Combination therapy

Patent metadata

Field	Value
Publication number	US-2016243105-A1
Application number	US-201615142461-A
Country	US
Kind code	A1
Filing date	Apr 29, 2016
Priority date	Mar 15, 2013
Publication date	Aug 25, 2016
Grant date	—

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.

First claim

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 any of claims 1 - 2 , 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 any of claims 1 - 5 , wherein R 1 and R 2 are each independently selected from hydrogen and C 1 -C 4 alkyl.

7 . The composition of any of claims 1 - 6 , 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 any of claims 8 - 12 , 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 any of claims 1 - 13 , 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 any of claims 1 - 14 , 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 any of claims 16 - 17 , wherein B is —NR 1 R 2 .

19 . The compound of any of claims 16 - 18 , 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 any of claims 16 - 19 , 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 any of claims 16 - 20 , 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 any of claims 22 - 23 , 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 any of claims 22 - 26 , 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 a

Assignees

• Aerie Pharmaceuticals Inc

Inventors

• Kopczynski Casey
• Lin Cheng-Wen
• Sturdivant Jill Marie
• Delong Mitchell A

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K31/559

  having heterocyclic rings containing hetero atoms other than oxygen · CPC title