CANNABINOID RECEPTOR ANTAGONISTS/INVERSE AGONISTS USEFUL FOR TREATING OBESITY

Abstract

The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, and/or cardiometabolic disorders.

Description

Claims

1. A compound of of formula I or a stereoisomer or pharmaceutically acceptable salt thereof:

2. A compound of claim 1, wherein the compound is of formula II or a stereoisomer or pharmaceutically acceptable salt thereof:

3. A compound of claim 1, wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:

4. A compound of claim 2, wherein: X and Y are independently selected from H, halogen, C1-4 alkyl, CF3, —CN, NO2, NR2, and OR;X′ and Y′ are independently selected from H, halogen, C1-4 alkyl, CF3, —CN, NO2, NR2, and OR;Z is selected from (CH2)mC(NH)NH2, (CH2)mCO2R, O(CH2)nCO2R, CH2O(CH2)nCO2R, NRaCH(A)CO2R, CH2NRaCH(A)CO2R, NRa(CH2)nCO2R CH2NRa(CH2)nCO2R OCH2CH═CHCO2R, CH20CH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, O(CH2)nC6H4CO2R, CH2O(CH2)nC6H4CO2R, (CH2)mCONR2, O(CH2)nCONR2, CH2O(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, CH2NRa(CH2)ntetrazole, CH2O(CH2)ntetrazole, and (CH2)mtetrazole;Q is selected from N and CH;V is selected from H, C1-6 alkyl, C2-6 alkenyl, CF3, aryl, and —CN;R is selected from H, C1-4 alkyl, and C2-4 alkenyl; and,n is selected from 1 and 2.

5. A compound of claim 2, wherein: X and Y are independently selected from H, halogen, C1-6 alkyl, NO2, CF3, NR2, OR, —CN, (CH2)mC(NH)NH2, (CH2)mCO2R, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2,CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONH2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)4-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2,-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;provided that at least one of X and Y is other than H, halogen, C1-6 alkyl, —CN, NO2, CF3, and OR;X′ and Y′ are independently selected from H, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;Z is selected from H, C1-4 alkyl, and aryl;Q is selected from N and CH;V is selected from H, C1-4 alkyl, and aryl;R is selected from H, C1-4 alkyl, and C2-4 alkenyl; and,n is selected from 1 and 2.

6. A compound of claim 2, wherein: X and Y are independently selected from H, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;X′ and Y′ are independently selected from H, halogen, C1-6 alkyl, —CN, NO2, CF3, NR2, OR, CO2R, (CH2)nCO2R, (CH2)mC(NH)NH2, O(CH2)nCO2R, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2,CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2CH3, NRaCO(CH2)nCO2R, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONH2, O(CH2)nC6H4(CH2)nCONH2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONH2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4CONH2, CH2NRa(CH2)nC6H4CONH2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, CONR2, (CH2)nCONR2, O(CH2)nCONR2, CH2O(CH2)nCONH2, NRa(CH2)nCONR2, OCH2CH═CHCONR2, CH2OCH2CH═CHCONR2, NRaCH2CH═CHCONR2,-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NRaCH3;provided that at least one of X′ and Y′ is other than halogen, C1-4 alkyl, —CN, NO2, and OR;Z is selected from H, C1-4 alkyl, and aryl;Q is selected from N and CH;V is selected from H, C1-4 alkyl, and aryl;R is selected from H, C1-4 alkyl, and C2-4 alkenyl;n is selected from 1 and 2; and,p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12.

