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Pyrimidinoindole compound as well as preparation method and application thereof

A technology for compounds, pyrimidines, applied in the field of medicinal chemistry

Inactive Publication Date: 2019-08-23
GUANGZHOU JINAN BIOMEDICINE RES & DEV CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these signaling regulators, transcription factors, cytokines, etc. also lead to the differentiation of hematopoietic stem cells

Method used

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  • Pyrimidinoindole compound as well as preparation method and application thereof
  • Pyrimidinoindole compound as well as preparation method and application thereof
  • Pyrimidinoindole compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1. Intermediate 5-(3-nitrophenyl) tetrazole (B1) synthesis

[0054] Take 30.0g (202.69mmol) of m-nitrobenzonitrile, 14.5g (222.96mmol) of sodium azide, and 45.7g (202.69mol) of zinc bromide in a 1000ml flask, add 500ml of water, reflux at 100°C for 24h, then cool down To room temperature, pour the reaction solution into 500ml of water, add 100ml of 3N hydrochloric acid, extract with ethyl acetate (3×200ml), collect the organic phase, spin dry the ethyl acetate under reduced pressure to obtain a white solid, add 800ml of 0.25mol / L NaOH, stirred, the solid dissolved first and then re-precipitated white flocculent zinc hydroxide, suction filtered, the filtrate was adjusted to pH=5 with 3.0mol / L hydrochloric acid, a large amount of white solid was precipitated, and the dry white B1 product was 34.8g, the yield was 90 %. 1 H NMR (DMSO-d 6 , ppm) δ8.85-8.86 (t, 1H), 8.48-8.51 (dt, 1H), 8.43-8.46 (dq, 1H), 7.91-7.95 (t, 1H).

Embodiment 2

[0055] Embodiment 2. the synthesis of intermediate 2-methyl-5-(3-nitrophenyl) tetrazole (B2)

[0056] Take 33.0g (172.64mmol) of intermediate B1 and dissolve it in 150ml DMF, add 28.63g (207.17mmol) of anhydrous potassium carbonate, 29.41g (207,17mmol) of methyl iodide, react at 90°C for 1h, cool to room temperature, and the reaction solution has Dark yellow, the reaction solution was slowly dropped into 1L of water, a large amount of white solid was precipitated, filtered by suction, and dried to obtain a white solid. Recrystallization with ethyl acetate and petroleum ether gave 26 g of product B2, with a yield of 72.2%. 1 H NMR (DMSO-d 6 , ppm) δ8.66-8.67 (t, 1H), 8.40-8.42 (dt, 1H), 8.33-8.35 (dt, 1H), 7.81-7.85 (t, 1H), 4.46 (s, 3H).

Embodiment 3

[0057] Example 3. Synthesis of intermediate N-hydroxyl-N-acetyl-4-(2-methyltetrazol-5-yl)aniline (B4)

[0058] Take 30g (146.22mmol) of intermediate B2, dissolve it in 350ml tetrahydrofuran at room temperature, add 10.0g NI powder, cool down to 0°C in an ice bath, slowly drop in 7.3g (143,49mmol) of hydrazine hydrate in batches, and stir at 0°C After 30 minutes, slowly warm up to room temperature and continue to react for 24 hours. The solution turns light yellow. After TLC monitors that the raw materials disappear, cool down to 0°C, add 4 equivalents of sodium bicarbonate 54g, gas is generated, stir for 30mim, and drop in acetyl chloride 13.77g at 0°C. g (175.46mmol), slowly warmed up to room temperature for 2h, suction filtered, and the filter cake was washed with THF (3×50ml), the filtrate was collected, and THF was spin-dried under reduced pressure to obtain a yellow solid. The solid was recrystallized from ethyl acetate to obtain 28 g of product B4 with a yield of 84%. 1...

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Abstract

The invention relates to the technical field of medicine chemistry and in particular to a pyrimidinoindole compound as well as a preparation method and application thereof. The invention mainly relates to synthesis of a pyrimidinoindole-containing compound and application thereof in the field of medicines. Specifically, the invention relates to the pyrimidinoindole compound which is capable of stimulating self replication of stem cells in vitro without differentiation, and thus the pyrimidinoindole compound has application prospects in expanding application of stem cells in various treatment fields.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a pyrimidoindole compound and its preparation method and application, and the use of the pyrimidoindole compound in in vitro expansion of stem cells, especially in in vitro expansion of hepatocytes the use of. Background technique [0002] Two important characteristics of hematopoietic stem cells are self-renewal ability and the potential to differentiate into other blood cells. According to their source, they can be divided into bone marrow, peripheral blood and umbilical cord blood stem cells. Hematopoietic stem cell transplantation is the current treatment for malignant tumors of the blood system such as acute leukemia, chronic myelogenous leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, etc., and some non-malignant tumors of the blood system, such as severe aplastic anemia, Mediterranean The main treatment for anemia. It should be emphasized that ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C12N5/0775C12N5/0789
CPCC07D487/04C12N5/0647C12N5/0665C12N2500/30
Inventor 王一飞黄云生冯悦谢晓阳
Owner GUANGZHOU JINAN BIOMEDICINE RES & DEV CENT
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