CONTRACEPTIVE COMPOSITIONS CONTAINING 3,3-SUBSTITUTED INDOLINE DERIVATIVES AND USES THEREOF

Abstract: 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, COR<A>; or optionally substituted alkenyl or alkynyl groups; R<A> = H or optionally substituted alkyl, alkoxy, or aminoalkyl groups; R4 = H, halo, CN, NH2, or optionally substituted alkyl, alkoxy, or aminoalkyl; R5 is selected from optionally substituted benzene ring; a five or six membered heterocyclic ring; a 4 or 7-substituted indole or a substituted benzothiophene; or pharmaceutically acceptable salt thereof. 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.

Description: CONTRACEPTIVE COMPOSITIONS CONTAI NING 3 , 3-SUBSTITUTED INDOLINE DERIVATIVES AND USES THEREOF 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), glucocorticoid 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 antagonists may be used in contraception. In this context they may be administered 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, published July 4, 1996). PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) 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 endometriosis (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 (U.S. Patent No. 5,719,136). PR antagonists, such as mifepristone and onapristone, 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. Set, 761, 224, 1995). Jones, et al, (U.S. Patent No. 5,688,810) describe the PR antagonist dihydroquinoline A. Jones, et al, described the enol ether B (U.S. Patent No. 5,693,646) as a PR ligand. B Jones, et al, described compound C (U.S. Patent No. 5,696,127) as a PR ligand. Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). D E Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). Combs, et al, disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). H Perlman, et. al., described the vitamin D analog I as a PR ligand (7et. Letters, 35, 2295, 1994). Hamann, et al, described the PR antagonist J (Ann. N. Y. Acad. Sci., 761, 383, 1995). Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16 th Int. Cong. Het. Chem., Montana, 1997). K Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and N0 2 . > Pi and P 2 : = H, 1-8 C alkyl, Ph (substituted) M wherein: R 4 = H, Ar, R,„ OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), -S(O) q R„, N(R,) 2 , XR„, halogen or NHCOR,; X = (CH 2 ) n , O, NR, or S(O) q ; n = 0-6; q = 0-2; R^ = H or 1-4 C alkyl; R„ = 1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynyl (all optionally substituted); Ar = (i) optionally substituted phenyl or benzo-fused group of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrimidyl, all optionally substituted by one or more R t or R 2 groups. A = CO or (CiR J n B = CH 2 or O U.S Patent No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising 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 period of from 2 to 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 antiprogestins and progestins, an estrogen, such as ethinyl estradiol. These regimens and combinations may be administered to a mammal to induce 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, and 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 described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effective 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 combination 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 to 24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 μg to about 1 0 μg levonorgestrel per day, preferably equal in activity to from about 35 μg to about 100 μg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 1 1 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered 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 include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered. In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with an estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days. The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol. Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone. Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 μg of levonorgestrel. An antiprogestin compound of this invention 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 into a combined, single daily dosage unit, totaling 28 daily units per 28- day cycle. In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in 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 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. Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in 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 invention also provides kits or packages of pharmaceutical formulations designed for use in the regimens described 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 indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated. According to the regimens described above, one 28-day kit may comprise: a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to from 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 1 1 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin 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 remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered. A preferred embodiment of this kit may comprise: a) an initial phase of 21 daily dosage units of a progestational agent equal in 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 antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin 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 packaging regimen or kit of this invention comprises: 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 in activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethinyl 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 antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered. A preferred embodiment of the kit described above may comprise: 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, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, and, as an estrogen, ethinyl 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 antiprogestin administered 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 invention comprises: a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal in activity to from about 35 to about 100 μg levonorgestrel, and ethinyl 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 containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl 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 remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered. A preferred embodiment of the package or kit just described comprises: a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 μg levonorgestrel, preferably from about 35 to about 100 μg levonorgestrel, and ethinyl 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 antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl 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 described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be administered in the order described, with the first phase followed in 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 comprise 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 in the art. In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, 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 increased or reduced as indicated by the exigencies of the therapeutic situation. In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated. Compounds of this invention that may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula I: I wherein: R, and R 2 are chosen independently from H, alkyl, substituted alkyl; OH; O(alkyl); 0(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; l-propynyl; or 3- propynyl; or R, and R 2 are joined to form a ring comprising one of the following: -CH 2 (CH 2 ) n CH 2 -; -CH 2 CH 2 CMe 2 CH 2 CH 2 - ; -0(CH 2 ) m CH 2 - ; 0(CH 2 ) p O- ; - CH 2 CH 2 0CH 2 CH 2 -; -CH 2 CH 2 N(H or alkyl)CH 2 CH 2 -; n is an integer from 0 to 5; m is an integer from 1 to 4; p is an integer from 1 to 4; or R, and R 2 together comprise a double bond to =C(CH 3 ) 2 ; =C(C 3 -C 6 cycloalkyl), =0, or =C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl; R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, alkynyl or substituted alkynyl, or COR A ; R A is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C ] to C 3 aminoalkyl; R 4 is H, halogen, CN, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, C, to C 6 alkoxy, substituted C, to C 6 alkoxy, C, to C 6 aminoalkyl, or substituted C, to C 6 aminoalkyl; R 5 is selected from the groups a), b) or c): a) R 5 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: X is selected from halogen, OH, CN, C, to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 thioalkyl, substituted C, to C 3 thioalkyl, S(0)alkyl, S(0) 2 alkyl, C, to C 3 aminoalkyl, substituted C ] to C 3 aminoalkyl, N0 2 , C, to C 3 perfiuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, COR B , OCOR B , or NR c COR B ; R B is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; R c is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl: Y and Z are independent substituents taken from the group including H, halogen, CN, N0 2 , C, to C 3 alkoxy, C, to C 3 alkyl, or C> to C 3 thioalkyl; or b) R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, S0 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, N0 2 and C, to C 3 alkyl, C, to C 3 alkoxy, C, to C 3 aminoalkyl, COR D , or NR E COR D ; R D is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; R E is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl; R^ is H or C, to C 3 alkyl; or c) R 5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, N0 2 , lower alkoxy, or CF 3 ; wherein R^, and R 7 are independently chosen from H, methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, cyclohexyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or pharmaceutically acceptable salt thereof. A preferred set of antiprogestin compounds of this invention is depicted by structure II: II wherein: R 5 is a disubstituted benzene ring containing the substituents X, and Y as shown below: X is selected from halogen, CN, C, to C 3 alkoxy, C, to C 3 alkyl, N0 2 , C, to C 3 perfiuoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, or C, to C 3 thioalkoxy; Y is a substituent on the 4' or 5 'position selected from H, halogen, CN, N0 2 , C, to C 3 alkoxy, C, to C 4 alkyl, or C, to C 3 thioalkyl; or R 5 is a five membered ring having the structure: U is O, S, or NR«, R^ is H, or C, to C 3 alkyl, or C, to C 4 C0 2 alkyl; X' is selected from halogen, CN, N0 2 , C, to C 3 alkyl or C, to C 3 alkoxy; Y' is selected from the group H, F, CN, N0 2 or C, to C 4 alkyl; or R 5 is a six-membered ring with the structure: X 1 is N or CX 2 ; X 2 is halogen, CN or N0 2 ; or pharmaceutically acceptable salt thereof. The antiprogestin compounds of the formulations and regimens of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I and II the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically 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 herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms; "alkenyl" is intended to include both straight- and branched-chain alkyl group with 1 or 2 carbon-carbon double bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms; "alkynyl" group is intended to cover both straight- and branched-chain alkyl group with at least 1 or 2 carbon-carbon triple bonds and containing 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms. The terms "substituted alkyl", "substituted alkenyl", and "substituted alkynyl" refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, N0 2 , amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, 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 herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthryl. The term "substituted aryl" refers to an aryl as just defined having 1 to 4 substituents from the group including halogen, CN, OH, N0 2 , amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term "heterocyclic" is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl. The term "substituted heterocyclic" is used herein to describe the heterocyclic just defined having 1 to 4 substituents selected from the group which includes halogen, CN, OH, N0 2 , amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term "thioalkyl" is used herein to refer to the SR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term "alkoxy" refers to the OR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms. The term "aryloxy" refers to the OR group, where R is aryl or substituted aryl, as defined above. The term "alkylcarbonyl" refers to the RCO group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term "alkylcarboxy" indicates the COOR group, where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term "aminoalkyl" refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing 1 to 8 carbon atoms, which may be either the same or different and the point of attachment is on the nitrogen atom. The term "halogen" refers to Cl, Br, F, or I. The antiprogestational compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, 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 include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo. When the active compounds of these regimens are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. The pharmacologically active agents of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. 