Substituted 2-arylimino heterocycles and compositions containing them for use as progesterone receptor binding agents

Abstract

This invention relates to 2-arylimino heterocycles, including 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidin-4-ones, 2-arylimino-1,3-thiazolidin-5-ones, and 2-arylimino-1,3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.

We claim:  
     
         1 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R is 
 aryl of 6-14 carbons; or  
 heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S, with the proviso that R is other than benzofuran or benzothiophene;  
 
 R 1  is 
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons and containing 1-3 rings;  
 heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons and containing 1-3 rings; or  
 alkynyl of 3-10 carbons;  
 
 R 2 , R 3 , and R 4  are independently selected from the group consisting of 
 H;  
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons;  
 aryl of 6-13 carbons;  
 heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 R 5 ; wherein 
 R 5  is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;  
 
 halogen; and  
 ═O, representing two of the groups R 2 , R 3 , and R 4 ;  
 
 X is O or S(O) y ; wherein 
 y is 0, 1, or 2;  
 
 n is 2, 3, 4, or 5;  
 p is the sum of non-H substituents R 2 , R 3 , and R 4 ;  
 T is a substituent selected from the group consisting of alkyl of 1-4 carbons; 
 alkoxy of 1-4 carbons;  
 aryl of 6-10 carbons;  
 CO 2 H;  
 CO 2 R 5 ;  
 alkenyl of 2-4 carbons;  
 alkynyl of 2-4 carbons;  
 C(O)C 6 H 5 ;  
 C(O)N(R 6 )(R 7 ); wherein 
 R 6  is H or alkyl of 1-5 carbons; and  
 R 7  is H or alkyl of 1-5 carbons;  
 
 S(O) y R 8 ; wherein 
 y′ is 1 or 2; and  
 R 8  is alkyl of 1-5 carbons;  
 
 SO 2 F;  
 CHO;  
 OH;  
 NO 2 ;  
 CN;  
 halogen;  
 OCF 3 ;  
 N-oxide;  
 O—C(R 9 ) 2 —O, the oxygens being connected to adjacent positions on R; and wherein 
 R 9  is H, halogen, or alkyl of 1-4 carbons;  
 
 C(O)NHC(O) , the carbons being connected to adjacent positions on R; and  
 C(O)C 6 H 4  , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R;  
 
 t is 1-5; 
 provided that when substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 carbons, aryl of 6-10 carbons, CO 2 R 5 , alkenyl of 2-4 carbons, alkynyl of 2-4 carbons, C(O)C 6 H 5 , C(O)N(R 6 )(R 7 ), S(O) y R 8 , O—C(R 9 ) 2 —O , or C(O)C 6 H 4  , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; CO 2 R 5 ; CO 2 H; C(O)N(R 6 )(R 7 ); CHO; OH; NO 2 ; CN; halogen; S(O) y R 8 ; or ═O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;  
 
 G is a substituent selected from the group consisting of 
 halogen;  
 OH;  
 OR 5 ;  
 ═O, representing two substituents G;  
 alkyl of 1-4 carbons;  
 alkenyl of 1-4 carbons;  
 cycloalkyl of 3-7 carbons;  
 heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 cycloalkenyl of 5-7 carbons; heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 R 5 ;  
 C(O)N(R 6 )(R 7 );  
 aryl of 6-10 carbons;  
 heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 NO 2 ;  
 CN;  
 S(O) y R 8 ;  
 SO 3 R 8 ; and  
 SO 2 N(R 6 )(R 7 );  
 
 g is 0-4, with the exception of halogen, which may be employed up to the perhalo level; 
 provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;  
 
 Q is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 haloalkyl of 1-4 carbons;  
 cycloalkyl of 3-8 carbons;  
 alkoxy of 1-8 carbons;  
 alkenyl of 2-5 carbons;  
 cycloalkenyl of 5-8 carbons;  
 aryl of 6-10 carbons;  
 heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 RW;  
 ═O, representing two substituents Q;  
 OH;  
 halogen;  
 S(O) y R 8 ;  
 
 SO 3 R 8 ; and  
 SO 2 N( 6 )(R 7 );  
 q is 0-4 
 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and  
 with the further provisos that:  
 
 a) two of (Q) q R 1 , (Q) q R 2 , (Q) q R 3 , and (Q) q R 4  may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N,O and S;  
 b) when n=2 or 3, at least one of R 2 , R 3 , and R 4  is other than H;  
 c) when n=2, and X═O, if t=1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3-oxazolidine ring must bear a substituent;  
 d) when n=3 and X═O, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy;  
 e) when n=2 or 3 and X═O or S, then the sum of non-hydrogen atoms in R 1 , R 2 , R 3 , and R 4  is at least 5;  
 f) when n=2, X═O, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2- and 4- positions, then the 5-position of R bears H;  
 g) when n=2 and X═O, the 4-position of the 1,3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent;  
 h) when n=2, X═S(O) y , the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R 1  is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent;  
 i) when n=4, X═S, and G is CO 2 R 5 , then R 5  contains at least two carbons;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R is 
 phenyl; or  
 pyridyl;  
 
 R 1  is 
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons and containing 1-3 rings;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons;  
 
 R 2 , R 3 , and R 4  are independently selected from the group consisting of 
 H;  
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons; and  
 ═O, representing two of the groups R 2 , R 3 , and R 4 ;  
 
 X is O or S(O) y ; wherein 
 y is 0, I, or 2;  
 
 n is 2 or 3;  
 p is the sum of non-H substituents R 2 , R 3 , and R 4 ;  
 T is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 alkoxy of 1-4 carbons;  
 alkenyl of 2-4 carbons;  
 alkynyl of 2-4 carbons;  
 NO 2 ;  
 CN; and  
 halogen;  
 
 t is 1-5; 
 provided that when substituent moiety T is alkyl of 1-4 carbons, alkoxy of 1-4 - carbons, alkenyl of 2-4 carbons, or alkynyl of 2-4 carbons, then T optionally may bear secondary substituents selected from the group consisting of 
 alkyl of 1-4 carbons;  
 alkoxy of 1-4 carbons;  
 CO 2 R 5 ; wherein 
 R 5  is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;  
 
 CO 2 H;  
 C(O)N(R 6 )(R 7 ); wherein 
 R 6  is H or alkyl of 1-5 carbons; and  
 R 7  is H or alkyl of 1-5 carbons;  
 
 CHO;  
 OH;  
 NO 2 ;  
 CN;  
 halogen;  
 S(O) y R 8 ; wherein 
 R 8  is alkyl of 1-5 carbons; and  
 ═O, representing two secondary substituents;  
 
 
 the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;  
 
 G is a substituent selected from the group consisting of 
 halogen;  
 OR 5 ;  
 alkyl of 1-4 carbons;  
 alkenyl of 1-4 carbons;  
 cycloalkyl of 3-7 carbons;  
 cycloalkenyl of 5-7 carbons;  
 aryl of 6-10 carbons; and  
 CN;  
 
 g is 0-4, with the exception of halogen, which may be employed up to the perhalo level; 
 provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, or cycloalkenyl of 5-7 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;  
 
 Q is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 haloalkyl of 1-4 carbons;  
 cycloalkyl of 3-8 carbons;  
 alkoxy of 1-8 carbons;  
 alkenyl of 2-5 carbons;  
 cycloalkenyl of 5-8 carbons;  
 CO 2 R 5 ;  
 ═O, representing two substituents Q;  
 OH;  
 halogen;  
 N(R 6 )(R 7 ); and  
 S(O) y R 8 ;  
 
 q is 0-4; and  
 with the further provisos that:  
 a) two of (Q) q R 1 , (Q) q R 2 , (Q) q R 3 , and (Q) q R 4  may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N,O and S;  
 b) when n=2 or 3, at least one of R 2 , R 3 , and R 4  is other than H;  
 c) when n=2, and X═O, if t=1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3-oxazolidine ring must bear a substituent;  
 d) when n=3 and X═O, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl and alkoxy;  
 e) when n=2 or 3 and X═O or S, then the sum of non-hydrogen atoms in R 1 , R 2 , R 3 , and R 4  is at least 5;  
 f) when n=2, X═O, the 4-position of the 1,3-oxazolidine ring bears a carbonyl group, and R bears halogen at its 2- and 4- positions, then the 5-position of R bears H;  
 g) when n=2 and X═O, the 4-position of the 1,3-oxazolidine ring may bear a carbonyl only if the 5-position of said ring bears at least one non-H substituent; and  
 h) when n=2, X═S(O) y , the 4-position of the 1,3-thiazolidine ring bears a carbonyl group, R 1  is a substituted methyl group, and G is a phenyl group, then said phenyl group bears a secondary substituent;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R is 
 phenyl; or  
 pyridyl;  
 
 R 1  is 
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons and containing 1-3 rings;  
 alkenyl of 2-10 carbons; or  
 cycloalkenyl of 5-12 carbons and containing 1-3 rings;  
 
