公开(公告)号：US06521657B2

公开(公告)日：2003-02-18

申请号：US10022467

申请日：2001-10-30

Applicant: Andrew Fensome ,  Puwen Zhang ,  Marci C. Koko ,  Lin Zhi ,  Todd K. Jones ,  Jay E. Wrobel ,  Christopher M. Tegley ,  James P. Edwards ,  Edward G. Melenski

Inventor： Andrew Fensome ,  Puwen Zhang ,  Marci C. Koko ,  Lin Zhi ,  Todd K. Jones ,  Jay E. Wrobel ,  Christopher M. Tegley ,  James P. Edwards ,  Edward G. Melenski

IPC: A61K31404

CPC classification number: C07D209/40 ,  C07D209/08 ,  C07D209/30

Abstract: This invention relates to compounds which are agonists of the progesterone receptor which have the general structure: wherein: R1, R2, R3, R4, R5 and Q1 are as defined herein, or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.

公开(公告)号：US06509334B1

公开(公告)日：2003-01-21

申请号：US09552633

申请日：2000-04-19

Applicant: Puwen Zhang ,  Eugene A. Terefenko ,  Andrew Fensome ,  Jay E. Wrobel ,  Horace Fletcher, III ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley

Inventor： Puwen Zhang ,  Eugene A. Terefenko ,  Andrew Fensome ,  Jay E. Wrobel ,  Horace Fletcher, III ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley

IPC: C07D26518

CPC classification number: C07D265/18 ,  C07D413/04 ,  C07D413/10 ,  C07D417/04

Abstract: This invention provides compounds of Formula (I): wherein R1 and R2 may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alkynyl, CORC; RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl, alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; and R5 is selected from a trisubstituted benzene ring of a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, N02, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF; or pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods using the compounds as antagonists of the progesterone receptor.

Abstract translation: 本发明提供式（I）化合物：其中R 1和R 2可以是单个取代基或稠合形成螺环或杂 - 六环环; R 3是H，OH，NH 2，C 1 -C 6烷基，取代的C 1 -C 6烷基，C 3至C 6烯基，取代的C 1至C 6烯基，炔基或取代的炔基，CORC; RC为H，C1至C3烷基，取代C1至C3烷基，芳基，取代芳基，C1至C3烷氧基，取代C1至C3烷氧基，C1至C3氨基烷基或取代C1至C3氨基烷基; R 4是H，卤素，CN，NO 2，C 1至C 6烷基，取代的C 1 -C 6烷基，炔基或取代的炔基，C 1至C 6烷氧基，取代的C 1至C 6烷氧基，氨基，C 1至C 6氨基烷基或取代的C 1至C 6 氨基烷基; 并且R 5选自具有1,2或3个杂原子的五元或六元环的三取代苯环，所述杂原子包括O，S，SO，SO 2或NR 6，并且包含一个或两个独立的取代基，包括H， 卤素，CN，NO 2，氨基和C 1至C 3烷基，C 1至C 3烷氧基，C 1至C 3氨基烷基，CORF或NRGCORF; 或其药学上可接受的盐，以及使用该化合物作为孕酮受体的拮抗剂的药物组合物和方法。

公开(公告)号：US06444668B1

公开(公告)日：2002-09-03

申请号：US09552350

申请日：2000-04-19

Applicant: Gary S. Grubb ,  Puwen Zhang ,  Eugene A. Terefenko ,  Andrew Fensome ,  Jay E. Wrobel ,  Horace Fletcher, III ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

Inventor： Gary S. Grubb ,  Puwen Zhang ,  Eugene A. Terefenko ,  Andrew Fensome ,  Jay E. Wrobel ,  Horace Fletcher, III ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

IPC: A61K31535

CPC classification number: A61K31/535 ,  A61K31/56 ,  Y10S514/843 ,  A61K2300/00

Abstract: This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: wherein R1 and R2 may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 allyl C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alknyl, CORC; RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NO2, C1 to C6 alkyl, substituted C1 to C6 alkyl alkynyl, or substituted alkynyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, amino, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; and R5 is selected from a trisubstituted benzene ring of a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR6 and containing one or two independent substituents from the group including H, halogen, CN, NO2, amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF; or pharmaceutically acceptable salt thereof. These methods of treatment may be used for contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or inmization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

