Pyrazolopyrimidinones for the treatment of female sexual dysfunction

Abstract

The use of a compound of formula (I) wherein R 1 is H; C 1 -C 3 alkyl; C 1 -C 3 perfluomalkyl; or C 3 -C 5 cycloalkyl; R 2 is H; optionally substituted C 1 -C 6 alkyl; C 1 -C 3 pefluoroalkyl; or C 3 -C 6 cycloalkyl; R 3 is optionally substituted C 1 -C 6 alkyl; C 1 -C 6 perfluoroalkyl; C 3 -C 5 cycloalkyl; C 3 -C 6 alkenyl; or C 3 -C 6 alkynyl; R 4 is optionally substituted C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkanoyl, (hydroxy)C 2 -C 4 alkyl or (C 2 -C 3 alkoxy)C 1 -C 2 alkyl; CONR 5 R 6 ; CO 2 R 7 ; halo; NR 5 R 6 ; NHSO 2 NR 5 R 6 ; NHSO 2 R 8 ; SO 2 NR 9 R 10 ; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R 5 and R 6 are each independently H or C 1 -C 4 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R 11 )-piperazinyl or imidazolyl group; R 7 is H or C 1 -C 4 alkyl; R 8 is optionally substituted C 1 -C 3 alkyl; R 9 and R 10 together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R 12 )-piperazinyl group; R 11 is H; optionally substituted C 1 -C 3 alkyl; (hydroxy)C 2 -C 3 alkyl; or C 1 -C 4 alkanoyl; R 12 is H; optionally substituted C 1 -C 6 alkyl; CONR 13 R 14 . CSNR 13 R 14 ; or C(NH)NR 13 R 14 ; and R?13? and R 14 are each independently H; C 1 -C 4 alkyl; or substituted C 2 -C 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.

1 . The use of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is H; C 1 -C 3  alkyl; C 1 -C 3  perfluoroalkyl; or C 3 -C 5  cycloalkyl;  
 R 2  is H; C 1 -C 6  alkyl optionally substituted with C 3 -C 6  cycloalkyl; C 1 -C 3  perfluoroalkyl;  
 or C 3 -C 6  cycloalkyl;  
 R 3  is C 1 -C 6  alkyl optionally substituted with C 3 -C 6  cycloalkyl; C 1 -C 6  perfluoroalkyl; C 3 -C 5  cycloalkyl; C 3 -C 6  alkenyl; or C 3 -C 6  alkynyl;  
 R 4  is C 1 -C 4  alkyl optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6  or CO 2 R 7 ; C 2 -C 4  alkenyl optionally substituted with CN, CONR 5 R 6  or CO 2 R 7 ; C 2 -C 4  alkanoyl optionally substituted with NR 5 R 6 ; (hydroxy)C 2 -C 4  alkyl optionally substituted with NR 5 R 6 ; (C 2 -C 3  alkoxy)C 1 -C 2  alkyl optionally substituted with OH or NR 5 R 6 ; CONR 5 R 6 ; CO 2 R 7 ; halo; NR 5 R 6 ; NHSO 2 NR 5 R 6 ;  
 NHSO 2 R 8 ; SO 2 NR 9 R 10 ; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;  
 R 5  and R 6  are each independently H or C 1 -C 4  alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R 11 ) -piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;  
 R 7  is H or C 1 -C 4  alkyl;  
 R 8  is C 1 -C 3  alkyl optionally substituted with NR 5 R 6 ;  
 R 9  and R 10  together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R 12 )-piperazinyl group wherein said group is optionally substituted with C 1 -C 4  alkyl, C 1 -C 3  alkoxy, NR 13 R 14  or CONR 13 R 14 ;  
 R 11  is H; C 1 -C 3  alkyl optionally substituted with phenyl; (hydroxy)C 2 -C 3  alkyl; or C 1 -C 4  alkanoyl;  
 R 12  is H; C 1 -C 6  alkyl; (C 1 -C 3  alkoxy)C 2 -C 6  alkyl; (hydroxy)C 2 -C 6  alkyl; (R 13 R 14 N )C 2 -C 6  alkyl; (R 13 R 14 NOC)C 1 -C 6  alkyl; CONR 13 R 14 ;  
 CSNR 13 R 14 ; or C(NH)NR 13 R 14 ; and  
 R 13  and R 14  are each independently H; C 1 -C 4  alkyl; (C 1 -C 3  alkoxy)C 2 -C 4  alkyl; or (hydroxy)C 2 -C 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.  
 