 R 2 , R 3 , and R 4  are independently selected from the group consisting of 
 H;  
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons;  
 alkenyl of 2-10 carbons; and  
 cycloalkenyl of 5-12 carbons;  
 
 X is O or S(O) y ; wherein 
 y is 0, 1, or 2;  
 
 n is 2 or 3;  
 p is the sum of non-H substituents R 2 , R 3 , and R 4 ;  
 T is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 alkenyl of 2-4 carbons;  
 NO 2 ;  
 CN; and  
 halogen;  
 
 t is 1-5; 
 provided that when substituent moiety T is alkyl of 1-4 carbons, or alkenyl of 2-4 carbons, then T optionally may bear secondary substituents selected from the group consisting of 
 alkyl of 1-4 carbons;  
 alkoxy of 1-4 carbons;  
 CO 2 R 5 ; wherein 
 R 5  is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;  
 CO 2 H;  
 C(O)N(R 6 )(R 7 ); wherein  
 R 6  is H or alkyl of 1-5 carbons; and  
 R 7  is H or alkyl of 1-5 carbons;  
 CHO;  
 OH;  
 NO 2 ;  
 CN;  
 halogen;  
 S(O) y R 8 ; wherein  
 R 8  is alkyl of 1-5 carbons; and  
 ═O;  
 
 
 the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;  
 
 G is a substituent selected from the group consisting of 
 halogen;  
 alkyl of 1-4 carbons;  
 alkenyl of 1-4 carbons;  
 cycloalkyl of 3-7 carbons;  
 cycloalkenyl of 5-7 carbons; and  
 aryl of 6-10 carbons;  
 
 g is 0-4, with the exception of halogen, which may be employed up to the perhalo level; 
 provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, or cycloalkenyl of 5-7 carbons, then G optionally may bear secondary substituents of halogen optionally may bear secondary substiti nts independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;  
 
 Q is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 haloalkyl of 1-4 carbons;  
 cycloalkyl of 3-8 carbons;  
 alkoxy of 1-8 carbons;  
 alkenyl of 2-5 carbons;  
 cycloalkenyl of 5-8 carbons; and  
 halogen;  
 
 q is 0-4; and  
 with the further provisos that:  
 a) two of (Q) q R 1 , (Q) q R 2 , (Q) q R 3 , and (Q) q R 4  may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N,O and S;  
 b) when n=2 or 3, at least one of R 2 , R 3 , and R 4  is other than H;  
 c) when n=2, and X═O, if t=1, then T is selected from the list of substituents T above excepting alkyl, and the 4-position of the 1,3-oxazolidine ring must bear a substituent;  
 d) when n =3 and X═O, if t is equal to or greater than 1, then at least one T is selected from the list of substituents T above, excepting alkyl;  
 e) when n=2 or 3 and X═O or S, then the sum of non-hydrogen atoms in R 1 , R 2 , R 3 , and R 4  is at least 5;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         4 . A compound of  claim 1  selected from the group consisting of: 
 (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine;  
 (4S)-2-(2-methyl4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine;  
 (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(trifluoromethyl)-1,3-thiazolidine;  
 (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isobutyl-1,3-thiazolidine;  
 (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-thiazolidine;  
 (4S)-2-(2-methyl-4-nitrophenylimino)-3-cyclopentyl-4-isopropyl-1,3-thiazolidine;  
 (4R)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyltetrahydro-2H-1,3-thiazine;  
 (4S)-2-(4-nitro-1-naphthylimino)-3-cyclopentyl-4-((1R)-1-hydroxyethyl)-1,3-thiazolidine;  
 2-(4-cyano-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(4-cyanophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(4-cyano-2-methylphenylimino)-1-isobutyl-3-thia-l -azaspiro[4.4]nonane;  
 2-(4-cyano-2,3-dimethylphenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(4-cyano-2-methylphenylimino)-1-(1-ethyl-i -propyl)-3-thia-1-azaspiro[4.4]nonane;  
 2-(4-cyano-1-naphthylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(2-methyl-4-nitrophenylimino)-1-(prop-2-en-1-yl)-3-thia-1-azaspiro[4.4]nonane;  
 2-(2-methyl-4-nitrophenylimino)-1-isopropyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(2-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro[4.4]nonane;  
 2-(2,3-dimethyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane; and  
 2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.  
 
