公开(公告)号：US5506244A

公开(公告)日：1996-04-09

申请号：US263859

申请日：1994-06-22

申请人： Cynthia A. Fink

发明人： Cynthia A. Fink

IPC分类号： A61K38/00 ,  C07K5/065 ,  C07K5/078 ,  A61K31/44 ,  A61K31/195 ,  C07C235/82 ,  C07D213/82

CPC分类号： C07K5/06139 ,  C07K5/06078 ,  A61K38/00

摘要： Disclosed are the compounds of formula I ##STR1## wherein R represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl or cycloalkyl-lower alkyl; R.sub.1 represents hydrogen, lower alkyl, cycloalkyl, carbocyclic aryl or heterocyclic aryl, or biaryl; R.sub.3 represents hydrogen or acyl; R.sub.4 represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl; R.sub.5 represents hydrogen or lower alkyl; or R.sub.4 and R.sub.5 together with the carbon atom to which they are attached represent cycloalkylidene or benzo-fused cycloalkylidene; A together with the carbon atom to which it is attached represents 3 to 10 membered cycloalkylidene or 5 to 10 membered cycloalkenylidene radical which may be substituted by lower alkyl or aryl-lower alkyl or may be fused to a saturated or unsaturated carbocyclic 5-7-membered ring; or A together with the carbon to which it is attached represents 5 or 6 membered oxacycloalkylidene, thiacycloalkylidene or azacycloalkylidene optionally substituted by lower alkyl or aryl-lower alkyl; or A together with the carbon atom to which it is attached represents 2,2-norbornylidene; m is 0, 1, 2 or 3; and COOR.sub.2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester, disulfide derivatives derived from said compounds wherein R.sub.3 is hydrogen; and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; methods for preparation of said compounds; intermediates; and methods of treating disorders in mammals which are responsive to ACE and NEP inhibition by administration of said compounds to mammals in need of such treatment.

摘要翻译： 公开了式I的化合物其中R表示氢，低级烷基，碳环或杂环芳基 - 低级烷基或环烷基 - 低级烷基; R 1表示氢，低级烷基，环烷基，碳环芳基或杂环芳基，或联芳基; R3代表氢或酰基; R 4表示氢，低级烷基，碳环或杂环芳基，碳环或杂环芳基 - 低级烷基，环烷基，环烷基 - 低级烷基，联芳基或联芳基 - 低级烷基; R5代表氢或低级烷基; 或R 4和R 5与它们所连接的碳原子一起代表亚环烷基或苯并稠合的环亚烷基; A与其连接的碳原子一起表示3至10元环亚烷基或5至10元环烯基，其可以被低级烷基或芳基 - 低级烷基取代，或可以与饱和或不饱和的碳环5-7- 元环 或A与其连接的碳一起表示5或6元环亚烷基，硫代亚烷基或氮杂环烷叉基，其任选被低级烷基或芳基 - 低级烷基取代; 或A与连接的碳原子一起代表2,2-降冰片烯; m为0,1,2或3; COOR2表示衍生自药学上可接受的酯的羧基或羧基，衍生自所述化合物的二硫化物衍生物，其中R 3是氢; 及其药学上可接受的盐; 包含该化合物的药物组合物 所述化合物的制备方法; 中间体 以及通过向需要这种治疗的哺乳动物施用所述化合物来治疗对ACE和NEP抑制有反应的哺乳动物疾病的方法。

公开(公告)号：US06201133B1

公开(公告)日：2001-03-13

申请号：US09435550

申请日：1999-11-08

申请人： Cynthia A. Fink

发明人： Cynthia A. Fink

IPC分类号： C07D33502

CPC分类号： C07D213/75 ,  C07C323/60 ,  C07C327/32 ,  C07C2601/14 ,  C07D213/82 ,  C07D333/20 ,  C07D333/24

摘要： Disclosed are compound of formula I wherein R represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl; R1 represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl; R2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl); R3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C2-C7-alkyl interrupted by S, SO, SO2, O or N—R5; R4 represents hydrogen or acyl; R5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl; A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH2)P which may be interrupted by S, SO, SO2, O, or N—R5; n represents an integer from zero to four; p represents an integer from 2 to 6; any pharmaceutically acceptable salts thereof; and disulfides corresponding to said compounds of formula I wherein R4 is hydrogen; methods for preparation thereof; pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinases in mammals using such compounds.

摘要翻译： 公开了式I化合物，其中R表示氢，低级烷基，环烷基，双环烷基，金刚烷基，芳基，联芳基或单 - 或二 - （环烷基，芳基或联芳基） - 低级烷基，二 - （低级烷基或芳基 - 低级烷基） 氨基 - 低级烷基或（哌啶子基，吗啉代，吡咯烷子基） - 低级烷基; R1代表氢，低级烷基，环烷基，芳基，联芳基或（环烷基，芳基或联芳芳基） - 低级烷基; R2代表氢，低级烷基，低级 烷氧基，芳基 - 低级烷基，芳基 - 低级烷氧基，氨基，单 - 或二 - （低级烷基或芳基 - 低级烷基） - 氨基，酰氨基或（低级烷基或芳基 - 低级烷基） - （硫代，亚磺酰基或磺酰基 ）; R3表示氢，低级烷基，环烷基，芳基 - 低级烷基，环烷基 - 低级烷基或被S，SO，SO2，O或N-R5间断的C2-C7-烷基; R4表示氢或酰基; R5表示氢 ，低级烷基，芳基 - 低级烷基，酰基或（低级烷基，芳基或芳基 - 低级烷基） - 磺酰基; A与连接的碳一起形成环，代表一个bivale 可以被S，SO，SO2，O或N-R5中断的式（CH2）P的nt基团; n表示0至4的整数; p表示2至6的整数;其任何药学上可接受的盐 ;和对应于其中R 4为氢的所述式I化合物的二硫化物;其制备方法;包含所述化合物的药物组合物; 以及使用这些化合物抑制哺乳动物中的基质降解金属蛋白酶的方法。

