Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity

• US 7,268,157 B2
• Filed: 11/18/2003
• Issued: 09/11/2007
• Est. Priority Date: 11/26/2002
• Status: Active Grant

• Current Assignee: Shenzhen ChipScreen Biosciences, Ltd.
• Original Assignee: Shenzhen ChipScreen Biosciences, Ltd., Shenzhen Tsinghua University Research Institute
• Inventors: Li, Zhibin, Liu, Zhende, Ning, Zhiqiang, Shan, Song, Liao, Chenzhong, Shi, Leming, Deng, Tuo, Ma, Baoshun, Lu, Xian-Ping
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/715,622
• Publication Number:
  US 20040142921A1
• Time in Patent Office: 1,393 Days
• Field of Search: 514/411, 548/444
• US Class Current: 514/411
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 209/86 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed is the preparation and pharmaceutical use of substituted arylalcanoic acid derivatives of Formula I, wherein ring A, ring B, R¹, R², R³, R⁴, R⁵, X, Alk¹, Alk², Ar¹, and Ar² are as defined in the specification. These compounds, as selective agonists activating peroxisome proliferator-activated receptors (PPAR), in particularly the RXR/PPARalpha, RXR/PPARgamma, and RXR/PPARdelta heterodimers, are useful in the treatment and/or prevention of type 2 diabetes and associated metabolic syndrome such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders with improved side effects profile commonly associated with conventional PPARgamma agonists.

Claims

1. An isolated compound of Formula I

2. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H or alkyl;

R² is H or alkyl;

R³ is H or alkyl;

R⁴ and R⁵ are independently H or alkyl;

Alk¹ is C_2-3alkylene;

Alk² is C_1-2alkylene;

Ar¹ is an arylene group; and

,

Ar² is a substituted aryl group.

3. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H or alkyl;

R² is H or alkyl;

R³ is H or alkyl;

R⁴ and R⁵ form a 6 membered aromatic ring;

Alk¹ is C_2-3alkylene;

Alk² is C_1-2alkylene;

Ar¹ is 6 membered aromatic ring; and

,

Ar² is a substituted aryl group.

4. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H;

R² is H;

R³ is H;

R⁴ is methyl;

R⁵ is H;

Alk¹ is CH₂CH₂;

Alk² is CH₂;

Ar¹ is benzene ring;

Ar² is a substituted benzene ring with one or more fluorine.

5. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H;

R² is H;

R³ is H;

R⁴ and R⁵ form a benzene ring;

Alk¹ is CH₂CH₂;

Alk² is CH₂;

Ar¹ is benzene ring;

Ar² is a substituted benzene ring with one or more fluorine.

6. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H;

R² is H;

R³ is H;

R⁴ is methyl;

R⁵ is H;

Alk¹ is CH₂CH₂;

Alk² is CH₂;

Ar¹ is benzene ring;

Ar² is pyridine ring substituted with none, one or more halogen.

7. A compound according to claim 1, wherein

ring A is a benzene ring;

ring B is a benzene ring;

X is a valence bond;

R¹ is H;

R² is H;

R³ is H;

R⁴ and R⁵ form a benzene ring;

Alk¹ is CH₂CH₂;

Alk² is CH₂;

Ar¹ is benzene ring;

Ar² is pyridine ring substituted with none, one or more fluorine.

10. A pharmaceutical composition comprising an effective amount of a

compound according to claim 1 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier or diluent.

11. The pharmaceutical composition according to claim 10 in unit dosage form, comprising from about 0.05 to about 200 mg of the compound.

12. The pharmaceutical composition according to claim 11 which is suitable for administration by an oral, nasal, transdermal, pulmonary, or parenteral route.

13. A method of treatment of type 2 diabetes comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

14. A method of treatment of at least one condition selected from the group consisting of type 1 diabetes, type 2 diabetes, dyslipidemia, syndrome X, cardiovascular disease, atherosclerosis, hypercholesteremia, and obesity, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

15. The method according to claim 14, wherein the effective amount of the compound is in the range of from about 0.05 to about 200 mg/kg body weight per day.

8. A process for the preparation of a compound of Formula I

9. A process according to claim 8 wherein:

(a) the condensation reaction is carried out in ethanol at reflux temperature;

(b) the O-alkylation is achieved by treatment of 3 with KOH and dibromoalkane in ethanol;

(c) the N-alkylation is achieved by treating compound 4 with NaOH and compound 5 in the presence of tetrabutyl ammonium bromide.