2H，t，J＝6.2Hz)，2.85-2.95(1H，m)，3.2-3.35(4H，m)，3.54(1H，d，J＝16.5Hz)，3.55-3.7(3H，m)，3.9-4.0(3H，m)，4.05-4.15(3H，m)，4.19(1H，dd，J＝12.4Hz，4.4Hz)，4.55-4.65(1H，m)，5.05-5.2(2H，m)，5.35-5.45(1H，m)，5.58(1H，d，J＝8.1Hz)，6.43(1H，dd，J＝8.4Hz，2.3Hz)，6.64(1H，d，J＝2.3Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 106
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-1-(3-hydroxypropyl)-5-sec.-propyl-1H-pyrazoles
To 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-solution of 1H-pyrazoles (0.3g) in methyl alcohol (6mL); add sodium methylate (28% methanol solution; 0.25mL), mixture spends the night 50 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (0.16g) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.9-2.05(4H，m)，2.3(3H，s)，2.42(2H，t，J＝6.8Hz)，2.77(2H，t，J＝7.1Hz)，2.84(2H，t，J＝6.8Hz)，3.0-3.15(1H，m)，3.2-3.4(4H，m)，3.55-3.75(5H，m)，3.8(1H，dd，J＝12.1Hz，2.1Hz)，3.99(2H，t，J＝6.2Hz)，4.11(2H，t，J＝7.2Hz)，5.03(1H，d，J＝7.6Hz)，6.6(1H，dd，J＝8.3Hz，2.6Hz)，6.72(1H，d，J＝2.6Hz)，6.74(1H，d，J＝8.3Hz)
Embodiment 107
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-1-(2-hydroxyethyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 106; wherein use 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(2-hydroxyethyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.85-2.0(2H，m)，2.3(3H，s)，2.41(2H，t，J＝6.8Hz)，2.77(2H，t，J＝7.1Hz)，2.84(2H，t，J＝6.8Hz)，3.05-3.2(1H，m)，3.2-3.4(4H，m)，3.6-3.75(3H，m)，3.79(1H，dd，J＝12.0Hz，2.2Hz)，3.85(2H，t，J＝5.7Hz)，3.99(2H，t，J＝6.0Hz)，4.09(2H，t，J＝5.7Hz)，5.06(1H，d，J＝7.7Hz)，6.6(1H，dd，J＝8.4Hz，2.7Hz)，6.72(1H，d，J＝2.7Hz)，6.77(1H，d，J＝8.4Hz)
Embodiment 108
4-{[4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-
4-base oxo) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 106; wherein use 4-{[4-{3-[1-formamyl-1-(methyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.29(6H，s)，1.7-1.85(2H，m)，1.85-1.95(2H，m)，1.95-2.1(2H，m)，2.64(2H，t，J＝6.9Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.55-3.75(5H，m)，3.8-3.9(1H，m)，3.9-4.05(4H，m)，4.5-4.65(1H，m)，5.0-5.1(1H，m)，6.4(1H，dd，J＝8.4Hz，2.0Hz)，6.53(1H，d，J＝2.0Hz)，6.9(1H，d，J＝8.4Hz)
Embodiment 109
4-{[4-{3-[2-(formamyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo)
Phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 106; wherein use 4-{[4-{3-[2-(formamyl) ethylamino] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-1-(3-hydroxypropyl)-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.7-1.85(2H，m)，1.9-2.1(4H，m)，2.43(2H，t，J＝6.8Hz)，2.79(2H，t，J＝7.0Hz)，2.8-2.95(3H，m)，3.25-3.4(4H，m)，3.55-3.75(5H，m)，3.8-3.85(1H，m)，3.9-4.05(4H，m)，4.55-4.65(1H，m)，5.0-5.1(1H，m)，6.41(1H，dd，J＝8.4Hz，2.4Hz)，6.54(1H，d，J＝2.4Hz)，6.9(1H，d，J＝8.4Hz)
Embodiment 110
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-solution of 1H-pyrazoles (1.25g) in methyl alcohol (13mL); add sodium methylate (28% methanol solution; 0.25mL), mixture stirred 6 hours at 50 ℃ then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: methylene chloride=10/1-5/1), obtain title compound (0.5g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-1.95(2H，m)，2.28(3H，s)，2.4(2H，t，J＝6.9Hz)，2.55-2.65(2H，m)，2.75-2.85(3H，m)，3.25-3.4(4H，m)，3.55-3.75(5H，m)，3.75-3.85(1H，m)，3.92(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.55(1H，dd，J＝8.5Hz，2.8Hz)，6.62(1H，d，J＝2.8Hz)，6.83(1H，d，J＝8.5Hz)，7.15-7.35(5H，m)
Embodiment 111
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-
Pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (0.5g) is dissolved in methyl alcohol (8mL).Add 10% palladium-carbon dust (0.1g) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.A part (0.1g) residue is dissolved in the mixed solvent of methyl alcohol (1mL) and ethyl acetate (1.5mL).Add crystal seed in this solution, mixture was stirring at room 3 days then.Sedimentary crystal is collected by filtration.Crystal washs with the mixed solvent of methyl alcohol and ethyl acetate (2/3), and drying under reduced pressure, obtains title compound (85mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.85-2.0(2H，m)，2.29(3H，s)，2.42(2H，t，J＝6.9Hz)，2.7-2.9(5H，m)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.4Hz)
Fusing point: 191-193 ℃
Embodiment 112
4-[(4-{ (S)-3-[2-(formamyl) ethylamino]-2-hydroxyl propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.3g) and salt of wormwood (84mg) is at N; in the suspension in the dinethylformamide (3mL); add (S)-1-(p-tosyloxy)-2, the cesium fluoride of 3-propylene oxide (0.1g) and catalytic amount, mixture is in stirred overnight at room temperature then.Pour reaction mixture into saturated aqueous ammonium chloride solution, and the mixture ethyl acetate extraction that forms.Extract is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution and salt water washing.Solvent is removed in decompression, then residue is dissolved in methyl alcohol (5mL).Add 3-benzylamino propionic acid amide (0.14g) in this solution, mixture spends the night 50 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2-methylene chloride=10/1) by silica gel column chromatography then; obtain 4-[(4-{ (S)-3-[N-benzyl-N-(2-formamyl ethyl) amino]-2-hydroxyl propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.23g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (0.1g) in this solution, mixture stirred 4 days under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.Residue is dissolved in methyl alcohol (5mL).In this solution, (28% methanol solution, 0.085mL), mixture spends the night 50 ℃ of stirrings then to add sodium methylate.To the reaction mixture concentrating under reduced pressure.Then, residue successively on ODS by Solid-Phase Extraction (cleaning solvent: distilled water, eluent: methyl alcohol) and the reverse column chromatography of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ m,
20 * 50mm, flow velocity 30mL/ minute linear gradient, the purifying of water/methyl alcohol=90/10-10/90) and in addition obtains title compound (23mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.43(2H，t，J＝6.7Hz)，2.65-2.95(5H，m)，3.25-3.4(4H，m)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.9(2H，d，J＝5.3Hz)，3.95-4.05(1H，m)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.4Hz，2.4Hz)，6.74(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 113
4-[(4-{ (R)-3-[2-(formamyl) ethylamino]-2-hydroxyl propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 112, wherein uses (R)-1-(p-tosyloxy)-2, and the 3-propylene oxide is replaced (S)-1-(p-tosyloxy)-2,3-propylene oxide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.43(2H，t，J＝6.7Hz)，2.65-2.95(5H，m)，3.25-3.4(4H，m)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.9(2H，d，J＝5.3Hz)，4.0-4.05(1H，m)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.4Hz，2.5Hz)，6.74(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
The comparative example 67
3-benzylamino benzyl propionate
To the solution of benzyl acrylate (2g) in ethanol (15mL), add benzene methanamine (1.75mL), mixture is in stirred overnight at room temperature then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: n-hexane/ethyl acetate=2/1-1/1), obtain title compound (2.91g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.59(2H，t，J＝6.5Hz)，2.92(2H，t，J＝6.5Hz)，3.79(2H，s)，5.13(2H，s)，7.2-7.4(10H，m)
Embodiment 114
4-{[4-(3-{2-[(S)-1-formamyl-2-hydroxyethylamino formyl radical] ethylamino } third oxygen
Base)-and the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (1g) and the solution of triethylamine (0.29mL) in methylene dichloride (10mL); add methylsulfonyl chloride (0.13mL), mixture was stirring at room 1 hour then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (1.12g).With this substance dissolves in acetonitrile (7mL)-ethanol (7mL).In this solution, add 3-benzylamino benzyl propionate (1.27g) and sodium iodide (240mg), mixture stirred 2 days at 60 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=30/1-20/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[N-benzyl-N-(2-benzyloxycarbonyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (1.3g).This material is dissolved in methyl alcohol (10mL).In this solution, add 10% palladium-carbon dust (0.65g), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering; then filtrate is carried out concentrating under reduced pressure, obtain 3-(2,3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(2-carboxyl ethylamino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (0.95g).With this substance dissolves in 1,4-diox (10mL).In this solution, add sodium bicarbonate (0.45g) and water (10mL), stirred the mixture then 15 minutes.In reaction mixture, add benzyloxycarbonyl chlorine (0.23mL), mixture is in stirred overnight at room temperature then.In reaction mixture, add benzyloxycarbonyl chlorine (0.23mL), mixture was stirring at room 3 hours then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[N-benzyloxycarbonyl-N-(2-propyloic) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.86g).To the 3-(2 that obtains; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[N-benzyloxycarbonyl-N-(2-propyloic) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.17g) is at N; solution in the dinethylformamide (3mL); add L-silk amide hydrochloride (37mg), I-hydroxybenzotriazole (30mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (77mg) and triethylamine (0.11mL), mixture was stirring at room 8 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=20/1-10/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[3-(the N-benzyloxycarbonyl-N-{2-[(S)-1-formamyl-2-hydroxyethylamino formyl radical] ethyl } amino) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (81mg).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (10mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.Residue is dissolved in methyl alcohol (4mL).In this solution, (28% methanol solution, 0.02mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (38mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.0-1.2(6H，m)，1.85-2.0(2H，m)，2.28(3H，s)，2.4-2.55(2H，m)，2.7-2.95(5H，m)，3.25-3.4(4H，m)，3.55-3.85(6H，m)，3.99(2H，t，J＝6.1Hz)，4.35-4.45(1H，m)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.2Hz)，6.71(1H，d，J＝2.2Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 115
4-[(4-{3-[2-(formamyl methylamino formyl radical) ethylamino] propoxy-}-the 2-aminomethyl phenyl)
Methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 114, wherein uses glycyl amide hydrochloride to replace L-silk amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.9-2.0(2H，m)，2.29(3H，s)，2.46(2H，t，J＝6.6Hz)，2.7-2.85(3H，m)，2.88(2H，t，J＝6.6Hz)，3.3-3.4(4H，m)，3.6-3.7(3H，m)，3.75-3.85(3H，m)，3.99(2H，t，J＝6.1Hz)，5.0-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 116
4-{[4-(3-{2-[(S)-1-(formamyl) ethylamino formyl radical] ethylamino } propoxy-)-2-
Aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 114, wherein uses L-alanimamides hydrochloride to replace L-silk amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.33(3H，d，J＝7.2Hz)，1.9-2.0(2H，m)，2.29(3H，s)，2.35-2.5(2H，m)，2.7-2.9(5H，m)，3.3-3.4(4H，m)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.1Hz)，4.32(1H，q，J＝7.2Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.3Hz)，6.71(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 117
4-{[4-(3-{2-[(S)-5-amino-1-(formamyl) amyl group formamyl] ethylamino } third
The oxygen base)-and the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 114, wherein uses (S)-2-amino-6-(benzyloxycarbonyl amino) hexanamide hydrochloride to replace L-silk amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.25-2.0(8H，m)，2.29(3H，s)，2.35-2.55(2H，m)，2.63(2H，t，J＝7.0Hz)，2.7-2.95(5H，m)，3.25-3.4(4H，m)，3.55-3.75(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.25-4.35(1H，m)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.2Hz)，6.71(1H，d，J＝2.2Hz)，6.84(1H，d，J＝8.4Hz)
The comparative example 68
3-amino-2,2-two (methyl) benzyl propionate
To 3-amino-2, the 2-dimethyl-solution of 1-propyl alcohol (5g) in methyl alcohol (50mL), (12.7g), mixture is in stirred overnight at room temperature then to add dimethyl dicarbonate butyl ester (di-tert-butyl dicarbonate).Reaction mixture is through concentrating under reduced pressure.Residue (solid-state) is handled with normal hexane-ether, filters then and collects, and with normal hexane washing and drying under reduced pressure, obtains 3-(tert-butoxycarbonyl amino)-2,2-dimethyl-1-propyl alcohol (7.48g).In this material, add tetracol phenixin (40mL), acetonitrile (40mL), water (48mL) successively, sodium periodate (38.8g) and ruthenium trichloride-n hydrate (1g), mixture is in stirred overnight at room temperature then.Reaction mixture dilute with water, and the mixture ethyl acetate extraction that forms.Organic layer water and salt water washing.In organic layer, add the unsaturated carbonate aqueous solutions of potassium, separate water layer then.Water layer carries out acidifying with 2mol/L hydrochloric acid, then the mixture ethyl acetate extraction.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 3-(tert-butoxycarbonyl amino)-2,2-two (methyl) propionic acid (2.78g).With this substance dissolves in N, dinethylformamide (30mL).In this solution, add salt of wormwood (3.54g) and cylite (2.28mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=2/1), obtain 3-(tert-butoxycarbonyl amino)-2,2-two (methyl) benzyl propionate (2.72g) by silica gel column chromatography then.In this material, add hydrochloric acid (4mol/L 1, the 4-dioxane solution, 10mL), mixture was stirring at room 3 days then.Reaction mixture is through concentrating under reduced pressure.In residue, add saturated sodium bicarbonate aqueous solution, then the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains title compound (1.61g).
1H-NMR(DMSO-d
6)δppm：
1.09(6H，s)，1.35-1.7(2H，br)，2.63(2H，s)，5.09(2H，s)，7.25-7.45(5H，m)
Embodiment 118
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(piperazine-1-yl) carbonyl]-2-(first
Base) third amino } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (1g) and the solution of triethylamine (0.25mL) in methylene dichloride (5mL); add methylsulfonyl chloride (0.13mL), mixture was stirring at room 1 hour then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (1.12g).3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-of obtaining ({ 4-[3-(mesyloxy) propoxy-]-2-aminomethyl phenyl } methyl)-1H-pyrazoles (0.36g) is dissolved in 2-propyl alcohol (2mL)-acetonitrile (2mL).In this solution, add 3-amino-2,2-two (methyl) benzyl propionate (0.26g) and sodium iodide (75mg), mixture stirred 2 days at 60 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/5-methylene chloride=20/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-benzyloxycarbonyl-2-(methyl) third amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.35g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (0.1g) in this solution, mixture stirred 5 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering; then filtrate is carried out concentrating under reduced pressure, obtain 3-(2,3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-carboxyl-2-(methyl) third amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.31g).This material is dissolved in tetrahydrofuran (THF) (4mL).In this solution, add triethylamine (0.094mL) and N-(benzyloxycarbonyloxy base) succinimide (64mg), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=20/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-{N-benzyloxycarbonyl-N-[2-carboxyl-2-(methyl) propyl group] amino } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.3g).To the 3-(2 that obtains; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(3-{N-benzyloxycarbonyl-N-[2-carboxyl-2-(methyl) propyl group] amino } propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.1g) is at N; solution in the dinethylformamide (2mL); add 1-benzyl diethylenediamine (26mg), I-hydroxybenzotriazole (17mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (44mg) and triethylamine (0.064mL), mixture was stirring at room 6 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=40/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-{N-benzyloxycarbonyl-N-[2-(4-benzyl diethylenediamine-1-yl) carbonyl-2-(methyl) propyl group] amino } propoxy-)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (45mg).This material is dissolved in tetrahydrofuran (THF) (4mL).In this solution, add 10% palladium-carbon dust (20mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.In reaction mixture, add methyl alcohol (2mL), mixture stirred 5 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.Residue is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.02mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, then residue successively on ODS by Solid-Phase Extraction (cleaning solvent: distilled water, eluent: methyl alcohol) and the reverse column chromatography of preparation property (Shiseido CAPCELL PAKUG120 ODS, 5 μ m,
20 * 50mm, flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90) is purifying in addition, obtains title compound (12mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.29(6H，s)，1.85-2.0(2H，m)，2.3(3H，s)，2.65-2.9(9H，m)，3.25-3.4(4H，m)，3.5-3.75(7H，m)，3.75-3.85(1H，m)，4.0(2H，t，J＝5.8Hz)，5.0-5.1(1H，m)，6.62(1H，dd，J＝8.4Hz，2.0Hz)，6.72(1H，d，J＝2.0Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 119
4-{[4-(3-{2-[(S)-1-formamyl-2-hydroxyethylamino formyl radical]-2-(methyl) third ammonia
Base } propoxy-)-the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 118, wherein uses L-silk amide hydrochloride to replace the 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.17(3H，s)，1.19(3H，s)，1.9-2.0(2H，m)，2.28(3H，s)，2.7(2H，s)，2.75-2.85(3H，m)，3.25-3.4(4H，m)，3.6-3.7(3H，m)，3.76(1H，dd，J＝11.1Hz，4.7Hz)，3.8-3.9(2H，m)，4.0(2H，t，J＝6.1Hz)，4.35-4.4(1H，m)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.3Hz)，6.71(1H，d，J＝2.3Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 120
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(4-methylpiperazine-1-yl) carbonyl
Base]-2-(methyl) third amino } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 118, wherein uses the 1-methylpiperazine to replace the 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.29(6H，s)，1.85-2.0(2H，m)，2.26(3H，s)，2.29(3H，s)，2.3-2.45(4H，m)，2.6-2.85(5H，m)，3.25-3.4(4H，m)，3.55-3.75(7H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 121
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-
2-(methyl) third amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 118, wherein uses 1-(2-hydroxyethyl) piperazine to replace the 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.29(6H，s)，1.85-2.0(2H，m)，2.29(3H，s)，2.4-2.55(6H，m)，2.65-2.85(5H，m)，3.25-3.4(4H，m)，3.55-3.75(9H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝5.8Hz)，5.0-5.05(1H，m)，6.61(1H，dd，J＝8.3Hz，1.9Hz)，6.71(1H，d，J＝1.9Hz)，6.85(1H，d，J＝8.3Hz)
The comparative example 69
3-amino-benzyl 3-methylbutyrate
To 3,3-dimethacrylate (1.3g) and salt of wormwood (2.07g) is at N, and the suspension in the dinethylformamide (15mL) adds cylite (1.19mL), and mixture was stirring at room 4 hours then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, then residue is dissolved in 2-propyl alcohol (20mL).Under-15 ℃, ammonia is frothed into solution until saturated, mixture spends the night 80 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: methylene chloride=15/1-7/1), obtain title compound (0.31g) by silica gel column chromatography then.
1H-NMR(DMSO-d
6)δppm：
1.08(6H，s)，1.78(2H，brs)，2.38(2H，s)，5.08(2H，s)，7.3-7.4(5H，m)
Embodiment 122
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-
1,1-two (methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
With 4-{[4-(3-chlorine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (1g) and the mixture of sodium iodide (0.27g) in acetonitrile (5mL), reflux 10 hours.After being cooled to 60 ℃, in reaction mixture, add the solution of 3-amino-benzyl 3-methylbutyrate (0.31g) in 2-propyl alcohol (5mL), mixture stirred 6 days at 55 ℃ then.To the reaction mixture concentrating under reduced pressure, then residue is dissolved in ethyl acetate-water.Separate organic layer.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2-methylene chloride=20/1) by silica gel column chromatography then; obtain 4-[(4-{3-[2-benzyloxycarbonyl-1; 1-two (methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.63g).This material is dissolved in methyl alcohol (5mL).In this solution, add 10% palladium-carbon dust (65mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering; then filtrate is carried out concentrating under reduced pressure; obtain 4-[(4-{3-[2-carboxyl-1; 1-two (methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.52g).To 4-[(4-{3-[2-carboxyl-1; 1-two (methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.1g) is at N; solution in the dinethylformamide (2mL); add 1-(2-hydroxyethyl) piperazine (19mg); I-hydroxybenzotriazole (17mg); 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (43mg) and triethylamine (0.062mL), mixture was stirring at room 20 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, then residue is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.1mL), mixture spends the night 50 ℃ of stirrings then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, then residue successively on ODS by Solid-Phase Extraction (cleaning solvent: distilled water, eluent: methyl alcohol) and the reverse column chromatography of preparation property (Shiseido CAPCELLPAK UG120 ODS, 5 μ m,
20 * 50mm, flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90) carry out purifying obtains title compound (13mg).
