1,8-anhydride naphthalene derivative with side chain containing isoquinoline and synthesis and application thereof

A technology of isoquinoline and naphthalene anhydrides, which is applied in the field of bioorganic synthesis, can solve the problems of limited clinical application, high toxicity of arinafetide and mitonaftamide, etc.

Inactive Publication Date: 2017-01-04
DALIAN UNIV OF TECH
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Classical naphthalimide DNA intercalators include naphfetamide and mitonaphtamide, wherein mitonaftamide is a 3-nitromononaphthimide derivative, and its mechanism of action is similar to that of naphfetamide, but Aminafetide and Mitonaphthamide are highly toxic and their clinical application is limited

Method used

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  • 1,8-anhydride naphthalene derivative with side chain containing isoquinoline and synthesis and application thereof
  • 1,8-anhydride naphthalene derivative with side chain containing isoquinoline and synthesis and application thereof
  • 1,8-anhydride naphthalene derivative with side chain containing isoquinoline and synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Synthesis of N-[3'-(3",4"-dihydroisoquinolin-2(1H)-yl)-propyl]-4-piperidinyl-1,8-naphthalene anhydride:

[0021] (1) Synthesis of intermediate 1 4-R base-1.8-naphthalene anhydride:

[0022]

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

[0024] 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 °C, stirred and refluxed for 3 hours, cooled at room temperature for half an hour, poured into 200ml of water to precipitate precipitates, filtered with suction and dried to obtain 2.6g of the product with a yield of 92.53%.

[0025] (2) Synthesis of intermediate N-(3'-hydroxyl-propyl)-4-R base-1,8-naphthalene anhydride:

[0026]

[0027] Synthesis of intermediate N-(3'-hydroxy-propyl)-4-piperidinyl-1,8-naphthalene anhydride:

[0028] Take 2.5g (8.8mmol) of 4-piperidiny...

Embodiment 2

[0040] Synthesis of N-[3'-(3",4"-dihydroisoquinolin-2(1H)-yl)-propyl]-4-thiomorpholinyl-1,8-naphthalene anhydride:

[0041] (1) Synthesis of intermediate 4-thiomorpholino-1,8-naphthalene anhydride:

[0042] 1.01 mL (10 mmol) of thiomorpholine was added instead of piperidine, and the rest of the synthesis process was the same as in Example 1 to obtain 2.7 g of the product with a yield of 90.30%.

[0043] (2) Synthesis of intermediate N-(3'-hydroxy-propyl)-4-thiomorpholino-1,8-naphthalene anhydride:

[0044] Take 2.5g (8.4mmol) of 4-thiomorpholino-1,8-naphthalene anhydride instead of 4-piperidinyl-1,8-naphthalene anhydride, add 0.7mL (9.24mmol) of n-propanolamine, and the rest of the synthesis process Same as in Example 1, 2.5 g of product was obtained with a yield of 83.61%.

[0045] (3) Synthesis of intermediate N-(3'-bromo-propyl)-4-thiomorpholino-1,8-naphthalene anhydride:

[0046] Take 2.2g (6.2mmol) of N-(3'-hydroxy-propyl)-4-thiomorpholino-1,8-naphthalene anhydride inste...

Embodiment 3

[0054] Synthesis of N-[3'-(3",4"-dihydroisoquinolin-2(1H)-yl)-propyl]-4-morpholinyl-1,8-naphthalene anhydride:

[0055] (1) Synthesis of intermediate 4-morpholino-1,8-naphthalene anhydride:

[0056] 0.87mL (10mmol) morpholine was added instead of piperidine, and the rest of the synthesis process was the same as in Example 1 to obtain 2.5g of product with a yield of 88.34%.

[0057] (2) Synthesis of intermediate N-(3'-hydroxyl-propyl)-4-morpholinyl-1,8-naphthalene anhydride:

[0058] Take 2.4g (8.5mmol) 4-morpholino-1,8-naphthalene anhydride instead of 4-piperidinyl-1,8-naphthalene anhydride, add 0.71mL (9.35mmol) n-propanolamine, and carry out the rest of the synthesis process Example 1, 2.3g of product was obtained, yield 79.58%.

[0059] (3) Synthesis of intermediate N-(3'-bromo-propyl)-4-morpholinyl-1,8-naphthalene anhydride:

[0060] Take 2.2 g (6.5 mmol) of N-(3'-hydroxy-propyl)-4-morpholinyl-1,8-naphthalene anhydride instead of N-(3'-hydroxy-propyl)-4-piperidinyl- Fo...

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Abstract

The invention discloses a 1,8-anhydride naphthalene derivative with the side chain containing isoquinoline and synthesis and application thereof, and belongs to the field of biological organic synthesis. According to the 1,8-anhydride naphthalene derivative with the side chain containing isoquinoline, 1,2,3,4-tetrahydro naphthalene is introduced into one end of naphthalimide through an alkyl chain to serve as pharmacophore, a different cyclammonium side chain is introduced into the other end of naphthalimide, the purpose is to introduce isoquinoline pharmacophore with the antitumor activity to increase the conjugate area and improve biological activity of molecules, and therefore the antitumor effect is improved.

Description

technical field [0001] The invention relates to the synthesis and application of a class of 1,8-naphthalene anhydride derivatives containing isoquinoline in the side chain 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. Naphthalimide derivatives are very classic DNA intercalator precursors, which have a planar three-membered ring rigid structure and are easy to modify. Classical naphthalimide DNA intercalators include naphfetamide and mitonaphtamide, wherein mitonaftide is a 3-nitromononaphthimide derivative, and its mechanism of action is similar to that of naphfetamide, but Aminafetide and Mitonaphthamide are highly toxic and their clini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06A61P35/00
CPCC07D401/06
Inventor 李晓莲赵蓉雷延鸣
Owner DALIAN UNIV OF TECH
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