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    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metaloproteinase and tace inhibitors
    2.
    发明授权
    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metaloproteinase and tace inhibitors 失效
    邻氨基磺酰氨基杂芳基异羟肟酸作为基质金属蛋白酶和抑制剂的制备和应用

    公开(公告)号：US06162814A

    公开(公告)日：2000-12-19

    申请号：US330877

    申请日：1999-06-11

    申请人： Jeremy Ian Levin ,  Frances Christy Nelson

    发明人： Jeremy Ian Levin ,  Frances Christy Nelson

    IPC分类号： C07D213/79 ,  C07D213/81 ,  C07D233/90 ,  C07D333/38 ,  C07D409/12 ,  A61K31/381

    CPC分类号： C07D213/79 ,  C07D213/81 ,  C07D233/90 ,  C07D333/38 ,  C07D409/12

    摘要： The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-.alpha. converting enzyme (TACE, tumor necrosis factor-.alpha. converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamide aryl hydroxamic acids of the present invention are represented by the formula ##STR1## where the hydroxamic acid moiety and the sulfanamido moiety are bonded to adjacent carbons on group A where A is defined as:a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R.sup.1, R.sup.2 and R.sup.3 ;and Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are described in the specification,and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

    摘要翻译： 本发明涉及基因金属蛋白酶（例如明胶酶，基质溶质蛋白和胶原酶）和TNF-α转换酶（TACE，肿瘤坏死因子-α转化酶）的新型低分子量非肽抑制剂的发现，其可用于 这些酶涉及的疾病如关节炎，肿瘤生长和转移，血管生成，组织溃疡，伤口愈合异常，牙周病，骨病，蛋白尿，动脉瘤主动脉疾病，创伤性关节损伤后退行性软骨损失，脱髓鞘疾病 的神经系统，移植排斥反应，恶病质，厌食，炎症，发烧，胰岛素抵抗，脓毒性休克，充血性心力衰竭，中枢神经系统炎性疾病，炎症性肠病，HIV感染，年龄相关性黄斑变性，糖尿病性视网膜病变，增殖性 玻璃体视网膜病变，早产儿视网膜病变，眼部炎症，角蛋白 职业，干燥综合征，近视眼眼肿瘤，眼血管生成/新生血管形成。 本发明的TACE和MMP抑制邻氨基磺酰基芳基异羟肟酸由下式表示，其中异羟肟酸部分和磺酰氨基部分键合到基团A上的相邻碳上，其中A定义为：5-6元杂芳基， 独立地选自N，O和S且任选被R 1，R 2和R 3取代的1至3个杂原子; 并且Z，R 1，R 2，R 3，R 4，R 5，R 6，R 7，R 8和R 9在本说明书及其药学上可接受的盐及其旋光异构体和非对映体中描述。

    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
    3.
    发明授权
    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors 失效
    邻氨基磺酰氨基杂芳基异羟肟酸作为基质金属蛋白酶和抑制剂的制备和应用

    公开(公告)号：US06197795B1

    公开(公告)日：2001-03-06

    申请号：US09330717

    申请日：1999-06-11

    申请人： Jeremy Ian Levin ,  Frances Christy Nelson

    发明人： Jeremy Ian Levin ,  Frances Christy Nelson

    IPC分类号： C07D21378

    CPC分类号： C07D213/79 ,  C07D213/81 ,  C07D233/90 ,  C07D333/38 ,  C07D409/12

    摘要： The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-&agr; converting enzyme (TACE, tumor necrosis factor-&agr; converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arhritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where A is defined as: a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R1, R2 and R3; and Z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are described in the specification, and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

    摘要翻译： 本发明涉及基因金属蛋白酶（例如明胶酶，基质溶质蛋白和胶原酶）和TNF-α转化酶（TACE，肿瘤坏死因子-α转化酶）的新型低分子量非肽抑制剂的发现，其可用于 治疗这些酶涉及的疾病如肾炎，肿瘤生长和转移，血管生成，组织溃疡，创伤愈合异常，牙周病，骨病，蛋白尿，动脉瘤主动脉疾病，创伤性关节损伤后退行性软骨损失，脱髓鞘疾病 的神经系统，移植排斥反应，恶病质，厌食，炎症，发烧，胰岛素抵抗，脓毒性休克，充血性心力衰竭，中枢神经系统炎性疾病，炎症性肠病，HIV感染，年龄相关性黄斑变性，糖尿病性视网膜病变，增殖性 玻璃体视网膜病变，早产儿视网膜病变，眼部炎症，圆锥角膜炎 s，干燥综合征，近视眼，眼肿瘤，眼血管生成/新血管形成。 本发明的TACE和MMP抑制邻氨基磺酰氨基芳基异羟肟酸由异羟肟酸部分和亚磺酰氨基部分与基团A上的相邻碳键合的表示，其中A定义为：具有 1至3个独立地选自N，O和S并且任选被R 1，R 2和R 3取代的杂原子;且Z，R 1，R 2，R 3，R 4，R 5，R 6，R 7，R 8和R 9在本说明书中描述， 其药学上可接受的盐及其旋光异构体和非对映体。