MS(ESI，m/z)：678[M+H]
+
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.18(6H，s)，1.85-2.0(2H，m)，2.29(3H，s)，242(2H，t，J＝5.0Hz)，2.45-2.55(6H，m)，2.71(2H，t，J＝7.0Hz)，2.75-2.9(1H，m)，3.25-3.4(4H，m)，3.5-3.75(9H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 123
4-{[4-(3-{2-[(S)-1-formamyl-2-hydroxyethylamino formyl radical]-1,1-two (methyl)
Ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrrole
Azoles
The preparation method of title compound is similar to embodiment 122, wherein uses L-silk amide hydrochloride to replace 1-(2-hydroxyethyl) piperazine.
MS(ESI，m/z)：652[M+H]
+
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.19(6H，s)，1.85-2.0(2H，m)，2.2-2.5(5H，m)，2.7-2.95(3H，m)，3.25-3.4(4H，m)，3.55-3.9(6H，m)，4.01(2H，t，J＝6.1Hz)，4.35-4.45(1H，m)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.3Hz，2.3Hz)，6.72(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.3Hz)
Embodiment 124
4-{[4-(3-{2-[(S)-5-amino-1-(formamyl) amyl group formamyl]-1,1-two (first
Base) ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-
The 1H-pyrazoles
4-{[4-(3-{2-[(S)-5-benzyloxycarbonyl amino-1-(formamyl) amyl group formamyl]-1; 1-two (methyl) ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-preparation method of 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles is similar to embodiment 122; wherein use 2-amino-6-(benzyloxycarbonyl amino) hexanamide hydrochloride to replace 1-(2-hydroxyethyl) piperazine; the preparation method of title compound is similar to embodiment 79 then, wherein uses this substitution of materials 4-[(4-{3-[(S)-5-benzyloxycarbonyl amino-1-(formamyl) penta amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles.
MS(ESI，m/z)：693[M+H]
+
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.17(6H，s)，1.25-1.85(6H，m)，1.85-2.0(2H，m)，2.2-2.45(5H，m)，2.55-2.9(5H，m)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，4.02(2H，t，J＝5.8Hz)，4.25-4.35(1H，m)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.3Hz)，6.72(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 125
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{2-[(piperazine-1-yl) carbonyl]-1,1-two
(methyl) ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
4-{[4-(3-{2-[(4-benzyl diethylenediamine-1-yl) carbonyl]-1,1-two (methyl) ethylamino } propoxy-)-the 2-aminomethyl phenyl] methyl }-preparation method of 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles is similar to embodiment 122, wherein uses the 1-benzyl diethylenediamine to replace 1-(2-hydroxyethyl) piperazine.Then; the preparation method of title compound is similar to embodiment 79, wherein uses this substitution of materials 4-[(4-{3-[(S)-5-benzyloxycarbonyl amino-1-(formamyl) penta amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles.
MS(ESI，m/z)：634[M+H]
+
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.19(6H，s)，1.85-2.0(2H，m)，2.29(3H，s)，2.52(2H，s)，2，6-2.9(7H，m)，3.25-3.4(4H，m)，3.4-3.55(4H，m)，3.6-3.75(3H，m)，3.75-3.85(1H，m)，3.99(2H，t，J＝6.0Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.84(1H，d，J＝8.4Hz)
The comparative example 70
The 3-amino-butanamide
To the mixture of 3-aminobutyric acid (0.52g), 2mol/L aqueous sodium hydroxide solution (10mL) and tetrahydrofuran (THF) (10mL), add benzyloxycarbonyl chlorine (1.07mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 2mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression.Residue (solid-state) washs with normal hexane.Crystal is collected by filtration, with normal hexane washing and drying under reduced pressure, obtains 3-benzyloxycarbonyl aminobutyric acid (0.59g).This material is dissolved in tetrahydrofuran (THF) (5mL).In this solution, add 1,1 '-carbonyl diurethane-1H-imidazoles (0.59g), mixture was stirring at room 1 hour then.In reaction mixture, add 28% ammonia soln (5mL), mixture was stirring at room 1 hour then.Reaction mixture dilutes with ether.Insoluble substance is collected by filtration, and water and ether washing, and drying under reduced pressure obtain 3-benzyloxycarbonyl amino-butanamide (0.54g).The 3-benzyloxycarbonyl amino-butanamide (76mg) that obtains is dissolved in methyl alcohol (3mL).Add 10% palladium-carbon dust (20mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (32mg).
1H-NMR(CD
3OD)δppm：
1.14(3H，d，J＝6.6Hz)，2.2-2.35(2H，m)，3.25-3.35(1H，m)
The comparative example 71
3-amino-2-methyl propionic acid amide
The preparation method of title compound is similar to comparative example 70, wherein uses 3-amino-2-methyl propionic acid to replace the 3-aminobutyric acid.
1H-NMR(CD
3OD)δppm：
1.13(3H，d，J＝6.9Hz)，2.4-2.5(1H，m)，2.6-2.7(1H，m)，2.8-2.9(1H，m)
The comparative example 72
3-amino-2,2-two (methyl) propionic acid amide
To 3-amino-2, the 2-dimethyl-solution of 1-propyl alcohol (2g) in tetrahydrofuran (THF) (20mL) adds N-(benzyloxycarbonyloxy base) succinimide (7.25g), and mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=3/1-1/1), obtain 3-benzyloxycarbonyl amino-2,2-dimethyl-1-propyl alcohol (4.6g) by silica gel column chromatography then.In this material, add tetracol phenixin (40mL), acetonitrile (40mL), water (48mL), sodium periodate (11.6g) and ruthenium trichloride (0.2g) successively, mixture is in stirred overnight at room temperature then.In reaction mixture, add sodium periodate (11.6g) ruthenium trichloride (0.2g), mixture was stirring at room 3 days then.Reaction mixture dilute with water, and the mixture ethyl acetate extraction that forms.The extract anhydrous sodium sulfate drying.Solvent is removed in decompression, then residue is dissolved in the unsaturated carbonate aqueous solutions of potassium.This solution washs with ethyl acetate, then water layer 2mol/L hcl acidifying.The mixture ethyl acetate extraction, anhydrous sodium sulfate drying is used in extract water and salt water washing then then.Solvent is removed in decompression, obtains 3-benzyloxycarbonyl amino-2,2-two (methyl) propionic acid (3.6g).This material is dissolved in tetrahydrofuran (THF) (25mL).In this solution, add 1,1 '-carbonyl diurethane-1H-imidazoles (3.39g), mixture was stirring at room 1 hour then.In reaction mixture, add 28% ammonia soln (25mL), mixture was stirring at room 1 hour then.Reaction mixture dilute with water, and the mixture ethyl acetate extraction that forms.Extract is used anhydrous sodium sulfate drying then with 1mol/L hydrochloric acid, water and salt water washing.Solvent is removed in decompression, obtains 3-benzyloxycarbonyl amino-2,2-two (methyl) propionic acid amide (3.35g).With the 3-benzyloxycarbonyl amino-2 that obtains, 2-two (methyl) propionic acid amide (0.13g) is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (30mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (61mg).
1H-NMR(DMSO-d
6)δppm：
1.0(6H，s)，1.4-2.0(2H，br)，2.52(2H，s)，6.69(1H，brs)，7.36(1H，brs)
Embodiment 126-137
Compound described in the table 1-2 uses corresponding raw material, prepares by the similar fashion described in embodiment 57 or 72.
[table 1]
[table 2]
The comparative example 73
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(3-nitrine third oxygen
Base)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 29; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.82(3H，s)，1.95-2.1(8H，m)，2.16(3H，s)，2.27(3H，s)，2.75-2.85(1H，m)，3.45-3.55(3H，m)，3.61(1H，d，J＝16.3Hz)，3.95-4.1(3H，m)，4.1-4.2(2H，m)，5.07(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.52(1H，d，J＝8.2Hz)，6.58(1H，dd，J＝8.3Hz，2.6Hz)，6.69(1H，d，J＝2.6Hz)，6.81(1H，d，J＝8.3Hz)
The comparative example 74
4-{[4-(3-nitrine propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl } 5-different third
Base-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
To 4-{[(3-chlorine propoxy-))-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base) 1H-pyrazoles (0.3g) is at N; solution in the dinethylformamide (5mL); add sodiumazide (43mg), mixture stirred 3 hours at 80 ℃ then.Add entry in reaction mixture, sedimentary then crystal is collected by filtration.Crystal water and normal hexane washing, and drying under reduced pressure obtain title compound (0.3g).
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.9(2H，m)，1.95-2.1(4H，m)，2.85-2.95(1H，m)，3.45-3.65(6H，m)，3.8-3.9(1H，m)，3.95-4.05(4H，m)，4.1-4.25(2H，m)，4.4-4.55(1H，m)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.2Hz)，5.67(1H，d，J＝8.0Hz)，6.33(1H，dd，J＝8.5Hz，2.4Hz)，6.4(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.5Hz)
Embodiment 138
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(amino third oxygen of 3-
Base)-and the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-nitrine propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.84(3H，s)，1.85-2.0(8H，m)，2.14(3H，s)，2.27(3H，s)，2.75-2.9(3H，m)，3.53(1H，d，J＝16.5Hz)，3.59(1H，d，J＝16.5Hz)，4.0(2H，t，J＝6.2Hz)，4.05-4.2(3H，m)，5.1-5.2(1H，m)，5.2-5.3(1H，m)，5.35-5.45(2H，m)，6.61(1H，dd，J＝8.3Hz，2.3Hz)，6.71(1H，d，J＝2.3Hz)，6.78(1H，d，J＝8.3Hz)
Embodiment 139
4-{[4-(the amino propoxy-of 3-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-different third
Base-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 4-{[4-(3-nitrine propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-nitrine propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.95(4H，m)，1.95-2.1(2H，m)，2.8-3.0(3H，m)，3.5-3.7(4H，m)，3.8-3.9(1H，m)，3.9-4.05(4H，m)，4.05-4.25(2H，m)，4.4-4.55(1H，m)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.3Hz)，5.67(1H，d，J＝7.4Hz)，6.3-6.45(2H，m)，6.85(1H，d，J＝8.6Hz)
Embodiment 140
3-(β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[2-hydroxyl-1,1-two (methylol) ethyl] urea
Base } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-the 5-sec.-propyl-solution of 1.H-pyrazoles (60mg) in methylene dichloride (3mL); add triethylamine (0.016mL) and 4-chloroformate nitrophenyl ester (21mg), mixture was stirring at room 1 hour then.In reaction mixture, add three (methylol) aminomethane (35mg) and methyl alcohol (3mL), mixture was stirring at room 3 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=10/1-6/1) by silica gel column chromatography then; obtain 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[2-hydroxyl-1,1-two (methylol) ethyl] urea groups } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (36mg).This material is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.018mL), mixture was stirring at room 1 hour then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (22mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.44(2H，t，J＝5.3Hz)，3.6-3.75(9H，m)，3.81(1H，d，J＝11.7Hz)，3.95(2H，t，J＝5.3Hz)，5.02(1H，d，J＝6.6Hz)，6.63(1H，dd，J＝8.5Hz，2.4Hz)，6.73(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.5Hz)
Embodiment 141-151
Compound described in the table 3-4 uses corresponding raw material, prepares by the similar fashion described in the embodiment 140.Embodiment's 151 is synthetic, is after the operation of having finished embodiment 140, carries out shortening by embodiment 79 described similar fashion.
