Anthranilic acid derivatives as inhibitors of the CGMP-phosphodiesterase

Abstract

Novel anthranilic acid derivatives having an inhibiting activity of cGMP-PDE are represented by the formula I where A is a lower alkylene group: The anthranilic acid derivatives show pharmacological activity and may be used in pharmaceutical compositions as medications. The anthranilic acid derivatives can be formed by the reaction of a fluoro precursor with an amine. Pharmaceutical compositions containing the anthranilic acid derivatives can be used to treat or prevent human health disorders.

1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen atom or a halogen atom;  
 R 2  is an electron withdrawing group;  
 R 3  is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;  
 A is a lower alkylene group;  
 R 4  is a lower alkoxy group, 
 a substituted or unsubstituted, saturated or unsaturated heterocyclic group,  
 an amino group optionally substituted with halo(lower)alkyl or lower alkyl,  
 a group —CH 2 —R 5  
 wherein R 5  is a cycloalkyl group or an unsaturated heterocyclic group, or  
 
 a group —CR 6 R 7 R 8  wherein 
 R 6  and R 7  are each independently carboxy group, 
 a protected carboxy group,  
 a carbamoyl group optionally substituted with lower alkyl, or  
 a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alkyl, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or aryloxycarbonyl, or  
 
 R 6  and R 7  together with the carbon atom to which R 6  and R 7  are attached may form a substituted or unsubstituted, saturated carbocyclic group, or an unsaturated carbocyclic group optionally substituted with hydroxy, and  
 R 8  is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or a lower alkoxy;  
 provided that  
 
 
 when R 4  is the group —CR 6 R 7 R 8  wherein 
 R 6  is a lower alkyl group optionally substituted with halogen,  
 R 7  is a lower alkyl group optionally substituted with halogen,  
 and R 8  is hydrogen atom or a lower alkyl group, or 
 when R 4  is the group —CH 2 —R 5  wherein R 5  is the same as the above,  
 R 3  should be hydrogen atom, hydroxy group or a cycloalkyl group; and a pro-drug thereof, and a salt thereof.  
 
 
 
     
     
         2 . A compound of  claim 1 , 
 wherein 
 the electron withdrawing group for R 2  is selected from a group consisting of nitro group; cyano group; acyl group; halo(lower)alkyl group; sulfamoyl group; carbarnoyl group optionally substituted with lower alkyl; halogen atom; lower alkenyl group optionally substituted with protected carboxy; lower alkanesulfonyl group; saturated heterocyclic sulfonyl group optionally substituted with protected carboxy; and unsaturated heterocyclic group,  
 the substituent(s) on the aryl group for R 3  is/are selected from a group consisting of lower alkyl group; halo(lower)alkyl group; lower alkylthio group; halogen atom; hydroxy group; lower alkylenedioxy group; cyano group; nitro group; carboxy group; protected carboxy group; sulfarnoyl group; acyl group; aryl group; ar(lower)alkoxy group; aryloxy group; lower alkoxy group which may be substituted with lower alkoxy or cycloalkyl; amino group which may be substituted with acyl, protected carboxy or lower alkyl and carbamoyl group which may be substituted with lower alkyl,  
 the substituent(s) on the saturated or unsaturated heterocyclic group for R 4  is/are selected from a group consisting of oxo group; acyl group; protected carboxy group; lower alkanesulfonyl group; sulfamoyl group which may be substituted with protected carboxy; ar(lower)alkyl group; lower alkyl group which may be substituted with hydroxy or aryl; ureido group which may be substituted with lower alkyl; guanidino group which may be substituted with protected carboxy; arnidino group which may be substituted with protected carboxyl; and carbamoyl group which may be substituted with lower alkyl, and  
 the substituent(s) on the saturated carbocyclic group formed by combination of R 6  and R 7  is/are selected from a group consisting of lower alkyl group; halogen atom; hydroxy group; lower alkoxy group; acyloxy group; carboxy group; protected carboxy group; oxo group; amidino group which may be substituted with protected carboxy; ureido group which may be substituted with lower alkyl or aryl; guanidino group which may be substituted with protected carboxy; amino group which may be substituted with acyl, lower alkanesulfonyl or protected carboxy; and carbamoyl group which may be substituted with lower alkyl or hydroxy(lower) alkyl.  
   
