CYCLIC REGIMENS USING CYCLIC UREA AND CYCLIC AMIDE DERIVATIVES

Abstract: 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 R<2> are H, COR<A>, NR<B>COR<A>, or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or aryl groups; or R<1> and R<2> form a spirocyclic ring; R<A> is H or optionally substituted alkyl, aryl, alkoxy, or aminoalkyl; R<B> is H, alkyl alkyl; R<3> is H, OH, NH2, alkyl, alkenyl, or COR<C>; R<C> is H, alkyl, aryl, alkoxy, or aminoalkyl; R<4> is benzene or a 5 or 6 memebered heteroaromatic ring; R<F> is H, alkyl, aryl, alkoxy, or aminoalkyl; R<G> is H or alkyl; R<5> 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.

Description: CYCLIC REGIMENS USING CYCLIC UREA AND CYCLIC AMIDE DERIVATIVES Field of the Invention This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both. Background of the Invention Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), gluco corticoid receptor (GR), and mineralocorticoid receptor (MR). The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene. A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist. PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk. PR antagonists may also be used in contraception In this context they may be admimstered alone (Ulmann, et al, Ann N Y Acad Sci , 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 Al, July 4, 1996) PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Hor Cancer, 283, pub Birkhaeuser, Boston, Mass , ed Nedeckis) as well as uterine and ovarian cancers PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J Clin Endo Metab , 76, 513, 1993) and endometπosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991) PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (US 5719136) PR antagonists, such as mifepnstone and onapπstone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann N Y Acad Sci , 761, 224, 1995) Jones, et al, (U S Patent No 5,688,810) descπbe the PR antagonist dihydroquinohne 1 Jones, et al, described the enol ether 2 (U S Patent No 5,693,646) as a PR ligand Jones, et al, described compound 3 (U.S. Patent No. 5,696,127) as a PR ligand. Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem, 41, 291, 1998). Zhi, et al, described the ether 7 as a PR antagomst (J Med Chem, 41, 291, 1998) Combs, et al , disclosed the amide 8 as a ligand for the PR (J Med Chem , 38, 4880, 1995) 8 Perlman, et al , descnbed the vitamin D analog 9 as a PR hgand (7et Letters, 35, 2295, 1994) Hamann, et al, descnbed the PR antagomst 10 (Ann N Y Acad Sci , 761, 383, 1995) 10 Chen, et al, descnbed the PR antagomst 11 (Chen, et al, POI-37, 16 th Int Cong Het Chem, Montana, 1997) 11 Kunhan, et al , descnbed the PR ligand 12 (J Antibiotics. 50, 360, 1997) 12 The patent by Christ et al (WO 9814436) claims cyclo amide such as compound A as inhibitors of HIV reverse transcnptase Other pnor art includes pyπdazine cyclo amide such as compound B by Turck et al (Tetrahedron, 49(3), 599- 606 (1993) ) and compound such as C by Canonne et al (J heterocyclic Chem 26, 113(1989) ) No activity data were reported in Turck's and Canonne' publications B Regarding cyclic amides, Singh et al and Kumar et al (Singh et al J Med Chem 37(2), 248-254(1994), Kumar et al J Org Chem 57(25), 6995-6998(1992) ) disclose compounds such as D and E claimed as cAMP PDE III inhibitors U S Patent No 5,521,166 (Grubb) teaches cyclophasic hormonal regimens compnsing an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin The disclosed regimens also provide for use of an estrogen for a penod of from 2-4 days to prevent breakthrough bleeding Description of the Invention This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestrns and progestins, an estrogen, such as ethinyl estradiol These regimens and combinations may be admmistered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adeno carcinomas of the endometnum, ovary, breast, colon, prostate Additional uses of the invention include stimulation of food intake The uses herein for the treatment and/or prevention of the conditions or diseases descnbed above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combmation with an estrogen or progestin or both These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being admmistered at a dosage range equal in progestational activity to about 35 μg to about 150 μg levonorgestrel per day, preferably equal m activity to from about 35 μg to about 100 μg levonorgestrel per day An antiprogestin may then be administered alone or m combmation with an estrogen for a penod of 1 to 11 days to begm on any cycle day between day 14 and 24 The anti-progestin m these combmations may be admmistered at a dose of from about 2μg to about 50 μg per day and the estrogen may be administered at a dose of from about 10 μg to about 35 μg per day In an oral administration, a package or kit containing 28 tablets will mclude a placebo tablet on those days when the antiprogestin or progestm or estrogen is not administered In a prefened embodiment of this invention, the progestins of this mvention may be admmistered alone or in combmation with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or m combmation with an estrogen, for from 1 to 7 days The estrogen to be used m the combmations and formulations of this mvention is preferably ethinyl estradiol Progestational agents useful with this mvention mclude, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, tnmegestone, dienogest. drospirenone, nomegestrol, or (17-deacetyl)norgestιmate Among the preferred progestms for use m the combmations of this mvention are levonorgestrel, gestodene and tnmegestone Examples of orally administered regimens of this mvention over a 28 day cycle mclude administration of a progestational agent solely for the first 21 days at a daily dose equal m progestational activity to from about 35 to about 100 μg of levonorgestrel An antiprogestin compound of this mvention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28 It is most preferred that the daily dosages of each relevant active ingredient be incorporated mto a combined, smgle daily dosage unit, totaling 28 daily units per 28-day cycle In another regimen, a progestational agent may be coadrmnistered for the first 21 days at a daily dose equal m progestational activity to from about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 μg This may be followed as described above with an antiprogestin admmistered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28 Still another regimen withm the scope of this mvention will mclude coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, bemg admmistered at a daily dose equal m progestational activity to from about 35 to about 100 μg levonorgestrel, and an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 μg This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 μg From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo This mvention also kits or packages of pharmaceutical formulations designed for use m the regimens descnbed herein These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to mdicate a smgle oral formulation or combmation of oral formulations to be taken on each day of the 28-day cycle Preferably each kit will mclude oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combmed daily dosages mdicated Accordmg to the regimens descnbed above, one 28-day kit may compnse a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 μg levonorgestrel, b) a second phase of from 1 to 11 daily dosage units of an antiprogestm compound of this mvention, each daily dosage umt containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remainmg days of the cycle m which no antiprogestin, progestm or estrogen is admmistered A preferred embodiment of this kit may compnse a) an initial phase of 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 μg levonorgestrel, b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm compound of this mvention, each daily dosage umt containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg; and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28 Another 28-day cycle packagmg regimen or kit of this mvention compnses a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal m activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of from 1 to 7 daily dosage units of an antiprogestm of this mvention at a daily dose of from about 2 to 50 mg, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remainmg 0-9 days m the 28-day