[table 3]
[table 4]
The comparative example 75
4-(2-benzyloxy ethyl)-1-bromobenzene
To sodium hydride (60%, 1.09g) 1, the suspension in the 2-glycol dimethyl ether (25mL), at ice-cooled 2-(4-bromophenyl) ethanol (5g) that adds down, mixture was stirring at room 1.5 hours then.In reaction mixture, add cylite (3.25mL), mixture stirs down at 80 ℃ and spends the night then.In reaction mixture, add saturated aqueous ammonium chloride solution, then the mixture extracted with diethyl ether of Xing Chenging.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: normal hexane-n-hexane/ethyl acetate=50/1-20/1), obtain title compound (6.8g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.86(2H，t，J＝6.8Hz)，3.66(2H，t，J＝6.8Hz)，4.5(2H，s)，7.05-7.15(2H，m)，7.2-7.35(5H，m)，7.35-7.45(2H，m)
The comparative example 76
[4-(2-benzyloxy ethyl) phenyl] methyl alcohol
To 4-(2-benzyloxy the ethyl)-solution of 1-bromobenzene (6.8g) in tetrahydrofuran (THF) (80mL), under-78 ℃ and argon gas atmosphere, (the 2.6mol/L hexane solution 8.98mL), stirred the mixture 30 minutes then to add n-Butyl Lithium.In reaction mixture, add N, dinethylformamide (20mL) allows mixture be warmed to 0 ℃ and stirred 2 hours then.Pour reaction mixture into saturated aqueous ammonium chloride solution, and the mixture ethyl acetate extraction that forms.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 4-(2-benzyloxy ethyl) phenyl aldehyde (5.6g).This material is dissolved in methyl alcohol (80mL).Add sodium borohydride (1.77g) down in this solution ice-cooled, mixture is in stirred overnight at room temperature then.In reaction mixture, add saturated aqueous ammonium chloride solution, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue (solid-state) is handled with normal hexane then, collects and drying under reduced pressure by filtering, and obtains title compound (5.41g).
1H-NMR(CDCl
3)δppm：
2.93(2H，t，J＝7.1Hz)，3.68(2H，t，J＝7.1Hz)，4.52(2H，s)，4.65(2H，s)，7.15-7.4(9H，m)
The comparative example 77
4-{[4-(2-benzyloxy ethyl) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses [4-(2-benzyloxy ethyl) phenyl] methyl alcohol to replace [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.07(6H，d，J＝7.1Hz)，2.75-2.9(3H，m)，3.54(2H，s)，3.59(2H，t，J＝6.9Hz)，4.45(2H，s)，7.0-7.15(4H，m)，7.2-7.35(5H，m)
The comparative example 78
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxy ethyl) phenyl]
Methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(2-benzyloxy ethyl) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，2.01(3H，s)，2.03(3H，s)，2.05(3H，s)，2.8-2.95(3H，m)，3.55-3.7(4H，m)，3.8-3.9(1H，m)，4.14(1H，dd，J＝12.5Hz，2.4Hz)，4.31(1H，dd，J＝12.5Hz，3.9Hz)，4.5(2H，s)，5.15-5.3(3H，m)，5.5-5.6(1H，m)，7.0-7.1(4H，m)，7.2-7.35(5H，m)
The comparative example 79
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(2-benzyloxy ethyl) benzene
Base] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-{[4-(2-benzyloxy ethyl) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(3-benzyloxy propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.85(3H，s)，1.99(3H，s)，2.02(3H，s)，2.17(3H，s)，2.85-2.95(3H，m)，3.61(1H，d，J＝15.9Hz)，3.65(2H，t，J＝7.2Hz)，3.69(1H，d，J＝15.9Hz)，4.0-4.25(3H，m)，4.51(2H，s)，5.09(1H，dd，J＝10.6Hz，3.3Hz)，5.4-5.5(2H，m)，5.55(1H，d，J＝8.2Hz)，7.0-7.1(4H，m)，7.2-7.35(5H，m)
The comparative example 80
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-hydroxyethyl) phenyl] first
Base }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-benzyloxy ethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.18(6H，d，J＝7.2Hz)，1.87(3H，s)，2.0(3H，s)，2.02(3H，s)，2.05(3H，s)，2.81(2H，t，J＝6.6Hz)，2.85-3.0(1H，m)，3.62(1H，d，J＝16.0Hz)，3.67(1H，d，J＝16.0Hz)，3.75-3.9(3H，m)，4.12(1H，dd，J＝12.4Hz，2.4Hz)，4.29(1H，dd，J＝12.4Hz，3.8Hz)，5.15-5.3(3H，m)，5.57(1H，d，J＝7.5Hz)，7.05-7.15(4H，m)
The comparative example 81
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(2-hydroxyethyl) phenyl] first
Base }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 23; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(2-benzyloxy ethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.15-1.2(6H，m)，1.88(3H，s)，1.98(3H，s)，2.02(3H，s)，2.17(3H，s)，2.81(2H，t，J＝6.4Hz)，2.85-3.0(1H，m)，3.63(1H，d，J＝16.1Hz)，3.7(1H，d，J＝16.1Hz)，3.8-3.9(2H，m)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.08(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.56(1H，d，J＝8.1Hz)，7.05-7.15(4H，m)
Embodiment 152
4-{[4-(2-{3-[(S)-1-formamyl-2-(methyl) propyl group] urea groups } ethyl) phenyl] first
Base }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-hydroxyethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (2.13g) and the solution of triethylamine (0.65mL) in methylene dichloride (20mL); at the ice-cooled methylsulfonyl chloride (0.36mL) that adds down, mixture was stirring at room 1 hour then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-mesyloxy ethyl) phenyl] methyl }-1H-pyrazoles (2.4g).With this substance dissolves in N, dinethylformamide (20mL).Add sodiumazide (0.71g) in this solution, mixture stirred 3 hours at 80 ℃ then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-1/2) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-azidoethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (1.55g).With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-azidoethyl) phenyl that obtains] methyl }-5-sec.-propyl-1H-pyrazoles (1g) is dissolved at tetrahydrofuran (THF) (5mL).Add 10% palladium-carbon dust (0.15g) in this solution, mixture stirred 6 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino-ethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.96g).With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino-ethyl) phenyl that obtains] methyl }-5-sec.-propyl-1H-pyrazoles (0.48g) is dissolved in methylene dichloride (5mL).In this solution, at ice-cooled triethylamine (0.13mL) and the 4-chloroformate nitrophenyl ester (0.18g) of adding down, mixture was stirring at room 2 hours then.Tell the reaction mixture of 1/6 amount.In this partial reaction mixture, add triethylamine (0.084mL), L-valine amide hydrochloride (45mg) and tetrahydrofuran (THF) (1mL), mixture was stirring at room 5 hours then.Reaction mixture carries out purifying (eluent: ethyl acetate-ethyl acetate/methanol=10/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[(S)-1-formamyl-2-(methyl) propyl group] urea groups } ethyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (48mg).This material is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.013mL), mixture was stirring at room 1 hour then to add sodium methylate.In reaction mixture, add acetate (0.2mL).The mixture that obtains is through concentrating under reduced pressure, and residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (29mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
0.9(3H，d，J＝7.0Hz)，0.95(3H，d，J＝6.5Hz)，1.1-1.2(6H，m)，2.0-2.1(1H，m)，2.71(2H，t，J＝7.1Hz)，2.85-3.0(1H，m)，3.25-3.45(6H，m)，3.6-3.75(2H，m)，3.78(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，4.04(1H，d，J＝5.9Hz)，5.04(1H，d，J＝7.4Hz)，7.05-7.15(4H，m)
Embodiment 153-172
Compound described in the table 5-8 uses corresponding raw material, prepares by the similar fashion described in the embodiment 152.Embodiment 171 and 172 synthetic, be after the operation of having finished embodiment 152, carry out shortening by embodiment 79 described similar fashion.
[table 5]
[table 6]
[table 7]
[table 8]
The comparative example 82
4-bromo-2-methylbenzyl alcohol
Under ice-cooled,, add borane-dimethyl sulphide mixture (7.07g) to the solution of 4-bromo-2-tolyl acid (10g) in tetrahydrofuran (THF) (60mL).Reaction mixture at room temperature stirred 5 minutes, and stirred 2 days at 75 ℃.Reaction mixture is cooled to room temperature.Saturated wet chemical is added in the reaction mixture, separate organic layer then.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (9.0g).
1H-NMR(CDCl
3)δppm：
1.55-1.65(1H，m)，2.36(3H，s)，4.64(2H，d，J＝5.4Hz)，7.2-7.25(1H，m)，7.3-7.35(2H，m)
The comparative example 83
4-{[4-(2-amino-ethyl)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-
3-ketone
To the solution of 4-bromo-2-methylbenzyl alcohol (9.0g) in methylene dichloride (50mL), add thionyl chloride (3.8mL) down ice-cooled, at room temperature stirred reaction mixture spends the night then.Reaction mixture carries out concentrating under reduced pressure, obtains 4-bromo-2-methyl-benzyl chlorine (9.8g).With sodium hydride (55%, 0.84g) be suspended at tetrahydrofuran (THF) (80mL).To this suspension, at the ice-cooled 4-methyl-3-oxopentanoic acid methyl esters (2.94g) that adds down, mixture was stirring at room 1 hour then.In reaction mixture, add 4-bromo-2-methyl-benzyl chlorine (4.08g), mixture stirred 36 hours at 60 ℃ then.In reaction mixture, add saturated aqueous ammonium chloride solution, then the mixture extracted with diethyl ether of Xing Chenging.The extract anhydrous magnesium sulfate drying, solvent is removed in decompression then.Residue is dissolved in acetonitrile (24mL).In this solution, add N-vinyl phthalic imidine (3.29g), acid chloride (II) (0.42g), three (o-methyl-phenyl-) phosphine (2.27g) and N, N-diisopropylethylamine (13mL), mixture stirred 16 hours at 100 ℃ then.To the reaction mixture concentrating under reduced pressure, then residue by silica gel column chromatography carry out purifying (eluent: normal hexane-n-hexane/ethyl acetate=3/1-3/2), obtain N-{ (E)-2-[4-(2-methoxycarbonyl-4-methyl-3-oxo amyl group)-3-aminomethyl phenyl] vinyl phthalic imidine (6.45g).In this material, add methyl alcohol (50mL) and 10% palladium-carbon dust (3g), mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.A part (1g) residue is dissolved in ethanol (15mL).Add hydrazine monohydrate (1.38mL) in this solution, mixture stirred 13 hours at 80 ℃ then.Insoluble substance is removed by filtering, and filtrate is through concentrating under reduced pressure then.Residue on ODS methyl alcohol) and Phenylsulfonic acid resin (cleaning solvent: methyl alcohol, elutriant: 2mol/L ammonia-methanol solution) carry out purifying, obtain title compound (0.3g) by Solid-Phase Extraction (cleaning solvent: distilled water, eluent:.
