This invention relates to compounds which are agonists and antagonists of the progesterone receptor, their preparation and utility.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists and/or antagonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Jones, et al, (U.S. Pat. No. 5,688,810) disclose the PR antagonist dihydroquinoline 1. 
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound 3 (U.S. Pat. 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). 
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, described the PR antagonist 11 (Chen, et al, POI-37, 16th Int. Cong. Het. Chem, Montana, 1997). 
Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360, 1997). 
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 benzimidazolinone 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 benzoimidazolinones such as compound C. Used as cAMP PDE III inhibitors, benzoimidazolinones, benzoxazolinones, and benzothiazolinones as shown in formula D were reported by Singh et al (J. Med. Chem., 37, 248-254 (1994)). 
The compounds in the present invention contain a pendent aromatic substituent and other substructural features. The aromatic substituents and those substructural features proved to be critical for the resultant compounds being active as progesterone receptor modulators.
Related to quinoxalin-2-ones, European patent (Ganzer et al. EP 311135) discloses the compounds such as E as herbicides. 
This invention provides compounds of the formula: 
wherein:
A is O, S, or NR4;
B is a bond between A and Cxe2x95x90Q, or the moiety CR5R6;
R4, R5, R6 are independently selected from H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, cyclic alkyl constructed by fusing R4 and R5 to from a 5 to 7 membered ring;
R1 is selected from H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 aLkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, or CORA;
RA is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 akoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R2 selected from H, halogen, CN, NO,2, C1 C6 alkyl, subsituted C1 to C6 aLkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R3 is selected from a) or b):
a) R3 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from the group of halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORB, OCORB, or NRCCORB;
RB is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RC is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or
b) R3 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O S, SO, SO2 or NR7 and containing one or two independent substituents from the group of H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R7 is H, or C1 to C3 alkyl;
Q is O, S, NR8, or CR9R10;
R8 is selected from the group of CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, or substituted heterocyclic, SO2CF3;
R9 and R10 are independent substituents from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, or CO2R11;
R11 is C1 C3 alkyl;
or CR9R10 may comprise a six membered ring of the structure below: 
or a pharmaceutically acceptable salt thereof.
Preferred compounds of this invention include those of the general formula described above wherein:
A is O, S, or NR4;
B is a bond between A and Cxe2x95x90Q, or the moiety CR5R6;
R4, R5, R6 are independent substituents from the group including H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or cyclic alkyl constructed by fusing R4 and R5 to from a 5 to 7 membered ring;
R1 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORA;
RA is H, C1 to C4 alkyl, C1 to C4 alkoxy;
R2 is H, halogen, NO2, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R3 is a disubstituted benzene ring containing the substituents X and Y as shown below 
X is taken from the group of halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkoxy; or
R3 is a five membered ring with the structure: 
wherein:
U is O, S, or NR7;
R7 is H, C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from the group of halogen, CN, NO2, C1 to C3 alkyl or C1 to C3 alkoxy;
Yxe2x80x2 is H or C1 to C4 alkyl; or
R5is a six membered ring with the structure: 
X1 is N or CX2;
X2 is halogen, CN or NO2,;
Q is O, S, NR7, CR8R9;
R8 is from the group of CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, or SO2CF3;
R9 and R10 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, or CN CO2R10;
R11 is C1 to C3 alkyl;
or CR9R10 comprise a six membered ring as shown by the structure: 
or a pharmaceutically acceptable salt thereof.
Another preferred subgroup of this invention comprises compounds of the general formula: 
wherein:
R1 is selected from H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, alkynyl, substituted alkynyl, or CORA;
RA is selected from H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4 is H, C1 to C6 alkyl, substituted C1 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 ring containing the substituents X and Y as shown below 
X is taken from the group of halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkoxy; or a pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, II, and III, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms; xe2x80x9calkenylxe2x80x9d is intended 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; xe2x80x9calkynylxe2x80x9d group is intended 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 xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl. The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl. The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl. The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl. The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl. The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups, containing one to eight carbon atoms, which may be either same or different and the point of attachment is on the nitrogen atom. The term xe2x80x9chalogenxe2x80x9d refers to Cl, Br, F, or I.
