A solid dosage form of a prodrug derivative containing ubenimex and a preparation method thereof

The technology of a solid dosage form, ubenimex, is applied in the field of solid dosage forms of prodrug derivatives and its preparation, which can solve the problems of low bioavailability, large toxic and side effects, and poor fat solubility, etc., to prolong the residence time and improve biological Utilization, effect of improving pharmacokinetic properties

Active Publication Date: 2021-08-10
江西润泽药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical studies have found that cytarabine has a series of disadvantages: poor fat solubility, low bioavailability, large toxic and side effects, etc.

Method used

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  • A solid dosage form of a prodrug derivative containing ubenimex and a preparation method thereof
  • A solid dosage form of a prodrug derivative containing ubenimex and a preparation method thereof
  • A solid dosage form of a prodrug derivative containing ubenimex and a preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0042] For the compound pentafluorouracil-ubenimex (5FU-Bestatin), the preparation method may include: reacting pentafluorouracil with triphosgene under the catalysis of activated carbon, and then reacting with ubenimex to obtain the target compound 5FU-Bestatin.

[0043] Its specific synthetic route is as follows:

[0044]

[0045] Reaction condition a: BTC, activated carbon, Py, 0°C, where BTC is triphosgene, Py is pyridine

[0046] Concrete preparation steps are as follows:

[0047] Put 0.65g of pentafluorouracil (5mmol) in the reaction flask, add 20ml of pyridine to dissolve it completely, then add 0.65g of activated carbon, slowly add 0.5g of triphosgene under ice bath, continue to react under ice bath for 1 hour, draw out Phosgene, rushed into N 2 , for three times. Under ice-cooling, 1.7 g of ubenimex (5 mmol) was slowly added, followed by reaction at room temperature for 12 hours. Activated carbon was filtered, extracted with ethyl acetate, washed three times wi...

preparation example 1

[0072] Put 0.65g of pentafluorouracil (5mmol) in the reaction flask, add 20ml of pyridine to dissolve it completely, then add 0.65g of activated carbon, slowly add 0.5g of triphosgene under ice bath, continue to react under ice bath for 1 hour, draw out Phosgene, rushed into N 2 , for three times. Under ice-cooling, 1.7 g of ubenimex (5 mmol) was slowly added, followed by reaction at room temperature for 12 hours. Activated carbon was filtered, extracted with ethyl acetate, washed three times with 6 mol / L hydrochloric acid solution, washed three times with saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off until the precipitation of solids ceased, put into the refrigerator for crystallization, and filtered to obtain a white product, which was compound 5FU-Bestatin, a white solid, yield: 36.7%, melting point=165-167°C. MS-ESI: [M-1]=463.6; [M-1+Na]=485.8. Its proton nuclear magnetic resonance spectrum data are as follows:

[0073] 300M...

Embodiment 1

[0100]

[0101]

[0102] Compound 5FU-Bestatin, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were passed through a 100-mesh sieve. The sieved materials were placed in a three-dimensional mixer for total mixing, and the rotation speed of the three-dimensional mixer was 10 rpm for 15 minutes. The mixed materials were directly compressed into tablets or filled into capsules to prepare 100,000 units, each unit containing 20 mg of the compound 5FU-Bestatin.

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Abstract

The invention relates to the field of medicinal chemistry, and discloses a solid dosage form containing a prodrug derivative of ubenimex and a preparation method thereof. The solid dosage form contains pharmaceutically active components, fillers, disintegrants and lubricants, based on the total weight of the solid dosage form, the content of the pharmaceutically active components is 20-80% by weight, the content of the filler The content of the disintegrant is 10-70% by weight, the content of the disintegrant is 0.5-5% by weight, and the content of the lubricant is 0.5-5% by weight, wherein the active ingredient of the drug is the precursor of Ubenimex Drug derivatives or their optical isomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts thereof. The solid dosage form of the invention can prolong the residence time of the drug in the body, improve the pharmacokinetic properties of the drug, and increase the bioavailability of the drug, so as to achieve better anti-tumor effect.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a solid dosage form containing a prodrug derivative of ubenimex and a preparation method thereof. Background technique [0002] Ubenimex (Ubenimex, Bestatin) is a dipeptide compound found in the culture fluid of Streptomyces olivoreticuli, which was listed in Japan in 1987 as an immune enhancer for the treatment of leukemia; Ubenimex The company was listed in China in 1998. Ubenimex can inhibit the activity of APN (IC50 at 2.5-16.9μM), and can block the effect of tumor stem cells, but it has almost no ability to inhibit the proliferation of tumor cells, so Ubenimex is used in combination with other cell-based anti-tumor drugs will greatly improve its efficacy. Studies in the literature have shown that in mice liver cancer xenograft tumor experiments, the combined use of Ubenimex and pentafluorouracil is significantly better than the antitumor activity of using alone (J Clin I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/198A61K31/513A61K31/454A61K31/704A61K31/7068A61K9/20A61K9/48A61P35/00
CPCA61K9/2054A61K9/4866A61K31/198A61K31/454A61K31/513A61K31/704A61K31/7068A61P35/00A61K2300/00
Inventor 廖年生胡贤德潘宇
Owner 江西润泽药业有限公司
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