CN1990473B - Tri-substituted 1H-imidazoles compounds, preparation method and pharmaceutical composition and pharmacy use thereof - Google Patents

Tri-substituted 1H-imidazoles compounds, preparation method and pharmaceutical composition and pharmacy use thereof Download PDF

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CN1990473B
CN1990473B CN2005101355948A CN200510135594A CN1990473B CN 1990473 B CN1990473 B CN 1990473B CN 2005101355948 A CN2005101355948 A CN 2005101355948A CN 200510135594 A CN200510135594 A CN 200510135594A CN 1990473 B CN1990473 B CN 1990473B
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imidazol
picoline
phenyl
methylenedioxyphenyl
cyanophenyl
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CN1990473A (en
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李松
李行舟
代现平
郑志兵
王莉莉
肖军海
刘洪英
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to a compound with general formula (1) that can inhibit Smad protein phosphorylation by TGF- beta acceptor ALK5 and its salt and hydrate for medical use; the definition of each substituent group in general formula (1) is said in instruction book; the preparation method for compound of general formula (1); medical compound containing compound of general formula (1) or its salt or hydroate for medical use; the application in preparing drug of said compound of formula (1) and its salt and hydroate; the prepared drug is used to treat disease infected by acceptor ALK5, inhibit TGF- beta signal or inhibit formation of intercellular substance for mammals.

Description

Three replace 1H-glyoxaline compound, its preparation method, pharmaceutical composition and pharmaceutical applications thereof
Technical field
The present invention relates to three and replace 1H-imidazoles transforming growth factor-beta (transforminggrowth factor β, TGF-β) inhibitor of signal pathway, specifically be Type I acceptor or title activin sample kinases-5 acceptor (activin-like kinase-5 receptor, be called for short the ALK-5 acceptor) to the inhibitor of Smad (mother against dpp) 2 or Smad3 phosphorylation, and their preparation method and in the purposes of medical field, particularly treat the purposes with the unusual relevant various diseases of prevention and TGF-signal.
Background technology
Transforming growth factor-beta is a type cytokines superfamily, this superfamily member comprises transforming growth factor-beta s (TGF β s), activin (activines), statin (inhibins) and osteogenin [bone morphogenetic proteins (BMP)] and Miu Shi inhibition (Mullerian-inhibiting substance) etc., can regulate physiological process very widely, comprise cell propagation, break up, adhere to, move and downright bad.
The conduction of the signal of TGF-beta superfamily needs two types single span film serine/threonine acceptor, and these two kinds of acceptors are called Type I or ALK acceptor and Type II acceptor.The difference of TypeI or ALK acceptor and Type II acceptor is following three aspects: (1) ALK acceptor lacks an interior fragment of cell that is rich in serine/threonine; (2) serine/threonine kinase functional zone that are different from Type II acceptor height homology are arranged in various Type I acceptors; (3) at various Type I acceptors a common sequence fragment that is called the GS functional zone is arranged, comprise a zone of being rich in glycine and serine residue in these functional zone, be positioned at the N end in cell kinase function district, this zone is most important by Type II receptor activation to it.
Many studies show that: the TGF-signal needs the acting in conjunction of ALK and Type II acceptor.Substantially, the dimer of TGF-β (part) is combined with the dimer of a Type II acceptor earlier, then raise two Type I acceptors, by the GS functional zone of TGF-β activated T ype II receptor phosphorylation ALKs, and therefore make it to activate, the C end of the Smads (R-Smads) of the intracytoplasmic receptor activation of its downstream signaling molecule of ALKs phosphorylation of activation, the R-Smads of two phosphorylations can also claim general media Smad[commonmediator Smad (C-Smad) with a Smad4-] form trimer compositions, this mixture enters nucleus and regulates transcribing of target gene.
Usually, in most of kinds, Type II acceptor is regulated the differentiation of cell, and Type I acceptor is regulated the generation of intercellular substance, therefore the compound of Formula I that the present invention relates to is for suppressing Type I acceptor, and then regulate the synthetic of intercellular substance, rather than be used for regulating the cytodifferentiation of Type II institute media.
Seven kinds of Type I acceptors (ALK1-7) and five kinds of Type II acceptors in Mammals, have been found altogether, the combination of specific T ype I and Type II acceptor has determined specificity (the Piek and Roberts of part signal, 2001), activin (Activins) or TGF β s activated T ypeI acceptor ALK4 and ALK5 be phosphorylation Smad2 and Smad3 respectively, and ALK1, ALK2, ALK3 and ALK6 phosphorylation Smadl, Smad5 and the Smad8 (Heldin etal., 1997) of BMP activation.It must be noted that, evidence show that TGF β s also can activate ALK1 and Smad1 and Smad5 (Oh et al., 2000 in endotheliocyte; Goumans et al., 2002).Recently the ALK7 of Fa Xianing is considered to another kind of member Nodal (Reissmann et al., 2001, Watanabe et al., 1999 by activation Smad2 mediation TGF β Superfamily; Jornvall et al., 2001), although the Smad approach is studied in large quantities, the signal of TGF 'beta ' family part also can activate other signal pathways.Comprise MAKP approach and phosphatidyl-inositol 3-kinase, infer and also can pass through Type I acceptor (de Caestecker et al., 2000).
Unusual and the disease of TGF signal
Early stage studies show that, abnormal TGF β 1 (first be found and study the most thorough TGF β Superfamily member) signal with such as many pathologic processes such as fibrosis and canceration relevant (Border and Noble, 1994; Wakefield and Roberts, 2002).TGF β 1 also plays an important role in wound healing, its abnormal signal may with formation relevant (Bettinger et al., 1996 of scar and the keloid of excessive growth; O ' Kane and Ferguson, 1997).
In recent years more continuous report relevant for TGF signal relative disease.For example the activation of report TGF-β 1 signal such as Border W.A and the expansion of extracellular matrix are early stage performance and lasting inducement (Border W.A., Noble N.A., N.Engl.J.Med., Nov.10,1994 of chronic nephritis and vascular disease; 331 (19): 1286-92).In addition, TGF-β 1 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1 by the phosphorylation of the Smad3 of its acceptor ALK5, and these all are the sedimental moiety of sclera (Zhang Y., FengX.H., Derynck R., Nature, Aug.27,1998; 394 (6696): 909-13; UsuiT., Takase M., Kaji Y., Suzuki K., Ishida K., Tsuru T., MiyataK., Kawabata M., Yamashita H., Invest.Ophthalmol.Vis.Sci., October 1998; 39 (11): 1981-9).
Kidney and cardiovascular systems to carry out fibrosis be human underlying cause of death and be the person that mainly do not disappear of health resources.TGF-β 1 be proved fibrosis lesion with a lot of kidneys relevant (Border W.A., Noble N.A., N.Engl.J.Med., Nov 10,1994; 331 (19): 1286-92).Take place acute or chronic glomerulonephritis (Yoshioka K., Takemura T., Murakami K., Okada M., Hino S., Miyamoto H., MakiS., Lab.Invest., February 1993; 68 (2): 154-63), diabetic nephropathy (Yamamoto, T., Nakamura, T., Noble, N.A., Ruoslahti, E., Border, W.A., (Border W.A., Noble N.A., N.Engl.J.Med. during ephrosis that heteroplastic transplantation repulsion (1993) PNAS 90:1814-1818),, HIV ephrosis, Angiotensin are induced, Nov.10,1994; 331 (19): 1286-92), TGF-β 1 level in the body can raise.When these diseases took place, the expression of TGF-β 1 was relevant with the generation of extracellular matrix.Article three, the generation of evidence showed cell outer room matter is caused by TGF-β 1.The first, external, the TGF-β 1 of external source can induce normal renal glomerulus, mesangium and non-nephrocyte to produce extracellular matrix, and the activity of arrestin enzyme.The compacting antibody of the second, TGF-β 1 can stop the accumulation of extracellular matrix in the mouse kidney.The 3rd, in the mouse of genetically modified TGF-β 1 or the body transfection kidney of normal mouse of TGF-β 1 gene (the Kopp J.B. of glomerular sclerosis fast can take place, Factor V.M., Mozes M., Nagy P., Sanderson N., Bottinger E.P., Klotman P.E., Thorgeirsson S.S., Lab Invest, June 1996; 74 (6): 991-1003), the activity that therefore suppresses TGF-β 1 may be effective to the treatment chronic renal disease.
Studies show that, in the injured blood vessel TGF-β 1 and acceptor thereof increase to show relevant with the formation of neointima (Saltis J., Agrotis A., Bobik A., Clin Exp PharmacolPhysiol, March 1996; 23 (3): 193-200).In addition, TGF-β 1 be smooth muscle cell (" SMC ") the potent promotor of external transfer, the migration of the SMC on the ductus arteriosus wall helps to take place arteriosclerosis and valvular stenosis.In addition, TGF-beta receptor ALK5 shows relevant with total cholesterol (P＜0.001) (Blann A.D., Wang J.M. in the diversity of the anti-total cholesterol product of endotheliocyte is analyzed, Wilson P.B., Kumar S., Atherosclerosis, February1996; 120 (1-2): 221-6), high ALK5/TGF-β type II acceptor ratio is arranged among the SMC at atherosclerotic lesions position in addition, this is overexpression because of TGF-β 1 in the infringement of fibroplasia vascular, receptor variant cell can be with the growth of slow and not controlled way, excessively produce simultaneously extracellular matrix (McCaffrey T.A., Consigli S., DuB., Falcone D.J., Sanborn T.A., Spokojny A.M., Bush H.L., Jr., J Clin Inyest, December 1995; 96 (6): 2667-75).
In TGF-β 1 atherosclerotic lesions that matter is synthesized between taking place to enliven the scavenger cell of non-foam shape is shown the character of immunity trend, this shows that the scavenger cell of non-foam shape may participate in being responsible for the expression of gene of matter between adjusting by the mechanism that a kind of TGF-β relies in the plastotype again of atherosclerotic lesions, therefore can have therapeutic action to TGF-β 1 atherosclerosis and the stricture of artery that causes thus by the effect that suppresses 1 couple of ALK5 of TGF-β.
TGF-β also shows relevant with peritoneal adhesion (Saed G.M., Zhang W., Chegini N., Holmdahl L., and Diamond M P., Wound Repair Regeneration.7 (6): 504-510,1999 November-December).Therefore, suppress ALK5 and may be of value to fibrosis adhesion under prevention of postoperative peritonaeum and the corium.
The potent selective depressant of ALK5 may be used for the treatment of the various diseases relevant with the ALK5 kinases with prevention: as not syndromes, arteriosclerosis, peritonaeum or the subcutaneous adhesion of chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, congested heart necrosis, ulcer, corneal wound, diabetic nephropathy, nervous function damage, A Erzi sea, and any main pathology relevant with fibrosis, including, but not limited to pulmonary fibrosis, hepatic fibrosis and valvular stenosis.
The term ALK5 inhibitor here refers to that a compound can optionally suppress the ALK5 acceptor, and p38 kinases or Type II acceptor or some other kinases are not had restraining effect or have only weak restraining effect, and not to play a role by suppressing Smads albumen outside Smad2 and the Smad3 such as Smad6 and Smad7.
Here said term " ulcer " but comprise and be not limited to diabetic ulcer, chronic ulcer, stomach ulcer, duodenal ulcer etc.
Summary of the invention
The objective of the invention is to seek and developmental function in the micromolecular inhibitor of ALK5 receptor kinase functional zone, by suppressing ALK5 to the phosphorylation of its downstream signal Smad2 or Smad3, blocking-up or part are blocked the TGF signal to intramolecular propagation, thereby correct unusual TGF-signal, treat and prevent the various diseases relevant unusually with the TGF-signals of ALK5 media.
The inventor is through discovering, compound with following general formula I has the effect of the phosphorylation that suppresses the Smad3/2 of ALK5, can block or the part block the TGF-signal to intracellular propagation, therefore can be used for the treatment of and the unusual relevant various diseases of prevention and TGF-signal, thereby finish the present invention.
On the one hand, the present invention relates to compound, its all possible isomer or its pharmaceutically useful salt or the hydrate of general formula I
Figure S051D5594820060106D000051
Wherein:
R1 and R2 are optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl independently of each other; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R1 and R2 are and the first heterocyclic fused phenyl of a 5-7 fragrance or non-fragrance independently of each other, and said heterocycle refers to contain the heteroatomic ring that one or two is selected from N, O and S here;
Perhaps R1 and R2 be independently of each other replace containing the heterocyclic radical of proton donor or proton acceptor, for example pyridine of Qu Daiing-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base with the ortho position of parent nucleus connection site; Or replace at 2 substituent phenyl that contain as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R '.
Term " C used herein 1-6Alkyl ", no matter be himself or as other more macoradical such as C 1-6The part of alkoxyl group all refers to the atomic group that contains 1-6 carbon atom of straight or branched include but are not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl etc.
Term " C used herein 1-6Haloalkyl " refer to the C that one or more hydrogen are wherein replaced by halogen atom 1-6Alkyl need should be mentioned that trifluoromethyl (CF here especially 3).
Term used herein " halogen (halo) " refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) ".
Term used herein " aryl " refers to aromatic ring system replacement or non-replacement of 5-14 unit, maybe may comprise the aromatic ring systems of the dicyclo that condenses or three rings, but comprises and be not limited to phenyl and naphthyl.
In one embodiment, R1 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R1 is and the first heterocyclic fused phenyl of a 5-7 fragrance or non-fragrance, and said heterocycle refers to contain the heteroatomic ring that one or two is selected from N, O and S here;
R2 be replace containing the heterocyclic radical of proton donor or proton acceptor, for example pyridine of Qu Daiing-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base with the ortho position of parent nucleus connection site; Or replace at 2 substituent phenyl that contain as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
Perhaps R2 is and the first heterocyclic fused phenyl of a 5-7 fragrance or non-fragrance, and said heterocycle refers to contain the heteroatomic ring that one or two is selected from N, O and S here;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R '.
In another embodiment, R2 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example quinolyl, pyrryl, pyridyl, piperidyl, piperazinyl, morpholinyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from halogen for example fluorine, hydroxyl, amino, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, wherein n represent 1,2 or 3-O-(CH 2) n-Ph or-S-(CH 2) n-Ph, itrile group, wherein R ' is hydrogen or C 1-6Alkyl-CO 2R ' and aryl be phenyl for example;
Perhaps R2 is and the first heterocyclic fused phenyl of a 5-7 fragrance or non-fragrance, and said heterocycle refers to contain the heteroatomic ring that one or two is selected from N, O and S here;
R1 be replace containing the heterocyclic radical of proton donor or proton acceptor, for example pyridine of Qu Daiing-2-base, pyrroles-2-base, pyridazine-3-base, pyrimidine-2-base, imidazoles-2-base, pyrazole-3-yl, thiazol-2-yl and furans-2-base with the ortho position of parent nucleus connection site; Or replace at 2 substituent phenyl that contain as proton donor or proton acceptor, for example 2-fluorophenyl, 2-p-methoxy-phenyl, 2-hydroxy phenyl and 2-trifluoromethyl; Substituting group is independently selected from halogen for example fluorine, C 1-6Alkyl, C 1-6Haloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n-Ph, wherein R represents hydrogen or C 1-6Alkyl-CO 2R;
Perhaps R1 is and the first heterocyclic fused phenyl of a 5-7 fragrance or non-fragrance, and said heterocycle refers to contain the heteroatomic ring that one or two is selected from N, O and S here;
R3 is optional replacement or dibasic aryl, for example phenyl, naphthyl and an anthryl; Perhaps optional one replaces or the dibasic heteroatomic heterocyclic radical that one or more are selected from N, O and S, for example pyrryl, piperidyl, piperazinyl, pyridazinyl, pyrimidyl, imidazolyl, pyrazolyl, thiazolyl and furyl of containing; Substituting group is independently selected from-COOH ,-CONH 2,-CN ,-NO 2, C 1-6Alkylthio ,-SO 2-C 1-6Alkyl, C 1-6Alkoxyl group ,-SONH 2,-SONHR ' ,-CONHOH ,-NH 2,-CHO ,-CH 2OH ,-CH 2NH 2, wherein R ' represents H or C 1-6Alkyl-COOR ' ,-SONHR ' or-CONHR ' and wherein R ' represent C 1-6Alkyl or acyl group-NHR ';
Perhaps R3 is halogen, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, itrile group, amino, hydroxyl, thiol, phenyl, nitro, wherein n represent 1,2 or 3-O-(CH 2) n-Ph ,-S-(CH 2) n-Ph or-NH-(CH 2) n, or wherein R ' represent H or C 1-6Alkyl-CO 2R '.
