US 7,304,093 B2Granted

Ketone compounds and compositions for cholesterol management and related uses

AssigneeEsperion Therapeutics, Inc.

InventorsJean-Louis Dasseux, Daniela Carmen Oniciu

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Abstract

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.

Claims25

Dependent claims

A compound of the formula Ia:

or a pharmaceutically acceptable salt or a mixture thereof, wherein
(a) each occurrence of Z is CH2, wherein each occurrence of m is independently an integer ranging from 1 to 9;
(b) G is (CH2)x, where x is 2, 3, or 4;
(c) W1 and W2 are independently L;
(d) each occurrence of R1 and R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl
(e) L is C(R1)(R2)—(CH2)n—Y, where n is an independent integer ranging from 0 to 4;
(f) each occurrence of Y is independently OH, COOH, CHO, (CH2)nCOOR3, SO3H,
where
(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 R6 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;
and
(iii) each occurrence of R7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl;
and
provided that:
(i) if x is 4, each occurrence of Z is CH2, each occurrence of m is 4, and W1 is —CH(CH3)CO2H, then W2 is not the same as W1;
(ii) if x is 4, each occurrence of Z is CH2, each occurrence of m is 2, and W1 is —C(phenyl)2CH2CO2H, then W2 is not the same as W1.

13 more elements

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.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/743,952Filed 24 Dec 2003 · continuation in part
Priority: 11 Oct 2000
Published: US 2004/0198814 A17 Oct 2004
Granted: 4 Dec 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07C 49/17
Saturated compounds containing keto groups bound to acyclic carbon atoms: containing hydroxy groups
C07C 49/185
Saturated compounds containing keto groups bound to acyclic carbon atoms: containing —CHO groups
C07C 49/215
Containing six-membered aromatic rings: polycyclic
C07C 49/245
Containing hydroxy groups: containing six-membered aromatic rings

Family

Application60/239,232Us provisional application · filed 11 Oct 2000
Application09/976,938Parent of this continuation-in-part · filed 11 Oct 2001
US 2004/0198814 A1Pre-grant publication · published 7 Oct 2004
US 2007/0149615 A9Pre-grant publication · published 28 Jun 2007
US 6,699,910 B2Parent of this continuation-in-part
US 2003/0078239 A1Published application
US 7,304,093 B2This patent

From the US filing history. Foreign family members aren’t listed.