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1, 8-naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline as well as synthesis and application thereof

A benzoylamino, naphthalene anhydride technology, applied in the field of bio-organic synthesis, can solve the problems of high toxicity, limited clinical application and the like

Active Publication Date: 2021-02-19
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • 1, 8-naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline as well as synthesis and application thereof
  • 1, 8-naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline as well as synthesis and application thereof
  • 1, 8-naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline as well as synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Synthesis of D1:

[0018] (1) Synthesis of intermediate 14-morpholino-1,8-naphthalene anhydride:

[0019]

[0020] Take 2.77g of 4-bromo-1,8-naphthalene anhydride in a 100mL double-necked round bottom flask, add 40mL of ethylene glycol monomethyl ether as a solvent, add 3.52 g of piperidine, heat up to 125°C, stir and reflux for 3 hours, Cool to room temperature, pour into 200mL of water to precipitate precipitate, filter with suction, and dry to obtain 2.6g of product with a yield of 91.87%.

[0021] (2) Synthesis of intermediate 2N-(2'-carboxyacetic acid) 4-morpholinyl-1,8-naphthalene anhydride:

[0022]

[0023] Take 0.57g of 4-morpholino-1,8-naphthalene anhydride and 0.23g of aminoacetic acid in a 100mL double-neck round bottom flask, add 20mL of DMF as a solvent, stir and reflux for 9 hours, cool to room temperature, pour into 200mL of water to precipitate Precipitated, suction filtered and dried to obtain 0.58 g of yellow solid with a yield of 85.0%.

[0...

Embodiment 2

[0039] Synthesis of the final product D2:

[0040] (1) Synthesis of intermediate 14-morpholino-1,8-naphthalene anhydride:

[0041] Synthetic process is identical with example 1

[0042] (2) Synthesis of intermediate 6N-(2'-carboxybutanoic acid) 4-morpholinyl-1,8-naphthalene anhydride:

[0043]

[0044] Take 0.57g of 4-morpholino-1,8-naphthalene anhydride and 0.31g of aminobutyric acid into a 100mL double-neck round bottom flask, add 20mL of DMF as a solvent, heat up to 125°C, stir and reflux for 9 hours, and cool to room temperature , poured into 200mL of water to precipitate a precipitate, filtered with suction, and dried to obtain 0.62g of a yellow solid with a yield of 84.23%.

[0045] (3) Synthesis of intermediate 3 p-nitrobenzoyl chloride:

[0046] Synthetic process is identical with example 1

[0047] (4) Synthesis of intermediate 4N-1-naphthyl-4-nitrobenzamide:

[0048] Synthetic process is identical with example 1

[0049](5) Synthesis of intermediate 5N-1-nap...

Embodiment 3

[0057] Synthesis of the final product D3:

[0058] (1) Synthesis of intermediate 14-morpholino-1,8-naphthalene anhydride:

[0059] Synthetic process is identical with example 1

[0060] (2) Synthesis of intermediate 7N-(2'-carboxyhexanoic acid) 4-morpholinyl-1,8-naphthalene anhydride:

[0061]

[0062] Take 0.57g of 4-morpholino-1,8-naphthalene anhydride and 0.40g of aminobutyric acid into a 100mL double-neck round bottom flask, add 20mL of DMF as a solvent, heat up to 125°C, stir and reflux for 9 hours, and cool to room temperature , poured into 200mL of water to precipitate a precipitate, and dried to obtain 0.67g of a yellow solid with a yield of 84.59%.

[0063] (3) Synthesis of intermediate 3 p-nitrobenzoyl chloride:

[0064] Synthetic process is identical with example 1

[0065] (4) Synthesis of intermediate 4N-1-naphthyl-4-nitrobenzamide:

[0066] Synthetic process is identical with example 1

[0067] (5) Synthesis of intermediate 5N-1-naphthyl-4-aminobenzamide...

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Abstract

The invention discloses naphthalene anhydride derivatives containing 8-(benzoylamino) quinoline as well as a preparation method and application thereof, and belongs to the field of biological organicsynthesis. According to the naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline, 8-(benzoylamino) quinoline pharmacophores with anti-cancer activity are introduced into naphthalic anhydride, so that the biological activity of molecules is improved, and the anti-tumor effect is improved. According to the preparation method of the quinoline-containing naphthalic anhydride derivatives, morpholinyl is used to replace Br at the tail end of naphthalic anhydride, so that the biological activity of the derivatives is improved. Amino acids with different chain lengths are used as bridge chains, a naphthalimide parent and 8- (benzoylamino) quinoline are connected together through an amidation reaction, the structure-activity relationship of drug molecules is studied, and the naphthalic anhydride derivatives containing 8-(benzoylamino) quinoline and having an inhibition effect on in-vitro tumor cell growth is synthesized.

Description

technical field [0001] The invention relates to the synthesis and application of a class of 1,8-naphthalene anhydride derivatives containing 8-(benzoylamino)quinoline 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 embed in DNA base pairs, change their conformation, cause DNA chain unwinding and growth, change the DNA replication process, and exhibit significant anti-tumor 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. [0003] 8-(Benzoylamino)quinoline itself is a chemical s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P35/00
CPCC07D401/12A61P35/00
Inventor 李晓莲侯晓玲解璐同
Owner DALIAN UNIV OF TECH
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