Methods of treatment using ranolazine and related piperazine derivatives

• US 5,506,229 A
• Filed: 10/01/1992
• Issued: 04/09/1996
• Est. Priority Date: 06/23/1989
• Status: Expired due to Term

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntex Pharmaceuticals
• Inventors: Dow, Robert J., Ferrandon, Pierre
• Primary Examiner(s): FAY, ZOHREH A
• Application Number:
  US07/955,397
• Time in Patent Office: 1,286 Days
• Field of Search: 514/255
• US Class Current: 514/252.12
• 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 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 38/166 Streptokinase
• CPC Class Codes: A61K 38/168 from plants
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Piperazine derivatives, particularly ranolazine, are useful for treatment of tissues experiencing a physical or chemical insult, and specifically for treating cardioplegia, hypoxic and/or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.

Claims

1. A method of treating tissues experiencing a physical or chemical insult, said method comprising:

administering,

to protect skeletal muscles against damage resulting from trauma or subsequent to muscle or systemic diseases,

to treat shock conditions, or

to preserve donor tissues used in transplants, a therapeutically effective amount of a compound of the formula;

##STR2## or a pharmaceutically acceptable ester or acid addition salt thereof, wherein;

R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R¹ is methyl, R⁴ is not methyl;

or

R² and R³ taken together form --OCH₂ O--;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino;

R⁶ and R⁷ together form --CH═

CH--CH═

CH--;

or

R⁷ and R⁸ together form --OCH₂ O--;

R¹¹ and R¹² are each independently hydrogen or lower alkyl; and

W is oxygen or sulfur.

2. The method of claim 1 wherein R¹ and R⁵ are methyl.

3. The method of claim 2 wherein R², R³, R⁴, R¹¹ and R¹² are hydrogen.

4. The method of claim 3 wherein W is oxygen.

5. The method of claim 4 wherein R⁶ is methoxy and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen.

6. The method of claim 1 comprising a method for treating shock conditions, including cardiogenic shock.

7. The method of claim 6 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 comprising a method for preserving donor tissues used in transplants, by administration to the donor, the recipient and/or by adding to the ex-vivo perfusion fluid an effective amount of said compound.

9. The method of claim 8 comprising a method for preserving donor tissues used in renal transplants, skin grafts, cardiac transplants, lung transplants, corneal transplants, or liver transplants.

10. The method of claim 8 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof.

12. A perfusion solution for preserving donor tissue for transplantation comprising a therapeutically effective amount, up to 5 mg/ml, of a compound of the formula:

##STR3## or a pharmaceutically acceptable ester or acid addition salt thereof, wherein;

R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R¹ is methyl, R⁴ is not methyl;

or

R² and R³ together form --OCH₂ O--;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino;

R⁶ and R⁷ together form --CH═

CH--CH═

CH--;

or

R⁷ and R⁸ together form --OCH₂ O--;

R¹¹ and R¹² are each independently hydrogen or lower alkyl; and

W is oxygen or sulfur,

in a donor tissue perfusion solution carrier.

13. The perfusion solution of claim 12 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof.

14. The perfusion solution of claim 13 comprising from 0.0001 g to 5 g of ranolazine, or a pharmaceutically acceptable salt thereof, in 1000 ml of phosphate buffered sucrose.

18. The perfusion solution of claim 12 wherein the donor tissue perfusion solution carrier is selected from Eurocollins Solution, University of Wisconsin Fluid, phosphate buffered sucrose, and Hyperosmolar Citrate.

19. The perfusion solution of claim 18 wherein said compound is ranolazine, or a pharmaceutically acceptable salt thereof.

15. A method of treating hypoxic injury to skeletal muscle, said method comprising:

administering to a mammal in need thereof a therapeutically effective amount of a compound of the formula;

##STR4## or a pharmaceutically acceptable ester or acid addition salt thereof, wherein;

R¹, R², R³, R⁴ and R⁵ are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R¹ is methyl, R⁴ is not methyl;

or

R² and R³ taken together form --OCH₂ O--;

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino;

R⁶ and R⁷ together form --CH═

CH--CH═

CH--;

or

R⁷ and R⁸ together form --OCH₂ O--;

R¹¹ and R¹² are each independently hydrogen or lower alkyl; and

W is oxygen or sulfur.

16. The method of claim 15 wherein said compound is ranolazine or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 comprising administering ranolazine or a pharmaceutically acceptable salt thereof in an amount effective for preventing, inhibiting or relieving hypoxic reperfusion injury to skeletal muscles caused by peripheral vascular disease.