Hydroxyl compounds and compositions for cholesterol management and related uses
The present invention relates to novel hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, pancreatitius, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, metabolic syndrome disorders (e.g., Syndrome X), thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.
1. A method for treating dyslipidemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I to treat the dyslipidemia:
or a pharmaceutically acceptable salt thereof, wherein:
(a) each occurrence of m is independently an integer ranging from 0 to 5;
(b) each occurrence of n is independently an integer ranging from 3 to 7;
(c) X is (CH 2 ) z , wherein z is an integer from 0 to 4;
(d) each occurrence of R 1 , R 2 , R 11 , and R 12 is independently H, (C 1 -C 6 )alkyl, or phenyl, wherein R 1 , R 2 , R 11 , and R 12 are not each simultaneously H; and
(e) each occurrence of Y 1 and Y 2 is independently OH, COOH, COOR 3 ,
wherein:
R 3 is (C 1 -C 6 )alkyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, or (C 1 -C 6 )alkoxy.
2. The method of claim 1 , wherein each occurrence of Y 1 and Y 2 is independently OH, COOR 3 , or COOH.
3. The method of claim 1 , wherein m is 0.
4. The method of claim 1 , wherein m is 1.
5. The method of claim 1 , wherein n is 4.
6. The method of claim 1 , wherein n is 5.
7. The method of claim 1 , wherein z is 0.
8. The method of claim 1 , wherein the compound is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
9. A method for treating dyslipidemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the formula
or a pharmaceutically acceptable salt thereof, to treat the dyslipidemia.
10. The method of claim 9 , wherein the compound is
11. The method of claim 1 , wherein R 1 , R 2 , R 11 , and R 12 are (C 1 -C 6 )alkyl.
12. The method of claim 11 , wherein Y 1 and Y 2 are COOH.
13. The method of claim 12 , wherein X is (CH 2 ) z , and z is 0.
14. The method of claim 13 , wherein m is 0.
15. The method of claim 1 , wherein the dyslipidemia is hypercholesterolemia.
16. The method of claim 8 , wherein the dyslipidemia is hypercholesterolemia.
17. The method of claim 9 , wherein the dyslipidemia is hypercholesterolemia.
18. The method of claim 10 , wherein the dyslipidemia is hypercholesterolemia.
19. The method of claim 12 , wherein the dyslipidemia is hypercholesterolemia.
20. The method of claim 14 , wherein the dyslipidemia is hypercholesterolemia.
21. A method for treating a cardiovascular disease selected from the group consisting of atherosclerosis, stroke, ischemia, peripheral vascular disease, coronary heart disease, myocardial infarction, cerebral infarction, and restenosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I to treat the cardiovascular disease:
or a pharmaceutically acceptable salt thereof, wherein:
each occurrence of m is independently an integer ranging from 0 to 5;
each occurrence of n is independently an integer ranging from 3 to 7;
X is (CH 2 ) z , wherein z is an integer from 0 to 4;
each occurrence of R 1 , R 2 , R 11 , and R 12 is independently H or (C 1 -C 6 )alkyl, wherein R 1 , R 2 , R 11 , and R 12 are not each simultaneously H;
each occurrence of Y 1 and Y 2 is independently OH, COON, or COOR 3 ; and
R 3 is (C 1 -C 6 )alkyl.
22. The method of claim 21 , wherein R 1 , R 2 , R 11 , and R 12 are (C 1 -C 6 )alkyl.
23. The method of claim 22 , wherein Y 1 and Y 2 are COOH.
24. The method of claim 23 , wherein z is 0.
25. The method of claim 24 , wherein m is 0.
26. The method of claim 21 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
27. The method of claim 21 , wherein the compound is