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Cabazitaxel weakly basic derivatives and preparations thereof

A technology of cabazitaxel and its derivatives, which is applied in the field of medicine, can solve the problems of limiting the clinical application of drugs, toxic and side effects, etc., and achieve the effect of increasing anti-tumor effect, high drug loading, and reducing adverse reactions

Active Publication Date: 2022-01-28
SHENYANG PHARMA UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Tween 80 in the formulation has caused toxic and side effects related to excipients, which seriously limits the clinical application of the drug

Method used

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  • Cabazitaxel weakly basic derivatives and preparations thereof
  • Cabazitaxel weakly basic derivatives and preparations thereof
  • Cabazitaxel weakly basic derivatives and preparations thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Synthesis of a cabazitaxel derivative (CN1) whose base is 4-(4-methylpiperazinemethyl)phenyl

[0042] Weigh cabazitaxel (200mg, 0.24mmol) and 4-(4-methylpiperazinemethyl) benzoyl chloride (156mg, 0.48mmol) and dissolve in dichloromethane, add 0.25mL triethylamine, under ice-cooling Slowly add DMAP (5.9 mg, 0.048 mmol) in dichloromethane solution, N 2 Stir overnight at room temperature under protection. After the reaction was completed, it was separated and purified by column chromatography to obtain a white powder of the cabazitaxel derivative (yield 95.01%). Adopt proton nuclear magnetic resonance spectrum to determine the structure of compound in embodiment 1, the result is as follows figure 2 , the spectral analysis results are as follows:

[0043] 1H NMR (Chloroform-d, 400MHz) δ8.11 (2H, d, J = 7.4Hz), 7.94 (2H, d, J = 8.1 Hz), 7.61 (1H, t, J = 7.4Hz), 7.51 (1H ,d,J=7.8Hz),7.48(1H,d,J=7.8Hz),7.45– 7.35(6H,m),7.32–7.27(1H,m),6.26(1H,t,J=9.1Hz) ,5.64...

Embodiment 2

[0044] Example 2: Synthesis of Cabazitaxel derivatives (CN2) whose base is 4-(1-piperidinyl)piperidinyl

[0045] Weigh cabazitaxel (200mg, 0.24mmol) and 4-piperidinylpiperidine carboxylic acid chloride (111mg, 0.48mmol) and dissolve in dichloromethane, add 0.25mL triethylamine, slowly add DMAP (5.9 mg, 0.048mmol) in dichloromethane solution, N 2 Stir overnight at room temperature under protection. After the reaction was completed, it was separated and purified by column chromatography to obtain a white powder of the cabazitaxel derivative (yield 95%). Adopt proton nuclear magnetic resonance spectrum to determine the structure of compound in embodiment 2, the result is as follows Figure 4 , the spectral analysis results are as follows:

[0046] 1 H NMR (400MHz, Chloroform-d) δ8.07–8.00(m, 2H), 7.54(t, J=7.4Hz, 1H), 7.43(t, J=7.6Hz, 2H), 7.33(t, J= 7.6Hz, 2H), 7.22(m, 3H), 6.32–5.95(m, 1H), 5.56(d, J=7.0Hz, 1H), 5.44–5.26(m, 2H), 5.23(s, 1H), 5.20(d, J=3.8Hz, 1H), 4.92(d,...

Embodiment 3

[0047] Embodiment 3: the synthesis of the cabazitaxel derivative (CN3) that the base part is 4-methylpiperazine-1-methyl

[0048] Weigh cabazitaxel (200mg, 0.24mmol) and 4-methylpiperazine-1-formyl chloride (78mg, 0.48mmol) and dissolve in dichloromethane, add 0.25mL triethylamine, slowly add DMAP under ice-cooling (5.9mg, 0.048mmol) in dichloromethane, N 2 Stir overnight at room temperature under protection. After the reaction was completed, it was separated and purified by column chromatography to obtain a white powder of the cabazitaxel derivative (yield 93.8%). Adopt proton nuclear magnetic resonance spectrum to determine the structure of compound in embodiment 3, the result is as follows Image 6 , the spectral analysis results are as follows:

[0049] 1 H NMR (400MHz, Chloroform-d) δ8.03(d, J=7.5Hz, 2H), 7.54(t, J=7.4Hz, 1H), 7.43(t, J=7.6Hz, 2H), 7.32(t ,J=7.6Hz,2H),7.26–7.20(m,3H),6.17(t,J=9.3Hz,1H),5.56(d,J=7.0Hz,1H),5.36(s,1H),5.25 (s,1H),5.23(s,1H),4.92(dd, J=...

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Abstract

The present invention relates to weakly basic derivatives of cabazitaxel and preparations thereof, in particular to the synthesis of weakly basic derivatives of cabazitaxel, liposome preparations containing the derivatives and their application in drug delivery systems, belonging to medical technology field. The weakly basic derivative of cabazitaxel is connected with a weakly basic intermediate through an ester bond, and the ester bond can be broken by the action of esterase in the body to release the active drug. Its structural general formula is as follows: wherein, linking group is C 1 -C 4 Alkyl, C 3 -C 6 Cycloalkyl or phenyl; [N] is N-methylpiperazinyl, piperidinyl, 4-(1-piperidinyl) piperidinyl, morpholinyl, tetrahydropyrrolyl or other tertiary amine structures. The weakly basic derivatives of cabazitaxel of the present invention can be prepared into liposome preparations. The liposome preparation has the characteristics of high drug loading, high encapsulation efficiency, good stability and the like. After injection, it can greatly increase the circulation time of the drug in the body, increase the accumulation of the drug in the tumor site, and improve the anti-tumor effect and tolerance dose. .

Description

【Technical field】 [0001] The present invention relates to weakly basic derivatives of cabazitaxel and preparations thereof, in particular to the synthesis of weakly basic derivatives of cabazitaxel, liposome preparations containing the derivatives and their application in drug delivery systems, belonging to medical technology field. 【Background technique】 [0002] Cabazitaxel (CTX) is a new generation of taxane-like tubulin-binding agents. Compared with paclitaxel and docetaxel, due to the methylation of the 7- and 10-hydroxyl groups, cabazitaxel has a lower affinity for P-glycoprotein, which is closely related to tumor drug resistance, and reduces drug efflux, so The defect of multidrug resistance can be better overcome. In June 2010, the U.S. Food and Drug Administration (FDA) approved the Cabazitaxel injection (trade name ) in combination with prednisone for the treatment of hormone-resistant prostate cancer. However, Tween 80 in the formulation has caused toxic and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14A61K9/127A61P35/00
CPCC07D305/14A61K9/1271A61P35/00A61K9/1278A61K9/0019C07D405/12A61K31/337A61K9/127A61K9/1277
Inventor 王永军杨子蒙何仲贵刘洪卓迟东旭
Owner SHENYANG PHARMA UNIVERSITY
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