Abstract translation: 本发明涉及使用具有以下通式结构的孕酮受体的拮抗剂的取代的二氢吲哚衍生物化合物的环状组合疗法和方案：其中R1和R2可以是单取代基或稠合形成螺环或异 - 螺环; R 3是H，OH，NH 2，C 1至C 6烷基，取代的C 1 -C 6烯丙基C 3至C 6烯基，取代的C 1至C 6烯基，炔基或取代的烷基，CORC; RC为H，C1至C3烷基，取代C1至C3烷基，芳基，取代芳基，C1至C3烷氧基，取代C1至C3烷氧基，C1至C3氨基烷基或取代C1至C3氨基烷基; R 4是H，卤素，CN，NO 2，C 1至C 6烷基，取代的C 1至C 6烷基炔基或取代的炔基，C 1至C 6烷氧基，取代的C 1至C 6烷氧基，氨基，C 1至C 6氨基烷基或取代的C 1至C 6氨基烷基 ; 并且R 5选自具有1,2或3个杂原子的五元或六元环的三取代苯环，所述杂原子包括O，S，SO，SO 2或NR 6，并且包含一个或两个独立的取代基，包括H， 卤素，CN，NO 2，氨基和C 1至C 3烷基，C 1至C 3烷氧基，C 1至C 3氨基烷基，CORF或NRGCORF; 或其药学上可接受的盐。 这些治疗方法可用于避孕或治疗和/或预防继发性闭经，功能障碍性出血，子宫平滑肌瘤，子宫内膜异位症; 多囊卵巢综合征，子宫内膜癌，卵巢癌，乳腺癌，结肠癌，前列腺癌，腺癌，副作用或周期性月经出血。 本发明的额外用途包括刺激食物摄取。

公开(公告)号：US06441019B2

公开(公告)日：2002-08-27

申请号：US09906875

申请日：2001-07-17

Applicant: Arthur A. Santilli ,  Andrew Q. Viet ,  Puwen Zhang ,  Andrew Fensome ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

Inventor： Arthur A. Santilli ,  Andrew Q. Viet ,  Puwen Zhang ,  Andrew Fensome ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

IPC: A61K31535

CPC classification number: C07D498/04 ,  A61K31/5365

Abstract: This invention provides compounds of the formula: wherein A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, one N may be optionally substituted with an C1 to C6 alkyl group; R1 and R2 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA; or R1 and R2 are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. The compounds of this invention are useful as agonists and antagonists of the progesterone receptor and in methods of inducing contraception and in the treatment or prevention of benign or malignant neoplastic diseases.

Abstract translation: 本发明提供下式的化合物：其中A和B是选自S，CH或N的独立取代基; 条件是当A为S时，B为CH或N; 当B为S时，A为CH或N; A和B不能同时为CH; 并且当A和B均等于N时，一个N可以任选地被C 1至C 6烷基取代; R1和R2是选自H，C1至C6烷基，取代C1至C6烷基，C2至C6烯基，取代C2至C6烯基，C2至C6炔基，取代C2至C6炔基，C3至C8环烷基的独立取代基 取代的C 3至C 8环烷基，芳基，取代的芳基，杂环，取代的杂环，CORA或NRBCORA; 或R 1和R 2稠合形成任选取代的3至8元螺环烷基，烯基或杂环，所述杂环含有一至三个选自O，S和N的杂原子; 或其药学上有用的盐。 本发明的化合物可用作孕激素受体的激动剂和拮抗剂以及诱导避孕和治疗或预防良性或恶性肿瘤疾病的方法。

公开(公告)号：US06436929B1

公开(公告)日：2002-08-20

申请号：US09552354

申请日：2000-04-19

Applicant: Puwen Zhang ,  Andrew Fensome ,  Eugene A. Terefenko ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley ,  Jay E. Wrobel ,  Mark A. Collins

Inventor： Puwen Zhang ,  Andrew Fensome ,  Eugene A. Terefenko ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley ,  Jay E. Wrobel ,  Mark A. Collins

