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Paclitaxel and fluoropyridazine BTK (Bruton 's tyrosine kinase) inhibitor combined pharmaceutical composition and application thereof

An inhibitor, paclitaxel technology, applied in the field of medicinal chemistry, can solve the problems of multiple side effects, drug resistance, unsatisfactory selectivity, etc.

Inactive Publication Date: 2019-02-15
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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  • Paclitaxel and fluoropyridazine BTK (Bruton 's tyrosine kinase) inhibitor combined pharmaceutical composition and application thereof
  • Paclitaxel and fluoropyridazine BTK (Bruton 's tyrosine kinase) inhibitor combined pharmaceutical composition and application thereof
  • Paclitaxel and fluoropyridazine BTK (Bruton 's tyrosine kinase) inhibitor combined pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation of 8-fluoro-2H-phthalazin-1-one

[0025]

[0026] Step 1: Weigh 3-fluoro-1-dimethoxymethylbenzene (500mmol) into a reaction flask, add tetrahydrofuran (800ml) to dissolve, add s-BuLi (565mmol) under nitrogen protection at 60°C, and react The solution was stirred at -60°C for 1 h.

[0027] 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 3-fluoro-2-dimethoxy Toluic acid.

[0028] Step 3: Weigh the product obtained in Step 2 (400mmol), acetic acid (93mmol), and hydrazine (600mmol) into a reaction flask, add 300ml of isopr...

Embodiment 2

[0030] The preparation of embodiment 2 (3,4-dihydroisoquinoline-2(1H)-formic acid tert-butyl ester-5-yl)-carbamic acid o-chlorobenzyl ester

[0031]

[0032] 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 O-chlorobenzyl chloroformate (51mmol), after dropping, 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 sulfuric acid Dry over sodium, filter, and concentrate to give the title compound, which is used directly in the next step.

[0033] ESI–MS:[M+H] + m / z 417.

Embodiment 3

[0034] Example 3 (3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate-5-yl)-carbamic acid-2-[8-fluoro-(2H)-phthalazin-1-one group ] Preparation of benzyl ester

[0035]

[0036]Weigh 2H-phthalazin-1-one (150mmol), 8-fluoro-2H-phthalazin-1-one and (3,4-dihydroisoquinoline-2(1H)-tert-butyl formate-5- Base)-o-chlorobenzyl carbamate (195mmol) in a reaction flask, add DMF100ml, react overnight at 55°C, stop the reaction, add 100ml of water, 200ml of dichloromethane, extract, separate the organic phase, and continue to use dichloromethane for the aqueous phase Extracted with methane (3*50ml), combined the organic phases, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound.

[0037] ESI–MS:[M+H] + m / z 545.

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Abstract

The invention provides a paclitaxel and fluoropyridazine BTK (Bruton 's tyrosine kinase) inhibitor combined pharmaceutical composition, characterized by comprising: an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient is composed of paclitaxel and a BTK inhibitor represented by the formula (I); the mole ratio of the paclitaxel to the BTK inhibitor represented by the formula (I) in the active ingredient is (0.14-0.20):1. The pharmaceutical composition can be used for preparing a medicament for preventing and / or treating a disease associated with Bruton's tyrosine kinase, and the therapeutic effect is good.

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