4-aminoacylphenoxyacetamide compound and medicine uses thereof

A technology of aminoacylphenoxyacetamide and compound, which is applied in the field of medicinal chemistry, can solve the problems of short half-life, poor water solubility and stability and other physical and chemical properties, weak inhibitory effect, etc., and achieve small toxic and side effects, good potential and application foreground effect

Inactive Publication Date: 2016-03-30
FUDAN UNIV
View PDF4 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] One of the sphingomyelin synthase inhibitors currently reported in the literature is D609 (Aimin Meng; Chiara Luberto; et al. Experimental Cell Research, 2004, 292, 385–392.), which has a weak inhibitory effect on sphingomyelin synthase (IC 50 =375μM), and its chemical structure contains orthosulfonate which makes the structure highly unstable (Bai, A. et al. J. Pharmacol. Exp. Ther. 2004, 309, 1051-1059), and the half-life is short; in addition, there are The study used the method of homology modeling to construct the three-dimensional protein structure model of hSMS1 (human SMS1 type) for the first time (ZhangYa; LinFu; etal.Chin.J.Chem.2011,29,2421-2429), and determined the The substrate-binding active site was verified by biological experiments (CalvinYeang; ShwetaVarshney; etal.BiochimicaetBiophysicaActa, 2008, 1781, 610–617.); using the three-dimensional protein structure model and the verified enzyme and substrate binding The active site of sphingomyelin synthase small molecule inhibitor compound D2 was found (Xiaodong Deng, Fu Lin, et al. European Journal of Medicinal Chemistry, 2014, 73, 1-7), although its inhibitory activity on SMS2 in vitro was improved compared with 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 the physical and chemical properties such as water solubility and stability are not good

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 4-aminoacylphenoxyacetamide compound and medicine uses thereof
  • 4-aminoacylphenoxyacetamide compound and medicine uses thereof
  • 4-aminoacylphenoxyacetamide compound and medicine uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Preparation of N-(4-chlorophenyl)-2-(4-(N-phenylethylsulfamoyl) phenoxy)acetamide (formula Ⅰ-5)

[0046] One, the synthesis of 4-hydroxyphenyl-1-sulfonyl chloride (compound 4)

[0047]

[0048] Dissolve 1.96g (10mmol, 1.0eq) of sodium p-hydroxybenzenesulfonate in 3.7ml of thionyl chloride, add 0.06ml of DMF, and react at 60°C for 3.5h, then pour the reaction solution into ice water and stir 5min, extracted with dichloromethane, washed the organic phase with saturated brine, anhydrous Na 2 SO 4 After drying and concentrating, 1.93 g of a crude product of colorless transparent oil was obtained, which could be directly used in the next reaction without purification. MS(ESI)(m / z):193.0(M+H) + .

[0049] Two, the synthesis of 4-hydroxyl-N-phenethylbenzenesulfonamide (compound 6)

[0050]

[0051] 1.21g (10mmol, 1.0eq) of phenethylamine was dissolved in 5ml of dichloromethane, and 1.6ml of pyridine was added dropwise thereto. Under ice bath, 1.93g (10mm...

Embodiment 2

[0060] Embodiment 2: compound formula I-1, I-2, I-3, I-4, I-6, I-7, I-8, I-9, I-10, I-11 synthesis

[0061] 1. Synthesis of intermediate compounds 2-a~2-d and 2-f~2-k

[0062]

[0063]

[0064] Referring to the conditions for the synthesis of compound 2-e in the third step in Example 1, intermediate compounds 2-a~2-d and 2-f~2-k were prepared from substituted benzylamine or aniline and chloroacetyl chloride.

[0065] Two, compound formula I-1, I-2, I-3, I-4, I-6, I-7, I-8, I-9, I-10, I-11 synthesis

[0066]

[0067]

[0068] With reference to the conditions of the fourth step synthesis compound formula I-5 in the embodiment example 1, from 4-hydroxyl-N-phenylethylbenzenesulfonamide (compound 6) and intermediate compounds 2-a~2-d and 2-f~ 2-k obtains compound formula I-1 to I-4 and formula I-6 to I-11, specifically: N-(4-methoxybenzyl)-2-(4-(N-phenethylamine Sulfonyl)phenoxy)acetamide (formula Ⅰ-1); N-(4-bromobenzyl)-2-(4-(N-phenethylsulfamoyl)phenoxy)acetamide (f...

Embodiment 3

[0080] Example 3: Preparation of 4-(2-((4-chlorobenzyl)amino)-2-oxoethoxy)-N-(4-methylbenzyl)benzamide (formula Ⅰ-12)

[0081] 1. Synthetic intermediate 2-chloro-N-(4-chlorobenzyl)acetamide (compound 2-1)

[0082]

[0083] 5.00g (35mmol, 1.0eq) of 4-chlorobenzylamine was added to a mixed solution of 5.6ml of pyridine and 70ml of water, and 5.90g (52.5mmol, 1.5eq) of chloroacetyl chloride was added dropwise under ice-bath conditions. React at 0°C for 1.0 h, add 175 ml of water to the system, filter, filter out the solid and dry to obtain 6.50 g of a light yellow solid with a yield of 84.4%. The crude product can be carried out in the next step without purification.

[0084] Two, synthetic 4-hydroxybenzoic acid methyl ester (compound 8)

[0085]

[0086] Add 10.00 g (72 mmol) of 4-hydroxybenzoic acid (compound 7) and 20 mL of methanol to the reaction flask, and add 6.8 mL (94 mmol) of thionyl chloride dropwise to the above system under ice cooling. Afterwards, the reacti...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to 4-aminoacylphenoxyacetamide compound shown as an I formula and medicine uses thereof, and in the formula, G, Z, R, m and n are described in the specification in detail. The compounds are capable of inhibiting sphingomyelin synthase activity, and are applicable to treat diseases caused by abnormal increase of sphingomyelin level. The invention further comprises compounds shown as the formula I structure, pharmaceutically-acceptable salts thereof, and application of pharmaceutical composition taking the compounds or salts thereof as an effective active composition to prevent and treat diseases caused by abnormal increase of sphingomyelin level. The diseases caused by abnormal increase of sphingomyelin level comprise atherosclerosis, fatty liver, obesity, II type diabetes and other metabolic syndrome.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to 4-aminoacylphenoxyacetamide compounds and their medicinal uses, in particular to 4-aminoacylphenoxyacetamide compounds and their use in the preparation of sphingomyelin synthase inhibitors and their use in Use in the preparation of medicines for preventing or treating diseases caused by abnormally increased levels of sphingomyelin. Background technique [0002] According to reports, with the development of the economy and society and the aging of the population, the morbidity and mortality of cardiovascular and cerebrovascular diseases in my country have increased significantly in recent years to the second place in the total cause of death except tumors, and have become one of the major diseases that endanger human health. Studies have shown that atherosclerosis (AS) is one of the main pathological bases of many cardiovascular and cerebrovascular diseases. Therefore, research on...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07C311/29C07C303/40C07C235/46C07C231/02C07D213/75C07D213/40A61K31/4402A61K31/4409A61K31/18A61K31/166A61P9/10A61P1/16A61P3/04A61P3/10
Inventor 叶德泳李亚莉周璐邓晓东楚勇董艳萍
Owner FUDAN UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap