公开(公告)号：US4992465A

公开(公告)日：1991-02-12

申请号：US481770

申请日：1990-02-16

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： C07D311/58 ,  C07D311/64 ,  C07D335/06

CPC分类号： C07D335/06 ,  C07D311/58 ,  C07D311/64

摘要： R represents hydrogen or lower alkyl; R.sub.1 represents hydrogen, lower alkyl or aryl-lower alkyl; R.sub.2 represents hydrogen, lower alkyl or aryl-lower alkyl; or R.sub.1 and R.sub.2 together represent alkylene of 4 to 6 carbon atoms; R.sub.3 represents hydrogen, hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy or aryloxy in compounds wherein Z represents S; or R.sub.3 represents hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy or aryloxy, and is attached only at the 5- or 8- position in compounds wherein Z represents O; R.sub.4 and R.sub.5 represent independently hydrogen, lower alkyl or halogen; and pharmaceutically acceptable salts thereof; and mono or di- S-oxides of compounds of formula I wherein Z represents S and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof; and use thereof as central nervous system active agents for the treatment of central nervous system disorders.

摘要翻译： （I）其中Z表示O或S; R代表氢或低级烷基; R1代表氢，低级烷基或芳基 - 低级烷基; R2代表氢，低级烷基或芳基 - 低级烷基; 或R 1和R 2一起表示4至6个碳原子的亚烷基; R 3表示其中Z表示S的化合物中的氢，羟基，低级烷氧基，芳基 - 低级烷氧基，酰氧基或芳氧基; 或R 3表示羟基，低级烷氧基，芳基 - 低级烷氧基，酰氧基或芳氧基，并且仅在其中Z表示O的化合物中的5-或8-位上连接; R4和R5独立地表示氢，低级烷基或卤素; 及其药学上可接受的盐; 和其中Z表示S的式I化合物的单或二 - S-氧化物及其药学上可接受的盐，其药物组合物; 并将其用作治疗中枢神经系统疾病的中枢神经系统活性剂。

公开(公告)号：US4968697A

公开(公告)日：1990-11-06

申请号：US389663

申请日：1989-08-04

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： C07H19/16

CPC分类号： C07H19/16

摘要： The compounds of the formula I ##STR1## wherein R represents hydrogen or lower alkyl; R.sub.1 represents C.sub.3 -C.sub.6 -cycloalkyl optionally substituted by lower alkyl, C.sub.3 -C.sub.6 -cycloalkyl-lower alkyl optionally substituted by lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, aryl, aryl-lower alkyl, aryl-C.sub.3 -C.sub.6 -cycloalkyl, 9-fluorenyl, diaryl-lower alkyl, 9-fluorenyl-lower alkyl, cycloalkenyl-lower alkyl, bicycloalkenyl-lower alkyl, tetrahydropyranyl-lower alkyl, tetrahydrothiopyranyl-lower alkyl or adamantyl-lower alkyl; or R.sub.1 represents a bicyclic benzo-fused 5- or 6-membered saturated carbocyclic radical or a benzo-fused 5- or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur which is directly attached to the fused benzene ring, any said bicyclic radical being unsubstituted or substituted on the benzo portion by lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or by a substituent -W-Z in which W represents a direct bond, lower alkylene, lower alkenylene, thio-lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or amide, or R.sub.1 represents any said bicyclic radical substituted-lower alkyl; or R.sub.1 represents aryl-hydroxy-lower alkyl; R.sub.2 represents hydrogen, lower alkyl or aryl-lower alkyl; R.sub.3 represents hydrogen or hydroxy; R.sub.4 represents hydrogen, lower alkyl, aryl-lower alkyl, C.sub.3 -C.sub.6 -cycloalkyl or hydroxy-lower alkyl; aryl represents an optionally substituted carbocyclic aromatic radical, being preferably 1- or 2-naphthyl, phenyl, or naphthyl or phenyl substituted by one to three of lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl, or naphthyl or phenyl substituted by a substitutent -W-Z in which W represents a direct bond, lower alkylene, lower alkenylene, thio-lower alkylene or oxy-lower alkylene and Z represents cyano, carboxy or carboxy derivatized in the form of a pharmaceutically acceptable ester or amide; or aryl represents a heterocyclic aromatic radical, being preferably pyridyl or thienyl, each optionally substituted as described above for phenyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof; their preparation; and their use as adenosine-2 receptor agonists are disclosed.