     
     
         5 . A compound of  claim 1  selected from the group consisting of: 
 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one;  
 2-(3-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one;  
 2-(2-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one;  
 2-(3-methyl-4-nitrophenylimino)-3-benzyl-1,3-thiazolidin-4-one;  
 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one;  
 2-(2-ethyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidin-4-one;  
 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazolidin-4-one;  
 2-(3-methyl-4-nitrophenylimino)-3-(1-cyclohexyl-1-ethyl)-1,3-thiazolidin-4-one;  
 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-1,3-thiazolidin-4-one;  
 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methylene-1,3-thiazolidin-4-one; and  
 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-5-methyl-1,3-thiazolidin-4-one.  
 
     
     
         6 . A compound of  claim 1  selected from the group consisting of: 
 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4,4-dimethyl-1,3-oxazolidine;  
 1-cyclopentyl-2-(4-cyano-2-ethylphenylimino)-3-oxa-1-azaspiro[4.4]nonane;  
 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane; and  
 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-1-azaspiro[4.4]nonane.  
 
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1 ,  2 ,  3 ,  4 ,  5  or  6 , and a pharmaceutically acceptable carrier.  
     
     
         8 . A method of treating a mammal by administering to said mammal an effective amount of a compound for: 
 A1) enhancement of bone formation in bone weakening diseases for the treatment or prevention of osteopenia or osteoporosis;    A2) enhancement of fracture healing;    B 1) use as a female contragestive agent;    B2) prevention of endometrial implantation;    B3) induction of labor;    B4) treatment of luteal deficiency;    B5) enhanced recognition and maintanence of pregnancy;    B6) counteracting of preeclampsia, eclampsia of pregnancy, and preterm labor;    B7) treatment of infertility, including promotion of spermatogenesis, induction of the acrosome reaction, maturation of oocytes, or in vitro fertilization of oocytes;    C1) treatment of dysmenorrhea;    C2) treatment of dysfunctional uterine bleeding;    C3) treatment of ovarian hyperandrogynism;    C4) treatment of ovarian hyperaldosteronism;    C5) alleviation of premenstral syndrome and of premenstral tension;    C6) alleviation of perimenstrual behavior disorders;    C7) treatment of climeracteric disturbance, including, menopause transition, mood changes, sleep disturbance, and vaginal dryness;    C8) enhancement of female sexual receptivity and male sexual receptivity;    C9) treatment of post menopausal urinary incontinence;    C10) improvement of sensory and motor functions;    C11) improvement of short term memory;    C12) alleviation of postpartum depression;    C13) treatment of genital atrophy;    C14) prevention of postsurgical adhesion formation;    C15) regulation of uterine immune function;    C16) prevention of myocardial infarction;    D1) hormone replacement;    E1) treatment of cancers, including breast cancer, uterine cancer, ovarian cancer, and endometrial cancer;    E2) treatment of endometriosis;    E3) treatment of uterine fibroids;    F1) treatment of hirsutism;    F2) inhibition of hair growth;    G1) activity as a male contraceptive;    G2) activity as an abortifacient; and    H1) promotion of mylin repair;    wherein said compound has the general formula                          wherein    R is 
 aryl of 6-14 carbons; or  
 heteroaryl of 3-10 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S, with the proviso that R is other than benzofuran or benzothiophene;  
   R 1  is 
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons and containing 1-3 rings;  
 heterocycloalkyl of 4-7 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N, O, and S;  
 aryl of 6-10 carbons;  
 heteroaryl of 3-9 carbons and containing 1-3 rings and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons and containing 1-3 rings; or alkynyl of 3-10 carbons;  
   R 2 , R 3 , and R 4  are independently selected from the group consisting of 
 H;  
 alkyl of 1-10 carbons;  
 cycloalkyl of 3-12 carbons;  
 alkenyl of 2-10 carbons;  
 cycloalkenyl of 5-12 carbons;  
 aryl of 6-13 carbons;  
 heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 R 5 ; wherein 
 R 5  is alkyl of 1-4 carbons, haloalkyl of 1-4 carbons, cycloalkyl of 3-6 carbons, or halocycloalkyl of 3-6 carbons;  
 
 halogen; and  
 ═O, representing two of the groups R 2 , R 3 , and R 4 ;  
   X is O or S(O) y ; wherein 
 y is 0, 1, or 2;  
   n is 2, 3, 4, or 5;    p is the sum of non-H substituents R 2 , R 3 , and R 4 ;    s represents the number of double bonds in the ring, and is 0, 1, or 2;    T is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 alkoxy of1-4 carbons;  
 aryl of 6-10 carbons;  
 CO 2 H;  
 CO 2 R 5 ;  
 alkenyl of 2-4 carbons;  
 alkynyl of 2-4 carbons;  
 C(O)C 6 H 5 ;  
 C(O)N(R 6 )(R 7 ); wherein 
 R 6  is H or alkyl of 1-5 coarbons; and  
 R 7  is H or alkyl of 1-5 carbons;  
 