IPC: A61K31535

CPC classification number: A61K31/536 ,  A61K31/538 ,  C07D265/18 ,  C07D413/04

Abstract: The present invention provides compounds which are agonists of the progesterone receptor and have the structures: wherein R1 and R2 are independent substituents selected from the group of H, optionally substituted C1 to C6 alkyl, alkenyl, alkynyl, or alkynyl groups C3 to C8 cycloalkyl, aryl, substituted aryl, or heterocyclic groups, or CORA or NRBCORA; or R1 and R2 are fused to form an optionally substituted 3 to 8 membered Spiro cyclic alkyl or alkenyl ring or a Spiro cyclic ring containing one to three heteroatoms selected from O, S and N; RA is selected from H, amino, or optionally substituted C1 to C3 alkyl, aryl, C1 to C3 alkoxy, or C1 to C3 aminoalkyl groups; RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl; R3 is H, OH, NH2, CORC, or optionally substituted C1 to C6 alkyl, C3 to C6 alkenyl, or alkynyl groups; RC is selected from H or optionally substituted C1 to C3 alkyl, aryl, C1 to C3 alkoxy, or C1 to C3 aminoalkyl groups; Q1 is S, NR7, or CR8R9; R5 is an optionally trisubstituted benzene ring or an optionally substituted five or six membered heterocyclic ring with 1, 2, or 3 ring heteroatoms selected from the group of O, S, SO, SO2 or NR6; or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds for contraception and the treatment of progesterone-related maladies.

Abstract translation: 本发明提供作为孕酮受体的激动剂并具有以下结构的化合物：其中R 1和R 2是选自H，任选取代的C 1至C 6烷基，烯基，炔基或炔基的独立取代基C 3至C 8环烷基， 芳基，取代的芳基或杂环基，或CORA或NRBCORA; 或R 1和R 2稠合形成任选取代的3至8元螺环烷基或烯基环或含有一至三个选自O，S和N的杂原子的螺环; RA选自H，氨基或任选取代的C 1至C 3烷基，芳基，C 1至C 3烷氧基或C 1至C 3氨基烷基; RB是H，C 1至C 3烷基或取代的C 1至C 3烷基; R 3是H，OH，NH 2，CORC或任选取代的C 1至C 6烷基，C 3至C 6烯基或炔基; RC选自H或任选取代的C 1至C 3烷基，芳基，C 1至C 3烷氧基或C 1至C 3氨基烷基; Q1是S，NR7或CR8R9; R5是任选的三取代的苯环或具有1,2或3个选自O，S，SO，SO 2或NR 6的环杂原子的任选取代的五元或六元杂环; 或其药学上可接受的盐，以及使用这些化合物用于避孕和治疗孕酮相关性疾病的方法。

公开(公告)号：US06423699B1

公开(公告)日：2002-07-23

申请号：US09552355

申请日：2000-04-19

Applicant: Gary S. Grubb ,  Puwen Zhang ,  Reinhold R. W. Bender ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

Inventor： Gary S. Grubb ,  Puwen Zhang ,  Reinhold R. W. Bender ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

IPC: A61K3156

CPC classification number: A61K45/06 ,  A61K31/415 ,  A61K31/535 ,  A61K31/54 ,  A61K31/56 ,  A61K31/57 ,  A61K2300/00

Abstract: This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having the general structure: wherein: A is O, S, or NR4; B is a bond between A and C═Q, or the moiety CR5R6; R4, R5, R6 are independently selected from H or optionally substituted C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, or heterocyclic groups, or cyclic alkyl constructed by fusing R4 and R5 to from a 5 to 7 membered ring; R1 is selected from H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, —COH, or optionally substituted —CO(C1 to C3 alkyl), —CO(aryl), —CO(C1 to C3 alkoxy), or —CO(C1 to C3 aminoalkyl) groups; R2 is selected from H, halogen, CN, NO2, or optionally substituted C1 to C6 alkyl C1 to C6 alkoxy, or C1 to C6 aminoalkyl groups; R3 is selected from a trisubstituted benzene ring; or a 5- or 6-membered heteroaromnatic ring containing 1 or 2 substituents; or a pharmaceutically acceptable salt thereof, in combination with a progestational agent, an estrogen, or both or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. These combinations may also be used to in methods of contraception, to stimulate food intake or for minimization of side effects or cyclic menstrual bleeding.

Abstract translation: 本发明涉及使用具有以下通式结构的孕酮受体的拮抗剂的取代的二氢吲哚衍生物化合物的循环组合疗法和方案：其中：A是O，S或NR4; B是A和C = Q之间的键，或 CR5R6部分; R4，R5，R6独立地选自H或任选取代的C1至C6烷基，C2至C6烯基，C2至C6炔基，C3至C8环烷基，取代C3至C8环烷基，芳基或杂环基，或由 将R4和R5与5至7元环融合; R1选自H，OH，NH2，C1至C6烷基，取代C1至C6烷基，C3至C6烯基，取代C1至C6烯基，炔基，取代炔基，-COH或任选取代的-CO（C 1至C 3烷基 ），-CO（芳基），-CO（C 1〜C 3烷氧基）或-CO（C 1〜C 3氨基烷基） R2选自H，卤素，CN，NO2或任选取代的C1至C6烷基C1至C6烷氧基或C1至C6氨基烷基; R3选自三取代苯环; 或含有1或2个取代基的5-或6-元杂芳族环; 或其药学上可接受的盐与促孕剂，雌激素或两者组合，或用于治疗和/或预防继发性闭经，功能障碍性出血，子宫平滑肌瘤，子宫内膜异位症; 多囊卵巢综合征，子宫内膜，卵巢，乳腺，结肠，前列腺癌和腺癌。 这些组合也可用于避孕方法，刺激食物摄取或最小化副作用或周期性月经出血。

公开(公告)号：US06417214B1

公开(公告)日：2002-07-09

申请号：US09552352

申请日：2000-04-19

Applicant: John W. Ullrich ,  Andrew Fensome ,  Jay E. Wrobel ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley

Inventor： John W. Ullrich ,  Andrew Fensome ,  Jay E. Wrobel ,  Lin Zhi ,  Todd K. Jones ,  James P. Edwards ,  Christopher M. Tegley

IPC: A61K3142

CPC classification number: C07D209/08

Abstract: This invention provides compounds of the formula 1: wherein: R1 and R2 are chosen independently from each other from H, OH; OAc; alkylaryl; alkylheteroaryl; 1-propynyl; 3-propynyl; and optionally substituted alkyl, O(alkyl); aryl; or heteroaryl groups; or R1 and R2 are joined to form a ring comprising —CH2(CH2)nCH2— where n=0-5; —CH2CH2CMe2CH2CH2—; —O(CH2)mCH2— where m=1-4; O(CH2)pO— where p=1-4; —CH2CH2OCH2CH2—; —CH2CH2N(H or alkyl)CH2CH2—; or R1 and R2 together comprise a double bond to CMe2; C(cycloalkyl), O, or C(cycloether); R3 is H, OH, NH2, CORA, or optionally substituted alkenyl or alkynyl groups; RA=H or optionally substituted alkyl, alkoxy, or aminoalkyl groups; R4=H, halo, CN, NH2, or optionally substituted alkyl, alkoxy, or aminoalkyl; R5 is selected from optionally substituted benzene ring; a five or six membered heterocyclic ring; a 4 or 7-substituted indole or a substituted benzothiophene; or pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions and methods of using the compounds as progesterone receptor antagonists.

Abstract translation: 本发明提供式1化合物：其中：R 1和R 2彼此独立地选自H，OH; OAc; 烷基芳基 烷基杂芳基 1-丙炔基; 3-丙炔基; 和任选取代的烷基，O（烷基）; 芳基; 或杂芳基; 或R 1和R 2连接形成包含-CH 2（CH 2）n CH 2 - 的环，其中n = 0-5; -CH2CH2CMe2CH2CH2-; -O（CH 2）m CH 2 - ，其中m = 1-4; O（CH 2）p O-，其中p = 1-4; -CH2CH2OCH2CH2-; -CH 2 CH 2 N（H或烷基）CH 2 CH 2 - ;或R 1和R 2一起包含与CMe2的双键; C（环烷基），O或C（环醚）; R 3是H，OH，NH 2，CORA或任选取代的烯基或炔基; RA = H或任选取代的烷基，烷氧基或氨基烷基; R 4 = H， ，CN，NH 2或任选取代的烷基，烷氧基或氨基烷基; R 5选自任选取代的苯环; 五元或六元杂环; 4或7-取代的吲哚或取代的苯并噻吩; 或其药学上可接受的盐，以及使用该化合物作为孕酮受体拮抗剂的药物组合物和方法。

公开(公告)号：US06399593B1

公开(公告)日：2002-06-04

申请号：US09552037

申请日：2000-04-19

Applicant: Gary S. Grubb ,  Puwen Zhang ,  Arthur A. Santilli ,  Andrew Fensome ,  Eugene A. Terefenko ,  Andrew Q. Viet ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

Inventor： Gary S. Grubb ,  Puwen Zhang ,  Arthur A. Santilli ,  Andrew Fensome ,  Eugene A. Terefenko ,  Andrew Q. Viet ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

IPC: A61K3156

CPC classification number: A61K45/06 ,  A61K31/565 ,  A61K31/57 ,  A61K31/535 ,  A61K2300/00

Abstract: This invention concerns cyclic combination therapies using progestational agents and indoline derivatives which are progesterone receptor antagonists of the general structure: wherein: A, B and D are N or CH, though not all can be CH; R1 and R2 are H, CORA, NRBCORA, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or aryl groups; or R1 and R2 form a spirocyclic ring; RA is H or optionally substituted alkyl aryl, alkoxy, or aminoalkyl; RB is H, alkyl alkyl; R3 is H, OH, NH2, alkyl, alkenyl, or CORC; RC is H, alkyl, aryl, alkoxy, or aminoalkyl; R4 is benzene or a 5 or 6 membered heteroaromatic ring; RF is H, alkyl, aryl, alkoxy, or aminoalkyl; RG is H or alkyl; R5 is H or alkyl; W is O or a chemical bond; or a pharmaceutically acceptable salt thereof. These methods may be used for contraception.

Abstract translation: 本发明涉及使用孕激素和二氢吲哚衍生物的循环联合疗法，其为一般结构的孕酮受体拮抗剂：其中：A，B和D为N或CH，尽管不是全部可以是CH; R1和R2是H，CORA，NRBCORA或任选取代的烷基，烯基，炔基，环烷基或芳基; 或R 1和R 2形成螺环; RA为H或任选取代的烷基芳基，烷氧基或氨基烷基; RB是H，烷基烷基; R3是H，OH，NH2，烷基，烯基或CORC; RC是H，烷基，芳基，烷氧基或氨基烷基; R4是苯或5或6元杂芳环; RF是H，烷基，芳基，烷氧基或氨基烷基; RG为H或烷基; R5是H或烷基; W是O或化学键; 或其药学上可接受的盐。 这些方法可用于避孕。

公开(公告)号：US06355648B1

公开(公告)日：2002-03-12

申请号：US09552033

申请日：2000-04-19

Applicant: Andrew Fensome ,  Puwen Zhang ,  Marci C. Koko ,  Lin Zhi ,  Todd K. Jones ,  Jay E. Wrobel ,  Christopher M. Tegley ,  James P. Edwards ,  Edward G. Melenski

Inventor： Andrew Fensome ,  Puwen Zhang ,  Marci C. Koko ,  Lin Zhi ,  Todd K. Jones ,  Jay E. Wrobel ,  Christopher M. Tegley ,  James P. Edwards ,  Edward G. Melenski

IPC: A61K31505

CPC classification number: C07D209/40 ,  C07D209/08 ,  C07D209/30

Abstract: This invention relates to compounds which are agonists of the progesterone receptor which have the general structures: wherein: R1 and R2 are H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; substituted aryl; heteroaryl; substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl; or R1 and R2 are joined to form an alkyl, alkenyl or heterocyclic ring; or R1 and R2 together comprise a double bond to CMe2; C(cycloalkyl), O, or C(cycloether); R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl, substituted alkynyl, or CORA; RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; R4 is H, halogen, CN, NH2, NO2, C1 to C6 alkyl, or substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl; R5 is optionally substituted and selected from a benzene ring, a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO2 or NR6; or an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety; Q1 is S, NR7, CR8R9; or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.

