Medicinal composition combining paclitaxel with novel phthalazinone compound

A compound, the technology of phthalazinone, which is applied in the field of the combined pharmaceutical composition of paclitaxel and novel phthalazinone compounds, can solve the problem of ineffectiveness of anticancer agents, and achieve the effect of improving biological activity and anticancer curative effect

Inactive Publication Date: 2019-02-01
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

While regimens involving combinations of anticancer agents with different mechanisms of action may work in the context of some combinations, the same approach may not work for other combinations of anticancer agents, and such combinations may not always produce a Combinations with favorable therapeutic effects

Method used

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  • Medicinal composition combining paclitaxel with novel phthalazinone compound
  • Medicinal composition combining paclitaxel with novel phthalazinone compound
  • Medicinal composition combining paclitaxel with novel phthalazinone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 12

[0028] Example 1 [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1- Preparation of keto]benzyl ester

[0029]

[0030] Step 1: Weigh 5-amino-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate (50mmol) and DIPEA (100mmol) in a reaction flask, add 300ml of dichloromethane, and stir at room temperature Slowly add p-chlorobenzyl chloroformate (51 mmol) dropwise, after the drop is complete, continue to stir at room temperature for 1 h, stop the reaction, concentrate the reaction mixture, add 70 ml of ethyl acetate, wash with dilute aqueous hydrochloric acid (0.2-0.3N) and saturated brine, Dry over anhydrous sodium sulfate, filter, and concentrate to give (3,4-dihydroisoquinoline-2(1H)-tert-butyl-5-yl carbamate)-p-chlorobenzyl carbamate, which is directly used in the next step, ESI –MS:[M+H] + m / z417.

[0031]Step 2: Weigh 3-fluoro-1-dimethoxymethylbenzene (500mmol) into a reaction flask, add tetrahydrofuran (800ml) to dissolve, add...

Embodiment 2

[0036] Example 2: [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 Preparation of -keto]benzyl ester methanesulfonate

[0037] Weigh the compound of Example 1 (0.5 mmol) into a reaction flask, add 5 mL of acetone and stir at room temperature for 0.5 h, add dropwise 1 mL of methanesulfonic acid acetone solution (containing 0.55 mmol of methanesulfonic acid), and continue stirring for 1 h at room temperature. The solvent was distilled off under pressure and dried under vacuum at room temperature to obtain the title compound.

[0038] 1 H NMR (600MHz, CDCl 3 )(δ,ppm):9.50(s,1H,disappeared after heavy water exchange),8.10(s,1H),7.88~7.85(m,1H),7.77~7.75(m,1H),7.54~7.52(m, 3H),7.34~7.32(m,2H),7.21~7.18(m,3H),6.57~6.55(m,1H),6.41~6.39(m,1H),5.17(s,2H),4.22(s, 2H), 3.61~3.59(m,2H), 3.13~3.11(m,2H), 2.84~2.81(s,3H), 2.05~2.03(m,3H).

Embodiment 3

[0039] Example 3: [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 Preparation of N crystal form of -keto]benzyl ester methanesulfonate

[0040] Weigh 1.0g [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1 -Keto]benzyl ester methanesulfonate in the reaction flask, add 5mL ethanol-dichloromethane-water mixed solution with a volume ratio of 15:5:3, reflux for 30min, cool naturally to room temperature, and crystallize at 0-5°C 12h, [2(1H)-but-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazine-1- Keto]benzyl ester methanesulfonate N crystal form.

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Abstract

A medicinal composition combining paclitaxel with a novel phthalazinone compound, provided by the invention, comprises an active component and a pharmaceutically-acceptable auxiliary material, the active component is composed of paclitaxel and the phthalazinone compound with an N crystal form, represented by formula I, and a mass ratio of the paclitaxel to the phthalazinone compound of the formulaI in the active component is (0.1-0.3):1, wherein the chemical name of the phthalazinone compound of the formula I is [2(1H)-butyl-2-enoyl-3,4-dihydroisoquinolin-5-yl]-carbamic acid-4-[8-fluoro-(2H)-phthalazin-1-one]benzyl ester mesylate. The medicinal composition has a good anticancer effect. It is found that the paclitaxel and the phthalazinone compound with an N crystal form, represented by formula I, are combined to greatly enhance the antitumor growth bioactivity and achieve antitumor proliferation synergistic effects, so the medicinal composition is expected to be developed into clinically anti-pancreatic cancer first-line drugs.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and relates to a pharmaceutical composition for combining paclitaxel and novel phthalazinone compounds. 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: Ibrutinib and 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 BTK gene plays a key role in the function of B cells and various transduction pathways. [0003] The development of small-molecule targeted drugs based on the BTK signaling pathway provides a new w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/337A61K31/502A61P35/00A61P35/02C07D401/12
CPCA61P35/00A61P35/02A61K31/337A61K31/502C07D401/12C07B2200/13
Inventor 郭程杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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