Granted Patent B2

US 8,410,121 · App. 13/006,592 · Granted Apr 2, 2013

Abstract

Claims (31)

1. A method of treating pulmonary hypertension, which comprises administering to a patient in need thereof therapeutically effective amounts of a prostacyclin and a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted cycloalkyl, aryl, or heterocycle;

X is a bond, —O—, —S—, —C(O)—, —C(R 4 )═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—, —N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—, —C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—;

D is optionally substituted aryl or heterocycle;

E is optionally substituted aryl or heterocycle;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;

R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;

R 5 is hydrogen or optionally substituted alkyl or aryl; and

n is 0-3.

2. The method of claim 1 , wherein the compound is of the formula:

wherein:

each of Z″ 1 , Z″ 2 , Z″ 3 , and Z″ 4 is independently N or CR 10 ;

each R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

each R 13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle.

3. The method of claim 2 , wherein the compound is of the formula:

4. The method of claim 3 , wherein A is optionally substituted biphenyl.

5. The method of claim 3 , wherein R 3 is trifluoromethyl.

6. The method of claim 3 , wherein E is optionally substituted phenyl.

7. The method of claim 3 , wherein R 10 is amino.

8. The method of claim 1 , wherein the prostacyclin is epoprostenol, iloprost or treprostinil.

9. A method of treating pulmonary hypertension, which comprises administering to a patient in need thereof therapeutically effective amounts of a prostacyclin and a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted cycloalkyl, aryl, or heterocycle; and R 2 is hydrogen or lower alkyl.

10. The method of claim 9 , wherein A is optionally substituted biphenyl.

11. The method of claim 9 , wherein the prostacyclin is epoprostenol, iloprost or treprostinil.

12. A method of treating pulmonary hypertension, which comprises administering to a patient in need thereof therapeutically effective amounts of a prostacyclin and (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 , wherein the prostacyclin is epoprostenol, iloprost or treprostinil.

Assignments (10)