Substituted 1,3-dioxanes useful as ppar modulators
AssigneeEvolva SA
InventorAlexandra Santana Sorensen
Life of this patent
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Abstract
Specifically useful stereoisomers of 1,3-dioxane derivatives are described and their use in the treatment of a disease or condition dependent on PPAR modulation, such as diabetes, cancer, inflammation, neurodegenerative disorders and infections as well as their use in the treatment of a disease related to TP, such as cardiovascular diseases.
Claims59
A compound of formula X
- wherein
- A is a branched or linear carbon chain of 3 to 7 carbons, optionally containing 1 or 2 double bonds;
- and
- W is COOH, C(O)NH—OH, NH2, SO3H, OSO3H, an aromatic group (optionally substituted with COOH, OH or NH2) or —C(O)-Rd,
- wherein Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear) or a saccharide;
- and
- Ar is a phenyl, or a 5 or 6 membered heterocyclic aromatic group optionally substituted with O—Rc,
- wherein Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- and
- Rb is 2-6C alkenyl, 1-8C alkyl optionally substituted with up to three halogeno substituents, saccharide, pentafluorophenyl, aryl or aryl(1-4C)alkyl, the latter two of which may optionally have up to five substituents selected from halogeno, (1-6C)alkyl, branched or linear (1-6C)alkoxy, (1-4C)alkylenedioxy, trifluoromethyl, cyano, nitro, hydroxyl, (2-6C)alkanoyloxy, (1-6C)alkylthio, (1-6C)alkanesulphonyl, (1-6C)alkanoylamino and oxapolymethylene of 2 to 4 carbon atoms.
A compound of formula XI:
- wherein
- X is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl and —H;
- and
- Y is selected from the group consisting of fluoro, chloro, bromo, trifluoromethyl, substituted phenyl, cyano, methoxy, nitro, hydroxyl, —C(O)-saccharide and —H;
- and
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), a saccharide or —OH.
A compound of formula XIII:
- wherein X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
- and
- Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- and
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), glycosyl or —OH.
25-39. (canceled)
A method of treating or preventing a clinical condition that is a PPAR-mediated disease or condition in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of the compound of formula XIII:
- wherein X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
- and
- Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- and
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), glycosyl or —OH.
42-49. (canceled)
A method of treating or preventing a clinical condition associated with TP in an individual in need thereof, said method comprising a therapeutically effective amount of a compound of formula XIII:
- wherein X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
- and
- Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- and
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), glycosyl or —OH.
52-56. (canceled)
A crystalline compound of formula XIV:
- wherein X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
- and
- Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), glycosyl or —OH;
- and
- Z+ is a counterion.
A crystalline solvate comprising a compound of formula XIV:
- wherein X is selected from fluoro, chloro, bromo, trifluoromethyl, optionally substituted phenyl, cyano, methoxy and nitro;
- and
- Rc is C1-6-alkyl (branched or linear, preferably linear), —C(O)—C1-6-alkyl (branched or linear, preferably linear), —CH(O), a saccharide or —H;
- Rd is —NH—C1-6-alkyl (branched or linear, preferably linear), —O—C1-6-alkyl (branched or linear, preferably linear), glycosyl or —OH;
- Z+ is a tert-butyl amine;
- and
- a solvent selected from group consisting of tert-butyl methyl ether, isopropyl alcohol, nitromethane, and combinations thereof.
The crystalline solvate of claim 64 wherein the solvent is isopropyl alcohol.
The method of 40, wherein said clinical condition is a cardiovascular disorder resistant to clopidogrel and/or asprin.
The method of 40, wherein said clinical condition is a nephrotic syndrome.
The method of 69, wherein said nephrotic syndrome is diabetic nephropathy.
A compound of the structure:
- or a salt hydrate or solvate thereof.
A crystalline compound of the structure:
Dependencies are inferred from the claim text.