4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs

An alkyl and phenyl technology, applied in the field of 4-((phenoxyalkyl)thio)-phenoxyacetic acid and its analogs, can solve problems such as low efficacy and elevated HDL-C

Active Publication Date: 2006-12-20
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current therapies for hypercholesterolemia include statins, which lower LDL-C but have little effect on HDL-C

Method used

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  • 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
  • 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
  • 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs

Examples

Experimental program
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preparation example Construction

[0196] If mixtures of stereoisomers are obtained during the preparation of the compounds of the present invention, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, either by enantiospecific synthesis or by resolution of the individual enantiomers. Said compounds may be resolved into their individual component enantiomers by standard techniques such as salt formation to form diastereomers. The compounds can also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

[0197] Examples of such synthetic routes include Examples 1-9. Compounds similar to the target compounds of these Examples can be prepared by similar routes. The disclosed compounds are useful in basic research and as pharmaceutical formulations as described in the fol...

Embodiment A

[0232]

[0233] Compound 1

[0234] {2-Methyl-4-[2-methyl-3-(4-trifluoromethyl-phenoxy)-propylthio]-phenoxy}-acetic acid

[0235] Process A1

[0236]

[0237] To a flask containing chlorosulfonic acid (15.0 ml, 226 mmol) was slowly added ethyl (2-methylphenoxy)acetate A1a (10.0 g, 51.6 mmol) at 4°C according to Scheme A1. The mixture was stirred at 4°C for 30 minutes and at room temperature for 2 hours, then poured into ice water. The precipitated white solid was filtered, washed with water, and dried in vacuo overnight to afford 14.0 g (93%, white solid) of A1b;

[0238] 1H NMR (300MHz, CDCl 3 )δ7.87-7.84(m, 2H), 6.80(d, J=9.5Hz, 1H), 4.76(s, 2H), 4.29(q, J=7.1Hz, 2H), 2.37(s, 3H), 1.31(t, J=7.1Hz, 3H); MS(ES) m / z: 315(M+Na+).

[0239] To a solution of Alb (4.70 g, 16.1 mmol) in EtOH (20 ml) was added 4.0 M HCl in dioxane (20 ml), and then 100 mesh tin powder (9.80 g, 82.6 mmol) was added in portions. The mixture w...

Embodiment B

[0255]

[0256] Compound 2

[0257] {2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-butylthio]-phenoxy}-acetic acid

[0258] Process B

[0259]

[0260] To a solution of (S)-(+)-2-phenylbutyric acid B1 (352mg, 2.14mmol) in THF (3ml) at 0°C, 1.0M BH 3 • THF complex in THF (2.14ml, 2.14mmol). The mixture was allowed to warm to room temperature, stirred at room temperature overnight, quenched with water, then with 1.0N HCl, and washed with Et 2 O extraction (3 times). The extract was dried, concentrated and subjected to column chromatography to obtain 283 mg (88%) of B2;

[0261] 1H NMR (300MHz, CDCl 3 )δ7.34-7.29 (m, 2H), 7.24-7.16 (m, 3H), 3.70 (m, 2H), 2.65 (m, 1H), 1.79-1.67 (m, 1H), 1.63-1.48 (m, 2H), 0.82 (t, J=7.4Hz, 3H); MS (ES) m / z: 173 (M+Na+).

[0262] Add B2 (283mg, 1.88mmol), pyridine (0.76ml, 9.4mmol) and DMAP (23mg, 0.19mmol) in CH2Cl at 0°C 2 (3ml), acetyl chloride (369mg, 4.70mmol) was added. The mix...

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Abstract

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR delta modulators to treat or inhibit the progression of, for example, dyslipidemia.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 60 / 504,146, filed September 19, 2003, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Funded Research or Development [0004] Research and development of the inventions described below have not received federal funding. Background of the invention [0005] Cardiovascular disease (CVD) is prevalent throughout the world, often in association with other disease states such as diabetes and obesity. Large population studies have attempted to identify risk factors for CVD; among these, high plasma levels of low-density lipoprotein cholesterol (LDL-C), high plasma levels of triglycerides (>200 mg / dl), and high-density lipoprotein cholesterol Low levels of protein cholesterol (HDL-C) is the most important factor. Currently, there are few treatments for l...

Claims

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Application Information

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IPC IPC(8): C07C323/20C07C323/62C07D333/28A61K31/192A61K31/277A61K31/381A61P3/06A61P3/10C07C59/68C07C59/70C07C317/22C07C323/22C07C323/60C07D333/16
CPCC07C323/62C07C323/60C07D333/28C07C59/68C07C323/20C07D333/16C07C317/22C07C59/70A61K31/277A61K31/192A61P3/00A61P3/04A61P3/06A61P43/00A61P7/00A61P9/00A61P9/10A61P9/12A61P3/10A61K31/10C07C59/58C07C323/19
Inventor G·-H·郭R·张A·王A·R·迪安吉利斯
Owner JANSSEN PHARMA NV
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