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Indene derivatives and process for the preparation thereof

一种茚衍生物、化合物的技术，应用在新型茚衍生物领域，能够解决体重增加等问题

Inactive Publication Date: 2007-04-04
KOREA RES INST OF CHEM TECH +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, this full agonist of PPARγ has also been known to cause adverse side effects, which include weight gain, cardiac hypertrophy, edema, and liver damage due to promotion of differentiation of adipocytes

Method used

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  • Indene derivatives and process for the preparation thereof
  • Indene derivatives and process for the preparation thereof
  • Indene derivatives and process for the preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] Embodiment 1: Preparation 1-(trans-methylimino-N-oxygen)-3-phenyl-6-(3-phenylpropoxy)-1H-indene-2-carboxylic acid ethyl ester (table 1 Compound No. 9)

[0215] (step 1) prepare 3-hydroxybenzyl chloride (formula (VI))

[0216] 3-Hydroxybenzyl alcohol (5g, 40mmol) and triethylamine (5.2ml, 60mmol) were dissolved in benzene (250ml), and thionyl chloride (5.2ml) dissolved in benzene (50ml) was added thereto at 0°C . The brownish reaction solution was stirred at room temperature for 6 hours. When the reaction was complete, the solution was washed with brine, and the aqueous layer was extracted with dichloromethane. The organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (5.7 g, 99%).

[0217] 1 H NMR (CDCl 3 , 200MHz) δ7.22(t, J=7.7Hz, 1H), 6.96-6.78(m, 3H), 5.73(s, 1H), 4.52(s, 2H)

[0218] (Step 2) Preparation of ethyl 2-(3-hydroxybenzyl)-3-oxo-3-phenylpropionate (formula VII)

[0219] Ethy...

Embodiment 2

[0240] Example 2: Preparation of 1-(trans-methylimino-N-oxygen)-6-(2-morpholin-4-ylethoxy)-3-phenyl-1H-indene-2-carboxylic acid Ethyl ester (Compound No. 33 of Table 1)

[0241] (Step 1) Preparation of ethyl 3-phenyl-6-(2-morpholin-4-ylethoxy)-1-oxo-1H-indene-2-carboxylate [compound of formula (II)] (reaction Diagram (VII))

[0242] 6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester [compound of formula (II)] (10.90 g, 26.75 mmol) prepared in step 4 of Example 1 was dissolved in Tetrahydrofuran: benzene (270ml: 90ml). Subsequently, 4-(2-hydroxyethyl)morpholine (5.83 g, 44.45 mmol) and triphenylphosphine (11.66 g, 44.45 mmol) were added thereto. Diisopropyl azodicarboxylate (8.99 g, 44.45 mmol) was added dropwise to the mixture at 0°C, and stirred at room temperature for 2 hours. The reaction mixture was washed with saturated sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the r...

Embodiment 3

[0246] Example 3: Preparation of ethyl 1-(trans-methylimino-N-oxygen)-5,6-methylenedioxy-1-oxo-3-phenyl-1H-indene-2-carboxylate (Compound No. 48 in Table 1)

[0247] (Step 1) Preparation of 5-chloromethylbenzo[1,3]dioxole [compound of chemical formula (VI)]

[0248] Piperonyl alcohol (10 g, 65.7 mmol) was dissolved in benzene. Triethylamine (11 ml, 78.8 mmol) and thionyl chloride (11 ml, 131.4 mmol) were added dropwise thereto and stirred at 0° C. for 24 hours. The reaction mixture was extracted with sodium bicarbonate and ethyl acetate, and the organic layer was separated and dried over anhydrous magnesium sulfate to obtain 5-chloromethylbenzo[1,3]dioxole (11.2 g, yield 100 %).

[0249] 1 H NMR (200MHz, CDCl 3 ): δ6.88-6.75(m, 3H), 5.97(s, 2H), 4.53(s, 2H).

[0250] (Step 2) Preparation of ethyl 2-benzo[1,3]dioxol-5-ylmethyl-3-oxo-3-phenylpropanoate [compound of formula (VII)]

[0251] 5-Chloromethylbenzo[1,3]dioxole (11.2 g, 65.7 mmol) was dissolved in dimethylformami...

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Abstract

The inventive indene derivatives of formula (I) are capable of selectively modulating the activities of peroxisome proliferator activated receptors (PPARs), causing no adverse side effects, and thus, they are useful for the treatment and prevention of disorders modulated by PPARs, i.e., metabolic syndromes such as diabetes, obesity, arteriosclerosis, hyperlipidemia, hyperinsulinism and hypertension, inflammatory diseases such as osteoporosis, liver cirrhosis and asthma, and cancer.

Description

technical field [0001] The present invention relates to a novel indene derivative, which can be used as a modulator of peroxisome proliferator-activated receptor (PPAR), a preparation method thereof, and a pharmaceutical composition containing the indene derivative as an active ingredient. Background technique [0002] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and function as transcription factors in the form of heterodimers with retinoid X receptors (RXR) to regulate gene expression . PPARs are divided into three subtypes, "PPARα", "PPARγ" and "PPARδ", and are generally involved in maintaining energy homeostasis in vertebrates by controlling the metabolism of fat and glucose. [0003] Therefore, there have been some attempts to develop PPARα and PPARγ full agonists for the treatment and prevention of diseases mediated by PPARs, for example, metabolic syndromes such as diabetes, o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C251/44C07C291/02C07C309/66C07D213/30C07D213/53C07D233/54C07D277/24C07D295/092C07D295/185C07D307/54C07D317/60C07D317/70C07D333/24C07D333/28C07D417/12
CPCC07D213/30C07C291/02C07C309/66C07C2101/02C07C2101/14C07C2102/08C07C2103/74C07D213/53C07D233/64C07D277/24C07D295/088C07D295/185C07D307/54C07D317/60C07D317/70C07D333/24C07D333/28C07D417/12A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/10A61P9/12A61P11/06A61P19/10A61P29/00A61P35/00A61P43/00C07C2601/02C07C2601/14C07C2602/08C07C2603/74A61K31/15A61K31/41A61K31/535C07C251/44
Inventor 千惠庆柳圣殷金性洙梁承敦金侊禄李相达安镇熙姜升圭郑元勋朴盛大金南基李章赫许善哲李在睦宋硕范权顺智金钟勋李定炯金承俊
Owner KOREA RES INST OF CHEM TECH
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