SUBSTITUTED PYRAZINONE MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS AND METHODS

• US 20110144060A1
• Filed: 02/16/2011
• Published: 06/16/2011
• Est. Priority Date: 07/06/2007
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Washburn, William N., Ahmad, Saleem, Stein, Philip D., Bisaha, Sharon N., Ngu, Khehyong
• Granted Patent: US 8,067,420 B2
• Time in Patent Office: Days
• US Class Current: 514/85
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 241/18 Oxygen or sulfur atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I

wherein

R¹, R², R³, R⁸, and R⁹ are defined herein.

Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof

2. The compound or salt of claim 1 wherein

3. The compound or salt of claim 1 wherein

4. The compound as defined in claim 1 wherein

X is O;

Y is a bond or an alkylene chain of 1 to 3 carbon atoms;

Z is aryl or heteroaryl;

wherein Z may be substituted with 1, 2 or 3 of halo,

C_1-6 alkyl, C_1-3 alkoxy, C_1-3 thioalkyl, C_1-3 trifluoroalkoxy, trifluoromethyl, cycloalkyl, cycloalkoxy, or heteroaryl;

R² is -E-G-J;

E is O or S;

G is lower alkyl or alkylcycloalkyl;

J is H, OH, SO₂R⁷, lower alkyl, lower alkoxy, or CF₃;

R³ is C_1-6 alkyl, C_1-6 alkoxy, H, or halo;

R⁸ is H or lower alkyl; and

R⁹ is H.

5. The compound as defined in claim 1, wherein the compound is of Formula IA or a pharmaceutically acceptable salt thereof

6. The compound of claim 1 wherein:

X is O;

Y is a bond or alkylene chain of 1 to 3 carbon atoms;

Z is

(1) aryl, which is optionally substituted with;

a) halo,

b) C_1-6 alkyl,

c) C_1-3 alkoxy,

d) trifluoromethyl,

e) C_1-3 trifluoroalkoxy, or

g) C_1-3 alkylthio,

(2) heteroaryl which is;

a) pyridinyl,

b) pyrazinyl, or

c) pyrimidinyl,

each of a), b) or c) being optionally substituted with C_1-6 alkyl, trifluoromethyl, C_1-3 alkoxy, or halogen,

(3) benzothiazole optionally substituted with halo or C_1-3 alkoxy,

(4) benzoxazole optionally substituted with halo,

(5) benzimidazole,

(6) thiazole optionally substituted with C_1-6 alkyl,

(7) indanyl, or

(8) quinolinyl optionally substituted with trifluoromethyl;

J is

(1) H,

(3) OH,

(4) COOH,

(5) COO(C_1-6 alkyl),

(6) SO₂R⁷, or

(7) prodrug esters which are selected from glycine

7. The compound of claim 5, wherein Z is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, and benzoxazolyl.

8. The compound of claim 5, wherein R³ is C₁-C₆ alkoxy or C_1-6 alkyl.

9. The compound of claim 5, wherein R¹ is selected from the group consisting of:

10. The compound of claim 5 wherein

R² is

11. The compound of claim 1 in a prodrug ester form, wherein R² is

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1, in association with a pharmaceutically acceptable carrier or diluent.

14. A method for treating obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin resistance, hypercholesterolemia, hypertriglyceridemia, choletithiasis, dyslipidemia, bulimia nervosa and compulsive eating disorders;

sleep disorders; and

psychiatric disorders, depression, anxiety, schizophrenia, substance abuse, cognition-enhancement or Parkinson'"'"'s disease, which comprises administering to a patient in need of treatment, a compound as defined in claim 1.

15. The method as defined in claim 13 for treating obesity or Type II diabetes.

16. A method of treating Type II diabetes, which comprises administering to a patient in need of treatment a compound as defined in claim 1.

12. A compound selected from the group consisting of the following structures or pharmaceutically acceptable salts thereof: