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Thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof

A pyrimidine hydroxamic acid, 3-d technology, applied in the field of antitumor drugs, can solve problems such as single effect, achieve good therapeutic effect, novel structure, and increase the effect of cytotoxic T cell infiltration

Active Publication Date: 2021-04-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Existing BRD4 inhibitors or HDACs inhibitors are all single-effect, and due to the drug resistance of tumor cells, more anti-tumor compounds with novel structures are needed

Method used

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  • Thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof
  • Thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof
  • Thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof

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Experimental program
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preparation example Construction

[0048] The compound of the present invention can be prepared by conventional chemical synthesis methods, specifically, the following process flow is used for synthesis:

[0049]

[0050] Reagents and conditions: (a) NCCH 2 CO 2 Et, S 8 ,Et 3 N, EtOH, reflux, 12h; (b) DBU, THF, reflux, 24h; (c) CH 3 OH, NaOH, 30min; (d) DCC / HOBt, DCM, 24h; (e) ethyl chloroformate, N-methylmorpholine, 1,4-dioxane, 15min, then NH 2 OH, CH 3 OH, 20min; (f) compound 2a-e, HCl-1,4-dioxane, 25°C, 48h.

Embodiment 1

[0052] Example 1 N-(2-aminophenyl)-4-(2,6-dimethyl-4-(7-methyl-4-oxo-3,4,5,6,7,8-hexa Preparation of hydropyridin[4',3':4,5]thiophene[2,3-d]pyrimidin-2-yl)phenoxy)butyramide (8b)

[0053]

[0054] Reaction a: Preparation of ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2a)

[0055] Mix N-methylpiperidone (4.90 g, 50 mmol), ethyl cyanoacetate (5.66 g, 100.0 mmol), triethylamine (10 mL) and sublimed sulfur (1.60 g, 50.0 mmol) in 100 mL of absolute ethanol The reaction was refluxed for 12 hours, the reaction solution was concentrated, the residue was extracted with water and ethyl acetate, the organic layer was separated and concentrated, and 2a was recrystallized with 100ml of ethanol, the yield was 79%, light yellow powder. 1 H NMR (400MHz, DMSO-d 6 )δ7.23(s,2H,NH 2 ), 4.15 (q, J=7.2Hz, 2H, OCH 2 CH 3 ),3.22(t,J=2.0Hz,2H,N-CH 2 -Thiophene), 2.66 (t, J=5.2Hz, 2H, N-CH 2 -CH 2 ),2.53(t,J=6.0Hz,2H,N-CH 2 -CH 2 ),2.29(s,3H,N-CH 3 ), 1.2...

Embodiment 2

[0064] Example 2 N-(2-aminophenyl)-2-(2,6-dimethyl-4-(7-methyl-4-oxo-3,4,5,6,7,8-hexa Preparation of hydropyridin[4',3':4,5]thiophene[2,3-d]pyrimidin-2-yl)phenoxy)acetamide (8a)

[0065]

[0066] Referring to the preparation method of Example 1, the raw material 4-bromobutyrate methyl ester in reaction b was changed to 4-bromoacetate methyl ester to obtain compound 8a.

[0067] Pale yellow solid, yield 35%. mp:243.7-245.8℃. 1 H NMR (400MHz, DMSO-d 6 )δ12.39(brs,1H,Pyrimidine-H),9.80(s,1H,CONH),8.15(s,1H,Ar-H),8.02(d,J=7.6Hz,1H,Ar-H), 7.92(s, 2H, Ar-H), 7.72(d, J=7.6Hz, 1H, Ar-H), 7.57(t, J=7.6Hz, 1H, Ar-H), 7.19(d, J=7.8 Hz,1H,Ar-H),6.98(t,J=7.6Hz,1H,Ar-H),6.80(d,J=8.0Hz,1H,Ar-H),6.61(t,J=7.6Hz, 1H,Ar-H),4.95(s,4H,O-CH 2 ,NH 2 ),3.56(s,2H,N-CH 2 -Thiophene), 2.97(t, J=5.6Hz, 2H, N-CH 2 -CH 2 ), 2.67(t, J=5.6Hz, 2H, N-CH 2 -CH 2 ),2.38(s,3H,N-CH 3 ),2.35(s,6H,2Ar-CH 3 ). 13 C NMR (100MHz, DMSO-d 6 )δ165.61,164.26,160.45,158.33,153.33,143.66,137.97,135.27,131....

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Abstract

The invention relates to thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof, and belongs to the technical field of antitumor drugs. The technical problem solved by the invention is to provide a novel dual-target inhibitor of BRD4 and HDACs. The structure of the thieno[2,3-d]pyrimidinyl hydroxamic acid derivative of the present invention is shown in formula I or formula II. The compound of the present invention has a novel structure and can be used as a small molecule BRD4 and HDACs dual inhibitor. Compared with RVX‑208 and vorinostat, it has better anti-proliferation ability of colorectal cancer, by selectively inhibiting BRD4 and HDACs and subsequent autophagy Sexual cell death is a promising anticancer drug.

Description

technical field [0001] The invention relates to thieno[2,3-d]pyrimidinyl hydroxamic acid derivatives and uses thereof, and belongs to the technical field of antitumor drugs. Background technique [0002] Colorectal cancer is one of the most common malignancies worldwide and is the second and third leading cause of cancer-related death in male and female adults, respectively. Although there have been improvements in diagnosis and effective treatment methods, new approaches to the treatment of advanced colorectal cancer are still urgently needed. In addition, clinically used epidermal growth factor receptor (EGFR) inhibitors, cetuximab Molecularly targeted drugs for colorectal cancer, such as anticancer drugs and bevacizumab, seem to have a limited role in patients with metastatic colorectal cancer (mCRC), but they greatly increase the cost of treatment. [0003] Histone acetylation in tumor tissue is one of the most common changes in mCRC. Immunohistochemical detection of hi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/14A61K31/519A61P35/00
CPCA61P35/00C07D495/14
Inventor 何谷李响蒋庆琳
Owner SICHUAN UNIV