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    Renal-selective biphenylmethyl imidazole angiotensin II antagonists for treatment of hypertension
    21.
    发明授权
    Renal-selective biphenylmethyl imidazole angiotensin II antagonists for treatment of hypertension 失效
    肾选择性联苯甲基咪唑血管紧张素II拮抗剂治疗高血压

    公开(公告)号：US5302610A

    公开(公告)日：1994-04-12

    申请号：US810321

    申请日：1991-12-19

    申请人： Robert E. Manning ,  David B. Reitz

    发明人： Robert E. Manning ,  David B. Reitz

    IPC分类号： A61K47/48 ,  C07D233/68 ,  C07D403/10 ,  A61K31/415 ,  A61K31/495 ,  C07D233/54 ,  C07D241/04 ,  C07D257/04 ,  C07D265/30

    CPC分类号： C07D403/10 ,  A61K47/48023 ,  A61K47/48061 ,  C07D233/68

    摘要： Renal-selective compounds are described which, in one embodiment, are prodrugs preferentially converted in the kidney to compounds capable of blocking angiotensin II (AII) receptors. These prodrugs are conjugates formed from two components, namely, a first component provided by an AII antagonist compound and a second component which is capable of being cleaved from the first component when both components are chemically linked within the conjugate. The two components are chemically linked by a bond which is cleaved selectively in the kidney, for example, by an enzyme. The liberated AII antagonist compound is then available to block AII receptors within the kidney. Conjugates of particular interest are glutamyl derivatives of biphenylmethyl 1H-substituted imidazole compounds, of which N-acetyl-L-glutamic acid, 5-[[4'-[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-ylmethyl][1,1'-biphenyl]-2-yl]carbonyl]hydrazide (shown below) is an example: ##STR1##

    摘要翻译： 描述了肾选择性化合物，其在一个实施方案中是优先在肾中转化为能够阻断血管紧张素II（AII）受体的化合物的前药。 这些前药是由两种组分形成的缀合物，即由AII拮抗剂化合物提供的第一组分和当两种组分在缀合物内化学连接时能够从第一组分切割的第二组分。 两种组分通过在肾脏中有选择性地切割的键化学连接，例如通过酶。 然后释放的AII拮抗剂化合物可用于阻断肾脏内的AII受体。 特别感兴趣的缀合物是联苯甲基1H-取代的咪唑化合物的谷氨酰基衍生物，其中N-乙酰基-L-谷氨酸5 - （（4' - （2-丁基-4-氯-5-（羟甲基） 咪唑-1-基甲基）（1,1'-联苯）-2-基）羰基）酰肼（如下所示）是一个实例：（*化学结构*）

    N-substituted N-(alpha-triazolyl-toluyl)pyrrole compounds and use for treatment of circulatory disorders
    22.
    发明授权
    N-substituted N-(alpha-triazolyl-toluyl)pyrrole compounds and use for treatment of circulatory disorders 失效
    N-取代的N-（ALPHA-TRIAZOLYL-TOLUYL）吡咯烷酮化合物和用于治疗循环障碍的用途

    公开(公告)号：US5175180A

    公开(公告)日：1992-12-29

    申请号：US630714

    申请日：1990-12-20

    申请人： Philippe R. Bovy ,  David B. Reitz ,  Robert E. Manning

    发明人： Philippe R. Bovy ,  David B. Reitz ,  Robert E. Manning

    IPC分类号： C07D403/10 ,  C07D403/14

    CPC分类号： C07D403/10 ,  C07D403/14

    摘要： A class of N-substituted N-(.alpha.-triazolyltoluyl)pyrrole compounds described for use in treatment of circulatory disorders. Compounds of particular interest are angiotensin II antagonists of the formula ##STR1## wherein m is one; wherein R.sup.1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cyclohexanoyl, 1-oxo-2-cyclohexylethyl, benzoyl, 1-oxo-2-phenethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl and 2-hydroxybutyl; wherein R.sup.2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, and hydroxyalkyl; wherein each of R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 is independently selected from hydrido, halo, nitro, trifluoromethyl, hydroxy, alkoxy, cyano, carboxyl and methoxycarbonyl; with the proviso that at least one of R.sup.5 and R.sup.8 must be selected from COOH, SH, PO.sub.3 H.sub.2, SO.sub.3 H, CONHNH.sub.2, CONHNHSO.sub.2 CF.sub.3, OH, ##STR2## wherein each of R.sup.42 and R.sup.43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.

