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Isotretinoin amido derivative, preparation method thereof and applications thereof

A technology of isotretinoin and its derivatives, which is applied in the field of biomedicine, can solve problems such as the activation ability of retinoic acid nuclear receptors and its side effects, the reduction of electron cloud density, and the reduction of amino nucleophilicity. Minimal adverse reactions, increased activity, reduced acylation activity

Active Publication Date: 2013-09-25
CHUGOKU IGAKU KAGAKUIN HIFUBIYOU KENKYUSHO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis of isotretinoin fatty acid amides and fatty alcohol amides has been reported in literature (Y.Fulmer Shealy et al.Synthesis and Properties of Some 13-cis-and All-trans-retinamides.Journal of Pharmaceutical Sciences.1984,73(6) : 745-751), but none of them mentioned the activation ability of retinoic acid nuclear receptors and their side effects, nor did they involve the amide formed by isotretinoin and alkyl aminobenzoate, the latter may be due to the aromatic amine Due to the conjugation effect of the aromatic ring and the inductive effect of the electron-withdrawing substituent (alkoxycarbonyl) on the aromatic ring, the amino group reduces the electron cloud density on the nitrogen atom of the amino group, reduces the nucleophilicity of the amino group, and acylation reaction The activity is much lower than that of fatty amines, and it is not easy to be related to the formation of high-yield amides from isotretinoin

Method used

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  • Isotretinoin amido derivative, preparation method thereof and applications thereof
  • Isotretinoin amido derivative, preparation method thereof and applications thereof
  • Isotretinoin amido derivative, preparation method thereof and applications thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Embodiment 1: the synthesis of p-(isotretinoin amido) methyl benzoate

[0054] In a 250ml three-necked flask, add 4-dimethylaminopyridine (DMAP) (0.1g, 0.8mmol), p-toluenesulfonic acid (0.14g, 0.8mmol), add CH 2 Cl 2 110ml, then added isotretinoin (2.4g, 8mmol), methyl p-aminobenzoate (1.21g, 8.0mmol), stirred at room temperature for 10min, then added DCC (1.82g, 8.8mmol), stirred at 10°C for about 4 hours, stop the reaction. The above reactions were carried out under the protection of nitrogen and away from light. The above reaction mixture was placed at 0-5°C for about 12 hours, taken out and filtered, and the filtrate was rotary evaporated to obtain a crude product, which was separated by column chromatography (200-300 mesh silica gel, eluent: ethyl acetate:petroleum ether 1:15 ( V / V) ~ 1:10 (V / V)), gradient elution, and the resulting product was recrystallized from ethanol to obtain the reaction product (3.02g). The molecular mass of the reaction product is 433....

Embodiment 2

[0055] Embodiment 2: the synthesis of p-(isotretinoin amido) ethyl benzoate

[0056] In a 250ml three-necked flask, add 4-dimethylaminopyridine (DMAP) (0.1g, 0.8mmol), p-toluenesulfonic acid (0.14g, 0.8mmol), add CH 2 Cl 2 110ml, then added isotretinoin (2.4g, 8mmol), ethyl p-aminobenzoate (1.4g, 8.4mmol), stirred at room temperature for about 15min, then added DCC (1.87g, 9.1mmol), 40°C Stir and reflux for about 3 hours to stop the reaction. The above reactions were carried out under the protection of nitrogen and away from light. The above reaction mixture was placed at 0-5°C for about 12 hours, taken out and filtered, and the filtrate was rotary evaporated to obtain a crude product, which was separated by column chromatography (200-300 mesh silica gel, eluent: ethyl acetate:petroleum ether 1:20 ( V / V)), and the resulting product was recrystallized from ethanol to obtain a reaction product (3.58 g). The molecular mass of reaction product is 447.62, proton nuclear magneti...

Embodiment 3

[0057] Embodiment 3: the synthesis of p-(isotretinoin amido) propyl benzoate

[0058] In a 250ml three-necked flask, add 4-dimethylaminopyridine (DMAP) (0.12g, 0.96mmol), p-toluenesulfonic acid (0.17g, 0.96mmol), add CH 2 Cl 2 110ml, then added isotretinoin (2.4g, 8mmol), p-propyl aminobenzoate (1.72g, 9.6mmol), stirred at room temperature for 15min, then added DCC (2.15g, 10.4mmol), stirred at 30°C for about After 5 hours, the reaction stopped. The above reactions were carried out under the protection of nitrogen and away from light. The above reaction mixture was placed at 0-5°C for about 12 hours, taken out and filtered, and the filtrate was rotary evaporated to obtain a crude product, which was separated by column chromatography (200-300 mesh silica gel, eluent: ethyl acetate:petroleum ether 1:20 ( V / V)), and the resulting product was recrystallized from ethanol to obtain a reaction product (2.9 g). The molecular mass of the reaction product is 461.65, and the proton n...

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Abstract

The invention discloses an isotretinoin amido alkyl benzoate derivative, a preparation method thereof and applications thereof. The derivative has stronger inhibition and differentiation regulating effects than isotretinoin on psoriasis, acne and epithelial cell tumors including, but not limited to skin squamous epithelial cell carcinoma, stomach cancer, lung cancer, and cervical cancer; the derivative has less influence on normal tissue cells, has a certain targeting effect on inhibiting proliferating cells, and has very less side effects than isotretinoin; and the derivative has wide promising prophylaxis and treatment applications such as cornification abnormality diseases and cell abnormal proliferation including tumors, psoriasis, acne, and other cornification abnormality dermatopathy.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to an isotretinoin amide derivative and its preparation method and pharmaceutical use. Background technique [0002] Isotretinoin, also known as 13-cis-retinoic acid (abbreviated as 13-cisRA), is a metabolite of vitamin A, belonging to a kind of retinoic acid, and its molecular formula is C 20 h 28 o 2 , the molecular weight is 300.44, and its structural formula is as follows: [0003] [0004] Isotretinoin has more advantages than all-trans retinoic acid in affecting the proliferation and differentiation of epithelial cells. It can inhibit the occurrence of tumors and the proliferation and spread of cancer cells. It has been widely used in the treatment of keratosis such as acne and psoriasis. Prevention and treatment of abnormal sexual proliferation and differentiation diseases, precancerous lesions and tumors. Retinoids play a very important role in the chemical preven...

Claims

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Application Information

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IPC IPC(8): C07C233/55C07C231/02A61K31/245A61P17/00A61P17/10A61P17/06A61P35/00
Inventor 马鹏程张孟丽魏峻傅友军
Owner CHUGOKU IGAKU KAGAKUIN HIFUBIYOU KENKYUSHO
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