Hydroxyl cycloadipamide compound as well as preparation method and application thereof

A technology of hydroxycycloadipamide and compound, which is applied in the fields of antiviral infection drugs and chemical drugs, can solve problems such as instability, unstable structure, and easy hydrolysis, and achieve high stability, high anti-oxidation stability, and cell The effect of low toxicity

Active Publication Date: 2022-03-01
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, 1α,2β-O,O-dicaffeoyl cyclopentan-3β-ol is structurally unstable, easily hydrolyzed in blood, and has a short half-life, which directly affects its clinical application
[0005] Chinese invention patent CN110156628A partially solves the instability problem of 1α,2β-O,O-dicaffeoylcyclopent-3β-ol, but there is still the problem that candidate compounds are easily oxidized

Method used

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  • Hydroxyl cycloadipamide compound as well as preparation method and application thereof
  • Hydroxyl cycloadipamide compound as well as preparation method and application thereof
  • Hydroxyl cycloadipamide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Preparation, separation and purification of 3-hydroxycyclohexyl-1,2-di(β-naphthyl)acetamide (CL-A1-1~CL-A1-8)

[0113] (1) Preparation of β-naphthylacetic acid: purchased through conventional market channels.

[0114] (2) Preparation of 2,3-diaminocyclohexyl-1-benzyl ether

[0115] 2.1. Preparation of 2-cyclohexen-1-ol

[0116] Measure 2-cyclohexen-1-one (0.49mL, 5mmol) in a dry 50mL round bottom flask, dissolve it with an appropriate amount of dry methanol, place the flask in a low-temperature constant temperature stirring reaction bath, and then weigh cerium trichloride (1.60g, 6.5mmol) was added to the flask, kept at -15°C and stirred for 0.5h, then slowly added sodium borohydride (245.92mg, 6.5mmol) in 3 portions within 15 minutes, and kept at -15°C for 3h. After the reaction is complete, slowly add 3mL of saturated ammonium chloride solution dropwise at -10°C to quench the reaction, then transfer the reaction solution to a separatory funnel, extract with DCM (3×5...

Embodiment 2

[0142] Preparation and Purification of 3-Hydroxycyclohexyl-1,2-bis(3,4-dimethoxyphenyl)formamide (CL-A2-1~CL-A2-8)

[0143] (1) Preparation of 3,4-dimethoxybenzoic acid. Buy from commercial sources.

[0144] (2) Preparation of 2,3-diaminocyclohexyl-1-benzyl ether. Prepare according to step 2.1 to step 2.6 of Example 1.

[0145] (3) Preparation and separation and purification of 3-hydroxycyclohexyl-1,2-bis(3,4-dimethoxyphenyl)formamide (CL-A2-1~CL-A2-8).

[0146] 3.1. Carry out according to step 3.1 of Example 1, wherein the raw material β-naphthaleneacetic acid is replaced by 3,4-dimethoxybenzoic acid (364.4mg, 2.0mmol), the amount of 2,3-diaminocyclohexyl-1-benzyl ether As (180.7mg, 0.82mmol). TLC developer condition is V DCM :V CH3OH =25:1, separated and purified by silica gel column chromatography, collected R f =0.61 fraction, 242.9mg of white solid was obtained, the yield was 54%. 1 H NMR (400MHz, CDCl 3 )δ8.17(d, J=9.1Hz, 1H), 7.84(d, J=8.6Hz, 1H), 7.14(dd, J=26...

Embodiment 3

[0159] Preparation and Purification of 3-Hydroxycyclohexyl-1,2-bis((E)-3-(2-bromo-4-fluorophenyl))acrylamide (CL-A3-1~CL-A3-8)

[0160] (1) Preparation of (E)-3-(2-bromo-4-fluorophenyl)acrylic acid

[0161] 1.1. Dissolve 2-bromo-4-fluorobenzaldehyde (203.0mg, 1.0mmol) and maleic acid (260.2mg, 2.5mmol) in 30mL of pyridine, then add a catalytic amount of piperidine (12.8mg, 0.15mmol), and the mixture Slowly raise the temperature to 110° C., and keep stirring at this temperature for 15 hours, followed by TLC until the end of the reaction. The reaction mixture was cooled to room temperature, and 30mL of 1M NaOH solution was added until the solution was in a clear state, washed with ethyl acetate (20mL×2), and the aqueous layer was adjusted to pH 2.0 with 50% sulfuric acid solution, a precipitate was precipitated, cooled in an ice bath, and suction filtered The solid compound was collected, washed successively with cold water and cold diethyl ether, sucked dry, and dried in vacuo...

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Abstract

The invention discloses a hydroxyl cyclohexanediamide compound and a preparation method and application thereof, the compound has a structure as shown in a formula I, and the structure of an R group is as shown in A1-A5. According to the drug nucleus similarity principle and the bioisostere principle, 1 alpha, 2 beta-O, O-dicaffeoyl cyclopent-3beta-alcohol which is naturally sourced is used as a primer, and the hydroxyl cyclohexanediamide compound with the antiviral effect is designed and synthesized. The hydroxyl cyclohexanediamide compounds designed and synthesized by the invention have strong anti-respiratory syncytial virus activity and low cytotoxicity, the anti-RSV selectivity index of the hydroxyl cyclohexanediamide compounds is higher than that of a positive control drug ribavirin and a natural primer methyl 3, 4-O, O-dicaffeoylquinate, and part of the hydroxyl cyclohexanediamide compounds are superior to that of 1 alpha, 2 beta-O, O-dicaffeoylcyclopent-3 beta-alcohol. Meanwhile, the half-life period is prolonged, and the oxidation stability is improved.

Description

technical field [0001] The invention belongs to the fields of chemical medicines and antiviral infection medicines, and in particular relates to a hydroxycycloadipamide compound and its preparation method and application. Background technique [0002] Human respiratory syncytial virus (respiratory syncytial virus, RSV) is an enveloped, non-segmented, single-stranded negative-sense RNA virus of the genus Pneumovirus in the family Paramyxoviridae. The main pathogen is that infants under 6 months of age have the highest risk of infection with RSV. After being infected with RSV, the human body cannot obtain life-long immunity. Therefore, RSV can also cause severe respiratory diseases in the elderly and immunocompromised people. The main symptoms are fever, cough, and rhinitis and difficulty breathing. [0003] Currently, there are no safe RSV vaccines and small-molecule drugs for the specific treatment of RSV infection in clinical practice. Humanized monoclonal antibody and ri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/23
CPCC07C233/23C07C235/54C07C235/36C07C231/02C07C213/02C07C247/14C07C303/28C07C303/30C07C41/26C07C41/16C07C29/143A61K31/165A61K31/166A61P31/14C07C2601/14C07C2601/16C07B2200/07C07C35/18C07C43/188C07C43/196C07C309/66C07C217/52Y02P20/55
Inventor 陈河如李药兰唐维饶舒文刘志军朱皓月
Owner JINAN UNIVERSITY
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