    摘要翻译： 描述用于治疗循环系统疾病的一类N-取代的N-（α-三唑基甲苯磺酰基）吡咯化合物。 特别感兴趣的化合物是式IMAMA的血管紧张素II拮抗剂，其中m是1; 其中R1选自甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，4-甲基丁基，正戊基，新戊基，苯基，苄基，苯乙基，环己基，环己基甲基，环己基乙基 ，环己酰基，1-氧代-2-环己基乙基，苯甲酰基，1-氧代-2-苯乙基，1-氧代丙基，1-氧代丁基，1-氧代戊基和2-羟基丁基; 其中R2选自甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，苯基，苄基，苯乙基，环己基，环己基甲基，丙硫基，丁硫基 ，和羟烷基; 其中R 3，R 4，R 5，R 6，R 7，R 8，R 9和R 10各自独立地选自氢，卤素，硝基，三氟甲基，羟基，烷氧基，氰基，羧基和甲氧基羰基; 条件是R 5和R 8中的至少一个必须选自COOH，SH，PO3H2，SO3H，CONHNH2，CONHNHSO2CF3，OH，其中R42和R43各自独立地选自氯，氰基，硝基，三氟甲基， 甲氧基羰基和三氟甲基磺酰基; 或其互变异构体或其药学上可接受的盐。 这些化合物特别可用于治疗或控制高血压和充血性心力衰竭。

    1H-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders
    23.
    发明授权
    1H-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders 失效
    1H-取代的1,2,4-三唑化合物及其用于治疗心血管疾病的方法

    公开(公告)号：US5098920A

    公开(公告)日：1992-03-24

    申请号：US519380

    申请日：1990-05-04

    申请人： David B. Reitz

    发明人： David B. Reitz

    IPC分类号： A61K31/41 ,  A61K31/4196 ,  A61P9/00 ,  A61P9/12 ,  C07D249/06 ,  C07D249/08 ,  C07D249/10 ,  C07D249/12 ,  C07D249/14 ,  C07D403/10 ,  C07D409/10 ,  C07D409/14 ,  C07D521/00

    CPC分类号： C07D249/08 ,  C07D231/12 ,  C07D233/56 ,  C07D249/10 ,  C07D403/10

    摘要： A class of 1H-substituted-1,2,4-triazole compounds is described for use in treatment of cardiovascular disorders. Compounds of particular interest are angiotensin II antagonists of the formula ##STR1## wherein R.sup.1 is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxy-butyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoro-methyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-di-fluorobotyl and 1,1-difluoropentyl; wherein R.sup.2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neo-pentyl; wherein each of R.sup.3 through R.sup.11 is hydrido with the provision that at least one of R.sup.5 and R.sup.9 must be selected from COOH, SH, PO.sub.3 H.sub.2, SO.sub.3 H, CONHNH.sub.2, CONHNHSO.sub.2 CF.sub.3, OH, ##STR2## wherein each of R.sup.40 and R.sup.41 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl. These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.

    摘要翻译： 描述了一类用于治疗心血管疾病的1H-取代-1,2,4-三唑化合物。 特别感兴趣的化合物是下式的血管紧张素II拮抗剂，其中R1选自羟基，甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，4-甲基丁基，n 戊基，新戊基，苯基，苄基，苯乙基，环己基，环己基甲基，1-氧代乙基，1-氧代丙基，1-氧代丁基，1-氧代戊基，1,1-二甲氧基丙基，1,1-二甲氧基丁基，1,1-二甲氧基丁基 ，羟基烷基，卤素，二氟甲基，1,1-二氟乙基，1,1-二氟丙基，1,1-二氟代丁基和1,1-二氟戊基; 其中R2选自乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，4-甲基丁基，叔丁基，正戊基和新戊基; 其中R 3至R 11中的每一个是氢的，条件是R 5和R 9中的至少一个必须选自COOH，SH，PO 3 H 2，SO 3 H，CONHNH 2，CONHNHSO 2 CF 3，OH，其中R 40和R 41各自独立地选自 氯，氰基，硝基，三氟甲基，甲氧基羰基和三氟甲基磺酰基。 这些化合物特别可用于治疗或控制高血压和充血性心力衰竭。

    N-substituted imidazol-2-one compounds for treatment of circulatory disorders
    24.
    发明授权
    N-substituted imidazol-2-one compounds for treatment of circulatory disorders 失效
    用于治疗循环系统疾病的N-取代咪唑-2-酮化合物

    公开(公告)号：US5087634A

    公开(公告)日：1992-02-11

    申请号：US606806

    申请日：1990-10-31

    申请人： David B. Reitz ,  Robert E. Manning

    发明人： David B. Reitz ,  Robert E. Manning

    IPC分类号： C07D233/70 ,  C07D403/10 ,  C07D409/14

    CPC分类号： C07D403/10 ,  C07D233/70 ,  C07D409/14

    摘要： A class of N-substituted imidazol-2-one compounds is described for use in treatment of circulatory disorders. Compounds of particular interest are angiotensin II antagonists of the formula ##STR1## wherein m is one; wherein R.sup.1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cyclohexanoyl, 1-oxo-2-cyclohexylethyl, benzoyl, 1-oxo-2-phenethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl and 2-hydroxybutyl; wherein R.sup.0 is selected from hydrido, methyl, fluoro, chloro, monofluoromethyl, difluoromethyl, trifluoromethyl, formyl, carboxyl and dimethoxymethyl; wherein R.sup.2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, and hydroxyalkyl; wherein each of R.sup.3, R.sup.4, R.sup.6, R.sub.7, R.sup.8, R.sup.10 and R.sup.11 is hydrido; with the proviso that at least one of R.sup.5 and R.sup.9 must be selected from COOH, SH, PO.sub.3 H.sub.2, SO.sub.3 H, CONHNH.sub.2, CONHNHSO.sub.2 CF.sub.3, OH, ##STR2## wherein each of R.sup.42 and R.sup.43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.

    摘要翻译： 描述了一类用于治疗循环障碍的N-取代咪唑-2-酮化合物。 特别感兴趣的化合物是式IMAMA的血管紧张素II拮抗剂，其中m是1; 其中R1选自甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，4-甲基丁基，正戊基，新戊基，苯基，苄基，苯乙基，环己基，环己基甲基，环己基乙基 ，环己酰基，1-氧代-2-环己基乙基，苯甲酰基，1-氧代-2-苯乙基，1-氧代丙基，1-氧代丁基，1-氧代戊基和2-羟基丁基; 其中R 0选自氢，甲基，氟，氯，单氟甲基，二氟甲基，三氟甲基，甲酰基，羧基和二甲氧基甲基; 其中R2选自甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，正戊基，异戊基，新戊基，苯基，苄基，苯乙基，环己基，环己基甲基，丙硫基，丁硫基 ，和羟烷基; 其中R3，R4，R6，R7，R8，R10和R11各自为氢; 条件是R 5和R 9中的至少一个必须选自COOH，SH，PO 3 H 2，SO 3 H，CONHNH 2，CONHNHSO 2 CF 3，OH，其中R 42和R 43各自独立地选自氯， 氰基，硝基，三氟甲基，甲氧基羰基和三氟甲基磺酰基; 或其互变异构体或其药学上可接受的盐。 这些化合物特别可用于治疗或控制高血压和充血性心力衰竭。