The compounds of the present invention can be prepared as described in the following schemes: 
As illustrated in Scheme I, the compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step and further converted to the thiourea analogues. Thus, appropriately protected benzoimidazolinones 1 (numerous protecting groups including but not limited to alkyloxycarbonyls, such as BOC group, can be employed in the starting material 1) readily prepared according to the procedure of Meanwell et al. (J. Org. Chem. 60, 1565-1582(1995)) can be alkylated at position-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 in an appropriate nonprotic solvent such as DMF followed by addition of an alkylating agent such as alkyl iodide or triflate. Alternatively, the compound 2 can be effected employing a Mitsunobu protocol. The conventional Mitsunobu reaction can couple the compound 1 with an appropriate alcohol using a phosphorous reagent such as triphenyl phosphine and a dehydrating agent such as DEAD (diethyl azodicarboxylate) in a suitable solvent such as THF at temperatures ranging from 0xc2x0 C. to the boiling point of the solvent employed. Deprotection of compound 2 to give 3 can be furnished via numerous conditions, such as acidic deprotection, using an acid such as neat trifluoroacetic acid or basic deprotection employing a base, such as sodium alkoxide in a suitable solvent, such as THF or alcohol at temperature ranging from ambient temperature to the boiling point of the solvent employed. The compounds of this invention, 4, can be readily prepared by employing various coupling reactions including Suzuki, Stille protocols. These reactions are commonly performed in the presence of transition metallic catalyst, e.g., palladium or nickel complex often with phosphino ligands, e.g., Ph3P, 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane or a catalyst such as palladium acetate. Under this catalytic condition, an appropriately substituted nucleophilic reagent, e.g., aryl boronic acid, arylstannane, or aryl zinc compound, is coupled with bromobenzoimidazolinones 3 to give compounds 4. An appropriate base is often needed in the reaction; the commonly used bases include but are 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, isopropanol, ethanol, DME, ether, acetone or a mixture of above solvent and water. The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95xc2x0 C.
The compounds of this invention, 5, can be easily prepared 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. 
As shown in scheme II, 5-aryl benzothiazolinones 7 can be readily prepared from an appropriate 5-bromo-benzothiazolinone 6 and a suitable electrophile such as an aryl boronic acid, aryl tin reagent, or aryl zinc reagent via a suitable coupling reaction as described for the synthesis of benzimidazolinones 4. Conversion of 7b into 7a can be effected 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.
The synthetic approaches leading to the 5-aryl benzoxazolinones 11 is described in scheme III. As illustrated in scheme III, an appropriately substituted bromo o-anisidine can be coupled with an appropriate electrophile such as aryl boronic acid or aryl tin reagent via a coupling reaction as described for the synthesis of compounds 4 to give the biaryl 9. Demethylation of biaryl 9 to give amino phenol 10 can be accomplished via various conditions including treatment of 9 with a strong Lewis acid such as boron tribromide in 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 in a suitable solvent such as methylene chloride under an inert atmosphere such as argon or nitrogen. Ring closure of amino phenol 10 to produce the compounds of this invention, 11, can be effected by using a appropriate condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65xc2x0 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 benzoxazolinone bioisosteres. Using 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 R9 or R10 is an electron withdrawing group) in a suitable solvent such as toluene or anhydrous ethanol under an inert atmosphere such as nitrogen or argon at reflux. In a similar fashion, compounds 13, 16, or 19 can be prepared by reaction of compound 10, 14, or 17 with appropriate imino-S, S-acetals or imino-acetals (R9 is an electron withdrawing group) employing a procedure similar to that of Evers, et al. (I. Prakt. Chem. 333(5), 699-710 (1991)) or Haake et al. (Synthesis-Stuttgart 9, 753-758 (1991)) in a suitable solvent such as ethanol under an inert atmosphere such as argon or nitrogen at reflux. 