公开(公告)号：US4954504A

公开(公告)日：1990-09-04

申请号：US193969

申请日：1988-05-13

申请人： Jen Chen ,  Alan J. Hutchison

发明人： Jen Chen ,  Alan J. Hutchison

IPC分类号： C07D303/46 ,  C07D473/00 ,  C07D473/16

CPC分类号： C07D473/00 ,  C07D303/46 ,  C07D473/16

摘要： The compound of the formula I ##STR1## wherein R, R.sub.3 and R.sub.5 independently represent hydrogen or hydroxy provided that at least one of R, R.sub.3 and R.sub.5 represents hydroxy; R.sub.1 represents hydrogen, lower alkyl, C.sub.3 -C.sub.7 -alkenyl, hydroxy-lower alkyl, optionally substituted cycloalkyl or optionally substituted cycloalkyl-lower alkyl, bicycloalkyl, bicycloalkyl-lower alkyl, adamantyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl-lower alkyl, tetrahydrothiopyranyl-lower alkyl, adamantyl-lower alkyl, aryl-hydroxy-lower alkyl, aryl, aryl-lower alkyl, aryl-C.sub.3 -C.sub.6 -cycloalkyl, 9-fluorenyl, 9-fluorenyl-lower alkyl or cycloalkenyl-lower alkyl; or R.sub.1 represents a bicyclic benzo-fused 5 or 6-membered saturated cyabocyclic radical or a benzo-fused 5 or 6-membered saturated heterocyclic radical containing a heteroatom selected from oxygen and sulfur directly attached to the fused benzene ring, any said bicyclic radicals being optionally substituted on the benzo portion by lower alkyl, lower alkoxy or halogen, or R.sub.1 represents any said bicyclic radical substituted-lower alkyl; R.sub.2 represents hydrogen, halogen, --S--R.sub.1 ', --NR.sub.b --R.sub.1 ', or --NH--R.sub.1 ' in each of which R.sub.1 ' has meaning as defined for R.sub.1 provided that R.sub.1 ' in --SR.sub.1 ' does not represent hydrogen; R.sub.b represents lower alkyl; R.sub.4 represents hydroxymethyl provided that R.sub.2 does not represent either hydrogen or --NHR.sub.1 ' in which R.sub.1 ' represents either hydrogen or lower alkyl; or R.sub.4 represents lower alkoxymethyl or lower alkylthiomethyl; or R.sub.4 represents --CONHR.sub.6 in which R.sub.6 represents lower alkyl; aryl-lower alkyl, C.sub.3 -C.sub.6 -cycloalkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which free hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof; methods for their preparation; and their use as adenosine receptor agonists are disclosed.

公开(公告)号：US5185446A

公开(公告)日：1993-02-09

申请号：US577203

申请日：1990-09-04

申请人： Kenneth Shaw ,  Alan J. Hutchison

发明人： Kenneth Shaw ,  Alan J. Hutchison

IPC分类号： A61K31/505 ,  A61P25/20 ,  C07D487/04

CPC分类号： C07D487/04

摘要： This invention encompasses compounds of the formula: ##STR1## and pharmaceutically acceptable non-toxic salts thereof wherein n is 0,1 or 2 and X is --N.dbd.C--R.sub.9 or NR.sub.10 --C.dbd.Twhere R.sub.1, R.sub.2, R.sub.3, and R.sub.9 and R.sub.10 and X, Y, W and T are variables.These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdoes with benzodiazepine type drugs, and enhancement of alertness.

摘要翻译： 本发明包括下式的化合物及其药物上可接受的无毒盐，其中n为0,1或2，X为-N = C-R 9或NR 10 -C = T，其中R 1，R 2，R 3和 R9和R10以及X，Y，W和T是变量。 这些化合物是GABAa脑受体或前药的高选择性激动剂，拮抗剂或反向激动剂，并且可用于诊断和治疗焦虑症，睡眠和癫痫发作障碍，用苯二氮卓类药物过度使用，并提高警觉性。

公开(公告)号：US5159083A

公开(公告)日：1992-10-27

申请号：US635256

申请日：1990-12-28

申请人： Andrew Thurkauf ,  Alan J. Hutchison

发明人： Andrew Thurkauf ,  Alan J. Hutchison

IPC分类号： A61K31/415 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/445 ,  A61K31/47 ,  A61K31/495 ,  A61K31/505 ,  A61K31/55 ,  A61P25/00 ,  A61P25/24 ,  A61P25/26 ,  C07D233/54 ,  C07D233/64 ,  C07D401/04 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D403/14

CPC分类号： C07D233/64 ,  C07D401/04 ,  C07D401/06 ,  C07D401/12 ,  C07D401/14 ,  C07D403/12

摘要： This invention encompasses compounds of the formula: ##STR1## where X, Y, Z, T, R.sub.1, R.sub.3, R.sub.4, and R.sub.5 are variables representing various organic and inorganic substituents;M is ##STR2## R.sub.2 and R.sub.6 represent hydrogen or alkyl substituents; or R.sub.1 and R.sub.2 together may represent --(CH.sub.2).sub.n1 where n.sub.1 is 1, 2, or 3; orNR.sub.4 R.sub.5 represents substituted or unsubstituted-tetrahydroisoquinolinyl; or ##STR3## where n is 1, 2, or 3; W is N or CH; and R.sub.7 represents hydrogen or aryl; or W--R.sub.7 is oxygen or sulfur.These compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Futhermore compounds of this invention may be useful in treating the extraparamidyl side effects associated with the use of conventional neuroleptic agents.

摘要翻译： 本发明包括下式的化合物：其中X，Y，Z，T，R 1，R 3，R 4和R 5是表示各种有机和无机取代基的变量; M是R 2和R 6代表氢或烷基取代基; 或者R 1和R 2一起可以表示 - （CH 2）n1，其中n 1是1,2或3; 或NR4R5表示取代或未取代的四氢异喹啉基; 或，其中n为1,2或3; W是N或CH; 并且R 7表示氢或芳基; 或W-R7是氧或硫。 这些化合物是脑多巴胺受体亚型或其前药的高选择性部分激动剂或拮抗剂，可用于诊断和治疗情感障碍如精神分裂症和抑郁症以及某些运动障碍如帕金森综合征。 本发明的更多的化合物可用于治疗与使用常规的精神抑制剂相关的外贴剂副作用。

公开(公告)号：US4977144A

公开(公告)日：1990-12-11

申请号：US405926

申请日：1989-09-12

申请人： Roger A. Fujimoto ,  John E. Francis ,  Alan J. Hutchison

发明人： Roger A. Fujimoto ,  John E. Francis ,  Alan J. Hutchison

IPC分类号： C07H19/052

CPC分类号： C07H19/052

摘要： Disclosed are the compounds of the formula ##STR1## wherein R represents hydrogen, lower alkyl, aryl or aryl-lower alkyl; R.sub.1 represents hydrogen, lower alkyl, C.sub.3 -C.sub.7 -alkenyl, carbocyclic or heterocyclic aryl, carbocyclic or heterocyclic aryl-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, or optionally lower alkyl substituted (C.sub.3 -C.sub.7 -cycloalkyl, bicycloheptyl, bicycloheptenyl, adamantyl, tetrahydropyranyl or tetrahydrothiopyranyl)-lower alkyl, or diaryl-lower alkyl; R.sub.2 represents hydrogen or lower alkyl; R.sub.3 represents hydroxymethyl or --CONHR.sub.4 in which R.sub.4 represents hydrogen, lower alkyl, aryl-lower alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-lower alkyl or hydroxy-lower alkyl; pharmaceutically acceptable ester derivatives thereof in which one or more of the hydroxy groups are esterified in form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof; methods of preparation; pharmaceutical compositions; and their use as adenosine-2 agonists in mammals.

