2-benzyloxyphenyloxazolopyridine compound and medicinal application thereof

A technology of benzyloxyphenyl oxazole and pyridine, applied in the field of medicinal chemistry, can solve the problems of short half-life, highly unstable structure, weak enzyme inhibitory activity and the like

Active Publication Date: 2018-07-27
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] One of the currently reported sphingomyelin synthase inhibitors is D609 (Aimin Meng; ChiaraLuberto; et al. Expert Cell Res . 2004, 292 : 385–392.), the enzyme inhibitory activity of this compound is weak (SMS inhibitory activity IC 50 = 402.7 ± 8.6 μM in mouse liver homogenate; SMS2 inhibitory activity IC 50 = 224.6 ±4.5 μM, for homogenate of insect cells with high expression of SMS2), and the chemical structure contains orthosulfonate, which makes the structure highly unstable (Bai, A. et al. J Pharmacol Exp Ther. 2004, 309 : 1051-1059.), with a short half-life; in addition, some studies used the method of homology modeling to construct for the first time h A three-dimensional protein structure model of SMS1 (human SMS1 type) (ZhangYa; Lin Fu; et al. Chin J Chem 2011, 29 : 2421-2429.), using the three-dimensional protein structure model and the verified active site of the enzyme binding to the substrate, discovered the small molecule inhibitor compound D2 of sphingomyelin synthase (Xiaodong Deng, Fu Lin, et al. Eur J Med Chem, 2014, 73 : 1-7.), its in vitro SMS inhibitory activity (SMS inhibitory activity IC 50 = 23.5 ± 3.2 μM in mouse liver homogenate; SMS2 inhibitory activity IC 50 = 13.3±0.26 μM, although the insect cells with high SMS2 expression) are higher than D609, but there are still the following defects: the inhibitory activity to SMS2 needs to be improved, it contains a cyano group with a high potential toxicity risk, and it is water-soluble and Poor physical and chemical properties such as stability

Method used

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  • 2-benzyloxyphenyloxazolopyridine compound and medicinal application thereof
  • 2-benzyloxyphenyloxazolopyridine compound and medicinal application thereof
  • 2-benzyloxyphenyloxazolopyridine compound and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Preparation of (2-(benzyloxy)phenyl)oxazolo[5,4-b]pyridine (Formula I-1)

[0059] 1. Synthesis of (oxazolo[5,4-b]pyridin-2-yl)phenol (compound 1c)

[0060]

[0061] Dissolve 1.0 g (9.08 mmol, 1.05 eq) of 3-amino-2-hydroxypyridine in 34.6 mL of sodium hydroxide aqueous solution (1 mol / L, 34.60 mmol, 4.0 eq) at room temperature, stir well and add to it 1.4 g (8.65 mmol, 1.0 eq) 2-trifluoromethylphenol, 80 o C oil bath heating reaction for 2.0 h. TLC detects the disappearance of the raw materials, and stops heating. Cool to room temperature, extract with dichloromethane, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, purify by PE-EA system column chromatography, and concentrate to obtain 1.40 g of compound 1c as a white solid with a yield of 76.3%;

[0062] After testing, the structure is correct and the testing results are as follows:

[0063] Compound 1c m.p. 153.7-154.5 o C; 1 H NMR (400 MHz, DMSO) δ 11....

Embodiment 2

[0069] Example 2: Synthesis of formula I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, Compounds of I-13, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25

[0070]

[0071] Formula I

R

Ⅰ-2

2-Cl

Ⅰ-3

3-Cl

Ⅰ-4

4-Cl

Ⅰ-5

4-CH 3

Ⅰ-6

2-F

Ⅰ-7

3-F

Ⅰ-8

4-F

Ⅰ-9

2-CH 3

Ⅰ-10

3-CH 3

Ⅰ-11

2-NO 2

Ⅰ-12

3-NO 2

Ⅰ-13

4-NO 2

Ⅰ-17

2-Et

Ⅰ-18

2-OCF 3

Ⅰ-19

3-OCF 3

Ⅰ-20

4-OCF 3

Ⅰ-21

2-CN

Ⅰ-22

3-CN

Ⅰ-23

4-CN

Ⅰ-24

3-F; 5-OCH3

Ⅰ-25

3,5-Difluoro

[0072] With reference to the conditions of the second step synthesis of compound formula I-1 in Example 1, from (oxazolo[5,4-b]pyridin-2-yl)phenol (compound 1c) and the corresponding commercially available substituted benzyl bromide (compound 2d ~ 13d and compound 17d ~ 25d) to obtain compound formula I-2 to I-13 and formula I-17 to I-25, specifically: (2-((2-chlorobenzyl)oxy)phenyl)oxa Azolo[5,4-b]pyridine (formula I-2); (2-((3-chlorobenzyl)oxy)phenyl)oxazolo[5,4-b]pyridine (formula I-3 ); (2-((4-...

Embodiment 3

[0095] Example 3: Synthesis of compounds of formula I-14, I-15, I-16, I-26, I-27

[0096] Synthesis of compounds 14d, 15d, 16d, 26d and 27d:

[0097]

[0098] Compound

R

14e

2-OCH 3

15e

3-OCH 3

16e

4-OCH 3

26e

2-CH 3 ; 3-F

27e

2-CH 3 ; 5-F

[0099] Dissolve 1.0 g (7.24 mmol, 1.0 eq) 3-fluoro-2-methylbenzaldehyde (compound 26e) in 15 ml absolute ethanol, and add 328.6 mg (8.69 mmol, 1.2 eq) NaBH 4 , React at room temperature for 3.0 h, add a small amount of water to quench the reaction, evaporate ethanol, add 15 ml of water, extract with EA (20 ml*2), wash twice with saturated sodium chloride solution, add anhydrous sodium sulfate and stir to dry. Concentrated to obtain 0.7 g of colorless and transparent oil (compound 26g), with a yield of 69.0%. According to the above reaction operation, compounds 14g, 15g, 16g and 27g were prepared from compounds 14e, 15e, 16e and 27e respectively;

[0100] Dissolve 0.7 g (4.99 mmol, 1.0 eq) of compound 26g in 15 ml CH 2 Cl 2 , Add 1.62 g (...

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Abstract

The invention belongs to the field of medicine chemistry and relates to a 2-benzyloxyphenyloxazolopyridine compound represented as the formula (I), and a medicinal application thereof, wherein the R,X, Y and Z are coincided with details in specification. The compound can inhibit activity of sphingomyelin synthase and can be used for preparing a sphingomyelin synthase small-molecular inhibitor. The invention provides the compound represented as the formula (I) or a medicine composition employing the compound (I) as an active component, and the application of the medicine composition for preparing a medicine for preventing / treating diseases caused by abnormal increasing of sphingomyelin level, wherein the diseases include following metabolic syndromes: atherosclerosis, fatty liver, obesity,diabetes type II and the like.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to 2-benzyloxyphenyl oxazolopyridine compounds and their pharmaceutical uses, in particular to 2-benzyloxyphenyl oxazolopyridine compounds and their use in the preparation of sphingomyelin synthase inhibitors the use of. Background technique [0002] According to data, in my country, with the development of the economy and society and the aging of the population, the incidence and mortality of cardiovascular and cerebrovascular diseases have increased significantly in recent years to the second place in the total cause of death except for tumors, and they have become the main diseases endangering human health. one. It is predicted that from 2010 to 2030, China’s cardiovascular disease patients will increase by 21.3 million, and the number of cardiovascular deaths will increase by 7.7 million. Studies have shown that atherosclerosis (AS) is the main cause of cardiovascular and cerebrovas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/437A61K31/444A61P9/10A61P1/16A61P3/04A61P3/10
CPCC07D498/04
Inventor 叶德泳齐翔宇李亚莉莫明广周璐楚勇王鹏辉
Owner FUDAN UNIV
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