CN111777577A

CN111777577A - Taxol derivative and application thereof in preparation of medicine for preventing and treating human malignant tumor

Info

Publication number: CN111777577A
Application number: CN202010627868.XA
Authority: CN
Inventors: 刘立仁; 刘洪斌; 代霖霖; 潘博宇
Original assignee: Tianjin Renyu Biotechnology Co ltd
Current assignee: Tianjin Renyu Biotechnology Co ltd
Priority date: 2020-07-01
Filing date: 2020-07-01
Publication date: 2020-10-16

Abstract

The invention discloses a taxol derivative which has a structure shown in a general formula (I), an optical isomer, a diastereoisomer, a racemate mixture and pharmaceutically acceptable salts thereof. The invention further discloses the application of the taxol derivative and the pharmaceutically acceptable salt thereof in preparing antitumor drugs. Mainly comprises lung cancer, breast cancer, ovarian cancer, gastric cancer and colorectal cancer, and the experimental result shows that: the taxol derivative has low toxicity in vivo, has obvious effect of inhibiting the described tumor cells, and has potential value of further research.

Description

Taxol derivative and application thereof in preparation of medicine for preventing and treating human malignant tumor

Technical Field

The invention relates to the technical field of medicines, in particular to a taxol derivative with anti-tumor activity and application thereof in preparing medicines for preventing and treating human malignant tumors.

Background

Currently, malignant tumors have become serious health and life threatening diseases for humans. Due to the growing population, the aging is too fast and peopleThe incidence of malignant tumors has been increasing worldwide in recent years due to adverse living habits^[1]. However, the prevention and treatment of malignant tumors is always a research hotspot of experts and scholars in the industry. Drug therapy, starting in the fortieth of the last century, is one of the three major therapies for cancer treatment, and the history of drug therapy is much shorter than surgery and radiation therapy. However, after decades of development, the total number of the anti-tumor drugs invented and approved by various countries around the world is hundreds, the total number of the anti-cancer drug preparations prepared from the raw material drugs is about 1200-1400, and the drugs are mainly chemotherapy drugs or biological drugs. Although these drugs have high efficacy and strong specificity, their toxicity and drug resistance are not negligible. Therefore, the method continues to deeply search and screen novel clinical anticancer drugs, and has important significance for finding new methods for preventing and treating human malignant tumors and seeking breakthrough of broad-spectrum treatment of the malignant tumors.

The related effective components extracted from natural plants play a very important role in the field of chemotherapy of malignant tumors. It is reported that nearly 47% of 155 small-molecule anti-malignant tumor drugs developed from 1940 to 2006 are natural plant extracts or their derivatives^[2]This includes Taxol (Taxol) derived from Taxus chinensis. Paclitaxel is a complex tetracyclic diterpenoid compound, and is firstly extracted from the bark of Taxus brevifolia Nutt by Wani et al in 1971 and the structure of the paclitaxel is determined^[3]. Currently, paclitaxel is widely used in clinical treatment for lung cancer, breast cancer, ovarian cancer and some malignant tumors of digestive tract, but it still has many defects, such as: after a period of administration, the tumor cells can generate drug resistance phenomenon in vivo and the like. Therefore, the taxol derivative is prepared and synthesized by a chemical synthesis method, has better treatment effect in the aspect of preventing and treating human malignant tumors (particularly preventing and treating drug-resistant tumors), and has no report on related contents.

Disclosure of Invention

The first purpose of the present invention is to provide a kind of paclitaxel derivative and its pharmaceutically acceptable salt, which can overcome the disadvantages of the prior art.

The second object of the present invention is to provide a pharmaceutical use of the paclitaxel derivative as described above.

It is a third object of the present invention to provide a method for preparing the paclitaxel derivative as described above.

The technical scheme of the invention is summarized as follows:

in order to achieve the first purpose, the invention adopts the technical scheme that:

a kind of paclitaxel derivative, this kind of derivative possesses antitumor activity, characterized by having the structure shown in general formula I, and its optical isomer, diastereomer and racemate mixture, its pharmaceutically acceptable salt;

wherein:

z is benzoyl or tert-butyloxycarbonyl;

r is hydrogen atom, methoxy or acetyl;

a and B are aryl with substituent, heteroaryl with substituent or aroyl with substituent;

l is phenyl, heterocycle, alkyl or heteroalkyl of 1 to 8 carbon atoms, a group in which alkyl or heteroalkyl of 1 to 8 carbon atoms is attached to phenyl, a group in which alkyl or heteroalkyl of 1 to 8 carbon atoms is attached to heterocycle, a saturated or unsaturated straight or heteroalkyl of 1 to 8 carbon atoms, a group in which alkyl or heteroalkyl of 1 to 8 carbon atoms is attached to carbonyl, a group in which phenyl is attached to an amide bond-containing alkane chain, phenyl.

The terms and definitions used in the present invention have the following meanings:

the substituent is selected from any one or more of the following groups: hydrogen atom, halogen atom, straight-chain alkyl group of 1 to 6 carbon atoms, branched-chain alkyl group of 3 to 6 carbon atoms, hydroxyl group, mercapto group, carboxyl group, alkenyl group, cyano group, cyanomethyl group, amino group, aminoalkyl group (e.g., aminomethyl group and the like) nitro group, trifluoromethyl group, trifluoromethoxy group, methoxy group, methylthio group, ethoxy group, propoxy group, isopropoxy group, butoxy group, acetyl group and the like.

"aryl" refers to an aromatic carbocyclic group. Preferred aromatic rings contain 5 to 10 carbon atoms.

"heteroaryl" refers to an aromatic heterocycle which may be a monocyclic, bicyclic, or fused ring group. Preferred heteroaryl groups include thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, benzothiazolyl, benzofuryl or indolyl and the like.

"aroyl" refers to a group having a carbonyl group attached to the end of an aromatic carbocyclic ring, preferably an aromatic ring containing 5 to 10 carbon atoms.

"heteroalkyl" is a saturated or unsaturated chain containing carbon atoms and at least one heteroatom, any one of which is not adjacent. Heteroalkyl groups may be straight or branched chain, substituted or unsubstituted.

By "pharmaceutically acceptable salt" is meant a therapeutically effective and non-toxic salt form of the compound of formula (I). Many such salts are known in the art. Cationic salts formed at any acidic group (e.g., carboxyl) or anionic salts formed at any basic group (e.g., amino), many of which are known in the art, e.g., cationic salts including salts of alkali metals (e.g., sodium and potassium) and alkaline earth metals (magnesium and calcium) and organic salts (e.g., ammonium salts). The anion salt can also be conveniently obtained by treating the basic form of (I) with a corresponding acid, such acids including inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropanoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3-propanedioic acid, ethanesulfonic acid, phenylmethanesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. In addition, the skilled artisan may select one salt and select another salt depending on solubility, stability, ease of formulation, and the like. The determination and optimization of these salts is within the experience of the skilled artisan.

In the paclitaxel derivative and the pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt does not contain crystal water, or contains one or more crystal water.

The terms "optical isomers", "enantiomers", "diastereomers", "racemates" and the like as used herein define all possible stereoisomeric forms of the compounds or physiological derivatives of the present invention. Unless otherwise indicated, the chemical designation of the compounds of the invention includes mixtures of all possible stereochemical forms, which mixtures comprise all diastereomers and enantiomers of the basic structural molecule, as well as the substantially pure individual isomeric forms of the compounds of the invention, i.e. containing less than 10%, preferably less than 5%, in particular less than 2%, most preferably less than 1% of other isomers.

The compounds of formula (I) may also exist in other protected forms or derivatives which will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

As a preferred embodiment of the present invention, the paclitaxel derivative is preferably:

compound a1:

(1S,2R) -1-benzamido-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-carbonyl-1-phenylpropan-2-yl (4- ((E) -3, 5-dihydroxybenzethenyl) phenyl) succinate);

compound a2:

(1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (3-hydroxy-5- ((E) -4-hydroxystyryl) phenyl) succinate;

compound a3:

(1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-dimethoxystyryl) phenyl) succinate;

compound a4:

(1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-diacetoxystyrenyl) phenyl) succinate;

compound a5:

(1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (2, 4-dimethoxy-6- ((E) -4-methoxystyryl) phenyl) succinate.

Their structural formulae and nuclear magnetic mass spectrometry data are shown in table 1 below:

TABLE 1 structural formula and NMR Mass Spectroscopy data for preferred Compounds of the invention

The second objective of the present invention is to provide the medical use of the above paclitaxel derivative and the pharmaceutically acceptable salts thereof.

The invention provides the application of the taxol derivative and the pharmaceutically acceptable salt thereof in preparing antitumor drugs. Preferably, the tumor disease types mainly comprise lung cancer, breast cancer, ovarian cancer and some malignant tumors of the digestive system (such as gastric cancer, colorectal cancer and the like).

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective dose of one or more paclitaxel derivatives or pharmaceutically acceptable salts, excipients, carriers or diluents thereof as described above. The pharmaceutical composition is effective in preventing or treating neoplastic diseases (including the types of neoplastic diseases already mentioned above).

In order to achieve the third object of the invention, the technical scheme adopted by the invention is as follows:

the paclitaxel derivatives A1, A2, A3, A4 and A5 as described above were prepared by the following methods:

the general method of the reaction process is as follows: synthesis of Compounds A1 and A2

Reagents and conditions:

(a) pyridine, rt, 12 hours, yield 61%; (b) paclitaxel, DCC, DMAP, THF, rt, 20 hours, yield 50%.

Taking resveratrol (1) as a starting material and pyridine as a solvent, sequentially adding p-dimethylaminopyridine and succinic anhydride, and reacting at room temperature to obtain a compound 3 and a compound 4; and reacting the compound 3 or the compound 4 with paclitaxel respectively by using p-dimethylaminopyridine as a catalyst and Dicyclohexylcarbodiimide (DCC) as a condensing agent to obtain target compounds A1 and A2.

The general method of the reaction flow is as follows: synthesis of Compound A3

Reagents and conditions:

(a) pyridine, rt, 12 hours, yield 80%; (b) paclitaxel, DCC, DMAP, THF, rt, 20 hours, yield 55%.

