Ketone compounds and compositions for cholesterol management and related uses
The present invention relates to novel ketone compounds, compositions comprising ketone compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising a ketone compound. The compounds, compositions, and methods of the invention are also useful for treating and preventing Alzheimer's Disease, Syndrome X, peroxisome proliferator activated receptor-related disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence. 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 Ia:
or a pharmaceutically acceptable salt or a mixture thereof, wherein
(a) each occurrence of Z is CH 2 , wherein each occurrence of m is independently an integer ranging from 1 to 9;
(b) G is (CH 2 ) x , where x is 2, 3, or 4;
(c) W 1 and W 2 are independently L;
(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, or benzyl
(e) L is C(R 1 )(R 2 )—(CH 2 ) n —Y, where n is an independent integer ranging from 0 to 4;
(f) each occurrence of Y is independently OH, COOH, CHO, (CH 2 ) n COOR 3 , SO 3 H,
where
(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 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; and
(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
provided that:
(i) if x is 4, each occurrence of Z is CH 2 , each occurrence of m is 4, and W 1 is —CH(CH 3 )CO 2 H, then W 2 is not the same as W 1 ;
(ii) if x is 4, each occurrence of Z is CH 2 , each occurrence of m is 2, and W 1 is —C(phenyl) 2 CH 2 CO 2 H, then W 2 is not the same as W 1 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt or a mixture thereof, wherein each occurrence of Y is independently OH, COOR 3 , or COOH.
3. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, or a mixture thereof, and a pharmaceutically acceptable vehicle, excipient, or diluent.
4. A method of increasing HDL levels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a mixture thereof.
5. A method of lowering LDL levels, which comprises administering to such patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, or a mixture thereof.
6. A compound or a pharmaceutically acceptable salt thereof represented by formulae Ib-1 to Ib-9, Ib-12 to Ib-14, Ib-25 to Ib-32, Ib-35 to Ib-37, Ib-50 to Ib-67, Ib-70 to Ib-72, Ib-83 to Ib-90, Ib-93 to Ib-95, Ib-106 to Ib-113, Ib-116 to Ib-126, Ib-129 to Ib-131, Ib-144 to Ib-149, Ib-152 to Ib-154, Ib-157 to Ib-158, or Ib-161 to Ib-163, as follows:
Ib-1 2,12-Dihydroxy-2,12-dimethyl-tridecane-5,9-dione;
Ib-2 1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecane-5,9-dione;
Ib-3 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid;
Ib-4 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedial;
Ib-5 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dimethyl ester;
Ib-6 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid diphenyl ester;
Ib-7 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dibenzyl ester;
Ib-8 2,12-Dimethyl-5,9-dioxo-tridecane-2,12-disulfonic acid;
Ib-9 Phosphoric acid mono-(1,1,11-trimethyl-4,8-dioxo-11-phosphonooxy-dodecyl) ester;
Ib-12 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid dicyanimide;
Ib-13 Phosphoramidic acid mono-[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-dioxo-dodecyl]ester;
Ib-14 2,12-Dimethyl-2,12-bis-(amino-hydroxy-phosphoryloxy)-tridecane-5,9-dione;
Ib-25 1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecane-6,10-dione;
Ib-26 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid;
Ib-27 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedial;
Ib-28 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid dimethyl ester;
Ib-29 2,2,12,12-Tetramethyl-5,9-dioxo-tetradecanedioic acid diphenyl ester;
Ib-30 3,3,13,13-Tetramethyl-6,10,14-trioxo-16-phenyl-hexadecanoic acid benzyl ester;
Ib-31 2,2,12,12-Tetramethyl-5,9-dioxo-tridecane-1,13-disulfonic acid;
Ib-32 Phosphoric acid mono-(2,2,12,12-tetramethyl-5,9-dioxo-13-phosphonooxy-tridecyl) ester;
Ib-35 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide;
Ib-36 Phosphoramidic acid mono-[13-(amino-hydroxy-phosphoryloxy)-2,2,12,12-tetramethyl-6,9-dioxo-tridecyl] ester;
Ib-37 Phosphoramidic acid mono-[11-(amino-hydroxy-phosphoryloxy)-1,1,11-trimethyl-4,8-dioxo-dodecyl]ester;
Ib-50 2,11-Dihydroxy-2,11-dimethyl-dodecane-5,8-dione;
Ib-51 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione;
Ib-52 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid;
Ib-53 2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid;
Ib-54 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial;
Ib-55 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dimethyl ester;
Ib-56 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester;
Ib-57 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dibenzyl ester;
Ib-58 Phosphoric acid mono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester;
Ib-59 2,14-Dihydroxy-2,14-dimethyl-pentadecane-6,10-dione;
Ib-60 1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecane-6,10-dione;
Ib-61 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid;
Ib-62 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedial;
Ib-63 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dimethyl ester;
Ib-64 2,2,14,14-Tetramethyl-6,10-dioxo-hexadecanedioic acid diphenyl ester;
Ib-65 2,2,14,14-Tetramethyl-6,10-dioxo-hexadecanedioic acid dibenzyl ester;
Ib-66 2,14-Dimethyl-6,10-dioxo-pentadecane-2,14-disulfonic acid;
Ib-67 Phosphoric acid mono-(1,1,13-trimethyl-5,9-dioxo-13-phosphonooxy-tetradecyl) ester;
Ib-70 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid dicyanimide;
Ib-71 Phosphoramidic acid mono-[13-(amino-hydroxy-phosphoryloxy)-1,1,13-trimethyl-5,9-dioxo-tetradecyl] ester;
Ib-72 2,14-Dimethyl-2,14-bis-(amino-hydroxy-phosphoryloxy)-pentadecane-6,10-dione;
Ib-83 1,14-Dihydroxy-3,3,12,12-tetramethyl-tetradecane-6,9-dione;
Ib-84 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid;
Ib-85 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedial;
Ib-86 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid dimethyl ester;
Ib-87 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid diphenyl ester;
Ib-88 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid dibenzyl ester;
Ib-89 2,2,11,11-Tetramethyl-5,8-dioxo-dodecane-1,12-disulfonic acid;
Ib-90 Phosphoric acid mono-(2,2,11,11-tetramethyl-5,8-dioxo-12-phosphonooxy-dodecyl) ester;
Ib-93 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid dicyanimide;
Ib-94 Phosphoramidic acid mono-[12-(amino-hydroxy-phosphoryloxy)-2,2,11,11-tetramethyl-5,8-dioxo-dodecyl] ester;
Ib-95 2,2,11,11-Tetramethyl-1,12-bis-(aminohydroxyphosphoryloxy)-dodecane-5,8-dione;
Ib-106 1,16-Dihydroxy-4,4,13,13-tetramethyl-hexadecane-7,10-dione;
Ib-107 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid;
Ib-108 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedial;
Ib-109 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dimethyl ester;
Ib-110 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid diphenyl ester;
Ib-111 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dibenzyl ester;
Ib-112 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecane-1,14-disulfonic acid;
Ib-113 Phosphoric acid mono-(3,3,12,12-tetramethyl-6,9-dioxo-14-phosphonooxy-tetradecyl) ester;
Ib-116 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid dicyanimide;
Ib-117 Phosphoramidic acid mono-[14-(amino-hydroxy-phosphoryloxy)-3,3,12,12-tetramethyl-6,9-dioxo-tetradecyl] ester;
Ib-118 3,3,12,12-Tetramethyl-1,14-bis-(amino-hydroxy-phosphoryloxy)-tetradecane-6,9-dione;
Ib-119 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione;
Ib-120 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid;
Ib-121 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedial;
Ib-122 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dimethyl ester;
Ib-123 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid diphenyl ester;
Ib-124 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dibenzyl ester;
Ib-125 2,11-Dimethyl-5,8-dioxo-dodecane-2,11-disulfonic acid;
Ib-126 Phosphoric acid mono-(1,1,10-trimethyl-4,7-dioxo-10-phosphonooxy-undecyl) ester;
Ib-129 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanimide;
Ib-130 Phosphoramidic acid mono-[10-(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-dioxo-undecyl] ester;
Ib-131 2,2,11,11-Tetramethyl-1,12-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dione;
Ib-144 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione;
Ib-145 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedial;
Ib-146 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid dimethyl ester;
Ib-147 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione;
Ib-148 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid diphenyl ester;
Ib-149 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid dibenzyl ester;
Ib-152 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid dicyanamide;
Ib-153 Phosphoramidic acid mono-[10-(amino-hydroxy-phosphoryloxy)-1,1,10-trimethyl-4,7-dioxo-undecyl] ester;
Ib-154 2,11-Dimethyl-2,11-bis-(amino-hydroxy-phosphoryloxy)-dodecane-5,8-dione;
Ib-157 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecane-1,15-disulfonic acid;
Ib-158 Phosphoric acid mono-(2,2,14,14-tetramethyl-6,10-dioxo-15-phosphonooxy-pentadecyl)ester;
Ib-161 3,3,15,15-Tetramethyl-7,11-dioxo-heptadecanedioic acid dicyanamide;
Ib-162 Phosphoramidic acid mono-[16-(amino-hydroxy-phosphoryloxy)-4,4,15,15-tetramethyl-7,11-dioxo-hexadecyl] ester; or
Ib-163 2,2,14,14-Tetramethyl-1,15-bis-(amino-hydroxy-phosphoryloxy)-pentadecane-6,10-dione.
7. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-2 1,13-Dihydroxy-2,2,12,12-tetramethyl-tridecane-5,9-dione.
8. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-3 2,2,12,12-Tetramethyl-5,9-dioxo-tridecanedioic acid.
9. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-25 1,15-Dihydroxy-3,3,13,13-tetramethyl-pentadecane-6,10-dione.
10. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-26 3,3,13,13-Tetramethyl-6,10-dioxo-pentadecanedioic acid.
11. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-51 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione.
12. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-52 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid.
13. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-60 1,15-Dihydroxy-2,2,14,14-tetramethyl-pentadecane-6,10-dione.
14. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-61 2,2,14,14-Tetramethyl-6,10-dioxo-pentadecanedioic acid.
15. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-83 1,14-Dihydroxy-3,3,12,12-tetramethyl-tetradecane-6,9-dione.
16. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-84 3,3,12,12-Tetramethyl-6,9-dioxo-tetradecanedioic acid.
17. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-106 1,16-Dihydroxy-4,4,13,13-tetramethyl-hexadecane-7,10-dione.
18. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-107 4,4,13,13-Tetramethyl-7,10-dioxo-hexadecanedioic acid.
19. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-119 1,12-Dihydroxy-2,2,11,11-tetramethyl-dodecane-5,8-dione.
20. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-120 2,2,11,11-Tetramethyl-5,8-dioxo-dodecanedioic acid.
21. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-144 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione.
22. A compound or a pharmaceutically acceptable salt thereof of claim 6 represented by the formula: Ib-147 1,17-Dihydroxy-3,3,15,15-tetramethyl-heptadecane-7,11-dione.
23. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable vehicle, excipient, or diluent.
24. A method of increasing HDL levels, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt thereof.
25. A method of lowering LDL levels, which comprises administering to such patient in need thereof a therapeutically effective amount of a compound of claim 6 , or a pharmaceutically acceptable salt thereof.