1H-NMR(DMSO-d
6)δppm：
1.04(6H，d，J＝6.7Hz)，2.25(3H，s)，2.53(2H，t，J＝7.2Hz)，2.65-2.8(3H，m)，3.47(2H，s)，6.75-6.9(2H，m)，6.93(1H，s)
The comparative example 84
4-(4-[2-(benzyloxycarbonyl amino) ethyl]-the 2-aminomethyl phenyl } methyl)-1,2-dihydro-5-different third
Base-3H-pyrazoles-3-ketone
To 4-{[4-(2-amino-ethyl)-2-aminomethyl phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-the solution of 3-ketone (0.3g) in tetrahydrofuran (THF) (5mL), add N-(benzyloxycarbonyloxy base) succinimide (0.33g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Extract washs 2 times with saturated sodium bicarbonate aqueous solution, water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (0.34g).
1H-NMR(CDCl
3)δppm：
1.11(6H，d，J＝6.7Hz)，2.31(3H，s)，2.65-2.95(3H，m)，3.35-3.5(2H，m)，3.63(2H，s)，4.65-4.8(1H，m)，5.09(2H，s)，6.85-7.0(3H，m)，7.25-7.4(5H，m)
Embodiment 173
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[2-(benzyloxycarbonyl amino)
Ethyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-({ 4-[2-(benzyloxycarbonyl amino) ethyl]-2-aminomethyl phenyl } methyl)-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(3-benzyloxy propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.79(3H，s)，1.98(3H，s)，2.02(3H，s)，2.05(3H，s)，2.26(3H，s)，2.73(2H，t，J＝6.7Hz)，2.75-2.9(1H，m)，3.35-3.45(2H，m)，3.53(1H，d，J＝16.5Hz)，3.62(1H，d，J＝16.5Hz)，3.75-3.85(1H，m)，4.08(1H，dd，J＝12.5Hz，2.7Hz)，4.27(1H，dd，J＝12.5Hz，4.1Hz)，4.8-4.9(1H，m)，5.09(2H，s)，5.1-5.3(3H，m)，5.55(1H，d，J＝7.7Hz)，6.8-6.9(2H，m)，6.93(1H，s)，7.25-7.4(5H，m)
Embodiment 174
4-{[4-(2-amino-ethyl)-2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-different third
Base-1H-pyrazoles
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[2-(benzyloxycarbonyl amino) ethyl]-2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (20mg) is dissolved in methyl alcohol (1mL).In this solution, (28% methanol solution, 0.005mL), mixture was stirring at room 2 hours then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water by Solid-Phase Extraction on ODS then, eluent: methyl alcohol), obtain 4-({ 4-[2-(benzyloxycarbonyl amino) ethyl]-2-aminomethyl phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles.This material is dissolved in methyl alcohol (1mL).Add 10% palladium-carbon dust (5mg) in this solution, mixture stirred 6 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (11mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.31(3H，s)，2.67(2H，t，J＝7.0Hz)，2.75-2.9(3H，m)，3.25-3.4(4H，m)，3.6-3.85(4H，m)，4.95-5.05(1H，m)，6.85-7.0(3H，m)
Embodiment 175
4-{[4-(2-{3-[(1S, 2R)-1-formamyl-2-hydroxypropyl] urea groups } ethyl)-the 2-methyl
Phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-({ 4-[2-(benzyloxycarbonyl amino) ethyl]-2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (0.3g) is dissolved in tetrahydrofuran (THF) (2mL).Add 10% palladium-carbon dust (20mg) in this solution, mixture stirred 6 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-amino-ethyl)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.24g).With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-the amino-ethyl)-2-aminomethyl phenyl that obtains] methyl }-5-sec.-propyl-1H-pyrazoles (0.13g) is dissolved in methylene dichloride (2.6mL).In this solution, at ice-cooled triethylamine (0.042mL) and the 4-chloroformate nitrophenyl ester (52mg) of adding down, mixture was stirring at room 2 hours then.Tell the reaction mixture of 1/4 amount.In this partial reaction mixture, add triethylamine (0.028mL) and L-threonyl amine hydrochlorate (23mg), mixture is in stirred overnight at room temperature then.Reaction mixture carries out purifying (eluent: ethyl acetate-ethyl acetate/methanol=10/1) by silica gel column chromatography; obtain 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-{3-[(1S, 2R)-1-formamyl-2-hydroxypropyl] urea groups } ethyl)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (30mg).This material is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.006mL), mixture was stirring at room 1 hour then to add sodium methylate.In reaction mixture, add acetate (0.005mL).The mixture that obtains is through concentrating under reduced pressure, and residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (21mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.1-1.2(9H，m)，2.31(3H，s)，2.7(2H，t，J＝7.0Hz)，2.8-2.9(1H，m)，3.2-3.45(6H，m)，3.6-3.75(3H，m)，3.8(1H，dd，J＝12.1Hz，2.1Hz)，4.05-4.15(1H，m)，4.15-4.25(1H，m)，4.97(1H，d，J＝7.0Hz)，6.85-6.95(2H，m)，7.0(1H，s)
Embodiment 176-181
Compound described in the table 9-10 uses corresponding raw material, prepares by the similar fashion described in the embodiment 175.Embodiment 180 and 181 synthetic, be after the operation of having finished embodiment 175, carry out shortening by embodiment 79 described similar fashion.
[table 9]
[table 10]
Embodiment 182
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-[(4-{3-[3-(dimethylamino) third amino] third
The oxygen base }-the 2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 51; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and N; N-dimethyl-N '-(2-oil of mirbane alkylsulfonyl)-1; the 3-diaminopropanes; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-methyl-2-(2-nitrobenzene sulfonyl ammonia base) propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.65-1.75(2H，m)，1.9-2.0(2H，m)，2.23(6H，s)，2.28(3H，s)，2.3-2.4(2H，m)，2.61(2H，t，J＝7.3Hz)，2.7-2.85(3H，m)，3.49(1H，dd，J＝9.8Hz，3.5Hz)，3.55-3.8(6H，m)，3.84(1H，d，J＝3.5Hz)，3.99(2H，t，J＝6.1Hz)，5.03(1H，d，J＝7.9Hz)，6.6(1H，d，J＝8.7Hz，2.4Hz)，6.7(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.7Hz)
The comparative example 85
3-amino-3-methylbutyryl amine
To 3, the solution of 3-dimethacrylate (5g) in tetrahydrofuran (THF) (15mL) adds 1,1 '-carbonyl diurethane-1H-imidazoles (10.5g), and mixture was stirring at room 30 minutes then.In reaction mixture, add 28% ammonia soln (30mL), mixture was stirring at room 1 hour then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: methylene chloride=10/1), obtain 3,3-DMAA (2.05g) by silica gel column chromatography then.With this substance dissolves in 2-propyl alcohol (20mL).Under-15 ℃, ammonia is frothed into solution, until saturated, mixture stirred 40 hours at 80 ℃ then.To the reaction mixture concentrating under reduced pressure, residue is by Phenylsulfonic acid resin purification (cleaning solvent: methyl alcohol, elutriant: 2mol/L ammonia-methanol solution), obtain title compound (0.13g).
1H-NMR(CD
3OD)δppm：
1.19(6H，s)，2.27(2H，s)
Embodiment 183
4-[(4-{3-[2-formamyl-1,1-two (methyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) first
Base]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 72; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-hydroxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 3-amino-3-methylbutyryl amine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-hydroxyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-[2-amino-2-(methyl) propionamido] ethanol.
MS(ESI，m/z)：565[M+H]
+
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.18(6H，s)，1.85-2.0(2H，m)，2.28(3H，s)，2.32(2H，s)，2.7-2.85(3H，m)，3.49(1H，dd，J＝9.7Hz，3.3Hz)，3.58(1H，t，J＝5.8Hz)，3.6-3.8(5H，m)，3.8-3.9(1H，m)，4.0(2H，t，J＝5.9Hz)，5.03(1H，d，J＝7.9Hz)，6.55-6.65(1H，m)，6.65-6.75(1H，m)，6.8-6.9(1H，m)
The comparative example 86
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-the 5-Trifluoromethyl-1,2-dihydro-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein uses (4-benzyloxy-2-aminomethyl phenyl) methyl alcohol and trifluoroacetic ethyl acetoacetate, replaces [4-(3-benzyloxy propoxy-) phenyl] methyl alcohol and 4-methyl-3-oxopentanoic acid ethyl ester respectively.
1H-NMR(DMSO-d
6)δppm：
2.24(3H，s)，3.58(2H，s)，5.02(2H，s)，6.65(1H，d，J＝8.5Hz)，6.7(1H，dd，J＝8.5Hz，2.7Hz)，6.81(1H，d，J＝2.7Hz)，7.25-7.45(5H，m)
The comparative example 87
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-benzyloxy-2-aminomethyl phenyl)
Methyl]-5-Trifluoromethyl-1 H-pyrazoles
With 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-the 5-Trifluoromethyl-1,2-dihydro-3H-pyrazoles-3-ketone (0.5g), acetyl bromide-α-D-semi-lactosi (0.62g) and salt of wormwood (0.29g) at room temperature stir and spend the night at the suspension of acetonitrile (5mL).Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=2/1-1/1), obtain title compound (0.66g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.78(3H，s)，1.98(3H，s)，2.05(3H，s)，2.17(3H，s)，2.3(3H，s)，3.67(1H，d，J＝16.4Hz)，3.72(1H，d，J＝16.4Hz)，3.98(1H，t，J＝6.3Hz)，4.1-4.25(2H，m)，5.0-5.1(3H，m)，5.15-5.4(2H，m)，5.42(1H，dd，J＝3.4Hz，1.0Hz)，6.67(1H，dd，J＝8.5Hz，2.6Hz)，6.75(1H，d，J＝8.5Hz)，6.8(1H，d，J＝2.6Hz)，7.25-7.45(5H，m)
The comparative example 88
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-5-trifluoromethyl-4-[(4-hydroxyl
Base-2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to comparative example 58; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-Trifluoromethyl-1 H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.83(3H，s)，1.98(3H，s)，2.05(3H，s)，2.18(3H，s)，2.27(3H，s)，3.66(1H，d，J＝16.4Hz)，3.71(1H，d，J＝16.4Hz)，3.95-4.0(1H，m)，4.05-4.2(2H，m)，4.84(1H，brs)，5.03(1H，dd，J＝10.3Hz，3.4Hz)，5.2-5.4(2H，m)，5.41(1H，dd，J＝3.4Hz，1.1Hz)，6.54(1H，dd，J＝8.3Hz，2.7Hz)，6.64(1H，d，J＝2.7Hz)，6.72(1H，d，J＝8.3Hz)
Embodiment 184
4-[(4-{3-[2-(formamyl) ethylamino] propoxy-}-the 2-aminomethyl phenyl) methyl]-the 5-trifluoro
Methyl-3-(β-D-galactopyranose oxygen base)-1H-pyrazoles
3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[N-benzyloxycarbonyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-preparation method of 5-Trifluoromethyl-1 H-pyrazoles is similar to embodiment 96; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 5-trifluoromethyl-4-[(4-hydroxy-2-methyl phenyl) methyl]-1H-pyrazoles replacement 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.And the preparation method of title compound is similar to embodiment 94; wherein use above-mentioned this substitution of materials 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[N-benzyl-N-(2-formamyl ethyl) amino] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
MS(ESI，m/z)：563[M+H]
+
1H-NMR(CD
3OD)δppm：
1.95-2.1(2H，m)，2.25(3H，s)，2.41(2H，t，J＝6.9Hz)，2.63(2H，t，J＝7.1Hz)，2.83(2H，t，J＝6.9Hz)，3.53(1H，dd，J＝9.8Hz，3.4Hz)，3.55-3.8(6H，m)，3.87(1H，d，J＝3.4Hz)，4.21(2H，t，J＝6.7Hz)，5.28(1H，d，J＝7.9Hz)，6.45(1H，dd，J＝8.4Hz，2.4Hz)，6.55-6.65(2H，m)
Embodiment 185
4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] second
The oxygen base }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-amino ethoxy)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.5g) is at N; solution in the dinethylformamide (10mL); add 1-benzyloxycarbonyl-4-[2-carboxyl-2-(methyl) propionyl] piperazine (0.28g); I-hydroxybenzotriazole (0.22g); triethylamine (0.18mL) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.46g), mixture was stirring at room 2 days then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer is used saturated sodium bicarbonate aqueous solution, water and salt water washing successively, with anhydrous magnesium sulfate drying and concentrating under reduced pressure.Residue carries out purifying (eluent: methylene chloride=30/1) by silica gel column chromatography; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.3g).This material is dissolved in methyl alcohol (4mL).In this solution, (28% methanol solution, 0.06mL), mixture was stirring at room 30 minutes then to add sodium methylate.In reaction mixture, add acetate (0.035mL), the mixture of Xing Chenging is through concentrating under reduced pressure then.Residue carries out purifying (eluent: methylene chloride=10/1-5/1), obtain title compound (0.23g) by silica gel column chromatography.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.37(6H，s)，2.25(3H，s)，2.7-2.85(1H，m)，3.15-3.75(17H，m)，3.81(1H，d，J＝12.0Hz)，4.02(2H，t，J＝5.2Hz)，5.02(1H，d，J＝7.4Hz)，5.09(2H，s)，6.55-6.65(1H，m)，6.69(1H，d，J＝2.2Hz)，6.84(1H，d，J＝8.7Hz)，7.25-7.4(5H，m)
The comparative example 89
4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] second
The oxygen base }-the 2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
With 4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (0.23g), the mixture of tosic acid monohydrate (0.41g) and 2-propyl alcohol (10mL) stirred 2 days down at 50 ℃.Pour reaction mixture into saturated sodium bicarbonate aqueous solution, and the mixture ethyl acetate extraction that forms.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=10/1), obtain title compound (0.18g) by silica gel column chromatography then.
1H-NMR(CD
3OD)δppm：
1.06(6H，d，J＝6.7Hz)，1.37(6H，s)，2.25(3H，s)，2.7-2.85(1H，m)，3.15-3.7(12H，m)，4.02(2H，t，J＝5.3Hz)，5.09(2H，s)，6.6(1H，dd，J＝8.6Hz，2.3Hz)，6.7(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.6Hz)，7.25-7.4(5H，m)
Embodiment 186
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{2-[2-{[4-(benzyloxy
Carbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-the 5-sec.-propyl
-1H-pyrazoles
The preparation method of title compound is similar to comparative example 17, wherein use 4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(3-benzyloxy propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.41(6H，s)，1.83(3H，s)，1.98(3H，s)，2.02(3H，s)，2.15(3H，s)，2.25(3H，s)，2.7-2.85(1H，m)，3.25-3.7(12H，m)，3.97(2H，t，J＝4.9Hz)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.08(1H，dd，J＝10.4Hz，3.5Hz)，5.12(2H，s)，5.35-5.45(2H，m)，5.52(1H，d，J＝8.1Hz)，5.92(1H，t，J＝5.7Hz)，6.53(1H，dd，J＝8.4Hz，2.6Hz)，6.63(1H，d，J＝2.6Hz)，6.81(1H，d，J＝8.4Hz)，7.25-7.4(5H，m)
Embodiment 187
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(2-{2-methyl-2-[(piperazine-1-yl) carbonyl
Base] propionamido } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (0.14g) in methyl alcohol (3mL); add sodium methylate (28% methanol solution; 0.015mL), mixture was stirring at room 30 minutes then.Reaction mixture by silica gel column chromatography carry out purifying (eluent: methylene chloride=5/1), obtain 4-[(4-{2-[2-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-2-(methyl) propionamido] oxyethyl group-the 2-aminomethyl phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles (70mg).This material is dissolved in methyl alcohol (4mL).Add 10% palladium-carbon dust (10mg) in this solution, mixture stirred 1 hour under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (54mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.37(6H，s)，2.3(3H，s)，2.35-2.9(5H，m)，3.1-3.8(13H，m)，3.85(1H，d，J＝3.3Hz)，4.02(2H，t，J＝5.5Hz)，5.04(1H，d，J＝8.0Hz)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.72(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Test implementation example 1
Test is to the active restraining effect of people SGLT1
1) carrier of clone and construction expression people SGLT1
As primer, be used for the cDNA library of pcr amplification with oligomerization dT by the reverse transcription preparation from the total RNA of people's small intestine (Ori gene).This cDNA library as template, is amplified the dna fragmentation (accession number: M24847 is by people such as Hediger report) of the 1-2005bp of coding people SGLT1 with the PCR method, be inserted into pcDNA3.1 (-) multiple clone site (Invitrogen) then.The dna sequence dna that inserts mates fully with the sequence of reporting in the past.
2) set up the clone of stably express people SGLT1
Expression vector with ScaI digestion people SGLT1 forms linear DNA.By lipofection (Effectene transfection reagent: QIAGEN), change this linear DNA over to the CHO-K1 cell.By in the substratum that contains G418 (1mg/mL, LIFE TECHNOLOGIES), cultivating, select neomycin resistance clone.Then, measure the activity of antagonism methyl-α-D-Glucopyranose picked-up with following method.Select and have the active clone of maximum ingestion, called after CS1-5-11D.In the presence of 200 μ g/mL G418, cultivate the CS1-5-11D cell.
3) measure methyl-α-D-Glucopyranose (inhibition activity of picked-up of α-MG)
(density is 3 * 10 in the 96-well culture plate with the CS1-5-11D cell inoculation
4Cells/well) and cultivated 2 days, be used for the picked-up test then.With cold (Sigma) and
14The mixture of the α-MG of C-mark (AmershamPharmcia Biotec) adds to (pH7.4 in the picked-up damping fluid; Contain 140mM sodium-chlor, 2mM Repone K, 1mM calcium chloride, 1mM magnesium chloride, 10mM 2-[4-(2-hydroxyethyl)-1-piperazinyl] ethyl sulfonic acid and 5mM three (methylol) aminomethane), make that final concentration is 1mM.Test compounds is dissolved in methyl-sulphoxide, suitably dilutes then with distilled water.Test compounds solution is added the picked-up damping fluid (being called assay buffer) that contains 1mM α-MG.For control group, preparation does not contain the assay buffer of test compounds.For the Fundamentals of Measurement picked-up, preparation basis picked-up assay buffer (it contains 140mM choline chloride 60 (chorine chloride) to replace sodium-chlor).After the substratum of having removed the CS1-5-11D cell, 180 μ L pretreatment buffer liquids (the basis picked-up damping fluid that does not contain α-MG) are added each hole, hatched 10 minutes at 37 ℃ then.After repeating same processing, remove pretreatment buffer liquid.In each hole, add 75 μ L assay buffer or add basis picked-up damping fluid, hatched 1 hour at 37 ℃ then.After removing assay buffer, with 180 μ L/ hole lavation buffer solutions (damping fluid is absorbed on the basis that contains the unmarked α-MG of 10mM) washed cell 2 times.0.2mol/L sodium hydroxide with 75 μ L/ holes makes lysis.Cell lysate is changed over to Pico plate (Packard), adds 150 μ L MicroScint-40 (Packard) and mixing then.Measure radioactivity with micro-scintillation detector TopCount (Packard).Difference between control group and the basis picked-up is made as 100%, calculates the picked-up of methyl α-D-Glucopyranose under each drug level then.Calculate drug level (IC when suppressing 50% methyl α-D-Glucopyranose picked-up with logarithmic curve
50Value).These the results are shown in table 11.
[table 11]
| Test compounds | IC 50Value (nM) |
| Embodiment 6 | 304 |
| Embodiment 9 | 42 |
| Embodiment 10 | 169 |
| Embodiment 13 | 267 |
| Embodiment 21 | 127 |
| Embodiment 22 | 233 |
| Embodiment 24 | 61 |
| Embodiment 28 | 90 |
| Embodiment 29 | 19 |
| Embodiment 30 | 257 |
| Embodiment 31 | 166 |
| Embodiment 32 | 113 |
| Embodiment 33 | 65 |
| Embodiment 35 | 160 |
| Embodiment 36 | 383 |
| Embodiment 37 | 158 |
| Embodiment 38 | 246 |
| Embodiment 45 | 68 |
| Embodiment 48 | 54 |
| Embodiment 49 | 148 |
| Embodiment 50 | 159 |
| Embodiment 51 | 22 |
| Embodiment 52 | 131 |
| Embodiment 55 | 98 |
| Embodiment 56 | 38 |
| Embodiment 57 | 43 |
| Embodiment 58 | 100 |
| Embodiment 59 | 71 |
| Embodiment 61 | 199 |
| Embodiment 62 | 138 |
| Embodiment 63 | 322 |
| Embodiment 64 | 178 |
Test implementation example 2
The restraining effect that test raises to blood glucose level in the rat
1) preparation diabetes rat model
Male Wistar rat (Japan Charles River) peritoneal injection niacinamide (230mg/kg) to 8 ages in week.Injected back 15 minutes, under etherization, from the tail vein by intravenous injection U-9889 (85mg/kg).After one week, the rat overnight fasting carries out glucose tolerance test (2g/kg) then.Select after giving glucose 1 hour plasma glucose concentration rat, be used for the test of liquid food tolerance greater than 300mg/dL.
2) liquid food tolerance test
After overnight fasting, give the oral test compounds of diabetes rat (1mg/kg) (being dissolved in distilled water or 0.5% carboxymethyl cellulose aqueous solution, medication therapy groups) or only give distilled water or only give 0.5% carboxymethyl cellulose aqueous solution (control group).After giving compound, per os gives the 17.25kcal/kg liquid food (No.038 is furnished with the control food of dextrin and maltose at once; Oriental Yeast Co., Ltd.).Just the fixed time before giving and after giving, collect blood, handle with heparin at once then from caudal artery.Centrifugal blood is collected blood plasma then, so that with the quantitative plasma glucose concentration of glucose oxidase method.(0 hour), the plasma glucose concentration that gives behind the medicine 0.5 hour and 1 hour are shown in table 12 before processing.Numeric representation is mean value ± S.E in the table.
[table 12]
Test implementation example 3
Acute toxic test
With 6 the week age male ICR mouse (CLEA Japan, Inc.; 32-37g, n=5) fasting is 4 hours.To be dissolved in the test compounds of distilled water, give, observe mouse then 24 hours with the oral dose of 1g/kg.The results are shown in following table 13.
[table 13]
| Test compounds | Mortality |
| Embodiment 52 | 0/5 |
Industrial applicability
Pyrazole derivatives, its pharmaceutically acceptable salt and the prodrug of following formula of the present invention (I) expression; people SGLT1 is had and suppresses active; and can suppress the rising of blood glucose levels in the absorption of small intestine by suppressing carbohydrate such as glucose; especially make the rising of remarkable blood glucose level and/or reduce the blood galactose level by the absorption that postpones glucose and galactolipin based on this mechanism, and can make postprandial hyperglycemia normalization. Therefore, the outstanding medicine that the invention provides, this medicine can prevent or treat hyperglycaemia relevant disease (as diabetes, impaired glucose tolerance, the too much obstacle of fasting blood-glucose, diabetic complication, obesity etc.) and the disease (as galactosemia) relevant with the rising of blood galactose level. In addition, because the pyrazole derivatives of following formula of the present invention (II) expression and salt thereof are the pyrazole derivatives main intermediate of production following formula of the present invention (I) expression, so the compound of following formula of the present invention (I) expression can be prepared by these compounds easily.
Claims (42)
1. the pyrazole derivatives that general formula is represented below a kind:
In the formula,
R
1Represent hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group or can on ring, have identical or different 1-3 substituent aryl C
1-6Alkyl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group;
One among Q and the T is the group shown in the following formula:
Or the group shown in the following formula:
And another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
2Be hydrogen atom, halogen atom, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Alkoxyl group or-A-R
AIn the formula A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
ABe C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, carboxyl, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
The C of Y for being replaced by hydroxyl
1-6Alkylidene group or C
2-6Alkylene group;
Z is-R
B,-COR
C,-SO
2R
C,-CON (R
D) R
E,-SO
2NHR
FOr-C (=NR
G) N (R
H) R
I
R
CRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl;
R
4, R
B, R
D, R
EAnd R
FCan be identical or different, and each naturally hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl, or R
4And R
BBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, or R
DAnd R
EBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
G, R
HAnd R
ICan be identical or different, and each hydrogen atom, cyano group, formamyl, C naturally
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, nitro, C
1-6Alkyl sulphonyl, sulfoamido, amidino groups or C
1-6Alkyl, they can have 1-5 the identical or different group that is selected from following substituting group group (i), or R
GAnd R
HBoth are in conjunction with the formation ethylidene, or R
HAnd R
IBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
3, R
5And R
6Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; And
Substituting group group (i) is made of following:
Hydroxyl,
C
1-6Alkoxyl group,
C
1-6Alkylthio,
Amino,
List or two (C
1-6Alkyl) amino,
List or two [hydroxyl (C
1-6Alkyl)] amino,
Urea groups,
Sulfoamido,
List or two (C
1-6Alkyl) urea groups,
List or two (C
1-6Alkyl) sulfoamido,
C
2-7Amido,
C
1-6Alkyl sulfonyl-amino,
C
1-6Alkyl sulphonyl,
Carboxyl,
C
2-7Alkoxy carbonyl,
-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl,
On ring, can have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
Can on ring, have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
C
3-7Cycloalkyl,
C
2-6Heterocyclylalkyl,
Can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group,
The substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl,
The substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and
Can have C
1-6Alkyl is as substituent C
1-6Aromatic ring amino,
Or its pharmacy acceptable salt.
2. pyrazole derivatives as claimed in claim 1 is characterized in that R
4Represent hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl; R
BRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from following substituting group group (i)
1-6Alkyl; R
CExpression can have 1-3 the identical or different substituent aryl of the group of being selected from down: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from substituting group group (i)
1-6Alkyl; With
Substituting group group (i) is made of following:
Hydroxyl,
C
1-6Alkoxyl group,
C
1-6Alkylthio,
Amino,
List or two (C
1-6Alkyl) amino,
List or two [hydroxyl (C
1-6Alkyl)] amino,
Urea groups,
Sulfoamido,
List or two (C
1-6Alkyl) urea groups,
List or two (C
1-6Alkyl) sulfoamido,
C
2-7Amido,
C
1-6Alkyl sulfonyl-amino,
C
1-6Alkyl sulphonyl,
Carboxyl,
C
2-7Alkoxy carbonyl,
-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl,
On ring, can have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
Can on ring, have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
C
3-7Cycloalkyl,
C
2-6Heterocyclylalkyl,
Can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group,
The substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl,
The substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and
Can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt.
3. pyrazole derivatives as claimed in claim 2 is characterized in that Z is-R
BR
BExpression has 1-3 the identical or different substituent aryl of the group of being selected from down: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl maybe can have the C of 1-5 the identical or different group that is selected from substituting group group (i)
1-6Alkyl; With
Substituting group group (i) is made of following:
Hydroxyl,
C
1-6Alkoxyl group,
C
1-6Alkylthio,
Amino,
List or two (C
1-6Alkyl) amino,
List or two [hydroxyl (C
1-6Alkyl)] amino,
Urea groups,
Sulfoamido,
List or two (C
1-6Alkyl) urea groups,
List or two (C
1-6Alkyl) sulfoamido,
C
2-7Amido,
C
1-6Alkyl sulfonyl-amino,
C
1-6Alkyl sulphonyl,
Carboxyl,
C
2-7Alkoxy carbonyl,
-CON (R
J) R
K, R wherein
JAnd R
KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
JAnd R
KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl,
On ring, can have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkoxyl group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
Can on ring, have identical or different 1-3 and be selected from the substituent aryl C of group down
1-6Alkylthio: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group,
C
3-7Cycloalkyl,
C
2-6Heterocyclylalkyl,
Can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group,
The substituent heteroaryl that can have the group of being selected from down: halogen atom, amino and C
1-6Alkyl,
The substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, C
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, hydroxyl C
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and
Can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt.
4. pyrazole derivatives as claimed in claim 3 is characterized in that R
4Represent hydrogen atom; R
BExpression C
1-6Alkyl, it can have 1-5 the identical or different group that is selected from substituting group group (iA); With
Substituting group group (iA) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, carboxyl, C
2-7Alkoxy carbonyl and-CON (R
JA) R
KA, R wherein
JAAnd R
KACan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino and formamyl, or R
JAAnd R
KABoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl,
Or its pharmacy acceptable salt.
5. pyrazole derivatives as claimed in claim 4 is characterized in that R
BExpression has the C of formamyl
1-6Alkyl, or its pharmacy acceptable salt.
6. pyrazole derivatives as claimed in claim 2 is characterized in that, Z is-CON (R
D) R
E, or its pharmacy acceptable salt.
7. pyrazole derivatives as claimed in claim 6 is characterized in that R
DRepresent hydrogen atom; R
EExpression has the C of 1-5 the identical or different group that is selected from substituting group group (iB)
1-6Alkyl; And substituting group group (iB) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino and-CON (R
JB) R
KB, R wherein
JBAnd R
KBCan be identical or different, and each hydrogen atom, C naturally
1-6Alkyl, they can have the substituting group that identical or different 1-3 is selected from down group: hydroxyl, amino and singly or two (C
1-6Alkyl) amino, or its pharmacy acceptable salt.
8. pyrazole derivatives as claimed in claim 2 is characterized in that, Z is-C (=NR
G) N (R
H) R
I, or its pharmacy acceptable salt.
9. pyrazole derivatives as claimed in claim 8 is characterized in that R
GRepresent hydrogen atom or C
1-6Alkyl sulphonyl; R
HRepresent hydrogen atom; R
1The C of the 1-5 that represents hydrogen atom maybe can have to be selected from substituting group group (iC) identical or different group
1-6Alkyl; And substituting group group (iC) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, or its pharmacy acceptable salt.
10. pyrazole derivatives as claimed in claim 2 is characterized in that Z is-COR
CR
CExpression can have the C of the group that is selected from substituting group group (iD)
1-6Alkyl; And substituting group group (iD) is made of following: amino and-CON (R
JC) R
KC, R wherein
JCAnd R
KCBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, or its pharmacy acceptable salt.
11., it is characterized in that X is singly-bound or Sauerstoffatom as arbitrary described pyrazole derivatives among the claim 1-10; With Y be ethylene or trimethylene, or its pharmacy acceptable salt.
12., it is characterized in that R as arbitrary described pyrazole derivatives among the claim 1-10
1Be hydrogen atom or hydroxyl C
2-6Alkyl; T represents the group shown in the following formula:
Or the group shown in the following formula:
Q is C
1-6Alkyl or halo C
1-6Alkyl; And R
3, R
5And R
6Be hydrogen atom or its pharmacy acceptable salt.
