Claims for Patent: 6,469,012

Summary for Patent: 6,469,012

Title:	Pyrazolopyrimidinones for the treatment of impotence
Abstract:	The use of a compound of formula (I) ##STR1## wherein R.sup.1 is H; C.sub.1 -C.sub.3 alkyl; C.sub.1 -C.sub.3 perfluoroalkyl; or C.sub.3 -C.sub.5 cycloalkyl; R.sup.2 is H; optionally substituted C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.3 perfluoroalkyl; or C.sub.3 -C.sub.6 cycloalkyl; R.sup.3 is optionally substituted C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 perfluoroalkyl; C.sub.3 -C.sub.5 cycloalkyl; C.sub.3 -C.sub.6 alkenyl; or C.sub.3 -C.sub.6 alkynyl; R.sup.4 is optionally substituted C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkanoyl, (hydroxy)C.sub.2 -C.sub.4 alkyl or (C.sub.2 -C.sub.3 alkoxy)C.sub.1 -C.sub.2 alkyl; CONR.sup.5 R.sup.6 ; CO.sub.2 R.sup.7 ; halo; NR.sup.5 R.sup.6 ; NHSO.sub.2 NR.sup.5 R.sup.6 ; NHSO.sub.2 R.sup.8 ; SO.sub.2 NR.sup.9 R.sup.10 ; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R.sup.5 and R.sup.6 are each independently H or C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R.sup.11)-piperazinyl or imidazolyl group; R.sup.7 is H or C.sub.1 -C.sub.4 alkyl; R.sup.8 is optionally substituted C.sub.1 -C.sub.3 alkyl; R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R.sup.12)-piperazinyl group; R.sup.11 is H; optionally substituted C.sub.1 -C.sub.3 alkyl; (hydroxy)C.sub.2 -C.sub.3 alkyl; or C.sub.1 -C.sub.4 alkanoyl; R.sup.12 is H; optionally substituted C.sub.1 -C.sub.6 alkyl; CONR.sup.13 R.sup.14 ; CSNR.sup.13 R.sup.14 ; or C(NH)NR.sup.13 R.sup.14 ; and R?13? and R.sup.14 are each independently H; C.sub.1 -C.sub.4 alkyl; or substituted C.sub.2 -C.sub.4 alkyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man; a pharmaceutical composition for said treatment; and a method of said treatment of said male animal with said pharmaceutical composition or with said either entity.
Inventor(s):	Ellis; Peter (Sandwich, GB), Terrett; Nicholas Kenneth (Sandwich, GB)
Assignee:	Pfizer Inc (New York, NY)
Application Number:	08/549,792
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,469,012
Patent Claims:	1. A method of treating erectile dysfunction in a male animal, comprising administering to a male animal in need of such treatment an effective amount of a compound of formula (I): ##STR3## wherein: R.sup.1 is H; C.sub.1 -C.sub.3 alkyl; C.sub.1 -C.sub.3 perfluoroalkyl; or C.sub.3 -C.sub.5 cycloalkyl; R.sup.2 is H; C.sub.1 -C.sub.6 alkyl optionally substituted with C.sub.3 -C.sub.6 cycloalkyl; C.sub.1 -C.sub.3 perfluoroalkyl; or C.sub.3 -C.sub.6 cycloalkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl optionally substituted with C.sub.3 -C.sub.6 cycloalkyl; C.sub.1 -C.sub.6 perfluoroalkyl; C.sub.3 -C.sub.5 cycloalkyl; C.sub.3 -C.sub.6 alkenyl; or C.sub.3 -C.sub.6 alkynyl; R.sup.4 is C.sub.1 -C.sub.4 alkyl optionally substituted with OH, NR.sup.5 R.sup.6, CN, CONR.sup.5 R.sup.6 or CO.sub.2 R.sup.7 ; C.sub.2 -C.sub.4 alkenyl optionally substituted with CN, CONR.sub.5 R.sup.6 or CO.sub.2 R.sup.7 ; C.sub.2 -C.sub.4 alkanoyl optionally substituted with NR.sup.5 R.sup.6 ; (hydroxy)C.sub.2 -C.sub.4 alkyl optionally substituted with NR.sup.5 R.sup.6 ; (C.sub.2 -C.sub.3 alkoxy)C.sub.1 -C.sub.2 alkyl optionally substituted with OH or NR.sup.5 R.sup.6 ; CONR.sup.5 R.sup.6 ; CO.sub.2 R.sup.7 ; halo; NR.sup.5 R.sup.6 ; NHSO.sub.2 NR.sup.5 R.sup.6 ; NHSO.sub.2 R.sup.8 ; SO.sub.2 NR.sup.9 R.sup.10 ; or phenyl pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R.sup.5 and R.sup.6 are each independently H or C.sub.1 -C.sub.4 alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R.sup.11)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH; R.sup.7 is H or C.sub.1 -C.sub.4 alkyl; R.sup.8 is C.sub.1 -C.sub.3 alkyl optionally substituted with NR.sup.5 R.sup.6 ; R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R.sup.12)-piperazinyl group wherein said group is optionally substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.13 