Bismuth (Ⅲ) complex of substituted pyrrolidinylcarbamate and its preparation method and application in the preparation of antitumor drugs

A technology of bismuth pyrrolidine amino acid and complexes, which is applied in the field of anti-tumor drugs, can solve the problems of few anti-tumor cell lines, single structure, low clinical application value, etc., and achieves significant anti-tumor activity, wide application prospect, good The effect of antitumor activity

Active Publication Date: 2016-03-09
TIANJIN BOMEIKAITAI BIOPHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are problems of single structure, few anti-tumor cell lines, and low clinical application value, and there is still a long way to go before clinical application

Method used

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  • Bismuth (Ⅲ) complex of substituted pyrrolidinylcarbamate and its preparation method and application in the preparation of antitumor drugs
  • Bismuth (Ⅲ) complex of substituted pyrrolidinylcarbamate and its preparation method and application in the preparation of antitumor drugs
  • Bismuth (Ⅲ) complex of substituted pyrrolidinylcarbamate and its preparation method and application in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment one: (2R)-2-Methylpyrrolidine bismuth dicarbamate and its preparation

[0032] Add 0.426g (5mmol) (2R)-2-methylpyrrolidine, 0.25g (6mmol) sodium hydroxide, 15mL anhydrous methanol into a round bottom flask, stir and dissolve with a magnetic force, put in a cold water bath at 0-5°C, add dropwise 0.76g (10mmol) CS 2 , Magnetic stirring reaction 5h.

[0033] 0.53g (1.7mmol) BiCl 3 Dissolve in 15 mL of anhydrous methanol, drop into the above reaction solution, stir at room temperature for 3 h, filter with suction, wash with anhydrous methanol, and dry in vacuo. The solid was recrystallized from dichloromethane and ethanol to obtain 0.82 g of a yellow powder solid with a yield of 71.3%. Melting point: 224-226°C, specific rotation =-205 ° (HCl 3 ), number N062.

[0034] 1 HNMR (400MHz, CDCl 3 ),δ:1.362~1.378(9H,d,-CH 3 ,J=6.4Hz),1.692~1.731(3H,m,Cy-CH,J=5.2Hz),2.035~2.071(3H,m,Cy-CH,J=4.0-4.8Hz),2.088~2.161(6H ,m,Cy-CH 2 -,J=4.0-6.8Hz),3.890~3.952(6H...

Embodiment 2

[0036] Embodiment two: (S)-2-Carboxypyrrolidinyl bismuth dicarbamate and its preparation

[0037] Add 0.576g (5mmol) L-proline, 0.759g (7.5mmol) triethylamine, and 15mL anhydrous methanol into a 50mL round bottom flask, stir and dissolve with magnetic force, and add 0.76g ( 10mmol) CS 2 , magnetically stirred for 1 h, stirred at room temperature for 3 h.

[0038] 0.53g (1.7mmol) BiCl 3 Dissolve in 15mL of anhydrous methanol, drop into the above reaction solution, and stir at room temperature for 4h. Use glacial acetic acid to adjust the pH value to 5-6, and a yellow precipitate precipitates, which is suction filtered, washed with anhydrous methanol, and dried. The solid was recrystallized from methanol to obtain 1.05 g of a yellow solid. Yield 80.8%. Melting point: 186-188℃, specific rotation =-103 ° (DMSO).

[0039] 1 HNMR (400MHz, DMSO- d 6 ), δ: 1.971~2.014 (6H, m, Cy-CH 2 ,J=6.4~7.2Hz), 2.272~2.318(6H,m,Cy-CH 2 , J=6.4-7.6Hz), 3.818~3.848(6H,t,N-CH 2 , J=7...

Embodiment 3

[0041] Embodiment three: (S)-2-Ethoxycarbonyl pyrrolidinyl bismuth dicarbamate and its preparation

[0042] Add 0.898g (5mmol) L-proline ethyl ester hydrochloride, 0.44g (11mmol) sodium hydroxide, and 15mL anhydrous methanol into a 50mL round-bottomed flask. Add 0.76g (10mmol) CS 2 , magnetically stirred for 2h, stirred at room temperature for 4h.

[0043] 0.53g (1.7mmol) BiCl 3 Dissolve in 15 mL of anhydrous methanol, drop into the above reaction solution, stir at room temperature for 3 h, filter with suction, wash with anhydrous methanol, and dry in vacuo. The solid was recrystallized from acetonitrile to obtain 1.15 g of bright yellow crystals. Yield 79.9%. Melting point: 89-91℃, specific rotation =-393 ° (CHCl 3 ), number N048.

[0044] 1 HNMR (400MHz, CDCl 3 ),δ:1.261~1.297(9H,t,-CH 3 ,J=7.2Hz),2.069~2.091(3H,m,Cy-CH, J=4.4-6.8Hz),2.092~2.155(6H,m,Cy-CH 2 ,J=5.6-8.2Hz),2.314~2.400(3H,m,Cy-CH,J=6.4-8.0Hz),3.929~3.998(3H,m,N-CH,J=4.4-7.6Hz),4.061 ~4.108(3H,m...

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Abstract

The invention relates to a substituted bismuth (Ⅲ) pyrrolidinylcarbamate complex, the simplified structure of which is as follows. The substituted bismuth (Ⅲ) pyrrolidinylcarbamate complex has good antitumor activity and is effective against gastric cancer, lung cancer, liver cancer, Colorectal cancer, cervical cancer, ovarian cancer, breast cancer, leukemia, colon cancer and other malignant tumors have significant anti-tumor activity, and their development as new anti-tumor drugs has broad application prospects. .

Description

technical field [0001] The invention relates to the technical field of antitumor drugs, in particular to a substituted bismuth (III) pyrrolidinylcarbamate complex, a preparation method thereof and an application in the preparation of antitumor drugs. Background technique [0002] Malignant tumors (cancer) are a serious threat to human health and life. Every year, patients who die from cancer account for about a quarter of the total death toll, and the incidence rate is increasing year by year. Cancer prevention and treatment has become a major issue for medical and life science workers. one of the research topics. The incidence of cancer in my country is astonishing and has become the second most cancer-incidence country in the world. Statistical data (WHOGLOBOCAN2008) shows that all new cancer cases in China are 2.8 million, which is twice the number of new cancer cases in the United States (1.4 million in the United States); In the same year, the number of cancer deaths in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/06C07D207/16C07D207/10A61K31/555A61P35/00A61P35/02
CPCC07D207/06C07D207/10C07D207/16
Inventor 张健郭应臣卓立宏张强
Owner TIANJIN BOMEIKAITAI BIOPHARM TECH CO LTD
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