cycle in which no progestational agent, estrogen or antiprogestm is admmistered A prefened embodiment of the kit descnbed above may compnse a) a first phase of 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal m activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestm admmistered at a daily dose of from about 2 to 50 mg, and c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28 A further 28-day packaged regimen or kit of this mvention compnses a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this mvention at a daily dose equal m progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal m activity to from about 35 to about 100 μg levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, b) a second phase of from 1 to 7 daily dose units, each daily dose umt containmg an antiprogestm of this mvention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remainmg 0-9 days m the 28-day cycle m which no progestational agent, estrogen or antiprogestm is admmistered A preferred embodiment of the package or kit just described compnses a) a first phase of 21 daily dosage units, each containmg a progestational agent of this mvention at a daily dose equal m progestational activity to about 35 to about 150 μg levonorgestrel, preferably from about 35 to about 100 μg levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestm of this mvention at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28 In each of the regimens and kits just descnbed, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed m each particular phase m which it is admmistered It is also understood that the daily dose units described are to be admmistered m the order descnbed, with the first phase followed m order by the second and third phases To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle It is further preferred that each package or kit compnse a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known m the art In this disclosure, the terms anti-progestational agents, anti-progestms and progesterone receptor antagonists are understood to be synonymous Similarly, progestms, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity These dosage regimens may be adjusted to provide the optimal therapeutic response For example, several divided doses of each component may be administered daily or the dose may be proportionally mcreased or reduced as mdicated by the exigencies of the therapeutic situation In the descnptions herein, reference to a daily dosage unit may also mclude divided units winch are administered over the course of each day of the cycle contemplated Compounds of this mvention which may be used as the anti-progestational agents in the kits, methods and regimens herem are those of the Formula I wherem A, B and D are N or CH, with the proviso that A, B and D can not all be CH, R 1 and R 2 are mdependent substituents selected from H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic, COR A , NR B COR A , or R 1 and R 2 are fused to form a spirocychc πng selected from a), b) or c), each spirocychc nng optionally substituted by from 1 to 3 C1-C3 alkyl groups a) a 3 to 8 membered spirocychc alkyl nng, b) a 3 to 8 membered spirocychc alkenyl nng, or c) an optionally substituted 3 to 8 membered heterocychc nng containmg one to three heteroatoms from the group mcludmg O, S and N, the spirocychc nngs of a), b) and c) bemg optionally substituted by from 1 to 4 groups selected from fluorine, Ci to C 6 alkyl, Ci to Cβ alkoxy, Ci to C 6 thioalkyl, -CF 3 , -OH, - CN, NH 2 , -NH(C, to C 6 alkyl), or -N(C, to C 6 alkyl) 2 , R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R B is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, substituted C, to C 6 alkenyl, or COR c , R c is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R 4 is a tnsubstituted benzene rmg containmg the substituents X, Y and Z as shown below X is taken from the group mcludmg halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, ammo, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocychc nng containmg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy, or R 4 is a five or six membered nng with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, S0 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO 2 and Ci to C 3 alkyl, Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, COR F , or NR G COR F , R F is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl. or substituted Ci to C 3 ammoalkyl, R G is H, Ci to C alkyl, or substituted d to C 3 alkyl, R 5 is H or Ci to C 3 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof When W is a chemical bond, it is understood that Formula I exists as Preferred antiprogestm compounds are those of the formula wherem A, B and D are N or CH, with the proviso that A, B and D can not all be CH, R 1 is H, C, to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocyclic. COR A , or NR B COR A , R 2 is H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A , or NR B COR A , or R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocychc nngs descnbed above, R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, d to C 3 alkoxy. substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl. R B is H, Ci to C 3 alkyl, or substituted d to C 3 alkyl, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted Ci to C 6 alkenyl, or COR c , R c is H, Ci to C alkyl, substituted Ci to C 4 alkyl, aryl, substituted aryl, Ci to C 4 alkoxy, substituted Ci to C 4 alkoxy, Ci to C ammoalkyl, or substituted Ci to C 4 ammoalkyl, R 4 is a tnsubstituted benzene nng containmg the substituents X, Y and Z as shown below X is selected from halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, a 5 membered heterocychc nng containmg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, Y and Z are mdependent substituents selected from H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy, or R 4 is a five or six membered nng with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, SO 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO2 and Ci to C 3 alkyl, or Ci to C 3 alkoxy, R 5 is H or Ci to C 3 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof Still, more prefened antiprogestm compounds are those of the formula wherem A, B and D are N or CH, with the proviso that A, B and D cannot all be CH, R 1 = R 2 and are selected from the group of Ci to C 3 alkyl, substituted Ci to C 3 alkyl, or spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 3 to 6 membered spirocychc nng, R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted d to C 6 alkyl, or COR c , R c is H, Ci to C 4 alkyl, or Ci to C 4 alkoxy, R 4 is a disubstituted benzene nng containmg the substituents X, and Y as shown below X is selected from the group of halogen, CN, Ci to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocychc nng containmg 1 to 3 heteroatoms, or Ci to C 3 thioalkoxy, Y is a substituent on the 4' or 5 'position from the group mcludmg H. halogen, CN, NO 2 , C, to C 3 alkoxy, d to C 4 alkyl, or Ci to C 3 thioalkoxy, or R is a five membered rmg with the structure U is O, S, or NR ,5 D R 5 is H, or Ci to C 3 alkyl, or d to C 4 CO 2 alkyl, X' is selected from halogen, CN, NO 2 , Ci to C 3 alkyl, or Ci to C 3 alkoxy, Y' is selected from H and Ci to C alkyl, or R 4 is a six membered nng with the structure X 2 is halogen, CN or NO 2 , or a pharmaceutically acceptable salt thereof Further prefened antiprogestational compounds include those of the formula wherem N B and D are Ν or CH, with the proviso that A, B and D can not all be CH, R 1 = R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 6 membered spirocychc nng, R 3 is H, OH, ΝH 2 , CH 3 , substituted methyl, or COR c , R c is H, Ci to C 3 alkyl, or Ci to C 4 alkoxy, R 4 is a disubstituted benzene nng containmg the substituents X and Y as shown below X is halogen, CN, methoxy, NO 2 , or 2-thιazole, Y is a substituent on the 4' or 5'posιtιon selected from H and F, or R 4 is a five membered rmg of the structure X " is halogen, CN, or NO 2 , Y' is H or Ci to C 4 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof The antiprogestm compounds of this mvention may contam an asymmetric carbon atom and some of the compounds of this mvention may contam one or more asymmetnc centers and may thus give rise to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, the present mvention mcludes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomeπcally pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof The term "alkyl" is used herem to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups havmg one to eight carbon atoms, preferably one to six carbon atoms, "alkenyl" is mtended to mclude both straight- and branched- chain alkyl group with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms, "alkynyl" group is mtended to cover both straight- and branched-chain alkyl group with at least one carbon-carbon tnple bond and two to eight carbon atoms, preferably two to six carbon atoms The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl" refer to alkyl, alkenyl, and alkynyl as just descnbed havmg one or more substituents from the group mcludmg halogen, CN, OH, N0 2 , ammo, aryl, heterocyclic, substituted aryl, substituted heterocychc, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio These substituents may be attached to any carbon of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety The term "aryl" is used herem to refer to an aromatic system which may be a smgle nng or multiple aromatic rmgs fused or lmked together as such that at least one part of the fused or linked nngs forms the conjugated aromatic system The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl The term "substituted aryl" refers to aryl as just defined havmg one to four substituents from the group mcludmg halogen, CN, OH, NO 2 , ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino. or arylthio The term "heterocyc c" is used herem to descnbe a stable 4- to 7-membered monocychc or a stable multicyclic heterocychc nng which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group mcludmg N, O, and S atoms The N and S atoms may be oxidized The heterocychc nng also mcludes any multicyclic rmg in which any of above defined heterocychc rmgs is fused to an aryl nng The heterocychc rmg may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable Such heterocychc groups mclude, for example, tetrahydrofuran, prpendinyl, piperazmyl, 2-oxopιpendιnyl, azepmyl, pyπo dinyl, lmidazolyl, pyπdyl, pyrazmyl, pynmidmyl, pyπdazmyl, oxazolyl, isoxazolyl, morphohnyl, mdolyl, qumolmyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpho nyl, thiamorpholinyl sulfoxide, and isoquinolinyl The term "substituted heterocychc" is used herem to descnbe the heterocychc just defined havmg one to four substituents selected from the group which mcludes halogen, CN, OH, NO 2 , ammo, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio The term "alkoxy" is used herem to refer to the OR group, where R is alkyl or substituted alkyl The term "aryloxy" is used herem to refer to the OR group, where R is aryl or substituted aryl The term "alkylcarbonyl" is used herem to refer to the RCO group, where R is alkyl or substituted alkyl The term "alkylcarboxy" is used herem to refer to the COOR group, where R is alkyl or substituted alkyl The term "ammoalkyl" refers to both secondary and tertiary amines wherem the alkyl or substituted alkyl groups containmg one to eight carbon atoms, which may be either same or different and the pomt of attachment is on the nitrogen atom 'Halogen" refers to Cl, Br, F, or I The antiprogestm compounds of the present mvention can be used m the form of salts denved from pharmaceutically or physiologically acceptable acids or bases These salts mclude, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid Other salts mclude salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium m the form of esters, carbamates and other conventional "pro-drug" forms, which, when admmistered m such form, convert to the active moiety in vivo These methods may be used for contraception or treatment and/or prevention of secondary amenonhea, dysfunctional bleedmg, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcinomas and adeno carcinomas of the endometnum, ovary, breast, colon, prostate, or minimization of side effects or cychc menstrual bleedmg Additional uses of the mvention mclude stimulation of food intake When the compounds are employed for the above utilities, they may be combmed with one or more pharmaceutically acceptable earners or excipients, for example, solvents, diluents and the like, and may be admmistered orally m such forms as tablets, capsules, dispersible powders, granules, or suspensions containmg, for example, from about 0 05 to 5% of suspendmg agent, syrups containmg, for example, from about 10 to 50% of sugar, and elixirs containmg, for example, from about 20 to 50% ethanol, and the like, or parenterally m the form of stenle injectable solutions or suspensions containmg from about 0 05 to 5% suspendmg agent m an lsotonic medium Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient m combmation with the earner, more usually between about 5% and 60% by weight These active agents of the methods and regimens herem may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes Solid earners mclude starch, lactose, dicalcium phosphate, microcrystalhne cellulose, sucrose and kaolin, while liquid earners mclude stenle water, polyethylene glycols, non-ionic surfactants and edible oils such as com, peanut and sesame oils, as are appropnate to the nature of the active mgredient and the particular form of administration desired Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously mcluded, such as flavoring agents, colormg agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA The prefened pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or hquid-filled capsules Oral administration of the compounds is preferred These active compounds may also be administered parenterally or intrapentoneally Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof m oils Under ordmary conditions of storage and use, these preparations contam a preservative to prevent the growth of microorganisms The pharmaceutical forms suitable for mjectable use mclude sterile aqueous solutions or dispersions and stenle powders for the extemporaneous preparation of sterile mjectable solutions or dispersions In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi The carrier can be a solvent or dispersion medium containmg, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil The antiprogestm compounds of this mvention can be prepared following the Schemes illustrated below As demonstrated m Scheme I, the antiprogestin compounds of this invention are generally prepared by employmg the suitable couphng reaction as a final step An appropriately substituted ortho-ammo acid or its denvatives such as ethyl ester (X = Br, I, Cl, or a latent couphng precursor such as alkoxy group which can be converted mto OTf group suitable m the couphng reaction) is treated with a suitable organo metallic reagent, e g Gngnard reagent, m appropriate nonprotic solvents which mclude but not limited to THF or ether to give ortho-ammo carbinol 2 under an inert atmosphere such as argon or nitrogen at -78 °C to room temperature Rmg closure of carbinol 2 to yield oxazm-2-ones 3 is commonly effected by a condensing agent such as carbonyldnmidazole, phosgene, dimethylcarbonate, or diethylcarbonate m a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C The arylation of oxazm-2-ones 3 to yield 4 can be effected by vanous couphng reactions mcludmg Suzuki, Stille reactions etc These reactions are commonly performed m the presence of transition metallic catalyst, e g , palladium or mckel complex often with phosphino ligands, e g , Ph 3 P, 1,1 '- bιs(dιphenylphosphιno)fenocene, l,2-bιs(dιphenylphosphιno)ethane or palladium salt such as palladium acetate Under this catalytic condition, an appropnately substituted nucleophihc reagent, e g , aryl boromc acid, arylstannane, or aryl zmc compound, is coupled with oxazmones 3 to give compounds 4 If a base is needed m the reaction, the commonly used bases mclude but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, banum carbonate, potassium acetate, or cesium fluoride The most commonly used solvents m these reactions mclude benzene, DMF, isopropanol, ethanol, DME, ether, acetone or a mixture of any one of these solvent and water The couphng reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95 °C Oxazmones 3 can be converted mto a nucleophile such as boromc acid which can be coupled with an appropnate electrophile, e g , aryl bromide or aryl iodide, to yield 6 employmg the couphng reaction condition as described above Scheme I RMgBr, THF, rt, N 2 , CDL THF, 50 degrees C, N 2 , The transformation