Pharmaceutically active compounds

Abstract

Compounds of the formula (I): wherein R 1 , R 2 , R 4 and R 13 are as defined or a pharmaceutically or veterinarily acceptable salt or polymorph thereof, or a pharmaceutically or veterinarily acceptable solvate or pro-drug thereof: are potent and selective inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5) and have utility in the treatment of, inter alia, male erectile dysfunction (MED) and female sexual dysfunction (FSD).

1 . A method of treating or preventing benign prostatic hyperplasia, bladder outlet obstruction or incontinence comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically or veterinarily acceptable salt, or a pharmaceutically or veterinarily acceptable solvate or pro-drug thereof, wherein 
 R 1  is C 1  to C 6  alkyl or C 3  to C 6  alkenyl, C 3  to C 6  cycloalkyl or C 4  to C 6  cycloalkenyl wherein said alkyl group may be branched or straight chain and wherein 
 when R 1  is C 1  to C 3  alkyl said alkyl group is substituted by;  
 
 and wherein when R 1  is C 4  to C 6  alkyl, C 3  to C 6  alkenyl or C 3  to C 6  cycloalkyl said alkyl, alkenyl or cycloalkyl group is optionally substituted by;  
 one or more substituents selected from: hydroxy; C 1  to C 4  alkoxy; C 3  to C 6  cycloalkyl; phenyl substituted with one or more substitutents selected from C 1  to C 3  alkyl, C 1  to C 4  alkoxy, C 1  to C 4  haloalkyl, C 1  to C 4  haloalkoxy, halo, CN, NO 2 , NHR 11 , NHCOR 12 , NHSO 2 R 12 , SO 2 R 12 , SO 2 NHR 11 , COR 11  or CO 2 R 11  wherein said haloalkyl and haloalkoxy groups contain one or more halo atoms; NR 7 R 8 , CONR 7 R 8  or NR 7 COR 11  wherein R 7  and R 8  are each independently selected from H, C 1  to C 4  alkyl, C 3  to C 4  alkenyl, CO 2 R 9  or SO 2 R 9  and wherein said alkyl or alkenyl groups are optionally substituted by C 1  to C 4  haloalkyl or C 1  to C 4  haloalkoxy; Het 1 ; Het 2  or Het 3 ;  
 or R 1  is Het 4  or phenyl wherein said phenyl group is optionally substituted by one or more substituents selected from C 1  to C 4  alkyl, C 3  to C 4  alkenyl, C 1  to C 4  alkoxy, halo, CN, CF 3 , OCF 3 , NO 2 , NHR 11 , NHCOR 12 , NHSO 2 R 12 , SO 2 R 12 , SO 2 NHR 11 , COR 11 , CO 2 R 11 ;  
 R 2  is C 1  to C 6  alkyl, C 3  to C 6  alkenyl or (CH 2 ) n (C 3  to C 6  cycloalkyl) wherein n is 0, 1 or 2;  
 R 13  is OR 3  or NR 5 R 6 ;  
 R 3  is C 1  to C 6  alkyl optionally substituted with one or two substituents selected from C 3  to C 5  cycloalkyl, hydroxy, C 1  to C 4  alkoxy, benzyloxy, NR 5 R 6 , phenyl, Het 1 , Het 2 , Het 3  or Het 4  wherein the C 1  to C 6  alkyl and C 1  to C 4  alkoxy groups may optionally be terminated by a haloalkyl group such as CF 3  and wherein the C 3 -C 5  cycloalkyl group may optionally be substituted by C 1 -C 4  alkyl, hydroxy or halo;  
 C 3  to C 6  cycloalkyl; Het 1 , Het 2 , Het 3  or Het 4 ;  
 R 4  is a piperazin-1-ylsulphonyl group having a substituent R 10  at the 4-position of the piperazinyl group wherein said piperazinyl group is optionally substituted with one or two C 1  to C 4  alkyl groups and is optionally in the form of its 4-N-oxide;  
 R 5  and R 6  are each independently selected from H and C 1  to C 4  alkyl optionally substituted with C 3  to C 5  cycloalkyl or C 1  to C 4  alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;  
 R 7  and R 8  are each independently selected from H, C 1  to C 4  alkyl, C 3  to C 4  alkenyl, CO 2 R 9  or SO 2 R 9 ;  
 R 9  is C 1  to C 4  alkyl optionally substituted with C 1  to C 4  haloalkyl, C 1  to C 4  haloalkoxy or phenyl wherein said phenyl group is optionally substituted by one or more substituents selected from C 1  to C 4  alkyl optionally substituted by C 1  to C 4  haloalkyl or C 1  to C 4  haloalkoxy, C 1  to C 4  alkoxy, halo, CN, NO 2 , NHR 11 , NHCOR 12 , NHSO 2 R 12 , SO 2 R 12 , SO 2 NHR 11 , COR 11  or CO 2 R 11 ;  
 R 10  is H; C 1  to C 4  alkyl optionally substituted with one or two substituents selected from hydroxy, NR 5 R 6 , CONR 5 R 6 , phenyl optionally substituted with C 1  to C 4  alkyl or C 1  to C 4  alkoxy; C 3  to C 6  alkenyl or Het 4 ;  
 R 11  is H, C 1  to C 4  alkyl, C 3  to C 4  alkenyl, CO(C 1  to C 4  alkyl) or C 1  to C 4  haloalkyl;  
 R 12  is C 1  to C 4  alkyl, C 3  to C 4  alkenyl, C 1  to C 4  haloalkyl or C 1  to C 4  haloalkoxy;  
 Het 1  is an N-linked 4-, 5or 6-membered nitrogen-containing heterocyclic group optionally containing one or more further heteroatoms selected from S, N or O;  
 Het 2  is a C-linked 5-membered heterocyclic group containing an O, S or N heteroatom optionally containing one or more heteroatoms selected from N, O or S;  
 Het 3  is a C-linked 6-membered heterocyclic group containing an O or S heteroatom optionally containing one or more heteroatoms selected from O S or N or Het 3  is a C-linked 6-membered heterocyclic group containing three N heteroatoms;  
 Het 4  is a C-linked 4-, 5or 6-membered heterocyclic group containing one, two or three heteroatoms selected from S, O or N; and  
 wherein any of said heterocyclic groups Het 1 , Het 2 , Het 3  or Het 4  may be saturated, partially unsaturated or aromatic and wherein any of said heterocyclic groups may be optionally substituted with one or more substituents selected from C 1  to C 4  alkyl, C 3  to C 4  alkenyl, C 1  to C 4  alkoxy, halo, CF 3 , CO 2 R 11 , COR 11 , SO 2 R 12 , NHR 11  or NHCOR 12  and/or wherein any of said heterocyclic groups is benzo-fused;  
 with the provisos that (a) when R 1  is C 1  to C 3  alkyl then Het 1  is not morpholinyl or piperidinyl and (b) when R 1  is C 1  to C 3  alkyl substituted by phenyl then said phenyl group is not substituted by C 1  to C 4  alkoxy, CN, halo, CF 3 , OCF 3  or C 1  to C 4  alkyl.  
 
   
   
       2 - 4 . (canceled)  
   
   
       5 . The method of  claim 1 , wherein the compound has the general formula (IA) or (IB):  
     
       
         
         
             
             
         
       
       wherein R 1  is —(CH 2 ) n (C 3 -C 4 )cycloalkyl wherein n is 1 or 2; or R 1  is —(CH 2 ) n (C 3 -C 5 )cycloalkyl wherein n is 0; or R 1  is —(CH 2 ) n (C 5 )cycloalkyl wherein n is 1; or R 1  is methyl, ethyl, i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may be directly attached to any C-atom within the ethyl, iso-propyl or n-propyl groups; or R 1  is i-, n-, secor t-butyl;  
       R 2  is C 2  to C 4  alkyl;  
       R 13  is OR 3  wherein the R 3  alkyl group is methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl or t-butyl optionally substituted with one or two methoxy, ethoxy, n-propoxy or i-propoxy substituents; and  
       R 4  is a 4-methyl or 4-ethylpiperazin-1-ylsulphonyl group.  
     
   
   
       6 . A method according to  claim 5 , wherein the compound has the general formula (IB):  
     
       
         
         
             
             
         
       
       wherein R 1  is —(CH 2 ) n (C 3 -C 4 )cycloalkyl wherein n is 1 or 2; or R 1  is —(CH 2 ) n (C 3 -C 5 )cycloalkyl wherein n is 0; or R 1  is —(CH 2 ) n (C 5 )cycloalkyl wherein n is 1; or R 1  is methyl, ethyl, i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxy wherein said alkoxy substituent may be directly attached to any C-atom within the ethyl, iso-propyl or n-propyl groups; or R 1  is i-, n-, secor t-butyl;  
       R 2  is C 2  to C 4  alkyl;  
       R 13  is OR 3  wherein the R 3  alkyl group is methyl, ethyl, n-propyl, i-propyl, i-butyl, n-butyl, sec-butyl or t-butyl optionally substituted with one or two methoxy, ethoxy, n-propoxy or i-propoxy substituents; and  
       R 4  is a 4-methyl or 4-ethylpiperazin-1-ylsulphonyl group.  
     
   
   
       7 . The method according to claims  1 ,  5 , or  6 , wherein the compound is selected from: 
 5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-methoxyethyl]-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(sec-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(iso-Butyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(Cyclopropylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(Cyclobutylmethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxy-1-methylethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-(methylamino)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-dimethylaminoethyl-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2, 6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-{2-[Acetyl(methyl)amino]ethyl}-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(1-Acetylazetidin-3-yl)-5-[2-n-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-iso-Butoxy-5-(4-ethylpiperazin1-ylsulphonyl)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Benzyloxy-5-(4-ethylpiperazin1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-ethylazetidin-3-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-iso-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-iso-propoxypyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[(S)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[(R)-2-sec-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethanol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-{(pyridin-2-yl)methyl}pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-Cyclobutylmethyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(S)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[5-(4-Ethylpiperazin-1-ylsulphonyl)-2-(R)-(2-methoxy-1-methylethoxy)pyridin-3-yl]-2-(2-methoxyethyl)-3-n-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-hydroxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(2-Dimethylaminoethyl)-5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-iso-Butyl-3-ethyl-5-[2-(2-m ethoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-iso-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-Cyclobutylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-[2-(dimethylamino)-2-oxoethyl]-3-ethyl-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one,    5-[2-n-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-{2-[methyl(methylsulphonyl)amino]ethyl}-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-Cyclobutylpropylmethyl-3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-n-Butyl-3-ethyl-5-[2-(2-m ethoxyethoxy)-5-(4-m ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[ 2 -n-Butoxy-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(2-Ethoxyethyl)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2 ,6-di hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(3-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(S)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(R)-(2-methoxypropyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    2-(S)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or    2-(R)-sec-Butyl-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2,6-di hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and pharmaceutically acceptable salts or polymorphs thereof.    
   
   
       8 - 38 . (canceled)