Combination therapeutic compositions and methods of use

• US 20060035928A1
• Filed: 10/26/2005
• Published: 02/16/2006
• Est. Priority Date: 05/03/2000
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Jaen, Juan C., Chen, Jin-Long
• Granted Patent: US 7,939,551 B2
• Time in Patent Office: Days
• US Class Current: 514/310
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones, α-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I.

Claims

1. A pharmaceutical composition, said composition comprising:

(i) a compound having the formula I or a pharmaceutically acceptable salt thereof;

wherein

Ar¹ is an aryl group;

X is a divalent linkage selected from the group consisting of (C₁-C₆)alkylene, (C₁-C₆)alkylenoxy, (C₁-C₆)alkylenamino, (C₁-C₆)alkylene-S(O)_k—

, —

O—

, —

C(O)—

, —

N(R¹¹), —

N(R¹¹)C(O)—

, —

S(O)_k— and

a single bond,

wherein

R¹¹ is a member selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and aryl(C₁-C₄)alkyl; and

the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of alkylene, —

O—

, —

C(O)—

, —

N(R¹²)—

S(O)_m—

, —

N(R¹²)—

S(O)_m—

N(R³)—

, —

N(R¹²)C(O)—

, —

S(O)_n— and

a single bond, wherein

R¹² and R¹³ are members independently selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and aryl(C₁-C₄)alkyl; and

the subscripts m and n are independently integers of from 0 to 2;

R¹ is a member selected from the group consisting of hydrogen, heteroalkyl, aryl, arylalkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —

C(O)R¹⁴, —

CO₂R¹⁴, —

C(O)NR¹⁵R⁶, —

S(O)_p—

R¹⁴, —

S(O)_q—

NR¹⁵R¹⁶, —

O—

C(O)—

OR¹⁷, —

O—

C(O)—

R¹⁷, —

O—

C(O)—

NR¹⁵R¹⁶, —

N(R¹⁴)—

C(O)—

NR¹⁵R¹⁶, —

N(R¹⁴)—

C(O)—

R¹⁷ and —

N(R¹⁴)—

C(O)—

OR¹⁷;

wherein

R¹⁴ is a member selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl;

R¹⁵ and R¹⁶ are members independently selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;

R¹⁷ is a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl;

the subscript p is an integer of from 0 to 3; and

the subscript q is an integer of from 1 to 2; and

R² is a member selected from the group consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; and

R³ is a member selected from the group consisting of halogen, cyano, nitro, (C₁-C₈)alkyl and (C₁-C₈)alkoxy; and

ii) one or more antidiabetic agents, prodrugs thereof, or pharmaceutically acceptable salts of said antidiabetic agent; and

optionally a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1, wherein said antidiabetic agent is a member selected from the group consisting of a sulfonylurea, a biguanide, a glitazone, a PPARγ

modulator, an α

-glucosidase inhibitor, a potassium channel antagonist, an aldose reductase inhibitor, a glucagon antagonist, an activator of RXR, insulin therapy, an anti-obesity agent and mixtures thereof.

3. The pharmaceutical composition of claim 2, wherein said sulfonyl urea is a member selected from the group consisting of acetohexamide, chlorpropamide, glyburide, glipizide, gliclazide, glimepiride, gliquidone, glisoxepid, glibomuride, gliamilide, glicetanile, gliflumide, glymidine, glyparamide, tolpyrramide, glyhexamide, phenbutamide, tolazamide, tolbutamide and tolcyclamide.

4. The pharmaceutical composition of claim 2, wherein said biguanide is a member selected from the group consisting of metformin, buformin, etoformin and phenformin.

5. The pharmaceutical composition of claim 2, wherein said glitazone is a member selected from the group consisting of troglitazone, rosiglitazone, pioglitazone, JTT-501, YM-440, ciglitazone, darglitazone, englitazone, AD-5075 and BM-131246.

6. The pharmaceutical composition of claim 2, wherein said α

-glucosidase inhibitor is a member selected from the group consisting of acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose and MDL-73,945.

7. The pharmaceutical composition of claim 1, wherein

X is selected from the group consisting of —

O—

, —

S(O)_k—

, —

N(R¹¹)—

, —

CH₂—

, —

C(O)— and

a single bond;

Y is —

N(R¹²)—

S(O)_m—

;

wherein

R¹¹ is hydrogen or (C₁-C₈) alkyl;

R¹² is selected from the group consisting of hydrogen and (C₁-C₈)alkyl; and

the subscript m is an integer of from 0 to 2;

R¹ is a member selected from the group consisting of hydrogen, halogen, cyano, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, —

C(O)R¹⁴, —

CO₂R⁴ and —

C(O)NR¹⁵R¹⁶;

wherein

R¹⁴ is a member selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl;

R¹⁵ and R¹⁶ are members independently selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;

R² is a member selected from the group consisting of aryl and aryl(C₁-C₄)alkyl; and

R³ is a member selected from the group consisting of halogen, cyano, (C₁-C₈)alkyl and (C₁-C₈)alkoxy.

8. The pharmaceutical composition of claim 7, wherein Ar¹ is a substituted or unsubstituted heteroaryl group having from 1 to 3 heteroatoms as ring members.

9. The pharmaceutical composition of claim 7, wherein Ar¹ is a phenyl, naphthyl, benzothiazole, benzimidazole, quinoline, isoquinoline or group having from 1 to 3 substituents selected from the group consisting of halogen, cyano, CF₃, nitro, (C₁-C₈)alkyl and (C₁-C₈)alkoxy.

10. The pharmaceutical composition of claim 1, wherein X is a divalent linkage selected from the group consisting of —

O—

, —

C(O)—

, N(R¹¹)—

, —

CH₂—

, —

S(O)_k— and

a single bond.

11. The pharmaceutical composition of claim 1, where Y is a divalent linkage —

N(R¹²)—

S(O)₂—

; and

R¹² is hydrogen or (C₁-C₈)alkyl, and R² is a member selected from the group consisting of aryl and arylalkyl.

12. The pharmaceutical composition of claim 1, wherein R¹ is selected from the group consisting of hydrogen, halogen, cyano, (C₁-C₈)alkoxy, (C₁-C₈)alkyl, —

C(O)R¹⁴, —

CO₂R¹⁴ and —

C(O)NR¹⁵R¹⁶ wherein R¹⁴ is (C₁-C₈)alkyl, and R¹⁵ and R¹⁶ are independently selected from the group consisting of hydrogen and (C₁-C₈)alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring.

13. The pharmaceutical composition of claim 1, wherein Ar¹ is substituted with from one to two substituents selected from the group consisting of halogen, —

OCF₃, —

OH, —

O(C₁-C₆)alkyl, —

CF₃, (C₁-C₈)alkyl and —

NO₂.

14. The pharmaceutical composition of claim 1, wherein Ar¹ is a mono- or bicycle heteroaryl group having from 1 to 2 nitrogen atoms as ring members.

15. The pharmaceutical composition of claim 1, wherein said compound is represented by a formula selected from the group consisting of

16. The pharmaceutical composition of claim 1, wherein X is a divalent linkage selected from the group consisting of —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

NH—

, —

CH₂—

, —

C(O)— and

a single bond.

17. The pharmaceutical composition of claim 1, wherein Y is —

NH—

S(O)₂—

or —

NH—

S(O)₂—

NH—

, and R² is aryl.

18. The pharmaceutical composition of claim 1, wherein R² is selected from the group consisting of substituted phenyl, substituted pyridyl and substituted naphthyl, wherein the substituents number from one to three and are independently selected from the group consisting of halogen, —

OCF₃, —

OH, —

O(C₁-C₈)alkyl, —

C(O)—

(C₁-C₈)alkyl, —

CN, —

CF₃, (C₁-C₈)alkyl and —

NH₂.

19. The pharmaceutical composition of claim 1, wherein R¹ is selected from the group consisting of —

H, halogen, C(O)R¹⁴, —

(C₁-C₈)alkyl, and —

CONR¹⁵R¹⁶ wherein R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, aryl and arylalkyl, and R¹⁴ is (C₁-C₈) alkyl.

