Micro-molecule modified taxane water soluble prodrug and pharmaceutical applications thereof

A taxane, water-soluble technology, applied in the field of biomedicine, can solve the problem of easily causing allergic reactions and the like

Active Publication Date: 2019-03-05
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is precisely because of the extremely low water solubility of paclitaxel and docetaxel that surfactants have to be used to aid dissolution during injection administration, which can easily cause allergic reactions. In clinical practice, anti-allergic drugs such as ground In spite of this, it is impossible to completely avoid adverse reactions, which brings great pain to patients and greatly limits the clinical use of such drugs.

Method used

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  • Micro-molecule modified taxane water soluble prodrug and pharmaceutical applications thereof
  • Micro-molecule modified taxane water soluble prodrug and pharmaceutical applications thereof
  • Micro-molecule modified taxane water soluble prodrug and pharmaceutical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Synthesis of 2'-O-[succinyl]-N-de-tert-butoxycarbonyl docetaxel (6).

[0035]

[0036] Take a 100 mL round bottom flask, add 200 mg (0.25 mmol) of docetaxel, then add 375 mg (3.75 mmol) of succinic anhydride, add 10 mL of anhydrous pyridine, and stir the reaction at room temperature. After 24 hours, monitor the reaction on a TLC plate (take a small amount of the reaction solution, Add saturated sodium bicarbonate solution and ethyl acetate, take the ethyl acetate layer and dot the plate), the raw material point basically disappeared, stop the reaction, evaporate the pyridine to dryness, then pump the oil for 30 minutes, after the pyridine is almost completely removed, add 30 mL ethyl acetate , Washed with saturated sodium bicarbonate (20mL), washed with saturated sodium chloride solution (20mL), dried the organic phase with anhydrous sodium sulfate, filtered and spin-dried the solvent to obtain the crude product purified by silica gel column chromatography (dichl...

Embodiment 2

[0037] Example 2: Synthesis of 2'-O-[succinyl]paclitaxel (7). The operation is the same as the synthesis of 6.

[0038]

[0039] The yield was 75%. 1 H NMR(400MHz, acetone-d 6 ):δ ppm 1.18(s,3H,17-CH 3 ), 1.19(s, 3H, 16-CH 3 ),1.66(s,3H,19-CH 3 ),1.94(s,3H,18-CH 3 ),1.78and 2.32(m,2H,6-CH 2 ), 2.16(s,3H,10-OAc), 2.20(m,2H,14-CH 2 ),2.46(s,3H,4-OAc),2.62and 2.69(m,4H,2’-COCH 2 CH 2 COOH), 3.83(d,1H,J=7.2Hz,3-CH),4.06(m,1H,7-OH),4.16(m,2H,20-CH 2 ), 4.42(m,1H,7-CH), 4.96(d,1H,J=9.6Hz,5-CH),5.55(d,1H,J=6Hz,2'-CH),5.67(d,1H ,J=7.2Hz,2-CH),5.96(m,1H,3'-CH),6.15(t,1H,J=8.4Hz,13-CH),6.42(s,1H,13-CH), 7.30(t,1H,J=7.6Hz,3'-CONH),7.46(m,4H,o,m-Ph),7.53(t,1H,J=7.2Hz,p-Ph),7.61(m, 4H, o, m-Ph), 7.69 (t, 1H, J = 7.2 Hz, p-Ph), 7.87 (d, 2H, J = 7.2 Hz, m-OBz), 8.13 (d, 2H, J = 7.2 Hz,o-OBz),8.48(d,1H,J=9.2Hz,p-OBz).ESI-MS:m / z 954.4[M+H] + ,976.3[M+Na] + .C 51 H 55 NO 17 ..

Embodiment 3

[0040] Example 3: 2'-O-[succinyl]-N-de-tert-butoxycarbonyl-N-[2-(1,1,1-trifluoro-2-methyl)-propoxycarbonyl]-2 -Synthesis of debenzoyl-2-m-fluorobenzoyl docetaxel (8). The operation is the same as the synthesis of 6.

[0041]

[0042] The yield was 68%. 1 H NMR(400MHz,acetone-d 6 ):δ ppm 1.13(s,3H,17-CH 3 ),1.17(s,3H,16-CH 3 ),1.59and 1.61(s,6H,3’-(CH 3 ) 2 ),1.71(s,3H,19-CH 3 ),1.89(s,3H,18-CH 3 ),1.97and2.30(m,2H,6-CH 2 ),2.21(m,2H,14-CH 2 ),2.44(s,3H,4-OAc),2.64and 2.69(m,4H,2’-COCH 2 CH 2 COOH),3.90(d,1H,J=7.2Hz,3-CH),4.17(s,2H,20-CH 2 ), 4.30(m,1H,7-CH), 4.96(d,1H,J=9.2Hz,5-CH),5.22(s,1H,10-CH),5.36-5.39(m,2H,2' and 3'-CH), 5.64(d,1H,J=7.6Hz,2-CH), 6.10(t,1H,J=8.4Hz,13-CH), 7.29(t,1H,J=6.4Hz, 3'-CONH-),7.45-7.53(m,5H,3'-Ph),7.66(m,2H,OBz),7.78(d,1H,J=9.2Hz,OBz),7.94(d,1H, J=8.4Hz,OBz); ESI-MS: m / z 980.3[M+H] + ,997.5[M+H 2 O] + .C 47 H 53 F 4 NO 17 ..

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Abstract

The invention belongs to the field of biomedicine, and relates to a micro-molecule modified taxane water soluble prodrug and pharmaceutical applications thereof. The invention provides a micro-molecule modified taxane water soluble prodrug represented by the formula (1) and an application of the novel taxane water soluble prodrug in the preparation of drugs for treating breast cancer, non-small cell lung cancer, and cervical cancer. Oxetane and azetidine are taken as the water soluble groups, docetaxel with good anti-cancer activity is taken as the main drug, through bridge chain molecules, the water soluble groups and the main drug are connected to obtain the prodrug; the using amount of clinical surfactants such as polyoxyethylene castor oil, tween 80, and the like, is reduced; a novel taxol water soluble prodrug is developed, and the toxic and side effects of the prodrug are reduced.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a new type of small molecule modified taxane water-soluble prodrug and its medicinal use. Background technique [0002] Paclitaxel and the second-generation taxane anti-cancer drug docetaxel, as the most successful anti-tumor drug in the history of human modern medical treatment, are widely used in the clinical treatment of ovarian cancer, breast cancer, non-small cell lung cancer and other cancers. Cumulative sales have exceeded 30 billion U.S. dollars. Although its clinical efficacy is irreplaceable, it still has many shortcomings that cannot be ignored, such as poor water solubility, metabolic instability, easy to cause drug resistance and toxic and side effects. Toxic reactions include bone marrow suppression, neurotoxicity, muscle and joint pain, and cardiotoxicity. [0003] At present, the biggest problem that is difficult to break through the clinical use of paclitaxel is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D495/10C07D409/12C07D305/14A61K31/337A61K31/397A61K31/385A61K31/4188A61P35/00
CPCC07D305/14C07D409/12C07D491/107C07D495/10
Inventor 孙逊唐美麟郝晓东刘正玉彭鹏韩吉来
Owner FUDAN UNIV
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