of 3 mto 5 can be effected by treatmg 3 with an organo metalhc reagent, e g , n-BuLi, m a nonprotic solvent such as THF or ether followed by quenching the reaction solution with a suitable electrophile such as tnmethyl borate, tnisopropyl borate, bishexalkyl tm reagent, or zmc chlonde at temperatures rangmg fiOm-78 °C to room temperature under an inert atmosphere such as argon or nitrogen Conversion of carbamate 6 to thiocarbamate 7 can be readily effected by treatment of 6 with a suitable sulfur reagent such as P 2 S 5 or Lawesson's reagent m a suitable non- protic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent Scheme II describes the procedures to prepare oxazmones beanng two different substituents at posιtιon-4 The Weinreb amide 9 can be prepared from an appropnately substituted isatoic anhydnde when treated with N-, O-dimethylhydroxyl- amine hydrochlonde salt m a protic solvent such as ethanol or isopropanol at reflux under an inert atmosphere such as argon or mtrogen Couphng of amide 9 with an aryl electrophile such as aryl boromc acid or arylstannane to give 10 can be effected by employing a typical couphng reaction such as Suzuki, Stille couphng procedure m a similar fashion as descnbed for the preparation of oxazmones 4 Treatment of Wemreb amide 10 with organo metalhc compounds, e g , alkylhthium, alkynylhthium, arylhthium, or their Gngnard counterpart m a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or mtrogen at -78° C to room temperature affords ammo ketone 11. Conversion of ketone 11 to carbinol 12 can be effected by treatment of 10 with an organo metalhc reagent such as alkyl, alkynyl, or aryl Gngnard compound m a nonprotic solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at -78°C to room temperature Conversion of ketone 11 to carbinol 12 can also be effected by reduction of ketone group of 11 to the carbinol moiety of 12 usmg an appropriate reducmg reagent such as lithium aluminum hydride, sodium borohydnde m a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere m the temperature ranging from 0°C to the boiling pomt of the solvent Rmg closure of carbinol 12 to produce the compounds of this mvention, 13, can be accomphshed with condensing agents such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate m a suitable nonprotic solvent such as THF at temperatures rangmg from room temperature to 65 °C Conversion of carbamate 13 to thiocarbamate 14 can be readily effected by treatment of 13 with a suitable sulfur reagent such as P 2 S 5 or Lawesson's reagent m a suitable nonprotic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent Scheme II Alternatively, ortho-ammo ketone 11 can be prepared by treatment of ortho- ammo nitnle 16 with an organo metallic compound such as organo hthium reagent or Grmgard reagent m a suitable solvent such as THF or ether under an mert atmosphere such as argon or mtrogen at temperatures rangmg from -78 °C to room temperature as illustrated m Scheme III Nitnle 16 can be readily prepared from an appropriately substituted mtnle such as bromobenzoratnle 15 usmg a suitable couplmg reaction such as Stille or Suzuki protocol earned out m a similar fashion as descnbed for the preparation of the Weinreb amide 10 Scheme III IS 16 R f iLi or R f iMgX, 0 degrees C 11 The following non- miting examples illustrate the compounds useful m the mvention EXAMPLE 1 2-Amino-5-bromo-3-pyridine carboxylic acid To a solution of 2-amιno-nιcotιnιc acid (10 g, 72 5 mmol) m acetic acid (70 mL) was dropwise added bromme (9 8 mL, 79 8 mmol) at room temperature under mtrogen Upon completion of the reaction, the solvent was removed in vacuo, the residue tnturated with ether and collected on a filter to give 2-amιno-5-bromo-3- pyπdine carboxylic acid as a yellow solid (15 7 g, 99%) mp 272 °C, (decomposed), 'H-NMR (DMSO-de) δ 8 8-7 8 (bs, 2H), 8 44 (d, IH, J = 2 48 Hz), 8 34 (d, IH, J = 2 48 Hz), MS (El) m/z 216/218 ([M +] + , 100%) EXAMPLE 2 2-(2-Amino-5-bromo-pyridin-3-yl)-DroDan-2-ol To a solution of 2-amιno-5-bromo-3-pyndιne carboxylic acid (5 g, 23 mmol) m THF (70 mL) at 0 °C was added methyl magnesium bromide (13 7 g, 115 mmol) under mtrogen After addition, the reaction mixture was heated at 65 °C for 12 hours, cooled to room temperature and quenched with saturated aqueous ammonium chlonde The ethyl acetate was added and organic layer was separated, dried over sodium sulfate and concentrated The residue was punfied via flash chromatography to give 2-(2-ammo-5-bromo-pyndm-3-yl)-propan-2-ol as a yellow solid (1 2 g, 23%) mp 107-108 °C, 'H-NMR (DMSO-d 6 ) δ 7 89 (d, IH, J= 2 3 Hz), 7 40 (d, IH, J= 2 3 Hz), 6 28 (bs, 2H), 5 51 (s, IH), 1 4 (s, 6H), MS (APCI) m/z 231 ([M + H] + , 100%) EXAMPLE 3 6-Bromo-4,4 , -dimethyI-l.,4-dihvdro-3-oxa-l,8-diaza-naphthalen-2-one A mixture of 2-(2-ammo-5-bromo-pyndm-3-yl)-propan-2-ol (0 86 g, 3 7 mmol) and lj '-carbonyldiimidazole (excess) m THF (10 mL) was heated at 35 °C overnight The reaction solution was cooled to room temperature, poured mto ethyl acetate (200 mL), washed with 1 N HC1 (2x50 mL), dned over sodium sulfate, and concentrated The residue was punfied by a flash chromatography (sihca gel, 25% ethyl acetate/hexane) to afford 6-bromo-4,4'-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza- naphthalen-2-one (0 9 g, 94%) as a white sohd mp 251-252 °C, Η-NMR (DMSO- ds) δ 10 9 (s, IH), 8 32 (d, IH, J = 2 19 Hz), 8 0 (d, IH, J = 2 22 Hz), 1 6 (s, 6H), MS (El) m/z 256 ([M] + , 80%), Anal Calc For C 9 H 9 BrN 2 θ2 C, 42 05, H, 3 53, N, 10 90 Found C, 42 15, H, 3 65, N, 10 80 EXAMPLE 4 6-(3-Chloro-phenyl)-4,4-dimethyl-l,4-dihvdro-3-oxa-l,8-diaza-naphthalene-2- one A mixture of 6-bromo-4,4'-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza-naphthalen- 2-one (0 1 g, 0 39 mmol), 3-chlorophenyl boromc acid (0 075 g, 0 47 mmol), tetrakιs(tnphenylphosphιne)-palladιum (0) (0 023 g, 0 02 mmol), and sodium carbonate (0 1 g, 0 94 mmol) m DME (8 mL) and water (5 mL) was subject to a blanket of mtrogen for 15 mmutes at 50 °C and then was heated at 85 °C for 30 minutes The reaction was cooled to room temperature and ethyl acetate (100 mL) was added The organic layer washed with aqueous ammonium chlonde (2x50 mL) and with brine (50 mL), dned over magnesium sulfate and concentrated The product was dissolved m dichloromethane and passed through a plug of magnesol The solvent was removed and the clear oil obtained tπturated with ether (25 mL) to give 6-(3- chloro-phenyl)-4,4-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza-naphthalene-2-one as a white solid (0 087 g, 80%) mp 214-215 °C, Η-NMR (DMSO-ds) δ 10 9 (s, IH), 8 56 (d, IH, J = 2 35 Hz), 8 06 (d, IH, J = 2 35 Hz), 7 86 (t, IH, J = 2 35 Hz), 7 72 (td, IH, J = 9 4, 2 35 Hz), 7 54-7 44 (m, 2H), 1 69 (s, 6H), MS (ESI) m/z 289 ([M+H] + , 100%), Anal Calc For CπHπNOj C, 62 40, H, 4 54, N, 9 70 Found C, 60 53, H, 4 40, N, 9 21 EXAMPLE 5 6-Chloro-3-nitro-pyrid.ne-2-carbonitr.le A mixture of 2, 6-dιchloro-3-mtropyndme and cuprous cyanide m l-methyl-2- pyrrohdmone was quickly heated to 180 °C and maintained at that temperature for 15 mmutes with vigorous stirring The mixture was cooled to -10 °C and the deep brown solution was poured mto ice water ( 3 5 L) and stirred for 30 mm The flocculent brown precipitate was collected and washed with H2O After drying for about 1 5 h, the moist solid was extracted with boiling toluene (3x300 mL) The combmed toluene extracts were washed with H2O, brine, and dried ( MgSO-i), concentrated The crude product was crystallized from EtOAc/hexane to afford the title compound mp 115- 117 °C, 1H NMR( DMSO-d 6 ) δ 8 16 (dd, IH, J = 8 7, 3 0 Hz), 8 82 (d, IH, J = 9 0 Hz), MS (El) m/z 183/185 (M+H) + , Anal Calc For C6H 2 ClN3θ2 C, 39 26, H, 1 10, N, 22 89 Found C, 39 47, H, 1 38, N, 22 77 EXAMPLE 6 3-Amino-6-chloro-pyridine-2-carbonitrile To a solution of 2,6-dιchloro-3-mtropyπdme(4 8 g, 26 15 mmol) in MeOH (60 mL) and concentrated HC1 (25 mL) was slowly added iron powder(5 12g, 91 53 mmol) After the completion of addition, the mixture was refluxed for 45 mmutes and poured mto a 700 mL of H 2 O Filtration of the resulting slurry gave a dull yellow solid The filtrate was made basic with concentrated NH4OH, the resultmg slurry was filtered and both the solid and the filtrates were extracted with ether The combmed extracts were dned ( MgSU4) and evaporated to give the title compound as a creamy solid (2 8g, 58%) mp 162-165 °C which was used m next