KR20040033377A - Water-soluble prodrug compound comprising residue of paclitaxel or derivatives thereof, its preparation method, and pharmaceutical composition comprising the same - Google Patents

Abstract

PURPOSE: A water-soluble prodrug compound comprising a residue of paclitaxel or derivatives thereof, a preparation method thereof, and a pharmaceutical composition comprising the same are provided, thereby rapidly and easily conducting hydrolysis of the prodrug, so that the prodrug can be rapidly converted into paclitaxel and derivatives thereof. CONSTITUTION: A water-soluble prodrug compound comprising a residue of paclitaxel or derivatives thereof represented by the formula(1) is provided, wherein R is polyethyleneglycol wherein hydroxy at the end is substituted by R'; and R' is C1 to C5 alkyl or the structure of the formula(a), wherein D is a residue of paclitaxel or derivatives thereof; R' is hydrogen or C1 to C3 alkyl; and X is O, S or N. A method for preparing the water-soluble prodrug compound comprising a residue of paclitaxel or derivatives thereof of the formula(1) comprises esterification of paclitaxel or derivatives thereof with polyethyleneglycol derivative of the formula(2) in the presence of base and solvent.

Description

WATER-SOLUBLE PRODRUG COMPOUND COMPRISING RESIDUE OF PACLITAXEL OR DERIVATIVES THEREOF, ITS PREPARATION METHOD, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME }

The present invention relates to a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient. More specifically, the prodrug of the prodrug by an enzyme in vivo is excellent in solubility. The present invention relates to a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof, which can be rapidly degraded to greatly maximize bioavailability by controlling hydrolysis half-life, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.

Paclitaxel (also known as taxol) is a natural product derived from the bark of yew trees, and derivatives of paclitaxel (eg docetaxel) are semisynthetic materials obtained by synthesis from baccatin III derivatives derived from the bark of yew trees. . Such paclitaxel or a derivative thereof has a diterpene structure of the following general formula (I).

Wherein R ₁ is C ₆ H ₆ , and R ₂ is CH ₃ CO, paclitaxel,

If R ₁ is (CH ₃ ) ₃ CO and R ₂ is H, it is docetaxel.

Paclitaxel was first isolated by Wall and Wani in 1967, and has been extensively studied for its mechanism of action, and found to exhibit strong cytotoxicity and anticancer activity in 1992. Bristol-Myers Squibbs (Bristol-Myers) It is commercialized by Squibb) and used as an anticancer agent.

Paclitaxel, unlike conventional anticancer drugs, became the most widely used anticancer drug in the 1990s due to its relatively low toxicity and potent anticancer activity by inhibiting mitotic cancer cell division. Paclitaxel was licensed for the treatment of Kaposi sarcoma in 1997 after it was approved by the US Food and Drug Administration (FDA) for ovarian cancer in 1992 and breast cancer in 1994. It became. In addition, indications are expanding for treatment of liver cancer, lung cancer, rheumatoid arthritis, Alzheimer's disease, etc., and clinical trials of various drugs and multiple prescriptions are in progress.

Paclitaxel is poorly soluble in water and is administered with a surfactant such as chromophor-EL (polyoxyethylated castor oil) or polysorbate. For example, Taxol, Bristol-Myers Squibb, currently used in clinical practice, contains 6 mg of paclitaxel and 527 mg of cremopherelel, a surfactant, in 1 ml of a 49.7% (v / v) alcohol solution, and paclitaxel. Taxotere injections formulated with the derivative docetaxel contain 20 mg of docetaxel and 0.5 ml of polysorbate 80 as a surfactant in 1.83 ml of 13% (w / w) alcohol solution (Taxotere, Rhone-Poulenc Rorer).

As such, the surfactants used for administering paclitaxel, the Cremopoiel and Polysorbate components, are commonly used to treat hypersensitivity reactions (Lorence, W., et al, Agents and actions, 12, 64-80, 1982) in some patients. It is known to cause serious side effects. In addition, the use of vegetable oils such as cremopoiel not only has low bioavailability, but also causes side effects such as hypersensitive reaction. In addition, the addition of highly viscous materials (solid materials at temperature), such as alcohol and chromophorel, to the development of injections is a consideration for parenteral use. In addition, the use of organic solvents such as alcohol has problems of hemolysis and local irritation at the injection site.

For these reasons, recent clinical trials showed side effects such as neuropathy, myopathy, myalgia, and neutropenia in paclitaxel (taxol), and docetaxel (taxotere). Taxotere) had side effects such as stomatitis, edema, and malaise.

Therefore, efforts to develop water-soluble prodrug compounds including paclitaxel are widely underway in order to reduce such side effects and increase bioavailability. Among them, the development of prodrug compounds using polyethylene glycol (PEG) is of great interest to scientists and much research is being conducted. Recently, Greenwald (Enzon, Inc.) has synthesized various paclitaxel prodrugs using polyethylene glycol (PEG) (US Pat. 5,614,549, 5,880,131, 5,965,566), Desai (Vivorx, Inc), etc. A water soluble prodrug has been synthesized (UP Pat. 5,648,506). Chun Li (PG-TXL Company) et al. Synthesizes 2'-succinyl-paclitaxel by reacting paclitaxel with succinic anhydride and adds methoxypolyoxyethyleneamine (methoxy polyoxyethylene amine) was combined to synthesize a water-soluble prodrug (US Pat. 5,977,163). However, these compounds synthesized so far have problems in formulating. Paclitaxel prodrugs should be hydrolyzed rapidly by hydrolase in vivo and converted to paclitaxel, a drug that has physiological activity. However, the half-life (T1 / 2) in which the synthesized paclitaxel prodrug is converted to paclitaxel was found to be 1-8 hours in rat plasma, and it is necessary to reduce the half-life to about 10 minutes for formulation.

In addition, since the prodrug using the ester bond is slow in hydrolysis by enzymes in vivo, it increases the molecular weight of polyethylene glycol and increases the time to be released in vivo, thereby controlling the half-life and half-hydrolysis of the prodrug. It was. When increasing the molecular weight of polyethylene glycol, not only the synthesis reaction rate for prodrug preparation is significantly reduced, but also the chemical reaction including polyethylene glycol as a reactant has a disadvantage that the yield is significantly reduced. In addition, since the solubility of polyethylene glycol in water is inversely proportional to the molecular weight, a prodrug prepared using a high molecular weight polyethylene glycol has a disadvantage in that water solubility is reduced.

The present invention has been made to solve the problems of the prior art, a novel water-soluble paclitaxel or derivatives thereof that maximize the bioavailability by reducing the side effects caused by the dissolution aid and to accelerate the hydrolysis of the prodrug by the enzyme in vivo It is an object to provide a prodrug compound comprising a moiety.

Another object of the present invention is to provide a prodrug compound comprising a residue of a water-soluble paclitaxel or a derivative thereof which can be formulated with a short hydrolysis half-life.

It is still another object of the present invention to provide a method for preparing a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof having high solubility and short hydrolysis half-life.

It is another object of the present invention to provide a pharmaceutical composition comprising a prodrug compound comprising a residue of the water-soluble paclitaxel or derivative thereof.

1 is a linear graph of the results of hydrolysis to paclitaxel over time in 37 ° C. Rat Plasma for a water-soluble prodrug compound prepared by the method of Example 1 of the present invention,

FIG. 2 is a linear graph of the hydrolysis results with paclitaxel over time in 37 ° C. Rat Plasma for the water soluble prodrug compound prepared by the method of Example 2 of the present invention.

In order to achieve the above object, the present invention provides a water-soluble prodrug compound represented by the formula (1) comprising a residue of paclitaxel or a derivative thereof:

[Formula 1]

Where

R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A)

[Formula a]

Where

D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; And X is O, S or N.

