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Folic acid compound, and preparation method and pharmaceutical application thereof

A compound, folic acid technology, applied in the field of medicinal chemistry and pharmacotherapeutics, which can solve the problems of lack of drugs, toxic and side effects, etc.

Active Publication Date: 2016-03-02
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a variety of anti-tumor drugs are available clinically, due to the drug resistance of tumors and the side effects of anti-tumor drugs, there is still a lack of effective and curable drugs, and it is urgent to develop new drugs to meet the needs of cancer patients

Method used

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  • Folic acid compound, and preparation method and pharmaceutical application thereof
  • Folic acid compound, and preparation method and pharmaceutical application thereof
  • Folic acid compound, and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Synthesis of 6-bromohexyl rhein

[0061] Add rhein (284mg, 1mmol) into a 50mL round-bottomed flask, use THF as a solvent, stir at room temperature for 5 minutes, then add 1,6-dibromohexane (4mmol), triethylamine (4mmol), tetra-n-butyl bromide Ammonium chloride (40.3 mg, 0.25 mmol) was added into the round bottom flask, and the stirring was continued at room temperature. The reaction progress was detected by TLC, and the reaction was complete after 18 h. Concentrate under reduced pressure and separate by silica gel column chromatography. Concentrate under reduced pressure and dry to obtain 404.1 mg of rhein-6-bromohexyl ester as an orange solid, with a yield of 90.6%. m.p.: 131.4-132.6°C.

[0062] Synthesis of Folate-6-Rheinyl Hexyl Ester

[0063] Put 6-bromohexyl rhein (111.5mg, 0.25mmol), folic acid (132.3mg, 0.3mmol), 5 drops of pyridine, KI (49.8mg, 0.3mmol) in a 50mL round bottom flask, add DMSO8mL, 45 The reaction was carried out in the dark at ℃, and the progr...

Embodiment 2

[0065] Synthesis of Gambogic Acid-2-Bromoethyl Ester

[0066] Add gambogic acid (628mg, 1mmol), 1,2-dibromoethane (4mmol), potassium carbonate (138mg, 1mmol), DMF15mL into a 100mL round bottom flask, stir at room temperature, TLC to detect the reaction process, and the reaction is complete after 2h . Add 150 mL of water, extract with ethyl acetate (50 mL×3), combine the organic layers, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and separate by silica gel column chromatography. Obtained 589.4 mg of gambogic acid-2-bromoethyl ester as an orange solid, with a yield of 80.3%. m.p.: 85.6-86.1°C.

[0067] Synthesis of Folate-2-Gambozoyl Ethyl Ester

[0068] Take folic acid (83.8mg, 0.19mmol), gambogic acid-2-bromoethyl ester (117.4mg, 0.16mmol), 4 drops of pyridine, and 10mL of DMSO in a 100mL round bottom flask, react in the dark at 45°C, and detect the reaction by TLC Process, the reaction was complete after 10.5h. Co...

Embodiment 3

[0070] Synthesis of Neogambogic Acid-3-Bromopropyl Ester

[0071] In a dry 50ml round bottom flask, neogambogic acid (320mg, 0.5mmol), K 2 CO 3 (140mg, 1mmol) and 1,3-dibromopropane (4mmol) were dissolved in 10mL DMF, stirred at room temperature for 1h. Filtrate, add 100 mL of water to the filtrate, extract with ethyl acetate (3×30 mL), combine the organic layers, wash with saturated brine, wash with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated and separated by silica gel column chromatography. 345mg of bromopropanol neogambogic acid was obtained as a bright yellow oily substance, yield: 92%.

[0072] Synthesis of folate-3-neogamboyl propyl ester

[0073] Take folic acid (132.3mg, 0.3mmol), neogambogic acid-3-bromopropyl ester (187.5mg, 0.25mmol), 7 drops of pyridine, and 10mL of DMSO in a 100mL round bottom flask, react in the dark at 45°C, and detect the reaction by TLC Process, the reaction is complete after 10h. Cool to room temperat...

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Abstract

The invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a folic acid compound or a pharmaceutically acceptable salt thereof. The invention also relates to the preparation method of the compound and a pharmaceutical composition containing the compound. The compound has antineoplastic effect and can be used for the preparation of antineoplastic drugs.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to folic acid compounds or pharmaceutically acceptable salts thereof, preparation methods and pharmaceutical compositions containing these compounds, and their medical use, especially in the preparation of antitumor drugs Applications. Background technique [0002] Malignant tumors are a type of disease that seriously threatens human life. The "Global Cancer Report 2014" released by the World Health Organization predicts that global cancer cases will show a rapid growth trend, from 14 million in 2012 to 19 million in 2025. people, reaching 24 million by 2035. Although a variety of anti-tumor drugs are available clinically, due to the drug resistance of tumors and the side effects of anti-tumor drugs, there is still a lack of effective and curable drugs. It is urgent to develop new drugs to meet the needs of cancer patients. Because of its strong...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/04C07D519/00A61K31/519A61P35/00A61P35/02
CPCC07D475/04C07D519/00
Inventor 何黎琴黄骏凯王蓉张汪伟
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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