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Hedgehog pathway inhibitor

A technology of hedgehog pathway and solvent medium, applied in the field of hedgehog pathway inhibitors, can solve the problem of lack of effective drugs for medulloblastoma, and achieve the effect of good growth and inhibition of growth

Active Publication Date: 2019-04-26
苏州麦迪耐斯医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a hedgehog pathway inhibitor and its preparation method and application to solve the problem of lack of effective drugs for the treatment of medulloblastoma in the current market. The hedgehog pathway inhibitor provided by the present invention can be used to prepare and treat medulloblastoma Drugs for diseases related to the activation of hedgehog pathway, the hedgehog pathway inhibitor can especially well inhibit the growth of medulloblastoma, and can be used to prepare medicines for treating medulloblastoma-related diseases

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The abbreviation HATU in this embodiment refers to the compound of the following formula I structure

[0036] Formula (I)

[0037]

[0038] (1) 2-(4-isobutylphenyl)propionic acid (formula (2), 10g, 49mmol) was placed in tetrahydrofuran (100mL), and dimethylhydroxylamine hydrochloride (5g, 49mmol) was added at room temperature, Triethylamine (15g, 150mmol) and HATU (23g, 60mmol), the reaction mixture was stirred at room temperature for 16 hours, concentrated, and was purified by silica gel column (mobile phase PE (petroleum ether):EA (ethyl acetate)=20:1) Purification gave the product 2-(4-isobutylphenyl)-N-methoxy-N-methylpropanamide (formula (3), 10 g, 40 mmol) as a colorless oil. Formula (3)LCMS(ESI):m / z250.1[M+1] + .

[0039] (2) 2-(4-isobutylphenyl)-N-methoxy-N-methylpropionamide (formula (3), 11g, 44.2mmol) obtained in step (1) was added to tetrahydrofuran (200mL ), at 0°C, methyl Grignard reagent (14.7mL, 3mol / L) was added dropwise, after the dropwise add...

Embodiment 2

[0043]

[0044] According to the method described in Embodiment 1, the difference between the method described in Embodiment 2 and the method described in Embodiment 1 is that it also includes the following steps (5):

[0045] (5) Place the compound (0.35g, 0.83mmol) of the formula (1-1) obtained in step (4) in Example 1 in dichloromethane (20ml), add tert-butylmercaptan (720mg), and react Add aluminum trichloride at 0°C, react for 2 hours and then gradually raise the temperature to room temperature. After quenching with water, extract with dichloromethane, concentrate and purify by preparative chromatography to obtain the oily product formula (1-2) (0.3g, 0.72 mmol). Formula (1-2)LCMS(ESI):m / z418.3[M+1] + ; 1 H NMR (400MHz, DMSO): δ (ppm) 0.88 (s, 3H) 0.90 (s, 3H) 1.81 (s, 3H) 1.81-1.88 (m, 1H), 2.44 (d, 2H), 5.72 (s, 2H) 6.75 (d, 2H) 6.93 (m, 2H) 7.10-7.22. (m, 6H) 7.37 (m, 1H) 7.41 (m, 1H) 7.47 (m, 1H).

Embodiment 3

[0047] This example is used to illustrate the effect of the compound of formula (1) of the present invention on tumor proliferation associated with the activation of hedgehog pathway.

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Abstract

The invention relates to a compound with an inhibition effect on activation of hedgehog pathways. The structural formula of the compound is shown in formula (1), wherein R is H or CH3. The invention also provides a method for preparing the compound. The invention also provides an application of the compound or pharmaceutically acceptable salt, a solvate or a medicine compound of the compound to preparation of drugs for treating diseases related to activation of hedgehog pathways. The compound can be used for preparing the drugs for treating diseases related to activation of hedgehog pathways.The compound can particularly well inhibit growth of medulloblastoma and can be used for preparing drugs for treating medulloblastoma related diseases.

Description

technical field [0001] The invention relates to a hedgehog pathway inhibitor. Background technique [0002] Medulloblastoma is the most common brain tumor in children, accounting for about 30% of childhood tumors. Medulloblastoma is the most malignant intracranial tumor, mainly manifested in: extremely rapid growth; difficult to remove completely by surgery; tumor cells tend to produce seeding planting along the brain and spinal cord. The current general treatment methods include surgery, chemotherapy and radiation therapy, but there are still many patients who die from this disease, and even if they survive, they will leave various sequelae, including cognitive deficits and endocrine disorders, so people urgently need to improve the efficacy of the treatment. A strategic approach to blastoma. Data show that nearly 30% of medulloblastoma patients are due to abnormal activation of the hedgehog (hedgehog) pathway, which has also been found in other malignant tumors, includin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08A61K31/404A61P35/00
CPCA61P35/00C07D209/08
Inventor 杜芳胡晓伟
Owner 苏州麦迪耐斯医药科技有限公司
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