Patent EA-002057-B1 (EA)
Title: PYRAZOLLOPYRIMIDINONES WHICH INHIBIT TYPE 5 CYCLIC GUANOSINE 3',5'-MONOPHOSPHATE PHOSPHODIESTERASE (cGMP PDES) FOR THE TREATMENT OF SEXUAL DYSFUNCTION
Inventor: BUNNAGE MARK EDWARD
IPC: C07D231/40
Filed: 1998-04-10
Abstract: 1. A compound of formula (IA) or (IB):              or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein R<1> is C1-C3 alkyl substituted with C3-C6 cycloalkyl, CONR<5>R<6> or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R<9>-piperazinyl; (CH2)nHet or (CH2)nAr; R<2> is C1-C6 alkyl; R<3> is C1-C6 alkyl optionally substituted with C1-C4 alkoxy; R<4> is SO2NR<7>R<8>; R<5> and R<6> are each independently selected from H and C1-C4 alkyl optionally substituted with C1-C4 alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R<9>-piperazinyl group; R<7> and R<8>, together with the nitrogen atom to which they are attached, form a 4-R<10>-piperazinyl group; R<9> is C1-C4 alkyl; R<10> is H or C1-C4 alkyl optionally substituted with OH, C1-C4 alkoxy or CONH2; Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C1-C4 alkyl optionally substituted with C1-C4 alkoxy, C1-C4 alkoxy, halo and NH2; Ar is phenyl optionally substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 alkoxy, halo, CN, CONH2, NO2, NH2, NHSO2(C1-C4alkyl) and SO2NH2; and n is 0 or 1. 2. A compound according to Claim 1 wherein R<1> is C1-C2 alkyl substituted with C3-C5 cycloalkyl, CONR<5>R<6> or a N-linked heterocyclic group selected from pyrazolyl, triazolyl, morpholinyl and 4-R<9>-piperazinyl; (CH2)nHet or (CH2)nAr; R<5> is H and R<6> is C1-C4 alkyl optionally substituted with C1-C4 alkoxy or R<5> and R<6>, together with the nitrogen atom to which they are attached, form a morpholinyl group; Het is selected from pyridinyl, 1-oxidopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl and oxadiazolyl, any of which is optionally substituted with one or two substituents selected from CH3, CH2CH2OCH3, OCH3 and NH2; and R<2>, R<3>, R<4>, R<9>, Ar and n are as previously defined in Claim 1. 3. A compound according to Claim 2 wherein R<1> is C1-C2 alkyl substituted with cyclobutyl, CONR<5>R<6>, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl; pyrimidin-2-yl; CH2Het or (CH2)nAr; R<2> is C1-C3 alkyl; R<3> is C1-C3 alkyl optionally substituted with C1-C2 alkoxy; R<5> is H and R<6> is C1-C2 alkyl optionally substituted with C1-C2 alkoxy or R<5> and R<6>, together with the nitrogen atom to which they are attached, form a morpholin-4-yl group; R<10> is C1-C2 alkyl optionally monosubstituted with OH, OCH3 or CONH2; Het is selected from pyridin-2-yl, 1-oxidopyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-methylthiazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl, 4-methyl-1,2,4-triazol-3-yl, 3-methyl-1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 4-chlorophenyl, 4-bromophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-carbamoylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl, 4-(prop-2-ylsulphonamido)phenyl and 4-sulphamoylphenyl; and n is as previously defined in Claim 2. 4. A compound according to Claim 3 wherein R<1> is cyclobutylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl)ethyl, pyrimidin-2-yl, CH2Het or (CH2)nAr; R<2> is CH2CH3 or CH2CH2CH3; R<3> is CH2CH3, CH2CH2CH3 or CH2CH2OCH3; R<10> is CH3, CH2CH3 or CH2CH2OH; Het is selected from pyridin-2-yl, pyridazin-3-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 2-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl and 4-(prop-2-ylsulphonamido)phenyl; and n is as previously defined in Claim 3. 5. A compound according to Claim 4 wherein the compound of formula (IA) or (IB) is selected from 5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-1-(pyridin-2-yl)methyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; 1-(1-methylimidazol-2-yl)methyl-5-[5-(4-methylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; 5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridazin-3-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyrazin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one; and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. 6. A pharmaceutical composition comprising a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any one of Claims 1 to 5, together with a pharmaceutically acceptable diluent or carrier. 7. A veterinary formulation comprising a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any one of Claims 1 to 5, together with a veterinarily acceptable diluent or carrier. 8. A compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any one of Claims 1 to 5 for use as a human medicament. 9. The use of a pharmaceutical composition according to Claim 6 as a human medicament. 10. A compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any one of Claims 1 to 5 for use as an animal medicament. 11. The use of a veterinary formulation according to Claim 7, as an animal medicament. 12. The use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any one of Claims 1 to 5, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated. 13. The use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any one of Claims 1 to 5, for the manufacture of an animal medicament for which a cGMP PDE5 inhibitor is indicated. 14. The use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate containing either entity, according to any one of Claims 1 to 5, for the manufacture of a human medicament for the curative or prophylactic treatment of male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility. 15. The use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any one of Claims 1 to 5, for the manufacture of an animal medicament for the curative or prophylactic treatment of male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility. 16. A method for treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in a mammal (including a human), wherein a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, according to any one of Claims 1 to 5, or a pharmaceutical composition or veterinary formulation containing any of the foregoing according to Claim 6 or Claim 7, is administered to said mammal in need. 17. A method for treating or preventing of male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, s