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Novel derivates of camptothecin 10-position coupled bile acid

A technology of derivatives and camptothecin, applied in the field of preparation of camptothecin derivatives, can solve the problems of light and heat instability, low bioavailability, large toxic and side effects, etc., and achieve reduced toxicity, good water solubility, strong The effect of inhibition

Inactive Publication Date: 2011-02-09
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to provide a camptothecin derivative that fully maintains the anti-tumor pharmacological activity of camptothecin and solves the problems of poor solubility, light and heat instability, poor targeting, low bioavailability, and large toxic and side effects.

Method used

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  • Novel derivates of camptothecin 10-position coupled bile acid
  • Novel derivates of camptothecin 10-position coupled bile acid
  • Novel derivates of camptothecin 10-position coupled bile acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of cholic acid-10-O-acetyl camptothecin:

[0048] (1) Synthesis of 10-O-ethyl acetate camptothecin

[0049] Add 182mg (0.5mmol) of 10-hydroxycamptothecin, 1.5mL DMF and 138mg (1mmol) of anhydrous potassium carbonate into a 25mL round-bottomed flask, stir and dissolve, then add 50μl of ethyl bromoacetate, N 2 Heated to 60°C under protection, stirred for 0.5h, and followed the reaction by TLC. After the reaction was complete, potassium carbonate was removed by filtration, concentrated in vacuo, and the resulting solid was dissolved in chloroform and methanol, separated and purified by silica gel column chromatography to obtain compound 10-O - Camptothecin ethyl acetate. Light yellow powder, yield 75%, molecular weight: 436, structural formula as follows:

[0050]

[0051] (2) Synthesis of 10-O-acetoxycamptothecin:

[0052] Into a 25 mL round bottom flask was added 218 mg (0.5 mmol) of 10-O-ethyl acetate camptothecin. Add KOH (0.1mol / L) 5...

Embodiment 2

[0060] Embodiment 2: the synthesis of deoxycholic acid-10-O-acetyl camptothecin:

[0061] (1) Synthesis of 10-O-ethyl acetate camptothecin

[0062] Same as (1) in Example 1

[0063] (2) Synthesis of 10-O-acetoxycamptothecin:

[0064] Same as (2) in embodiment 1

[0065] (3) Synthesis of methyl deoxycholate:

[0066] Add 196mg (0.5mmol) of deoxycholic acid into a 25ml three-necked flask, add 5ml of methanol to dissolve, add 100μl of acetyl chloride, and follow the reaction by TLC. After the reaction is complete, add 15ml of distilled water to precipitate a white solid, filter, and dry in vacuo to obtain the target product. The yield is 95%; the molecular weight is 406; the structural formula is as follows:

[0067]

[0068] (4) Synthesis of deoxycholic acid-10-O-acetylcamptothecin: (A2)

[0069] In a 25ml three-necked flask, 204mg (0.5mmol) of 10-acetoxycamptothecin, 406mg (1mmol) of methyl deoxycholate, 1-[(3-dimethylamino)propyl]-3-ethylcarbonyl Amine hydrochloride (...

Embodiment 3

[0071] Embodiment 3: Synthesis of chenodeoxycholic acid-10-O-acetylcamptothecin:

[0072] (1) Synthesis of 10-O-ethyl acetate camptothecin

[0073] Same as (1) in Example 1

[0074] (2) Synthesis of 10-O-acetoxycamptothecin:

[0075] Same as (2) in embodiment 1

[0076] (3) Synthesis of methyl chenodeoxycholic acid:

[0077] Add 196 mg (0.5 mmol) of chenodeoxycholic acid in a 25 ml three-necked flask, add 5 ml of methanol to dissolve, add 100 μl of acetyl chloride, and follow the reaction by TLC. After the reaction is complete, add 15 ml of distilled water to precipitate a white solid, filter, and dry in vacuo to obtain the target product. Yield 96%; Molecular weight 406; Structural formula is as follows:

[0078]

[0079] (4) Synthesis of chenodeoxycholic acid-10-O-acetylcamptothecin (A3):

[0080] Add 204mg (0.5mmol) of 10-acetoxycamptothecin, 406mg (1mmol) of methyl chenodeoxycholate, and 1-[(3-dimethylamino)propyl]-3-ethylcarbonyl in a 25ml three-necked flask. Imi...

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Abstract

The invention relates to camptothecin derivates of a formal (I) and medicaments thereof, in particular to a method for preparing the compounds of the invention and the use of the compounds as medicaments in tumor treatment. In the formula (I), R1 may be hydrogen and ethyl; R2 may be hydrogen and nitryl; and R3 and R4 may be hydrogen and hydroxyl.

Description

technical field [0001] The invention relates to a preparation method of a class of camptothecin derivatives and their application in antitumor therapy. Background technique [0002] In 1966, camptothecin was discovered by American scientist Monroe E.Wall et al. who studied natural products due to its remarkable anti-tumor activity. In the past 38 years, medicinal chemists have made researches on the structural modification of camptothecin. A lot of work, the United States, Japan, the United Kingdom, Canada and other countries have actively invested in the research and development of camptothecin derivatives, and have made great achievements. A large number of camptothecin derivatives have been designed and synthesized, and there are two camptothecin derivatives successively. Derivatives Topotecan and Irinotecan have been approved as anti-tumor drugs and have been marketed around the world, and more than a dozen other camptothecin derivatives are in different stages of clinic...

Claims

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Application Information

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IPC IPC(8): A61P35/00C07J43/00A61K31/585
Inventor 李庆勇高洋祖元刚张宝友何乌娜赵腾飞邓晓秋朱翅楚
Owner NORTHEAST FORESTRY UNIVERSITY