CN104418820A - Carboxylic acid derivative as lysophosphatidic acid receptor antagonist - Google Patents
Carboxylic acid derivative as lysophosphatidic acid receptor antagonist Download PDFInfo
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- CN104418820A CN104418820A CN201410451313.9A CN201410451313A CN104418820A CN 104418820 A CN104418820 A CN 104418820A CN 201410451313 A CN201410451313 A CN 201410451313A CN 104418820 A CN104418820 A CN 104418820A
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- 0 CCC(*C(CCC(C)c1ccccc1)I=C)=C(*)c(cc1)ccc1-c1ccc(C2(CCCCC2)C(C=C)=C)cc1 Chemical compound CCC(*C(CCC(C)c1ccccc1)I=C)=C(*)c(cc1)ccc1-c1ccc(C2(CCCCC2)C(C=C)=C)cc1 0.000 description 9
- SJHSFKBITYOJFY-PQFMSKKISA-N CC(c1ccccc1F)OC(N/C(/C(C)=N)=C(\c1ccc(-c2ccc(C3(CCCCC3)C(O)=O)cn2)nc1)/O)=O Chemical compound CC(c1ccccc1F)OC(N/C(/C(C)=N)=C(\c1ccc(-c2ccc(C3(CCCCC3)C(O)=O)cn2)nc1)/O)=O SJHSFKBITYOJFY-PQFMSKKISA-N 0.000 description 1
- ZRCVPTVPQDQMIJ-UHFFFAOYSA-N CC(c1ccccc1F)OC(Nc1c(-c(cc2)ccc2-c2ccc(C3(CCCCC3)C(O)=O)nc2)[o]nc1C)O Chemical compound CC(c1ccccc1F)OC(Nc1c(-c(cc2)ccc2-c2ccc(C3(CCCCC3)C(O)=O)nc2)[o]nc1C)O ZRCVPTVPQDQMIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention belongs to the technical field of medicine, and particularly relates to a carboxylic acid derivative as a lysophosphatidic acid receptor antagonist as shown in a general formula (I) and a pharmaceutically acceptable salt thereof or an stereomer thereof, wherein A, B, C, D, E, R1, R3, R4, R5, RA, RB, RC, m and p are as defined in the specification. The invention also relates to preparation methods of the compounds, a drug composition or a drug preparation which contains the compounds and an important application of the compounds in preparing a drug for treating and/or preventing LPA-dependence or LPA-mediation diseases.
Description
1, technical field
The invention belongs to medical art, be specifically related to as the carboxylic acid derivative of lpa receptor antagonist, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, pharmaceutical composition containing these compounds or pharmaceutical preparation, and these compounds play an important role to the disease treating and/or preventing LPA-dependency or LPA-mediation.
2, background technology
Ultrapole L (lysophosphatidic acid, LPA) is the simple water-soluble glycerol phosphatide of a kind of structure, is the bioactive lipid mediators that film is derivative.Thought that LPA was lipid synthesis precursor in the past, progressively found that LPA had biological effect widely afterwards, inducing neural aixs cylinder retraction, stress fiber can be formed, promote cell proliferation/apoptosis, platelet aggregation, tumor cell invasion etc.Its biological action is mainly realized by G-protein linked receptor mediate downstream signal path, and impact comprises propagation, breaks up, survives, moves, sticks, attacks and morphogenetic elementary cell function.The many biological processess of these function effects, it comprises neural generation, blood vessel generation, wound healing, fibrosis, immunity and carcinogenesis.
Ultrapole L (LPA) is for show the lysophospholipid worked with autocrine and paracrine mode through specific G-protein coupled receptor (GPCR) group.LPA is bonded to its homology GPCR (LPA
1, LPA
2, LPA
3, LPA
4, LPA
5, LPA
6) in active cells signal transduction path to produce various biological respinse.Find disease, obstacle or illness that the antagonist of LPA acceptor is used for the treatment of LPA and works.
Recent study finds, LPA
1extensively distribute in Various Tissues, by receptor-mediated downstream signaling pathway (the PI3K and Ca of G-albumen coupling
2+influx), induced interstitial cellular contraction, by activating ERK
1/2passage, p38MAPK, or Rho albumen, stimulate cell growth, subsequently LPA collaborative with platelet derived growth factor (PDGF)
1in the induced interstitial Growth of Cells and apoptosis of different densities, there is bimodulus effect, relevant with diseases such as various fibrotic disease, neuropathic pain, atherosclerotic lesion, cancers.
Compd A M-095 (structure is as follows) the conduct optionally LPA of Amira company
1receptor antagonist enters preclinical phase, in the pulmonary fibrosis model of animal, have activity, but the transformation period of compound is short, can make troubles to clinical administration.
The present invention treats and/or prevents the medicine of the disease of LPA-dependency or LPA-mediation for target with exploitation, found the LPA inhibitor of the highly selective being adapted to clinical needs.
3, summary of the invention
The present invention treats and/or prevents the medicine of the disease of LPA-dependency or LPA-mediation for target with exploitation, found the cyclic carboxylic acids class lysophospholipid acid inhibitor of the highly selective being adapted to clinical needs.
Specifically, the invention provides the compound shown in following general formula (I), its pharmacy acceptable salt or its steric isomer:
Wherein, R
1for-COOR
d,-SR
d,-SOR
d,-SO
2r
d,-CONHSO
2r
d,-CON (R
e)
2,-N (R
e) COR
d,-N (R
e) COOR
d,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom, C
1-6alkyl, C
3-8cycloalkyl, 6-14 unit's aryl or 3-14 unit heterocyclic radical;
Ring A and ring B is separately 6-14 unit aryl, 3-14 unit's heterocyclic radical or C
3-8cycloalkyl;
Ring C is 6-14 unit's aryl or 4-7 unit heteroaryl;
Ring D and ring E is separately C
3-8cycloalkyl or C
3-8heterocyclylalkyl, and the shared carbon atom of ring D and ring E is fused into volution, described C
3-8cycloalkyl and C
3-8heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group or halo C
1-6alkoxyl group;
R
aand R
bbe separately hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
3-8cycloalkyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
5-8cycloalkenyl group C
1-6alkyl, C
2-6alkynyl, C
1-6alkylthio, phenyl, phenyl C
1-6alkyl, naphthyl, C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, C
1-6alkyl-carbonyl, C
1-6alkyl-carbamoyl, formamido group, C
1-6alkyl amido, C
1-6alkyl sulphonyl, C
1-6alkyl amino sulfonyl, C
1-6alkyl sulfonyl is amino, two (C
1-6alkyl) formamyl, two (C
1-6alkyl) amino-sulfonyl, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
cfor hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkylthio, C
1-6alkylamino or two (C
1-6alkyl) amino;
R
3for hydrogen atom, hydroxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkylthio, C
1-6alkylamino or two (C
1-6alkyl) amino;
R
4for hydrogen atom, C
1-6alkyl or C
3-8cycloalkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl or C
1-6alkoxyl group;
M is selected from 0,1,2,3,4 or 5;
P is selected from 0,1,2,3 or 4.
In a preferred embodiment, the invention provides the compound shown in above-mentioned general formula (I), its pharmacy acceptable salt or its steric isomer, wherein:
R
1for-COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-N (R
e) COR
d,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom, C
1-6alkyl or C
3-8cycloalkyl;
Ring A and ring B is separately 6-14 unit aryl, 4-7 unit's heteroaryl or C
3-8cycloalkyl; Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
Ring D and ring E is separately C
3-6cycloalkyl or C
4-6heterocyclylalkyl, and the shared carbon atom of ring D and ring E is fused into volution, described C
3-6cycloalkyl and C
4-6heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4 or 5: halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
3-8cycloalkyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
5-8cycloalkenyl group C
1-6alkyl, C
2-6alkynyl, C
1-6alkylthio, phenyl, phenyl C
1-6alkyl, naphthyl, C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino or C
1-6alkyl-carbonyl;
R
cfor hydrogen atom, cyano group, nitro, hydroxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group or C
3-8cycloalkyl C
1-6alkyl;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl, C
3-8cycloalkyl or C
3-8cycloalkyl C
1-6alkyl;
R
4for hydrogen atom or C
1-6alkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2,3 or 4.
In a preferred embodiment, the invention provides the compound shown in above-mentioned general formula (I), its pharmacy acceptable salt or its steric isomer, wherein:
R
1for-COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
Ring A and ring B is separately phenyl, naphthyl, benzo C
3-8cycloalkyl or 5-6 unit heteroaryl;
Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
Ring D and ring E is separately C
3-6cycloalkyl or C
4-6heterocyclylalkyl, and the shared carbon atom of ring D and ring E is fused into volution, described C
3-6cycloalkyl and C
4-6heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3 or 4: halogen atom, C
1-6alkyl or halo C
1-6alkyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino or C
1-6alkoxyl group;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl or C
3-8cycloalkyl;
R
4for hydrogen atom or C
1-6alkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2 or 3.
Another concrete technical scheme of the present invention is as follows, provides the compound shown in following logical formula II, its pharmacy acceptable salt or its steric isomer:
Wherein, general formula (I) has following structure:
R
1for COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, halo C
1-6alkyl, halo C
1-6alkoxyl group, halogen atom, C
1-6alkyl, C
1-6alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl or C
1-6alkylamino;
Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl or C
3-8cycloalkyl;
R
4for hydrogen atom or C
1-4alkyl;
R
5for hydrogen atom, C
1-4alkyl, halo C
1-4alkyl or C
3-8cycloalkyl;
Y is CH
2or NR
2;
R
2for hydrogen atom, C
1-6alkyl or halo C
1-6alkane;
N
1, n
2, n
3, n
4be separately 0,1,2 or 3, and n
1and n
2can not be 0, n simultaneously
3and n
4can not be 0 simultaneously;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2 or 3.
In a preferred embodiment, the invention provides the compound shown in above-mentioned general formula (I), its pharmacy acceptable salt or its steric isomer, wherein:
R
1for COOR
d,-CON (R
e)
2or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, halo C
1-4alkyl, halo C
1-4alkoxyl group, halogen atom, C
1-6alkyl, C
1-6alkoxyl group or C
3-8cycloalkyl;
Ring C is phenyl, naphthyl or pyridyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl or halo C
1-6alkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, fluorine atom, chlorine atom, halo C
1-3alkyl or C
1-3alkyl;
R
4for hydrogen atom or C
1-4alkyl;
R
5for hydrogen atom, C
1-4alkyl, halo C
1-4alkyl or C
3-6cycloalkyl;
Y is CH
2or NR
2;
R
2for hydrogen atom or C
1-6alkyl;
N
1, n
2, n
3, n
4be separately 0,1 or 2, and n
1and n
2can not be 0, n simultaneously
3and n
4can not be 0 simultaneously;
M is selected from 0,1,2 or 3;
P is selected from 0,1 or 2.
Another concrete technical scheme of the present invention is as follows, provides the compound shown in following logical formula III, its pharmacy acceptable salt or its steric isomer:
Wherein, general formula (I) has following structure:
R
1for COOR
dor tetrazole base;
R
dfor hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, F atom, Cl atom, C
1-3alkyl or C
1-3alkoxyl group;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, amino, C
1-3alkyl or halo C
1-3alkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-3alkyl, halo C
1-3alkyl or C
1-3alkoxyl group;
R
3for hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl or C
1-3alkyl;
R
4for hydrogen atom or C
1-3alkyl;
R
5for hydrogen atom, C
1-3alkyl or halo C
1-3alkyl;
M is 0,1 or 2.
Detailed Description Of The Invention
" C of the present invention
1-6alkyl " refer to the alkyl of the straight or branched containing 1-6 carbon atom, comprising " C
1-4alkyl ", " C
1-3alkyl " etc., the example includes but not limited to such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1,1-dimethyl ethyl etc.Term " C
1-4alkyl ", " C
1-3alkyl " refer in above-mentioned example containing the specific examples of 1 to 4,1 to 3 carbon atom.
" C of the present invention
2-4thiazolinyl " refer to containing double bond carbonatoms and be the straight or branched thiazolinyl of 2-4; The example includes but not limited to such as vinyl, 1-propenyl, 2-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.
" C of the present invention
2-4alkynyl " refer to containing three key carbonatoms and be the alkynyl of the straight or branched of 2-4; The example includes but not limited to such as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl etc.
" C of the present invention
1-4alkoxyl group ", " C
1-4alkylamino ", " two (C
1-4alkyl) amino ", " C
1-4alkoxy carbonyl ", " C
1-4alkyl sulfenyl ", " C
1-4alkyl sulphonyl ", " C
1-4alkyl sulphinyl ", " C
1-4alkyl amino sulfonyl ", " C
1-4alkylamino sulfinyl ", refer to " C respectively
1-4alkyl-O-" group, " C
1-4alkyl-NH-" group, " (C
1-4alkyl)
2n-" group, " C
1-4alkyl-O-C (O)-" group, " C
1-4alkyl-S-" group, " C
1-4alkyl-SO
2-" group, " C
1-4alkyl-SO-" group, " C
1-4alkyl-SO
2-NH-", " C
1-4alkyl-SO-NH-" group, wherein " C
1-4alkyl " as defined hereinabove.
" C of the present invention
1-6alkoxyl group " refer to term " C
1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Preferred C
1-4alkoxyl group, more preferably C
1-3alkoxyl group.Term " C
1-4alkoxyl group ", " C
1-3alkoxyl group " refer to term " C
1-4alkyl ", " C
1-3alkyl " group that is connected with other structures by Sauerstoffatom.
" C of the present invention
1-6alkylamidoalkyl " refer to " C
1-6alkyl " group that is connected with other structures by amide group.
" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine etc.
" C of the present invention
3-8cycloalkyl " be the cyclic alkyl containing 3-8 carbon atom; comprising such as " 3-6 unit cycloalkyl ", " 4-6 unit cycloalkyl ", " 5-7 unit cycloalkyl ", " 5-6 unit cycloalkyl "; 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.
" 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.
" 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.
" C of the present invention
3-8heterocyclylalkyl " refer to C
3-8one or more carbon atom in cycloalkyl by S, O, N, C (O), SO and/or SO atom replace the group that derives, wherein said " C
3-8cycloalkyl " as mentioned before.Comprise 3-8 unit single heterocyclic radical, C hereinafter described
4-6heterocyclylalkyl.C of the present invention
4-6heterocyclylalkyl " refer in above-mentioned example containing the specific examples of 4-6 annular atoms.
" 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.
" 3-14 unit heterocyclic radical " of the present invention refers to that described " heteroatoms " refers to N, S, O, SO and/or SO containing one or more heteroatomic 3-14 cyclic group
2deng.Comprise saturated, fractional saturation, the undersaturated 1-4 of having and be selected from N, S, O, SO and/or SO
2the two heterocyclic radical of the heteroatomic 3-8 single heterocyclic radical of unit and 5-14 unit.Also comprise 5-14 unit's heteroaryl and dihydro and tetrahydro-analogue.The two heterocyclic radical of 5-14 unit comprises saturated, fractional saturation, a undersaturated 1-4 of having and is selected from N, S, O, SO and/or SO
2heteroatomic and ring, volution, bridged ring.Preferred 3-8 unit heterocyclic radical, further preferred saturated, the single heterocyclic radical of fractional saturation, undersaturated 3-8 unit.More preferably 5-8 unit, first, the first heterocyclic radical of 5-6 of 5-7, further preferred first, the first single heterocyclic radical of 5-6 of saturated, fractional saturation, undersaturated 5-8 unit, 5-7.
The single heterocyclic radical of 3-8 unit, refers to the monocyclic heterocycles base containing 3-8 annular atoms (wherein at least containing a heteroatoms), comprises the unsaturated single heterocyclic radical of 3-8 unit, 3-8 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 3-8 unit.The unsaturated single heterocyclic radical of preferred 5-7 unit, 5-7 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 5-7 unit.The unsaturated single heterocyclic radical of 3-8 unit, what refer to aromaticity contains heteroatomic cyclic group, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 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, 2, 4, 5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.3-8 unit fractional saturation list heterocyclic radical, refer to containing double bond, heteroatomic cyclic group, specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline bases, 3,4-dihydro-2H-pyranyls, 5,6-dihydro-4H-1,3-oxazinyl etc.The saturated single heterocyclic radical of 3-8 unit, refer to be all saturated bond containing heteroatomic cyclic group, specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
The described 1-4 of having is selected from N, S, O and/or SO
2heteroatomic and ring, volution, bridged ring, specifically refer to and a non-common carbon atom in ring, volution, bridged ring by N, S, O and/or SO
2heteroatoms substitute formed 6-14 unit and heterocyclic radical, 5-14 unit spiro heterocyclic radical, 5-14 unit bridge heterocyclic radical.
