Pharmaceutical composition

• US 6,169,099 B1
• Filed: 04/30/1999
• Issued: 01/02/2001
• Est. Priority Date: 06/20/1995
• Status: Expired due to Term

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Sohda, Takashi, Odaka, Hiroyuki, Ikeda, Hitoshi
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US09/302,468
• Time in Patent Office: 613 Days
• Field of Search: 514/340, 514/342, 514/369, 514/376, 546/269.7, 546/271.4, 548/183, 548/227
• US Class Current: 514/342
• 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 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 31/70 : Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2018 : Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4858 : Organic compounds
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin

Abstract

Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with other antidiabetics differing from the enhancer in the mechanism of action, which shows a potent depressive effect on diabetic hyperglycemia and is useful for prophylaxis and treatment of diabetes.

Claims

1. A pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with a squalene synthesis inhibitor.

2. The pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer is a compound represented by the formula:

wherein R represents an optionally substituted hydrocarbon or heterocyclic group;

Y represents a group represented by —

CO—

, —

CH(OH)—

or —

NR³—

wherein R³ represents an optionally substituted alkyl group;

m is 0 or 1;

1 or 2;

represents CH or N;

A represents a bond or a C_1-7 divelent aliphatic hydrocarbon group;

Q represents oxygen atom or sulfur atom;

R¹ represents hydrogen aton or an alkyl group;

ring E may optionally have further 1 to 4 substituents, and the substituents may optionally be combined with R¹ to form a ring;

L and M respectively represent hydrogen atom, or L and M may optionally be combined with each other to form a bond;

or a pharmacologically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, wherein R is an optionally substituted heterocyclic group.

4. The pharmaceutical composition according to claim 2 wherein m is 0.

5. The pharmaceutical composition according to claim 2, wherein X is CH.

6. The pharmaceutical composition according to claim 2, wherein R¹ is hydrogen atom.

7. The pharmaceutical composition according to claim 2, wherein the partial formula:

wherein R² represents hydrogen atom, an alkyl group, an optionally substituted hydroxyl group, a halogen atom, an optionally substituted acyl group, nitro group of an optionally substituted amino group.

8. The pharmaceutical composition according to claim 2, wherein L and M are hydrogen atom.

9. The pharmaceutical composition according to claim 2, wherein R is pyridyl, oxazolyl or thiazolyl group optionally having 1 to 3 substituents selected from C_1-3 alkyl, furyl, thienyl, phenyl and napthyl;

m is 0, n is 1;

X is CH;

A is a bond or —

(CH₂)₂—

;

R¹ is hydrogen atom;

the partial formula;

and R² is hydrogen atom or C_1-4 alkoxy group; and

L and M are both hydrogen atom.

10. The pharmaceutical composition according to claim 2, wherein the compound represented by the formula (I) is pioglitazone.

11. The pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer is pioglitazone or its hydrochloride.

12. The pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer is troglitazone.

13. The pharmaceutical composition according to claim 1, wherein the insulin sensitivity enhancer is 5-[[4-[2-(methyl-2-pyridlamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or its phamacologically accepted salt.

14. The pharmaceutical composition according to claim 1, which is for prophylaxis or treatment of diabetes.

15. The pharmaceutical composition according to claim 1, which is for prophylaxis or treatment of diabetic complications.

16. A method for treating diabetes in a mammal in need thereof, which comprises administering to such a mammal a therapeutically effective amount of an insulin sensitivity enhancer in combination with a squalene synthesis inhibitor.

17. The method according to claim 16, wherein the insulin sensitivity enhancer is pioglitazone or its hydrochloride.

18. The method according to claim 16, wherein the insulin sensitivity enhancer is troglitazone.

19. The method according to claim 16, wherein the insulin sensitivity enhancer is 5-[[4-[2-(methyl-2-pyridlamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione or its phamacologically accepted salt.

20. The method according to claim 16, wherein the insulin sensitivity enhancer and squalene synthesis inhibitor are mixed together to form an admixture and the admixture is administered to the mammal.

21. The method according to claim 16, wherein the insulin sensitivity enhancer and squalene synthesis inhibitor are not mixed together but are administered independently to the mammal.