4-nitro-L-phenylalanine dipeptide derivatives as well as preparation method and applications thereof

A technology of nitrophenylalanine dipeptide and nitrophenylalanine methyl ester, which is applied in the field of dipeptide derivatives, can solve problems such as large side effects and unsatisfactory treatment effects, and achieve convenient post-processing, low cost, The effect of mild reaction conditions

Inactive Publication Date: 2012-07-25
SOUTHWEST UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, there are many kinds of antidiabetic drugs, and the types are different. The clinically used type II diabetes treatment drugs mainly include sulfonylurea and non-sulfonylurea insulin secretagogues, biguanides, thiazolidinediones and other insulin sensitizers. , glycogenogenesis inhibitors, α-glucosidase inhibitors and new hypoglycemic drugs dipeptidyl peptidase-IV (DPP-IV) inhibitors, but the therapeutic effects of these drugs are not ideal or have relatively large side effects, so , the development of diabetes drugs with novel chemical structures, high efficiency and low toxicity is still an important task in the prevention and treatment of diabetes

Method used

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  • 4-nitro-L-phenylalanine dipeptide derivatives as well as preparation method and applications thereof
  • 4-nitro-L-phenylalanine dipeptide derivatives as well as preparation method and applications thereof
  • 4-nitro-L-phenylalanine dipeptide derivatives as well as preparation method and applications thereof

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Effect test

Embodiment 1

[0036] The preparation of embodiment 1, L-p-nitrophenylalanine (compound III)

[0037] L-p-nitrophenylalanine can be purchased directly from the market, or can be prepared by itself. The present invention adopts the following improved method to prepare: in a round-bottomed flask, add a mixed solution of concentrated nitric acid and concentrated sulfuric acid with a volume ratio of 1:1.3, cool to a temperature of 0 DEG C in an ice bath, and slowly add L-phenylalanine in batches , the molar ratio of L-phenylalanine and concentrated nitric acid is 1: 1.3, and the addition is completed, and the temperature is 0 ℃ of stirring for 60 minutes, then warming up to room temperature for 60 minutes, after the reaction is completed, add a small amount of ice-water mixture, stir Cool to 0°C, adjust pH to 6 with concentrated ammonia water under ice bath condition, separate out a large amount of precipitation, refrigerate, filter, wash the filter cake successively with ice water and ethanol, ...

Embodiment 2

[0062] The preparation of embodiment 2, L-p-nitrophenylalanine methyl ester hydrochloride (compound IV)

[0063] L-p-nitrophenylalanine methyl ester hydrochloride can be purchased directly from the market, and can also be prepared by itself. The present invention adopts the following improved method to prepare: adding anhydrous methanol to a round-bottomed flask, cooling to a temperature of 0 °C in an ice bath, slowly adding thionyl chloride, after the addition, stirring and reacting at a temperature of 0 °C for 20 minutes, adding compound III in batches That is, L-p-nitrophenylalanine, stir until the raw material gradually dissolves into a white turbid liquid, then heat up to 70 ° C and stir the reaction, it can be seen that the raw material is quickly dissolved into a yellow clear liquid, and the reaction is monitored by thin layer chromatography (TLC). Process; after the reaction of L-p-nitrophenylalanine is completed, rotary distillation under reduced pressure is carried o...

Embodiment 3

[0067] Embodiment 3, L-p-nitrophenylalanine dipeptide derivative Fmoc-AA-Phe (p-NO 2 )-OMe Preparation

[0068] General method: Dissolve Fmoc-AA-OH (20mmol) in 10mL of anhydrous THF, add HOBt (24mmol), DIC (24mmol) and DIPEA (20mmol) under ice bath and stirring, after the addition is complete, stir the reaction under ice bath for 30 ~60 minutes, monitor the generation of activated ester by TLC method; Dissolve compound IV, i.e., L-p-nitrophenylalanine methyl ester hydrochloride (20mmol) in anhydrous THF 15mL, add DIPEA (30mmol), stir, Standby; mix the above two solutions, stir and react at room temperature, and monitor the reaction process by TLC method; after the reaction is completed, remove THF by distillation under reduced pressure, add 150 mL of water to the residual liquid, extract with 150 mL of ethyl acetate, and collect the water layer respectively and the organic layer, and the aqueous layer was extracted with 80 mL of ethyl acetate, and all the organic layers were ...

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Abstract

The invention discloses 4-nitro-L-phenylalanine dipeptide derivatives which have the general formula I disclosed in the specification. The detection indicates that the 4-nitro-L-phenylalanine dipeptide derivatives have favorable PPAR agonist activity and are excellent antidiabetic lead compounds. The 4-nitro-L-phenylalanine dipeptide derivatives can be further developed to prepare antidiabetic medicines, and have wide potential application prospects in the field of diabetes therapy. The invention also provides a preparation method of the 4-nitro-L-phenylalanine hydrate dipeptide derivatives, which comprises the step that 4-nitro-L-phenylalanine methyl ester hydrochlorides and protective amino acid are coupled under the action of a condensing agent. The preparation method has the advantages of mild reaction conditions, convenient post-treatment, high yield and low cost.

Description

technical field [0001] The invention relates to a dipeptide derivative, in particular to an L-p-nitrophenylalanine dipeptide derivative, and also relates to its preparation method and application in medicine. Background technique [0002] Diabetes mellitus (Diabetes Mellitus) is an endocrine and metabolic disease characterized by high blood sugar that seriously endangers health. It is the third largest non-communicable chronic disease in the world. According to the latest data from the International Diabetes Federation (IDF), there were approximately 239 million diabetics in the world in 2007. Diabetics are expected to reach 246 million in 2010 and 380 million in 2025, or 7.1% of the adult population. At present, the number of diabetic patients in China ranks second in the world and is expected to reach 59.31 million in 2025. In 2006, diabetes ranked the tenth cause of inpatients in China and the sixth cause of death among urban residents. Therefore, the prevention and tr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K5/065C07K5/078C07K1/12A61K38/05A61P3/10
Inventor 杨大成晏菊芳刘建叶飞范莉陈欣孔令强蒋汉文汪林发张坤
Owner SOUTHWEST UNIV
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