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A kind of puma inhibitor and its preparation method and use

A technology of inhibitors and uses, applied in the field of medicine, to achieve the effect of blocking apoptosis, good physical and chemical properties, and good resistance to apoptosis

Inactive Publication Date: 2020-06-30
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Radiation-damaged drugs targeting PUMA proteins are innovative fields worldwide, with few reports in the literature

Method used

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  • A kind of puma inhibitor and its preparation method and use
  • A kind of puma inhibitor and its preparation method and use
  • A kind of puma inhibitor and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0056]

[0057] Add 2.0 g (15 mmol) of rhodanine, 20 mL of anhydrous methanol, and 0.1 mL of glacial acetic acid in a three-necked flask. 2 Under protection, 2.9 g (22.6 mmol) of hydroxyethylpiperazine and 22.6 mmol of benzaldehyde were added, and the oil bath was refluxed to obtain a light yellow clear reaction liquid, which was monitored by TLC in time. After 1-2 hours, the reaction was completed, and a yellow solid was precipitated in an ice bath. Suction filtration, washing with methanol, the crude product was purified by silica gel column chromatography (DCM:MeOH 10:1) to obtain pure compound 1 with a yield of 35-55%.

[0058] Yellow solid, 46% yield. 1 H NMR (400MHz, CDCl 3 )δ=7.83(s,1H),δ=7.56(d,2H),δ=7.47(m,2H),δ=7.41(t,1H),δ=4.1(t,2H),δ=3.69( m, 4H), δ=2.72(t, 2H), δ=2.66(m, 4H). 13 CNMR (400MHz, CDCl 3 ) 180.84, 175.22, 134.16, 131.94, 129.78, 129.74, 129.03, 127.88, 59.26, 58.05, 52.53, 52.11, 48.68, 48.34, HRMS (ESI) calcd.for C 16 h 19 N 3 o 2 S:317.1[M...

preparation Embodiment 2

[0060] Compound 2 was prepared in the same manner as in Preparation Example 1 except that p-phenylbenzaldehyde was used instead of benzaldehyde.

[0061] Pale yellow solid, yield = 52.9%, 1 H NMR (400MHz, CDCl 3 )δ=7.87(s,1H),δ=7.69(d,2H),δ=7.63(m,4H),δ=7.48(t,2H),δ=7.42(t,1H),δ=5.32( s,1H),δ=4.1(t,2H),δ=3.71(m,4H),δ=2.73(t,2H),δ=2.68(m,4H)HRMS(ESI)calcd.for C 22 h 23 N 3 o 2 S 394.2[M+H] + ,found 394.2[M+H] + .

preparation Embodiment 3

[0063] Compound 3 was prepared in a similar manner to Preparation Example 1 except that p-tolualdehyde was used instead of benzaldehyde.

[0064] Pale yellow solid, yield = 49.1%, 1 H NMR (400MHz, CDCl 3 )δ=7.81(s,1H),δ=7.43(d,2H),δ=7.27(t,3H),δ=4.12(t,2H),δ=3.70(m,4H),δ=2.73( t,2H), δ=2.68(m,4H), δ=2.40(s,3H)HRMS(ESI)calcd.for C 17 h 21 N 3 o 2 S 331.4[M+H] + ,found 331.8[M+H] + .

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Abstract

The present invention relates to the technical field of medicine, and specifically relates to a PUMA inhibitor, a method for preparation thereof, and a use thereof. The PUMA inhibitor is the compound as shown in (I) or a pharmaceutically acceptable salt thereof. The definitions of its substituent groups are as described in the description. The compound (I) or pharmaceutically acceptable salt thereof is capable of targeting a PUMA protein and has very good physicochemical properties, very good apoptosis resistance and radiation protection effects; it can selectively inhibit the competitive combined effect of a PUMA protein and a Bcl-2 apoptosis-resistant protein, block apoptosis, and effectively protects against bone marrow damage. The present invention provides a new idea for, and powerful proof of, the application of a PUMA-protein small molecule inhibitor in radiation-protection pharmaceuticals, and is likely to become a highly effective, low-toxicity, and stable clinical radiation-protection pharmaceutical.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of PUMA inhibitors and a preparation method and application thereof. Background technique [0002] The rapid development of nuclear radiation technology has been widely used in many economic and military fields, such as medical diagnosis and treatment, nuclear power generation, radiation breeding, terrorist activities, nuclear war, etc. The widespread use of these nuclear energies has resulted in more and more people being exposed to high-energy ionizing radiation. Radiation can cause serious damage to the body, such as hematopoietic stem cell damage, organ lesions, radiation mutagenesis, and radiation-induced cancer. [0003] Myeloid injury is the most basic and common type of radiation injury. Immediately interrupting such injuries is the primary measure for most acute radiation protection. Starting from the mechanism of radiation injury, identifying drug targets an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/54C07D417/06C07D417/04A61K31/496A61K31/501A61K31/454A61P9/10A61P9/04A61P25/28A61P31/18
CPCC07D277/54C07D417/04C07D417/06A61P1/00A61P9/04A61P9/10A61P25/28A61P31/18C07D417/14
Inventor 陈惠刘吉元周楠张生勇
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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