公开(公告)号：US5030654A

公开(公告)日：1991-07-09

申请号：US354170

申请日：1989-05-19

申请人： Ian T. Barnish ,  John C. Danilewicz ,  Keith James ,  Gillian M. R. Samuels ,  Nicholas K. Terrett ,  Michael T. Williams ,  Martin J. Wythes

发明人： Ian T. Barnish ,  John C. Danilewicz ,  Keith James ,  Gillian M. R. Samuels ,  Nicholas K. Terrett ,  Michael T. Williams ,  Martin J. Wythes

IPC分类号： A61K31/16 ,  A61K31/335 ,  A61K31/395 ,  C07C235/52 ,  C07C235/82 ,  C07C237/24 ,  C07C311/01 ,  C07D207/30 ,  C07D209/46 ,  C07D213/02 ,  C07D213/56 ,  C07D231/00 ,  C07D233/00 ,  C07D235/00 ,  C07D237/00 ,  C07D239/00 ,  C07D241/12 ,  C07D261/10 ,  C07D277/36 ,  C07D277/46 ,  C07D295/00 ,  C07D295/185 ,  C07D307/04 ,  C07D307/16 ,  C07D307/68 ,  C07D309/02 ,  C07D319/00 ,  C07D321/02 ,  C07D321/08 ,  C07D321/12 ,  C07D333/34 ,  C07D521/00

CPC分类号： C07D241/12 ,  C07D209/46 ,  C07D213/56 ,  C07D231/12 ,  C07D233/56 ,  C07D249/08 ,  C07D261/10 ,  C07D277/36 ,  C07D277/46 ,  C07D295/185 ,  C07D307/16 ,  C07D307/68 ,  C07D321/08 ,  C07D333/34

摘要： A series of novel spiro-substituted glutaramide derivatives have been prepared, including the pharmaceutically acceptable salts thereof and bioprecursors therefor, wherein the spiro-substituent completes a 5- or 6-membered carbocycyclic ring and is located at the carbon atom adjacent to the carbamoyl group. These particular compounds are inhibitors of the neutral endopeptidase E.C.3.4.24.11 enzyme and are therefore useful in therapy as diuretic agents for the treatment of hypertension, heart failure, renal insufficiency and other disorders. Methods for preparing these compounds from known starting materials are provided.

公开(公告)号：US5192800A

公开(公告)日：1993-03-09

申请号：US707559

申请日：1991-05-30

申请人： Ian T. Barnish ,  John C. Danilewicz ,  Keith James ,  Gillian M. B. Samuels ,  Nicholas K. Terrett ,  Michael T. Williams ,  Martin J. Wythes

发明人： Ian T. Barnish ,  John C. Danilewicz ,  Keith James ,  Gillian M. B. Samuels ,  Nicholas K. Terrett ,  Michael T. Williams ,  Martin J. Wythes

IPC分类号： C07D209/46 ,  C07D213/56 ,  C07D241/12 ,  C07D261/10 ,  C07D277/36 ,  C07D277/46 ,  C07D295/185 ,  C07D307/16 ,  C07D307/68 ,  C07D321/08 ,  C07D333/34 ,  C07D521/00

CPC分类号： C07D241/12 ,  C07D209/46 ,  C07D213/56 ,  C07D231/12 ,  C07D233/56 ,  C07D249/08 ,  C07D261/10 ,  C07D277/36 ,  C07D277/46 ,  C07D295/185 ,  C07D307/16 ,  C07D307/68 ,  C07D321/08 ,  C07D333/34

摘要： A series of novel spiro-substituted glutaramide derivatives have been prepared, including the pharmaceutically acceptable salts thereof and bioprecursors therefor, wherein the spiro-substituent completes a 5- or 6- membered carbocyclic ring and is located at the carbon atom adjacent to the carbamoyl group. These particular compounds are inhibitors of the neutral endopeptidase E.C.3,4.24.11 enzyme and are therefore useful in therapy as diuretic agents for the treatment of hypertension, heart failure, renal insufficiency and other disorders. Methods for preparing these compounds from known starting materials are provided.

