US 6,703,422 B2Granted

Sulfide and disulfide compounds and compositions for cholesterol management and related uses

AssigneeEsperion Therapeutics, Inc.

InventorsJean-Louis Henri Dasseux, Carmen Daniela Oniciu

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Abstract

The present invention relates to novel sulfide and disulfide compounds, compositions comprising sulfide and disulfide compounds, and methods useful for treating and preventing cardiovascular diseases, dyslipidemias, dysproteinemias, and glucose metabolism disorders comprising administering a composition comprising an ether 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.

Claims16

Dependent claims

A compound of formula II:

or a pharmaceutically acceptable salt, hydrate, solvate, or a mixture thereof, wherein
(a) R1 and R2 are independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or R1, R2, and the carbon to which they are both attached are taken together to form a (C3-C7)cycloalkyl group;
(b) each occurrence of m is independently an integer ranging from 0 to 4;
(c) each occurrence of n is independently an integer ranging from 1 to 5;
(d) W1 and W2 are independently CH2OH, COOH, CHO, OC(O)R3, C(O)OR3, SO3H,
wherein:
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6) alkoxy, or phenyl groups;
(iii) each occurrence of R7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl;
and
provided that if each R1 and R2 is CH3, and W1 is —CO2CH3 then W2 is not the same as W1.

8 more elements

A compound of the formula:

