CN103450218B - As the indoles three also ring derivatives of CRTH2 receptor antagonist - Google Patents
As the indoles three also ring derivatives of CRTH2 receptor antagonist Download PDFInfo
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- CN103450218B CN103450218B CN201310204284.1A CN201310204284A CN103450218B CN 103450218 B CN103450218 B CN 103450218B CN 201310204284 A CN201310204284 A CN 201310204284A CN 103450218 B CN103450218 B CN 103450218B
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Abstract
The invention belongs to medical art, be specifically related to the indoles three as CRTH2 receptor antagonist shown in logical formula I and ring derivatives, its pharmacy acceptable salt, and isomer: wherein X
1, X
2, X
3, X
4, X
5,
y, Z, R
1a, R
1b, R
2, R
3, R
4with n as in specification sheets define; The invention still further relates to the preparation method of these compounds, the pharmaceutical preparation containing these compounds and pharmaceutical composition, and these compounds treat and/or prevent the application in the medicine of relevant disease active in CRTH2 in preparation.
Description
Technical field
The invention belongs to medical art, be specifically related to the indoles three as CRTH2 receptor antagonist and ring derivatives, its pharmacy acceptable salt and steric isomer thereof, the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and these compounds, its pharmacy acceptable salt or its steric isomer treat and/or prevent the application in the medicine of relevant disease active in CRTH2 in preparation.
Background technology
CRTH2 is the chemoattractant receptor of G-protein coupling, and Th2 cell, eosinophilic granulocyte are expressed.In anaphylactic disease, as observed Th2-polarization in asthma, allergic rhinitis, atopic dermatitis and anaphylaxis conjunctivitis.Th2 cell passes through to produce Th2 cytokine, as IL-4, IL-5 and IL-3 regulate anaphylactic disease.In anaphylactic disease, these Th2 cytokines directly or indirectly induction of effector cell, as the survival of the migration of eosinophilic granulocyte and basophilic granulocyte, activation, triggering and prolongation.
PGD
2(PGD2), the aglucon of CRTH2, in anaphylactic disease, is produced by mastocyte and other important effector cell.In people's cell, PGD
2by CRTH2 induction of Th2 cell, eosinophilic granulocyte and basophilous migration and activation.Thus, CRTH2 and PGD is suppressed
2in conjunction with antagonist to treatment anaphylactic disease, as asthma, allergic rhinitis, atopic dermatitis and anaphylaxis conjunctivitis should be useful.
In addition, the experimental evidence of several series demonstrates the effect of eosinophilic granulocyte in sinusitis paranasal sinusitis and Churg-Strauss syndromes.In the tissue of these patients, mastocyte can be observed and eosinophilic granulocyte is located jointly.This shows the PGD that mastocyte produces
2raising induction of eosinophilic granulocyte.Thus, the disease that CRTH2 receptor antagonist is relevant to the eosinophilic granulocyte for the treatment of other, if Churg-Strauss syndromes and sinusitis paranasal sinusitis are also useful.Due to the high level expression of CRTH2 on basophilic granulocyte, the disease that CRTH2 receptor antagonist is relevant to some basophilic granulocyte for the treatment of, if Basophilic leukemia, chronic urticaria and basophilic leukocytosis are also useful.
Ramatroban (Ramatroban) goes on the market as thromboxane A2 receptor antagonist, there is extremely strong platelet activation effect, weak to the antagonistic action of CRTH2 acceptor, its poor selectivity, main adverse reaction is purple plague purpura, prothrombin time/activated partial thromboplastin time extends, subcutaneous hemorrhage.
MK-7246 be publication number disclosed in US20090286825 three and cyclic cpds, have inhibit activities to CRTH2, but PK is bad, the transformation period falls short of, and duration of efficacy is short.
Therefore lack the medicine of effective CRTH2 antagonistic activity in the market, need the compound developing highly selective, high reactivity, novel structure, optimize physico-chemical property, improve druggability.
Summary of the invention
The technical problem to be solved in the present invention is, provides the CRTH2 receptor antagonist of a kind of indoles three ring derivatives.
Technical scheme of the present invention is as follows:
Logical compound shown in formula I, its pharmacy acceptable salt, and steric isomer:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
When
during for N-, R
1aand R
1bbe separately hydrogen atom, cyano group, nitro, carboxyl, C
1-6alkyl, hydroxyl C
1-6alkyl, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl, halo C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl or R
1aand R
1bform carbonyl;
When
during for C=, R
1aand R
1bbe separately hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, halo C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, halo C
1-6alkoxyl group, C
1-6alkylthio, C
3-8cycloalkylsulfanyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, C
1-6alkylamidoalkyl, two (C
1-6alkyl) amido formacyl or R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl;
during for C=, Y is-(C (R
7ar
7b))
p-,-CR
7a=CR
7a-,-O-(C (R
7ar
7b))
p-or-S-(C (R
7ar
7b))
p-,
during for N-, Y is-(C (R
7ar
7b))
p-or-CR
7a=CR
7a-;
Z is-S (O)
m-,-S (O)
mn (R
6)-,-C (O)-,-C (O) O-or-C (O) N (R
6)-;
R
2for hydrogen atom, C
1-6alkyl, C
1-6assorted alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl or halogeno-benzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor 6-14 unit aryl, benzo C
3-8cycloalkyl, benzo 3-8 unit Heterocyclylalkyl, 5-14 unit's heteroaryl or 3-8 unit Heterocyclylalkyl, described 6-14 unit aryl, benzo C
3-8cycloalkyl, benzo 3-8 unit Heterocyclylalkyl, 5-14 unit's heteroaryl or 3-8 unit Heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom, cyano group, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group, C
3-8cycloalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group or C
2-6alkynyl;
R
4for-OR
4a,-C (O) OR
4a,-C (O) N (R
4a)
2,-C (O) NHC (O) R
4a, tetrazole base or-C (O) NHS (O)
2r
4a;
R
4afor hydrogen, C
1-6alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, 6-14 unit aryl, 5-14 unit's heteroaryl or C
2-6thiazolinyl;
R
5for hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkylthio, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl-carbonyl, C
1-6alkyl amine group formyl radical, C
1-6alkylamidoalkyl, C
1-6alkyl sulphonyl, C
1-6alkyl amine group alkylsulfonyl, C
1-6alkylsulfonamido, two (C
1-6alkyl) amido formacyl, two (C
1-6alkyl) amido alkylsulfonyl, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
6for hydrogen atom, C
1-6alkyl, C
3-8cycloalkyl, 3-8 unit Heterocyclylalkyl, C
2-6thiazolinyl or C
2-6alkynyl;
R
7aand R
7bbe separately hydrogen atom, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl or C
2-6alkynyl, described C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl and C
2-6alkynyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3,4,5 or 6.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
When
during for N-, R
1aand R
1bbe separately hydrogen atom, cyano group, C
1-6alkyl, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl or R
1aand R
1bform carbonyl;
When
during for C=, R
1aand R
1bbe separately hydrogen atom, cyano group, amino, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, C
1-6alkylamidoalkyl, two (C
1-6alkyl) amido formacyl or R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl;
during for C=, Y is-(C (R
7ar
7b))
p-,-O-(C (R
7ar
7b))
p-or-S-(C (R
7ar
7b))
p-,
during for N-, Y is-(C (R
7ar
7b))
p-;
Z is-S (O)
m-,-S (O)
mn (R
6)-,-C (O)-or-C (O) N (R
6)-;
R
2for hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit Heterocyclylalkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group or halogeno-benzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor 6-14 unit aryl, benzo C
3-8cycloalkyl, 5-14 unit's heteroaryl or 3-8 unit Heterocyclylalkyl, described 6-14 unit aryl, benzo C
3-8cycloalkyl, 5-14 unit's heteroaryl or 3-8 unit Heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4 or 5: halogen atom, cyano group, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl, halo C
1-6alkoxyl group or C
3-8cycloalkyl;
R
4for-C (O) OR
4a,-C (O) N (R
4a)
2,-C (O) NHC (O) R
4aor tetrazole base;
R
4afor hydrogen, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit Heterocyclylalkyl, 6-14 unit aryl, 5-14 unit's heteroaryl or C
2-6thiazolinyl;
R
5for hydrogen atom, carboxyl, cyano group, amino, halogen atom, C
1-6alkyl, C
3-8cycloalkyl, halo C
1-6alkyl, C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, two (C
1-6alkyl) amido formacyl, C
1-6alkylamidoalkyl, C
1-6alkylsulfonamido, C
1-6alkyl amine group alkylsulfonyl or two (C
1-6alkyl) amido alkylsulfonyl;
R
6for hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit's Heterocyclylalkyl or C
2-6thiazolinyl;
R
7aand R
7bbe separately hydrogen atom, halogen atom, C
1-6alkyl or C
3-6cycloalkyl, described C
1-6alkyl and C
3-6cycloalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom;
M is 0,1 or 2;
N is 1,2 or 3;
P is 0,1,2,3 or 4.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
When
during for N-, R
1aand R
1bbe separately hydrogen atom, cyano group, C
1-6alkyl, C
3-8cycloalkyl, C
2-6thiazolinyl, R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl or R
1aand R
1bform carbonyl;
When
during for C=, R
1aand R
1bbe separately hydrogen atom, C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
2-6thiazolinyl, C
2-6alkynyl, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkyl amine group formyl radical, C
1-6alkylamidoalkyl or R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl;
during for C=, Y is-(C (R
7ar
7b))
p-or-S-(C (R
7ar
7b))
p-,
during for N-, Y is-(C (R
7ar
7b))
p-;
Z is-S (O)
m-or-C (O)-;
R
2for hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit's Heterocyclylalkyl or halogeno-benzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor 6-14 unit's aryl or benzo C
3-8cycloalkyl, described 6-14 unit's aryl and benzo C
3-8cycloalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4 or 5: halogen atom, cyano group, amino, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl or halo C
1-6alkoxyl group;
R
4for-C (O) OR
4aor tetrazole base;
R
4afor hydrogen, C
1-6alkyl or C
3-6cycloalkyl;
R
5for hydrogen atom, halogen atom, cyano group, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylsulfonamido, C
1-6alkyl amine group formyl radical or C
1-6alkylamidoalkyl;
R
6for hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit's Heterocyclylalkyl or C
2-6thiazolinyl;
R
7aand R
7bbe separately hydrogen atom, halogen atom or C
1-6alkyl, described C
1-6alkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom;
M is 0,1 or 2;
N is 1 or 2;
P is 0,1,2 or 3.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bbe separately hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl or R
1aand R
1bcoupled carbon atom forms C together
3-6cycloalkyl or 3-6 unit Heterocyclylalkyl;
Y is-(C (R
7ar
7b))
p-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, C
1-6alkyl, C
3-6cycloalkyl, 3-6 unit's Heterocyclylalkyl or halogeno-benzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor 6-10 unit aryl, described 6-10 unit aryl can optionally be replaced independently selected from following substituting group by 1,2,3 or 4: halogen atom, amino, cyano group, hydroxyl, C
1-6alkyl, C
1-6alkoxyl group, halo C
1-6alkyl or halo C
1-6alkoxyl group;
R
4for-C (O) OH;
R
5for hydrogen atom, halogen atom, cyano group, C
1-6alkyl, halo C
1-6alkyl, C
3-6cycloalkyl, C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylsulfonamido, C
1-6alkyl amine group formyl radical or C
1-6alkylamidoalkyl;
R
6for hydrogen atom or C
1-6alkyl;
R
7aand R
7bbe separately hydrogen atom, fluorine atom, trifluoromethyl or C
1-6alkyl;
M is 0,1 or 2;
N is 1;
P is 0,1 or 2.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bbe separately hydrogen atom or C
1-6alkyl;
Y is-CH
2-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, C
1-4alkyl, cyclopropane base, tetramethylene base or 4-luorobenzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor 6-10 unit aryl, described 6-10 unit aryl can optionally be replaced independently selected from following substituting group by 1,2,3 or 4: halogen atom, cyano group, amino, hydroxyl, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
4for-C (O) OH;
R
5for hydrogen atom, halogen atom, cyano group, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group, C
1-6alkyl amine group, two (C
1-6alkyl) amido, C
1-6alkylsulfonamido or C
1-6alkylamidoalkyl;
R
6for hydrogen atom or C
1-4alkyl;
M is 0,1 or 2;
N is 1;
P is 0 or 1.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bit is separately hydrogen atom;
Y is-CH
2-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, C
1-4alkyl, cyclopropane base or 4-luorobenzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor phenyl, described phenyl can optionally be replaced independently selected from following substituting group by 1,2,3 or 4: halogen atom, cyano group, C
1-4alkyl or trifluoromethyl;
R
4for-C (O) OH;
R
5for hydrogen atom, halogen atom or C
1-4alkyl;
R
6for hydrogen atom or C
1-4alkyl;
M is 0,1 or 2;
N is 1;
P is 0 or 1.
The preferred technical scheme of the present invention is:
Wherein, X
1, X
2, X
3and X
4be separately N or C (R
5);
X
5for-O-,-S (O)
m-or-N (R
6)-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bit is separately hydrogen atom;
Y is-CH
2-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, methyl, cyclopropane base or 4-luorobenzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor phenyl, described phenyl can be replaced by fluorine atoms;
R
4for-C (O) OH;
R
5for hydrogen atom, fluorine atom or methyl;
R
6for hydrogen atom or methyl;
M is 0,1 or 2;
N is 1;
P is 0 or 1.
Present invention also offers the steric isomer of compound shown in general formula (I), the compound as shown in logical formula II, and pharmacy acceptable salt:
Wherein, X
1, X
2, X
3, X
4, X
5,
y, Z, R
1a, R
1b, R
2, R
3, R
4with n as defined hereinabove.
To give a definition, present invention is described in utilization, and concrete definition mode includes but not limited to following description.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine.
" C of the present invention
1-6alkyl " refer to that the alkane containing 1-6 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives, specific examples includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1, 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1, 2-dimethyl propyl etc." C of the present invention
1-4alkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" hydroxyl C of the present invention
1-6alkyl " refer to that one or more hydroxyl replaces C
1-6alkyl the group that derives, comprise methyl alcohol, ethanol, ethylene glycol, n-propyl alcohol, Virahol, glycerol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-methyl isophthalic acid, 2-bis-propyl alcohol, amylalcohol, 1,2-pentanediol, 2-methyl-2-butanols, hexanol etc., described " C
1-6alkyl " as defined hereinabove.
" C of the present invention
3-8cycloalkyl " be the cyclic alkyl containing 3-8 carbon atom; and specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1-methylcyclopropyl groups, 1-pentylcyclopropyl, 1; 2-diethyl cyclobutyl, 1-methyl-cyclobutyl, 1-butyl cyclobutyl, 1,3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butyl cyclopentyl, 1-methylcyclohexyl, 1-ethylcyclopentyl etc.
" C of the present invention
3-8cycloalkyl C
1-6alkyl " be an extremely multiple C
3-8cycloalkyl substituted C
1-6alkyl the group that derives, described " C
3-8cycloalkyl ", " C
1-6alkyl " as defined hereinabove.
" halo C of the present invention
1-6alkyl " refer to that one or more " halogen " atom replaces " C
1-6alkyl " the group that derives, described " halogen " and " C
1-6alkyl " as defined hereinabove.
" C of the present invention
2-6thiazolinyl " refer to containing double bond carbonatoms and be the thiazolinyl of the straight or branched of 2-6, specific examples includes but not limited to: vinyl, 1-propenyl, 2-propenyl, 3-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, Isosorbide-5-Nitrae-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene base, Isosorbide-5-Nitrae-pentadienyl, Isosorbide-5-Nitrae-hexadienyl, 1,3,5-hexatriene base etc.
" C of the present invention
5-8cycloalkenyl group " refer to that carbonatoms is the cyclic alkenyl radical of 5-8, its double bond is positioned at ring, and specific examples includes but not limited to:
deng.
" C of the present invention
2-6alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 2-6, specific examples includes but not limited to: ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1,1-dimethyl-2-butyne base, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention
1-6alkoxyl group " refer to " C
1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propyl group oxygen base, sec.-propyl oxygen base, butyl oxygen base, isobutyl-oxygen base, tertiary butyl oxygen base, sec-butyl oxygen base, amyl group oxygen base, neo-pentyl oxygen base, hexyl oxygen base etc.
" halo C of the present invention
3-8cycloalkyl C
1-6alkyl " be an extremely multiple halo C
3-8cycloalkyl substituted C
1-6alkyl the group that derives, described " C
3-8cycloalkyl ", " C
1-6alkyl " as defined hereinabove.
" halo C of the present invention
1-6alkoxyl group " refer to that one or more " halogen " atom replaces " C
1-6alkoxyl group " the group that derives, described " halogen " and " C
1-6alkoxyl group " as defined hereinabove.
" C of the present invention
1-6alkylthio " refer to C
1-6alkyl to be connected with other parts derived group, i.e. C by sulphur atom (-S-)
1-6alkyl-S-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
3-8cycloalkylsulfanyl " refer to C
3-8cycloalkyl to be connected with other parts derived group, i.e. C by sulphur atom (-S-)
3-8cycloalkyl-S-, described " C
3-8cycloalkyl " as mentioned before.
" C of the present invention
1-6alkyl amine group " refer to a C
1-6a hydrogen atom in alkyl-substituted amino the group that derives, i.e. C
1-6alkyl-NH-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkyl amine group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido " refer to two C
1-6two hydrogen atoms of alkyl respectively in substituted-amino the group that derives, i.e. (C
1-6alkyl)
2-N-, described " C
1-6alkyl " as mentioned before." two (C of the present invention
1-4alkyl) amido " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention
1-6alkyl amine group formyl radical " refer to C
1-6alkyl amine group to be connected derived group, i.e. (C by carbonyl-C (O)-with other parts
1-6alkyl) NHC (O)-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkylamidoalkyl " refer to C
1-6alkyl to be connected with other parts derived group, i.e. (C by amide group-C (O) NH-
1-6alkyl) C (O) NH-, described " C
1-6alkyl " as mentioned before." C of the present invention
1-4alkylamidoalkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido formacyl " refer to two (C
1-6alkyl) amido to be connected derived group, i.e. (C by carbonyl-C (O)-with other parts
1-6alkyl)
2nC (O)-, described " two (C
1-6alkyl) amido " as mentioned before.
" C of the present invention
1-6alkyl-carbonyl " refer to C
1-6alkyl to be connected derived group, i.e. C by carbonyl-C (O)-with other parts
1-6alkyl-C (O)-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl sulphonyl " refer to C
1-6alkyl is by alkylsulfonyl (-SO
2-) be connected with other parts derived group, i.e. (C
1-6alkyl) S (O)
2-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6alkyl amine group alkylsulfonyl " refer to " C
1-6alkyl-NHSO
2-" mode connects derived group, i.e. (C
1-6alkyl) NHS (O)
2-, described " C
1-6alkyl amine group " as mentioned before.
" C of the present invention
1-6alkylsulfonamido " refer to a C
1-6a hydrogen atom in alkyl sulphonyl substituted-amino the group that derives, i.e. (C
1-6alkyl) S (O)
2nH-, described " C
1-6alkyl sulphonyl " as mentioned before." C of the present invention
1-4alkylsulfonamido " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" two (C of the present invention
1-6alkyl) amido alkylsulfonyl " refer to two (C
1-6alkyl) amido is by alkylsulfonyl-SO
2-be connected with other parts derived group, i.e. (C
1-6alkyl)
2nS (O)
2-, described " C
1-6alkyl " as mentioned before.
" C of the present invention
1-6carbalkoxy " refer to C
1-6alkoxyl group to be connected derived group, i.e. (C by-C (O)-with other parts
1-6alkyl) OC (O)-, described " C
1-6alkoxyl group " as mentioned before.
" C of the present invention
1-6alkyl carbonyl oxy " refer to C
1-6alkyl to be connected with other parts derived group, i.e. (C by carbonyl oxygen base-C (O) O-
1-6alkyl) C (O) O-, described " C
1-6alkyl " as mentioned before.
" 6-14 unit aryl " of the present invention refers to that annular atoms is all the 6-14 unit cyclic aromatic groups of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.
6-8 unit monocyclic aryl refers to whole undersaturated aryl, and specific examples includes but not limited to: phenyl, cyclooctatetraenyl etc.
8-14 unit fused ring aryl refers to and to be shared by two or more ring texturees that two adjacent carbon atoms are formed each other, for the condensed ring group of whole undersaturated aromatic nucleus, comprise the whole unsaturated fused ring aryl of 8-14 unit, specific examples includes but not limited to: naphthalene, phenanthrene etc.
Described " 6-10 unit aryl " refers to that annular atoms is above-mentioned monocyclic aryl or the fused ring aryl of 6-10 unit.
" benzo C of the present invention
3-8cycloalkyl " refer to phenyl ring and C
3-8cycloalkyl shares two adjacent undersaturated condensed ring groups of carbon atom institute forming section each other, described " C
3-8cycloalkyl " as mentioned before.
" 3-8 unit Heterocyclylalkyl " of the present invention refers to C
3-8one or more carbon atom in cycloalkyl by S, O, N or C (O) atom replace the group that derives, described " C
3-8cycloalkyl " as mentioned before." 3-6 unit Heterocyclylalkyl " of the present invention refers to the specific examples containing 3-6 annular atoms in above-mentioned example.
" benzo 3-8 unit Heterocyclylalkyl " of the present invention refers to that phenyl ring and 3-8 unit Heterocyclylalkyl share two adjacent undersaturated condensed ring groups of atom institute forming section each other, described " the first Heterocyclylalkyl of 3-8 " as mentioned before.
" 5-14 unit heteroaryl " of the present invention, refer to the undersaturated cyclic group with aromaticity containing 5-14 annular atoms (wherein at least containing a heteroatoms), comprise the single heteroaryl of 5-8 unit, the thick heteroaryl of 6-14 unit, described heteroatoms has nitrogen, oxygen and sulphur etc., and the carbon atom on ring, nitrogen-atoms and sulphur atom can by oxos.
The single heteroaryl of 5-8 unit refer to aromaticity containing heteroatomic cyclic group, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, pyrimidyl, 1, 4-Dioxin base, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 3, 4-triazinyl, 1, 2, 4, 5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.
The thick heteroaryl of 6-14 unit, refer to that sharing two adjacent atoms containing 6-14 annular atoms (wherein at least containing a heteroatoms) each other by two or more ring texturees couples together the undersaturated condensed cyclic structure with aromaticity formed, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
" C of the present invention
1-6assorted alkyl " refer to C
1-6one or more carbon atom in alkyl by S, O, N or C (O) atom replace the group that derives, described " C
1-6alkyl " as mentioned before.
The preferred compound of the present invention:
The preferred compound of the present invention:
Logical formula I compound of the present invention can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
(1) preparation of intermediate 1
By 5 equivalent NaBH
4be dissolved in alcohol-water, then drip the ethanolic soln that 1 works as content of starting materials 1, system heating reflux reaction a few hours.React complete solvent is spin-dried for, purify with reversed-phase preparative chromatography, obtain intermediate 1.
(2) preparation of intermediate 2
In dry reaction flask, adding 1 equivalent intermediate 1, is solvent with pyridine, and add 2 equivalent Tosyl chlorides, low temperature stirring reaction spends the night.In system, add frozen water, be adjusted to neutrality with dilute hydrochloric acid, extraction into ethyl acetate, organic phase is spin-dried for, column chromatography, obtain intermediate 2.
(3) preparation of intermediate 3
By 1 equivalent intermediate 2,2 when content of starting materials 2, join in DMF, low-temp reaction a few hours.Solvent is spin-dried for, is directly used in next step reaction.
(4) preparation of intermediate 4
1 equivalent intermediate 3 is dissolved in methylene dichloride and propylene oxide, slowly adds the dichloromethane solution being dissolved with 1.2 equivalent NBS in 2 hours under cryogenic, dropwise, continue to react then slow under cold condition and system is heated up.In system, add tetrahydrofuran (THF) dilution, the NaOH solution adding 10% is adjusted to alkalescence.Separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, concentrate and obtain intermediate 4.
(5) preparation of intermediate 5
Joined by about 5 equivalent naphthalenes in dry THF, add 5 equivalents of metal Na, stirring at room temperature is reacted, and is added drop-wise in system, stoichiometric number hour by the THF solution of 1 equivalent intermediate 4.Add water cancellation, adds dilute hydrochloric acid acidifying, and ethyl acetate washing aqueous phase, discards organic phase.Add sodium hydroxide in aqueous phase and be adjusted to alkalescence, extraction into ethyl acetate is dry, is spin-dried for, and preparative chromatography is separated and obtains intermediate 5.
(6) preparation of intermediate 6
In dry reaction flask, add methylene dichloride, 1 equivalent intermediate 5,2, when content of starting materials 3, take pyridine as alkali, stoichiometric number hour under ice bath.Shrend on the rocks is gone out, and sodium bicarbonate is adjusted to alkalescence, extraction into ethyl acetate.Concentrated organic phase, preparative chromatography purifying obtains intermediate 6.
(7) preparation of intermediate 7
In dry reaction flask, 1 equivalent intermediate 6 is dissolved in DMF, adds 1.5 equivalent inorganic basis as K
2cO
3, slowly add 1.2 under ice bath when content of starting materials 4, TLC monitoring reaction end.Add water in system, extraction into ethyl acetate, water washing, dry, preparative chromatography is separated and obtains intermediate 7.
(8) preparation of formula I
In dry reaction flask, 1 equivalent intermediate 7 is dissolved in DMF, adds 2 equivalent inorganic basis as cesium carbonate, 2 when content of starting materials 5, and ambient temperature overnight is reacted.Add water cancellation, extraction into ethyl acetate, water washing organic phase, dry, is spin-dried for, and preparative chromatography is separated and obtains formula I.
X in upper reaction equation
1, X
2, X
3, X
4, X
5,
y, Z, R
1a, R
1b, R
2, R
3, R
4with n as defined hereinabove.
Steric isomer of the present invention comprises all optically active isomers, diastereomer, geometrical isomer and tautomer, the compound of formula (I) comprises one or more asymmetric centers, and can exist as raceme and racemic mixture, single enantiomorph, non-enantiomer mixture and single non-enantiomer mixture thus.It is two strong that the compound that some the present invention describe comprises alkene, and unless specifically stated otherwise, be intended to comprise E geometrical isomer and Z geometrical isomer.Can be there is different hydrogen tie points in the compound that some the present invention describe, be called as tautomer.This example can be ketone and Enol forms thereof, is called keto-enol tautomerism body.The compound of formula (I) comprises single tautomer and composition thereof.The invention is intended to compound this type of isomeric form all of contained (I).Described isomer can obtain abundant purity isomer by standard separation techniques and zinc bromide synthesis.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid comprising mineral acid and organic acid, this type of acid comprises: halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.In order to avoid query, one, two or three salt-forming cations may be had, but this depends on the quantity of carboxyl functional group and described cationic valence mumber.It is evident that for those skilled in the art, the pharmacy acceptable salt of the compounds of this invention in formation such as the free carboxy places of this compound, can be obtained by ordinary method.
" pharmaceutical preparation " of the present invention, refer to and comprise containing activeconstituents, i.e. formula I compound of the present invention, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers make the traditional drug formulations used clinically, the mode such as oral or administered parenterally can be applied to the patient needing this treatment.As oral preparations (as tablet, particle, capsule, syrup etc.), injection, inhalation, sublingual administration preparation, ointment, lotion, nasal formulations, sprays, transdermal formulation, rectal administration preparation, ointment or gelifying agent etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.