step without further punfication EXAMPLE 7 l-(3-Amino-6-chloro-pyridin-2-yl)-ethanone To a solution of 3-amιno- 6-chloro-pyndιne-2-carbonιtnle (0 75g, 4 88 mmol) m anhydrous THF (25 mL) under mtrogen was added a solution of methylmagnesium bromide (3M in ether, 8 1 mL, 24 3 mmol) The reaction mixture was stirred for 30 mmutes and then slowly quenched with H2O, treated with 5N HC1 solution The mixture was extracted with ethyl acetate (3x100 mL) and organic extracts were washed with brine, and dned (MgSO ) After removal of solvent, the residue was punfied by chromatography usmg EtOAc/hexane mixture (1 3) as eluent to afford the title compound as a greenish crystalline solid (0 71g, 85%) mp 108-110 °C 1H NMR (DMSO-d 6 ) δ 2 51 (s, 3H), 7 28-7 39 (m, 4H), MS(ESI) m/z 171/173 (M+H) + , Anal Calc For C 7 H 7 ClN 2 O C, 49 28, H, 4 14, N, 16 14 Found C, 49 70, H, 4 03, N, 16 41 EXAMPLE 8 l-(3-Amino-6-chloro-pyridin-2-yl)-propan-2-oI To a solution of l-(3-ammo-6-chloro-pyndm-2-yl)-ethanone m anhydrous THF under N2 was added a solution of methylmagnesium bromide (3N m ether, ) The resulting reaction mixture was stirred at room temperature for 4 h, then slowly quenched with H2O, treated with 0 5 N HC1 and stirred for 30 mmutes, diluted with ethyl acetate, washed with bπne, dried (MgSO-i), concentrated, and chromatographed usmg a mixture of EtOAc/Hexane ( 3 5 6 5) to afford the title compound as a white crystals (0 45g, 82%) mp 118-121 °C 1H NMR(DMSO-d 6 ) δ 1 45(s, 6H), 3 35(s, IH), 5 51(s, IH), 5 68(s, IH), 7 02(s, IH), MS((+)APCI) m/z 187/189 (M+H) + , Anal Calc For C 8 H π ClN 2 O C, 51 48, H, 5 94, N, 15 01 Found C, 51 22, H, 5 99, N, 14 47 EXAMPLE 9 6-Ch.oro-4,4-dimethyl-l,4-dihydro-3-oxa-l,5-diaza-naphthalen-2-one To a solution of l-(3-ammo-6-chloro-3-mtro-pyndm-2-yl)-propan-2-ol (0 3g, 1 67 mmol) m anhydrous THF (20 mL) was added a solution of 1,1 '- carbonyldnmidazole (0 68g, 4 12 mmol) m anhydrous THF (10 mL) The reaction mixture was heated under reflux for 3 h The reaction mixture was treated with 0 5N HC1, washed with brine, H2O, dned (MgSO-i.), concentrated and crystallized from EtOAc/hexane to obtain the title compound as a white crystalline solid (0 2g, 56%) mp 175-178 °C 1H NMR( DMSO-d 6 ) δ 1 60 (s, 6H), 7 30 (d, 1H, J= 8 41 Hz), 7 41 (d, 1H, J = 8 41 Hz), 10 47 (s, IH), MS((+)APCI) m/z 213 (M+H) + , Anal Calc For C9H9CIN2O2 C 50 84, H, 4 27, N, 13 17 Found C, 50 99, H, 4 28, N. 12 98 EXAMPLE 10 The compounds of this mvention were tested m the relevant assay as descnbed below and their potency are m the range of 0 01 nM to 5 μM m the in vitro assays and 0 001 to 300 mg/kg m the in vivo assays The selected example is example 4 Example 4, hPR CV-1, ICso = 0.8 μM A In-vitro biology The m- vitro biology is determmed by (1) competitive Radiohgand Bmdmg usmg the A-form of the human progesterone receptor with progesterone as the radiohgand, (2) co-transfection assay, which provides functional activity expressed as agomst EC50 and Antagomst IC50 values, (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagomst data, and (4) T47D cell alkaline phosphatase assay, which is a further functional assay which also provides agonist and antagomst data 1. hPR Bmdmg assay - This assay is carried out m accordance with Pathirana, C , Stem, R B , Berger, T S , Fenical, W , Ianiro, T , Mais, D E , Torres, A , Glodman, M E , Nonsteroidal human progesterone receptor modulators from the marine alga cymop a barbata, J Steroid Biochem Mol Biol , 1992, 41, 733-738 2. PRE-luciferase assay m CV-1 cells The object of this assay is to determine a compound's progestational or antiprogestational potency based on its effect on PRE-luciferase reporter activity m CN-1 cells co-transfected with human PR and PRE-luciferase plasmids The materials methods used in the assay are as follows a Medium The growth medium was as follows DMEM (BioWhittaker) containmg 10% (v/v) fetal bovme serum (heat mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml pemcillm, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) The expeπmental medium was as follows DMEM (BioWhittaker), phenol red-free, containmg 10% (v/v) charcoal-stnpped fetal bovme serum (heat -mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml pemcillm, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Cell culture, transfection. treatment, and luciferase assay Stock CN-1 cells are maintained m growth medium Co-transfection is done usmg 1 2x10 7 cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamHI sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg somcated calf thymus DΝA as earner DΝA m 250 ml Electroporation is earned out at 260 N and 1,000 mF in a Biorad Gene Pulser II After electroporation, cells are resuspended m growth medium and plated m 96-well plate at 40,000 cells/well m 200 μl Following overnight incubation, the medium is changed to experimental mediu Cells are then treated with reference or test compounds m experimental medium Compounds are tested for antiprogestational activity m the presence of 3 nM progesterone Twenty-four hr after treatment, the medium is discarded, cells are washed three times with D-PBS (GIBCO, BRL) Fifty μl of cell lysis buffer (Promega, Madison, WI) is added to each well and the plates are shaken for 15 mm m a Titer Plate Shaker (Lab Lme Instrument, Inc ) Luciferase activity is measured usmg luciferase reagents from Promega c Analysis of Results Each treatment consists of at least 4 replicates Log transformed data are used for analysis of vanance and nonlinear dose response curve fitting for both agonist and antagomst modes Huber weightmg is used to downweight the effects of outliers. EC 50 or IC 5 o values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both one-way analysis of variance and non-linear response analyses. d. Reference Compounds: Progesterone and tnmegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose- response curves and the EC 5 o or IC 5 o values are calculated. Table 1. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for reference progestins from three individual studies EC50 95% CI Compound Exp. (nM) SE lower upper Progesterone 1 0.616 0.026 0.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637 Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.0094 3 0.0067 0.0003 0.0055 0.0082 Table 2. Estimated ICso, standard error (SE), and 95% confident interval (CI) for the antiprogestin, RU486 from three individual studies IC 50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.042 2 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027 Progestational activity Compounds that increase PRE-luciferase activity significantly (p<0 05) compared to vehicle control are considered active Antiprogestational activity Compounds that decrease 3 nM progesterone mduced PRE-luciferase activity significantly (p<0 05) EC 5 o Concentration of a compound that gives half-maximal mcrease PRE- luciferase activity (default-nM) with SE IC50 Concentration of a compound that gives half-maximal decrease m 3 nM progesterone mduced PRE-luciferase activity (default-nM) with SE 3 T47D cell proliferation assay The objective of this assay is the determination of progestational and antiprogestational potency by usmg a cell proliferation assay m T47D cells A compound's effect on DNA synthesis m T47D cells is measured The matenals and methods used in this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovme serum (not heat- lnactivated), lOOU/ml pemcillm, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Treatment medium Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 0 5% charcoal stnpped fetal bovine serum, lOOU/ml pemcillm, 200 mg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) c Cell culture Stock T47 D cells are maintained m growth medium For BrdU mcorporation assay, cells are plated m 96- well plates (Falcon, Becton Dickinson Labware) at 10,000 cells/well in growth medium After overnight mcubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment Stock compounds are dissolved m appropnate vehicle (100% ethanol or 50% ethanol/50% DMSO), subsequently diluted m treatment medium and added to the cells Progestm and antiprogestm reference compounds are run m full dose-response curves The final concentration of vehicle is 0 1% In control wells, cells receive vehicle only Antiprogestins are tested m the presence of 0 03 nM tnmegestone, the reference progestm agomst Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) m treatment medium for 4 hr d Cell Proliferation Assay At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured usmg a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to manufacturer's instructions Bnefly, cells are fixed m an ethanol containmg fixative for 30 mm, followed by mcubation m a blockmg buffer for 30 mm to reduce background Peroxidase-labeled anti-BrdU antibody is added to the wells and mcubated for 60 mm The cells are rinsed three times with PBS and mcubated with 3,3'5,5'-tetramethylbenzιdιne (TMB) substrate for 10-20 mm depending upon the potency of tested compounds Then 25 μl of 1 M sulfunc acid is added to each well to stop color reaction and optical density is read m a plate reader at 450 nm withm 5 mm e Analysis of Results Square root-transformed data are used for analysis of vanance and nonlinear dose response curve fitting for both agomst and antagomst modes Huber weightmg is used to downweight the effects of outhers EC 5 o or ICso values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of vanance and non-hnear dose response analyses in both smgle dose and dose response studies f Reference Compounds Tnmegestone and medroxyprogesterone acetate (MPA) are reference progestms and RU486 is the reference antiprogestm All reference compounds are run m full dose-response curves and the EC 50 or IC 50 values are calculated Table 3. Estimated ECso > standard error (SE), and 95% confidence intervals (CI) for individual studies Compound Exp (nM) SE lower upper Tnmegestone 1 0 017 0 003 0 007 0 040 2 0 014 0 001 0 011 0 017 3 0 019 0 001 0 016 0 024 MPA 1 0 019 0 001 0 013 0 027 2 0 017 0 001 0 011 0 024 Table 4. Estimated ICso, standard error, and 95% confident interval for the antiprogestin, RU486 IC 50 95% CI Compound Exp (nM SE lower upper RU486 1 0 011 0 001 0 008 0 014 2 0 016 0 001 0 014 0 020 3 0 018 0 001 0 014 0 022 EC50 Concentration of a compound that gives half-maximal increase m BrdU mcorporation with SE, IC 50 Concentration of a compound that gives half-maximal decrease m 0 1 tnmegestone mduced BrdU mcorporation with SE 4 T47D cell alkalme phosphatase assay The purpose of this assay is to identify progestins or antiprogestins by determmmg a compound's effect on alkalme phosphatase activity m T47D cells The materials and methods used in this assay are as follows a. Culture medium DMEM F12 (1 1) (GIBCO. BRL) supplemented with 5% (v/v) charcoal stripped fetal bovme serum (not heat-mactivated), lOOU/ml pemcillm, 100 μg/ml streptomycm, and 2 mM GlutaMax (GIBCO. BRL) b Alkalme phosphatase assay buffer I 0 1 M Tns-HCl, pH 9 8, containmg 0 2% Tnton X-100 II 0 1 M Tns-HCl, pH 9 8 containmg 4 mM p-mtrophenyl phosphate (Sigma) c Cell Culture and Treatment Frozen T47D cells were thawed m a 37°C water bath and diluted to 280,000 cells/ml m culture mediu To each well m a 96-well plate (Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspension was added Twenty μl of reference or test compounds diluted m the culture medium was then added to each well When testmg for progestm antagonist activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C m a 5% CO /humιdιfied atmosphere for 24 hr d Alkalme Phosphatase Enzyme Assay At the end of treatment, the medium was removed from the plate and fifty μl of assay buffer I was added to each well The plates were shaken m a titer plate shaker for 15 mm Then 150 μl of assay buffer II was added to each well Optical density measurements were taken at 5 mm intervals for 30 mm at a test wavelength of 405 nM e. Analysis of Results Analysis of dose-response data For reference and test compounds, a dose response curve is generated for dose (X-axis) vs the rate of enzyme reaction (slope) (Y-axis) Square root-transformed data are used for analysis of vanance and nonlinear dose response curve fitting for both agomst and antagomst modes Huber weightmg is used to downweight the effects of outliers EC 50 or IC 5 o values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of variance and non-hnear dose response analyses m both smgle dose and dose response studies f Reference Compounds Progesterone and tnmegestone are reference progestms and RU486 is the reference antiprogestm All reference compounds are run m full dose response curves and the EC 50 or IC 50 values are calculated Table 5. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for reference progestins from three independent experiments EC50 95% CI 0 Compound Exp (nM) SE lower upper Progesterone 1 0 839 0 030 0 706 0 996 2 0 639 0 006 0 611 0 669 3 1 286 0 029 1 158 1 429 j c Tnmegestone 1 0 084 0 002 0 076 0.091 2 0 076 0 001 0 072 0 080 3 0 160 0 004 0 141 0 181 0 Table 6. Estimated IC50, standard error, and 95% confident interval for the reference antiprogestin RU486 from three independent experiments IC 50 95% CI Compound Exp (nM) SE lower upper 5 RU486 1 0 103 0 002 0 092 0 115 2 0 120 0 001 0 115 0 126 3 0 094 0 007 0 066 0 134 0 B. In-vivo Biology The primary m-vivo assay is the rat decidua zation model, which may be used to determme progestational effects of both agomsts and antagomsts The secondary m- vivo assay is the rat ovulation inhibition model, which is under development, and hence the protocol is un-available 1 Rat deciduahzation assay The objective of this procedure is used to evaluate the effect of progestins and antiprogestins on rat uterme deciduahzation and compare the relative potencies of vanous test compounds The materials and methods used m this assay are as follows a Methods: Test compounds are dissolved m 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil (MazolaTM) ^Q en prepared by heatmg (-80 °C) the mixture to evaporate ethanol Test compounds are subsequently diluted with 100% corn oil or 10% ethanol m corn oil pnor to the treatment of animals No difference m decidual response was found when these two vehicles were compared b Animals (RACUC protocol #5002) Ovanectomized mature female Sprague-Dawley rats (~60-day old and 230g) are obtamed from Tacomc (Tacomc Farms, NY) followmg surgery Ovanectomy is performed at least 10 days pnor to treatment to reduce circulating sex steroids Animals are housed under 12 hr light/dark cycle and given standard rat chow and water ad libitum c Treatment Rats are weighed and randomly assigned to groups of 4 or 5 before treatment Test compounds m 0 2 ml vehicle are admmistered by subcutaneous injection m the nape of the neck or by gavage usmg 0 5 ml The animals are treated once daily for seven days For testmg antiprogestins, animals are given the test compounds and a EC50 dose of progesterone (5 6 mg/kg) during the first three days of treatment Followmg decidual stimulation, animals contmue to receive progesterone until necropsy four days later d Dosmg Doses are prepared based upon mg/kg mean group body weight In all studies, a control group receivmg vehicle is included Determination of dose-response curves is earned out usmg doses with half log mcreases (e g 0 1, 0 3, 1 0, 3 0 mg/kg ) e Decidual mduction Approximately 24 hr after the third injection, deciduahzation is mduced in one of the uterme horns by scratching the antimesometnal luminal epithehum with a blunt 21 G needle The contralateral hom is not scratched and serves as an unstimulated control Approximately 24 hr followmg the final treatment, rats are sacrificed by CO2 asphyxiation and body weight measured Uten are removed and trimmed of fat Deciduahzed (D-hom) and control (C-hom) uterme horns are weighed separately f Analysis of Results The mcrease m weight of the deciduahzed uterme hom is calculated by D-horn/C-horn and loganthmic transformation is used to maximize normality and homogeneity of vanance The Huber M-estimator is used to down weight the outlymg transformed observations for both dose-response curve fittmg and one-way analysis of vanance JMP software (SAS Institute, Inc ) is used for both oneway ANONA and non-linear dose-response analyses g Reference Compounds All progestm reference compounds were run in full dose- response curves and the EC 5 o for uterme wet weight were calculated Table 7. Estimated ECso, standard error (SE), and 95% confidence intervals for individual studies Compound Exp (mg/kε. s.c.) SE lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.76 3-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.06 0.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.09 0.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.29 0.