Pterostilbene (2) is used as a starting material, pyridine is used as a solvent, p-dimethylaminopyridine and succinic anhydride are sequentially added, and reaction is carried out at room temperature to obtain an intermediate 6; and reacting the intermediate 6 with paclitaxel by using p-dimethylaminopyridine as a catalyst and Dicyclohexylcarbodiimide (DCC) as a condensing agent to obtain a target compound A3.

The general method of the reaction flow is three: synthesis of Compound A4

Reagents and conditions:

(a) acetic anhydride, triethylamine, DMSO, 65 ℃, 47% (b) pyridine, rt, 12 hours, yield 61%; (c) paclitaxel, DCC, DMAP, THF, rt, 20 hours, yield 60%.

Taking resveratrol (1) as an initial raw material, in a dimethyl sulfoxide solvent, taking triethylamine as an alkali, and carrying out selective acylation reaction with two equivalents of acetic anhydride to obtain 4', 3-diacetyl resveratrol 7. Pyridine is taken as a solvent, p-dimethylaminopyridine, succinic anhydride and an intermediate 7 are sequentially added, and a reaction is carried out at room temperature to obtain a compound 8; and reacting the intermediate 8 with paclitaxel by using p-dimethylaminopyridine as a catalyst and Dicyclohexylcarbodiimide (DCC) as a condensing agent to obtain a target compound A4.

The general method of the reaction flow is four: synthesis of Compound A5

Reagents and conditions:

(a)NaBH₄methanol, 0 deg.C (b) pyridine, rt, 4 hours, yield61%; (b) pyridine, rt, 12 hours, yield 70%; (c) paclitaxel, DCC, DMAP, THF, rt, 20 hours, yield 56%.

Using (E) -2, 4-dimethoxy-6- (4-methoxy styrene) benzaldehyde (9) which is sold in the market as a starting material, and reducing the starting material by sodium borohydride in methanol under the ice bath condition to obtain a compound 10; dissolving the compound 10 in pyridine, adding p-dimethylamino pyridine and succinic anhydride in sequence, and reacting at room temperature to obtain a compound 11 (obtained by the reaction in the step); and reacting the compound 11 with paclitaxel by using p-dimethylaminopyridine as a catalyst and Dicyclohexylcarbodiimide (DCC) as a condensing agent to obtain a target compound A5.

Drawings

FIG. 1 is a graph showing the in vivo tumor-suppressing effect of the target compound A4 on human breast cancer tumor (MDA-MB-231 cell line tumor) using an immunodeficient mouse model;

FIG. 2 is a graph showing the in vivo tumor-suppressing effect of the target compound A5 on human breast cancer tumor (MDA-MB-231 cell line tumor) using an immunodeficient mouse model;

FIG. 3 compares the body weight change trend of mice between the blank control group (physiological saline treatment), the object compound A4-treated group (80mg/kg), and the A5-treated group (80 mg/kg).

FIG. 4 shows a structural formula of a paclitaxel derivative.

Detailed Description

The invention is described below by means of specific embodiments. Unless otherwise specified, the technical means used in the present invention are well known to those skilled in the art. In addition, the embodiments should be considered illustrative, and not restrictive, of the scope of the invention, which is defined solely by the claims. It will be apparent to those skilled in the art that various changes or modifications in the components and amounts of the materials used in these embodiments can be made without departing from the spirit and scope of the invention. The raw materials and reagents used in the present invention are commercially available.

The experimental human lung cancer cell LTEP-A-2 is purchased from cell resource center of Shanghai Life science research institute of Chinese academy of sciences;

the human lung cancer cell A549 is purchased from the basic medical cell center of the institute of basic medical science of Chinese academy of medical sciences;

human breast cancer cell MDA-MB-231(

HTB-26^TM)

And MDA-MB-453(

HTB-131^TM) Purchased from the American ATCC deposit center;

human ovarian cancer cell SKOV-3: (

HTB-77^TM) Purchased from the American ATCC deposit center;

human ovarian cancer cell 3AO was purchased from shanghai relay and biotechnology limited;

human gastric cancer cell SGC-7901 was purchased from Kjekay Gene science and technology, Inc., Shanghai;

AGS human gastric carcinoma cells purchased from ATCC (ATCC No. CRL-1739)

The raw materials of resveratrol, paclitaxel, pterostilbene and the like are all sold in the market.

Example 1:

preparation of (1S,2R) -1-benzamido-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-carbonyl-1-phenylpropan-2-yl (4- ((E) -3, 5-dihydroxybenzenyl) phenyl) succinate (a 1).

Preparation of intermediate 3: (E) -4- (4- (3, 5-dihydroxystyryl) phenoxy) -4-oxobutanoic acid

About 22.82mg (1.00mmol) of resveratrol 1 was placed in a 25mL round-bottom flask, and 5mL of dried pyridine was added as a solvent to dissolve sufficiently, and 10.01mg (1.00mmol) of succinic anhydride was added thereto, and the reaction was stirred at room temperature overnight. Reaction ofAfter the reaction is finished, 15mL of water is added for quenching reaction, 50mL of chloroform is used for extraction for three times, organic phases are combined, the mixture is washed by saturated saline solution and then added with a proper amount of anhydrous sodium sulfate for full drying, a crude product is obtained after reduced pressure evaporation to dryness, and the crude product is purified by silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 200.27mg of a white solid in 61% yield.¹H NMR(500MHz,Chloroform)7.72–7.57(m,2H),7.31–7.17(m,2H),7.13(d,J＝9.2Hz,2H),6.49–6.45(m,2H),6.23(s,1H),5.35(s,2H),2.97(s,2H),2.81(s,2H).

(II) preparing the target product

A1: (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-carbonyl-1-phenylpropan-2-yl (4- ((E) -3, 5-dihydroxybenzethenyl) phenyl) succinate).

About 853.91mg (1.00mmol) of paclitaxel was placed in a 25mL round-bottomed flask, 5mL of anhydrous tetrahydrofuran was added as a solvent to dissolve it sufficiently, and then Compound 3(656.64mg, 2.00mmol), DCC (618.99mg, 3mmol) and dimethylaminopyridine (40.32mg, 0.33mmol) were added, and the reaction was stirred at room temperature for 20 hours. After the reaction is finished, adding 40mL of water, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate for full drying, and evaporating to dryness under reduced pressure to obtain a crude product, purifying by using silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether (2:1) gave 582.11mg of a white solid in 50% yield.¹³C NMR(100MHz,DMSO-d₆)205.36,172.49,171.92,171.27,170.52,169.91,167.64,167.10,159.21,153.40,141.20,138.95,137.66,135.47,133.57,133.31,131.74,131.45,130.56,129.70,129.24,128.83,128.62,128.43,128.30,128.12,127.29,127.17,126.93,121.74,107.10,104.17,84.87,82.14,77.43,76.81,76.21,74.26,74.12,72.74,70.48,57.82,53.99,47.09,42.34,38.95,37.16,30.52,29.83,24.57,21.73,21.24,17.20,13.62.MS-ESI m/z:[M+H]⁺:1165.27.

Example 2

Preparation of (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (3-hydroxy-5- ((E) -4-hydroxystyryl) phenyl) succinate (a 2).

Preparation of intermediate 4: (E) -4- (4- (3, 5-dihydroxystyryl) phenoxy) -4-oxobutanoic acid

About 22.82mg (1.00mmol) of resveratrol 1 was placed in a 25mL round-bottom flask, and 5mL of dried pyridine was added as a solvent to dissolve sufficiently, and 10.01mg (1.00mmol) of succinic anhydride was added thereto, and the reaction was stirred at room temperature overnight. After the reaction is finished, adding 15mL of water to quench the reaction, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate to fully dry, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 200.27mg of a white solid in 61% yield.¹H NMR(500MHz,Chloroform)7.44–7.30(m,2H),7.13(d,J＝25.0Hz,2H),6.77(dd,J＝24.0,5.5Hz,4H),6.39(s,1H),5.89(s,1H),5.35(s,1H),2.95(s,2H),2.81(s,2H).

(II) preparing a target product A2:

(1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (3-hydroxy-5- ((E) -4-hydroxystyryl) phenyl) succinate.

About 853.91mg (1.00mmol) of paclitaxel was placed in a 25mL round-bottomed flask, 5mL of anhydrous tetrahydrofuran was added as a solvent to dissolve it sufficiently, and then Compound 3(656.64mg, 2.00mmol), DCC (618.99mg, 3mmol) and dimethylaminopyridine (40.32mg, 0.33mmol) were added, and the reaction was stirred at room temperature for 20 hours. After the reaction, 40mL of water was added, and the mixture was extracted three times with 50mL of chloroform, and the organic phases were combined and saturated with foodWashing with saline water, adding an appropriate amount of anhydrous sodium sulfate, fully drying, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography, wherein the eluent is ethyl acetate: petroleum ether (2:1) gave 582.11mg of a white solid in 50% yield.¹³C NMR(100MHz,DMSO-d₆)205.36,172.49,171.92,171.27,170.52,169.91,167.64,167.10,159.83,159.66,153.84,141.20,139.90,137.66,135.47,133.57,133.31,131.45,130.56,130.02,129.70,129.24,128.83,128.43,128.30,128.12,127.29,127.17,126.96,126.93,116.40,112.49,111.51,106.32,84.87,82.14,77.43,76.81,76.21,74.26,74.12,72.74,70.48,57.82,53.99,47.09,42.34,38.95,37.16,30.52,29.83,24.57,21.73,21.24,17.20,13.62.MS-ESI m/z:[M+H]⁺:1165.32.

Example 3

Preparation of (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-dimethoxystyryl) phenyl) succinate (a 3).

Preparation of intermediate 6: (E) -4- (4- (3, 5-dimethoxystyryl) phenoxy) -4-oxobutanoic acid

About 256.30mg (1.00mmol) of pterostilbene 5 was placed in a 25mL round-bottom flask, 5mL of dried pyridine was added as a solvent to dissolve sufficiently, 10.01mg (1.00mmol) of succinic anhydride was added, and the reaction was stirred at room temperature overnight. After the reaction is finished, adding 15mL of water to quench the reaction, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate to fully dry, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 285.10mg of a white solid in 80% yield.¹H NMR(500MHz,Chloroform)7.66(d,J＝7.5Hz,4H),7.27(s,1H),7.21(dd,J＝56.0,4.8Hz,6H),6.84–6.79(m,4H),6.59(s,2H),3.85(s,11H),2.92(s,3H),2.79(s,3H).

