Novel Hedgehog signaling pathway inhibitor

A solvate and compound technology, applied in the field of novel Hedgehog signaling pathway inhibitors, can solve the problems of unsuccessful treatment of medulloblastoma, muscle tremor, dysgeusia, etc., achieve good application prospects, prevent proliferation, and low clearance rate Effect

Pending Publication Date: 2022-07-26
BEIJING TIANTAN HOSPITAL AFFILIATED TO CAPITAL MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many Smo inhibitors have been used in clinical trials for tumor treatment, most of them show drug resistance and various adverse reactions such as muscle tremors and dy

Method used

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  • Novel Hedgehog signaling pathway inhibitor
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  • Novel Hedgehog signaling pathway inhibitor

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0070] Another aspect of the present disclosure relates to the preparation method of any of the compounds of formula (I) as described above, which specifically comprises the following steps:

[0071] a) the compound of formula III is obtained from formula II through condensation and cyclization reaction with o-phenylenediamine;

[0072] b) the compound of formula III is subjected to alkylation to obtain formula IV;

[0073] c) formula IV reacts with 1-Boc-piperazine to obtain the compound of formula V;

[0074] d) compound of formula V obtains the compound of formula (I) through reduction and addition reaction;

[0075] where X 1 , X 2 , R 1 , R 2 The definition is as described above; specifically, it can be carried out with reference to the following reaction formula:

[0076]

[0077] In a specific embodiment, more preferably, the present invention provides a compound of the following formula 0025A or a pharmaceutically acceptable salt thereof, or an isomer thereof,...

Example Embodiment

[0111] Example 1: Compound 1-(4-(6-Chloro-2-fluoro-3-(1-methyl-1H-benzo[d]imidazol-2yl]phenyl)piperazin-1-yl)- Synthesis of 3-(methylsulfonyl)propan-1-one (0025A)

[0112]

[0113] resolve resolution:

[0114] Step 1): Synthesis of N-(2-aminophenyl)-3-bromo-4-chloro-2 fluorobenzamide

[0115]

[0116]Compound 1 (6.5g, 25.9mmol), compound 2 (o-phenylenediamine, 5.6g, 51.8mmol) were dissolved in 50ml DMF, EDCI (5.9g, 31.07mmol,), HOBT (4.19g, 31.07mmol) were added DMAP (316 mg, 2.59 mmol), stirred at room temperature, after the reaction was complete, 150 ml of water was added, extracted with ethyl acetate three times (150 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography 5.2 g of the product compound 3 (N-(2-aminophenyl)-3-bromo-4-chloro-2fluorobenzamide) was obtained as a yellow solid with a yield of 58.8%.

[0117] Structural characterization of compound 1:

...

Example Embodiment

[0146] Example 2: In vitro pharmacokinetic detection of 0025A

[0147] Using human liver microsomes, the metabolic stability of 0025A was tested in vitro, and compared with the positive control compounds (testosterone, propranolol) and negative control compounds (warfarin), 0025A showed low clearance and high metabolism Stability characteristics (Table 1).

[0148] Table 1 shows the in vitro pharmacokinetic analysis of 0025A:

[0149]

[0150] K, clearing coefficient; T 1 / 2 , half-life; Cl int , the intrinsic elimination rate; Cl app , the apparent half-life; Cl h , liver elimination rate; E h , the uptake rate.

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Abstract

The invention relates to a novel Hedgehog signaling pathway inhibitor and a preparation method thereof, and the Hedgehog signaling pathway inhibitor can effectively inhibit SMO receptor activity and block an SHH signaling pathway, has a good effect of blocking tumor cell proliferation, and has a good application prospect as a candidate drug for tumor treatment.

Description

technical field [0001] The present disclosure relates to the field of biomedicine, in particular to a novel Hedgehog signaling pathway inhibitor. Background technique [0002] Hedgehog (HH) is an evolutionarily highly conserved gene family that contains three homologous genes in mammals: Sonic Hedgehog (SHH), Desert Hedgehog (DHH) and Indian Hedgehog (IHH). Among them, SHH signaling pathway plays a very important role in embryonic development and tissue and organ formation, mainly including: SHH ligand, transmembrane protein Patched (PTCH1), transmembrane protein Smoothened (Smo), Suppressor of Fused (SUFU), G protein-coupled receptor kinases (GRKs), β-arrestins and downstream GLI transcription factors [Gorojankina, T., Cell Mol Life Sci, 2016.73(7): p.1317-32; Ruch, J.M. and E.J. Kim, Drugs, 2013.73(7):p.613-23; Chen, W., et al., Science, 2004.306(5705):p.2257-60]. The transduction of the Hedgehog signaling pathway is mainly mediated by the transmembrane proteins PTCH1 an...

Claims

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Application Information

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IPC IPC(8): C07D235/18A61K31/496A61P35/00A61P35/02
CPCC07D235/18A61P35/00A61P35/02A61K31/496A61K31/4184
Inventor 陈伟范俊婉王拥军李昊文
Owner BEIJING TIANTAN HOSPITAL AFFILIATED TO CAPITAL MEDICAL UNIV
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