公开(公告)号：US06034136A

公开(公告)日：2000-03-07

申请号：US40093

申请日：1998-03-17

申请人： Cynthia A. Fink

发明人： Cynthia A. Fink

IPC分类号： C07D295/14 ,  A61K31/16 ,  A61K31/198 ,  A61K31/265 ,  A61K31/381 ,  A61K31/4402 ,  A61K31/4406 ,  A61K31/5375 ,  A61P19/02 ,  A61P29/00 ,  A61P35/00 ,  C07C323/53 ,  C07C323/60 ,  C07C327/22 ,  C07C327/26 ,  C07C327/32 ,  C07D213/56 ,  C07D213/75 ,  C07D213/81 ,  C07D213/82 ,  C07D333/20 ,  C07D333/24 ,  C07D333/38 ,  A61K31/165 ,  C07C233/05 ,  C07C233/58

CPC分类号： C07D213/75 ,  C07C323/60 ,  C07C327/32 ,  C07D213/82 ,  C07D333/20 ,  C07D333/24 ,  C07C2101/14

摘要： Disclosed are compound of formula I whereinR represents hydrogen, lower alkyl, cycloalkyl, bicycloalkyl, adamantyl, aryl, biaryl, or mono- or di-(cycloalkyl, aryl or biaryl)-lower alkyl, di-(lower alkyl or aryl-lower alkyl)amino-lower alkyl, or (piperidino, morpholino, pyrrolidino)-lower alkyl;R.sub.1 represents hydrogen, lower alkyl, cycloalkyl, aryl, biaryl, or (cycloalkyl, aryl or biaryl)-lower alkyl;R.sub.2 represents hydrogen, lower alkyl, lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy, amino, mono- or di-(lower alkyl or aryl-lower alkyl)-amino, acylamino, or (lower alkyl or aryl-lower alkyl)-(thio, sulfinyl or sulfonyl);R.sub.3 represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, cycloalkyl-lower alkyl, or C.sub.2 -C.sub.7 -alkyl interrupted by S, SO, SO.sub.2, O or N--R.sub.5 ;R.sub.4 represents hydrogen or acyl;R.sub.5 represents hydrogen, lower alkyl, aryl-lower alkyl, acyl, or (lower alkyl, aryl or aryl-lower alkyl)-sulfonyl;A together with the carbon to which it is attached forms a ring and represents a bivalent radical of the formula (CH.sub.2).sub.P which may be interrupted by S, SO, SO.sub.2, O, or N--R.sub.5 ;n represents an integer from zero to four;p represents an integer from 2 to 6;any pharmaceutically acceptable salts thereof;and disulfides corresponding to said compounds of formula I wherein R.sub.4 is hydrogen;methods for preparation thereof;pharmaceutical compositions comprising said compounds; and a method of inhibiting matrix-degrading metalloproteinases in mammals using such compounds.

摘要翻译： 公开了式I化合物，其中R代表氢，低级烷基，环烷基，双环烷基，金刚烷基，芳基，联芳基或单或二（环烷基，芳基或联芳芳基） - 低级烷基，二 - （低级烷基或芳基 - 低级 烷基）氨基 - 低级烷基，或（哌啶子基，吗啉代，吡咯烷子基） - 低级烷基; R 1表示氢，低级烷基，环烷基，芳基，联芳基或（环烷基，芳基或联芳基） - 低级烷基; R 2表示氢，低级烷基，低级烷氧基，芳基 - 低级烷基，芳基 - 低级烷氧基，氨基，单 - 或二 - （低级烷基或芳基 - 低级烷基） - 氨基，酰氨基或（低级烷基或芳基 - ） - （硫基，亚磺酰基或磺酰基）; R3表示氢，低级烷基，环烷基，芳基 - 低级烷基，环烷基 - 低级烷基或被S，SO，SO2，O或N-R5间断的C2-C7-烷基; R4代表氢或酰基; R5代表氢，低级烷基，芳基 - 低级烷基，酰基或（低级烷基，芳基或芳基 - 低级烷基） - 磺酰基; A与其连接的碳一起形成环，并且表示可被S，SO，SO 2，O或N-R 5中断的式（CH 2）p的二价基团; n表示0至4的整数; p表示2〜6的整数， 其任何药学上可接受的盐; 和对应于所述式I化合物的二硫化物，其中R 4是氢; 制备方法; 包含所述化合物的药物组合物; 以及使用这些化合物抑制哺乳动物中的基质降解金属蛋白酶的方法。