     
     
         2 . The use according to  claim 1  wherein in the compound of formula (I) R 1  is H, methyl or ethyl; R 2  is C 1 -C 3  alkyl; R 3  is C 2 -C 3  alkyl or allyl; R 4  is C 1 -C 2  alkyl optionally substituted with OH, NR 5 R 6 , CN, CONR 5 R 6  or CO 2 R 7 ; acetyl optionally substituted with NR 5 R 6 ; hydroxyethyl optionally substituted with NR 5 R 6 ; ethoxymethyl optionally substituted with OH or NR 5 R 6 ; CH═CHCN; CH═CHCONR 5 R 6 ; CH═CHCO 2 R 7 ; CONR 5 R 6 ; CO 2 H; Br; NR 5 R 6 ; NHSO 2 NR 5 R 6 ; NHSO 2 R 8 ; SO 2 NR 9 R 10 ; or pyridyl or imidazolyl either of which is optionally substituted with methyl; R 5  and R 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 11 )-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH; R 7  is H or t-butyl; R 8  is methyl or CH 2 CH 2 CH 2 NR 5 R 6 ; R 9  and R 10  together with the nitrogen atom to which they are attached form a piperidino or 4-N(R 12 )-piperazinyl group wherein said group is optionally substituted with NR 13 R 14  or CONR 13 R 14 ; R 11  is H, methyl, benzyl, 2-hydroxyethyl or acetyl; R 12  is H, C 1 -C 3  alkyl, (hydroxy)C 2 -C 3  alkyl, CSNR 13 R 14  or C(NH)NR 13 R 14 ; and R 13  and R 14  are each independently H or methyl.  
     
     
         3 . The use according to  claim 2  wherein in the compound of formula (I) R 1  is methyl or ethyl; R 2  is C 1 -C 3  alkyl; R 3  is ethyl, n-propyl or allyl; R 4  is CH 2 NR 5 R 6 , COCH 2 NR 5 R 6 , CH(OH)CH 2 NR 5 R 6 , CH 2 OCH 2 CH 3 , CH 2 OCH 2 CH 2 OH, CH 2 OCH 2 CH 2 NR 5 R 6 , CH═CHCON(CH 3  ) 2 , CH═CHCO 2 R 7 , CONR 5 R 6 , CO 2 H, Br, NHSO 2 NR 5 R 6 , NHSO 2 CH 2 CH 2 CH 2 NR 5 R 6 , SO 2 NR 9 R 10 , 2-pyridyl, 1-imidazolyl or 1-methyl-2-imidazolyl; R 5  and R 6  together with the nitrogen atom to which they are attached form a piperidino, 4-hydroxypiperidino, morpholino, 4-N(R 11 )-piperazinyl or 2-methyl-1-imidazolyl group; R 7  is H or t-butyl; R 9  and R 10  together with the nitrogen atom to which they are attached form a 4-carbamoylpiperidino or 4-N(R 12 )-piperazinyl group; R 11  is H, methyl, benzyl, 2-hydroxyethyl or acetyl; and R 12  is H, C 1 -C 3  alkyl, 2-hydroxyethyl or CSNH 2 .  
     
     
         4 . The use according to  claim 3  wherein in the compound of formula (I) R 1  is methyl or ethyl; R 2  is n-propyl; R 3  is ethyl, n-propyl or allyl; R 4  is COCH 2 NR 5 R 6 , CONR 5 R 6  , SO 2 NR 9 R 10  or 1-methyl-2-imidazolyl; R 5  and R 6  together with the nitrogen atom to which they are attached form a morpholino or 4-N(R 11 )-piperazinyl group; R 9  and R 10  together with the nitrogen atom to which they are attached form a 4-N(R 12 )-piperazinyl group; R 11  is methyl or acetyl; and R 12  is H, methyl, 2-propyl or 2-hydroxyethyl.  
     
     
         5 . The use according to  claim 4  wherein the compound of formula (I) is selected from: 
 5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[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-propyl-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-propyl-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-methyl-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-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.  
 
     
     
         6 . A pharmaceutical composition for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man, comprising a compound of formula (I) according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.  
     
     
         7 . A process for the preparation of a pharmaceutial composition for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man, comprising formulating a compound of formula (I) according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable diluent or carrier.  
     
     
         8 . A method of treating a male animal, including man, to cure or prevent erectile dysfunction which comprises treating said male animal with an effective amount of a compound of formula (I) according to any one of  claims 1  to  5 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.  
     
     
         9 . The use of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the treatment of erectile dysfunction in a male animal, including man.  
     
     
         10 . A method of treating a male animal, including man, to cure or prevent erectile dysfunction, which comprises treating said male animal with an effective amount of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity.  
     
     
         11 . The use of a cGMP PDE inhibitor, 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.