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7-ethyl-10-hydroxycamptothecin derivatives, and preparation and application thereof

A technology of hydroxycamptothecin and derivatives, applied in the field of medicine, can solve the problems of carcinogenicity, human safety is not as good as fatty acid, improving and other problems

Inactive Publication Date: 2016-07-20
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Chinese patent CN03818985.2 discloses a preparation method using a conjugate of camptothecin derivatives and long-chain unsaturated fatty acids. The publication number is CN1675219A. Although this patent mentions modifying SN-38 with long-chain unsaturated fatty acids, However, in this method, an intermediate "adapter chain" is used to link SN-38 with long-chain unsaturated fatty acids. Due to the existence of the "adapter chain", the compound synthesized by it is relatively inferior to irinotecan. Whether it can be more effectively converted into SN-38 is not reflected in the patent, and due to the existence of the intermediate "connecting chain", the synthesized compound will definitely produce long-chain unsaturated fatty acids and SN-38 in the process of human metabolism. 38, and whether these "other" substances are harmful to the human body is not stated in the patent, and so far there are no related compounds synthesized by this synthesis method for clinical research, so the synthetic method synthesized The effectiveness and safety of the compound is questionable
[0008] Chinese patent application CN200410017128.5 discloses a carbonate prodrug of hydroxycamptothecin and its derivatives and its preparation method. The publication number is CN1673226A. The compound synthesized in this patent mentions SN-38 and unsaturated long chain The alkyl group is connected by the structure of carbonate. Although the carbonate compound can effectively degrade the original drug in the body, according to the chemical theory, in addition to generating SN-38, this structure compound will also generate formaldehyde and unsaturated Long-chain fatty alcohols, among these metabolic compounds, formaldehyde has high toxicity and is a carcinogenic and teratogenic substance. The safety of unsaturated long-chain fatty alcohols is definitely not as clear as that of fatty acids, let alone natural omega-3 fatty acids.
[0009] Chinese patent CN02112268.7 discloses a class of camptothecin derivatives and a preparation method, the publication number is CN1465577A, the patent uses carboxylate or carbonate to simultaneously modify 10-OH and 20-OH of camptothecin compounds, Its main purpose is to improve the water solubility of camptothecin compounds, but from the content of the invention of the patent, it cannot be concluded that the water solubility of related compounds is improved compared with the compound before modification

Method used

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  • 7-ethyl-10-hydroxycamptothecin derivatives, and preparation and application thereof
  • 7-ethyl-10-hydroxycamptothecin derivatives, and preparation and application thereof
  • 7-ethyl-10-hydroxycamptothecin derivatives, and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1: Preparation of 7-ethyl-10-cis-4,7,10,13,16,19-docohexenoyloxycamptothecin

[0050] 1mol 7-ethyl-10-hydroxycamptothecin, 1.2mol cis-4,7,10,13,16,19-docosahexaenoic acid and 1.2mol p-nitrobenzoyl chloride were dissolved in 2L chloroform, After 24 hours of reaction, the solvent was spin-dried, and the obtained drug powder was rinsed twice with ether, dried, dissolved in chloroform, and recrystallized to obtain the pure target product. Yield: 82%.

[0051] 1 HNMR (CDCl 3 , 400MHz, ppm) δ: 8.73 (1H, d, J = 9.14Hz), 8.22 (1H, d, J = 2.46Hz), 8.15 (1H, s), 7.75 (1H, dd, J = 9.14and2.46Hz ), 5.41-5.38 (10H, m), 5.10-5.05 (2H, m), 4.76-4.64 (2H, m), 4.25-4.20 (2H, m), 2.73-2.48 (18H, m), 1.27-1.14 (6H, m), 1.02 (3H, t), 0.87 (3H, t)

[0052] MS (ESI + )m / z:703(M+H + , 100%)

Embodiment 2

[0053] Example 2: Preparation of 7-ethyl-10-cis-4,7,10,13,16,19-docohexenoyloxycamptothecin

[0054] 1mol 7-ethyl-10-hydroxycamptothecin, 1.1mol cis-4,7,10,13,16,19-docosahexaenoic acid and 1.5mol N,N'-dicyclohexylcarbodiimide were dissolved In 2L of chloroform, add a small amount of chloroform to dissolve 2.1mol N, N-diisopropylethylamine, and then add it to the dissolved drug solution using a constant pressure titration funnel. Rinse twice with ether, dry, dissolve in chloroform, and recrystallize to obtain the pure target product. Yield: 74%.

Embodiment 3

[0055] Example 3: Preparation of 7-ethyl-10-cis-4,7,10,13,16,19-docohexenoyloxycamptothecin

[0056] 1mol 7-ethyl-10-hydroxycamptothecin, 1.5mol cis-4,7,10,13,16,19-docosahexaenoic acid and 1.5mol 1-ethyl-(3-dimethylaminopropane Base) carbodiimide hydrochloride was dissolved in 2L dichloromethane, 2.1mol N-hydroxysuccinimide and 1.2mol triethylamine were dissolved in a small amount of dichloromethane and then added to the dissolved drug solution using a constant pressure titration funnel , reacted for 10 hours after sample addition, spin-dried the solvent, rinsed the obtained drug powder twice with ether, dried and dissolved in chloroform, and recrystallized to obtain the pure target product. Yield: 92%.

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Abstract

The invention relates to the technical field of medicine. According to the invention, omega-3 unsaturated fatty acid is used for modifying the 10-site hydroxyl group of 7-ethyl-10-hydroxycamptothecin (SN-38), such that a type of novel 7-ethyl-10-hydroxycamptothecin derivatives are formed. The invention further provides a preparation method of the type of compounds, and an application thereof in preparing anti-tumor drugs. The compound provided by the invention has relatively high lipid solubility, such that medicine preparation is facilitated. The type of compounds have a targeting effect upon tumor tissues, and have good anti-tumor effects and low toxic and side effects.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel ω-3 unsaturated fatty acid modified 7-ethyl-10-hydroxycamptothecin derivative, a preparation method thereof, and an application as an antitumor drug. Background technique [0002] Camptothecin (camptothecin, CPT) is a kind of alkaloid with excellent anti-tumor activity isolated from the plant camptothecin and green brittle branches. In its chemical structure, the lactone ring (E ring), pyridone ring ( D ring) and 20-hydroxyl group are essential groups for camptothecin to exert the inhibitory effect on topoisomerase Ⅰ to achieve anti-tumor effect (SriramD, YogeeswariP, ThirumuruganR, et al.Camptothecinanditsanalogues:reviewontheirchemotherapeuticpotential[J]. 4):393-412.), passed in C 7 、C 9 and C 10 Appropriate modification of camptothecin can often enhance the antitumor effect of camptothecin, and currently among various camptothecin derivatives, 7-ethyl-10-hydroxyca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22A61P35/00
Inventor 陈建明张元声吴婵余侬高保安姚建忠刘文丽陈丽娜邓莉马娟娟
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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