Compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity

A technology of compounds and mixtures, applied in the direction of organic active ingredients, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve problems such as aggravating depression symptoms, slow onset of action, and affecting the treatment effect of depression.

Active Publication Date: 2019-10-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the current research on antidepressants has been greatly developed, and safe and effective antidepressants are constantly being discovered, the current first-line antidepressants all have certain side effects, and at the same time, they have slow onset of effect, low efficiency, and even aggravated The defect of depressive symptoms seriously affects the treatment effect of depression (Canadian Journal of Psychiatry Revue Canadienne De Psychiatrie,2016,61(9):540-560)

Method used

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  • Compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity
  • Compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity
  • Compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity

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preparation example Construction

[0038] The preparation method of above-mentioned compound is:

[0039]

[0040] Intermediate 1 reacts with thionyl chloride to prepare acid chloride, and then reacts with intermediate 2 to obtain intermediate 3 through acylation reaction, and intermediate 3 reacts with hydroxylamine potassium prepared from hydroxylamine hydrochloride to obtain the target compound through aminolysis.

[0041] Wherein, the molar ratio of the intermediate 1 added in step a to thionyl chloride is 1:1 to 1:3, the reaction solvent is one of methylene chloride, tetrahydrofuran or a mixed solvent thereof, and the reaction temperature is from room temperature to the solvent used reflux temperature; the solvent used in the acylation reaction is dichloromethane, tetrahydrofuran, ethyl acetate, pyridine, and the acid-binding agent used is triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium carbonate, carbonic acid One of cesium and sodium bicarbonate.

[0042] The reaction solv...

Embodiment 1

[0076] N-Hydroxy-6-(4-chlorobenzamido)benzo[d]oxazole-2-carboxamide (Ⅱ-1)

[0077] Step 1, Ethyl 6-nitrobenzo[d]oxazole-2-carboxylate

[0078]

[0079] Take 1.60 g (10.38 mmol) of 2-amino-5-nitrophenol into a 100 mL eggplant-shaped flask, and add 30 mL of pyridine dried with potassium hydroxide to dissolve. Under stirring, 7.75 mL (72.67 mmol) of monoethyl oxalyl chloride was added dropwise with a constant pressure dropping funnel. After the dropwise addition was completed, the reaction was heated at 100°C for 4h. The reaction solution was cooled and stirred in an ice-water bath, diluted with 20 mL of ethyl acetate, and added dropwise with 15% hydrochloric acid. Add 100 mL of saturated sodium chloride solution for dilution, extract three times with ethyl acetate, combine the organic phases, and dry the organic phases with anhydrous sodium sulfate. The organic phase was made into sand, and silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) gave 1.23 g...

Embodiment 2

[0091] N-Hydroxy-6-(3,4-dimethoxybenzamido)benzo[d]oxazole-2-carboxamide (Ⅱ-2)

[0092] Referring to the synthesis method of II-1 in Example 1, 4-chlorobenzoic acid in step 3 was replaced by 3,4-dimethoxybenzoic acid to obtain 50 mg of white solid with a yield of 40.8%. M.P.198-201℃, 1 H-NMR (300MHz, DMSO-d 6 ): δ12.03(s,1H),10.42(s,1H),9.59(s,1H),8.41(s,1H),7.85(d,J=8.7Hz,1H),7.78(d,J= 8.7Hz, 1H), 7.67(d, J=8.4Hz, 1H), 7.57(s, 1H), 7.12(d, J=8.7Hz, 1H), 3.86(s, 6H); HRMS(ESI-TOF) :calcd for C 17 h 15 N 3 o 6 [M+H] + 358.1039, found 358.1036.

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Abstract

The invention discloses a compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity. The compound has good PDE4D / ASM double-target inhibitory activity and can be used for preventing and / or treating diseases associated with the phosphodiesterase 4D and the acid sphingomyelinase, and the diseases particularly include inflammatory diseases, autoimmune diseases such as dermatitis, atopic dermatitis, psoriasis and multiple sclerosis, cardiovascular diseases such as atherosclerosis and ischemia reperfusion injury, hepatic diseases such as non-alcoholic steatohepatitis, alcoholic steatohepatitis and hepatic fibrosis, mental and neurological diseases such as depression and anxiety disorder, neurodegenerative diseases such as Alzheimer's diseases, respiratory system diseasessuch as chronic obstructive pulmonary diseases, cystic fibrosis, pulmonary fibrosis, pulmonary edema and lung injury and metabolic diseases such as diabetes.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a compound with phosphodiesterase 4D and acid sphingomyelinase inhibitory activity and application thereof. Background technique [0002] Depression is a common mental illness. The clinical manifestations of patients are mainly depression, low mood, loss of interest in things, and severe cases have self-mutilation and suicide tendencies. With the accelerated pace of life, people are facing more and more pressure, the incidence of the disease is increasing year by year, and has the characteristics of high recurrence, high disability and high suicide rate, which seriously affects the quality of human life and economic development ( Journal of Ethnopharmacology, 2016, 194:819-826). According to the latest statistics from the World Health Organization, there are about 50 million depression patients in China, with an incidence rate of 4.2%; and there are 300 mi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/58C07D271/06C07D213/79C07D213/80C07C229/60C07C235/84C07C323/52A61P25/00A61P25/28A61P25/18A61P25/22A61P25/24A61P29/00A61P17/00A61P17/06A61P11/00A61P9/10A61P1/16A61P37/06A61P3/10A61K31/421A61K31/423A61K31/4245A61K31/44A61K31/196A61K31/165
CPCC07D263/58C07D271/06C07D213/79C07D213/80C07C229/60C07C235/84C07C323/52A61P25/00A61P25/28A61P25/18A61P25/22A61P25/24A61P29/00A61P17/00A61P17/06A61P11/00A61P9/10A61P1/16A61P37/06A61P3/10C07C2601/02
Inventor 王进欣农克意徐正文王有志顾勤兰
Owner CHINA PHARM UNIV
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