CN101528260A - Therapeutic agents for irritable bowel syndrome - Google Patents

Therapeutic agents for irritable bowel syndrome Download PDF

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CN101528260A
CN101528260A CNA2007800399715A CN200780039971A CN101528260A CN 101528260 A CN101528260 A CN 101528260A CN A2007800399715 A CNA2007800399715 A CN A2007800399715A CN 200780039971 A CN200780039971 A CN 200780039971A CN 101528260 A CN101528260 A CN 101528260A
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unsubstituted
bowel syndrome
irritable bowel
therapeutic agents
acceptable salt
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山形强
柴田健志
西谷阳一
势子孝士
佐久间隆史
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Kyowa Kirin Co Ltd
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Kyowa Hakko Kirin Co Ltd
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Abstract

The present invention provides a therapeutic agent for irritable bowel syndrome which comprises, as an active ingredient, a compound having an adenosine uptake inhibitory activity, a therapeutic agent for irritable bowel syndrome which comprises, as an active ingredient, a tricyclic compound represented by formula (I) [wherein L represents -NHC(=O)- or the like, R 1 represents a hydrogen atom, halogen, or the like, X 1 -X 2 -X 3 represents S-CR 7 =CR 8 (wherein R 7 and R 8 may be the same or different and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, or the like), or the like, Y represents -CH 2 SO 2 -, -SO 2 CH 2 - or the like, R 2 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or the like] or a pharmaceutically acceptable salt thereof, and the like.

Description

Therapeutic agents for irritable bowel syndrome
Technical field
The present invention relates to contain have adenosine absorb inhibiting chemical compound as the therapeutic agents for irritable bowel syndrome of effective ingredient, contain tricyclic compound or its on the pharmacology acceptable salt as therapeutic agents for irritable bowel syndrome of effective ingredient etc.
Background technology
Knownly cause under the condition of cell injury when oxygen supplies such as ischemia are low or during inflammation etc., adenosine in blood or in the tissue concentration rise.As adenosine receptor, known have an A 1Receptor, A 2AReceptor, A 2BReceptor, A 3Receptor, adenosine shows following various physiological action by these receptors: platelet aggregation, inhibition multinuclear leucocyte, vasodilator, defence ischemia injury, sensation neural activity, vasodilator smooth muscle, diastole intestinal tube smooth muscle, inhibition mononuclear cell and macrophage function, inhibition cell injury etc. are regulated, suppressed to the sensorimotor integration of bradycardia, the hyperpolarization that suppresses steatolysis, the reduction of glomerular filtration amount, analgesia, sympathetic nerve and the minimizing of parasympathetic nervous activity, nerve, cerebral basal ganglia.Because adenosine receptor is present in the cell membrane, therefore in order to show physiological action, the extracellular adenosine concentration is very important.Under the normal condition, adenosine is produced by adenosylhomocysteine (S-adenosylhomocysteine:SAH) by the SAH hydrolytic enzyme in cell.On the other hand, at ischemia, wound, stress, under the pathological state such as inflammation, produce adenosine in the extracellular by the metabolite list adenosine phosphate (adenosine monophosphate:AMP) of adenosine triphosphate (adenosinetriphosphate:ATP) by extracellular 5 '-nucleotidase.Known adenosine mainly is present in the inside and outside ADA Adenosine deaminase of cell and decomposes, but as the disappearance approach of extracellular adenosine, mechanism of absorption has played important function in the cell of nucleoside transporting body mediation.The nucleoside transporting body roughly is divided into 2 kinds of diffused (equilibrativenucleoside transporter:ENT) and concentrated types (concentrative nucleosidetransporter:CNT), known ENT-1,2 and 3, CNT-1,2 and 3 three hypotypes of each having.In most cells, ENT expresses, and adenosine moves inside and outside cell according to Concentraton gradient.Therefore, as disease conditions, result under the extracellular condition at adenosine, adenosine is absorbed in the cell by ENT.Because adenosine is to work by being present in extracellular receptor, therefore acting in the short time of the adenosine that is produced disappears, and perhaps can not keep sufficient adenosine concentration and acts on and weakening.By whole body use adenosine or adenosine agonists, can expect various pharmacological effects, but also visible desired effects not simultaneously.Have adenosine by inhibition ENT and absorb inhibiting chemical compound, work owing to only produce in hyperfunction such pathological tissue, therefore probability (ヨ one ロ ピ ア Application ジ ヤ one Na Le オ Block Off ア one マ コ ロ ジ one (European Journal of Pharmacology), the 495th volume, 1 page (2004) that can become the useful preventing/treating agent of certain pathological state are arranged at the extracellular adenosine.
On the other hand, irritable bowel syndrome (irritable bowel syndrome:IBS) but shows the abdominal discomfort sense relevant with defecation or stomachache and the unusual syndrome of relieving constipation though there is not tangible intestinal organic disorder, is one of functional bowel disease.The formation of known this condition of illness and gastrointestinal motor are unusual, digestive tract paraesthesia, psychosocial factor (pressure) are relevant.Symptom is diarrhoea, stomachache, abdominal distention sense, constipation etc., is divided into diarrhea-type, constipation type, alternating diarrhea and constipation type according to the difference of cardinal symptom.And, as the mental status, sometimes with anxiety, allergy, anxiety, impatience, depression etc.Digestive organs function height is subjected to neuroregulation, and receptor diversely exists, and uses cholilytic drug, diarrhea, cathartic respectively for digestive organs symptoms such as stomachache, diarrhoea, constipation, and use antidepressants as required, antianxiety drugs.In addition, as diarrhea-type IBS therapeutic agent, known have 5-hydroxy tryptamine (5-HT3) receptor antagonist alosetron HCl, but because therefore visible serious gastrointestinal damage, particularly ischemic colitis (ischemic colitis) and serious constipation be only applicable to the serious symptom female patient.In addition, as constipation type IBS therapeutic agent, known have a 5-hydroxy tryptamine (5-HT 4) receptor stimulating agent tegaserod maleate, but be only applicable to female patient.In addition, as diarrhea-type and both therapeutic agents of constipation type IBS, known have high water absorbency polymer Polycarbophil calcium.But the selection of IBS treatment is restricted.Therefore at present seeking not have on the drug effect novel I BS therapeutic agent (レ PVC ユ one ズ イ Application ガ ス ト ロ エ Application テ ロ ロ ジ カ Le デ イ ス オ one ダ, one ズ (Reviews inGastroenterological Disorders), the 1st volume, No. 1,2 pages (calendar year 2001) of sex difference; Block リ テ イ Star シ ユ ジ ヤ one Na Le オ Block Network リ ニ カ Le Off ア one マ コ ロ ジ one (British Journal of Clinical Pharmacology), the 56th volume, 362 pages (2003)).
Known with tricyclic compound or its on the pharmacology acceptable salt as the treatment of urinary incontinence agent (with reference to patent documentation 1 and 2) of effective ingredient, bladder excessive activities therapeutic agent (with reference to patent documentation 3), the irritated therapeutic agent (with reference to patent documentation 4) of bladder sensation, follow the irritation sign of bladder therapeutic agent (with reference to patent documentation 5) of prostate hyperplasia, follow the bladder excessive activities therapeutic agent (with reference to patent documentation 6) of cerebrovascular disorders, pruritus therapeutic agent (with reference to patent documentation 7), anti-tussive agents (with reference to patent documentation 8), pain therapy agent (with reference to patent documentation 9), bronchial asthma therapeutic agent (with reference to patent documentation 10).
Patent documentation 1: the international pamphlet that discloses No. 97/14672
Patent documentation 2: the international pamphlet that discloses No. 98/46587
Patent documentation 3: the international pamphlet that discloses No. 02/078710
Patent documentation 4: the international pamphlet that discloses No. 02/078711
Patent documentation 5: the international pamphlet that discloses No. 02/078712
Patent documentation 6: the international pamphlet that discloses No. 2005/000293
Patent documentation 7: the international pamphlet that discloses No. 03/041704
Patent documentation 8: the international pamphlet that discloses No. 2004/087131
Patent documentation 9: the international pamphlet that discloses No. 2005/007154
Patent documentation 10: the international pamphlet that discloses No. 2005/011674
Summary of the invention
The object of the present invention is to provide contain have adenosine absorb inhibiting chemical compound as the therapeutic agents for irritable bowel syndrome of effective ingredient, contain tricyclic compound or its on the pharmacology acceptable salt as therapeutic agents for irritable bowel syndrome of effective ingredient etc.
The present invention relates to following (1)～(77).
(1) a kind of therapeutic agents for irritable bowel syndrome contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
(2) a kind of diarrhea contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
(3) a kind of cathartic contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
(4) a kind of therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (I) or its on the pharmacology acceptable salt as effective ingredient,
Figure A20078003997100161
In the formula, L represent oxygen atom, sulphur atom ,-N (R 9In)-(the formula, R 9Expression hydrogen atom or replacement or unsubstituted low alkyl group) ,-NHC (=O)-or-C (=O) NH-,
R 1Expression hydrogen atom, halogen, replacement or unsubstituted low alkyl group or replacement or unsubstituted lower alkoxy,
X 1-X 2-X 3Expression CR 5=CR 6-CR 7=CR 8(in the formula, R 5, R 6, R 7And R 8Identical or different, expression hydrogen atom, halogen, hydroxyl, nitro, amino, list (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, replacement or unsubstituted low alkyl group, replacement or unsubstituted lower alkoxy or replacement or unsubstituted low-grade alkane acidyl amino), N (O) m=CR 6-CR 7=CR 8(in the formula, R 6, R 7And R 8Identical with aforementioned implication separately, m represents 0 or 1), CR 5=CR 6-N (O) m=CR 8(in the formula, R 5, R 6, R 8And m is identical with aforementioned implication separately), CR 5=CR 6-CR 7=N (O) m(in the formula, R 5, R 6, R 7And m is identical with aforementioned implication separately), CR 5=CR 6-O (in the formula, R 5And R 6Identical with aforementioned implication separately), CR 5=CR 6-S (in the formula, R 5And R 6Identical with aforementioned implication separately), O-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately), S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately) or O-CR 7=N (in the formula, R 7Identical with aforementioned implication),
Y represents-CH 2S-,-CH 2SO-,-CH 2SO 2-,-CH 2O-,-CH=CH-,-(CH 2) p-(in the formula, p represents 0～2 integer) ,-SCH 2-,-SOCH 2-,-SO 2CH 2-or-OCH 2-,
R 2Expression hydrogen atom, amino, replacement or unsubstituted low alkyl group, replacement or unsubstituted low-grade alkenyl, replacement or unsubstituted lower alkoxy, list (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aryl alkyl amino, replacement or unsubstituted fragrant amino or replacement or unsubstituted heterocyclic.
(5) a kind of diarrhea, contain above-mentioned (4) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(6) a kind of cathartic, contain above-mentioned (4) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(7) a kind of adenosine uptake inhibitor, contain above-mentioned (4) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(8) a kind of therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (Ia) or its on the pharmacology acceptable salt as effective ingredient,
In the formula, R 1And X 1-X 2-X 3Identical with aforementioned implication separately, Y aExpression-CH 2SO 2-,-SCH 2-,-SOCH 2-,-SO 2CH 2-or-OCH 2-,
Work as Y aFor-CH 2SO 2-,-SCH 2-,-SOCH 2-or-SO 2CH 2-time, R 2aThe expression hydrogen atom, amino, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade alkenyl, replace or unsubstituted lower alkoxy, single (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl alkyl amino, replace or unsubstituted virtue amino, replace or unsubstituted ester ring type heterocyclic radical or replacement or unsubstituted nitrogen heterocycle
Work as Y aFor-OCH 2-time, R 2aThe expression hydrogen atom, amino, trifluoromethyl, replace or unsubstituted low-grade alkenyl, replace or unsubstituted lower alkoxy, single (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl alkyl amino, replace or unsubstituted virtue amino, replace or unsubstituted ester ring type heterocyclic radical, replace or unsubstituted nitrogen heterocycle or formula (II)
Figure A20078003997100181
In the formula, n is 0 or 1, R 3And R 4Can be identical or different, expression hydrogen atom, replacement or unsubstituted low alkyl group, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl, perhaps, R 3And R 4Also can form cycloalkyl with the carbon atom of adjacency, Q represents halogen, amino, hydroxyl or replacement or unsubstituted lower alkoxy.
