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Aryl alkyl acid-cyclophosphamide derivative as well as preparation method and application thereof

A technology of cyclophosphamide and aryl alkanoic acid, which can be used in chemical instruments and methods, drug combinations, pharmaceutical formulations, etc., and can solve problems such as bladder toxicity

Inactive Publication Date: 2014-11-26
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, cyclophosphamide has a broad antibacterial spectrum and less toxicity than other nitrogen mustards, so it is widely used in clinical practice, but its disadvantage is bladder toxicity

Method used

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  • Aryl alkyl acid-cyclophosphamide derivative as well as preparation method and application thereof
  • Aryl alkyl acid-cyclophosphamide derivative as well as preparation method and application thereof
  • Aryl alkyl acid-cyclophosphamide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Dihydro-1,3,2-benzoxaphos-7-carboxypropyl-2-amino, N,N-bis(2-chloroethyl)-3,4-dihydro-,2-oxide ( 1) Preparation:

[0018] (1) has a structure such as Figure 5 shown.

[0019] In the dry reactor, put 66.5g (0.5mol) aluminum trichloride and 100mL carbon disulfide, stir and cool to 7-8°C, quickly put 10.8g (0.1moL) anisole and 10.0g (0.1moL) succinic anhydride The mixture was reacted at 30-45°C for 1 hour, stood still for several hours, ice-thawed, and filtered to obtain 15.6 g of 4-methoxybenzoylpropionic acid with a yield of 75% and a melting point of 148-150°C.

[0020] Throw 10.4g (0.05moL) 4-methoxybenzoylpropionic acid and 2.4g (0.06moL) 80% hydrazine hydrate into the reactor, heat to about 140°C, react for 20 minutes, cool down to 100°C, brown solid Precipitate, slowly add 3.92g (0.07moL) KOH, after being completely dissolved, heat to 140°C to denitrify, complete, cool, add water, adjust pH to acidic with hydrochloric acid, precipitate solid, filter, and dry ove...

Embodiment 2

[0024] Dihydro-1,3,2-benzoxaphos-7-carboxypropyl-2-amino, N,N-bis(2-chloroethyl)-3-carboxymethyl-3,4-dihydro- , Preparation of 2-oxide (2):

[0025] (2) has a structure such as Figure 6 shown.

[0026] Add 3.88g (20 mmol) 4-hydroxyphenylbutyric acid to dissolve in 50 mL THF in the reactor, add 3mL (40mmol) formaldehyde, 1.96g (22mmoL) glycine methyl ester, heat, react for 8h, cool, concentrate, The crude product of Mannich base was obtained, and the pure product was obtained by column chromatography. Take 0.24g (1mmol) of this Mannich base, 0.26g (1mmol) of phosphoryl mustard, dissolve in 15 mL of dry tetrahydrofuran, add dropwise 0.3mL of Et 3 The mixed solution of N and 5mL dry tetrahydrofuran was dripped over 30min, reacted at room temperature for 2h, then heated to reflux, monitored by TLC, filtered after stopping the reaction, removed insoluble matter, concentrated the filtrate, dissolved the residue in ethanol, and washed with sodium hydroxide Hydrolyze at room temp...

Embodiment 3

[0028] Dihydro-1,3,2-benzoxaphos-7-carboxypropyl-2-amino, N,N-bis(2-chloroethyl)-3-hydroxyethyl-3,4-dihydro- , Preparation of 2-oxide (3):

[0029] (3) has a structure such as Figure 7 shown.

[0030] Add 3.88g (20 mmol) 4-hydroxyphenylbutyric acid to dissolve in 50 mL THF in the reaction kettle, add 3 mL (40 mmol) formaldehyde, 1.34 g (22mmoL) monoethanolamine, heat, react for 6h, cool, and concentrate to obtain The crude product of Mannich base was purified by column chromatography. Take 0.23g (1mmol) of this Mannich base, 0.26g (1mmol) of phosphoryl mustard, dissolve in 15 mL of dry tetrahydrofuran, add dropwise 0.3mL of Et 3The mixed solution of N and 5mL dry tetrahydrofuran was dripped over 30min, reacted at room temperature for 2h, then heated to reflux, monitored by TLC, filtered after stopping the reaction, removed insoluble matter, concentrated the filtrate, and separated by column chromatography to obtain the target compound dihydrofuran -1,3,2-benzoxaphos-7-car...

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Abstract

The invention discloses an aryl alkyl acid-cyclophosphamide derivative of a general formula I or a pharmaceutically acceptable hydrate and a pharmaceutically acceptable salt thereof. The aryl alkyl acid-cyclophosphamide derivative comprises a stereoisomer or a tautomer. In the formula, R1 is H or various alkyls, and the alkyls can be arbitrarily substituted with substituent groups of halogen, amino, substituted amino, carboxyl, hydroxyl, ester, cyan, nitryl, aryl and substituted aryl; R2 is H or various substituent groups; q is an integer of 0-4; n and m are integers of 1-3; and X is C1, OSO2Me, OH, OSO2Ar, Br or OCOR. The aryl alkyl acid-cyclophosphamide derivative has a remarkable inhibition effect on a mouse liver cancer 22 (H22), so that the aryl alkyl acid-cyclophosphamide derivative can be applied to the preparation of anti-tumor drugs. The invention further discloses a preparation method for the aryl alkyl acid-cyclophosphamide derivative.

Description

technical field [0001] The invention relates to aryl alkanoic acid cyclophosphamide derivatives, their preparation method and their application as anticancer drugs. Background technique [0002] Nitrogen mustard compounds are the earliest and most important class of antineoplastic drugs, and play an important role in the treatment of tumors. Among them, cyclophosphamide has a broad antibacterial spectrum and is less toxic than other nitrogen mustards. It is widely used in clinical practice, but its disadvantage is bladder toxicity. In order to reduce its toxic and side effects, chemists at home and abroad have carried out various structural modifications on it, and found some ideal compounds, such as: Telcyta (Lyttle MH, Satyam A, Hocker MD, et al. J. Med. Chem. 1994,37,1501), chlorambucil and melphalan, etc. [0003] Nitrogen mustard antitumor compounds are generally divided into two parts: an alkylating part and a carrier part. The alkylation part is the functional grou...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6584A61K31/675A61P35/00
Inventor 史兰香张宝华何敬宇刘斯婕
Owner SHIJIAZHUANG UNIVERSITY
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