4-Carboxyphenyl retinamide ethanolate and its preparation method and pharmaceutical composition

A technology of retinamide and carboxyphenyl, which is applied in the field of retinoid drug compounds, can solve problems affecting the quality control and practicability of drugs, unstable physical and chemical properties, and affecting industrial production, storage and transportation, and listing.

Active Publication Date: 2011-11-30
BEIJING JI KE TE TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 4-CPR has some shortcomings when it is developed as a new drug: (1) its unstable physical and chemical properties affect the quality control and practicability of drugs: because it belongs to retinoids, it is like alcohols, aldehydes, acids and absolutes of retinoids. Like most derivatives, they are afraid of light, heat, air and moisture, and are prone to produce oxides, polymers, and cis-trans isomers. According to modern new drug approval, it highlights the ...

Method used

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  • 4-Carboxyphenyl retinamide ethanolate and its preparation method and pharmaceutical composition
  • 4-Carboxyphenyl retinamide ethanolate and its preparation method and pharmaceutical composition
  • 4-Carboxyphenyl retinamide ethanolate and its preparation method and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Preparation and identification of 4-CPRE:

[0140] Add 95% ethanol (1 g: 2.5 ml) to the yellow 4-CPR solid, stir and react at room temperature for 30-60 minutes, and the solid turns from bright yellow to blood red completely. Filtrate, wash 3 times with 95% ethanol, avoid light, dry naturally to constant weight, the total yield is 62%, and the final product 4-CPRE in the form of blood red powder is obtained, which is a common crystal sample of type V (or directly prepared into other preferred crystal forms ); TLC (silica gel plate, petroleum ether / ethyl acetate / glacial acetic acid 1.5ml: 1ml: 1 drop development) Rf=0.62; other detections meet the pharmaceutical standards.

[0141] Melting point; 192~194℃

[0142] Infrared spectrum and data: KBr sheet, wavelength cm -1 , the data table is as follows:

[0143]3645, 3440, 3400, 3300-3050 (alcohol O-H stretching vibration, associative hydroxyl group), 2918, 2655, 2536, 2366, 1780, 1687 (aromatic acid carbonyl), 1665 (ami...

Embodiment 2

[0150] Preparation and Identification of Type IV Single Crystal of 4-CPRE:

[0151] Solvent method: In ethanol with low temperature (-18°C) and vigorous and rapid stirring, quickly add 4-CPRE samples dissolved in ethyl acetate (or ethylene glycol dimethyl ether) at room temperature, and continue to stir the mixture vigorously and rapidly until the crystallization is complete , filtered, washed, and dried to obtain type IV crystals, which should be stored away from light. The identification is as follows:

[0152] ①Differential thermal DSC spectrum:

[0153] Ti169.0°C, Tp181.8°C peaks and pseudopolymorph II Ti112.6°C, Tp126.1°C peaks, valley peak temperature 157.0°C, stable crystal form, proved to be a single crystal form, as shown in Figure 12.

[0154] ②Crystal X-ray diffraction spectrum and data:

[0155] The results proved that the type IV single crystal form: (i) the nitrogen atom and amide oxygen atom of 4-CPR and the ethanol hydroxyl group were combined into 4-CPRE in...

Embodiment 3

[0161] 4-CPRE type IV single crystal energy conversion method:

[0162] ①Solid heating transformation method: the solid containing type III or type V is irradiated with infrared lamps and heated at 30-50°C for 12-6 hours, and the crystal is transformed into a single crystal type of type IV, see attached figure 2 , 3 . ②Refrigeration conversion method: When the solid containing type III or type V is placed at 4°C for about 730 days, 386 days or 275 days, it can be transformed into a single crystal form of type IV or an incompletely transformed polymorph, such as Figure 4 , 6 , 7.

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Abstract

The invention relates to a 4-carboxylphenyl retinamide ethanol compound, a preparation method thereof, and a medicinal composition and application thereof. The structural formula is shown as the specifications.

Description

Technical field: [0001] The present invention relates to a class of retinoid pharmaceutical compounds, 4-carboxyphenyl retinamide ethanolate (abbreviated as 4-CPRE) and its preparation method and pharmaceutical composition and its application in cancer chemoprevention and / or treatment, and its application in skin disease application. Background technique: [0002] In view of the fact that retinol, the representative of retinoid drugs, has the biological activity and function of vitamins (maintaining vision, growth, reproduction and epithelial integrity); its metabolite retinoic acid has a strong new mechanism of action for inducing differentiation of cancer cells (reversing abnormal or cancerous cells to make it "correct") and different from the "poison killing" mechanism of conventional cytotoxic anticancer drugs, it is an effective drug for the treatment and prevention of precancerous lesions, cancer and skin diseases, but it is used as a chemopreventive drug for cancer ,...

Claims

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Application Information

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IPC IPC(8): C07C233/55C07C231/12A61K31/196A61P15/02A61P1/02A61P1/00A61P35/00A61P17/00A61P17/10A61P17/06
CPCC07C2101/16C07C233/55A61K31/196C07C403/20C07C231/12C07C31/08C07B2200/13A61P1/00A61P1/02A61P15/02A61P17/00A61P17/06A61P17/10A61P35/00C07C2601/16
Inventor 吴素珍刘瑞文同琴刘海宁张毅
Owner BEIJING JI KE TE TECH
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