In a preferred embodiment, R1 is 3,4-methylenedioxyphenyl, 2-fluorophenyl, phendioxin-6-base, 3,4-dimethoxy phenyl, 4-fluorophenyl or 3-fluoro-4-p-methoxy-phenyl; R2 is 6-picoline-2-base, 2-fluorophenyl, pyridine-2-base, 3,4-methylenedioxyphenyl or 2-p-methoxy-phenyl; And R3 is to cyano-phenyl, to formamyl phenyl or the tertiary butyl.
Compound below the particularly preferred compound of Formula I of the present invention or its pharmaceutically useful salt or hydrate are preferred:
(1) 4-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(2) 4-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(3) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] cyanophenyl;
(4) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] benzamide;
(5) 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(6) 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(7) 4-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] cyanophenyl;
(8) 4-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] benzamide;
(9) 4-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(10) 4-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(11) 4-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(12) 4-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(13) 4-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(14) 4-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(15) 2-[(1-(4-fluorophenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(16) 2-[(1-(phendioxin-6-the yl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(17) 2-[(1-(3-fluoro-4-the p-methoxy-phenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(18) 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(19) 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(20) 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(21) 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(22) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] cyanophenyl;
(23) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] benzamide;
(24) 1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-2-(2-p-methoxy-phenyl)-1H-imidazoles;
(25) 4-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(26) 4-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(27) 2-(1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-1H-imidazoles-2-yl)-6-picoline;
And pharmacologically acceptable salt or hydrate.
The invention still further relates to suitable pharmaceutically useful salt or the hydrate of compound shown in general formula I, but wherein pharmaceutically useful salt comprise be not limited to salt that compound of Formula I becomes with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that becomes as toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetic acid, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, may form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.Part of compounds may exist with the form of optical isomer or tautomer among the present invention, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and perhaps synthetic method or the three-dimensional method single-minded or asymmetric synthesis that certain isomer can various routines obtains.Since compound of Formula I is purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% refers to weight percent).The preparation method of pure compound not can be used to for the purer form of medicinal compositions.These contain 1% in the pure product inadequately at least, be more suitable for 5%, better at least 10% the compound shown in general formula I or its pharmaceutically useful derivative.
On the other hand, the present invention relates to prepare the synthetic method of compound of Formula I.The compound of general formula I can be raw material from the known compound that maybe can buy, through the method preparation of synthetic.If raw material can not be buied, then provide their preparation method here, or they can be by the method preparation of bibliographical information.
Specifically, the invention provides the method for preparing general formula (I) compound or pharmaceutically acceptable salt thereof or hydrate, it comprises the steps:
(i) at organic bases, as NaN (SiMe 3) 2Exist down, at inert solvent, as making fragrant nitrile and arylamine reaction among the THF, generate the aryl carbonamidine that the N-aryl replaces
Figure S051D5594820060106D000121
Wherein R1 and R2 are with the definition of preamble;
(ii) make aryl carbonamidine and the general formula of the N-aryl replacement of generation be
Figure S051D5594820060106D000122
Compound at the lower alcohol of C1-C6, in the preferred Virahol, at organic bases or mineral alkali, as NaHCO 3Be heated to 50-100 ℃ of reaction under existing, generate the compound with 1,2,4-tri-substituted imidazole structure
Figure S051D5594820060106D000123
Wherein R3 is with the definition of preamble.
In the process of synthetic compound of Formula I, variable or reaction process had dysgenic group, as acid amides, the N on carboxyl, hydroxyl, carbonyl or amino and the pyridine can be protected earlier, sloughs protection at proper step again.About the protection of organo-functional group and deprotection at pertinent literature such as Protective Groups in Organic Chemistry; T.W.Greene andP.G.M.Wuts, (Wiley-Interscience, New York; 2nd edition, 1991). in existing detailed argumentation.Also can be earlier exist with the form of its potential functional group, change into required group at proper step again.
For example, when R3 is 4-itrile group phenyl, itrile group can be converted into acid amides or carboxyl.
Figure S051D5594820060106D000124
Compound of Formula I can be single synthetic with ordinary method, also mixed-separating method or the parallel synthetic method of available combination chemistry (contain two at least with the storehouse in each storehouse, or 5-1000,10-100 compound preferably) synthetic for unit, namely can in liquid phase, synthesize also and can use solid phase synthesis process.
See embodiment about the more detailed data of preparation compound of Formula I.
On the other hand, the present invention relates to the compound of general formula I, its all possible isomer or its pharmaceutically useful salt or hydrate are for the production of the purposes of the medicine of the mammiferous disease by the ALK5 acceptor media for the treatment of, described disease by the ALK5 acceptor media is including, but not limited to following disease: chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, kidney disease, congested heart necrosis, ulcer, eye disease, corneal wound, diabetic nephropathy, nervous function damage, the A Erzi sea is syndromes not, arteriosclerosis, peritonaeum or subcutaneous adhesion, and any main pathology relevant with fibrosis, including, but not limited to pulmonary fibrosis, hepatic fibrosis and valvular stenosis.
The invention still further relates to the method for the mammiferous disease by the ALK5 acceptor media for the treatment of, this method comprises compound, its all possible isomer or its pharmaceutically useful salt or the hydrate that the Mammals of needs treatment is given the general formula I of effective dose with suitable manner.The invention also discloses the effective dose to mammiferous administering mode, compound of Formula I or its suitable pharmacologically acceptable salt or the hydrate of needs treatment.
On the other hand, the present invention relates to compound, its all possible isomer or its pharmaceutically useful salt of general formula I or hydrate for the production of the purposes that can suppress the medicine of TGF-signal in the mammalian body.
The invention still further relates to the method that suppresses TGF-signal in the mammalian body, for example suppress Type I or ALK5 acceptor to the phosphorylation of Smad2 or Smad3, this method comprises that the Mammals to needs inhibition TGF-signal gives compound of Formula I, its all possible isomer or suitable pharmacologically acceptable salt or the hydrate of effective dose with suitable manner.
On the other hand, the present invention relates to compound, its all possible isomer or its pharmaceutically useful salt of general formula I or hydrate for the production of the purposes that is used for suppressing the medicine that matter forms between the Mammals cells in vivo.
The invention still further relates to and in Mammals, suppress the method that intercellular substance forms, for example by suppressing Type I or ALK5 acceptor to the phosphorylation of Smad2 and Smad3, this method comprises that the Mammals that needs inhibition intercellular substance is formed gives compound of Formula I, its all possible isomer or its pharmaceutically useful salt or the hydrate of effective dose with suitable manner.
On the other hand; the compound of general formula I of the present invention or its pharmaceutically useful salt can use separately; or use with the form of pharmaceutical composition with pharmaceutically useful carrier or vehicle; when using with the form of pharmaceutical composition; usually with the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salt or hydrate and one or more pharmaceutically acceptable carrier or thinner in conjunction with making suitable administration form or dosage form, this program comprises by suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer or its pharmaceutically useful salt or hydrate and at least a pharmaceutically useful carrier of general formula I.
The pharmaceutical composition of The compounds of this invention, any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.
Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.
Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent is as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.
Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir also can be made dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas is as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.Can add seasonings or tinting material as needs.
Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.
Stomach is offerd medicine outward, and liquid formulation is made by the carrier of compound and a kind of sterilization usually.The first-selected water of carrier.Different according to selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when making injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.
When topical application, The compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
According to the difference of administering mode, can contain weight ratio 0.1% in the component, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 50-500 milligram activeconstituents.Different according to route of administration and administration frequency, the suitable therapeutic dose that is used for the adult is 100-3000 milligram every day, as 1500 milligrams of every days.This dosage is corresponding to 1.5-50 milligram/kg/day, and proper dosage is 5-20 milligram/kg/day.
Must recognize, the best dosage of compound of Formula I and be to determine by compound property with such as form, path and the position of administration and the external conditionss such as specific Mammals for the treatment of at interval, and this best dosage can be determined with conventional technology.Also must recognize simultaneously, the best course for the treatment of, i.e. the dosage of compound of Formula I every day in the specified time, available method well known in the art is determined.
Embodiment
Following specific embodiment is the preferred embodiments of the invention, and it should not be construed as the present invention is constituted any restriction.
The fusing point of compound is measured by RY-1 fusing point instrument, and thermometer is calibration not.Mass spectrum is measured by Micromass ZabSpec high resolution mass spectrometer (resolving power 1000). 1H NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency 1H NMR 400MHz.