II-1 6-(6-Hydroxy-5,5-dimethyl-hexylsulfanyl)-2,2-dimethyl-hexan-1-ol;
II-2 6-(5-Carboxy-5-methyl-hexylsulfanyl)-2,2-dimethyl-hexanoic acid;
II-3 5-(5-Hydroperoxy-4,4-dimethyl-pentylsulfanyl)-2,2-dimethyl-pentanoic acid;
II-4 5-(5-Hydroxy-4,4-dimethyl-pentylsulfanyl)-2,2-dimethyl-pentan-1-ol;
II-5 5-(5-Hydroxy-4,4-dimethyl-pentylsulfanyl)-2,2-dimethyl-pentanoic acid;
II-6 5-(4-Carboxy-4-methyl-pentylsulfanyl)-2,2-dimethyl-pentanoic acid;
II-7 7-(7-Hydroxy-6,6-dimethyl-heptylsulfanyl)-2,2-dimethyl-heptan-1-ol;
II-8 7-(7-Hydroxy-6,6-dimethyl-heptylsulfanyl)-2,2-dimethyl-heptanoic acid;
II-9 7-(6-Carboxy-6-methyl-heptylsulfanyl)-2,2-dimethyl-heptanoic acid;
II-10 2,2,12,12-Tetramethyl-7-oxo-tridecanedial;
II-11 6-(5-Methoxycarbonyl-5-methyl-hexylsulfanyl)-2,2-dimethyl-hexanoic acid methyl ester;
II-12 6-(5,5-Dimethyl-6-oxo-6-phenyl-hexylsulfanyl)-2,2-dimethyl-1-phenyl-hexan-1-one;
II-13 7-(5,5-Dimethyl-6-oxo-7-phenyl-heptylsulfanyl)-3,3-dimethyl-1-phenyl-heptan-2-one;
II-14 2,12-Dimethyl-7-oxo-tridecane-2,12-disulfonic acid;
II-15 Phosphoric acid mono-[1,1-dimethyl-5-(5-methyl-5-phosphonooxy-hexyl sulfanyl)-pentyl]ester;
II-16 2,2,14,14-Tetramethyl-8-oxo-pentadecanedial;
II-17 7-(6-Methoxycarbonyl-6-methyl-heptylsulfanyl)-2,2-dimethyl-heptanoic acid methyl ester;
II-18 7-(6,6-Dimethyl-7-oxo-7-phenyl-heptylsulfanyl)-2,2-dimethyl-1-phenyl-heptan-1-one;
II-19 8-(6,6-Dimethyl-7-oxo-8-phenyl-octylsulfanyl)-3,3-dimethyl-1-phenyl-octan-2-one;
II-20 2-Methyl-7-(6-methyl-6-sulfo-heptylsulfanyl)-heptane-2-sulfonic acid;
II-21 Phosphoric acid mono-[1,1-dimethyl-6-(6-methyl-6-phosphonooxy-heptylsulfanyl)-hexyl]ester;
II-22 7-(7-Hydroxy-5,5-dimethyl-heptylsulfanyl)-3,3-dimethyl-heptan-1-ol;
II-23 7-(7-Hydroxy-5,5-dimethyl-heptylsulfanyl)-3,3-dimethyl-heptanoic acid;
II-24 7-(6-Carboxy-5,5-dimethyl-hexylsulfanyl)-3,3-dimethyl-heptanoic acid;
II-25 6-(6-Hydroxy-4,4-dimethyl-hexylsulfanyl)-3,3-dimethyl-hexan-1-ol;
II-26 6-(6-Hydroxy-4,4-dimethyl-hexylsulfanyl)-3,3-dimethyl-hexanoic acid;
II-27 6-(5-Carboxy-4,4-dimethyl-pentylsulfanyl)-3,3-dimethyl-hexanoic acid;
II-28 8-(8-Hydroxy-6,6-dimethyl-octylsulfanyl)-3,3-dimethyl-octan-1-ol;
II-29 8-(8-Hydroxy-6,6-dimethyl-octylsulfanyl)-3,3-dimethyl-octanoic acid;
II-30 8-(7-Carboxy-6,6-dimethyl-heptylsulfanyl)-3,3-dimethyl-octanoic acid;
II-31 8-(7-Hydroxy-5,5-dimethyl-heptylsulfanyl)-4,4-dimethyl-octan-1-ol;
II-32 8-(8-Hydroxy-5,5-dimethyl-octane-1-sulfanyl)-4,4-dimethyl-octanoic acid;
II-33 8-(6-Carboxy-5,5-dimethyl-hexylsulfanyl)-4,4-dimethyl-octanoic acid;
II-34 7-(7-Hydroxy-4,4-dimethyl-heptylsulfany)-4,4-dimethyl-heptan-1-ol;
II-35 7-(7-Hydroxy-4,4-dimethyl-heptylsulfanyl)-4,4-dimethyl-heptanoic acid;
II-36 7-(6-Carboxy-4,4-dimethyl-hexylsulfanyl)-4,4-dimethyl-heptanoic acid;
