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Indole derivatives or salts thereof as well as preparation method and application of indole derivatives or salts thereof

A kind of technology of indoles and derivatives, applied in the field of chemical medicine

Inactive Publication Date: 2019-01-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to provide a small molecule inhibitor of SMO with a new structure based on solving the current clinical problems related to the Hh signaling pathway, in particular to a new inhibitor of the SMO inhibitory activity of a G protein-coupled 7-times transmembrane receptor Structured indole derivatives or their salts and their preparation and use

Method used

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  • Indole derivatives or salts thereof as well as preparation method and application of indole derivatives or salts thereof
  • Indole derivatives or salts thereof as well as preparation method and application of indole derivatives or salts thereof
  • Indole derivatives or salts thereof as well as preparation method and application of indole derivatives or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1 Preparation of N-(1-benzoyl-1H-indol-6-yl)-2,5-dichlorobenzamide

[0102] (N-(1-benzoyl-1H-indol-5-yl)-2,5-dichlorobenzamide)

[0103]

[0104] Step 1: Synthesis of (5-nitro-1H-indol-1-yl)(phenyl)methanone

[0105] Benzoic acid (293mg, 2.39mmol, 1.2equiv.), HATU (912mg, 2.40mmol, 1.3equiv.), DIPEA (310mg, 2.40mmol, 1.3equiv.) were dissolved in an appropriate amount of DCM, stirred for 10 minutes and then added 5-nitro -1H-indole (324 mg, 2.00 mmol, 1.0 equiv.), stirred at room temperature for 8 hours. TLC monitored the reaction in real time. After the reaction is complete, dilute with water, extract three times with an appropriate amount of ethyl acetate, combine the organic phases, and successively dilute with water, saturated NaHCO 3 solution, saturated NaCl solution, and the organic layer was washed with anhydrous NaSO 4 Dry and distill under reduced pressure to obtain a crude product, which is purified on a silica gel column to obtain (5-nitro-1H-in...

Embodiment 2

[0111] Example 2 Preparation of N-(1-benzoyl-1H-indazol-5-yl)-2,5-dichlorobenzamide

[0112] (N-(1-benzoyl-1H-indazol-5-yl)-2,5-dichlorobenzamide)

[0113]

[0114] Step 1: Synthesis of 1H-indazol-5-amine

[0115] 5-Nitro-1H-indazole (430 mg, 1.0 equiv.) was dissolved in ethyl acetate, a catalytic amount of Pd / C (40 mg, 10% w / w) was added under nitrogen protection, replaced by hydrogen, and stirred at room temperature for 1.5 hours. TLC monitored the reaction in real time. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, washed with an appropriate amount of methanol, and the organic phase was distilled under reduced pressure to obtain the crude product 1H-indazol-5-amine (330 mg, yield: 94.3%).

[0116] Step 2: Synthesis of 2,5-dichloro-N-(1H-indazol-5-yl)benzamide

[0117] 1H-Indazol-5-amine (130mg, 1.0equiv.), K 2 CO 3 (165mg, 1.2equiv.) dissolved in anhydrous CH 3 CN, newly prepared 2,5-dichlorobenzoyl chloride (250 m...

Embodiment 3

[0121] Example 3 Preparation of N-(1-benzoyl-1H-benzo[d]imidazol-5-yl)-2,5-dichlorobenzamide

[0122] (N-(1-benzoyl-1H-benzo[d]imidazol-5-yl)-2,5-dichlorobenzamide)

[0123]

[0124] Step 1: Synthesis of (5-nitro-1H-benzo[d]imidazol-1-yl)(phenyl)methanone

[0125] 5-nitro-1H-benzo[d]imidazole (820mg, 5.03mmol, 1.0equiv.), Et 3 N (560mg, 5.53mmol, 1.1equiv.) was dissolved in an appropriate amount of DMF, and newly prepared benzoyl chloride (770mg, 5.47mmol, 1.1equiv.) was dissolved in anhydrous DCM, slowly added dropwise at 0°C, and stirred for 4 hours under nitrogen protection. TLC monitored the reaction in real time. After the reaction is complete, dilute with water, extract three times with an appropriate amount of ethyl acetate, combine the organic phases, and successively dilute with water, saturated NaHCO 3 solution, saturated NaCl solution, and the organic layer was washed with anhydrous NaSO 4 Dry and distill under reduced pressure to obtain a crude product, whic...

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PUM

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Abstract

The invention belongs to the technical field of chemical medicine, and relates to an Hh (Hedgehog) signal pathway Smoothed (SMO) receptor small molecule inhibitor, in particular to indole derivativesor salts thereof with Smoothed inhibitory activity, which are shown in chemical general formula (I) in the description, as well as a preparation method and pharmaceutical composition of the indole derivatives or salts thereof. Tests on inhibitory activity of Hh signal pathways show that most compounds have better inhibitory activity on the Hh signal pathways. The invention further discloses the application of the compounds to preparation of medicines for treating diseases associated with Hh, wherein the diseases are BCC (basal cell carcinoma), MB (medullblastoma), SCLC (small cell lung cancer), medulloblastoma, rhabdomyosarcoma, or a combination of the diseases.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and relates to indole derivatives or salts thereof and preparation methods and applications thereof, in particular to an indole derivative or its derivatives having G protein-coupled 7-times transmembrane receptor SMO inhibitory activity Salt and its preparation and use. Background technique [0002] According to reports, due to the destruction of the ozone layer and the deterioration of the environment, the problem of skin cancer has also attracted more and more attention. Skin cancer mainly includes three types: basal cell carcinoma (BCC), skin squamous cell carcinoma (CSCC) and melanoma (melanoma), among which BCC and CSCC are the most common, accounting for 70% Studies have shown that the occurrence of this type of cancer is closely related to the Hedgehog (Hh) signaling pathway, and inhibiting the activity of the key receptor protein Smoothened (SMO) in this pathway can effectively curb the...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D231/56C07D235/06C07D471/04C07D403/06C07D403/12C07D401/12A61K31/4439A61K31/4155A61K31/416A61K31/404A61K31/4184A61K31/437A61P35/00
CPCC07D209/08C07D231/56C07D235/06C07D401/12C07D403/06C07D403/12C07D471/04
Inventor 王永辉余发志李炜
Owner FUDAN UNIV
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