公开(公告)号：US06420438B1

公开(公告)日：2002-07-16

申请号：US09865418

申请日：2001-05-29

申请人： John Walter Liebeschuetz ,  William Alexander Wylie ,  Bohdan Waszkowycz ,  Christopher William Murray ,  Andrew David Rimmer ,  Pauline Mary Welsh ,  Stuart Donald Jones ,  Jonathan Michael Ernest Roscoe ,  Stephen Clinton Young ,  Phillip John Morgan ,  Nicholas Paul Camp ,  Andrew Philip Austin Crew

发明人： John Walter Liebeschuetz ,  William Alexander Wylie ,  Bohdan Waszkowycz ,  Christopher William Murray ,  Andrew David Rimmer ,  Pauline Mary Welsh ,  Stuart Donald Jones ,  Jonathan Michael Ernest Roscoe ,  Stephen Clinton Young ,  Phillip John Morgan ,  Nicholas Paul Camp ,  Andrew Philip Austin Crew

IPC分类号： A61K4360

CPC分类号： C07D401/12 ,  A61K38/00 ,  C07D217/22 ,  C07D217/24 ,  C07D401/14 ,  C07D405/12 ,  C07D409/14 ,  C07K5/0207

摘要： The invention relates to serine protease inhibitor compounds of formula (I) where R1 is hydrogen, halo, cyano, nitro or hydroxyl, amino, alkoxy, alkyl, aminoalkyl, hydroxyalkyl, thiol, alkylthio, aminosulphonyl, alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl, cycloalkyl, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, alkylsulphonamido, alkylaminosulphonyl, haloalkoxy and haloalkyl; R2 is hydrogen, halo, methyl, amino, hydroxy, or oxo; and R is X—X—Y(R7)—L—Lp(D)n; wherein each X independently is C, N, O or S atom or a CO, CR1, C(R1)2 or NR1 group, at least one X being C, CO, CR1 or a C(R1)2 group; Y (the &agr;-atom) is a nitrogen atom or a CR1 group or Y and L taken together form a cyclic group; R7 is a lipophilic group selected from alkyl, alkenyl, mono- or bi-cycloalkyl, aryl, heteroaryl, mono- or bicycloalkylalkyl, mono- or bicycloalkylalkenyl, aralkyl, heteroaryl-alkyl, arylalkenyl, heteroarylalkenyl all optionally substituted by a group R1; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group; Lp is a lipophilic organic group selected from alkyl, heterocyclic, alkenyl, alkaryl, cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally substituted by one or more of oxa, thia, aza or R1 groups; D is a hydrogen bond donor group; and n is 0, 1 or 2 and salts thereof.

摘要翻译： 本发明涉及式（I）的丝氨酸蛋白酶抑制剂化合物，其中R1是氢，卤素，氰基，硝基或羟基，氨基，烷氧基，烷基，氨基烷基，羟基烷基，硫醇，烷硫基，氨基磺酰基，烷氧基烷基，烷氧基羰基，酰氧基甲氧基羰基或烷基氨基 被羟基，烷基氨基，烷氧基，氧代，芳基，环烷基，氨基，卤素，氰基，硝基，硫醇，烷硫基，烷基磺酰基，烷基亚磺酰基，烷基磺酰氨基，烷基氨基磺酰基，卤代烷氧基和卤代烷基取代。 R2是氢，卤素，甲基，氨基，羟基或氧代; R为X-X-Y（R7）-L-Lp（D）n; 其中每个X独立地为C，N，O或S原子或CO，CR1，C（R1）2或NR1基团，至少一个X为C，CO，CR1或C（R1）2基团; Y（α原子）是氮原子或CR 1基，Y或L一起形成环状基团; R 7是选自烷基，烯基，单 - 或双 - 环烷基，芳基，杂芳基，单 - 或双环烷基烷基，单或双环烷基烯基，芳烷基，杂芳基 - 烷基，芳基烯基，杂芳基烯基的亲油基团，全部任选被基团R 1取代; L是含有1至5个选自C，N，O和S的骨架原子或支链烷基或环状基团的有机连接基团; Lp是选自烷基，杂环，烯基，烷芳基，环烷基，多环烷基，环烯基，芳基，芳烷基或卤代烷基中的亲脂性有机基团或两个或更多个这样的基团的组合，其任选被一个或多个氧杂，硫杂，氮杂或 R1组; D是氢键供体基团; 和n为0,1或2及其盐。

