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1. 6-disubstituted-benzo five-membered heterocyclic derivatives and their uses

A substituent, C1-C6 technology, applied in the field of medicine, can solve problems such as large toxic and side effects, and achieve the effects of good anti-tumor activity, important practical value and application prospects

Active Publication Date: 2020-11-24
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many PI3K inhibitors cannot be used as drugs due to their high toxicity and side effects and causing drug resistance in tumors. Therefore, it is very critical and necessary to develop new anti-tumor drugs with low toxicity and good effects.

Method used

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  • 1. 6-disubstituted-benzo five-membered heterocyclic derivatives and their uses
  • 1. 6-disubstituted-benzo five-membered heterocyclic derivatives and their uses
  • 1. 6-disubstituted-benzo five-membered heterocyclic derivatives and their uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 6-(6-methoxy-5-(2,4-difluorobenzenesulfonamido)pyridin-3-yl)-N-3-(4-hydroxyphenyl)-1H-benzo[ b] Preparation of imidazole (compound 1)

[0066] Step 1) Synthesis of 5-bromo-2-nitro-N-(4-hydroxyphenyl)-aniline

[0067]

[0068] Dissolve 0.219g (1mmol) of 4-bromo-2-fluoronitrobenzene in 5ml of DMF, add 0.11g (1mmol) of p-aminophenol and 0.26g (2mmol) of DIEA in sequence, stir at room temperature for 24h, then pour the reaction solution into In 20ml of water, a solid was precipitated and filtered with suction to obtain 0.23g of a deep orange-red solid, with a yield of 74.7%.

[0069] The structural confirmation data are as follows:

[0070] MS: m / z 309.0[M+H] +

[0071] Step 2) Synthesis of 4-(6-bromo-1H-benzo[d]imidazol-1-yl)phenol

[0072]

[0073] Dissolve 0.1g (0.32mmol) of 5-bromo-2-nitro-N-(4-hydroxyphenyl)-aniline in 5ml of glacial acetic acid, add 0.5ml of trimethyl orthoformate, 0.2g (3.5mmol) of iron powder, reacted at 100°C for 2.5h, after t...

Embodiment 2

[0084] Example 2 6-(6-methoxy-5-(2,4-difluorobenzenesulfonamido)pyridin-3-yl)-N-3-(4-methoxyphenyl)-1H-benzene Preparation of [b] imidazole (compound 2)

[0085]

[0086] The preparation method is the same as compound 1.

[0087] 1 H NMR (400MHz, DMSO-d6) δ9.28(s, 1H), 8.43(t, J=5.3Hz, 1H), 8.17(dd, J=15.1, 8.3Hz, 1H), 7.85(d, J= 9.3Hz, 1H), 7.80-7.76(m, 2H), 7.75(t, J=9.0Hz, 1H), 7.61-7.57(m, 2H), 7.20-7.09(m, 2H), 6.97(d, J =7.8Hz,2H),3.83(s,3H),3.78(s,3H).

[0088] 13 C NMR(100MHz,DMSO-d6)δ162.17,158.42,157.16,147.46,146.76,144.38,142.73,135.18,134.36,134.12,133.54,128.95,125.33,124.64,124.47,123.44,118.03,116.68,116.39,114.57,113.12 ,106.11,56.08,54.00.

[0089] MS: m / z 523.1[M+H] + .

Embodiment 3

[0090] Example 3 6-(6-methoxy-5-(2,4-difluorobenzenesulfonamido)pyridin-3-yl)-N-3-(3,4-dimethoxyphenyl)- Preparation of 1H-Benzo[b]imidazole (Compound 3)

[0091]

[0092] The preparation method is the same as compound 1.

[0093] The structural confirmation data are as follows:

[0094] 1 H NMR (400MHz, DMSO-d6) δ9.29(s, 1H), 8.37(t, J=5.3Hz, 1H), 8.19(dd, J=15.1, 8.3Hz, 1H), 7.92(d, J= 9.3Hz, 1H), 7.80-7.75(m, 2H), 7.72(d, J=2.0Hz, 1H), 7.29(dd, J=12.0, 2.4Hz, 1H), 7.20-7.14(m, 1H), 7.12-7.05(m,1H),6.93(d,J=12.0Hz,1H),3.83(s,3H),3.78(s,6H).

[0095] 13 C NMR(100MHz,DMSO-d6)δ162.17,157.16,149.30,149.16,147.46,146.76,144.38,142.73,137.41,134.36,134.12,133.54,128.95,125.33,124.64,123.44,121.41,118.03,116.68,116.39,113.12 ,112.49,106.11,105.00,56.83,54.00.

[0096] MS: m / z 553.1[M+H] + .

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Abstract

The invention belongs to the technical field of medicine, and discloses a novel 1, 6-disubstitution-benzo five-membered heterocycle compound and a preparation method and application thereof. The structural formula of the compound is shown in a formula I (please see the specification for the formula I), wherein R1, R2, R3, X, Y, Z, n and the circle are stated as the claim and the specification. Thecompound has good anti-tumor activity, can be used as a treatment agent for treating tumors in the field of preparation of anti-tumor drugs, and meanwhile can also serve as PI3K, PI4K and m-TOR inhibitors.

Description

technical field [0001] The present invention relates to the field of medical technology, and relates to a 1,6-disubstituted-benzo five-membered heterocyclic derivative and its application, in particular to a 1,6-diaryl-substituted-benzimidazole derivative and Its preparation method and application in the preparation of antitumor drugs. Background technique [0002] PI3K (phosphatidylinositol 3-kinases, phosphatidylinositol 3-kinase) is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3), and then activate the downstream protein kinase B (Akt), and the activated Akt transmits signals to several downstream substrates, thereby controlling biological effects such as transcription, translation, cell cycle, and apoptosis. PI3K is divided into three types according to structure and phosphorylation substrate: I, II, and III. People usually refer to type I PI3K as PI3K. Type I PI3Ks are...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D401/14A61P35/00A61K31/4439A61K31/5377
CPCA61P35/00C07D401/04C07D401/14
Inventor 丁怀伟宋宏锐
Owner SHENYANG PHARMA UNIVERSITY