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Non-natural peptide IDH1 inhibitor synthesized based on UGI reaction as well as preparation method and application of non-natural peptide IDH1 inhibitor

An IDH1, non-natural technology, applied in the field of chemical biology, can solve the problems of cumbersome preparation methods, high cost, raw materials that cannot be directly purchased from the market, etc., and achieve the effect of improving cytotoxicity and good inhibitory effect

Pending Publication Date: 2021-12-28
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The FDA approved Agios Pharmaceuticals' ivosidenib ( AG-120), for the treatment of relapsed / refractory AML (R / R AML) with IDH1 mutation, and the preparation method of AG-120 is cumbersome and costly, and the raw materials used cannot be directly purchased from the market, and multi-step synthesis is required preparation

Method used

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  • Non-natural peptide IDH1 inhibitor synthesized based on UGI reaction as well as preparation method and application of non-natural peptide IDH1 inhibitor
  • Non-natural peptide IDH1 inhibitor synthesized based on UGI reaction as well as preparation method and application of non-natural peptide IDH1 inhibitor
  • Non-natural peptide IDH1 inhibitor synthesized based on UGI reaction as well as preparation method and application of non-natural peptide IDH1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-4

[0033] Synthesis of Example 1-4 Linear Unnatural Peptide Analog 1-4

[0034] Embodiment 1 reaction formula:

[0035] Dissolve 2-methylbenzaldehyde (60mg, 0.5mmol) in 2mL of methanol, under stirring conditions, add 1.0 equivalent of 3-fluoroaniline successively and stir at room temperature for 0.5 hours, then add 1.0 equivalent of formic acid and cyclohexyl isocyanide, Continue to stir at room temperature for 2-10 hours, the product precipitates, and is filtered and washed to obtain the pure white solid linear unnatural peptide analog 1 with a yield of 39%. The structure of 1 was confirmed to be correct by NMR detection. HRMS(pos.ESI):m / z[M+Na] + for C 22 h 25 FN 2 NaO 2 calcd: 391.1792, found: 391.1785.

[0036] Embodiment 2 reaction formula:

[0037] Same as Example 1, except that acetic acid was used instead of formic acid to obtain linear non-natural peptide analog 2 with a yield of 49%. Through NMR detection, it was confirmed that the structure of 2 was correc...

Embodiment 3

[0038] Embodiment 3 reaction formula

[0039] Same as Example 1, except that propionic acid was used instead of formic acid to obtain linear non-natural peptide analog 3 with a yield of 22%. Through NMR detection, it was confirmed that the structure of 3 was correct. HRMS(pos.ESI):m / z[M+Na] + for C 24 h 29 FN 2 NaO 2 calcd: 419.2105, found: 419.2108.

[0040] Embodiment 4 reaction formula:

[0041] Same as Example 1, except that butyric acid was used instead of formic acid to obtain linear non-natural peptide analog 4 with a yield of 50%. Through NMR detection, it was confirmed that the structure of 4 was correct. HRMS(pos.ESI):m / z[M+Na] + for C 25 h 31 FN 2 NaO 2 calcd: 433.2262, found: 433.2262.

Embodiment 5

[0042] Synthesis of Example 5 Linear Unnatural Peptide Analog 5

[0043]

[0044] Same as Example 1, except that phenylpropionic acid was used instead of formic acid to obtain linear non-natural peptide analog 5 with a yield of 64%. Through NMR detection, it was confirmed that the structure of 5 was correct. HRMS(pos.ESI):m / z[M+Na] + for C 30 h 33 FN 2 NaO 2 calcd: 495.2418, found: 495.2410.

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Abstract

The invention discloses a non-natural peptide IDH1 inhibitor synthesized based on UGI reaction as well as a preparation method and application thereof, and belongs to the technical field of chemical biology. The non-natural peptide IDH1 inhibitor synthesized based on the UGI reaction, shown in a general formula I, or pharmaceutically acceptable salt, hydrate or prodrug of the non-natural peptide IDH1 inhibitor are provided. The invention also discloses a pharmaceutical composition containing the non-natural peptide IDH1 inhibitor synthesized based on the UGI reaction. The non-natural peptide IDH1 inhibitor synthesized based on the UGI reaction can be combined with IDH1 mutant protein, inhibit the activity of IDH1 mutant enzyme and reduce the generation of 2-HG in cells, and is used for treating tumors and / or other diseases. R1, R2, R3 and R4 in the general formula I are described in the claims and the specifications.

Description

technical field [0001] The invention relates to the synthesis of novel IDH1 inhibitors and belongs to the technical field of chemical biology. The invention specifically relates to a non-natural peptide IDH1 inhibitor synthesized based on UGI reaction, its preparation method and application. The new non-natural peptide IDH1 inhibitor synthesized based on UGI reaction can bind to IDH1 mutant protein, inhibit the activity of IDH1 mutant enzyme, reduce the generation of 2-HG in cells, and be used for treating tumors and / or other diseases. Background technique [0002] Isocitrate dehydrogenase (IDH) is a key rate-limiting enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid cycle. Homologous IDH1 and IDH2 are located in peroxisomes and mitochondria in the cytoplasm, respectively, and have similar structures, both of which depend on nicotinamide adenine dinucleoside phosphate (NADP + ). Point mutations in three a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/22C07C271/22C07C323/60C07D209/42C07D231/56C07D333/38C07D213/81C07C255/60C07D317/66C07D213/75C07D333/24C07D207/337C07C231/02C07C231/06A61K31/167A61K31/405A61K31/404A61K31/416A61K31/381A61K31/44A61K31/277A61K31/27A61K31/36A61K31/40A61P35/00A61P35/02
CPCC07C237/22C07C271/22C07C323/60C07D209/42C07D231/56C07D333/38C07D213/81C07C255/60C07D317/66C07D213/75C07D333/24C07D207/337A61P35/00A61P35/02C07C2601/14C07C2601/02
Inventor 李华陈丽霞周宜荣郑梦竹周雪琛
Owner SHENYANG PHARMA UNIVERSITY
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