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61 Table 8. Estimated average EC50, standard error, and 95% confidence intervals for dose-response curves of 3 reference compounds EC50 95% CI Compound (ma/kε, s.c.) SE lower upper Progesterone 5.62 0.62 4.55 7.00 3-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12 Table 9. Estimated ICso, standard error, and 95% confident interval for the antiprogestin, RU 486 ICso 95% CI Compound Exp (mg/kg. p o ) SE lower upper RU 486 1 0 21 0 07 0 05 0 96 2 0 14 0 02 0 08 0 27 Concentration Compound concentration m assay(default-mg/kg body weight) Route of administration Route the compound is admmistered to the animals Body weight Mean total animal body weight (default-kg) D-hom Wet weight of deciduahzed uterme hom (default -mg) C-hom Wet weight of control uterme hom (default-mg) Decidual response [(D-C)/C]xl00% Progestational activity Compounds that mduce deciduahzation significantly (p<0 05) compared to vehicle control are considered active Antiprogestational activity Compounds that decrease ECso progesterone mduced deciduahzation significantly (p<0 05) EC 50 for uterme weight Concentration of compound that gives half-maximal mcrease m decidual response (default-mg/kg) IC50 for uterme weight Concentration of compound that gives half-maximal decrease in EC 50 progesterone mduced decidual response (default-mg/kg) All publications cited m this specification are incorporated herem by reference herem While the invention has been descnbed with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departmg from the spint of the mvention Such modifications are mtended to fall withm the scope of the appended claims

Claims: What is Claimed: 1 A method of contraception which compnses administering to a female of child bearing age for 28 consecutive days a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 100 μg levonorgestrel, b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestm compound of Formula I wherem A, B and D are N or CH, with the proviso that A, B and D can not all be CH, R 1 and R 2 are mdependent substituents selected from H, Ci to C 6 alkyl, substituted G to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyc c, substituted heterocychc, COR A , NR B COR A , or R 1 and R 2 are fused to form a spirocychc nng selected from a), b) or c), each spirocychc ring optionally substituted by from 1 to 3 C 1 -C3 alkyl groups a) a 3 to 8 membered spirocychc alkyl nng, b) a 3 to 8 membered spirocychc alkenyl nng, or c) an optionally substituted 3 to 8 membered heterocychc nng containmg one to three heteroatoms from the group mcludmg O, S and N, the spirocychc rmgs of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorme, C, to C 6 alkyl, G to C 6 alkoxy, Ci to C 6 thioalkyl, -CF 3 , -OH, -CN, NH 2 , -NH(C, to C 6 alkyl), or -N(Q to C 6 alkyl) 2 , R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 aminoalkyl, R B is H, C, to C 3 alkyl, or substituted G to C 3 alkyl, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 6 alkenyl, substituted Ci to C 6 alkenyl, or COR' R c is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl. aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R 4 is a tnsubstituted benzene rmg containmg the substituents X, Y and Z as shown below X is taken from the group mcludmg halogen, CN, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, d to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, amino, Ci to C 3 ammoalkyl, substituted Ci to C 3 aminoalkyl, N0 2 , Ci to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic rmg containmg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 aminoalkyl, R E is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C 3 alkyl, or Ci to C 3 thioalkoxy, or R 4 is a five or six membered rmg with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, SO 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO 2 and Ci to C 3 alkyl, Ci to C 3 alkoxy, d to C 3 ammoalkyl, COR F , or NR G COR F , R F is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted Ci to C 3 alkoxy, Ci to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R G is H, Ci to C 3 alkyl, or substituted Ci to C 3 alkyl, R 5 is H or C, to C 3 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof, and c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remammg days of the 28 consecutive days m which no antiprogestm, progestin or estrogen is admmistered, wherem the total daily dosage units of the first, second and third phases equals 28 2 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestin compound has the structure wherem A, B and D are N or CH, with the proviso that N B and D can not all be CH, R 1 is H, Ci to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, COR A , orNR B COR A , R 2 is H, Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 3 to C 8 cycloalkyl, substituted C to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocychc, COR A , or NR B COR A , or R 1 and R 2 are fused to form the optionally substituted 3 to 8 membered spirocychc alkyl, alkenyl or heterocychc rmgs descnbed above, R A is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, Ci to C 3 alkoxy, substituted Ci to C 3 alkoxy, G to C 3 ammoalkyl, or substituted Ci to C 3 ammoalkyl, R B is H, Ci to C 3 alkyl, or substituted G to C 3 alkyl, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted G to C 6 alkyl, C 3 to C 6 alkenyl, substituted G to C 6 alkenyl, or COR c , R c is H, Ci to C 4 alkyl, substituted Ci to C 4 alkyl, aryl, substituted aryl, d to C 4 alkoxy, substituted G to C 4 alkoxy, G to C ammoalkyl, or substituted G to C 4 ammoalkyl, R 4 is a tnsubstituted benzene nng containmg the substituents X, Y and Z as shown below X is selected from halogen, CN, Ci to C 3 alkyl, substituted G to C 3 alkyl, G to C 3 alkoxy, substituted G to C alkoxy, Ci to C 3 thioalkoxy, substituted Ci to C 3 thioalkoxy, Ci to C 3 ammoalkyl, substituted Ci to C 3 ammoalkyl, NO 2 , Ci to C 3 perfluoroalkyl, a 5 membered heterocychc rmg containmg 1 to 3 heteroatoms, COR D , OCOR D , or NR E COR D , R D is H, Ci to C 3 alkyl, substituted Ci to C 3 alkyl, aryl, substituted aryl, G to C 3 alkoxy, substituted G to C3 alkoxy, Ci to C3 ammoalkyl, or substituted G to C ammoalkyl, R E is H, Ci to C 3 alkyl, or substituted C, to C 3 alkyl, Y and Z are mdependent substituents selected from H, halogen, CN, NO 2 , Ci to C 3 alkoxy, Ci to C3 alkyl, or Ci to C 3 thioalkoxy, or R 4 is a five or six membered rmg with 1, 2, or 3 heteroatoms from the group mcludmg O, S, SO, SO 2 or NR 5 and containmg one or two mdependent substituents from the group mcludmg H, halogen, CN, NO 2 and Ci to C 3 alkyl, or G to C 3 alkoxy, R 5 is H or C, to C 3 alkyl, Q is O, S, NR 6 , or CR 7 R 8 , W is O or a chemical bond, or a pharmaceutically acceptable salt thereof 3 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestin compound has the structure wherem A, B and D are N or CH, with the proviso that A, B and D cannot all be CH, R 1 = R 2 and are selected from the group of Ci to C 3 alkyl, substituted G to C 3 alkyl, or spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 3 to 6 membered spirocychc nng, R 3 is H, OH, NH 2 , Ci to C 6 alkyl, substituted G to C 6 alkyl, or COR c , R c is H, Ci to C 4 alkyl, or Ci to C 4 alkoxy, R 4 is selected from a), b) or c) a) R 4 is a benzene rmg of the formula X is selected from the group of halogen, CN, Q to C 3 alkoxy, Ci to C 3 alkyl, NO 2 , Ci to C 3 perfluoroalkyl, 5 membered heterocychc nng containmg 1 to 3 heteroatoms, or C, to C 3 thioalkoxy, Y is a substituent on the 4' or 5 'position from the group mcludmg H, halogen, CN, NO 2 , Ci to C 3 alkoxy, d to C 4 alkyl, or d to C 3 thioalkoxy, or b) R 4 is a five membered rmg of the structure R 5 is H, or C, to C 3 alkyl, or d to C 4 CO 2 alkyl, X' is selected from halogen, CN, NO , Ci to C 3 alkyl, or Ci to C 3 alkoxy, Y' is selected from H and Ci to C 4 alkyl, or c) R 4 is a six membered rmg of the structure X 2 is halogen, CN or NO 2 , or a pharmaceutically acceptable salt thereof 4 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestin compound has the structure wherem N B and D are Ν or CH, with the proviso that A, B and D can not all be CH, R 1 = R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusing R 1 and R 2 to form a 6 membered spirocychc nng, R 3 is H, OH, ΝH 2 , CH 3 , substituted methyl, or COR c , R c is H, Ci to C 3 alkyl, or Ci to C alkoxy, R 4 is a disubstituted benzene