US 7,335,689 B2Granted

Dihydroxyl 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 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.

Claims31

Dependent claims

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 CH2, 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 (CH2)x, where x is 1-7, CH2CH═CHCH2, CH═CH, CH2-phenyl-CH2, or phenyl;
(c) W1 and W2 are independently L, V, C(R1)(R2)—(CH2)c—C(R3)(R4)—(CH2)n—Y or C(R1)(R2)—(CH2)c—V where c is 1 or 2 and n is an integer ranging from 0 to 7;
(d) each occurrence of R1 or R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or when one or both of W1 and W2 is C(R1)(R2)—(CH2)c—C(R3)(R4)—(CH2)n—Y, then R1 and R2 can both be H to form a methylene group;
or R1 and R2 and the carbon to which they are both attached are taken together to form a (C3-C7)cycloakyl group;
(e) R3 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxyl, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(f) R4 is OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxyl, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(g) L is C(R1)(R2)—(CH2)n—Y, wherein n is an integer from 1 to 5;
(h) V is:
(i) each occurrence of Y is independently (C1-C6)alkyl, OH, COOH, COOR5, SO3H,
wherein:
(i) R5 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;
(iii) each occurrence of R7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl;
and
(j) X is (CH2)z or Ph, wherein z is an integer from 0 to 4.

14 more elements

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 CH2, 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 (CH2)x, CH2CH═CHCH2, CH═CH, CH2-phenyl-CH2, or phenyl, where x is an integer ranging from 1 to 7;
(c) W1 and W2 are independently C(R8)(R9)—(CH2)n-Y, where n is an integer ranging from 0 to 7;
(d) each occurrence of R8 and R9 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or R8 and R9 can be taken together to form a carbonyl group;
(e) each occurrence of R1 and R2 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or R1 and R2 can be taken together to form a carbonyl group or R1 and R2 and the carbon to which they are both attached are taken together to form a (C3-C7)cycloakyl group;
(f) each occurrence of R6 and R7 is independently H, (C1-C6)alkyl, or R6 and R7 can be taken together to form a carbonyl group or R6 and R7 and the carbon to which they are both attached are taken together to form a (C3-C7)cycloakyl group;
(g) Y is (C1-C6)alkyl, OH, COOH, COOR3, 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 R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)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 (CH2)z or Ph, wherein z is an integer from 0 to 4.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/743,109Filed 23 Dec 2003 · us provisional application
Priority: 23 Jan 2003
Published: US 2004/0214887 A128 Oct 2004
Granted: 26 Feb 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification90 codes

C07C 31/27
Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms: polyhydroxylic alcohols containing saturated rings
A61K 31/191
Carboxylic acids, e.g. valproic acid: having two or more hydroxy groups, e.g. gluconic acid
A61K 31/194
Carboxylic acids, e.g. valproic acid: having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
A61K 31/20
Carboxylic acids, e.g. valproic acid: having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids