Method of reducing intraocular pressure in humans

Abstract

Provided herein are compounds of Formula I, compositions comprising an effective amount of a compound of Formula I, and methods for reducing intraocular pressure comprising administering an effective amount of compounds of Formula I to a subject in need thereof.

1 - 18 . (canceled) 
     
     
         19 . A method of treating diseases and conditions caused by elevated intraocular pressure (IOP) in a human subject in need thereof by administering an effective amount of a selective adenosine A 1  agonist to an affected eye of the subject. 
     
     
         20 . The method of  claim 19 , wherein the diseases and conditions caused by elevated IOP in a human are selected from the group consisting of normal-tension glaucoma, ocular hypertension (OHT), and primary open-angle glaucoma (POAG). 
     
     
         21 . The method as claimed in  claim 19 , wherein the selective adenosine A 1  agonist is a compound of Formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
 A is —CH 2 ONO 2 , —CH 2 OSO 3 Na or —CH 2 OSO 3 H; 
 B and C are —OH; 
 D is 
 
       
       
         
           
           
               
               
           
         
         
           A and B are trans with respect to each other; 
           B and C are cis with respect to each other; 
           C and D are cis or trans with respect to each other; 
           R 1  is —H, —C 1 -C 10  alkyl, -aryl, -3- to 7-membered monocyclic heterocyclyl, -8- to 12-membered bicyclic heterocyclyl, —C 3 -C 8  monocyclic cycloalkyl, —C 3 -C 8  monocyclic cycloalkenyl, —C 8 -C 12  bicyclic cycloalkyl, —C 8 -C 12  bicyclic cycloalkenyl —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkenyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkenyl), or —(CH 2 ) n -aryl; 
           R 2  is —H, halo, —CN, —NHR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHNHC(O)R 4 , —NHNHC(O)OR 4 , —NHNHC(O)NHR 4 , or —NH—N═C(R 6 )R 7 ; 
           R 4  is —C 1 -C 15  alkyl, -aryl, —(CH 2 ) n -aryl, —(CH 2 ) n -(3- to 7-membered monocyclic heterocyclyl), —(CH 2 ) n -(8- to 12-membered bicyclic heterocyclyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkenyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkenyl), —C≡C—(C 1 -C 10  alkyl) or —C≡C-aryl; 
           R 6  is —C 1 -C 10  alkyl, -aryl, —(CH 2 ) n -aryl, —(CH 2 ) n -(3- to 7-membered monocyclic heterocyclyl), —(CH 2 ) n -(8- to 12-membered bicyclic heterocyclyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkenyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkenyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkenyl), -phenylene-(CH 2 ) n COOH, or -phenylene-(CH 2 ) n COO—(C 1 -C 10  alkyl); 
           R 7  is —H, —C 1 -C 10  alkyl, -aryl, —(CH 2 ) n -aryl, —(CH 2 ) n -(3- to 7-membered monocyclic heterocyclyl), —(CH 2 ) n -(8- to 12-membered bicyclic heterocyclyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkyl), —(CH 2 ) n —(C 3 -C 8  monocyclic cycloalkenyl), —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkenyl) or —(CH 2 ) n —(C 8 -C 12  bicyclic cycloalkyl) each n is independently an integer ranging from 1 to 5, 
           wherein-3- to 7-membered monocyclic heterocyclyl is a 3- or 4-membered non-aromatic monocyclic cycloalkyl in which 1 of the ring carbon atoms has been replaced with an N, O or S atom; or a 5-, 6-, or 7-membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom, and 
           wherein-8- to 12-membered bicyclic heterocyclyl is a bicyclic 8- to 12-membered aromatic or non-aromatic bicyclic cycloalkyl in which one or both of the rings of the bicyclic ring system have 1-4 of its ring carbon atoms independently replaced with a N, O or S atom. 
         
       
     
     
         22 . The method as claimed in  claim 19  wherein the selective A 1  agonist is a compound of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein
 A is —CH 2 ONO 2 ; 
 B and C are —OH; 
 D is 
 
       
       
         
           
           
               
               
           
         
         
           A and B are trans with respect to each other; 
           B and C are cis with respect to each other; 
           C and D are cis or trans with respect to each other; 
           R 1  is —C 3 -C 8  monocyclic cycloalkyl, -3- to 7-membered monocyclic heterocyclyl or —C 8 -C 12  bicyclic cycloalkyl; and 
           R 2  is —H or -halo. 
         
       
     
     
         23 . The method as claimed in  claim 21  wherein the compound of Formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate, 
       
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate, 
       
       
         
           
           
               
               
           
         
         sodium ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxyetrahydrofuran-2-yl)methyl sulfate, 
       
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(tetrahydrofuran-3-ylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl nitrate, 
       
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-5-(6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate, 
       
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-5-(6-(bicycle-[2.2.1]-heptan-2-ylamino)-9H-purin-9-yl)-3,4-dihydroxyetrahydrofuran-2-yl)methyl nitrate, 
       
       
         
           
           
               
               
           
         
         sodium ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl sulfate, and 
       
       
         
           
           
               
               
           
         
         ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate, 
       
       or pharmaceutically acceptable salts thereof. 
     
     
         24 . The method as claimed in  claim 19  wherein the selective adenosine A 1  agonist is selected from the group consisting of:
 ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate; 
 ((2R,3S,4R,5R)-5-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate; 
 sodium ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl sulfate; and 
 ((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(tetrahydrofuran-3-ylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl nitrate. 
 
     
     
         25 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by at least 10%. 
     
     
         26 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by about 10-20%. 
     
     
         27 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by 20% or more. 
     
     
         28 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by at least 10% for more than 3 hours. 
     
     
         29 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by about 10-20% for more than 3 hours. 
     
     
         30 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by 20% or more for more than 3 hours. 
     
     
         31 . The method as claimed in  claim 19  wherein the IOP of the affected eye is reduced by at least 10% for at least 6 hours. 
     
     
         32 . The method as claimed in  claim 19  wherein the effective amount of the selective adenosine A 1  agonist is at least 20 μg. 
     
     
         33 . The method as claimed in  claim 19  wherein the effective amount of the selective adenosine A 1  agonist is between 60 μg and 350 μg. 
     
     
         34 . The method as claimed in  claim 19  wherein the effective amount of the selective adenosine A 1  agonist is administered as a single dose. 
     
     
         35 . The method as claimed in  claim 19  wherein the effective amount of the selective adenosine A 1  agonist is administered as a twice daily dose. 
     
     
         36 - 43 . (canceled)