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    Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties
    2.
    发明授权
    Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties 失效
    具有抗高血压，心脏保护作用，抗缺血性和抗脂解性的化合物

    公开(公告)号：US5561134A

    公开(公告)日：1996-10-01

    申请号：US316761

    申请日：1994-10-03

    申请人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers

    发明人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers

    IPC分类号： C07D473/34 ,  A61K31/435 ,  A61K31/52 ,  A61K31/70 ,  A61K31/7042 ,  A61K31/7052 ,  A61K31/7076 ,  A61P3/06 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12 ,  C07D471/04 ,  C07D473/00 ,  C07H19/04 ,  C07H19/052 ,  C07H19/16

    CPC分类号： C07D473/00 ,  C07D471/04 ,  C07H19/052 ,  C07H19/16

    摘要： Compounds of the Formula ##STR1## wherein: K is N or N.fwdarw.O; Q is CH.sub.2 or O; T is ##STR2## or R.sub.3 O--CH.sub.2 ; X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group, each of which is optionally substituted by at least one CH.sub.3, CH.sub.3 CH.sub.2, Cl, F, CF.sub.3 or CH.sub.3 O; Y is NR.sub.4, O or S; a=0 or 1; Z is of the formula ##STR3## Z.sub.1 is N, CR.sub.5, (CH).sub.m --CR.sub.5 or (CH).sub.m --N, m being 1 or 2; Z.sub.2 is N, NR.sub.6, O or S, n being 0 or 1; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently H, alkyl, aryl or heterocyclyl; R.sub.a and R.sub.b are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl; and R' and R" are independently hydrogen, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl aralkoxycarbonyl, aryloxycarbonyl, or R' and R" together may form ##STR4## where R.sub.c is hydrogen or alkyl, ##STR5## where R.sub.d and R.sub.e are independently hydrogen, alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; provided that when X is straight chain alkylene and Q is oxygen, then Z represents a heterocyclyl including at least two heteroatoms, which are adenosine agonists useful as antihypertensive, cardioprotective, antiischemic, and antilipolytic agents, pharmaceutical compositions including such compounds, and their use in treating hypertension, myocardial ischemia, ameliorating ischemic injury and myocardial infarct size consequent to myocardial ischemia, hyperlipidemia and hypercholesterolemia are claimed.

    摘要翻译： 式的化合物其中：K为N或N-> O; Q是CH 2或O; T为或R3O-CH2; X是直链或支链亚烷基，亚环烷基或环亚烯基，其各自任选被至少一个CH 3，CH 3 CH 2，Cl，F，CF 3或CH 3 O取代; Y为NR4，O或S; a = 0或1; Z为式（Ⅰ）Z1为N，CR5，（CH）m-CR5或（CH）m-N，m为1或2; Z2为N，NR6，O或S，n为0或1; R1，R2，R3，R4，R5和R6独立地为H，烷基，芳基或杂环基; R a和R b独立地是H，OH，烷基，羟基烷基，烷基硫醇基，硫代烷基，烷氧基，烷氧基烷基，氨基，烷基氨基，羧基，酰基，卤素，氨基甲酰基，烷基氨基甲酰基，芳基或杂环基。 并且R'和R“独立地是氢，烷基，芳烷基，氨基甲酰基，烷基氨基甲酰基，二烷基氨基甲酰基，酰基，烷氧基羰基芳烷氧基羰基，芳氧基羰基或R'和R”可一起形成其中R c是氢或烷基， 其中Rd和Re独立地是氢，烷基或与它们所连接的碳原子一起形成1,1-环烷基; 条件是当X是直链亚烷基并且Q是氧时，Z代表包括至少两个杂原子的杂环基，它们是可用作抗高血压，心脏保护，抗缺血和抗脂肪分解剂的腺苷激动剂，包括这些化合物的药物组合物，以及它们在 要求治疗高血压，心肌缺血，改善缺血性损伤和心肌缺血，高脂血症和高胆固醇血症引起的心肌梗死面积。

    Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties
    3.
    发明授权
    Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties 失效
    具有抗高血压，心脏保护作用，抗缺血性和抗脂解性的化合物