(II) preparing the target product

A3: (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-dimethoxystyryl) phenyl) succinate.

About 853.91mg (1.00mmol) of paclitaxel was placed in a 25mL round-bottomed flask, 5mL of anhydrous tetrahydrofuran was added as a solvent to dissolve it sufficiently, and then Compound 6(712.74mg, 2.00mmol), DCC (618.99mg, 3mmol) and dimethylaminopyridine (40.32mg, 0.33mmol) were added, and the reaction was stirred at room temperature for 20 hours. After the reaction is finished, adding 40mL of water, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate for full drying, and evaporating to dryness under reduced pressure to obtain a crude product, purifying by using silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether (2:1) gave 655.75mg of a white solid in 55% yield.¹³C NMR(100MHz,DMSO-d₆)205.36,172.49,171.92,171.27,170.52,169.91,167.64,167.10,161.83,153.40,141.20,138.99,137.66,135.47,133.57,133.31,131.74,131.45,130.56,129.70,129.24,128.83,128.62,128.43,128.30,128.12,127.29,127.17,126.93,121.74,106.39,100.19,84.87,82.14,77.43,76.81,76.21,74.26,74.12,72.74,70.48,57.82,56.04,53.99,47.09,42.34,38.95,37.16,30.52,29.83,24.57,21.73,21.24,17.20,13.62.MS-ESI m/z:[M+H]⁺:1193.25.

Example 4

Preparation of (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-diacetoxystyrenyl) phenyl) succinate (a 4).

Preparation of intermediate 7: (E) -4- (3-acetoxy-5-hydroxystyryl) phenyl acetate

Placing about 22.82mg (1.00mmol) of resveratrol 1 in 25mLIn a round-bottomed flask, 5mL of dried dimethyl sulfoxide was added as a solvent to dissolve the resulting solution sufficiently, 204.18mg (2.00mmol) of acetic anhydride and 303.57mg (3.00mmol) of triethylamine were added thereto, and the reaction was stirred at 65 ℃ for 4 hours. After the reaction is finished, adding 15mL of water to quench the reaction, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate to fully dry, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 146.79mg of a white solid in 47% yield.¹H NMR(500MHz,Chloroform)7.68–7.53(m,2H),7.32–7.18(m,2H),6.83(d,J＝12.2Hz,2H),6.75(s,1H),6.71(s,1H),6.58(s,1H),5.32(s,1H),2.28(d,J＝13.0Hz,6H).

(II) preparation of intermediate 8: (E) -4- (3-acetoxy-5- (4-acetoxystyryl) phenoxy) -4-oxobutanoic acid

About 312.32mg (1.00mmol) of intermediate 7 was placed in a 25mL round-bottomed flask, 5mL of dried pyridine was added as a solvent to dissolve it sufficiently, 20.02mg (2.00mmol) of succinic anhydride was added thereto, and the reaction was stirred at room temperature overnight. After the reaction is finished, adding 15mL of water to quench the reaction, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate to fully dry, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 251.56mg of a white solid in 61% yield.¹H NMR(500MHz,Chloroform)7.69–7.54(m,2H),7.32–7.17(m,2H),7.09(s,1H),7.03(d,J＝19.5Hz,2H),6.85(d,J＝11.7Hz,2H),2.90(s,2H),2.80(s,2H),2.29(s,6H).

(III) preparation of the target product

A4: (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (4- ((E) -3, 5-diacetoxystyrenyl) phenyl) succinate.

Placing about 853.91mg (1.00mmol) of paclitaxel in a 25mL round-bottom flask, adding5mL of anhydrous tetrahydrofuran was added as a solvent and dissolved sufficiently, and then Compound 8(824.78mg, 2.00mmol), DCC (618.99mg, 3mmol) and dimethylaminopyridine (40.32mg, 0.33mmol) were added thereto, followed by reaction with stirring at room temperature for 20 hours. After the reaction is finished, adding 40mL of water, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate for full drying, and evaporating to dryness under reduced pressure to obtain a crude product, purifying by using silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether (2:1) gave 748.98mg of a white solid in 60% yield.¹³C NMR(100MHz,DMSO-d₆)205.36,172.49,171.92,171.27,170.52,169.91,169.71,167.64,167.10,153.40,152.51,141.20,140.01,137.66,135.47,133.57,133.31,131.74,131.45,130.56,129.70,129.24,128.83,128.62,128.43,128.30,128.12,127.29,127.17,126.93,121.74,117.86,115.25,84.87,82.14,77.43,76.81,76.21,74.26,74.12,72.74,70.48,57.82,53.99,47.09,42.34,38.95,37.16,30.52,29.83,24.57,21.73,21.24,20.89,17.20,13.62.MS-ESI m/z:[M+H]⁺:1249.29.

Example 5

Preparation of (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12 aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecan [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (2, 4-dimethoxy-6- ((E) -4-methoxystyryl) phenyl) succinate (a 5).