     
     
         3 . A compound of  claim 1 , 
 wherein 
 R 3  is a substituted or unsubstituted aryl group;  
 R 4  is a group —CR 6 R 7 R 8  wherein 
 R 6  and R 7  together with the carbon atom to which R 6  and R 7  are attached may form a substituted or unsubstituted, saturated carbocyclic group, and  
 R 8  is hydrogen atom.  
 
   
     
     
         4 . A compound of  claim 3 , 
 wherein 
 R 2  is nitro group, cyano group or a halo(lower)alkyl group;  
 R 3  is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy;  
 R 4  is a group —CR 6 R 7 R 8  wherein 
 R 6  and R 7  together with the carbon atom to which R 6  and R 7  are attached may form a saturated carbocyclic group optionally substituted with hydroxy or amino which may be substituted with acyl; and  
 R 8  is hydrogen atom.  
 
   
     
     
         5 . A compound of  claim 4  which is 
 N-(2-chlorobenzyl)-2-cyclopentylamino-5-nitrobenzamide,  
 N-(3-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,  
 N-(4-chlorobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,  
 2-(cyclopentylamino)-N-(2,4-dichlorobenzyl)-5-nitrobenzamide,  
 2-(cyclopentylamino)-N-(3,4-dichlorobenzyl)-5-nitrobenzamide,  
 2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl) benzamide,  
 2-(cyclopentylamino)-N-(4-fluorobenzyl)-5-nitrobenzamide,  
 2-(cyclopentylamino)-N-(4-methoxybenzyl)-5-nitrobenzamide,  
 N-(2-chloro-4-methoxybenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,  
 N-(4-bromobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide,  
 2-(cvclopentylamino)-5-nitro-N-phenethylbenzamide,  
 2-(cyclopentylamino)-5-nitro-N-(3-ph enylpropyl)benzamide,  
 N-benzyl-2-(cyclobutylamino)-5-nitrobenzamide,  
 N-benzyl-2-cycloheptylamino-5-nitrobenzamide,  
 N-benzyl-2-(cyclohexylamino)-5-nitrobenzamide,  
 N-benzyl-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-(cyclopentylamino)-N-(2,4-difluoro benzyl)-5-nitrobenzamide, N-benzyl-2-(cyclopropylamino)-5-nitrobenzamide,  
 N-benzyl-2-(2-hydroxy cyclohexylamino)-nitrobenzamide,  
 N-benzyl-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide,  
 2-(cyclopentylamino)-5-formyl-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-(trans-2-hydroxycyclopentylarino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-[cis-4-(benzoyloxy)cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,  
 2-(cis-4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 N-(3,4-dimethoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 N-benzyl-2-(3-hydroxycyclopentylamino)-5-nitrobenzamide,  
 2-[3-(benzoyloxy)cyclopentylamino]-N-benzyl-5-nitrobenzamide,  
 N-(3,4-dimethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(trans-2-aminocyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 N-(3-chloro-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-[cis4-(benzoyloxy)cyclohexylamino]-N-(3-chloro-4-methoxybenzyl)-5-nitrobenzamide,  
 N-(3-chloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 N-(3,4-dimethoxybenzyl)-2-(trans-2-hydroxycyclopentylamino)-5-nitrobenzamide,  
 5 N-(3,5-dichloro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 N-(3,4-ethylenedioxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(3,4,5-trimethoxybenzyl)benzamide,  
 2-[cis-4-(acetoxy) cyclohexylamino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,  
 2-[(trans-4-aminocyclohexyl)amino]-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,  
 2-(cis-4-hydroxycyclohexylamino)-N-(1-naphthylmethyl)-5-nitrobenzamide,  
 2-(trans-4-acetamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,  
 N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl) amino]-5-nitrobenzamide,  
 N-(2-chloro-5-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(cis-4-benzoyloxycyclohexylamino)-N-(3-filuoro-4-methoxybenzyl)-5-nitrobenzamide,  
 N-(3-ethoxy-4-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 N-(4-chloro-4-ethoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitro-benzamide,  
 N-(4-ethoxy-3-methoxybenzyl)-2-(cis-4-hydroxycyclohexylamino)-5-nitrobenzamide,  
 2-(trans-4-aminocyclohexylamino)-N-(4-ethoxy-3-methoxybenzyl)-5-nitrobenzamide,  
 N-(4-ethoxy-3-methoxybenzyl)-2-(trans4-fonnamidocvclohexylamino)-5-nitrobenzamide,  
 5-cyano-2-(trans-4-hydroxycyclohexylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-(cis-4-formamidocyclohexylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide,  
 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-[(1S)-1-phenylethyl]benzamide,  
 5-bromo-N-(3-chloro-4-methoxybenzyl)-2-(cyclopentylamino)benzamide,  
 5-chloro-2-(cyclopentylamino)-N-(1,3-benzodioxo-5-ylmethyl)benzamide,  
 4-chloro-N-(3,4-dimethoxybenzyl)-5-fluoro-2-(trans-4-hydroxycyclohexylarninc)benzamide, or  
 2-(cis-4-aminocyclohexylamino)-N-(3,4-dirnethoxybenzyl)-5-nitrobenzamide,  
 or a salt thereof.  
 
     
     
         6 . A compound of  claim 1 , 
 wherein 
 R 3  is a substituted or unsubstituted aryl group;  
 R 4  is a group —CR 6 R 7 R 8  wherein 
 R 6  is a lower alkyl group substituted with hydroxy,  
 R 7  is a lower alkyl which may be substituted with hydroxy, and  
 R 8  is hydrogen atom or a lower alkyl group which may be substituted with hydroxy.  
 
   
     
     
         7 . A compound of  claim 6 , 
 wherein 
 R 2  is nitro group, cyano group or a halo(lower)alkyl group; and  
 R 3  is an aryl group optionally substituted with one or more substituent(s) selected from halogen and lower alkoxy.  
   
     
     
         8 . A compound of  claim 7  which is 
 N-benzyl-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,  
 (R)-2(1-ethyl-2-hydroxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 (S)-2-[1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 (R)-2-(2-hydroxy-1-methylethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl) benzamide,  
 2-[2-hydroxy-1,1-bis(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-(2-hydroxy-1,1-dimethylethylamino)-5-nitro-N-(1, 3-benzodioxol-5-ylmethyl)benzamide,  
 2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-[2-hydroxy-1-(hydroxymethyl)-1-methylethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 (S)-2-[1-(hydroxymethyl)-2-methylpropylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 2-[(1R, 2R)-2-hydroxy-1-(hydroxymethyl)propylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 N-(3-chloro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxy-methyl)ethylamino]-5-nitrobenzamide,  
 2-[1-(hydroxyethyl)pentylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide,  
 (S)-N-(3,4-dimethoxybenzyl)-2-[1-(hydroxymethyl)propylamino]-5-nitrobenzamide,  
 N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1,1-dimethylethylamino)-5-nitrobenzamide,  
 N-(3-fluoro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-nitrobenzamide,  
 N-(4-chloro-3-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl) ethylamino]-5-nitrobenzamide,  
 2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-N-(2-naphthylmethyl)-5-nitrobenzamide,  
 2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-N-[2-(2-methoxyphenyl)ethyl]-5-nitrobenzamide,  
 N-(3-chloro-4-fluorobenzyl)-2-[2-hydroxy-1-(hydroxymethyl) ethylamino]-5-nitrobenzamide,  
 (S)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide,  
 (S)-N-(3,5-dimethoxybenzyl)-2-(2-hydroxy-1-methylethyl) amino-5-nitrobenzamide,  
 N-(3-chioro-4-methoxybenzyl)-2-[2-hydroxy-1-(hydroxymethyl)ethylamino]-5-(trifluoromethyl)benzamide,  
 (R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide,  
 (S)-S-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide,  
 (R)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)benzamide, or  
 (R)-N-(4-chloro-3-methoxybenzyl)-5-cyano-2-(hydroxy-1-methylethylamino)benzamide,  
 or a salt thereof.  
 
