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Compound PAC-1 or salt thereof, and medicinal composition containing compound or salt thereof

A technology of PAC-1 and composition, applied in the field of preparation of PAC-1), can solve the problems of strong neurotoxicity, unsatisfactory prospects, and failure to effectively control the harm.

Inactive Publication Date: 2015-09-16
王智民
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the middle of the 20th century, human beings have invested a lot of manpower and material resources in the prevention and treatment of tumors, but its harm has not been effectively controlled, and its morbidity and mortality are still on the rise year by year.
Moreover, it has been reported in the literature that the existing crystalline form of PAC-1 has strong neurotoxicity (see Q P. Peterson, D C. Hsu, C J. Novotny, et al. Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase- 3-Activating Compound, Cancer Res2010;70:7232-7241), which leads to the prospect of PAC-1 being developed into a drug that is not optimistic. For example, its discoverer, Professor Quinn P.Peterson, has turned to PAC-1 with low toxicity 1 Development of the analogue S-PAC-1

Method used

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  • Compound PAC-1 or salt thereof, and medicinal composition containing compound or salt thereof
  • Compound PAC-1 or salt thereof, and medicinal composition containing compound or salt thereof
  • Compound PAC-1 or salt thereof, and medicinal composition containing compound or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0040] The ZYS-1 can be prepared by, for example, the following method, but the preparation method is not limited thereto. The methods include:

[0041] Step (1): dissolving the crystal of PAC-1 in an organic solvent to obtain the first solution of PAC-1;

[0042] Step (2): under stirring, add water to the solution of PAC-1 obtained in step (1) to obtain a second solution of PAC-1;

[0043] Step (3): Stir continuously, and when the precipitated solid is white or milky white, filter, remove the solvent, and obtain the precipitate;

[0044] Step (4): drying the obtained precipitate to obtain PAC-1 in an amorphous form.

[0045] In step (1), relative to 1 g of PAC-1 crystals, the amount of organic solvent used may be, for example, 1-20 mL, preferably 2-10 mL, more preferably 4-6 mL. Ultrasonic treatment, stirring, shaking and other means can be used to promote the dissolution of PAC-1 crystals. The organic solvent may be, for example, one or more selected from absolute ethano...

Embodiment 1

[0060] Embodiment 1: Preparation of ZYS-1

[0061] Take 1 g of PAC-1 needle crystal (prepared according to the method of Quinn P. Peterson et al., J. Med. Chem. 2009, 52, 5721–5731), dissolve it in DMSO (5 mL) by ultrasonic, and stir at a speed of 500 r / min 50 mL of water was added, and the mixture was continuously stirred for 10 min until the precipitate was milky white, filtered under reduced pressure, and dried in vacuo to obtain a white solid.

[0062] After identification by microscope, scanning electron microscope and X-powder diffraction, it is obvious that the obtained powder is amorphous PAC-1 (ZYS-1). Under the microscope and scanning electron microscope, it can be seen that the morphology of amorphous and needle crystals is completely different. The surface of needle crystals is relatively smooth, showing a typical needle crystal shape, while ZYS-1 presents a loose and porous structure. The results are shown in Figure 2-3 . Comparing the X-powder diffraction patt...

Embodiment 2

[0063] Example 2: Comparison of ZYS-1 and PAC-1 needle crystal solubility

[0064] Take an appropriate amount of ZYS-1 and PAC-1 needle crystals and dissolve them in an appropriate amount of methanol, absolute ethanol, 95% ethanol, acetonitrile, ether, ethyl acetate, propanol, and acetone, ultrasonically for 1 hour, and stand at room temperature for 24 hours. Make a supersaturated solution. Centrifuge at 4000r / min for 5min, take the supernatant and dilute appropriately, filter with a 0.45μm syringe filter, measure the concentration by HPLC, and calculate the solubility.

[0065] The experimental results show that the solubility of ZYS-1 is higher than that of PAC-1 needle crystals, and the results are shown in Table 1.

[0066] Table 1 ZYS-1 and PAC-1 needle crystal solubility comparison

[0067]

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Abstract

The invention provides a compound PAC-1 with an amorphous form, an oral medicinal composition containing the compound PAC-1 with an amorphous form, and a use of the compound PAC-1 with an amorphous form in the preparation of the oral medicinal composition. The PAC-1 with an amorphous form has obviously lower neurotoxicity than PAC-1 crystals, so the PAC-1 with an amorphous form is suitable for being used to develop medicines for treating tumors, especially metastatic tumors.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a preparation method of ZYS-1 (amorphous form of PAC-1), a pharmaceutical composition containing it and a pharmaceutical use thereof. technical background [0002] Tumor is the number one killer that endangers human health, and the mortality rate of malignant tumors ranks first among all death diseases. Since the middle of the 20th century, human beings have invested a lot of manpower and material resources in the prevention and treatment of tumors, but the harm has not been effectively controlled, and its morbidity and mortality are still increasing year by year. At present, the three major means of tumor treatment are chemotherapy, radiotherapy and surgery, among which chemotherapy is the main means. With the continuous development and rational application of antineoplastic drugs, chemotherapy plays an increasingly important role in the treatment of mali...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/15A61K31/495A61P35/04A61P35/00
CPCC07D295/15
Inventor 王智民刘晓谦游云高慧敏刘菊妍
Owner 王智民
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