R.sup.14 or CONR.sup.13 R.sup.14 ; R.sup.11 is H; C.sub.1 -C.sub.3 alkyl optionally substituted with phenyl; (hydroxy)C.sub.2 -C.sub.3 alkyl; or C.sub.1 -C.sub.4 alkanoyl; R.sup.12 is H; C.sub.1 -C.sub.6 alkyl; (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.6 alkyl; (hydroxy)C.sub.2 -C.sub.6 alkyl; (R.sup.13 R.sup.14 N)C.sub.2 -C.sub.6 alkyl; (R.sup.13 R.sup.14 NOC)C.sub.1 -C.sub.6 alkyl; CONR.sup.13 R.sup.14 ; CSNR.sup.13 R.sup.14 ; or C(NH)NR.sup.13 R.sup.14 ; and R.sup.13 and R.sup.14 are each independently H; C.sub.1 -C.sub.4 alkyl; (C.sub.1 -C.sub.3 alkoxy)C.sub.2 -C.sub.4 alkyl; or (hydroxy)C.sub.2 -C.sub.4 alkyl; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable composition containing either entity. 2. A method as defined in claim 1, wherein said treatment is veterinary treatment. 3. A method as defined in claim 1, wherein said compound is 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-p yrazolo[4,3-d]pyrimidin-7-one. 4. A method as defined in claim 1, wherein said compound is 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propy l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 5. A method as defined in claim 1, wherein said compound, salt or composition is administered orally, intravenously, sublingually, or buccally. 6. A method as defined in claim 1, wherein said compound, salt or composition is administered orally. 7. A method as defined in claim 6 wherein in the compound of formula (I) R.sup.1 is H, methyl or ethyl; R.sup.2 is C.sub.1 -C.sub.3 alkyl; R.sup.3 is C.sub.2 -C.sub.3 alkyl or allyl; R.sup.4 is C.sub.1 -C.sub.2 alkyl optionally substituted with OH, NR.sup.5 R.sup.6, CN, CONR.sup.5 R.sup.6 or CO.sub.2 R.sup.7 ; acetyl optionally substituted with NR.sup.5 R.sup.6 ; hydroxyethyl optionally substituted with NR.sup.5 R.sup.6 ; ethoxymethyl optionally substituted with OH or NR.sup.5 R.sup.6 ; CH.dbd.CHCN; CH.dbd.CHCONR.sup.5 R.sup.6 ; CH.dbd.CHCO.sub.2 R.sup.7 ; CONR.sup.5 R.sup.6 ; CO.sub.2 H; Br; NR.sup.5 R.sup.6 ; NHSO.sub.2 NR.sup.5 R.sup.6 ; NHSO.sub.2 R.sup.8 ; SO.sub.2 NR.sup.9 R.sup.10 ; or pyridyl or imidazolyl either of which is optionally substituted with methyl; R.sup.5 and R.sup.6 are each independently H, methyl or ethyl, or together with the nitrogen atom to which they are attached form a piperidino, morpholino, 4-N(R.sup.11)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH; R.sup.7 is H or t-butyl; R.sup.8 is methyl or CH.sub.2 CH.sub.2 CH.sub.2 NR.sup.5 R.sup.6 ; R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form a piperidino or 4-N(R.sup.12)-piperazinyl group wherein said group is optionally substituted with NR.sup.13 R.sup.14 or CONR.sup.13 R.sup.14 ; R.sup.11 is H, methyl, benzyl, 2-hydroxyethyl or acetyl; R.sup.12 is H, C.sub.1 -C.sub.3 alkyl, (hydroxy)C.sub.2 -C.sub.3 alkyl, CSNR.sup.13 R.sup.14 or C(NH)NR.sup.13 R.sup.14 ; and R.sup.13 and R.sup.14 are each independently H or methyl. 8. A method as defined in claim 7 wherein in the compound of formula (I) R.sup.1 is methyl or ethyl; R.sup.2 is C.sub.1 -C.sub.3 alkyl; R.sup.3 is ethyl, n-propyl or allyl; R.sup.4 is CH.sub.2 NR.sup.5 R.sup.6, COCH.sub.2 NR.sup.5 R.sup.6, CH(OH)CH.sub.2 NR.sup.5 R.sup.6, CH.sub.2 OCH.sub.2 CH.sub.3, CH.sub.2 OCH.sub.2 CH.sub.2 OH, CH.sub.2 OCH.sub.2 CH.sub.2 NR.sup.5 R.sup.6, CH.dbd.CHCON(CH.sub.3).sub.2, CH.dbd.CHCO.sub.2 R.sup.7, CONR.sup.5 R.sup.6, CO.sub.2 H, Br, NHSO.sub.2 NR.sup.5 R.sup.6, NHSO.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 NR.sup.5 R.sup.6, SO.sub.2 NR.sup.9 R.sup.10, 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolyl; R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a piperidino, 4-hydroxypiperidino, morpholino, 4-N(R.sup.11)-piperazinyl or 2-methyl-1-imidazolyl group; R.sup.7 is H or t-butyl; R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form a 4-carbamoylpiperidino or 4-N(R.sup.12)-piperazinyl group; R.sup.11 is H, methyl, benzyl, 2-hydroxyethyl or acetyl; and R.sup.12 is H, C.sub.1 -C.sub.3 alkyl, 2-hydroxyethyl or CSNH.sub.2. 9. A method as defined in claim 8 wherein in the compound of formula (I) R.sup.1 is methyl or ethyl; R.sup.2 is n-propyl; R.sup.3 is ethyl, n-propyl or allyl; R.sup.4 is COCH.sub.2 NR.sup.5 R.sup.6, CONR.sup.5 R.sup.6, SO.sub.2 NR.sup.9 R.sup.10 or 1-methyl-2-imidazolyl; R.sup.5 and R.sup.6 together with the nitrogen atom to which they are attached form a morpholino or 4-N(R.sup.11)-piperazinyl group; R.sup.9 and R.sup.10 together with the nitrogen atom to which they are attached form a 4-N(R.sup.12)-piperazinyl group; R.sup.11 is methyl or acetyl; and R.sup.12 is H, methyl, 2-propyl or 2-hydroxyethyl. 10. A method as defined in claim 9 wherein the compound of formula (I) is selected from: 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-py razolo[4,3-d]pyrimidin-7-one; 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H -pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-prop yl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-pr opyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl- 3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methy l-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl- 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydr o-7H-pyrazolo[4,3-d]pyrimidin-7-one. 11. A method as defined in claim 10 wherein the compound of formula (I) is 5-(2-ethoxy-5-morpholino-acetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one. 12. A method as defined in claim 10 wherein the compound of formula (I) is 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one. 13. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propy l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 14. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-pro pyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 15. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-p ropyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 16. A method as defined in claim 10 wherein the compound of formula (I) is 5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl -3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 17. A method as defined in claim 10 wherein the compound of formula (I) is 5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-meth yl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 18. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 19. A method as defined in claim 10 wherein the compound of formula (I) is 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihyd ro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 20. A method as defined in claim 6, wherein said animal is a human. 21. A method as defined in claim 1, wherein said compound, salt or composition is administered intravenously. 22. A method as defined in claim 1, wherein said compound, salt or composition is administered sublingually. 23. A method as defined in claim 1, wherein said compound, salt or composition is administered buccally. 24. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE.sub.v inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity. 25. A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a compound selected from: 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-py razolo[4,3-d]pyrimidin-7-one; 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H -pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-prop yl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl-3-n-pr opyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinyl-sulphonyl]phenyl}-1-methyl- 3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methy l-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)-phenyl]-1-methyl-3-n-propyl- 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydr o-7H-pyrazolo[4,3-d]pyrimidin-7-one; or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition containing either entity. 26. A method as defined in claim 25, wherein said compound is 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)-phenyl]-1-methyl-3-n-propy l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.