公开(公告)号：US5807868A

公开(公告)日：1998-09-15

申请号：US564156

申请日：1995-12-21

申请人： Bruce Jeremy Sargent ,  David Norman Johnston ,  Andrew Philip Austin Crew

发明人： Bruce Jeremy Sargent ,  David Norman Johnston ,  Andrew Philip Austin Crew

IPC分类号： C07D217/14 ,  A61K31/47 ,  A61K31/472 ,  A61K31/4725 ,  A61P21/00 ,  A61P25/16 ,  A61P25/18 ,  A61P25/28 ,  C07D217/04 ,  C07D401/08 ,  C07D405/08 ,  C07D409/08

CPC分类号： C07D401/08 ,  C07D217/04 ,  C07D405/08 ,  C07D409/08

摘要： Tetrahydroisoquinoline compounds of formula I ##STR1## and pharmaceutically acceptable salts thereof, in which: R.sub.1 represents one or more substituents selected from H, halo, hydroxy, alkyl (optionally substituted by hydroxy), alkoxy, alkylthio, alkylsulphinyl, alkyl-sulphonyl, nitro, cyano, polyhaloalkyl, polyhaloalkoxy, phenyl (optionally substituted by one or more of halo, alkyl or alkoxy), or R.sub.1 is optionally alkylated carbamoyl; R.sub.2 represents a saturated or unsaturated aliphatic group optionally substituted by hydroxy or alkoxy; E represents an alkylene chain optionally substituted by one or more alkyl groups; and G represents (a) optionally substituted saturated or unsaturated alicyclic group containing 3 to 8 carbon atoms, or (b) optionally substituted saturated or unsaturated aliphatic chain containing 1 to 12 carbon atoms, or (c) optionally substituted 5 or 6 membered heterocyclic ring containing one or more N or O atoms or SO.sub.n groups in which n is 0, 1 or 2; and O-acylated derivatives thereof which provide lipophilic esters have utility in analgesia or in the treatment of psychoses (e.g. schizophrenia), Parkinson's disease, Lesch-Nyan syndrome, attention deficit disorder or cognitive impairment or in the relief of drug dependence or tardive dyskinesia.

摘要翻译： PCT No.PCT / EP94 / 01926 Sec。 371 1995年12月21日第 102（e）日期1995年12月21日PCT提交1994年6月10日PCT公布。 公开号WO95 / 00489 日期1995年1月5日式Ⅰ的四氢异喹啉化合物及其药学上可接受的盐，其中：R1表示一个或多个选自H，卤素，羟基，烷基（任选被羟基取代），烷氧基，烷硫基，烷基亚磺酰基 ，烷基磺酰基，硝基，氰基，多卤代烷基，多卤代烷氧基，苯基（任选被卤素，烷基或烷氧基中的一个或多个取代），或R 1任选被烷基化的氨基甲酰基; R2表示任选被羟基或烷氧基取代的饱和或不饱和脂族基; E表示任选被一个或多个烷基取代的亚烷基链; G表示（a）含有3〜8个碳原子的任选取代的饱和或不饱和脂环基，或（b）任选取代的含有1至12个碳原子的饱和或不饱和脂族链，或（c）任选取代的5或6元杂环 含有一个或多个N或O原子或其中n为0,1或2的SO n基团; 提供亲脂性酯的O-酰化衍生物可用于镇痛或治疗精神病（例如精神分裂症），帕金森病，莱斯奈恩综合症，注意力缺陷障碍或认知障碍或缓解药物依赖或迟发性运动障碍。

公开(公告)号：US06262069B1

公开(公告)日：2001-07-17

申请号：US09485677

申请日：2000-02-25

申请人： John Walter Liebeschuetz ,  William Alexander Wylie ,  Bohdan Waszkowycz ,  Christopher William Murray ,  Andrew David Rimmer ,  Pauline Mary Welsh ,  Stuart Donald Jones ,  Jonathan Michael Ernest Roscoe ,  Stephan Clinton Young ,  Phillip John Morgan ,  Nicholas Paul Camp ,  Andrew Philip Austin Crew

发明人： John Walter Liebeschuetz ,  William Alexander Wylie ,  Bohdan Waszkowycz ,  Christopher William Murray ,  Andrew David Rimmer ,  Pauline Mary Welsh ,  Stuart Donald Jones ,  Jonathan Michael Ernest Roscoe ,  Stephan Clinton Young ,  Phillip John Morgan ,  Nicholas Paul Camp ,  Andrew Philip Austin Crew

