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A class of phthalimide-containing 1,8-naphthalene anhydride derivatives, their pharmaceutically acceptable salts and their antitumor drug applications

A technology of phthalimide and anti-tumor drug, applied in the field of bio-organic synthesis, can solve the problems of limited clinical application and high toxicity

Inactive Publication Date: 2020-08-14
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the toxicity of the two is relatively high, and the clinical application is limited.

Method used

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  • A class of phthalimide-containing 1,8-naphthalene anhydride derivatives, their pharmaceutically acceptable salts and their antitumor drug applications
  • A class of phthalimide-containing 1,8-naphthalene anhydride derivatives, their pharmaceutically acceptable salts and their antitumor drug applications
  • A class of phthalimide-containing 1,8-naphthalene anhydride derivatives, their pharmaceutically acceptable salts and their antitumor drug applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Synthesis of target compound N1:

[0023] (1) Synthesis of intermediate 1 4-piperidinyl-1,8-naphthalene anhydride:

[0024]

[0025] Take 2.77g (10mmol) of 4-bromo-1,8-naphthalene anhydride and place it in a 100mL double-neck round bottom flask, add 40mL of ethylene glycol monomethyl ether as a solvent, add 0.92mL (10mmol) of piperidine, and heat up to 125 ℃, stirred and refluxed for 3 hours, cooled to room temperature, poured into 200mL water to precipitate precipitate, filtered with suction and dried to obtain 2.6g product, yield 92.44%, melting point: 176.0-177.5℃.

[0026] (2) Synthesis of intermediate 2 N-(3'-hydroxy-propyl)-4-piperidinyl-1,8-naphthalene anhydride:

[0027]

[0028] Take 2.5g (8.8mmol) 4-piperidinyl-1,8-naphthalene anhydride and place it in a 100mL double-necked round bottom flask, add 30mL absolute ethanol as a solvent, stir and add n-propanolamine 0.74mL (9.68mmol ), heated and refluxed for 3 hours, cooled to room temperature, poured into...

Embodiment 2

[0038] Synthesis of target compound N2:

[0039] (1) Synthesis of intermediate 1 4-piperidinyl-1,8-:

[0040]

[0041] Take 2.77g (10mmol) of 4-bromo-1,8-naphthalene anhydride and place it in a 100mL double-neck round bottom flask, add 40mL of ethylene glycol monomethyl ether as a solvent, add 0.92mL (10mmol) of piperidine, and heat up to 125 ℃, stirred and refluxed for 3 hours, cooled to room temperature, poured into 200mL water to precipitate precipitates, filtered with suction, and dried to obtain 2.6g of product with a yield of 92.44% and a melting point of 176.0-177.5°C.

[0042] (2) Synthesis of intermediate 2 N-(3'-hydroxy-propyl)-4-piperidinyl-1,8-naphthalene anhydride:

[0043]

[0044]Take 2.5g (8.8mmol) 4-piperidinyl-1,8-naphthalene anhydride and place it in a 100mL double-necked round bottom flask, add 30mL absolute ethanol as a solvent, stir and add n-propanolamine 0.74mL (9.68mmol ), heated and refluxed for 3 hours, cooled to room temperature, poured into...

Embodiment 3

[0054] Synthesis of target compound N3:

[0055] (1) Synthesis of intermediate 1 4-piperidinyl-1,8-:

[0056]

[0057] Take 2.77g (10mmol) of 4-bromo-1,8-naphthalene anhydride and place it in a 100mL double-neck round bottom flask, add 40mL of ethylene glycol monomethyl ether as a solvent, add 0.92mL (10mmol) of piperidine, and heat up to 125 ℃, stirred and refluxed for 3 hours, cooled to room temperature, poured into 200mL water to precipitate precipitate, filtered with suction and dried to obtain 2.6g product, yield 92.44%, melting point: 176.0-177.5℃.

[0058] (2) Synthesis of intermediate 2 N-(3'-hydroxy-propyl)-4-piperidinyl-1,8-naphthalene anhydride:

[0059]

[0060] Take 2.5g (8.8mmol) 4-piperidinyl-1,8-naphthalene anhydride and place it in a 100mL double-necked round bottom flask, add 30mL absolute ethanol as a solvent, stir and add n-propanolamine 0.74mL (9.68mmol ), heated and refluxed for 3 hours, cooled to room temperature, poured into 150mL water to preci...

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Abstract

The invention discloses a phthalimide-containing 1,8-naphthalic anhydride derivative as well as a preparation method and an application thereof, and belongs to the field of biological organic synthesis. According to the phthalimide-containing 1,8-naphthalic anhydride derivative disclosed by the invention, phthalimide pharmacophores with anti-cancer activity are introduced into 1,8-naphthalic anhydride , so that the anti-tumor activity and selectivity of molecules are improved. According to the preparation method of the phthalimide-containing 1,8-naphthalic anhydride derivative, 4-piperidyl-1,8-naphthalic anhydride is synthesized by using piperidyl to substitute Br at the tail end of naphthalene anhydride, and the biological activity is improved; a naphthalimide parent and the phthalimide pharmacophores substituted by different chain ammonia N are connected together through esterification reaction by taking alcohol amine as a bridge chain, the structure-function relationship of drug molecules is studied, and the phthalimide-containing 1,8-naphthalic anhydride derivative with inhibition on growth of in-vitro tumor cells is synthesized.

Description

technical field [0001] The invention relates to the synthesis and application of a class of phthalimide-containing 1,8-naphthalene anhydride derivatives in the field of bioorganic synthesis. Background technique [0002] DNA-targeted antitumor drugs have always been a research hotspot in medicinal chemistry and molecular biology. DNA intercalators can intercalate into DNA base pairs, change their conformation, lead to unwinding and growth of DNA chains, change the process of DNA replication, and exhibit significant antitumor activity. Naphthalimides have been widely used as DNA intercalating agents for anti-tumor, anti-virus, anti-trypanosoma and so on. The earliest reported IC50 values ​​of Amonafide and Mitonafide on Hela cells by Brana's research group are 0.47 μM and 8.80 μM, respectively, and they have now entered phase II clinical trials. However, both are highly toxic and their clinical application is limited. Therefore, in order to reduce toxicity and improve anti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61P35/00A61K31/4545A61K31/496
CPCA61P35/00C07D401/12
Inventor 李晓莲侯晓玲
Owner DALIAN UNIV OF TECH