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Antineoplastic compound, medicament composition and use thereof

A compound and mixture technology, applied in the field of anti-tumor compounds and its preparation, can solve the problems of low solubility, low bioavailability, high side effects, etc.

Inactive Publication Date: 2008-12-03
BEIJING LABSOLUTIONS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The low bioavailability of Dasatinib is an important reason for the large differences in the treatment of individual patients, and the side effects are higher than that of Imatinib. At the same time, the low bioavailability also limits its wider application in anti-tumor diseases
[0006] Dasatinib is a compound that is almost insoluble in water (solubility is 0.008mg / ml), and its extremely low solubility hinders its absorption in the intestine, which is an important reason for its low bioavailability

Method used

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  • Antineoplastic compound, medicament composition and use thereof
  • Antineoplastic compound, medicament composition and use thereof
  • Antineoplastic compound, medicament composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0239] Example 1: 2-aminopropionic acid (S)-2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2 -Methylpyrimidin-4-yl)piperazin-1-yl)ethyl ester

[0240] At room temperature, N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidine- 4-ylamino)thiazole-5-carboxamide (487mg, 1.0mmol) was dissolved in anhydrous dimethylformamide (8mL), the solution was placed in an ice bath at 0°C and N-(tert-butoxy Carbonyl) L-alanine (567mg, 3.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (582mg, 3.05mmol), N-hydroxybenzotri Azole (411 mg, 3.05 mmol) and N-methylmorpholine (303 mg, 3.0 mmol). The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 20 hours. The above reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (200 mL). The organic extract was washed successively with aqueous sodium bicarbonate solution (5%), water and saturated sodium chloride solution, dri...

Embodiment 2

[0242] Example 2: 2-amino-4-methylpentanoic acid (S)-2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazole-2- Amino)-2-methylpyrimidin-4-yl)piperazin-1-yl)ethyl ester

[0243] Prepared as described in Example 1 except that N-(tert-butoxycarbonyl)L-leucine was used in place of N-(tert-butoxycarbonyl)L-alanine. The resulting compound is C 28 h 37 ClN 8 o 3 S, the calculated value of MS-ESI (m / z) is 600.2; the measured value is 601.5 (100, MH + ), 603.0 (40, (MH +2 ) + ).

Embodiment 3

[0244] Example 3: 2-Aminoacetic acid (S)-2-(4-(6-(5-((2-chloro-6-methylphenyl)carbamoyl)thiazol-2-ylamino)-2- Methylpyrimidin-4-yl)piperazin-1-yl)ethyl ester

[0245] Prepared as described in Example 1 except that N-(tert-butoxycarbonyl)L-glycine was used in place of N-(tert-butoxycarbonyl)L-alanine. The resulting compound is C 24 h 29 ClN 8 o 3 S, the calculated value of MS-ESI (m / z) is 544.2; the measured value is 545.3 (100, MH + ), 546.9 (40, (MH +2 ) + ).

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Abstract

The invention relates to an anti-tumor compound, the pharmaceutical composition thereof and the application thereof, particularly an anti-tumor compound shown as the formula (I) or pharmaceutically acceptable salt thereof, solvate thereof, polymorph thereof, enantiomer thereof or racemic mixture thereof; the pharmaceutical composition thereof, the application in the preparation of antitumor drugs, and the preparation method thereof. The compounds can be used as the prodrug of Dasatinib to produce Dasatinib by enzymolysis. The compounds interact with intestinal protein transporters (such as PEPT1 or PEPT2) so that the compounds can be easily absorbed in an intestinal tract in comparison with the Dasatinib to generate higher Dasatinib bioavailability.

Description

technical field [0001] The invention relates to a class of anti-tumor compounds and a preparation method thereof, as well as a pharmaceutical composition containing the anti-tumor compounds and the use of the anti-tumor compounds in the preparation of anti-tumor drugs. Background technique [0002] Leukemia is a common tumor disease, and its incidence rate is about 3-4 per 100,000 people, ranking sixth in the incidence rate of various tumor diseases. The incidence of leukemia in China is similar to that of other Asian countries, but higher than that of European and American countries. Among them, Chronic Myeloid Leukaemia (CML, also known as Chronic Myelogenous Leukemia) is more common. Chronic myelogenous leukemia is a hematopoietic stem cell disorder associated with the Philadelphia chromosome resulting from a reciprocal translocation of chromosomes 9 and 22. This chromosomal translocation results in the chimeric protein product Bcr-Abl, which is a constitutively active f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61K31/496A61P35/00
Inventor 王建民
Owner BEIJING LABSOLUTIONS PHARMA
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