Adenosine A1 agonists for the treatment of glaucoma and ocular hypertension

Abstract

The present invention relates to the use of selective adenosine A 1 agonists, in particular the dicyanopyridines of formula (I), for the treatment and/or prophylaxis of glaucoma and ocular hypertension as well as the their use for the production of a medicament for the treatment and/or prophylaxis of glaucoma and ocular hypertension.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         in which 
         A is oxygen or sulfur, 
         R 1  is hydrogen or a group of the formula 
       
       
         
           
           
               
               
           
         
         
           in which 
           # is the attachment to the oxygen-atom, 
           L 1  is linear (C 2 -C 4 )-alkanediyl, 
           L 2  is linear (C 1 -C 3 )-alkanediyl, 
           R 5  and R 8  are identical or different and independently selected from the group consisting of hydrogen or a side group of a natural α-amino acid or its homologues or isomers, 
           R 6  and R 9  are independently selected from hydrogen or methyl, 
           R 7  is hydrogen or (C 1 -C 4 )-alkyl, or 
           R 7  and R 5  form together with the atoms which they are attached to a pyrrolidine- or piperidine-ring, 
           R 10  and R 11  are identical or different and are independently selected from hydrogen or (C 1 -C 4 )-alkyl,
 wherein (C 1 -C 4 )-alkyl may be substituted with one group selected from hydroxy, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino, or 
 
           R 10  and R 8  form together with the atoms which they are attached to a pyrrolidine- or piperidine-ring, and 
           R 12  is hydrogen or hydroxycarbonyl, 
         
         R 2  is hydrogen or a group of the formula —CH 2 OR 1 ,
 wherein R 1  is defined as above, 
 
         R 3  is hydrogen, methyl or ethyl, 
         R 4  is hydrogen, methyl or ethyl, or 
         R 3  and R 4  form together with the nitrogen-atom, which they are bound to, a azetidine-, pyrrolidine- or piperidine-ring,
 wherein the azetidine-, pyrrolidine- or piperidine-ring may be substituted with one or 2 substituents independently selected from the group fluoro, trifluoromethyl, methyl, ethyl, methoxy and ethoxy, and the salts thereof. 
 
       
     
     
         2 . The compound of  claim 1 , wherein
 A is sulfur,   R 1  is a group of the formula   
       
         
           
           
               
               
           
         
         
           in which 
           # is the attachment to the oxygen-atom, 
           L 1  is ethane-1,2-diyl, 
           R 5  is hydrogen, methyl, propane-2-yl, 1-methylpropane-1-yl, 2-methyl-propane-1-yl, hydroxymethyl or 1-hydroxymethyl, 
           R 6  is hydrogen, 
           R 7  is hydrogen, 
           R 8  is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, hydroxyethyl, 2-carboxyethyl, 4-aminobutan-1-yl or 2-aminoethyl, 
           R 9  is hydrogen, 
           R 10  is hydrogen, 
           R 11  is hydrogen, or 
           R 10  and R 8  form together with the atoms which they are attached to a pyrrolidine-ring, 
         
         R 2  is hydrogen 
         R 3  is hydrogen, 
         R 4  is hydrogen, or 
         R 3  and R 4  form together with the nitrogen-atom, which they are bound to, a azetidine-pyrrolidine- or piperidine-ring, and the salts thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein
 A is sulfur,   R 1  is a group of the formula   
       
         
           
           
               
               
           
         
         
           in which 
           # is the attachment to the oxygen-atom, 
           R 5  is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, benzyl, hydroxy-methyl or 1-hydroxyethyl, 
           R 6  is hydrogen, 
           R 7  is hydrogen, 
           R 8  is hydrogen, methyl, propan-2-yl, 1-methylpropan-1-yl, 2-methyl-propan-1-yl, imidazol-4-ylmethyl, 4-aminobutan-1-yl, 2-amino ethyl, 3-aminopropan-1-yl, aminomethyl or 3-guanidinopropan-1-yl, 
           R 9  is hydrogen, 
           R 10  is hydrogen, 
           R 11  is hydrogen, 
         
         R 2  is hydrogen, 
         R 3  is hydrogen, 
         R 4  is hydrogen, and 
         the salts thereof. 
       
     
     
         4 . The compound of  claim 1 , selected from the group consisting of:
 2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-alaninate-Dihydrochloride,   2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-alaninate-Dihydrochloride,   2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-valinate-Dihydrochloride,   2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-arginyl-D-valinate-Dihydrochloride,   2-{4-[2-Amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-D-phenylalaninate-Dihydrochloride,   2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl) -3,5-dicyanopyridin-4-yl]phenoxy}ethyl-beta-alaninate-Trifluoroacetate,   2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl) -3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-ornithinate-Bis(trifluoroacetate),   2-{4-[2-(Azetidin-1-yl)-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl) -3,5-dicyanopyridin-4-yl]phenoxy}ethyl-L-lysyl-L-alaninate-Bis(trifluoroacetate),   2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-alanyl-L-alaninate-Hydrochloride,   2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-L-isoleucyl-L-alaninate-Hydrochloride, and   2-{4-[2-({[2-(4-Chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl]phenoxy}ethyl-glycyl-L-leucinate-Hydrochloride,   
       and the salts thereof. 
     
     
         5 . (canceled) 
     
     
         6 . A method for the treatment of glaucoma and ocular hypertension in humans and animals by administering a therapeutically effective amount of at least one compound according to  claim 1  or a medicament comprising at least one compound according to  claim 1  in combination with a inert, non-toxic, pharmaceutically acceptable additive. 
     
     
         7 . A method for the treatment of glaucoma and ocular hypertension in humans and animals by administering topically a therapeutically effective amount of at least one compound according to  claim 1  or a medicament comprising at least one compound according to  claim 1  in combination with a inert, non-toxic, pharmaceutically acceptable additive.