II-37 9-(9-Hydroxy-6,6-dimethyl-nonylsulfanyl)-4,4-dimethyl-nonan-1-ol;
II-38 9-(9-Hydroxy-6,6-dimethyl-nonane-1-sulfanyl)-4,4-dimethyl-nonanoic acid;
II-39 8-(7-Carboxy-6,6-dimethyl-heptylsulfanyl)-3,3-dimethyl-octanoic acid;
II-40 5-[1,1-Dimethyl-4-(4-{3,3a-dihydro-4,6-dioxo-2H-thieno[3,2-c]pyridin-5-yl}-4-ethyl-pentane-1-sulfanyl)-butyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dione;
II-41 5-[1,1-Dimethyl-4-(4-{3,3a-dihydro-4,6-dithioxo-2H-thieno[3,2-c]pyridin-5-yl}-4-methyl-pentane-1-sulfanyl)-butyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-ithione;
II-42 5-(4-Cyanocarbamoyl-4-methyl-pentane-1-sulfanyl)-2,2-dimethyl-pentanoic acid cyanimide;
II-43 Phosphoramidic acid mono-{4-[4-(amino-hydroxy-phosphoryloxy)-4-methyl-pentylsulfanyl]-1,1-dimethyl-butyl}ester;
II-44 4-(Amino-hydroxy-phosphoryloxy)-4-methyl-1-(4-[amino-hydroxy-phosphoryloxy]-4-methyl-pentane-1-sulfanyl)-pentane;
II-45 5-[1,1-Dimethyl-5-(5-{3,3a-dihydro-4,6-dioxo-2H-thieno[3,2-c]pyridin-5-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dione;
II-46 5-[1,1-Dimethyl-5-(5-{3,3a-dihydro-4,6-dithioxo-2H-thieno[3,2-c]pyridin-5-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dithione;
II-47 6-(5-Cyanocarbamoyl-5-methyl-hexylsulfanyl)-2,2-dimethyl-hexanoic acid cyanimide;
II-48 Phosphoramidic acid mono-{5-[5-(amino-hydroxy-phosphoryloxy)-5-methyl-hexylsulfanyl]-1,1-dimethyl-pentyl}-ester;
II-49 5-(Amino-hydroxy-phosphoryloxy)-5-methyl-1-([5-amino-hydroxy-phosphoryloxy]-5-methyl-hexane-1-sulfanyl)-hexane;
II-50 1-[1,1-Dimethyl-5-(5-methyl-5-tetrazol-1-yl-hexane-1-sulfanyl)-pentyl]-1H-tetrazole;
II-51 5-[1,1-Dimethyl-5-(5-methyl-5-tetrazol-5-yl-hexane-1-sulfanyl)-pentyl]-1H-tetrazole;
II-52 2,12-Bis-(3-hydroxy-isoxazol-5-yl)-2,12-dimethyl-tridecan-7-one;
II-53 4-[1,1-Dimethyl-5-(5-{isoxazol-3-4-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-isoxazol-3-ol;
II-54 4-[1,1-Dimethyl-5-(5-{2-oxo-oxetan-4-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-oxetan-2-one;
II-55 3-[1,1-Dimethyl-5-(5-{2-oxo-oxetan-3-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-oxetan-2-one;
II-56 5-[1,1-Dimethyl-5-(5-(2-oxo-dihydro-furan-5-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-dihydro-furan-2-one;
II-57 3-[1,1-Dimethyl-5-(5-(2-oxo-dihydro-furan-3-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-dihydro-furan-2-one;
II-58 4-[1,1-Dimethyl-5-(5-(2-oxo-dihydro-furan-4-yl}-5-methyl-hexane-1-sulfanyl)-pentyl]-dihydro-furan-2-one;
II-59 2-[1,1-Dimethyl-5-{tetrahydro-pyran-2-oxy}-5-methyl-hexane-1-sulfanyl)-pentyloxy]-tetrahydro-pyran;
II-60 (2-{5-[5-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-5-methyl-hexylsulfanyl]-1,1-dimethyl-pentyl}-4-hydroxy-6-oxo-tetrahydro-pyran-4-yl)-acetic acid;
IIa-1 7-(7-Hydroxy-6-methyl-6-phenyl-heptylsulfanyl)-2-methyl-2-phenyl-heptan-1-ol;
IIa-2 7-(7-Hydroxy-6-methyl-6-phenyl-heptylsulfanyl)-2-methyl-2-phenyl-heptanoic acid;
IIa-3 7-(6-Carboxy-6-phenyl-heptylsulfanyl)-2-methyl-2-phenyl-heptanoic acid;
IIa-4 6-(6-Hydroxy-5-methyl-5-phenyl-hexylsulfanyl)-2-methyl2-phenyl-hexan-1-ol;
IIa-5 6-(6-Hydroxy-5-methyl-5-phenyl-hexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid;
IIa-6 6-(5-Carboxy-5-phenyl-hexylsulfanyl)-2-methyl-2-phenyl-hexanoic acid;
IIa-7 5-(5-Hydroxy-4-methyl-4-phenyl-pentylsulfanyl)-2-methyl-2-phenyl-pentan-1-ol;
IIa-8 5-(5-Hydroxy-4-methyl-4-phenyl-pentylsulfanyl)-2-methyl-2-phenyl-pentanoic acid;
IIa-9 5-(4-Carboxy-4-phenyl-pentylsulfanyl)-2-methyl-2-phenyl-pentanoic acid;
IIa-10 2-Methyl-7-(6-methyl-7-oxo-6-phenyl-heptylsulfanyl)-2-phenyl-heptanal;
IIa-11 7-(6-Methoxycarbonyl-6-phenyl-heptylsulfanyl)-2-methyl-2-phenyl-heptanoic acid methyl ester;
IIa-12 2-Methyl-7-(6-methyl-7-oxo-6,7-diphenyl-heptylsulfanyl)-1,2-diphenyl-heptan-1-one;
IIa-13 3-Methyl-8-(6-methyl-7-oxo-6,8-diphenyl-octylsulfanyl)-1,3-diphenyl-octan-2-one;
IIa-14 2-Phenyl-7-(6-phenyl-6-sulfo-heptylsulfanyl)-heptane-2sulfonic acid;
IIa-15 Phosphoric acid mono-[1-methyl-1-phenyl-6-(6-phenyl-6-phosphonooxy-heptylsulfanyl)-hexyl]ester;
IIa-16 8-(8-Hydroxy-6-methyl-6-phenyl-octylsulfanyl)-3-methyl-3-phenyl-octan-1-ol;
IIa-17 8-(8-Hydroxy-6-methyl-6-phenyl-octylsulfanyl)-3-methyl-3-phenyl-octanoic acid;
IIa-18 3,15-Dimethyl-9-oxo-3,15-diphenyl-heptadecanedioic acid;
IIa-19 7-(7-Hydroxy-5-methyl-5-phenyl-heptylsulfanyl)-3-methyl-3-phenyl-heptan-1-ol;
IIa-20 15-Hydroxy-3,13-dimethyl-8-oxo-3,13-diphenyl-pentadecanoic acid;
IIa-21 7-(6-Carboxy-5-methyl-5-phenyl-hexylsulfanyl)-3-methyl-3-phenyl-heptanoic acid;
IIa-22 6-(6-Hydroxy-4-methyl-4-phenyl-hexylsulfanyl)-3-methyl-3-phenyl-hexan-1-ol;
IIa-23 6-(6-Hydroxy-4-methyl-4-phenyl-hexylsulfanyl)-3-methyl-3-phenyl-hexanoic acid;
IIa-24 6-(5-Carboxy-4-methyl-4-phenyl-pentylsulfanyl)-3-methyl-3-phenyl-hexanoic acid;
IIa-25 6-(6-Hydroxy-4-methyl-4-phenyl-hexylsulfanyl)-3-methyl-3-phenyl-hexanoic acid
IIa-26 6-(5-Carboxy-4-methyl-4-phenyl-pentylsulfanyl)-3-methyl-3-phenyl-hexanoic acid;
IIa-27 9-(9-Hydroxy-6-methyl-6-phenyl-nonylsulfanyl)-4-methyl-4-phenyl-nonan-1-ol;
IIa-28 8-(9-Hydroxy-6-methyl-6-phenyl-nonylsulfanyl)-3-methyl-3-phenyl-octanoic acid;
IIa-29 9-(8-Carboxy-6-methyl-6-phenyl-octane-1-sulfanyl)-4-methyl-4-phenyl-nonanoic acid;
IIa-30 8-(8-Hydroxy-5-methyl-5-phenyl-octylsulfanyl)-4-methyl-4-phenyl-octan-1-ol;
IIa-31 8-(8-Hydroxy-5-methyl-5-phenyl-octane-1-sulfanyl)-4-methyl-4-phenyl-octanoic acid;
IIa-32 8-(7-Carboxy-5-methyl-5-phenyl-heptylsulfanyl)-4-methyl-4-phenyl-octanoic acid;
IIa-33 7-(7-Hydroxy-4-methyl-4-phenyl-heptylsulfanyl)-4-methyl-4-phenyl-heptan-1-ol;
IIa-34 7-(7-Hydroxy-4-methyl-4-phenyl-heptane-1-sulfanyl)-4-methyl-4-phenyl-heptanoic acid;
IIa-35 7-(6-Carboxy-4-methyl-4-phenyl-hexane-1-sulfanyl)-4-methyl-4-phenyl-heptanoic acid;
IIa-36 5-[1-Methyl-1-phenyl-5-(5-phenyl-5-{3,3a-dihydro-4,6-dioxo-2H-thieno[3,2-c]pyridin-5-yl}-hexane-1-sulfanyl)-pentyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dione;
IIa-37 5-[1-Methyl-1-phenyl-5-(5-phenyl-5-{3,3a-dihydro-4,6-dithioxo-2H-thieno[3,2-c]pyridin-5-yl}-hexane-1-sulfanyl)-pentyl]-3,3a-dihydro-2H-thieno[3,2-c]pyridine-4,6-dithione;
IIa-38 6-(5-Cyanocarbamoyl-5-phenyl-hexane-1-sulfanyl)-2-methyl-2-phenyl-hexanoic acid cyanimide;
IIa-39 Phosphoramidic acid mono-{5-[5-(amino-hydroxy-phosphoryloxy)-5-phenyl-hexylsulfanyl]-1-methyl-1-phenyl-pentyl}ester;
IIa-40 1-(5-[Amino-hydroxy-phosphoryloxy]-5-phenyl-hexane-1-sulfanyl)-5-[amino-hydroxy-phosphoryloxy]-5-phenyhexane;
IIa-41 1-[1-Methyl-1-phenyl-5-(5-phenyl-5-{tetrazol-1-yl}-hexane-1-sulfanyl)-pentyl]-1H-tetrazole;
IIa-42 5-[1-Methyl-1-phenyl-5-(5-phenyl-5-{tetrazol-5-yl}-hexane-1-sulfanyl)-pentyl]-1H-tetrazole;
IIa-43 5-[1-Methyl-1-phenyl-5-(5-{3-hydroxy-isoxazol-5-yl}-5-phenyl-hexane-1-sulfanyl)-pentyl]-isoxazol-3-ol;
IIa-44 4-[1-Methyl-1-phenyl-5-(5-{3-hydroxy-isoxazol-4-yl}-5-phenyl-hexane-1-sulfanyl)-pentyl]-isoxazol-3-ol;
IIa-45 2-[1-Methyl-1-phenyl-5-(5-{2-hydroxy-tetrahydro-pyranoxy}-5-phenyl-hexane-1-)-pentyloxy]-tetrahydro-pyran;
IIa-46 5-[1-Methyl-1-phenyl-5-(5-{2-oxo-dihydro-furan-5-yl}-5-phenyl-hexane-1-)-pentyl]-dihydro-furan-2-one;
IIa-47 4-[1-Methyl-1-phenyl-5-(5-{2-oxo-oxetan-4-yl}-5-phenyl-hexane-1-sulfanyl)-pentyl]-oxetan-2-one;
IIa-48 4-[1-Methyl-1-phenyl-5-(5-{2-oxo-dihydro-furan-4-yl}-5-phenyl-hexane-1-)-pentyl]-dihydro-furan-2-one;
IIa-49 3-[1-Methyl-1-phenyl-5-(5-{2-oxo-dihydro-furan-3-yl}-5-phenyl-hexane-1-)-pentyl]-dihydro-furan-2-one;
IIa-50 (2-{5-[5-(4-Carboxymethyl-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-5-phenyl-hexylsulfanyl]-1-methyl-1-phenyl-pentyl}-4-hydroxy-6-oxo-tetrahydro-pyran-4-yl)-acetic acid.

107 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/976,898Filed 11 Oct 2001 · us provisional application
Priority: 11 Oct 2000
Published: US 2002/0077316 A120 Jun 2002
Granted: 9 Mar 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07F 9/2408
The ester moiety containing a substituent or a structure which is considered as characteristic: of hydroxyalkyl compounds
A61K 31/194
Carboxylic acids, e.g. valproic acid: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings
A61K 31/382
Having sulfur as a ring hetero atom: having six-membered rings, e.g. thioxanthenes