CN103373996A - Bicyclic derivatives serving as CRTH2 receptor antagonist - Google Patents
Bicyclic derivatives serving as CRTH2 receptor antagonist Download PDFInfo
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- CN103373996A CN103373996A CN2013101364180A CN201310136418A CN103373996A CN 103373996 A CN103373996 A CN 103373996A CN 2013101364180 A CN2013101364180 A CN 2013101364180A CN 201310136418 A CN201310136418 A CN 201310136418A CN 103373996 A CN103373996 A CN 103373996A
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Abstract
The invention belongs to the technical field of medicine, and particularly relates to bicyclic derivatives (shown in a general formula (I)) serving as CRTH2 receptor antagonist and pharmaceutically acceptable salt and stereoisomeride thereof, wherein in the general formula (I), X1, X2, X3, X4, X5, X6, X7, X8, Y, Z, R1 and R2 are as defined in the specification. The invention also relates to a preparation method of these compounds, a pharmaceutical preparation and pharmaceutical composition containing these compounds, and application of these compounds in preparation of medicaments for treating and/or preventing diseases related to CRTH2 activity.
Description
Technical field
The invention belongs to medical technical field, be specifically related to two and ring derivatives as the CRTH2 receptor antagonist, its pharmacy acceptable salt and steric isomer thereof, the preparation method of these compounds, the pharmaceutical preparation and the pharmaceutical composition that contain these compounds, and these compounds, its pharmacy acceptable salt or its steric isomer treat and/or prevent application in the medicine with the active relevant disease of CRTH2 in preparation.
Background technology
CRTH2 is the chemical inhibitor acceptor of G albumen coupling, expresses at Th2 cell, eosinophilic granulocyte.In anaphylactic disease, as having observed the Th2-polarization in asthma, allergic rhinitis, the irritated dermatitis of heredity and the anaphylaxis conjunctivitis.The Th2 cell is regulated anaphylactic disease by producing the Th2 cytokine such as IL-4, IL-5 and IL-3.In anaphylactic disease, these Th2 cytokines have directly or indirectly been induced the effector cell, such as the survival of migration, activation, triggering and the prolongation of eosinophilic granulocyte and basophilic granulocyte.
PGD
2(PGD2), the aglucon of CRTH2 in anaphylactic disease, is to be produced by mastocyte and other important effector cell.In people's cell, PGD
2Th2 cell, eosinophilic granulocyte and basophilous migration and activation have been induced by CRTH2.Thereby, suppress CRTH2 and PGD
2In conjunction with antagonist to the treatment anaphylactic disease, should be useful such as the irritated dermatitis of asthma, allergic rhinitis, heredity and anaphylaxis conjunctivitis.
In addition, the experimental evidence of several series has proved the effect of eosinophilic granulocyte in sinusitis paranasal sinusitis and Churg-Strauss syndromes.In these patients' tissue, mastocyte can be observed and eosinophilic granulocyte is located jointly.This shows the PGD that mastocyte produces
2Induced raising of eosinophilic granulocyte.Thereby the eosinophilic granulocyte relevant disease of CRTH2 receptor antagonist to treating other also is useful such as Churg-Strauss syndromes and sinusitis paranasal sinusitis.Because the high level expression of CRTH2 on basophilic granulocyte, the CRTH2 receptor antagonist also is useful to treating the relevant disease of some basophilic granulocyte such as basophilia leukemia, chronic urticaria and basophilic leukocytosis.
Ramatroban (Ramatroban) goes on the market as the thromboxane A2 receptor antagonist, has extremely strong platelet activation effect, a little less than the antagonistic action to the CRTH2 acceptor, its poor selectivity, main adverse reaction are that purple plague purpura, prothrombin time/activated partial thromboplastin time prolong, subcutaneous hemorrhage.
Therefore the medicine that lacks in the market effective CRTH2 antagonistic activity, the compound of needs exploitation highly selective, high reactivity, novel structure is optimized physico-chemical property, improves into the property of medicine.
Summary of the invention
The technical problem to be solved in the present invention is, provides a kind of two and the CRTH2 receptor antagonist of ring derivatives.