nng containmg the substituents X and Y as shown below X is halogen, CN, methoxy, NO 2 , or 2-thιazole, Y is a substituent on the 4' or 5'posιtιon selected from H or F, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof 5 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestin compound has the structure wherem A, B and D are N or CH, with the proviso that A, B and D can not all be CH, R 1 = R 2 and are selected from CH 3 and spirocychc alkyl constructed by fusmg R 1 and R 2 to form a 6 membered spirocychc nng, R 3 is H, OH, NH 2 , CH 3 , substituted methyl, or COR c , R c is H, Ci to C 3 alkyl, or Ci to C 4 alkoxy, R 4 is a five membered nng of the structure X' is halogen, CN, or N0 2 , Y' is H or C, to C 4 alkyl, W is O or a chemical bond, or a pharmaceutically acceptable salt thereof 6 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Chloro-phenyl)-4,4-dιmethyl-l,4-dιhydro-3-oxa-l,8-dιaza-naphthalene-2-one or a pharmaceutically acceptable salt thereof 7 The method of Claim 1 wherem the progestational agent is selected from the group of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethmdrone, gestodene, norethmdrone acetate, norgestimate, osaterone, cyproterone acetate, tnmegestone, dienogest, drospirenone, nomegestrol, or (17- deacetyl)norgestιmate 8 A method of Claim 1 which compnses administering to a female of child bearing age consecutively over a 28 day cycle a) a first phase of 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 100 μg levonorgestrel, b) a second phase of 3 daily dosage units of an antiprogestm compound of Claim 1, each daily dosage umt containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) optionally, 4 daily dosage units of an orally and pharmaceutically acceptable placebo to be admmistered on each day of the 28-day cycle followmg the first phase and second phase 9 A method of contraception which compnses administering to a female of child bearing age over a penod of 28 consecutive days a) a first phase of from 18 to 21 daily dosage units of a progestostational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel, and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of from 1 to 7 daily dosage units of an antiprogestm of Claim 1 at a daily dose of from about 2 to 50 mg, and c) optionally, an orally and pharmaceutically acceptable placebo for each remainmg day of the 28 consecutive days 10 A method of contraception of Claim 15 which compnses administering to a female of child bearing age over a penod of 28 consecutive days a) a first phase of 21 daily dosage units of a progestostational agent equal m progestational activity to about 35 to about 100 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of 3 daily dosage units of an antiprogestm of Claim 1 at a daily dose of from about 2 to 50 mg, and c) optionally, a third phase of 4 daily dosage units of an orally and pharmaceutically acceptable placebo 11 A method of contraception which compnses administering to a female of child bearing age over a penod of 28 consecutive days a) a first phase of from 18 to 21 daily dosage units containmg a progestational agent at a daily dose equal m progestational activity to from about 35 to about 150 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg b) a second phase of from 1 to 7 daily dose units, each daily dose umt containmg an antiprogestm of Claim 1 at a concentration of from 2 to 50 mg and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo, the total of the daily dosage units bemg 28 12 A method of contraception of Claim 11 which compnses administering to a female of child bearing age over a penod of 28 consecutive days a) a first phase of 21 daily dosage units, each daily dosage umt containmg a progestational agent at a daily dose equal m progestational activity to about 35 to about 100 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg b) a second phase of 3 daily dose, each daily dose unit containmg an antiprogestm of Claim 1 at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) optionally, a third phase of 4 daily dosage units of an orally and pharmaceutically acceptable placebo 13 A pharmaceutically useful kit adapted for daily oral administration which compnses a) a first phase of from 14 to 21 daily dosage units of a progestational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel, b) a second phase of from 1 to 11 daily dosage units of an antiprogestm compound of Claim 1, each daily dosage unit containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo, wherem the total number of the daily dosage units m the first phase, second phase and third phase equals 28 14 A pharmaceutically useful kit adapted for daily oral administration of Claim 13 which comprises a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, b) a second phase of 3 daily dosage units of an antiprogestm compound of Claim 1, each daily dosage unit containmg an antiprogestm compound at a daily dosage of from about 2 to 50 mg, and c) a third phase of 4 daily dosage units of an orally and pharmaceutically acceptable placebo 15 A pharmaceutically useful kit adapted for daily oral administration which comprises a) a first phase of from 18 to 21 daily dosage units of a progestostational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of from 1 to 7 daily dosage units of an antiprogestm of Claim 1 at a daily dose of from about 2 to 50 mg, and c) a third phase of from 0 to 9 daily dosage units of an orally and pharmaceutically acceptable placebo, wherem the total number of the daily dosage units in the first phase, second phase and third phase equals 28 16 A pharmaceutically useful kit adapted for daily oral administration of Claim 15 which compnses a) a first phase of 21 daily dosage units of a progestostational agent equal m progestational activity to about 35 to about 150 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg, and b) a second phase of three daily dosage units of an antiprogestm of Claim 1 admmistered at a daily dose of from about 2 to 50 mg, and c) a third phase of 4 daily dosage units of an orally and pharmaceutically acceptable placebo 17 A pharmaceutically useful kit adapted for daily oral administration which compnses a) a first phase of from 18 to 21 daily dosage units, each daily dosage umt compnsmg a progestational agent at a daily dose equal progestational activity to from about 35 to about 150 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg b) a second phase of from 1 to 7 daily dose units, each daily dose unit containmg an antiprogestm of Claim 1 at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) a third phase of from 0 to 9 daily dosage units of an orally and pharmaceutically acceptable placebo, wherem the total number of the daily dosage units m the first phase, second phase and third phase equals 28 18 A pharmaceutically useful kit adapted for daily oral administration of Claim 17 which compnses a) a first phase of 21 daily dosage units, each containmg a progestational agent of this mvention at a daily dose equal progestational activity to about 35 to about 150 μg levonorgestrel and ethmyl estradiol at a daily dose range of from about 10 to about 35 μg b) a second phase of 3 daily dose units, each daily dose umt containmg an antiprogestm of Claim 1 at a concentration of from 2 to 50 mg, and ethmyl estradiol at a concentration of from about 10 to about 35 μg, and c) a third phase of 4 daily dosage units of an orally and pharmaceutically acceptable placebo

Inventors: EDWARDS JAMES P, FENSOME ANDREW, GRUBB GARY S, JONES TODD K, PUWEN ZHANG, SANTILLI ARTHUR A, TEGLEY CHRISTOPHER M, TEREFENKO EUGENE A, VIET ANDREW Q, WROBEL JAY E, ZHI LIN, EDWARDS, JAMES, P., FENSOME, ANDREW, GRUBB, GARY, S., JONES, TODD, K., PUWEN, ZHANG, SANTILLI, ARTHUR, A., TEGLEY, CHRISTOPHER, M., TEREFENKO, EUGENE, A., VIET, ANDREW, Q., WROBEL, JAY, E., ZHI, LIN
Applicants: AMERICAN HOME PROD, EDWARDS JAMES P, FENSOME ANDREW, GRUBB GARY S, JONES TODD K, LIGAND PHARM INC, PUWEN ZHANG, SANTILLI ARTHUR A, TEGLEY CHRISTOPHER M, TEREFENKO EUGENE A, VIET ANDREW Q, WROBEL JAY E, ZHI LIN, AMERICAN HOME PRODUCTS CORPORATION, EDWARDS, JAMES, P., FENSOME, ANDREW, GRUBB, GARY, S., JONES, TODD, K., LIGAND PHARMACEUTICALS, INC., PUWEN, ZHANG, SANTILLI, ARTHUR, A., TEGLEY, CHRISTOPHER, M., TEREFENKO, EUGENE, A., VIET, ANDREW, Q., WROBEL, JAY, E., ZHI, LIN
Application year: 2000
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P5, A61P15, A61P35, C07D498