13., it is characterized in that one among Q and the T is the group shown in the following formula as arbitrary described pyrazole derivatives among the claim 1-10:
Another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl, or its pharmacy acceptable salt.
14. pyrazole derivatives as claimed in claim 12 is characterized in that, T is the group shown in the following formula:
Or its pharmacy acceptable salt.
15. pyrazole derivatives as claimed in claim 13 is characterized in that, T is the group shown in the following formula:
Or its pharmacy acceptable salt.
16. pyrazole derivatives as claimed in claim 12 is characterized in that, Q is a sec.-propyl, or its pharmacy acceptable salt.
17. pyrazole derivatives as claimed in claim 11 is characterized in that, R
1Be hydrogen atom or hydroxyl C
2-6Alkyl; T represents the group shown in the following formula:
Or the group shown in the following formula:
Q is C
1-6Alkyl or halo C
1-6Alkyl; And R
3, R
5And R
6Be hydrogen atom or its pharmacy acceptable salt.
18. pyrazole derivatives as claimed in claim 11 is characterized in that, one among Q and the T is the group shown in the following formula:
Another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl, or its pharmacy acceptable salt.
19. pyrazole derivatives as claimed in claim 14 is characterized in that, Q is a sec.-propyl, or its pharmacy acceptable salt.
20. pyrazole derivatives as claimed in claim 15 is characterized in that, Q is a sec.-propyl, or its pharmacy acceptable salt.
21. pyrazole derivatives as claimed in claim 18 is characterized in that, T is the group shown in the following formula:
Or its pharmacy acceptable salt.
22. pyrazole derivatives as claimed in claim 19 is characterized in that, T is the group shown in the following formula:
Or its pharmacy acceptable salt.
23. pyrazole derivatives as claimed in claim 18 is characterized in that, Q is a sec.-propyl, or its pharmacy acceptable salt.
24. pyrazole derivatives as claimed in claim 21 is characterized in that, Q is a sec.-propyl, or its pharmacy acceptable salt.
25. pyrazole derivatives as claimed in claim 1 is characterized in that, it is compound and the pharmacy acceptable salt thereof that is selected from down group:
26. a pharmaceutical composition is characterized in that, contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
27. a people SGLT1 inhibitor is characterized in that, contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
28. a preparation that suppresses postprandial hyperglycemia is characterized in that, contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
29. a preparation that is used to prevent or treat the hyperglycemia relative disease is characterized in that, it contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
30. the preparation that prevents or treat of being used to as claimed in claim 29, it is characterized in that wherein the hyperglycemia relative disease is the disease that is selected from down group: diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia and gout.
31. one kind is suppressed in the individuality preparation that develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose, it is characterized in that it contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
32. one kind is used to prevent or the preparation of treatment and blood semi-lactosi level rising diseases associated, it is characterized in that, it contains among the claim 1-25 arbitrary described pyrazole derivatives or its pharmacy acceptable salt as activeconstituents.
33. the preparation that prevents or treat of being used to as claimed in claim 32 is characterized in that, is galactosemia with the blood semi-lactosi level relevant disease that raises.
34. pharmaceutical composition as claimed in claim 26 is characterized in that, described formulation is a sustained release preparation.
35., it is characterized in that described formulation is a sustained release preparation as arbitrary described preparation among the claim 27-33.
36. the purposes of arbitrary described pyrazole derivatives or its pharmacy acceptable salt is characterized in that among the claim 1-25, is used to prepare the pharmaceutical composition of prevention or treatment hyperglycemia relative disease.
37. the purposes of arbitrary described pyrazole derivatives or its pharmacy acceptable salt is characterized in that among the claim 1-25, is used for preparing being suppressed at individuality develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose pharmaceutical composition.
38. the purposes of arbitrary described pyrazole derivatives or its pharmacy acceptable salt is characterized in that among the claim 1-25, is used to prepare be used to prevent or the pharmaceutical composition of treatment and blood semi-lactosi level rising diseases associated.
39. pharmaceutical composition; it is characterized in that; it contains arbitrary described pyrazole derivatives among (A) claim 1-25; or its pharmacy acceptable salt, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; the D-chiro-inositol; glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than the More; sulosemide; Y-128; anti-diarrhea agents; cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; fiber acid derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents, uric acid synthetic inhibitor, uricosuric agent and urine basifier.
40. (A) arbitrary described pyrazole derivatives among the claim 1-25; or its pharmacy acceptable salt, and (B) at least a purposes of member's material that is selected from down group: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; the D-chiro-inositol; glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than the More; sulosemide; Y-128; anti-diarrhea agents; cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; fiber acid derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents, uric acid synthetic inhibitor, uricosuric agent and urine basifier is characterized in that, be used to prepare prevention or treatment hyperglycemia relative disease or with the pharmaceutical composition of blood semi-lactosi level rising diseases associated.
41. (A) arbitrary described pyrazole derivatives among the claim 1-25; or its pharmacy acceptable salt, and (B) at least a purposes of member's material that is selected from down group: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; the D-chiro-inositol; glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than the More; sulosemide; Y-128; anti-diarrhea agents; cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; fiber acid derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents, uric acid synthetic inhibitor, uricosuric agent and urine basifier, it is characterized in that, be used for preparing and be suppressed at individuality develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose pharmaceutical composition.
42. the pyrazole derivatives shown in the general formula below a kind:
In the formula
R
11Represent hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, the hydroxyl C that can have protecting group
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group or can on ring, have identical or different 1-3 substituent aryl C
1-6Alkyl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group;
Q
2And T
2In one be 2,3,4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base group, 2,3,4; 6-four-O-valeryl-β-D-pyranoglucose oxygen base group, 2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base group or 2; 3; 4,6-four-O-valeryl-β-D-galactopyranose oxygen base group, and another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
12Be hydrogen atom, halogen atom, the hydroxyl that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Alkoxyl group or-A-R
1AIn the formula A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
1ABe C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl, the carboxyl that can have protecting group, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
Y
1Expression can be able to be had the C that hydroxyl replaced of protecting group
1-6Alkylidene group or C
2-6Alkylene group;
Z
1Expression-R
1B,-COR
1C,-SO
2R
1C,-CON (R
1D) R
1E,-SO
2NHR
1FOr-C (=NR
1G) N (R
1H) R
1I
R
1CRepresentative can have identical or different 1-3 substituent aryl, and described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl maybe can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl;
R
14, R
1B, R
1D, R
1EAnd R
1FCan be identical or different, and each naturally hydrogen atom, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl maybe can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl, or R
14And R
1BBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, or R
1DAnd R
1EBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
1G, R
1HAnd R
1ICan be identical or different, and each hydrogen atom, cyano group, formamyl, C naturally
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl, nitro, C
1-6Alkyl sulphonyl, sulfoamido, amidino groups, maybe can have the C that is selected from following substituting group group 1-5 (ii) identical or different group
1-6Alkyl, or R
1GAnd R
1HBoth are in conjunction with the formation ethylidene, or R
1HAnd R
1IBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl;
R
3, R
5And R
6Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; And
The substituting group group (ii) is made of following: hydroxyl, the C that can have protecting group
1-6Alkoxyl group, C
1-6Alkylthio, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6Alkyl) sulfoamido, C
2-7Amido, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl sulphonyl, the carboxyl that can have protecting group, C
2-7Alkoxy carbonyl ,-CON (R
1J) R
1K, R wherein
1JAnd R
1KCan be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Amido, C
1-6Alkyl sulfonyl-amino and formamyl, or R
1JAnd R
1KBoth and adjacent nitrogen atom are combined together to form the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkoxyl group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group can have identical or different 1-3 and be selected from the substituent aryl C of group down on ring
1-6Alkylthio: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl sulfonyl-amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom, the amino that can have protecting group and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: hydroxyl, formamyl, the C that can have protecting group
1-6Alkyl, oxo base, formamyl C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl and C
1-6The amino C that replaces of alkyl sulfonyl
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino, or its salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP244381/2002 | 2002-08-23 | ||
| JP2002244381 | 2002-08-23 | ||
| JP324076/2002 | 2002-11-07 |
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|---|---|
| CN1688597A CN1688597A (en) | 2005-10-26 |
| CN100413878C true CN100413878C (en) | 2008-08-27 |
Family
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| CNB038244993A Expired - Lifetime CN100413878C (en) | 2002-08-23 | 2003-08-21 | Pyrazole derivatives, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof |
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| RU2482122C2 (en) * | 2007-12-27 | 2013-05-20 | Киссеи Фармасьютикал Ко., Лтд. | Monosebacate of pyrazole derivative |
| CA2725230C (en) * | 2008-04-16 | 2016-05-17 | Kissei Pharmaceutical Co., Ltd. | Hemifumarate of a pyrazole derivative |
| EP2298782A1 (en) * | 2009-08-26 | 2011-03-23 | Sanofi-Aventis | Method for producing pyrazole glycoside derivatives |
| JO3298B1 (en) * | 2013-11-01 | 2018-09-16 | Lilly Co Eli | Glucopyranosyl-substituted indole-urea derivatives and their use as sglt inhibitors |
| CN110054657B (en) | 2018-01-18 | 2021-06-29 | 亚宝药业集团股份有限公司 | Glucopyranosyl substituted pyrazole compound and preparation method thereof |
| CN108383801B (en) * | 2018-01-25 | 2023-05-26 | 于磊 | Inhibitors of SGLT2 proteins and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002036602A1 (en) * | 2000-11-02 | 2002-05-10 | Ajinomoto Co., Inc. | Novel pyrazole derivatives and diabetes remedies containing the same |
| EP1213296A1 (en) * | 1999-08-31 | 2002-06-12 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| WO2002053573A1 (en) * | 2000-12-28 | 2002-07-11 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and use thereof in medicines |
-
2003
- 2003-08-21 ZA ZA200501549A patent/ZA200501549B/en unknown
- 2003-08-21 CN CNB038244993A patent/CN100413878C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1213296A1 (en) * | 1999-08-31 | 2002-06-12 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| WO2002036602A1 (en) * | 2000-11-02 | 2002-05-10 | Ajinomoto Co., Inc. | Novel pyrazole derivatives and diabetes remedies containing the same |
| WO2002053573A1 (en) * | 2000-12-28 | 2002-07-11 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and use thereof in medicines |
Non-Patent Citations (1)
| Title |
|---|
| Sugar analogues as potential inhibitors of the intestinal Na+/glucose co-transporter(SGLT1). Jane DYER, et al.Biochemical Society Transactions,Vol.26 No.2. 1998 * |
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| ZA200501549B (en) | 2006-07-26 |
| CN1688597A (en) | 2005-10-26 |
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