公开(公告)号：US5470878A

公开(公告)日：1995-11-28

申请号：US164081

申请日：1993-12-08

申请人： John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

发明人： John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

IPC分类号： A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D207/40 ,  C07D207/404 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10 ,  A61K31/20 ,  C07C233/00

CPC分类号： C07D207/404 ,  A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10

摘要： Therapeutic compounds have the formula:(X)j-(non-cyclic core moiety),j being an integer from one to three, the core moiety is non-cyclic and X is a racemic mixture, R or S enantiomer, solvate, hydrate, or salt of: ##STR1## *C is a chiral carbon atom, n is an integer from one to four (preferably from one to three), one or more carbon atoms of (CH.sub.2).sub.n may be substituted by a keto or hydroxy group, and m is an integer from one to fourteen. Independently, R.sub.1 and R.sub.2 may be a hydrogen, a straight or branched chain alkane or alkene of up to twelve carbon atoms in length, or --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxy. Or jointly, R.sub.1 and R.sub.2 form a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms, N being a hetero atom. R.sub.3 is a hydrogen or C.sub.1-3. Or, therapeutic compounds may also have the formula: ##STR2## R.sub.4 is a hydrogen, a straight or branched chain alkane or alkene of up to eight carbon atoms in length, --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxy, or a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms. r and s are independently integers from one to four, the sum (r+s) not being greater than five. t is an integer from one to fourteen and one or more carbon atoms of (CH.sub.2).sub.s or (CH.sub.2).sub.t may be substituted by a keto or hydroxy group.

摘要翻译： 治疗化合物具有下式：（X）j-（非环核心部分），j为1至3的整数，核心部分为非环状，X为外消旋混合物，R或S对映异构体，溶剂合物，水合物 或其盐：C是手性碳原子，n是1-4的整数（优选1至3），（CH 2）n的一个或多个碳原子可被酮或羟基取代 组，m是从1到14的整数。 独立地，R 1和R 2可以是氢，长或多至十二个碳原子的直链或支链烷烃或烯烃，或 - （CH 2）w R 5，w为2至14的整数，R 5为单 - ，二 - 或三取代或未取代的芳基，R 5上的取代基是羟基，氯，氟，溴或C 1-6烷氧基。 或者共同地，R 1和R 2形成具有4至8个碳原子的取代或未取代的饱和或不饱和杂环基，N是杂原子。 R3是氢或C1-3。 或者，治疗性化合物也可以具有下式：R 4是氢，长或多至八个碳原子的直链或支链烷烃或烯烃， - （CH 2）w R 5，w是2至14的整数， R5是一个，二或三取代或未取代的芳基，R 5上的取代基是羟基，氯，氟，溴或C 1-6烷氧基，或取代或未取代的饱和或不饱和杂环基， 八个碳原子。 r和s独立为从1到4的整数，并且（r + s）不大于5。 t是1至14的整数，（CH 2）s或（CH 2）t的一个或多个碳原子可以被酮基或羟基取代。

公开(公告)号：US5837703A

公开(公告)日：1998-11-17

申请号：US152650

申请日：1993-11-12

申请人： Anil M. Kumar ,  John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

发明人： Anil M. Kumar ,  John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

IPC分类号： A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D207/40 ,  C07D207/404 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10 ,  A61K31/55 ,  A61K31/445 ,  A61K31/515 ,  A61K31/52

CPC分类号： C07D207/404 ,  A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10

摘要： Therapeutic compounds have the formula: (X)j-(core moiety), j being an integer from one to three, the core moiety comprising a core moiety, the core moiety being a heterocycle having one ring or two-fused rings, each ring having five or six ring atoms, A being a carbon atom of the core moiety and attached to a terminal carbon atom of (CH.sub.2).sub.m, and X has a structure and X being a racemic mixture, R or S enantiomer, solvate, hydrate, or salt of: ##STR1## *C is a chiral carbon atom, n is an integer from one to four (preferably from one to three), one or more carbon atoms of (CH.sub.2).sub.n may be substituted by a keto or hydroxy group, and m is an integer from one to fourteen. Independently, R.sub.1 and R.sub.2 may be a hydrogen, a straight or branched chain alkyl or alkenyl of up to twelve carbon atoms in length, or --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxyl. Or jointly, R.sub.1 and R.sub.2 form a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms, N being a hetero atom. R.sub.3 is a hydrogen or C.sub.1-3. Or, therapeutic compounds may also have the formula: ##STR2## R.sub.4 is a hydrogen, a straight or branched chain alkyl or alkenyl of up to eight carbon atoms in length, --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxyl, or a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms, r and s are independently integers from one to four, the sum (r+s) not being greater than five. t is an integer from one to fourteen and one or more carbon atoms of (CH.sub.2).sub.s or (CH.sub.2).sub.t may be substituted by a keto or hydroxyl group.

摘要翻译： 治疗性化合物具有下式：（X）j-（核心部分），j是1至3的整数，核心部分包含核心部分，核心部分是具有一个环或双稠环的杂环，每个环 具有五个或六个环原子，A是核心部分的碳原子并且连接到（CH 2）m的末端碳原子，X具有结构，X是外消旋混合物，R或S对映异构体，溶剂合物，水合物， 或盐：C是手性碳原子，n是1至4（优选1至3）的整数，（CH 2）n的一个或多个碳原子可以被酮基或羟基取代 ，m为1〜14的整数。 独立地，R 1和R 2可以是氢，长或多至十二个碳原子的直链或支链烷基或链烯基，或 - （CH 2）w R 5，w为2至14的整数，R 5为单 - ，二 - 或三取代或未取代的芳基，R5上的取代基是羟基，氯，氟，溴或C1-6烷氧基。 或者共同地，R 1和R 2形成具有4至8个碳原子的取代或未取代的饱和或不饱和杂环基，N是杂原子。 R3是氢或C1-3。 或者，治疗性化合物还可以具有如下分子式：长达8个碳原子的链长链烷基或链烯基， - （CH 2）w R 5，w为2至14的整数，R 5为单 - ，二 - 或三 - 取代或未取代的芳基，R 5上的取代基为羟基，氯，氟，溴或C 1-6烷氧基，或具有4至8个碳原子的取代或未取代的饱和或不饱和杂环基，r和s独立地为 一到四，总和（r + s）不大于五。 t是1至14的整数，（CH 2）s或（CH 2）t的一个或多个碳原子可以被酮基或羟基取代。

公开(公告)号：US5801181A

公开(公告)日：1998-09-01

申请号：US474820

申请日：1995-06-07

申请人： John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

发明人： John Michnick ,  Gail E. Underiner ,  J. Peter Klein ,  Glenn C. Rice

IPC分类号： A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D207/40 ,  C07D207/404 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10 ,  A01N43/00 ,  A01N43/42 ,  A01N43/58 ,  A01N43/90

CPC分类号： C07D207/404 ,  A61K31/404 ,  A61K31/45 ,  A61K31/47 ,  A61K31/513 ,  A61K31/519 ,  A61K31/522 ,  C07C215/08 ,  C07C215/56 ,  C07C217/62 ,  C07C229/22 ,  C07C233/36 ,  C07C233/78 ,  C07C233/91 ,  C07D209/48 ,  C07D211/76 ,  C07D211/88 ,  C07D217/24 ,  C07D239/54 ,  C07D239/90 ,  C07D239/96 ,  C07D295/13 ,  C07D473/10

摘要： Therapeutic compounds have the formula: (X)j--(core moiety), J being an integer from one to three, the core moiety having at least one, five- to seven-membered ring and X being a racemic mixture, R or S enantiomer, slovate, hydrate, or salt of: ##STR1## *C is a chiral carbon atom, n is an integer from one to four (preferably from one to three), one or more carbon atoms of (CH.sub.2).sub.n may be substituted by a keto or hydroxy group, and m is an integer from one to fourteen. Independently, R.sub.1 and R.sub.2 may be a hydrogen, a straight or branched chain alkane or alkene of up to twelve carbon atoms in length, or --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxy. Or jointly, R.sub.1 and R.sub.2 form a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms, N being a hetero atom. R.sub.3 is a hydrogen or C.sub.1-3. Or, therapeutic compounds may also have the formula: ##STR2## R.sub.4 is a hydrogen, a straight or branched chain alkane or alkene of up to eight carbon atoms in length, --(CH.sub.2).sub.w R.sub.5, w being an integer from two to fourteen and R.sub.5 being a mono-, di- or tri-substituted or unsubstituted aryl group, substituents on R.sub.5 being hydroxy, chloro, fluoro, bromo, or C.sub.1-6 alkoxy, or a substituted or unsubstituted, saturated or unsaturated heterocyclic group having from four to eight carbon atoms, N being a hetero atom. r and s are independently integers from one to four, the sum (r+s) not being greater than five. t is an integer from one to fourteen and one or more carbon atoms of (CH.sub.2).sub.s or (CH.sub.2).sub.t may be substituted by a keto or hydroxy group.

摘要翻译： 治疗性化合物具有下式：（X）j-（核心部分），J为1至3的整数，核心部分具有至少一个五至七元环，X为外消旋混合物，R或S 对映异构体，疏水盐，水合物或盐：C是手性碳原子，n是1至4（优选1至3）的整数，（CH 2）n的一个或多个碳原子可以被取代 通过酮或羟基，m是1至14的整数。 独立地，R 1和R 2可以是氢，长或多至十二个碳原子的直链或支链烷烃或烯烃，或 - （CH 2）w R 5，w为2至14的整数，R 5为单 - ，二 - 或三取代或未取代的芳基，R 5上的取代基是羟基，氯，氟，溴或C 1-6烷氧基。 或者共同地，R 1和R 2形成具有4至8个碳原子的取代或未取代的饱和或不饱和杂环基，N是杂原子。 R3是氢或C1-3。 或者，治疗性化合物也可以具有下式：R 4是氢，长或多至八个碳原子的直链或支链烷烃或烯烃， - （CH 2）w R 5，w是2至14的整数， R5是一个，二或三取代或未取代的芳基，R 5上的取代基是羟基，氯，氟，溴或C 1-6烷氧基，或取代或未取代的饱和或不饱和杂环基， 八个碳原子，N是杂原子。 r和s独立为从1到4的整数，并且（r + s）不大于5。 t是1至14的整数，（CH 2）s或（CH 2）t的一个或多个碳原子可以被酮基或羟基取代。

公开(公告)号：US5807861A

公开(公告)日：1998-09-15

申请号：US476911

申请日：1995-06-07

申请人： J. Peter Klein ,  Gail E. Underiner ,  Anil M. Kumar ,  Lance H. Ridgers ,  Glenn C. Rice ,  David W. Leung

发明人： J. Peter Klein ,  Gail E. Underiner ,  Anil M. Kumar ,  Lance H. Ridgers ,  Glenn C. Rice ,  David W. Leung

IPC分类号： C07D239/54 ,  C07D473/04 ,  C07D473/06 ,  C07D487/04 ,  C07D513/04 ,  A61K31/52

CPC分类号： C07D239/54 ,  C07D473/04 ,  C07D473/06 ,  C07D487/04 ,  C07D513/04

摘要： A method for treating a disease caused by an undesirable cell response mediated by a proliferative intracellular signaling pathway is provided wherein an effective amount of a compound is administered. The compound, resolved enantiomers, diastereomers, hydrates, salts, solvates and mixtures thereof, has the formula CORE MOIETY--(R).sub.j wherein j is an integer from one to three; the core moiety is xanthinyl; and R is independently selected from the group consisting of amine, hydrogen, halogen, hydroxyl, C.sub.(1-10) alkyl, C.sub.(2-10) alkenyl, 2-bromopropyl, 4-chloropentyl, cyclohexyl, cyclopentyl, 3-dimethylaminobutyl, 2-hydroxyethyl, 5-hydroxyhexyl, 3-hydroxy-n-butyl, 3-hydroxypropyl, 2-methoxyethyl, 4-methoxy-n-butyl, phenyl, and formula I, at least one R comprising formula I ##STR1## wherein (CH.sub.2).sub.n is optionally substituted; n is an integer from five to twenty; each R.sub.1 or R.sub.2 is independently hydrogen or an optionally substituted group that is herein defined; and wherein, when the (CH.sub.2).sub.n, R.sub.1 or R.sub.2 is substituted, a substituent is selected from the group consisting of carbamoyl, primary, secondary and tertiary amino, C.sub.(2-8) alkenyl, C.sub.(1-8) alkyl, C.sub.(1-8) alkoxyl, C.sub.(1-8) hydroxyalkyl, azido, carbonato, carbonyl, carboxyl, cyano, C.sub.(1-8) haloalkyl, isocyano, isomercaptocyano, phospho, phosphonato, sulfonato, alkylsulfonyl, alkylsulfoxidyl, mercaptocarbonyl, mercaptocarbonato, thioureido and ureido.

摘要翻译： 提供了治疗由增殖性细胞内信号传导途径介导的不良细胞应答引起的疾病的方法，其中施用有效量的化合物。 化合物，拆分的对映体，非对映异构体，水合物，盐，溶剂合物及其混合物具有式CORE MOIETY-（R）j，其中j是1至3的整数; 核心部分是xanthinyl; 并且R独立地选自胺，氢，卤素，羟基，C（1-10）烷基，C（2-10）烯基，2-溴丙基，4-氯戊基，环己基，环戊基，3-二甲基氨基丁基， 2-羟基乙基，5-羟基己基，3-羟基 - 正丁基，3-羟基丙基，2-甲氧基乙基，4-甲氧基 - 正丁基，苯基和式I，至少一个R包括式I其中 （CH 2）n任选被取代; n是从5到20的整数; 每个R 1或R 2独立地为氢或本文定义的任选取代的基团; 并且其中当（CH 2）n，R 1或R 2被取代时，取代基选自氨基甲酰基，伯，仲和叔氨基，C（2-8）烯基，C（1-8）烷基， C（1-8）烷氧基，C（1-8）羟基烷基，叠氮基，碳酸根，羰基，羧基，氰基，C（1-8）卤代烷基，异氰基，异构体巯基，磷酸根，膦酸根，磺酸根，烷基磺酰基，烷基亚砜基，巯基羰基， 巯基羰基，硫脲基和脲基。

公开(公告)号：US6043250A

公开(公告)日：2000-03-28

申请号：US472296

申请日：1995-06-07

申请人： J. Peter Klein ,  Alistair J. Leigh ,  Gail E. Underiner ,  Anil M. Kumar ,  Glenn C. Rice

发明人： J. Peter Klein ,  Alistair J. Leigh ,  Gail E. Underiner ,  Anil M. Kumar ,  Glenn C. Rice