7. A compound of claim 2, wherein: X and Y are independently selected from H, CF3, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;X′ and Y′ are independently selected from H, CF3, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;Z is selected from H, C1-4 alkyl, and aryl;Q is selected from N and CH;V is selected from (CH2)mCO2R, (CH2)mCONR2, (CH2)mC(NH)NH2, (CH2)m-tetrazole, (CH2)mCONRaCH(A)-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)mCO2R, (CH2)mCONRa(CH2)m-phenyl-(CH2)m-tetrazole, CH2O(CH2)nCO2R, CH2NRa(CH2)nCO2R, CH2O(CH2)nCONH2, CH2NRa(CH2)nCONH2, and CH2O(CH2)ntetrazole;A is selected from H, C1-4 alkyl, and (CH2)m-aryl, wherein each aryl is optionally substituted with 0-1 groups selected from CF3, halogen, C1-4 alkyl, —CN, CONR2, NO2, NR2, and OR;R is selected from H, C1-4 alkyl, and C2-4 alkenyl;m is selected from 0, 1, and 2; and,n is selected from 1 and 2.

8. A compound of claim 1, wherein: X and Y are independently selected from H, CF3, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;X′ and Y′ are independently selected from H, CF3, halogen, C1-4 alkyl, —CN, NO2, NR2, and OR;R′ is selected from CH(A)-(CH2)mCO2R, CH(A)-(CH2)mCONH2, CH(A)-(CH2)mC(NH)NH2, (CH2)m-phenyl-(CH2)mCO2R, (CH2)m-pyridyl-(CH2)mCO2R, (CH2)m-phenyl-(CH2)mCONH2, (CH2)m-pyridyl-(CH2)mCONH2, (CH2)m-phenyl-(CH2)mC(NH)NH2, (CH2)m-pyridyl-(CH2)m(CN)NH2, (CH2)m-phenyl-(CH2)m-tetrazole, and (CH2)m-pyridyl-(CH2)m-tetrazole;A is selected from H, C1-6 alkyl, (CH2)m-C3-6-cycloalkyl, (CH2)m-phenyl, (CH2)m-aryl, and (CH2)m-heteroaryl, wherein each aryl, phenyl, and heteroaryl is optionally substituted with 0-1 groups selected from CF3, halogen, C1-4 alkyl, —CN, CONR2, NO2, NR2, and OR;V is selected from H, C1-4 alkyl, and aryl;R is selected from H, C1-4 alkyl; and,m is selected from 0, 1, and 2.

9. A compound of claim 1, wherein the compound is selected from:

10. A compound of claim 1, wherein the compound is selected from the compounds of Table 1a, 1b, 1c, 2a, 2b, 3a, 3b, 4, 5a, 5b, 5c, 5d, 5e, 5f, 5g, 6a, and 6b or stereoisomer or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising: a compound according to claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of according to claim 1, wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof.

13. The method of claim 12, wherein the cardiometabolic disorder is selected from hypertension, dyslipidemia, high blood pressure, and insulin resistance.

14. The method of claim 13, wherein the dyslipidemia is selected from elevated blood lipid levels and elevated cholesterol levels.

15. A method of treating a co-morbidity of obesity, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

16. The method of claim 15, wherein the co-morbidity is selected from diabetes, Metabolic Syndrome, dementia, and heart disease.

17. The method of claim 15, wherein the co-morbidity is selected from hypertension; gallbladder disease; gastrointestinal disorders; menstrual irregularities; degenerative arthritis; venous statis ulcers; pulmonary hypoventilation syndrome; sleep apnea; snoring; coronary artery disease; arterial sclerotic disease; pseudotumor cerebri; accident proneness; increased risks with surgeries; osteoarthritis; high cholesterol; and, increased incidence of malignancies of the ovaries, cervix, uterus, breasts, prostrate, and gallbladder.

18. The method of claim 12, wherein the diabetes disorder is selected from: Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, and insulin resistance.

19. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a. a compound of according to claim 1, andb. a second therapeutic agent;wherein the disease is selected from obesity, diabetes, cardiometabolic disorders, and a combination thereof and the second therapeutic agent is useful for treating the disease.

20. The method of claim 19, wherein the second component is selected from the appetite suppressant sibutramine and the gut lipase inhibitor or list at.

21. The method of claim 20, wherein the second component is useful for treating diabetes.