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Pexoxisome proliferator activated receptor alpha agonists

一种化合物、溶剂化物的技术，应用在过氧化物酶体增殖子激活受体α激动剂领域，能够解决不能降低甘油三酯和LDL-胆固醇水平、体重增加、增加HDL-胆固醇水平等问题

Inactive Publication Date: 2004-03-03
ELI LILLY & CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TZDs and ISEs are generally ineffective in preventing the cardiovascular manifestations of Syndrome X because their administration fails to lower triglyceride and LDL-cholesterol levels while increasing HDL-cholesterol levels
In addition, side effects commonly associated with TZD treatment include severe weight gain and—in the case of troglitazone—hepatotoxicity

Method used

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  • Pexoxisome proliferator activated receptor alpha agonists
  • Pexoxisome proliferator activated receptor alpha agonists
  • Pexoxisome proliferator activated receptor alpha agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] Compound 1(1)

[0222] Compound 1 shown below was prepared according to the following steps: Step A: Preparation:

[0223] To a suspension of 4-(4-hydroxyphenyl)butanylhydrazide (0.5 g, 2.58 mmol) in isopropanol (5 mL) was added 3-chlorobenzaldehyde (Aldrich, 420 mg, 3 mmol) followed by p-toluene Sulfonic acid (25 mg). The reaction was stirred at room temperature for 20 hours. A solid precipitated out which was filtered, washed with isopropanol (0.25 mL) and dried to give the product as a solid. MS: m / z (M + +1): 317

[0224] R

MS: m / z (M + +1)

3-Methylphenyl

297

Phenyl

283

2,4-Difluorophenyl

319

2-Methylphenyl

297

3-methoxyphenyl

313

[0225] To a solution of the product from Step A (650 mg, 2.05 mmol, Example 1) in 5 mL of a mixture of isopropanol, tetrahydrofuran and acetic acid (1:1:0.3) was added sodium cyanoborohydride (1.25 g, 20 mmol)....

Embodiment 2

[0236] Compound 2(1)

[0237] The compound represented by the following formula was prepared as follows: Step A: Preparation:

[0238] Add boron tribromide (50 g, 200 mmol) to CH in CH over 1 hour 2 Cl 2 To a cold (0°C) solution in (50 mL) was added dropwise methyl 4-(4-methoxyphenyl)butanoate (15.5 g, 74.4 mmol) in CH 2 Cl 2 (100mL). After continuing to stir at 0 °C for 1 hour, the reaction mixture was washed with 1:1 CH 3 OH:CH 2 Cl 2 (120 mL) and stirred overnight at room temperature. The mixture was concentrated to give an oil which was partitioned between ethyl acetate (150 mL) and water (150 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined organic extracts were washed with water (50 mL), brine (50 mL), and dried (Na 2 SO 4 ), followed by concentration to obtain the desired phenol as an oil. C 11 h 14 o 3 (MW=194.23); MS: m / z (M + +1)=195 Step B: Preparation:

[0239] The phenol (18.6 g, 96 mmo...

Embodiment 3

[0248] Compound 3(1) Step A: Preparation:

[0249] To a solution of the methyl ester—compound 2(1) (100 mg, 0.29 mmol) in DMF (2 mL) was added 3,4,5-trimethoxybenzyl chloride (129 mg, 0.6 mmol) and potassium carbonate powder (350 mg , 2.53 mmol), and the resulting mixture was heated at 45°C for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 3 mL). The combined organic extracts were concentrated to an oil and purified by flash chromatography (gradient elution, 1:4 EtOAc:Hexane - 4:1 EtOAc:Hexane) to afford the desired product as an oil thing. C 27 h 35 N 3 o 7 (MW=513.60); MS: m / z (M + +1)=514

[0250] R

MS: m / z (M + +1)

3,5-dimethoxyphenyl

484

4-biphenyl

500

3-Chlorophenyl

458

3-Chloro-4-methylphenyl

472

Bis-trifluoromethylphenyl

560

3,4-Difluorophenyl ...

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Abstract

The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts, solvates and hydrates thereof, R1 is a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-2-alkyl, heteroaryl-C0-2-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl or phenyl. W is O or S. R2 is H or a substituted or unsubstituted group selected from C1-C6 alkyl, C3-C6 cycloalkyl and heteroaryl. X is a C2-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S. Y is C, O, S, NH or a single bond. Furthermore, E is (CH2)nCOOH, wherein n is 0, 1, 2 or 3, or C(R3)(R4)A, wherein A is an acidic functional group such as carboxyl, carboxamide substituted or unsubstituted sulfonamide, or substituted or unsubstituted tetrazole. R3 is H, saturated or unsaturated C1-C5 alkyl, C1-C5 alkoxy. Additionally, R4 is H, halo, a substituted or unsubstituted group selected from C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, arylC0-C4alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl.

Description

Background of the invention [0001] Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, are ligand-activated transcription factors that regulate gene expression. A number of different PPAR isoforms have been discovered. These subtypes include PPARaα, NUC1, PPARγ and PPAR8. [0002] The PPARα receptor subtype has been reported to be activated by medium-chain and long-chain fatty acids. They are involved in stimulating β-oxidation of fatty acids and have activity as fibrates, which have been reported to significantly reduce plasma triglycerides and moderate low-density lipoprotein (LDL) cholesterol reduction. [0003] PPARα, PPARγ and PPAR8 receptors have been implicated in diabetes, cardiovascular disease, obesity, Syndrome X and gastrointestinal disorders such as inflammatory bowel disease. Syndrome X is a group of syndromes that includes hyperinsulinemia in combination with hypertension, weight gain, high triglycerides,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4196A61K31/42A61K31/4245A61K31/4439A61K31/4709A61K31/5377A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P43/00C07C257/22C07C281/04C07C281/06C07D249/12C07D401/06C07D403/12C07D405/06C07D405/12C07D407/06C07D409/06C07D409/12C07D413/06C07D417/12
CPCC07D405/06C07C281/04C07C257/22C07D401/06C07D409/12C07D417/12C07C281/06C07D249/12C07D409/06C07D413/06A61P3/00A61P3/04A61P3/06A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10
Inventor N·B·曼特洛I·科拉多卡诺S·J·多米尼尔尼G·J·小埃特根C·加西亚-帕雷德斯R·D·约翰斯顿M·E·莱托尔诺M·J·马蒂内利D·R·迈胡A·赛德R·C·汤普森王晓东D·S·科菲C·R·施密德J·T·维岑茨徐彦平
Owner ELI LILLY & CO
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