NON-BASIC MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS AND METHODS

• US 20090011994A1
• Filed: 06/18/2008
• Published: 01/08/2009
• Est. Priority Date: 07/06/2007
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Washburn, William N., Stein, Philip D., Bisaha, Sharon N., Ngu, Khehyong, Ahmad, Saleen
• Application Number:
  US12/141,228
• Publication Number:
  US 20090011994A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 as defined in claim 1 wherein

3. The compound as defined in claim 1 wherein

4. The compound as defined in claim 1 wherein

5. The compound as defined in claim 1 having the structure

6. The compound as defined in claim 4 wherein

X is O or S;

and/or

R¹ is Z-Y—

X,

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

/or

wherein Z is phenyl or aryl;

wherein Z is heteroaryl; and

/or

wherein R² is -E-G-J; and

/or

wherein E is O or S; and

/or

wherein G is an alkylene chain or alkylcycloalkyl; and

/or

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

/or

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

or

R⁸ is H or alkyl; and

/or

R⁹ is H; and

or

R² and R³ may optionally be taken together to form a 5- to 7-membered ring which is saturated, unsaturated or partially unsaturated, and may include an O atom or 1 or 2 N atoms, which ring is substituted with one or two —

O-G-(J)_m groups wherein at least one J is OH, and which may be optionally substituted with other substituents as set out for “

alkyl”

or “

heteroaryl”

.

7. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof

8. The compound as defined in claim 7 wherein

R¹ is Z-Y—

X;

X is S; and

/or

Y is a bond or alkylene chain; and

/or

Z is phenyl or pyridyl; and

/or

E is O; and

/or

G is an alkylene chain or alkylcycloalkyl; and

/or

J is H or OH; and

/or

R³ is H, alkoxy, alkyl, or halo; and

/or

R⁸ is H or CH₃; and

/or

R⁹ is H;

wherein R² and R³ may be taken together to form a 5- to 7-membered ring which is saturated, unsaturated or partially unsaturated, and may include an O atom or 1 or 2 N atoms, which ring is substituted with 1 or 2 —

O-G-(J)_m groups wherein at least one J is OH, and which may be further optionally substituted with alkyl and/or OH.

9. The compound as defined in claim 1 wherein

Z is aryl or heteroaryl, with any of the foregoing Z moieties either unsubstituted or substituted with 1, 2 or 3 of amino, halo, C_1-6 alkyl, C_1-3 alkylamino, di-C_1-3 alkylamino, C_1-3 alkoxy, C_1-3 thioalkyl, C_1-3 trifluoroalkoxy, trifluoromethyl, cycloalkyl, cycloalkoxy, or heteroaryl;

and or

J is hydrogen, hydroxyl, CN, —

SO₂R⁷, —

SR⁷, —

SOR⁷, lower alkyl, lower alkoxy, CF₃, CF₃O—

, —

COOR⁵, or —

CO—

NR^5aR⁶, wherein R^5a and R⁶ are each independently selected from the group consisting of H, C_1-3 alkyl, and cycloalkyl, or R^5a and R⁶ taken together can be propanediyl, butanediyl or pentanediyl with the N atom to which they are attached to form a 4-, 5- or 6-membered cyclic amine optionally substituted with lower alkyl, lower alkoxy, hydroxyl, CF₃, or CF₃O.

10. The compound of claim 1 wherein:

Z is

(1) aryl, which is optionally substituted with;

a) halogen,

b) alkyl,

c) alkoxy,

d) polyhaloalkyl,

e) polyhaloalkoxy,

f) amino, alkylamino or dialkylamino,

g) alkylthio,

h) OH,

i) an ester, or

j) aryl,

(2) heteroaryl which is;

a) pyridinyl,

b) pyrazinyl, or

c) pyrimidinyl,

each of a), b) or c) being optionally substituted with alkyl, polyhaloalkyl, alkoxy, or halogen,

(3) benzothiazole optionally substituted with halo or alkoxy,

(4) benzoxazole optionally substituted with halo,

(5) benzimidazole,

(6) thiazole optionally substituted with aryl or alkyl,

(7) indanyl,

(8) quinolinyl optionally substituted with CF₃, or

(9) imidazolidinyl; and

/or

Y is a bond or alkylene; and

/or

X is S, O, SO, or SO₂; and

/or

J is

(1) H,

(2) —

CO—

NR^5aR⁶ wherein R^5a and R⁶ together with the N to which they are attached form a pyrrolidinyl ring,

(3) OH,

(4) COOH,

(5) COOalkyl,

(6) SO₂R⁷, or

(7) prodrug esters which are selected from glycine

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

12. The compound of claim 7, wherein R³ is C₁-C₆ alkoxy or C_1-6 alkyl.

13. The compound of claim 7, wherein R¹ is selected from the group consisting of:

14. The compound of claim 7 wherein

15. The compound as defined in claim 7 wherein

X is S;

Y is a bond or (CH₂)₂;

16. The compound as defined in claim 1 having the following formula:

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

21. The compound of claim 1 wherein

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1, alone or in combination with at least one additional therapeutic agent, in association with a pharmaceutically acceptable carrier or diluent.

23. A pharmaceutical combination comprising:

at least one compound according to claim 1, and

at least one additional therapeutic agent.

24. The combination as defined in claim 23 wherein the additional therapeutic agent is an acetyl-cholinesterase inhibitor, a muscarinic receptor-1 agonist, a nicotinic agonist, a glutamic acid receptor (AMPA and NMDA) modulator, a nootropic agent, an agent for Alzheimer'"'"'s disease, an agent for treatment of Parkinson'"'"'s disease, anti-hyperlipidemia agent, an anti-obesity agent;

anti-diabetic agent, appetite suppressant;

cholesterol/lipid-lowering agent, HDL-raising agent, cognition enhancing agent, an agent used to treat neurodegeneration, an agent used to treat respiratory conditions, an agent used to treat bowel disorders, an anti-inflammatory agent;

anti-anxiety agent;

an anti-depressant;

an anti-hypertensive agent;

an anti-sleep disorder agent;

a cardiac glycoside;

or an anti-tumor agent.

25. The combination as defined in claim 24 wherein the anti-obesity agent is a melanocortin receptor (MC4R) agonist, a cannabinoid receptor modulator, a growth hormone secretagogue receptor (GHSR) antagonist, a galanin receptor modulator, an orexin antagonist, a CCK agonist, a GLP-1 agonist, a Pre-proglucagon-derived peptides;

an NPY1 or NPY5 antagonist, an NPY2 or NPY4 modulator, a corticotropin releasing factor agonist, a histamine receptor-3 (H3) modulator, an aP2 inhibitor, a PPAR gamma modulator, a PPAR delta modulator, an acetyl-CoA carboxylase (ACC) inhibitor, an 11-β

-HSD-1 inhibitor, an adinopectin receptor modulator;

a beta 3 adrenergic agonist, a thyroid receptor beta modulator, a lipase inhibitor, a serotonin receptor agonist, a monoamine reuptake inhibitor or releasing agent, an anorectic agent, a CNTF (ciliary neurotrophic factor), a BDNF (brain-derived neurotrophic factor), a leptin and leptin receptor modulator, or a cannabinoid-1 receptor antagonist, and the antidiabetic agent is an insulin secretagogue or insulin sensitizer, which is a biguanide, a sulfonyl urea, a glucosidase inhibitor, an aldose reductase inhibitor, a PPAR γ

agonist, a PPAR α

agonist, a PPAR δ

antagonist or agonist, a PPAR α

/γ

dual agonist, anl 1-β

-HSD-1 inhibitor, a dipeptidyl peptidase IV (DP4) inhibitor, a SGLT2 inhibitor, a glycogen phosphorylase inhibitor, a meglitinide, a glucagon-like peptide-1 (GLP-1), a GLP-1 agonist, and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor), and wherein the additional therapeutic agent is an anti-hyperlipidemia agent, or agent used to treat arteriosclerosis, which is an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, aspirin, a bile acid sequestrant, an ACAT inhibitor, an upregulator of LDL receptor activity, a cholesterol absorption inhibitor, a cholesteryl transfer protein (CETP) inhibitor, an ileal Na+/bile acid cotransporter inhibitor, a phytoestrogen, a beta-lactam cholesterol absorption inhibitor, an HDL upregulator, a PPAR α

-agonist and/or an FXR agonist;

an LDL catabolism promoter such, a sodium-proton exchange inhibitor, an LDL-receptor inducer or a steroidal glycoside, an anti-oxidant, or an antihomocysteine agent, isoniazid, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor, a PPAR δ

agonist, or a sterol regulating element binding protein-I (SREBP-1), and the anti-hypertensive agent, which is a beta adrenergic blocker, a calcium channel blocker (L-type and/or T-type), a diuretic, a renin inhibitor, an ACE inhibitor, an AT-1 receptor antagonist, an ET receptor antagonist, a Dual ET/AII antagonist, a neutral endopeptidase (NEP) inhibitor, a vasopeptidase inhibitor (dual NEP-ACE inhibitor) or a nitrate;

the sleep disorder agent is a melatonin analog, a melatonin receptor antagonist, an ML 1 B agonist, a GABA receptor modulator, an NMDA receptor modulator, a histamine-3 (H3) receptor modulator, a dopamine agonist or an orexin receptor modulator;

an agent for treating substance abuse or, addictive disorders which is a cannabinoid receptor modulator, a selective serotonin reuptake inhibitor (SSRI), methadone, buprenorphine, nicotine or bupropion;

the anti-anxiety agents or antidepressants, which is a benzodiazepine, a 5HT1A receptor agonist, or a corticotropin releasing factor (CRF) antagonist;

or a norepinephrine reuptake inhibitor (tertiary and secondary amine tricyclics), a selective serotonin reuptake inhibitor (SSRI), a monoamine oxidase inhibitor (MAOI), a reversible inhibitor of monoamine oxidase (RIMA), a serotonin and norepinephrine reuptake inhibitor (SNRI), a corticotropin releasing factor (CRF) receptor antagonist, an alpha-adrenoreceptor antagonist, or an atypical antidepressant.

26. 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.

27. The method as defined in claim 26 for treating obesity or Type II diabetes.

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

29. Use of a compound as defined in claim 1 in the manufacture of a medicament for the treatment of diabetes.

30. Use of a compound as defined in claim 1 in the manufacture of a medicament for treatment of diabetes, in which such treatment comprises a combination with another therapeutic agent, for concurrent or sequential use, in any order.

31. Combination of a compound as defined in claim 1 and another therapeutic agent as a medicament for the treatment of diabetes.

18. A compound of Formula IB or a pharmaceutically acceptable salt thereof having the structure

19. The compound as defined in claim 18 wherein

R¹ is Z-Y—

X—

wherein

X is S,

Y is an alkyl chain of 1 to 3 carbons or a bond,

Z is heteroaryl or phenyl,

each of which Z is optionally substituted with CF₃, CF₃O, or halo;

R² is -E-G-J wherein

E is O,

G is lower alkyl or alkylcycloalkyl, and

J is OH;

R³ is alkoxy, alkyl or halo;

R⁸ is H or alkyl; and

R⁹ is H.

20. The compound as defined in claim 18 wherein

X is S;

Y is a bond or (CH₂)₂;