公开(公告)号：EP1173443A1

公开(公告)日：2002-01-23

申请号：EP00928699.8

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： ZHANG, Puwen ,  SANTILLI, Arthur, A. ,  FENSOME, Andrew ,  TEREFENKO, Eugene, A. ,  VIET, Andrew Q. ,  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

摘要： This invention provides compounds of formula (I) wherein: A, B and D are N or CH, with the proviso that A, B and D can not all be CH; R?1 and R2¿ are independent substituents selected from H, COR?A, NRBCORA¿, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or groups; or R?1 and R2¿ are fused to form an optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring; RA is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; RB is H, C¿1? to C3 alkyl, or substituted C1 to C3 alkyl; R?3¿ is H, OH, NH¿2?, or optionally substituted alkyl, or alkenyl, or COR?C; Rc¿ is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R4 is a substituted benzene ring or a five or six membered ring with 1, 2 or 3 heteroatoms from the group including O, S, SO, SO¿2? or NR?5; RF¿ is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; RG is H, alkyl, or substituted alkyl; R5 is H or alkyl; Q is O, S, NR?6, or CR7R8; R6¿ is CN, SO¿2?CF3, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic ring; R?7 and R8¿ are H, NO¿2?, CN CO2R?9¿, or optionally substituted alkyl, cycloalkyl, aryl, or heterocyclic; R9 is C1 to C3 alkyl; or CR7R8 form a six membered ring of structure (a): W is O or a chemical bond; or a pharmaceutically acceptable salt thereof, as well as their use and pharmaceutical compositions as agonists and antagonists of the progesterone receptor.

公开(公告)号：EP1173426A1

公开(公告)日：2002-01-23

申请号：EP00928689.9

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： ZHANG, Puwen ,  TEREFENKO, Eugene, A. ,  FLETCHER, Horace, III ,  FENSOME, Andrew ,  WROBEL, Jay, E. ,  ZHI, Lin ,  JONES, Todd, K. ,  MARSCHKE, Keith, B. ,  TEGLEY, Christopher, M.

IPC分类号： C07D265/18 ,  C07D413/04 ,  C07D417/04 ,  C07D413/10 ,  A61K31/536 ,  A61P15/00 ,  A61P35/00

CPC分类号： C07D265/18 ,  C07D413/04 ,  C07D413/10 ,  C07D417/04

摘要： This invention provides compounds of Formula (I) wherein R?1 and R2¿ may be single substituents or fused to form spirocyclic or heterospirocyclic 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, 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, as well as pharmaceutical compositions and methods using the compounds as antagonists of the progesterone receptor.

公开(公告)号：EP1173423A1

公开(公告)日：2002-01-23

申请号：EP00928690.7

申请日：2000-05-01

申请人： American Home Products Corporation ,  LIGAND PHARMACEUTICALS INCORPORATED

发明人： ZHANG, Puwen ,  BENDER, Reinhold, H., W. ,  ZHI, Lin ,  JONES, Todd, K. ,  EDWARDS, James, P. ,  TEGLEY, Christopher, M. ,  WROBEL, Jay, E.

IPC分类号： C07D235/26 ,  C07D263/58 ,  C07D277/68 ,  C07D279/16 ,  C07D241/44 ,  C07D235/28 ,  C07D487/04 ,  C07D409/04 ,  A61K31/4184 ,  A61K31/423 ,  A61K31/429 ,  A61K31/498 ,  A61K31/4985 ,  A61K31/5415 ,  A61P5/24 ,  C07C215/76

CPC分类号： C07D263/58 ,  C07C215/76 ,  C07C229/18 ,  C07D235/26 ,  C07D235/28 ,  C07D241/44 ,  C07D277/68 ,  C07D279/16 ,  C07D409/04 ,  C07D487/04