Present invention also offers the compound shown in logical formula I, its pharmacy acceptable salt and steric isomer thereof preparing the application in the medicine treating and/or preventing relevant disease active in CRTH2, being selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, Basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease to the active relevant disease of CRTH2.
" treatment " of the present invention, refers to and alleviates, improves, eliminates or reduce the sign relevant to disease or illness and symptom.
" prevention " of the present invention, refers to the generation or development that prevent or postpone disease or illness or prevents or postpone disease therewith or the relevant sign of illness or symptom.
Present invention also offers and comprise the compound shown in general formula (I), the pharmaceutical composition of its pharmacy acceptable salt and steric isomer and one or more therapeutic active substance, described therapeutic active substance is selected from TNF-alpha inhibitor, COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, leukotriene D receptor antagonist, leukotriene antagonist, LTD4 antagonist, VLA-4 antagonist, reflunomide, the similar thing of reflunomide, β 2-agonist, theophylline, inhibitors of leukotriene biosynthesis, epoxy enzyme-2 inhibitor, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
Set forth the beneficial effect of the compounds of this invention below by way of external pharmacology activity experiment further, but this should be interpreted as compound of the present invention only has following beneficial effect.
The external pharmacologically active of experimental example 1 the compounds of this invention
Trial-product:
The compounds of this invention, prepares according to embodiment method;
Contrast medicine: Ramatroban: commercial, Hangzhou Rui De Chemical Co., Ltd..
Experimental technique: this experiment is completed by calcium current detection method.Experimental technique is as follows:
Accurately take trial-product, add DMSO and dissolve, fully mix, be made into 50mM.Then the HEPES(hydroxyethyl piperazine second thiosulfonic acid of the 20mM of pH7.4 is used) damping fluid is diluted to 50 μMs, and compound maximum concentration is 10000nM, then 3 times of a series of dilutions, serial dilution 10 concentration, for subsequent use.
FLIPR detects (real-time fluorescence imaging analysis)
20 μ l are added containing 20000 CHO-K1/CRTH2/G in 384 black microwell plates
α 15cell solution, 37 DEG C, 5%CO
220 μ l are added after hatching 18h
calcium4assaykit(test kit) in staining agent, then add 10 μ l compound solutions, then hatch 60min, incubated at room 15min for 37 DEG C.Agonist PGD is added in 20 seconds
2(PGD2) EC
80pGD under concentration
2hEPES damping fluid, detects the fluorescent value of 21-120 second.
Data processing
Δ RFU(relative intensity of fluorescence) the maximum fluorescent value of=21-120 second deducts the mean value of the fluorescent value of 1-20 second.
Inhibiting rate={ 1-(Δ RFU
compound-Δ RFU
background)/(Δ RFU
agonist control-Δ RFU
background) × 100
The IC of each compound is calculated according to inhibiting rate
50value (namely blocks PGD
2at EC
80concentration lower induce the concentration of the testing compound required for CRTH2 receptor activation 50%).
Experimental result and conclusion:
Table 1 the compounds of this invention is to the antagonistic action of CRTH2
| Trial-product | IC 50（nM） |
| Ramatroban | 10300 |
| Compound 1 | 3.4 |
| Compound 12 | 9.54 |
From upper table comparing result, the antagonistic action of the application's compound to CRTH2 acceptor is much better than Ramatroban, has outstanding substantive distinguishing features and significant progress.
Determination of pharmacological activity (oral administration) in experimental example 2 body
Trial-product the compounds of this invention, prepares according to embodiment method.
By OVA inducing mouse asthmatic model, this experiment of experimental technique verifies that compound is to the therapeutic action of mouse asthmatic.
After female BAl BIc/c mouse conforms, be divided into blank group, model group and administration group at random by body weight.Animal grouping, dosage and administration volume refer to table 2.Model group and administration group were in the 1st, 14 day abdominal injection OVA(ovalbumin) solution (containing a 20 μ gOVA and 2mg potassium aluminium sulfate) 0.1mL/ sensitization, blank group injection PBS(phosphoric acid buffer).28th, 29,30 days continuous Neulized inhalation 1%OVA excite 30min, and blank group PBS substitutes.27th, 28,29,30,31 days, animal oral administration and solvent.Blank group every day before suction PBS 1h and after sucking 7h to solvent 2 times; Model group every day excites front 1h in suction OVA and excites rear 7h to solvent 2 times; Administration group excites front 1h in suction OVA and excites rear 7h administration 2 times every day.32nd day, animal was condemned to death, and contained 1%FBS immediately with 0.5mLPBS() through bronchial lavage lung, then repeat lavation 2 times, and merge irrigating solution, centrifugal, cell contains 1%FBS with 1.5mLPBS() resuspended.Bronchoalveolar Lavage Fluid Cells counts.
Table 2 animals administer table
The impact (× 10 of the BALB/c mouse asthmatic model bronchoalveolar lavage fluid total cellular score that table 3 oral administration is induced OVA and classification
4/ ml) (Mean ± SEM)
#p<0.05,
##p<0.01, model group compares with blank group;
*p<0.05,
*p<0.01, compound group compares with model group.
Conclusion: from table 3, the application's compound significantly can reduce total white blood cells, especially significantly can reduce the number of eosinophil, has good therapeutic action to the mouse asthmatic inflammation of OVA induction.
Experimental example 3 P of Rats K evaluation test
1. experimental design
2. trial-product
Contrast medicine MK-7246, structural formula, as described in background technology, is made by oneself;
The compounds of this invention, according to the preparation of embodiment method, dissolves with Suitable vehicles.
3. equipment
Plant and instrument: API4000LC-MS/MS
Chromatographic column: AgilentXDBC
18(2.1 × 50mm, 5 μm)
4. blood collection
Rat blood gathers: fixing animal, before each time point, 10min water-bath heats afterbody, by the blood of tail venous collection 100 μ about l, is placed into containing in heparin sodium anticoagulant tube after blood collection.Blood sample centrifugal 6min of 8000rpm under 4 DEG C of conditions obtains plasma sample, and blood plasma must be prepared in the 30min after blood collection.Leave in-80 DEG C of refrigerators before blood plasma test.
5. experimental technique
(1) from refrigerator, take out testing sample (-80 DEG C), room temperature melts rear vortex 5min naturally;
(2) precision pipettes 20 μ l samples in 1.5ml centrifuge tube;
(3) 200 μ l inner mark solutions are added;
(4) after vortex 5min, centrifugal 5min(12000 rev/min);
(5) precision pipettes 60 μ l supernatant liquors and adds 140 μ l water, and vortex 5min, is analyzed by LC-MS/MS sample introduction.
6. data processing method
Tested material (plasma sample) concentration uses ABSCIEX(Shanghai to like rich imaginative power analytical instrument trade Co., Ltd) the Analyst1.5.1 Output rusults of company.The parameters such as MicrosoftExcel computation of mean values, standard deviation, the variation coefficient (Analyst1.5.1 directly export need not calculate), PK parameter adopts PharsightPhoenix6.1 computed in software.
7. experimental result and conclusion
The transformation period result of table 4 the compounds of this invention in SD rat body
Conclusion: compared with MK-7246, the compounds of this invention transformation period measured by the mode of IV in rat body is longer than MK-7246, the pharmacologically active time length is long, better can be used for the treatment of relevant disease active in CRTH2, have better potential applicability in clinical practice.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
the preparation of embodiment 1 (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 1)
(1) preparation of (S)-2-amino-3-(1H-indol-3-yl) propane-1-alcohol
By 4.0g (106mmol) NaBH
4be dissolved in the ethanol of 60mL75%, then drip 5.0g (19.6mmol) L-Trp methyl ester hydrochloride (being dissolved in the ethanol of 90mL75%), system heating reflux reaction 5 hours.React complete solvent is spin-dried for, purify with reversed-phase preparative chromatography, obtain colorless oil 1.9g, yield 51.0%.
(2) preparation of (S)-3-(1H-indol-3-yl)-2-(4-Methyl benzenesulfonyl is amino) propyl group 4-toluene sulfonic acide ester
In dry reaction flask, add 1.64g (8.62mmol) (S)-2-amino-3-(1H-indol-3-yl) propane-1-alcohol, 15mL pyridine, 3.38g (17.7mmol) Tosyl chloride, at 0 DEG C, stirring reaction spends the night.In system, add frozen water, be adjusted to neutrality with dilute hydrochloric acid, extraction into ethyl acetate, organic phase is spin-dried for, column chromatography, obtain white solid 2.4g, yield 55.8%.
(3) preparation of (S)-S-3-(1H-indol-3-yl)-2-(4-Methyl benzenesulfonyl is amino) propyl dithiocarbamate acetic ester
By 1.9g (3.81mmol) (S)-3-(1H-indol-3-yl)-2-(4-Methyl benzenesulfonyl is amino) propyl group 4-toluene sulfonic acide ester, 866mg (7.58mmol) thioacetic acid potassium, join in 6mLDMF, 70 DEG C are reacted two hours.Solvent is spin-dried for, is directly used in next step reaction.
(4) preparation of (S)-N-[1-(1H-indol-3-yl)-3-thio propane-2-base]-4-methyl benzenesulfonamide
(S)-S-3-(1H-indol-3-yl)-2-(4-Methyl benzenesulfonyl is amino) the propyl dithiocarbamate acetic ester upper step obtained is dissolved in 12mL water and 3mL ethanol, add 400mg (7.13mmol) KOH, heating reflux reaction 1 hour.Cooling, adds dilute hydrochloric acid acidifying, extraction into ethyl acetate, and dry, be spin-dried for, products therefrom is directly used in next step.