(9) as above-mentioned (8) described therapeutic agents for irritable bowel syndrome, wherein, Y aFor-CH 2SO 2-,-SCH 2-,-SOCH 2-or-SO 2CH 2-.
(10) as above-mentioned (8) described therapeutic agents for irritable bowel syndrome, wherein, Y aFor-OCH 2-.
(11) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8)～(10), wherein, R 1Be hydrogen atom, halogen or replacement or unsubstituted lower alkoxy.
(12) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8)～(10), wherein, R 1Be hydrogen atom.
(13) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8), (11) and (12), wherein, Y aFor-CH 2SO 2-,-SO 2CH 2-or-OCH 2-.
(14) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8), (11) and (12), wherein, Y aFor-CH 2SO 2-or-SO 2CH 2-.
(15) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8), (11) and (12), wherein, Y aFor-CH 2SO 2-.
(16) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8)～(15), wherein, X 1-X 2-X 3Be S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately).
(17) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8)～(15), wherein, X 1-X 2-X 3Be CR 5=CR 6-CR 7=CR 8(in the formula, R 5, R 6, R 7And R 8Identical with aforementioned implication separately).
(18) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (8)～(17), wherein, R 2aBe formula (II),
Figure A20078003997100191
In the formula, n, R 3, R 4And Q is identical with aforementioned implication separately.
(19) as above-mentioned (18) described therapeutic agents for irritable bowel syndrome, wherein, n is 0.
(20) as above-mentioned (19) described therapeutic agents for irritable bowel syndrome, wherein, R 3Be methyl, R 4Be trifluoromethyl, Q is a hydroxyl.
(21) as above-mentioned (8) described therapeutic agents for irritable bowel syndrome, wherein, R1 is a hydrogen atom, Y aFor-CH 2SO 2-, X 1-X 2-X 3Be S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately), R 2aBe formula (III).
Figure A20078003997100192
(22) a kind of diarrhea, contain in above-mentioned (8)～(21) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(23) a kind of cathartic, contain in above-mentioned (8)～(21) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(24) a kind of adenosine uptake inhibitor, contain in above-mentioned (8)～(21) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(25) a kind of therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (Ib) or its on the pharmacology acceptable salt as effective ingredient,
Figure A20078003997100201
In the formula, R 1And X 1-X 2-X 3Identical with aforementioned implication separately, Y bExpression-CH 2O-,-CH 2S-,-CH 2SO-,-CH=CH-or-(CH 2) p-(in the formula, p is identical with aforementioned implication), R 2bExpression (III).
Figure A20078003997100202
(26) as above-mentioned (25) described therapeutic agents for irritable bowel syndrome, wherein, X 1-X 2-X 3Be CR 5=CR 6-CR 7=CR 8(in the formula, R 5, R 6, R 7And R 8Identical with aforementioned implication separately) or CR 5=CR 6-CR 7=N (in the formula, R 5, R 6And R 7Identical with aforementioned implication separately).
(27) as above-mentioned (25) described therapeutic agents for irritable bowel syndrome, wherein, X 1-X 2-X 3Be CR 5=CR 6-O (in the formula, R 5And R 6Identical with aforementioned implication separately) or CR 5=CR 6-S (in the formula, R 5And R 6Identical with aforementioned implication separately).
(28) as above-mentioned (25) described therapeutic agents for irritable bowel syndrome, wherein, X 1-X 2-X 3Be O-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately) or S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately).
(29) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (25)～(28), wherein, Y bFor-CH 2O-.
(30) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (25)～(28), wherein, Y bFor-(CH 2) p-(in the formula, p is identical with aforementioned implication).
(31) as above-mentioned (30) described therapeutic agents for irritable bowel syndrome, wherein, p is 0.
(32) as above-mentioned (30) described therapeutic agents for irritable bowel syndrome, wherein, p is 2.
(33) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (25)～(28), wherein, Y bFor-CH=CH-.
(34) as each described therapeutic agents for irritable bowel syndrome in above-mentioned (25)～(28), wherein, Y bFor-CH 2S-or-CH 2SO-.
(35) a kind of diarrhea, contain in above-mentioned (25)～(34) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(36) a kind of cathartic, contain in above-mentioned (25)～(34) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(37) a kind of adenosine uptake inhibitor, contain in above-mentioned (25)～(34) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(38) tricyclic compound or its acceptable salt on the pharmacology, by formula (Ic) expression,
Figure A20078003997100221
In the formula, L 1Expression oxygen atom or sulphur atom,
R 1cExpression hydrogen atom or replacement or unsubstituted low alkyl group,
X 1c-X 2c-X 3cExpression O-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately) or S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately),
Y cExpression-CH 2S-,-CH 2SO-or-CH 2SO 2-,
R 2cExpression replaces or unsubstituted low alkyl group.
(39) as above-mentioned (38) described tricyclic compound or its acceptable salt on the pharmacology, wherein, R 1cBe hydrogen atom, X 1c-X 2c-X 3cBe S-CR 7c=CR 8c(in the formula, R 7cAnd R 8cIdentical or different, expression hydrogen atom or replacement or unsubstituted low alkyl group), Y cFor-CH 2SO 2-, R 2cFor replacing or unsubstituted benzyl.
(40) a kind of medicine, contain above-mentioned (38) or (39) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(41) a kind of therapeutic agents for irritable bowel syndrome, contain above-mentioned (38) or (39) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(42) a kind of diarrhea, contain above-mentioned (38) or (39) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(43) a kind of cathartic, contain above-mentioned (38) or (39) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(44) a kind of adenosine uptake inhibitor, contain above-mentioned (38) or (39) described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(45) tricyclic compound or its acceptable salt on the pharmacology, by formula (Id) expression,
Figure A20078003997100231
In the formula, R 9It is identical with aforementioned implication,
R 1dExpression hydrogen atom or replacement or unsubstituted low alkyl group,
X 1d-X 2d-X 3dExpression O-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately) or S-CR 7=CR 8(in the formula, R 7And R 8Identical with aforementioned implication separately),
Y dExpression-CH 2S-,-CH 2SO-or-CH 2SO 2-,
R 2dExpression replaces or unsubstituted low alkyl group or replacement or unsubstituted aryl.
(46) as above-mentioned (45) described tricyclic compound or its acceptable salt on the pharmacology, wherein, R 1dBe hydrogen atom, X 1d-X 2d-X 3dBe S-CR 7d=CR 8d(in the formula, R 7dAnd R 8dIdentical or different, expression hydrogen atom or replacement or unsubstituted low alkyl group), Y dFor-CH 2SO 2-, R 9Be hydrogen atom.
(47) as above-mentioned (46) described tricyclic compound or its acceptable salt on the pharmacology, wherein, R 2dFor replacing or unsubstituted low alkyl group.
(48) as above-mentioned (46) described tricyclic compound or its acceptable salt on the pharmacology, wherein, R 2dFor replacing or unsubstituted aryl.
(49) a kind of medicine, contain in above-mentioned (45)～(48) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(50) a kind of therapeutic agents for irritable bowel syndrome, contain in above-mentioned (45)～(48) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(51) a kind of diarrhea, contain in above-mentioned (45)～(48) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(52) a kind of cathartic, contain in above-mentioned (45)～(48) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(53) a kind of adenosine uptake inhibitor, contain in above-mentioned (45)～(48) each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
(54) a kind of method for the treatment of irritable bowel syndrome comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
(55) a kind of treatment diarrheal method comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
(56) a kind of method for the treatment of constipation comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
(57) a kind of method for the treatment of irritable bowel syndrome comprises that above-mentioned (4), (8)～(21) of using effective dose reach the step of each described tricyclic compound in (25)～(34).
(58) a kind of treatment diarrheal method comprises that above-mentioned (4), (8)～(21) of using effective dose reach the step of each described tricyclic compound in (25)～(34).
(59) a kind of method for the treatment of constipation comprises that above-mentioned (4), (8)～(21) of using effective dose reach the step of each described tricyclic compound in (25)～(34).
(60) a kind of method for the treatment of irritable bowel syndrome comprises above-mentioned (38) or the step of (39) described tricyclic compound of using effective dose.
(61) a kind of treatment diarrheal method comprises above-mentioned (38) or the step of (39) described tricyclic compound of using effective dose.
(62) a kind of method for the treatment of constipation comprises above-mentioned (38) or the step of (39) described tricyclic compound of using effective dose.
(63) a kind of method for the treatment of irritable bowel syndrome comprises the step of each described tricyclic compound in above-mentioned (45)～(48) of using effective dose.
(64) a kind of treatment diarrheal method comprises the step of each described tricyclic compound in above-mentioned (45)～(48) of using effective dose.
(65) a kind of method for the treatment of constipation comprises the step of each described tricyclic compound in above-mentioned (45)～(48) of using effective dose.
(66) have adenosine and absorb the application of inhibiting chemical compound in making therapeutic agents for irritable bowel syndrome.
(67) have adenosine and absorb the application of inhibiting chemical compound in making diarrhea.
(68) have adenosine and absorb the application of inhibiting chemical compound in making cathartic.
(69) application of each described tricyclic compound in making therapeutic agents for irritable bowel syndrome in above-mentioned (4), (8)～(21) and (25)～(34).
(70) application of each described tricyclic compound in making diarrhea in above-mentioned (4), (8)～(21) and (25)～(34).
(71) application of each described tricyclic compound in making cathartic in above-mentioned (4), (8)～(21) and (25)～(34).
(72) above-mentioned (38) or (39) described tricyclic compound application in making therapeutic agents for irritable bowel syndrome.
(73) above-mentioned (38) or (39) described tricyclic compound application in making diarrhea.
(74) above-mentioned (38) or (39) described tricyclic compound application in making cathartic.
(75) application of each described tricyclic compound in making therapeutic agents for irritable bowel syndrome in above-mentioned (45)～(48).
(76) application of each described tricyclic compound in making diarrhea in above-mentioned (45)～(48).
(77) application of each described tricyclic compound in making cathartic in above-mentioned (45)～(48).
The invention effect
According to the present invention, can provide contain have adenosine absorb inhibiting chemical compound as the therapeutic agents for irritable bowel syndrome of effective ingredient, contain tricyclic compound or its on the pharmacology acceptable salt as therapeutic agents for irritable bowel syndrome of effective ingredient etc.
Description of drawings
Fig. 1 illustrates in each administration group of test example 3 figure of 0～8 hour feces volume (g) after the loperamide administration.The longitudinal axis weight (g) of representing to be hard and dry.A: normal group, B: matched group, C: chemical compound 1-10.001mg/kg administration group, D: chemical compound 1-10.01mg/kg administration group, E: chemical compound 1-10.1mg/kg administration group, F: chemical compound 1-11mg/kg administration group, * * *: P＜0.001vs. normal group, : P＜0.05vs. matched group, : P＜0.01vs. matched group
Fig. 2 is the figure that the number of times of pain corelation behaviour in each administration group of testing example 4 is shown.The longitudinal axis represent pain corelation behaviour number of times (inferior), transverse axis express time (minute).Zero: normal group, ●: matched group, △: chemical compound 1-13mg/kg administration group, ▲: chemical compound 1-110mg/kg administration group,: chemical compound 1-130mg/kg administration group, *: P＜0.05vs. normal group, * *: P＜0.01vs. normal group, * * *: P＜0.001vs. normal group,
Figure A20078003997100271
: P＜0.05vs. matched group
The specific embodiment
Below, will be called chemical compound (I) by the chemical compound of formula (I) expression.For adopting in the same way by the chemical compound of other formula numbering expressions.
In the definition of each group of formula (I), as low alkyl group, can enumerate for example alkyl of the carbon number 1～8 of straight or branched, more specifically, can enumerate methyl, ethyl, propyl group, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, 1,2,2-trimethyl propyl group, heptyl, octyl group etc.
Halogen is meant fluorine, chlorine, bromine, each atom of iodine.
Low alkyl group part in lower alkoxy, list (low alkyl group) substituted-amino and two (low alkyl group) substituted-amino is identical with above-mentioned low alkyl group implication.
As the low-grade alkane acidyl in the low-grade alkane acidyl amino, can enumerate for example alkanoyl of carbon number 1～6, more specifically, can enumerate formoxyl, acetyl group, propiono, bytyry, valeryl, 2,2-dimethyl propylene acyl group, caproyl etc.
As low-grade alkenyl, can enumerate for example thiazolinyl of the carbon number 2～6 of straight or branched, more specifically, can enumerate vinyl, pi-allyl, 1-acrylic, methylpropenyl, 1-butylene base, crotyl, pentenyl, hexenyl etc.
As the aryl moiety of aryl and arylamino, can enumerate for example phenyl, naphthyl etc., as heteroaryl, can enumerate for example pyridine radicals, furyl, thienyl, quinolyl, imidazole radicals, benzimidazolyl, thiazolyl etc.
As the aralkyl moiety of aryl alkyl amino, can enumerate for example aralkyl of carbon number 7～12, more specifically, can enumerate benzyl, phenethyl, menaphthyl etc.
As heterocyclic radical, can enumerate for example ester ring type heterocyclic radical, nitrogen heterocycle etc.As the ester ring type heterocyclic radical, can enumerate for example tetrahydrofurfuryl, tetrahydro-thienyl, chromanyl etc.Nitrogen heterocycle is for example for containing the heterocyclic radical of 1～2 nitrogen-atoms at its ring, hetero atoms such as aerobic, sulfur can also be contained, for example pyrrolidinyl, pipecoline base (pipecolinyl), piperazinyl, piperidyl, morpholinyl, thio-morpholinyl, oxazolyl etc. can be enumerated.
As replacing low alkyl group; replace lower alkoxy; single (replacement low alkyl group) substituted-amino; two (replacement low alkyl group) substituted-amino; replace the substituent group in low-grade alkane acidyl amino and the replacement low-grade alkenyl; identical or different; can enumerate that to replace number be 1 (to be preferably 1～6 to possible replacement number; be more preferably 1～4) for example halogen; hydroxyl; nitro; amino; single (low alkyl group) substituted-amino; two (low alkyl group) substituted-amino; cycloalkyl; [substituent group in this substituted cycloalkyl is identical or different for substituted cycloalkyl; can enumerate that for example to replace number be 1～3 halogen; hydroxyl; nitro; amino; single (low alkyl group) substituted-amino; two (low alkyl group) substituted-amino; lower alkoxy etc.]; aryl; substituted aryl (substituent group in this substituted aryl is identical with substituent group implication in the aftermentioned substituted aryl); aralkyl; substituted aralkyl (substituent group in this substituted aralkyl is identical with substituent group implication in the aftermentioned substituted aralkyl); lower alkoxy; [this substituent group that replaces in the lower alkoxy is identical or different to replace lower alkoxy; can enumerate that for example to replace number be 1～3 halogen; hydroxyl; nitro; amino; single (low alkyl group) substituted-amino; two (low alkyl group) substituted-amino; lower alkoxy etc.]; lower alkoxycarbonyl; [this substituent group that replaces in lower alkoxycarbonyl is identical or different, can enumerate that for example to replace number be 1～3 halogen to replace lower alkoxycarbonyl; hydroxyl; nitro; amino; single (low alkyl group) substituted-amino; two (low alkyl group) substituted-amino; lower alkoxy etc.] etc.And, in above-mentioned replacement low alkyl group, can have 2 substituent groups on the same carbon atom in this low alkyl group, and described 2 substituent groups form the aliphatic ring with described carbon atom.In addition, when the replacement low alkyl group is substituent methyl or replacement ethyl, its substituent group also can be identical or different, can be for for example replacing several 1～3 low alkyl group or replacing low alkyl group [substituent group in this replacement low alkyl group is identical or different, can enumerate for example replace number be 1～3 halogen, hydroxyl, nitro, amino, list (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.].
Here, halogen is identical with aforementioned implication, low alkyl group part in low alkyl group, list (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxycarbonyl and the lower alkoxy is identical with aforementioned low alkyl group implication, and aryl is identical with aforementioned implication.As the cyclic alkyl part of cycloalkyl and aliphatic ring, can enumerate for example cyclic alkyl of carbon number 3～8, more specifically, can enumerate cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.As aralkyl, can enumerate for example aralkyl of carbon number 7～12, more specifically, can enumerate benzyl, phenethyl, menaphthyl etc.
Substituent group in substituted aryl, substituted heteroaryl, substituted aralkyl amino and the substituted aryl amino is identical or different, can enumerate for example to replace several 1～3 halogen, hydroxyl, amino, low alkyl group etc.
Wherein, halogen and low alkyl group are identical with aforementioned implication separately.
In the definition of formula (Ia), (Ib), (Ic) and each group (Id), as low alkyl group, can enumerate for example alkyl of the carbon number 1～6 of straight or branched, more specifically can enumerate methyl, ethyl, propyl group, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, 1,2,2-trimethyl propyl group etc.
Halogen is meant fluorine, chlorine, bromine, each atom of iodine.
Low alkyl group part in lower alkoxy, list (low alkyl group) substituted-amino and two (low alkyl group) substituted-amino is identical with aforementioned low alkyl group implication.
As low-grade alkenyl, can enumerate for example thiazolinyl of the carbon number 2～6 of straight or branched, more specifically, can enumerate vinyl, pi-allyl, 1-acrylic, methylpropenyl, 1-butylene base, crotyl, pentenyl, hexenyl etc.
As the aryl moiety of aryl and arylamino, comprise for example phenyl, naphthyl etc., as heteroaryl, can enumerate for example pyridine radicals, furyl, thienyl, quinolyl, imidazole radicals, benzimidazolyl, thiazolyl etc.
As the aralkyl moiety of aralkyl and aryl alkyl amino, can enumerate for example aralkyl of carbon number 7～12, more specifically, can enumerate benzyl, phenethyl, menaphthyl etc.
As the ester ring type heterocyclic radical, can enumerate for example tetrahydrofurfuryl, tetrahydro-thienyl, chromanyl etc.Nitrogen heterocycle is for example for containing the heterocyclic radical of 1～2 nitrogen-atoms at its ring, can also contain hetero atoms such as aerobic, sulfur, and the bonded heterocyclic radical of carbonyl of representing nitrogen-atoms adjacency intra-annular with it can be enumerated for example pyrrolidinyl, pipecoline base, piperazinyl, piperidyl, morpholinyl, thio-morpholinyl, oxazolyl etc.
As cyclic alkyl, can enumerate for example cyclic alkyl of carbon atom 3～8, more specifically, can enumerate cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group etc.
As replacing low alkyl group, replace lower alkoxy, single (replacement low alkyl group) substituted-amino, two (replacement low alkyl group) substituted-amino, replace the substituent group in low-grade alkenyl and the replacement low-grade cycloalkyl, identical or different, can enumerate that for example to replace number be 1～3 halogen, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy, [this substituent group that replaces in the lower alkoxy is identical or different to replace lower alkoxy, can enumerate that for example to replace number be 1～3 halogen, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.], lower alkoxycarbonyl, [this substituent group that replaces in lower alkoxycarbonyl is identical or different, can enumerate that for example to replace number be 1～3 halogen to replace lower alkoxycarbonyl, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.] etc.
In addition, when the replacement low alkyl group is substituent methyl or replacement ethyl, this substituent group also can be identical or different, can be for for example replacing several 1～3 low alkyl group, [this substituent group that replaces in the low alkyl group is identical or different to replace low alkyl group, can enumerate that for example to replace number be 1～3 halogen, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.], cyclic alkyl, [substituent group in this substituted cyclic alkyl is identical or different for the substituted cyclic alkyl, can enumerate that for example to replace number be 1～3 halogen, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.], aryl, [substituent group in this substituted aryl is identical or different for substituted aryl, can enumerate that for example to replace number be 1～3 halogen, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.], aralkyl, [substituent group in this substituted aralkyl is identical or different, can enumerate that for example to replace number be 1～3 halogen for substituted aralkyl, hydroxyl, nitro, amino, single (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxy etc.] etc.And, can have 2 substituent groups on the methyl of substituent methyl or replacement ethyl or the same carbon atom in the ethyl, and described 2 substituent groups form the aliphatic ring with described carbon atom.
Here, halogen, cycloalkyl, aryl and aralkyl are identical with aforementioned implication separately, low alkyl group part in low alkyl group, list (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, lower alkoxycarbonyl and the lower alkoxy is identical with aforementioned low alkyl group implication, and the cycloalkyl moiety of aliphatic ring is identical with aforementioned cycloalkyl implication.
Substituent group in substituted aryl, substituted heteroaryl, substituted aralkyl, substituted benzyl, substituted aralkyl amino and the substituted aryl amino is identical or different, can enumerate for example to replace several 1～3 halogen, hydroxyl, amino, low alkyl group etc.
Wherein, halogen and low alkyl group are identical with aforementioned implication separately.
The substituent group that replaces in ester ring type heterocyclic radical and the substituted nitrogen-containing heterocyclic base is identical or different, can enumerate for example to replace several 1～3 halogen, hydroxyl, low alkyl group etc.
Wherein, halogen and low alkyl group are identical with aforementioned implication separately.
Go up acceptable salt as chemical compound (Ia), (Ib), (Ic) and pharmacology (Id), can enumerate the pharmacology and go up acceptable acid-addition salts, can enumerate for example inorganic acid salts such as hydrochlorate, hydrobromate, hydriodate, nitrate, sulfate, phosphate; Acylates such as formates, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalates, glyoxylate, aspartate, mesylate, esilate, benzene sulfonate.
The tricyclic compound that uses among the present invention can be made according to disclosed method in the above-mentioned publication or method similarly, can be by method of purification commonly used in the Synthetic Organic Chemistry, for example neutralize, filter, extract, wash, dry, concentrate, recrystallization, various chromatographs etc. separate, purify.
When wishing the salt of the tricyclic compound obtain using among the present invention, when this tricyclic compound obtains with the form of salt, can directly purify, in addition, when the form with free alkali obtains, can with the dissolving of this free alkali or suspendible in appropriate solvent, add acid then and make it form salt.
In addition, have possibility in the tricyclic compound that uses among the present invention and have the chemical compound of optical isomer, all possible stereoisomer and their mixture all can be as the effective ingredient of therapeutic agents for irritable bowel syndrome of the present invention or adenosine uptake inhibitor.
And, the tricyclic compound that uses among the present invention or its be acceptable salt on the pharmacology, sometimes exist with the form with the adduct of water or all kinds of solvents, these adducts also can be as the effective ingredient of therapeutic agents for irritable bowel syndrome of the present invention or adenosine uptake inhibitor.
Adenosine uptake inhibitor of the present invention is useful as following purposes the time: ischemic diseases (ischemic heart desease for example for example, ischemic cerebrovascular, spinal cord injury etc.), follow the immunoreation of organ transplantation, epilepsy, thrombosis, arrhythmia, insomnia, pain, inflammatory diseases (glomerulonephritis for example, acute pancreatitis, rheumatic arthritis, inflammatory bowel, edema etc.), IBS, optic nerve disorder, diabetes, viral disease, tumor, hypertension, the Lei Er syndrome, spasm, wound, sleep apnea syndrome, cerebral trauma, parkinson, Alzheimer, amyotrophic lateral sclerosis, the therapeutic agent of Huntington Chorea etc., the potentiator of anticarcinogen, hair growth promoter, fat-splitting agent etc.
Absorb inhibiting chemical compound as having adenosine, known have a for example Dilazep, Draflazine, KF24345, Dipyridamole, S6-(4-nitrobenzyl) mercaptopurineriboside (Nitrobenzyl thioinosine), Lidoflazine, Mioflazine, Soluflazine, R75231, Nimodipine, Diazepam, Clonazepam, Midazolam, Propentofylline, (ヨ one ロ ピ ア Application ジ ヤ one Na Le オ Block Off ア one マ コ ロ ジ one (European Journal of Pharmacology) such as Cilostazol, the 495th volume, 1 page (2004)).
As the tricyclic compound that uses among the present invention, can enumerate the chemical compound of record in table 1～6 for example.In the table, Me and Et represent methyl and ethyl respectively.
Table 1
Figure A20078003997100342
Figure A20078003997100351
Table 2
Figure A20078003997100352
Figure A20078003997100353
Table 3
Figure A20078003997100354
Table 4
Figure A20078003997100361
Figure A20078003997100362
Table 5
Figure A20078003997100363
Figure A20078003997100371
Table 6
Figure A20078003997100372
Next to test example the pharmacological action of the chemical compound that uses among the present invention is described.
The adenosine of testing in the routine 1:HEK293 cell absorbs inhibitory action
Method (バ イ オ ケ ミ カ Le Off ア one マ コ ロ ジ one (Biochemical Pharmacology), 70 volumes, 355-362 page or leaf (2005)) according to Leung etc. is tested.In containing Dulbecco ' s modified Eagle ' the s culture medium (Invitrogen corporate system) of 10% hyclone, the 10cm plate (rising sun テ Network ノ グ ラ ス corporate system) that uses poly-l-lysine bag quilt is at CO with HEK293 cell (ATCC, accession designation number CRL-1537) 2The cultivation of going down to posterity in the incubator.Seed cells into bag by in 24 orifice plates of poly-l-lysine (rising sun テ Network ノ グ ラ ス corporate system), be cultured to and converge.Use the no Na of 0.5mL +Buffer (140mmol/LN-methyl D-glucose, 5mmol/L HEPES[4-(2-ethoxy)-1-piperazine ethane sulfonic acid], 5mmol/L KH 2PO 4, 11mmol/L CaCl 2, 1mmol/L MgCl 2, the 10mmol/L glucose, pH 7.4) with the cell washing in the hole 2 times, add respectively in each hole that final concentration is the no Na of 50nmol/L and 500nmol/L behind each chemical compound of dissolving of 0.2mL +Buffer (n=2).After hatching 15 minutes under the room temperature, in each hole, add respectively 0.2mL contain 100nmol/L [ 3H] the no Na of each chemical compound of adenosine (GE ヘ Le ス ケ ア バ イ オ サ イ エ Application ス corporate system) and 50nmol/L and 500nmol/L +Buffer.After 1 minute, remove reactant liquor with suction pump, use the ice-cold PBS (phosphate-buffered saline) of 0.5mL to wash 2 times.In each hole, add the PBS that 0.5mL contains 5%Triton X-100, after with scraper cell being scraped, in the scintillation vial by the Network リ ア ゾ Le (clear sol) (Na カ ラ イ テ ス Network corporate system) that in the entry needle of 20G, carries out homogenate, be transferred to having added 4mL by 10 times.Then, contain the PBS washing hole of 5%Triton X-100 with 0.5mL, and join in the same scintillation vial.Fully stir the back and measure radioactivity by liquid scintillation counter (ア ロ カ company, LSC-3500).Represent that with percent absorbtivity with contrast was as 100% o'clock relative value.
The result is illustrated in table 7-1 and 7-2.
Table 7-1
Figure A20078003997100381
Table 7-2
Figure A20078003997100391
By above result as can be known, chemical compound (I) has adenosine absorption inhibitory action.
In addition, as shown in the following Table 8, adenosine in the HEK293 cell absorbs as can be known, and the nitrobenzyl sulfo-inosine (Nitrobenzyl-thioinosine) that is only suppressed the concentration (100nmol/L) (ザ ジ ヤ one Na Le オ Block バ イ オ ロ ジ カ Le ケ ミ ス ト リ one, the 275th volume, No. 12,8375-8381 page or leaf (2000)) of ENT-1 almost completely suppresses.Therefore, think that the adenosine of chemical compound (I) absorbs inhibitory action and mainly caused by the ENT-1 inhibitory action.
Table 8
Test example 2: to the effect of constraint stress induction defecation
The method of experimental basis Kishibayashi etc. (ジ ヤ パ ニ one ズ ジ ヤ one Na Le オ Block Off ア one マ コ ロ ジ one (Japanese Journal of Pharmacology), the 63rd volume, No. 4,495-502 page or leaf (1993)) is carried out.
Using male Wistar in the experiment is 6～7 ages (Japanese チ ヤ one Le ス リ バ one provides) in week of rat.Rat is at 7 o'clock in 7 o'clock～afternoon in the morning in the receptacle of 19～25 ℃ of room temperatures, humidity 30～70%, illumination 12 hours every days (), and per 5～7 metal cages of packing into make it freely absorb commercially available solid feed and water is raised.
By the slight anesthetized rat of ether, with belt chest and forelimb are rolled, slightly stress apply.The stool weight in wet base that mensuration stress be loaded back 1 hour.Each medicinal liquid is orally give before Restraint Stress was loaded 1 hour.In addition, test compound is suspended to the concentration of 2mg/mL with 0.5w/v% methylcellulose 400cP aqueous solution, with the capacity oral administration (dosage 10mg/kg) of 5mL/kg.Contrast gives 0.5w/v% methylcellulose 400cP aqueous solution.In addition, each group of rat is used 10.Difference oral administration 300,100,10 and the existing adenosine uptake inhibitor Dilazep of 300mg/kg, Draflazine, KF24345 and Dipyridamole (ヨ one ロ ピ ア Application ジ ヤ one Na Le オ Block Off ア one マ コ ロ ジ one (European Journal of Pharmacology), the 495th volume, 1 page (2004)).Use 5-hydroxy tryptamine (5-HT3) receptor antagonist YM060 in the application (ザ ジ ヤ one Na Le オ Block Off ア one マ コ ロ ジ one ア Application De エ Network ス ペ リ メ Application Le セ ラ ピ ユ one テ イ Network ス (The Journal ofPharmacology and Experimental Therapeutics), the 259th volume, No. 2,815-819 page or leaf (1991) with 0.1mg/kg; ア ス テ ラ ス Pharmaceutical Co., Ltd, online, the Internet＜URL:http: //www.astellas.com/jp/company/news/2006/pdf/060131.pdf 〉).The result is illustrated in table 9.
Table 9-1
Figure A20078003997100401
Table 9-2
Table 9-3
Figure A20078003997100412
Table 9-4
Table 9-5
Figure A20078003997100414
Table 9-6
Figure A20078003997100421
Table 9-7
Figure A20078003997100422
Table 9-8
Table 9-9
Figure A20078003997100424
Table 9-10
Table 9-11
Figure A20078003997100432
Show that by above result chemical compound (I) has improved Restraint Stress and brought out defecation.This results suggest, chemical compound (I) has improved diarrhea-type IBS patient's defecation symptom.
Test example 3: loperamide is brought out the effect of constipation
According to following method, estimate the treatment constipation effect of The compounds of this invention.Use chemical compound 1-1 as test compound.
IBS patient's intestinal movement is hyperfunction, shows the spastic constipation symptom of following stomachache.Known spastic constipation is brought out by using opium such as morphine, loperamide, uses opium to bring out constipation (ザ ジ ヤ パ ニ one ズ ジ ヤ one Na Le オ Block Off ア, one マ コ ロ ジ one (The Japanese Journal of Pharmacology), the 86th volume, No. 3,281-288 page or leaf (calendar year 2001) as the model of constipation type IBS; ザ ジ ヤ パ ニ one ズ ジ ヤ one Na Le オ Block Off ア, one マ コ ロ ジ one (The Japanese Journal of Pharmacology), the 89th volume, No. 2,133-141 page or leaf (2002)).
In chemical compound 1-1, add 0.5w/v% methylcellulose 400 (the pure pharmaceutical worker's industry of MC and light), mix gently with mixer (TTM-1, bavin field science).Then, carry out supersound process (1 minute), mix making its suspendible once more by mixer, the suspension of preparation concentration 0.2mg/mL by using ultrasonic cleaner (SineSonic UA100, the international electric エ Application ジ ニ ア リ Application グ of Hitachi).0.5w/v%MC further dilutes this suspension by use, the solution of preparation 0.02,0.002 and 0.0002mg/mL concentration.
To loperamide hydrochloride (hereinafter referred to as loperamide; Sigma-Aldrich) add distilled water in, utilize magnetic stirring apparatus to mix, the solution of preparation 1mg/mL.This solution of capacity oral administration with 5mL/kg.
It is that rat (Japanese チ ヤ one Le ス リ バ one) carries out that male SD is used in test.Report that this rat is because loperamide and feces volume reduce (ザ ジ ヤ パ ニ one ズ ジ ヤ one Na Le オ Block Off ア, one マ コ ロ ジ one (The Japanese Journal of Pharmacology), the 89th volume, No. 2,133-141 page or leaf (2002)).Buy this rat in 6 ages in week, after 1 week of domestication is above, use the rat in 7 ages in week.Rat is at 7 o'clock in 7 o'clock～afternoon in the morning in the receptacle of 19～25 ℃ of room temperatures, humidity 30～70%, illumination 12 hours every days (), and per 5,6 metal cages of packing into make it freely absorb commercially available solid feed (F-2, bridge farm) and water.Gather when defecating, per 1 is packed into is used for the metal cage of raising separately, under going on a hunger strike it is freely drunk water.No abnormality seen is gone up on the surface in the test, does not see the individuality of diarrhoea (not having dirt around the anus) on the previous day of service test and the same day.
Test the previous day,, on the tail of rat, number, and measure body weight in order to be used for individual identification.Confirm the character of perianal dirt and stool simultaneously.Test the morning on the same day, oral administration 0.5w/v%MC or chemical compound 1-1.Administration is the oral administration loperamide after 1 hour.To normal group oral administration distilled water.All all use injection tube and conduit to force oral administration for medicinal liquid.Behind administration loperamide or the distilled water, rat is transferred in the independent cage, begins to gather stool.Administration loperamide or distilled water are gathered stool after 8 hours.Use that drying machine (SH42, ヤ マ ト science) dry (100 ℃, 6 hours) collects greatly after an action of the bowels, by electronic balance (AB54, Mettler-Toledo) gravimetry.
It is as follows that group constitutes (respectively organizing n=15):
Normal group: 0.5w/v%MC 5mL/kg+ distilled water 5mL/kg
Matched group: 0.5w/v%MC 5mL/kg+ loperamide 5mL/kg
Chemical compound 1-1 0.001mg/kg group: chemical compound 1-1 0.001mg/kg+ loperamide 5mg/kg
Chemical compound 1-1 0.01mg/kg group: chemical compound 1-1 0.01mg/kg+ loperamide 5mg/kg
Chemical compound 1-1 0.1mg/kg group: chemical compound 1-1 0.1mg/kg+ loperamide 5mg/kg
Chemical compound 1-1 1mg/kg group: chemical compound 1-1 1mg/kg+ loperamide 5mg/kg.
Feces volume uses dry weight, with 0～8 hour feces volume as location parameter.Stool gathers in the prior weighing bag (aluminium foil) of having measured weight, calculate by deducting weighing bag weight with the gross weight that comprises the weighing bag.
Statistical analysis uses statistical analysis software SAS (Release 9.1.3, SAS InstituteInc.) to carry out.When comparing the feces volume between normal group and the matched group, carry out the F check.When F checks, carry out Student ' s t-test under the situation of unknown significance difference, when F checks, think to have and carry out Aspin-Welch test under the situation of significant difference.
When comparative control group and chemical compound 1-1 administration group, carry out Bartlett test.When Bartletttest, under the situation of unknown significance difference, confirmed to carry out Dunnett test after the significant difference with one factor analysis of variance.Confirming when Bartlett test has under the situation of significant difference, carries out Kruskal-Wallis test.Judge that P＜0.05 is for there being significant difference.
0～8 hour feces volume is illustrated in Fig. 1 after the loperamide administration.The feces volume of matched group is compared with normal group and is shown low value significantly.
Chemical compound 1-1 0.01,0.1 and the consumption of 1mg/kg under feces volume after significantly having suppressed the loperamide administration reduce.
Show that by above result chemical compound 1-1 has suppressed loperamide and brought out constipation.This results suggest, chemical compound (I) has improved constipation type IBS patient's defecation symptom.
Test example 4: capsaicin is brought out the effect of Encelialgia model
Report and cause Encelialgia (ペ イ Application (Pain), the 92nd volume, No. 3,335-342 page or leaf (calendar year 2001)) when capsaicin is applied to colonic.
In 0.5w/v%MC, use agate mortar to make suspension chemical compound 1-1.
Capsaicin (Sigma-Aldrich) is dissolved in the normal saline that contains 10% ethanol (Northeast chemistry) and 10% polyoxyethylene (20) dehydrating sorbitol monooleate (the pure pharmaceutical worker's industry of Tween 80 and light) uses again.With the capacity oral administration test compound of 10mL/kg, matched group is given the MC of equivalent.
The ddY that buys body weight 27～29g is that male mice (Japanese エ ス エ Le シ one) is used for experiment.Quarantine, domestication more than 2 days after, use smoothly and the in appearance individuality of no abnormality seen of weight increase.Animal makes it freely absorb commercially available solid feed (F-2, bridge farm) and raises with water in the receptacle of 19～25 ℃ of room temperatures, humidity 30～70%, illumination 12 hours every days () at 7 o'clock in 7 o'clock～afternoon in the morning.
Behind oral administration (p.o.) chemical compound 1-1 or the 0.5w/v%MC, put into cage and place.After 30 minutes, give 0.1% capsaicin or the solvent of 50 μ L apart from the colonic of anus 4cm to every mice.Each mice is put into acrylic resin cage (long 8cm * wide 8cm * high 15cm), with video camera (Sony) photography 1 hour.After photography finished, mensuration was brought out following 4 behaviors of the index of Encelialgia as capsaicin in per 5 minutes.60 minutes accumulated result is summarized as chart.
(1) licks the abdominal part behavior of licking
(2) stretch
(3) press to the abdominal part floor
(4) the strong contraction of abdominal part
1 group is made as 10, and all the result represents with mean+SD.Statistical analysis use statistical analysis software SAS (Release 8.2, SAS Institute Inc, and Cary, NC USA) carries out.Comparison between matched group and the compound administration group is after confirming that with nested-analysis of variance there was no significant difference is arranged, by the homogeneous of Bartlett test check variance.Under the neat situation of variance, carry out one factor analysis of variance, carry out Dunnetttest confirming to have under the situation of significant difference.Under the situation of heterogeneity of variance, carry out Kruskal-Wallis test, use Steel test to test confirming to have under the situation of significant difference.Judge that P＜0.05 is for there being significant difference.
The result is illustrated in Fig. 2.In 0.1% capsaicin, 50 μ L colonic administration groups (matched group), to compare with solvent administration group (normal group), pain corelation behaviour increases.Chemical compound 1-1 3 and 30mg/kg, p.o. under inhibition of pain corelation behaviour.
Show that by above result it is effective that chemical compound 1-1 brings out Encelialgia to capsaicin.This results suggest, chemical compound (I) is effective to IBS patient's stomachache treatment.
By test example 1 as can be known, chemical compound (I) has adenosine absorption inhibitory action.And, by test example 2 as can be known chemical compound (I) have the effect that reduces the stress induction defecation, by test example 3 as can be known chemical compound (I) have the constipation of inhibition effect, chemical compound (I) is to treatment stomachache effectively as can be known by test example 4, these results suggest, chemical compound (I) is useful as the IBS therapeutic agent.And prompting has adenosine and absorbs inhibiting chemical compound and 5-HT 3Receptor antagonist is similarly useful as therapeutic agents for irritable bowel syndrome.
Test example 5: acute toxicity test
1 group is used 3 male dd is mice (body weight 20+1g), oral or intraperitoneal administration test compound.The 7th day death state is obtained minimum lethal dose (MLD) after the observation administration.
The MLD of test compound is at oral administration time＞1000mg/kg as a result.
Chemical compound (I) or its acceptable salt on the pharmacology can directly or with various preparation forms use.Preparation compositions of the present invention can be made by making as chemical compound (I) or its acceptable carrier uniform mixing on acceptable salt and pharmacology on the pharmacology of the effective dose of active component.These medicament compositions are preferably the unit that for example is applicable to oral or non-oral administrations such as (comprising intravenous) and take form.
In the compositions of the oral form of preparation, can use any useful pharmacology to go up acceptable carrier.For example the such liquid oral prepared product of suspensoid and syrup can make perfumeries such as antiseptic, strawberry flavor, Herba Menthae such as glycolss such as saccharides such as water, sucrose, sorbitol, fructose, Polyethylene Glycol, propylene glycol, Oleum sesami, olive oil, Semen sojae atricolor wet goods oils, parabens wait to make.Capsule, tablet, powder, granule etc. can use plasticizers such as surfactants such as binding agents such as lubricants such as disintegrating agents such as excipient such as lactose, glucose, sucrose, mannitol, starch, sodium alginate, magnesium stearate, Pulvis Talci, polyvinyl alcohol, hyprolose, gelatin, fatty acid ester, glycerol to make.Tablet and capsule are owing to the reason of administration easily is the most useful unit oral administration agent.Can use the solid preparation carrier when making tablet or capsule.
And injection can use the carrier of for example being made up of the mixture of distilled water, saline solution, glucose solution or saline and glucose solution to prepare.At this moment, use proper assistant, preparation solution, suspension or dispersion liquid according to well-established law.
Chemical compound (I) or its acceptable salt on the pharmacology is can be with above-mentioned preparation form oral or as non-oral administrations such as injections, its effective dose and administration number of times are according to administering mode, patient's age, body weight, symptom etc. and different, but suitable is 1～900mg/60kg/ days, is preferably 1～200mg/60kg/ days.
Below, by reference example and embodiment mode of the present invention is described, but the present invention is not limited to them.
Following chemical compound is identical chemical compound with each chemical compound of WO98/46587 record, and its synthetic method of also putting down in writing according to WO98/46587 is carried out.
The chemical compound 1-25 of chemical compound 1-1:WO98/46587 record
The chemical compound 3-19 of chemical compound 1-2:WO98/46587 record
The chemical compound 3-12 of chemical compound 1-3:WO98/46587 record
The chemical compound 2-1 of chemical compound 1-5:WO98/46587 record
The chemical compound 3-6 of chemical compound 1-6:WO98/46587 record
The chemical compound 3-24 of chemical compound 1-7:WO98/46587 record
The chemical compound 3-22 of chemical compound 1-8:WO98/46587 record
The chemical compound 1-5 of chemical compound 2-1:WO98/46587 record
The chemical compound 1-7 of chemical compound 2-2:WO98/46587 record
The chemical compound 1-11 of chemical compound 2-3:WO98/46587 record
The chemical compound 1-3 of chemical compound 2-4:WO98/46587 record
The chemical compound 1-24 of chemical compound 2-5:WO98/46587 record
The chemical compound 1-19 of chemical compound 2-6:WO98/46587 record
The chemical compound 1-35 of chemical compound 3-1:WO98/46587 record
The chemical compound 1-33 of chemical compound 3-2:WO98/46587 record
The chemical compound 1-29 of chemical compound 3-4:WO98/46587 record
Chemical compound 4 synthesizes according to the reference example 14 or 15 of WO98/46587.
Reference example 1:5,5-dioxo-9-(2-ethyl-2-maloyl group amino)-4,10-dihydro-thiophene And [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 1-4)
Step 1:9-(t-butoxycarbonyl amino)-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo also -10-ketone
To 9-amino-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-1-ketone (WO98/46587) oxolane (THF) (20g) (40mL) adds Bis(tert-butoxycarbonyl)oxide (35.3g) in the solution, and stir about is 16 hours under refluxing.Add Bis(tert-butoxycarbonyl)oxide (17.7g) once more, stir about is 24 hours under refluxing.Reactant mixture is cooled to room temperature, adds silica gel, and carry out concentrating under reduced pressure.By silica gel chromatography (hexane/ethyl acetate=10/1) purification residue.In the gained coarse crystallization, add hexane, after stirring under the room temperature, filter and use hexane wash, make its drying under the decompression then, obtain title compound (26.75g).
Step 2:9-(t-butoxycarbonyl amino)-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] also Benzo thia Zhuo-10-ketone
With the 9-(t-butoxycarbonyl amino)-4 that obtains in the step 1,10-dihydro-thiophene also [3,2-c] ethyl acetate (534mL) the solution ice bath of [1] benzo thia Zhuo-10-ketone (26.68g) is cooled to 5 ℃, slowly adds metachloroperbenzoic acid (66.26g) when remaining on below 10 ℃.Ice bath cooling was stirred 5 minutes down, then stir about 24 hours at room temperature.Splash into 1mol/L sodium sulfite aqueous solution (940mL) in the ice bath cooling downhill reaction mixture.Stir about is after 17 hours under stirring 40 minutes under the ice bath cooling, room temperature with mixture, and adding ethyl acetate (300mL), saturated sodium bicarbonate aqueous solution (300mL) extract.After water layer reuse ethyl acetate (300mL) extraction 2 times, merge organic layer, wash with saturated sodium bicarbonate aqueous solution, water, saturated aqueous common salt successively, carry out drying with anhydrous sodium sulfate after, concentrating under reduced pressure.Make residue be dissolved in acetone, add silica gel and distillation under reduced pressure except that desolvating.By silica gel chromatography (hexane/ethyl acetate=2/1) purification residue, in the gained coarse crystallization, add diisopropyl ether and also at room temperature stir.Filtration obtains crystallization and with after the diisopropyl ether washing, under reduced pressure makes its drying, obtains title compound (27.74g).
Step 3:9-amino-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo also -10-ketone
Under nitrogen current, trifluoroacetic acid (227mL) ice bath is cooled to-7 ℃, slowly add the 9-(t-butoxycarbonyl amino)-5 that obtains in the step 2,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (27.68g) also ,-7 ℃～0 ℃ following stir about 3 hours.Reactant mixture is injected frozen water (1L), at room temperature stir, after adding 10mol/L sodium hydrate aqueous solution was adjusted to pH=10, adding ethyl acetate, acetone extracted.Organic layer is washed with water, saturated aqueous common salt successively, and after carrying out drying with anhydrous sodium sulfate, concentrating under reduced pressure.In the gained coarse crystallization, add acetone (590mL), after making its dissolving under the backflow, under refluxing, slowly add entry (590mL), crystallization is separated out.After being cooled to room temperature, ice bath cooling was stirred 3 hours down, filter obtain crystallization and wash with water after, under reduced pressure make its drying, obtain the coarse crystallization (18.54g) of title compound.This coarse crystallization by acetone recrystallization, is obtained title compound.
