Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition

A gemcitabine and composition technology, which is applied in the directions of drug combination, pharmaceutical formula, sugar derivative preparation, etc., can solve the problems of stability and bioavailability difference, affecting drug efficacy, etc., and achieves stable curative effect, easy automatic control, and convenient operation. Effect

Inactive Publication Date: 2017-07-14
TETRANOV PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The crystal form is the solid state in which the drug exists. The study of the drug crystal form is the study of the basic state of the drug. Only with a full and comprehensive understanding of the chemical drug crystal form can it be possible to find a more suitable drug crystal for the treatment of dis

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  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition
  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition
  • Crystal form of gemcitabine predrug, preparation method and use of crystal form and pharmaceutical composition

Examples

Experimental program
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Example Embodiment

[0044] 1. Preparation of gemcitabine prodrug compound

[0045] In a specific embodiment, the gemcitabine prodrug (formula I) used is prepared with reference to the method in patent CN102532199 and journal paper J. Med. Chem. 2016, 59, 3661-3670. The specific preparation method is as follows, but not limited to this method:

[0046] synthetic route:

[0047]

[0048] Synthesis of compound b: Dissolve 8.8g (33.5mmol) of compound a in 200ml of DMF, add 6.8g (100.5mmol) of imidazole and 5.1ml (36.9mmol) of triethylamine, and then add TBSCl in batches under ice bath. 12.7g (83.8mmol), after the addition, it was naturally raised to room temperature and reacted overnight. TLC monitoring is basically complete. The reaction was quenched by adding saturated aqueous ammonium chloride solution to the system, extracted three times with ethyl acetate (EA), combined the organic phases, washed five times with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and passed through the...

Example Embodiment

[0056] Example 1

[0057] The gemcitabine prodrug crystal form of this example is the gemcitabine prodrug crystal form shown in Formula I, and the preparation method is as follows: Take 4.4g of the gemcitabine prodrug solid shown in Formula I and disperse into 800 mL ethyl acetate and 8 mL isopropanol In the mixed solvent, heated to 95°C and refluxed and stirred for 1 hour. The solids were completely dissolved. The temperature was lowered by 10°C per hour to 15°C. The crystals were precipitated out after standing for 15 hours. The filter cake was collected by filtration and dried at 30°C to obtain 1.5g Solid, ready.

[0058] The crystal prepared in this example was subjected to X-ray powder diffraction measurement under the following conditions: working voltage 35KV, tube current 30mA, angle range: 2-40°, step size: 0.01° / step, wavelength 1.5406. Its X-ray diffraction pattern is as figure 1 As shown, more detailed parameters are shown in Table 1.

[0059] Table 1 XRD peak values ​...

Example Embodiment

[0063] Example 2

[0064] The gemcitabine prodrug crystal form of this example is the gemcitabine prodrug crystal form shown in formula I, and its preparation method is as follows: take 0.4 g of the gemcitabine prodrug solid shown in formula I and disperse it into 60 mL ethyl acetate and 2 mL isopropanol In the mixed solvent, heated to 80°C and refluxed for 2 hours. The solids were completely dissolved. The temperature was lowered by 10°C per hour to 15°C. After standing for 10 hours, crystals were precipitated. The filter cake was collected by filtration and dried at 30°C to obtain 0.2g Solid, ready.

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Abstract

The invention relates to a compound crystal form, a preparation method and use thereof and a pharmaceutical composition and particularly relates to a crystal form of a gemcitabine predrug, a preparation method and use of the crystal form and an anti-cancer pharmaceutical composition containing the crystal form of the gemcitabine predrug. The crystal form is a crystal form of the gemcitabine predrug represented by a formula I (shown in the description), and an X-ray powder diffraction pattern of the crystal form has a characteristic peak when a diffraction angle 2theta is 6.30+/-0.2 degrees, 8.88+/-0.2 degrees, 9.15+/-0.2 degrees, 12.52+/-0.2 degrees, 14.85+/-0.2 degrees, 15.86+/-0.2 degrees, 17.24+/-0.2 degrees, 17.66+/-0.2 degrees, 18.26+/-0.2 degrees, 20.37+/-0.2 degrees, 21.74+/-0.2 degrees, 22.14+/-0.2 degrees and the like. The invention further discloses the preparation method of the crystal form of the gemcitabine predrug, use of the crystal form for preparation of anti-cancer drugs and the anti-cancer pharmaceutical composition containing the crystal form of the gemcitabine predrug.

Description

technical field [0001] The present invention relates to a crystal form, a preparation method, an application and a pharmaceutical composition of a compound, in particular to a crystal form, a preparation method, an application and an anticancer pharmaceutical composition of a gemcitabine prodrug. Background technique [0002] Gemcitabine (Gemcitabine) is a difluoronucleoside antimetabolite anticancer drug that destroys cell replication. Break, play a cytotoxic effect to produce drug effect (Journal of Clinical Oncology 2006, 11, 828-829; Journal of Second Military Medical University 2006, 27, 1154-1156). The FDA approved it as a first-line drug for pancreatic cancer, which can significantly improve the quality of life and prolong the survival of patients with pancreatic cancer (Annals of Oncology 1996, 7, 347-353; Journal of Clinical Oncology 1997, 15, 2403-2413). The gold standard for pancreatic cancer treatment. Gemcitabine has a broad anti-tumor spectrum and has a certa...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/06A61K31/7068A61P35/00
CPCC07H19/10C07B2200/13C07H1/06
Inventor 吴豫生牛成山梁阿朋韩兴旺郭瑞云李敬亚邹大鹏
Owner TETRANOV PHARMA CO LTD
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