IPC分类号： C07D239/54 ,  A61K31/42 ,  A61K31/421 ,  A61K31/496 ,  A61K31/505 ,  A61K31/52 ,  A61K31/522 ,  A61P9/10 ,  A61P9/14 ,  A61P11/16 ,  A61P13/02 ,  A61P15/00 ,  A61P25/28 ,  A61P29/00 ,  A61P31/12 ,  A61P31/18 ,  A61P35/00 ,  A61P37/04 ,  A61P37/08 ,  A61P43/00 ,  C07C47/198 ,  C07C47/277 ,  C07C49/175 ,  C07C49/255 ,  C07C57/46 ,  C07C59/64 ,  C07C65/21 ,  C07C69/06 ,  C07C69/14 ,  C07C69/24 ,  C07C69/608 ,  C07C69/612 ,  C07C225/06 ,  C07C233/01 ,  C07D239/56 ,  C07D241/18 ,  C07D263/30 ,  C07D473/04 ,  C07D473/06 ,  C07D473/10 ,  C07D487/04 ,  C07D513/04 ,  C07D521/00 ,  A61K3/52

CPC分类号： C07D487/04 ,  C07D473/04 ,  C07D473/06 ,  C07D473/10 ,  C07D513/04

摘要： Therapeutic compounds with at least one carboxylic acid, ester or amide-substituted side chain have the formula:CORE MOIETY --(R).sub.jwherein j is an integer from one to three. The core moiety is non-cyclic or cyclic (carbocyclic or heterocyclic). R may be selected from among hydrogen, halogen, hydroxyl, amino, substituted or unsubstituted C(.sub.1-10) alkyl, C(.sub.2-10) alkenyl, carbocyclic or heterocyclic groups and at least one R has the formula I: ##STR1## wherein: one or two p are the integer one, otherwise p is two; and n is an integer from three to twenty; R.sub.1 is selected from the group consisting of substituted and unsubstituted CH.sub.2 ; NR.sub.3, R.sub.3 being hydrogen, substituted or unsubstituted C(.sub.1-20) alkyl, C.sub.(1-20) alkoxyl, C.sub.(2-20) alkenyl or C.sub.(1-20) hydroxyalkyl, or carbocyclic or heterocyclic group; O; --CHR.sub.4 O--, R.sub.4 being substituted or unsubstituted C.sub.(1-20) alkyl, C.sub.(1-20) alkoxyl, C.sub.(2-20) alkenyl, C.sub.(1-20) hydroxyalkyl, or R.sub.2 and R.sub.4 join to form a substituted or unsubstituted heterocycle having four to seven ring atoms, the ether group --O-- of --CHR.sub.4 O-- being a member of the heterocycle. R.sub.2 is selected from the group consisting of hydrogen; halogen; substituted or unsubstituted C.sub.(1-10) alkyl; C.sub.(1-10) alkoxyl; C.sub.(2-10) alkenyl; C.sub.(1-10) hydroxyalkyl; --A(R.sub.5).sub.m, A being N or 0, m being one or two and R.sub.5 being hydrogen, a substituted or unsubstituted C.sub.(1-10) alkyl, C.sub.(1-10) alkoxyl, C.sub.(2-10) alkenyl or C.sub.(1-10) hydroxyalkyl), or carbocyclic or heterocyclic group. At least one of R.sub.1 is NR.sub.3, O or --CHR.sub.4 O--, or R.sub.2 is --A(R.sub.5).sub.m. The compounds and pharmaceutical compositions thereof are useful as therapies for diseases advanced via intracellular signaling through specific intracellular signaling pathways by mediating a signaling response to an external stimuli.