Technical scheme of the present invention is as follows:
Compound shown in the logical formula I, its pharmacy acceptable salt, and steric isomer:
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-, (R
4)
2NC (O)-, R
4C (O) NHC (O)-or the tetrazole base;
R
2Be aryl, benzo C
3-8Cycloalkyl or heteroaryl, described aryl, benzo C
3-8Cycloalkyl and heteroaryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group or C
3-8Cycloalkyl;
R
3Be hydrogen atom, cyano group, nitro, hydroxyl, oxo, carboxyl, amino, halogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-8Cycloalkyl, halo C
3-8Cycloalkyl, C
3-8Cycloalkyl C
1-6Alkyl, halo C
3-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-8Cycloalkyl sulfenyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, 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 or two (C
1-6Alkyl) amido alkylsulfonyl;
R
4Be hydrogen, C
1-6Alkyl, C
1-6Assorted alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or aryl, described C
1-6Alkyl, C
1-6Assorted alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or aryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-8Cycloalkyl, described C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
3-8Cycloalkyl, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1,2,3 or 4.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-, (R
4)
2NC (O)-or the tetrazole base;
R
2Be aryl or benzo C
3-8Cycloalkyl, described aryl and benzo C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-8Cycloalkyl, halo C
3-8Cycloalkyl, C
3-8Cycloalkyl C
1-6Alkyl, halo C
3-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl amine group alkylsulfonyl or C
1-6Alkylsulfonamido;
R
4Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or phenyl, described C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-8Cycloalkyl, described C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1,2 or 3.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-or the tetrazole base;
R
2Be aryl, described aryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, C
3-8Cycloalkyl C
1-6Alkyl, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl or C
1-6Alkylsulfonamido;
R
4Be hydrogen, C
1-6Alkyl or C
3-8Cycloalkyl, described C
1-6Alkyl or C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-6Cycloalkyl, described C
3-6Cycloalkyl is optional to be independently selected from following substituting group replacement by 1-3: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1 or 2.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Y is-CH
2-;
Z is-S-;
R
1For-C (O) OH or tetrazole base;
R
2Be phenyl, described phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, trifluoromethyl, C
1-6Alkyl or C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, C
1-6Alkylamidoalkyl or C
3-8Cycloalkyl C
1-6Alkyl.
Compound shown in the logical formula I, its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Y is-CH
2-;
Z is-S-;
R
1For-C (O) OH;
R
2Be phenyl, described phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-4Alkyl or trifluoromethyl;
R
3Be hydrogen atom, hydroxyl, oxo, halogen atom or C
1-4Alkyl.
Technical scheme of the present invention also comprises the compound shown in the general formula (II), its pharmacy acceptable salt, and steric isomer:
Wherein, Y is-CH
2-;
R
1For-C (O) OH;
Z is-S-;
R
2Be phenyl, described phenyl can be independently selected from following substituting group by 1-3 and replace: halogen atom, hydroxyl, amino, cyano group, C
1-4Alkyl or trifluoromethyl.
Compound shown in the general formula (II), its pharmacy acceptable salt, and the optimal technical scheme of steric isomer is:
Wherein, Y is-CH
2-;
R
1For-C (O) OH;
Z is-S-;
R
2Be phenyl, described phenyl can be selected from following substituting group by 1 and replace: halogen atom, hydroxyl, amino, C
1-4Alkyl or trifluoromethyl.
Present invention is described to give a definition in utilization, and the specific definition mode includes but not limited to following description.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-6Alkyl " alkane that refers to contain 1-6 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives; and specific examples includes but not limited to: methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, the 2-methyl-propyl, the 1-methyl-propyl, 1, the 1-dimethyl ethyl, n-pentyl, the 3-methyl butyl, the 2-methyl butyl, the 1-methyl butyl, the 1-ethyl propyl, n-hexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2,3-dimethylbutyl, the 2-ethyl-butyl, 1-methyl-2-methyl-propyl etc." C of the present invention
1-4Alkyl " refer to the specific examples that contains 1-4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkoxyl group " refer to " C
1-6Alkyl " group that is connected with other structures by Sauerstoffatom, such 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.