(5) preparation of (S)-4-methyl-N-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) benzsulfamide
(S)-N-[1-(1H-indol-3-yl)-3-thio propane-2-the base]-4-methyl benzenesulfonamide upper step obtained is dissolved in 40mL methylene dichloride, add 20mL propylene oxide, be cooled to-78 DEG C, methylene dichloride (68mL) solution being dissolved with 812mg (4.56mmol) NBS is slowly added in 2 hours, dropwise, continue reaction at-78 DEG C two hours, in two hours, system is warming up to 0 DEG C afterwards.In system, add tetrahydrofuran (THF) dilution, the NaOH solution adding 10% is adjusted to alkalescence.Separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, concentrate and obtain light red solid 840mg.Above three step yields 61.4%.
(6) (S)-2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indoles-3-amine preparation
1.38g (10.8mmol) naphthalene is joined in the THF of 5mL drying, add 248mg (10.8mmol) metal Na, stirring at room temperature 2 hours, by (S)-4-methyl-N-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) the 12mLTHF solution of benzsulfamide 840mg (2.34mmol) is added drop-wise in system, reacts two hours.Add water cancellation, adds dilute hydrochloric acid acidifying, and ethyl acetate washing aqueous phase, discards organic phase.Add sodium hydroxide in aqueous phase and be adjusted to alkalescence, extraction into ethyl acetate 4 times, merge organic phase saturated nacl aqueous solution and wash, dry, be spin-dried for, preparative chromatography is separated and obtains 330mg white solid, yield 69.2%.(7) preparation of the fluoro-N-of (S)-4-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) benzsulfamide
In dry reaction flask, add 10mL methylene dichloride, 330mg (1.62mmol) (S)-2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indoles-3-amine, 623mg (3.20mmol) is to fluorophenylsulfonyl chloride, and 256mg (3.24mmol) pyridine, reacts 3 hours under ice bath.Shrend on the rocks is gone out, and sodium bicarbonate is adjusted to alkalescence, extraction into ethyl acetate.Concentrated organic phase, preparative chromatography purifying obtains 510mg white solid, yield 87.0%.
(8) preparation of the fluoro-N-methyl of (S)-4--N-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) benzsulfamide
In dry reaction flask, add the fluoro-N-of 490mg (1.35mmol) (S)-4-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) benzsulfamide, 10mLDMF, 279mg (2.02mmol) K
2cO
3, slowly add 250mg (1.76mmol) methyl iodide under ice bath, react two hours, terminate through TLC monitoring reaction.Add water in system, extraction into ethyl acetate, water washing, dry, preparative chromatography is separated and obtains white solid 320mg, yield 63.0%.
(9) preparation of (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate
In dry reaction flask, add the fluoro-N-methyl of 320mg (0.85mmol) (S)-4--N-(2,3,4,9-tetrahydrochysene thia pyrans also [2,3-b] indol-3-yl) benzsulfamide, 10mLDMF, 553mg (1.70mmol) cesium carbonate, 284mg (1.70mmol) ethyl bromoacetate, ambient temperature overnight is reacted.Add water cancellation, extraction into ethyl acetate, water washing organic phase, dry, is spin-dried for, and preparative chromatography is separated and obtains white solid 370mg, yield 94.1%.
(10) preparation of (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 1)
130mg (0.28mmol) (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3 is added in reaction flask, 4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate, 3mLTHF, 1mL methyl alcohol, 3mL water, adds 59mg (1.40mmol) hydronium(ion) Lithium Oxide 98min, stirred overnight at room temperature.Aftertreatment thin up, extraction into ethyl acetate, dry, be spin-dried for, obtain white solid 110mg (0.25mmol), yield 90.4%.
Molecular formula: C
20h
19fN
2o
4s
2lC-MS (M+H): 435.1
1HNMR(d
6-DMSO,400MHz)δ:7.93(dd,2H),7.48(t,2H),7.27(d,1H),7.20(d,1H),7.02(t,1H),6.96(t,1H),4.74(d,1H),4.62(d,1H),4.45-4.34(m,1H),2.93(dd,2H),2.84(s,3H),2.69(d,1H),2.58(dd,1H).
the preparation of embodiment 2 (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-1,1-dioxo-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 2)
(1) [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] (methyl) is amino]-1; 1-dioxo-3; 4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] preparation of ethyl acetate
By 230mg (0.50mmol) (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate is dissolved in 10mLTHF, 300mg (1.74mmol) metachloroperbenzoic acid is added under ice bath, react two hours at 0 DEG C, thin up, sodium bicarbonate neutralizes, extraction into ethyl acetate, concentrated organic phase, preparative chromatography is separated and obtains white solid 130mg (0.26mmol), yield 52.0%.
(2) preparation of (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-1,1-dioxo-3,4-dihydro thia pyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid
130mg (0.26mmol) [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] (methyl) is amino]-1 is added in reaction flask; 1-dioxo-3; 4-dihydro thia pyrans also [2; 3-b] indoles-9 (2H)-Ji] ethyl acetate; 3mLTHF, 1mL methyl alcohol, 3mL water; add 59mg (1.40mmol) hydronium(ion) Lithium Oxide 98min, stirred overnight at room temperature.Aftertreatment thin up, extraction into ethyl acetate, dry, be spin-dried for, obtain white solid 100mg, yield 82.6%.
Molecular formula: C
20h
19fN
2o
6s
2lC-MS (M+H): 467.1
1HNMR(d
6-DMSO,400MHz)δ:7.95-7.89(m,2H),7.59(d,1H),7.55-7.46(m,3H),7.36(t,1H),7.18(t,1H),5.12(d,1H),4.99(d,1H),4.75-4.65(m,1H),4.07(t,1H),3.12(d,2H),2.92(d,1H),2.88(s,3H).
the preparation of embodiment 3 [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] methylamino-]-1-oxo-3,4-dihydrogen phosphorothioate pyrans also [2,3-b] indoles-9(2H)-Ji] acetic acid (compound 3)
(1) preparation of [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] methylamino-]-1-oxo-3,4-dihydrogen phosphorothioate pyrans also [2,3-b] indoles-9(2H)-Ji] ethyl acetate
By 300mg (0.65mmol) (S)-2-[3-(the fluoro-N-methylphenylsulfonyl of 4-)-3; 4-dihydrogen phosphorothioate pyrans also [2; 3-b] indoles-9 (2H)-Ji] ethyl acetate is dissolved in 10mLTHF; 123mg (0.71mmol) metachloroperbenzoic acid is added under ice bath; react two hours at 0 DEG C; thin up; sodium bicarbonate neutralizes; extraction into ethyl acetate; concentrated organic phase; preparative chromatography is separated and obtains white solid 290mg(0.61mmol), yield 93.8%.
(2) preparation of [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] methylamino-]-1-oxo-3,4-dihydrogen phosphorothioate pyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid
290mg (0.61mmol) [(3S)-3-[[(4-fluorophenyl) alkylsulfonyl] methylamino-]-1-oxo-3 is added in reaction flask; 4-dihydrogen phosphorothioate pyrans also [2; 3-b] indoles-9 (2H)-Ji] ethyl acetate; 3mLTHF; 1mL methyl alcohol; 3mL water, adds 128mg (3.04mmol) hydronium(ion) Lithium Oxide 98min, stirred overnight at room temperature.Thin up, extraction into ethyl acetate, dry, be spin-dried for, high pressure preparative chromatography is separated and obtains white solid 70mg, yield 25.5%.
Molecular formula: C
20h
19fN
2o
5s
2lC-MS(M+H): 451.1
1HNMR(d
6-DMSO,400MHz)δ:7.90(m,2H),7.59(d,1H),7.55-7.44(m,3H),7.33(m,1H),7.14(t,1H),5.35-5.13(m,1H),5.06-4.86(m,2H),3.19-3.05(m,2H),2.95-2.88(m,1H),2.87(s,3H),2.75(d,1H).
the preparation of embodiment 4 (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydropyrane also [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 5)
(1) preparation of (S)-2-amino-3-(1H-indol-3-yl) propane-1-alcohol
By 10.5g (278mmol) NaBH
4be dissolved in the ethanol of 150mL75%, then drip 15.0g (58.9mmol) L-Trp methyl ester hydrochloride (being dissolved in the ethanol of 300mL75%), system heating reflux reaction 5 hours.React complete solvent is spin-dried for, purify with reversed-phase preparative chromatography, obtain white solid 11.0g, yield 98.1%.
(2) preparation of the fluoro-N-of (S)-4-[1-hydroxyl-3-(1H-indol-3-yl) propane-2-base] benzsulfamide
In dry reaction flask, 3.0g (15.78mmol) (S)-2-amino-3-(1H-indol-3-yl) propane-1-alcohol is dissolved in 30mL methylene dichloride, add 2.00g (10.28mmol) successively to fluorophenylsulfonyl chloride, 1.62g (20.48mmol) pyridine, reacts 3 hours under ice bath.Shrend on the rocks is gone out, extraction into ethyl acetate, uses sodium bicarbonate aqueous solution, water washing successively.Concentrated organic phase, column chromatography obtains 1.5g faint yellow solid, yield 41.9%.
(3) preparation of the fluoro-N-of (S)-4-(2,3,4,9-tetrahydropyrans is [2,3-b] indol-3-yl also) benzsulfamide
The fluoro-N-of (S)-4-[1-hydroxyl-3-(1H-indol-3-yl) propane-2-base] benzsulfamide 1.5g (4.31mmol) is dissolved in 120mL methylene dichloride, add 80mL propylene oxide, be cooled to-78 DEG C, methylene dichloride (50mL) solution being dissolved with 0.92g (5.17mmol) NBS is slowly added in 2 hours, dropwise, continue reaction at-78 DEG C two hours, in two hours, system is warming up to 0 DEG C afterwards.In system, add tetrahydrofuran (THF) dilution, the NaOH solution adding 10% is adjusted to alkalescence.Separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, concentrate and obtain white solid 600mg, yield 40.1%.
(4) preparation of the fluoro-N-methyl of (S)-4--N-(2,3,4,9-tetrahydropyrans is [2,3-b] indol-3-yl also) benzsulfamide
In dry reaction flask, add the fluoro-N-of 400mg (1.15mmol) (S)-4-(2,3,4,9-tetrahydropyrans is [2,3-b] indol-3-yl also) benzsulfamide, 8mLDMF, 480mg (3.47mmol) K
2cO
3, slowly add 181mg (1.28mmol) methyl iodide under ice bath, react two hours, terminate through TLC monitoring reaction.Add water in system, extraction into ethyl acetate, water washing, dry, concentrate and obtain white solid 320mg, yield 77.4%.
(5) preparation of (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydropyrane also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate
In dry reaction flask, add the fluoro-N-methyl of 320mg (0.89mmol) (S)-4--N-(2,3,4,9-tetrahydropyrans is [2,3-b] indol-3-yl also) benzsulfamide, 8mLDMF, 850mg (2.61mmol) cesium carbonate, 296mg (1.77mmol) ethyl bromoacetate, ambient temperature overnight is reacted.Add water cancellation, extraction into ethyl acetate, water washing organic phase, and dry, be spin-dried for, column chromatography obtains white solid 280mg, yield 70.8%.
(6) preparation of (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3,4-dihydropyrane also [2,3-b] indoles-9 (2H)-Ji] acetic acid
280mg (0.63mmol) (S)-2-[3-(the fluoro-N-Methyl benzenesulfonyl of 4-is amino)-3 is added in reaction flask, 4-dihydropyrane also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate, 15mLTHF, 15mL water, add 106mg (2.52mmol) hydronium(ion) Lithium Oxide 98min, stirring at room temperature 3 hours.Cooling, regulates pH to be about 6, extraction into ethyl acetate with 1NHCl, dry, is spin-dried for, obtains white solid 180mg, yield 68.3%.
Molecular formula: C
20h
19fN
2o
5sLC-MS(M+H): 419.1
1HNMR(d
6-DMSO,400MHz)δ:7.94(dd,2H),7.48(t,2H),7.10(dd,1H),7.05(dd,1H),6.90-6.84(m,2H),4.38-4.28(m,1H),4.23(s,2H),4.20(t,1H),4.11(dd,1H),2.79(s,3H),2.66(dd,1H),2.52(dd,1H).
the preparation of embodiment 5 (S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-acetic acid (compound 6)
(1) preparation of (S)-2-(t-butoxycarbonyl amino)-3-methyl chloropropionate
In dry reactor, add (R)-2-(t-butoxycarbonyl amino)-3-hydroxy methyl propionate (10.0g, 45.6mmol), 100mL methylene dichloride dissolves, the dichloromethane solution being dissolved with triphenylphosphine (13.2g, 50.3mmol) and hexachloroethane (11.96g, 50.5mmol) is slowly added under room temperature, after dropwising, room temperature reaction 2h, adds sodium bicarbonate aqueous solution, separates organic phase, saturated common salt washing once, dried over sodium sulfate, concentrated, column chromatography, obtain white solid 5.8g, yield 53.5%.
(2) preparation of (S)-1-chloro-3-hydroxyl propane-2-carbamate
In dry reaction flask, add (S)-2-(t-butoxycarbonyl amino)-3-methyl chloropropionate (5.13g, 21.6mmol), 5mL tetrahydrofuran (THF), 15mL methyl alcohol, adds lithium borohydride (0.54g under low temperature in batches, 24.8mmol), be slowly warming up to 30 DEG C of reactions afterwards and spend the night, add saturated ammonium chloride solution, stir 0.5h, revolve and desolventize, water layer extracted with diethyl ether three times, merge, dry, concentrated, column chromatography, obtains white solid 3.8g, yield 83.8%.
(3) preparation of 2-(2-oxindole quinoline-3-base) methyl acetate
By 2-(1H-indol-3-yl) methyl acetate (8g, 42.3mmol) be dissolved in DMSO(30mL, 0.423mol) in, slowly drip concentrated hydrochloric acid (60mL) under ice bath, react one hour under low temperature, slow thin up, extraction into ethyl acetate three times, merges, dry, concentrated, crude product obtains light yellow solid 7.1g through column chromatography, yield 81.8%.
(4) preparation of 2-(2-thioindole quinoline-3-base) methyl acetate
By 2-(2-oxindole quinoline-3-base) methyl acetate (4.1g; 20.0mmol) with thiophosphoric anhydride (2.6g; 11.7mmol) join in 10mL pyridine, be warming up to 120 DEG C of reactions 4 hours under nitrogen protection, join in the frozen water containing 20mL concentrated hydrochloric acid after being down to room temperature; stir; filter, filter cake is washed, dry; recrystallizing methanol obtains off-white color solid 2.8g, yield 63.3%.(5) preparation of (S)-2-[2-[2-(t-butoxycarbonyl amino)-3-hydroxyl third sulfydryl]-1H-indol-3-yl] methyl acetate
In dry reaction flask, add (S)-1-chloro-3-hydroxyl propane-2-carbamate (2.0g, 9.54mmol); 2-(2-thioindole quinoline-3-base) methyl acetate (1.76g; 7.95mmol), salt of wormwood (2.2g, 15.9mmol); 10mL acetone; room temperature reaction 3 hours under nitrogen protection, elimination residue salt of wormwood, filtrate concentrates; cross column chromatography and obtain red-brown oily matter 1.56g, yield 49.7%.
(6) preparation of (S)-2-[2-[2-(t-butoxycarbonyl amino)-3-(to Methyl benzenesulfonyl oxygen base) the third sulfydryl]-1H-indol-3-yl] methyl acetate
By (S)-2-[2-[2-(t-butoxycarbonyl amino)-3-hydroxyl third sulfydryl]-1H-indol-3-yl] methyl acetate (0.51g, 1.29mmol) with Tosyl chloride (0.288g, 1.51mmol) be dissolved in 5mL methylene dichloride, drip triethylamine (0.27mL, 1.94mmol), under room temperature, reaction is spent the night, add saturated sodium bicarbonate solution to stir, separate organic phase, saturated sodium-chloride is washed once, drying is concentrated to obtain oily matter 0.70g, yield 99.2%.
(7) preparation of (S)-2-[3-(t-butoxycarbonyl amino)-3,4-dihydro-2H-[1,3] thiazine is [3,2-a] indoles-10-base also] methyl acetate
By (S)-2-[2-[2-(t-butoxycarbonyl amino)-3-(to Methyl benzenesulfonyl oxygen base) the third sulfydryl]-1H-indol-3-yl] methyl acetate (0.70g, 1.28mmol) with cesium carbonate (0.60g, 1.84mmol) join room temperature for overnight in 3mLDMF, filter, add ethyl acetate, saturated common salt washes three times, and organic phase is dry, concentrate and obtain yellow oil 0.36g, yield 75%.
(8) preparation of (S)-2-(amino-3,4-dihydro-2H-[1, the 3] thiazine of 3-also [3,2-a] indoles-10-base) methyl acetate
By (S)-2-[3-(t-butoxycarbonyl amino)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base] methyl acetate (0.36g, 0.96mmol) is dissolved in 3mL methylene dichloride, adds (1.54mL under room temperature, 20.0mmol) trifluoroacetic acid, react 1 hour under room temperature, concentrating under reduced pressure obtains light yellow oil 0.26g, yield 99%.
(9) preparation of (S)-2-[3-(4-fluorobenzenesulfonamide base)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base] methyl acetate
By (S)-2-(3-amino-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base) methyl acetate (0.26g, 0.94mmol) and be dissolved in 3mL methylene dichloride to fluorophenylsulfonyl chloride (0.20g, 1.03mmol), (0.44mL is dripped under low temperature, 3.16mmol) triethylamine, react one hour under room temperature, add saturated sodium bicarbonate solution, separate organic phase, aqueous phase dichloromethane extraction three times, merge the washing of organic phase saturated common salt, dry, concentrated, column chromatography obtains 0.16g light yellow oil, yield 39.1%.(10) preparation of (S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-methyl acetate
By (S)-2-[3-(4-fluorobenzenesulfonamide base)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base] methyl acetate (0.39g, 0.898mmol) be dissolved in 3mLDMF, add salt of wormwood (186mg, 1.35mmol), stir and drip methyl iodide (153mg after ten minutes, 1.08mmol), room temperature lucifuge reacts one hour, adds water, ethyl ester extracts three times, once, organic phase drying is concentrated, column chromatography in saturated common salt washing, obtain light yellow oil 330mg, yield 82%.