摘要翻译： 具有至少一个羧酸，酯或酰胺取代的侧链的治疗化合物具有下式：CORE MOIETY - （R）j，其中j是1至3的整数。 核心部分是非环状或环状的（碳环或杂环）。 R可以选自氢，卤素，羟基，氨基，取代或未取代的C（1-10）烷基，C（2-10）烯基，碳环或杂环基，并且至少一个R具有式I：其中： 或两个p为整数，否则p为2; n为3〜20的整数。 R1选自取代和未取代的CH 2; NR 1，R 3为氢，取代或未取代的C 1-20烷基，C（1-20）烷氧基，C（2-20）烯基或C（1-20）羟基烷基或碳环或杂环基; O; -CHR4O-，R4是取代或未取代的C（1-20）烷基，C（1-20）烷氧基，C（2-20）烯基，C（1-20）羟基烷基或R2和R4连接形成取代的 或具有4-7个环原子的未取代的杂环，-CHR4O-的醚基-O-是杂环的成员。 R2选自氢; 卤素; 取代或未取代的C（1-10）烷基; C（1-10）烷氧基; C（2-10）烯基; C（1-10）羟烷基; -A（R5）m，A为N或0，m为一个或两个，R5为氢，取代或未取代的C（1-10）烷基，C（1-10）烷氧基，C（2-10）烯基 或C（1-10）羟烷基）或碳环或杂环基。 R 1中的至少一个为NR 3，O或-CHR 4 O-，或R 2为-A（R 5）m。 这些化合物及其药物组合物可用作通过介导对外部刺激的信号反应的特异性细胞内信号通路的细胞内信号传导的疾病的治疗。

公开(公告)号：US5288721A

公开(公告)日：1994-02-22

申请号：US949330

申请日：1992-09-22

申请人： J. Peter Klein ,  David Porubek ,  Glenn C. Rice ,  Paul Woodson

发明人： J. Peter Klein ,  David Porubek ,  Glenn C. Rice ,  Paul Woodson

IPC分类号： C07D473/08 ,  C07D473/10 ,  A61K31/52 ,  C07D473/04

CPC分类号： C07D473/08 ,  C07D473/10

摘要： Compounds of the formula ##STR1## including the resolved enantiomers and/or diastereomers and mixtures thereof wherein each of one or two R is independently ##STR2## wherein n is 1-16 and R' is H or alkyl(1-4C); and wherein each remaining R is independently H, alkyl(1-6C), alkenyl(1-6C) or benzyl; an wherein said alkyl or alkenyl may be substituted by a hydroxyl, halo, or dimethylamino group, and/or interrupted by an oxygen atom, are useful in modulating the effects of internal and external stimuli on cells by reversing the effects of these stimuli on the short-term secondary messenger pathways. In particular, the compounds lower elevated levels of unsaturated, non-arachidonate phosphatidic acid (PA) and diacylglycerol (DAG) derived from said PA within seconds of the primary stimulus and their contact with said cells. The modulatory effect depends on the nature of the target cell and the stimulus applied.

摘要翻译： 式（1）的化合物包括拆分的对映体和/或非对映异构体及其混合物，其中一个或两个R R中的每一个独立地为（2），其中n为1-16且R'为H或烷基（ 1-4C）; 并且其中每个剩余的R独立地为H，烷基（1-6C），烯基（1-6C）或苄基; 其中所述烷基或烯基可以被羟基，卤素或二甲基氨基取代和/或被氧原子间隔，可用于通过将这些刺激的作用逆转到细胞上来调节内部和外部刺激对细胞的影响 短期二级信使途径。 特别地，所述化合物在主刺激的几秒钟内与所述细胞的接触降低了源自所述PA的不饱和，非花生四烯酸磷脂酸（PA）和二酰基甘油（DAG）的升高水平。 调节作用取决于靶细胞的性质和应用的刺激。

公开(公告)号：US5223408A

公开(公告)日：1993-06-29

申请号：US728456

申请日：1991-07-11

申请人： David V. Goeddel ,  Glenn C. Rice ,  David W. H. Leung

发明人： David V. Goeddel ,  Glenn C. Rice ,  David W. H. Leung

IPC分类号： A61K38/00 ,  C07K14/705 ,  C12N9/72 ,  C12N15/10 ,  C40B40/02

CPC分类号： C40B40/02 ,  C07K14/705 ,  C12N15/102 ,  C12N15/1037 ,  C12N9/6459 ,  C12Y304/21069 ,  A61K38/00 ,  C07K2319/00 ,  C07K2319/033 ,  C07K2319/33

摘要： A screening method for the selection of mutagenized proteins that are normally secreted by cells is described. The method includes the development of a cloning vector for the expression of secretory proteins as fusion proteins on the cell surface of transfected mammalian cells. The secreted protein is displayed on the cell surface by fusion with the glycophospholipid membrane anchor of decay accelerating factor (DAF). Tissue-type plasminogen activator (t-PA), which is normally secreted, is used as a model protein. PCR mutagenesis is used to generate random mutations within the Kringle 1 (K1) domain of t-PA. Fluorescence activated cell sorting (FACS) is employed to screen for t-PA mutants possessing a loss of an epitope to a specific Mab, whose nonlinear binding domains overlap with the t-PA clearance receptor contact regions novel t-PA mutants designated N115S, N1425S, and K159R were discovered by this method.

摘要翻译： 描述了通常由细胞分泌的诱变蛋白质的筛选方法。 该方法包括开发用于在转染的哺乳动物细胞的细胞表面上表达分泌蛋白作为融合蛋白的克隆载体。 分泌的蛋白质通过与衰老加速因子（DAF）的糖磷脂膜锚点融合而显示在细胞表面上。 通常分泌的组织型纤溶酶原激活物（t-PA）用作模型蛋白。 PCR诱变用于在t-PA的Kringle 1（K1）结构域内产生随机突变。 荧光活化细胞分选（FACS）用于筛选具有特异性Mab的表位损失的t-PA突变体，其特异性Mab的非线性结合域与t-PA清除受体接触区重叠，称为N115S，N1425S的新型t-PA突变体 ，K159R。

公开(公告)号：US5929081A

公开(公告)日：1999-07-27

申请号：US485320

申请日：1995-06-07

申请人： Paul A. Brown ,  Stuart L. Bursten ,  Glenn C. Rice ,  Jack W. Singer

发明人： Paul A. Brown ,  Stuart L. Bursten ,  Glenn C. Rice ,  Jack W. Singer

IPC分类号： A61K31/00 ,  A61K31/52 ,  A61K31/522 ,  A61K31/44 ,  A61K31/51 ,  A61K31/535

CPC分类号： A61K31/52 ,  A61K31/00 ,  A61K31/522

摘要： There is disclosed a method for:(1) inhibiting new blood vessel formation that is useful for treating or preventing progression of diabetic retinopathy, cavernous haemangiomas, Kaposi's sarcoma, tumors composed of endothelial-like cells, and growth of cancer cells by preventing their development of a new blood supply:(2) suppressing development of kidney diseases due to cytokine induced proliferation of mesangial cells and/or glomerular epithelial cells that is useful for treating or preventing progression of diabetic glomerulosclerosis and other glomerulonephritides of various types and etiologies;(3) preventing joint destruction accompanying rheumatoid arthritis due to proliferation of synovial cells;(4) suppressing manifestations of psoriasis due to proliferation of keratinocytes and accumulation of inflammatory cells;(5) suppressing accelerated atherogenesis involved in restenosis of coronary vessels or other arterial vessels following angioplasty;(6) suppressing atherogenesis, coronary artery disease and other vasculopathies due to atherogenesis; and(7) suppressing tumor growth via paracrine or autocrine mediated responses to PDGF, FGF EGF or VEGF that is useful for treating or preventing progression of tumors such as breast cancer stimulated through overexpression of her-2-neu receptor, wherein the inventive method comprises administering a compound that inhibits signal transduction through cellular accumulation of non-arachidonyl phosphatidic acid (PA) selected from the group consisting of 1-o-octadecanyl 2-oleoyl PA (687), 1-oleoyl 2-linoleoyl PA (697 or 698), 1-o-octadecanyl 2-linoleoyl PA (681), 1-o-octadecanyl-9,12-dienyl 2-linoleoyl PA (679), 1-myristoyl 2-oleoyl PA (645), 1-o-myristoyl 2-stearoyl PA (633), 1,2-sn-dilinoleoyl PA (695), 1-oleoyl 2-linoleoyl PA (697), 1-stearoyl 2-oleoyl PA (701), 1-o-oleoyl 2-20:4 PA (707), 1-o-linoleoyl 2-20:4 PA (705), 1-o-linoleoyl 2-20:5 PA (703), and combinations thereof.