Abstract translation: 本发明涉及作为孕酮受体激动剂的化合物，其具有以下通式结构：其中：R 1和R 2为H，烷基，取代的烷基; 哦; O（烷基）; O（取代的烷基）; OAc; 芳基; 取代芳基; 杂芳基; 取代的杂芳基; 烷基芳基 烷基杂芳基 1-丙炔基; 或3-丙炔基; 或R 1和R 2连接形成烷基，链烯基或杂环; 或R1和R2一起包含与CMe2的双键; C（环烷基），O或C（环醚）; R 3是H，OH，NH 2，C 1 -C 6烷基，取代的C 1 -C 6烷基，C 3至C 6烯基，炔基，取代的炔基或CORA; RA为H，C1至C3烷基，取代C1至C3烷基，C1至C3烷氧基，取代C1至C3烷氧基，C1至C3氨基烷基或取代C1至C3氨基烷基; R 4是H，卤素，CN，NH 2，NO 2，C 1至C 6烷基或取代的C 1 -C 6烷基，C 1至C 6烷氧基，取代的C 1至C 6烷氧基，C 1至C 6氨基烷基或取代的C 1至C 6氨基烷基; R5任选被取代并选自苯环，具有1,2或3个选自O，S，SO，SO 2或NR 6的杂原子的五元或六元杂环; 或吲哚基-4-基，吲哚-7-基或苯并-2-噻吩部分; Q1是S，NR7，CR8R9; 或其药学上可接受的盐，以及使用这些化合物诱导避孕或治疗孕酮相关的癌和腺癌的方法。

公开(公告)号：US06339098B1

公开(公告)日：2002-01-15

申请号：US09552630

申请日：2000-04-19

Applicant: Mark A. Collins ,  Valerie A. Mackner ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

Inventor： Mark A. Collins ,  Valerie A. Mackner ,  Jay E. Wrobel ,  James P. Edwards ,  Todd K. Jones ,  Christopher M. Tegley ,  Lin Zhi

IPC: A61K31428

CPC classification number: C07D275/06 ,  C07D413/04

Abstract: This invention provides a progesterone receptor antagonist of formula 1 having the structure wherein R1, and R2 are each, independently, hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, heteroarylalkyl, and alkynyl. R1 and R2 may be taken together to form a ring and together contain —CH2(CH2)nCH2—, —CH2CH2CMe2CH2CH2—, —O(CH2)PCH2—, O(CH2)qO—, —CH2CH2OCH2CH2—, —CH2CH2NR7CH2CH2—. R1 and R2 may be taken together to form a double bond, the double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end; or a double bond. R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl, substituted or, CORA. R4 is hydrogen, halogen, —CN, —NH2, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl; R5 is a trisubstituted phenyl ring having the structure, or is a five or six membered heteroaryl ring, containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6, or pharmaceutically acceptable salt thereof.

Abstract translation: 本发明提供了具有其中R1的结构的式1的孕酮受体拮抗剂，R 2各自独立地为氢，烷基，取代的烷基，羟基，烷氧基，取代的烷氧基，芳基，取代的芳基，杂芳基，取代的杂芳基，芳基烷基，杂芳基烷基， 和炔基。 R 1和R 2可以一起形成环，并且一起含有-CH 2（CH 2）n CH 2 - ， - CH 2 CH 2 CH 2 CH 2 CH 2 - ， - O（CH 2）PCH 2 - ，O（CH 2）q O - ， - CH 2 CH 2 OCH 2 CH 2 - ， - CH 2 CH 2 NR 7 CH 2 CH 2 - 。 R1和R2可以一起形成双键，该双键具有与末端键合的两个甲基，具有与末端键合的环烷基，具有与末端结合的氧，或具有环醚键合 到终端; 或双键。 R3是氢，羟基，NH2，烷基，取代的烷基，烯基，炔基，取代的或CORA。 R4是氢，卤素，-CN，-NH2，烷基，取代的烷基，烷氧基，烷氧基，氨基烷基或取代的氨基烷基; R5是具有结构的三取代的苯环，或是含有1,2或3个选自O，S，SO，SO 2和NR 6的杂原子的五或六元杂芳基环，或其药学上可接受的盐。