Preparation of intermediate 10: (E) - (2, 4-dimethoxy-6- (4-methoxystyryl) phenyl) methanol

About 298.34mg (1.00mmol) of commercially available (E) -2, 4-dimethoxy-6- (4-methoxystyryl) benzaldehyde 9 was placed in a 25mL round-bottomed flask, and 5mL of dry anhydrous methanol was added as a solvent to dissolve it sufficiently, and 75.66mg (2.00mmol) of sodium borohydride was added thereto, and the reaction was stirred under ice bath for 2 hours, warmed to room temperature and then reacted for 1 hour. After the reaction is finished, 15mL of water is added to quench the reaction, the solvent is evaporated to dryness and then extracted with 50mL of chloroform for three times, organic phases are combined, the mixture is washed by saturated saline solution and then added with a proper amount of anhydrous sodium sulfate to be fully dried, and the reaction is reducedEvaporating to dryness to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 183.21mg of a white solid in 61% yield.¹H NMR(500MHz,Chloroform)7.75–7.61(m,2H),7.15(t,J＝36.4Hz,3H),7.01(s,1H),6.70(s,1H),6.50(s,1H),4.63(s,2H),3.83(dd,J＝32.1,12.2Hz,10H).

(II) preparation of intermediate 11: (E) -4- ((2, 4-dimethoxy-6- (4-methoxystyryl) benzyl) oxy) -4-oxobutanoic acid

About 300.35mg (1.00mmol) of intermediate 10 was placed in a 25mL round-bottomed flask, 5mL of dried pyridine was added as a solvent to dissolve it sufficiently, 20.02mg (2.00mmol) of succinic anhydride was added thereto, and the reaction was stirred at room temperature overnight. After the reaction is finished, adding 15mL of water to quench the reaction, extracting with 50mL of chloroform for three times, combining organic phases, washing with saturated saline solution, adding a proper amount of anhydrous sodium sulfate to fully dry, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by using silica gel column chromatography, wherein an eluent is dichloromethane: methanol (30:1) gave 280.30mg of a white solid in 70% yield.¹H NMR(500MHz,Chloroform)7.69–7.54(m,2H),7.16–7.02(m,3H),7.00(s,1H),6.71(s,1H),6.51(s,1H),5.12(s,2H),3.89–3.79(m,9H),2.87(d,J＝4.5Hz,4H).

(III) preparation of the target product

A5: (1S,2R) -1-benzoylamino-3- (((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS) -6,12 b-diacetoxy-12- (benzoyloxy) -4, 11-dihydroxy-4 a,8,13, 13-tetramethyl-5-oxo-2 a,3,4,4a,5,6,9,10,11,12,12a,12 b-dodecahydro-1H-7, 11-methanocyclodecano [3,4] benzo [1,2-b ] oxetan-9-yl) oxy) -3-oxo-1-phenylpropan-2-yl (2, 4-dimethoxy-6- ((E) -4-methoxystyryl) phenyl) succinate.

About 853.91mg (1.00mmol) of paclitaxel was placed in a 25mL round-bottomed flask, 5mL of anhydrous tetrahydrofuran was added as a solvent to dissolve it sufficiently, and then Compound 11 (synthesized in the previous step) (800.86mg, 2.00mmol), DCC (618.99mg, 3mmol) and dimethylaminopyridine (40.32mg, 0.33mmol) were added thereto, and the reaction was stirred at room temperature for 20 hours. After the reaction, 40mL of water was added, and the mixture was extracted three times with 50mL of chloroform, the organic phases were combined, washed with saturated brine, and then added with an appropriate amount of waterFully drying the mixture by using anhydrous sodium sulfate, decompressing and evaporating the dried mixture to obtain a crude product, and purifying the crude product by using silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether (2:1) gave 692.34.98mg of a white solid in 56% yield.¹³C NMR(100MHz,DMSO-d₆)205.36,171.92,171.75,171.27,170.52,169.91,167.64,167.10,161.08,160.81,160.75,145.90,141.20,137.66,135.47,133.57,133.31,131.45,130.56,129.70,129.41,128.83,128.54,128.43,128.30,128.12,128.07,128.05,127.29,127.17,120.30,114.61,106.03,99.23,84.87,82.14,77.43,76.81,76.21,74.26,74.12,72.74,70.48,62.84,57.82,56.79,56.04,53.99,47.09,42.34,38.95,37.16,29.83,29.69,24.57,21.73,21.24,17.20,13.62.MS-ESI m/z:[M+H]⁺:1237.53.

Example 6

In vitro antitumor Activity test (CCK-8 method) of the target Compound

1. Experimental Material

CCK-8 reagent, RPMI-1640 cell culture medium, fetal bovine serum, 96-well plate, CO₂ｃA constant temperature incubator, ｃA BIO-TEKUquant multifunctional enzyme-labeling instrument, human lung cancer cell lines (LTEP-A-2, A549 and A549/taxol), human breast cancer cell lines (MDA-MB-231, MDA-MB-231/taxol and MDA-MB-453), human ovarian cancer cell lines (SKOV-3 and 3AO) and human gastric cancer cell lines (SGC-7901 and AGS).

2. Experimental methods

A) Cells were seeded, a single cell suspension was prepared from a culture medium containing 10% fetal bovine serum, 5000 cells per well were seeded in a 96-well plate with a volume of 100. mu.L per well, and cultured overnight.

B) Preparation of a target compound solution to be tested, DMSO stock solution of the compound was diluted with a culture solution in a sterile station to 5 drug concentrations to be tested (each: 0.625, 1.25, 2.5, 5, 10 μ M), two-fold dilution between adjacent concentrations.

C) Compound solutions of different concentrations were added to 96-well plates that had been incubated overnight, 100 μ L per well, 3 replicates per concentration. The periphery has edge effect and is easy to be infected by bacteria, so cells and compounds are not added, and 100 mu L of culture solution is added to be used as a blank. Another 100% well was set, i.e., 100. mu.L of the culture solution containing cells and no compound was added, and incubated in a 37 ℃ incubator for 48 hours.

D) And (3) detecting cytotoxicity, namely adding 10 mu L of CCK-8 solution into a 96-well plate, incubating for 2 hours at 37 ℃, shaking on a shaking table for 5 minutes to ensure that yellow crystals generated by living cells are fully and uniformly dissolved in a culture environment, and then measuring the OD value of each well at 450nm by using an enzyme-labeling instrument.

Inhibition (%) - (100% well mean OD value-compound well mean OD value)/(100% well mean OD value-blank well mean OD value) × 100% linear regression was performed based on the inhibition value of each concentration to calculate the drug concentration that inhibits cell growth by 50%, i.e., IC₅₀。

Experimental results show that after the medicine is treated for 48 hours, target compounds A1, A2, A3, A4 and A5 show better activity inhibition effects in human lung cancer, human breast cancer, human ovarian cancer and human gastric cancer cell lines, and are respectively superior to the condition that paclitaxel is used alone, so that the derivatives have potential better antitumor activity; meanwhile, the target compounds a4 and a5 have more obvious inhibition effect on the tumor cells compared with the other three compounds, as shown in table 2 below:

CCK-8 method for detecting activity Inhibition (IC) of target compounds A1, A2, A3, A4 and A5 for 48h after treatment on human lung cancer, breast cancer, ovarian cancer and gastric cancer cells₅₀) The unit: mu M;

in addition, we also performed in vitro activity inhibition tests on human lung cancer resistant cells (a549/taxol) and human breast cancer resistant cells (MDA-MB-231/taxol) by using the target compounds a1, a2, A3, a4 and A5, and found that after 48 hours of drug action, the activity inhibition effect on two resistant cells is more obvious compared with that of paclitaxel single drug use by using the above five target compounds (a1, a2, A3, a4 and A5), so that the target compounds a1, a2, A3, a4 and A5 have the potential of overcoming the clinical drug resistance problem of paclitaxel, see table 3:

CCK-8 method for detecting target compounds A1, A2, A3, A4 and A5 for 48hActivity Inhibition (IC) of drug-resistant cells of lung and breast cancer (with paclitaxel resistance)₅₀) The unit: mu M;

example 7

Antitumor effect of target compound on immunodeficient mouse model in vivo

According to the in vitro activity experiment results obtained above, a human breast cancer cell line MDA-MB-231 nude mouse transplantation tumor model is further selected to test the in vivo anti-tumor activity of the target compounds A4 and A5. Human breast cancer MDA-MB-231 cells 2x 10⁶And the drug experiment in vivo is started after 100 mu L of the drug is inoculated under the skin of Balb-c nude of an immunodeficient mouse and the tumor is visible by naked eyes, the target compound A4 and the A5 are administrated by intraperitoneal injection at three drug concentrations of 30,50 and 80mg/kg (a blank group is normal saline), the experiment period is 14 days in total, and the drug administration is carried out once every two days. The experimental result shows that: compared with the blank control group, the drug-treated groups of the compounds A4 and A5 have obvious tumor inhibition effect (figure 1 and figure 2). In addition, no obvious change in the body weight of mice was found between the blank control group and the target compound A4 and A5 treatment groups (both at the dose of 80mg/kg) during the administration period (FIG. 3), which indicates that the compounds A4 and A5 have low toxicity in vivo and have potential value for further intensive study.

The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several equivalent modifications or substitutions can be made without departing from the spirit of the present invention, and these equivalent modifications or substitutions should also be considered as the protection scope of the present invention.

Example 8

A4 or A5 is used as active ingredient, and pharmaceutically acceptable auxiliary materials are added to prepare the liquid injection with various specifications by a conventional method.

The administration route of A4 or A5 includes various routes, such as injection administration, intracavity administration and the like.

(1) Preparation of injection:

a4 or A5200 mg, mannitol 700mg, PEG 300010 mg, and distilled water 100ml, wherein the pH is 7.0-7.5, the filtrate concentration is 3mg/ml, 2 ml per ampoule is packaged, and freeze drying is performed to obtain injection.

(2) Preparation of tablets:

a3 or A410 mg, 35mg of microcrystalline cellulose, 45mg of starch, 4mg of polyvinylpyrrolidone, 4.5mg of sodium carboxymethyl starch, 0.5mg of magnesium stearate and 1mg of talcum powder; sieving A3 or A4 active ingredient, starch and cellulose, mixing thoroughly, mixing polyvinylpyrrolidone solution with the above powder, sieving, making into wet granule, drying at 50 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.

(3) Preparation of capsules

A2 or A510 mg, respectively sieving the active ingredient and the auxiliary materials with a 100-mesh sieve, weighing the main medicine and the auxiliary materials according to the prescription amount, fully mixing, adding a proper amount of hydroxypropyl methylcellulose solution to prepare a soft material, sieving with a 24-mesh sieve, drying the prepared wet granules in an oven at 50-60 ℃ for about 2-3 hours, uniformly mixing magnesium stearate and talcum powder with the granules, granulating, measuring the content of an intermediate, and filling with a No. 2 capsule.

The main references:

1.Jemal A,Bray F,Center MM,et al.Global cancer statistics.CA Cancer JClin.2011；61(2):69-90.

2.Newman DJ,Cragg GM.Natural products as sources of new drugsover thelast 25years.Nat Prod.2007；70(3):461–477.

3.Wani MC,Taylor HL,Wall M E,et al.Plant antitumor agents.VI.Theisolation and structure of taxol,a novel antileukemic and antitumor agentfrom Taxus brevifolia.J Am Chem Soc,1971,93(9):2325.

Claims

1. a paclitaxel derivative with a structure shown in a general formula I, an optical isomer, a diastereoisomer and a racemate mixture thereof, and pharmaceutically acceptable salts thereof;

wherein:

z is benzoyl or tert-butyloxycarbonyl;

r is hydrogen atom, methoxy or acetyl;

2. The paclitaxel derivative according to claim 1, wherein the typical compounds are as follows:

compound a1:

compound a2:

compound a3:

compound a4:

compound a5:

3. The method for preparing a paclitaxel derivative typical compound according to claim 2, wherein the paclitaxel derivative typical compound is prepared by the method of the present invention

Synthesis of compounds a1 and a2:

reagents and conditions:

(a) pyridine, rt, 12 hours; (b) paclitaxel, DCC, DMAP, THF, rt, 20 hours;

taking resveratrol (1) as a starting material and pyridine as a solvent, sequentially adding p-dimethylaminopyridine and succinic anhydride, and reacting at room temperature to obtain a compound 3 and a compound 4; then, taking the dimethylaminopyridine as a catalyst and the dicyclohexylcarbodiimide as a condensing agent, and reacting the compound 3 or the compound 4 with the paclitaxel respectively to obtain target compounds A1 and A2; synthesis of compound a3:

reagents and conditions:

(a) pyridine, rt, 12 hours; (b) paclitaxel, DCC, DMAP, THF, rt, 20 hours;

pterostilbene (5) is used as a starting material, pyridine is used as a solvent, p-dimethylaminopyridine and succinic anhydride are sequentially added, and reaction is carried out at room temperature to obtain an intermediate 6; then, taking the dimethylaminopyridine as a catalyst, taking Dicyclohexylcarbodiimide (DCC) as a condensing agent, and reacting the intermediate 6 with paclitaxel to obtain a target compound A3;

synthesis of compound a4:

reagents and conditions:

(a) acetic anhydride, triethylamine, DMSO, 65 ℃; (b) pyridine, rt, 12 hours; (c) paclitaxel, DCC, DMAP, THF, rt, 20 hours;

taking resveratrol (1) as an initial raw material, in a dimethyl sulfoxide solvent, taking triethylamine as an alkali, and carrying out selective acylation reaction with two equivalents of acetic anhydride to obtain 4', 3-diacetyl resveratrol 7; pyridine is taken as a solvent, p-dimethylaminopyridine, succinic anhydride and an intermediate 7 are sequentially added, and a reaction is carried out at room temperature to obtain a compound 8; then, taking the dimethylaminopyridine as a catalyst, taking Dicyclohexylcarbodiimide (DCC) as a condensing agent, and reacting the intermediate 8 with paclitaxel to obtain a target compound A4;

synthesis of compound a5:

reagents and conditions:

(a)NaBH₄methanol, 0 ℃ (b) pyridine, rt, 4 hours; (b) pyridine, rt, 12 hours; (c) paclitaxel, DCC, DMAP, THF, rt, 20 hours;

using (E) -2, 4-dimethoxy-6- (4-methoxy styrene) benzaldehyde (9) as an initial raw material, and reducing the initial raw material in methanol by sodium borohydride under the ice bath condition to obtain a compound 10; dissolving the compound 10 in pyridine, sequentially adding p-dimethylaminopyridine and succinic anhydride, and reacting at room temperature to obtain a compound 11; and reacting the compound 11 with paclitaxel by using p-dimethylaminopyridine as a catalyst and Dicyclohexylcarbodiimide (DCC) as a condensing agent to obtain a target compound A5.

4. The pharmaceutical composition of paclitaxel derivative and pharmaceutically acceptable salts thereof according to any of claims 1-2, wherein the pharmaceutical composition comprises a therapeutically effective dose of one or more of the paclitaxel derivatives or pharmaceutically acceptable salts, excipients, carriers, or diluents thereof as described above.

5. Use of the paclitaxel derivative and the pharmaceutically acceptable salts thereof according to any one of claims 1-2 in the preparation of antitumor drugs.

6. The use according to claim 5, wherein the types of neoplastic diseases mainly include lung cancer, breast cancer, ovarian cancer and certain digestive system malignancies.

7. The use of claim 6, wherein said certain digestive system malignancies are gastric cancer, colorectal cancer.