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Signal channel inhibiting agent as well as preparation method and application thereof

A signal pathway and inhibitor technology, applied in the field of chemical medicine

Inactive Publication Date: 2015-05-27
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, it can lead to osteoporosis

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  • Signal channel inhibiting agent as well as preparation method and application thereof
  • Signal channel inhibiting agent as well as preparation method and application thereof
  • Signal channel inhibiting agent as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Example 1 2-chloro-N-(4-chloro-3-(pyridin-2-ylcarbamoyl)phenyl)-4-(methylsulfonyl)benzamide (compound 1)

[0272]

[0273] Step 1: Take 2.34g 2-chloro-4-methanesulfonylbenzoic acid, add 40mL SOCl 2 , reflux reaction for 1h, after the reaction, spin dry. Add 30 mL of DMAC and stir to dissolve. 1.716 g of 2-chloro-5-aminobenzoic acid was dissolved in 10 mL of DMAC and added dropwise to the previous solution, followed by the addition of 1 mL of triethylamine. React at 80°C for 5h, and monitor the reaction by TLC. After the reaction was over, 250 mL of distilled water was added to the reaction system, and a white solid was precipitated, which was filtered by suction and dried in vacuo to obtain 3.1 g of 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)benzoic acid. The rate is 79.8%. 1 H-NMR (DMSO-d 6 )δ:13.51(s,1H),10.97(s,1H),7.54-8.21(m,6H),3.31(s,3H);ESI-MS:387.99(M+H) + .

[0274] Step 2: Take 77.6mg of 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)benzoic...

Embodiment 2

[0275] Example 2 2-chloro-N-(4-chloro-3-(3-hydroxyphenyl-2-ylcarbamoyl)phenyl)-4-(methylsulfonyl)benzamide (compound 2)

[0276]

[0277] Take 77.7mg of 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)benzoic acid, 61.9mg of DCC, 27.1mg of HOBT, add 4mL of DMF to dissolve, stir at 0℃ for 1h, add 35 mg of 3-aminophenol was stirred at 0°C for 1 hour, and the temperature was raised to 80°C for 5 hours. Cool and filter with suction, add 10ml of 1M hydrochloric acid to the filtrate, then extract with ethyl acetate, dry over sodium sulfate, filter with suction, concentrate to dryness, and purify with silica gel column chromatography (EA:PE=1:2) to obtain 75.8mg of 2-chloro -N-(4-chloro-3-(3-hydroxyphenyl-2-ylcarbamoyl)phenyl)-4-(methylsulfonyl)benzamide (2), yield 79.1%. 1 H-NMR (DMSO-d 6 ,400MHz)δ:11.04(s,1H),10.47(s,1H),9.56(s,1H),8.16(s,1H),7.34-8.04(m,6H),7.11(s,2H),6.56 (s,1H),3.63(s,3H); 13 C-NMR (DMSO-d 6 ,100MHz)δ:165.0,164.5,162.9,158.1,143.6,141.2,140.2,137.9,131....

Embodiment 3

[0278] Example 3 2-chloro-N-(4-chloro-3-(2,3-dimethylphenyl-2-ylcarbamoyl)phenyl)-4-(methylsulfonyl)benzamide (compound 3)

[0279]

[0280] Take 77.4mg of 2-chloro-5-(2-chloro-4-(methylsulfonyl)benzamido)benzoic acid, 61.8mg of DCC, 27.2mg of HOBT, add 4mL of DMF to dissolve, stir at 0°C for 1h, add 38 mg of 2-aminopyridine was stirred at 0°C for 1 hour, then heated to 80°C for 5 hours. Cool and filter with suction, add 10ml of 1M hydrochloric acid to the filtrate, extract with ethyl acetate, dry over sodium sulfate, filter with suction, concentrate to dryness, and purify with silica gel column chromatography (EA:PE=1:2) to obtain 82.1mg of 2-chloro -N-(4-chloro-3-(2,3-dimethylphenyl-2-ylcarbamoyl)phenyl)-4-(methylsulfonyl)benzamide (3), yield 83.8% . 1 H-NMR (DMSO-d 6 ,600MHz)δ:11.02(s,1H),10.09(s,1H),8.17(s,1H),7.83-8.05(m,4H),7.58(d,1H,J=8.4Hz),7.21(d ,1H,J=7.2Hz),7.09-7.14(m,2H),3.41(s,3H); 13 C-NMR (DMSO-d 6 ,150MHz)δ:165.4,164.5,143.7,141.3,138.0,137.7,135.9,1...

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Abstract

The invention belongs to the field of a chemical medical technology and particularly relates to a signal channel inhibiting agent as well as a preparation method and an application thereof. The signal channel inhibiting agent is characterized in that the structure is shown as the formula I (which is as shown in the description); and an experiment shows that the IC50 (half maximal inhibitory concentration) of the signal channel inhibiting agent to a Hedgehog signal channel is in a range of 30 nanomoles to 10 micromoles, and the signal channel inhibiting agent can be used for preparing a medicine for treating diseases which are related to abnormal activation of the Hedgehog signal channel.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and in particular relates to a signal pathway inhibitor and a preparation method and application thereof. Background technique [0002] The Hedgehog (Hh, a segmented polarity gene) signaling pathway is a highly conserved signal transduction pathway that plays a role in cell differentiation, embryonic development, organ formation, maintenance of internal environment stability in mature organs, tissue damage repair and regeneration. very important role. The signaling pathway is mainly composed of Hh protein, two transmembrane receptors Patched (Ptc) and Smoothened (Smo) and the downstream transcription factor Gli family. Under normal circumstances, Ptc inhibits the activity of Smo protein, thereby inhibiting the downstream pathway. At this time, the terminal transmitter of the downstream Hh signal-Gli protein is truncated in the proteasome, and enters the nucleus in the form of trun...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4402
Inventor 谢永美魏于全赵瀛兰
Owner SICHUAN UNIV