IPC分类号： A61K3147

CPC分类号： C07D401/12 ,  A61K38/00 ,  C07D217/22 ,  C07D217/24 ,  C07D401/14 ,  C07D405/12 ,  C07D409/14 ,  C07K5/0207

摘要： The invention relates to serine protease inhibitor compounds of fornula (I) where R1 is hydrogen, halo, cyano, nitro or hydroxyl, amino, alkoxy, alkyl amminoalkyl, hydroxyalkyl, thiol, alkylthio, aminosulphonyl alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycabonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl, cycloalkyl, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, alkylsulphonamido, alkylaminosulphonyl, haloalkoxy and haloalkyl; R2 is hydrogen, halo, methyl amino, hydroxy, or oxo; and R is X—X—Y(R7)—L—Lp(D)n; wheren each X independently is a C, N, O or S atom or a CO, CR1, C(R1)2 or NR1 group, at least one X being C, CO, CR1 or a C(R1)2 group; Y (the &agr;-atom) is a nitrogen atom or a CR1 group or Y and L taken together form a cyclic group; R7 is a lipophilic group selected from alkyl, alkenyl, mono- or bi-cycloalkyl, aryl, heteroaryl, mono- or bicycloalkylalkyl, mono- or bicycloalkylakenyl, aralkyl, heteroaryl-alkyl, arylalkenyl, heteroarylalkenyl all optionally substituted by a group R1; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group; Lp is a lipophilic organic group selected from alkyl, heterocyclic, alkenyl, alkaryl cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally substituted by one or more of oxa, thia, aza or R1 groups; D is a hydrogen bond donor group; and n is 0, 1 or 2 and salts thereof.

公开(公告)号：US5804586A

公开(公告)日：1998-09-08

申请号：US826012

申请日：1997-03-27

申请人： Bruce Jeremy Sargent ,  David Norman Johnston ,  Andrew Philip Austin Crew

发明人： Bruce Jeremy Sargent ,  David Norman Johnston ,  Andrew Philip Austin Crew

IPC分类号： C07D217/14 ,  A61K31/47 ,  A61K31/472 ,  A61K31/4725 ,  A61P21/00 ,  A61P25/16 ,  A61P25/18 ,  A61P25/28 ,  C07D217/04 ,  C07D401/08 ,  C07D405/08 ,  C07D409/08

CPC分类号： C07D401/08 ,  C07D217/04 ,  C07D405/08 ,  C07D409/08

摘要： Tetrahydroisoquinoline compounds of formula I ##STR1## and pharmaceutically acceptable salts thereof, in which: R.sub.1 represents one or more substituents selected from H, halo, hydroxy, alkyl (optionally substituted by hydroxy), alkoxy, alkylthio, alkylsulphinyl, alkyl-sulphonyl, nitro, cyano, polyhaloalkyl, polyhaloalkoxy, phenyl (optionally substituted by one or more of halo, alkyl or alkoxy), or R.sub.1 is optionally alkylated carbamoyl; R.sub.2 represents a saturated or unsaturated aliphatic group optionally substituted by hydroxy or alkoxy; E represents an alkylene chain optionally substituted by one or more alkyl groups; and G represents (a) optionally substituted saturated or unsaturated alicyclic group containing 3 to 8 carbon atoms, or (b) optionally substituted saturated or unsaturated aliphatic chain containing 1 to 12 carbon atoms, or (c) optionally substituted 5 or 6 membered heterocyclic ring containing one or more N or O atoms or SO.sub.n groups in which n is 0, 1 or 2; and O-acylated derivatives thereof which provide lipophilic esters have utility in analgesia or in the treatment of psychoses (e.g. schizophrenia), Parkinson's disease, Lesch-Nyan syndrome, attention deficit disorder or cognitive impairment or in the relief of drug dependence or tardive dyskinesia.

摘要翻译： 式I的四氢异喹啉化合物及其药学上可接受的盐，其中：R 1表示一个或多个选自H，卤素，羟基，烷基（任选被羟基取代），烷氧基，烷硫基，烷基亚磺酰基，烷基磺酰基， 硝基，氰基，多卤代烷基，多卤代烷氧基，苯基（任选被卤素，烷基或烷氧基中的一个或多个取代），或R 1任选被烷基化的氨基甲酰基; R2表示任选被羟基或烷氧基取代的饱和或不饱和脂族基; E表示任选被一个或多个烷基取代的亚烷基链; G表示（a）含有3〜8个碳原子的任选取代的饱和或不饱和脂环基，或（b）任选取代的含有1至12个碳原子的饱和或不饱和脂族链，或（c）任选取代的5或6元杂环 含有一个或多个N或O原子或其中n为0,1或2的SO n基团; 提供亲脂性酯的O-酰化衍生物可用于镇痛或治疗精神病（例如精神分裂症），帕金森病，莱斯奈恩综合症，注意力缺陷障碍或认知障碍或缓解药物依赖或迟发性运动障碍。