Combination therapy

Abstract

Described herein are compounds and compositions for treating glaucoma and/or reducing intraocular pressure. Compositions may comprise an isoquinoline compound and a prostaglandin or a prostaglandin analog. Compounds described herein include those in which an isoquinoline compound is covalently linked to a prostaglandin or a prostaglandin analog, and those in which an isoquinoline compound and a prostaglandin free acid together form a salt.

1 . A composition comprising:
 a) a compound according to formula (I):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof, wherein: 
           R 1  and R 2  are independently selected from the group consisting of hydrogen and C 1 -C 4  alkyl, or R 1  and R 2  are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms; 
           A is —CH 2 CH(R 10 )—; 
           each R 10  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; and 
           X 1  and X 2  are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl; and 
         
         b) a prostaglandin or a prostaglandin analog or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The composition of  claim 1 , wherein X 1  is hydrogen and X 2  is hydrogen. 
     
     
         3 . The composition of  claim 2 , wherein R 10  is a substituted aryl group. 
     
     
         4 . The composition of  claim 3 , wherein R 10  is a substituted phenyl group. 
     
     
         5 . The composition of  claim 4 , wherein the substituent is halo. 
     
     
         6 . The composition of  claim 4 , wherein R 10  is p-chloro-phenyl. 
     
     
         7 . The composition of  claim 1 , wherein the compound of formula (I) is selected from (R)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide, (S)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide, (rac)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide, and pharmaceutically acceptable salts thereof. 
     
     
         8 . The composition of  claim 7 , wherein the prostaglandin is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, latanoprostene bunod, and unoprostone. 
     
     
         9 . The composition of  claim 7 , wherein the prostaglandin analog is an ester of a prostaglandin selected from the group consisting of cloprostenol, 13,14-dihydrocloprostenol, PGE 1 , PGF 1α , PGF 2α , PGF 3α , and fluprostenol. 
     
     
         10 . The composition of  claim 9 , wherein the ester is an isopropyl ester. 
     
     
         11 . The composition of  claim 1 , further comprising at least one component selected from a buffer, a chelating agent, a tonicity agent, a preservative, a viscosity enhancer, a sugar or a sugar alcohol, and a surfactant. 
     
     
         12 . A compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently selected from the group consisting of hydrogen and C1-C4 alkyl, or R 1  and R 2  are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms; 
         A is —CH 2 CH(R 10 )—; 
         each R 10  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; 
         X 1  and X 2  are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl; and 
       
       PG ⊖  is a deprotonated free acid of a prostaglandin or a prostaglandin analog. 
     
     
         13 . The compound of  claim 12 , wherein X 1  is hydrogen and X 2  is hydrogen. 
     
     
         14 . The compound of  claim 12 , wherein R 10  is a substituted aryl group. 
     
     
         15 . The compound of  claim 12 , wherein R 10  is a substituted phenyl group. 
     
     
         16 . The compound of  claim 15 , wherein R 10  is p-substituted phenyl. 
     
     
         17 . The compound of  claim 16 , wherein the substituent is halo. 
     
     
         18 . The compound of  claim 17 , wherein the substituent is p-chloro. 
     
     
         19 . The compound of  claim 12 , wherein the PG ⊖  is selected from the group consisting of deprotonated free acids of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, 13,14-dihydrocloprostenol,latanoprostene bunod, unoprostone, PGE 1 , PGF 1α , PGF 2α , PGF 3α , and fluprostenol. 
     
     
         20 . A composition comprising a compound of  claim 12 , and at least one component selected from a buffer, a chelating agent, a tonicity agent, a preservative, a viscosity enhancer, a sugar or a sugar alcohol, and a surfactant. 
     
     
         21 . A composition comprising:
 a) (R)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanarmide, and   b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF 1α , isopropyl ester, PGF 2α  isopropyl ester, PGF 3α , isopropyl ester, and fluprostenol isopropyl ester.   
     
     
         22 . A composition comprising:
 a) (S)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide; and   b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF 1α  La isopropyl ester, PGF 2α , isopropyl ester, PGF 3α  isopropyl ester, and fluprostenol isopropyl ester.   
     
     
         23 . A composition comprising:
 a) (rac)-3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide; and   b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF1, isopropyl ester, PGF2c, isopropyl ester, PGF3, isopropyl ester, and fluprostenol isopropyl ester.   
     
     
         24 . A method of treating an ocular disorder in a subject in need of treatment, comprising administering to the subject a compound or composition of any of  claims 1 - 23 . 
     
     
         25 . The method of  claim 24 , wherein the ocular disorder is glaucoma. 
     
     
         26 . The method of  claim 25 , wherein the compound or composition is administered topically to an eye of the subject. 
     
     
         27 . A method of reducing intraocular pressure in a subject in need thereof, comprising topically administering to an eye of the subject a compound or composition of any of  claims 1 - 23 . 
     
     
         28 . A compound selected from the group consisting of:
 a) (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate;   b) (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate; and   c) (rac)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate.