Use of substituted (5,6) dihydronaphthalenyl compounds having retinoid-like activity to prevent or reduce ischemic injury

• US 6,063,817 A
• Filed: 02/19/1998
• Issued: 05/16/2000
• Est. Priority Date: 02/21/1997
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Shannon, Ronald J., Monte, Karyn A., Tramposch, Kenneth
• Primary Examiner(s): Jones, Dwayne C.
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US09/026,404
• Time in Patent Office: 817 Days
• Field of Search: 514/513, 514/561, 514/562, 514/563, 514/569, 514/887, 514/928, 514/617, 514/619, 514/533
• US Class Current: 514/617
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention relates to methods of preventing, or reducing the severity of, an ischemic injury originating in an animal'"'"'s dermal tissue by applying to the animal a composition comprising a compound of formula I*: ##STR1## or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which

X is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH₂ --, --CH₂ --CH₂ --, --CH═CH--, --C.tbd.C--, --CH₂ --NH--, --COCH₂ --, --NHCS--, --CH₂ S--, --CH₂ O--, --OCH₂ --, --NHCH₂ -- or --CR⁵ ═CR⁶ --;

n is 1 or 0;

R^m and R^k are independently hydrogen, halogen, C_1-6 alkyl, hydroxy, C_1-6 alkyloxy or nitro;

R⁴ is --(CH₂)_t --Y^b, C_1-6 alkyl, or C_3-6 cycloalkyl;

R¹ is --CO₂ Z, C_1-6 alkyl, CH₂ OH, --CONHR^y, or CHO;

R^a and R^b are independently hydrogen or C_1-6 alkyl, or R^a and R^b together can form a radical of the formula: ##STR2## Y^b is naphthyl or phenyl, both radicals can be optionally substituted with one to three of C_1-6 alkyl or halogen, which substituents can be the same or different;

Z is hydrogen or C_1-6 alkyl;

R², R³, R⁵, R⁶, and R^y are independently hydrogen or C_1-6 alkyl; and

t is zero to six.

Claims

1. A method of preventing or reducing the severity of an ischemic injury originating in an animal'"'"'s dermal tissue comprising administering to the animal a composition comprising a compound of formula I*:

##STR9## or a nontoxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, in which

X is --O--CO--, --NH--CO--, --CS--NH--, --CO--O--, --CO--NH--, --COS--, --SCO--, --SCH₂ --, --CH₂ --CH₂ --, --C.tbd.C--, --CH₂ --NH--, --COCH₂ --, --NHCS--, --CH₂ S--, --CH₂ O--, --OCH₂ --, --NHCH₂ -- or --CR⁵ ═

CR⁶ --;

n is 1 or 0;

R^m and R^k are independently hydrogen, halogen, C_1-6 alkyl, hydroxy, C_1-6 alkyloxy or nitro;

R⁴ is --(CH₂)_t --Y^b, C_1-6 alkyl, or C_3-6 cycloalkyl;

R¹ is --CO₂ Z, C_1-6 alkyl, CH₂ OH, -CONHR^y, or CHO;

R^a and R^b are independently hydrogen or C_1-6 alkyl, or R^a and R^b together can form a radical of the formula;

##STR10## Y^b is naphthyl or phenyl, both radicals can be optionally substituted with one to three of C_1-6 alkyl or halogen, which substituents can be the same or different;

Z is hydrogen or C_1-6 alkyl;

R², R³, R⁵, R⁶, and R^y are independently hydrogen or C_1-6 alkyl; and

t is zero to six.

2. The method of claim 1, in which R¹ is --CO₂ H;

n is one;

R² and R³ are independently methyl or hydrogen; and

R^a and R^b are independently hydrogen or C_1-6 alkyl.

3. The method of claim 1, in which the compound is 4-[[(E)-(5,6,-dihydro-5,5-dimethyl-8-phenyl)-2-naphthalenyl]vinyl]benzoic acid.

4. The method of claim 1, in which R² is methyl.

5. The method of claim 4, in which R³ is methyl.

6. The method of claim 1, in which R^m and R^k are hydrogen.

7. The method of claim 1, in which R^a and R^b are hydrogen.

8. The method of claim 1, in which X is --CH═

CH--.

9. The method of claim 1, in which R¹ is CO₂ Z.

10. The method of claim 9, in which Z is hydrogen.

11. The method of claim 1, wherein the composition comprises a compound of formula I¹¹ :

##STR11## in which R⁴ is --(CH₂)_t --Y^b, C_1-6 alkyl, or C_3-6 cycloalkyl.

12. The method of claim 1, wherein the composition is administered in a medicant bandage or dressing having an adhesive layer or surface for adhering to the animal'"'"'s skin.

13. The method of claim 12, wherein the compound is incorporated within an adhesive layer or is coated onto an adhesive surface or is located at an adhesive surface and adjacent strata of a bandage or dressing.

14. The method of claim 12, wherein the dressing comprises a hydrocolloid adhesive.

15. The method of claim 12, wherein the compound is present at about 0.5 to about 1.0 mg/in² of the skin contacting adhesive surface of the bandage or dressing.

16. The method of claim 12, wherein the medicant bandage or dressing is applied prior to the development of visually discernible damage to dermal tissue.

17. The method of claim 1, wherein the compound is present in a topical composition at about 0.01% to about 1% by weight of the composition.

18. The method of claim 1, wherein the reduction or prevention of injury is determined by measuring microcirculatory blood flow.

19. The method of claim 1, wherein the reduction or prevention of injury is determined by histological examination of a dermal tissue sample.

20. The method of claim 1, wherein the composition is applied to prevent or reduce the damaging effects of an ischemic injury resulting from removal of an adhesive from the animal.

21. The method of claim 1, wherein the composition is applied to prevent or reduce the damaging effects of an ischemic injury resulting from pressure on dermal tissue covering a bony protuberance.