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Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof

A technology of compounds and solvates, applied in the field of medicine, can solve the problems of increased acetylation level and degradation of HSP90

Active Publication Date: 2017-01-11
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of HDAC6 leads to increased acetylation of HSP90, leading to degradation of some HSP90 client proteins

Method used

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  • Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof
  • Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof
  • Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: (Compound 1) Preparation

[0071] Step 1a, preparation of 6-iodoquinazolin-4-one (102)

[0072] Formamide (13.7 g, 304 mmol) and 2-amino-5-iodobenzoic acid (compound 101, 20 g, 76.0 mmol) were reacted at 190° C. for 4 hours. After the reaction, 100 mL of methanol was added, the reaction solution was filtered, the filter cake was rinsed with methanol, and compound 102 was obtained after drying. Yield 80.6%.

[0073] The confirmed data of the compound structure are:

[0074] 1 H NMR (400MHz, DMSO) δ12.42(s, 1H), 8.42–8.34(m, 1H), 8.14(d, J=1.4Hz, 1H), 8.12–8.05(m, 1H), 7.46(t, J=6.8Hz,1H).

[0075] Step 1b, preparation of 4-chloro-6-iodoquinazoline (103)

[0076] Compound 102 (14.4 g) was dissolved in thionyl chloride (50 ml), 1 mL of catalytic amount of anhydrous DMF was added, and the reaction was refluxed for 4 hours. After the reaction, excess thionyl chloride was distilled off under reduced pressure to obtain compound 103. Yield 92.4%.

[0077] ...

Embodiment 2

[0105] Example 2: (Compound 2) Preparation

[0106] Compound 2 was prepared according to the steps of Example 1, except that:

[0107] 1. Preparation of 7-azidoheptanoic acid (108b)

[0108] 107a in step 1f in Example 1 was replaced with 7-bromoheptanoic acid (107b) for reaction. Yield 81.5%.

[0109] The confirmed data of the compound structure are:

[0110] 1 H NMR (400MHz, CDCl 3 )δ11.36(s,1H),3.27(t,J=6.9Hz,2H),2.36(t,J=7.4Hz,2H),1.70–1.56(m,4H),1.45–1.34(m,4H ).

[0111] 2. Preparation of 7-azido-N-((tetrahydropyran-2-substituted) oxy)heptanamide (109b)

[0112] 108a in step 1g in Example 1 was replaced by 108b for reaction. Yield 89.8%.

[0113] The confirmed data of the compound structure are:

[0114] 1 H NMR (400MHz, CDCl 3 )δ8.76(s,1H),4.89(s,1H),3.95(d,J=9.4Hz,1H),3.63(m,1H),3.26(t,J=6.9Hz,3H),2.19– 1.76(m,4H),1.73–1.48(m,8H),1.45–1.29(m,4H).

[0115] 3. Preparation of 7-(4-(4-((3-chloro-4-fluorophenylamino)quinazoline-6-substituted)-1 hydrogen-1,2,3...

Embodiment 3

[0123] Example 3: (Compound 3) Preparation

[0124] Compound 3 was prepared according to the steps of Example 1, except that:

[0125] 1. Preparation of N-(3-chloro-2-fluorophenyl)-6-iodoquinazolin-4-amine (104b)

[0126] The 3-chloro-4-fluoroaniline in step 1c in Example 1 was replaced with 3-chloro-2-fluoroaniline for the reaction. Yield 95.1%.

[0127] The confirmed data of the compound structure are:

[0128] 1 H NMR (400MHz,DMSO)δ12.26(s,1H),9.48–9.34(m,1H),8.97(d,J=2.8Hz,1H),8.41(dd,J=8.8,1.3Hz,1H) ,7.87–7.77(m,1H),7.66(t,J=7.4Hz,1H),7.58–7.50(m,1H),7.37(t,J=8.1Hz,1H).

[0129] 2. Preparation of N-(3-chloro-2-fluorophenyl)-6-ethynylquinazolin-4-amine (106b)

[0130] The reaction was carried out by replacing 104a in step 1d / e of Example 1 with 104b. Yield 69.3%.

[0131] The confirmed data of the compound structure are:

[0132] 1 H NMR(400MHz,DMSO)δ10.13(s,1H),8.69(s,1H),8.55(s,1H),7.90(d,J=8.5Hz,1H),7.79(d,J=8.6Hz ,1H),7.52(t,J=7.4Hz,2H),7.29(t,J=8.0Hz,1H),...

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Abstract

The invention relates to compounds capable of inhibiting ErbB / HDAC and a preparation method thereof, and a pharmaceutical composition comprising the compounds and application thereof. The compounds are disclosed as Formula 1. The compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, or the pharmaceutical composition comprising the compounds can be used for preparing ErbB kinases and HDAC activity inhibitors and also preparing ErbB-kinase / HDAC-activated mediated disease curatives.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a compound capable of inhibiting ErbB / HDAC, a preparation method thereof, a drug combination containing it and an application thereof. Background technique [0002] The ErbB protein tyrosine kinase family contains four homologous members: EGFR (ErbB1, HER1), HER2 (ErbB2, Neu), HER3 (ErbB3) and HER4 (ErbB4), when the ligand binds to the receptor, It can stimulate ErbB to undergo homodimerization or heterodimerization. After that, a series of tyrosine residues are induced to phosphorylate, thereby recruiting a series of aptamers and signaling proteins containing SH2 domains, providing binding sites for some downstream proteins, and finally activating downstream pathways such as PI3K and MAPK, Thereby regulating cell proliferation and survival and other physiological processes. [0003] Therefore, selectively blocking EGFR and HER2 by monoclonal antibodies or small molecule inh...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/14C07D413/14A61K31/517A61P35/00
CPCC07D401/14C07D403/04C07D413/14
Inventor 蒋宇扬丁超张存龙谭春燕高春梅袁梓高李文璐
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV