WO2000066168A1 - Compositions containing benzimidazolones and progestogens - Google Patents

Abstract

This invention relates to cyclic combination therapies and regimens utilizing substituted indoline derivative compounds which are antagonists of the progesterone receptor having general structure (1) wherein: A is O, S, or NR4; B is a bond between A and C=Q, or the moiety CR?5R6; R4, R5, R6¿ are independently selected from H or optionally substituted C¿1? to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, or heterocyclic groups, or cyclic alkyl constructed by fusing R?4 and R5¿ to form a 5 to 7 membered ring; R1 is selected from H, OH, NH¿2?, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, -COH, or optionally substituted -CO(C1 to C3 alkyl), -CO(aryl), -CO(C1 to C3 alkoxy), or -CO(C1 to C3 aminoalkyl) groups; R?2¿ is selected from H, halogen, CN, NO¿2?, or optionally substituted C1 to C6 alkyl, C1 to C6 alkoxy, or C1 to C6 aminoalkyl groups; R?3¿ is selected from a trisubstituted benzene ring; or a 5- or 6-membered heteroaromatic ring containing 1 or 2 substituents; or a pharmaceutically acceptable salt thereof, in combination with a progestational agent, an estrogen, or both or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. These combinations may also be used in methods of contraception, to stimulate food intake or for minimization of side effects or cyclic menstrual bleeding.

Description

COMPOSITIONS CONTAINING BENZIMIDAZOLONES AND PROGESTOGENS

Field of the Invention

This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor

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/hgand 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 prohferative effect on the uterus which can lead to an increased risk of uterine cancers Co-administration of a PR agonist reduces/ablates PR antagonists may also be used in contraception In this context they may be administered alone (Ulmann, et ai, Ann N Y Acαd 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, 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 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 (U S Patent No 5,719,136) PR antagonists, such as mifepπstone 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) disclose the PR antagonist dihydroquinoline 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 (TJ 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 antagonist (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)

Perlman, et al , described the vitamin D analog 9 as a PR ligand (Tet Letters, 35, 2295, 1994)

Hamann, et al, described the PR antagonist 10 (Ann N Y Acad Sci , 761, 383,

1995)

Chen, et al, descπbed the PR antagonist 11 (Chen, et al, POI-37. 16^th Int Cong Het Chem , Montana, 1997)

11 Kurihaπ, et al , described the PR ligand 12 (J Antibiotics, 50, 360, 1997)

12

Among the examples of the prior art, Ueda et al (EP 22317) claimed benzothiazoline and benzoxazoline compounds of formula A as the inhibitors of aldose reductase The benzimidazolmone derivatives such as compound B were disclosed by Hara et al (EP 454330) and claimed as lung surfactant secretion promoters In their preparation of benzoimidazole and analogues as antiulcer and cardiovascular agents, Bru-Magniez et al (EP 385850) synthesized the benzoimidazohnones such as compound C. Used as cAMP PDE III inhibitors, benzoimidazohnones, benzoxazolinones, and benzothiazohnones as shown in formula D were reported by Singh et al (J Med Chem , 37, 248-254 (1994) )

B

Related to qumoxalm-2-ones, European patent (Ganzer et al EP 311135) discloses the compounds such as E as herbicides

U S Patent No 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestm and a progestm wherem the progestm is admmistered m the alternating presence and absence of an antiprogestm The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding Description of the Invention

This mvention provides combmation therapies and dosmg regimens utilizing antiprogestational agents in combmation with one or more progestational agents This mvention further provides methods of treatment and dosmg regimens further utilizing m combmation with these antiprogestins and progestins, an estrogen, such as ethmyl estradiol

These regimens and combmations may be admmistered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleedmg, uterme leiomyomata, endometπosis, polycystic ovary syndrome, carcmomas and adenocarcmomas of the endometπum, ovary, breast, colon, prostate Additional uses of the invention mclude stimulation of food intake The uses herem for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the mvention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleedmg

The use of this mvention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestm m combination with an estrogen or progestm or both These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cyc^**j containing administration of no progestins, estrogens or anti-pro gestms

The progestms of these combmations may be administered alone or m combination with an estrogen for the first 14 to 24 days of the cycle, the progestins being admmistered at a dosage range equal m 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 antiprogestm may then be administered alone or m combmation with an estrogen for a period of 1 to 11 days to begm on any cycle day between day 14 and 24 The anti-pro gestm 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 include a placebo tablet on those days when the antiprogestm or progestm or estrogen is not admmistered

In a preferred embodiment of this invention, the progestins of this mvention may be admmistered alone or m combmation with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestm, 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 ethmyl estradiol

Progestational agents useful with this mvention mclude, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethmdrone, gestodene, norethmdrone acetate, norgestimate, osaterone, cyproterone acetate, tπmegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestιmate Among the preferred progestins for use in the combinations of this mvention are levonorgestrel, gestodene and tπmegestone Examples of orally admmistered regimens of this mvention over a 28 day cycle mclude admmistration 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 antiprogestm 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 admmistration or admmistration of a placebo for days 25 to 28 It is most preferred that the daily dosages of each relevant active mgredient be mcorporated mto 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 m progestational activity to from about 35 to about 150 μg levonorgestrel, preferably equal m activity to from about 35 to about 100 μg levonorgestrel, with an estrogen, such as ethmyl estradiol, at a daily dose range of from about 10 to about 35 μg This may be followed as described above with an antiprogestm admmistered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no admmistration or admmistration 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 administered at a daily dose equal m progestational activity to from about 35 to about 100 μg levonorgestrel, and an estrogen, such as ethmyl 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 antiprogestm (2 to 50 mg/day) and an estrogen, such as ethmyl 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 admmistration of a placebo This mvention also kits or packages of pharmaceutical formulations designed for use m the regimens descπbed herem These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral admmistration per day, and organized so as to mdicate a single 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 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 m progestational activity to about 35 to about 150 μg levonorgestrel, preferably equal m 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 invention, each daily dosage unit containing 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 remaining days of the cycle in which no antiprogestm, progestm 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 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 unit containing 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 invention comprises a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal m 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, 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 remaining 0-9 days m the 28-day cycle m which no progestational agent, estrogen or antiprogestm is admmistered

A preferred embodiment of the kit descnbed 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 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 comprises 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 in 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 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, 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 prefeπed 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 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 oi ήom 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 described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remam fixed m each particular phase m which it is administered It is also understood that the daily dose units described are to be admmistered in the order described, 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 comprise a pharmaceutically acceptable package havmg mdicators 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, 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 admmistered daily or the dose may be proportionally mcreased or reduced as mdicated by the exigencies of the therapeutic situation In the descriptions herein, reference to a daily dosage unit may also include divided units which are admmistered over the course of each day of the cycle contemplated

Compounds of this mvention which may be used as the anti-pro gestational agents m the kits, methods and regimens herem are those of the Formula 1

wherem

B is a bond between A and C=Q, or the moiety CR⁵R⁶, R⁴, R⁵, R⁶ are mdependently selected from H, C* to C₆ alkyl, substituted C, to

C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, cyclic alkyl constructed by fusing R⁴ and R⁵ to from a 5 to 7 membered rmg, R¹ is selected from H, OH, NH₂, C, to C₆ alkyl, substituted C, to C₆ alkyl, C₃ to C₆ alkenyl, substituted Ci to C₆ alkenyl, alkynyl, substituted alkynyl, or COR^A,

R^A is selected from H, Ci to C₃ alkyl, substituted C, to C₃ alkyl, aryl, substituted aryl, C* to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted C- to C3 ammoalkyl,

R² is selected from H, halogen, CN, N0₂, C- to C₆ alkyl, substituted C- to C₆ alkyl, Ci to C₆ alkoxy, substituted Ci to C₆ alkoxy, Ci to C₆ ammoalkyl, or substituted Ci to C₆ ammoalkyl,

R³ is selected from a) or b) a) R³ is a trisubstituted benzene rmg containing the substituents X,

Y and Z as shown below

X is selected from the group of halogen, CN, d to C₃ alkyl, substituted Ci to C₃ alkyl, Ci to C₃ alkoxy, substituted Ci to C alkoxy, Ci to C₃ thioalkoxy, substituted Ci to C₃ thioalkoxy, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 or 6 membered heterocychc rmg containing 1 to 3 heteroatoms, COR^B, OCOR^B, or NR^cCOR^B,

R^B is H, Ci to C alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ aminoalkyl, or substituted Ci to C₃ aminoalkyl,

R^c is H, Ci to C₃ alkyl, or substituted Ci to C₃ alkyl,

Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, N0₂, Ci to C alkoxy, Ci to C alkyl, or Ci to C₃ thioalkoxy, or b) R³ is a five or six membered rmg with 1 , 2, or 3 heteroatoms from the group mcludmg O S, SO, S0₂ or NR⁷ and containing one or two mdependent substituents from the group of H, halogen, CN, N0₂ and Ci to C₃ alkyl, Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, COR^D, or NR^ECOR^D, R^D is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to

C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ aminoalkyl,

R^E is H, Ci to C₃ alkyl, or substituted d to C alkyl,

R⁷ is H, or C, to C₃ alkyl, or a pharmaceutically acceptable salt thereof

Preferred anti-pro gestational compounds of this mvention mclude those of the general formula described above wherein

A is O, S, or NR⁴,

B is a bond between A and C=Q, or the moiety CR⁵R⁶, R⁴, R⁵, R⁶ are mdependent substituents from the group mcludmg H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, or cyclic alkyl constructed by fusing R⁴ and R⁵ to from a 5 to 7 membered ring, R¹ is H, OH, NH₂, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, or COR^A,

R^A is H, Ci to C₄ alkyl, C, to C₄ alkoxy,

R² is H, halogen, N0₂, Ci to C₃ alkyl, or substituted Ci to C₃ alkyl,

R³ is a disubstituted benzene rmg containing the substituents X and Y as shown below

X is taken from the group of halogen, CN, Ci to C₃ alkoxy, Ci to C₃ alkyl, NO₂, Ci to C3 perfluoroalkyl, 5 membered heterocychc ring containing 1 to 3 heteroatoms, or d to C₃ thioalkoxy,

Y is a substituent on the 4' or 5' position from the group of H, halogen, CN, N0 , Ci to C₃ alkoxy, Ci to C alkyl, or Ci to C thioalkoxy, or

R³ is a five membered rmg with the structure

wherem

R⁷ is H, C, to C₃ alkyl, or C, to C₄ C0₂alkyl,

X' is selected from the group of halogen, CN, N0 , Ci to C₃ alkyl or Ci to C₃ alkoxy,

Y' is H or Ci to C₄ alkyl, or

R is a six membered ring with the structure

X¹ is halogen, CN or N0₂ ,

or a pharmaceutically acceptable salt thereof

Another preferred progesterone receptor antagonist subgroup of this invention comprises compounds of the general formula

wherem

R¹ is selected from H, OH, NH₂, Ci to C₆ alkyl, substituted C, to C₆ alkyl, C₃ to C₆ alkenyl, substituted Ci to C₆ alkenyl, alkynyl, substituted alkynyl, or COR^A,

R^A is selected from H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to O* alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C3 ammoalkyl,

R⁴ is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C3 to C₈ cycloalkyl, benzyl, or substituted benzyl, and

R³ is selected from halogen or a disubstituted benzene rmg contammg the substituents X and Y as shown below

X is taken from the group of halogen, CN, G to C₃ alkoxy, Ci to C₃ alkyl, N0₂, Ci to C₃ perfluoroalkyl, or Ci to C thioalkoxy,

Y is a substituent on the 4' or 5' position from the group of H, halogen, CN, N0₂, Ci to C₃ alkoxy, G to C₄ alkyl, or G to C₃ thioalkoxy, or a pharmaceutically acceptable salt thereof

The anti-pro gestational compounds of this mvention may contam an asymmetπc carbon atom and some of the compounds of this mvention may contam one or more asymmetric centers and may thus give rise to optical isomers and diastereomers While shown without respect to stereochemistry m Formula I, II. and III, the present mvention mcludes such optical isomers and diastereomers of these compounds, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereo isomers and pharmaceutically acceptable salts thereof

The term "alkyl" is used herein 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 include 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 triple 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 described having one or more substituents from the group mcludmg halogen, CN, OH, N0₂, ammo, aryl, heterocychc, 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 ring or multiple aromatic rmgs 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 mclude but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthr l The term "substituted aryl" refers to aryl as just defined havmg one to four substituents from the group mcludmg halogen, CN, OH, N0₂, ammo, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio The term "heterocychc" is used herem to descπbe a stable 4- to 7-membered monocyclic or a stable multicychc heterocychc rmg 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 rmg also mcludes any multicychc rmg m which any of above defined heterocychc rmgs is fused to an aryl rmg The heterocychc ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable Such heterocychc groups mclude, for example, tetrahydrofuran, p peπdinyl, piperazinyl, 2- oxopipeπdinyl, azepmyl, pyrrolidinyl, lrrudazolyl, pyπdyl, pyrazmyl, pyπmidinyl, pyπdazinyl, oxazolyl, isoxazolyl, morpho nyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholmyl, thiamorpho nyl sulfoxide, and lsoquino nyl The term "substituted heterocychc" is used herein to describe the heterocychc just defined having one to four substituents selected from the group which mcludes halogen, CN, OH, N0₂, 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 herein 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 herein 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, containing one to eight carbon atoms, which may be either same or different and the pomt of attachment is on the nitrogen atom The term "halogen" refers to Cl, Br, F, or I

The anti-pro gestm compounds of the present mvention can be prepared as described m the following schemes Sc eme I

As illustrated in Scheme I, these compounds are generally prepared by employing the suitable couplmg reaction as a final step and further converted to the thiourea analogues Thus, an appropriately protected benzoimidazolinones 1 (Numerous protecting groups mcludmg but not limited to alkyloxycarbonyl such as BOC group can be employed in the starting material 1) readily prepared accordmg to the procedure of Meanwell et al (J Org Chem 60, 1565-1582(1995) can be alkylatmg at posιtιon-3 under a number of conditions Among the reaction protocols, compound 1 can be alkylated by treatment of 1 with a suitable base such as sodium hydride m an appropriate nonprotic solvent such as DMF followed by addition of an alkylatmg agent such as alkyl iodide or tπflate Alternatively, the compound 2 can be effected employmg a Mitsunobu protocol The conventional Mitsunobu reaction can couple the compound 1 with an appropπate alcohol usmg a phosphorous reagent such as tπphenyl phosphme and a dehydratmg agent such as DEAD (diethyl azodicarboxylate) m a suitable solvent such as THF at the temperature ranging from 0 °C to the boiling point of the solvent which was employed Deprotection of compound 2 to give 3 can be furnished via numerous conditions such as acidic deprotection usmg an acid such as neat tπfluoroacetic acid or basic deprotection employing a base such as sodium alkoxide m a suitable solvent such as THF or alcohol at temperature ranging from ambient temperature to the boiling pomt of the solvent employed The compounds of this mvention, 4, can be readily prepared by employmg various couplmg reactions mcludmg Suzuki, Stille protocols These reactions are commonly performed m the presence of transition metallic catalyst, e g , palladium or nickel complex often with phosphmo ligands, e g , Ph₃P, 1,1 '- bιs(dιphenylphosphιno)ferrocene, l,2-bιs(dιphenylphosphιno)ethane or a catalyst such as palladium acetate Under this catalytic condition, an appropriately substituted nucleophihc reagent, e g , aryl bororac acid, arylstarmane, or aryl zmc compound, is coupled with bromobenzoimidazolmones 3 to give compounds 4 An appropriate base is often needed m the reaction, the commonly used bases mclude but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, cesium fluoride, or potassium acetate The most commonly used solvents in these reactions include benzene, DMF, lsopropanol, ethanol, DME, ether, acetone or a mixture of above solvent and water The couplmg reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95 °C

The anti-progestin compounds of this mvention, 5, can be easily prepared usmg an appropriate sulfur reagent such as Lawesson's reagent or P₂Ss in a suitable solvent such as toluene, xylene, chlorobenzene at reflux under an inert atmosphere such as nitrogen or argon Scheme

Scheme

As shown m scheme II, 5-aryl benzothiazolinones 7 can be readily effected from an appropriate 5-bromo-benzothιazolmone 6 and a suitable electrophile such as aryl boronic acid, aryl tin reagent, or aryl zmc reagent via a suitable couplmg reaction as described for the synthesis of benzimidazo nones 4 Conversion of 7 into 7a can be effected usmg an appropriate sulfur reagent such as Lawesson's reagent or P₂Ss in a suitable solvent such as toluene, xylene, chlorobenzene at reflux under an inert atmosphere such as nitrogen or argon

The synthetic approaches leadmg to the 5-aryl benzoxazo nones 11 are described m scheme III As illustrated m scheme III, an appropriately substituted bromo o-arasidme can be coupled with an appropriate electrophile such as aryl boronic acid or aryl tm reagent via a couplmg reaction as described for the synthesis of compounds 4 to give the biaryl 9 Demethylation of biaryl 9 to give ammo phenol 10 can be furnished via various conditions including treatment of 9 with strong Lewis acid such as boron tπbromide m a suitable solvent such as methylene chloride or treatment of 9 with a mixture of a suitable Lewis acid such as aluminum chloride and a soft nucleophile such as thiol m a suitable solvent such as methylene chloride under an inert atmosphere such as argon or nitrogen Rmg closure of amino phenol 10 to produce the compounds of this mvention 11 can be effected by using a appropriate condensmg agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate m a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65 °C Conversion of 11 into 11a can be accomplished using an appropriate sulfur reagent such as Lawesson's reagent or P₂S₅ in a suitable solvent such as toluene, xylene, chlorobenzene at reflux under an inert atmosphere such as nitrogen or argon Schemes IV, V, and VI describe the synthesis of other 5-aryl benzoimidazolinone, 5-aryl benzothiazolinone, 5-aryl benzoxazohnone bioisosteres Usmg a similar procedure reported by Kondo et al (Kondo, et al J Med Chem 33(7), 2012-2015(1990)) compound 12, 15, or 18 can be effected by treatment of compound 10, 14, or 17 with an appropriate ketene-S, S-acetals (at least one of R₂ or R₃ is an electron withdrawmg group ) m a suitable solvent such as toluene or anhydrous ethanol under an mert atmosphere such as nitrogen or argon at reflux In a similar fashion, compound 13, 16, or 19 can be accomplished by reaction of compound 10, 14, or 17 with an appropriate lmino-S, S-acetals or lmino-acetals (R₂ is an electron withdrawmg group ) employmg a procedure similar to that of Evers, et al (Evers, et al / Prakt Chem 333(5), 699-710 (1991)) or Haake et al (Haake et al Synthesis- Stuttgart 9, 753-758 (1991)) in a suitable solvent such as ethanol under an mert atmosphere such as argon or nitrogen at reflux

Scheme IV

Compounds 14 and 17 can be prepared as shown m schemes V and VI from compound 4 and 7 using a strong basic condition such as heatmg the compound m a mixture of potassium hydroxide and ethylene glycol at 165 °C under an mert atmosphere such as argon or nitrogen

Scheme VI

As illustrated m Scheme VII, the compounds of this invention can be further deπvatized at position- 1 via numerous approaches leading to a variety of the novel derivatives mcludmg 20. 21, and 22 Thus, alkyl or substituted alkyl derivatives 20 can be effected by treatment of compound A with a suitable base such as sodium hydride m suitable solvent such as DMF under an mert atmosphere such as argon or nitrogen followed by addition of an appropriate electrophile such as alkyl or substituted alkyl bromide, iodide, or inflate Such transformation of A at position- 1 can also be effected usmg a biphasic condition as mdicated m scheme VII m which alkylation is executed using a biphasic catalyst such as tπbutylammonium bromide in a suitable solvent such as acetonitπle A further example of such modification mcludes, but is not limited to, the one depicted in Scheme VIII in that heatmg of A with triethyl ortho formate affords 1 -substituted deπvatives 20 Scheme VII

(X=0, S or NR

CINH₂ , NaH, THF, Et₂0 Ar

R 1 22 NH-

The acylation or carboxylation of the compound A at position- 1 to give compound 21 can be readily effected by treatment of A with a suitable acylating or carboxylatmg reagent such as di-t-butyl dicarbonate m the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitπle under an mert atmosphere such as argon or nitrogen The animation of position- 1 of compound A to give compound 22 can be furnished usmg a suitable aminating reagent such as chloroamine m the presence of a suitable base such as sodium hydride in a suitable solvent such as THF or diethyl ether following the literature procedure (Metlesics et al J Org Chem 30, 1311(1965)) Scheme XIII

Scheme VIII descπbes a procedure to prepare qumoxalm-4-ones An appropriate o-fluoro mtro-benzene 23 (X = I, Br, Cl) is reacted with an appropriate substituted ammo acid derivatives m the presence of a suitable base in a protic solvent such as alcohol to give compound 24 which is readily reduced by a suitable reducmg agent such as tin chloride to furnish quιnoxalιn-2-one 25 The anti-progestational compounds of this invention, 26, can be easily effected by couplmg an appropriate aryl boronic acid with compound 25 m a similar fashion as for the preparation of compound 9 Conversion of 26 to 27 can be readily effected following the procedure of compound 11a

Scheme IX

Scheme IX illustrates an approach to prepare the benzothiazinones Thus, an appropriately substituted o-amino benzenethiol 28 is treated with an appropriately substituted α-bromoacetate m a suitable solvent such as ethanol to afford compound 29 which can be readily coupled with an appropriate aryl boronic acid following the protocol of compound 9 to afford the compounds of this mvention, 30 Conversion of - SO -

SO to 31 can be earned out using a suitable sulfur reagent such as Lawesson's reagent according to procedure of compounds 11a

The compounds of the present mvention can be used m the form of salts derived 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, sulfunc acid, nitπc 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 in such form, convert to the active moiety in vivo

This mvention includes pharmaceutical compositions compnsmg one or more compounds of this invention, preferably m combmation with one or more pharmaceutically acceptable earners and/or excipients The mvention also mcludes methods of contraception and methods of treatmg or preventing maladies associated with the progesterone receptor, the methods compnsmg administering to a mammal m need thereof a pharmaceutically effective amount of one or more compounds as described above wherem Q is oxygen as antagonists of the progesterone receptor The mvention further provides comparable methods and compositions which utilize one or more compounds herein wherem Q is S, NR⁶, or CR⁷R⁸ as agonists of the progesterone receptor

The progesterone receptor antagonists of this mvention, used alone or m combination, can be utilized m methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of mvention mclude the treatment and/or prevention of uterme myometπal fibroids, endometπosis, benign prostatic hypertrophy, carcmomas and adenocarcmomas of the endometπum, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagonists mclude the synchronization of the estrus m livestock

When used m contraception the progesterone receptor antagonists of the current mvention may be used either alone m a contmuous administration of between 0 1 and 500 mg per day, or alternatively used in a different regimen which would entail 2-4 days of treatment with the progesterone receptor antagonist after 21 days of a progestm In this regimen between 0 1 and 500 mg daily doses of the progestm (e g levonorgestrel, tπmegestone, gestodene, norethistrone acetate, norgestimate or cyproterone acetate) would be followed by between 0 1 and 500 mg daily doses of the progesterone receptor antagonists of the current mvention