    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
    4.
    发明授权
    Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors 失效
    邻氨基磺酰氨基杂芳基异羟肟酸作为基质金属蛋白酶和抑制剂的制备和应用

    公开(公告)号：US5962481A

    公开(公告)日：1999-10-05

    申请号：US944400

    申请日：1997-10-06

    申请人： Jeremy Ian Levin ,  Frances Christy Nelson

    发明人： Jeremy Ian Levin ,  Frances Christy Nelson

    IPC分类号： C07D213/79 ,  C07D213/81 ,  C07D233/90 ,  C07D333/38 ,  C07D409/12 ,  C07D213/78 ,  A61K31/44

    CPC分类号： C07D213/79 ,  C07D213/81 ,  C07D233/90 ,  C07D333/38 ,  C07D409/12

    摘要： The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-.alpha. converting enzyme (TACE, tumor necrosis factor-.alpha. converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization.The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula ##STR1## where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where A is defined as:a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R.sup.1, R.sup.2 and R.sup.3 ;and Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are described in the specification,and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

    摘要翻译： 本发明涉及基因金属蛋白酶（例如明胶酶，基质溶质蛋白和胶原酶）和TNF-α转换酶（TACE，肿瘤坏死因子-α转化酶）的新型低分子量非肽抑制剂的发现，其可用于 这些酶涉及的疾病如关节炎，肿瘤生长和转移，血管生成，组织溃疡，伤口愈合异常，牙周病，骨病，蛋白尿，动脉瘤主动脉疾病，创伤性关节损伤后退行性软骨损失，脱髓鞘疾病 的神经系统，移植排斥反应，恶病质，厌食，炎症，发烧，胰岛素抵抗，脓毒性休克，充血性心力衰竭，中枢神经系统炎性疾病，炎症性肠病，HIV感染，年龄相关性黄斑变性，糖尿病性视网膜病变，增殖性 玻璃体视网膜病变，早产儿视网膜病变，眼部炎症，角蛋白 职业，干燥综合征，近视眼眼肿瘤，眼血管生成/新生血管形成。 本发明的TACE和MMP抑制邻氨基磺酰氨基芳基异羟肟酸由下式表示，其中异羟肟酸部分和亚磺酰氨基部分与基团A上的相邻碳键合，其中A定义为：5-6元杂芳基， 独立地选自N，O和S且任选被R 1，R 2和R 3取代的1至3个杂原子; 并且Z，R 1，R 2，R 3，R 4，R 5，R 6，R 7，R 8和R 9在本说明书及其药学上可接受的盐及其旋光异构体和非对映体中描述。

    Mercaptoketones and mercaptoalcohols and a process for their preparation
    5.
    发明授权
    Mercaptoketones and mercaptoalcohols and a process for their preparation 失效

    公开(公告)号：US06124502A

    公开(公告)日：2000-09-26

    申请号：US169661

    申请日：1998-10-09

    申请人： Jeremy Ian Levin

    发明人： Jeremy Ian Levin

    IPC分类号： C07C319/20 ,  C07C323/60 ,  C07D307/33 ,  C07C233/05 ,  C07C321/12

    CPC分类号： C07D307/33 ,  C07C319/20 ,  C07C323/60

    摘要： This invention relates to matrix metalloproteinase (MMP) inhibiting compounds of the formula: ##STR1## where R.sup.1 is C.sub.1 -C.sub.12 alkyl, straight or branched and optionally substituted by halogen, hydroxy, C.sub.1 -C.sub.6 alkoxy, amino, carboxyl, C.sub.1 -C.sub.6 alkoxycarbonyl, carboxamido, nitrile, mono- or di-(C.sub.1 -C.sub.6)alkylamino, thio, C.sub.1 -C.sub.6 alkylthio, aryl, --Oaryl or --OCH.sub.2 aryl where aryl is optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, carboxy, halogen, cyano, nitro, carboxamido, or hydroxy; and C.sub.1 -C.sub.6 alkanesulfonyloxy. R.sup.2 is .alpha.-OH or .beta.-OH and R.sup.6 is H or R.sup.2 and R.sup.6 together are carbonyl; the chemical intermediates; and processes for the preparation of these compounds and the intermediates thereto.Matrix metalloproteinases (MMP) are a family of zinc-containing calcium dependent proteinases, including stromelysins, collagenases, and gelatinases. These MMP enzymes are capable of degrading the proteinaceous components of connective tissue and appear to be involved in tissue remodeling, i.e., wound healing and connective tissue turnover. Unexpectedly, the mercaptoalcohols with the S-configuration at the hydroxyl-bearing carbon have been found to be at least 4 times more potent than the analogous (R)-alcohols both in vitro and in vivo in inhibiting the MMP enzyme.