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Carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient

a technology of carboxylic acid and active ingredient, which is applied in the direction of application, extracellular fluid disorder, metabolic disorder, etc., and can solve the problem that the direct impact of s1p on intracellular substances has never been identified

Inactive Publication Date: 2007-04-19
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a new compound, carboxylic acid derivative represented by formula (I), which has superior agonistic action for EDG-1 and is very safe. This compound has never been prepared before and is a new member of the carboxylic acid derivative family. The invention also includes prodrugs and non-toxic salts of this compound. The technical effects of this invention include improved safety and more effective treatment for EDG-1 related disorders.

Problems solved by technology

However, intracellular substance affected directly by S1P has never identified.

Method used

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  • Carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient
  • Carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient
  • Carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

methyl 3-[4-(5-phenylpentyloxy)phenyl]propanoate

[0231]

[0232] To a mixture of 5-phenylpentanol (3.7 mL), methyl 3-(4-hydroxyphenyl)propanoate (3.6g), triphenylphosphine (5.77 g) and dichloromethane (200 mL) was added 1,1′-(azodicarbonyl)dipiperidine (5.55 g). The reaction mixture was stirred at room temperature for 4 days. Diethyl ether was added to the reaction mixture, which was filtered and the filtrate was concentrated. Hexane-diethyl ether (1:1) (200 mL) was added to the residue, which was filtered and the filtrate was concentrated. The obtained residue was purified by column chromatography on silica gel (hexane: ethyl acetate=9:1→4:1) to give the title compound (6.16 g) having the following physical data.

[0233] TLC: Rf 0.46 (hexane: ethyl acetate=9:1);

[0234] NMR (CDCl3): δ7.32-7.06 (m, 7H), 6.84-6.77 (m, 2H), 3.92 (t, J=6.6 Hz, 2H), 3.66 (s, 3H), 2.89 (t, J=7.6 Hz, 2H), 2.68-2.55 (m, 4H), 1.87-1.41 (m, 6H).

reference example 2

3-[4-(5-phenylpentyloxy)phenyl]propanoic acid

[0235]

[0236] To a solution of the compound prepared in Reference Example 1 (12 g) in methanol (60 mL) and tetrahydrofuran (80 mL) was added 2N aqueous sodium hydroxide solution (40 mL). The reaction mixture was refluxed for 4 hours. On ice bath, 1N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give the title compound (11.32 g) having the following physical data.

[0237] TLC: Rf 0.40 (chloroform: methanol=9:1);

[0238] NMR (CDCl3): δ7.31-7.09 (m, 7H), 6.85-6.78 (m, 2H), 3.92 (t, J=6.6 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 4H), 1.87-1.42 (m, 6H).

reference example 3

3-[4-(5-phenylpentyloxy)phenyl]propanoyl chloride

[0239]

[0240] To a solution of the compound prepared in Reference Example 2 (151 mg) in dichloromethane (1 mL) was poured a drop of dimethylformamide. Further, to the mixture was added oxalyl chloride (0.13 mL) on ice bath. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (167 mg).

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Abstract

Compounds represented by formula (I), prodrugs thereof and salts thereof, and pharmaceutical compositions comprising the same as an active ingredient (wherein each symbol has the meaning as defined in the specification.). Because of having an EDG-1 agonism, the compounds represented by formula (I) are useful in preventing and / or treating peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy, sepsis, angiitis, nephritis, pneumonia, stroke, myocardial infarction, edematous state, atherosclerosis, varicosity such as hemorrhoid, anal fissure or fistula ani, dissecting aneurysm of the aorta, angina, DIC, pleuritis, congestive heart failure, multiple organ failure, bedsore, burn, chronic ulcerative colitis, Crohn's disease, heart transplantation, renal transplantation, dermal graft, liver transplantation, osteoporosis, pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure, or glomerular sclerosis.

Description

TECHNICAL FIELD [0001] The present invention relates to carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient. More specifically, the present invention relates to (1) carboxylic acid derivatives represented by formula (I) prodrugs thereof, non-toxic salts thereof, (2) the process for preparation thereof, and (3) EDG-1 agonist comprising carboxylic acid derivatives represented by above formula (I), prodrugs thereof and non-toxic salts thereof as an active ingredient. BACKGROUND ART [0002] In recent years, it is known that various lipid mediators such as eicosanoid, platelet activating factor (PAF) and lysophosphatidic acid (LPA) are produced by the activity of phospholipase from cell membranes. Moreover, sphingosine 1-phosphate (hereinafter abbreviated as S1P) is a lipid which is produced by metabolic turnover of sphingolipid, acts as a mediator for signal transduction and delivers various signals into cells. Firstly, it was reporte...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/54A61K31/5377A61K31/495A61K31/445A61K31/44A61K31/426A61K31/166A61K31/167A61K31/192A61K31/194A61K31/196A61K31/216A61K31/343A61K31/381A61K31/402A61K31/4184A61K31/4402A61K31/4409A61K31/5375A61P1/00A61P1/04A61P1/16A61P9/00A61P9/10A61P9/14A61P11/00A61P13/12A61P17/00A61P17/02A61P19/10A61P27/02A61P29/00A61P31/04A61P43/00C07C59/68C07C229/14C07C229/60C07C229/62C07C233/17C07C233/51C07C233/73C07C235/34C07C235/38C07C235/66C07C237/20C07C237/30C07C237/32C07C237/42C07C311/17C07C323/62C07C323/63C07D213/30C07D213/40C07D213/79C07D213/80C07D213/82C07D235/12C07D295/155C07D307/60C07D333/16
CPCA61K31/166A61K31/167A61K31/192A61K31/194A61K31/196A61K31/216A61K31/343A61K31/381A61K31/402A61K31/4184A61K31/44A61K31/4402A61K31/4409A61K31/5375C07C59/68C07C229/14C07C229/60C07C229/62C07C233/17C07C233/51C07C233/73C07C235/34C07C235/38C07C235/66C07C237/20C07C237/30C07C237/32C07C237/42C07C311/17C07C323/62C07C323/63C07D213/30C07D213/40C07D213/79C07D213/80C07D213/82C07D235/12C07D295/155C07D307/60C07D333/16A61P1/00A61P1/04A61P1/16A61P11/00A61P13/12A61P17/00A61P17/02A61P19/00A61P19/08A61P19/10A61P27/02A61P29/00A61P3/10A61P31/04A61P43/00A61P7/02A61P7/10A61P9/00A61P9/04A61P9/10A61P9/14
Inventor SEKO, TAKUYATERAKADO, MASAHIKOKOHNO, HIROSHITAKAHASHI, SHINYA
Owner ONO PHARMA CO LTD
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