公开(公告)号：US5859018A

公开(公告)日：1999-01-12

申请号：US485322

申请日：1995-06-07

申请人： Paul A. Brown ,  Stuart L. Bursten ,  Glenn C. Rice ,  Jack W. Singer

发明人： Paul A. Brown ,  Stuart L. Bursten ,  Glenn C. Rice ,  Jack W. Singer

IPC分类号： A61K31/00 ,  A61K31/52 ,  A61K31/522 ,  A61K31/44 ,  A61K31/445 ,  A61K31/50

CPC分类号： A61K31/52 ,  A61K31/00 ,  A61K31/522

摘要： There is disclosed a method for:(1) inhibiting new blood vessel formation that is useful for treating or preventing progression of diabetic retinopathy, cavernous haemangiomas, Kaposi's sarcoma, tumors composed of endothelial-like cells, and growth of cancer cells by preventing their development of a new blood supply:(2) suppressing development of kidney diseases due to cytokine induced proliferation of mesangial cells and/or glomerular epithelial cells that is useful for treating or preventing progression of diabetic glomerulosclerosis and other glomerulonephritides of various types and etiologies;(3) preventing joint destruction accompanying rheumatoid arthritis due to proliferation of synovial cells;(4) suppressing manifestations of psoriasis due to proliferation of keratinocytes and accumulation of inflammatory cells;(5) suppressing accelerated atherogenesis involved in restenosis of coronary vessels or other arterial vessels following angioplasty;(6) suppressing atherogenesis, coronary artery disease and other vasculopathies due to atherogenesis; and(7) suppressing tumor growth via paracrine or autocrine mediated responses to PDGF, FGF EGF or VEGF that is useful for treating or preventing progression of tumors such as breast cancer stimulated through overexpression of her-2-neu receptor, wherein the inventive method comprises administering a compound that inhibits signal transduction through cellular accumulation of non-arachidonyl phosphatidic acid (PA) selected from the group consisting of 1-o-octadecanyl 2-oleoyl PA (687), 1-oleoyl 2-linoleoyl PA (697 or 698), 1-o-octadecanyl 2-linoleoyl PA (681), 1-o-octadecanyl-9,12-dienyl 2-linoleoyl PA (679), 1-myristoyl 2-oleoyl PA (645), 1-o-myristoyl 2-stearoyl PA (633), 1,2-sn-dilinoleoyl PA (695), 1-oleoyl 2-linolcoyl PA (697), 1-stearoyl 2-oleoyl PA (701), 1-o-oleoyl 2-20:4 PA (707), 1-o-linoleoyl 2-20:4 PA (705), 1-o-linoleoyl 2-20:5 PA (703), and combinations thereof.

公开(公告)号：US5856331A

公开(公告)日：1999-01-05

申请号：US948747

申请日：1997-10-10

申请人： Stuart L. Bursten ,  Jack W. Singer ,  Glenn C. Rice

发明人： Stuart L. Bursten ,  Jack W. Singer ,  Glenn C. Rice

IPC分类号： A61K31/00 ,  A61K31/52 ,  A61K31/415 ,  A61K31/42 ,  A61K31/425

CPC分类号： A61K31/00 ,  A61K31/52

摘要： There is disclosed a method for preventing tissue injury caused by tissue hypoxia and reoxygenation, comprising administering a compound that inhibits signal transduction by inhibiting cellular accumulation of linoleoyl phosphatidic acid (PA) through an inhibition of the enzyme LPAAT (lysophosphatidic acyltransferase).