Combination therapeutic compositions and method of use

• US 6,653,332 B2
• Filed: 05/02/2001
• Issued: 11/25/2003
• Est. Priority Date: 05/03/2000
• Status: Expired due to Term

• Current Assignee: Amgen Inc.
• Original Assignee: Tularik, Inc. (Amgen Inc.)
• Inventors: Jaen, Juan C., Chen, Jin-Long
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US09/847,887
• Publication Number:
  US 20020037928A1
• Time in Patent Office: 937 Days
• Field of Search: 514/347, 514/635, 514/866
• US Class Current: 514/347
• 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 method for modulating medical conditions associated with metabolic disorders, said method comprising administering to a 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)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 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, 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.

2. The method of claim 1, wherein said medical condition is a member selected from the group consisting of diabetes and diabetic neuropathy.

3. The method of claim 1, wherein said compound of Formula I and said at least one therapeutically active agent are formulated together.

4. The method of claim 1, where said compound of Formula I and said at least one therapeutically active agent are formulated separately.

5. The method of claim 1, wherein said medical condition is diabetes, and said therapeutically active agent is an antidiabetic agent.

6. The method of claim 1, 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.

7. The method of claim 1, wherein said compound of formula I is administered before said therapeutically active agent.

8. The method of claim 1, wherein said therapeutically active agent is administered before said compound of formula I.

9. The method of claim 1, wherein said compound of formula I is administered simultaneously with said therapeutically active agent.

10. The method of claim 1, wherein said administration is parenteral.

11. The method of claim 1, wherein said administration is oral.

12. The method of claim 1, wherein said administration is topical.

13. The method of claim 1, wherein said administration is local.

14. The method 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.

15. The method of claim 6, wherein said sulfonyl urea is a member selected from the group consisting of acetohexamide, chlorpropamide, glyburide, glipizide, gliclazide, glimepiride, gliquidone, glisoxepid, glibornuride, gliamilide, glicetanile, gliflumide, glymidine, glyparamide, tolpyrramide, glyhexamide, phenbutamide, tolazamide, tolbutamide and tolcyclamide.

16. The method of claim 6, wherein said biguanide is a member selected from the group consisting of metformin, buformin, etoformin and phenformin.

17. The method of claim 6, 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.

18. The method of claim 6, 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.

19. The method 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, —

CO₂R¹⁴ and —

C(O)NR¹⁵R¹⁶;

wherein

R¹⁴ 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.

20. The method of claim 19, wherein Ar¹ is a substituted or unsubstituted heteroaryl group having from 1 to 3 heteroatoms as ring members.

21. The method of claim 19, wherein Ar¹ is a phenyl, naphthyl, benzothiazole, benzimidazole, quinoline, or isoquinoline group having from 1 to 3 substituents selected from the group consisting of halogen, cyano, CF₃, nitro, (C₁-C₈)alkyl and (C₁-C₈)alkoxy.

22. The method 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.

23. The method of claim 1, wherein 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.

24. The method 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.

25. The method 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.