 S(O) y R 8  wherein 
 y′ is 1 or 2; and  
 R 8  is alkyl of 1-5 carbons;  
 
 SO 2 F;  
 CHO;  
 OH;  
 NO 2 ;  
 CN;  
 halogen;  
 OCF 3 ;  
 N-oxide;  
 O—C(R 9 ) 2 —O, the oxygens being connected to adjacent positions on R; and wherein 
 R 9  is H, halogen, or alkyl of 1-4 carbons;  
 
 C(O)NHC(O) , the carbons being connected to adjacent positions on R; and  
 C(O)C 6 H 4 , the carbonyl carbon and the ring carbon ortho to the carbonyl being connected to adjacent positions on R;  
   t is 1-5; 
 provided that when substituent moiety T is alkyl of 1-4 carbons; alkoxy of 1-4 carbons; aryl of 6-10 carbons; CO 2 R 5 ; alkenyl of 2-4 carbons; alkynyl of 2-4 carbons; C(O)C 6 H 5 ; C(O)N(R 6 )(R 7 ); S(O) y R 8 ; O—C(R 9 ) 2 —O, or C(O)C 6 H 4  , then T optionally may bear secondary substituents selected from the group consisting of alkyl of 1-4 carbons; alkoxy of 1-4 carbons; CO 2 R 5 ; CO 2 H; C(O)N(R 6 )(R 7 ); CHO; OH; NO 2 ; CN; halogen; S(O) y R 8 ; or ═O, the number of said secondary substituents being 1 or 2 with the exception of halogen, which may be employed up to the perhalo level;  
   G is a substituent selected from the group consisting of 
 halogen;  
 OH;  
 OR 5 ;  
 ═O, representing two substituents G;  
 alkyl of 1-4 carbons;  
 alkenyl of 1-4 carbons;  
 cyclolkeyl of 3-7 carbons;  
 heterocycloalkyl of 3-5 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 cycloalkenyl of 5-7 carbons;  
 heterocycloalkenyl of 4-6 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 R 5 ;  
 C(O)N(R 6 )(R 7 );  
 aryl of 6-10 carbons;  
 heteroaryl of 3-9 carbons and 1-3 heteroatoms selected from the group consisting of N,O and S;  
 NO 2 ;  
 CN;  
 S(O) y R 8 ;  
 SO 3 R 8 ; and  
 SO 2 N(R 6 )(R 7 );  
   g is 0-4, with the exception of halogen, which may be employed up to the perhalo level;    provided that when substituent G is alkyl of 1-4 carbons, alkenyl of 1-4 carbons, cycloalkyl of 3-7 carbons, heterocycloalkyl of 3-5 carbons, cycloalkenyl of 5-7 carbons, or heterocycloalkenyl of 4-6 carbons, then G optionally may bear secondary substituents of halogen up to the perhalo level; and when substituent G is aryl or heteroaryl, then G optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties, and up to the perhalo level for halogen;    Q is a substituent selected from the group consisting of 
 alkyl of 1-4 carbons;  
 haloalkyl of 1-4 carbons;  
 cycloalkyl of 3-8 carbons;  
 alkoxy of 1-8 carbons;  
 alkenyl of 2-5 carbons;  
 cycloalkenyl of 5-8 carbons;  
 aryl of 6-10 carbons;  
 heteroaryl of 3-9 carbons and containing 1-3 heteroatoms selected from the group consisting of N,O and S;  
 CO 2 R 5    
 ═O, representing two substituents O;  
 OH;  
 halogen;  
 N(R 6 )(R 7 );  
 S(O) y R 8 ;  
 SO 3 R 8 ; and  
 SO 2 N(R 6 )(R 7 );  
   q is 0-4 
 provided that when substituent Q is aryl or heteroaryl, then Q optionally may bear secondary substituents independently selected from the group consisting of alkyl of 1-4 carbons and halogen, the number of said secondary substituents being up to 3 for alkyl moieties and up to the perhalo level for halogen; and  
 with the further proviso that two of (Q) q R 1 , (Q) q R 2 , (Q) q R 3 , and (Q) q R 4  may be joined, and taken together with the atom(s) to which they are attached, form a spiro or nonspiro nonaromatic ring of 3-8 members containing 0-2 heteroatoms selected from the group consisting of N,O and S;  
 and pharmaceutically acceptable salts thereof.  
   
     
     
         9 . The method of  claim 8  wherein said mammal is a human.