(2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative as well as preparation method and application thereof

An amino and nitro group technology, which is applied in the preparation of carbamic acid derivatives, carboxylic acid amides, and cyanide reactions, etc., can solve the problems of no symptom-relieving drugs and no curable drugs for lymphedema.

Active Publication Date: 2021-02-09
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no curable drugs for primary and secondary lymphedema, or even drugs for relieving symptoms. Therefore, it is of great significance to find a safe and effective anti-lymphoedema drug

Method used

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  • (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative as well as preparation method and application thereof
  • (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative as well as preparation method and application thereof
  • (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of compound 1

[0049]

[0050] Preparation of intermediate 1b:

[0051]

[0052] Compound 1a (31g, 0.16mol) was dissolved in 310mL tetrahydrofuran / water (1:1) mixed solvent, triethylamine (32g, 0.32mol), di-tert-butyl dicarbonate (42g, 0.19mol) were added under ice-cooling ), react at room temperature after addition. After the reaction of the raw materials is complete, add water to quench the reaction under an ice-water bath, then add dilute hydrochloric acid to adjust the pH value to acidity, extract twice with ethyl acetate, combine the organic phases, wash with water once, and dry with anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated to obtain 38g of intermediate 1b, yield: 81.0%;

[0053] ESI-MS:m / z=296(M+H) + .

[0054] Preparation of intermediate 1d:

[0055]

[0056] Compound 1c (1.2g, 10mmol) was dissolved in 10mL of methanol, thionyl chloride (5.95g, 50mmol) was added under ice-cooling, and...

Embodiment 2

[0070] Embodiment 2: the preparation of compound 2

[0071]

[0072] Preparation of Intermediate 2b:

[0073]

[0074] Compound 2a (1.2 g, 10 mmol) was dissolved in 10 mL of methanol, and thionyl chloride (5.95 g, 50 mmol) was added under ice-cooling, and reacted at room temperature after the addition was complete. After the raw materials reacted completely, the reaction system was concentrated to obtain 1.7 g of intermediate 2b, yield: 100%.

[0075] Preparation of Intermediate 2c:

[0076]

[0077] Intermediate 1b (2.2g, 7.46mmol), Intermediate 2b (1.39g, 8.2mmol) were dissolved in 20mL of dichloromethane, and triethylamine (3.03g, 30mmol), 1-hydroxybenzene Add triazole (1.2g, 8.95mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72g, 8.95mmol), react at room temperature after addition. After the reaction of the raw materials is complete, concentrate, then add water and ethyl acetate to dissolve, adjust the pH to 5-6 with dilute hydrochloric a...

Embodiment 3

[0088] Embodiment 3: the preparation of compound 3

[0089]

[0090] Preparation of Intermediate 3b:

[0091]

[0092] Compound 3a (1.2 g, 10 mmol) was dissolved in 10 mL of methanol, and thionyl chloride (5.95 g, 50 mmol) was added under ice-cooling, and reacted at room temperature after the addition was complete. After the raw materials reacted completely, the reaction system was concentrated to obtain 1.7 g of intermediate 3b, yield: 100%.

[0093] Preparation of Intermediate 3c:

[0094]

[0095]Intermediate 1b (2.2g, 7.46mmol), intermediate 3b (1.39g, 8.2mmol) were dissolved in 20mL of dichloromethane, triethylamine (3.03g, 30mmol), 1-hydroxybenzene Add triazole (1.2g, 8.95mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72g, 8.95mmol), react at room temperature after addition. After the reaction of the raw materials is complete, concentrate, then add water and ethyl acetate to dissolve, and adjust the pH to 5-6 with dilute hydrochloric ac...

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PUM

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Abstract

The invention discloses a (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative shown as a formula (I) or an optical isomer, a diastereomer and racemate mixture and pharmaceutically acceptable salt thereof as well as a preparation method and application of the (2S, 3R)-3-amino-2-hydroxy-4-phenylbutyrylamide derivative. It is shown by comparison of results of a positive control group and a model group on lymphedema prevention experiments that the compound disclosed in the invention shows obvious anti-edema activity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of (2S,3R)-3-amino-2-hydroxyl-4-phenylbutyramide derivatives, a preparation method and application thereof. Background technique [0002] Ubenimex, its drug name is Bestatin; alias: Ubenimex; trade name: Baishixin; chemical name: N-[(2S,3R)-3-amino-2-hydroxy-4- phenylbutyryl]-L-leucine. Ubenimex is a small-molecule dipeptide compound isolated from the culture fluid of Streptomyces olivine reticulum by the Japanese scholar Umezawa Hamao in 1976, which can inhibit the activities of various aminopeptidases. In addition, Ubenimex can also enhance host immune function, inhibit tumor angiogenesis, and thus inhibit tumor invasion and metastasis. In 1987, Ubenimex was officially launched in Japan as an anticancer drug. In the domestic market, Ubenimex is used as an adjuvant drug for anticancer chemotherapy and radiotherapy, especially for prolonging the survival period and ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/20C07C269/04C07C269/06C07C271/22C07C227/18C07C229/22C07C231/12C07D209/20A61P7/10
CPCC07C237/20C07D209/20C07C269/04C07C269/06C07C227/18C07C231/12A61P7/10C07C271/22C07C229/22Y02P20/55
Inventor 罗新峰马云龙向永哲舒天波张济兵王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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