公开(公告)号：EP1173210A1

公开(公告)日：2002-01-23

申请号：EP00928611.3

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： GRUBB, Gary, S. ,  ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY,Christopher, M ,  EDWARDS, James, P. ,  FLETCHER, Horace, A. ,  WROBEL, Jay, E. ,  FENSOME, Andrew ,  ZHANG, Puwen ,  TEREFENKO, Eugene, A.

IPC分类号： A61K45/06 ,  A61K31/57 ,  A61K31/565 ,  A61P15/18

CPC分类号： A61K45/06 ,  A61K31/565 ,  A61K31/57 ,  A61K31/535 ,  A61K2300/00

摘要： This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having general structure (I): wherein R?1 and R2¿ may be single substituents or fused to form spirocyclic or hetero-spirocyclic rings; R3 is H, OH, NH¿2?, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, or substituted alkynyl, COR?C; RC¿ is H, C¿1? 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; R?4¿ is H, halogen, CN, NO¿2?, 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 R?5¿ 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, SO¿2? or NR?6¿ and containing one or two independent substituents from the group including H, halogen, CN, NO¿2? , amino, and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, COR?F, 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 endormetrium, ovary, breast, colon, prostate, or minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention inlcude stimulation of food intake.

公开(公告)号：EP1173208A2

公开(公告)日：2002-01-23

申请号：EP00928519.8

申请日：2000-05-01

申请人： AMERICAN HOME PRODUCTS CORPORATION ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： GRUBB, Gary, S. ,  ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY, Christopher, M. ,  PUWEN, Zhang ,  FENSOME, Andrew ,  VIET, Andrew, Q. ,  SANTILLI, Arthur, A. ,  TEREFENKO, Eugene, A. ,  WROBEL, Jay, E. ,  EDWARDS, James, P.

IPC分类号： A61K45/06 ,  A61K31/57 ,  A61K31/565 ,  A61P15/18 ,  A61K31/495 ,  A61K31/12

CPC分类号： A61K45/06 ,  A61K31/565 ,  A61K31/57 ,  A61K31/535 ,  A61K2300/00

摘要： This invention concerns cyclic combination therapies using indoline derivatives which are progesterone receptor antagonists of general structure (I) wherein: A, B and D are N or CH, though not all can be CH; R?1 and R2¿ are H, COR?A, NRBCORA¿, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or aryl groups; or R?1 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, NH¿2?, alkyl, alkenyl, or COR?C; RC¿ is H, alkyl, aryl, alkoxy, or aminoalkyl; R4 is benzene or a 5 or 6 memebered 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 or 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 minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

公开(公告)号：EP1212330B1

公开(公告)日：2006-04-19

申请号：EP00957854.3

申请日：2000-08-25

申请人： LIGAND PHARMACEUTICALS INCORPORATED

发明人： HIGUCHI, Robert ,  ARIENTI, Kristen, L. ,  MANI, Neelakandha S. ,  PIO, Barbara ,  ZHI, Lin ,  CHEN, Penghui ,  CAFERRO, Thomas, R.

IPC分类号： C07D498/04 ,  C07D471/04 ,  C07D513/04 ,  A61K31/538 ,  A61K31/5415 ,  A61K31/502 ,  A61P5/26 ,  A61P5/28 ,  C07D265/00 ,  C07D221/00 ,  C07D241/00 ,  C07D279/00 ,  C07D209/00

CPC分类号： C07D471/04 ,  C07D498/04 ,  C07D498/14 ,  C07D513/04

摘要： Compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. In particular, preparation and methods of use of non-steroidal compounds and compositions that are agonists, partial agonists, and antagonists for the androgen receptor (AR) are described. Further, described are the methods of making and use of critical intermediates including a stereoselective synthetic route to intermediates for the AR modulators.

公开(公告)号：EP1363909A2

公开(公告)日：2003-11-26

申请号：EP02702589.9

申请日：2002-02-23

申请人： LIGAND PHARMACEUTICALS INCORPORATED

发明人： ZHI, Lin ,  VAN OEVEREN, Cornelis, Arjan ,  CHEN, Jyun-Hung ,  HIGUCHI, Robert, I.

IPC分类号： C07D471/06

CPC分类号： C07D471/04 ,  C07D491/04 ,  C07D493/04

摘要： This invention relates to non-steroidal tricyclic compounds that are modulators of androgen receptors and to methods for making and using such compounds.

公开(公告)号：EP1185535A1

公开(公告)日：2002-03-13

申请号：EP00928691.5

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： SANTILLI, Arthur, A. ,  VIET, Andrew, Q. ,  ZHANG, Puwen ,  FENSOME, Andrew ,  ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY, Christopher, M. ,  WROBEL, Jay, E. ,  EDWARDS, James, P.

IPC分类号： C07D498/04 ,  A61K31/535 ,  A61P15/18 ,  A61P35/00

CPC分类号： C07D498/04 ,  A61K31/5365

摘要： This invention provides compounds of formula (I) 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 a 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 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, COR?A, 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.

