Cycloalkyl-hydroxyl compounds and compositions for cholesterol management
The present invention relates to novel cycloalkyl-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, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, 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 or preventing a cardiovascular disease in a patient, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate or a mixture 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 or Ph; wherein z is an integer from 0 to 4;
(d) each occurrence of R 1 and R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(e) each occurrence of R 11 and R 12 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(f) each occurrence of Y 1 and Y 2 is independently (C 1 -C 6 )alkyl, OH, COOH, COOR 3 , SO 3 H,
wherein:
(i) R 3 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups,
(ii) each occurrence of R 4 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6 alkoxy, or phenyl groups; and
(iii) each occurrence of R 5 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
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 X is (CH 2 ) z and z is 0.
8. The method of claim 1 , wherein each occurrence of R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group.
9. The method of claim 1 , wherein Y 1 and Y 2 are each independently (C 1 -C 6 )alkyl.
10. The method of claim 1 , wherein Y 1 and Y 2 are each methyl.
11. A method of increasing HDL levels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate or a mixture 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 or Ph; wherein z is an integer from 0 to 4;
(d) each occurrence of R 1 and R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken to form a (C 3 -C 7 )cycloakyl group;
(e) each occurrence of R 11 and R 12 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(f) each occurrence of Y 1 and Y 2 is independently (C 1 -C 6 )alkyl, OH, COOH, COOR 3 , SO 3 H,
wherein:
(i) R 3 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups,
(ii) each occurrence of R 4 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6 alkoxy, or phenyl groups; and
(iii) each occurrence of R 5 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
12. A method of decreasing LDL levels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt, hydrate, solvate or a mixture 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 or Ph; wherein z is an integer from 0 to 4;
(d) each occurrence of R 1 and R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, benzyl, or R 1 and R 2 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(e) each occurrence of R 11 and R 12 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(f) each occurrence of Y 1 and Y 2 is independent (C 1 -C 6 )alkyl, OH, COOH, COOR 3 , SO 3 H,
wherein:
(i) R 3 is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups,
(ii) each occurrence of R 4 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6 alkoxy, or phenyl groups; and
(iii) each occurrence of R 5 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl.
13. A method according to claim 1 wherein the compound of formula I is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
14. A method according to claim 11 wherein the compound of formula I is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
15. A method according to claim 12 wherein the compound of formula I is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
16. A method according to claim 1 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
17. A method according to claim 1 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
18. A method according to claim 1 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
19. A method according to claim 1 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
20. A method according to claim 12 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
21. A method according to claim 12 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
22. A method according to claim 12 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.
23. A method according to claim 12 wherein the compound is represented by the formula
or a pharmaceutically acceptable salt thereof.