(11) preparation of (S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-acetic acid
By (S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-methyl acetate (140mg, 0.312mmol) be dissolved in the mixed solution of 5mL methyl alcohol and 1mL tetrahydrofuran (THF), drip lithium hydroxide aqueous solution (2N, 0.45mL, 0.90mmol), under room temperature, reaction is spent the night, dilute hydrochloric acid adjusts pH to about 5, separates out white solid, filters, the a small amount of methanol wash column of filter cake, drying, concentrates to obtain white solid 0.10g, yield 73.7%.
Molecular formula: C
20h
19fN
2o
4s
2molecular weight: 434.1 mass spectrums (M+H): 435.1
1H-NMR(CDCl
3,400MHz)：δ7.90(dd,2H),7.47(d,1H),7.30-7.24(m,2H),7.20-7.07(m,3H),4.89-4.79(m,1H),4.25(dd,1H),3.92(dd,1H),3.95-3.90(m,1H),3.73(d,1H),3.64(d,1H),3.00(dd,1H),2.86(s,3H),2.72(dd,1H).
the preparation of embodiment 6 (3S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-1-oxo-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-acetic acid (compound 7)
(1) preparation of (3S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-1-oxo-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-methyl acetate
By (S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-3, 4-dihydro-2H-[1, 3] thiazine also [3, 2-a] indoles-10-base]-methyl acetate (0.22g, 0.49mmol) be dissolved in 5mL tetrahydrofuran (THF), metachloroperbenzoic acid (0.10g is added under ice-water bath, 0.58mmol), react 2 hours under low temperature, add saturated sodium bicarbonate solution cancellation reaction, concentrating under reduced pressure revolves except most of tetrahydrofuran (THF), water layer extraction into ethyl acetate three times, merge washing once, dry, concentrated, crude product obtains light yellow oil 190mg through column chromatography, yield 83.3%.
(2) preparation of (3S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-1-oxo-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-acetic acid
By (3S)-2-[3-(4-fluoro-N-Methyl benzenesulfonyl amido)-1-oxo-3,4-dihydro-2H-[1,3] thiazine also [3,2-a] indoles-10-base]-methyl acetate (190mg, 0.41mmol) be dissolved in the mixing solutions of 4mL methyl alcohol and 1mL tetrahydrofuran (THF), add lithium hydroxide aqueous solution (2N, 0.6mL, 1.2mmol) stirred at ambient temperature reacts 2 hours, and add dilute hydrochloric acid and adjust about pH to 5, be stirred to precipitation solid, filter, filter cake water, methyl alcohol are washed once respectively, dry, obtain white solid 140mg, yield 75.6%.
Molecular formula: C
20h
19fN
2o
5s
2molecular weight: 450.1 mass spectrums (M+H): 451.1
1H-NMR(d
6-DMSO,400MHz)：δ7.93(dd,1.5H),7.86(dd,0.5H),7.70,7.67(twoduet,1H),7.42,7.40(twoduet,1H),7.32-7.20(m,4H),5.62-5.50(m,0.7H),4.84-4.75(m,0.3H),4.59(dd,0.7H),4.38(dd,0.3H),4.08-3.91(m,3H),3.18-2.84(m,2H),3.02,2.89(twosinglet,3H).
the preparation of embodiment 7 (S)-2-[3-(the fluoro-N-methyl-benzamide of 4-)-3,4-tetrahydric thiapyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 11)
(1) preparation of (S)-N, 4-dimethyl-N-(2,3,4,9-tetrahydric thiapyran is [2,3-b] indol-3-yl also) benzsulfamide
By 500mg(1.39mmol) (S)-4-methyl-N-(2,3,4,9-tetrahydric thiapyran also [2,3-b] indol-3-yl) benzsulfamide is dissolved in 10mLDMF, adds 289mg(2.09mmol) salt of wormwood, and add 219mg(1.54mmol under ice bath) methyl iodide, react two hours, terminate through TLC monitoring reaction.Add water in system, extraction into ethyl acetate, water washing, dry, obtain crude white solid 550mg.
(2) preparation of (S)-N-methyl-2,3,4,9-tetrahydric thiapyran also [2,3-b] indoles-3-amine
946mg (7.38mmol) naphthalene is joined in the THF of 10mL drying, add 170mg (7.39mmol) metal Na, stirring at room temperature 2 hours, by (S)-N, 4-dimethyl-N-(2,3,4,9-tetrahydric thiapyran is [2,3-b] indol-3-yl also) the 20mLTHF solution of benzsulfamide (550mg crude product) is added drop-wise in system, reacts two hours.Add water cancellation, adds ethyl acetate, and dilute hydrochloric acid extracts, and ethyl acetate washing aqueous phase, discards organic phase.Add sodium hydroxide in aqueous phase and be adjusted to alkalescence, suction filtration obtains 100mg white solid, above two step yields 33.1%.
(3) preparation of the fluoro-N-methyl of (S)-4--N-(2,3,4,9-tetrahydric thiapyran is [2,3-b] indol-3-yl also) benzamide
In dry reaction flask, add 10mL methylene dichloride, 100mg (0.46mmol) (S)-N-methyl-2,3,4,9-tetrahydric thiapyran also [2,3-b] indoles-3-amine, 80mg (0.50mmol) is to fluorobenzoyl chloride, and 0.19mL (1.36mmol) triethylamine, reacts 3 hours under ice bath.Shrend on the rocks is gone out, and sodium bicarbonate is adjusted to alkalescence, extraction into ethyl acetate.Concentrated organic phase, obtains crude product 250mg.(4) preparation of (S)-2-[3-(the fluoro-N-methyl-benzamide of 4-)-3,4-tetrahydric thiapyrans also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate
In dry reaction flask, add the fluoro-N-methyl of 250mg (S)-4--N-(2 that step obtains, 3,4,9-tetrahydric thiapyran is [2,3-b] indol-3-yl also) benzamide, 15mLDMF, 479mg (1.47mmol) cesium carbonate, 245mg (1.47mmol) ethyl bromoacetate, ambient temperature overnight is reacted.Add water cancellation, extraction into ethyl acetate, water washing organic phase, dry, is spin-dried for, and preparative chromatography is separated and obtains white solid 120mg, above two step yields 60.9%.
(5) preparation of (S)-2-[3-(the fluoro-N-methyl-benzamide of 4-)-3,4-tetrahydric thiapyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid
120mg (0.28mmol) (S)-2-[3-(the fluoro-N-methyl-benzamide of 4-)-3 is added in reaction flask, 4-tetrahydric thiapyran also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate, 3mLTHF, 1mL methyl alcohol, 3mL water, adds 59mg (1.40mmol) hydronium(ion) Lithium Oxide 98min, stirring at room temperature half an hour.Aftertreatment thin up, extraction into ethyl acetate, dry, be spin-dried for, preparative chromatography purifying obtains white solid 60mg(0.15mmol), yield 53.6%.
Molecular formula: C
21h
19fN
2o
3sLC-MS(M+H): 399.2
1HNMR(MeOD,400MHz)δ:7.73(2H,dd),7.62(2H,dd),7.59-7.52(1H,m),7.45-7.32(1H,m),7.30-7.15(2H,m),5.49(1H,m),5.39-5.31(2H,m),4.07(3H,d),2.23-2.15(2H,m),2.10-1.98(2H,m).
embodiment 82-[(3S)-3-[2-(4-fluorophenyl)-N-methyl propanamide base]-3,4-dihydro thiapyrans also [2,3-b] indoles-9(2H)-Ji] preparation of acetic acid (compound 12)
(1) preparation of 2-(4-fluorophenyl) propionyl chloride
336mg (2.0mmol) 2-(4-fluorophenyl) propionic acid is dissolved in 10mL methylene dichloride, under ice bath, 330mg (2.6mmol) oxalyl chloride is added wherein, add 1 DMF, terminate through TLC monitoring reaction after 10 minutes.Be spin-dried for solvent, be directly used in the next step.
(2) preparation of 2-(4-fluorophenyl)-N-methyl-N-((S)-2,3,4,9-tetrahydric thiapyrans also [2,3-b] indol-3-yl) propionic acid amide
By 300mg (1.37mmol) (S)-N-methyl-2,3,4,9-tetrahydric thiapyran also [2,3-b] indoles-3-amine is dissolved in 10mL methylene dichloride and 5mLDMA, add 0.31mL (2.23mmol) triethylamine under ice bath, 2-(4-fluorophenyl) propionyl chloride upper step obtained is added dropwise in system, room temperature reaction 3 hours.Be spin-dried for solvent, add water, extraction into ethyl acetate, preparation liquid phase separation, obtains white solid 110mg, yield 21.9%.
(3) preparation of 2-[(3S)-3-[2-(4-fluorophenyl)-N-methyl propanamide base]-3,4-dihydro thiapyrans also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate
By 110mg (0.30mmol) 2-(4-fluorophenyl)-N-methyl-N-((S)-2,3,4,9-tetrahydric thiapyran also [2,3-b] indol-3-yl) propionic acid amide is dissolved in 3mLDMF, add 195mg (0.60mmol) cesium carbonate, add 55mg (0.33mmol) ethyl bromoacetate under ice bath, lucifuge reaction overnight.Add water in system, extraction into ethyl acetate, dry, be spin-dried for and be directly used in the next step.
(4) preparation of 2-[(3S)-3-[2-(4-fluorophenyl)-N-methyl propanamide base]-3,4-dihydro thiapyrans also [2,3-b] indoles-9 (2H)-Ji] acetic acid
2-[(3S)-3-[2-(4-fluorophenyl)-N-methyl propanamide base]-3 that upper step is obtained, 4-dihydro thiapyran also [2,3-b] indoles-9 (2H)-Ji] ethyl acetate is dissolved in 3mLTHF, add 1mL methyl alcohol, 3mL water, 73mg (1.74mmol) one hydronium(ion) Lithium Oxide 98min is added under ice bath, after 5min, TLC monitoring reaction terminates, thin up, add dilute hydrochloric acid adjust ph to 4-5, suction filtration, obtains white solid 120mg(0.28mmol), above two step yields 93.3%.
Molecular formula: C
23h
23fN
2o
3sLC-MS(M+H): 427.1
1HNMR(d
6-DMSO,400MHz)δ:13.12(1H,brs),7.45-6.92(8H,m),4.97(1H,m),2.85(3H,s),2.80-2.72(1H,m),3.07-2.88(2H,m),4.90-4.63(2H,m),4.18-4.05(1H,m),1.98(1H,q),1.29(3H,d).
the preparation of embodiment 9 (S)-2-[3-[the fluoro-N-of 4-(4-luorobenzyl) phenylsulfonamido]-3,4-dihydro thiapyran [2,3-b] indoles-9 (2H)-Ji] acetic acid (compound 17)
(1) preparation of (S)-3-[the fluoro-N-of 4-(4-luorobenzyl) phenylsulfonamido]-3,4-dihydro thiapyrans also [2,3-b] indoles-9 (2H)-t-butyl formate
By (S)-3-(4-fluorobenzene sulfonamido)-3 under ice bath, 4-dihydro thiapyran also [2,3-b] indoles-9 (2H)-t-butyl formate 300mg (0.65mmol) is dissolved in 10mLDMF, add 117mg (0.85mmol) salt of wormwood, slowly add 122mg (0.85mmol) to fluorine benzyl chlorine, move to room temperature reaction 15h.Add water cancellation, extraction into ethyl acetate, saturated common salt water washing, and dry organic phase is spin-dried for obtain faint yellow solid, is directly used in the next step.
2. the preparation of the fluoro-N-of (S)-4-(4-luorobenzyl)-N-(2,3,4,9-tetrahydric thiapyran is [2,3-b] indol-3-yl also) benzsulfamide
Be dissolved in 5mL methylene dichloride by upper step product, add 3mL trifluoroacetic acid under ice bath, react 3 hours, TLC monitors reaction and completes.Add frozen water, saturated solution of sodium bicarbonate, extraction into ethyl acetate, dry organic phase, is spin-dried for, and is directly used in the next step.
3. the preparation of (S)-2-[3-[the fluoro-N-of 4-(4-luorobenzyl) phenylsulfonamido]-3,4-dihydro thiapyran [2,3-b] indoles-9 (2H)-Ji] ethyl acetate
The fluoro-N-of (S)-4-(4-the luorobenzyl)-N-(2 under room temperature, upper step obtained, 3,4,9-tetrahydric thiapyran also [2,3-b] indol-3-yl) benzsulfamide is dissolved in 5mLDMF, add 277mg (0.85mmol) cesium carbonate, then add 142mg (0.85mmol) ethyl bromoacetate, lucifuge reaction 15h.Add water, extraction into ethyl acetate, dry organic phase, concentrated, be anti-phasely prepared into white solid 290mg, above three step total recoverys 80%.
4. the preparation of (S)-2-[3-[the fluoro-N-of 4-(4-luorobenzyl) phenylsulfonamido]-3,4-dihydro thiapyran [2,3-b] indoles-9 (2H)-Ji] acetic acid
By (S)-2-[3-[the fluoro-N-of 4-(4-luorobenzyl) phenylsulfonamido]-3 under ice bath, 4-dihydro thiapyran [2,3-b] indoles-9 (2H)-Ji] ethyl acetate 290mg (0.52mmol) is dissolved in 3mLTHF, add 1mL methyl alcohol, 109mg (2.60mmol) one hydronium(ion) Lithium Oxide 98min is dissolved in 3mL water, slowly drop in system, react 5 minutes, TLC monitoring reaction terminates.Thin up, adds dilute hydrochloric acid and is adjusted to slightly acidic (pH=5), extraction into ethyl acetate, dry organic phase, concentrated, anti-phasely prepares white solid 150mg, yield 54.6%.
Molecular formula: C
26h
22f
2n
2o
4s
2lC-MS(M+H): 528.7
1H-NMR(d
6-DMSO,400MHz)：δ7.98(dd,2H),7.51-7.43(m,4H),7.26(d,1H),7.18(t,2H),7.12(d,1H),7.00(t,1H),6.95(t,1H),4.76-4.50(m,4H),4.42-4.31(m,1H),3.10(t,1H),2.92(dd,1H),2.70(d,1H),2.58(dd,1H)。
Claims (9)
1. the compound shown in general formula (I) and pharmacy acceptable salt thereof:
Wherein, X
1, X
2, X
3and X
4be separately C (R
5);
X
5for-O-,-S (O)
m-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bit is separately hydrogen atom;
Y is-CH
2-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, C
1-4alkyl or 4-luorobenzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor phenyl, described phenyl is replaced by 1,2,3 or 4 halogen atom;
R
4for-C (O) OH;
R
5for hydrogen atom;
R
6for hydrogen atom or C
1-4alkyl;
M is 0,1 or 2;
N is 1;
P is 0 or 1.
2. compound as claimed in claim 1 and pharmacy acceptable salt thereof:
Wherein, X
1, X
2, X
3and X
4be separately C (R
5);
X
5for-O-,-S (O)
m-;
When
during for N-,
for C=; When
during for C=,
for N-;
R
1aand R
1bit is separately hydrogen atom;
Y is-CH
2-;
Z is-S (O)
2-or-C (O)-;
R
2for hydrogen atom, methyl or 4-luorobenzyl;
R
3for-(C (R
5r
6))
pr
3a, wherein R
3afor phenyl, described phenyl can be replaced by fluorine atoms;
R
4for-C (O) OH;
R
5for hydrogen atom;
R
6for hydrogen atom or methyl;
M is 0,1 or 2;
N is 1;
P is 0 or 1.
3. compound as claimed in claim 2 and pharmacy acceptable salt thereof:
4. logical compound shown in formula II, and pharmacy acceptable salt,
Wherein, X
1, X
2, X
3, X
4, X
5,
y, Z, R
1a, R
1b, R
2, R
3, R
4with n as claim 2 define.
5. compound as claimed in claim 4, and pharmacy acceptable salt,
6. a pharmaceutical preparation, it comprises compound described in any one of Claims 1 to 5 and pharmacy acceptable salt thereof and one or more pharmaceutical carriers.
7. pharmaceutical preparation according to claim 6 is oral preparations, injection, inhalation, nasal formulations, transdermal formulation, rectal administration preparation, ointment or gelifying agent.
8. the compound described in any one of Claims 1 to 5 and pharmacy acceptable salt thereof treat and/or prevent the application in the medicine of relevant disease active in CRTH2 in preparation, are selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, Basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease to the active relevant disease of CRTH2.
9. pharmaceutical composition, it is characterized in that comprising compound described in any one of claim 1-5 and pharmacy acceptable salt thereof and one or more therapeutic active substance, described therapeutic active substance is selected from TNF-alpha inhibitor, COX-1/COX-2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, leukotriene antagonist, VLA-4 antagonist, reflunomide, the similar thing of reflunomide, β 2-agonist, theophylline, inhibitors of leukotriene biosynthesis, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
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| CN108047237B (en) * | 2017-12-14 | 2019-11-05 | 中国医药集团总公司四川抗菌素工业研究所 | A kind of oxinane [2,3-b] indoles skeleton object and its crystal and preparation method and purposes |
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| CN1867547A (en) * | 2003-10-14 | 2006-11-22 | 奥克萨根有限公司 | Compounds having crth2 antagonist activity |
| US20090286825A1 (en) * | 2005-08-12 | 2009-11-19 | Zhaoyin Wang | Indole derivatives as crth2 receptor antagonists |
| WO2011117798A1 (en) * | 2010-03-22 | 2011-09-29 | Actelion Pharmaceuticals Ltd | 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9h-carbazole derivatives and their use as prostaglandin d2 receptor modulators |
| CN102333771A (en) * | 2009-02-24 | 2012-01-25 | 默沙东公司 | Indole derivatives as crth2 receptor antagonists |
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| CN1867547A (en) * | 2003-10-14 | 2006-11-22 | 奥克萨根有限公司 | Compounds having crth2 antagonist activity |
| US20090286825A1 (en) * | 2005-08-12 | 2009-11-19 | Zhaoyin Wang | Indole derivatives as crth2 receptor antagonists |
| CN102333771A (en) * | 2009-02-24 | 2012-01-25 | 默沙东公司 | Indole derivatives as crth2 receptor antagonists |
| WO2011117798A1 (en) * | 2010-03-22 | 2011-09-29 | Actelion Pharmaceuticals Ltd | 3-(heteroaryl-amino)-1,2,3,4-tetrahydro-9h-carbazole derivatives and their use as prostaglandin d2 receptor modulators |
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