WO2007137513A1

WO2007137513A1 - A TYPE OF NOVEL 2'-α-HYDROXYALKYL TAXEL COMPOUNDS AND THE PREPARATION METHODS THEREOF

Info

Publication number: WO2007137513A1
Application number: PCT/CN2007/001733
Authority: WO
Inventors: Fajun Nan; Jia Li; Jing Zhou; Chuanming Xie; Yangming Zhang
Original assignee: Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date: 2006-05-29
Filing date: 2007-05-29
Publication date: 2007-12-06
Also published as: CN101081841A

Abstract

The present application discloses a type of 2'-α-hydroxyalkyl taxel compounds with following formula (I), the compositions containing the same and uses thereof. These compounds can effectively inhibit the growth of tumor cells, especially can effectively inhibit the growth of tumor cells having multi-drugs resistance (such as MCF-7/ADR), which are better than Paclitaxel (Taxol®) or Docetaxel (Taxotere®).

Description

FIELD OF THE INVENTION The present invention relates to a class of semi-synthetic paclitaxel compounds, and more particularly to a class of 2,-α-hydroxyalkyl taxanes Class of compounds. Background

Cancer is a large group of diseases characterized by abnormal cell proliferation and metastasis. It has become one of the most serious diseases that endanger human health. According to the World Health Organization, there are 6 million new cancer cases every year worldwide. In China, cancer has become the second leading cause of death after cardiovascular and cerebrovascular diseases.

Paclitaxel (trade name Taxol) is a diterpenoid compound having anticancer activity isolated from the yew tree. By binding to cellular tubulin, paclitaxel promotes the polymerization of tubulin to form stable microtubules and inhibits the depolymerization of microtubules, ultimately leading to the loss of function of microtubule bundles, thereby blocking cell mitosis and achieving anticancer effects. Recent studies have shown that in addition to inhibiting the mitosis of cancerous cells, paclitaxel also has a strong ability to promote cancerous cell apoptosis. Docetaxel (trade name Taxotere) is synthesized by semi-synthetic methods during structural modification and modification of paclitaxel. The anticancer mechanism of docetaxel is the same as that of paclitaxel, but it has better bioavailability and less toxic side effects than paclitaxel. Anticancer activity is superior to paclitaxel, and due to its increased water solubility, it makes Dorsey Paclitaxel is easier to formulate.

Taxus drunk: R ₁ =CH ₃ CO; R ₂ =C _e H ₅

Docetaxel: ^H; R ₂ =(CH ₃ ) ₃ CO

Since the US FDA approved paclitaxel for the treatment of advanced ovarian cancer in December 1992, the application of paclitaxel has gradually expanded, and it has become the first choice for anticancer drugs widely used in clinical practice. While bringing hope to cancer patients, it has also brought huge economic benefits to pharmaceutical companies. In 2000, sales of paclitaxel preparations reached $1.592 billion.

Since paclitaxel is only found in the bark of the yew plant, the number of the tree species is scarce and the growth is slow. The actual production of 1 kg of paclitaxel requires about 30 tons of yew bark, and the simple extraction and separation is far from meeting the market demand. In 1988, Denis et al. first obtained paclitaxel by semi-synthetic method using 10-deacetylbaccatin III ( 10-DAB) (J. -N. Denis, AE Greene, D. Guenard, LM Gueritte-Voegelein, P Potier, J. Am. Chem. Soc. 1988, 110, 5917-5919 λ In 1993, Holton first used β-lactam coupling with 10-DAB to efficiently obtain semi-synthesis of paclitaxel (US-05254703, 1993) .

10-Deacetylbaccatin ΙΠ (10-DAB)

Since the 1980s, people have been working on the structure and activity relationship of paclitaxel. It is hoped that the structural modification and modification of paclitaxel will be carried out through these studies, in order to find a new generation of paclitaxel anticancer drugs with high efficiency and low toxicity. The structural modification of the 2, position of paclitaxel phenyl isoserine is relatively rare. Denis et al. synthesized 2,-mercapto docetaxel (J.-N. Denis, A. Fkyerat, Y. Gimbert, C. Coutterez, P. Mantellier, S. Jost and AE Greene, J. Chem. Soc, Perkin Trans. 1, 1995, 1811 ), activity tests showed that cytotoxicity (KB-VI) and microtubule depolymerization activity were stronger than docetaxel . This may be due to the introduction of 2,-mercapto, which reduces the rotational freedom of C-2, -C-3.

