Phenylpiperazine derivatives for inhibiting tumor metastasis and tumor angiogenesis

A technology of phenylpiperazine and derivatives, which is applied in the field of medicine, can solve the problems of different mechanisms and degrees of tumor metastasis and spread, and achieves the effects of improved pharmacological activity, suitable molecular weight and low cost

Active Publication Date: 2011-11-30
蒋杰 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Due to the differences in types, the mechanisms and degrees of tumor metastasis and spread are different. So far, there are few drugs with a strong inhibitory effect on tumor metastasis that are actually used clinically.

Method used

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  • Phenylpiperazine derivatives for inhibiting tumor metastasis and tumor angiogenesis
  • Phenylpiperazine derivatives for inhibiting tumor metastasis and tumor angiogenesis
  • Phenylpiperazine derivatives for inhibiting tumor metastasis and tumor angiogenesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of intermediate 1-(4-methoxyphenyl)piperazine

[0053] Slowly add the mixture of diethanolamine diluted with chloroform dropwise under stirring to the mixed solution of thionyl chloride (the molar ratio of diethanolamine is 1:4) and chloroform cooled to about 0°C. After the dropwise addition, Continue to stir and react at room temperature for 2-5h, then gradually raise the temperature to 30-70°C, maintain this temperature for 2h, after the reaction is completed, add absolute ethanol, cool, filter under reduced pressure, wash the solid with ethanol and ether, and dry to obtain Bis(2-chloroethyl)amine hydrochloride, yield 97.8%, mp: 205.1-207.0°C.

[0054] Add 4.3g (24mmol) of bis(2-chloroethyl)amine hydrochloride and 2.5g (20mmol) of 4-methoxyaniline solid into 50mL of n-butanol, stir and mix evenly, irradiate with microwave for 6min under 195w power, and cool slightly Finally, add 1.3g (12mmol) of anhydrous sodium carbonate powder, continue microwave radiatio...

Embodiment 2

[0056] Synthesis of 3-Phenylcycloglutaric Anhydride

[0057] Mix 10.6g of benzaldehyde (0.1mol), 26.0mL (0.2mol) of ethyl acetoacetate, and 100mL of 95% ethanol, and slowly add 4.0mL of hexahydropyridine solution dropwise to the above mixture under stirring at room temperature, and stir for 1h to 3h . Filtrate under reduced pressure, wash the filter cake three times with absolute ethanol, recrystallize the resulting white precipitate with absolute ethanol, and dry in vacuo to obtain 32.6 g of white needle crystals, namely 2,4-diacetyl-3-phenylpentadiene Acid diethyl ester, the yield is 93.5%, and the melting point is 155.1-156.9°C.

[0058] Add 32.6g (0.094mol) diethyl 2,4-diacetyl-3-phenylglutarate in batches to 100mL 50% KOH solution under stirring, and control the temperature between 30-80°C for 2 hours. Stop heating, cool to room temperature, and adjust the reaction solution with concentrated hydrochloric acid in an ice-water bath until the pH is approximately equal to 2...

Embodiment 3

[0065] Synthesis of 5-oxo-3-(4-methoxyphenyl)-5-(4-tolylpiperazine)pentanoic acid (No. JA3031)

[0066]Add 1.0g (5mmol) 1-(4-methylphenyl) piperazine hydrochloride, 1.1g (5mmol) 3-(4-methoxyphenyl) cyclopentanedioic anhydride, 0.5 mL of pyridine, 15mL of absolute ethanol, microwave radiation reaction under 130w power for 25-30min, TLC monitoring until the reaction is complete (petroleum ether: ethyl acetate: methanol: glacial acetic acid = 0.5mL: 0.5mL: 1 drop: 1 drop), while Filtrate hot, rinse with absolute ethanol, and the obtained filtrate stands overnight for crystallization. Suction filtration under reduced pressure, and the resulting filter cake was rinsed with a small amount of absolute ethanol. Recrystallized from absolute ethanol and dried in vacuo to obtain 1.5 g of a colorless needle crystal, yield 65.2%, mp: 157.4-159.4°C. UV(λ / nm): λmax=247; HPLC(min): Rt=6.990; IR(KBr, σ / cm-1): 3064~2510(m, ν O-H , νAr-HB), 3029 (s, νasCH 3 ), 2006 (s, νasCH 2 ), 2911(s, νa...

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Abstract

The invention discloses phenylpiperazine derivatives and pharmaceutically acceptable salts thereof. The invention is characterized in that: the derivatives have the structure shown as a formula I; and in the formula, R1 refers to -H, -R, -OR, -COOR, halogen or -CN group, R refers to alkyl, the substitution position of R1 on a benzene ring is a para-position, ortho-position or meta-position of piperazine, m is a natural number ranging from 0 to 2, and R2 refers to a substituted or unsubstituted carboxyl group or sulfonic acid group. The phenylpiperazine derivatives and pharmaceutically acceptable salts thereof can be prepared into medicines for inhibiting tumor cell metastasis and tumor angiogenesis, medicines for treating liver cancer, breast cancer, ovarian cancer, gastric cancer, colon cancer, lung cancer or melanoma, tumor chemotherapy medicines and auxiliary medicines in surgical therapy.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a phenylpiperazine derivative that inhibits tumor metastasis and tumor growth to further kill tumors by inhibiting tumor angiogenesis, a preparation method of the derivative and its intermediate, At the same time, it also relates to the use of such derivatives in the preparation of inhibiting tumor angiogenesis, preventing tumor metastasis and inhibiting tumor growth, and as auxiliary drugs in general tumor chemotherapy drugs and surgical treatment. Background technique [0002] Often when a patient is diagnosed with a tumor, due to the infiltration of tumor cells, the tumor may have already metastasized and spread, resulting in poor treatment effect and ultimately treatment failure. Therefore, controlling the spread and metastasis of tumor cells is considered to be the key to the complete treatment of tumors, no matter in the process of surgical treatment or chemotherapy. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/145C07D295/15C07D295/26A61K31/495A61P35/00A61P31/00
CPCC07D295/18A61K31/495C07D295/26A61P31/00A61P35/00
Inventor 姜凤超丁玉兰蒋杰
Owner 蒋杰
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