摘要翻译： 公开了式（I）的化合物，其中R表示氢，低级烷基，芳基或芳基 - 低级烷基; 碳原子或杂环芳基 - 低级烷基，C 3 -C 7 - 环烷基或任选的低级烷基取代的（C 3 -C 7 - 环烷基，双环庚基，双环庚烯基，金刚烷基， 四氢吡喃基或四氢噻喃基） - 低级烷基或二芳基 - 低级烷基; R2代表氢或低级烷基; R3表示羟甲基或-CONHR4，其中R4表示氢，低级烷基，芳基 - 低级烷基，C3-C7-环烷基，C3-C7-环烷基 - 低级烷基或羟基 - 低级烷基; 其药学上可接受的酯衍生物，其中一个或多个羟基以药学上可接受的酯的形式酯化; 及其药学上可接受的盐; 准备方法; 药物组合物; 以及它们在哺乳动物中作为腺苷-2激动剂的用途。

公开(公告)号：US4816474A

公开(公告)日：1989-03-28

申请号：US20053

申请日：1987-02-27

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： A61K31/38 ,  A61P25/00 ,  C07D495/04

CPC分类号： C07D495/04

摘要： Disclosed are compounds of the formula ##STR1## wherein A represents the divalent radical --S--CR.sub.4 .dbd.CR.sub.5 -- in which R.sub.4 and R.sub.5 independently represent hydrogen or lower alkyl; R.sub.1 represents hydrogen, lower alkyl or aryl-lower alkyl; R.sub.2 represents hydrogen, lower alkyl or aryl-lower alkyl; or R.sub.1 and R.sub.2 combined represent alkylene of 4 to 6 carbon atoms; R.sub.3 represents hydrogen or lower alkyl; an S-oxide thereof; or a pharmaceutically acceptable salt thereof; which are useful as presynaptic dopamine receptor agonists for the treatment of central nervous system disorders; processes for preparing same; and pharmaceutical compositions comprising said compounds.

摘要翻译： 公开了式（I）的化合物，其中A表示二价基团-S-CR 4 = CR 5 - ，其中R 4和R 5独立地表示氢或低级烷基; R1代表氢，低级烷基或芳基 - 低级烷基; R2代表氢，低级烷基或芳基 - 低级烷基; 或R 1和R 2组合​​表示4至6个碳原子的亚烷基; R3代表氢或低级烷基; 其S-氧化物; 或其药学上可接受的盐; 其可用作用于治疗中枢神经系统疾病的突触前多巴胺受体激动剂; 制备方法; 和包含所述化合物的药物组合物。

公开(公告)号：US4801605A

公开(公告)日：1989-01-31

申请号：US20054

申请日：1987-02-27

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： A61K31/35 ,  A61K31/352 ,  A61K31/38 ,  A61K31/382 ,  A61K31/395 ,  A61P25/00 ,  A61P25/18 ,  A61P25/20 ,  A61P25/24 ,  A61P25/26 ,  C07D311/04 ,  C07D311/58 ,  C07D335/06 ,  C07D409/02

CPC分类号： C07D335/06 ,  C07D311/58

摘要： ##STR1## wherein Z represents O or S; R represents hydrogen or lower alkyl; R
1 represents hydrogen, lower alkyl or aryl-lower alkyl; R
2 represents hydrogen, lower alkyl or aryl-lower alkyl; or R
1 and R
2 together represent alkylene of 4 to 6 carbon atoms; R
3 represents hydrogen, hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy or aryloxy in compounds wherein Z represents S; or R
3 represents hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy or aryloxy, and is attached only at the 5- or 8- position in compounds wherein Z represents O; R
4 and R
5 represent independently hydrogen, lower alkyl or halogen; and pharmaceutically acceptable salts thereof; and mono or di- S-oxides of compounds of formula I wherein Z represents S and pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof; and use thereof as central nervous system active agents for the treatment of central nervous system disorders.

摘要翻译： （I）其中Z表示O或S; R代表氢或低级烷基; R1代表氢，低级烷基或芳基 - 低级烷基; R2代表氢，低级烷基或芳基 - 低级烷基; 或R 1和R 2一起表示4至6个碳原子的亚烷基; R 3表示其中Z表示S的化合物中的氢，羟基，低级烷氧基，芳基 - 低级烷氧基，酰氧基或芳氧基; 或R 3表示羟基，低级烷氧基，芳基 - 低级烷氧基，酰氧基或芳氧基，并且仅在其中Z表示O的化合物中的5-或8-位上连接; R4和R5独立地表示氢，低级烷基或卤素; 及其药学上可接受的盐; 和其中Z表示S的式I化合物的单或二 - S-氧化物及其药学上可接受的盐，其药物组合物; 并将其用作治疗中枢神经系统疾病的中枢神经系统活性剂。

公开(公告)号：US4533667A

公开(公告)日：1985-08-06

申请号：US600759

申请日：1984-04-16

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： C07D487/10 ,  A61K31/41 ,  C07D471/20

CPC分类号： C07D487/10

摘要： A series of novel spiro-oxindole imidazolidinedione derivatives have been prepared, including their pharmaceutically acceptable salts. These compounds are useful in therapy as aldose reductose inhibitors for the control of certain chronic diabetic complications. Preferred compounds include 6'-amino-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 5'-chloro-7'-aminospiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3-pyridylmethyl)-5'-fluoro-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3-pyridylmethyl)-5',7'-dichloro-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione and spiro-[imidazolidine-4,3'-(6-azaindoline)]-2,2',5-trione. 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 - 羟吲哚咪唑烷二酮衍生物，包括其药学上可接受的盐。 这些化合物可用于治疗某些慢性糖尿病并发症的醛糖还原抑制剂。 优选的化合物包括6'-氨基 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮，5'-氯-7'-氨基螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮，1' - （3-吡啶基甲基）-5'-氟 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮，1' - （ 3-吡啶基甲基）-5'，7'-二氯 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮和螺 - [咪唑烷-4,3' - （6-氮杂二氢吡啶） ] -2,2'，5-三酮。 提供了从已知原料制备这些化合物的方法。

公开(公告)号：US4464380A

公开(公告)日：1984-08-07

申请号：US497962

申请日：1983-05-25

申请人： Alan J. Hutchison

发明人： Alan J. Hutchison

IPC分类号： C07D471/20 ,  A61K31/415 ,  A61K31/435 ,  A61K31/44 ,  A61P3/08 ,  A61P25/02 ,  A61P27/02 ,  C07D403/02 ,  C07D487/10 ,  C07D401/14

CPC分类号： C07D487/10

摘要： A series of novel spiro-oxindole imidazolidinedione derivatives have been prepared, including their pharmaceutically acceptable salts. These compounds are useful in therapy as aldose reductose inhibitors for the control of certain chronic diabetic complications. Preferred compounds include 6'-amino-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 5'-chloro-7'-amino-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3-pyridylmethyl)-5'-fluoro-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione, 1'-(3-pyridylmethyl)-5',7'-dichloro-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione and spiro-[imidazolidine-4,3'-(6-azaindoline)]-2,2',5-trione. 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 - 羟吲哚咪唑烷二酮衍生物，包括其药学上可接受的盐。 这些化合物可用于治疗某些慢性糖尿病并发症的醛糖还原抑制剂。 优选的化合物包括6'-氨基 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮，5'-氯-7'-氨基 - 螺 - [咪唑烷-4,3'- 二氢吲哚] -2,2'，5-三酮，1' - （3-吡啶基甲基）-5'-氟 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮，1' - （3-吡啶基甲基）-5'，7'-二氯 - 螺 - [咪唑烷-4,3'-二氢吲哚] -2,2'，5-三酮和螺 - [咪唑烷-4,3' 氮杂吲哚）] - 2,2'，5-三酮。 提供了从已知原料制备这些化合物的方法。