20. The pharmaceutical composition of claim 1, wherein said compound of Formula I is selected from the group consisting of

21. A method for modulating medical conditions associated with metabolic disorders, said method comprising administering to said host an efficacious amount of

(i) a compound having the formula:

wherein

Ar¹ is an aryl group;

X is a divalent linkage selected from the group consisting of (C₁-C₆)alkylene, (C₁-C₆)alkylenoxy, (C₁-C₆)alkylenamino, (C₁-C₆)alkylene-S(O)_k—

, —

O—

, —

C(O)—

, —

N(R¹¹)—

, —

N(R¹¹)C(O)—

, —

S(O)_k— and

a single bond,

wherein

R¹¹ is a member selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and aryl(C₁-C₄)alkyl; and

the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of alkylene, —

O—

, —

C(O)—

, —

N(R¹²)—

S(O)_m—

, —

N(R¹²)S(O)_m—

N(R¹³)—

, —

N(R¹²)C(O)—

, —

S(O)_n— and

a single bond,

wherein

R¹² and R¹³ are members independently selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl and aryl(C₁-C₄)alkyl; and

the subscripts m and n are independently integers of from 0 to 2;

R¹ is a member selected from the group consisting of hydrogen, heteroalkyl, aryl, arylalkyl, halogen, cyano, nitro, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, —

C(O)R¹⁴, —

CO₂R¹⁴, —

C(O)NR¹⁵R¹⁶, —

S(O)_p—

R¹⁴, —

S(O)_q—

NR¹⁵R¹⁶, —

O—

C(O)—

R¹⁷, —

O—

C(O)—

R¹⁷, —

O—

C(O)—

NR¹⁵R¹⁶, —

N(R¹⁴)—

C(O)—

NR¹⁵R¹⁶, —

N(R¹⁴)—

C(O)—

R¹⁷ and —

N(R¹⁴)—

C(O)—

OR¹⁷;

wherein

R¹⁴ is a member selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl;

R¹⁵ and R¹⁶ are members independently selected from the group consisting of hydrogen, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl, and aryl(C₁-C₄)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;

R¹⁷ is a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl;

the subscript p is an integer of from 0 to 3; and

the subscript q is an integer of from 1 to 2; and

R² is a member selected from the group consisting of (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl and aryl(C₁-C₄)alkyl; and

R³ is a member selected from the group consisting of halogen, cyano, nitro, (C₁-C₈)alkyl and (C₁-C₈)alkoxy; and

ii) at least one therapeutically active agents or a prodrug thereof, or a pharmaceutically acceptable salt of said agent, and a pharmaceutically acceptable carrier or diluent.

22. The method of claim 21, wherein said medical condition is a member selected from the group consisting of diabetes, hypertension, angina, dyslipidemias, gout, diabetic neuropathy, obesity, polyeystic ovarian syndrome, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, bone disorders and acne, proliferative diseases, cancer, vascular restenosis, CNS disorders, Alzheimer'"'"'s disease neuroinflammation, inflammatory disorders, ophthalmic disorders, and reproductive system disorders,

23. The method of claim 21, wherein said compound of Formula I and said at least one therapeutically active agent are formulated together.

24. The method of claim 21, where said compound of Formula I and said at least one therapeutically active agent are formulated separately.

25. The method of claim 21, wherein said medical condition is diabetes, and said therapeutically active agent is an antidiabetic agent.

26. The method of claim 21, wherein said therapeutically active agent is selected from the group consisting of a sulfonylurea, a biguanide, a glitazone, a PPARγ

modulator, an α

-glucosidase inhibitor, a potassium channel antagonist, an aldose reductase inhibitor, a glucagon antagonist, an activator of RXR, insulin therapy, an anti-obesity agent, and mixtures thereof.

27. The method of claim 21, wherein said medical condition is hypertension, and said therapeutically active agent is selected from the group consisting of α

₂-adrenergic agonists, α

₁-adrenergic antagonists, β

-adienergic antagonists, calcium blockers, ACE inhibitors, ATII receptor blockers and vasodilators.

28. The method of claim 27, wherein said therapeutically active agent is selected from the group consisting of clonidine, prazocin, propanololverapamil, captopril, losartan and hydralazine.

29. The method of claim 21, wherein said medical condition is gout, and said therapeutically active agent is selected from the group consisting of colchicine and allopurinol.

30. The method of claim 21, wherein said medical condition is obesity, and said therapeutically active agent is a stimulant selected from the group consisting of amphetamine and sibutramine.

31. The method of claim 21, wherein said medical condition is a member selected from the group consisting of hypertriglyceridemia and hypercholesterolemia and said therapeutically active agent is selected from the group consisting of bile-acid sequestrants, HMG-CoA inhibitors, niacin, and fibrates.

32. The method of claim 31, wherein said therapeutically active agent is selected from the group consisting of colestipol, simvastatin, niacin, and gemfibrozil.

33. The method of claim 21, wherein said medical condition is angina, and said therapeutically active agent is selected from the group consisting of nitroglycerine, β

-adrenergic blockers and calcium blockers.

34. The method of claim 33, wherein said therapeutically active agent is selected from the group consisting of nitroglycerine, propanolol, diltiazem and verapamil.

35. The method of claim 21, wherein said medical condition is atherosclerosis, and said therapeutically active agents is selected from the group consisting of HMG-CoA inhibitors, bile-acid sequestrants and fibrates.

36. The method of claim 35, wherein said therapeutically active agent is selected from the group consisting of simvastatin, colesteramine and gemfibrozil.

37. The method of claim 21, wherein said medical condition are bone disorders/osteoporosis, and said therapeutically active agent is selected from the group consisting of estrogen supplements, and bisphosphonates.

38. The method of claim 37, wherein said therapeutically active agent is alendronate.

39. The method of claim 21, wherein said medical condition is acne, and said therapeutically active agent is selected from the group consisting of antibiotics, isotretinoin, and steroid anti-inflammatories.

40. The method of claim 39, wherein said therapeutically active agent is selected from the group consisting of erythromycin and triamcinolone.

41. The method of claim 21, wherein said medical condition is cancer, and said therapeutically active agent is selected from the group consisting of alkylating drugs, antimetabolites, microtubule inhibitors, podophyllotoxins, antibiotics, nitrosoureas metal derivatives, hormone therapies and biological therapies.

42. The method of claim 41, wherein said therapeutically active agent is selected from the group consisting of cyclophospharmide, methotrexate, paclitaxel, etoposide, doxorubicin, camiustine, cisplatin, tamoxifen and Interferon.

43. The method of claim 21, wherein said medical condition is Alzheimer'"'"'s disease, and said therapeutically active agent is selected from the group consisting of acetylcholinesterase inhibitors, estrogen therapy and NSAIDs.

44. The method of claim 43, wherein said therapeutically active agent is selected from the group consisting of donepezil and indomethacin.

45. The method of claim 21, wherein said medical condition is neuroinflammation, and said therapeutically active agent is selected from the group consisting of NSAIDs, aspirin, vitamin E, and inhibitors of neuronal nitric oxide synthase.

46. The method of claim 45, wherein said therapeutically active agents is indomethacin.

47. The method of claim 21, wherein said medical condition is an immune-system dysfunction, and said therapeutically active agent is selected from the group consisting of corticosteroids, interferon-β

, cyclosporine, FK-506 and methotrexate.

48. The method of claim 47, wherein said therapeutically active agent is prednisone.

49. The method of claim 21, wherein said medical condition is opthalmic disorders associated with neovascularization and said therapeutically active agent is selected from the group consisting of visodyne, laser photothereapy and VEGF anitbodies.

50. The method of claim 21, wherein said medical condition is vascular restenosis, and such therapeutically active agent is selected from the group consisting of β

-adrenergic antagonists, Calcium blockers, aspirin and ACE inhibitors.

51. The method of claim 50, wherein said therapeutically active agent is selected from the group consisting of propanolol, verapamil and captopril.