Embodiment
Embodiment 14-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000161
Step 1N-(3, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) preparation of carbonamidine slowly splashes into 508mg (3.6mmol) 3 in 5mL THF (anhydrous) solution of two trimethyl silicon based sodium amides of 4.0mL 1M, 3mL THF (anhydrous) solution of 4-methylene dioxo group aniline, this mixture is at room temperature stirred 3mL THF (anhydrous) solution that splashes into 425mg (3.6mmol) 6-methyl-2-itrile group pyridine after 20 minutes, this mixture at room temperature reacted spend the night, pour in the frozen water then, there is not product with ethyl acetate extraction to water layer, organic layer washes with water, the anhydrous NaCl solution washing, anhydrous MgSO 4Drying, resistates obtains 495mg N-(3,4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine with silica gel column chromatography (methylene chloride 100/0.5 wash-out) behind the evaporating solvent, yield 54%, mp:108-110 ℃, 1H-NMR (400M, CDCl3) δ 2.59 (3H, s, CH3), 5.96 (2H, s, O-CH2-O), 6.49 (1H, dd, J=8.12,1.40Hz), 6.59 (1H, d, J=1.40Hz), 6.83 (1H, d, J=8.12Hz), 7.24 (1H, d, J=7.68Hz), (7.70 1H, dd (t), J=7.68,7.6 8Hz), 8.21 (1H, d, J=7.68Hz) .EIMS (m/e, %) 255 (M +, 100), 137 (85).
Step 2The preparation of 4-itrile group bromoacetyl benzene
In the 25mL glacial acetic acid solution of 1.45g (10mmol) 4-itrile group phenyl methyl ketone, splash into 5 solution that are made into by 1.10g bromine and glacial acetic acid, being stirred to the bromine water color under oil bath 35-40 ℃ disappears, slowly splash into the glacial acetic acid solution of above-mentioned bromine water again, keep temperature of reaction about 30 ℃, after dripping off, reaction mixture continues reaction 3 hours about 30 ℃, at room temperature uncovered stirring is spent the night then, the pressure reducing and steaming glacial acetic acid, resistates solidifies the back and obtains 1.36g4-itrile group bromoacetyl benzene with the ether washing, yield 61%, mp:84-86 ℃ 1H-NMR (400M, CDCl 3) δ 4.44 (3H, s), 7.83 (2H, d, J=8.40Hz), 8.09 (2H, d, J=8.40Hz).
Step 34-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
With 220mg, (0.86mmol) N-, (3, the 4-methylenedioxyphenyl)-, (6-picoline-2-yl) carbonamidine and 309mg, (1.38mmol) 4-itrile group bromoacetyl benzene is dissolved in the 14mL Virahol, add 108mg, (1.29mmol) sodium bicarbonate, this reaction mixture is heated to 50 ℃ of reactions 1.5 hours, reacted 3 hours down at 80 ℃ then, be down to concentration of reaction solution after the room temperature, resistates separates with silica gel column chromatography, (methylene chloride 100/0.3 wash-out) obtains 210mg purpose compound, yield 64%, mp:185-187 ℃ 1H-NMR (400M, CDCl 3) δ 2.38 (3H, s, CH 3), 6.05 (1H, s, O-CH 2-O), 6.78 (1H, dd, J=7.84,1.92Hz), 6.79 (1H, d, J=1.92Hz), 6.80 (1H, d, J=7.84Hz), 7.07 (1H, d, J=7.28Hz), 7.51 (1H, s, C5H), 7.58 (1H, dd, J=7.28,7.56Hz), 7.63 (1H, d, J=7.56Hz), 7.68 (1H, d, J=8.40Hz), 7.98 (1H, d, J=8.40) .EIMS (m/e, 100), 380 (M +, 93), 379 (M +-H, 100).
Embodiment 24-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Figure S051D5594820060106D000181
Get 100mg 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 1), heating is dissolved in the 5mL trimethyl carbinol, add 60mg KOH powder again, 100 ℃ of following reacting by heating of oil bath 4 hours, raw material disappears, reaction mixture is down to pressure reducing and steaming solvent after the room temperature, resistates purification by silica gel column chromatography (methylene chloride 100/2 wash-out) obtains 62mg 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide, yield 60%, mp:218-220 ℃ 1H-NMR (400M, CDCl 3) δ 2.21 (3H, s, CH 3), 6.11 (1H, s, O-CH 2-O), 6.82 (1H, dd, J=8.12,2.24Hz), 6.97 (1H, d, J=8.12Hz), 7.02 (1H, d, J=2.24Hz), 7.17 (1H, dd, J=7.08,1.40Hz), 7.32 (1H, brs, NH D 2O is interchangeable), 7.75 (1H, dd, J=7.08,7.00Hz), 7.77 (1H, dd, J=7.00,1.40Hz), 7.93 (1H, d, J=8.40Hz), 7.96 (1H, d, J=8.40), 7.97 (1H, brs, NH, D 2O is interchangeable), 8.10 (1H, s) .EIMS (m/e, %) 398 (M +, 100) and .HR-EIMS calculated value C 23H 18N 4O 3398.1379, measured value 398.1360.
Embodiment 34-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000182
Step 1The preparation of N-(3,4-methylenedioxyphenyl)-(2-fluorophenyl) carbonamidine
Method just replaces 6-methyl-2-itrile group pyridine with the 2-fluorobenzonitrile with embodiment 1 step 1, obtains 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] the cyanophenyl crude product, yield 38%, oily matter, 1H-NMR (400M, CDCl 3) δ 5.94 (2H, s, O-CH2-O), 6.42 (1H, d, J=8.12Hz), 6.53 (1H, s), 6.79 (1H, d, J=8.12Hz), 7.09-7.14 (1H, m), 7.21-7.25 (1H, m7.43), 7.40-7.46 (1H, m), 8.04 (1H, m) .FAB-MS (m/e, %), 259 (M +, 100), 242 (M +-NH 2, 15).
Step 24-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(3, the 4-methylenedioxyphenyl)-(2-fluorophenyl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] cyanophenyl, yield 74%, mp:168-170 ℃ 1H-NMR (400M, CDCl 3) δ 6.04 (2H, s, O-CH 2-O), 6.66 (1H, dd, J=8.12,1.68Hz), 6.68 (1H, d, J=1.68Hz), 6.75 (01H, d, J=8.12Hz), 7.01 (1H, dd, J=9.24,8.68Hz), 7.24 (1H, dd, J=7.28,7.5 6Hz), 7.40 (1H, m), 7.59 (1H, s, C5H), 7.63 (1H, m), 7.70 (2H, d, J=8.40Hz), 7.98 (2H, d, J=8.40Hz), FABMS (m/e, %), 384 (MH +, 100).
Embodiment 44-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(2-fluorophenyl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 3) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] benzamide, yield 63%, mp:111-113 ℃ 1H-NMR (400M, CDCl 3) δ 5.69 (1H, brs, NH, interchangeable), 6.02 (2H, s, O-CH 2-O), 6.18 (1H, brs, NH, interchangeable), 6.67 (1H, dd, J=8.12,1.96Hz), 6.70 (1H, d, J=1.96Hz), 6.74 (1H, d, J=8.12Hz), 6.99 (1H, dd, J=9.56,8.68Hz), 7.22 (1H, ddd, J=7.56,7.56,0.84Hz), 7.37 (1H, m), 7.67 (1H, s), 7.62 (1H, ddd, J=7.28,7.56,1.40Hz), 7.87 (2, d, J=8.40Hz), 7.94 (2H, d, J=8.40Hz) .EIMS (m/e, %) 401 (M +, 100), 383 (M +-H 2O, 18), 255 (80) .HR-EIMS calculated value C 23H 16FN 3O 3401.1176, measured value 401.1178.
Embodiment 54-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000201
Step 1The preparation of N-(3,4-methylenedioxyphenyl)-(pyridine-2-yl) carbonamidine
Method just replaces 6-methyl-pyridine-2-base with pyridine-2-base with embodiment 1 step 1, obtains N-(3,4-methylenedioxyphenyl)-(pyridine-2-yl) carbonamidine, yield 36%, and oily matter, 1H-NMR (400M, CD 3COCD 3) δ 5.96 (2H, s, O-CH 2-O), 6.43 (1H, dd, J=8.00,1.92Hz), 6.51 (1H, d, J=1.92Hz), 6.80 (1H, d, J=8.00Hz), 7.51 (1H, dd, J=7.72,4.68Hz), 7.92 (1H, dd, J=8.00,7.72Hz), 8.37 (1H, d, J=8.00Hz), 8.61 (1H, d, J=4.68Hz) .FAB-MS (m/e, %), 242 (MH +, 100), 225 (MH +-NH 3, 70).
Step 24-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(3, the 4-methylenedioxyphenyl)-(pyridine-2-yl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield 30%, mp:187-189 ℃ 1H-NMR (400M, CDCl 3) δ 6.06 (2H, s, O-CH 2-O), 6.77,6.80 (2H, Absystem, J=9.00Hz, C5 ' H), 6.78 (1H, s), 7.22 (1H, dd, J=7.60,5.64Hz), 7.52 (1H, s, C5H), 7.70 (2H, d, J=8.16Hz), 7.72 (1H, dd, J=7.60,7.88Hz), 7.88 (1H, d, J=7.88Hz), 7.99 (2H, d, J=8.16Hz), 8.45 (1H, d, J=5.64Hz) .EIMS (m/e, %) 366 (M +, 80), 365 (M +-H, 100).
Embodiment 64-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Figure S051D5594820060106D000211
Method is with embodiment 2, just with 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 5) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide, yield 83%, mp:218-220 ℃ 1H-NMR (400M, DMSO-d6) δ 6.10 (2H, s, O-CH 2-O), 6.81 (1H, dd, J=8.32,2.08Hz), 6.94 (1H, d, J=8.32Hz), 6.98 (1H, d, J=2.08Hz), 7.33 (1H, dd, J=7.40,4.76Hz), 7.88 (1H, dd, J=7.40,7.88Hz), 8.00 (1H, d, J=7.88Hz), 7.93 (2H, d, J=8.60Hz), 7.96 (2H, d, J=8.60Hz), 8.06 (1H, s, C5H), 8.37 (1H, d, J=4.76Hz) .FABMS (m/e, %) 385 (MH +, 25), 69 (100).
Embodiment 74-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000212
Step 1The preparation of N-(2-fluorophenyl)-(3,4-methylenedioxyphenyl) carbonamidine
Method just replaces 3 respectively with 2-fluoroaniline and 3,4-methylene-dioxy cyanophenyl with embodiment 1 step 1,4-methylene dioxo group aniline and 6-methyl-2-itrile group pyridine obtains N-(2-fluorophenyl)-(3,4-methylenedioxyphenyl) carbonamidine crude product, yield 38% is directly used in the next step.
Step 24-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(2-fluorophenyl)-(3, the 4-methylenedioxyphenyl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(2-fluorophenyl)-2-(3, the 4-methylenedioxyphenyl)-and the 1H-imidazol-4 yl] cyanophenyl, mp:204-206 ℃ 1H-NMR (400M, CDCl 3) δ 5.97 (2H, s, O-CH 2-O), 6.72 (1H, d, J=8.08Hz), 6.90 (1H, dd, J=8.08,1.36Hz), 7.00 (1H, d, J=1.36Hz), 7.2-7.31 (3H, m), 7.45-7.48 (1H, m), 7.48 (1H, s, C 5H), 7.70 (2H, d, J=8.32Hz), 7.98 (2H, d, J=8.32Hz) .FABMS (m/e, %) 384 (MH +, 100).
Embodiment 84-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] preparation of benzamide
Figure S051D5594820060106D000221
Method is with embodiment 2, just with 4-[1-(2-fluorophenyl)-2-(3, the 4-methylenedioxyphenyl)-and the 1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 7) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] benzamide, yield 82%, mp:185-186 ℃ 1H-NMR (400M, CDCl 3) δ 5.6-6.2 (2H, br, NH, interchangeable), 5.95 (2H, s, O-CH 2-O), 6.71 (1H, d, J=8.12Hz), 6.90 (1H, dd, J=8.12,1.68Hz), 7.00 (1H, d, J=1.68Hz), and 7.21-7.33 (3H, m), 7.41-7.46 (1H, m), 7.46 (1H, s, C5H), 7.87 (2H, d, J=8.04Hz), 7.96 (2H, d, J=8.04Hz) .EIMS (m/e, %), 401 (M +, 100), 383 (M +-H2O, 30) .HR-EIMS calculated value C 23H 16FN 3O 3401.1176, measured value 401.1169.
Embodiment 94-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Step 1The preparation of N-(phendioxin-6-yl)-(pyridine-2-yl) carbonamidine
Method just replaces 3 respectively with 6-amino-phendioxin and 2-itrile group pyridine with embodiment 1 step 1,4-methylene dioxo group aniline and 6-methyl-2-itrile group pyridine obtains N-(phendioxin-6-yl)-(pyridine-2-yl) carbonamidine, yield 32%, mp:101-103 ℃ 1H-NMR (400M, CDCl 3) δ 4.28 (4H, s, O-CH 2-CH 2-O), 6.54 (1H, dd, J=8.40,2.24Hz), 6.58 (1H, d, J=2.24Hz), 6.86 (1H, d, J=8.40Hz), 7.39 (1H, dd, J=7.28,4.76Hz), 7.80 (1H, dd, J=7.28,7.28Hz), 8.40 (1H, d, J=7.28Hz), 8.56 (1H, d, J=4.76Hz) .EIMS (m/e, %), 255 (M +, 100).
Step 24-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(phendioxin, 4-dioxane-6-yl)-(pyridine-2-yl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 4-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield 43%, mp:193-195 ℃ 1H-NMR (400M, CDCl 3) δ 4.28 (4H, dd, J=0.76Hz, O-CH 2-CH 2-O), 6.75 (1H, dd, J=8.68,2.24Hz), 6.85 (1H, d, J=2.24Hz), 6.86 (1H, d, J=8.68Hz), 7.23 (1H, m), 7.53 (1H, m), 7.73 (1H, m), 7.88 (1H, m), 7.69 (2H, d, J=8.03Hz), 8.00 (2H, d, J=8.03Hz) .FABMS (m/e, %) 381 (MH +, 100).
Embodiment 104-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[2-(phendioxin, 4-dioxane-6-yl)-and 1-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 9) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[2-(3,4-methylenedioxyphenyl)-1-(2-fluorophenyl)-1H-imidazol-4 yl] benzamide, yield 73%, mp:225-227 ℃ 1H-NMR (400M, CDCl 3) δ 4.31 (4H, AB system, J=0.76Hz, O-CH 2-CH 2-O), 5.5 (1H, brs, NH, interchangeable), 6.1 (1H, brs, NH, interchangeable), 6.76 (1H, dd, J=8.40,2.80Hz), 6.87 (1H, d, J=2.80Hz), 6.89 (1H, d, J=8.40Hz), 7.26 (2H, m), 7.52 (1H, s, C5H), 7.78 (1H, m), 8.48 (1H, m), 7.90 (2H, d, J=8.12Hz), 8.00 (2H, d, J=8.03Hz) .EIMS (m/e, %) 398 (M +, 100), 380 (M +-H 2O, 20) .HR-EIMS calculated value C 23H 18N 4O 3398.1379, measured value 398.1371.
Embodiment 114-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Step 1The preparation of N-(phendioxin-6-yl)-(6-picoline-2-yl) carbonamidine
Method just replaces 3 with 6-amino-phendioxin with embodiment 1 step 1, the 4-methylene dioxo group aniline obtains N-(phendioxin-6-yl)-(pyridine-2-base 6-picoline-2-yl) carbonamidine crude product, yield: 87%, be directly used in the next step.
Step 24-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(phendioxin, 4-dioxane-6-yl)-(pyridine-2-yl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 4-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield 43%, mp:146-148 ℃ 1H-NMR (400M, CDCl 3) δ 2.39 (3H, s), 4.31 (4H, m), 6.78 (1H, dd, J=8.44,2.52Hz), 6.87 (1H, d, J=2.52Hz), 6.89 (1H, d, J=8.44Hz), 7.11 (1H, d, J=7.84Hz), 7.37 (1H, d, J=7.56Hz), 7.52 (1H, s), 7.60 (1H, 7.84,7.56Hz), 7.70 (2H, d, J=8.40Hz), 8.02 (2H, J=8.40Hz) .EIMS (m/e, 100), 394 (M +, 90), 393 (M +, 100).
