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Niclosamide cyclo-propyl derivative as well as preparation method and application thereof

A technology of drugs and compounds, applied in the field of medicine and chemical industry, to achieve the effect of simple and safe reaction process, good therapeutic effect and good therapeutic effect

Pending Publication Date: 2020-06-05
CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The content disclosed in the above-mentioned patent shows that niclosamide has a certain curative effect on inhibiting fibrosis, but there is still a lot of room for improvement in its effect. In order to better serve patients with fibrotic diseases, it is necessary to treat niclosamide Further improvement to develop a new compound with better anti-fibrotic activity

Method used

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  • Niclosamide cyclo-propyl derivative as well as preparation method and application thereof
  • Niclosamide cyclo-propyl derivative as well as preparation method and application thereof
  • Niclosamide cyclo-propyl derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] This embodiment provides compound IIIa and its preparation method:

[0038]

[0039] The concrete preparation process of above-mentioned compound IIIa is:

[0040] Under ice-water bath conditions, cyclopropylamine (1.47mmol) was dissolved in dichloromethane (2mL), triethylamine 0.21mL (1.47mmol) was added, compound Iva bromoacetyl bromide (1.47mmol) was slowly added dropwise, and stirred for 15min. After the reaction was completed, water (6 mL) was added to the reaction solution, extracted with dichloromethane (3×3 mL), the organic phases were combined, washed with saturated brine (1×3 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a residue Compound IIIa was obtained by silica gel column chromatography. Compound IIIa 1 H NMR (300MHz, CDCl 3 )δ: 6.66(s, 1H), 3.83(d, J=2.2Hz, 2H), 2.71(tq, J=7.2, 3.8Hz, 1H), 0.91~0.67(m, 2H), 0.55(ddd, J =6.9, 5.3, 3.8Hz, 2H).

Embodiment 2

[0042] The present embodiment provides a kind of niclosamide cyclopropyl derivative Ia and preparation method thereof:

[0043]

[0044] The concrete preparation process of above-mentioned compound Ia is:

[0045]Compound IIIa (0.85mmol) prepared in Example 1 was dissolved in acetonitrile (15mL), 235mg (1.70mmol) of potassium carbonate and 277mg (0.85mmol) of niclosamide were added, and reacted for 3h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain product Ia. Compound Ia 1 H NMR (300MHz, DMSO-d 6 )δ: 10.86(s, 1H), 8.63(d, J=9.2Hz, 1H), 8.43(d, J=2.6Hz, 1H), 8.37(s, 1H), 8.29(dd, J=9.2, 2.6 Hz,1H),7.93(d,J=2.8Hz,1H),7.66(dd,J=9.0,2.8Hz,1H),7.19(d,J=9.0Hz,1H),4.88(s,2H), 2.63(dq, J=7.1, 3.5Hz, 1H), 0.61(dd, J=7.1, 2.3Hz, 2H), 0.47~0.24(m, 2H). HR-MS (ESI) m / z: Calcdfor C 18 h 15 Cl 2 N 3 o 5 Na{[M+Na] +} 446.0286, found 446.0278.

Embodiment 3

[0047] The present embodiment provides a kind of niclosamide cyclopropyl derivative Ia and preparation method thereof:

[0048]

[0049] The concrete preparation process of above-mentioned compound Ia is:

[0050] Compound IIIa (0.85mmol) prepared in Example 1 was dissolved in dichloromethane (15mL), 172mg (1.70mmol) of triethylamine and 277mg (0.85mmol) of niclosamide were added, and reacted for 3h. Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography to obtain product Ia.

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Abstract

The invention provides a niclosamide cyclo-propyl derivative shown as a formula I. The anti-fibrosis activity of the niclosamide cyclo-propyl derivative is better than that of niclosamide, and meanwhile, the niclosamide cyclo-propyl derivative also has very good anti-tumor activity and can better serve fibrosis and tumor disease patients. The invention further provides a preparation method of theniclosamide cyclo-propyl derivative. The niclosamide cyclo-propyl derivative can be prepared safely and conveniently.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a cyclopropyl derivative of niclosamide, its preparation method and application. Background technique [0002] Fibrosis refers to the pathological process of reduction or necrosis of parenchymal cells in patients' organs, increase of extracellular matrix in tissues and diffuse excessive deposition caused by various pathogenic factors. Continuous progress can lead to destruction of organ structure, functional decline, and even failure. Fibrosis can occur in many organs, and the most common clinical fibrosis mainly includes: (1) pulmonary fibrosis; (2) liver fibrosis; (3) cardiac fibrosis; (4) renal fibrosis and (5) Fibrosis of the pancreas; in addition, fibrosis of the eye, blood vessels, and nervous system may also occur. [0003] Pulmonary fibrosis (PF) is a lung disease of various etiologies (such as SARS, idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/84C07C231/12A61K31/167A61P35/00
CPCC07C235/84A61P35/00C07C2601/02
Inventor 黄晴菲王启卫韩英蕾叶庭洪谭醉张雪梅范挺
Owner CHENGDU ORGANIC CHEM CO LTD CHINESE ACAD OF SCI
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