" C of the present invention
3-8Cycloalkyl " for containing the cyclic alkyl of 3-8 carbon atom; specific examples includes but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1-methyl cyclopropyl, 1-amyl group cyclopropyl, 1; 2-diethyl cyclobutyl, 1-methyl cyclobutyl, 1-butyl cyclobutyl, 1,3-dimethylcyclobutyl, 1-methylcyclopentyl, 1-butyl cyclopentyl, 1-methylcyclohexyl, 1-ethyl cyclopentyl etc.
" halo C of the present invention
1-6Alkyl " refer to one or more " halogen atom " replacement " C
1-6Alkyl " group of deriving, described " halogen atom " and " C
1-6Alkyl " define such as preamble.
" C of the present invention
2-6Thiazolinyl " carbonatoms that refers to contain two keys is the straight or branched of 2-6 or the thiazolinyl of ring-type; and specific examples includes but not limited to: vinyl; the 1-propenyl; the 2-propenyl; the 3-propenyl; the 1-methyl ethylene, the 1-butylene base, crotyl, the 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 1-methyl isophthalic acid-butenyl, the 2-methyl-1-butene thiazolinyl, the 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, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, the 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, the 1-methyl-3-pentenyl, the 2-methyl-3-pentenyl, the 3-methyl-3-pentenyl, the 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-3-butenyl, 1,4-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, the 3-butadienyl, 1, the 4-pentadienyl, 1, the 4-hexadienyl, cyclopentenyl, 1, the 3-cyclopentadienyl, cyclohexenyl, 1, the 4-cyclohexadienyl, 1,3,5-hexatriene base etc.
" halo C of the present invention
1-6Alkoxyl group " refer to one or more " halogen atom " replacement " C
1-6Alkoxyl group " group of deriving, described " halogen atom " and " C
1-6Alkoxyl group " define such as preamble.
" C of the present invention
1-6Alkylthio " refer to C
1-6Alkyl is by sulphur atom (group that S-) is connected and derives with other parts, i.e. C
1-6Alkyl-S-, described " C
1-6Alkyl " as mentioned before.
" aryl " of the present invention refers to that annular atoms all is the ring-type aromatic group 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.
It is formed that 8-14 unit fused ring aryl refers to share each other two adjacent carbon atoms by two or more ring texturees, the condensed ring group that to have a ring at least be aromatic nucleus, comprise the whole unsaturated fused ring aryl of 8-14 unit, specific examples includes but not limited to: naphthalene, phenanthrene etc.
" C of the present invention
3-8Heterocyclylalkyl " refer to C
3-8One or more carbon atom in the cycloalkyl is replaced the group of being derived, described " C by S, O, N or C (O) atom
3-8Cycloalkyl " as mentioned before." C of the present invention
3-6Heterocyclylalkyl " refer to the specific examples that contains 3-6 annular atoms in the above-mentioned example.
" heteroaryl " of the present invention, refer to contain 5-14 the annular atoms undersaturated cyclic group with aromaticity of (wherein containing at least 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., comprises that simultaneously carbon atom and sulphur atom can be by oxos.
The single heteroaryl of 5-8 unit refers to heteroatomic cyclic group of containing of aromaticity, and specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group oxazolyl isoxazolyl oxadiazolyl, imidazolyl, pyrazolyl, 1,2, the 3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2, the 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, Isosorbide-5-Nitrae-Dioxin base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 4H-1, the 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, the 4-triazinyl, the 1,3,5-triazines base, 1,3, the 4-triazinyl, 1,2,4,5-tetrazine base, the 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 contain 6-14 annular atoms (wherein containing at least a heteroatoms) and share each other two adjacent annular atomses by two or more ring texturees and couple together the undersaturated condensed ring structure with aromaticity that forms, specific examples includes but not limited to: benzofuryl, the benzisoxa furyl, benzothienyl, indyl benzoxazolyl, benzimidazolyl-, indazolyl, the benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, the 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 the alkyl is replaced the group of being derived, described " C by S, O, N or C (O) atom
1-6Alkyl " as mentioned before.
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, unless and specialize, be intended to comprise E geometrical isomer and Z geometrical isomer.Can there be different hydrogen tie points in the compound that some the present invention describe, is called as tautomer.This example can for ketone and enol form thereof, be called the keto-enol tautomerism body.The compound of formula (I) comprises single tautomer and composition thereof.The invention is intended to comprise all these type of isomeric form of compound of formula (I).Described isomer can be by standard isolation technique and the abundant purity isomer of the synthetic acquisition of zinc bromide.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, such as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is such as calcium salt, magnesium salts etc.; Other metal-salts are such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is such as ammonium salt; Organic alkali salt, such as uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethyl amine 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) amido methane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid that comprises mineral acid and organic acid, this type of acid comprises: halogen acid salt, such as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is such as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate is such as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is such as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is such as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts is such as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.For fear of query, one, two or three salt-forming cations may be arranged, but this depends on quantity and the described cationic valence mumber of carboxyl functional group.It is evident that for those skilled in the art the pharmacy acceptable salt of the compounds of this invention can in the formation such as free carboxy place of this compound, can make by ordinary method.
Thereby can produce with the carrier substance combination amount of the activeconstituents of single dose form, will change according to treatment individuality and concrete mode of administration.For example, dosage forms for oral administration can comprise about 0.05mg to about 5g active agent and in conjunction with the carrier substance with appropriate amount and convention amount to people patient's preparation, wherein the amount of carrier substance can be about 5% finger about 99.95% of whole composition.Dosage unit form usually comprise about 0.1mg to the compound of about 0.4g formula (I) as activeconstituents, be generally 0.5mg, 1mg, 2mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg or 400mg.
" pharmaceutical composition " of the present invention refers to the compound shown in the logical formula I and the pharmaceutical composition of pharmaceutically acceptable carrier.Its pharmacy acceptable salt and steric isomer thereof and one or more pharmaceutical carriers are made pharmaceutically acceptable pharmaceutical preparation, are applied to the patient who needs this treatment in modes such as oral, parenterals.During oral administration, can make conventional solid preparation with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc., such as tablet, capsule, pill, granule etc.; When being used for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the ordinary method production in the existing pharmacy field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The present invention also provides the compound shown in the logical formula I, its pharmacy acceptable salt and steric isomer thereof to treat and/or prevent application in the medicine with the active relevant disease of CRTH2 in preparation, and the disease relevant with the CRTH2 activity is selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, basophilia leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease.
The present invention also provides and has comprised the compound shown in the logical formula I, the pharmaceutical composition of its pharmacy acceptable salt and steric isomer thereof and one or more therapeutic active substance, described therapeutic active substance is selected from the TNF-alpha inhibitor, the COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, the leukotriene D receptor antagonist, leukotriene antagonist, the LTD4 antagonist, the 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, the beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
" treatment " of the present invention refers to alleviate, improvement, elimination or minimizing sign and the symptom relevant with disease or illness.
" prevention " of the present invention refers to prevent or postpones generation or the development of disease or illness or prevent or postpone therewith disease or relevant sign or the symptom of illness.
" composition " of the present invention, refer in pharmaceutical composition, be intended to comprise the inertia complexing or the polymerization that contain activeconstituents and consist of carrier, perhaps from the decomposition of one or more compositions, perhaps from the reaction of other type of one or more compositions or any product that interacts and produce, therefore, pharmaceutical composition of the present invention comprises any composition for preparing by compound and one or more pharmaceutically acceptable mixed with excipients with formula (I).
Part of compounds of the present invention:
Below further set forth the beneficial effect of the compounds of this invention by external pharmacology activity experiment, but this should be interpreted as that the compounds of this invention only has following beneficial effect.
The experimental example the compounds of this invention is to the external pharmacologically active of CRTH2 acceptor
Trial-product:
The compounds of this invention 1 is made by oneself by embodiment 1 method;
Experimental technique: accurately take by weighing trial-product, add the DMSO dissolving, fully mixing is made into 10mM.Then use the HEPES(hydroxyethyl piperazine second thiosulfonic acid of the 20mM of pH7.4) damping fluid is diluted to 50 μ M, and 5 times of dilutions are that 10000,2000,400,80,16,3.2,0.64,0.128,0.0256nM is for subsequent use again.
FLIPR detects (real-time fluorescence imaging analysis)
In 384 black microwell plates, add 20 μ l and contain 20000 CHO-K1/CRTH2/G
α 15Cell solution, 37 ℃, 5%CO
2Add 20 μ l after hatching 18h
Calcium4assay kit(test kit) staining agent in adds 10 μ l compound solutions again, then hatches 60min, incubated at room 15min for 37 ℃.In 20 seconds, add agonist PDG
2(prostacyclin) EC
80PDG under the concentration
2The HEPES damping fluid detects the 21-120 fluorescent value of second.
Data processing
Δ RFU(relative intensity of fluorescence)=fluorescent value of the maximum 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
The agonist contrast-Δ RFU
Background) * 100
Calculate the IC of each compound according to inhibiting rate
50Value (is namely blocked PGD
2At EC
80Lower concentration of inducing CRTH2 receptor activation 50% needed testing compound of concentration).
Experimental result and conclusion:
Table 1 the compounds of this invention is to the antagonistic action of CRTH2 acceptor
| Trial-product | IC 50(μM) |
| Compound 1 | ++ |
+++expression IC
50Be 0-300nM, illustrate that compound has good antagonistic action; ++ expression IC
50Be 0.3-3 μ M, illustrate that compound has preferably antagonistic action; + expression IC
50For 3 μ M, illustrate that the antagonistic action of compound is general;
As seen from the above table, 1 pair of CRTH2 acceptor of the application's compound has preferably antagonistic action.
Embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1 2-[1-(4-chlorobenzene sulfenyl) imidazo [1,5-a] pyridin-3-yl] preparation of acetic acid (compound 1)
(1) malonic ester list acyl chlorides
With malonic ester (13.2g, 100.0mmol) and N, dinethylformamide (0.05mL) stirs and is dissolved in the methylene dichloride (200mL), ice-water bath is cooled to 0 ℃, drips oxalyl chloride (25.4g, 200mmol), stir 2h under the mixture room temperature, concentrate and obtain malonic ester list acyl chlorides (14.5g, 97%), be white oily matter.
(2) 3-oxo-3-(pyridine-2-methylene amido) ethyl propionate
With malonic ester list acyl chlorides (14.5g, 96.7mmol) be dissolved in the methylene dichloride (150mL), ice-water bath is cooled to 0 ℃, dropping is dissolved in the triethylamine (19.5g of 50mL methylene dichloride, 193mmol) with 2-amine picoline (13.6g, 125.7mmol), stirring at room 3 hours.Then revolve the steaming desolventizing, resistates separates to get 3-oxo-3-(pyridine-2-methylene amido) ethyl propionate (16.0g, 75%) through silica gel column chromatography (V (EtOAc)/V (PE)=1/5～2/1), is yellow oil.
(3) 2-(imidazo [15-a] pyridin-3-yl) ethyl acetate
3-oxo-3-(pyridine-2-methylene amido) ethyl propionate (16.0g, 72.1mmol) is dissolved in 1, the 2-ethylene dichloride (150mL), ice-water bath is cooled to 0 ℃, drip phosphorus oxychloride (20mL, 216.2mmol), then refluxed 4 hours.Be cooled to room temperature after complete, mixture inclines to mixture of ice and water, and yellow soda ash is transferred pH to 8, dichloromethane extraction.The organic phase that merges successively water, saturated nacl aqueous solution is washed, and anhydrous sodium sulfate drying is concentrated.The gained resistates separates to get 2-(imidazo [1,5-a] pyridin-3-yl) ethyl acetate (8.0g, 54%) through column chromatography (V (EtOAc)/V (PE)=0～1/2), is faint yellow solid.
(4) 2-(1-bromine imidazo [1,5-a] pyridin-3-yl) ethyl acetate
2-(imidazo [1,5-a] pyridin-3-yl) ethyl acetate (8.0g, 39.2mmol) is dissolved in the glacial acetic acid (100mL), then drip bromine (6.2g, 38.8mmol) the 60mL glacial acetic acid solution, complete rear stirring at room 2 hours, then concentrated.Resistates is dissolved in the 400mL ethyl acetate, uses successively saturated sodium carbonate, and salts solution is washed, and dried over anhydrous sodium carbonate is concentrated.The gained crude product gets 2-(1-bromine imidazo [1,5-a] pyridin-3-yl) ethyl acetate (4.0g, 36%) through silicagel column (V (EtOAc)/V (PE)=0～1/4) purifying, is brown oil.
(5) 2-[1-(4-chlorobenzene sulfenyl) imidazo [1,5-a] pyridin-3-yl] ethyl acetate
With 2-(1-bromine imidazo [1,5-a] pyridin-3-yl) ethyl acetate (500mg, 1.75mmol) and 4-chlorothio-phenol (500mg, 3.5mmol) place 50mL dimethylbenzene to be heated to 140 ℃ of maintenances 16 hours, then be cooled to room temperature, revolve the steaming desolventizing, silicagel column (V (EtOAc)/V (PE)=0～1/3) chromatography gets 2-[1-(4-chlorobenzene sulfenyl) imidazo [1,5-a] pyridin-3-yl] ethyl acetate (200mg, 33%), be faint yellow solid.
(6) 2-[1-(4-chlorobenzene sulfenyl) imidazo [1,5-a] pyridin-3-yl] acetic acid
With 2-[1-(4-chlorobenzene sulfenyl) imidazo [1,5-a] pyridin-3-yl] ethyl acetate (200mg, 0.57mmol) be dissolved in the tetrahydrofuran (THF) and methyl alcohol (volume ratio 1/1) mixed solution of 15mL, add water (7.5mL) solution of lithium hydroxide (48mg, 2mmol).Reaction solution stirring at room 4 hours.Revolve the steaming desolventizing, add the dilution of 20mL water, transfer pH to 3 with the hydrochloric acid of 1N, Precipitation is arranged, suction filtration and dry product 2-[1-(4-chlorobenzene sulfenyl) imidazo [1, the 5-a] pyridin-3-yl that gets] acetic acid (170mg, 92%), be white solid.Mass spectrum (m/e): 320.0 (M+1)
1H-NMR(DMSO-d
6,400MHz)δ:8.30(m,1H),7.53(m,1H),7.27(m,2H),7.00(m,3H),6.84(m,1H),4.19(m,2H).
With reference to aforesaid method, can also prepare other compounds of the present invention:
Claims (11)
1. the compound shown in the general formula (I), its pharmacy acceptable salt, and steric isomer,
Cycloalkyl sulfenyl and steric isomer thereof wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-, (R
4)
2NC (O)-, R
4C (O) NHC (O)-or the tetrazole base;
R
2Be aryl, benzo C
3-8Cycloalkyl or heteroaryl, described aryl, benzo C
3-8Cycloalkyl and heteroaryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group or C
3-8Cycloalkyl;
R
3Be hydrogen atom, cyano group, nitro, hydroxyl, oxo, carboxyl, amino, halogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-8Cycloalkyl, halo C
3-8Cycloalkyl, C
3-8Cycloalkyl C
1-6Alkyl, halo C
3-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-8Cycloalkyl sulfenyl, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, 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 or two (C
1-6Alkyl) amido alkylsulfonyl;
R
4Be hydrogen, C
1-6Alkyl, C
1-6Assorted alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or aryl, described C
1-6Alkyl, C
1-6Assorted alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or aryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-8Cycloalkyl, described C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
3-8Cycloalkyl, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1,2,3 or 4.
2. compound as claimed in claim 1, its pharmacy acceptable salt, and steric isomer,
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-, (R
4)
2NC (O)-or the tetrazole base;
R
2Be aryl or benzo C
3-8Cycloalkyl, described aryl and benzo C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-8Cycloalkyl, halo C
3-8Cycloalkyl, C
3-8Cycloalkyl C
1-6Alkyl, halo C
3-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl amine group alkylsulfonyl or C
1-6Alkylsulfonamido;
R
4Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or phenyl, described C
1-6Alkyl, C
3-8Cycloalkyl, C
3-8Heterocyclylalkyl or phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-8Cycloalkyl, described C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1,2 or 3.
