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Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof

A technology of acetylaminohydroxime and sirtuin, which is applied in the field of medicine and can solve problems such as toxicity, heart disease, and clinical application limitations

Active Publication Date: 2014-06-18
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical studies have found that the marketed HDAC inhibitors still have many shortcomings, especially ineffective against solid tumors and cardiotoxicity at normal doses, which greatly limits the clinical application of such drugs

Method used

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  • Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof
  • Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof
  • Substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0094] Example 1. Synthesis of 2-[2-(6-benzylamine-9H-purin-9-yl)acetamido]-N-hydroxyacetamide (5A1)

[0095] Synthesis of ethyl 2-(6-benzylamino-9H-purin-9-yl)acetate (2A)

[0096] Compound 6-benzylamine-9H-purine (1A, 6.76g, 30mmol) was dissolved in 50mL DMSO, and K 2 CO 3 (12.4g, 90mmol) and ethyl chloroacetate (4mL, 36mmol), react at room temperature for 4h. After the reaction, 5 times the volume of water was added, then extracted with ethyl acetate, dried over magnesium sulfate, concentrated, and recrystallized at P / E=1:2 to obtain a white solid (6.07g, 65%). m.p.182-183℃; 1 H NMR (400MHz, DMSO-d 6 )δ:1.22(t,3H,J=7.2Hz),4.18(q,2H,J=7.2Hz),4.77(br s,2H),5.08(s,2H),7.20–7.38(m,5H) ,8.14(s,1H),8.20(s,1H),8.25(s,1H).

[0097]Compounds 2B-2G were synthesized according to the method of 2A.

[0098] Synthesis of 2-(6-benzylamino-9H-purin-9-yl)acetic acid (3A)

[0099] Starting material 2A (4.67g, 15mmol) was dissolved in 30mL THF / MeOH (volume ratio 3:1), and 23mL of 2M N...

Embodiment 2

[0110] Example 2. Synthesis of 3-[2-(6-benzylamine-9H-purin-9-yl)acetamido]-N-hydroxypropionamide (5A2)

[0111] The preparation methods of intermediates and target compounds are as in Example 1. Yield 78%; m.p.201–202°C; 1 H NMR (300MHz, DMSO-d 6 )δ:2.15(t,J=7.2Hz,2H),3.25–3.29(m,2H),4.72(br s,2H),4.81(s,2H),7.18–7.22(m,1H),7.26– 7.35(m,4H),8.07(s,1H),8.16(s,1H),8.23(br s,1H),8.37(t,J=5.4Hz,1H),8.71(s,1H),10.41( s,1H); HRMS calcd for C 17 h 19 N 7 o 3 370.1622, found 370.1615.

Embodiment 34

[0112] Example 3. Synthesis of 4-[2-(6-benzylamine-9H-purin-9-yl)acetamido]-N-hydroxybutyramide (5A3)

[0113] The preparation methods of intermediates and target compounds are as in Example 1. Yield 84%; m.p.198-199°C; 1 H NMR (300MHz, DMSO-d 6 )δ:1.64(quint,J=7.2Hz,2H),1.98(t,J=7.2Hz,2H),3.08(q,J=6.0Hz,2H),4.72(br s,2H),4.82(s ,2H),7.18-7.23(m,1H),7.26-7.35(m,4H),8.08(s,1H),8.17(s,1H),8.27-8.30(m,2H),8.68(s,1H ),10.33(s,1H); HRMS calcd for C 18 h 21 N 7 o 3 384.1779, found 384.1785.

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Abstract

The invention discloses a substituted purin-9-acetamino isohydroxamic acid histone deacetylase inhibitor and a preparation method and application thereof. The inhibitor has the structure as shown in formula I described in the specification. The inhibitor disclosed by invention has strong inhibitory activity on HDAC (histone deacetylase) and can be used for the prevention or treatment of related mammalian diseases caused by abnormal expression of histone deacetylase. The invention also relates to an application of the inhibitor having the general formula I in preparing the medicines.

Description

technical field [0001] The invention relates to a substituted purine-9-acetylamino hydroxamic acid histone deacetylase inhibitor and its preparation, pharmaceutical composition and medical application, belonging to the technical field of medicine. Background technique [0002] Histone deacetylases (histone deacetylases, HDACs) are one of the key enzymes that maintain the balance of histone acetylation in nucleosomes, the basic unit of chromosomes. It catalyzes the deacetylation of histones, is closely related to the repression of gene transcription, and involves many processes of promoting gene silencing, and is a popular target in the design of anti-tumor drugs. [0003] Histones are important components of eukaryotic chromosomes. Changes in the local conformation of chromosomes caused by histone modifications play an important role in the regulation of eukaryotic gene expression, among which the acetylation modification of histones is currently the most profoundly studied...

Claims

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Application Information

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IPC IPC(8): C07D473/34A61K31/52A61K31/5377A61P35/00A61P25/00A61P31/12A61P29/00A61P35/02A61P33/06A61P3/10
CPCC07D473/16C07D473/34Y02A50/30
Inventor 方浩王军华杨新颖徐文方易凡
Owner SHANDONG UNIV
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