The inventors of the present invention synthesized a novel 2,-α-hydroxyalkyl taxane compound by coupling 10-DAB with a suitable substituted β-lactam. SUMMARY OF THE INVENTION One object of the present invention is to structurally modify and design a novel 2,-α-hydroxyalkyl taxane compound for paclitaxel and the phenylisoserine side chain 2 of docetaxel. In-depth study of its structure and activity. Another object of the present invention is to provide a process for preparing the 2,-α-hydroxyalkyl taxane compound. A further object of the invention is to provide the use of the compound in a pharmaceutical composition for the treatment of cancer. The compound of the present invention has a structure represented by the following formula 1: Formula 1

among them:

Represents -C(0)C ₆ 3⁄4, -C(0)OC(CH ₃ ) ₃ ;

R ₂ represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

R ₃ represents -H or -C(0)CH ₃ ;

R4 represents -H, -OH or -F;

And includes 2, 3', and 2,0! All possible stereoisomers. Wherein when -C(0)C ₆ H ₅ , R ₃ is -C(0)CH ₃ ;

R ₂ is -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

Is -H, -OH or -F, the compound is a compound having the formula:

Wherein, when -C(0)OC(CH ₃ ) ₃ , R ₃ is -H;

R ₂ is -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

R4 is -H, -OH or -F, and the compound is a compound having the following structural formula:

The compounds of the invention are selected from the group comprising the following compounds:

Compound la

Compound lb

Compound If

Compound li

Compound lj

The invention also provides a method for preparing a 2,-o;-hydroxyalkyl taxane compound, which comprises the following steps: after esterification of compound 2 with compound 3 to obtain a coupled product, the protective group is removed to obtain a final Compound 1. Wherein, the esterification reaction uses THF, toluene or pyridine as a solvent, and a condensing agent such as DCC, 72-BuLi, bistridecylsilylamide or bistrimethylsilylamide is used, and DMAP can be added as a catalyst according to the reaction requirement. The reaction temperature is between -50 ° C and 90 ° C. Different protection group removal methods can be selected depending on the protecting group. The reaction time is usually determined according to the specific conditions. TLC is usually used to track the completion degree of the reaction. After the reaction is completed, it is generally extracted with a solvent such as ethyl acetate or dichloromethane, and then washed with 5% HCl, water and saturated saline. After drying, the solvent is removed under reduced pressure at a low temperature, and the concentrate is separated and purified by column chromatography, and the final product is proved by a method such as nuclear magnetic. The specific preparation process can be represented by the following reaction scheme:

among them:

Represents -C(0)C ₆ 3⁄4, -C(0)OC(CH ₃ ) ₃ ;

R ₂ represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; methoxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

R ₃ represents -H or -C(0)C3⁄4;

R4 represents -H, -OH or -F;

It also includes all possible stereoisomers of the 2, 3, and 2, alpha positions.

among them:

R ₅ represents a hydroxyl protecting group such as TMS, TES, TBDMS, EE;

R6 represents a hydroxy protecting group such as -C(0)C3⁄4, TMS, TES, Troc;

R ₇ represents a hydroxy protecting group such as TMS, TES, Troc or the like.

Among them, compound 2 adopts two different synthesis methods according to its cis-trans isomerization difference:

(1) The synthetic route of trans compound 2 is as follows:

3A-anti-2 3A-ant 6

Ri represents -C(0)C ₆ 3⁄4, -C(0)OC(CH ₃ ) ₃ ;

R ₂ represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; decyloxy, ethoxy or hydroxy substituted C1-C6 alkyl; methoxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

Represents -H, -OH or -F;

Represents a hydroxyl protecting group such as TMS, TES, TBDMS or EE.

Compound 4 is reacted with PhS0 ₂ Na in a mixed solvent of THF/3⁄40 to obtain compound 5; using THF as a solvent, compound 5 is reacted with Grignard reagent PhMgBr to obtain compound 6;

C3⁄4C1 _{2 is} used as a solvent, and compound 6 is reacted with PhC(0)Cl or (Boc) ₂₀ under TEA and a small amount of catalyst DMAP to give compound 3,4-α«ζ·-2.

Among them, the compound 4 can be synthesized according to the method of Patent ΕΡ 0369691.