Step 4: chemical compound 1-4
With 2-ethyl-2-hydroxybutyric acid (44.1g, 334mmol) be dissolved into dimethyl acetylamide (DMA) (416mL) in, add down thionyl chlorides (22.3mL, 306mmol) at-13 ℃, and under this temperature, stirred 1 hour.Under this temperature, add the 9-amino-5 that obtains in the step 3,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (20.7g, 74.2mmol), at room temperature stirred overnight also.Add the acyl chlorides with above-mentioned same preparation once more, at room temperature stirred overnight.In reactant mixture, splash into water (416mL) (1.5 hours), stirred 2.5 hours down at 0 ℃.The solid that filtration obtains separating out, the ethanol water with 70% (100mL) washs, and obtains chemical compound 1-4 (27.8g, 95.1%) thus.
1H-NMR(300MHz，DMSO-d 6，δ)δ：0.79(t，J＝7.3Hz，6H)，1.46-1.78(m，4H)，7.18(d，J＝5.0Hz，1H)，7.80-7.88(m，2H)，8.09(d，J＝5.0Hz，1H)，8.44(dd，J＝7.2，2.6Hz，1H)，10.6(br，1H).
ESI-MS?m/z?392(M-H) -
Reference example 2:5,5-dioxo-9-[(5-methylpyrazole-3-base carbonyl) amino]-4,10-dihydro thiophene Fen is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 1-9) also
Step 1:5-methylpyrazole-3-carboxyl acid
(1.00g, 6.49mmol) is dissolved in methanol (6.5mL) with 5-methylpyrazole-3-carboxyl acid methyl ester, at room temperature adds 3.5mol/L sodium hydrate aqueous solution (6.5mL), stirs 1.5 hours.In reactant mixture, add entry, wash, and add after 1mol/L hydrochloric acid regulates pH and be 1, extract with ethyl acetate with ether.Organic layer water and saturated aqueous common salt are washed, and after carrying out drying with anhydrous magnesium sulfate, concentrating under reduced pressure.The white crystals that obtains is washed with ether, obtain title compound (0.25g, 31%).
Step 2:9-[(5-methylpyrazole-3-base carbonyl) amino]-4, the 10-dihydro-thiophene is [3,2-c] [1] also Benzo thia Zhuo-10-ketone
The 5-methylpyrazole-3-carboxyl acid (0.13g, 1.03mmol) that obtains in the step 1 is dissolved among the DMA (5mL), on ice-methanol bath, adds thionyl chloride (0.07mL, 0.96mmol), stirred 1 hour.Then, add the 9-amino-4 that is dissolved among the DMA under this temperature, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (WO98/46587) (120mg, 0.52mmol) also, stirred 1 hour under the room temperature.In reactant mixture, add saturated sodium bicarbonate aqueous solution, and after stirring, add 1mol/L hydrochloric acid.Reactant mixture is extracted with ethyl acetate, organic layer water and saturated aqueous common salt are washed, and, carry out concentrating under reduced pressure with after the dried over mgso.Residue is purified with silica gel column chromatography (ethyl acetate/hexane=2/1), obtains title compound (103mg, 55.6%).
Step 3: chemical compound 1-9
With the 9-[(5-methylpyrazole-3-base carbonyl that obtains in the step 2) amino]-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (87.8mg, 0.25mmol) is dissolved in ethyl acetate (10mL), add metachloroperbenzoic acid (170mg, 0.985mmol) under the room temperature, stirred overnight.In reactant mixture, add sodium thiosulfate solution, after stirring under the room temperature, extract with ethyl acetate.Organic layer is washed with saturated sodium bicarbonate aqueous solution, water and saturated aqueous common salt, and after carrying out drying with anhydrous magnesium sulfate, concentrating under reduced pressure.Residue is purified with silica gel column chromatography (ethyl acetate/hexane=2/1), obtain chemical compound 1-9 (51.3g, 36.8%).
ESI-MS?m/z?386(M-H) -
Following chemical compound can use each self-corresponding carboxylic acid and amine to synthesize according to the step 2 and the step 3 of reference example 2.
5,5-dioxo-9-(2,2-dimethyl-3-oxobutanoyl amino)-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 1-10): ESI-MS m/z:390 (M-H) also -
5,5-dioxo-9-(2-hydroxyl-3,3,3-trifluoropropyl acyl amino)-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 1-11): ESI-MS m/z 404 (M-H) also -
6-bromo-5,5-dioxo-9-(3,3,3-three fluoro-2-hydroxy-2-methyl propiono amino)-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 3-3) also
Embodiment 1
5,5-dioxo-9-phenyl amino-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-1) also
Step 1:9-phenyl amino-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo-10-ketone also
With 9-amino-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (WO98/46587) (200mg, 0.81mmol) and phenylboric acid (0.4g, 3.3mmol) be dissolved in the dichloromethane (5mL), add copper acetate (0.44g, 2.4mmol) and triethylamine (0.5mL), stirred overnight under the room temperature.Add copper acetate (0.29g, 1.6mmol) and triethylamine (0.23mL) once more, stirred 4.5 hours under the room temperature.The concentrating under reduced pressure reactant mixture is purified residue with silica gel column chromatography (ethyl acetate/hexane=1/4), obtain title compound (236mg, 90%).
Step 2: chemical compound 5-1
Use the 9-phenyl amino-4 that obtains in the step 1, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone also, obtains chemical compound 5-1 according to the step 3 of reference example 2.
ESI-MS?m/z?356(M-H) -
Embodiment 2
9-(5-chloro-2-hydroxy phenyl amino)-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-2) also
Step 1:9-[(5-chloro-2-methoxy oxo) phenyl amino]-4, the 10-dihydro-thiophene is also [3,2-c] [1] benzo thia Zhuo-10-ketone
Under argon atmospher gas, add cesium carbonate (0.73g, 2.2mmol), two (dibenzyl acetyl) palladium (46mg, 0.080mmol), 2 to toluene (6mL), 2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene (75mg, 0.12mmol), 9-amino-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (WO98/46587) (474mg, 1.92mmol) and 5-chloro-2-(methoxy oxo) bromobenzene (400mg, 1.60mmol), 110 ℃ were stirred 4 hours down.Add cesium carbonate (0.52g, 1.60mmol) and 5-chloro-2-(methoxy oxo) bromobenzene (400mg, 1.60mmol), 110 ℃ of following stirred overnight.The concentrating under reduced pressure reactant mixture, residue is purified with silica gel column chromatography (ethyl acetate/hexane=1/4), obtains title compound (313mg, 47%).
Step 2:9-[(5-chloro-2-hydroxy phenyl amino]-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo also Thia Zhuo-10-ketone
With the 9-[(5-chloro-2-methoxy oxo that obtains in the step 1) phenyl amino]-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (244mg, 0.58mmol) is dissolved among the THF (2mL), adds 1mol/L hydrochloric acid (2mL), 70 ℃ of following stirred overnight.In reactant mixture, add entry, extract with ethyl acetate.Water and saturated common salt water washing organic layer, and after carrying out drying with anhydrous magnesium sulfate, concentrating under reduced pressure.Residue is purified with silica gel column chromatography (ethyl acetate/hexane=1/4), obtains title compound (187mg, 86.3%).
Step 3: chemical compound 5-2
Use the 9-[(5-chloro-2-hydroxy phenyl amino that obtains in the step 2]-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone also, obtains chemical compound 5-2 according to the step 3 of reference example 2.
ESI-MS?m/z?404(M-H) -
Embodiment 3
9-benzylamino-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-3) also
Step 1:9-fluoro-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-also Ketone
With 9-fluoro-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (TOHKEMY 2000-053580) (5.0g, 20.0mmol) is dissolved in acetonitrile (200mL) and the water (100mL), add Potassium Monopersulfate double salt (オ キ ソ Application (registered trade mark)) (61.5g, 100mmol), 60 ℃ of following stirred overnight.This mixture is cooled to room temperature, adds 1mol/L sodium thiosulfate solution (100mL) and also at room temperature stirred 30 minutes, extract with ethyl acetate then.With organic layer water and saturated common salt water washing, and use anhydrous magnesium sulfate drying, carry out concentrating under reduced pressure then.With gained solid washing with alcohol, obtain title compound (4.43g, 78%).
Step 2: chemical compound 5-3
The 9-fluoro-5 that in step 1, obtains, 5-dioxo-4, the 10-dihydro-thiophene also adds benzylamine (1.5mL) in [3,2-c] [1] benzo thia Zhuo-10-ketone (150mg, 0.530mmol), at room temperature stirs 4.5 hours.In reactant mixture, add 1mol/L hydrochloric acid, and extract with ethyl acetate.Organic layer with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, and is used anhydrous magnesium sulfate drying, and compression concentrates then.After residue usefulness silica gel column chromatography (ethyl acetate/hexane=3/10) purification, make it crystallization in diisopropyl ether, obtain chemical compound 5-3 (174mg, 88.7%).
ESI-MS?m/z?370(M+H) +
Chemical compound 5-4 uses 2-methoxybenzylamine and synthetic according to the step 2 of embodiment 3.
5,5-dioxo-9-(2-methoxybenzylamine)-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-4): ESI-MS m/z 400 (M+H) also +
Embodiment 4
5,5-dioxo-9-ethoxy carbonyl methylamino-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-5) also
Step 1:9-ethoxy carbonyl methylamino-4,10-dihydro-thiophene be [3,2-c] [1] benzimidazole thiophanate also Assorted Zhuo-10-ketone
With 9-fluoro-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (TOHKEMY 2000-053580) (100mg, 0.39mmol) is dissolved to 1-Methyl-2-Pyrrolidone (3mL), add glycine ethyl ester hydrochloride (540mg, 3.87mmol) and triethylamine (1.1mL), stir 3 hours, 90 ℃ down at 80 ℃ and stirred 2.5 hours down.Add triethylamine (1.1mL) then, 110 ℃ of following stirred overnight.Add glycine ethyl ester hydrochloride (540mg, 3.87mmol) and triethylamine (1.1mL), 110 ℃ of following stirred overnight.In reactant mixture, add entry, extract with ethyl acetate.Organic layer water and saturated aqueous common salt wash, behind anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Residue is purified with silica gel column chromatography (ethyl acetate/hexane=1/5), obtains title compound (63.7mg, 49.0%).
Step 2: chemical compound 5-5
With the 9-ethoxy carbonyl methylamino-4 that obtains in the step 1,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (54.7mg, 016mmol) is dissolved to acetonitrile (4mL) and water (2mL), add オ キ ソ Application (registered trade mark) (0.49g, 0.80mmol), 50 ℃ were stirred 1 hour down.In reactant mixture, add sodium thiosulfate, extract with ethyl acetate.With organic layer water and saturated common salt water washing, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.Residue is got thin layer chromatography (preparative layer chromatography) with branch and is purified, and obtains chemical compound 5-5 (37.5mg, 64.1%).
ESI-MS?m/z?366(M+H) +
Embodiment 5
5,5-dioxo-9-[1-(ethoxy carbonyl) ethylamino]-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-6) also
The 9-fluoro-5 that obtains in the step 1 with embodiment 3,5-dioxo-4,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (250mg, 0.890mmol) is dissolved to 1-Methyl-2-Pyrrolidone (8mL), add DL-alanine ethyl ester hydrochlorate (4.0g, 26mmol) and triethylamine (5.0mL), 50 ℃ of following stirred overnight.In reactant mixture, add entry and 1mol/L hydrochloric acid, extract with ethyl acetate.Organic layer water and saturated aqueous common salt wash, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.Residue is purified with silica gel column chromatography (ethyl acetate/hexane=1/2), obtains chemical compound 5-6 (159mg, 51.4%).
ESI-MS?m/z?380(M+H) +
Following chemical compound uses corresponding amine synthetic according to embodiment 5.
5,5-dioxo-9-{[1-(methoxycarbonyl)-3-methyl butyl] amino }-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-7): ESI-MS m/z 408 (M+H) also +
5,5-dioxo-9-{[1-(methoxycarbonyl)-2-phenylethyl] amino }-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 5-8): ESI-MS m/z 442 (M+H) also +
Embodiment 6
9-dibenzylsulfide. generation-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 6-1) also
Potassium tert-butoxide (48mg, 0.43mmol) is suspended among the THF (2.0mL), and THF (1.0mL) solution that the ice bath cooling splashes into benzyl mercaptan (0.05mL, 0.43mmol) down stirred 30 minutes under ice bath then.In this mixture, add the 9-fluoro-5 that obtains in the step 1 of embodiment 3,5-dioxo-4, the 10-dihydro-thiophene is THF (1.0mL) solution of [3,2-c] [1] benzo thia Zhuo-10-ketone (100mg, 0.35mmol) also, stirred 2 hours under the room temperature.In reactant mixture, add saturated aqueous ammonium chloride, extract with ethyl acetate.With organic layer saturated common salt water washing, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.The solid that obtains is washed with the 2-propanol, obtain chemical compound 6-1 (74mg, 45%).
ESI-MS?m/z?387(M+H) +； 1H-NMR(300MHz，CDCl 3，δ)：4.13(s，2H)，4.55(s，2H)，6.97(d，J＝4.8Hz，1H)，7.17-7.26(m，5H)，7.55(t，J＝7.5Hz，1H)，7.67(d，J＝4.8Hz，1H)，7.76(d，J＝7.5Hz，1H)，7.91(d，J＝7.5Hz，1H).
ESI-MS?m/z?387(M+H) +
Embodiment 7
9-benzyl oxo-5,5-dioxo-4, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-10-ketone (chemical compound 6-2) also
Step 1:2-dimethyl disulfide is for carbamoyloxy group-6-methoxyl methyl benzoate
(16.9g, 89.2mmol) is dissolved to N with 2-hydroxyl-6-methoxyl methyl benzoate, dinethylformamide (DMF) (150mL), add dimethyl disulfide for chloroformamide. (16.3g, 132mmol), 1,4-diazabicyclo [2.2.2] octane (18.5g, 165mmol), stirred overnight under the room temperature.In mixture, add entry, and extract with ethyl acetate.With organic layer water and saturated common salt water washing, and use anhydrous magnesium sulfate drying, carry out concentrating under reduced pressure then.Residue is purified with silica gel column chromatography, obtain title compound (20.7g, 86%).
Step 2:2-dimethyl thiocarbamoyl sulfenyl-6-methoxyl methyl benzoate
The 2-dimethyl disulfide that obtains in step 1 stirred 30 minutes down at 220 ℃ for adding phenylate (30mL) in carbamoyloxy group-6-methoxyl methyl benzoate (20.0g, 74.3mmol).Mixture is purified with silica gel column chromatography, obtain title compound (20.0g, quantitative).
Step 3:2-dimethoxy-6-(thiene-3-yl-methyl sulfenyl) essence of Niobe
The 2-dimethyl thiocarbamoyl sulfenyl-6-methoxyl methyl benzoate (20.0g, 74.3mmol) that obtains in the step 2 is dissolved to methanol (300mL), adds 28% Feldalat NM/methanol solution (43g, 223mmol), stirred 2 hours under the room temperature.The ice bath cooling mixture, methanol (30mL) solution of adding 3-chloromethyl thiophene (15.3g, 127mmol) stirred 30 minutes down at 0 ℃.Add saturated aqueous ammonium chloride in reactant mixture, filter the solid that obtains separating out, water, normal hexane washing solid obtain title compound (19.5g, 89%) thus.
Step 4:2-methoxyl group-6-(thiene-3-yl-methyl sulfenyl) lithium benzoate
2-dimethoxy-6-(the thiene-3-yl-methyl sulfenyl) essence of Niobe (19.5g, 66.2mmol) that obtains in the step 3 is dissolved in the methanol (300mL), adds 1mol/L Lithium hydrate (306mL, 306mmol), stirred 48 hours under the room temperature.In reactant mixture, add entry, filter the solid that obtains separating out, obtain title compound (18.0g, 97%).
Step 5:9-methoxyl group-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo-10-ketone also
2-methoxyl group-6-(the thiene-3-yl-methyl sulfenyl) lithium benzoate (18.0g, 64.3mmol) that obtains in the step 4 is suspended in the dichloromethane (300mL), and 0 ℃ adds trifluoroacetic anhydride (10.0mL, 70.7mmol), stirred overnight under the room temperature down.In mixture, add 1mol/L hydrochloric acid, extract with dichloromethane.Organic layer water and saturated common salt water washing, and use anhydrous magnesium sulfate drying, concentrating under reduced pressure then.Residue is purified with silica gel column chromatography, obtain title compound (15.2g, 90%).
Step 6:9-hydroxyl-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo-10-ketone also
The 9-methoxyl group-4 that obtains in step 5,10-dihydro-thiophene also in [3,2-c] [1] benzo thia Zhuo-10-ketone (15.2g, 57.8mmol), add acetic acid (150mL), hydrobromic acid (100mL), reflux 24 hours.After reactant was cooled to room temperature, concentrating under reduced pressure added entry then, and uses dichloromethane extraction in residue.Organic layer is washed with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.Residue is purified with silica gel column chromatography, obtain title compound (12.9g, 90%).
Step 7:9-hydroxyl-4,10-dihydro-thiophene be [3,2-c] [1] benzo thia Zhuo-5,5 also, the 10-triketone
With the 9-hydroxyl-4 that obtains in the step 6,10-dihydro-thiophene also [3,2-c] [1] benzo thia Zhuo-10-ketone (1.0g, 4.03mmol) is dissolved in acetonitrile (100mL) and the water (50mL), adds オ キ ソ Application (registered trade mark) (9.90g, 16.1mmol), stirred 3 hours down at 60 ℃.In reactant mixture, add sodium thiosulfate solution, after stirring under the room temperature, extract with ethyl acetate.With organic layer water and saturated common salt water washing, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.With the solids washed with acetone that obtains, obtain title compound (0.79g, 74%).
Step 8: chemical compound 6-2
With the 9-hydroxyl-4 that obtains in the step 7, the 10-dihydro-thiophene is [3,2-c] [1] benzo thia Zhuo-5 also, 5,10-triketone (0.1g, 0.357mmol) is dissolved among the DMF (2mL), adds potassium carbonate (0.1g, 0.714mmol) and cylite (0.047mL, 0.428mmol), stirred overnight under the room temperature.In reactant mixture, add entry, extract with ethyl acetate.Organic layer washs with saturated aqueous common salt, and with behind the anhydrous magnesium sulfate drying, concentrating under reduced pressure.The solid that obtains is purified with silica gel column chromatography, obtains chemical compound 6-2 (0.042g, 32%).
ESI-MS?m/z?371(M+H) +； 1H-NMR(270MHz，CDCl 3，δ)：4.68(s，2H)，5.21(s，2H)，7.12(d，J＝5.0Hz，1H)，7.23-7.43(m，6H)，7.69-7.73(m，2H)，8.10(d，J＝7.3Hz，1H).
ESI-MS?m/z?371(M+H) +
Embodiment 8
Formulation example 1: tablet
Prepare by the following tablet that forms of forming according to well-established law.
According to well-established law mixing cpd 1-1250g, mannitol 1598.5g, carboxymethyl starch sodium 100g, light anhydrous silicic acid 10g, magnesium stearate 40g and yellow iron sesquioxide 1.5g.Use this mixture, use the tablet machine (chrysanthemum waters corporation system PurepressCorrect-12 type) of drift to carry out tabletting, obtain tablet (every contains active component 25mg) with diameter 8mm.Prescription is illustrated in table 10.
Table 10
Figure A20078003997100591
Embodiment 9
Formulation example 2: injection
Prepare by the following injection that forms of forming according to well-established law.
Be added in the distilled water for injection 1g chemical compound 1-1 and D-mannitol 5g and mixing, add hydrochloric acid and sodium hydrate aqueous solution again, behind the adjusting pH to 6, making total amount with distilled water for injection is 1000mL.The gained mixed liquor sterilely is packed in the vial, and each vial 2mL obtains injection (every bottle contains active component 2mg).Prescription is illustrated in table 11.
Table 11
Figure A20078003997100601
Utilize possibility on the industry
According to the present invention, can provide to contain to have adenosine and absorb inhibiting compound conduct The therapeutic agents for irritable bowel syndrome of active ingredient, contain tricyclic compound or it can on pharmacology The salt of accepting is as the therapeutic agents for irritable bowel syndrome of active ingredient etc.

Claims (77)

1. therapeutic agents for irritable bowel syndrome contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
2. diarrhea contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
3. cathartic contains and has adenosine and absorb inhibiting chemical compound as effective ingredient.
4. therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (I) or its on the pharmacology acceptable salt as effective ingredient,
Figure A2007800399710002C1
In the formula, L represent oxygen atom, sulphur atom ,-N (R 9)-,-NHC (=O)-or-C (=O) NH-, wherein, R 9Expression hydrogen atom or replacement or unsubstituted low alkyl group,
R 1Expression hydrogen atom, halogen, replacement or unsubstituted low alkyl group or replacement or unsubstituted lower alkoxy,
X 1-X 2-X 3Expression CR 5=CR 6-CR 7=CR 8, N (O) m=CR 6-CR 7=CR 8, CR 5=CR 6-N (O) m=CR 8, CR 5=CR 6-CR 7=N (O) m, CR 5=CR 6-O, CR 5=CR 6-S, O-CR 7=CR 8, S-CR 7=CR 8Or O-CR 7=N, wherein, R 5, R 6, R 7And R 8Identical or different; expression hydrogen atom, halogen, hydroxyl, nitro, amino, list (low alkyl group) substituted-amino, two (low alkyl group) substituted-amino, replacement or unsubstituted low alkyl group, replacement or unsubstituted lower alkoxy or replacement or unsubstituted low-grade alkane acidyl amino; m represents 0 or 1
Y represents-CH 2S-,-CH 2SO-,-CH 2SO 2-,-CH 2O-,-CH=CH-,-(CH 2) p-,-SCH 2-,-SOCH 2-,-SO 2CH 2-or-OCH 2-, wherein, p represents 0～2 integer,
R 2Expression hydrogen atom, amino, replacement or unsubstituted low alkyl group, replacement or unsubstituted low-grade alkenyl, replacement or unsubstituted lower alkoxy, list (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aryl alkyl amino, replacement or unsubstituted fragrant amino or replacement or unsubstituted heterocyclic.
5. diarrhea, contain the described tricyclic compound of claim 4 or its on the pharmacology acceptable salt as effective ingredient.
6. cathartic, contain the described tricyclic compound of claim 4 or its on the pharmacology acceptable salt as effective ingredient.
7. adenosine uptake inhibitor, contain the described tricyclic compound of claim 4 or its on the pharmacology acceptable salt as effective ingredient.
8. therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (Ia) or its on the pharmacology acceptable salt as effective ingredient,
Figure A2007800399710003C1
In the formula, R 1And X 1-X 2-X 3Identical with aforementioned implication separately, Y aExpression-CH 2SO 2-,-SCH 2-,-SOCH 2-,-SO 2CH 2-or-OCH 2-,
Work as Y aFor-CH 2SO 2-,-SCH 2-,-SOCH 2-or-SO 2CH 2-time, R 2aThe expression hydrogen atom, amino, replace or unsubstituted low alkyl group, replace or unsubstituted low-grade alkenyl, replace or unsubstituted lower alkoxy, single (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl alkyl amino, replace or unsubstituted virtue amino, replace or unsubstituted ester ring type heterocyclic radical or replacement or unsubstituted nitrogen heterocycle
Work as Y aFor-OCH 2-time, R 2aThe expression hydrogen atom, amino, trifluoromethyl, replace or unsubstituted low-grade alkenyl, replace or unsubstituted lower alkoxy, single (replacing or unsubstituted low alkyl group) substituted-amino, two (replacing or unsubstituted low alkyl group) substituted-amino, replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl alkyl amino, replace or unsubstituted virtue amino, replace or unsubstituted ester ring type heterocyclic radical, replace or unsubstituted nitrogen heterocycle or formula (II)
Figure A2007800399710004C1
In the formula, n is 0 or 1, R 3And R 4Can be identical or different, expression hydrogen atom, replacement or unsubstituted low alkyl group, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl, perhaps, R 3And R 4Also can form cycloalkyl with the carbon atom of adjacency, Q represents halogen, amino, hydroxyl or replacement or unsubstituted lower alkoxy.
