Preparation and clinic application of hydroxycamptothecin derivative and preparation thereof

A technology of hydroxycamptothecin and its derivatives, which is applied in the preparation and clinical application of a class of hydroxycamptothecin derivatives and their preparations, and can solve the problems of high anti-tumor effect, poor water solubility and ester solubility, and poor ring-opening effect And other problems, to achieve the effect of high curative effect, stable quality, good water solubility

Inactive Publication Date: 2012-10-10
肖文辉 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Hydroxycamptothecin is a cutting-edge drug of the camptothecin class. Its anti-tumor effect is higher than that of camptothecin, and its toxicity is lower than that of camptothecin. However, its water solubility and ester solubility are poor, and it is difficult to make suitable preparations. It must be ring-opened. Otherwise, it will not be absorbed when it is made into an oral preparation, and it will be unstable if it is made into an injection (opening ring), and the ring-opening effect is poor.

Method used

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  • Preparation and clinic application of hydroxycamptothecin derivative and preparation thereof
  • Preparation and clinic application of hydroxycamptothecin derivative and preparation thereof
  • Preparation and clinic application of hydroxycamptothecin derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0063] Synthesis of bipiperine hydrochloride (from hydroxycamptothecin)

[0064] (1) Synthesis of 4-piperidinylpiperidinecarbonyl chloride

[0065] Add 2.82g (9.5mmol) of triphosgene and 20ml of dichloromethane into a 100ml reaction flask equipped with a drying tube, cool to -10°C, add dropwise 1.6g (9.5mmol) of 4-piperidinylpiperidine, dichloromethane The mixture composed of 20ml and 63.9ml (28.5mmol) of triethylamine was naturally warmed to room temperature after the addition, filtered, and the filtrate was concentrated to half, and filtered again. The filter cake was discarded, and the filtrate was concentrated to dryness to obtain 2.02 g of the product, yield: 81%.

[0066] (2) Synthesis of Bipiperidin Hydrochloride

[0067] Take 1.4g (2.6mmol) of 10-hydroxycamptothecin and 50ml of pyridine, dissolve them with an electromagnetic stirrer, dissolve 1.16g (5.04mmol) of 4-piperidinylpiperidinecarbonyl chloride in 30ml of dichloromethane, add dropwise to react solution, stir...

example 2

[0069] Synthesis of bipiperine hydrochloride (from hydroxycamptothecin)

[0070] (1) Synthesis of 10-chloroformyloxycamptothecin:

[0071] Suspend 500 mg (1.27 mmol) of 7-ethyl-10-hydroxycamptothecin in dry dioxane (400 ml), add 2 ml of triethylamine, and heat to dissolve it. While stirring at room temperature while temporarily adding phosgene, the phosgene dimer (trichloromethyl chloroformate) (400 ml) was decomposed in the presence of activated carbon catalyst. After 0.5 hours, when the disappearance of the raw materials was confirmed, the insoluble matter was filtered off, and the solvent was evaporated under reduced pressure to obtain 565 mg (97.0%) of white powder of 10-chloroformyloxycamptothecin.

[0072] (2) Synthesis of Bipiperidin Hydrochloride

[0073] Suspend 300mg (0.66mmol) of 10-chloroformyloxycamptothecin in dry dioxane (50ml), add 330mg (1.96mmol) of 4-piperidinylpiperidine, and stir without heating or heating. Raw material disappears. Then the solvent was...

example 3

[0075] Preparation of biphenhydrin hydrochloride for injection

[0076] (1) Prescription

[0077]

[0078]

[0079] (2) Operation method

[0080] Take bipiperidine hydrochloride (equivalent to 500mg of hydroxycamptothecin) and dissolve it in water, add 0.1mol / L hydrochloric acid solution to adjust the pH value to 2.5-6.0, add 10g of mannitol, decolorize with activated carbon, remove pyrogen, and filter through microporous Membrane filtration, dilute to 200ml, divide into 2ml / bottles, freeze-dry to obtain.

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Abstract

A product of the invention is a variety of hydroxycamptothecin derivative referred to as bipiperidine hydroxycamptothecin {chemical name: (+)-(4S)-4-ethyl-4-hydroxy-9 [ (4-piperidyl piperidine) carbonyl]-1H-pyrano [ 3 ', 4 ', 6 ', 7 '] butoprizine [1, 2-b] quinoline-3, 14-( 4H, 12H ) dione and (0-10) hydrate thereof}. The derivative is a broad-spectrum antineoplastic drug, and has curative effects on primary liver cancer, gastric cancer, head and neck adenoid epithelial cancer, leukemia, colon cancer, bladder cancer and other malignant tumors. The ipiperidine hydroxycamptothecin, salts thereof and (0-10) hydrate of the salts are prodrugs for hydroxycamptothecin and converted into closed hydroxycamptothecin in vivo, so as to overcome defects of open loop, poor effect and instability of a hydroxycamptothecin preparation (injection, lyophilized injection and oral preparation); and the derivative has good water solubility and is suitable for preparation of various types of preparations. The bipiperidine hydroxycamptothecin can be added with different salts to be prepared into different water-soluble compounds and hydrates thereof, is beneficial to preparation of various preparations, and has stable quality and curative effect obvious better than that of hydroxycamptothecin and preparation thereof. The bipiperidine hydroxycamptothecin, salts thereof, (0-10) hydrate of the salts and preparations thereof are in forms of tablet, capsule, particulate agent, oral liquid, injection, infusion solutions and lyophilized injection.

Description

1. Technical field [0001] The invention belongs to the preparation and clinical application of a class of hydroxycamptothecin derivatives (abbreviated as hydroxycamptothecin) and its preparations. 2. Background technology [0002] Hydroxycamptothecin is a cutting-edge drug of the camptothecin class. Its anti-tumor effect is higher than that of camptothecin, and its toxicity is lower than that of camptothecin. However, its water solubility and ester solubility are poor, and it is difficult to make suitable preparations. It must be ring-opened. Otherwise, it is not absorbed when it is made into an oral preparation, and it is unstable when it is made into an injection (opening ring), and the ring-opening effect is relatively poor. Therefore, making hydroxycamptothecin into a prodrug not only solves the shortcomings of hydroxycamptothecin instability and poor ring-opening curative effect, but also absorbs well and is easy to be made into different preparations, which will comple...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61K31/4745A61P35/00A61P35/02
Inventor 肖文辉熊祥珍
Owner 肖文辉
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