Details for Patent: 6,140,329

Title:	Use of cGMP-phosphodiesterase inhibitors in methods and compositions to treat impotence
Abstract:	The use of (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-p yrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione, (3S 6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyhenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione, and physiologically acceptable salts and solvates thereof, in methods and compositions for the treatment of impotence.
Inventor(s):	Daugan; Alain Claude-Marie (Les Ulis, FR)
Assignee:	ICOS Corporation (Bothell, WA)
Filing Date:	Mar 10, 1998
Application Number:	08/981,989
Claims:	1. A method for the treatment of erectile dysfunction in a male animal comprising administration of a compound of formula (I): ##STR6## and salts and solvates thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl; R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, haloC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-3 alkyl, arylC.sub.1-3 alkyl or heteroarylC.sub.1-3 alkyl; R.sup.2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR7## attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain. 2. A method for the treatment of erectile dysfunction in a male animal comprising administration of a compound selected from (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; and (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphe nyl)pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione and physiologically acceptable salts and solvates thereof. 3. A pharmaceutical composition for the treatment of erectile dysfunction in a male animal comprising a compound selected from (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; and (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphe nyl)pyrazino[2'1':6,1]pyrido[3,4-b]indole-14-dione and physiologically acceptable salts and solvates thereof, together with a pharmaceutically acceptable siluent or carrier. 4. A process for the preparation of a pharmaceutical composition according to claim 3 for the treatment of erectile dysfunction in a male animal comprising formulating a compound selected from (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; and (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphe nyl)pyrazino[2'1':6,1]pyrido[3,4-b]indole-1,4-dione and physiologically acceptable salts and solvates thereof, with a pharmaceutically acceptable diluent or carrier. 5. A method of treating male animal for erectile dysfunction which comprises treating said male animal with an effective amount of a pharmaceutical composition according to claim 3. 6. A composition comprising a compound selected from (6R,12aR)-2,3,6,7,12,12-a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)py razino[2'1':6,1]pyrido[3,4-b]indole-1,4-dione; and (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphe nyl)pyrazino[2'1':6,1]pyrido[3,4-b]indole-1,4-dione and physiologically acceptable salts and solvates thereof, together with another therapeutically active agent, for simultaneous, separate, or sequential use in the treatment of erectile dysfunction in a male animal. 7. A pharmaceutical formulation comprising a composition according to claim 6 together with a pharmaceutically acceptable diluent or carrier. 8. The method of claim 1 wherein the compound of formula (I) is administered orally. 9. A method for the treatment of erectile dysfunction in a male animal comprising administration of a compound selected from the group consisting of cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',1': 6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2',1':6,1] pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)- pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-py razino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl)-pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione; (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1",2":4',5']pyrazino-[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyr azino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; and physiologically acceptable salts and solvates thereof. 10. The method of claim 9 wherein the compound is administered orally. 11. A pharmaceutical composition for the treatment of erectile dysfunction in a male animal comprising a compound selected from the group consisting of cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',1': 6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2',1':6,1] pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)- pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxy-phenyl)-2-methyl-p yrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl)-pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione; (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1", 2":4',5']pyrazino-[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyr azino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; and physiologically acceptable salts and solvates thereof, together with a pharmaceutically acceptable diluent or carrier. 12. A method of treating a male animal for erectile dysfunction which comprises treating said male animal with an effective amount of a pharmaceutical composition according to claim 11. 13. A composition comprising a compound selected from the group consisting of cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',1': 6,1]pyrido[3,4-b]indole-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2',1':6,1] pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxypheny l)-pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)- pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxy-phenyl)-2-methyl-p yrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl)-pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione; (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1",2":4',5']pyrazino-[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione; cis-2,3,6,7,12,12a-hexahydro-2-cyclopropyl-6-(3,4-methylenedioxyphenyl)-pyr azino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; and physiologically acceptable salts and solvates thereof, together with another therapeutically active agent, for simultaneous, separate, or sequential use in the treatment of erectile dysfunction in a male animal. 14. A pharmaceutical formulation comprising a combination according to claim 13, together with a pharmaceutically acceptable diluent or carrier. 15. A method of treating a male animal for erectile dysfunction comprising treating said male animal with an effective amount of a pharmaceutical composition comprising a compound of formula (I): ##STR8## and salts and solvates thereof, in which: R.sup.0 represents hydrogen, halogen, or C.sub.1-6 alkyl R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, haloC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-3 alkyl, arylC.sub.1-3 alkyl, or heteroarylC.sub.1-3 alkyl; R.sup.2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bi-cyclic ring ##STR9## attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulfur, and nitrogen; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain; together with a pharmaceutically acceptable diluent or carrier. 16. A method for the treatment of erectile dysfunction in a male animal comprising administration of a compound of formula ##STR10## and salts and solvates thereof, in which: R.sup.0 represents hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or haloC.sub.1-6 alkyl; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain. 17. The method of claim 16 wherein the compound is administered orally. 18. A method of treating a male animal for erectile dysfunction comprising treating said male with an effective amount of a pharmaceutical composition comprising a compound having a formula ##STR11## and salts and solvates thereof, in which: R.sup.0 represents hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, or haloC.sub.1-6 alkyl; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain together with a pharmaceutically acceptable diluent or carrier. 19. A method for the treatment of erectile dysfunction in a male animal comprising administration of a compound selected from the group consisting of (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxy-phenyl)-pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione; (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1",2":4',5']pyrazino-[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione; (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; and physiologically acceptable salts and solvates thereof. 20. The method of claim 18 wherein the compound is administered orally. 21. A method of treating a male animal for erectile dysfunction comprising treating said male animal with an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; (6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2' ,1':6,1]pyrido[3,4-b]indole-1,4-dione; (5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1",2":4',5']pyrazino-[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione; (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-3-methyl-6-(3,4-methylenedioxyphenyl) -pyrazino[2',1':6,1]pyrido[3,4-b]-indole-1,4-dione; and physiologically acceptable salts and solvates thereof, together with a pharmaceutically acceptable diluent or carrier.