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Medicine composition using taxol and p-phenylphthalazinone type BTK inhibitor in combined way and application thereof

A phenylphthalazinone and inhibitor technology, which can be used in drug combinations, antitumor drugs, pharmaceutical formulations, etc., can solve problems such as unsatisfactory selectivity, drug resistance, multiple side effects, etc.

Inactive Publication Date: 2019-03-01
NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] It is currently known that the selectivity of BTK inhibitors is not ideal. In addition to inhibiting BTK, it also inhibits various other kinases (such as ETK, EGF, BLK, FGR, HCK, YES, BRK and JAK3, etc.), resulting in more side effects; at the same time , BTK binding site mutations often lead to drug resistance

Method used

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  • Medicine composition using taxol and p-phenylphthalazinone type BTK inhibitor in combined way and application thereof
  • Medicine composition using taxol and p-phenylphthalazinone type BTK inhibitor in combined way and application thereof
  • Medicine composition using taxol and p-phenylphthalazinone type BTK inhibitor in combined way and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Preparation of 2H-phthalazin-1-one

[0027]

[0028] Step 1: Weigh dimethoxymethylbenzene (500mmol) into a reaction flask, add tetrahydrofuran (800ml) to dissolve, add s-BuLi (565mmol) under nitrogen protection at 60°C, and store the reaction solution at -60°C Stir for 1h.

[0029] Step 2: Weigh dry ice (50mmol) into a reaction flask, add tetrahydrofuran (200ml), add n-BuLi (5ml), stir for 2h under nitrogen protection, add the mixture of step 1, continue stirring for 30min, stop the reaction, add water 1000ml, adjust the pH to 2 with concentrated hydrochloric acid, separate the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and recrystallize to obtain 2-dimethoxymethylbenzoic acid .

[0030] Step 3: Weigh the product obtained in Step 2 (400mmol), acetic acid (93mmol), and hydrazine (600mmol) into a reaction flask, add 300ml of isopropanol, under nitroge...

Embodiment 2

[0032] The preparation of embodiment 2 (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid p-chlorophenyl ester

[0033]

[0034] Weigh 5-amino-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate (50mmol) and DIPEA (100mmol) into a reaction flask, add 300ml of dichloromethane, and slowly add it dropwise under stirring at room temperature and p-chlorophenyl chloroformate (51mmol), dropwise, continue to stir at room temperature for 1h, stop the reaction, concentrate the reaction mixture, add 70ml of ethyl acetate, wash with dilute aqueous hydrochloric acid (0.2-0.3N) and saturated brine, anhydrous Dried over sodium sulfate, filtered, and concentrated to give (3,4-dihydroisoquinoline-2(1H)-tert-butyl-carboxylate-5-yl)-p-chlorophenylcarbamate, which was used directly in the next step, ESI–MS :[M+H] + m / z 403.

Embodiment 3

[0035] Example 3 Preparation of (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid-4-(2H)-phthalazin-1-one phenyl ester

[0036]

[0037] Weigh 2H-phthalazin-1-one (150mmol), (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid p-chlorophenyl ester (195mmol) in In the reaction bottle, add DMF100ml, react overnight at 55°C, stop the reaction, add water 100ml, dichloromethane 200ml, extract, separate the organic phase, continue to extract the water phase with dichloromethane (3*50ml), combine the organic phase, Dry over sodium sulfate and purify by column chromatography to obtain the title compound.

[0038] ESI–MS:[M+H] + m / z 513.

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Abstract

The invention provides a medicine composition using taxol and a p-phenylphthalazinone type BTK inhibitor in a combined way. The medicine composition contains active ingredients and pharmaceutically acceptable auxiliary materials. The active ingredients is prepared from taxol and BTK inhibitors as shown in a formula (I) according to the mol ratio of (0.14 to 0.20):1. The medicine composition can beused for preparing medicine for preventing and / or treating diseases relevant to Bruton's tyrosine kinase; the treatment effect is good. The formula (I) is as shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to phthalazinone BTK inhibitors and applications thereof, in particular to phthalazinone BTK inhibitors, a preparation method thereof, a pharmaceutical composition containing the compound, and its application in the treatment of Bruton casein Use in amino acid kinase-associated diseases. Background technique [0002] Bruton's tyrosine kinase (BTK) is a member of the Tec family. It consists of a unique N-terminal domain, namely PH (pleckstrin homology) domain, TH (Tec homology) homology region, SH3 (Srchomology3) domain, SH2 (Src homology2) domain and catalytic domain, also known as SH1 / TK (Srchomologyl / Tyrosine kinase) domain or kinase domain composition (Akinleye et al: Ibrutiniband novel BTK inhibitors in clinical development. Journal of Hematology & Oncology 2013, 6: 59). During the normal development of B lymphocytes, the correct expression of different protein regions of the...

Claims

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Application Information

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IPC IPC(8): A61K31/502A61K31/337A61K31/454A61P35/00A61P35/02C07D401/12
CPCA61P35/00A61P35/02A61K31/337A61K31/454A61K31/502C07D401/12A61K2300/00
Inventor 郭程杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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