6-14 unit heterocyclic radical refer to containing 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees share each other two adjacent atoms couple together is formed and ring structure, comprise the unsaturated and first fractional saturation of heterocyclic radical, 6-14 of 6-14 unit and the first saturated and heterocyclic radical of heterocyclic radical, 6-10.Unsaturated and the heterocyclic radical of 6-14 unit, refer to that whole rings is undersaturated condensed cyclic structure, the structure that single heterocyclic radical as unsaturated in benzo 3-8 unit is formed, the structure etc. that the 3-8 unsaturated single heterocyclic radical of unit the unsaturated single heterocyclic radical of 3-8 unit are 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. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.6-14 unit fractional saturation heterocyclic radical, refer to the condensed cyclic structure at least containing a fractional saturation ring, as the structure that benzo 3-8 unit fractional saturation list heterocyclic radical is formed, the structure etc. that 3-8 unit's fractional saturation list heterocyclic radical 3-8 unit fractional saturation list heterocyclic radical are formed, specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1,2,3,4-Pyrrolidine also [3,4-c] pyrroles,
etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.Saturated and the heterocyclic radical of 6-10 unit, refer to that whole rings is saturated condensed cyclic structure, as the 3-8 saturated single heterocyclic radical of unit and the saturated single heterocyclic radical of 3-8 unit the structure that formed, specific examples includes but are not limited to: tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl,
etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-14 unit bridge heterocyclic radical refers to the caged scaffold formed by 5-14 annular atoms (wherein at least containing a heteroatoms).
Specific examples includes but not limited to:
etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-14 unit spiro heterocyclic radical refers to the spirane structure formed by 5-14 annular atoms (wherein at least containing a heteroatoms).Specific examples includes but are not limited to:
etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
" 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 4-7 unit, the single heteroaryl of 5-8 unit, the single heteroaryl of 5-6 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.
" 4-7 unit heteroaryl " refers to the aromatic radical formed containing 4-7 annular atoms (wherein at least containing a heteroatoms), comprise " 5-7 unit heteroaryl " " 5-6 unit heteroaryl ", its specific examples includes but not limited to such as furans, pyrroles, thiophene, imidazoles, oxazole, isoxzzole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine etc.
" volution base " of the present invention refers to that a class has at least two rings to share the 5-14 unit condensed cyclic structure of an atom formation.Its specific embodiment includes but are not limited to: spiral shell [3.3] heptane base, spiral shell [3.4] octyl, spiral shell [3.5] nonyl, spiral shell [4.4] nonyl, spiral shell [3.4] oct-6-ene base, spiral shell [3.5]-6-in ninth of the ten Heavenly Stems thiazolinyl, spiral shell [4.4]-6-in ninth of the ten Heavenly Stems thiazolinyl, spiral shell [4.4] ninth of the ten Heavenly Stems-2,7-dialkylene, 2-oxa-spiroheptane base, 6-oxaspiro [2.5] octyl, 4-oxa--7-amido spiral shell [2.5] octyl, 2-amido spiral shell [3.3] heptane base, 2-oxa--6-amido spiral shell [3.3] heptane base, 2-amido spiral shell [3.4] octyl, 6-oxa--2-amido spiral shell [3.4] octyl, 2-oxa--6-amido spiral shell [3.4] octyl, 2-oxaspiro [3.4] octyl, 5-oxaspiro [3.5] nonyl, 7-amido spiral shell [3.5] nonyl, 2-amido spiral shell [4.4] nonyl, 2-oxa--7-amido spiral shell [4.4] nonyl, 2-oxaspiro [4.4] nonyl, 1,7-dioxo spiro [4.4] nonyl, Isosorbide-5-Nitrae, 7-trioxa spiral shell [4.4] nonyl, pungent-7-the thiazolinyl of 6-amido spiral shell [3.4], pungent-7-the thiazolinyl of 2-oxa--6-amido spiral shell [3.4], 7-amido spiral shell [3.5]-5-in ninth of the ten Heavenly Stems thiazolinyl, 2-amido spiral shell [4.4]-7-in ninth of the ten Heavenly Stems thiazolinyl etc.
The above all group all can further by one to four Q in those skilled in the art's cognitive range
1replace, Q
1represent halogen atom, C
1-3alkyl, amino, C
1-3alkylamino, two-(C
1-3alkyl) amino, hydroxyl, C
1-3alkoxyl group, C
1-3carbalkoxy, formamyl, C
1-3alkyl-carbamoyl, two-(C
1-3alkyl) formamyl or 3-6 unit cycloalkyl, wherein Q
1can be identical or different.
Particularly preferred compound comprises:
The present invention includes all stereoisomeric forms in any ratio of formula (I) compound, such as all enantiomers and diastereomer, comprise cis/trans isomer.The present invention also comprises the mixture of two or more stereoisomeric forms in any ratio, all proportions mixture of such as enantiomer and/or diastereomer (comprising cis/trans isomer).The asymmetric center (such as in the alkyl not replacing or replace) comprised in formula (I) compound all can have S configuration or R configuration independently of one another.The present invention relates to enantiomer and comprise levo-enantiomer and dextrorotatory antipode, it is the form of mixtures of the substantially pure form of enantiomeric pure form and enantiomer (such as, the mol ratio of two kinds of enantiomers is 99:1 or larger) and all proportions in racemate forms with in two kinds of enantiomers.The invention still further relates to diastereomer, it is the substantially pure form of diastereisomericallypure pure form and diastereomer and all proportions form of mixtures in two or more diastereomers.The present invention also comprises all cis/trans isomer of formula (I) compound, and it is pure form and substantially pure form (mol ratio of such as cis/trans isomer is 99:1 or larger) and in cis-isomeride with all proportions form of mixtures of trans-isomer(ide).Cis/trans isomery such as can to betide in the ring of replacement (such as in ring A) and betide in double bond.If needed, independent steric isomer can be prepared as follows: split mixture according to conventional methods, such as, by chromatography or crystallization, or in synthesis, uses initial compounds homogeneous with regard to stereochemistry, or passes through Stereoselective reaction.Optionally, derivatize can be carried out before separation of stereoisomers.The separation of stereoisomer mixture can be carried out or intermediate stage in building-up process carries out in formula (I) the compound stage.The present invention also comprises all tautomeric forms of formula (I) compound.
Clinically, formula (I) compound, its steric isomer can in a free form or its pharmacy acceptable salt form use.On the physiology of formula (I) compound, acceptable salt (comprising pharmacologically acceptable salt) generally includes non-toxic salt component.They can comprise component of inorganic salts or organic salt component.Above-mentioned salt can such as be formed by comprising formula (I) compound of acidic-group (such as carboxyl (hydroxycarbonyl group or HO-C (O)-)) and non-toxic inorganic or organic bases.Suitable alkali is such as alkali metal compound or alkaline earth metal compound (as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate) or ammonia, organic amino compounds and quaternary ammonium hydroxide.Formula (I) compound and alkali carry out usually according to conventional methods for the preparation of the reaction of salt in solvent or thinner.Therefore, the example of the salt of acidic-group is sodium salt, sylvite, magnesium salts, calcium salt or ammonium salt, and described ammonium salt also can with one or more organic group on nitrogen-atoms.Comprise basic group can formula (I) compound of protonated group (the such as amino or basic heterocycle) form of acid salt that can be formed by acid acceptable on itself and physiology exist, such as exist by the form of the salt formed with following acid: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, phenylformic acid, methylsulfonic acid, tosic acid, described acid salt usually can according to conventional methods in solvent or thinner through type (I) compound and acid-respons prepare.If formula (I) compound comprises acidity and basic group in the molecule simultaneously, then the present invention also comprises inner salt (betaine or zwitter-ion compounds) except mentioned salt form.The present invention also comprises all following salt of formula (I) compound, described salt is unsuitable for because physiological tolerance is low being directly used as medicine, but is suitable for as intermediate for chemical reaction or for the preparation of salt acceptable on physiology (such as by anionresin or cationic exchange).The present invention also comprises the active metabolite of formula (I) compound; With the prodrug of formula (I) compound, namely not necessarily may demonstrate pharmacologically active in vitro but be converted into the compound of pharmaceutically active compounds formula (I) in vivo, such as be hydrolyzed by metabolism and be converted into the compound of formula (I) compound, as the compound that wherein carboxyl exists with esterified form or amide form thereof.
