Claims for Patent: 5,250,534

Summary for Patent: 5,250,534

Title:	Pyrazolopyrimidinone antianginal agents
Abstract:	Compounds of the formula: wherein R1 is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2 is H, C1-C6 alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R3 is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or (C3-C6 cycloalkyl)C1-C6 alkyl; R4 taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, morpholino, or 4-N-(R6)-piperazinyl group; R5 is H, C1-C4 alkyl, C1-C3 alkoxy, NR7R8, or CONR7R8; R6 is H, C1-C6 alkyl, (C1-C3 alkoxy) C2- C6 alkyl, hydroxy C2-C6 alkyl, (R7R8N)C2-C6 alkyl, (R7R8NCO)C1-C6 alkyl, CONR7R8, CSNR7R8 or C(NH)NR7R8; R7 and R8 are each independently H, C1-C4 alkyl, (C1-C3 alkoxy)C2-C4 alkyl or hydroxy C2-C4 alkyl; and pharmaceutically acceptable salts thereof, are selective cGMP PDE inhibitors useful in the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.
Inventor(s):	Andrew S. Bell, David Brown, Nicholas K. Terrett
Assignee:	Pfizer Corp SRL
Application Number:	US07/882,988
Patent Claims:	1. A compound of the formula: ##STR22## wherein R1 is H, C1 -C3 alkyl, C3 -C5 cycloalkyl or C1 -C3 perfluoroalkyl;R2 is H, C1 -C6 alkyl optionally substituted by OH, C1 -C3 alkoxy or C3 -C6 cycloalkyl, or C1 -C3 perfluoroalkyl; R3 is C1 -C6 alkyl, C3 -C6 alkenyl, C3 -C6 alkynyl, C3 -C7 cycloalkyl, C1 -C6 perfluoroalkyl or (C3 -C6 cycloalkyl)C1 -C6 alkyl; R4 taken together with the nitrogen atom to which it is attached completes a 4-N-(R6)-piperazinyl group; R5 is H, C1 -C4 alkyl, C1 -C3 alkoxy, NR7 R8, or CONR7 R8 ; R6 is H, C1 -C6 alkyl, (C1 -C3 alkoxy) C2 -C6 alkyl hydroxy C2 -C6 alkyl, (R7 R8 N)C2 -C6 alkyl, (R7 R8 NCO)C1 -C6 alkyl, CONR7 R8, CSNR7 R8 or C(NH)NR7 R8 ; R7 and R8 are each independently H, C1 -C4 alkyl, (C1 -C3 alkoxy)C2 -C4 alkyl or hydroxy C2 -C4 alkyl; andpharmaceutically acceptable salts thereof. 2. A compound as claimed in claim 1 wherein R1 is H, methyl or ethyl; R2 is C1 -C3 alkyl optionally substituted by OH or methoxy; R3 is C2 -C3 alkyl or allyl; R5 is H, NR7 R8 or CONR7 R8 ; R6 is H, C1 -C3 alkyl, hydroxy C2 -C3 alkyl, CONR7 R8, CSNR7 R8 or C(NH)NR7 R8 ; and R7 and R8 are each independently H or methyl. 3. A compound as claimed in claim 2 wherein R1 is methyl; R2 is n-propyl; R3 is ethyl, n-propyl or allyl; R5 is H, and R6 is H, C1 -C3 alkyl or 2-hydroxyethyl. 4. A compound as claimed in claim 3 wherein said compound is selected from:5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, andpharmaceutically acceptable salts thereof. 5. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, together with a pharmaceutically acceptable diluent or carrier. 6. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for use in medicine, particularly for the treatment of angina, hypertension, heart failure or atherosclerosis. 7. A pharmaceutical composition as defined in claim 5, for the treatment of angina, hypertension, heart failure or atherosclerosis. 8. A method of treating, in a human being, angina, hypertension, heart failure or atherosclerosis which comprises administering to said human being an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, or a pharmaceutical composition as claimed in claim 5. 1. A compound of the formula: ##STR22## wherein R.sup.1 is H, C.sub.1 -C.sub.3 alkyl, C.sub.3 -C.sub.5 cycloalkyl or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.2 is H, C.sub.1 -C.sub.6 alkyl optionally substituted by OH, C.sub.1 -C.sub.3 alkoxy or C.sub.3 -C.sub.6 cycloalkyl, or C.sub.1 -C.sub.3 perfluoroalkyl; R.sup.3 is C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 alkenyl, C.sub.3 -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.1 -C.sub.6 perfluoroalkyl or (C.sub.3 -C.sub.6 cycloalkyl)C.sub.1 -C.sub.6 alkyl; R.sup.4 taken together with the nitrogen atom to which it is attached completes a 4-N-(R.sup.6)-piperazinyl group; R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, NR.sup.7 R.sup.8, or CONR.sup.7 R.sup.8 ; R.sup.6 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.7 R.sup.8 N)C.sub.2 -C.sub.6 alkyl, (R.sup.7 R.sup.8 NCO)C.sub.1 -C.sub.6 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; R.sup.7 and R.sup.8 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; and pharmaceutically acceptable salts thereof. 2. A compound as claimed in claim 1 wherein R.sup.1 is H, methyl or ethyl; R.sup.2 is C.sub.1 -C.sub.3 alkyl optionally substituted by OH or methoxy; R.sup.3 is C.sub.2 -C.sub.3 alkyl or allyl; R.sup.5 is H, NR.sup.7 R.sup.8 or CONR.sup.7 R.sup.8 ; R.sup.6 is H, C.sub.1 -C.sub.3 alkyl, hydroxy C.sub.2 -C.sub.3 alkyl, CONR.sup.7 R.sup.8, CSNR.sup.7 R.sup.8 or C(NH)NR.sup.7 R.sup.8 ; and R.sup.7 and R.sup.8 are each independently H or methyl. 3. A compound as claimed in claim 2 wherein R.sup.1 is methyl; R.sup.2 is n-propyl; R.sup.3 is ethyl, n-propyl or allyl; R.sup.5 is H, and R.sup.6 is H, C.sub.1 -C.sub.3 alkyl or 2-hydroxyethyl. 4. A compound as claimed in claim 3 wherein said compound is selected from: 5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro -7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6 -dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n- propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 1-methyl-5-[5-piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihyd ro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and 5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3 -n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and pharmaceutically acceptable salts thereof. 5. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, together with a pharmaceutically acceptable diluent or carrier. 6. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, for use in medicine, particularly for the treatment of angina, hypertension, heart failure or atherosclerosis. 7. A pharmaceutical composition as defined in claim 5, for the treatment of angina, hypertension, heart failure or atherosclerosis. 8. A method of treating, in a human being, angina, hypertension, heart failure or atherosclerosis which comprises administering to said human being an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, or a pharmaceutical composition as claimed in claim 5.