     
     
         9 . A compound of  claim 1  for use as a medicament.  
     
     
         10 . A process for preparing a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen atom or a halogen atom;  
 R 2  is an electron withdrawing group;  
 R 3  is hydrogen atom; hydroxy group; a lower alkoxy group; a cycloalkyl group; a substituted or unsubstituted aryl group; or an unsaturated heterocyclic group optionally substituted with lower alkyl;  
 A is a lower alkylene group;  
 R 4  is a lower alkoxy group, 
 a substituted or unsubstituted, saturated or unsaturated heterocyclic group,  
 an amino group optionally substituted with halo(lower)alkyl or lower alky,  
 a group —CH 2 —R 5  
 wherein R 5  is a cycloalkyl group or an unsaturated heterocyclic group, or  
 
 a group —CR 6 R 7 R 8  wherein 
 R 6  and R 7  are each independently carboxy group, 
 a protected carboxy group,  
 a carbamoyl group optionally substituted with lower alkyl, or  
 a lower alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atom; hydroxy group; cyano group; azido group; lower alkoxy group; lower alkylthio group; protected carboxy group; lower alkanesulfonyl group; acyloxy group; lower alkanesulfonyloxy group; aryl group; aryloxy group which may be substituted with cyano; unsaturated heterocyclic group which may be substituted with lower alkyl; guanidino group which may be substituted with lower alky, cyano and/or halogen; isothioureido group which may be substituted with lower alkyl and/or cyano; and amino group which may be substituted with acyl, protected carboxy, lower alkanesulfonyl, lower alkanesulfonyloxy or an aryloxycarbonyl, or  
 
 R 6  and R 7  together with the carbon atom to which R 6  and R 7  are attached may form a substituted or unsubstituted, saturated carbocyclic group, or 
 an unsaturated carbocyclic group optionally substituted with hydroxy, and  
 
 R 8  is hydrogen atom; a lower alkoxy group; or a lower alkyl group optionally substituted with hydroxy or lower alkoxy;  
 provided that  
 
 
 when R 4  is the group —CR 6 R 7 R 8 wherein 
 R 6  is a lower alkyl group optionally substituted with halogen,  
 R 7  is a lower alkyl group optionally substituted with halogen,  
 and R 8  is hydrogen atom or a lower alkyl group, or  
 
 when R 4  is the group —CH 2 -R 5  wherein R 5  is the same as the above,  
 R 3  should be hydrogen atom, hydroxy group or a cycloalkyl group; and a salt thereof,  
 which comprises  
 (1) reacting a compound of the formula (II):  
                     
 or its salt, with a compound of (III)  
 H 2 N—R 4  (III)  
 or its salt,  
 wherein R 1 , R 2 , R 3 , R 4  and A are as defined above, or  
 (2) reacting a compound of the formula (IV):  
                     
 or its salt, with a compound of the formula (V):  
 H 2 N—A—R 3  (V)  
 or its salt,  
 wherein R 1 , R 2 , R 3 , R 4  and A are as defined above, or  
 (3) subjecting a compound of the formula (VI):  
                     
 or its salt, to reductive alkylation with a compound of formula (VII):  
                     
 or its salt,  
 wherein R 1 , R 2 , R 3 , R 6 , R 7  and A are as defined above.  
 
     
     
         11 . A pharmaceutical composition which comprises, as an active ingredient, a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.  
     
     
         12 . A pharmaceutical composition comprising a compound of  claim 1 , as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.  
     
     
         13 . A composition of  claim 11  for the use of the treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, electile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder.  
     
     
         14 . A composition of  claim 11  for the use of the treatment of electile dysfunction or impotence.  
     
     
         15 . A use of the compound of  claim 1  for the manufacture of a medicament for inhibiting cGMP-PDE.  
     
     
         16 . A use of the compound of  claim 1  for the manufacture of a medicament for treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, electile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder.  
     
     
         17 . A method for the treatment and/or prevention of angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tubulo-intestitinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, asthma, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility, electile dysfunction, female sexual dysfunction, impotence, diabetic complications, micturition disorder, or incontinence or storage of urine disorder, by administering the compound of  claim 1.