    公开(公告)号：US5736554A

    公开(公告)日：1998-04-07

    申请号：US455361

    申请日：1995-05-31

    申请人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers

    发明人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers

    IPC分类号： C07D473/34 ,  A61K31/435 ,  A61K31/52 ,  A61K31/70 ,  A61K31/7042 ,  A61K31/7052 ,  A61K31/7076 ,  A61P3/06 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  A61P9/12 ,  C07D471/04 ,  C07D473/00 ,  C07H19/04 ,  C07H19/052 ,  C07H19/16 ,  A61K31/44

    CPC分类号： C07D473/00 ,  C07D471/04 ,  C07H19/052 ,  C07H19/16

    摘要： Compounds of the Formula ##STR1## wherein: K is N or N.fwdarw.O; Q is CH.sub.2 or O; T is ##STR2## or R.sub.3 O--CH.sub.2 ; X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group, each of which is optionally substituted by at least one CH.sub.3, CH.sub.3 CH.sub.2, Cl, F, CF.sub.3 or CH.sub.3 O; Y is NR.sub.4, O or S; a=0 or 1; Z is of the formula ##STR3## Z.sub.1 is N, CR.sub.5, (CH).sub.m --CR.sub.5 or (CH).sub.m --N, m being 1 or 2; Z.sub.2 is N, NR.sub.6, O or S, n being 0 or 1; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are independently H, alkyl, aryl or heterocyclyl; R.sub.a and R.sub.b are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl; and R' and R" are independently hydrogen, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or R' and R" together may form ##STR4## where R.sub.c is hydrogen or alkyl, ##STR5## where R.sub.d and R.sub.e are independently hydrogen, alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; provided that when X is straight chain alkylene and Q is oxygen, then Z represents a heterocyclyl including at least two heteroatoms, which are adenosine agonists useful as antihypertensive, cardioprotective, antiischemic, and antilipolytic agents, pharmaceutical compositions including such compounds, and their use in treating hypertension, myocardial ischemia, ameliorating ischemic injury and myocardial infarct size consequent to myocardial ischemia, hyperlipidemia and hypercholesterolemia are claimed.

    摘要翻译： 式的化合物其中：K为N或N-> O; Q是CH 2或O; T为或R3O-CH2; X是直链或支链亚烷基，亚环烷基或环亚烯基，其各自任选被至少一个CH 3，CH 3 CH 2，Cl，F，CF 3或CH 3 O取代; Y为NR4，O或S; a = 0或1; Z为式（Ⅰ）Z1为N，CR5，（CH）m-CR5或（CH）m-N，m为1或2; Z2为N，NR6，O或S，n为0或1; R1，R2，R3，R4，R5和R6独立地为H，烷基，芳基或杂环基; R a和R b独立地是H，OH，烷基，羟基烷基，烷基硫醇基，硫代烷基，烷氧基，烷氧基烷基，氨基，烷基氨基，羧基，酰基，卤素，氨基甲酰基，烷基氨基甲酰基，芳基或杂环基。 并且R'和R“独立地为氢，烷基，芳烷基，氨基甲酰基，烷基氨基甲酰基，二烷基氨基甲酰基，酰基，烷氧基羰基，芳烷氧基羰基，芳氧基羰基或R'和R”一起可以形成E>，其中Rd和Re独立地为氢， 烷基或与它们所连接的碳原子一起可以形成1,1-环烷基; 条件是当X是直链亚烷基并且Q是氧时，Z代表包括至少两个杂原子的杂环基，它们是可用作抗高血压，心脏保护，抗缺血和抗脂肪分解剂的腺苷激动剂，包括这些化合物的药物组合物，以及它们在 要求治疗高血压，心肌缺血，改善缺血性损伤和心肌缺血，高脂血症和高胆固醇血症引起的心肌梗死面积。

    DI (1R)-(-)camphosulfonic acid) salt, preparation thereof and use thereof
    4.
    发明授权
    DI (1R)-(-)camphosulfonic acid) salt, preparation thereof and use thereof 失效
    DI（1R） - （ - ）樟脑磺酸）盐，其制备及其用途

    公开(公告)号：US5652366A

    公开(公告)日：1997-07-29

    申请号：US484811

    申请日：1995-06-07

    申请人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers ,  Laurence W. Reilly ,  Benoit J. Vanasse

    发明人： Alfred P. Spada ,  Cynthia A. Fink ,  Michael R. Myers ,  Laurence W. Reilly ,  Benoit J. Vanasse

    IPC分类号： C07D471/04 ,  C07D473/00 ,  C07H19/052 ,  C07H19/16

    CPC分类号： C07D471/04 ,  C07D473/00 ,  C07H19/052 ,  C07H19/16

    摘要： This invention relates to di[(1 R)-(-)-camphosulfonic acid) salt of [1S-[1.alpha.,2.beta.,3.beta.,4.alpha.,(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]3 H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide, and a process for preparing the compound, comprising reacting a reaction mixture of (-)-1.beta.-N-ethyl-2.alpha.,3.alpha.-isopropylidenedioxy-4.beta.-[3-amino-4-[2-(5-chloro-2-thienyl)-(1R)-1-ethylethyl]amino-2-pyridyl]aminocyclopentanecarboxamide and formamidine acetate, and then treating the reaction mixture with (1 R)-(-)-10-camphorsulfonic acid.The salt is useful in purifying [1 S-[1.alpha.,2.beta.,3.beta.,4.alpha.,(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethylethyl]amino]-3 H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide which possesses adenosine agonist activity and is useful as an anti-hypertensive, cardioprotective, anti-ischemic, and antilipolytic agent.

    摘要翻译： 本发明涉及[1S- [1α，2β，3β，4α，（S *）]] - 4- [7 - [[ 2-（3-氯-2-噻吩基）-1-乙基乙基]氨基] 3 H-咪唑并[4,5-b]吡啶-3-基] -N-乙基-2,3-二羟基环戊烷甲酰胺，以及 制备该化合物，包括使（ - ） - 1β-N-乙基-2α，αα-异亚丙基二氧基-4β-[3-氨基-4- [2-（5-氯-2-噻吩基） ） - （1R）-1-乙基乙基]氨基-2-吡啶基]氨基环戊烷甲酰胺和甲脒乙酸盐，然后用（1R） - （ - ） - 10-樟脑磺酸处理反应混合物。 该盐可用于纯化[1 S- [1α，2β，3β，4α，（S *）]] -4- [7 - [[2-（3-氯-2-噻吩基） - 乙基]氨基] -3H-咪唑并[4,5-b]吡啶-3-基] -N-乙基-2,3-二羟基环戊烷甲酰胺，其具有腺苷激动剂活性，可用作抗高血压，心脏保护，抗 - 抗血清剂和抗脂肪分解剂。

    Cyclic amino acid derivatives
    6.
    发明授权
    Cyclic amino acid derivatives 失效
    环状氨基酸衍生物

    公开(公告)号：US5432186A

    公开(公告)日：1995-07-11

    申请号：US153395

    申请日：1993-11-19

    申请人： Cynthia A. Fink

    发明人： Cynthia A. Fink

    IPC分类号： A61K38/00 ,  C07K5/065 ,  C07K5/078 ,  C07D213/02 ,  A61K31/44

    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;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;m is 0, 1, 2 or 3; andCOOR.sub.2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester;disulfide derivatives of 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; 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; m为0,1,2或3; COOR2表示以药学上可接受的酯的形式衍生的羧基或羧基; 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; 包含所述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。

    Gem-disubstituted amino acid derivatives
    7.
    发明授权
    Gem-disubstituted amino acid derivatives 失效
    双取代氨基酸衍生物

