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    Use of imidazoles for the treatment of atherosclerosis
    3.
    发明授权
    Use of imidazoles for the treatment of atherosclerosis 失效

    公开(公告)号：US5166214A

    公开(公告)日：1992-11-24

    申请号：US533241

    申请日：1990-06-04

    申请人： Jeffrey T. Billheimer ,  Peter J. Gillies ,  C. Anne Higley ,  Thomas P. Maduskuie, Jr. ,  Ruth R. Wexler

    发明人： Jeffrey T. Billheimer ,  Peter J. Gillies ,  C. Anne Higley ,  Thomas P. Maduskuie, Jr. ,  Ruth R. Wexler

    IPC分类号： C07D233/54 ,  C07D233/70 ,  C07D233/84 ,  C07D233/88 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/14 ,  C07D409/04 ,  C07D409/14 ,  C07D491/04

    CPC分类号： C07D233/64 ,  C07D233/70 ,  C07D233/84 ,  C07D233/88 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/14 ,  C07D409/04 ,  C07D409/14 ,  C07D491/04

    摘要： This invention relates to imidazoles as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT), processes for their preparation, and their use as antihypercholesterolemic agents or antiatherosclerotic.The compounds for use in the described method are compounds of Formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 aralkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4, alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; 2-, 3-, or 4- or pyrindinyl, pyrimidinyl, or biphenyl; R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl of alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; Y is O; Z is NHR.sup.4, OR.sup.4, or R.sup.4 ; r is 0-2, or a pharmaceutically acceptable salt thereof.

    Detection of patients at risk for developing integrin antagonist/agonist mediated disease states
    5.
    发明授权
    Detection of patients at risk for developing integrin antagonist/agonist mediated disease states 有权
    检测患有发展为整合素拮抗剂/激动剂介导的疾病状态的患者

    公开(公告)号：US06623981B2

    公开(公告)日：2003-09-23

    申请号：US09237061

    申请日：1999-01-26

    申请人： Jeffrey T. Billheimer ,  Dietmar A. Seiffert ,  Leah A. Breth ,  Timothy C. Burn ,  Ira B. Dicker ,  Henry J. George ,  Gregory F. Hollis ,  Jeannine M. Hollis ,  Jennifer E. Kochie ,  Karyn T. O'Neil

    发明人： Jeffrey T. Billheimer ,  Dietmar A. Seiffert ,  Leah A. Breth ,  Timothy C. Burn ,  Ira B. Dicker ,  Henry J. George ,  Gregory F. Hollis ,  Jeannine M. Hollis ,  Jennifer E. Kochie ,  Karyn T. O'Neil

    IPC分类号： G01N33553

    CPC分类号： G01N33/6893 ,  C07K14/70557 ,  C07K16/2848 ,  G01N33/566 ,  G01N33/68 ,  G01N2333/70546 ,  G01N2500/00 ,  Y10S435/968 ,  Y10S436/811

    摘要： This invention relates to the detection of patients at risk for developing integrin antagonist/agonist mediated disease states. This invention relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies which bind to integrins, or intergrin-associated proteins or complexes thereof in the presence of an integrin antagonist/agonist. This invention also relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies (DDABS) that bind to integrins, including the platelet glycoprotein IIb/IIIa (GPIIb/IIIa), in the presence of a integrin agonist and/or antagonist. This invention also relates to procedures for identifying integrin antagonists/agonists that are less prone to elicit integrin antagonist/agonist mediated disease states. This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection. This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays. Such methods, procedures and assays are useful for identifying patients who may be at risk to develop disease states mediated by treatment with integrin antagonists/agonists.

    摘要翻译： 本发明涉及检测发展为整合素拮抗剂/激动剂介导的疾病状态的风险的患者。 本发明涉及可用于在整联蛋白拮抗剂/激动剂存在下结合整联蛋白或整合蛋白相关蛋白或其复合物的药物依赖性抗体的患者体液样品中的检测。 本发明还涉及用于在整联蛋白激动剂存在下结合整联蛋白（包括血小板糖蛋白IIb / IIIa（GPIIb / IIIa））的药物依赖性抗体（DDABS）的患者体液样品中检测的测定法， /或拮抗剂。 本发明还涉及识别不易引起整联蛋白拮抗剂/激动剂介导的疾病状态的整联蛋白拮抗剂/激动剂的方法。本发明还涉及增加体液中整联蛋白定向抗体的回收率的方法，导致敏感性增加 和DDAB检测测定的特异性。 本发明还涉及用于治疗血液样品的方法，其从血小板表面解离GPIIb / IIIa的抗体，从而增加血小板上清液的回收。 本发明还涉及使用不同的GPIIb / IIIa制剂来鉴定在用GPIIb / IIIa拮抗剂/激动剂治疗时患有早发性血小板减少症的患者，从而增加抗体检测的特异性。本发明还涉及使用DDAB 作为DDAB测定的阳性对照和校准标准。这些方法，程序和测定法可用于鉴定可能患有通过用整联蛋白拮抗剂/激动剂治疗介导的疾病状态的风险的患者。

    Imidazoles for the treatment of atherosclerosis
    6.
    发明授权
    Imidazoles for the treatment of atherosclerosis 失效

    公开(公告)号：US5318984A

    公开(公告)日：1994-06-07

    申请号：US940372

    申请日：1992-09-03

    申请人： Jeffrey T. Billheimer ,  Peter J. Gillies ,  C. Anne Higley ,  Thomas P. Maduskuie, Jr. ,  Ruth R. Wexler

    发明人： Jeffrey T. Billheimer ,  Peter J. Gillies ,  C. Anne Higley ,  Thomas P. Maduskuie, Jr. ,  Ruth R. Wexler

    IPC分类号： C07D233/54 ,  C07D233/70 ,  C07D233/84 ,  C07D233/88 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/14 ,  C07D409/04 ,  C07D409/14 ,  C07D491/04 ,  A61K31/415 ,  C07D233/66

    CPC分类号： C07D233/64 ,  C07D233/70 ,  C07D233/84 ,  C07D233/88 ,  C07D401/04 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D405/14 ,  C07D409/04 ,  C07D409/14 ,  C07D491/04

    摘要： Disclosed are compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 unbranched alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3- or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; or ##STR2## where L is O, O(CH.sub.2).sub.m+1 O, or (CH.sub.2).sub.m where m is 0-4; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ;R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; C.sub.3 --C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, pyrimidinyl, or biphenyl;R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl;R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or NCOR.sup.7 ;R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl;X is S(O).sub.r, O, NR.sup.5, CH.sub.2 ;A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl;Y is O, S, H.sub.2, or NH;Z is NHR.sup.4, OR.sup.4, or R.sup.4 ;r is 0-2,or a pharmaceutically acceptable salt thereof and their use as antihypercholesterolemic agents or antiatherosclerotic agents.