N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as preparation method and purpose thereof

A technology for indole derivatives and derivatives, applied in the field of N-substituted-5-amino) indole derivatives and their preparation, capable of solving problems such as toxic and side effects, achieving simple preparation methods, low reaction costs, and simple reaction processes easy to control effects

Inactive Publication Date: 2018-02-27
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Malignant tumors are still one of the major diseases that threaten people's lives. Small-molecule anti-tumor drugs that are now on the market have certain curative effects, but have serious toxic and side effects. Therefore, research on new targeted anti-tumor drugs has become a top priority

Method used

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  • N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as preparation method and purpose thereof
  • N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as preparation method and purpose thereof
  • N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as preparation method and purpose thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of N-butyl-5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide

[0037] Preparation of ethyl 5-aminoindole-2-carboxylate

[0038]

[0039] Add p-nitrophenylhydrazine (10g, 0.065mol) and absolute ethanol (85mL) sequentially into a 250mL dry two-necked bottle, then add ethyl pyruvate (8.14g, 0.072mol) dropwise under stirring, and the addition ends Afterwards, the temperature was raised and heated to reflux, and after 2 hours of reflux reaction, TLC detected that the reaction was over, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was collected and dried to obtain 13.8 g of ethyl pyruvate p-nitrophenylhydrazone as a yellow solid product, with a yield of 89.6% and a melting point (m.p.): 197-199°C.

[0040] In a dry 500mL reaction flask, first add ethyl pyruvate p-nitrophenylhydrazone (10g, 0.042mol) and polyphosphoric acid (110g) in sequence, then raise...

Embodiment 2

[0049] Example 2: N-(3-(diethylamino)propyl)-5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide preparation of

[0050] The reaction procedure was the same as that in Example 1, except that n-butylamine was replaced by 3-diethylaminopropylamine (39 mg, 0.3 mmol), and finally 67.18 mg of a pale yellow solid product was obtained with a yield of 26.6%. Spectral data: 1 H NMR (600MHz, DMSO-d6): δ11.45 (d, J = 0.9Hz, 1H), 9.56 (s, 1H), 9.35 (d, J = 1.6Hz, 1H), 8.73 (dd, J = 1.6 ,4.8Hz,1H),8.57(d,J=4.9Hz,1H),8.49(td,J=1.9,8.0Hz,1H),8.47(t,J=5.5Hz,1H),8.13(s,1H ),7.58(ddd,J=0.6,4.8,7.9Hz,1H),7.48(dd,J=2.0,8.8Hz,1H),7.43(d,J=5.1Hz,1H),7.37(d,J= 8.8Hz, 1H), 7.04(d, J=1.4Hz, 1H), 3.28~3.33(m, 2H), 2.46(quin, J=7.4Hz, 6H), 1.67(quin, J=7.0Hz, 2H) ,0.96(t,J=7.1Hz,6H); 13 C NMR (151MHz, DMSO-d6): δ161.9, 161.4, 161.1, 159.8, 151.9, 148.6, 134.8, 133.4, 133.2, 132.9, 132.8, 127.5, 124.4, 118.8, 112.5, 111.6, 107.8, 102.4, 5( *2),38.0,27.2,12.2(*2);ESI-MS(+):[M+H] + ,44...

Embodiment 3

[0051] Example 3: Preparation of N-benzyl-5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide (WSQ-1026)

[0052] The reaction procedure was the same as that in Example 1, except that n-butylamine was replaced by benzylamine (32.01 mg, 0.3 mmol), and finally 56.8 mg of a light yellow solid product was obtained by isolation, with a yield of 43%. Spectral data: 1H NMR (600MHz, DMSO-d6): δ11.52(brs, 1H), 9.58(br s, 1H), 9.36(d, J=2.0Hz, 1H), 9.00(t, J=6.0Hz, 1H) ,8.73(dd,J=1.6,4.7Hz,1H),8.57(d,J=5.1Hz,1H),8.49(td,J=1.9,8.0Hz,1H),8.15(s,1H),7.59( dd,J=4.6,7.9Hz,1H),7.50(dd,J=1.9,8.8Hz,1H),7.43(d,J=5.1Hz,1H),7.39(d,J=8.8Hz,1H), 7.34~7.37(m,4H),7.26(dt,J=2.7,5.8Hz,1H),7.16(d,J=1.4Hz,1H),4.53(d,J=6.0Hz,2H); 13 C NMR (151 MHz, DMSO-d6): δ161.9, 161.6, 161.1, 159.8, 151.9, 148.6, 140.1, 134.8, 133.5, 133.3, 132.9, 132.4, 128.8, 127.7, 127.5, 127.3, 126.4, 11129.5, ,107.8,103.0,42.6; ESI-MS(+):[M+H] + ,421.17.

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Abstract

The invention discloses an N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative as well as a preparation method and a purpose thereof, and relates to malignant tumor drugs. A structure of the N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative is shown as a formula I. For application of the N-substituted-5-((4-substituted pyrimidine-2-yl)amino)indole derivative in preparing an antitumor drug and an anti-HIV drug, a novel derivative which inhibits the signal pathway activities of CDK9 and HDACs is applied to blocking tumor cell proliferation and inducing cells apoptosis by inhibiting relative signal pathway activities of the CDK9 and the HDACs, and thus can be used for treating and preventing various diseases such as malignant tumors of humans and animals.

Description

technical field [0001] The present invention relates to malignant tumor drugs, in particular to N-substituted-5-((4-substituted pyrimidin-2-yl)amino)indole derivatives and their preparation method and application. Background technique [0002] Malignant tumors are still one of the major diseases that threaten people's lives. Small-molecule anti-tumor drugs that are now on the market have certain curative effects, but have serious side effects. Therefore, research on new targeted anti-tumor drugs has become a top priority. [0003] The most basic characteristics of tumor cells are abnormal cell cycle and infinite cell proliferation, among which the cell cycle-dependent kinase family (cyclin-dependent kinases, CDKs) is at the core. The CDKs family is divided into two categories according to their intracellular functions: CDKs that regulate cell cycle and CDKs that regulate gene transcription. As a key factor in the regulation of eukaryotic gene transcription, positive transcr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D403/12C07D417/14A61P35/00A61P31/18
CPCC07D401/14C07D403/12C07D417/14
Inventor 吴振方美娟秦静波陈晓惠唐博文郭凯强
Owner XIAMEN UNIV
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