摘要翻译： 已经制备了一系列新的螺取代的戊二酰胺衍生物，包括其药学上可接受的盐和其生物前体，其中螺 - 取代基完成5-或6-元碳环并且位于与氨基甲酰基相邻的碳原子 。 这些特定化合物是中性肽链内切酶E.C.3,4.24.11酶的抑制剂，因此可用于治疗高血压，心力衰竭，肾功能不全和其他疾病的利尿剂。 提供了从已知原料制备这些化合物的方法。

公开(公告)号：US5591742A

公开(公告)日：1997-01-07

申请号：US379531

申请日：1995-01-31

申请人： Andrew S. Bell ,  Nicholas K. Terrett

发明人： Andrew S. Bell ,  Nicholas K. Terrett

IPC分类号： A61K31/505 ,  A61P9/00 ,  A61P9/10 ,  A61P9/12 ,  A61P43/00 ,  C07D471/04 ,  A61K31/535 ,  A61K31/435 ,  C07D413/14 ,  C07D487/02

CPC分类号： C07D471/04

摘要： Compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof, wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl CN or CONR.sup.4 R.sup.5 ; R.sup.2 is C.sub.2 -C.sub.4 alkyl; R.sup.3 is SO.sub.2 NR.sup.6 R.sup.7, NO.sub.2, NH.sub.2, NHCOR.sup.8 NHSO.sub.2 R.sup.8 or N(SO.sub.2 R.sup.8).sub.2 ; R.sup.4 and R.sup.5 are each independently selected from H and C.sub.1 -C.sub.4 alkyl; R.sup.6 and R.sup.7 are each independently selected from H and C.sub.1 -C.sub.4 alkyl optionally substituted with CO.sub.2 R.sup.9, OH, pyridyl 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl; or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or 4-(NR.sup.10)-1-piperazinyl group wherein any of said groups may optionally be substituted with one or two substituents selected from C.sub.1 -C.sub.4 alkyl, CO.sub.2 R.sup.9, NH.sub.2 and OH; R.sup.8 is C.sub.1 -C.sub.4 alkyl or pyridyl; R.sup.9 is H or C.sub.1 -C.sub.4 alkyl; and R.sup.10 is H, C.sub.1 -C.sub.4 alkyl or (hydroxy) C.sub.2 -C.sub.3 alkyl; are selected cGMP PDE inhibitors useful in the treatment of, inter alia, cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

摘要翻译： PCT No.PCT / EP93 / 02097 371日期1995年1月31日 102（e）日期1995年1月31日PCT提交1993年8月4日PCT公布。 公开号WO94 / 05661 日期：1994年3月17日化学式＆lt; IMAGE＆gt;及其药学上可接受的盐，其中R 1是H，C 1 -C 4烷基CN或CONR 4 R 5; R2是C2-C4烷基; R3是SO2NR6R7，NO2，NH2，NHCOR8 NHSO2R8或N（SO2R8）2; R 4和R 5各自独立地选自H和C 1 -C 4烷基; R 6和R 7各自独立地选自H和任选被CO 2 R 9，OH，吡啶基-5-异恶唑啉-3-基，吗啉代或1-咪唑烷-2-基基取代的C 1 -C 4烷基; 或与它们所连接的氮原子一起形成吡咯烷子基，哌啶子基，吗啉代，1-吡唑基或4-（NR10）-1-哌嗪基，其中任何所述基团可任选被一个或两个选自C 1 -C4烷基，CO 2 R 9，NH 2和OH; R8是C1-C4烷基或吡啶基; R 9为H或C 1 -C 4烷基; R 10为H，C 1 -C 4烷基或（羟基）C 2 -C 3烷基; 被选择用于治疗尤其是心血管疾病如心绞痛，高血压，心力衰竭和动脉粥样硬化的cGMP PDE抑制剂。