The progesterone receptor antagonists of this mvention, used alone or m combmation, can also be utilized in methods of treatment and/or prevention of benign and malignant neoplastic disease Specific uses of the compounds and pharmaceutical compositions of mvention include the treatment and/or prevention of uterme myometnal fibroids, endometnosis, benign prostatic hypertrophy, carcinomas and adenocarcmomas of the endometπum, ovary, breast, colon, prostate, pituitary, memngioma and other hormone-dependent tumors Additional uses of the present progesterone receptor antagonists mclude the synchronization of the estrus m livestock The progesterone receptor agonists of this mvention, used alone or in combination, can be utilized m methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometnosis, polycystic ovary syndrome, carcmomas and adenocarcmomas of the endometπum, ovary, breast, colon, prostate Additional uses of the mvention include stimulation of food intake When used m contraception the progesterone receptor agonists of the current mvention are preferably used m combmation or sequentially with an estrogen agonist (e g ethmyl estradiol) The preferred dose of the progesterone receptor agonist is between 0 01 and 500 mg per day This mvention also mcludes pharmaceutical compositions compnsmg one or more compounds descnbed herein, preferably m combmation with one or more pharmaceutically acceptable carriers or excipients When the compounds are employed for the above utilities, they may be combmed with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally m such forms as tablets, capsules, dispersible powders, granules, or suspensions contammg, for example, from about 0 05 to 5% of suspending agent, syrups contammg, 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 stenle injectable solutions or suspensions contammg from about 0 05 to 5% suspending agent m an lsotonic medium Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active mgredient m combmation with the earner, more usually between about 5% and 60% by weight The effective dosage of active mgredient employed may vary dependmg on the particular compound employed, the mode of administration and the seventy of the condition bemg treated However, m general, satisfactory results are obtained when the compounds of the mvention are administered at a daily dosage of from about 0 5 to about 500 mg/kg of animal body weight, preferably given m dπ ιued doses two to four times a day, or m a sustamed release form For most large mammals, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg Dosage forms suitable for internal use comprise from about 0 5 to 500 mg of the active compound m intimate admixture with a solid or liquid pharmaceutically acceptable carrier This dosage regimen may be adjusted to provide the optimal therapeutic response For example, several divided doses may be administered daily or the dose may be proportionally reduced as mdicated by the exigencies of the therapeutic situation

These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes Solid earners mclude starch, lactose, dicalcium phosphate, microcrystalhne cellulose, sucrose and kaolm, while liquid carriers mclude steπle 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 mgredient and the particular form of admmistration desired Adjuvants customarily employed m the preparation of pharmaceutical compositions may be advantageously included, such as flavormg agents, colormg agents, preservmg 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 hquid-filled capsules Oral admmistration of the compounds is preferred These active compounds may also be administered parenterally or mtrapeπtoneally 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 m glycerol, liquid, polyethylene glycols and mixtures thereof m oils Under ordinary conditions of storage and use, these preparations contam 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 syrmge 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 contammg, for example, water, ethanol (e g , glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil

The following non-limiting examples illustrate preparation and use of the compounds of the mvention EXAMPLE 1 5-Bromo-2-oxo-2,3-dihydro-benzoimidazole-l-carboxyIic acid ferf-butyl ester

Prepared via a literature procedure (J Org Chem 60(6), 1565-82 (1995)) White solid mp 148-149 °C, 'H-NMR (DMSO-d₆) δ 11 4 (s, IH), 7 6 (d, IH, J = 8 57 Hz), 7 2 (dd, IH, J= 8 57, 4 29 Hz), 7 1 (s, IH), 1 6 (s, 9H), MS (ES) m/z 311([M-H] , 70%), 313 ([M-H]\ 70%)

EXAMPLE 2 l-Benzyl-6-bromo-l,3-dihvdro-benzoimidazol-2-one A mixture of 5-bromo-2-oxo-2,3-dιhydro-benzoιmιdazole-l-carboxylιc acid tert-butyl ester (2 5g, 8 mmol), benzyl bromide (1 2 mL, 10 mmol), potassium carbonate (1 38g, 10 mmol), and potassium iodide (50 mg) m the anhydrous acetonitπle was heated at 80 °C under nitrogen for 1 hour The reaction mixture was cooled to room temperature and treated with a saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (50 mL) The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x30 mL) The combmed organic layers were washed with brme (30 mL) and dried (MgS0₄) After removal of the solvent, the residue was taken up m tπfluoro acetic acid (10 mL, neat) and the solution was stirred at room temperature under nitrogen for 10 minutes The reaction solution was then treated with brme (30 mL) and ethyl acetate (50 mL) The organic layer was separated and dried (MgS0₄) After removal of the solvent, the residue was applied to a pad of silica gel to afford the title compound as white solid (1 89, 78%) mp 245-246 °C, 'H-NMR (DMSO-d₆) δ 11 2 (s, IH), 7 37-7 27 (m, 6H), 7 13 (dd, IH, J = 8 25, 2 25 Hz), 6 95 (d, IH, J= 8 25 Hz), 5 0 (s, 2H), MS (ES) m/z 301 ([M - H]^", 50%), 303([M - H] , 50%) EXAMPLE 3 5-Bromo-3-methyl-2-oxo-2, 3-dihydro-benzoimidazole-l-carboxylic acid tert- butyl ester

A mixture of 5-bromo-2-oxo-2,3-dιhydro-benzoιmιdazole-l-carboxylιc acid tert-butyl ester (4 0 g, 12 8 mmol), lodomethane (2 74 g, 9 2 mmol), and K₂C0₃ in CH₃CN (60 mL) was stirred at room temperature under a blanket of nitrogen overnight Upon completion of the reaction, ethyl acetate (200 mL) was added and the organic layer was washed with H₂0 (200 mL), dned over Na₂S0 , and concentrated The residue was purified via chromatography (sihca gel, 25% ethyl acetate/hexane) to give 5-bromo-3-methyl-2-oxo-2,3-dιhydro-benzoιmιdazole-l- carboxy c acid tert-butyl ester as a white solid mp 98-99 °C, Η-NMR (CDC1₃) δ 7 7 (d, IH, J= 8 5 Hz), 7 27 (bs, 2H), 7 09 (d, IH, J= 2 Hz), 3 4 (s, 3H), 1 7 (s, 9H), MS (ES) m/z 349([M + Na]⁺, 20%), 351([M + Na]⁺, 20%), Anal Calc For C₁₃H₁₅BrN₂O₃ C, 47 73, H, 4 62, N, 8 56 Found C, 47 46, H, 4 5, N, 8 29

EXAMPLE 4 6-Bromo-l-methyl-l,3-dihydro-benzoimidazoI-2-one Prepared from 5-bromo-3-methyl-2-oxo-2,3-dιhydro-benzoιmιdazole-l- carboxyhc acid tert-butyl ester in the same fashion as that of Example 2 White solid mp 237-238 °C, Η-NMR (DMSO-d₆) δ 11 0 (s, IH), 7 35 (d, IH, J= 1 58 Hz), 7 14 (dd, IH, J = 7 89, 1 58 Hz), 6 92 (d, IH, J= 7 89 Hz), 3 3 (s, 3H), MS (ES) m/z 227([M + H]⁺, 50%), 229([M + H]⁺, 50%), Anal Calc For C₈H₇BrN₂O C, 42 32, H. 3 11, N, 12 3*4 Found C, 42 35, H, 3 07 N, 11 89

EXAMPLE 5 l-Benzyl-6-(3-chloro-phenyl)-l,3-dihydro-benzoimidazol-2-one

A mixture of l-benzyl-6-bromo-l,3-dιhydro-benzoιmιdazol-2-one (0 75 g, 2 5 mmol), 3-chloro-phenyl boronic acid (0 4 g, 2 6 mmol), tetrakιs(tnphenylphosphιne)- palladium (0) (0 23 g, 0 2 mmol), and potassium carbonate (0 72 g, 5 2 mmol) m toluene (15 mL) and H₂0 (8 mL) was subject to a blanket of nitrogen for 15 minutes at 50 °C and then heated to 85 °C for 1 hour The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added The organic layer was washed twice with aqueous ammonium chlonde (30 mL) and once with brme (30 mL), dned over magnesium sulfate and concentrated After removal of the solvent, the residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give l-benzyl-6-(3-chloro-phenyl)-l,3-dιhydro-benzoιmιdazol-2-one as a white solid (0 134 g, 16%) mp 168-169 °C, Η-NMR (DMSO-d₆) δ 11 0 (s, IH), 7 66 (t, IH, J= 2 05 Hz), 7 58-7 5 (m, IH), 7 45 (t, 2H, J= 8 18 Hz), 7 37-7 22 (m, 7 H), 7 08 (d, IH, J = 8 18 Hz), 5 1 (s, 2H), MS (ES) m/z 333([M - H]\ 100%), Anal Calc For C₂₀H₁₅ClN₂O C, 71 75, H, 4 52, N, 8 37 Found C, 70 27, H, 4 56, N, 8 0

EXAMPLE 6 l-Benzyl-6-(3-nitro-phenyl)-l,3-dihydro-benzoimidazol-2-one Prepared from l-benzyl-6-bromo-l,3-dιhydro-benzoιmιdazol-2-one and 3- nitro-phenyl boronic acid m the same fashion as that of Example 5 White solid mp 202-203 °C, 'H-NMR (DMSO-d₆) δ 11 2 (s, IH), 8 38 (t, IH, J= 1 97 Hz), 8 15 (dd, IH, J = 7 83, 1 97 Hz), 8 80 (d, IH, J= 7 83 Hz), 7 72 (t, IH, J = 7 83 Hz), 7 56 (bs, IH), 7 43-7 22 (m, 6H), 7 13 (d, IH, J= 7 83 Hz), 5 1 (s, 2H), MS (ES) m/z 344([M - H] , 100%), Anal Calc For C₂oH₁₅N₃θ₃ 0 25 H₂0 C, 68 66, H, 4 46, N, 12 01 Found C, 68 42, H, 4 44, N, 11 77

EXAMPLE 7 l-Methyl-6-(3-nitro-phenyl)-l., 3-dihydro-benzoimidazol-2-one Prepared from l-methyl-6-bromo-l,3-dιhydro-benzoιmιdazol-2-one and 3- nitro-phenyl boronic acid m the same fashion as that of Example 5 White solid mp 264-265 °C, 1H-NMR (DMSO-d₆) δ 11 0 (s, IH), 8 47 (t, IH, J = 1 5 Hz), 8 19-8 15 (m, 2H), 7 75 (t, IH, J = 8 25 Hz), 7 58 (d, IH, J = 1 5 Hz), 7 43 (dd, IH, J = 8 25, 1 5 Hz), 7 1 (d, IH, J= 8 25 Hz), 3 37 (s, 3H), MS (ES) m/z 268([M - H] , 50%), Anal Calc For C₁₄H„N₃θ₃ C, 62 45, H, 4 12, N, 15 61 Found C, 61 48, H, 4 36

N, 14 75

EXAMPLE 8 6-(3-chloro-phenyl)- 1-methyl- 1,3-dihyd ro-benzoimidazol-2-one

Prepared from l-methyl-6-bromo-l, 3-dιhydro-benzoιmιdazol-2-one and 3- chloro-phenyl boronic acid m the same fashion as that of Example 5 mp 219-220 °C, Η-NMR (DMSO-d₆) δ 11 0 (s, IH), 7 75 (bs, IH), 7 65 (dd, IH, J= 7 5, 1 76 Hz). 7 49-7 44 (m, 2H), 7 39-7 32 (m, 2H), 7 06 (d, IH, J= 7 94 Hz), 3 35 (s, 3H), MS (ES) m/z 259([M + H]⁺, 100%), Anal Calc For C₁₄H* ,C1N₂0 C, 65, H, 4 29, N, 10 83 Found C, 64 44, H, 4 36 N, 10 6

EXAMPLE 9 5-(3-Nitro-phenyl)-l,3-dihydro-benzoimidazol-2-one Prepared from 5-bromo-l,3-dιhydro-benzoιmιdazol-2-one and 3-nιtro-phenyl boronic acid m the same fashion as that of Example 5 White solid mp 324-325 °C, Η-NMR (DMSO-d₆) δ 10 8 (s, 2H), 8 4 (m, IH), 8 15 (d, IH, J = 7 5 Hz), 8 1 (d, IH, J= 7 5 Hz), 7 7 (t, IH, J = 7 5 Hz), 7 35 (d, IH, J= 7 5 Hz), 7 3 (s, IH), 7 05 (d, IH, J= 7 5 Hz), MS (ES) m/z 254 ([M - H] , 100%), Anal Calc For C13H9N3O3 C, 61 18, H, 3 55, N, 16 46 Found C, 60 5, H, 3 69 N, 15 53