    公开(公告)号：US5508266A

    公开(公告)日：1996-04-16

    申请号：US263855

    申请日：1994-06-22

    申请人： Cynthia A. Fink

    发明人： Cynthia A. Fink

    IPC分类号： A61K38/00 ,  C07K5/06 ,  C07K5/065 ,  A61K38/05 ,  C07C323/41 ,  C07C327/06

    CPC分类号： C07K5/06034 ,  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 cycloalylidene or benzo-fused cycloalkylidene;R.sub.6 represents lower alkyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, biaryl or biaryl-lower alkyl;R.sub.7 represents lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, cycloalkyl-lower alkyl or biaryl-lower alkyl;m is 0, 1, 2 or 3; andCOOR.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; R 6表示低级烷基，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; R 7表示低级烷基，碳环或杂环芳基 - 低级烷基，环烷基 - 低级烷基或联芳基 - 低级烷基; m为0,1,2或3; COOR2表示以药学上可接受的酯的形式衍生的羧基或羧基; 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。

    Amino-benzocycloalkane derivatives
    10.
    发明授权
    Amino-benzocycloalkane derivatives 失效
    氨基 - 苯并环烷烃衍生物

    公开(公告)号：US06197798B1

    公开(公告)日：2001-03-06

    申请号：US09357041

    申请日：1999-07-20

    申请人： Cynthia A. Fink ,  Gary M. Ksander ,  Paivi J. Kukkola ,  Eli M. Wallace ,  Mahavir Prashad

    发明人： Cynthia A. Fink ,  Gary M. Ksander ,  Paivi J. Kukkola ,  Eli M. Wallace ,  Mahavir Prashad

    IPC分类号： A61K3144

    CPC分类号： C07D213/82 ,  A61K31/17 ,  A61K31/44 ,  C07C233/80 ,  C07C235/22 ,  C07C235/56 ,  C07C237/20 ,  C07C237/40 ,  C07C237/42 ,  C07C271/24 ,  C07C271/34 ,  C07C271/36 ,  C07C271/56 ,  C07C275/26 ,  C07C301/00 ,  C07C307/08 ,  C07C311/07 ,  C07C311/08 ,  C07C311/20 ,  C07C311/29 ,  C07C313/06 ,  C07C313/12 ,  C07C317/14 ,  C07C323/60 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2602/08 ,  C07C2602/12 ,  C07D213/71 ,  C07D261/18 ,  C07D295/088 ,  C07D295/15 ,  C07D295/215 ,  C07D333/34

    摘要： Compounds of the formula I wherein R2—C, R3—C, R4—C or R5—C may be replaced by N; and wherein n is 1, 2 or 3; R1 is aryl, cycloalkyl or heterocyclyl; R2, R3, R4 and R5 are independently hydrogen, optionally substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two of R2, R3, R4 and R5 at adjacent positions are alkylenedioxy; R6 is hydrogen, optionally substituted alkyl, amino, substituted amino, acylamino, wherein Ra is hydrogen or optionally substituted alkyl, Rb and Rc are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or Rb and Rc together represent lower alkylene or lower alkylene interrupted by O, S, or N—(H, alkyl or aralkyl); Rd is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; and Re is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino; and pharmaceutically acceptable salts thereof; and enantiomers thereof; which are useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (ApoB) secretion.

    摘要翻译： R 1，R 2，R 3，R 4和R 5可以被N代替，其中n是1,2或3; R 1是芳基，环烷基或杂环基; R 2，R 3，R 4和R 5 （烷基，芳基或芳烷基） - 硫代，（烷基，芳基或芳烷基） - 氧基，酰氧基，（烷基，芳基或芳烷基） 芳基或芳烷基） - 氨基羰基氧基; 或相邻位置的R 2，R 3，R 4和R 5中的任何两个是亚烷基二氧基; R 6是氢，任选取代的烷基，氨基，取代的氨基，酰氨基，其中R a是氢或任选取代的烷基，R b和R c独立地是氢，任选取代的烷基 ，环烷基，芳基或杂环基; 或R b和R c一起表示被O，S或N-（H，烷基或芳烷基）间隔的低级亚烷基或低级亚烷基; Rd为任选取代的烷基，环烷基，芳基或杂环基; 并且Re是任选取代的烷基，芳基，杂环基，环烷基，氨基或取代的氨基;及其药学上可接受的盐; 及其对映异构体; 其可用作微粒体甘油三酯转运蛋白（MTP）和载脂蛋白B（ApoB）分泌的抑制剂。