Dihydroxyl compounds and compositions for cholesterol management and related uses
The present invention relates to novel dihydroxyl 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, 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 compound of the formula I:
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) each occurrence of Z is independently CH 2 , CH═CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 9, but when Z is phenyl then m is 1;
(b) G is (CH 2 ) x , where x is 1-7, CH 2 CH═CHCH 2 , CH═CH, CH 2 -phenyl-CH 2 , or phenyl;
(c) W 1 and W 2 are independently L, V, C(R 1 )(R 2 )—(CH 2 ) c —C(R 3 )(R 4 )—(CH 2 ) n —Y or C(R 1 )(R 2 )—(CH 2 ) c —V where c is 1 or 2 and n is an integer ranging from 0 to 7;
(d) each occurrence of R 1 or R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl or when one or both of W 1 and W 2 is C(R 1 )(R 2 )—(CH 2 ) c —C(R 3 )(R 4 )—(CH 2 ) n —Y, then R 1 and R 2 can both be H to form a methylene group; 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) R 3 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxyl, phenyl, benzyl, Cl, Br, CN, NO 2 , or CF 3 ;
(f) R 4 is OH, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxyl, phenyl, benzyl, Cl, Br, CN, NO 2 , or CF 3 ;
(g) L is C(R 1 )(R 2 )—(CH 2 ) n —Y, wherein n is an integer from 1 to 5;
(h) V is:
(i) each occurrence of Y is independently (C 1 -C 6 )alkyl, OH, COOH, COOR 5 , SO 3 H,
wherein:
(i) R 5 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 6 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;
(iii) each occurrence of R 7 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl; and
(j) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4.
2. The compound of claim 1 , wherein G is (CH 2 ) 2 .
3. The compound of claim 1 , wherein each occurrence of Z m is independently (CH 2 ) and m is 1-4.
4. The compound of claim 1 , wherein each occurrence of W 1 and W 2 is independently L.
5. The compound of claim 2 , wherein L is C(CH 3 ) 2 —(CH 2 )—OH.
6. The compound of claim 1 , wherein each occurrence of W 1 and W 2 is independently V.
7. The compound of claim 6 , wherein V is
8. A compound of the formula II:
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of Z is independently CH 2 or CH═CH, wherein each occurrence of m is independently an integer ranging from 1 to 9;
(b) Q is (CH 2 ) x , CH 2 CH═CHCH 2 , or CH═CH, where x is 2, 3, or 4;
(c) W 1 and W 2 are independently L, V, or C(R 1 )(R 2 )—(CH 2 )—V, where c is 1 or 2;
(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 )cycloalkyl group;
(e) L is C(R 1 )(R 2 )(CH 2 ) n —Y, where n is an integer ranging from 0 to 5;
(f) V is:
(g) each occurrence of Y 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; and
(h) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4.
9. The compound of claim 8 , wherein each occurrence of W 1 and W 2 is independently L.
10. The compound of claim 9 , wherein L is C(CH 3 ) 2 —(CH 2 ) n —Y.
11. The compound of claim 10 , wherein each occurrence of Y is independently OH, COOR 7 , or COOH.
12. The compound of claim 8 , wherein Q is CH═CH.
13. The compound of claim 8 , wherein Z m is CH 2 and m is 1-3.
14. The compound of claim 8 , wherein each of W 1 and W 2 is independently C(R 1 )(R 2 )—(CH 2 ) x —V.
15. The compound of claim 14 , wherein R 1 and R 2 are each independently (C 1 -C 6 )alkyl.
16. The compound of claim 15 , wherein R 1 and R 2 are each methyl.
17. A compound of the formula III
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of m is independently an integer ranging from 1 to 9;
(b) r is 2, 3, or 4;
(c) each occurrence of n is independently an integer ranging from 0 to 7;
(d) each occurrence of R 1 , R 2 , R 11 , and R 12 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, or 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; and
(e) each occurrence of Y 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;
(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; and
(f) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4.