On formula (I) compound and physiology thereof, acceptable salt such as can be used for the treatment of cardiovascular disorder such as heart failure and (comprise systole heart failure, diastolic heart failure, the diabetic heart failure with keeping ejection fraction in heart failure), myocardosis, myocardial infarction, Myocardial Remodeling (Myocardial Remodeling after comprising infraction or after heart operation), vascular remodeling (comprising arteriosclerosis), hypertension (comprises pulmonary hypertension, portal hypertension and systolic hypertension), atherosclerosis, Peripheral arterial occlusive disease (PAOD), restenosis, thrombosis or vascular permeability disease, for Cardioprotective as the Cardioprotective after myocardial infarction or after heart operation, for protection renal or be used for the treatment of inflammation or inflammatory diseases as rheumatoid arthritis, osteoarthritis, ephrosis is as necrosis of renal papillae or renal failure (comprising the renal failure after ischemia/reperfusion), pulmonary disorder is as chronic obstructive pulmonary disease (COPD), asthma or adult respiratory distress syndrome (ARDS), immunological disease, allergic disease, tumor growth, transfer, metabolic trouble, fibrotic conditions is as pulmonary fibrosis (comprising idiopathic pulmonary fibrosis), cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis (comprising renal interstitial fibrosis), hepatic fibrosis, fibering skin disorder (comprises keloid to be formed, collagenosis, scleroderma, progressive systemic sclerosis and kidney source property fibering tetter) or the fibrosis (comprising Dupuytren ' s contracture) of other type, psoriasis, pain is (as neuropathic pain, diabetic pain or inflammatory pain), itch, retinal ischemia/reperfusion injury, macular degeneration, psychosis, neurodegenerative disease, cranial nerve disorder, peripheral nerve obstacle, endocrine disorder is as hyperthyroidism, cicatrization obstacle or wound healing obstacle.Following implication should be interpreted as: treat existing pathology or the dysfunction in organism or treat existing symptom by the treatment of disease, its objective is alleviation, improve or cure, with prevention or prevent the pathology in organism or dysfunction or prevention or prevent the symptom in the mankind or animal, the described mankind or animal are easy to occur described symptom and need above-mentioned prevention or prevent, and its objective is the generation preventing or suppress them or the effect weakening them when they occur.Such as, in the patient thinking easy trouble myocardial infarction based on its medical history, by preventative or protective medical treatment, the generation of myocardial infarction or recurrence can be prevented or reduce its degree and sequela, or in the patient to be easily disturbed in wound healing, by preventative or protective medical treatment, can advantageously affect postoperative wound healing.Can carry out under acute situations and chronic case the treatment of disease.Effect of formula (I) compound can confirm in following pharmacology test and other test well known by persons skilled in the art.
Therefore, acceptable salt on formula (I) compound and physiology thereof, by with the form of mixtures of another kind of formula (I) compound or the form of pressing pharmaceutical composition and for animal, particularly Mammals and the especially mankind.The present invention's theme is also for being used as acceptable salt on formula (I) compound of medicine and physiology thereof and comprising acceptable salt at least one formula (I) compound of effective dose and/or its physiology as the pharmaceutical composition of activeconstituents and pharmaceutically acceptable carrier (i.e. the vehicle of one or more pharmaceutical innocuous and/or vehicle) and one or more optional other medicines active compounds and medicine.The present invention's theme is also for being used for the treatment of acceptable salt on formula (I) compound of above-mentioned or following disease and physiology thereof, comprise treatment described disease in any one, such as heart failure or fibrotic conditions are as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, hepatic fibrosis or fibering skin disorder, the present invention's theme is also the purposes of acceptable salt in the medicine for the preparation of the above-mentioned or following disease for the treatment of on formula (I) compound and physiology thereof, comprise treatment described disease in any one, such as heart failure or fibrotic conditions are as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, hepatic fibrosis or fibering skin disorder, wherein above-mentioned treatment and prevention are comprised to the treatment of disease, and the present invention's theme be also on formula (I) compound and physiology thereof acceptable salt for the preparation of suppression LPA
1purposes in the medicine of acceptor.
The present invention's theme is also the method for the above-mentioned or following disease for the treatment of, described method comprise treatment described disease in any one, such as in heart failure or fibrotic conditions is as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, hepatic fibrosis or fibering skin disorder, and described method comprises to there being acceptable salt at least one formula (I) compound of the mankind of these needs or animals administer significant quantity and/or its physiology.Formula (I) compound and comprise their pharmaceutical composition and medicine can administration as follows: by mode in stomach such as by oral, sublingual or rectal administration, by parenteral modes such as by intravenously, intramuscular, subcutaneous or peritoneal injection or infusion or by other administering mode such as by locally, in skin, transdermal, intraarticular, nose or eye drops.
Formula (I) compound, its pharmacy acceptable salt or its steric isomer also can with other therapeutic active substance coupling, described therapeutic active substance is as 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, autotaxin inhibitors, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anodyne, cough medicine, timid phlegm medicine, anticholinergic, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
On formula (I) compound and physiology thereof acceptable salt and solvate thereof also can with the coupling of other medicines active compound, wherein in above-mentioned coupling, on formula (I) compound and/or its physiology, acceptable salt and one or more other medicines active compounds can be present in same pharmaceutical composition, maybe can be present in two or more pharmaceutical compositions with separately, simultaneously or administration in succession.The example of above-mentioned other medicines active compound is angiotensin-converting enzyme (ACE) inhibitor, Ramipril, Angiotensin (I) (I) receptor subtype 1 (AT1) antagonist, irbesartan, antiarrhythmics, Dronedarone, peroxisome proliferator activated receptor-α (PPAR-α) activator, peroxisome proliferator activated receptor-γ (PPAR-γ) activator, pioglitazone, rosiglitazone, prostanoid, endothelin receptor antagonists, bosentan, elastase inhibitor, calcium antagonist, beta blocker, diuretic(s), aldosterone receptor antagonist, eplerenone, renin inhibitor, rho kinase inhibitor, soluble guanylate cyclase (sGC) activator, sGC sensitizer, phosphodiesterase (PDE) inhibitor, PDE5 type (PDE5) inhibitor, NO donor, purple foxglove medicine, angiotensin-converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, Statins (stains), bile acide reuptake inhibitor, platelet-derived growth factor (PDGF) receptor antagonist, vasopressin antagonists, decorporation aqua, Sodium-hydrogen exchanger hypotype 1 (NHE1) inhibitor, prothrombin/prothrombin a antagonist, plasma thromboplastin component/factor IXa antagonist, factor X/factor Xa antagonist, factor XIII/factor XIII a antagonist, anti-coagulant, antithrombotic agent, platelet suppressant drug, short fibrinolytic agent, activated by thrombin fibrinolysis inhibitor (TAFI), PAI-1 (PAI 1), tonka bean camphor, heparin, thromboxane antagonist, 5-hydroxytryptamine antagonist, cyclooxygenase-2 inhibitors, acetylsalicylic acid, treatment antibody, glycoprotein iib/iiia (GPIIb/IIIa) antagonist (comprising ReoPro), chymotrypsin inhibitor, cytostatics, Taxan, taxol, Docetaxel, aromatase inhibitor, estrogen receptor antagon, selective estrogen receptor modulators (SERM), tyrosine kinase inhibitor, imatinib, receptor tyrosine kinase inhibitors, RAF kinase inhibitor, p38 mitogen-activated protein kinase (p38MAPK) inhibitor, pirfenidone, multiple kinase inhibitor and Xarelto.
The present invention's theme is also the described coupling of acceptable salt on any one or multiple formula (I) compound disclosed herein and physiology thereof and any one or multiple such as other medicines active compound described in one or both.
Pharmaceutical composition of the present invention and medicine usually comprise about 0.5 to about 90 % by weight formula (I) compound and/or its physiology on acceptable salt, and the amount of acceptable salt in each unitary dose is generally about 0.2mg to about 1000mg on formula (I) activeconstituents and/or its physiology, particularly about 0.2mg to about 500mg is such as about 1mg to about 300mg.According to kind and other concrete particular case of pharmaceutical composition, amount can depart from shown amount.Described pharmaceutical composition and medicine itself can be prepared in the known manner.Therefore, by acceptable salt on formula (I) compound and/or its physiology together with one or more solids or liquid vehicle and/or mixed with excipients, as required also with one or more other medicines active compound as described above, and be prepared as the form being suitable for administration, then can use it for people's medication or veterinary medicine.
As vehicle (it also can be described as thinner or weighting agent) and vehicle, can use suitable organic and inorganic substance, it can not react with formula (I) compound in an undesired manner.As the type instance of the vehicle that can comprise in pharmaceutical composition and medicine or additive, lubricant, sanitas, thickening material, stablizer, disintegrating agent, wetting agent can be mentioned, for realizing the material of depot effect, emulsifying agent, salt (such as affecting osmotic pressure), buffer reagent, tinting material, correctives and aromatoising substance.The example of vehicle and vehicle is that water, vegetables oil, wax, alcohol are (as ethanol, Virahol, 1,2-propylene glycol, phenylcarbinol or glycerine), polyvalent alcohol, polyoxyethylene glycol, polypropylene glycol, vanay, Polyvinylpyrolidone (PVP), gelatin, Mierocrystalline cellulose, carbohydrate (if lactose or starch are as W-Gum), sodium-chlor, stearic acid and salt thereof as Magnesium Stearate, talcum, lanolin, vaseline or their mixture, the mixture of such as salt solution or water and one or more organic solvents is as the mixture of water and alcohol.Oral and rectum is used, medicament forms can be used as tablet, film-coated tablet, sugar coated tablet, granule, hard-gelatin capsules and Gelseal, suppository, solution (comprising oily solution agent, alcoholic solution or aqueous solution agent), syrup, fruit juice agent or drops and suspensoid or emulsion.Parenteral is used, such as, by injection or infusion, medicament forms can be used as solution (such as aqueous solution agent).Local is used, medicament forms can be used as ointment, ointment, paste, lotion, gelifying agent, sprays, foaming agent, aerosol, solution or powder agent.Other suitable medicament forms is, such as implant and patch and be suitable for suck form.Also can by salt freeze-drying acceptable on formula (I) compound and physiology thereof, and the lyophilized products obtained, such as, for the preparation of composition for injection.Special in topical, liposome components is also suitable.Described pharmaceutical composition and medicine also can comprise one or more other activeconstituentss and/or such as one or more VITAMIN.Such as, described pharmaceutical preparation is oral preparations, injection, inhalation, nasal formulations, ophthalmic preparation, nasal formulations, transdermal formulation, rectal administration preparation, ointment or gelifying agent etc.
Usually, the dosage of formula (I) compound depends on concrete situation and is adjusted according to customary rule and method by doctor.Its such as depend on formula (I) compound of institute's administration and effect thereof and acting duration, individual syndromic character and severity, the sex of the mankind to be treated or animal, age, body weight and individual response, treatment be whether acute chronic or preventative or except formula (I) compound whether also administration other medicines active compound.Usually, when to body weight being adult's administration of about 75kg, the dosage of about 0.1mg/kg/ days to the about 100mg/kg/ days particularly dosage (in each case with mg/kg batheroom scale) of about 1mg/kg/ days to about 10mg/kg/ days is enough.Per daily dose or can be divided into multiple independent dosage form (such as two, three or four independent dosage) and carrys out administration by single dose form.Administration also can be carried out continuously, such as, by injecting continuously or infusion.Individual behavior as the case may be, may need to depart from shown dosage up or down.
Except in people's medication and veterinary medicine as except pharmaceutical active compounds, formula (I) compound also can as auxiliary or be used as science tools or for diagnostic purpose (such as needing to suppress in the biological sample in-vitro diagnosis of Edg-2 acceptor) in biochemical research.Formula (I) compound and salt thereof also can be used as the intermediate for the preparation of other medicines active substance.
The compounds of this invention, compared with immediate prior art, has the following advantages:
(1) formula (I) compound or its pharmacy acceptable salt have good LPA
1restraining effect and side effect is little;
(2) formula (I) compound or its pharmacy acceptable salt demonstrate good biologically stable, and effect is more lasting, and bioavailability is high;
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.
Set forth the compounds of this invention beneficial effect further below by way of pharmacological evaluation, but this should be interpreted as the compounds of this invention only has following beneficial effect.
the pharmacological activity test of test example the compounds of this invention
the external hLPA1 avidity experiment of I the compounds of this invention
Trial-product:
Cell: the LPA of stably express people
1the mammalian cell of acceptor
Part: [H
3] LPA
The compounds of this invention: self-control, its chemical name and structural formula and preparation method are shown in the preparation embodiment of each compound.
Experimental technique:
Select the cell of suitable concn, overnight incubation.Add 2nM [H
3] LPA, detection compound and 10 μMs of LPA incubated at room 90min.By detecting [H
3] binding activities of LPA, the combination rate of non-specific binding 10 μMs of LPA can be drawn.
Data analysis: detect and LPA non-specific binding rate according to result, then with add the concentration of compound
Analysis software Prism5.0 is utilized to carry out calculating IC
50value.
Experimental result: as follows:
The antagonistic action of the external LPA1 receptor affinity of table 1 the compounds of this invention
Experiment conclusion:
From table, the compounds of this invention has good antagonistic action to LPA1 receptor affinity.
the hLPA1 cell calcium current experiment of I the compounds of this invention
Experiment material:
Cell: the LPA of stably express people
1the mammalian cell (Cat#C1048-6) of acceptor
Blank: LPA
1(Cayman Cat#10010291)
Calcium current detection kit: (AAT Bioquest, Cat#36315)
Instrument: fluorescence imaging plate reader 3 (Molecular Devices)
Experimental technique:
Select suitable cell concn, join on 384 orifice plates, overnight incubation.Add agonist LPA and calcium fluoroscopic examination damping fluid 37 DEG C hatches 1h, monitoring cell calcium current 90s, by software prism5.0, calculates EC
80value.Add detection compound (amounting to 8 concentration gradients), hatch 30min, adopt the method for fluorescence to detect cell calcium current.
Data analysis: compound on intracellular calcium current detected by the method for fluorescence, with the EC of LPA to cell calcium current
80value does ratio, obtains the inhibiting rate of compound on intracellular calcium current.Again by adding the concentration of compound, prism5.0 software is utilized to carry out calculating IC
50value.
Experimental result: as follows:
Table 2 the compounds of this invention to hLPA
1the antagonistic action of cell calcium current
Experiment conclusion:
According to hLPA1 cell calcium current experimental result, compound all presents the drug effect of dose-dependently substantially, according to IC
50value judges, drug effect is relatively better.
4, 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.
Reference literature US20100152257A1 synthesizes following intermediate:
the embodiment 1 2-(preparation of 4 '-(3-methyl-4-(((R)-(1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid (compound 1)
(1) preparation of cyclobutyl-1,1-dimethanol
In 500mL reaction flask, by cyclobutyl-1,1-dicarboxylic acid (14.4g, 0.1mol) is dissolved in 300mL THF, under ice-water bath, add LiALH4 (15.2g in batches, 0.4mol), after reacting 2h under frozen water, use ethyl acetate cancellation, add 4N hydrochloric acid tune and be dissolved in clarification, separatory, obtains the thick product of 11g after drying is concentrated.Rate 95%, this product is directly used in next step reaction.
The preparation of (2) 1,1-bis-(methylsulfonyl methylene radical) tetramethylene
In 500mL reaction flask, by cyclobutyl-1,1-dimethanol (11g, 95mmol) is dissolved in 300mL DCM, drips methylsulfonyl chloride (22.9g under ice-water bath, 0.2mol), after reacting 2h under room temperature, add water, concentrated after saturated sodium bicarbonate washing, 8.9g product is obtained, productive rate 34% with Diethyl ether recrystallization.
The preparation of (3) 1,1-bis-(brooethyl) tetramethylene
In 500L reaction flask, by 1,1-bis-(methylsulfonyl methylene radical) tetramethylene (2.63g; 13.3mmol) be dissolved in 20mL DMF with lithiumbromide (4.75g, 53.3mmol), 85 degree of reaction 16h; extraction into ethyl acetate, concentrates to obtain 3.2g, productive rate 99%.This product is directly used in next step reaction.
(4) preparation of 2-(4-bromophenyl) spiral shell [3.3] heptane-2-ethyl formate
In 50mL reaction flask, 4-bromo-acid ethyl ester (3.2g, 13.2mmol) is dissolved in 20mL DMF, 60%NaH (1.58g is added under ice-water bath, 40mol), after stirring reaction half an hour, 1 is added, 1-bis-(brooethyl) tetramethylene (3.2g, 13.3mmol), react 16h under room temperature and to add water cancellation, extraction into ethyl acetate, 2.27g product is obtained, productive rate 53% after drying is concentrated.。
(5) 2-4-(4,4,5,5-tetramethyl--1,3,2-dioxaborolane-2-base) phenyl) preparation of spiral shell [3.3] heptane-2-ethyl formate
By 2-(4-bromophenyl) spiral shell [3.3] heptane-2-ethyl formate (2.27g, 7mmol), Potassium ethanoate (1.37g, 14mmol), duplex tetramethyl ethylene ketone boric acid ester (1.79g, 7mmol) and 50mg Pd (dppf) Cl2 are dissolved in 50ml Isosorbide-5-Nitrae-dioxane, lower the temperature after back flow reaction 2h, add 100ml water, PE extracts (100ml X 3), saturated common salt water washing, anhydrous sodium sulfate drying, obtains 3.0g crude product after concentrated.
