Cabazitaxel weakly-alkaline derivative and preparation thereof

A technology of cabazitaxel and derivatives, applied in the field of medicine, can solve the problems of limited clinical application of drugs, toxic and side effects, etc., and achieve the effects of increasing anti-tumor effect, high drug loading, and good stability

Active Publication Date: 2020-04-14
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • 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-alkaline derivative and preparation thereof
  • Cabazitaxel weakly-alkaline derivative and preparation thereof
  • Cabazitaxel weakly-alkaline derivative and preparation 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 Figure 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 invention relates to a cabazitaxel weakly-alkaline derivative and a preparation thereof, in particular to synthesis of the cabazitaxel weakly-alkaline derivative, a liposome preparation containingthe cabazitaxel weakly-alkaline derivative and application of the cabazitaxel weakly-alkaline derivative in a drug delivery system, and belongs to the technical field of medicines. According to the cabazitaxel weakly-alkaline derivative, cabazitaxel is connected with a weakly-alkaline intermediate through an ester bond, the ester bond can be broken under the action of esterase in vivo, and an active drug is released. The structural general formula is shown in the specification, wherein a connecting group is C1-C4 alkyl, C3-C6 naphthenic base or phenyl; [N] is an N-methyl piperazinyl group, apiperidinyl group, a 4-(1-piperidinyl) piperidinyl group, a morpholinyl group, a pyrrolidine group or other tertiary amine structures. The cabazitaxel weakly-alkaline derivative disclosed by the invention can be prepared into the liposome preparation. The liposome preparation has the characteristics of high drug loading capacity, high encapsulation efficiency, good stability and the like. After injection administration, the in-vivo circulation time of the drug can be greatly prolonged, the accumulation amount of the drug at a tumor part is increased, and the anti-tumor effect and the tolerancedose are improved. .

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 Applications(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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