18. The compound of claim 17 , wherein each occurrence of Y 1 and Y 2 is independently OH, COOR 3 , or COOH.
19. A compound of the formula IV
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of m is an independent integer ranging from 1 to 9;
(b) x is 2, 3, or 4;
(c) each of V 1 and V 2 is independently:
20. A compound of the formula V:
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein:
(a) each occurrence of Z is independently CH 2 , CH═CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 5, but when Z is phenyl then its associated m is 1;
(b) G is (CH 2 ) x , CH 2 CH═CHCH 2 , CH═CH, CH 2 -phenyl-CH 2 , or phenyl, where x is an integer ranging from 1 to 7;
(c) W 1 and W 2 are independently C(R 8 )(R 9 )—(CH 2 ) n -Y, where n is an integer ranging from 0 to 7;
(d) each occurrence of R 8 and R 9 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl or R 8 and R 9 can be taken together to form a carbonyl group;
(e) each occurrence of R 1 and R 2 is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl or R 1 and R 2 can be taken together to form a carbonyl group 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;
(f) each occurrence of R 6 and R 7 is independently H, (C 1 -C 6 )alkyl, or R 6 and R 7 can be taken together to form a carbonyl group or R 6 and R 7 and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloakyl group;
(g) Y is (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;
(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;
(h) each occurrence of b is independently 0 or 1 or optionally the presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds; and
(i) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4.
21. The compound of claim 20 , wherein each occurrence of W 1 and W 2 is an independent C(R 1 )(R 2 )—(CH 2 ) n —Y group and each occurrence of Y is independently OH, COOR 3 , or COOH.
22. A compound of the formula VI:
or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) each occurrence of m is independently an integer ranging from 1 to 5;
(b) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4;
(c) W 1 and W 2 are independently C(R 1 )(R 2 )—(CH 2 ) n -Y, where n is an integer ranging from 0 to 7;
(d) each occurrence of R 1 or R 2 is independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, 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) Y is (C 1 -C 6 )alkyl, (CH 2 ) n OH, (CH 2 ) n COOH, (CH 2 ) n 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,
(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;
(f) each occurrence of b is independently 0 or 1; and
(g) X is (CH 2 ) z or Ph, wherein z is an integer from 0 to 4.
23. The compound of claim 22 , wherein each occurrence of W 1 and W 2 independently C(R 1 )(R 2 )—(CH 2 ) n —Y and each occurrence of Y is independently OH, COOR 3 , or COOH.
24. A compound of structure:
6,9-Dihydroxy-2,2,13,13-tetramethyl-tetradecanedioic acid;
2,2,13,13-Tetramethyl-tetradecane-1,6,9,14-tetraol;
6,10-Dihydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid; and
2,2,14,14-Tetramethyl-pentadecane-1,6,10,15-tetraol,
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
25. A pharmaceutical composition comprising a compound of claim 1 , 8 , 17 , 19 , 20 , 22 , or 24 and a pharmaceutically acceptable vehicle, excipient, or diluent.
26. A pharmaceutical composition comprising a compound of claim 1 , 8 , 17 , 19 , 20 , 22 , or 24 and further comprising a second therapeutic agent.
27. A pharmaceutical composition comprising a compound of claim 1 , 8 , 17 , 19 , 20 , 22 , 24 , or 26 and a pharmaceutically acceptable vehicle, excipient, or diluent which is administered in combination with a statin.
28. A compound according to claim 1 wherein said compound has the structure:
6,9-Dihydroxy-2,2,13,13-tetramethyl-tetradecanedioic acid;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
29. A compound according to claim 1 wherein said compound has the structure:
2,2,13,13-Tetramethyl-tetradecane-1,6,9,14-tetraol;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
30. A compound according to claim 1 wherein said compound has the structure:
6,10-Dihydroxy-2,2,14,14-tetramethyl-pentadecanedioic acid;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.
31. A compound according to claim 1 wherein said compound has the structure:
2,2,14,14-Tetramethyl-pentadecano-1,6,10,15-tetraol;
or a pharmaceutically acceptable salt, hydrate, or solvate thereof.