Metalloenzyme inhibitor compounds 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
CA2846117 A1 2013-03-07 [CA2846117] / 2013-03-07
申请号/申请日
2012CA-2846117 / 2012-08-27
发明人
HOEKSTRA WILLIAM J;SCHOTZINGER ROBERT J;
申请人
VIAMET PHARMACEUTICALS;
主分类号
IPC分类号
A61K-031/427A61K-031/542A61P-031/18C07D-417/12C07D-513/04
摘要
(CA2846117) The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2011US-61528953 2011-08-30 2012WO-US52483 2012-08-27
主权利要求
(CA2846117)  What is claimed: 1. A compound of formula (I),, wherein: Each R1 and R2 is independently optionally substituted aryl, optionally substituted naphthyl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl-alkyl;   R3 is H, OH, alkoxy, amino, alkylamino, or dialkylamino;   R4 is H or halo. 2. The compound of claim 1, wherein R3 is OH. 3. The compound of claim 1, wherein R2 is optionally substituted alkyl, and R3 is OH. 4. The compound of claim 1, wherein R1 is optionally substituted aryl, R2 is alkyl, and R3 is OH. 5. The compound of claim 1, wherein R1 is optionally substituted heteroaryl, R2 is alkyl, and R3 is OH. 6. The compound of claim 1, wherein R1 is substituted aryl, R2 is alkyl, and R3 is OH. 7. The compound of claim 1, wherein R1 is optionally substituted naphthyl, R2 is alkyl, and R3 is OH. 8. The compound of claim 7, wherein R1 is substituted naphthyl, R2 is alkyl, and R3 is OH. 9. The compound of claim 8, wherein R1 is naphthyl substituted with 1, 2, 3 or 4 substituents, independently selected from alkyl, alkoxy, haloalkoxy, cyano, halo, amino, mono-alkylamino, di-alkylamino, or heteroaryl. 10. The compound of claim 1 having the structure of formula (II): wherein R5 and R6 are independently H, halogen, alkoxy, fluoroalkoxy containing 1-5 fluorines, cyano, carboxamido, optionally substituted aryl, or optionally substituted heteroaryl. 11. The compound of formula (I) in claim 1 wherein R4 is H. 12. The compound of formula (I) in claim 1 wherein R4 is chloro. 13. The compound of claim 1 that is: 1-(2-Chloro-thiazol-5-yl)-1-(6, 7-dimethoxynaphthalen-2-yl)-2-methylpropan-1- ol (1);   or 1-(6,7-dimethoxynaphthalen-2-yl)-2-methyl-1-(thiazol-5-yl)propan-1-ol (2). 14. The compound of any one of claims 1-13, wherein the compound attains affinity for a metalloenzyme by formation of one or more of the following types of chemical interactions or bonds to a metal: sigma bonds, covalent bonds, coordinate-covalent bonds, ionic bonds, pi bonds, delta bonds, or backbonding interactions. 15. The compound of any one of claims 1-13, wherein the compound binds to a metal. 16. The compound of any one of claims 1-13, wherein the compound binds to iron, zinc, heme iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper. 17. The compound of any one of claims 1-13, wherein the compound inhibits an enzyme class selected from cytochrome P450 family, histone deacetylases, matrix metalloproteinases, phsophodiesterases, cycloxygenases, carbonic anhydrases, and nitric oxide synthases. 18. The compound of any one of claims 1-13, wherein the compound inhibits an enzyme selected from 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family, catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidine dehydrogenase- 1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, and xanthine oxidase. 19. The compound of any one of claims 1-13, wherein the compound inhibits an enzyme selected from 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase p, anthrax lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopamine betahydroxylase, endothelin converting enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase, indoleamine 2,3- dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide deformylase, phosphodiesteraseVII, relaxase, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), and vitamin D hydroxylase (CYP24). 20. The compound of any one of claims 1-13, wherein the compound is identified as binding to a metal. 21. The compound of any one of claims 1-13, wherein the compound is identified as binding to iron, zinc, heme-iron, manganese, magnesium, iron-sulfide cluster, nickel, molybdenum, or copper. 22. The compound of any one of claims 1-13, wherein the compound is identified as inhibiting an enzyme class selected from cytochrome P450 family, histone deacetylases, matrix metalloproteinases, phsophodiesterases, cycloxygenases, carbonic anhydrases, and nitric oxide synthases. 23. The compound of any one of claims 1-13, wherein the compound is identified as inhibiting an enzyme selected from 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family, catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, and xanthine oxidase. 24. The compound of any one of claims 1-13, wherein the compound is identified as an inhibitor of CYP17. 25. The compound of any one of claims 1-13, wherein the compound is identified as having an activity range against a target enzyme and an activity range against an offtarget enzyme (e.g., CYP17 IC50<0.35 uM and IC50>0.75 .micro.M for CYP2C9, CYP2C19 and CYP3A4). 26. A method of inhibiting metalloenzyme activity comprising contacting a compound of any one of claims 1-13 with a metalloenzyme. 27. The method of claim 26, wherein the contacting is in vivo. 28. The method of claim 26, wherein the contacting is in vitro. 29. The method of claim 26, wherein the metalloenzyme comprises a metal atom that is iron, zinc, heme iron, manganese, magnesium, iron sulfide cluster, nickel, molybdenum, or copper;  30. The method of claim 26, wherein the metalloenzyme is a member of an enzyme class selected from cytochrome cytochrome P450 family, histone deacetylases, matrix metalloproteinases, phsophodiesterases, cycloxygenases, carbonic anhydrases, and nitric oxide synthases;  the metalloenzyme is aromatase (CYP19), a cyclooxygenase, lanosterol demethylase (CYP51), a nitric oxide synthase, thromboxane synthase (CYP5a), thyroid peroxidase, 17-alpha hydroxylase/17,20-lyase (CYP17), aldosterone synthase (CYP11B2), cytochrome P450 2A6, heme oxygenase, indoleamine 2,3-dioxygenase, retinoic acid hydroxylase (CYP26), or vitamin D hydroxylase (CYP24). 31. The method of claim 26, wherein the metalloenzyme is 17-alpha hydroxylase/17,20-lyase (CYP17). 32. The method of claim 26, wherein the metalloenzyme is 4-hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family, catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, and xanthine oxidase. 33. The method of claim 26, wherein the metalloenzyme is 1-deoxy-d-xylulose-5- phosphate reductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase p, anthrax lethal factor, arginase, beta-lactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin converting enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide deformylase, phosphodiesteraseVII, relaxase, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP-(3-O-(R-3-hydroxymyristoyl))-N- acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24). 34. The method of claim 26, further comprising administering the compound to a subject. 35. The method of claim 26, wherein the compound of formula (I) is identified as having an activity range against CYP17 IC50 < 0.35 uM and IC50 > 0.75 .micro.M for CYP2C9, CYP2C19 and CYP3A4. 36. A method of modulating metalloenzyme activity in a subject, comprising contacting the subject with a compound of claim 1, in an amount and under conditions sufficient to modulate metalloenzyme activity. 37. A method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, comprising administering to the subject an effective amount of a compound of claim 1. 40. A method of treating a subject suffering from or susceptible to a metalloenzyme-related disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-related disorder or disease, comprising administering to said subject in need thereof, an effective amount of a compound of claim 1, such that said subject is treated for said disorder.  41 A method of treating a subject suffering from or susceptible to a metalloenzyme-mediated disorder or disease, wherein the subject has been identified as in need of treatment for a metalloenzyme-mediated disorder or disease, comprising administering to said subject in need thereof, an effective amount of a compound of claim 1, such that metalloenzyme activity in said subject is modulated (e.g., down regulated, inhibited). 42. The method of claim 40, wherein the disease or disorder is mediated by any of 4- hydroxyphenyl pyruvate dioxygenase, 5-lipoxygenase, adenosine deaminase, alcohol dehydrogenase, aminopeptidase n, angiotensin converting enzyme, aromatase (CYP19), calcineurin, carbamoyl phosphate synthetase, carbonic anhydrase family, catechol o-methyl transferase, cyclooxygenase family, dihydropyrimidine dehydrogenase-1, DNA polymerase, farnesyl diphosphate synthase, farnesyl transferase, fumarate reductase, GABA aminotransferase, HIF-prolyl hydroxylase, histone deacetylase family, HIV integrase, HIV-1 reverse transcriptase, isoleucine tRNA ligase, lanosterol demethylase (CYP51), matrix metalloprotease family, methionine aminopeptidase, neutral endopeptidase, nitric oxide synthase family, phosphodiesterase III, phosphodiesteraseIV, phosphodiesteraseV, pyruvate ferredoxin oxidoreductase, renal peptidase, ribonucleoside diphosphate reductase, thromboxane synthase (CYP5a), thyroid peroxidase, tyrosinase, urease, or xanthine oxidase. 43. The method of claim 40, wherein the disease or disorder is mediated by any of 1-deoxy-dxylulose-5-phosphate reductoisomerase (DXR), 17-alpha hydroxylase (CYP17), aldosterone synthase (CYP11B2), aminopeptidase p, anthrax lethal factor, arginase, betalactamase, cytochrome P450 2A6, d-ala d-ala ligase, dopamine beta-hydroxylase, endothelin converting enzyme-1, glutamate carboxypeptidase II, glutaminyl cyclase, glyoxalase, heme oxygenase, HPV/HSV E1 helicase, indoleamine 2,3-dioxygenase, leukotriene A4 hydrolase, methionine aminopeptidase 2, peptide deformylase, phosphodiesteraseVII, relaxase, retinoic acid hydroxylase (CYP26), TNF-alpha converting enzyme (TACE), UDP-(3-O-(R-3- hydroxymyristoyl))-N-acetylglucosamine deacetylase (LpxC), vascular adhesion protein-1 (VAP-1), or vitamin D hydroxylase (CYP24). 44. The method of claim 40, wherein the disease or disorder is cancer, cardiovascular disease, inflammatory disease, infectious disease, metabolic disease, opthalmologic disease, central nervous system (CNS) disease, urologic disease, or gastrointestinal disease. 45. The method of claim 40, wherein the disease or disorder is prostate cancer, breast cancer, endometriosis, uterine fibroids, inflammatory bowel disease, psoriasis, systemic fungal infection, onychomycosis, cardiovascular disease, prostate hypertrophy, testicular cancer, virilism, hirsutism, male pattern alopecia, precocious puberty, uterine cancer, ovarian cancer, mastopathy, uterine myoma, uterine adenomyosis, or polycystic ovarian syndrome. 46. A composition comprising a compound of claim 1 and an agriculturally acceptable carrier. 47. A method of treating or preventing a metalloenzyme-mediated disease or disorder in or on a plant comprising contacting a compound of claim 1 with the plant. 48. A method of inhibiting metalloenzyme activity in a microorganism on a plant comprising contacting a compound of claim 1 with the plant. 49. A method of treating or preventing a fungal disease or disorder in or on a plant comprising contacting a compound of any of claims 1-25 with the plant. 50. A method of treating or preventing fungi growth in or on a plant comprising contacting a compound of any of claims 1-25 with the plant. 51. A method of inhibiting microorganisms in or on a plant comprising contacting a compound of any of claims 1-25 with the plant. 52. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 53. The composition of claim 52 further comprising an additional therapeutic agent. 54. The composition of claim 53 further comprising an additional therapeutic agent that is an anti-cancer agent, antifungal agent, cardiovascular agent, antiinflammatory agent, chemotherapeutic agent, an anti-angiogenesis agent, cytotoxic agent, an antiproliferation agent, metabolic disease agent, opthalmologic disease agent, central nervous system (CNS) disease agent, urologic disease agent, or gastrointestinal disease agent.
法律状态
(CA2846117) LEGAL DETAILS FOR CA2846117  Actual or expected expiration date=2032-08-27    Legal state=ALIVE    Status=PENDING     Event publication date=2012-08-27  Event code=CA/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=CA CA2846117  Application date=2012-08-27  Standardized application number=2012CA-2846117     Event publication date=2013-03-07  Event code=CA/A1  Event type=Examination events  Application laid open  Publication country=CA  Publication number=CA2846117  Publication stage Code=A1  Publication date=2013-03-07  Standardized publication number=CA2846117     Event publication date=2017-08-17  Event code=CA/EEER  Event indicator=Pos  Event type=Examination events  Examination request  Effective date of the event=2017-08-09
专利类型码
A1
国别省市代码
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