EXAMPLE 10 4-Amino-3'-nitro-biphenyl-3-ol

4-Ammo-3-methoxy-3'-nιtro-bιphenyl was prepared from 4-bromo-2- methoxyaralme (Synth Commun 23(6), 855-9(1993)) and 3-nιtrophenyl boronic acid accordmg to the procedure of Example 5 White solid mp 167-168 °C, Η-NMR (CDCI₃) δ 8 39 (t, IH, J- 1 97 Hz), 8 13-8 09 (m, IH), 7 88-7 84 (m, IH), 7 55 (t, IH, J= 8 0 Hz), 7 09 (dd, IH, J= 7 98, 1 94 Hz), 7 04 (d, IH, J= 1 89 Hz), 6 80 (d, lH, J = 8 04 Hz), 4 0 (s, 5H) 4-Amιno-3-methoxy-3'-nιtro-bιphenyl was then stirred with boron tπbromide m dichloromethane to give 4-ammo-3'-nιtro-bιphenyl-3-ol as an orange solid mp 175-176 °C, 'H-NMR (DMSO-d₆) δ 9 3 (s, IH), 8 25 (bs, IH), 8 05 (d, IH, J = 8 33 Hz), 7 95 (d, IH, J= 8 33 Hz), 7 66 (t, IH, J = 7 5 Hz), 7 06-7 02 (m, 2H), 6 70 (d, IH, J= 8 33 Hz), 4 9 (s, 2H), MS (ES) m/z 229 ([M - H]\ 100%)

EXAMPLE 11 6-(3-Nitro-phenyl)-3H-benzooxazol-2-one

A solution of 4-amιno-3'-nιtro-bιphenyl-3-ol (0 115 g, 0 5 mmol) in dry THF (2 5 mL) was treated with a solution of 1 , 1 '-carbonyldiimidazole (0 098 g, 0 6 mmol) m dry THF (2 5 mL) The reaction mixture was stirred at room temperature under a blanket of nitrogen for 6 hours A precipitate formed, was collected and washed with methylene chloride (50 mL) to give 6-(3-nιtro-phenyl)-3H-benzooxazol-2-one (0 095 g, 74%) as a white solid mp 280-281 °C, Η-NMR (DMSO-d₆) δ 11 7 (s, IH), 8 43 (t, IH, J= 1 15 Hz), 8 2-8 13 (m, 2H), 7 79-7 72 (m, 2H), 7 59 (dd, IH, J = 8 08, 2 31 Hz), 7 21 (d, IH, J= 8 08 Hz), MS (ES) m/z 255([M - H] , 100%), Anal Calc For C₁₃H₈N₂0₄ C, 60 94, H, 3 15, N, 10 93 Found C, 59 95, H, 3 17 N, 10 77

EXAMPLE 12 6-(3-Nitro-phenyl)-3H-benzothiazol-2-one

A mixture of 6-bromo-2-benzothιazolmone (5 0 g, 21 7 mmol), 3-nιtrophenyl boronic acid (5 0 g, 30 0 mmol), tetrakιs(tnphenylphosphme)-palladιum (0) (1 73 g, 1 5 mmol), and potassium carbonate (8 0 g, 58 0 mmol) m toluene (100 mL), H₂O (20 mL), and ethanol (30 mL) was subject to a blanket of nitrogen for 15 mmutes at 50 °C and then was heated at 85 °C for 24 hours The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) was added The organic layer was washed with aqueous ammonium chloride (2x50 mL) and with brme (100 mL), dried over magnesium sulfate and concentrated The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 6-(3-nιtro-phenyl)-3H-benzothιazol-2- one as a brown solid (0 1 g, 1 8 %) mp 276-277 °C, Η-NMR (DMSO-dg) δ 11 (s, IH), 8 44 (t, IH, J = 2 7 Hz), 8 21-8 08 (m, 3H), 7 78-7 69 (m, 2H), 7 24 (d, IH, J = 9 23 Hz), MS (ES) m/z 271 ([M - H] , 100%), Anal Calc For C₁₃H₈N₂O₃S 0 25 H₂0 C, 56 41, H, 3 10, N, 10 12 Found C, 56 48, H, 3 11, N, 9 99

EXAMPLE 13 6-(3-Chloro-phenyl)-3H-benzothiazoI-2-one Prepared from 6-bromo-2-benzothιazolmone, 3-nιtrophenyl boronic acid accordmg to the procedure of example 12 A white solid mp 195-196 °C, ^]H-NMR (DMSO-dβ) δ 1 1 95 (s, IH), 7 96 (d, IH, J = 1 17 Hz), 7 7 (t, IH, J= 1 76 Hz), 7 62- 7 59 (m, 2H), 7 46 (t, IH, J = 7 65 Hz), 7 4-7 38 (m, IH), 7 18 (d, IH, J = 8 24 Hz), MS (El) m/z 261 (M⁺, 30%), Anal Calc For C₁₃H₈C1N0S 0 5 H₂0 C, 57 67, H, 3 35, N, 5 17 Found C, 57 98, H, 3 11, N, 4 98

EXAMPLE 14

7-(3-Nitro-phenyl)-4H-benzo[l,41thiazin-3-one

A mixture of 2-amιno-5-bromo-benzenethιol (20 g, 0 1 mol), ethyl bromoacetate (19 g, 0 1 mol), and sodium bicarbonate (8 8 g, 0 i mol) m DMF (200 ml) was heated to reflux for 2 hours The mixture was diluted with water and extracted with ethyl acetate (2x100 mL) The combmed organic extracts were washed with water, then brine, dried (MgS0₄) and evaporated to obtain the crude 7-bromo- 4H-benzo[l,4]thιazm-3-one (20 g, 82%) A small portion of sample was recrystallized from ethanol to afford pure 7-bromo-4H-benzo[l,4]thιazm-3-one mp 212 -213 °C, MS (El) m/z 243/245 (M⁺) A solution of 7-bromo-4H-benzo[l,4]thιazιn-3-one (2 g, 8 2 mmol), 3- nitrophenyl boronic acid (2 72 g, 16 4 mmol), potassium carbonate (6 85 g, 49 2 mmol), and tetrakιs(tπphenylphosphιne) palladιum(O) (0 95 g, 0 82 mmol) m dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3x50 mL) The combmed organic extracts were washed with water, then brme, dried (MgS0₄) and evaporated to obtain crude 7-(3-nιtro-phenyl)- 4H-benzo[l,4]thιazιn-3-one (0 15 g, 6%) Recrystalhzation of crude sample from EtOAc afforded the title compound mp 290-292 °C, MS (El) m/z 286 (NT )

EXAMPLE 15

2-Ethyl-7-(3-nitro-phenyl)-4H-benzo[l,41thiazin-3-one

To a mixture of 2-amιno-5-bromo-benzenethιol (20 g, 0 1 mol) and cesium carbonate (33 g, 0 1 mol) in DMF (500 ml) at -35 °C was added dropwise 2- bromobutyrylbromide (23 g, 0 1 mol) The mixture was allowed to warm to room temperature, poured mto ice/water, and extracted with CH₂C1₂ (2x50 mL) The combmed organic extracts were washed with water, then brme, dried (MgS0₄) and evaporated The residue was purified by column chromatography (Sι0₂, ethyl acetate hexane/1 6) to afford 7-bromo-2-ethyl-4H-benzo[l,4]thιazιn-3-one (3 7 g, 14%) mp 100 °C, MS (El) m/z 271/273 (M⁺)

A solution of 7-bromo-2-ethyl-4H-benzo[l,4]thιazm-3-one (2 g, 7 3 mmol), 3- nitrophenyl boronic acid (1 22 g. 7 3 mmol), potassium carbonate (3 g, 22 mmol), and tetrakιs(tπphenylphosphme)palladιum(0) (0 84 g, 0 72 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3x40 mL) The combmed organic extracts were washed with water, then brme, dried (MgSO₄) and evaporated The residue was recrystallized from ethanol to afford the title compound as tan crystals (0 17 g, 7 3%) mp 180 °C, MS (El) m/z 314 (M") EXAMPLE 16

8-(3-Chloro-phenyl-l,2,3-,3a-tetrahydro-5H-pyrrolo[l,2- al q uinoxalin-4-one

To a mixture of acetic acid (500 ml), 30% hydrogen peroxide (250 ml), and concentrated sulfuric acid (10 ml) was added 4-bromo-2-fluoroaniline (50 g, 0 26 mol) at 85 ± 5 °C over 20 mmutes The reaction mixture was allowed to cool to room temperature and filtered The solution was diluted with water and extracted with EtOAc (2x100 mL) The combined organic extracts were washed with water, then brme, dried (MgSO₄) and evaporated The semisolid residue was filtered and the crude 4-bromo-2-fluoro-l -mtro-benzene was sublimed in vacuo to afford 4-bromo-2- fluoro-1 -mtro-benzene (23 g, 40%) mp 82-83 °C, Η-NMR (DMSO-d₆) δ 7 64 - 7 70 (m, IH), 8 0 (dd, IH, J= 11 0, 1 98 Hz), 8 1 (t, IH, J = 8 57 Hz), MS (El) m/z 219/221 (M")

A mixture of 4-bromo-2-fluoro-l -mtro-benzene (9 g, 40 mmol). L-prolme (4 6g, 40 mmol), and potassium carbonate (7 g, 50 mmol) m ethanol (50 ml) and water (40 ml) was heated to reflux for 5 hours After coolmg to room temperature, the mixture was diluted with water and was adjusted to pH 6 with IN aqueous HCl solution The mixture was extracted with EtOAc (2x100 mL), the combmed organic extracts were washed with water, then brme, dried (MgS0₄) and evaporated to afford iV-(5-bromo-2-nιtro-phenyl)-pyrrolιdme-2-carboxyhc acid (6 g, 48%) which was used m next step without further purification

A solution of iV-(5-bromo-2-nιtro-phenyι)-pyrrolιdιne-2-carboxylιc acid (6g, 23 mmol) and tιn(II) chloride dmydrate (16 5 g, 73 mmol) m ethanol (200 ml), water (30 ml) and concentrated HCl (10 ml) was heated to reflux for 6 hours After cooled to room temperature, the mixture was diluted with water and was adjusted to pH 9 with 2N aqueous sodium hydroxide solution After addition of EtOAc, the precipitated tin hydroxide was filtered off The layers were separated and the organic layer was washed with water, then brme. dried (MgS0₄) and evaporated to afford 8-bromo- 1,2,3, 3a-tetrahydro-5H-pyrrolo[l,2-a]qumoxalιn-4-one (3 7 g, 60%), which was used without further purification

A solution of 8-bromo-l,2,3,3a-tetrahydro-5H-pyrrolo[l,2-a]qumoxalιn-4-one (2 7 g, 10 mmol), 3-chlorophenyl boromc acid (1 6 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakιs(tnphenylphosphιne) palladιum(0) (0 5 g, 0 43 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours After cooled to room temperature, the mixture was diluted with water and extracted with EtOAc (3x60 mL) The combmed organic extracts were washed with water, then brine, dned (MgS0₄) and evaporated The crude product (1 5 g) was recrystallized from EtOAc/hexane to afford the title compound (0 2 g, 7%) mp 210°C, MS (+APCI) m/z 299 ([M+H]⁺)

EXAMPLE 17 6-(3-Chloro-phenyl)-4-methyl-3,4-dihvdro-lH-quinoxalin-4-one (5-Bromo-2-nitro-phenyl)-methyl-aminol-acetic acid

A mixture of 4-bromo-2-fluoro-l -mtro-benzene (9 g, 40 mmol), sarcosme (3 6g, 40 mmol), and potassium carbonate (5 5 g, 40 mmol) m ethanol (100 ml) and water (40 ml) was heated to reflux for 5 hours After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with IN aqueous HCl solution The yellow precipitate was collected, washed with water and dried in vacuo to obtain crude [(5-bromo-2-nιtro-phenyl)-methyl-amιno]-acetιc acid (10 g, 87%) A portion of the crude sample was recrystallized from EtOAc/hexane to afford the pure [(5-bromo-2-nιtro-phenyl)-methyl-amιno]-acetιc acid mp 152-155 °C, Η-NMR (DMSO-ds) δ 2 81 (s, 3H), 4 00 (s, 2H), 7 06 (dd, IH, J = 8 79, 1 98 Hz), 7 22 (d, IH, J = 1 98 Hz), 7 69 (d, IH, J = 8 79 Hz), 12 8 (s, IH), MS (+APCI) m/z 289/291 (M+H)⁺ A solution of [(5-bromo-2-nιtro-phenyl)-methyl-amιno]-acetιc acid (8g, 27 6 mmol) and tιn(II) chloride dihydrate (20 g, 88 mmol) m ethanol (200 ml), water (30 ml) and concentrated HCl (10 ml) was heated to reflux for 6 hours After coolmg to room temperature the mixture was diluted with water and was adjusted to pH 9 with 2N aqueous sodium hydroxide solution After addition of EtOAc, the precipitated tin hydroxide was filtered off The layers were separated and the organic layer was washed with water, then brme, dned (MgS0 ) and evaporated The residue was recrystallized from ethanol to afford 6-bromo-4-methyl-3,4-dιhydro-lH-quιoxalιn-2- one (2 4 g, 36%), which was used without further purification Η-NMR (DMSO-dg) δ 2 78 (s, 3H), 3 89 (s, 2H), 6 81 (d, IH, J= 1 76 Hz), 6 95 (dd, 1H, J = 8 49, 1 81 Hz), 7 05 (d, IH, J= 8 47 Hz), 10 63 (s, IH)

A solution of 6-bromo-4-methyl-3,4-dιhydro-lH-quιoxahn-2-one (2 4 g, 10 mmol), 3-chlorophenyl boronic acid (1 6 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakιs(tπphenylphosphιne) palladιum(0) (0 5 g, 0 43 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for

6 hours After coolmg to room temperature, the mixture was diluted with water and extracted with EtOAc (3x50 mL) The combmed organic extracts were washed with water, then brine, dned (MgS0₄) and evaporated The residue was purified by column chromatography (Sι0₂, EtOAc hexane/1 6) to afford the title compound (0 58 g, 21%) mp 140 °C, ^]H-NMR (DMSO-dβ) δ 2 82 (s, 3H), 3 65 (s, 2H), 6 82 (d, IH, J =

7 91 Hz), 6 90 (d, IH, J= 1 76 Hz), 6 99 (dd, IH, J= 8 13, 1 98 Hz), 7 3-7 32 (m, IH), 7 39 (t, lH, J = 7 91 Hz), 7 55 (dt, 1H, J= 7 91, 1 10 Hz), 7 64 (t, 1H, J= 1 98 Hz), 10 47 (s, IH), MS ((+)APCI) m/z 299 (M+H)⁺

EXAMPLE 18 5-(3, 4-Dihvdro-4-methyl-2-oxo-quinaxaIin-6-yl) thiophene-3-carbonitrile

3.4-Dιhydro-4-methyl-2-oxo-qumoxalm-6-yl) bororac acid

To a solution of 6-bromo-4-methyl-3,4-dιhydro-lH-qumoxahn-2-one (3 6g, 15 mmol) in THF (100ml) was added sodium hydride (0 6g, 15 mmol, 60% dispersion in mmeral oil) After stimng 30 mm at room temperature, the mixture was cooled to - 78°C and butyl lithium (2 5M in hexanes, 6 ml, 15 mmol) was added slowly After 30 mm trusopropyl bo rate (7ml, 30 mmol) was added and the mixture was allowed to warm to room temperature After 2 hrs hydrochlonc acid (IN, 200 ml) and EtOAc (200 ml) were added After stirring for 30 m , the pH was adjusted to 6 and the layers were separated The aqueous phase was extracted with EtOAc, then the combined organic layers were washed with water, brine, dried (MgSO₄) and evaporated The residue was triturated with ether, the precipitate was filtered off and dned in vacuo to obtain the subtitled compound (1 6g, 52%) as an off-white solid Η- NMR (DMSO-d₆) δ 2 78 (s, 3H), 3 62 (s, 2H), 6 75 (d, J = 7 58Hz, IH), 7 16 (s,lH), 7 18 (d, J= 7 86 Hz, IH), 7 85 (s, 2H), 10 45 (s, IH) MS (El) m/z 207 (M+H)⁺

A mixture of 3,4-dιhydro-4-methyl-2-oxo-qumoxalm-6-yl) bororac acid (1 6g, 80 mmol), 2-bromo-4-cyanothιophene (1 5 g, 80 mmol), potassium carbonate (3 3g, 24 mmol) and tetrakιs(tnphenylphosphme) palladium (0) (0 25g, 0 2 mmol) in dimethoxyethane (70 ml), ethanol (15 ml), and water (15 ml) was heated to reflux for 6 hrs After coolmg to room temperature the mixture was diluted with water and extracted with EtOAc (3x40 mL) The combmed organic layers were washed with water, then brine, dried (MgS0 ) and evaporated to obtain crude product (0 85g, 40%) The residue was purified by column chromatography (Sι0₂, 40% acetonitπle, 60% water) to afford the title compound mp 270 °C, Η-NMR (DMSO-d₆) δ 2 84 (s, 3H), 3 70 (s, 2H), 6 82 (d, J= 7 91 Hz, IH), 6 96 (d, J= 1 76 Hz, IH), 7 02 (dd. J = 7 91, 1 76 Hz, IH), 7 83 (d, J= 1 32 Hz, IH) 8 44 (d, J= 1 32 Hz, IH), 10 56 (s, IH), MS (El) m/z 269 (M⁺)

EXAMPLE 19

4-(«-Butyl)-6-(3-chloro-phenyl)-3,4-dihydro-lH quinoxalin-2-one

[(5-Bromo-2-nitro-phenyl)-n-butyl-amino]acetic acid

A mixture of 4-bromo-2-fluoro-nιtro benzene (34 g, 0 15 mol), N-w-butyl glycme (20 g, 0 15 mol) m ethanol (600 ml), and water (150 ml) was heated to reflux for 6 hours After cooling to room temperature, the mixture was diluted with 2N sodium hydroxide, extracted with CH₂C1₂ and pH was adjusted to 5 with IN HCl The mixture was extracted with CH₂C1₂ the CH₂C1₂ solution was dried (MgS0₄) and evaporated to obtain the crude product (11 g, 22%) as a brown oil, which was used without further punfication Η-NMR (DMSO-d₆) δ 0 84 (t, J = 7 30 Hz, 3H), 1 23 (m, 2H), 1 45 (m, 2H), 3 18 (t, J= 7 30 Hz, 2H), 3 91 (s, 2H), 7 16 (dd, J= 8 68, 1 91 Hz, IH), 7 40 (d, J = 1 94 Hz, IH), 7 69 (d, J= 8 68 Hz, IH), MS (El) m/z 331

(

6-Bromo-4-(n-butyl)-3.4-dιhvdro-lH-qumoxalm-2-one To a solution of [(5-bromo-2-nιtro-phenyl)-n-butyl-amιno]acetιc acid (1 lg, 33 mmol) in acetic acid (150 ml) was added iron powder (6g, 107 mmol) and the mixture was stirred for 2 hrs at 90°C The reaction mixture was cooled and filtered and the acetic acid was evaporated The remaining slurry was extracted with CH₂C1₂ (3x50 mL) The combmed CH₂C1₂ extracts were combmed, dried (MgS0₄) and evaporated (8 5 g, 90%) The product was used without further purification Η-NMR (DMSO- ds) δ 0 93 (t, J= 6 81 Hz, 3H), 1 35 (m, 2H), 1 51 (m, 2H), 3 18 (t, J = 6 92 Hz, 2H), 3 75 (s, 2H), 6 6-6 9 (m, 3H), 10 50 (s, IH)

A solution of 6-bromo-4-(n-butyl)-3,4-dehydro-lH-quιnoxalιn-2-one (8 5g, 30 mmol), 3-chlorophenyl boronic acid (5g, 30 mmol), potassium carbonate (12 5g, 90 mmol) and tetrakis- (tnphenylphosphme) palladium (0) (1 3g, 1 1 mmol) in dimethoxyethane (200 ml), ethanol (50 ml), and water (50 ml) was heated to reflux for 6 hrs After coolmg to room temperature, the mixture was diluted with water and extracted with EtOAc (3x) The combmed organic layers were washed with water, then brme, dried (MgS0₄) and evaporated to obtain crude product (7g, 74%) The residue was purified by column chromatography (Sι0₂, 20% EtOAc, 80% hexane) to afford the title compound, mp 110-115°C Η-NMR (DMSO-d₆) δ 0 93 (t, J = 7 35 Hz, 3H), 1 36 (m, 2H), 1 56 (m, 2H), 3 30 (m, 2H), 3 74 (s, 2H), 6 84 (d, J= 8 13 Hz, IH), 6 90 (d, J= 1 54 Hz, IH), 6 95 (dd, J = 8 13, 1 54 Hz, IH) 7 35 (m, IH), 7 43 (t, J= 7 91 Hz, IH), 7 55 (m, IH), 7 63 (t, 1 76 Hz, IH), 10 50 (s, 1Hz) MS ([+] APC I) m z 315 [M+H]⁺ + 1 chlonne

EXAMPLE 20 6-(3-Cvano-5-fluorophenyl)-4-isopropyl-3,4-dihvdro-lH- quinoxalin-2-one f(5-Bromo-2-nιtro-phenyl)-ιsopropyl-ammol-acetιc acid

A mixture of 4-bromo-2-fluoro-l -nitrobenzene (52 g, 0 24 mol), n- lsopropylglycine (26 g, 0 22 mol), potassium carbonate (32 g, 0 23 mol) in ethanol (700 ml) and water (140 ml) was heated to reflux for 3 hrs After coolmg to room temperature the mixture was diluted with water, extracted with CHC1 , and the pH was adjusted to 5 with IN HCl The yellow precipitate was filtered off, washed with water and dried m vacuo (31 g, 44%) Η-NMR (DMSO-d₆) δ 1 08 (d, J= 6 50 Hz, 6H), 3 55 (septet, J= 6 50 Hz, IH), 3 92 (s, 2H), 7 25 (dd, J= 8 65, 1 72 Hz, IH), 7 53 (d, J= 1 69 Hz, IH), 7 69 (d, J= 8 65 Hz, IH), 12 52 (bs, IH) 6-Bromo-4-ιsopropyl-3,4-dιhydro-lH-quιnoxalιn-2-one.

To a solution of [(5-bromo-2-nιtro-phenyl)-ιsopropyl-amιno] acetic acid (27 g, 85 mmol) m acetic acid (400 ml) was added iron powder (15 g, 0 27 mol) and the mixture was stirred for 2 hrs at 90 °C The reaction mixture was cooled, filtered, and the acetic acid was evaporated The remaining slurry was extracted with CH₂C1₂ (3 x 300 ml) The CH₂C1₂ extracts were combmed, dned (MgS0 ) and evaporated to afford the subtitled compound (16 8 g, 73%) Η-NMR (DMSO-d₆) δ 1 13 (d, J = 6 54 Hz, 6H), 3 57 (s, 2H), 3 99 (septet, J= 6 54 Hz, IH), 6 82 (dd, J = 8 23, 1 88 Hz, IH), 6 72 (d, J = 8 17 Hz, IH), 6 90 (d, J= 1 59 Hz, IH), 10 50 (s, IH) MS (El) 267/269 (M)⁺ + 1 bromine

(4-Isopropyl-2-oxo-3,4-dihydro-qumoxalm-6-yl)boronic acid.

To a solution of 6-bromo-4-ιsopropyl-3,4-dιhydro-lH-qumoxalm-2-one (8 1 g, 30 mmol) m THF (200 ml) was added sodium hydride (60% dispersion m mineral oil, 1 2 g, 30 mmol) After stirrmg for 30 mm at room temperature, the mixture was cooled to -78 °C and butyl lithium (2 5 M in hexanes, 12 5 ml, 30 mmol) was added slowly After 30 mm tπisopropyl borate (19 ml, 83 mmol) was added and the mixture was allowed to warm to room temperature After 2 hours, hydrochloric acid (IN, 350 ml) and ethyl acetate (350 ml) were added After stimng for 30 mm , the pH was adjusted to 6 and the layers were separated The aqueous phase was extracted with ethyl acetate, the combmed organic layers were washed with water, bnne, dried (MgSO ) and evaporated The residue was tnturated with ether, the precipitate filtered off and dried m vacuo to obtain the subtitled compound (3 5 g, 50%) as an off- white solid that was used without further purification Η-NMR (DMSO-d₆) δ 1 15 (d, J= 6 56 Hz, 6H), 3 51 (s, 2H), 4 04 (septet, J = 6 57 Hz, IH), 6 76 (d, J = 7 65 Hz, IH), 7 14 (d, J = 7 66 Hz, IH), 7 27 (s, IH), 7 84 (s, 2H), 10 41 (s, IH)

A solution of (3,4-dιhydro-4-ιsopropyl-2-oxoquιnoxalιn-6-yl)boronιc acid (1 15 g, 4 9 mmol), 3-bromo-5-fluoro-benzonιtπle (1 08 g, 5 4 mmol), potassium carbonate (2 75 g, 22 mmol), and tetrakis(tnphenylphosphine)palladium(0) (0 25 g, 0 2 mmol) m dimethoxyethane (70 ml), ethanol (15 ml) and water (15 mol) was heated to reflux for 6 hrs After cooling to room temperature the mixture was concentrated and the residue was dissolved m ethyl acetate and 2N sodium hydroxide The organic layer was washed with water, then brme, dried (MgS0₄) and evaporated The residue was triturated with ether, and the precipitate was filtered off to jiiord the title compound, mp 238-240 °C (0 5 g, 30%), Η-NMR (DMSO-d₆) δ 1 17 (d, J= 6 49 Hz, 6H), 3 59 (s, IH), 4 30 (septet, J= 6 54 Hz, IH), 6 89 (d, J = 8 00 Hz, IH), 7 11 (d, J= 8 08 Hz, IH), 7 76 (d, J= 8 34 Hz, IH), 7 91 (d, J= 10 47 Hz, IH), 8 06 (s, IH), 10 56 (s, IH) MS (ESI) m/z 308 [M-H]

EXAMPLE 21

6-(3-Chloro-4-fluoro-phenyl)-4-isopropyI-3,4-dihvdro-lH-quinoxalin-2-one

A mixture of (3,4-dιhydro-4-ιsopropyl-2-oxoquιnoxalιn-6-yl)boronιc acid (2 4 g, 10 mmol), 4-bromo-2-chlorofluorobenzene (2 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis(triphenylphosphme)palladium(0) (0 46 g, 0 4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml) and water (25 mol) was heated to reflux for 6 hrs After coolmg to room temperature the mixture was diluted with water and extracted with ethyl acetate (3x) The combmed organic layers were washed with water, then bnne, dned (MgS0₄) and evaporated to obtain crude product (2 9 g, 91%) Recrystalhzation from EtOAc/hexane afforded the title compound, mp 208-213 °C 'H-NMR (DMSO-ds) δ 1 16 (d, J = 6 59 Hz, 6H), 3 56 (s, 2H), 4 22 (septet, J = 6 59 Hz, IH), 6 86 (d, J= 7 91 Hz, IH), 6 96 (dd, 7 = 7 91, 1 76 Hz, IH), 7 01 (d, J =1 76 Hz, IH), 7 43 (t, J = 9 01 Hz, IH), 7 61 (m, IH), 7 82 (dd, J = 7 14, 2 31 Hz, IH), 10 47 (s, IH) MS (El) m/z 318 [M]⁺ + 1 chlorine

EXAMPLE 22 6-(3-Chloro-phenyl)-4-isopropyl-3,4-dihvdro-lH-quinoxalin-2-one

A mixture of 6-bromo-4-ιsopropyl-3,4-dιhydro-lH-qumoxalm-2-one (2 g, 75 mmol), 3-chlorophenylboronιc acid (1 6 g, 10 mmol), potassium carbonate (4g, 30 mmol) and tetrakis(triphenylphosphme)palladium(0) (0 4 g, 0 35 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hrs After coolmg to room temperature the mixture was diluted with water and extracted with EtOAc (3x50 mL) The combmed organic layers were washed with water, then brine, dried (MgS0 ) and evaporated to give crude product (1 5 g, 66%) Recrystallization from EtOAc/hexane afforded the title compound mp 146-150 °C

*H-NMR (DMSO-d₆) δ 1 16 (d, J= 6 37 Hz, 6H), 3 57 (s, 2H), 4 21 (septet, J= 6 59 Hz, IH), 6 87 (d, J= 7 91 Hz, IH), 6 98 (dd, J= 7 91, 1 76 Hz, IH), 7 02 (d, J = 1 76 Hz, IH), 7 35 (m, IH), 7 43 (t, J= 7 69 Hz, IH), 7 57 (m, IH), 7 66 (t, J = 1 76 Hz, IH), 10 48 (s, IH) MS (El) m/z 300 (M)⁺ + 1 chlorine EXAMPLE 23 -Pharmacology

The compounds of this invention were tested m the relevant assay as described below and their potency are m the range of 0 01 nM to 5 mM m the in vitro assays and 0 001 to 300 mg/kg m the in vivo assays The selected examples are listed in Table 1 and 2

Table 1

Alkaline Phosphatase hPR CV-1

Compound R, R₂ R₃ IC50 (nM) IC₅₀ (nM)

3-chlorophenyl Bn H 412

3-nιtrophenyl Bn H 230

3-chlorophenyl Me H 1370 phenyl

3-nιtrophenyl Me H 1529

3-nιtrophenyl H Me 750

3-nιtrophenyl isopropyl H 147

3-chlorophenyl isopropyl H 155 Table 2

B

Alkalme Phosphatase hPR CV-1

Compound Ri R₂ IC₅₀ (nM) IC₅₀ (nM)

Bl 3-nιtrophenyl H 220

B2 3-nιtrophenyl Et 295

Cl 3-chlorophenyl Me 600 1585

C2 3-chlorophenyl H 550 525

C3 2-(4-cyanothιo- Me 300 phenyl)

C4 3-chlorophenyl isopropyl 850

C5 3-chloro-4-fluoro- isopropyl 700 phenyl C6 3-chlorophenyl n-Bu 500 1 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 in T47D cells is measured The materials and methods used m this assay are as follows a Growth medium DMEM F12 (1 1) (GIBCO, BRL) supplemented with 10% (v/v) fetal bovme serum (not heat- mactivated), 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 stnpped fetal bovme serum, lOOU/ml penicillin, 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 Dickmson 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 appropriate vehicle (100% emanol 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 tπmegestone, the reference progestm agonist Twenty-four hours after treatment, the medium is discarded and cells are labeled with 10 mM BrdU (Amersham Life Science, Arlmgton Heights, IL) m treatment medium for 4 hr d Cell Proliferation Assay At the end of BrdU labeling, the medium is removed and BrdU mcorporation is measured usmg a cell proliferation ELISA kit (#RPN 250, Amersham Life Science) accordmg to manufacturer's mstructions Briefly, cells are fixed in an ethanol contammg fixative for 30 mm, followed by mcubation m a blocking 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'-tetramethylbenzιdme (TMB) substrate for 10-20 mm 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 m a plate reader at 450 nm withm 5 mm 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 EC₅₀ or IC₅₀ 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 in both smgle dose and dose response studies f Reference Compounds

Tπmegestone 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 EC₅₀ or IC₅₀ values are calculated

Table 3. Estimated EC50, standard error (SE), and 95% confidence intervals (CI) for individual studies

Compound Exp (nM) SE lower upper

Tπmegestone 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 IC50, standard error, and 95% confident interval for the antiprogestin, RU486

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 mcrease m BrdU mcorporation with SE, IC50 Concentration of a compound that gives half-maximal decrease m 0 1 tπmegestone induced BrdU mcorporation with SE 2 Rat decidualization assay

The objective of this procedure is used to evaluate the effect of progestms and antiprogestms on rat uterme decidualization and compare the relative potencies of various test compounds The materials and methods used m this assay are as follows a Methods: Test compounds are dissolved in 100% ethanol and mixed with corn oil (vehicle) Stock solutions of the test compounds m oil

(MazolaTM) are then 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 prior to the treatment of animals No difference m decidual response was found when these two vehicles were compared b Animals (RACUC protocol #5002)

Ovaπectomized mature female Sprague-Dawley rats (~60-day old and 230g) are obtained from Tacorac (Taconic Farms, NY) following surgery Ovaπectomy is performed at least 10 days prior 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 in 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 Folio wmg 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 receiving vehicle is included Determination of dose-response curves is carried out using 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, decidualization is induced in one of the uterme horns by scratching the antimesometπal luminal epithehum with a blunt 21 G needle The contralateral horn is not scratched and serves as an unstimulated control Approximately 24 hr following the final treatment, rats are sacrificed by Cθ2 asphyxiation and body weight measured Uteri are removed and trimmed of fat Decidualized (D-horn) and control (C-horn) uterme horns are weighed separately f Analysis of Results

The mcrease in weight of the decidualized uterme horn is calculated by D-horn/C-horn and logarithmic transformation is used to maximize normality and homogeneity of variance The Huber M-estimator is used to down weight the outlymg transformed observations for both dose-response curve fitting and one-way analysis of variance JMP software (SAS Institute, Inc ) is used for both oneway ANOVA and non-hnear dose-response analyses g Reference Compounds

All progestm reference compounds were run in full dose- response curves and the EC₅₀ for uterme wet weight were calculated

Table 5. Estimated ECso, standard error (SE), and 95% confidence intervals for individual studies

Compound Exp (mg/kg. 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 6. Estimated average ECso, standard error, and 95% confidence intervals for dose-response curves of 3 reference compounds

EC50 95% CI

Compound (mg/kg, 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 7. 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 admmistration Route the compound is administered to the animals Body weight Mean total animal body weight (default-kg)

D-hom Wet weight of decidualized uterme horn (default-mg)

C-horn Wet weight of control uterine horn (default-mg)

Decidual response [(D-C)/C]xl00%

Progestational activity Compounds that mduce decidualization significantly (p<0 05) compared to vehicle control are considered active Antiprogestational activity Compounds that decrease EC ₀ progesterone induced decidualization significantly (p<0 05)

EC₅₀ 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 m EC₅₀ progesterone mduced decidual response (default-mg/kg) 3 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 CV-1 cells co-transfected with human PR and PRE-luciferase plasmids The materials methods used in the assay are as follows a Growth medium DMEM (BioWhittaker) containing 10% (v/v) fetal bovme serum (heat mactivated), 0 1 mM MEM non- essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) Experimental medium DMEM (BioWhittaker), phenol red-free, contammg 10% (v/v) charcoal-stnpped fetal bovine serum (heat-mactivated), 0 1 mM MEM non-essential ammo acids, lOOU/ml penicillin, lOOmg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Cell culture, transfection. treatment, and luciferase assay

Stock CV-1 cells are maintained m growth medium Co-transfection is done using 1 2xl0⁷ 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 m 250 ml Electroporation is carried out at 260 V and 1,000 mF m a Biorad Gene Pulser II

After electroporation, cells are resuspended in growth medium and plated in 96-well plate at 40,000 cells/well m 200 μl Following overnight mcubation, 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 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 variance and nonlinear dose response curve fittmg for both agonist and antagonist modes Huber weightmg is used to downweight the effects of outliers EC₅₀ or IC₅₀ 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 tπmegestone are reference progestms and RU486 is the reference antiprogestm All reference compounds are run m full dose- response curves and the EC₅o or IC₅₀ values are calculated

Table 8. 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

Tπmegestone 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 9. Estimated IC_S0, standard error (SE), and 95% confident interval (CI) for the antiprogestin, RU486 from three individual studies

IC50 95% CI

Compound Exp (nM) SE lower upper

RU486 1 0028 0002 0019 0042

2 0037 0002 0029 0048

3 0019 0001 0013 0027

Progestational activity Compounds that mcrease 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)

ECso Concentration of a compound that gives half-maximal increase PRE- luciferase activity (default-nM) with SE

IC50 Concentration of a compound that gives half-maximal decrease in 3 nM progesterone mduced PRE-luciferase activity (default-nM) with SE 4 T47D cell alkalme phosphatase assay

The purpose of this assay is to identif) progestins or antiprogestins by determmmg a compound's effect on alkalme phosphatase activity m T47D cells The matenals 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 penicillin, 100 μg/ml streptomycm, and 2 mM GlutaMax (GIBCO, BRL) b Alkalme phosphatase assay buffer

I 0 1 M Tπs-HCL pH 9 8, contammg 0 2% Triton X-100

II 0 1 M Tπs-HCl, pH 9 8 contammg 4 mM p-nitrophenyl 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 medium. 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 antagorast activity, reference antiprogestins or test compounds were added m the presence of 1 nM progesterone The cells were mcubated at 37°C in a 5% C0₂/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 min 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 variance and nonlinear dose response curve fittmg for both agonist and antagonist modes Huber weighting is used to downweight the effects of outliers EC50 or IC50 values are calculated from the retransformed values JMP software (SAS Institute, Inc ) is used for both one-way analysis of variance and non-linear 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 EC50 or IC₅₀ values are calculated Table 10. Estimated EC50_? standard error (SE), and 95% confidence intervals (CI) for reference progestins from three independent experiments

EC50 95% CI

Compound Exp (nM) SE lower uDDer

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

Tπmegestone 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

Table 11. 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

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

EXAMPLE 24 l-Benzyl-6-(3-chlorophenyl)-l,3-dihvdro-2H-benzimidazole-2-thione

To a solution of l-benzyl-6-(3-chlorophenyl)-l,3-dιhydro-2H-benzιmιdazole-2- one (0 lg, 0 3 mmol) in anhydrous toluene was added under a blanket of nitrogen Lawesson's reagent (0 133g, 0 33 mmol) The mixture was heated to 110 °C under nitrogen for 3 hours, allowed to cool to ambient temperature, and the solvent was removed The residue was punfied by a silica gel chromatography (hexane ethyl acetate/5 1) to give the title compound as a yellow solid (0 03g, 29%) mp 211-212 °C, Η-NMR (DMSO-d₆) δ 12 99 (s, IH), 7 70 (t, IH, J = 1 7 Hz), 7 64 (m, IH), 7 58-7 61 (m, IH), 7 25-7 54 (m, 9H), 5 59 (s, 2H), MS (ESI) m/z 349 [M - H] , Anal Calc For C₂oH,5ClN₂S C, 68 46, H, 4 31, N, 7 98 Found C, 68 07, H, 4 23, N, 7 88

EXAMPLE 25 l-Benzyl-6-(3-nitrophenyl)-l,3-dihvdro-2H-benzimidazole-2-thione Prepared accordmg to the procedure for Example 24 from l-benzyl-6-(3- nιtrophenyl)-l,3-dιhydro-2H-benzιmιdazole-2-one (0 lg, 0 29 mmol) and Lawesson's reagent (0 13g, 0 32 mmol) A yellow solid (0 025g, 24%) mp 244-245 °C, Η-NMR (DMSO-d_δ) δ 13 08 (s, IH), 8 43 (s, IH), 8 20 (dd, IH, J= 8 2, 1 7 Hz), 8 12 (d, IH. J= 7 8 Hz), 7 72-7 78 (m, 2H), 7 62 (d, IH, J = 8 3 Hz), 7 25-7 43 (m, 6H), 5 62 (s, 2H), MS (ESI) m/z 360 [M - H] , Anal Calc For C₂oH₁₅ClN₂SO 2H₂0 C, 65 81, H, 4 25, N, 11 51 Found C, 65 56, H, 4 11, N, 11 29

EXAMPLE 26 6-(3-Nitro-phenyl )-4-methyl-3.4-dihvdro-lH-αuinoxalin-2-one Prepared accordmg to the procedure for Example 5 from 6-bromo-4-methyl-

3,4-dihydro-lH-quinoxahn-2-one ( 4 8 g, 20 mmol ), and 3-nιtrophenylboronιc acid (4 8 g, 30 mmol ) A red powder (0 95 g, 16 %) mp 237-243 °C 1H-NMR (DMSO- ds) δ 2 88 (s, 3H), 6 9 (d, J= 7 9 Hz, IH), 7 01 (d, J = 2 Hz, IH), 7 11 (dd, J = 7 9, 2 0 Hz, IH), 7 7 (t, J= 7 9 Hz, IH), 8 1 (m, 2H), 8 37 (t, J= 0 7 Hz), MS (ESI) m/z 283 ( M )⁺ EXAMPLE 27 6-( 4-Chloro-phenyl )-3-methyl-3,4-dihvdro-lH-quinoxalin-2-one

A mixture of 4-bromo-2-fluoro-l -mtro-benzene (22 g, lOOmmol), L-alarane (8 9 g, 100 mmol), and potassium carbonate (17 5 g, 125 mmol) m ethanol (250 ml), and water (200 ml) was heated to reflux for 5 hours After coolmg to room temperature, the mixture was diluted with water, and acidified with IN hydrochloric acid The precipitate was collected on a funnel and dried to afford N-(5-bromo-2- nιtrophenyl)-alanιne (28 9 g, 100%) A sample was recrystallized from ethanol m p 183-187 °C, Η-NMR (DMSO -d₆) δ 1 44 (d, J = 6 9 Hz, 3H), 4 56 (m, IH), 6 87 (d, J= 6 Hz, IH), 7 21 (d, J = 1 7 Hz, IH ), 7 99 (d, J= 7 Hz, IH), 8 36 (d, J = 7 Hz, IH), 13 27 (s, IH)

To a solution of N-(5-bromo-2-nιtrophenyl )-alarane (22 g, 76 mmol) m acetic acid (300 ml) was added iron powder (10 g, 180 mmol), and the mixture was stined for 2 hours at 90 °C The reaction mixture was cooled and filtered, and the acetic acid was evaporated The remainmg slurry was extracted with methylene chloride (3 x 200 ml ) The combmed extracts were combmed, dried over magnesium sulfate, filtered, and evaporated to afford 6-bromo-3-methyl-3,4-dιhydro-lH-qumoxalm-2-one (9 4 g, 51 %o ) A sample was recrystallized from ethanol mp 133-135 °C Η-NMR (DMSO-ds) δ 1 23 (d, J= 6 81 Hz, 3H), 3 80 (q, J= 6 81 Hz, ! ύ), 6 27 (bs, IH), 6 63 (d, J= 8 35 Hz, IH), 6 72 (dd, J= 8 35, 1 76 Hz, IH), 6 80 (d, J = 1 76 Hz, IH), 10 29 (s, IH)

A solution of 6-bromo-3-methyl-3,4-dιhydro-lH-qumoxalm-2-one ( 2 4 g, 10 mmol ), 4-chlorophenyl boronic acid ( 1 6 g, 10 mmol ), potassium carbonate ( 4 g, 30 mmol ), and tetrakιs-( tnphenylphosphme )palladιum (0) m dimethoxyethane ( 150 ml ), ethanol ( 25 ml ), and water ( 25 ml ) was heated to reflux for 6 hours After coolmg to room temperature the mixture was diluted with water, and extracted with ethyl acetate The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to obtam crude product (0 83 g, 30 %) A sample was recrystallized from ethanol to afford the title compound m p 228-230 °C Η-NMR (DMSO-d₆) δ 1 28 (d, J= 6 63 Hz, 3H), 3 83 (q, J= 6 63 Hz, IH), 6 16 (bs, IH), 6 81 (d, J= 8 00 Hz, IH), 6 91 (dd, J= 8 05, 1 9 Hz, IH), 6 95 (d, J= 1 7 Hz, IH), 7 46 (d, J = 8 6 Hz, 2H), 7 55 (d, J= 8 6 Hz, 2H), 10 32 (s, IH), MS (El) m/z 272/274

EXAMPLE 28

4-Benzyl-6-( 3-chlorophenyl)-3,4-dihvdroquinoxalin-2 (lH)-one

In a manner as descnbed above, 4-bromo-2-fluoro-l -mtro-benzene (11 g, 50 mmol), and N-benzyl-glycine ethyl ester (10 g, 50 mmol) were reacted to give crude [(5-bromo-nιtro-phenyl )-benzyl-amιno] -acetic acid (10 g, 55 %) This product was reacted with iron powder to obtam crude 4-benzyl-6-bromo-3,4-dιhydroquιnoxalιn- 2(lH)-one ( 5 g, 58 % ) A sample was recrystallized from ethyl acetate/hexane m p 174-176 °C Η-NMR (DMSO-d_≤) δ 3 75 (s, 2H), 4 43 (s, 2H), 6 71 (d, J = 1 9 Hz, IH), 6 81 (m, 2H), 7 32 (m, 5H), 10 57 (s, IH)

The title compound was prepared accordmg to the procedure for Example 5 from 4-benzyl-6-bromo-3,4-dιhydroqumoxalm-2(lH)-one (1 6 g, 5 mmol), and 3- chlorophenyl boronic acid (0 8 g, 5 mmol) An off-white powder (0 9 g, 51 %) m p 182-185 °C Η-NMR (DMSO-d₆) δ 3 74 (s, 2H), 4 54 (s, 2H), 6 87 (d, J = 0 7 Hz), 7 0 (m, 2H), 7 36 (m, 8H), 7 52 (t, J= 1 8 Hz, IH), 10 57 (s, IH), MS (ESI) m/z 349 (M+H) ⁺

EXAMPLE 29 Isopropyl 7-f 3-chlorophenyl )-3-oxo-3,4-dihydroquinoxalin-l(2H)-carboxylate To a solution of 7-bromo-3-oxo-3,4-dιhydroquιnoxahne (6 8 g, 30 mmol) m pyridme (50 ml) was added a solution of isopropyl chloroformate m toluene (35 ml, IM, 35 mmol) over 30 mmutes The mixture was triturated with water/chloroform, the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to obtain crude isopropyl 7-bromo-3-oxo-3,4-dιhydroqumoxalme-l(2H)- carboxylate(9 3 g, 97 %) A sample was recrystallized from ethanol m p 159-161 °C ^]H-NMR (DMSO-dβ) δ 1 25 (d, J= 6 2 Hz, 6H), 4 25 (s, 2H), 4 90 (sep, J = 6 2 Hz, 1H), 6 89 (d, J= 8 6 Hz, IH), 7 27 (dd, J= 9 1, 2 1 Hz, IH), 7 74 (s, IH), 12 51 (s, IH), MS (ESI) m/z 330/332 (M+NH₄ ) ⁺

The title compound was prepared accordmg to the procedure for Example 5 from isopropyl 7-bromo-3-oxo-3,4-dιhydroqumoxalme-l(2H)-carboxylate (6 3 g, 20 mmol), and 3-chlorophenyl bororac acid (3 2 g, 20 mmol) Off-white crystals (3 7 g, 49 %) m p 174-176 °C Η-NMR (DMSO-d₆) δ 1 27 (d, J = 6 4 Hz, 6H), 4 30 (s, 2H), 4 94 (sep, J = 6 2 Hz, IH), 7 04 (d, J = 8 3 Hz, IH), 7 50 ( m, 4H ), 7 61 (t, J = 1 9 Hz, 1 H), 7 86 (s, IH), 10 79 (s, IH), MS(APCI) m/z 345/347 ( M+H ) ⁺

EXAMPLE 30

Isopropyl 7-( 3-chlorophenyl)-3-thioxo-3,4-dihvdroquinoxaline-l(2H)- carboxylate

Prepared accordmg to the procedure for Example 24 from isopropyl 7-( 3- chlorophenyl)-3-oxo-3,4-dιhydroqumoxalme-l (2H)-carboxylate and Lawesson's reagent A yellowish solid m p 208-212 °C, Η-NMR (DMSO-dg) δ 1 27 (d, J = 6 1 Hz, 6H ), 4 62 (s, 2H), 4 94 (sep, J= 6 1 Hz, IH), 7 23 (m, 4H), 7 64 (t, J = 1 8 Hz, IH), 7 90 (s, IH), 12 80 (s, IH), MS (ESI) m/z 359/361 (M-H)

All publications cited m this specification are mcorporated herem by reference herem While the invention has been described with reference to a particularly preferred embodiment, it will be appreciated that modifications can be made without departing from the spirit 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 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 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 1

where

B is a bond between A and C=Q, or the moiety CR⁵R⁶,

R⁴, R⁵, R⁶ are mdependently selected from H, C* to C₆ alkyl, substituted C- to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, cyclic alkyl constructed by fusing R⁴ and R⁵ to from a 5 to 7 membered ring,

R¹ is selected from H, OH, NH₂, d to C₆ alkyl, substituted C* to C₆ alkyl, C₃ to C₆ alkenyl, substituted C* to C₆ alkenyl, alkynyl, substituted alkynyl, or COR^A, R^A is selected fromH, C* to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C alkoxy, Ci to C₃ ammoalkyl, or substituted C- to C₃ ammoalkyl,

R² is selected fromH, halogen, CN, N0₂, Ci to C₆ alkyl, substituted C- to C₆ alkyl, C* to C₆ alkoxy, substituted C* to C₆ alkoxy, Ci to C₆ ammoalkyl, or substituted Ci to C₆ ammoalkyl,

R³ is selected from a) or b)

a) R³ is a trisubstituted benzene rmg contammg the substituents X, Y and

Z as shown below

X is selected from the group of halogen, CN, Ci to C₃ alkyl, substituted Ci to C alkyl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ⁽hioalkoxy, substituted Ci to C₃ thioalkoxy, Ci to C₃ ammoalkyl, substituted Ci to C₃ ammoalkyl, N0₂, Ci to C perfluoroalkyl, 5 or 6 membered heterocychc rmg contammg 1 to 3 heteroatoms, COR^B, OCOR^B, or NR^cCOR^B,

R^B is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, C_t to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C aminoalkyl, or substituted Ci to C₃ aminoalkyl,

R^c is H, d to C₃ alkyl, or substituted Ci to C₃ alkyl, Y and Z are mdependent substituents taken from the group mcludmg H, halogen, CN, NO₂, Ci to C₃ alkoxy, Ci to C₃ alkyl, or Ci to C₃ thioalkoxy,

or b) R³ is a five or six membered rmg with 1, 2, or 3 heteroatoms from the group mcludmg O S, SO, S0₂ or NR⁷ and contammg one or two mdependent substituents from the group of H, halogen, CN, NO₂ and Ci to C₃ alkyl, Ci to C₃ alkoxy, G to C₃ ammoalkyl, COR^D, or NR^ECOR^D,

R^D is H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted G to C₃ alkoxy, G to C₃ ammoalkyl, or substituted G to C₃ aminoalkyl,

R^E is H, Ci to C₃ alkyl, or substituted G to C₃ alkyl,

R⁷ is H, or C, to C₃ alkyl,

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, progestm or estrogen is administered, 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 of Formula 1 m Claim 1 wherem

B is a bond between A and C=Q, or the moiety CR⁵R⁶, R⁴, R⁵, R⁶ are mdependent substituents from the group mcludmg H, G to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to Cβ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocychc, substituted heterocychc, or cyclic alkyl constructed by fusing R⁴ and R⁵ to from a 5 to 7 membered ring,

R¹ is H, OH, NH₂, C, to C₆ alkyl, substituted G to C₆ alkyl, or COR^A,

R^A is H, Ci to C₄ alkyl, C, to C₄ alkoxy,

R² is H, halogen, N0₂, G to C₃ alkyl. or substituted Ci to C₃ alkyl,

R³ is a disubstituted benzene rmg contammg the substituents X and Y as shown below

X is taken from the group of halogen, CN, Ci to C alkoxy, Ci to C₃ alkyl, N0₂, Ci to C₃ perfluoroalkyl, 5 membered heterocychc ring containing 1 to 3 heteroatoms, or Ci to C₃ thioalkoxy,

Y is a substituent on the 4' or 5' position from the group of H, halogen, CN, N0₂, Ci to C₃ alkoxy, Ci to C₄ alkyl, or Ci to C₃ thioalkoxy,

or a pharmaceutically acceptable salt thereof 3 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestm compound has the structure of Formula 1 m Claim 1 wherem

R³ is a five membered rmg with the structure

R⁷ is H, C, to C₃ alkyl, or C, to C₄ C0₂alkyl,

X' is selected from the group of halogen, CN, N0₂, Ci to C alkyl or Ci to C₃ alkoxy,

Y' is H or Ci to C₄ alkyl, and

N B, R¹, R², R⁴, R⁵, and R⁶ are as defined m Claim 2, or a pharmaceutically acceptable salt thereof

4 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestm compound has the structure of Formula 1 m Claim 1 wherein

R³ is a six membered ring with the structure

X¹ is Ν or CX²,

X² is halogen, CΝ or Ν0₂ , and A, B,

and R⁶ are as defined m Claim 2, or a pharmaceutically acceptable salt thereof

5 A method of Claim 1 wherem the progestational agent is levonorgestrel and the anti-progestm compound has the structure of Formula 1 m Claim 1 wherem

wherem

R¹ is selected fromH, OH, NH₂, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C to C₆ alkenyl, substituted Ci to C₆ alkenyl, alkynyl, substituted alkynyl, or COR^A,

R^A is selected from H, Ci to C₃ alkyl, substituted Ci to C₃ alkyl, aryl, substituted aryl, Ci to C₃ alkoxy, substituted Ci to C₃ alkoxy, Ci to C₃ ammoalkyl, or substituted Ci to C₃ ammoalkyl,

R⁴ is H, Ci to C₆ alkyl, substituted Ci to C₆ alkyl, C₂ to f alkenyl, substituted C to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to Cg cycloalkyl, substituted C to C₈ cycloalkyl, benzyl, or substituted benzyl, and

R³ is selected from halogen or a disubstituted benzene rmg contammg the substituents X and Y as shown below

X is taken from the group of halogen, CN, Q to C₃ alkoxy, Ci to O* alkyl, N0₂, Ci to C₃ perfluoroalkyl, or Ci to C₃ thioalkoxy,

Y is a substituent on the 4' or 5' position from the group of H, halogen, CN, N0₂, Ci to C alkoxy, Ci to C alkyl, or Ci to C₃ thioalkoxy, or a pharmaceutically acceptable salt thereof

6 A method of Claim 1 wherem the antiprogestm compound is 5-Bromo- 2-oxo-2,3-dihydro-benzoimidazole-l-carboxyhc acid tert-butyl ester or a pharmaceutically acceptable salt thereof

7 A method of Claim 1 wherem the antiprogestm compound is 1-Benzyl- 6-bromo-l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

8 A method of Claim 1 wherem the antiprogestm compound is 5-Bromo- 3-mefhyl-2-oxo-2, 3-dιhydro-benzoιmιdazole-l -carboxy lie acid tert-butyl ester or a pharmaceutically acceptable salt thereof

9 A method of Claim 1 wherem the antiprogestm compound is 6-Bromo- 1 -methyl- l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

10 A method of Claim 1 wherem the antiprogestm compound is 1-Benzyl- 6-(3-chloro-phenyl)-l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof 11 A method of Claim 1 wherem the antiprogestm compound is 1-Benzyl- 6-(3-nιtro-phenyl)-l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

12 A method of Claim 1 wherem the antiprogestm compound is 1-Methyl- 6-(3-nιtro-phenyl)-l, 3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

13 A method of Claim 1 wherem the antiprogestm compound is 6-(3- chloro-phenyl)-l -methyl- l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

14 A method of Claim 1 wherem the antiprogestm compound is 5-(3- Nιtro-phenyl)-l,3-dιhydro-benzoιmιdazol-2-one or a pharmaceutically acceptable salt thereof

15 A method of Claim 1 wherem the antiprogestm compound is 4-Amιno- 3'-nιtro-bιphenyl-3-ol or a pharmaceutically acceptable salt thereof

16 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Nιtro-phenyl)-3H-benzooxazol-2-one or a pharmaceutically acceptable salt thereof

17 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Nιtro-phenyl)-3H-benzothιazol-2-one or a pharmaceutically acceptable salt thereof

18 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Chloro-phenyl)-3H-benzothιazol-2-one or a pharmaceutically acceptable salt thereof 19 A method of Claim 1 wherem the antiprogestm compound is 7-(3- Nιtro-phenyl)-4H-benzo[l,4]thιazιn-3-one or a pharmaceutically acceptable salt thereof

20 A method of Claim 1 wherem the antiprogestm compound is 2-Ethyl-7- (3-mtro-phenyl)-4H-benzo[l,4]thιazιn-3-one or a pharmaceutically acceptable salt thereof

21 A method of Claim 1 wherem the antiprogestm compound is 8-(3- Chloro-phenyl-l,2,3,3a-tetrahydro-5H-pyrrolo[l,2-a]qumoxalin-4-one or a pharmaceutically acceptable salt thereof

22 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Chloro-phenyl)-4-methyl-3,4-dιhydro-lH-qumoxalm-4-one or a pharmaceutically acceptable salt thereof

23 A method of Claim 1 wherem the antiprogestm compound is 5-(3, 4- Dιhydro-4-methyl-2-oxo-qumaxalm-6-yl) thιophene-3-carbonιtπle or a pharmaceutically acceptable salt thereof

24 A method of Claim 1 wherem the antiprogestm compound is 4-(n- Butyl)-6-(3-chloro-phenyl)-3,4-dιhydro-lH quιnoxalιn-2-one [(5-Bromo-2-mtro- phenyl)-rø-butyl-ammo] acetic acid or a pharmaceutically acceptable salt thereof

25 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Cyano-5-fluorophenyl)-4-ιsopropyl-3,4-dιhydro-lH-qumoxalm-2-one or a pharmaceutically acceptable salt thereof 26 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Chloro-4-fluoro-phenyl)-4-ιsopropyl-3,4-dιhydro-lH-qumoxahn-2-one or a pharmaceutically acceptable salt thereof

27 A method of Claim 1 wherem the antiprogestm compound is 6-(3- Chloro-phenyl)-4-ιsopropyl-3,4-dιhydro-lH-quιnoxahn-2-one or a pharmaceutically acceptable salt thereof

28 The method of Claim 1 wherein 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

29 A method of Claim 1 which comprises admimstenng 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 levonorgesu ji, b) a second phase of 3 daily dosage units of an antiprogestm compound of Claim 1, each daily dosage unit contammg 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

30 A method of contraception which comprises admimstenng 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 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 remaining day of the 28 consecutive days

31 A method of contraception of Claim 30 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 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

32 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 contammg 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 unit contammg 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 33 A method of contraception of Claim 32 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 contammg 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 containing 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

34 A pharmaceutically useful kit adapted for daily oral admmistration 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 umt containing 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 in the first phase, second phase and third phase equals 28

35 A pharmaceutically useful kit adapted for daily oral admmistration of Claim 34 which compnses 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, b) a second phase of 3 daily dosage units of an antiprogestm compound of Claim 1, each daily dosage unit contammg 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

36 A pharmaceutically useful kit adapted for daily oral administration which compnses 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 m the first phase, second phase and third phase equals 28

37 A pharmaceutically useful kit adapted for daily oral admmistration of Claim 36 which comprises 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 38 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 unit compnsmg 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 unit contammg an antiprogestm of Claim 1 at a concentration of from 2 to 50 mg, and eth yl 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

39 A pharmaceutically useful kit adapted for daily oral administration of Claim 38 which comprises a) a first phase of 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 and ethmyl estradiol at a daily do^<*-c range of from about 10 to about 35 μg b) a second phase of 3 daily dose units, each daily dose unit contammg 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