US2016367586A1PendingUtilityA1
Combination, kit and method of reducing intraocular pressure
Assignee: INOTEK PHARMACEUTICALS CORPPriority: Jan 11, 2010Filed: May 18, 2016Published: Dec 22, 2016
Est. expiryJan 11, 2030(~3.5 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 27/00A61P 27/02A61P 27/06A61K 31/19C07H 19/16A61K 31/216A61K 9/0048A61K 31/7076A61K 31/165A61K 45/06A61K 31/5575
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Claims
Abstract
The present invention is directed to a combination or a kit comprising a prostaglandin analog and an adenosine receptor A 1 agonist and to a method of reducing intraocular pressure (IOP) in a subject using such combination or kit. The invention is particularly directed to a combination of latanoprost marketed under the brand Xalatan™ and Compound A.
Claims
exact text as granted — not AI-modified1 . An ophthalmic combination comprising i) an adenosine receptor A 1 agonist and ii) a prostaglandin analog formulated for administration to an eye of a subject in an amount effective to reduce intraocular pressure, wherein the adenosine receptor A 1 agonist is a compound of Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
A is —CH 2 OH, —CH 2 ONO 2 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) n -(CH 2 ) n —(C 8 -C 12 bicyclic cycloalkyl), —(CH 2 ) n —(C 8 -C 12 bicyclic cycloalkenyl) n -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) n -(CH 2 ) n —(C 3 -C 8 monocyclic cycloalkyl), —(CH 2 ) n —(C 3 -C 8 monocyclic cycloalkenyl) n -(CH 2 ) n —(C 8 -C 12 bicyclic cycloalkyl), —(CH 2 ) n —(C 8 -C 12 bicyclic cycloalkenyl) n -(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) and each n is independently an integer ranging from 1 to 5.
2 . The combination of claim 1 , wherein the prostaglandin analog is selected from the group consisting of latanoprost, travoprost, unoprostone and bimatoprost.
3 . The combination of claim 1 , 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-dihydroxytetrahydrofuran-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-dihydroxytetrahydrofuran-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,
((2R,3S,4R,5R)-5-(2-chloro-6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate,
(2R,3R,4S,5R)-2-(6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (N6 Cyclopentyl adenosine (CPA)),
(2R,3R,4S,5R)-2-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (N6 Cyclopentyl adenosine (CCPA)), and pharmaceutically acceptable salts thereof.
4 . The combination of claim 1 , wherein the adenosine receptor A 1 agonist is Compound A, ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate or a pharmaceutically acceptable salt thereof.
5 . The combination of claim 1 , wherein the A 1 agonist is formulated for administration to an eye of the subject simultaneously, separately or sequentially to the application of the prostaglandin analog to the eye of the subject.
6 . The combination of claim 1 , formulated for administration of about 0.05 mg/ml to about 7.0 mg/ml of the A 1 agonist with about 30 μg/ml to about 50 μg/ml of the prostaglandin analog to an eye of the subject.
7 . The combination of claim 6 , formulated for administration of about 20-700 μg of the A 1 agonist to an eye of the subject.
8 . The combination of claim 6 , formulated for administration of about 20-350 μg of the A 1 agonist to an eye of the subject.
9 . The combination of claim 1 , wherein the A 1 agonist and the prostaglandin analog are formulated for topical administration to the eye of the subject.
10 . A kit comprising i) an adenosine receptor A 1 agonist and ii) a prostaglandin analog formulated for administration to an eye of a subject, wherein the adenosine receptor A 1 agonist is a compound of Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
A is —CH 2 OH, —CH 2 ONO 2 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—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) n -(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 —CC-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) and each n is independently an integer ranging from 1 to 5.
11 . The kit of claim 10 , wherein the prostaglandin analog is selected from the group consisting of latanoprost, travoprost, unoprostone and bimatoprost.
12 . The kit of claim 10 , 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-dihydroxytetrahydrofuran-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-dihydroxytetrahydrofuran-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,
((2R,3S,4R,5R)-5-(2-chloro-6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate,
(2R,3R,4S,5R)-2-(6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (N6 Cyclopentyl adenosine (CPA)),
(2R,3R,4S,5R)-2-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (N6 Cyclopentyl adenosine (CCPA)), and pharmaceutically acceptable salts thereof.
13 . A method of reducing intraocular pressure (IOP) and associated diseases and conditions caused by elevated IOP in a subject in need thereof by administering to an affected eye of the subject, an effective amount of:
(i) an adenosine receptor A 1 agonist compound of Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
A is —CH 2 OH, —CH 2 ONO 2 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) and each n is independently an integer ranging from 1 to 5, and
(ii) a prostaglandin analog.
14 . The method of claim 13 , 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).
15 . The method of claim 13 , wherein the A 1 receptor agonist compound is applied to an eye of the subject in need thereof, simultaneously, separately or sequentially to the application of the prostaglandin analog to the eye of the subject.
16 . The method of claim 15 , wherein the A 1 receptor agonist compound is applied to an eye of the subject in need thereof, simultaneously to the application of the prostaglandin analog to the eye of the subject.
17 . The method of claim 15 , wherein the A 1 receptor agonist compound is applied to an eye of the subject in need thereof, sequentially to the application of the prostaglandin analogto the eye of the subject.
18 . The method of claim 13 , 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-dihydroxytetrahydrofuran-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-dihydroxytetrahydrofuran-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,
((2R,3S,4R,5R)-5-(2-chloro-6-(cyclohexylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate
(2R,3R,4S,5R)-2-(6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (N 6 -cyclopentyl adenosine (CPA)), and
(2R,3R,4S,5R)-2-(2-chloro-6-(cyclopentylamino)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (2-chloro-N 6 -cyclopentyl adenosine (CCPA)) or pharmaceutically acceptable salts thereof.
19 . The method of claim 13 , wherein the A 1 receptor agonist compound is compound A ((2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate.
20 . The method of claim 13 , wherein A 1 receptor agonist compound and the prostaglandin analog are administered topically to an eye of the subject.Cited by (0)
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