Combination therapy for the treatment of diabetes and related conditions

1. A pharmaceutical composition comprising:

(a) a GPR119 agonist of formula (10)

 (10), wherein one of X and Y is O and the other is N, R 1 is —SO 2 —C 1-3 alkyl, R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , and R 4 is C 2-5 alkyl;

formula (11)

 (11), wherein one of X and Y is O and the other is N, R 1 is —CONHR 5 , R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, and R 5 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy,

formula (12)

 (12), wherein one of X and Y is O and the other is N, R 1 is —CH 2 —SO 2 C 1-3 alkyl, R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , and R 4 is C 2-5 alkyl;

formula (13)

 (13), wherein one of X and Y is O and the other is N, one of E and Q is N and the other is CH, R 1 is —SO 2 R 5 or —CONHR 6 , R 2 is H or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, R 5 is C 1-3 alkyl, and R 6 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy;

formula (14)

 (14), wherein one of X and Y is O and the other is N, R 1 is —SO 2 R 5 , —NR 6 R 7 , or —CONR 6 R 7 , R 2 is H or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, R 5 is C 1-3 alkyl, R 6 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy, and R 7 is hydrogen, or

formula (15)

 (15), 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine,

or a pharmaceutically acceptable salt thereof; and

(b) a DPP-4 inhibitor of

wherein:

R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl; and

R2 is 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino, or (2-(S)-amino-propyl)-methylamino,

or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor is selected from the group consisting of

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,

1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,

1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine,

1-[(3-cyano-quinolin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine,

1-[(3-cyano-pyridin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

1-[(4-methyl-pyrimidin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

1-[(4,6-dimethyl-pyrimidin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine; and

1-[(quinoxalin-6-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,

or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 , wherein the DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl)-methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.

4. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (10)

or a pharmaceutically acceptable salt thereof.

5. A method of

preventing, slowing progression, delaying, or treating a metabolic disorder;

improving glycemic control and/or for reducing fasting plasma glucose, postprandial plasma glucose, and/or glycosylated hemoglobin HbA1c;

preventing, slowing, delaying, or reversing progression from impaired glucose tolerance, insulin resistance, and/or metabolic syndrome to type 2 diabetes mellitus;

preventing, slowing progression, delaying, or treating complications of diabetes mellitus;

reducing, preventing an increase, of the weight or facilitating a reduction of weight;

preventing or treating the degeneration of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or restoring the functionality of pancreatic insulin secretion; or

for maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance,

the method comprising administering to a patient in need thereof the pharmaceutical composition of claim 1 .

6. A method of lowering blood glucose level in a diabetic patients comprising administering to the patient a pharmaceutical composition of claim 1 .

7. A method of improving glycemic control in a diabetic patients comprising administering to the patient a pharmaceutical composition of claim 1 .

8. A method of improving glycemic control in the fasting and/or postprandial states in a diabetic patients comprising administering to the patient a pharmaceutical composition of claim 1 .

9. A method of increasing plasma GLP-1 level in a diabetic patients comprising administering to the patient a pharmaceutical composition of claim 1 .

10. A method of treating and/or preventing a disease, disorder, or condition responsive to the increase of plasma GLP-1 level in a patient in need thereof comprising administering to the patient a pharmaceutical composition of claim 1 .

11. A method of improving glycemic control in highly insulin-resistant diabetic in a diabetic patients comprising administering to the patient a pharmaceutical composition of claim 1 .

12. A method of treating and/or preventing Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypercholesterolemia, dyslipidemia, syndrome X, metabolic syndrome, obesity, hypertension, chronic systemic inflammation, retinopathy, neuropathy, nephropathy, atherosclerosis, endothelial dysfunction, and/or osteoporosis in a patient in need thereof comprising administering to the patient a pharmaceutical composition of claim 1 .

13. A method of reducing body weight or treating obesity in a patient in need thereof comprising administering to the patient a pharmaceutical composition of claim 1 .

14. A method of treating dyslipidemia, hyperlipidemia, or hypercholesterolemia in a patient in need thereof comprising administering to the patient a pharmaceutical composition of claim 1 .

15. A method of for treating metabolic syndrome (syndrome X) in a patient in need thereof comprising administering to the patient a pharmaceutical composition of claim 1 .

16. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (11) or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (12) or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (13) or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (14) or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 1 , wherein the GPR119 agonist is the GPR119 agonist of formula (15) or a pharmaceutically acceptable salt thereof.

21. A kit comprising:

(a) a first pharmaceutical composition comprising a GPR119 agonist of formula (10)

 wherein one of X and Y is O and the other is N, R 1 is —SO 2 —C 1-3 alkyl, R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , and R 4 is C 2-5 alkyl;

formula (11)

 wherein one of X and Y is O and the other is N, R 1 is —CONHR 5 , R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, and R 5 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy,

formula (12)

 wherein one of X and Y is O and the other is N, R 1 is —CH 2 —SO 2 C 1-3 alkyl, R 2 is H, F, Cl, or CH 3 , R 3 is H or CH 3 , and R 4 is C 2-5 alkyl;

formula (13)

 wherein one of X and Y is O and the other is N, one of E and Q is N and the other is CH, R 1 is —SO 2 R 5 or —CONHR 6 , R 2 is H or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, R 5 is C 1-3 alkyl, and R 6 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy;

formula (14)

 wherein one of X and Y is O and the other is N, R 1 is —SO 2 R 5 , —NR 6 R 7 , or —CONR 6 R 7 , R 2 is H or CH 3 , R 3 is H or CH 3 , R 4 is C 2-5 alkyl, R 5 is C 1-3 alkyl, R 6 is H, C 1-3 alkyl, or C 2-3 alkyl substituted by hydroxy, and R 7 is hydrogen, or

formula (15)

 (15), 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine,

or a pharmaceutically acceptable salt thereof; and

(b) a second pharmaceutical composition comprising a DPP-4 inhibitor of formula (I)

R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl; and

R2 is 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino, or (2-(S)-amino-propyl)-methylamino,

or a pharmaceutically acceptable salt thereof.