N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases

1. A compound having the formula

wherein,

a) “- - -” is absent or present;

b) Ar 1 has from six to 25 carbon atoms and has the formula

 wherein R 5 and R 6 together with the aromatic ring form a five, six, or seven membered non-aromatic cycloalkyl or substituted cycloalkyl ring which can optionally comprise one, or two ring heteroatoms independently selected from O, S, N, and NR N , wherein R N is hydrogen, hydroxyl, halogen, amino, or an organic radical comprising one to twelve carbon atoms; and wherein R 7 and R 8 are independently selected from hydrogen, alkyl, substituted alkyl, amino, mono-substituted amino, or di-substituted amino;

c) Ar 2 comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and

d) R 1 is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;

e) R 2 is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;

f) W is —S—, —O— or —N—R 3 wherein R 3 is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and

g) X is O or S;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 2 is an alkyl or substituted alkyl group.

3. The compound of claim 1 wherein R 2 is a —CH 2 CO 2 H group.

4. The compound of claim 1 wherein “- - -” is present.

5. The compound of claim 1 wherein R 7 is hydrogen.

6. The compound of claim 1 wherein R 8 is hydrogen.

7. The compound of claim 1 wherein R 1 is hydrogen.

8. The compound of claim 1 wherein W is —S—.

9. The compound of claim 1 wherein X is —O—, or —S—.

10. The compound of claim 1 wherein X is —O—.

11. The compound of claim 1 wherein W is —S—, and X is —O—.

12. The compound of claim 1 wherein W is —S—, and X is —S—.

13. The compound of claim 1 wherein R 5 and R 6 together with the aromatic ring form a cycloalkyl ring, or a substituted cyloalkyl ring having from one to four substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.

14. The compound of claim 13 wherein the cycloalkyl ring, or substituted cyloalkyl ring together with the aromatic ring comprise a fused ring having the structures

15. The compound of claim 13 wherein the cycloalkyl ring, or substituted cyloalkyl ring comprises 1, 2 or 3 heteroatoms or heteroatomic groups that can include O, S, SO, SO 2 and N, wherein N can be optionally further substituted with hydrogen, alkyl or substituted alkyl groups comprising one to ten carbon atoms.

16. The compound of claim 1 wherein Ar 1 has the structure

17. The compound of claim 1 wherein R 5 and R 6 together with the aromatic ring form a cycloalkenyl ring, or a substituted cyloalkenyl ring having from one to four substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.

18. The compound of claim 1 wherein Ar 2 is an aryl ring optionally substituted with one, two, or three substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, haloalkyl, haloalkoxy, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.

19. The compound of claim 1 wherein Ar 2 has the structure

wherein R 15 , R 16 , and R 17 are independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide radicals.

20. The compound of claim 1 wherein Ar 2 has the structure

21. The compound of claim 1 wherein Ar 2 has the structure

22. The compound of claim 1 wherein Ar 2 is a heteroaryl ring optionally substituted with one, two, or three substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide radicals.

23. The compound of claim 1 wherein Ar 2 has the structure

wherein x is one or two, and R 15 , and R 16 are independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.

24. The compound of claim 23 wherein Ar 2 comprises a heteroaryl ring having the structure

25. The compound of claim 23 wherein Ar 2 comprises a heteroaryl ring having the structure

26. The compound of claim 1 that when applied at a concentration of about 10 uM to a human tumor cell line culture for leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, or pancreatic cancer is effective to inhibit cell growth of the tumor cells by 50% or more.

27. A compound of claim 1 that is effective, when applied at a concentration of about 10 uM, to inhibit by at least 25% the adipocite differentiation induced by rosiglitazone which is applied at a concentration of 0.1 uM.

28. A compound having the formula

wherein,

a) “- - -” is absent or present;

b) Ar 1 has the formula

 Ar 2 has the formula

 wherein x is one or two, and R 15 , R 16 and R 17 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, or an organic radicals comprising one to four carbon atoms selected from an alkyl, substituted alkyl, haloalkyl, haloalkoxy, alkoxy, substituted alkoxy, mono-substituted amino, di-substituted amino having from one to four carbon atoms.

c) R 1 is hydrogen, or an alkyl or substituted alkyl group having one to four carbon atoms;

d) R 2 is a an alkyl or substituted alkyl group having one to four carbon atoms,

e) W is —S—; and

f) X is O or S;

or a pharmaceutically acceptable salt thereof.

29. The compound of claim 28 wherein “- - -” is present.

30. The compound of claim 28 wherein R 1 is hydrogen.

31. The compound of claim 28 wherein Ar 2 has the formula

32. A compound present as:

{5-[4-Methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

{5-[4-Trifluoromethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

{5-[6-Methoxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridin-3-yl methylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

3-Ethyl-{5-[4-Trifluoromethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-2-thioxo-thiazolidin-4-one;

3-Methyl-{5-[4-Trifluoromethoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-2-thioxo-thiazolidin-4-one;

5-[4-Methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-3-(2-pyridin-2-yl-ethyl)-thiazolidine-2,4-dione;

{5-[6-(3-Dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-naphthalen-2-yl methylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

{5-[5-Phenyl-3-methoxy-2-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

{5-[3-Methoxy-2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid;

{5-[4-Dimethylamino-3-(3-dimethylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzylidene]4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid; or

{5-[(3-t-Butyl-4-methoxyphenyl)-6-ethoxy-benzylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-acetic acid; or

a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition for administration in mammals comprising one or more pharmaceutically acceptable carriers and one or more compounds of claim 1 in an amount effective for modulating lipid metabolism or adipocyte differentiation.

34. A method of modulating lipid metabolism or adipocyte differentiation comprising administering to a mammal diagnosed as needing such modulation the pharmaceutical composition of claim 33 .

35. A method of treating hypercholesterimia comprising administering to a mammal diagnosed as needing such treatment the pharmaceutical composition of claim 33 .

36. The method of claim 35 , wherein the compound is applied in an amount effective to decrease serum cholesterol levels by at least about 5%.

37. A method of treating dyslipidemia comprising administering to a mammal diagnosed as needing such treatment the pharmaceutical composition of claim 33 in an amount effective to decrease serum cholesterol levels.

38. The method of claim 37 , wherein the compound is applied in an amount effective to decrease serum cholestrol levels by at least about by at least 5%.

39. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and one or more compounds of claim 1 .

40. A method of treatment for a disease of uncontrolled cellular proliferation selected from the group consisting of lung cancer, brest cancer, prostate cancer, or pancreatic cancer comprising administering to a mammal diagnosed as having lung cancer, breast cancer, prostate cancer, or pancreatic cancer the pharmaceutical composition of claim 39 in an amount that is effective to treat the disease of uncontrolled cellular proliferation selected from the group consisting of lung cancer, breast cancer, prostate cancer, or pancreatic cancer.

41. The method of claim 40 , wherein the disease of uncontrolled cellular proliferation is lung cancer.

42. The method of claim 40 , wherein the disease of uncontrolled cellular proliferation is prostate cancer.

43. The method of claim 40 , wherein the disease of uncontrolled cellular proliferation is pancreatic cancer.

44. A method of claim 40 , wherein the disease of uncontrolled cellular proliferation is breast cancer.

45. The method of claim 40 wherein the mammal is a human.