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 in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable 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 containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil. The compounds of this invention can be prepared by the procedures outlined in the Schemes illustrated below: Typically the antiprogestin compounds of this invention are prepared in a convergent manner as shown is Scheme 1, by a suitable coupling reaction. For example, a palladium mediated coupling of an aryl halide with an aryl boronic acid provides the desired bi-aryl substituted target. The choice of the aryl halide-aryl boronic acid combination is established experimentally. Scheme 1 Z=l, Br, or BfOHj j Z=l, Br, or B(OH)2 As outlined in Scheme 2, the "right side" of the antiprogestin compounds of this invention may be prepared by following the procedure described of Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1993, Vol. 1, pp. 939 - 944. Scheme 2 As an example the right side template, 2, is prepared by condensing an appropriately substituted phenyl hydrazine and a suitable ketone to give the corresponding hydrazone. This material is cyclized to an imine in refluxing acetic acid and then reduced to the desired indoline template 2. Examples 1-7 and 10-20 were prepared by this route using the appropriate ketone. Alternatively the right side template may be prepared as outlined in Scheme 3. The commercially available oxindole is di-alkylated at C-3 by using an appropriate base and the corresponding alkyl halide to give the 3,3-dialky-oxindole, 8, or the spiro-cyclic oxindole 9. These oxindoles are then brominated under standard conditions and the carbonyl group is reduced to the desired methylene using a hydride mediated reduction. The timing of the aryl coupling and the reduction of the 2- position carbonyl are established experimentally. Scheme 3 8 9 R2=R3= -(CH2)n- The right side templates are coupled with an appropriate aryl boronic acid using an appropriate palladium (0) catalyst, Scheme 4. For example compound 10 is coupled under standard Suzuki conditions with an appropriately substituted aryl- boronic acid to afford compound 11. Scheme 4 The compounds of this invention, are stable semi-solids and are conveniently converted into their corresponding salts by treatment with acid. Example 1, compound 11 (R, = R 2 = R 3 = Me), when treated with HCl in dioxane affords the HCl salt (Example 2) as a white solid. The racemic indolines can be separated into their enantiomers by Chiral HPLC, to provide the individual enantiomers in > 98% EE. This invention may be further understood by the following non-limiting examples. EXAMPLE 1 2,3,3-Trimethyl-5-(3-nitro-phenyI)-2,3-dihydro-lH-indole 5-Bromo-2,3,3-trimethyl-2,3-dihvdro-lH-indole This compound was prepared by the procedure of Letcher, R. M. et. al., J. Chem. Soc. Perkin Trans., 1: 939 - 944, 1993. To a solution of 4-bromo-phenyl hydrazine hydrochloride (2.59g, 1 1.6 mmol) and 3-methyl-2-butanone (1.0 g, 1 1.6 mmol) in 20 mL benzene was added acetic acid (catalytic amount) and the resulting solution was refluxed with azeotropic removal of H 2 0 for 14 h. The reaction mixture was cooled to room temperature and concentrated. The resulting semi-solid was extracted in acetic acid and refluxed for 12 hours. The reaction mixture was cooled to room temperature and concentrated. The semi-solid residue was extracted in ether and neutralized with K 2 C0 3 . The ether layer was dried and concentrated. The resulting solid imine was dissolved in THF- MeOH (6: 1), cooled to 0°C and sodium borohydride (0.5 g, 13.2 mmol) was added. The solution was allowed to warm to room temperature and stirred for 0.5 hours. The reaction mixture was poured into 15% aqueous HCl and then made basic with K 2 C0 3 . The organic layer was separated, washed with brine, dried (Na 2 S0 4 ), and concentrated. The crude product was purified by column chromatography (Si0 2 , hexane-ethyl acetate 9: 1). The product was isolated as an orange liquid (2.1 g, 75%): 'H-NMR (CDC1 3 ) δ 1.03 (s, 3H), 1.15 (d, J= 6.6 Hz, 3H), 1.25 (s, 3H), 3.50 (q, J = 6.6 Hz, 1H), 3.70 (br. s, 1H), 6.45 (d, J= 8.7 Hz, 1H), 7.09 (m, 2H); 13 C-NMR (CDCl 3 ) δ 15.10, 22.25, 26.11 (q), 43.72 (s), 65.47 (d), 1 10.32 (s), 1 10.70, 125.47, 129.75 (d), 141.48, 148.33 (s); MS (EIj mlz 240, 242 (M+H) + . A solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro-lH-indole (0.5 g, 2.1 mmol) and tetrakis-(triphenylphosphine) palladium (0.14 g, 0.12 mmol) in dimethoxy ethane (10 mL) was cycled under N 2 -vacuum (4x) and then stirred under N 2 for 0.5 hours. To this mixture was then added 3-nitrophenylboronic acid (0.42 g, 2.5 mmol) followed by a solution of Na 2 C0 3 (0.36 g, 3.4 mmol) in 5 mL water cycled under N 2 -vacuum (3x). The solution was brought to reflux for 6 hours then cooled to room temperature, poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (Na 2 S0 4 ), and evaporated. The residue was purified by column chromatography (Si0 2 , methylenechloride:hexane 1 :3) to afford the title compound (0.48 g, 82%) as an orange semi-solid: 'H NMR (CDCl 3 ) δ 1.12 (s, 3H), 1.21 (d, J= 6.6 Hz, 3H), 1.35 (s, 3H), 3.60 (q, J = 6.6 Hz, IH), 3.9 (br s, IH), 6.69 (d, J= 7.9 Hz, IH), 7.28-7.29 (m, 2H), 7.32 (d, J= 1.9 Hz, IH), 7.53 (dd, J= 7.9, 7.9 Hz, IH), 7.85 (ddd, J= 7.9, 2.0, 2.0 Hz, IH), 8.07 (ddd, J = 7.9, 2.0, 2.0 Hz, IH), 8.08 (d, J= 7.9 Hz, IH), 8.39 (dd, J= 2.0, 2.0 Hz, IH); l3 C- NMR (CDC1 3 ) δ 15.27, 22.54, 26.39 (q), 43.53 (s), 65.57 (d), 109.48, 120.67, 121.04, 121.10, 126.58 (d), 129.15 (s), 129.53, 132.35 (d), 140.18, 143.64, 148.78, 150.1 1 (s); MS (El) mlz 283 (M+H) + . EXAMPLE 2 2,3,3-Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indoIe Hydrochloride A solution of 2,3,3-trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole (0.8 g, 2.79 mmol) in 20 mL of 1 : 1 etheπdioxane at room temperature was treated with 1.5 mL of a 4 M HCl/dioxane solution. The resulting solid was isolated by filtration and washed with hexane to afford the title compound (0.81 g, 90%) as a tan solid: m.p. 240-241 °; 'H-NMR (CDC1 3 ) δ 1.37 (s, 3H), 1.51 (s, 3H), 4.01 (d, J= 6.5 Hz, IH), 7.51 (s, IH), 7.59 (d, J= 7.3 Hz, IH), 7.7 (dd, J= 7.9, 7.9 Hz, IH), 7.8 (d, J= 7.9, Hz, IH), 7.89 (d, J= 7.7 Hz, IH), 8.3 (dd, J= 7.9, 1.8 Hz, IH), 8.42 (s, IH), 1 1.9 (br s. 2H); 13 C-NMR (CDC1 3 ) δ; MS (ED mlz 283 (M+H) + . EXAMPLE 3 (2-R or S)-2,3,3-Trimethyl-5-(3-nitro-phenyπ-2,3-dihydro-lH-indole and and EXAMPLE 4 (2-S or R)-2,3,3-Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole A sample of racemic 2,3,3-trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH- indole (25 mg), as prepared in example 2, was separated by a chiral preparative HPLC [column: Chiralcel OD, 4.6 X 250 mm, isocratic, 5:95 IPA:hexane, flow rate = 1 mL/min; injection volume = 5 μL; retention times: 3, 9.2 min and 4, 10.39 min.] to provide the enantiomers 3 and 4 as orange semi-solids. Chiral Analytical HPLC determined that the enantiomers had > 99 % EE. Examples 3 and 4 have spectral data identical to the racemic material, example 1: Η- NMR (CDC1 3 ) δ 1.12 (s, 3H), 1.21 (d, J= 6.6 Hz, 3H), 1.35 (s, 3H), 3.60 (q, J= 6.6 Hz, IH), 3.9 (br s, IH), 6.69 (d, J = 7.9 Hz, IH), 7.28-7.29 (m, 2H), 7.32 (d, J= 1.9 Hz, IH), 7.53 (dd, J= 7.9, 7.9 Hz, IH), 7.85 (ddd, J= 7.9, 2.0, 2.0 Hz, IH), 8.07 (ddd, J= 7.9, 2.0, 2.0 Hz, IH), 8.08 (d, J= 7.9 Hz, IH), 8.39 (dd, J= 2.0, 2.0 Hz, IH); MS (ED mlz 283 (M+H) + . EXAMPLE 5 2,3,3-Diethyl-2-methyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole 5-Bromo-3,3-diethyl-2-methyl-2,3-dihydro-lH-indole This compound was prepared according to the procedure for Example 1 using 4-bromo-phenyl hydrazine hydrochloride (5.9 g, 26.3 mmol) and 3-ethyl-2-pentanone (3.0 g, 26.3 mmol). The subtitled compound (4.5 g) was obtained in 65 % yield as a yellowish oil: Η-NMR (CDC1 3 ) δ 0.8 l(t, J = 7.4 Hz, 3H), 0.83 (t, J= 7.4 Hz, 3H), 1.18 (d, J= 6.5 Hz, 3H), 1.42 (dq, J= 14.0, 7.4 Hz, IH), 1.66 (dq, J= 14.0, 7.4 Hz, 3H), 3.73 (q, J= 6.5 Hz, IH), 6.47 (d, J= 8.2 Hz, IH), 7.02 (d, J= 2 Hz, IH), 7.09 (dd, J= 8.2, 2.0 Hz, IH); l3 C-NMR (CDC1 3 ) δ 10.46, 10.66, 17.70 (q), 26.5, 29.67 (t), 52.25 (s), 64.80 (d), 111.64 (s), 112.41, 129.07, 131.58 (d), 139.57, 151.04 (s); MS (El) mlz 268, 270 (M+H) + . Using the standard coupling conditions given in Example 1 the title compound was prepared from 5-bromo-3,3-diethyl-2-methyl-2,3-dihydro-lH-indole (0.13 g, 0.45 mmol), tetrakis-(triphenylphosphine) palladium (0.05 g, 0.04 mmol) in dimethoxyethane (4 mL) with 3-nitrophenylboronic acid (0.09 g, 0.54 mmol) and sodium carbonate (0.15 g, 4.95 mmol) in 2 mL of water. The title compound (0.09 g, 65%o) was obtained as a red brown glass: 'H NMR (CDC1 3 ) δ 0.86 (dt, J= 4.0, 4.0 Hz, 3H), 0.88 (dt, J = 4.0, 4.0 Hz, 3H), 1.24 (d, J= 6.6 Hz, 3H), 1.5 (dq, J = 14.1, 7.3 Hz, IH), 1.66-1.84 (m, 3H), 3.81 (q, J= 6.6 Hz, IH), 6.69 (d, J= 8.0 Hz, IH), 7.20 (d, J = 1.9 Hz, IH), 7.32 (dd, J= 8.0, 1.9 Hz, IH), 7.53 (dd, J= 8.0, 8.0 Hz, IH), 7.85 (dd, J = 7.9, 1.1 Hz, IH), 8.09 (dd, J= 7.9, 1.1 Hz, IH), 8.4 (dd, J= 1.9 Hz, IH); 13 C-NMR (CDC1 3 ) δ 8.99, 9.14, 16.24 (q), 24.87, 28.14 (t), 50.30 (s), 63.31 (d), 109.56, 120.80, 121.22, 123.19, 126.76 (d), 128.64 (s), 129.67, 132.55 (d), 136.5, 143.92, 148.95, 151.07 (s); MS (ED mlz 310 (M) + . EXAMPLE 6 4a-Methyl-6-(3-nitro-phenyπ-2,3,4,4a,9,9a-hexahydro-lH-carbazole 6-Bromo-4a-methyl-2,3,4,4a,9,9a-hexahydro-lH-carbazole This compound was prepared by the procedure of Example 1 using 4-bromo- phenyl hydrazine hydrochloride (2.0 g, 8.95 mmol) and 2-methylcyclohexanone (1.0 g, 8.95 mmol). The subtitled compound (1.5 g, 65%>) was obtained as a yellow oil: 'H NMR (CDCI 3 ) δ 1.26 (s, 3H), 1.38-1.46 (m, 4H), 1.56-1.68 (m, 4H), 3.4 (t, J= A.A Hz, IH), 3.6 (br s, IH), 6.53 (d, J= 8 Hz, IH), 7.08 (d, J= 2.0 Hz, IH), 7.09 (dd, J = 8.0, 2.0 Hz, IH); 13 C-NMR (CDC1 3 ) δ 21.45, 21.87 (t), 23.96 (q), 27.92, 35.32 (t), 43.56 (s), 66.65 (d), 110.73 (s), 111.88, 125.25, 129.99 (d), 142.17, 149.03 (s) ; MS (El) mlz 268, 270 (M+H) + . Using the standard coupling conditions given in Example 1 , the title compound was prepared using 6-bromo-4a-methyl-2,3,4,4a,9,9a-hexahydro-lH- carbazole (1.6 g, 6.0 mmol), tetrakis(triphenylphosphine) palladium (0.4 g, 0.35 mmol) in dimethoxyethane (30 mL) with 3-nitrophenylboronic acid (1.2 g, 7.2 mmol) and sodium carbonate (1.9 g, 18 mmol) in 10 mL water. The pure product (1.2 g, 70%) was obtained as an orange foam: Η NMR (CDC1 3 ) δ 1.36 (s, 3H), 1.44-1.74 (m, 8H), 3.49 (t, J= 4.4 Hz, IH), 3.83 (br s, IH), 6.75 (d, J= 8.0 Hz, IH), 7.26 (d, J= 1.9 Hz, IH), 7.32 (dd, J= 8.0, 1.9 Hz, IH), 7.53 (dd, J= 8.0, 8.0 Hz, IH), 7.86 (d, J= 7.8 Hz, IH), 8.08 (dd, J= 8.0, 2.0 Hz, IH), 8.39 (dd, J= 2.0, 2.0 Hz, IH); 13 C-NMR (CDC1 3 ) δ 21.27, 21.71 (t), 23.87 (q), 27.76, 35.29 (t), 43.06 (s), 66.46 (d), 1 10.41 , 120.57, 120.83, 121.24, 126.55 (d), 129.26 (s), 129.68, 132.55 (d), 140.66, 143.86, 148.95, 150.51 (s); MS (EIj m/z 309 (M+H) + . EXAMPLE 7 l,2-Dihvdro-2-methyl-5-(3-nitro-phenyl)spiro[cyclohexane-l,3-[3Hlindolel 5-Bromo- 1 ,2-dihydro-2-methylspiro[cyclohexane- 1 ,3-f 3H1 indole] Using the conditions given in Example 1 the subtitled compound was prepared from 4-bromo-phenyl hydrazine HCl (3.5 g, 15.7 mmol) and cyclohexyl methyl ketone (2.0 g, 15.7 mmol). The pure material (3.0 g, 68%>) was obtained as an oil: Η NMR (CDCl 3 ) δ l .09 (d, J= 6.5 Hz, 3H), 1.25-1.73 (m, 10H), 3.45 (br s, IH), 3.71 (q, J= 6.5 Hz, IH), 6.47 (d, J= 8.2 Hz, IH), 7.09, dd, J= 8.2, 2.0 Hz, IH), 7.19 (d, J = 2.0 Hz, IH); l3 C-NMR (CDC1 3 ) δ 17.22 (q), 23.19, 23.44, 26.16, 30.17, 36.70 (t), 47.99 (s), 62.34 (d), 1 10.08 (s), 1 1 1.07, 126.83, 130.08 (d), 139.98, 148.49 (s); MS (El) mlz 280, 282 (M+H) + . Using the standard coupling conditions given in Example 1 the title compound was prepared from 5-bromo-l,2-dihydro-2-methylspiro[cyclohexane-l,3-[3H] indole] (0.5 g, 1.65 mmol), tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) in dimethoxy-ethane (5 mL) with 3-nitrophenylboronic acid (0.33 g, 1.98 mmol) and sodium carbonate (0.53 g, 4.95 mmol) in 5 mL water. The pure material (0.35 g, 55%>) was obtained as an orange brown semi-solid: 'H NMR (CDC1 3 ) δ 1.16 (d, J = 6.4 Hz, 3H), 1.38-1.83 (m, 10H), 3.7 (br s, IH), 3.8 (q, J= 6.4 Hz, IH), 6.69 (d, J = 8.0 Hz, IH), 7.31 (dd, J= 8.0, 1.8 Hz, IH), 7.53 (dd, J= 8.0, 8.0 Hz, IH), 7.86 (d, J = 7.3 Hz, IH), 8.09 (d, J= 8.0 Hz, IH), 8.39 (dd, J= 1.9, 1.9 Hz, IH); 1 C-NMR (CDC1 3 ) δ 17.45 (q), 23.32, 23.70, 26.21, 30.31, 37.07 (t), 47.77 (s), 62.11 (d), 109.81, 120.78, 121.23, 122.40, 126.92 (d), 128.96 (s), 129.66, 132.51 (d), 138.63, 143.92, 148.94, 150.1 (s); MS (Ei mlz 322 (M) + . EXAMPLE 8 3,3-DimethvI-5-(3-nitro-phenyl)-2,3-dihvdro-lH-indole (WAY-160655) 3,3-dimethyl-l,3-dihydro-2H-indol-2-one This compound was prepared using the general method described by A. Kende, Synth. Commun., 1: 12 (1982). The crude material was purified by column chromatography (Si0 2 , methylenechloride:hexane 1:3) to afford the subtitled compound which was consistent with the reported spectral data. The above oxindole (0.65 g, 4.03 mmol) and sodium acetate (0.334 g, 4.07 mmol) were stirred in acetic acid (5.0 mL). Bromine (0.66 g, 0.00413 mol) in acetic acid (5.0 mL) was added drop-wise to the reaction mixture. The reaction was stirred for 50 minutes, and then poured into water (10 mL). The mixture