3. compound as claimed in claim 2, its pharmacy acceptable salt, and steric isomer,
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-(C (R
aR
b))
p-;
Z is-(C (R
aR
b))
p-or-S-;
R
1Be R
4OC (O)-or the tetrazole base;
R
2Be aryl, described aryl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, C
3-8Cycloalkyl C
1-6Alkyl, C
1-6Alkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl or C
1-6Alkylsulfonamido;
R
4Be hydrogen, C
1-6Alkyl or C
3-8Cycloalkyl, described C
1-6Alkyl or C
3-8Cycloalkyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino or C
1-6Alkyl;
R
aAnd R
bBe hydrogen, C independently respectively
1-6Alkyl or halogen atom, wherein R
aAnd R
bThe carbon that can be connected with them forms C
3-6Cycloalkyl, described C
3-6Cycloalkyl is optional to be independently selected from following substituting group replacement by 1-3: halogen atom, oxo, cyano group, hydroxyl, carboxyl, amino, C
1-6Alkoxyl group or C
1-6Alkyl;
P is 0,1 or 2.
4. compound as claimed in claim 3, its pharmacy acceptable salt, and steric isomer,
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-CH
2-;
Z is-S-;
R
1For-C (O) OH or tetrazole base;
R
2Be phenyl, described phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, trifluoromethyl, C
1-6Alkyl or C
1-6Alkoxyl group;
R
3Be hydrogen atom, cyano group, hydroxyl, oxo, amino, halogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, C
1-6Alkoxyl group, C
1-6Alkylamidoalkyl or C
3-8Cycloalkyl C
1-6Alkyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt, and steric isomer,
Wherein, X
1, X
2, X
3, X
4And X
7Be N or C (R independently respectively
3);
X
5, X
6And X
8Be N or C independently respectively, and X
5And X
6Have at least one to be N;
Key on the representative ring is singly-bound or two key;
Y is-CH
2-;
Z is-S-;
R
1For-C (O) OH;
R
2Be phenyl, described phenyl can be chosen wantonly by 1-3 and be independently selected from following substituting group replacement: halogen atom, hydroxyl, amino, cyano group, C
1-4Alkyl or trifluoromethyl;
R
3Be hydrogen atom, hydroxyl, oxo, halogen atom or C
1-4Alkyl.
6. the compound shown in the general formula (II), its pharmacy acceptable salt and steric isomer thereof,
Wherein, Y is-CH
2-;
R
1For-C (O) OH;
Z is-S-;
R
2Be phenyl, described phenyl can be independently selected from following substituting group by 1-3 and replace: halogen atom, hydroxyl, amino, cyano group, C
1-4Alkyl or trifluoromethyl.
7. compound as claimed in claim 6, its pharmacy acceptable salt and steric isomer thereof,
Wherein, R
2Be phenyl, described phenyl can be selected from following substituting group by 1 and replace: halogen atom, hydroxyl, amino, C
1-4Alkyl or trifluoromethyl.
8. compound as claimed in claim 1, its pharmacy acceptable salt and steric isomer thereof,
9. contain the pharmaceutical preparation of each described compound of claim 1～8, its pharmacy acceptable salt or its steric isomer, it is characterized in that comprising one or more pharmaceutical carriers.
10. each described compound of claim 1～8, its pharmacy acceptable salt or its steric isomer treat and/or prevent application in the medicine with the active relevant disease of CRTH2 in preparation, and the disease relevant with the CRTH2 activity is selected from asthma, allergic rhinitis, allergic dermatitis, anaphylaxis conjunctivitis, Churg-Strauss syndromes, sinusitis paranasal sinusitis, basophilia leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, struvite intestinal disease, ulcerative colitis, Crohn disease, sacroiliitis or chronic obstructive pulmonary disease.
11. pharmaceutical composition, it is characterized in that comprising each described compound of claim 1～8, its pharmacy acceptable salt or its steric isomer and one or more therapeutic active substance, described therapeutic active substance is selected from the TNF-alpha inhibitor, the COX-1/COX-2 inhibitor, cox 2 inhibitor, glucocorticosteroid, the deactivation antibody of interleukin, chemokine receptor modulators, histamine H 1 receptor antagonist/antihistaminic agent, the leukotriene D receptor antagonist, leukotriene antagonist, the LTD4 antagonist, the 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, the beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
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| CN201210120408 | 2012-04-20 | ||
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