摘要： The present invention provides compounds and pharmaceutical formulations useful as progesterone receptor agonists and antagonists and having general formula (a): wherein A is O, S, or NR4; B is a bond between A and C=Q, or the moiety CR?5R6; R4, R5, R6¿ are independently selected from H or optionally substituted C¿1? to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, or heteorcyclic groups, or cyclic alkyl constructed by fusing R?4 and R5¿ to from a 5 to 7 membered ring; R1 is selected from H, OH, NH¿2?, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituded 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 toC3 aminoalkyl) groups; R?2¿ is selected from H, halogen, CN, NO¿2?, or optionally substituted C1 to C6 alkyl, C1 to C6 alkoxy, or C1 to C6 aminoalkyl groups; R?3¿ is selected from a trisubstituted benzene ring; or a 5- or 6- membered heteroaromatic ring containing 1 or 2 substituents; Q is O, S, NR?8, or CR9R10¿; or a pharmaceutically acceptable salt thereof. The invention also includes methods of contraception and methods of treating or preventing maladies associated with the progesterone receptor.

公开(公告)号：EP1173213A1

公开(公告)日：2002-01-23

申请号：EP00932006.0

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. ,  MARSCHKE, Keith, B. ,  TEGLEY, Christopher, M. ,  ZHANG, Puwen ,  BENDER, Reinhold,H.,W. ,  EDWARDS, JAMES, P. ,  WROBEL, Jay, E. ,  BENDER, Reinhold, H., W.

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

CPC分类号： A61K45/06 ,  A61K31/415 ,  A61K31/535 ,  A61K31/54 ,  A61K31/56 ,  A61K31/57 ,  A61K31/565 ,  A61K31/495 ,  A61K31/425 ,  A61K31/42 ,  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 (1) wherein: A is O, S, or NR4; B is a bond between A and C=Q, or the moiety CR?5R6; R4, R5, R6¿ are independently selected from H or optionally substituted C¿1? 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 R?4 and R5¿ to form a 5 to 7 membered ring; R1 is selected from H, OH, NH¿2?, 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; R?2¿ is selected from H, halogen, CN, NO¿2?, or optionally substituted C1 to C6 alkyl, C1 to C6 alkoxy, or C1 to C6 aminoalkyl groups; R?3¿ is selected from a trisubstituted benzene ring; or a 5- or 6-membered heteroaromatic 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 in methods of contraception, to stimulate food intake or for minimization of side effects or cyclic menstrual bleeding.

公开(公告)号：EP1173209A1

公开(公告)日：2002-01-23

申请号：EP00928610.5

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. ,  EDWARDS, James,P ,  COLLINS, Mark, A. ,  MACKNER,Valerie,A. ,  WROBEL, Jay,E

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

CPC分类号： A61K31/56 ,  A61K31/535 ,  A61K31/565 ,  A61K31/57 ,  A61K2300/00

摘要： This invention relates to cyclic combination therapies utilizing, in combination with a progestin, an estrogen, or both, progesterone receptor antagonists of general structure (1): wherein the substituents are as defined herein; or pharmaceutically acceptable salt thereof.

公开(公告)号：EP1173206A1

公开(公告)日：2002-01-23

申请号：EP00926488.8

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 ,  TEREFENKO, Eugene, A. ,  WROBEL, Jay, E. ,  EDWARDS, James, P ,  ZHANG, Puwen ,  FENSOME, Andrew

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

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

摘要： This invention relates to cyclic combination therapies utilizing, in combination with progestins, estrogens, or both, compounds which are progesterone receptor antagonists of general structure: (I) wherein: R?1 and R2¿ are H, COR?A, or NRBCORA¿, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclic; or R?1 and R2¿ fuse to form 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic rings; RA is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl groups; RB is H or alkyl; R3 is H, OH, NH¿2, COR?C or alkyl, alkenyl, or alkynyl; RC is H, alkyl, aryl, alkoxy, or aminoalkyl; R4 is H, halogen, CN, NO¿2?, alkyl, alkynyl, alkoxy, amino or aminoalkyl; R?5¿ is benzen or 5- or 6-membered heterocyclic ring; R6 is H or alkyl; G¿1? is O, NR7, or CR7R8; G2 is CO or CR7R8; provided that when G1 is O, G2 is CR7R8, and G1 and G2 cannot both be CR7R8; R7 and R8 are H or an optionally substituted alkyl, aryl, or heterocyclic moiety; or 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.