was made basic with sodium carbonate, extracted with ethyl acetate, dried (MgS0 4 ), filtered, and evaporated to give 5-bromo-l,3-dihydro-3,3-dimethyl-2H-indol-2-one ( 0.89 g, 92%): Η NMR (DMSO-d j ) 1.21 (s, 6 H), 6.76 (d, J= 8.22 Hz, IH), 7.29 (dd, J= 2.1, 8.2 Hz, IH), 7.49 (d, J= 2.0 Hz, IH), 10.4 (s, IH). To a solution of the 5-bromo-l,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.9 g, 3.7 mmol) in 20 mL THF at 0 °C was added a borane-methylsulfide complex (2M in THF, 38 mL, 75 mmol). The reaction mixture was warmed to room temperature then brought to reflux for 4 hours. The mixture was cooled to room temperature and poured into H 2 0/CH 2 C1 2 and washed with 5% NaHC0 3 . The organic layer was washed with brine, dried (Na 2 S0 4 ) and concentrated. The crude product was extracted in MeOH, trimethylamine N-oxide (2.0 g, 26.6 mmol) was added, and the solution was brought to reflux for 2 hours. The reaction mixture was cooled, concentrated and the crude residue purified by column chromatography (Si0 2 , methylene chloride) to afford 5-bromo-3,3-dimethyl-2,3-dihydro-lH-indole (0.074 g, 87%) as a yellow oil: Η NMR (CDC1 3 ) δ 1.29 (s, 6H), 3.30 (s, 2H), 3.5 (br s, IH), 6.49 (d, J= 8.8 Hz, IH), 7.08-7.12 (m, 2H); 13 C-NMR (CDC1 3 ) δ 27.69 (q), 42.21 (s), 62.01 (d), 110.38 (s), 11 1.09, 125.46, 130.09 (d), 141.03, 149.52 (s); MS (ED mlz 225, 227 (M) + . Using the standard coupling conditions given in Example 1 , the title compound was prepared from 5-bromo-3,3-dimethyl-2,3-dihydro-lH-indole (0.25 g, 1.1 mmol), tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) in dimethoxyethane (5 mL) with 3-nitrophenylboronic acid (0.22 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in 5 mL water. The title compound (0.17 g, 60%) was obtained as a brown semi-solid: Η NMR (CDC1 3 ) δ 1.38 (s, 3H), 3.40 (s, 2H), 6.72 (d, J= 8.0 Hz, IH), 7.29-7.34 (m, 2H), 7.54 (dd, J= 8.0, 8.0 Hz, IH), 7.86 (d, J= 7.8 Hz, IH), 8.09 (dd, J= 8.0, 1.5 Hz, IH), 8.40 (dd, J= 2.0, 2.0 Hz, IH); 13 C- NMR (CDC1 3 ) δ 27.89 (q), 41.93 (s), 62.05 (d), 109.78, 120.87, 121.02, 121.23, 126.87 (d), 129.19 (s), 129.69, 132.52 (d), 139.64, 143.75, 148.94, 151.17 (s); MS (El m/z 268 (M) + . EXAMPLE 9 5'-(3-Chlorophenyl)-r,2 , -dihydrospiro[cyclohexane-l,3 , -f3Hlindolel Spiro lcvclohexane-l,3'-r3H1indon-2 , -(rH) one A solution of the oxindole (25g, 190 mmol) in 800 mL of anhydrous THF was cooled to -20°C, «-butyllithium (2.5M in hexanes, 152 mL, 0.38 mol) slowly added, followed by the addition of N,N,N',N'-tetramethylenediamine (51 mL, 0.38 mol,). After 15 minutes, 1,5-diiodopentane (174g, 0.54 mol) was added slowly and the mixture was allowed to warm to room temperature. After stirring for 16 hours saturated aqueous ammonium chloride solution (IL) and ethylacetate (IL) were added. After 15 minutes, the layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were extracted with hydrochloric acid (IN, 500 mL), then washed with brine, dried (MgS0 4 ), and concentrated to obtain an oil. The oil was triturated with hexane (200 mL) and benzene (20 mL). The precipitate was collected and dried in vacuo to provide Spiro [cyclohexane-l,3'-[3H]indol]-2'-(l 'H) one (26.3g, 69.6%) as colorless crystals: mp 1 10-1 14°; 'H NMR (DMSO-d 6 ) δ 1.67 (m, 10H), 6.84 (d, 1H, J= 8 Hz), 6.94 (t, 1H, J = 8 Hz), 7.17 (t, lH, J= 8 Hz), 7.44 (d, lH, J= 8 Hz), 10.3 (s, IH). To a solution of the above oxindole (17.6 g, 90.0 mmol) in acetic acid (300 mL) was added sodium acetate (8.0 g, 100.0 mmol) and bromine (14.6g, 91.0 mmol) with stirring. After 30 minutes at room temperature, the reaction mixture was partitioned between water and ethylacetate. The aqueous phase was extracted with ethylacetate. The combined organic layers were washed with water, dried (MgS0 4 ) and evaporated. The residue was triturated with hexane. The precipitate was collected, and dried in vacuo to provide 5-Bromo-spiro[cyclohexane-l,3'-[3H]indol]- 2'(l 'H)-one (16.5g, 67%) as off-white crystals: m.p. 196-199°; Η NMR (DMSO-d 6 ) δ 1.62 (m, 10H), 6.8 (d, 1H, J= 6.8 Hz), 7.36 (d, 1H, J= 8.2, 1.8 Hz), 7.58 (dd, 1H, J = 8.2, 1.8 Hz), 10.44 (s, IH). Using the standard coupling conditions given in Example 1 , the title compound was prepared from the above bromo-oxindole (0.32 g, 1.14 mmol) tetrakis(triphenylphosphine) palladium (0.08g, 0.07 mmol) and 3- chlorophenylboronic acid (0.21 g, 1.37 mmol), and sodium carbonate (0.36 g, 3.4 mmol) in water (3 mL). 5-(3-chlorophenyl)-spiro[cyclohexane-l,3-[3H]indol]-2(lH)- one (0.28 g, 80%) was obtained as a yellow solid: m.p. 164-165 °; Η NMR (CDC1 3 ) δ 1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J= 8.1 Hz, IH), 7.22-7.47 (m, 4H), 7.53 (s, IH), 7.61 (s, IH), 9.28 (br s, IH); 13 C-NMR (CDC1 3 ) δ 20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94, 124.06, 125.50, 125.79, 125.97, 126.38, 128.96 (d), 132.88, 133.59, 135.60, 139.14, 142.17, 182.89 (s); MS (ED mlz 310, 312 (M-H) + . To a solution of 5-(3-chlorophenyl)-spiro[cyclohexane-l,3-[3H]indol]-2(lH)- one (0.42 g, 1.4 mmol) in 20 mL THF at 0 °C is added borane-dimethylsulfide complex, (2M in THF, 14 mL, 28 mmol). The reaction mixture was warmed to room temperature then brought to reflux for 4 hours. The mixture was cooled to room temperature and poured into H 2 0 with CH 2 C1 2 and washed with 5%> NaHC0 3 . The organic layer was washed with brine, dried over Na 2 S0 4 and concentrated. The crude product was extracted in MeOH and trimethylamine N-oxide (1.0 g, 9.0 mmol) was added. The solution was brought to reflux for 2 hours, the mixture was cooled, concentrated and the crude residue purified by column chromatography (Si0 2 , methylene chloride) to afford the title compound (0.25 g, 63%>) as a yellow oil: 'H NMR (CDC1 3 ) δ 1.3-1.55 (m, 3H), 1.6-1.85 (m, 7H), 3.1 (br s, IH). 3.5 (s, 2H), 6.6 (d, J= 8.0 Hz, IH), 7.18-7.32 (m, 4H), 7.4 (dd, J = 7.7, 1.5 Hz, IH), 7.5 (s, IH); 13 C- NMR (CDC1 3 ) δ 23.65, 26.24, 37.00 (t), 46.58 (s), 57.49 (t), 109.95, 121.82, 125.07, 126.36, 126.98, 127.08, 130.29 (d), 130.64, 134.91, 139.65, 144.29, 151.09 (s); MS (ED mlz 298, 300 (M+H) + . EXAMPLE 10 S-q' ' '-trimethyl^'J-dihvdro-lH-indol -S'-vD benzonitrile To a solution of 5-bromo-2,3,3-trimethyl-2,3-dihydro-lH-indole (2.03 g, 8.45 mmol) in dimethoxyethane (50 mL), under nitrogen was added tetrakis(triphenylphosphine)palladium (0.47 g, 0.4 mmol). After 20 minutes at room temperature, 3-formylphenylboronic acid (2.36 g, 16.4 mmol) and potassium carbonate (6.80 g, 55 mmol) in water (25 mL) was added, and the mixture was heated under reflux. After 2 hours, the mixture was cooled, poured into brine and extracted with EtOAc (x 2). The combined organic extracts were washed with brine, dried (MgS0 4 ) and evaporated. The residue was then subjected to column chromatography (Si0 2 , EtOAc: hexane, 1 :8) to afford 3-(2,3,3'-trimethyl-2',3-dihydro-lH-indol-5'-yl) benzaldehyde (0.96 g, 3.62 mmol, 43 %>) as a slightly impure solid that was used without further purification: Η NMR (CDC1 3 ) δ 1.11 (s, 3H), 1.22 (d, 3H, J = 6.5 Hz), 1.35 (s, 3H), 3.59 (dd, 1H, J= 13, 7 Hz), 6.69 (d, 1H, J= 1 Hz), 7.25 (s, IH), 7.32 (s, IH), 7.55 (t, IH, J= 7.6 Hz), 7.80 (d, IH, J= 1 Hz), 7.82 (d, IH, J= 1 Hz), 8.05 (s, IH), 10.07 (s, IH). To a solution of the above compound (0.96 g, 3.62 mmol) in MeCN/H 2 0 (20 mL, 95:5) was added hydroxylamine hydrochloride (0.82 g, 7.25 mmol). After 1 hour, the mixture was poured into a saturated sodium hydrogen carbonate solution and extracted with EtOAc (x2). The combined organic extracts were washed with water, dried (MgS0 4 ) and evaporated. The residue was then dissolved in dichloromethane (20 mL) and treated with thionyl chloride (0.53 mL, 7.25 mmol). After 16 hours, the mixture was quenched with saturated sodium hydrogen carbonate solution and concentrated, partitioned between water and EtOAc, and re-extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgS0 4 ) and evaporated. Purification by column chromatography (EtOAc: hexane, 1 :8) afforded a yellow oil (0.31 g) which was dissolved in methanol (5 mL) and treated with ethereal hydrogen chloride (1M, 1.3 mL, 1.3 mmol) and evaporated. Recrystallization from MeOH/Et 2 0 then afforded the title compound (0.20 g, 0.60 mmol, 18 %): mp >235 °C (decomp); 'H NMR (CDC1 3 ) δ 1.57 (s, 3H), 1.36 (d, 3H, J = 6.7 Hz), 1.40 (s, 3H), 3.72-3.76 (m, IH), 7.30 (d, IH, J= 8 Hz), 7.67 (t, 2H, J= 7 Hz), 7.79 - 7.84 (m, 2H), 8.03 (d, IH, J= 8 Hz), (8.2, s, IH); MS (El) m/z 262 (M) + . EXAMPLE 11 - Pharmacology The biological activity for the compounds of the current invention was evaluated in the in-vitro assays described below. In-vitro potencies lie in the range 0.01 nM - 10,000 nM, and in-vivo potencies in the range 1 μg/kg to 100 mg/kg. The in-vitro biology is determined by (1) competitive radioligand Binding: using the A-form of the human progesterone receptor with progesterone as the radioligand; (2) co-transfection assay, which provides functional activity expressed as agonist EC50 and Antagonist IC50 values; and (3) a T47D cell proliferation, which is a further functional assay which also provides agonist and antagonist data. 1. hPR Binding assay - This assay is carried out in accordance with: Pathirana, C; Stein, R.B.; Berger, T.S.; Fenical, W.; laniro, T.; Mais, D.E.; Torres, A.; Glodman, M.E., Nonsteroidal human progesterone receptor modulators from the marine alga cymoplia barbata, j. Steroid Biochem. Mol. Biol., 1992, 41, 733-738. 2. PRE-luciferase assay in 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 in CV- 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) containing 10%> (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows: DMEM (BioWhittaker), phenol red-free, containing 10%> (v/v) charcoal- stripped fetal bovine serum (heat-inactivated), 0.1 mM MEM non-essential amino acids, lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). b. Cell culture, transfection, treatment, and luciferase assay Stock CV-1 cells are maintained in growth medium. Co-transfection is done using 1.2xl0 7 cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl and BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNA in 250 ml. Electroporation is carried out at 260 V and 1,000 mF in a Biorad Gene Pulser II. After electroporation, cells are resuspended in growth medium and plated in 96-well plate at 40,000 cells/well in 200 μl. Following overnight incubation, the medium is changed to experimental medium. Cells are then treated with reference or test compounds in experimental medium. Compounds are tested for antiprogestational activity in 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 min in a Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase activity is measured using luciferase reagents from Promega. c. Analysis of Results: Each treatment consists of at least 4 replicates. Log transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC 50 or IC 50 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 trimegestone are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose- response curves and the EC 50 or IC 50 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 IC 50 , 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 induced PRE-luciferase activity significantly (p<0.05) EC 50 : Concentration of a compound that gives half-maximal increase PRE- luciferase activity (default-nM) with SE. IC 50 : Concentration of a compound that gives half-maximal decrease in 3 nM progesterone induced 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 using a cell proliferation assay in T47D cells. A compound's effect on DNA synthesis in T47D cells is measured. The materials and methods used in this assay are as follows. a. Growth medium: DMEM:F12 (1 : 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovine serum (not heat-inactivated), lOOU/ml penicillin, lOOmg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). b. Treatment medium: Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenol red-free supplemented with 0.5% charcoal stripped fetal bovine serum, lOOU/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL). c. Cell culture Stock T47 D cells are maintained in growth medium. For BrdU incorporation assay, cells are plated in 96-well plates (Falcon, Becton Dickinson Labware) at 10,000 cells/well in growth medium. After overnight incubation, the medium is changed to treatment medium and cells are cultured for an additional 24 hr before treatment. Stock compounds are dissolved in appropriate vehicle (100% ethanol or 50%) ethanol/50%) DMSO), subsequently diluted in treatment medium and added to the cells. Progestin and antiprogestin reference compounds are run in full dose- response curves. The final concentration of vehicle is 0.1 %>. In control wells, cells receive vehicle only. Antiprogestins are tested in the presence of 0.03 nM trimegestone, the reference progestin agonist. Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlington Heights, IL) in treatment medium for 4 hr. d. Cell Proliferation Assay At the end of BrdU labeling, the medium is removed and BrdU incorporation is measured using a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) according to manufacturer's instructions. Briefly, cells are fixed in an ethanol containing fixative for 30 min, followed by incubation in a blocking buffer for 30 min to reduce background. Peroxidase-labeled anti-BrdU antibody is added to the wells and incubated for 60 min. The cells are rinsed three times with PBS and incubated with 3,3'5,5'-tetramethylbenzidine (TMB) substrate for 10-20 min depending upon the potency of tested compounds. Then 25 μl of 1 M sulfuric acid is added to each well to stop color reaction and optical density is read in a plate reader at 450 nm within 5 min. e. Analysis of Results: Square root-transformed data are used for analysis of variance and nonlinear dose response curve fitting for both agonist and antagonist modes. Huber weighting is used to downweight the effects of outliers. EC 50 or IC 50 values are calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used for both oneway analysis of variance and non-linear dose response analyses in both single dose and dose response studies. f. Reference Compounds: Trimegestone and medroxyprogesterone acetate (MPA) are reference progestins and RU486 is the reference antiprogestin. All reference compounds are run in full dose-response curves and the EC 50 or IC 50 values are calculated. Table 3. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for individual studies EC 50 95% CI Compound Exp (nM) SE lower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014 0.001 0.01 1 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 0.01 1 0.024 Table 4. Estimated IC S0 , standard error, and 95% confident interval for the antiprogestin, RU486 ιc 50 95% CI Compound Exp (nM) SE lower upper RU486 1 0.01 1 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.001 0.014 0.022 EC 50 : Concentration of a compound that gives half-maximal increase in BrdU incorporation with SE; IC 50 : Concentration of a compound that gives half-maximal decrease in 0.1 trimegestone induced BrdU incorporation with SE. All above-noted published references are incorporated herein by reference. Numerous modification and variations of the present invention are included in the above-identified specification are expected to be obvious to one of skill in the art. Such modifications and alterations to the methods, solutions, apparatuses of the present invention are believed to be encompassed in the scope of the claims appended hereto.

Claims: What is Claimed; 1. A method of contraception which comprises 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 in 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 antiprogestin compound of Formula I: I wherein: R, and R 2 are chosen independently from H, alkyl, substituted alkyl; OH; O(alkyl); 0(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; l-propynyl; or 3- propynyl; or R, and R 2 are joined to form a ring comprising -CH 2 (CH 2 ) n CH 2 -; - CH 2 CH 2 CMe 2 CH 2 CH 2 -; -0(CH 2 ) m CH 2 -; 0(CH 2 ) p O-; -CH 2 CH 2 OCH 2 CH 2 -; -CH 2 CH 2 N(alkyl)CH 2 CH 2 -, or -CH 2 CH 2 NHCH 2 CH 2 -; n is an integer from 0 to 5; m is an integer from 1 to 4; p is an integer from 1 to 4; or R, and R 2 together comprise a double bond to =C(CH 3 ) 2 ; =C(C 3 -C 6 cycloalkyl), =0, or =C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl; R 3 is H, OH, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, C 3 to C 6 alkenyl, alkynyl or substituted alkynyl, or COR A ; R A = H, C, to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; R 4 = H, halogen, CN, NH 2 , C, to C 6 alkyl, substituted C, to C 6 alkyl, C, to C 6 alkoxy, substituted C, to C 6 alkoxy, C, to C 6 aminoalkyl, or substituted C, to C 6 aminoalkyl; R 5 is selected from the groups a), b) or c): a) R 5 is a benzene ring of the formula X is selected from halogen, OH, CN, C, to C 3 alkyl, substituted C, to C 3 alkyl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 thioalkyl, substituted C, to C 3 thioalkyl, S(0)alkyl, S(0) 2 alkyl, C, to C 3 aminoalkyl, substituted C, to C 3 aminoalkyl, N0 2 , C, to C 3 perfiuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, COR B , OCOR B , or NR c COR B ; R B is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; R c is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl: Y and Z are independently selected from H, halogen, CN, N0 2 , C, to C 3 alkoxy, C, to C 3 alkyl, or C, to C 3 thioalkyl; or b) R 5 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, S0 2 or NR 6 and containing one or two independent substituents from the group including H, halogen, CN, N0 2 and C, to C 3 alkyl, C, to C 3 alkoxy, C, to C 3 aminoalkyl, COR D , or NR E COR D ; R D is H, C, to C 3 alkyl, substituted C, to C 3 alkyl, aryl, substituted aryl, C, to C 3 alkoxy, substituted C, to C 3 alkoxy, C, to C 3 aminoalkyl, or substituted C, to C 3 aminoalkyl; R E is H, C, to C 3 alkyl, or substituted C, to C 3 alkyl; R 6 is H or C, to C 3 alkyl; or c) R 5 is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, N0 2 , lower alkoxy, or CF 3 ; wherein R 6 and R 7 are independently chosen from H, methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, cyclohexyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or pharmaceutically acceptable salt thereof; and c) optionally, a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered; wherein the total daily dosage units of the first, second and third phases equals 28. 2. A method of Claim 1 wherein the progestational agent is levonorgestrel and the anti-progestin compound has the structure: wherein: X is selected from halogen, CN, C, to C 3 alkoxy, C, to C 3 alkyl, N0 2 , C, to C 3 perfiuoroalkyl, 5-membered heterocyclic ring containing 1 to 3 heteroatoms, or C, to C 3 thioalkoxy; Y is a substituent on the 4' or 5 'position selected from H, halogen, CN, N0 2 , C, to C 3 alkoxy, C, to C 4 alkyl, or C, to C 3 thioalkyl; or pharmaceutically acceptable salt thereof. 3. A method of Claim 1 wherein the progestational agent is levonorgestrel and the anti-progestin compound has the structure: wherein: U is O, S, or NR,, R 6 is H, or C, to C 3 alkyl, or C, to C 4 C0 2 alkyl; X' is selected from halogen, CN, N0 2 , C, to C 3 alkyl or C, to C 3 alkoxy; Y' is selected from the group H, F, CN, N0 2 or C, to C 4 alkyl; or pharmaceutically acceptable salt thereof. 4. A method of Claim 1 wherein the progestational agent is levonorgestrel and the anti-progestin compound has the structure: wherein: X 1 is N or CX 2 ; X 2 is halogen, CN or N0 2 ; or pharmaceutically acceptable salt thereof. 5. A method of Claim 1 wherein the antiprogestin compound is 2,3,3- Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof. 6. A method of Claim 1 wherein the antiprogestin compound is 2,3,3- Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole Hydrochloride or a pharmaceutically acceptable salt thereof. 7. A method of Claim 1 wherein the antiprogestin compound is (2-R)- 2,3,3-Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof. 8. A method of Claim 1 wherein the antiprogestin compound is (2-S)- 2,3,3-Trimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof. 9. A method of Claim 1 wherein the antiprogestin compound is 2,3,3- Diethyl-2-methyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof. 10. A method of Claim 1 wherein the antiprogestin compound is 4a- Methyl-6-(3-nitro-phenyl)-2,3,4,4a,9,9a-hexahydro-lH-carbazole or a pharmaceutically acceptable salt thereof. 11. A method of Claim 1 wherein the antiprogestin compound is 1,2- Dihydro-2-methyl-5-(3-nitro-phenyl)spiro[cyclohexane-l,3-[3H]indole] or a pharmaceutically acceptable salt thereof. 12. A method of Claim 1 wherein the antiprogestin compound is 3,3- Dimethyl-5-(3-nitro-phenyl)-2,3-dihydro-lH-indole or a pharmaceutically acceptable salt thereof. 13. A method of Claim 1 wherein the antiprogestin compound is 5'-(3- Chlorophenyl)-l \2'-dihydrospiro[cyclohexane-l,3'-[3H]indole] or a pharmaceutically acceptable salt thereof. 14. A method of Claim 1 wherein the antiprogestin compound is 3- (2',3',3'-trimethyl-2',3-dihydro-lH-indol -5'-yl) benzonitrile or a pharmaceutically acceptable salt thereof. 15. The method of Claim 1 wherein the progestational agent is selected from the group of levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17- deacetyl)norgestimate. 16. A method of Claim 1 which comprises 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 in progestational activity to about 35 to about 100 μg levonorgestrel; b) a second phase of 3 daily dosage units of an antiprogestin compound of Claim 1, each daily dosage unit containing an antiprogestin 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 administered on each day of the 28-day cycle following the first phase and second phase. 17. A method of contraception which comprises administering to a female of child bearing age over a period of 28 consecutive days: a) a first phase of from 18 to 21 daily dosage units of a progestostational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel, and ethinyl 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 antiprogestin 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 remaining day of the 28 consecutive days. 18. A method of contraception of Claim 17 which comprises administering to a female of child bearing age over a period of 28 consecutive days: a) a first phase of 21 daily dosage units of a progestostational agent equal in progestational activity to about 35 to about 100 μg levonorgestrel and ethinyl 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 antiprogestin 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. 19. A method of contraception which comprises administering to a female of child bearing age over a period of 28 consecutive days: a) a first phase of from 18 to 21 daily dosage units containing a progestational agent at a daily dose equal in progestational activity to from about 35 to about 150 μg levonorgestrel and ethinyl 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 containing an antiprogestin of Claim 1 at a concentration of from 2 to 50 mg and ethinyl 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 being 28. 20. A method of contraception of Claim 19 which comprises administering to a female of child bearing age over a period of 28 consecutive days: a) a first phase of 21 daily dosage units, each daily dosage unit containing a progestational agent at a daily dose equal in progestational activity to about 35 to about 100 μg levonorgestrel and ethinyl 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 containing an antiprogestin of Claim 1 at a concentration of from 2 to 50 mg; and ethinyl 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. 21. A pharmaceutically useful kit adapted for daily oral administration which comprises: a) a first phase of from 14 to 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 from 1 to 1 1 daily dosage units of an antiprogestin compound of Claim 1 , each daily dosage unit containing an antiprogestin 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; wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28. 22. A pharmaceutically useful kit adapted for daily oral administration of Claim 21 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 antiprogestin compound of Claim 1, each daily dosage unit containing an antiprogestin 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. 23. 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 in progestational activity to about 35 to about 150 μg levonorgestrel and ethinyl 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 antiprogestin 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; wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28. 24. A pharmaceutically useful kit adapted for daily oral administration of Claim 23 which comprises: a) a first phase of 21 daily dosage units of a progestostational agent equal in progestational activity to about 35 to about 150 μg levonorgestrel and ethinyl 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 antiprogestin of Claim 1 administered 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. 25. A pharmaceutically useful kit adapted for daily oral administration which comprises: a) a first phase of from 18 to 21 daily dosage units, each daily dosage unit comprising a progestational agent at a daily dose equal in progestational activity to from about 35 to about 150 μg levonorgestrel and ethinyl 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 containing an antiprogestin of Claim 1 at a concentration of from 2 to 50 mg; and ethinyl 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; wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28. 26. A pharmaceutically useful kit adapted for daily oral administration of Claim 25 which comprises: a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 μg levonorgestrel and ethinyl 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 unit containing an antiprogestin of Claim 1 at a concentration of from 2 to 50 mg; and ethinyl 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, TEGLEY CHRISTOPHER M, ULLRICH JOHN W, WROBEL JAY E, ZHI LIN, EDWARDS, JAMES, P., FENSOME, ANDREW, GRUBB, GARY, S., JONES, TODD, K., TEGLEY, CHRISTOPHER, M., ULLRICH, JOHN, W., WROBEL, JAY, E., ZHI, LIN
Applicants: AMERICAN HOME PROD, EDWARDS JAMES P, FENSOME ANDREW, GRUBB GARY S, JONES TODD K, LIGAND PHARM INC, TEGLEY CHRISTOPHER M, ULLRICH JOHN W, WROBEL JAY E, ZHI LIN, AMERICAN HOME PRODUCTS CORPORATION, EDWARDS, JAMES, P., FENSOME, ANDREW, GRUBB, GARY, S., JONES, TODD, K., LIGAND PHARMACEUTICALS, INC., TEGLEY, CHRISTOPHER, M., ULLRICH, JOHN, W., WROBEL, JAY, E., ZHI, LIN
Application year: 2000
Main classification: A61K45
IPC codes: A61K31, A61K45, A61P15