(6) 2-(4 '-(3-methyl-4-(((R)-(1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid, ethyl ester
In 250ml single port bottle, 2-4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxaborolane-2-base) phenyl) spiral shell [3.3] heptane-2-ethyl formate (700mg, 1.89mmol), 5-(4-bromophenyl)-3-methyl-isoxazole-4-base amido carboxylic acid-((R)-1-phenyl chlorocarbonate) (370mg, 0.92mmol), anhydrous sodium carbonate (157mg, 1.48mmol) be dissolved in 20ml 1 with 50mg Pd (dppf) Cl2, in 4-dioxane, add 2ml water, after nitrogen exchanges after back flow reaction, extraction into ethyl acetate (200ml X 3), saturated common salt water washing, anhydrous sodium sulfate drying, directly next step is entered after concentrated.
(7) 2-(4 '-(3-methyl-4-(((R)-(1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid
In 100ml single port bottle, by previous step product 2-(4 '-(3-methyl-4-(((R)-(1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid, ethyl ester and sodium hydroxide (1g, 0.025mmmol), be dissolved in 10ml 1, in 4-dioxane and 10ml water, after 50 DEG C of reaction 2h, regulate pH<7, extraction into ethyl acetate (200ml X 3), saturated common salt water washing, anhydrous sodium sulfate drying, be dissolved in acetonitrile after concentrated and add ISCO reversed phase chromatography separation after 1g C18 spice, acetonitrile/water (40% ~ 60%) is concentrated after eluting target compound, DCM extracts, product 20mg is obtained after drying, 2 steps react total yield 4%.
Mass spectrum (m/e): 536.9 (M+1)
1H NMR(CD
3OD,400MHz,δppm)δ:7.60-7.90(m,6H),7.10-7.45(m,7H),5.80(d,1H),2.93(d,2H),2.53(d,2H),2.18(s,3H),2.10(t,2H),1.80-1.91(m,4H),1.60(d,3H).
embodiment 2 2-(4 '-4-((1-(4-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) preparation of spiral shell [3.3] heptane-2-carboxylic acid (compound 2)
(1) 3-methyl-5-(4-(4,4,5,5-tetramethyl--1,3,2-dioxaborinate-2-base) phenyl) isoxazole-4-base amidocarbonic acid-(1-(4-fluorophenyl) ethyl ester)
Operation is with embodiment 1 (5), and this product is directly used in next step reaction without purification.
(2) 2-(4 '-4-((1-(4-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid, ethyl ester
Operate with embodiment 1 (6), productive rate 54%.
(3) 2-(4 '-4-((1-(4-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid
Operation is with embodiment 1 (7), and productive rate is 2.5%.
Mass spectrum (m/e): 555.2 (M+1)
1H NMR(CD
3OD,400MHz,δppm)δ:7.79(d,2H),7.69(d,2H),7.62(d,2H),7.48(m,2H),7.44(d,2H),7.12(t,2H)，5.81(m,1H),2.93(d,2H),2.52(d,2H),2.18(s,3H),2.10(t,2H),1.80-1.91(m,4H),1.60(d,3H).
embodiment 3 2-(4 '-4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) preparation of spiral shell [3.3] heptane-2-carboxylic acid (compound 3)
(1) 2-(4 '-4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid, ethyl ester
Operate with embodiment 1 (6), productive rate 62%.
(2) 2-(4 '-4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) xenyl)-4-base) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 25%.
Mass spectrum (m/e): 555.2 (M+1)
1H-NMR(400MHz,CDCl
3,δppm)δ:1.40-1.50(m,3H),1.78-1.93(m,4H),2.10-2.20(m,2H),2.20-2.30(m,3H),2.50-2.60(d,2H),2.95-3.05(d,2H),6.00-6.20(m,1H),6.90-7.20(m,3H),7.30(m,1H),7.40-7.50(m,2H),7.52-7.64(m,4H),7.75-7.83(s,2H).
the embodiment 4 2-(preparation of 4-(5-(3-methyl-4-(((R)-1-phenyl ethoxy) carbonylamino) isoxazole-5-base) pyridine-2 base) phenyl) spiral shell [3.3] heptane-2-carboxylic acid (compound 4)
(1) 2-(4-(5-(3-methyl-4-(((R)-1-phenyl ethoxy) carbonylamino) isoxazole-5-base) pyridine-2 base) phenyl) spiral shell [3.3] heptane-2-carboxylic acid, ethyl ester
Operate with embodiment 1 (6), productive rate 50%.
(2) 2-(4-(5-(3-methyl-4-(((R)-1-phenyl ethoxy) carbonylamino) isoxazole-5-base) pyridine-2 base) phenyl) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 3.2%.
Mass spectrum (m/e): 538.2 (M+1)
1H NMR(MeOD,400MHz,ppm)δ:8.98(s,1H),8.10(m,1H),7.97(d,2H),7.87(d,1H),7.00-7.60(m,7H),5.81(d，1H),2.94(d,2H),2.53(d,2H),2.19(s,3H),2.10(t,2H),1.60-1.91(m,4H),1.60(d,3H).
the preparation of embodiment 5 2-(6-4-(3-methyl-4-(((R)-1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylic acid (compound 5)
(1) 2-(6-4-(3-methyl-4-(((R)-1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylate methyl ester
Operate with embodiment 1 (6), productive rate 33%.
(3) 2-(6-4-(3-methyl-4-(((R)-1-benzene oxyethyl group) carbonylamino) isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 21%.
Mass spectrum (m/e): 538.3 (M+1)
1H NMR(CD
3OD,400MHz,δppm)δ:8.6(s,1H),8.0(d,2H),7.9-7.8(m,4H),7.4-7.3(m,4H),7.1(d,1H),5.8(d,1H),2.9(d,2H),2,5(d,2H),2.1(s,3H),2.0(m,2H),1.9-1.8(m,4H),1.5(d,3H).
the preparation of embodiment 6 2-(6-(4-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylic acid (compound 6)
(1) 2-(6-(4-(4-((-1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylate methyl ester
Operate with embodiment 1 (6), productive rate 20%.
(2) 2-(6-(4-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridin-3-yl) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 40%.
Mass spectrum (m/e): 556.2 (M+1)
1H NMR(DMSO,400MHz,δppm)δ:12.6-12.4(br,1H),8.6(s,1H),8.2(d,2H),8.0(d,1H),7.9-7.8(m,2H),7.7(d,1H),7.5(m,1H),7.3(m,1H),7.2-7.1(m,2H),7.0-7.1(m,1H),5.9(d,1H),2.9(d,2H),2,5(d,2H),2.0(s,3H),2.0(m,2H),1.9-1.8(m,2H),1.5(m,2H),1.1(d,3H).
the preparation of embodiment 7 2-(5-(4-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridine-2-base) spiral shell [3.3] heptane-2-carboxylic acid (compound 7)
(1) 2-(5-(4-(4-((-1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridine-2-base) spiral shell [3.3] heptane-2-carboxylate methyl ester
Operate with embodiment 1 (6), productive rate 36%.
(2) 2-(5-(4-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) phenyl) pyridine-2-base) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 3.8%.
Mass spectrum (m/e): 556.2 (M+1)
1H NMR(DMSO,400MHz,δppm)δ:9.45(s,1H),8.73(s,1H),7.90-7.95(d,1H),7.80-7.85(m,4H),7.52-7.58(m,1H),7.38-7.43(m,2H),7.28-7.33(m,1H),7.20-7.26(m,1H),5.92-5.98(m,1H),2.68-2.72(m,2H),2.43-2.50(m,2H),2.12-2.17(s,3H),1.92-1.97(m,2H),1.68-1.73(m,4H),1.52-1.58(d,3H).
the preparation of embodiment 8 2-(4-(5-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridine-2-base) phenyl) spiral shell [3.3] heptane-2-carboxylic acid (compound 8)
(1) 2-(4-(5-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridine-2-base) phenyl) spiral shell [3.3] heptane-2-carboxylate methyl ester
Operate with embodiment 1 (6), productive rate 57%.
(2) 2-(4-(5-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridine-2-base) phenyl) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 26%.
Mass spectrum (m/e): 556.3 (M+1)
1H NMR(DMSO,400MHz,δppm)δ:12.38(s,1H),9.51(s,1H),9.00(s,1H),8.06-8.15(m,4H),7.53(s,1H),7.40(d,J＝8.0Hz,3H),7.22-7.30(m,2H),5.95(d,J＝6.8Hz,1H),2.84(d,J＝12.4Hz,2H),2.45(d,J＝12.4Hz,2H),2.14(s,3H),2.00-2.04(m,2H),1.74-1.83(m,4H),1.57(s,3H).
the preparation of embodiment 9 2-(4-(6-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridin-3-yl) phenyl) spiral shell [3.3] heptane-2-carboxylic acid (compound 9)
(1) 2-(4-(6-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridin-3-yl) phenyl) spiral shell [3.3] heptane-2-carboxylate methyl ester
Operate with embodiment 1 (6), productive rate 60%.
(2) 2-(4-(6-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base) pyridin-3-yl) phenyl) spiral shell [3.3] heptane-2-carboxylic acid
Operate with embodiment 1 (7), productive rate 25%.
Mass spectrum (m/e): 556.2 (M+1)
1H NMR(CD
3OD,400MHz,δppm)δ:8.85(s,1H),8.08(d,1H),7.82(d,2H),7.06-7.70(m,8H),6.06(m,1H),2.93(d,2H),2.51(d,2H),2.26(s,3H),2.10(s,2H),1.80-1.91(m,4H),1.60(d,3H).
the preparation of embodiment 10 2-(5'-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base)-2,2'-bis-pyridine-5-bases) spiral shell [3.3] heptane-2-carboxylic acid (compound 10)
(1) synthesis of compound 10-1
Add 10-0 (1g, 3.8mmol) in reaction flask, NaI (2.8g, 18.9mmol), be dissolved in 30mL acetonitrile, add 0.5mL hydrochloric acid, stir, 110 DEG C are reacted 10 hours.Then add diluted ethyl acetate, washing, adds saturated common salt water stratification, organic phase anhydrous Na
2sO
4drying, concentrated, column chromatography (PE/EA=50:1) purifying obtains compound 10-1, yellow oil, 1g, productive rate 77%.
(2) synthesis of compound 10-2
By 10-1 (1g, 2.8mmol), connection boric acid pinacol ester (853mg, 3.4mmol), KOAc (549mg, 5.6mmol) and Pd (dppf) Cl
2(100mg) 20mL Isosorbide-5-Nitrae-dioxane is dissolved in, microwave 90 DEG C of stirring reactions 1 hour. cooling, is spin-dried for solvent, and column chromatography purification (PE/EA=30:1) obtains 700mg compound 10-2, productive rate 70%.
(3) synthesis of compound 10-3
By compound 10-2 (700mg, 2mmol), compd A-7 (735mg, 2mmol), Cs
2cO
3(1.3g, 4mmol) and Pd (dppf) Cl
2(100mg) join in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water (20mL, 5:1), microwave 120 DEG C of stirring reactions 1 hour.Cooling, be spin-dried for solvent, column chromatography purification (PE/EA=3:1) to obtains 80mg compound 10-3, and productive rate is 7.2%.
(4) synthesis of 2-(5'-(4-((1-(2-fluorophenyl) oxyethyl group) carbonylamino)-3-methyl-isoxazole-5-base)-2,2'-bis-pyridine-5-bases) spiral shell [3.3] heptane-2-carboxylic acid
Compound 10-3 (80mg, 0.14mmmol) and NaOH (11mg, 0.28mmol) is joined MeOH/H
2in O (12mL, 5:1), 65 DEG C of stirring reactions 5 hours.Add water dilution after being spin-dried for solvent, reaction solution hcl acidifying generates to there being solid, and filter, it is 38% that solid drying obtains 30mg compound 10 productive rate.
LC-MS:(ES,m/z):557.2[M+H]
+
1H NMR(CDCl
3,400MHz,δppm)δ:1.62(m,3H),1.80～1.89(m,4H),2.12～2.19(m,2H),2.29(s,3H),2.58(d,J＝12.4Hz,2H),3.03(d,J＝12.4Hz,2H),6.13(d,J＝6.4Hz,1H),6.92～7.27(m,3H),7.40～7.56(m,1H),7.77(d,J＝8.4Hz,1H),8.11(s,1H),8.39(m,2H),8.67(s,1H),9.05(s,1H)。
Claims (10)
1. the compound shown in general formula (I), its pharmacy acceptable salt, and steric isomer:
Wherein, R
1for-COOR
d,-SR
d,-SOR
d,-SO
2r
d,-CONHSO
2r
d,-CON (R
e)
2,-N (R
e) COR
d,-N (R
e) COOR
d,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom, C
1-6alkyl, C
3-8cycloalkyl, 6-14 unit's aryl or 3-14 unit heterocyclic radical;
Ring A and ring B is separately 6-14 unit aryl, 3-14 unit's heterocyclic radical or C
3-8cycloalkyl;
Ring C is 6-14 unit's aryl or 4-7 unit heteroaryl;
Ring D and ring E is separately C
3-8cycloalkyl or C
3-8heterocyclylalkyl, and the shared carbon atom of ring D and ring E is fused into volution, described C
3-8cycloalkyl and C
3-8heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4,5 or 6: halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl, C
1-6alkoxyl group or halo C
1-6alkoxyl group;
R
aand R
bbe separately hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
3-8cycloalkyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
5-8cycloalkenyl group C
1-6alkyl, C
2-6alkynyl, C
1-6alkylthio, phenyl, phenyl C
1-6alkyl, naphthyl, C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino, C
1-6alkyl-carbonyl, C
1-6alkyl-carbamoyl, formamido group, C
1-6alkyl amido, C
1-6alkyl sulphonyl, C
1-6alkyl amino sulfonyl, C
1-6alkyl sulfonyl is amino, two (C
1-6alkyl) formamyl, two (C
1-6alkyl) amino-sulfonyl, C
1-6carbalkoxy or C
1-6alkyl carbonyl oxy;
R
cfor hydrogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkylthio, C
1-6alkylamino or two (C
1-6alkyl) amino;
R
3for hydrogen atom, hydroxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
2-6alkynyl, C
1-6alkylthio, C
1-6alkylamino or two (C
1-6alkyl) amino;
R
4for hydrogen atom, C
1-6alkyl or C
3-8cycloalkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl or C
1-6alkoxyl group;
M is selected from 0,1,2,3,4 or 5;
P is selected from 0,1,2,3 or 4.
2. compound as claimed in claim 1, its pharmacy acceptable salt, and steric isomer:
Wherein, R
1for-COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-N (R
e) COR
d,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom, C
1-6alkyl or C
3-8cycloalkyl;
Ring A and ring B is separately 6-14 unit aryl, 4-7 unit's heteroaryl or C
3-8cycloalkyl;
Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
Ring D and ring E is separately C
3-6cycloalkyl or C
4-6heterocyclylalkyl, and the shared carbon atom of ring D and ring E is fused into volution, described C
3-6cycloalkyl and C
4-6heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3,4 or 5: halogen atom, hydroxyl, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group, C
3-8cycloalkyl C
1-6alkyl, C
2-6thiazolinyl, C
3-8cycloalkyl C
2-6thiazolinyl, C
5-8cycloalkenyl group, C
5-8cycloalkenyl group C
1-6alkyl, C
2-6alkynyl, C
1-6alkylthio, phenyl, phenyl C
1-6alkyl, naphthyl, C
3-8heterocyclylalkyl, C
3-8heterocyclylalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino or C
1-6alkyl-carbonyl;
R
cfor hydrogen atom, cyano group, nitro, hydroxyl, amino, halogen atom, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
1-6alkoxyl group, halo C
1-6alkoxyl group or C
3-8cycloalkyl C
1-6alkyl;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl, C
3-8cycloalkyl or C
3-8cycloalkyl C
1-6alkyl;
R
4for hydrogen atom or C
1-6alkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2,3 or 4.
