Pharmaceutical composition of camptothecin derivative and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition, which comprises (+)-(4S)-11-succinyl oxyethyl-4-ethyl-4-hydroxy-1H pyran[3',4',6,7]indolizine[1,2-b]quinoline-3,14-(4H,12H)-dione or its pharmaceutically acceptable salt, a stabilizing agent and a pH conditioning agent, wherein the pH value is 6.0-7.2.

Description

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition of camptothecin derivatives, a preparation method thereof, and an application for treating tumors. Background technique

[0002] Camptothecin (CPT) is an alkaloid extracted from Camptotheca acuminata, a plant unique to China, which prevents the replication of cancer cells by selectively acting on DNA topoisomerase I (Top I). Play an anti-cancer role. The applications of camptothecin and hydroxycamptothecin are limited due to their poor solubility and large toxic and side effects. Since the first separation, hundreds of camptothecin derivatives and analogs have been synthesized in the world. The positions of structural modification are mostly at the 7, 9 and 10 carbons of camptothecin. By introducing different substituents at these positions In order to improve drug efficacy, reduce toxicity and improve solubility, etc., the representative drugs t...

Examples

Embodiment 1

[0030] Example 1 (+)-(4S)-11-succinyloxyethyl-4-ethyl-4-hydroxyl-1H pyrano[3',4',6,7]indoleazine[1,2 -b] Preparation of quinoline-3,14-(4H,12H)-dione

[0031] Dissolve 1g of 7-hydroxyethylcamptothecin in 40mL of dry dimethyl sulfoxide, add 2g of succinic anhydride, and then add 2mL of dry pyridine, then stir and reflux for 12 hours. The reaction mixture was poured into a separatory funnel, 50 mL of distilled water was added, the aqueous solution was extracted with dichloromethane (200 mL*3), combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. It was separated by silica gel column chromatography and eluted with dichloromethane / methanol 50:1.5 to obtain 840 mg of a light yellow solid (66% yield).

Embodiment 2

[0033] Sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride were dissolved in 500 mL of water for injection, and adjusted to a solution of pH 6.6. Add 25g of lactose to the above solution, stir until it is completely dissolved, then add 0.2% activated carbon to the solution, boil and cool to 60°C for 30 minutes to remove carbon. Add 1 g (calculated as dry product) of the compound of formula 1 into the above decarburized solution, and dissolve until clear. After primary filtration, the medicinal solution is sterilized and filtered through a 0.22 μm filter to obtain a semi-finished product solution. Check the semi-finished product solution to see foreign matter, content and pH. After passing the test, it will be divided into packages, and then put into a freeze-drying box after half-tightening, and then freeze-dried.

Embodiment 3

[0035] Dissolve sodium hydroxide in 500mL water for injection and adjust to pH 7.2. Add 5g of threonine to the above solution, stir until completely dissolved, then add 0.2% activated carbon to the solution, boil and cool to 60°C for 30 minutes to decarbonize. Add 1 g (calculated as dry product) of the compound of formula 1 into the above decarburized solution, and dissolve until clear. After primary filtration, the medicinal solution is sterilized and filtered through a 0.22 μm filter to obtain a semi-finished product solution. Check the semi-finished product solution to see foreign matter, content and pH. After passing the test, it will be subpackaged, and then put into a freeze-drying box after half-tightening, and freeze-dried.

technical field

[0001] The invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition of camptothecin derivatives, a preparation method thereof, and an application for treating tumors. Background technique

[0002] Camptothecin (CPT) is an alkaloid extracted from Camptotheca acuminata, a plant unique to China, which prevents the replication of cancer cells by selectively acting on DNA topoisomerase I (Top I). Play an anti-cancer role. The applications of camptothecin and hydroxycamptothecin are limited due to their poor solubility and large toxic and side effects. Since the first separation, hundreds of camptothecin derivatives and analogs have been synthesized in the world. The positions of structural modification are mostly at the 7, 9 and 10 carbons of camptothecin. By introducing different substituents at these positions In order to improve drug efficacy, reduce toxicity and improve solubility, etc., the representative drugs t...

Examples

Embodiment 1

[0030] Example 1 (+)-(4S)-11-succinyloxyethyl-4-ethyl-4-hydroxyl-1H pyrano[3',4',6,7]indoleazine[1,2 -b] Preparation of quinoline-3,14-(4H,12H)-dione

[0031] Dissolve 1g of 7-hydroxyethylcamptothecin in 40mL of dry dimethyl sulfoxide, add 2g of succinic anhydride, and then add 2mL of dry pyridine, then stir and reflux for 12 hours. The reaction mixture was poured into a separatory funnel, 50 mL of distilled water was added, the aqueous solution was extracted with dichloromethane (200 mL*3), combined, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. It was separated by silica gel column chromatography and eluted with dichloromethane / methanol 50:1.5 to obtain 840 mg of a light yellow solid (66% yield).

Embodiment 2

[0033] Sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride were dissolved in 500 mL of water for injection, and adjusted to a solution of pH 6.6. Add 25g of lactose to the above solution, stir until it is completely dissolved, then add 0.2% activated carbon to the solution, boil and cool to 60°C for 30 minutes to remove carbon. Add 1 g (calculated as dry product) of the compound of formula 1 into the above decarburized solution, and dissolve until clear. After primary filtration, the medicinal solution is sterilized and filtered through a 0.22 μm filter to obtain a semi-finished product solution. Check the semi-finished product solution to see foreign matter, content and pH. After passing the test, it will be divided into packages, and then put into a freeze-drying box after half-tightening, and then freeze-dried.

Embodiment 3

[0035] Dissolve sodium hydroxide in 500mL water for injection and adjust to pH 7.2. Add 5g of threonine to the above solution, stir until completely dissolved, then add 0.2% activated carbon to the solution, boil and cool to 60°C for 30 minutes to decarbonize. Add 1 g (calculated as dry product) of the compound of formula 1 into the above decarburized solution, and dissolve until clear. After primary filtration, the medicinal solution is sterilized and filtered through a 0.22 μm filter to obtain a semi-finished product solution. Check the semi-finished product solution to see foreign matter, content and pH. After passing the test, it will be subpackaged, and then put into a freeze-drying box after half-tightening, and freeze-dried.

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