COMBINATION THERAPY
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 selected from the group consisting of —CH 2 NH—, —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 any 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 1 , 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-dimethylbenzoate, (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 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 2α 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 . The compound of claim 16 , wherein X 1 and X 2 are hydrogen, and Y is selected from the group consisting of alkylene, aryl, heteroaryl, cycloalkyl, and heterocyclyl.
18 . The compound of claim 16 , wherein B is —NR 1 R 2 .
19 . The compound of claim 16 , wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl.
20 . The compound of claim 16 , wherein the PG acyl radical is selected from the group consisting of the acyl radicals of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
21 . A composition comprising a compound of claim 16 , 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.
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 —CH 2 NH—, —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 . The compound of claim 22 , wherein X 1 is hydrogen and X 2 is a hydroxy group.
24 . The compound of claim 22 , wherein A is —CH(R 10 )—, and R 10 is an optionally substituted aryl group or an optionally substituted heteroaryl group.
25 . The compound of claim 24 , wherein R 10 is an unsubstituted monocyclic heteroaryl group.
26 . The compound of claim 25 , wherein R 10 is an unsubstituted thienyl group.
27 . The compound of claim 22 , wherein R 1 and R 2 are each independently selected from hydrogen and C 1 -C 4 alkyl.
28 . The compound of claim 22 , wherein X 1 is hydrogen and X 2 is hydrogen.
29 . The compound of claim 28 , wherein —CH 2 CH(R 10 )—, and R 10 is a substituted aryl group.
30 . The compound of claim 29 , wherein R 10 is a substituted phenyl group.
31 . The compound of claim 30 , wherein R 10 is phenyl substituted with —CH 2 —OC(O)—R a , wherein R a is optionally substituted aryl group.
32 . The compound of claim 31 , wherein R a is 2,4-dimethylphenyl.
33 . The compound of claim 22 , wherein the PG ⊖ is selected from the group consisting of deprotonated free acids of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGE 1 , PGF 2α and fluprostenol.
34 . A composition comprising a compound of claim 22 , 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.
35 . A composition comprising:
a) (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
36 . A composition comprising:
a) (R)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
37 . A composition comprising:
a) (S)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
38 . A composition comprising:
a) (rac)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
39 . A composition comprising:
a) (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
40 . A composition comprising:
a) (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate; and
b) a prostaglandin selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol, latanoprostene bunod, unoprostone, PGF 2α and fluprostenol.
41 . The composition of claim 35 , 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.
42 . A method of treating an ocular disorder in a subject in need of treatment, comprising administering to the subject a compound or composition of claim 1 .
43 . The method of claim 42 , wherein the ocular disorder is glaucoma.
44 . The method of claim 42 , wherein the compound or composition is administered topically to an eye of the subject.
45 . 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 claim 1 .