    5-aryleheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders
    28.
    发明授权
    5-aryleheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds for treatment of circulatory disorders 失效
    5-芳基杂芳基烷基-1,3,5-三取代-1,2,4-三唑化合物，用于治疗循环障碍

    公开(公告)号：US6090828A

    公开(公告)日：2000-07-18

    申请号：US980632

    申请日：1997-12-01

    申请人： David B. Reitz

    发明人： David B. Reitz

    IPC分类号： C07D401/06 ,  C07D401/10 ,  C07D401/14 ,  A61K31/44 ,  A61K31/41

    CPC分类号： C07D401/06 ,  C07D401/10 ,  C07D401/14 ,  Y10S514/824 ,  Y10S514/913

    摘要： A class of 5-arylheteroarylalkyl-1,3,5-trisubstituted-1,2,4-triazole compounds is described for use in treatment of circulatory disorders such as hypertension. Compounds of particular interest are angiotensin II antagonists of the formula ##STR1## wherein A is selected from ##STR2## wherein m is one; wherein R.sup.1 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, benzyl, cyclohexyl, cyclohexylmethyl, 2-butenyl, 3-butenyl, 2-butynyl, 3-butynyl and 2-hydroxybutyl; wherein R.sup.2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neo-pentyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxypentyl, halo, difluoromethyl, 1-oxo-2-phenylethyl, 1-oxo-2-cyclohexylethyl, 1,1-difluoro-2-phenylethyl, 1,1-difluoro-2-cyclohexylethyl, 2-cyclohexylethyl, 1,1-difluoro-3-cyclohexylpropyl, 1,1-dimethoxybutyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl, 1,1-difluoropentyl, benzyl, 2-phenylethyl, 1,1-difluoro-3-phenylpropyl, cyclohexylmethyl, cyclohexanoyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-butynyl, 2-butynyl, 3-butynyl, propylthio and butylthio; wherein each of R.sup.3, R.sup.4, R.sup.6 through R.sup.11 is hydrido and R.sup.5 is selected from COOH, SH, PO.sub.3 H.sub.2, SO.sub.3 H, CONHNH.sub.2, CONHNHSO.sub.2 CF.sub.3, OH, ##STR3## wherein each of R.sup.42 and R.sup.43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl.

    摘要翻译： 描述了一类5-芳基杂芳基烷基-1,3,5-三取代-1,2,4-三唑化合物用于治疗循环系统疾病如高血压。 特别感兴趣的化合物是下式的血管紧张素II拮抗剂，其中A选自其中m是1; 其中R 1选自乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，4-甲基丁基，正戊基，新戊基，苄基，环己基，环己基甲基，2-丁烯基， ，2-丁炔基，3-丁炔基和2-羟基丁基; 其中R2选自乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，4-甲基丁基，叔丁基，正戊基，新戊基，1-氧代乙基，1-氧代丙基，1-氧代丁基 ，1-氧代戊基，1,1-二甲氧基丙基，1,1-二甲氧基戊基，卤代，二氟甲基，1-氧代-2-苯基乙基，1-氧代-2-环己基乙基，1,1-二氟-2-苯基乙基，1,1 2-氟-2-环己基乙基，2-环己基乙基，1,1-二氟-3-环己基丙基，1,1-二甲氧基丁基，1,1-二氟乙基，1,1-二氟丙基，1,1-二氟丁基，1,1-二氟戊基 苄基，2-苯基乙基，1,1-二氟-3-苯基丙基，环己基甲基，环己酰基，1-丁烯基，2-丁烯基，3-丁烯基，1-丁炔基，2-丁炔基，3-丁炔基，丙硫基和丁硫基; 其中R 3，R 4，R 6至R 11各自为氢，R 5选自COOH，SH，PO 3 H 2，SO 3 H，CONHNH 2，CONHNHSO 2 CF 3，OH，其中R 42和R 43各自独立地选自氯，氰基，硝基，三氟甲基， 和三氟甲基磺酰基。