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1,5-diazabicyclo[5,3,0]decane ketone amino acid derivative as well as preparation method and application thereof

A kind of technology of diazabicyclo and derivatives, applied in 1 field

Active Publication Date: 2020-09-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, no synthesis of novel 1,5-diazabicyclo[5,3,0]decanone amino acid derivatives represented by the previous general formula has been reported. Therefore, the design of new diazabicyclo[X.Y.0]alkanone amino acids Derivatives and the development of effective methods for synthesizing such compounds are of great significance in the development of new drugs

Method used

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  • 1,5-diazabicyclo[5,3,0]decane ketone amino acid derivative as well as preparation method and application thereof
  • 1,5-diazabicyclo[5,3,0]decane ketone amino acid derivative as well as preparation method and application thereof
  • 1,5-diazabicyclo[5,3,0]decane ketone amino acid derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Compound I-1

[0039] Reaction route:

[0040]

[0041] Specific preparation process:

[0042] 1. Preparation of (2S,5R)-5-(((tert-butyldimethylchloride) oxo)methyl) tetrahydropyrrole-2-carboxylate

[0043]

[0044] At room temperature, the raw material (2S,5R)-5-(hydroxymethyl)tetrahydropyrrole-2-carboxylate methyl ester (1.50g, 8.67mmol) was dissolved in 10mL of dichloromethane, and tert-butyl was added under stirring Dimethylchlorosilane (1.56g, 10.40mmol) and triethylamine (2.62g, 26.01mmol) were reacted at room temperature for 6h until the reaction was complete as monitored by TLC. It was extracted three times with DCM and water, and the combined organic phases were washed with saturated sodium chloride solution. It was dried over anhydrous sodium sulfate, filtered, concentrated, separated and concentrated by column chromatography to obtain 1.77 g of a colorless oil, with a yield of 71%. TLC (ethyl acetate:petroleum ether=2:1) ​​Rf=0.2.

...

Embodiment 2

[0071] Preparation of Compound I-2

[0072]

[0073] (700mg, 1.8mmol) of 2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)sulfonamido)propionic acid and 5-(((tert-butyl Dimethylchloro)oxo)methyl)tetrahydropyrrole-2-carboxylate ethyl ester (500mg, 1.74mmol), using Method 2 to obtain light yellow oily condensation product 2-((tert-butoxycarbonyl)amino) -3-((2-nitrophenyl)sulfonamido)propionyl)-5-(((tert-butyldimethylsilyl)oxo)methyl)tetrahydropyrrole-2-carboxylic acid ethyl ester (1.01 g, 1.53 mmol).

[0074] 2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)sulfonamido)propionyl)-5-(((tert-butyldimethylsilyl)oxo)methyl ) Ethyl tetrahydropyrrole-2-carboxylate Using method three to obtain light yellow oil 2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)sulfonamido)propionyl)- Ethyl 5-(hydroxymethyl)tetrahydropyrrole-2-carboxylate. (735 mg, 1.35 mmol).

[0075] 2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)sulfonamido)propionyl)-5-(hydroxymethyl)tetrahydropyrrole-2-carb...

Embodiment 3

[0078] Preparation of Compound I-6

[0079]

[0080] 2-Oxo-3-((tert-butoxycarbonyl)amino)-1,5-diazabicyclo[5,3,0]decane-10-carboxylic acid ethyl ester (100mg, 0.29mmol) was placed in React in methanolic hydrochloric acid solution for 2 hours at room temperature, spin dry the reaction solution, extract three times with ethyl acetate and saturated sodium bicarbonate solution, collect the organic phase, dry over sodium sulfate, and spin dry to obtain a colorless oily 2-oxo-3-amino- Ethyl 1,5-diazabicyclo[5,3,0]decane-10-carboxylate (78 mg, 0.28 mmol).

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Abstract

The invention discloses a 1,5-diazabicyclo[5,3,0]decane ketone amino acid derivative as well as a preparation method and application thereof, and particularly relates to a compound shown as a formulaI or pharmaceutically acceptable salt, ester or solvate thereof. The provided derivative can effectively simulate the spatial conformation of dipeptide, in particular, proline-containing dipeptide, can be used for designing mimetic peptide small molecule drugs, and can be used for development of mimetic peptide drugs. The invention also provides a brand-new synthesis method of the compounds, and through the synthesis route of the derivative, a target product can be obtained on the premise that the raw materials are easily available and simple, the synthesis route is short, and the yield is high. The 1,5-diazabicyclo[5, 3, 0]decane ketone amino acid derivative or the pharmaceutically acceptable salt or solvate thereof can be combined and inhibit IAPs and cancer cell growth, and can be usedfor preparing medicines for preventing and treating tumors.

Description

technical field [0001] The present invention relates to the field of biomedicine, and relates to dipeptide-simulating azabicycloalkanone amino acid derivatives and their preparation methods and uses, in particular to a 1,5-diazabicyclo[5,3,0]decanone Amino acid derivatives and their preparation methods and applications. Background technique [0002] Peptides and peptide derivatives have attracted more and more attention in the development of new drugs due to their structural diversity and wide range of pharmacological activities. However, due to the inherent defects of peptides, such as low bioavailability, poor metabolic stability, and poor cell penetration, etc. Seriously affect their application as drugs. Therefore, when developing new drugs led by peptides, it is usually necessary to structurally modify the peptides to overcome these defects. A common method is to design and synthesize peptides that can simulate the binding of proteins. Peptoids with enhanced biological...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078C07K5/065C07D487/04A61K38/05A61P35/00A61K31/551
CPCC07K5/06139C07K5/06078C07D487/04A61P35/00A61K38/00Y02P20/55
Inventor 孙海鹰王逸博
Owner CHINA PHARM UNIV