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Compound as well as preparation method and application thereof

A compound and composition technology, applied in the fields of compound and its preparation and application, can solve the problems of toxic and side effects, drug resistance, not being approved for medulloblastoma, etc., and achieve the effect of inhibiting growth

Inactive 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

[0004] Although these two hedgehog (hedgehog) inhibitors showed a good effect on inhibiting medulloblastoma in the initial clinical trials, they quickly developed drug resistance. More importantly, these two inhibitors are effective against cancer cells and normal The cells are not selective, leading to severe toxic side effects, especially permanent bone damage, and for these reasons, these two drugs are not currently approved for the treatment of medulloblastoma

Method used

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  • Compound as well as preparation method and application thereof
  • Compound as well as preparation method and application thereof
  • Compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046]

[0047] (1) Lithium diisopropylamide (LDA, 150mL, 2mol, in tetrahydrofuran) was added dropwise to tetrahydrofuran (500mL), cooled to -78°C, ethyl isobutyrate (formula (2), 33g , 0.284mol), the reaction mixture was kept at -70 to -65°C for 20 minutes, and then 2,3-dichloropropene (31 g, 0.279mol) was added dropwise. After the addition was completed, the reaction solution was gradually warmed to room temperature for 18 hours After the reaction was completed, it was quenched with saturated ammonium chloride, extracted twice with dichloromethane (2×300mL), the combined organic layer was dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain a brown oil compound 4-chloro-2, Ethyl 2-dimethyl-4-pentenoate (formula (3), 59 g, 0.279 mol, 93% yield) was directly used in the next reaction. Formula (3) 1 H NMR (400MHz, CDCl 3 ): δ (ppm) 1.24-1.28 (m, 9H), 2.65 (s, 2H), 4.15 (q, 4H), 5.13 (s, 1H), 5.24 (s, 1H).

[0048] (2) 4-chloro-2,2-dime...

Embodiment 2

[0056]

[0057] 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 the following steps (9) and (10) are used to replace the steps in Embodiment 1 ( 8):

[0058] (9) 3-(3-(tert-butylmercapto)-5-isopropyl-1-(4-methoxybenzyl)-1 hydrogen-indol-2-yl) obtained in step (7) -Ethyl 2,2-dimethylpropionate (formula (11), 1.5 g, 3 mmol) and tert-butylmercaptan (t-BuSH, 2.7 g, 30 mmol) were dissolved in CH 2 Cl 2 (40 mL), at 0°C, add AlCl in portions within 5 minutes 3 (2.0g, 15mmol), the reaction mixture was reacted at this temperature for 2h, poured into ice water after the reaction was completed, added 1 equivalent of HCl, extracted twice with dichloromethane, and the organic phase was washed with water, brine and anhydrous sulfuric acid successively. Na-dried, concentrated and purified by silica gel column (EA (ethyl acetate): PE (petroleum ether) = 10:1) to obtain the whi...

Embodiment 3

[0062]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. The structural formula of the compound is shown as formula (1) in the description, wherein R is H or CH3. The invention further provides a preparation method of the compound and an application of the compound or pharmaceutically acceptable salt, solvate or drug complex of the compound to preparation of drugs for treating hedgehog pathway activation-related diseases. The compound can be used for preparing the drugs for treating the hedgehog pathway activation-related diseases, can well inhibit medulloblastoma growth and can be used for preparing drugs for treating medulloblastoma-related diseases.

Description

technical field [0001] The present invention relates to a compound and its preparation method and application. 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...

Claims

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Application Information

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IPC IPC(8): C07D209/30A61K31/405A61P35/00
CPCA61P35/00C07D209/30
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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