Compounds that stimulate glucose utilization and methods of use

1. A sterile aqueous solution, dispersion or suspension of an injectable pharmaceutical composition comprising a physiologically acceptable carrier and a glucose utilization increasing amount of at least one compound represented by Formula (I)

W is C 1 –C 6 alkyl, halogen, or aryl;

Cyc is C 3 or C 4 cycloalkyl;

p is 0–3 for Cyc being C 4 cycloalkyl, or p=0–2 for Cyc being C 3 cycloalkyl;

Y is O, S, or NR , where R═H, alkyl or aryl;

X is O, S, NR, or CR 3 R 4 ;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R 1 is H, alkyl, aryl;

R 2 is H, alkyl, aryl or ═O;

R 3 and R 4 are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof; and a pharmaceutically acceptable carrier, diluent, excipient or mixtures thereof.

2. The pharmaceutical composition as claimed in claim 1 , wherein said compound is represented by Formula (I), and wherein p=0;

Y is O;

X is N or O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1–4; and

Z is lower alkyl, cycloalkyl or phenyl.

3. The pharmaceutical composition as claimed in claim 1 , wherein said compound is represented by the Formula (I), and wherein p=0;

Y is N;

X is O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1 or 2; and

Z is hydrogen.

4. The pharmaceutical compositions as claimed in claim 1 , wherein said composition is in the form of sterile suspensions or solutions.

5. The pharmaceutical composition according to claim 1 , wherein said at least one compound is selected from the group consisting of

cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; and

cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.

6. A method for increasing glucose utilization in a cell, tissue or organ of a warm blooded animal comprising treating said cell, tissue or organ with glucose utilization effective amount of at least one compound represented by Formula (I)

wherein

W is C 1 –C 6 alkyl, halogen, or aryl;

Cyc is C 3 or C 4 cycloalkyl;

p is an integer from 0 to 3 when Cyc is C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl;

Y is O, S, or NR, where R is H, alkyl, or aryl;

X is O, S, NR, or CR 3 R 4 ;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R 1 is H, alkyl or aryl;

R 2 is H, alkyl, aryl or O;

R 3 and R 4 are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.

7. The method as claimed in claim 6 , wherein said compound is represented by Formula (I), and wherein p=0;

Y is O;

X is N or O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1–4; and

Z is lower alkyl, cycloalkyl or phenyl.

8. The method as claimed in claim 6 , wherein said compound is represented by Formula (I), and wherein p=0;

Y is N;

X is O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1 or 2; and

Z is hydrogen.

9. The method as claimed in claim 6 , wherein said organ is heart.

10. The method according to claim 6 , wherein said cell is a myocardial cell.

11. The method according to claim 6 , wherein said at least one compound is selected from the group consisting of

cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; and

cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.

12. A method for treatment of physiological conditions or disorders treatable by increasing glucose utilization comprising:

administering to a patient in need of such treatment, effective amount to increase glucose utilization of a pharmaceutical composition comprising at least one compound represented by Formula (I)

wherein

W is C 1 –C 6 alkyl, halogen, or aryl;

Cyc is C 3 or C 4 cycloalkyl;

p is an integer from 0 to 3 when Cyc C 4 cycloalkyl, or p is an integer from 0 to 2 when Cyc is C 3 cycloalkyl;

Y is O, S, or NR, where R is H, alkyl, or aryl;

X is O, S, NR, or CR 3 R 4 ;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R 1 is H, alkyl, or aryl;

R 2 is H, alkyl aryl or O;

R 3 and R 4 are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.

13. The method as claimed in claim 12 , wherein said disorder or condition is ischemic/reperfusion injury, post myocardial infarction, angina, heart failure, a cardiomyopathy, peripheral vascular disease, diabetes, and lactic acidosis, or symptoms or side effects associated with open heart surgery, bypass surgery, or heart transplant.

14. The method as claimed in claim 13 , wherein said disorder or condition is ischemic/reperfusion injury.

15. The method as claimed in claim 12 , wherein said compound is represented by the Formula (I), and wherein p=0;

Y is O;

X is N or O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1–4; and

Z is lower alkyl, cycloalkyl or phenyl.

16. The method as claimed in claim 12 , wherein said compound is represented by the Formula (I), and wherein p=0;

Y is N;

X is O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1 or 2; and

Z is hydrogen.

17. The method according to claim 12 , wherein said at least one compound is selected from the group consisting of

cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; and

cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.

18. A kit containing a pharmaceutical composition as claimed in claim 1 .

19. The kit as claimed in claim 18 , wherein said kit comprises a label or packaging insert containing instructions for use, in vitro, in vivo, or ex vivo, of components of said kit.

20. A composition according to claim 1 wherein Y is O, X is NR or O, n is 1 to 4, p is 0; R 1 , R 2 , R 3 and R 4 are hydrogen and Z is cycloalkylcarbonyl.

21. A composition according to claim 20 wherein n is 3.

22. A composition according to claim 21 wherein Cyc is C 3 cycloalkyl.

23. A composition according to claim 22 wherein Z is cyclopropylcarbonyl.

24. An oral pharmaceutical composition for treatment of physiological conditions or disorders treatable by increasing glucose utilization in unit dosage form comprising a glucose utilization increasing amount of at least one compound represented by Formula (I):

wherein

W is C 1 –C 6 alkyl, halogen, or aryl;

Cyc is C 3 or C 4 cycloalkyl;

p is an integer from 0 to 3 when Cyc C 4 cycloalkyl, or p is 0 to 2 when Cys is C 3 cycloalkyl;

Y is O, S, or NR, where R is H, alkyl, or aryl;

X is O, S, NR, or CR 3 R 4 ;

Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

R 1 is H, alkyl, or aryl;

R 2 is H, alkyl aryl or O;

R 3 and R 4 are, independently, H, alkyl or aryl; and

n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof; and a pharmaceutically acceptable carrier, diluent, excipient or mixtures thereof.

25. The pharmaceutical composition as claimed in claim 24 , wherein said compound is represented by Formula (I), and wherein p=0;

Y is O;

X is N or O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1–4; and

Z is lower alkyl, cycloalkyl or phenyl.

26. The pharmaceutical composition as claimed in claim 24 , wherein said compound is represented by the Formula (I), and wherein p=O;

Y is N;

X is O;

R 1 , R 2 , R 3 and R 4 are hydrogens;

n is 1 or 2; and

Z is hydrogen.

27. The pharmaceutical compositions as claimed in claim 24 , wherein said composition is in the form of tablets, pills, or capsules.

28. the pharmaceutical composition according to claim 24 , wherein said at least one compound is selected from the group consisting of

cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; and

cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester.

29. A kit containing a pharmaceutical composition as claimed in claim 24 .

30. The kit as claimed in claim 29 , wherein said kit comprises a label or packaging insert containing instructions for use, in vitro, in vivo, or ex vivo, of components of said kit.

31. A composition according to claim 24 wherein Y is O, X is NR or O, n is 1 to 4, p is 0; R 1 , R 2 , R 3 and R 4 are hydrogen; and Z is cyclopropylcarbonyl.

32. A composition according to claim 31 wherein n is 3.

33. A composition according to claim 32 wherein Cyc is C 3 cycloalkyl.

34. A composition according to claim 33 wherein Z is cyclopropylcarbonyl.