公开(公告)号：US5426107A

公开(公告)日：1995-06-20

申请号：US96743

申请日：1993-07-23

申请人： Andrew S. Bell ,  Nicholas K. Terrett

发明人： Andrew S. Bell ,  Nicholas K. Terrett

IPC分类号： A61K31/505 ,  A61K31/519 ,  A61K31/535 ,  A61K31/635 ,  A61P1/00 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12 ,  A61P11/00 ,  A61P27/02 ,  A61P27/06 ,  A61P27/14 ,  A61P27/16 ,  A61P37/08 ,  C07D231/00 ,  C07D239/00 ,  C07D487/04

CPC分类号： C07D487/04

摘要： Compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof are selective cGMP PDE inhibitors which are useful in the treatment of such diseases and adverse conditions as angina, hypertension, congestive heart failure, reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of gut motility.

摘要翻译： 式（I）的化合物及其药学上可接受的盐是选择性cGMP PDE抑制剂，其可用于治疗诸如心绞痛，高血压，充血性心力衰竭，血管通畅性降低，外周血管疾病， 中风，支气管炎，慢性哮喘，过敏性哮喘，过敏性鼻炎，青光眼，肠蠕动障碍等疾病。

公开(公告)号：US5272147A

公开(公告)日：1993-12-21

申请号：US897735

申请日：1992-06-12

申请人： Andrew S. Bell ,  Nicholas K. Terrett

发明人： Andrew S. Bell ,  Nicholas K. Terrett

IPC分类号： A61K31/505 ,  A61K31/519 ,  A61K31/535 ,  A61K31/635 ,  A61P1/00 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12 ,  A61P11/00 ,  A61P27/02 ,  A61P27/06 ,  A61P27/14 ,  A61P27/16 ,  A61P37/08 ,  C07D231/00 ,  C07D239/00 ,  C07D487/04

CPC分类号： C07D487/04

摘要： Compounds of the formula ##STR1## and pharmaceutically acceptable salts thereof are selective cGMP PDE inhibitors which are useful in the treatment of such diseases and adverse conditions as angina, hypertension, congestive heart failure, reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of gut motility.

公开(公告)号：US5482941A

公开(公告)日：1996-01-09

申请号：US232284

申请日：1994-05-06

申请人： Nicholas K. Terrett

发明人： Nicholas K. Terrett

IPC分类号： A61K31/05 ,  A61K31/505 ,  A61K31/517 ,  A61K31/535 ,  A61P1/12 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12 ,  A61P11/00 ,  A61P11/08 ,  A61P27/02 ,  A61P27/14 ,  A61P37/08 ,  C07D239/91 ,  C07D401/08 ,  C07D401/12 ,  C07D403/10 ,  C07D521/00 ,  C07D413/14

CPC分类号： C07D231/12 ,  C07D233/56 ,  C07D239/91 ,  C07D249/08 ,  C07D401/12

摘要： Compounds of formula: ##STR1## and pharmaceutically acceptable salts thereof whereinR.sup.1 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or CONR.sup.5 R.sup.6 ;R.sup.2 is H or- C.sub.1 -C.sub.4 alkyl;R.sup.3 is C.sub.2 -C.sub.4 alkyl;R.sup.4 is H, C.sub.2 -C.sub.4 alkanoyl optionally substituted with NR.sup.7 R.sup.8, (hydroxy)C.sub.2 -C.sub.4 alkyl optionally substituted with NR.sup.7 R.sup.8, CH.dbd.CHCO.sub.2 R.sup.9, CH.dbd.CHCONR.sup.7 R.sup.8, CH.sub.2 CH.sub.2 CO.sub.2 R.sup.9, CH.sub.2 CH.sub.2 CONR.sup.7 R.sup.8, SO.sub.2 NR.sup.7 R.sup.8, SO.sub.2 NH(CH.sub.2).sub.n NR.sup.7 R.sup.8 or imidazolyl;R.sup.5 and R.sup.6 are each independently H or C.sub.1 -C.sub.4 alkyl;R.sup.7 and R.sup.8 are each independently H or C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-(NR.sup.10)-1-piperazinyl group wherein any of said groups is optionally substituted with CONR.sup.5 R.sup.6 ;R.sup.9 is H or C.sub.1 -C.sub.4 alkyl;R.sup.10 is H, C.sub.1 -C.sub.3 alkyl or (hydroxy)C.sub.2 -C.sub.3 alkyl; andn is 2, 3 or 4;with the proviso that R.sup.4 is not H when R.sup.1 is H, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

摘要翻译： PCT No.PCT / EP92 / 02746 Sec。 371日期：1994年5月6日 102（e）日期1994年5月6日PCT提交1992年11月27日PCT公布。 公开号WO93 / 12095 日期：1993年6月24日。式：其中R 1是H，C 1 -C 4烷基，C 1 -C 4烷氧基或CONR 5 R 6的药学上可接受的盐： R2是H或C1-C4烷基; R3是C2-C4烷基; R 4为H，任选被NR 7 R 8取代的C 2 -C 4烷酰基，任选被NR 7 R 8，CH = CHCO 2 R 9，CH = CHCONR 7 R 8，CH 2 CH 2 CO 2 R 9，CH 2 CH 2 CONR 7 R 8，SO 2 NR 7 R 8，SO 2 NH（CH 2）n NR 27 R 8或咪唑基取代的（羟基） R5和R6各自独立地为H或C1-C4烷基; R 7和R 8各自独立地为H或C 1 -C 4烷基，或与它们所连接的氮原子一起形成吡咯烷子基，哌啶子基，吗啉代或4-（NR10）-1-哌嗪基，其中所述基团任选被任选取代 与CONR5R6; R 9为H或C 1 -C 4烷基; R 10是H，C 1 -C 3烷基或（羟基）C 2 -C 3烷基; n为2,3或4; 条件是当R 1为H，C 1 -C 4烷基或C 1 -C 4烷氧基时，R 4不为H; 是用于治疗心血管疾病如心绞痛，高血压，心力衰竭和动脉粥样硬化的选择性cGMP PDE抑制剂。

公开(公告)号：US5346901A

公开(公告)日：1994-09-13

申请号：US84827

申请日：1993-06-29

申请人： Andrew S. Bell ,  David Brown ,  Nicholas K. Terrett

发明人： Andrew S. Bell ,  David Brown ,  Nicholas K. Terrett

IPC分类号： C07D487/04 ,  A61K31/505

CPC分类号： C07D487/04

摘要： Compounds of the formula: ##STR1## wherein R.sup.1 is H, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 cycloalkyl or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.2 is H, C.sub.1 -C.sub.6 alkyl optionally substituted by OH, C.sub.1 -C.sub.3 alkoxy or C.sub.3 -C.sub.6 cycloalkyl, or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 perfluoroalkyl or (C.sub.3 -C.sub.6 cycloalky)C.sub.1 -C.sub.6 alkyl; R.sup.4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R.sup.6)-piperazinyl group; R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.7 R.sup.8, or CONR.sup.7 R.sup.8 ; R.sup.6 is H, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.3 alkoxy) C.sub.2 -C.sub.6 alkyl, hydroxy C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 N)C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 NCO)C.sub.1 -C.sub.6 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; R.sup.7 and R.sup.8 are each independently H, C.sub.1 -C.sub.4 alkyl, (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.4 alkyl or hydroxy C.sub.2 -C.sub.4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

