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Peroxisome proliferator activated receptor modulators

A technology of compounds and intermediates, applied in the field of peroxide proliferator-activated receptor modulators, can solve the problems of drug treatment failure, adverse drug reactions, etc.

Inactive Publication Date: 2009-12-30
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Administration of the drug concomitantly with other drugs, or even in combination with plant extracts such as Hypericum perforatum or grapefruit juice has the potential to result in ineffective drug therapy or adverse drug reactions

Method used

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  • Peroxisome proliferator activated receptor modulators
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  • Peroxisome proliferator activated receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0079] Preparation via Alcohol Intermediate Route A

[0080] preparation 1

[0081] 2-Benzyloxy-N-isopropyl-acetamide

[0082]

[0083] To a solution of isopropylamine (10.7 mL, 125 mmol) in dichloromethane was added benzyloxyacetyl chloride (7.8 mL, 50 mmol) at 0°C. After stirring overnight at room temperature, it was concentrated and partitioned between ethyl acetate and 1N HCl. Dry the organic phase (Na 2 SO 4 ) and concentrated to give a white solid: 10.4 g. 1 H-NMR (CDCl 3 )δ7.36(m, 5H), 6.38(bs, 1H), 4.56(s, 2H), 4.11(m, 1H), 3.95(s, 2H), 1.73(d, 6H).

[0084] preparation 2

[0085] 2-Benzyloxy-N-isopropyl-thioacetamide

[0086]

[0087] Add Lawesson's reagent (12.1 g, 30 mmol) to a toluene (100 mL) suspension containing 2-benzyloxy-N-isopropyl-acetamide (10.4 g, 50 mmol), and stir under reflux The mixture was left overnight. evaporated to dryness in Et 2 The residue was suspended in O / hexane and filtered. The filtrate was concentrated and purifie...

Embodiment 1

[0134] 2-{4-[4-isopropyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4]triazole- 3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid

[0135]

[0136] To room temperature containing 2-{4-[4-isopropyl-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4 ]triazol-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (588mg, 1.12mmol) in dioxane (3ml) was added lithium hydroxide ( 1.69ml, 3.36mmol, 2.0M in water) and heated to 50°C overnight. The mixture was concentrated and in Et 2 Partition the residue between O and 1N HCl, wash the organic phase with water, dry (MgSO 4 ), filtered and concentrated to give the desired product 539mg. LC-MS: 494 (M+1).

[0137] Synthetic Method 2 (Scheme 2)

[0138] Formation of an ester-protected intermediate, N 4 deprotection of the position, followed by alkylation and base hydrolysis

[0139] Preparation 13

[0140]2-methyl-2-{2-methyl-4-[5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1,2,4 ]...

Embodiment 2

[0148] 2-{4-[4-(2-methoxy-ethyl)-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H-[1, 2,4]triazol-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid

[0149]

[0150] At room temperature, 2-{4-[4-(2-methoxy-ethyl)-5-oxo-1-(4-trifluoromethyl-phenyl)-4,5-dihydro-1H -[1,2,4]triazol-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (479 mg, 0.889 mmol) was dissolved in 30 mL of THF and 1:1 mixture of ethanol. Add 2.2 mL of potassium hydroxide 2N aqueous solution, and stir at room temperature for 18 hours. Concentrate in vacuo and acidify to pH4. Dilute with ethyl acetate and separate the phases. The aqueous layer was extracted twice with ethyl acetate. The organics were combined and washed successively with brine and water, dried over magnesium sulfate, filtered and the solvent was evaporated to give 417 mg of the title compound. ES-MS: 510 (M+1).

[0151] In Table 1, each example was prepared essentially as described in Example 1 by preparing an al...

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Abstract

The present invention is directed to compounds of the structural Formula: wherein: R<1> is -H or -C1-C3 alkyl; R<2> is selected from the group consisting of -H, -C1-C4 alkyl, -C1-C3 alkyl-CF3, phenyl, and pyridinyl; and R<3> is selected from the group consisting of -H, -C1-C4 alkyl, -C1-C3 alkyl-O-CH3, -CH2-cyclopropyl, -CH2-C=CH2, -CH2CH2-(2-F-phenyl), and phenyl substituted with from 1 to 2 fluorines; provided that when R<1> and R<2> are each H, then R<3> is selected from the group consisting of -C1-C4 alkyl, -C1-C3 alkyl-O-CH3, -CH2-cyclopropyl, -CH2-C=CH2, -CH2CH2-(2-F-phenyl), and phenyl substituted with from 1 to 2 fluorines; or stereoisomers and pharmaceutically acceptable salts thereof.

Description

[0001] cross reference [0002] This application claims the benefit of US Provisional Application No. 60 / 891,261, filed February 23, 2007. Background of the invention [0003] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, which are ligand-activated transcription factors that regulate gene expression. Various subtypes of PPARs have been discovered and are said to be targets for the development of novel therapeutic drugs. PPAR receptors include PPARα, PPARγ, and PPARδ. PPARα receptors and PPARδ receptors are involved in diabetes, cardiovascular disease, obesity and inflammation. Compounds that modulate PPAR alpha receptors and PPAR delta receptors are believed to be particularly useful in cardiovascular diseases such as hyperlipidemia, hypertriglyceridemia and atherosclerosis. PPAR[alpha] is the target of marketed hyperlipidemic fibrate drugs that are said to cause significant reductions in plasma triglycerides a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12C07D401/06A61P3/00A61K31/4196A61K31/4439
CPCC07D401/06C07D249/12A61P29/00A61P3/00A61P3/10A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61K31/4196
Inventor L·A·普菲菲尔T·马N·B·曼特洛L·F·麦克尔F·M·莫库贝C·蒙特罗斯-拉菲扎德
Owner ELI LILLY & CO
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