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Camptothecin silicone hybrid derivative, composition containing camptothecin silicone hybrid derivative and application thereof

A kind of derivative, camptothecin technology, applied in the field of drug synthesis, can solve the problems of complex synthetic process route, high production cost, low yield and the like

Active Publication Date: 2013-02-06
微缔医药科技(杭州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Using camptothecin 1 as the starting material, alkylate its 7-position to make 7-ethylcamptothecin 2, and further prepare 10-hydroxy-7-ethylcamptothecin 3, 3 and phosgene from 2 After the reaction, react with piperidinyl to obtain the target product 4 (Eckardt JR, Burris HA, Rothenberg ML, et al, Promising Novel Compounds Contemp[J], Oncol, 1993.4:47). The disadvantage of this type of technical solution is that : complex synthetic process route, low yield; and limited by the starting material camptothecin, it is difficult to produce on a large scale, and the production cost is higher

Method used

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  • Camptothecin silicone hybrid derivative, composition containing camptothecin silicone hybrid derivative and application thereof
  • Camptothecin silicone hybrid derivative, composition containing camptothecin silicone hybrid derivative and application thereof
  • Camptothecin silicone hybrid derivative, composition containing camptothecin silicone hybrid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: 4,11-diethyl-4-hydroxyl-9-[(4-dimethylsilapiperidinylpiperidinyl)carbonyloxy]-1H-pyrano[3',4': Preparation of 6,7]indoxazin[1,2-b]quinoline-3,14-(4H,12H)-dione·hydrochloride (SM01·HCl)

[0068] Step 1, Preparation of 1-(tert-butoxycarbonyl)-4-(dimethylsilapiperidinyl)piperidine (1)

[0069] Add 23.3g of dimethylsilapiperidine, 28.7g of N-Boc-piperidone, and 200mL of anhydrous methanol into the reaction flask, stir until dissolved, add 22.6g of sodium cyanoborohydride, and react overnight at room temperature. Rotary evaporation to remove methanol, add 200mL water, extract three times with ethyl acetate, combine organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, dichloromethane:methanol (20:1) column chromatography, get shallow 19.17 g of yellow oily substance, namely intermediate product 1.

[0070] Step 2, Preparation of 4-(dimethylsilapiperidinyl)piperidine (2)

[0071] The intermediate product 1 (1...

Embodiment 2

[0077] Example 2: 4,11-diethyl-4-hydroxy-9-[(4-methylphenylsilapiperidinylpiperidinyl)carbonyloxy]-1H-pyrano[3',4' : Preparation of 6,7]indoxazin[1,2-b]quinoline-3,14-(4H,12H)-dione hydrochloride (SM02·HCl)

[0078] Step 1, Preparation of 1-(tert-butoxycarbonyl)-4-(methylphenylsilapiperidinyl)piperidine (1)

[0079] Add 30.3g of methylphenylsilapiperidine, 23.6g of N-Boc-piperidone, and 200mL of anhydrous methanol into the reaction flask, stir until dissolved, add 20g of sodium cyanoborohydride, and react overnight at room temperature. Remove methanol by rotary evaporation, add 200mL of water, extract three times with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, dichloromethane:methanol 20:1 column chromatography, get light yellow oil The compound 21.3g is the intermediate product 1.

[0080] Step 2, Preparation of 4-(methylphenylsilapiperidinyl)piperidine (2)

[0081] Dissolve the int...

Embodiment 3

[0088] Example 3: Acute Toxicity Test of Camptothecin Silica Derivatives

[0089] Experimental animals: ICR mice, provided by the Zhejiang Provincial Experimental Animal Center, weighing 18-22g / mouse, 10 in each group, half male and half male; adaptive feeding in the laboratory at 25°C for 2 days before administration.

[0090] Test samples: Compounds SM01, SM02, SM03, SM04, SM01·HCl, SM02·HCl, SM03·HCl and SM04·HCl were prepared by dissolving in 5% glucose solution respectively, each given by single tail vein injection of 100mg / kg dose The drug was continuously observed for 7 days, and the toxicity reaction of animals and the distribution of dead animals were recorded day by day. At the end of the experiment, no experimental animals died, indicating that the median lethal dose (LD50) of compounds SM01, SM02, SM03, SM04, SM01·HCl, SM02·HCl, SM03·HCl and SM04·HCl administered intravenously was greater than 100 mg / kg.

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Abstract

The invention provides a camptothecin silicone hybrid derivative with a novel structure or a pharmaceutically acceptable salt or solvate thereof and also provides a medicine composition containing medicine effective quantity of the camptothecin silicone hybrid derivative or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient or additive. The general structural formula of the camptothecin silicone hybrid derivative is shown as a formula (I). According to the invention, a series of camptothecin silicone hybrid derivatives obtained through transformation and structural modification on irinotecan has an inhibition effect on multiple tumour cells, especially has a higher inhibition ratio to tumour cells of diseases such as lung caner, gastric cancer, ovarian cancer and rectal cancer and has obvious compound antitumour activity. According to the invention, the design is reasonable, preparation raw materials are available and easy to obtain, a preparation method is simple and convenient, operation is easy, reaction conditions are mild, and product yield is high, and industrialization mass production can be facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a camptothecin silica derivative, a composition containing the derivative and its pharmaceutical application, especially the application in preparing antitumor drugs. Background technique [0002] Camptothecin (hereinafter referred to as CPT) was extracted by Wall et al. from the stem bark of Campylodontaceae in 1966. It belongs to pentacyclic alkaloids. It targets DNA topoisomerase Ⅰ and inhibits The synthesis of biological DNA exerts an anti-tumor effect. Clinically, camptothecin is used to treat gastric cancer, colon cancer, rectal cancer and bladder muscle cancer. Its suspension is also used to treat liver cancer and leukemia. However, because camptothecin is insoluble in water, its sodium salt has serious side effects. In addition to gastrointestinal toxicity and bone marrow suppression, severe cases will damage the kidneys and produce hematuria. These...

Claims

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Application Information

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IPC IPC(8): C07F7/10A61K31/695A61P35/00
CPCY02P20/55
Inventor 马凤森方多凤
Owner 微缔医药科技(杭州)有限公司