3. compound as claimed in claim 2, its pharmacy acceptable salt, and steric isomer:
Wherein, R
1for-COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
Ring A and ring B is separately phenyl, naphthyl, benzo C
3-8cycloalkyl, 5-6 unit heteroaryl;
Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
Ring D and ring E is separately C
3-6cycloalkyl or C
4-6heterocyclylalkyl, and the public carbon atom of ring D and ring E is fused into volution, described C
3-6cycloalkyl and C
4-6heterocyclylalkyl can optionally be replaced independently selected from following substituting group by 1,2,3 or 4: halogen atom, C
1-6alkyl or halo C
1-6alkyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl, C
1-6alkylamino, two (C
1-6alkyl) amino or C
1-6alkoxyl group;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl or C
3-8cycloalkyl;
R
4for hydrogen atom or C
1-6alkyl;
R
5for hydrogen atom, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2 or 3.
4. compound as claimed in claim 1, its pharmacy acceptable salt, and steric isomer:
Wherein, general formula (I) has following structure (II):
R
1for-COOR
d,-CONHSO
2r
d,-CON (R
e)
2,-CN or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, halo C
1-6alkyl, halo C
1-6alkoxyl group, halogen atom, C
1-6alkyl, C
1-6alkoxyl group, C
3-8cycloalkyl, C
3-8cycloalkyl C
1-6alkyl or C
1-6alkylamino;
Ring C is phenyl, naphthyl, pyridyl, pyridazinyl or pyrimidyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl, halo C
1-6alkyl or C
3-8cycloalkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, halogen atom, halo C
1-6alkyl, C
1-6alkyl or C
3-8cycloalkyl;
R
4for hydrogen atom or C
1-4alkyl;
R
5for hydrogen atom, C
1-4alkyl, halo C
1-4alkyl or C
3-8cycloalkyl;
Y is CH
2or NR
2;
R
2for hydrogen atom, C
1-6alkyl or halo C
1-6alkane;
N
1, n
2, n
3, n
4be separately 0,1,2 or 3, and n
1and n
2can not be 0, n simultaneously
3and n
4can not be 0 simultaneously;
M is selected from 0,1,2,3 or 4;
P is selected from 0,1,2 or 3.
5. compound as claimed in claim 4, its pharmacy acceptable salt, and steric isomer:
Wherein, R
1for-COOR
d,-CON (R
e)
2or tetrazole base;
R
dand R
ebe separately hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, halo C
1-4alkyl, halo C
1-4alkoxyl group, halogen atom, C
1-6alkyl, C
1-6alkoxyl group or C
3-8cycloalkyl;
Ring C is phenyl, naphthyl or pyridyl;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, carboxyl, amino, C
1-6alkyl or halo C
1-6alkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-6alkyl, halo C
1-6alkyl or C
1-6alkoxyl group;
R
3for hydrogen atom, fluorine atom, chlorine atom, halo C
1-3alkyl or C
1-3alkyl;
R
4for hydrogen atom or C
1-4alkyl;
R
5for hydrogen atom, C
1-4alkyl, halo C
1-4alkyl or C
3-6cycloalkyl;
Y is CH
2or NR
2;
R
2for hydrogen atom or C
1-6alkyl;
N
1, n
2, n
3, n
4be separately 0,1 or 2, and n
1and n
2can not be 0, n simultaneously
3and n
4can not be 0 simultaneously;
M is selected from 0,1,2 or 3;
P is selected from 0,1 or 2.
6. compound as claimed in claim 1, its pharmacy acceptable salt, and steric isomer:
Wherein, general formula (I) has following structure (III):
R
1for-COOR
dor tetrazole base;
R
dfor hydrogen atom or C
1-6alkyl;
X
1, X
2, X
3, X
4, X
5, X
6, X
7or X
8be separately N or C (R
6);
R
6for hydrogen atom, cyano group, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, F atom, Cl atom, C
1-3alkyl or C
1-3alkoxyl group;
R
aand R
bbe separately hydrogen atom, halogen atom, hydroxyl, amino, C
1-3alkyl or halo C
1-3alkyl;
R
cfor halogen atom, hydroxyl, cyano group, amino, C
1-3alkyl, halo C
1-3alkyl or C
1-3alkoxyl group;
R
3for hydrogen atom, fluorine atom, chlorine atom, trifluoromethyl or C
1-3alkyl;
R
4for hydrogen atom or C
1-3alkyl;
R
5for hydrogen atom, C
1-3alkyl or halo C
1-3alkyl;
M is 0,1 or 2.
7. the compound as described in any one of claim 1-6, its pharmacy acceptable salt, and steric isomer:
With
8. a pharmaceutical preparation, its comprise compound, its pharmacy acceptable salt or its steric isomer described in any one of claim 1-7 with one or more pharmaceutical carriers.
9. pharmaceutical composition, it is characterized in that comprising the compound described in any one of claim 1-7, its pharmacy acceptable salt or its 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, autotaxin inhibitors, phosphodiesteraseⅳ type inhibitor, opium kind analgesics, anodyne, cough medicine, timid phlegm medicine, anticholinergic, anti-coagulant, beta blocker, beta-adrenergic agonist, angiotensin-convertion enzyme inhibitor or HMG-CoA reductase inhibitor.
10. the compound as described in any one of claim 1-7, its pharmacy acceptable salt or its steric isomer or pharmaceutical preparation as claimed in claim 8 or pharmaceutical composition as claimed in claim 9 treat and/or prevent the application in the medicine of the disease of LPA-dependency or LPA-mediation in preparation, pulmonary fibrosis is selected to the active relevant disease of LPA, asthma, chronic obstructive pneumonia (COPD), renal fibrosis, acute injury of kidney, chronic nephropathy, hepatic fibrosis, fibrosis of skin, Colon Fibrosis, mammary cancer, carcinoma of the pancreas, ovarian cancer, prostate cancer, glioblastoma, osteocarcinoma, colorectal carcinoma, intestinal cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphatic leukemia, Cancerous pain, metastases, transplant organ repels, scleroderma, eye fibrosis, the macular degeneration (AMD) relevant to the age, diabetic retinopathy, collagen vascular disease, atherosclerosis or neuropathic pain.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410451313.9A CN104418820A (en) | 2013-09-07 | 2014-09-05 | Carboxylic acid derivative as lysophosphatidic acid receptor antagonist |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013104037640 | 2013-09-07 | ||
| CN201310403764 | 2013-09-07 | ||
| CN201410451313.9A CN104418820A (en) | 2013-09-07 | 2014-09-05 | Carboxylic acid derivative as lysophosphatidic acid receptor antagonist |
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| Publication Number | Publication Date |
|---|---|
| CN104418820A true CN104418820A (en) | 2015-03-18 |
Family
ID=52969023
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908139A (en) * | 2018-12-28 | 2019-06-21 | 南京市儿童医院 | Cilomilast is preparing the purposes in the drug for treating acute kidney injury associated disease |
| CN111434655A (en) * | 2019-01-15 | 2020-07-21 | 武汉朗来科技发展有限公司 | Lysophosphatidic acid receptor antagonists and process for their preparation |
| CN114409610A (en) * | 2022-03-29 | 2022-04-29 | 山东大学 | Oxadiazole derivatives, their preparation and use |
| CN114621135A (en) * | 2020-12-11 | 2022-06-14 | 上海拓界生物医药科技有限公司 | LPA1 small molecule antagonist |
-
2014
- 2014-09-05 CN CN201410451313.9A patent/CN104418820A/en not_active Withdrawn
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908139A (en) * | 2018-12-28 | 2019-06-21 | 南京市儿童医院 | Cilomilast is preparing the purposes in the drug for treating acute kidney injury associated disease |
| CN109908139B (en) * | 2018-12-28 | 2022-02-22 | 南京市儿童医院 | Use of cilomilast for the preparation of a medicament for the treatment of a disorder associated with acute kidney injury |
| CN111434655A (en) * | 2019-01-15 | 2020-07-21 | 武汉朗来科技发展有限公司 | Lysophosphatidic acid receptor antagonists and process for their preparation |
| CN114621135A (en) * | 2020-12-11 | 2022-06-14 | 上海拓界生物医药科技有限公司 | LPA1 small molecule antagonist |
| CN114621135B (en) * | 2020-12-11 | 2024-01-30 | 上海拓界生物医药科技有限公司 | LPA1 small molecule antagonist |
| CN114409610A (en) * | 2022-03-29 | 2022-04-29 | 山东大学 | Oxadiazole derivatives, their preparation and use |
| CN114409610B (en) * | 2022-03-29 | 2022-06-10 | 山东大学 | Oxadiazole derivatives, their preparation and use |
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Application publication date: 20150318 |