9. therapeutic agents for irritable bowel syndrome as claimed in claim 8, wherein, Y aFor-CH 2SO 2-,-SCH 2-,-SOCH 2-or-SO 2CH 2-.
10. therapeutic agents for irritable bowel syndrome as claimed in claim 8, wherein, Y aFor-OCH 2-.
11. as each described therapeutic agents for irritable bowel syndrome in the claim 8～10, wherein, R 1Be hydrogen atom, halogen or replacement or unsubstituted lower alkoxy.
12. as each described therapeutic agents for irritable bowel syndrome in the claim 8～10, wherein, R 1Be hydrogen atom.
13. as each described therapeutic agents for irritable bowel syndrome in the claim 8,11 and 12, wherein, Y aFor-CH 2SO 2-,-SO 2CH 2-or-OCH 2-.
14. as each described therapeutic agents for irritable bowel syndrome in the claim 8,11 and 12, wherein, Y aFor-CH 2SO 2-or-SO 2CH 2-.
15. as each described therapeutic agents for irritable bowel syndrome in the claim 8,11 and 12, wherein, Y aFor-CH 2SO 2-.
16. as each described therapeutic agents for irritable bowel syndrome in the claim 8～15, wherein, X 1-X 2-X 3Be S-CR 7=CR 8, in the formula, R 7And R 8Identical with aforementioned implication separately.
17. as each described therapeutic agents for irritable bowel syndrome in the claim 8～15, wherein, X 1-X 2-X 3Be CR 5=CR 6-CR 7=CR 8, in the formula, R 5, R 6, R 7And R 8Identical with aforementioned implication separately.
18. as each described therapeutic agents for irritable bowel syndrome in the claim 8～17, wherein, R 2aBe formula (II),
Figure A2007800399710005C1
In the formula, n, R 3, R 4And Q is identical with aforementioned implication separately.
19. therapeutic agents for irritable bowel syndrome as claimed in claim 18, wherein, n is 0.
20. therapeutic agents for irritable bowel syndrome as claimed in claim 19, wherein, R 3Be methyl, R 4Be trifluoromethyl, Q is a hydroxyl.
21. therapeutic agents for irritable bowel syndrome as claimed in claim 8, wherein, R1 is a hydrogen atom, Y aFor-CH 2SO 2-, X 1-X 2-X 3Be S-CR 7=CR 8, in the formula, R 7And R 8Identical with aforementioned implication separately, R 2aBe formula (III),
Figure A2007800399710005C2
22. a diarrhea, contain in the claim 8～21 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
23. a cathartic, contain in the claim 8～21 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
24. an adenosine uptake inhibitor, contain in the claim 8～21 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
25. a therapeutic agents for irritable bowel syndrome, contain the tricyclic compound shown in the formula (Ib) or its on the pharmacology acceptable salt as effective ingredient,
Figure A2007800399710006C1
In the formula, R 1And X 1-X 2-X 3Identical with aforementioned implication separately, Y bExpression-CH 2O-,-CH 2S-,-CH 2SO-,-CH=CH-or-(CH 2) p-, in the formula, p is identical with aforementioned implication, R 2bExpression (III),
Figure A2007800399710006C2
26. therapeutic agents for irritable bowel syndrome as claimed in claim 25, wherein, X 1-X 2-X 3Be CR 5=CR 6-CR 7=CR 8Or CR 5=CR 6-CR 7=N, in the formula, R 5, R 6, R 7And R 8Identical with aforementioned implication separately.
27. therapeutic agents for irritable bowel syndrome as claimed in claim 25, wherein, X 1-X 2-X 3Be CR 5=CR 6-O or CR 5=CR 6-S, in the formula, R 5And R 6Identical with aforementioned implication separately.
28. therapeutic agents for irritable bowel syndrome as claimed in claim 25, wherein, X 1-X 2-X 3Be O-CR 7=CR 8Or S-CR 7=CR 8, in the formula, R 7And R 8Identical with aforementioned implication separately.
29. as each described therapeutic agents for irritable bowel syndrome in the claim 25～28, wherein, Y bFor-CH 2O-.
30. as each described therapeutic agents for irritable bowel syndrome in the claim 25～28, wherein, Y bFor-(CH 2) p-, in the formula, p is identical with aforementioned implication.
31. therapeutic agents for irritable bowel syndrome as claimed in claim 30, wherein, p is 0.
32. therapeutic agents for irritable bowel syndrome as claimed in claim 30, wherein, p is 2.
33. as each described therapeutic agents for irritable bowel syndrome in the claim 25～28, wherein, Y bFor-CH=CH-.
34. as each described therapeutic agents for irritable bowel syndrome in the claim 25～28, wherein, Y bFor-CH 2S-or-CH 2SO-.
35. a diarrhea, contain in the claim 25～34 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
36. a cathartic, contain in the claim 25～34 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
37. an adenosine uptake inhibitor, contain in the claim 25～34 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
38. tricyclic compound or its be acceptable salt on the pharmacology, by formula (Ic) expression,
Figure A2007800399710008C1
In the formula, L 1Expression oxygen atom or sulphur atom,
R 1cExpression hydrogen atom or replacement or unsubstituted low alkyl group,
X 1c-X 2c-X 3cExpression O-CR 7=CR 8Or S-CR 7=CR 8, in the formula, R 7And R 8It is identical with aforementioned implication separately,
Y cExpression-CH 2S-,-CH 2SO-or-CH 2SO 2-,
R 2cExpression replaces or unsubstituted low alkyl group.
39. tricyclic compound as claimed in claim 38 or its be acceptable salt on the pharmacology, wherein, and R 1cBe hydrogen atom, X 1c-X 2c-X 3cBe S-CR 7c=CR 8c, in the formula, R 7cAnd R 8cIdentical or different, expression hydrogen atom or replacement or unsubstituted low alkyl group, Y cFor-CH 2SO 2-, R 2cFor replacing or unsubstituted benzyl.
40. a medicine, contain claim 38 or 39 described tricyclic compounds or its on the pharmacology acceptable salt as effective ingredient.
41. a therapeutic agents for irritable bowel syndrome, contain claim 38 or 39 described tricyclic compounds or its on the pharmacology acceptable salt as effective ingredient.
42. a diarrhea, contain claim 38 or 39 described tricyclic compounds or its on the pharmacology acceptable salt as effective ingredient.
43. a cathartic, contain claim 38 or 39 described tricyclic compounds or its on the pharmacology acceptable salt as effective ingredient.
44. an adenosine uptake inhibitor, contain claim 38 or 39 described tricyclic compounds or its on the pharmacology acceptable salt as effective ingredient.
45. tricyclic compound or its be acceptable salt on the pharmacology, by formula (Id) expression,
Figure A2007800399710009C1
In the formula, R 9It is identical with aforementioned implication,
R 1dExpression hydrogen atom or replacement or unsubstituted low alkyl group,
X 1d-X 2d-X 3dExpression O-CR 7=CR 8Or S-CR 7=CR 8, in the formula, R 7And R 8It is identical with aforementioned implication separately,
Y dExpression-CH 2S-,-CH 2SO-or-CH 2SO 2-,
R 2dExpression replaces or unsubstituted low alkyl group or replacement or unsubstituted aryl.
46. tricyclic compound as claimed in claim 45 or its be acceptable salt on the pharmacology, wherein, and R 1dBe hydrogen atom, X 1d-X 2d-X 3dBe S-CR 7d=CR 8d, in the formula, R 7dAnd R 8dIdentical or different, expression hydrogen atom or replacement or unsubstituted low alkyl group, Y dFor-CH 2SO 2-, R 9Be hydrogen atom.
47. tricyclic compound as claimed in claim 46 or its be acceptable salt on the pharmacology, wherein, and R 2dFor replacing or unsubstituted low alkyl group.
48. tricyclic compound as claimed in claim 46 or its be acceptable salt on the pharmacology, wherein, and R 2dFor replacing or unsubstituted aryl.
49. a medicine, contain in the claim 45～48 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
50. a therapeutic agents for irritable bowel syndrome, contain in the claim 45～48 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
51. a diarrhea, contain in the claim 45～48 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
52. a cathartic, contain in the claim 45～48 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
53. an adenosine uptake inhibitor, contain in the claim 45～48 each described tricyclic compound or its on the pharmacology acceptable salt as effective ingredient.
54. a method for the treatment of irritable bowel syndrome comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
55. a treatment diarrheal method comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
56. a method for the treatment of constipation comprises the step that adenosine absorbs inhibiting chemical compound that has of using effective dose.
57. a method for the treatment of irritable bowel syndrome comprises the step of each described tricyclic compound in the claim 4,8～21 and 25～34 of using effective dose.
58. treat the diarrheal method for one kind, comprise the step of each described tricyclic compound in the claim 4,8～21 and 25～34 of using effective dose.
59. a method for the treatment of constipation comprises the step of each described tricyclic compound in the claim 4,8～21 and 25～34 of using effective dose.
60. a method for the treatment of irritable bowel syndrome comprises the claim 38 of using effective dose or the step of 39 described tricyclic compounds.
61. a treatment diarrheal method comprises the claim 38 of using effective dose or the step of 39 described tricyclic compounds.
62. a method for the treatment of constipation comprises the claim 38 of using effective dose or the step of 39 described tricyclic compounds.
63. a method for the treatment of irritable bowel syndrome comprises the step of each described tricyclic compound in the claim 45～48 of using effective dose.
64. treat the diarrheal method for one kind, comprise the step of each described tricyclic compound in the claim 45～48 of using effective dose.
65. a method for the treatment of constipation comprises the step of each described tricyclic compound in the claim 45～48 of using effective dose.
Absorb the application of inhibiting chemical compound in making therapeutic agents for irritable bowel syndrome 66. have adenosine.
Absorb the application of inhibiting chemical compound in making diarrhea 67. have adenosine.
Absorb the application of inhibiting chemical compound in making cathartic 68. have adenosine.
69. the application of each described tricyclic compound in making therapeutic agents for irritable bowel syndrome in the claim 4,8～21 and 25～34.
70. the application of each described tricyclic compound in making diarrhea in the claim 4,8～21 and 25～34.
71. the application of each described tricyclic compound in making cathartic in the claim 4,8～21 and 25～34.
72. claim 38 or the 39 described tricyclic compounds application in making therapeutic agents for irritable bowel syndrome.
73. claim 38 or the 39 described tricyclic compounds application in making diarrhea.
74. claim 38 or the 39 described tricyclic compounds application in making cathartic.
75. the application of each described tricyclic compound in making therapeutic agents for irritable bowel syndrome in the claim 45～48.
76. the application of each described tricyclic compound in making diarrhea in the claim 45～48.
77. the application of each described tricyclic compound in making cathartic in the claim 45～48.
CNA2007800399715A 2006-10-26 2007-10-26 Therapeutic agents for irritable bowel syndrome Pending CN101528260A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105687225B (en) * 2016-02-26 2018-07-06 四川好医生攀西药业有限责任公司 A kind of pharmaceutical composition for treating irritable bowel syndrome and its preparation method and application
TWI781960B (en) * 2016-10-03 2022-11-01 美商阿克思生物科學有限公司 Inhibitors of adenosine 5'-nucleotidase and related uses

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105687225B (en) * 2016-02-26 2018-07-06 四川好医生攀西药业有限责任公司 A kind of pharmaceutical composition for treating irritable bowel syndrome and its preparation method and application
TWI781960B (en) * 2016-10-03 2022-11-01 美商阿克思生物科學有限公司 Inhibitors of adenosine 5'-nucleotidase and related uses

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