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Last Updated: March 29, 2024

Claims for Patent: 7,851,622


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Summary for Patent: 7,851,622
Title:Non-basic melanin concentrating hormone receptor-1 antagonists
Abstract: The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. 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 ##STR00001## where R.sup.1, R.sup.1a, R.sup.1b, A, R.sup.3, R.sup.4, R.sup.5, R5.sup.b and R.sup.6 are as defined herein.
Inventor(s): Washburn; William N. (Titusville, NJ), Ahmad; Saleem (Wall, NJ), Hernandez; Andres S. (Lawrenceville, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:12/109,465
Patent Claims:1. A compound having the following Formula I, or a pharmaceutically acceptable salt thereof: ##STR00048## wherein, A is N; R.sup.1, R.sup.1b and R.sup.1a are the same or different and are each independently selected from the group consisting of H, halo, lower alkyl, cycloalkyl, CF.sub.3, alkoxy, and thioalkoxy; R.sup.3 is H, halo, lower alkyl, cycloalkyl, CF.sub.3, lower alkoxy, thioalkoxy, or CN; R.sup.4 is --OH or -G-D-Z.sub.n; R.sup.5 and R.sup.5b are the same or different and are each independently selected from the group consisting of H, halo, and lower alkyl; n is 1 to 3; G is O or S; D is selected from the group consisting of a lower alkyl, cycloalkylalkyl, cycloalkyl and ##STR00049## wherein X is --O--, --S--, --SO-- or --SO.sub.2--; Z is, independently, hydrogen, hydroxyl, polyhaloalkyl, lower alkyl, lower alkoxy, cycloalkyl, cycloalkoxy, OCONR.sup.6R.sup.7, CN, CONR.sup.8R.sup.9, SOR.sup.10, SO.sub.2R.sup.11, NR.sup.12COR.sup.13, NR.sup.14CO.sub.2R.sup.15, COR.sup.16, a 5- to 6-membered heteroaryl, or a 4- to 6-membered heterocycloalkyl containing no more that two heteroatoms wherein the heteroatoms are independently --O--, --S--, --SO-- or --SO.sub.2--; R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.12 and R.sup.14 are the same or different and are each independently selected from the group consisting of H, lower alkyl and cycloalkyl or R.sup.6 and R.sup.7 and/or R.sup.8 and R.sup.9 together with the atoms to which they are attached may form a 4- to 7-membered ring; and R.sup.10, R.sup.11 R.sup.13, R.sup.15 and R.sup.16 are the same or different and are each independently selected from the group consisting of lower alkyl, and cycloalkyl.

2. The compound of claim 1 wherein R.sup.4 is -G-D-Z.sub.n.

3. The compound as defined in claim 2 wherein D is selected from the group consisting of lower alkyl, cycloalkylalkyl, cycloalkyl and ##STR00050## wherein X is --O--, --S--, --SO-- or --SO.sub.2-- and is 1,3-dioxalane, 1,3-dithiolane, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-oxide, sulfolane, 1,4-oxathiane, 1,4-oxathiane-1-oxide, 1,4-oxathiane-1,1-dioxide, 1,3-dithiane, 1,4-dithiane, 1,3-dioxane, 1,4-dioxane, 1,3-oxathiolane, 1,3-oxathiolane-1-oxide, or 1,3-oxathiolane-1,1-dioxide.

4. The compound as defined in claim 3 wherein D is lower alkyl.

5. The compound of claim 1 wherein Z is COR.sup.16, --OH, dioxylanyl, or CF.sub.3.

6. The compound of claim 1 wherein R.sup.3 is alkoxy and R.sup.1 is halogen.

7. The compound of claim 1 wherein R.sup.3 is methoxy, R.sup.1 is Cl and R.sup.1a, R.sup.1b, R.sup.5 and R.sup.5b are H.

8. The compound of claim 1 wherein R.sup.4 is -G-D-Z.sub.n; D is lower alkyl; Z is --OH, dioxylanyl, or CF.sub.3R.sup.3 is methoxy; R.sup.1 is Cl; and R.sup.1a, R.sup.1b, R.sup.5, and R.sup.5b are H.

9. The compound as defined in claim 1 having the structure ##STR00051## ##STR00052##

10. A pharmaceutical composition, comprising one or more compounds according to claim 1 and at least one pharmaceutically acceptable diluent or carrier.

11. The pharmaceutical composition according to claim 10, further comprising at least one additional therapeutic agent.

12. A pharmaceutical combination, comprising one or more compounds according to claim 1 and at least one additional therapeutic agent selected from the group consisting of anti-obesity agents; anti-diabetic agents, appetite suppressants; cholesterol/lipid-lowering agents, and HDL-raising agents.

13. The pharmaceutical combination according to claim 12 wherein said additional therapeutic agent is an anti-diabetic agent.

14. The pharmaceutical combination of claim 13, wherein said anti-diabetic agent is selected from the group consisting of insulin secretagogues, insulin sensitizers, glucokinase inhibitors, glucocorticoid antagonist, fructose 1,6-bis phosphatase inhibitors, AMP kinase activators, incretin modulators glucosidase inhibitors, aldose reductase inhibitors, PPAR .gamma. agonists, PPAR .alpha. agonists, PPAR .delta. antagonists or agonists, PPAR .alpha./.gamma. dual agonists, 11-.beta.-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, insulin, glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and PTP-1B inhibitors.

15. The pharmaceutical combination of claim 14 wherein said additional therapeutic agent is an antiobesity agent selected from group consisting of melanocortin receptor (MC4R) agonists, cannabinoid receptor modulators, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonists; NPY2 and NPY4 modulators; orticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11-.beta.-HSD-1 inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, thyroid receptor beta modulators, lipase inhibitors, serotonin receptor agonists, monoamine reuptake inhibitors or releasing agents, anorectic agents, CNTF, BDNF, DGAT inhibitors, leptin, leptin receptor modulators, and cannabinoid-1 receptor antagonists.

16. A method for treating obesity in a patient in need of such treatment, comprising administering a therapeutically effective amount of one or more compounds according to claim 1 alone or in combination with one or more antiobesity agents.

17. The method of claim 16 wherein said antiobesity agent is selected from the group consisting of melanocortin receptor (MC4R) agonists, cannabinoid receptor modulators, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonists; NPY2 and NPY4 modulators; orticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11-.beta.-HSD-1 inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, thyroid receptor beta modulators, lipase inhibitors, serotonin receptor agonists, monoamine reuptake inhibitors or releasing agents, anorectic agents, CNTF, BDNF, DGAT inhibitors, leptin, leptin receptor modulators, and cannabinoid-1 receptor antagonists.

18. A method for treating diabetes in a patient in need of such treatment, comprising administering a therapeutically effective amount of one or more compounds according to claim 1 alone or in combination with one or more additional anti-diabetic agents.

19. The method according to claim 18 wherein said additional anti-diabetic agent is selected from the group consisting of insulin secretagogues, insulin sensitizers, glucokinase inhibitors, glucocorticoid antagonist, fructose 1,6-bis phosphatase inhibitors, AMP kinase activators, incretin modulators glucosidase inhibitors, aldose reductase inhibitors PPAR .gamma. agonists, PPAR .alpha. agonists, PPAR .delta. antagonists or agonists, PPAR .alpha./.gamma. dual agonists, 11-.beta.-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, insulin, glucagon-like peptide-1 (GLP-1), GLP-1 agonists, and PTP-1B inhibitors.

20. A method for treating depression or anxiety in a patient, comprising administering a therapeutically effective amount of one or more compounds according to claim 1.

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