Compounds 14 and 17 can be prepared as shown in schemes V and VI from compounds 4 and 7 using strong basic conditions such as heating the compound in a mixture of potassium hydroxide and ethylene glycol at 165xc2x0 C. under an inert atmosphere such as argon or nitrogen. 
As illustrated in Scheme VII, the compounds of this invention can be further derivatized at position-1 via numerous approaches leading to a variety of the novel compounds including 20, 21, and 22. Thus, alkyl or substituted alkyl derivatives 20 can be formed by treatment of compound A with a suitable base such as sodium hydride in suitable solvent such as DMF under an inert atmosphere such as argon or nitrogen followed by addition of an appropriate electrophile such as an alkyl or substituted alkyl bromide, iodide, or triflate. Such transformation of A at position-1 can also be effected using biphasic conditions as indicated in Scheme VII in which alkylation is executed using a biphasic catalyst such as tributylammonium bromide in a suitable solvent such as acetonitrile. A further example of such modification includes but is not limited to the one depicted in Scheme VIII via heating A with triethyl orthoformate to afford 1-substituted derivatives 20. 
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 carboxylating reagent such as di-t-butyl dicarbonate in the presence of a suitable basic catalyst such as DMAP in a suitable solvent such as acetonitrile under an inert atmosphere such as argon or nitrogen. The amination of position-1 of compound A to give compound 22 can be furnished using a suitable animating reagent such as chloroamine in 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 VIII describes a procedure to prepare quinoxalin-4-ones. An o-fluoro nitro-benzene 23 (X=I, Br, Cl) is reacted with an appropriately substituted amino acid derivative in the presence of a suitable base in a protic solvent such as alcohol to give compound 24 which is readily reduced by a suitable reducing agent such as tin chloride to furnish quinoxalin-2-one 25. The compounds of this invention, 26, can be easily produced by coupling an appropriate aryl boronic acid with compound 25 in a similar fashion as for the preparation of compound 9. Conversion of 26 to 27 can be readily effected following the procedure of synthesizing compound 11a. 
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
This invention includes pharmaceutical compositions comprising one or more compounds of this invention, preferably in combination with one or more pharmaceutically acceptable carriers and/or excipients. The invention also includes methods of contraception and methods of treating or preventing maladies associated with the progesterone receptor, the methods comprising administering to a mammal in need thereof a pharmaceutically effective amount of one or more compounds as described above wherein Q is oxygen as antagonists of the progesterone receptor. The invention further provides comparable methods and compositions which utilize one or more compounds herein wherein Q is S, NR6, or CR7R8 as agonists of the progesterone receptor.
The progesterone receptor antagonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Specific uses of the compounds and pharmaceutical compositions of invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometriun, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock.
When used in contraception the progesterone receptor antagonists of the current invention may be used either alone in a continuous 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 progestin. In this regimen between 0.1 and 500 mg daily doses of the progestin (e.g. levonorgestrel, trimegestone, 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 invention.
The progesterone receptor antagonists of this invention, used alone or in combination, 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 invention include the treatment and/or prevention of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors. Additional uses of the present progesterone receptor antagonists include the synchronization of the estrus in livestock.
The progesterone receptor agonists of this invention, used alone or in combination, can be utilized in methods of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake.
When used in contraception the progesterone receptor agonists of the current invention are preferably used in combination or sequentially with an estrogen agonist (e.g. ethinyl estradiol). The preferred dose of the progesterone receptor agonist is between 0.01 and 500 mg per day.
This invention also includes pharmaceutical compositions comprising one or more compounds described herein, preferably in combination with one or more pharmaceutically acceptable carriers or excipients. When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained 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 in 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 indicated by the exigencies of the therapeutic situation.
These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
USPTO Backgrounds
USPTO Backgrounds