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Salt of pomalidomide prodrug

A technology for drugs and maleates, applied in the field of medicine, can solve problems such as poor structural stability

Inactive Publication Date: 2020-07-21
NANJING NORATECH MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure is poor in stability, and it is easy to degrade when placed at room temperature

Method used

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  • Salt of pomalidomide prodrug
  • Salt of pomalidomide prodrug
  • Salt of pomalidomide prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The preparation of embodiment 1 salt

[0027] The inventor has selected a variety of acids (comprising sulfuric acid, phosphoric acid, hydrochloric acid, formic acid, acetic acid, oxalic acid, oleic acid, lactic acid, nicotinic acid, pamoic acid, methanesulfonic acid, maleic acid, citric acid, fumaric acid, benzenesulfonic acid) Acid, malic acid, lactobionic acid, hippuric acid, benzoic acid, cinnamic acid, adipic acid, stearic acid, orotic acid, glycolic acid, salicylic acid, citric acid, L-tartaric acid, p-toluenesulfonic acid, 4 - chlorobenzenesulfonic acid, D-glutamic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene disulfonic acid), various solvent systems (including ethyl acetate, isopropanol, acetonitrile, methylene chloride, n-propane One or more of alcohol, 2-butanone, tetrahydrofuran, isopropyl acetate, ethanol, n-butanol and n-heptane) for preliminary tests.

[0028] After extensive testing, only hydrochloric acid, sulfuric acid, phosphoric acid, maleic aci...

Embodiment 11

[0030] Preparation of Compound 1

[0031]

[0032] Step1: Under nitrogen protection, add S.M.B (20g, 73.2mmol, 1.00eq) and DMF (400ml) into a 1000mL three-neck reaction flask, and stir electromagnetically. Then sodium hydride (3.5g, 87.5mmol, 1.2eq) was added slowly, and after stirring for 30min, potassium iodide (12g, 72.2mmol, 0.99eq) and TBAB (tetrabutylammonium bromide) (3.52g, 10.9mmol, 0.15 eq), after stirring for 15min, S.M.1 (23.8g, 72.8mmol, 0.99eq) was added and stirred for 12h. Stop the reaction, pour the reaction system into 2L of water, stir for 1h, solids are precipitated, filter to obtain a yellow solid filter cake, the filter cake is washed with 500ml DCM (dichloromethane), separate the liquids, take the organic phase and concentrate it under reduced pressure. Analysis (PE:EA=1.5:1), 13.20g yellow solid product, yield 35.8%.

[0033] Step2: Under nitrogen protection, add Int 1-01 (500mg, 1mmol, 1.00eq) and DCM 5ml into a 100ml three-neck reaction flask, stir...

Embodiment 12

[0038] The preparation of embodiment 1.2 hydrochloride

[0039] 7.0 g of tert-butoxycarbonyl-L-valine (3-(4-(amino)-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiperidine -1-yl)methyl ester (Int 1-01) was suspended in 139 mL of dichloromethane and stirred at 0°C. Add 139mL of hydrochloric acid ethyl acetate solution, naturally rise to room temperature and react for 1 hour. Filter and dry the filter cake in vacuum. The dried solid was slurried with 100 mL of dichloromethane for 2 hours at room temperature. Filter and dry the filter cake in vacuum. 4.58 g of the target product was obtained.

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Abstract

The invention discloses a salt of a pomalidomide prodrug, and particularly relates to a salt of L-valine (3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1-yl) methyl ester, and an application of the salt as an immunomodulator.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to L-valine (3-(4-amino-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiperidine-1- A salt of a methyl ester, a pharmaceutical composition comprising the salt, and an application thereof in the preparation of a medicament for treating cancer. Background technique [0002] Pomalidomide (formula A structure) was developed by Celgene Corporation of the United States, and was approved for marketing in the United States for the first time in February 2013. Pomalidomide is the third immunomodulator of its kind on the market after thalidomide and lenalidomide, which can enhance the immune response mediated by T cells and natural killer cells, while inhibiting the production of pro-inflammatory cells by monocytes Factors (such as TNF-α, IL-6, etc.). In addition, pomalidomide can inhibit the proliferation of tumor cells and induce apoptosis, and it also has a strong inhibitory effect on the prolifera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/454A61P35/00
CPCA61P35/00C07D401/04A61K31/454
Inventor 刘飞赵欣吴刚蔡璇刘伟祁智杨许东
Owner NANJING NORATECH MEDICAL TECH CO LTD