Embodiment 124-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Figure S051D5594820060106D000251
Method is with embodiment 2, just with 4-[1-(phendioxin, 4-dioxane-6-yl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making see execute example 11) replaces 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl obtains 4-[1-(phendioxin, 4-dioxane-6-yl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide, yield 45%, mp:245-247 ℃ 1H-NMR (400M, CDCl 3) δ 4.30 (4H, s, O-CH 2-CH 2-O), 5.7 (1H, brs, NH, interchangeable), 6.2 (1H, brs, NH, interchangeable), 6.78 (1H, dd, J=8.68,2.52Hz), 6.87 (1H, d, J=2.52Hz), 6.85 (1H, d, J=8.68Hz), 7.06 (1H, d, J=7.28Hz), 7.50 (1H, s, C5H), 7.56 (1H, dd, J=7.84,7.28Hz), 7.59 (1H, d, J=7.84Hz), 7.82 (2H, d, J=8.44Hz), 7.97 (2H, d, J=8.44Hz) .EIMS (m/e, %) 412 (M +, 100), 393 (M +-F, 60) .HR-EIMS calculated value C 24H 20N 4O 3412.1535, measured value 412.1537.
Embodiment 134-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000252
Step 1The preparation of N-(3,4-dimethoxy phenyl)-(pyridine-2-yl) carbonamidine
Method just replaces 3 respectively with 3,4-dimethoxy phenyl aniline and 2-itrile group pyridine with embodiment 1 step 1,4-methylene dioxo group aniline and 6-methyl-2-itrile group pyridine obtains N-(3,4-dimethoxy phenyl)-(pyridine-2-yl) carbonamidine, yield 42%, mp:122-125 ℃ 1H-NMR (400M, CDCl 3) δ 3.88 (3H, s, O-CH 3), 3.89 (3H, s, O-CH 3), 6.60 (1H, dd, J=8.40,2.24Hz), 6.64 (1H, d, J=2.24Hz), 6.88 (1H, d, J=8.40Hz), 7.41 (1H, dd, J=7.84,4.48Hz), 7.82 (1H, dd, J=7.84,7.84Hz), 8.43 (1H, d, 7.84Hz), 8.58 (1H, d, J=4.48Hz) .FABMS (m/e, 100), 258 (MH +, 100), 241 (MH +-NH 3, 85).
Step 24-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(3, the 4-dimethoxy phenyl)-(pyridine-2-yl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 4-[1-(3, the 4-dimethoxy phenyl)-and 2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl, mp:189-191 ℃ 1H-NMR (400M, CDCl 3) δ 3.78 (3H, s, O-CH 3), 3.94 (3H, s, O-CH 3), 6.81 (1H, s), 6.87 (1H, s), 6.88 (1H, s), 7.22 (1H, dd, J=6.76,5.06Hz), 7.70 (2H, d, J=8.40Hz), 7.56 (1h, s, C5H), 7.71 (1H, m), 7.84 (1H, d, J=7.88Hz), 8.02 (2H, d, J=8.40Hz), 8.58 (1H, d, J=5.06Hz), FABMS (m/e, %) 383 (M +, 100).
Embodiment 144-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[1-(3, the 4-dimethoxy phenyl)-and 2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 13) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl obtains 4-[1-(3, the 4-dimethoxy phenyl)-and 2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide, yield 60%, 183-184 ℃: 1H-NMR (400M, CDCl 3) δ 3.72 (3H, s, O-CH 3), 3.88 (3H, s, O-CH 3), 5.68 (H, br, NH, interchangeable), 6.20 (H, br, NH, interchangeable), 6.77 (1H, d, J=1.68Hz), 6.85 (1H, d, J=8.40Hz), 6.86 (1H, s), 6.88 (1H, dd, J=8.40,1.68Hz), 7.28 (1H, dd, J=7.56,5.04Hz), 7.46 (1H, d, J=8.12Hz,), 7.80 (1H, dd, J=8.12,7.56Hz), 7.87 (2H, d, J=8.04Hz), 7.96 (2H, d, J=8.04Hz) .8.48 (1H, d, J=5.04Hz) .EIMS (m/e, %) 400 (M +, 100).
Embodiment 152-[(1-(4-the fluorophenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-preparation of 6-picoline
Figure S051D5594820060106D000271
Method is with embodiment 1 step 3, just replace 4-acetobrom cyanophenyl and N-(3 respectively with 1-bromine Pinacolone and N-(4-fluorophenyl)-(6-picoline-2-yl) carbonamidine, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 2-(1-(4-the fluorophenyl)-4-tertiary butyl-1H-imidazoles-2-yl)-6-picoline, yield: 67%, mp:177-179 ℃ 1H-NMR (400M, CDCl 3) δ 1.38 (9H, s ,-C (CH 3) 3), 2.24 (3H, s, CH3), 6.85 (1H, s), 6.99 (1H, d, J=7.56Hz, C5H), 7.03 (2H, dd, J=8.68,8.68Hz), 7.21 (2H, dd, J=8.96,4.76Hz), 7.55 (1H, dd, J=7.88,7.56Hz), 7.67 (1H, d, J=7.88Hz) .EIMS (m/e, 100), 309 (M +, 50), 294 (M +-CH 3, 100) and .EI-HRMS calculated value C 19H 20FN 3309.1642, measured value 309.1647.
Embodiment 162-[(1-(phendioxin-6-the yl)-4-tertiary butyl-1H-imidazoles-2-yl)]-preparation of 6-picoline
Method is with embodiment 1 step 3, just with 1-bromine Pinacolone and N-(phendioxin, 4-dioxane-6-yl)-(6-picoline-2-yl) carbonamidine replaces 4-acetobrom cyanophenyl and N-(3 respectively, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 2-(1-(phendioxin-6-the yl)-4-tertiary butyl-1H-imidazoles-2-yl)-6-picoline, yield 41%, mp:75-77 ℃ 1H-NMR (400M, CDCl 3) δ 1.38 (9H, s), 2.35 (3H, s), 4.27 (4H, s), 6.69 (1H, dd, J=9.24,2.52Hz), 6.79 (1H, d, J=9.24Hz), 6.82 (1H, d, J=2.52Hz), 6.84 (1H, s), 7.00 (1H, bs), 7.53 (2H, m) .EIMS (m/e, 100) 349 (M +, 75), 334 (M +-CH3,100) .EI-HRMS calculated value C 21H 23N 3O 2349.1790, measured value 349.1781.
Embodiment 172-[(1-(3-fluoro-4-the p-methoxy-phenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-preparation of 6-picoline
Figure S051D5594820060106D000281
Method is with embodiment 1 step 3, just replace 4-acetobrom cyanophenyl and N-(3 respectively with 1-bromine Pinacolone and N-(3-fluoro-4-p-methoxy-phenyl)-(6-picoline-2-yl) carbonamidine, the 4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine, obtain 2-(1-(3-fluoro-4-the p-methoxy-phenyl)-4-tertiary butyl-1H-imidazoles-2-yl)-6-picoline, yield: 61%, mp:98-100 ℃ 1H-NMR (400M, CDCl 3) δ 1.40 (9H, s ,-C (CH 3) 3), 2.28 (3H, s, CH 3), 3.92 (3H, s, O-CH 3), 6.84 (1H, s), 6.91 (1H, dd, J=8.72,8.68Hz), 6.97 (1H, m), 7.02 (1H, d, J=7.60, Hz), 7.07 (1H, dd, J=11.44,2.52Hz), 7.57 (1H, d, J=7.72,7.56Hz), 7.59 (1H, d, J=7.72Hz).EIMS (m/e, 100), 339 (M +, 45), 324 (M +-CH3,100) .EI-HRMS calculated value C 20H 22FN 3O 339.1747, measured value 339.1749.
Embodiment 184-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000291
Step 1The preparation of N-(3-fluoro-4-p-methoxy-phenyl)-(6-picoline-2-yl) carbonamidine
Method just replaces 3,4-methylene dioxo group aniline with 33-fluoro-4-anisidine with embodiment 1 step 1, obtains N-(3-fluoro-4-p-methoxy-phenyl)-(6-picoline-2-yl) carbonamidine, yield 58%, and oily matter, 1H-NMR (400M, CDCl 3) δ 2.59 (3H, s, CH3), 3.89 (3H, s, O-CH3), 6.77 (1H, d, J=8.96Hz), 6.84 (1H, dd, J=12.6,2.24Hz), 6.98 (1H, dd, J=8.96,9.00Hz), 7.27 (1H, d, J=7.60Hz), 7.71 (1H, dd, J=7.60,7.84Hz), 8.19 (1H, d, J=7.84Hz).FABMS(m/e，100)，260(MH +，100)，243(MH +-NH 3，95)。
Step 24-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just replace N-(3 with N-(3-fluoro-4-p-methoxy-phenyl)-(6-picoline-2-yl) carbonamidine, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield 61%, mp:162-164 ℃ 1H-NMR (400M, CDCl 3) δ 2.28 (3H, s, CH3), 3.92 (3H, s, O-CH3), 6.98 (1H, dd, J=8.68,8.68Hz), 7.06-7.08 (1H, m), 7.11 (1H, d, J=7.84Hz), 7.14 (1H, dd, J=11.24,2.52Hz), 7.51 (1H, s), 7.64 (1H, dd, J=7.84,7.56Hz), 7.72 (2H, d, J=8.40Hz, 7.86 (1H, d, J=7.56Hz), 8.03 (2H, d, J=8.40Hz).FABMS(m/e，100)，385(MH +，100)。
Embodiment 194-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 18) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide, yield 70%, mp:204-206 ℃ 1H-NMR (400M, CDCl 3) δ 2.16 (3H, s, CH3), 4.00 (3H, s, O-CH3), 7.15 (1H, m), 7.19 (1H, d, J=7.56Hz), 7.22 (1H, d, J=8.96,9.00Hz), 7.33 (1H, br s, interchangeable), 7.39 (1H, dd, J=11.76,2.24Hz), 7.76 (1H, dd, J=7.56,7.56Hz), 7.82 (1H, 7.56Hz, 7.93 (2H, d, J=8.72Hz), 7.97 (2H, d, J=8.72Hz), 8.14 (1H, s).EIMS (m/e, 100), 402 (M +, 100), 383 (M +-F, 88) .HR-EIMS calculated value C 23H 19FN 4O 2402.1492 measured value 401.1500.
Embodiment 204-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000302
Step 1The preparation of N-(4-fluorophenyl)-(6-picoline-2-yl) carbonamidine
Method just replaces 3,4-methylene dioxo group aniline with the 4-fluoroaniline with embodiment 1 step 1, obtains N-(4-fluorophenyl)-(6-picoline-2-yl) carbonamidine, yield: 74%, mp:82-85 ℃ 1H-NMR (400M, CDCl 3) δ 2.59 (3H, s), 6.96-7.00 (2H, m), 7.04-7.09 (2H, m), 7.27 (1H, d, J=7.56Hz), 7.71 (1H, dd, J=7.56,7.56Hz), 8.20 (1H, d, J=7.56Hz).EIMS(m/e，100)229(M +，88)，228(M +-1，85)，111(100)。
Step 24-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just replace N-(3 with N-(4-fluorophenyl)-(6-picoline-2-yl) carbonamidine, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield: 59%, mp:234-235 ℃ 1H-NMR (400M, CDCl 3) δ 2.25 (3H, s), 7.07 (1H, d, J=7.84Hz), 7.12 (2H, dd, J=8.96,8.40Hz), 7.30 (2H, dd, J=8.96,4.76Hz), 7.53 (1H, s), 7.62 (1H, dd, J=7.84,7.60Hz), 7.70 (2H, d, J=8.40Hz), 7.80 (1H, d, J=7.60Hz), 7.80 (2H, d, J=8.40Hz).FABMS(m/e，100)，355(MH +，68)，242(100)。
Embodiment 214-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 20) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide, yield: 65%, mp:236-238 ℃ 1H-NMR (400M, CDCl 3) δ 2.25 (3H, s), 5.68 (1H, brs, NH, interchangeable), 6.16 (1H, brs, NH, interchangeable), 7.05 (1H, d, J=7.56Hz), 7.10 (2H, dd, J=8.96,8.44Hz), 7.29 (2H, dd, J=8.96,4.76Hz), 7.51 (1H, s), 7.60 (1H, dd, J=7.84,7.56Hz), 7.88 (2H, d, J=8.40Hz), 7.97 (2H, d, J=8.40Hz).ESIMS(m/e，％)373(MH +，100)。
Embodiment 224-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Step 1The preparation of N-(3,4-dimethoxy phenyl)-(2-p-methoxy-phenyl) carbonamidine
Method just replaces 2-itrile group pyridine with 2-methoxyl group cyanophenyl with embodiment 1 step 1, obtains N-(3,4-methylenedioxyphenyl)-(2-p-methoxy-phenyl) carbonamidine, and yield 55%, crude product are directly used in next step reaction.
Step 24-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(3, the 4-methylenedioxyphenyl)-(2-p-methoxy-phenyl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] cyanophenyl, yield 66%, mp:182-184 ℃ 1H-NMR (400M, CDCl 3) δ 3.47 (3H, s, OCH3), 5.99 (2H, s, O-CH2-O), 6.65 (1H, dd, J=8.12,1.40Hz), 6.67 (1H, d, J=1.40Hz), 6.72 (1H, d, J=8.12Hz), 6.80 (1H, d, J=8.40Hz), 7.04 (1H, dd, J=7.60,7.28Hz), 7.38 (1H, dd, J=8.40,7.60Hz), 7.56 (1H, s), 7.57 (1H, d, J=7.28Hz), 7.67 (2H, d, J=8.16Hz), 7.96 (2H, d, J=8.16Hz) .FAB-MS (m/e, 100), 396 (MH +, 100).
Embodiment 234-[1-(3,4-methylene dioxy phenyl group)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] preparation of benzamide
Method is with embodiment 2, just with 4-[1-(3, the 4-methylene dioxy phenyl group)-and 2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] cyanophenyl (method for making see execute example 22) replaces 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl obtains 4-[1-(3, the 4-methylene dioxy phenyl group)-and 2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] benzamide, yield: 78%, mp:190-192 ℃ 1H-NMR (400M, CDCl 3) δ 3.48 (3H, s, OCH 3), 5.60 (1H, brs, NH), 5.99 (2H, s, O-CH 2-O), 6.20 (1H, brs, NH), 6.67 (1H, dd, J=8.12,1.96Hz), 6.68 (1H, d, J=1.96Hz), 6.72 (1H, d, J=8.12Hz), 6.80 (1H, dd, J=8.40,0.84Hz), 7.04 (1H, ddd, J=7.56,7.60Hz), 7.38 (1H, ddd, J=8.40,7.60,1.68Hz), 7.55 (1H, s), 7.58 (1H, dd, J=7.56,1.68Hz), 7.86 (2H, d, J=8.40Hz), 7.96 (2H, d, J=8.40Hz) .ESIMS (+Q) (m/e, 100), 414 (MH +, 100), 436 (MNa +, 15).
Embodiment 24The preparation of 1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-2-(2-p-methoxy-phenyl)-1H-imidazoles
Method is with embodiment 1 step 3, just with 1-bromine Pinacolone and N-(3, the 4-dimethoxy phenyl)-(2-p-methoxy-phenyl) (method for making is seen embodiment 22 to carbonamidine, step 1) replaces 4-acetobrom cyanophenyl and N-(3,4-methylenedioxyphenyl)-(6-picoline-2-yl) carbonamidine respectively, obtains 1-(3, the 4-methylene dioxy phenyl group)-the 4-tertiary butyl-2-(2-p-methoxy-phenyl)-1H-imidazoles, yield: 65%, mp:99-101 ℃ 1H-NMR (400M, CDCl 3) δ 1.38 (9H, s ,-C (CH 3) 3), 3.41 (3H, s, O-CH3), 5.95 (2H, s, O-CH 2-O), 6.59 (1H, dd, J=8.12,2.24Hz), 6.63 (1H, d, J=2.24Hz), 6.69 (1H, d, J=8.12Hz), 6.84 (1H, s), 7.74 (1H, d, J=8.16Hz), 6.99 (1H, dd, J=7.56,7.00Hz), 7.31 (1H, dd, J=8.16,7.00Hz), 7.52 (1H, d, J=7.56Hz).EIMS(m/e，100)，351(MH +，100)。
Embodiment 254-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Figure S051D5594820060106D000341
Step 1N-(3,4-dimethoxy phenyl)-(6-picoline-2-yl) carbonamidine
Method just replaces 2-itrile group pyridine and 3,4-dimethoxy aniline respectively with 6-methyl-2-itrile group pyridine and 3,4-dimethoxy aniline with embodiment 1 step 1, obtains N-(3,4-dimethoxy phenyl)-(6-picoline-2-yl) carbonamidine, yield 55%.
Step 24-[1-(3,4-dimethoxy phenyl)-2-(6-methyl-pyridine-2-yl)-1H-imidazol-4 yl] preparation of cyanophenyl
Method is with embodiment 1 step 3, just with N-(3, the 4-dimethoxy phenyl)-(6-methyl-pyridine-2-yl) carbonamidine replaces N-(3, the 4-methylenedioxyphenyl)-(6-methyl-pyridine-2-yl) carbonamidine, obtain 4-[1-(3, the 4-dimethoxy phenyl)-and 2-(6-methyl-pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl, yield: 36% 1H-NMR (400M, CDCl 3) δ 2.37 (3H, s), 3.79 (3H, s), 3.92 (3H, s), 6.84-6.86 (3H, m), 7.07 (1H, m), 7.55-7.57 (3H, m), 7.69 (2H, d, J=8.40Hz), 7.99 (2H, d, J=8.40Hz) .EIMS (m/e, %) 397 (MH +, 100).
Embodiment 264-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] preparation of benzamide
Figure S051D5594820060106D000342
Method is with embodiment 2, just with 4-[1-(3, the 4-Dimethoxyphenyl)-and 2-(6-picoline)-1H-imidazol-4 yl] cyanophenyl (method for making is seen embodiment 20) replacement 4-[1-(3, the 4-methylenedioxyphenyl)-and 2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl, obtain 4-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide, yield: 65%, mp:215-218 ℃ 1H-NMR (400M, CDCl 3) δ 2.21 (3H, s), 3.70 (3H, s), 3.79 (3H, s), 6.86 (1H, dd, J=8.68,1.32Hz), 6.98 (1H, d, J=8.68Hz), 7.02 (1H, d, J=1.32Hz), 7.19 (1H, m), (7.33 1H, br s, NH, but heavy water exchange), 7.73 (2H, m), 7.94 (2H, d, J=8.40Hz), 7.97 (2H, d, J=8.40Hz), 8.12 (1H, s) .EIMS (m/e, %), 415 (MH +, 100).
Embodiment 272-[(1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-1H-imidazoles-2-yl)]-preparation of 6-picoline
Method just replaces 4-acetobrom cyanophenyl with 1-bromine Pinacolone with embodiment 1 step 3, obtains 2-[(1-(3, the 4-methylene dioxy phenyl group)-the 4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline, yield: 37%, mp:100-102 ℃, 1H-NMR (400M, CDCl 3) δ 1.37 (9H, s ,-C (CH 3) 3), 2.34 (3H, s), 6.00 (2H, s), 6.71 (1H, dd, J=8.12,2.00Hz), 6.72 (1H, d, J=2.00Hz), 6.74 (1H, d, J=8.12Hz), 6.83 (1H, s), 6.99 (1H, m), 7.52 (2H, m) .EIMS (m/e, %), 336 (MH +, 100).
The ALK5 of the compound that the present invention relates to suppresses activity and can detect with the following method:
Embodiment 28
With the HB1117 cell cultures in the DMEM that contains 10% foetal calf serum, with the cell in recovery back 2-5 generation with 2-8 * 10 3The density of individual cells/well is seeded on 96 orifice plates.Renewed bright nutrient solution in 4-8 hour before the administration, to cell abundance 70-90% administration.Background contrast (nutrient solution), solvent control (nutrient solution that contains 0.1%DMSO) and positive control are established in administration, and (the positive medicine of SB431542 is referring to document J.Med.Chem. (2002) 45 (5); 999-1001), the compound final concentration is 0.1 μ mol/l and 1 μ mol/l.After the administration 4 hours, give final concentration 10ng/ml TGF-β 1Abduction delivering, nutrient solution is only given in the background contrast.Induce after 24 hours with chemoluminescence method examining report gene expression product Lampyridea luciferase activity.Detect the number of photons that each is organized with Chemiluminescence Apparatus, according to the inhibiting rate of following formula computerized compound to ALK5, the results are shown in subordinate list 1.
Multiple=abduction delivering is respectively organized number of photons average/background control group number of photons average
Compound inhibiting rate (%)=[(solvent control group multiple-administration group multiple)/solvent control group multiple] * 100%
The influence that table 1 compound is expressed the beta induced luciferase reporter gene of TGF-

Claims (13)

1. the compound of general formula I or its pharmaceutically useful salt
Wherein:
R1 is 3,4-methylenedioxyphenyl, 2-fluorophenyl, phendioxin-6-base, 3,4-dimethoxy phenyl, 4-fluorophenyl or 3-fluoro-4-p-methoxy-phenyl;
R2 is 6-picoline-2-base, 2-fluorophenyl, pyridine-2-base, 3,4-methylenedioxyphenyl or 2-p-methoxy-phenyl; And
R3 is to cyano-phenyl, to formamyl phenyl or the tertiary butyl.
2. according to the compound of claim 1, it is selected from:
(1) 4-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(2) 4-[1-(3,4-methylenedioxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(3) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] cyanophenyl;
(4) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-fluorophenyl)-1H-imidazol-4 yl] benzamide;
(5) 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(6) 4-[1-(3,4-methylenedioxyphenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(7) 4-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] cyanophenyl;
(8) 4-[1-(2-fluorophenyl)-2-(3,4-methylenedioxyphenyl)-1H-imidazol-4 yl] benzamide;
(9) 4-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(10) 4-[1-(phendioxin-6-yl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(11) 4-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(12) 4-[1-(phendioxin-6-yl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(13) 4-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(14) 4-[1-(3,4-dimethoxy phenyl)-2-(pyridine-2-yl)-1H-imidazol-4 yl] benzamide;
(15) 2-[(1-(4-fluorophenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(16) 2-[(1-(phendioxin-6-the yl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(17) 2-[(1-(3-fluoro-4-the p-methoxy-phenyl)-4-tertiary butyl-1H-imidazoles-2-yl)]-the 6-picoline;
(18) 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(19) 4-[1-(3-fluoro-4-p-methoxy-phenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(20) 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(21) 4-[1-(4-fluorophenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(22) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] cyanophenyl;
(23) 4-[1-(3,4-methylenedioxyphenyl)-2-(2-p-methoxy-phenyl)-1H-imidazol-4 yl] benzamide;
(24) 1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-2-(2-p-methoxy-phenyl)-1H-imidazoles;
(25) 4-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] cyanophenyl;
(26) 4-[1-(3,4-Dimethoxyphenyl)-2-(6-picoline-2-yl)-1H-imidazol-4 yl] benzamide;
(27) 2-(1-(3,4-the methylene dioxy phenyl group)-4-tertiary butyl-1H-imidazoles-2-yl)-6-picoline;
And pharmacologically acceptable salt.
3. preparation is according to the method for the compound of the general formula I of claim 1, and it comprises the steps:
(i) in the presence of organic bases, in inert solvent, make fragrant nitrile and arylamine reaction, generate the aryl carbonamidine that the N-aryl replaces
Figure FSB00000944993800031
Wherein the definition of R1 and R2 is with claim 1;
(ii) make aryl carbonamidine and the general formula of the N-aryl replacement of generation be Compound in the lower alcohol of C1-C6, in the presence of organic bases or mineral alkali, be heated to 50-100 ℃ of reaction, generate the compound with 1,2,4-tri-substituted imidazole structure
Wherein the definition of R3 is with claim 1.
4. according to the method for claim 3, wherein, in step (i), described organic bases is NaN (SiMe 3) 2
5. according to the method for claim 3 or 4, wherein, in step (i), described inert solvent is THF.
6. according to the method for claim 3 or 4, wherein, step (ii) in, the lower alcohol of described C1-C6 is Virahol.
7. according to the method for claim 3 or 4, wherein, step (ii) in, described mineral alkali is NaHCO 3
8. pharmaceutical composition, it comprises each compound or its pharmaceutically useful salt and at least a pharmaceutically useful carrier of general formula I according to claim 1-2.
According to claim 1-2 each the compound of general formula I or its pharmaceutically useful salt for the production of the purposes of the medicine of the mammiferous disease by the ALK5 acceptor media for the treatment of, described disease by the ALK5 acceptor media is selected from following disease: chronic nephritis, acute nephritis, wound healing, sacroiliitis, osteoporosis, kidney disease, ulcer, eye disease, diabetic nephropathy, nervous function damage, A Erzi sea be syndromes, arteriosclerosis, peritonaeum or subcutaneous adhesion, any fibrosis lesion and valvular stenosis not.
10. according to the purposes of claim 9, wherein said eye disease is corneal wound.
11. according to the purposes of claim 9, wherein said fibrosis lesion is selected from pulmonary fibrosis and hepatic fibrosis.
12. according to claim 1-2 each the compound of general formula I or its pharmaceutically useful salt for the production of the purposes that can suppress the medicine of TGF-signal in the mammalian body.
13. according to claim 1-2 each the compound of general formula I or its pharmaceutically useful salt for the production of the purposes that is used for suppressing the medicine that matter forms between the Mammals cells in vivo.
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CN1681805A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel imidazole compounds as transforming growth factor (TGF) inhibitors

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