Dihydropteridinone-sulfamide derivatives, pharmaceutically-acceptable salts of derivatives, preparation method of derivatives and application of derivatives and salts

A technology of dihydropteridone and sulfonamide, which can be applied in the fields of organic chemistry, drug combination, anti-tumor drugs, etc., can solve the problem that there are not many BRD4 small molecule inhibitors.

Active Publication Date: 2019-10-18
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are not many BRD4 small-molecule inhibitors that have entered the clinical stage, and it is urgent to find more new and efficient BRD4 inhibitors to provide new options for the treatment of tumors and other diseases

Method used

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  • Dihydropteridinone-sulfamide derivatives, pharmaceutically-acceptable salts of derivatives, preparation method of derivatives and application of derivatives and salts
  • Dihydropteridinone-sulfamide derivatives, pharmaceutically-acceptable salts of derivatives, preparation method of derivatives and application of derivatives and salts
  • Dihydropteridinone-sulfamide derivatives, pharmaceutically-acceptable salts of derivatives, preparation method of derivatives and application of derivatives and salts

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 29

[0091] Example 29: Synthesis of Compound 29

[0092] The preparation methods of compounds 1-35 are the same, and the preparation method of compound 29 is taken as an example.

[0093] With absolute ethanol and 1,4-dioxane as solvent, 40a and 46a prepared above were dissolved in the solvent according to the molar ratio of 1:1, and 2.5 equivalents (relative to 40a) of concentrated hydrochloric acid were added, and heated to reflux. 48h, after the reaction was completed, the solvent was spin-dried, washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, the ethyl acetate phases were combined, concentrated, and the final product 29 was obtained by column chromatography. Yield 76%, pale yellow solid, melting point: 146-147°C. 1 H NMR (400MHz, DMSO-d 6 )δ9.52(s,1H),8.44(s,1H),7.87(s,1H),7.83(d,J=8.0Hz,1H),7.77(d,J=1.8Hz,1H),7.44– 7.31(m, 5H), 7.27(d, J=7.2Hz, 2H), 5.48(d, J=15.3Hz, 1H), 4.36(d, J=15.3Hz, 1H), 4.09(t, J=4.8 Hz, 1H), 3.28 (s, 3H), 2.07 (s,...

Embodiment 1

[0094] Example 1: Synthesis of Compound 1

[0095] The method is the same as in Example 29. Yield 63%, pale yellow solid, melting point: 179-180°C. 1 H NMR (400MHz, DMSO-d 6 )δ9.41(s,1H),8.45(s,1H),8.04(t,J=6.3Hz,1H),7.87–7.80(m,2H),7.43(t,J=8.0Hz,1H), 7.32–7.21 (m, 6H), 4.62–4.51 (m, 1H), 4.23–4.17 (m, 1H), 3.99 (d, J=6.3Hz, 2H), 3.25 (s, 3H), 2.03 (d, J=6.2Hz, 1H), 1.93(d, J=6.4Hz, 1H), 1.71(d, J=10.8Hz, 5H), 1.64–1.55(m, 3H), 0.78(t, J=7.5Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 )δ162.83,154.92,151.58,141.88,140.90,138.53,137.81,129.11,128.17,127.50,127.07,121.30,117.82,115.73,115.60,58.84,57.42,46.15,28.94,28.74,27.78,26.46,23.06,22.66,9.05 .HR-MS(ESI):Calcd.C 27 H 32 N 6 O 3 S,[M+H] + m / z:521.2335,found:521.2334.

Embodiment 2

[0096] Example 2: Synthesis of Compound 2

[0097] The method is the same as in Example 29. Yield 63%, pale yellow solid, melting point: 155-156°C. 1 H NMR (400MHz, DMSO-d 6 )δ10.22(s, 1H), 9.40(s, 1H), 8.44(s, 1H), 7.82(s, 1H), 7.78(d, J=9.5Hz, 1H), 7.37(t, J=8.0 Hz, 1H), 7.25–7.18 (m, 3H), 7.10 (d, J=7.6Hz, 2H), 7.00 (t, J=7.3Hz, 1H), 4.60–4.48 (m, 1H), 4.24–4.18 (m, 1H), 3.25 (s, 3H), 2.03 (d, J=5.9Hz, 1H), 1.91 (d, J=9.3Hz, 1H), 1.78–1.65 (m, 5H), 1.65–1.55 ( m,3H),0.78(t,J=7.5Hz,3H). 13 C NMR (100MHz, DMSO-d 6 )δ162.84,154.80,151.57,141.86,139.93,138.42,137.88,129.11,129.02,123.77,121.66,119.80,117.86,115.79,58.83,57.40,28.93,28.71,27.78,26.46,23.05,22.64,9.04.HR-MS (ESI):Calcd.C 26 H 30 N 6 O 3 S,[M+H] + m / z:507.2178,found:507.2179.

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Abstract

The invention provides dihydropteridinone-sulfamide derivatives as well as a preparation method and application thereof aiming at problems in the prior art, and provides a novel choice for developmentof an antitumor drug for inhibiting a bromodomain (BRD4) protein. Activity experiments confirm that the novel compounds having the dihydropteridinone structure provided by the invention have a good inhibitory effect on the BRD4 protein and can inhibit proliferation of tumor cells, especially for gastric cancer cells, and the inhibitory activity of partial compounds reaches or is superior to thatof a positive control compound JQ1; and the derivatives provided by the invention provide a novel drug choice for a BRD4 inhibitor and treatment of diseases such as tumors.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a dihydropteridone-sulfonamide derivative and a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] Malignant tumors are the number one major disease threatening the health of the Chinese people. According to the National Cancer Center, 7.5 people are diagnosed with cancer every minute in my country. Therefore, the research on antitumor drugs and their related target inhibitors has important clinical significance and social value. [0003] BRD (Bromodomain), also known as bromodomain protein, is a class of conserved protein domains that can specifically recognize acetylated lysine residues, and play a key role in the regulation of chromatin assembly and gene transcription. Several studies have proved that BRD is a highly adaptable drug target, and small molecule inhibitors acting on BRD have broad prospects in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/00A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D475/00
Inventor 刘宏民孙凯郑一超李雯赵兵冯雪建符运栋宋启梦
Owner ZHENGZHOU UNIV
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