ARYLCYCLOAKYL-SUBSTITUTED ALKANOIC ACID DERIVATIVES USEFUL AS PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) LIGANDS FOR THE TREATMENT OF HYPERLIPIDEMIA AND DIABETES

• US 20070197605A1
• Filed: 02/07/2007
• Published: 08/23/2007
• Est. Priority Date: 08/14/2004
• Status: Active Grant

• Current Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Original Assignee: Sanofi-Aventis Deutschland GmbH (Sanofi )
• Inventors: Wendler, Wolfgang, Glombik, Heiner, Keil, Stefanie, Stapper, Christian, Falk, Eugen, Schaefer, Hans-Ludwig, Knieps, Stephanie
• Granted Patent: US 7,598,281 B2
• Time in Patent Office: Days
• US Class Current: 514/340
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

The present invention comprises compounds and compositions for the treatment of metabolic disorders and more particularly, those insulin-related metabolic disorders of the blood such as hyperlipidemia, diabetes, insulin-resistence and the like comprising acetic acid derivatives with arylcycloalkyl-substituted alkanoic acid derivatives and their salts. Known as peroxisome proliferator-activated receptors (PPAR) agonists/antagonists, the invention relates to compounds of the formula I wherein the various substituent R-groups are more specifically defined herein.

Claims

1. A compound of formula I

2. A compound of formula I as recited in claim 1 wherein:

Ring A is a (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, wherein one or more of the carbon atoms within the cycloalkanediyl or cycloalkenediyl rings may be optionally be replaced by oxygen atoms; and

X is (C1-C6)-alkanediyl, wherein an oxygen atom may optionally replace the C1 or C2 carbon atom (with respect to Ring A).

3. A compound of formula I as recited in claim 2 wherein:

R1 is a (C1-C4)-alkyl or O—

(C1-C4)-alkyl;

R2 is H;

R3 is (C1-C4)-alkyl;

W is CH, if o=1;

X is CH₂—

O—

CH₂;

n is 1;

R4 is H or F;

R5 is H or F;

R6 is H or F;

R5 and R6 including the carbon atom to which they are attached comprise a —

C3-C8)-cycloalkane-1,2-diyl;

R7 is selected from the group consisting of H, F, (C1-C6)-alkyl, phenyl and NH—

C(O)—

O—

CH2Ph;

R8 is H; and

R12 is H or benzyl.

4. A pharmaceutical composition comprising one or more of the compounds recited in claim 2.

5. The pharmaceutical composition of claim 4 in combination with one or more additional secondary active ingredients which is therapeutically effective when administered to a patient with metabolic disorders or diseases associated therewith.

6. The pharmaceutical composition of claim 4 in combination with one or more additional secondary active ingredients selected from the group consisting of anti-diabetic agents which is therapeutically effective when administered to a patient with diabetes, hyperglycemia and related metabolic disturbances or disorders associated therewith.

7. The pharmaceutical composition of claim 4 in combination with one or more additional secondary active ingredients selected from the group consisting of lipid modulators which is therapeutically effective when administered to a patient with diabetes, hyperglycemia and related metabolic disturbances or disorders associated therewith.

8. A method for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders comprising the administration of one or more of the compounds of claim 4 to a patient in need thereof.

9. A method for the treatment and/or prevention of insulin resistance-related disorders and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 to a patient in need thereof.

10. A method for the treatment and/or prevention of diabetes mellitus and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 to a patient in need thereof.

11. A method for the treatment and/or prevention of of dyslipidemias and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 to a patient in need thereof.

12. A method for the treatment and/or prevention of conditions associated with the metabolic syndrome and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 to a patient in need thereof.

13. A method for the treatment and/or prevention of conditions associated with disorders of fatty acid metabolism and/or glucose utilization and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 in combination with at least one additional secondary active ingredient to a patient in need thereof.

14. A method for the treatment and/or prevention of conditions associated with disorders in which insulin resistance is involved and the disease states or injury manifestations associated therewith comprising the administration of one or more of the compounds of claim 4 in combination with at least one additional secondary active ingredient to a patient in need thereof.

15. A process for producing a pharmaceutical composition comprising one or more of the compounds as recited in claim 4, which comprises mixing the active ingredient with a pharmaceutically suitable carrier, and converting this mixture into a form suitable for administration.

16. A pharmaceutical composition for the treatment of metabolic-related disorders and the disease states or injury manifestations associated therewith comprising one or more compounds of formula I

17. A pharmaceutical composition for the treatment of metabolic-related disorders and the disease states or injury manifestations associated therewith comprising one or more compounds as recited in claim 16 wherein:

Ring A is a (C3-C8)-cycloalkanediyl or (C3-C8)-cycloalkenediyl, wherein one or more of the carbon atoms within the cycloalkanediyl or cycloalkenediyl rings may be optionally be replaced by oxygen atoms; and

X is (C1-C6)-alkanediyl, wherein an oxygen atom may optionally replace the C1 or C2 carbon atom (with respect to Ring A).

18. A pharmaceutical composition for the treatment of metabolic-related disorders selected from the group consisting of diabetes, hyperglycemia, fatty acid metabolism, glucose utilization disorders, insulin resistance-related disorders and the disease states or injury manifestations associated therewith comprising one or more compounds as recited in claim 16 in a pharmaceutically acceptable carrier.