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 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 selected from the group consisting of —CH2NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —, —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —; 
         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. 
     
     
         2 . The composition of  claim 1 , wherein X 1  is hydrogen and X 2  is a hydroxy group. 
     
     
         3 . The composition of  claim 1 , wherein A is —CH(R 10 )—, and R 10  is an optionally substituted aryl group or an optionally substituted heteroaryl group. 
     
     
         4 . The composition of  claim 3 , wherein R 10  is an unsubstituted monocyclic heteroaryl group. 
     
     
         5 . The composition of  claim 4 , wherein R 10  is an unsubstituted thienyl group. 
     
     
         6 . The composition of  claim 1 , wherein R 1  and R 2  are each independently selected from hydrogen and C 1 -C 4  alkyl. 
     
     
         7 . The composition of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide, (R)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide and (S)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide, and pharmaceutically acceptable salts thereof 
     
     
         8 . The composition of  claim 1 , wherein X 1  is hydrogen and X 2  is hydrogen. 
     
     
         9 . The composition of  claim 8 , wherein —CH 2 CH(R 10 )—, and R 10  is a substituted aryl group. 
     
     
         10 . The composition of  claim 9 , wherein R 10  is a substituted phenyl group. 
     
     
         11 . The composition of  claim 10 , wherein R 10  is phenyl substituted with —CH 2 —OC(O)—R a , wherein R a  is optionally substituted aryl group. 
     
     
         12 . The composition of  claim 11 , wherein R a  is 2,4-dimethylphenyl. 
     
     
         13 . The composition of  claim 8 , wherein the compound of formula (I) is selected from the group consisting of (rac)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate, (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, and pharmaceutically acceptable salts thereof 
     
     
         14 . The composition of any of  claim 1 , wherein the prostaglandin or prostaglandin analog is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2a  and fluprostenol. 
     
     
         15 . 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. 
     
     
         16 . A compound according to formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y is selected from the group consisting of alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclyl, any of which may be optionally substituted; 
         B is selected from the group consisting of —NR 1 R 2 , —CH 2 NR 1 R 2 , —CH(R 10 )R 2 , —CCH 3 (R 10 ) R 2 , —NHCH(R 10 )R 2 , —N(CH 3 )R 2 , —CH 2 CH 2 R 2 , —CH(R 10 )CH 2 R 2 , and —CH 2 CH(R 10 )R 2 ; R 1 , R 2  and R 10  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl and 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 the acyl radical of a prostaglandin or a prostaglandin analog. 
       
     
     
         17 - 21 . (canceled) 
     
     
         22 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         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 selected from the group consisting of —CH2NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —, —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —; 
         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. 
       
     
     
         23 - 45 . (canceled) 
     
     
         46 . A method of influencing the action of a kinase in a subject, comprising administering to the subject a compound of  claim 1 , wherein the kinase is ROCK-I, ROCK-II, PKA, PKC, a CAM kinase, GRK-2, GRK-3, GRK-5, GRK-6, or a combination thereof. 
     
     
         47 . A method of influencing the action of a kinase in a subject, comprising administering to the subject a compound of  claim 16 , wherein the kinase is ROCK-I, ROCK-II, PKA, PKC, a CAM kinase, GRK-2, GRK-3, GRK-5, GRK-6, or a combination thereof. 
     
     
         48 . A method of influencing the action of a kinase in a subject, comprising administering to the subject a compound of  claim 22 , wherein the kinase is ROCK-I, ROCK-II, PKA, PKC, a CAM kinase, GRK-2, GRK-3, GRK-5, GRK-6, or a combination thereof.