A crystal form of a tubulin inhibitor (vda-1)

A crystal form, tert-butyl technology, applied in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve problems such as poor water solubility, unfavorable allergic reactions, and reduced curative effect, and achieve simple production and operation, chemical Good stability and convenient storage

Active Publication Date: 2020-11-20
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the current clinical drugs are affected by the following adverse problems: poor water solubility, unfavorable drug administration and easy to cause allergic reactions, severe toxic side effects and acquired drug resistance, resulting in reduced curative effect, complex chemical structure and difficulty in synthesis resulting in scarcity of sources, limiting their further use

Method used

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  • A crystal form of a tubulin inhibitor (vda-1)
  • A crystal form of a tubulin inhibitor (vda-1)
  • A crystal form of a tubulin inhibitor (vda-1)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 [crude product preparation of VDA-1]

[0036] step 1)

[0037]

[0038] The synthesis of Intermediate A refers to the preparation method described in Example 2 Route A in Chinese Patent Application CN1684955.

[0039] step (2)

[0040]

[0041] 3-Fluorobenzaldehyde (0.10mol), formylmethylenetriphenylphosphine (33.5g, 0.11mmol) and toluene (200ml) were added to a 1L dry one-necked flask. The reaction was refluxed for 16 hours and then concentrated. The crude product was purified by column chromatography (eluent: volume ratio of petroleum ether / ethyl acetate: 100 / 1 to 80 / 20) to obtain 3-(3-fluorophenyl)acrolein (yield: 62%).

[0042] step (3)

[0043]

[0044]DMF (100ml), intermediate A (1.38g, 5mmol), 3-(3-fluorophenyl)acrolein (10mmol) and cesium carbonate (3.26g, 10mmol) were added to a 250ml dry one-necked flask. The reaction system was stirred at 25°C for 12 hours, cooled to room temperature, and poured into ice water. Extracted with ethyl...

Embodiment 2

[0045] Embodiment 2 [VDA-1 recrystallization process screening]

[0046] Process 1: Take 200g of crude VDA-1 and add it to the reaction flask, add 2400ml of ethyl acetate and tetrahydrofuran mixed solvent (V / V=1:5), heat up to reflux to 60°C while stirring. After dissolving, stir for 10 minutes, then lower the temperature to 5-15°C, stir and crystallize for 4 hours after solid precipitation, filter with suction, and rinse the filter cake with acetone. The filter cake was air-dried at 45°C and assisted with phosphorus pentoxide. 166 g of off-white solid was obtained, with a yield of 83.0%. Moisture was measured to be 0.3% with a Karl Fischer analyzer. (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazolyl-4-yl)methylene]-6-((E)-3-(3-fluoro phenyl)-2-propenylidene)piperazine-2,5-dione (VDA-1).

[0047] Process 2: Take 200g of crude VDA-1 and add it to the reaction flask, add 1600ml of acetone and water mixed solvent (V / V=1:3), and heat up to reflux to 60°C while stirring. After dis...

Embodiment 3

[0060] Embodiment 3 [detection of VDA-1 crystal form]

[0061] The test condition of embodiment sample:

[0062] 3.1 XRD:

[0063] Testing instrument: Empyrean X-ray diffractometer

[0064] Detection conditions: Cu target Kα ray, voltage 40kV, current 40mA, divergence slit 1 / 32°, anti-scatter slit 1 / 16°, anti-scatter slit 7.5mm, 2θ range: 3°-50°, step size 0.02 °, the residence time of each step is 40S.

[0065] Test basis: People's Republic of China (2015 Edition IV) 0451 X-ray powder diffraction method

[0066] Test result: if figure 1 shown.

[0067] 3.2DSC:

[0068] Testing instrument: DSC 214 differential scanning calorimeter from NETZSCH, Germany

[0069] Detection conditions: Atmosphere: N 2 , 40ml / min

[0070] Scanning program: from room temperature to 250°C at 10°C / min, record the temperature rise curve.

[0071] Test sample quality: sample 1: 2.48mg (using aluminum sample pan)

[0072] Testing basis: JY / T 014-1996 General Rules for Thermal Analysis Methods...

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Abstract

The present invention provides an A crystal form of (3Z,6Z)-3-[((E)-3-(5-tert-butyl)-1H-imidazol-4-yl)methylene]-6-((E)-3-(3-fluorophenyl)-2-propenylidene)piperazine-2,5-dione (VDA-1). The A crystal form has a stable morphology, a definite melting point, and good chemical stability and is high-temperature resistant and suitable for pharmaceutical uses. The A crystal form can be used to treat a hyperproliferative disease.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a new crystal form of tubulin inhibitor (VDA-1). Background technique [0002] As the main means of tumor treatment, anticancer drugs have made considerable contributions to prolonging the survival time of patients and improving their quality of life. Among them, drugs that act on microtubules (microtubule inhibitors) play an important role in tumor drugs. However, the current clinical drugs are affected by the following adverse problems: poor water solubility, unfavorable drug administration and easy to cause allergic reactions, serious side effects and acquired drug resistance, resulting in reduced curative effect, complex chemical structure and difficulty in synthesis The resulting scarcity of sources limits their further use. Therefore, it is urgent to find and design new tubulin inhibitors, especially small molecule inhibitors with simple structure. Contents of the inve...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/06A61K31/496A61P35/00
CPCC07B2200/13C07D403/06A61K31/496A61P35/00
Inventor 唐田彭江华靳如意杨经安佘琴石涛
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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