摘要翻译： 下式的化合物：其中R 1是H，C 1 -C 3烷基，C 3 -C 5环烷基或C 1 -C 3全氟烷基; R2是H，任选被OH，C1-C3烷氧基或C3-C6环烷基取代的C1-C6烷基，或C1-C3全氟烷基; R3是C1-C6烷基，C3-C6炔基，C3-C6炔基，C3-C7环烷基，C1-C6全氟烷基或（C3-C6环烷基）C1-C6烷基; R4与其所连接的氮原子一起形成吡咯烷基，哌啶子基，吗啉代或4-N-（R6） - 哌嗪基; R5是H，C1-C4烷基，C1-C3烷氧基，NR7R8或CONR7R8; R6是H，C1-C6烷基，（C1-C3烷氧基）C2-C6烷基，羟基C2-C6烷基，（R7R8N）C2-C6烷基，（R7R8NCO）C1-C6烷基，CONR7R8，CSNR7R8或C（NH） NR7R8; R 7和R 8各自独立地为H，C 1 -C 4烷基，（C 1 -C 3烷氧基）C 2 -C 4烷基或羟基C 2 -C 4烷基; 及其药学上可接受的盐是用于治疗心血管疾病如心绞痛，高血压，心力衰竭和动脉粥样硬化的选择性cGMP PDE抑制剂。

公开(公告)号：US5250534A

公开(公告)日：1993-10-05

申请号：US882988

申请日：1992-05-14

申请人： Andrew S. Bell ,  David Brown ,  Nicholas K. Terrett

发明人： Andrew S. Bell ,  David Brown ,  Nicholas K. Terrett

IPC分类号： C07D487/04 ,  A61K31/505

CPC分类号： C07D487/04

摘要： Compounds of the formula: ##STR1## wherein R.sup.1 is H, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 cycloalkyl or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.2 is H, C.sub.1 -C.sub.6 alkyl optionally substituted by OH, C.sub.1 -C.sub.3 alkoxy or C.sub.3 -C.sub.6 cycloalkyl, or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 perfluoroalkyl or (C.sub.3 -C.sub.6 cycloalkyl)C.sub.1 -C.sub.6 alkyl; R.sup.4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R.sup.6)-piperazinyl group; R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.7 R.sup.8, or CONR.sup.7 R.sup.8 ; R.sup.6 is H, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.3 alkoxy) C.sub.2 - C.sub.6 alkyl, hydroxy C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 N)C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 NCO)C.sub.1 -C.sub.6 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; R.sup.7 and R.sup.8 are each independently H, C.sub.1 -C.sub.4 alkyl, (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.4 alkyl or hydroxy C.sub.2 -C.sub.4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

摘要翻译： 下式的化合物：其中R 1是H，C 1 -C 3烷基，C 3 -C 5环烷基或C 1 -C 3全氟烷基; R2是H，任选被OH，C1-C3烷氧基或C3-C6环烷基取代的C1-C6烷基，或C1-C3全氟烷基; R3是C1-C6烷基，C3-C6烯基，C3-C6炔基，C3-C7环烷基，C1-C6全氟烷基或（C3-C6环烷基）C1-C6烷基; R4与其所连接的氮原子一起形成吡咯烷基，哌啶子基，吗啉代或4-N-（R6） - 哌嗪基; R5是H，C1-C4烷基，C1-C3烷氧基，NR7R8或CONR7R8; R6是H，C1-C6烷基，（C1-C3烷氧基）C2-C6烷基，羟基C2-C6烷基，（R7R8N）C2-C6烷基，（R7R8NCO）C1-C6烷基，CONR7R8，CSNR7R8或C（NH） NR7R8; R 7和R 8各自独立地为H，C 1 -C 4烷基，（C 1 -C 3烷氧基）C 2 -C 4烷基或羟基C 2 -C 4烷基; 及其药学上可接受的盐是用于治疗心血管疾病如心绞痛，高血压，心力衰竭和动脉粥样硬化的选择性cGMP PDE抑制剂。