公开(公告)号：EP1175422A2

公开(公告)日：2002-01-30

申请号：EP00926495.3

申请日：2000-05-01

申请人： LIGAND PHARMACEUTICALS INCORPORATED ,  American Home Products Corporation

发明人： ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY, Christopher, M. ,  FENSOME, Andrew ,  ZHANG, Puwen ,  WROBEL, JAY,E ,  EDWARDS, James, P

IPC分类号： C07D498/04 ,  A61K31/5383 ,  A61P35/00 ,  A61P5/32

CPC分类号： C07D498/04

摘要： Nonsteroidal compounds that are high affinity, high selectivity modulators for progesterone receptors are disclosed. Also disclosed are pharmaceutical compositions incorporating such compounds, methods for employing the disclosed compounds and compositions for treating patients requiring progesterone receptor agonist, partial agonist or antagonist therapy, intermediates useful in the preparation of the compounds and processes for the preparation of the progesterone receptor modulator compounds.

公开(公告)号：EP1173433A1

公开(公告)日：2002-01-23

申请号：EP00932005.2

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： COLLINS, Mark, A. ,  MACKNER, Valerie, A. ,  ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY, Christopher, M. ,  WROBEL, Jay, E. ,  EDWARDS, James, P.

IPC分类号： C07D413/04 ,  C07D403/04 ,  A61K31/40 ,  A61P15/16

CPC分类号： C07D403/04 ,  A61K31/405 ,  A61K31/5415 ,  C07D413/04

摘要： This invention provides a progesterone receptor antagonist of formula (1) having the structure wherein T is O, S, or absent; R1, and R2 are each, independently, hydrogen, alkyl, substituted alkyl; or R1 and R2 are taken together to form a ring and together contain -CH2(CH2)nCH2-, -CH2CH2CMe2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or -CH2CH2NR7CH2CH2-; n=1-5; p=1-4; q=1-4; R3 is hydrogen, OH, NH2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or CORA; RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R¿4? is hydrogen, halogen, CN, NH2, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R5 is hydrogen, alkyl, or substituted alkyl; R6 is hydrogen, alkyl, substituted alkyl, or COR?B; RB¿ is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl; R¿7? is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

公开(公告)号：EP1173211A1

公开(公告)日：2002-01-23

申请号：EP00928667.5

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： GRUBB, Gary, S. ,  ZHI, Lin ,  JONES, Todd, K. ,  TEGLEY, Christopher, M. ,  ULLRICH, John, W. ,  FENSOME, Andrew ,  WROBEL, Jay, E. ,  EDWARDS, James, P.

IPC分类号： A61K45/06 ,  A61P15/18

CPC分类号： A61K31/57 ,  A61K45/06 ,  A61K2300/00

摘要： This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds that are antagonists of the progesterone receptor having general structure (I) 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; R¿4? = 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. 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 minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.

公开(公告)号：EP1212303A2

公开(公告)日：2002-06-12

申请号：EP00959507.5

申请日：2000-08-25

申请人： LIGAND PHARMACEUTICALS INCORPORATED

发明人： ZHI, Lin ,  TEGLEY, Christopher ,  PIO, Barbara ,  ARJAN VAN OEVEREN, Cornelis ,  MOTAMEDI, Mehrnouch ,  MARTINBOROUGH, Esther ,  WEST, Sarah ,  HIGUCHI, Robert ,  HAMANN, Lawrence ,  FARMER, Luc

IPC分类号： C07D215/00

CPC分类号： C07D215/227 ,  C07D209/34 ,  C07D209/96 ,  C07D215/36 ,  C07D215/38 ,  C07D239/80 ,  C07D265/18 ,  C07D265/36 ,  C07D277/68 ,  C07D311/14 ,  C07D311/20 ,  C07D401/04 ,  C07D401/12 ,  C07D405/04 ,  C07D405/12 ,  C07D409/04 ,  C07D409/12 ,  C07D413/04 ,  C07D417/04

摘要： The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by AR and PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for AR and PR. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.

公开(公告)号：EP1181275A1

公开(公告)日：2002-02-27

申请号：EP00928603.0

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： FENSOME, Andrew ,  ZHANG, Puwen ,  KOKO, Marci, C. ,  ZHI, Lin ,  JONES, Todd, K. ,  WROBEL, Jay, E. ,  TEGLEY, Christopher, M. ,  EDWARDS, James, P. ,  MELENSKI, Edward, G.

IPC分类号： C07D209/08 ,  C07D209/30 ,  C07D209/40 ,  A61K31/404 ,  A61P5/36

CPC分类号： C07D209/40 ,  C07D209/08 ,  C07D209/30

摘要： This invention relates to compounds which are agonists of the progesterone receptor which have general structures (1) or (2) wherein the substituents are as defined; or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.