Histone deacetylase and proteasome double-target inhibitor, and preparation method and application thereof

A sirtuin and proteasome technology, applied in chemical instruments and methods, anti-inflammatory agents, drug combinations, etc., can solve problems such as poor patient compliance, pharmacokinetic mismatch, and drug interactions

Active Publication Date: 2020-04-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In studies of many different types of tumors and other diseases, the combination of proteasome inhibitors and histone deacetylase inhibitors has shown strong synergy, but there are pharmacokinetic differences in multidrug combinations. Unfavorable factors such as mismatch, poor patient compliance, and drug-drug interactions

Method used

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  • Histone deacetylase and proteasome double-target inhibitor, and preparation method and application thereof
  • Histone deacetylase and proteasome double-target inhibitor, and preparation method and application thereof
  • Histone deacetylase and proteasome double-target inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1: tert-butyl ((S)-1-((((R)-3-methyl-1-((3aR,4R,6R,7aS)-5,5,7a-trimethylhexahydro -4,6-Methylbenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl) Urethane (2a)

[0073] Boc-L-Phe (3.6g, 13mmol) was dissolved in N,N-dimethylformamide under ice-cooling, and TBTU (4.2g, 13mmol), bortezomib intermediate I (4.56g, 12mmol) and N - Methylmorpholine (4ml, 36mmol). Under nitrogen protection, the reaction was continuously stirred for 16 hours, poured into water, and extracted 3 times with ethyl acetate (3×100 mL). The combined organic phases were washed with 2% citric acid, 2% sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and spin-dried to obtain a crude product. Chromatography on silica gel eluting with ethyl acetate, petroleum ether gradient (from 15% to 40%) afforded 6 g (97%) of 2a as a colorless transparent oil. Yield: 95%. 1 HNMR (400MHz, DMSO-d 6 ):δ8.85(brs,2H),7.35–7.07(m,5H),7.03(d,J=8.3Hz,1H),4.28–4.18(m,1H),4.08...

Embodiment 2

[0078] Example 2: (S)-1-((((R)-3-methyl-1-((3aR,4R,6R,7aS)-5,5,7a-trimethylhexahydro-4,6 -Methoxybenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxo-3-phenylpropane-2-ammonium chloride (3a )

[0079] 2a was dissolved in ethyl acetate saturated with hydrogen chloride and stirred overnight to obtain pure white powder 3a, yield: 90%, melting point: 208-212°C. 1 H NMR (400MHz, DMSO-d 6 )δ8.55(s,1H),8.29(s,3H),7.38–7.20(m,5H),4.29(dd,J=7.7,2.2Hz,1H),3.99(s,1H),3.00(d ,J=8.1Hz,2H),2.88(d,J=5.0Hz,1H),2.35–2.24(m,1H),2.12(dd,J=10.5,5.8Hz,1H),1.94(t,J= 5.5Hz, 1H), 1.85(s, 1H), 1.71(dt, J=14.3, 2.7Hz, 1H), 1.47(t, J=6.5Hz, 1H), 1.36–1.15(m, 9H), 0.81– 0.80(m,9H).

[0080] 2-((((R)-3-methyl-1-((3aR,4R,6R,7aS)-5,5,7a-trimethylhexahydro-4,6-methoxybenzo[d ][1,3,2]dioxaborol-2-yl)butyl)amino)-2-oxa-1-amine ammonium chloride (3b)

[0081] Similar to the synthesis of 3a, yield: 98%, colorless oil. 1 H NMR (400MHz, DMSO-d 6)δ8.48(d,J=5.2Hz,1H),8.10(s,3H),4.29(d,J=7.2Hz,1H),3.54(s,2H),3....

Embodiment 3

[0084] Example 3: Methyl 4-((2-aminophenyl)carbamoyl)benzoate (5a)

[0085] Monomethyl terephthalate (4a, 1.8g, 10mmol), o-phenylenediamine (1.08g, 10mmol), TBTU (3.5g, 12mmol) were dissolved in N,N-dimethylformamide under ice cooling. Join Et 3 N (1.5ml, 30mmol) was stirred for 8 hours in the dark. After the reaction was completed, it was poured into water and extracted three times with ethyl acetate (3×100 mL). The combined organic phases were washed with 2% citric acid, 2% sodium bicarbonate, and saturated brine, dried over magnesium sulfate, and spin-dried to obtain a crude product. The refined product 5a was obtained after methanol recrystallization. Yield: 56%, melting point: 190-194°C. 1 H NMR (400MHz, CDCl 3 )δ8.16(d, J=7.9Hz, 2H), 7.99(dd, J=15.1, 8.3Hz, 2H), 7.37(d, J=7.9Hz, 1H), 7.12(dd, J=8.7, 5.3 Hz,1H),6.87(t,J=6.3Hz,2H),3.97(s,3H),3.86(s,1H).

[0086] Methyl 3-((2-aminophenyl)carbamoyl)benzoate (5b)

[0087] Similar to the synthesis of 3a, yield: 56%, ye...

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Abstract

The invention relates to a protein deacetylase and proteasome double-target inhibitor, and a pharmaceutically acceptable salt, a stereoisomer, a preparation method and an application thereof. The compound is represented by general formula I, the compound has good histone deacetylase resisting activity, proteasome resisting activity and tumor cell proliferation resisting activity, and can be used for preparing medicines for preventing or treating related mammalian diseases caused by abnormal histone deacetylase expression or proteasome abnormality. The invention also relates to a pharmaceuticalapplication of a composition containing the compound with the structure of general formula I.

Description

technical field [0001] The invention relates to a histone deacetylase, a proteasome dual-target inhibitor and a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a preparation method, a pharmaceutical composition and a medical application thereof, belonging to the technical field of medicine. Background technique [0002] The proteasome is an important part of the ubiquitin-proteasome system (Ubiquitin-proteasome system, UPS). It is the main degradation pathway for misfolded proteins and other proteins to be hydrolyzed during protein synthesis. It is involved in cell growth, differentiation, DNA Replication and repair, cell metabolism, immune response and other important physiological and biochemical processes. UPS mainly plays two roles: one is to maintain the quality of cells by decomposing abnormal or damaged proteins; the other is to control the basic life activities of cells by decomposing proteins with specific functions; the two ultimately guarantee th...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K31/69A61P35/00A61P35/02A61P25/28A61P29/00A61P31/12A61P3/10A61P33/06
CPCA61P3/10A61P25/28A61P29/00A61P31/12A61P33/06A61P35/00A61P35/02C07F5/025Y02P20/55Y02A50/30
Inventor 方浩周易侯旭奔杨新颖
Owner SHANDONG UNIV
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