(2) The synthesis route of cis compound 2 is as follows: (Refer to the method of Am. Chem. Soc. 1998, 120, 5840-5841)

3,4-c«-6 3,4-"'s-2

R represents -C(0)C ₆ H ₅ , -C(0)OC(CH ₃ ) ₃ ;

R ₂ represents -H; C1-C6 alkyl; C3-C6 cycloalkyl; methoxy, ethoxy or hydroxy substituted C1-C6 alkyl; decyloxy, ethoxy or hydroxy substituted C3-C6 Cycloalkyl; phenyl; or benzyl;

Represents -H, -OH or -F;

R ₅ represents a hydroxy protecting group such as TMS, TES, TBDMS or EE.

The reaction temperature of the above reaction is usually from 0 ° C to room temperature or from heating to 80 ° C to 120 ° C. The reaction time depends on the specific reactants, and TLC is usually used to track the completion of the reaction. The post-treatment methods generally employed after the completion of the reaction include cooling, concentration of the reaction solution to remove the solvent, extraction, separation by column chromatography, and the like. The final product was tested by NMR.

The compound can be used to prepare a medicament for treating cancer. Hereinafter, the present invention will be more specifically described by way of examples and comparative examples. However, the following examples are provided for illustrative purposes only, and thus the invention is not limited to or by the embodiments. BEST MODE FOR CARRYING OUT THE INVENTION In the following examples, the conventional post-treatment method is: after the reaction is completed, an appropriate amount of water is added to the reaction liquid to separate the organic phase and the aqueous phase, and the aqueous phase is subjected to ethyl acetate, diethyl ether or dichloromethane. After the organic solvent is sufficiently extracted, the organic phases are combined. Use if necessary

Wash with 5% HCl solution and/or saturated NaHC0 ₃ solution, water and saturated brine. The organic phase was dried over anhydrous anhydrous Na ₂ S0 ₄ or MgS0 _4, then filtered under reduced pressure by rotary evaporation to give the crude product, after separation and purification by column chromatography to give the final product.

NMR was determined using a Mercury-Vx 300M instrument manufactured by Varian, NMR calibration: 6H 7.26 ppm (CDC13). The reagents are mainly supplied by Shanghai Chemical Reagent Co., Ltd. The product is mainly purified by column chromatography, silica gel (200-300 mesh), and the silica gel model used for column chromatography is coarse pore (ZLX-II), which is produced by Qingdao Ocean Chemical Plant. Example 1: Preparation of Compound 5a Compound 5a was prepared according to the following reaction formula. Into a 50 ml round bottom flask was added 718 mg of a solution of compound 4a (2.5 mmol) in 10 ml of THF, and 10 mg of sodium benzoic acid (5 mmol) in 10 ml of water. The reaction solution was refluxed at 80 ° C for 1 hour, and after completion of the reaction, it was cooled to room temperature, and 840 mg of compound 5a was obtained by conventional workup.

Compounds were prepared in the same manner as above except that the corresponding compound materials were used.

(±) 5a, 5b, (±) 5b, wherein (±) 5a, (±) 5b are racemic compounds containing 5a, 5b and their enantiomers, respectively. Its structural formula and nuclear magnetic data are shown in Table 1 below.

Purchase Example 2: Preparation of Compound 6a Compound 6a was prepared according to the following reaction formula. 840 mg of compound 5a (2.28 mmol) was dissolved in 10 ml of THF solution, stirred at -20 ° C for 15 minutes, and 4.6 ml of a solution of lM PhMgBr in THF was added dropwise. After completion of the dropwise addition, the reaction was carried out at -20 ° C for 2 hours, and the reaction was continued at 0 ° C for 1 hour. After completion of the reaction, the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride, and 472 mg of compound 6a was obtained by conventional workup.

TT

5a 6a Preparation of compounds in the same manner as above except using the corresponding compound materials

(±) 6a, 6b, (±)6b, wherein (±)6a, (±)6b are racemic compounds containing 6a, 6b and their enantiomers, respectively. Its structural formula and nuclear magnetic data are shown in Table 2 below. Table 2

Example 3: Preparation of Compound 2a Compound 2a was prepared according to the following reaction formula. 472 mg of compound 6a (1.55 mmol), 0.5 ml of triethylamine (2.3 mmol), 405 mg (Boc) ₂ 0 (1.86 mmol), and a catalytic amount of DMAP were added to 10 ml of dichloromethane. The reaction solution was stirred at room temperature for 6 hours, and after completion of the reaction, 564 mg of Compound 2a was obtained by conventional workup.

6a 2a In addition to the use of the corresponding compound starting materials, the compounds are prepared in the same manner as above.

(±) 2a, 2b, (+)2b, 2c, (±)2c, where (±)2a, (±)2b, (±)2c are respectively included 2a,

2b, 2c and racemic compounds of their enantiomers. Its structural formula and nuclear magnetic data are shown in Table 3 below. table 3

Buying Example 4: Preparation of Compound 2d

Compound 2d was prepared according to the following reaction formula.

472 mg of compound 6a (1.55 mmol) > 0.5 ml of triethylamine (2.3 mmol), 0.25 ml of benzoyl chloride (1.86 mmol) and a catalyst amount were added to 10 ml of dichloromethane solution. DMAP. The reaction solution was stirred at room temperature for 6 hours, and after completion of the reaction, 564 mg of compound 2d was obtained by conventional workup.

6a 2d In addition to the use of the corresponding compound starting materials, the compounds were prepared in the same manner as above.

(±) 2d, 2e, (±)2e, 2f, (±)2f, where (±)2d, (±)2e, (±)2f are 2d,

2e, 2f and racemic compounds of their enantiomers. Its structural formula and nuclear magnetic data are shown in Table 4 below. Table 4

Example 5: Preparation of compound la Compound 2d was prepared according to the following reaction formula.

178 mg of the compound 7,10-Di-TVoc-DAB (0.2 mmol) was dissolved in 1 ml of THF solution, and 0.22 ml of a 2.5 M «-BuLi n-hexane solution was added dropwise at -40 ° C, and the reaction solution was stirred at this temperature for 30 minutes. An additional 162 mg of compound 2a (0.4 mmol) in 1 ml of THF was added. After the reaction for 30 minutes, the temperature was naturally raised to 0 ° C, and the reaction was continued for 1 hour. The reaction was quenched with a saturated ammonium chloride solution and then worked up to afford 145 mg of the coupled product. In a water bath, 145 mg of the coupling product was dissolved in 2 ml of THF solution, 0.22 ml of 1 M tetrabutylammonium fluoride in THF was added, the reaction was allowed to rise to room temperature, and the progress of the reaction was followed by TLC. After completion of the reaction, 2 ml of acetic acid and 0.25 ml of water were added. Stir vigorously for 30 minutes, and then add zinc powder. After the completion of the reaction, it was post-treated to obtain 58 mg of compound la.

In addition to the use of the corresponding compound materials, the compounds lb, ld, le were prepared in the same manner as above, and their structural formulas and nuclear magnetic data are shown in Table 5 below. Table 5 "" No. Compound structure Nuclear magnetic data

_3⁄4 NMR (300MHz, CDC1 ₃ ) 1.05(s, 3H), 1.07(s, 3H), 1.14(s, 3H), 1.27(d, 3H), 1.42(s, 9H), 1.68(s, 3H), 2.11(m, 2H), 2.38(s, 3H), 2.53(m, 2H), 2.85(m, 1H), la

3.79(d, 1H), 4.12-4.30(m, 4H), 4.92(m, 1H), 5.04-5.10(m, 2H), 5.59(d, 1H), 6.03(m, 1H), 6.19(d, 1H), 7.24-7.38 (m, 5H), 7.43-8.05 (m, 5H)

_3⁄4 NMR (300MHz, CDC1 ₃ ) 1.07(s, 3H), 1.19(s, 3H), 1.40(s, 9H), 1.47(d, 3H), 1.69(s, 3H), 1.81(s, 3H) , 1.86(s, 3H),

2.08(m, 2H), 2.50(m, 2H), 2.65(m, 1H), lb

3.74(d, 1H), 4.08-4.25(m, 4H), 4.86(m, 1H), 5.00(m, 1H), 5.15(s, 1H), 5.57(d, 1H), 6.18(m, 1H) , 6.38(d, 1H), 7.20-7.36(m, 5H), 7.54-8.01(m, 5H)

'H NMR (300MHZ, CDC1 ₃ ) 1.06(s, 3H), 1.17(s, 3H), 1.34(d, 3H), 1.46(s, 9H), 1.58(m, 2H), 1.67(s, 3H) , 1.77(s, 3H), lc

1.85(s, 3H), 2.50(m, 2H), 2.66(dd, 1H), 3.75(d, 1H), 4.05-4.22(m, 4H), 4.85(m, 1H), 5.13(s, 1H) , 5.34(dd, 1H), 5.56(d, 1H), 6.00(d, 1H), 6.10(m, 1H),

7.14-7.36(m, 5H), 7.55-8.02(m, 5H)

_3⁄4 NMR (300MHz, CDC1 ₃ ) δ 0.92(s, 3H), 1.05(s, 3H), 1.15(s, 3H), 1.27(d, 3H), 1.49(s, 9H), 1.65(m, 2H) , 1.69(s, 3H), 2.35(s, 3H), 2.56(m, 2H), 2.86(dd, 1H),

Id

3.75(d, 1H), 3.99-4.32(m, 4H), 4.92(m, 1H), 4.99(s, 1H), 5.43(dd, 1H), 5.60(d, 1H), 6.06-6.12(m, 2H), 7.26-7.42 (m, 5H), work " "

7.45-8.05 (m, 5H)

_3⁄4 NMR (300MHz, CDC1 ₃ ) δ 0.99(s, 3H), 0.14(s, 3H), 1.37(m, 12H), 1.71(s, 3H), 1.78(m, 2H), 1.84(s, 3H) , 2.13(s, 3H), le 2.49(m, 2H), 2.97(m, 1H), 3.75(d, 1H),

4.11-4.39(m, 5H), 4.89(m, 1H), 5.16(s, 1H), 5.56(d, 1H), 6.03(t, 1H), 7.14- 7.34(m, 5H), 7.53-8.03( m, 5H) Example 6: Preparation of Compound If Compound 2d was prepared according to the following reaction formula.

140 mg of the compound 7-TES-Baccatin III ((mmol) was dissolved in 1 ml of THF solution, and 0.22 ml of a 2.5 M n-BuLi in n-hexane solution was added dropwise at -40 ° C. The reaction solution was stirred at this temperature for 30 minutes, and then 164 mg was added. Compound 2d (0.4 mmol) in 1 ml of THF. After 30 minutes of reaction, the temperature was naturally raised to 0 ° C, and the reaction was continued for 1 hour. The saturated ammonium chloride solution was quenched, and the conventional workup gave 122 mg of the coupled product. The co-product was dissolved in 2 ml of THF solution, 0.22 ml of a 1 M solution of tetrabutylammonium fluoride in THF was added, the reaction was allowed to warm to room temperature, and the reaction was followed by TLC. After the completion of the reaction, 62 mg of compound lf was obtained.

In addition to the use of the corresponding compound materials, the compositions lg, li, lj were prepared in the same manner as above, and their structural formulas and nuclear magnetic data are shown in Table 6 below. Table 6

6.10(m, 2H), 7.26-8.19(m, 15H)

_3⁄4 NMR (300MHz, CDC1 ₃ ) δ 0.88(s, 3H), 1.10(s, 3H), 1.16(s, 3H), 1.57(d, 3H), 1.64(m, 2H), 1.76(s, 3H) , 2.18(s, 3H), f . 2.47(s, 3H), 2.56(m, 2H), 3.08(m, 1H), li

3.58(d, 1H), 4.20(m, 2H), 4.37(m, 2H), 4.88(m, 1H), 5.48(d, 1H), 5.78(m, 1H), 6.08(s, 1H), 6.12 (t, 1H) 7.26-8.19(m, 15H)

• H NMR (300 MHZ, CDC1 ₃ ) δ 0.88 (s, 3H), 0.9 l (s, 3H), 1.23 (s, 3H), 1.42 (d, 3H), 1.47 (m, 2H), 1.63 (s, 3H), 1.74(s, 3H), lj 2.17(s, 3H), 2.25(m, 2H), 3.10(m, 1H),

3.32(d, 1H), 3.84(m, 2H), 4.3 l(m, 2H),

4.59 (m, 1H), 5.48 (d, 1H), , 6.08 (s, 1H), 6.12 (t, 1H), 7.26-8.09 (m, 15H). Example 7: Test of activity test drug screening model Principle:

To restore metabolic MTT assay 3- (4,5-dimethylthylthiazol-2- yl) -2,5- diphenyl tetrazolium bromide (MTT) is associated with the presence of NADP mitochondrial dehydrogenases in viable cells _s base, may be yellow The MTT is reduced to the insoluble blue-purple Formazan, the dead fine packet disappears and the MTT is not reduced. After dissolving Formazan in DMSO, the optical density can be measured at a wavelength of 550/690 nm using a microplate reader.

MTT assay cell proliferation assay procedure: Take the logarithmic growth phase, good cell growth state of the adherent fine MCF-7 and MCF-7/ADR by 0.05% trypsin digestion, counting, using the medium to prepare cell suspension Liquid, counted and inoculated into 96-well plates at 3000 cells per well of 3000 cells; The 96-well plate was transferred to a 37 ° C, 5 % (0 ₂ incubator overnight until the cells were attached; the next day, the dosing was started. Before the addition, some control wells were directly added to the MTT solution (5 mg/ml) 20 ul (no need to suck After 3 hours of action, A550/690 was read as the initial cell concentration, and 100 ul of medium containing 2 ul of compound was added to each well of the drug well. DMSO was used as the base control, and 2 ul of DMSO was also added to the medium of 100 ul per well. And each experiment has a positive control doxorubicin. Placed in a 37 ° C, 5 % C0 ₂ incubator for 72 hours, each compound made three duplicate wells (pipetting 6 ul of compound in the sterilized eppendorf tube, add 300 ul of medium was mixed and added to three wells), and each compound was subjected to six concentration gradients; three days later (72 hours), 40 ul of MTT solution (5 mg/ml) was directly added to each well (no need to aspirate the medium), After entering the incubator for three hours, take out the liquid in the well and add 100 μl of DMSO. Shake it gently to dissolve the crystals completely. Check the light absorption value of each well on the enzyme-linked detector (550/690) as the drug. Cell density. Drug on tumor cell MCF-7 The inhibition rate of MCF-7/ADR was reflected by the percent net growth rate, and the IC50 value was determined from the percent net growth-compound concentration function graph. The percent net growth rate was calculated as the percent net growth rate = [ (cell + drug) A550/690-initial A550/690] I [(cell + drug carrier) A550/690-initial A550/690] Table 7: Sample test results

No. IC ₅₀ (MCF-7) IC ₅₀ (MCF-7/ADR) No. IC ₅₀ (MCF-7) IC ₅₀ (MCF-7/ADR) Docetaxel 2.06nM 0.98 μΜ Paclitaxel 5.02nM 4.65 μΜ

(Taxotere) (Taxol)

Compound la 16.79μΜ 94.42μΜ Compound If 3.22μΜ 6.34μΜ Compound lb >20 μΜ >1ητΜ Compound lg >20μΜ 15.85μΜ Compound lc 18.09 μΜ >lmM Compound lh 4.96μΜ 12.14μΜ Compound Id >20 μΜ >lmM Compound li >20μΜ 50.88μΜ Compound le >20 μΜ >lmM compound lj >20μΜ 24.7 ΙμΜ It can be seen from the test results of the above table that the compound of the present invention has a stronger inhibitory effect on cancer cell growth than the prior art of Taxotere and Taxol.

Claims

Claim

1. A class of 2,-0;-hydroxyalkyl taxanes having the structure of the following formula 1 and all possible stereoisomers of the 2, 3, and 2, c positions:

among them:

Ri represents -C(0)C ₆ H ₅ or -C(0)OC(CH ₃ ) ₃ ;

R ₃ represents -H or -C(0)CH ₃ ;

R4 represents -H, -OH or -F.

The compound according to claim 1, wherein the compound is a compound having the following structural formula:

Wherein, when is - ((0) (3 _6, R ₃ is -C (0) C¾;

R4 is -H, -OH or -F.

Wherein, when -C(0)OC(C3⁄4) ₃ , R ₃ is -H;

R4 is -H, -OH or -F.

4. A compound according to claim 1 wherein: the compound is selected from the group consisting of:

Compound Id

Compound le o/u/ O s-oosld 2s/-2/-00iM

:

After the product

R4 represents -H-OH or -F;

R ₅ represents a -H TMS TES TBDMS or EE hydroxy protecting group.

The process according to claim 2, wherein the trans compound 2 is prepared according to the following reaction scheme:

among them:

Representative -C(0)C ₆ H ₅ -C(0)OC(CH ₃ ) ₃ ;

Represents -H -OH or -F;

R ₅ represents TMS TES TBDMS or EE hydroxy protecting group; compound 4 is reacted with PhS0 ₂ Na in a mixed solvent of THF/3⁄40 to obtain compound 5; using THF as a solvent, compound 5 is reacted with Grignard reagent PhMgBr to obtain compound 6; CH ₂ C1 _{2 was} used as a solvent, and compound 6 was reacted with PhC(0)Cl or (Boc) ₂₀ under TEA and a small amount of catalyst DMAP to give compound 3,4-α^-2.

A pharmaceutical composition for treating cancer, which comprises the compound of claim 1 and a pharmaceutically acceptable carrier.

The pharmaceutical composition according to claim 4, wherein the cancer is a multidrug resistant tumor.