In addition, the present invention is to prepare a water-soluble prodrug compound represented by the formula (1) comprising a residue of paclitaxel or derivatives thereof prepared by etherification of paclitaxel or derivatives thereof with a polyethylene glycol derivative of formula (2) in the presence of a base and a solvent Provide a method.

[Formula 2]

In the above formula, R is polyethylene glycol in which the hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure represented by the following Formula a,

[Formula a]

Where

D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N and Y is a suitable leaving group such as halogen.

The present invention also provides a method for preparing a water-soluble prodrug compound represented by Chemical Formula 1 prepared by reacting a compound of Chemical Formula 3 with a water-soluble polyethylene glycol derivative of Chemical Formula 2 in a presence of a base and a solvent, followed by deprotection reaction.

[Formula 2]

[Formula 3]

Where

R ₁ is C ₆ H ₆ ; R ₂ is CH ₃ CO or H; Pt is a silyl protecting group;

R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A)

[Formula a]

Where

D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N and Y is a suitable leaving group such as halogen.

The present invention also provides a pharmaceutical composition comprising the water-soluble prodrug compound of Formula 1.

Hereinafter, the present invention will be described in detail.

In order to solve the conventional problems, the chemically binding paclitaxel, which is a water-soluble derivative of Taxol, having antitumor activity and its derivatives to a water-soluble carrier under appropriate conditions, has excellent solubility and hydrolysis speed in vivo. It was confirmed that the half-life can be greatly reduced, and the present invention was completed.

The water-soluble prodrug compound of Chemical Formula 1 of the present invention is prepared by introducing a new self-immolating linker that can be spontaneously decomposed between paclitaxel and a water-soluble polymer and binding the water-soluble polymer thereto. The water-soluble prodrug compound of Chemical Formula 1 has a hydrolase easily accessible to the drug, and is rapidly degraded in vivo to hydrolyze paclitaxel and derivatives thereof having physiological activity.

The water-soluble prodrug compound represented by Chemical Formula 1 of the present invention will be described in more detail based on the preparation method as follows.

The compound of Chemical Formula 1 of the present invention may be prepared by the following two methods.

In a first method, the present invention can prepare a water-soluble prodrug compound by etherification of paclitaxel or a derivative thereof with a polyethylene glycol derivative of Formula 2 in the presence of a base and a solvent.

[Formula 2]

Where

R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A)

[Formula a]

D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N.

Alternatively, the water-soluble prodrug compound of Chemical Formula 1 may be prepared by reacting a compound represented by Chemical Formula 3 with a water-soluble polyethylene glycol derivative of Chemical Formula 2 in a second method and a deprotection reaction in the presence of a base and a solvent.

[Formula 3]

Where

R ₁ is C ₆ H ₆ ; R ₂ is CH ₃ CO or H; Pt is a silyl protecting group.

In the present invention, the reaction can be carried out under basic conditions. In particular, the reaction is preferably carried out in the presence of cesium carbonate (CsCO ₃ ).

The solvent is preferably N, N-dimethylformamide (DMF), dimethylacetamide (DMAc), or the like, but is not limited thereto.

The etherification reaction is preferably carried out for 1 to 72 hours.

The deprotection reaction may be carried out using a fluorine compound such as HF, Bu ₄ NF in a solvent, and the fluorine compound is preferably used at about 1%. It is preferable to use acetonitrile as the solvent.

In this case, the polyethylene glycol derivative of Formula 2 may be prepared by adding a base of polyethylene glycol of Formula 4 in anhydrous acetonitrile solvent and reacting with the compound of Formula 5.

[Formula 4]

[Formula 5]

In the above formula, R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of the formula (a),

[Formula a]

D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N; Y is a suitable leaving group such as halogen and n is an integer from 10 to 1200.

The water-soluble polyethylene glycol derivatives used in the present invention are linear or branched neutral polymers having various molecular weights, and are non-toxic as methylene chloride, an organic solvent, and a substance soluble in water. It is a safe substance approved for oral use by the US Food and Drug Administration. As a result, by using the water-soluble polyethylene glycol derivative, the prodrug compound of Formula 1 of the present invention can be well dissolved in water. It is preferable that the molecular weight of polyethyleneglycol used by this invention is 500-50,000. The content of the polyethylene glycol derivative of Chemical Formula 2 is preferably used in an amount of 1 to 2 equivalents based on 1 equivalent of paclitaxel or a derivative thereof. In addition, when the second method is used, the content of the polyethylene glycol derivative of Chemical Formula 2 is preferably used in an amount of 1 to 2 equivalents based on the compound of Chemical Formula 3.

The base is preferably used pyridine, the amount of the base may be used in 1 to 3 equivalents based on the compound of Formula 4.

In addition, the compound of Formula 3 may be prepared by reacting paclitaxel or a derivative thereof with a silylating agent in a solvent. The silylating agent serves to protect the OH group in the 2 'position in the paclitaxel or a derivative thereof. As the silylating agent, tert-butyldimethylsilyl chloride or trimethylsilyl chloride may be used. The amount of the silylating agent is preferably used in an amount of 1 to 3 equivalents based on 1 equivalent of paclitaxel or a derivative thereof. In this case, imidazole, pyridine, or the like may be used as the base, and the solvent may be anhydrous dichloromethane, but is not limited thereto.

The prodrug compound of the present invention thus obtained is rapidly hydrolyzed by a hydrolase upon administration in vivo, and hydrolyzed to paclitaxel and its derivatives as active ingredients. The prodrug compound of the present invention has a new intermediate conjugate that is capable of spontaneously decomposing when hydrolyzed by an enzyme, so that hydrolysis is rapidly achieved by reducing structural steric hindrance of paclitaxel upon access of the enzyme in vivo. Secondly, spontaneous degradation of the new intermediate binder is rapid, resulting in rapid conversion to paclitaxel.

In addition, since the prodrug compound of the present invention is very soluble in water (solubility> 400 mg / ml), it is not necessary to use surfactants and organic solvents, which cause serious hypersensitivity reactions in patients when the compound is administered. Therefore, it is possible to overcome side effects such as neuropathy, myopathy, myalgia, neutropenia, stomatitis, edema, and discomfort caused by surfactants and organic solvents as dissolution aids in existing products currently used in clinical practice (Tak, Taxoter). It has the advantage of being.

In addition, the water-soluble prodrug compound of Formula 1 of the present invention can be used as an active ingredient in pharmaceutical compositions used for the purpose of treating breast cancer, ovarian cancer, lung cancer and Kaposi's tumor. In addition, it can be used for the treatment of liver cancer, stomach cancer, rheumatoid arthritis, Alzheimer's disease, etc. Pharmaceutical compositions comprising the water-soluble prodrug compound of the present invention as an active ingredient may further comprise a pharmaceutically acceptable carrier.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are provided only to more easily understand the present invention, and the present invention is not limited to the following examples.

EXAMPLE

Example 1 Synthesis of 2 ′ (ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxypaclitaxe

(1) α-methoxy-ω-chloromethyloxy carbonyloxy polyethylene glycol 5000

10 g of monomethoxy polyethylene glycol (mPEG, molecular weight 5000) was dissolved in 100 ml of anhydrous acetonitrile, and 0.7 ml of pyridine was added and stirred at room temperature. 0.7 ml of chloromethyl chloroformate were added dropwise at room temperature and reacted for 72 hours. The precipitated pyridinium hydrochloride was filtered off, and the solvent was distilled under vacuum, and then dissolved in chloroform. Pentane was added thereto to precipitate the reaction product, the solvent was removed, and then dried to synthesize α-methoxy-ω-chloromethyloxy carbonyloxy polyethylene glycol 5000 having a yield of 61%. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.37-4.38 (m, mPEG), 5.73 (s, 2H)

(2) Synthesis of 2 '-(ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxypaclitaxel (2'-(ω-methoxypolyethyleneglycoloxy) carbonyloxymethoxypaclitaxel)

1.2 g of paclitaxel and 0.65 g of cesium carbonate (CsCO ₃ ) were added to 10 ml of dimethylformamide (DMF) and stirred at room temperature for 1 hour. 7 g of α-methoxy-ω-chloromethyloxy carbonyloxy polyethylene glycol 5000 was dissolved in 20 ml of DMF, and reacted for 72 hours. After filtering the reaction mixture, DMF was distilled under reduced pressure and dissolved in chloroform again. The chloroform solution was washed once with saturated aqueous sodium bicarbonate solution and again with distilled water. After drying over magnesium sulfate and filtration, the solvent was distilled under reduced pressure to give 2 '-(ω-methoxypolyethylene glycoloxy) carbonyloxymethyloxypaclitaxel in a yield of 61%. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.39-4.33 (m, mPEG), 5.75 (s, 2H)

Example 2:

Synthesis of 7- (ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxypaclitaxel (7- (ω-methoxypolyethyleneglycoloxy) carbonyloxymethoxypaclitaxel)

(1) Synthesis of 2 '-(tert-butyldimethylsilyl) paclitaxel (2'-(tert-butyl dimethysily) paclitaxel)

500 mg (0.586 mmol) of paclitaxel were dissolved in 10 ml of anhydrous dichloromethane. A solution of 106.0 mg (0.70 mmol) of tert-butyldimethylsilyl chloride and 71.8 mg (1.05 mmol) of imidazole in 1 ml of N, N-dimethylformamide was added thereto, followed by stirring for 6 hours. 20 ml of dichloromethane was added to the mixture, diluted, and washed twice with 5% hydrochloric acid solution and once with water. The organic layer was treated with anhydrous magnesium sulfate to remove the contained water, and then dried under reduced pressure to give 540 mg (95%) of the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.10 (s, 3H, -CH ₃ ), 0.03 (s, 3H, -CH ₃ ), -0.02 (s, 3H, -CH ₃ ), -0.26 (s, 3H, -CH ₃ )

(2) 2 '-(tert-butyldimethylsilyl) -7-((ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxy) -paclitaxel (2' (tert-butyldimethylsilyl) -7-((ω-methoxypolyethyleneglycoloxy Synthesis of Carbonyloxymethoxy)

540 mg (0.557 mmol) of 2 '-(tert-butyldecylsilyl) -paclitaxel and 325 mg (1.0 mmol) of cesium carbonate were added to 5 ml of dimethylformamide and stirred at room temperature for 1 hour. A solution of 3.5 g of α-methoxy-ω-chloromethyloxycarbonyloxypolyethylene glycol 5000 in 10 ml of DMF was added thereto and reacted for 72 hours. After filtration of the mixture, dimethylformamide was distilled under reduced pressure and dissolved in chloroform again. The chloroform solution was washed with sodium bicarbonate saturated aqueous solution and washed once with distilled water. Drying with magnesium sulfate, filtration and distillation of the solvent under reduced pressure yielded 2 '-(tert-butyldimethylsilyl) -7-((ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxy) -paclitaxel in 60% yield. It was. ¹ H NMR (300 MHz, CDCl ₃ ) δ0.10 (s, 3H, -CH ₃ ), 0.03 (s, 3H, -CH ₃ ), -0.02 (s, 3H, -CH ₃ ), -0.26 (s , 3H, -CH ₃ ), δ3.39-4.33 (m, mPEG), 5.75 (s, 2H)

(2) Synthesis of 7-((ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxy) paclitaxel (7- (ω-methoxypolyethyleneglycoloxy) carbonyloxymethoxy-paclitaxel)

2 g (0.33 mmol) of 2 '-(tert-butyldimethylsilyl) 7-((ω-methoxypolyethyleneglycoloxy) carbonyloxymethyloxy) -paclitaxel was added to 10 ml of acetonitrile. To the solution was mixed 10 ml of 1% hydrofluoric acid dissolved in acetonitrile. The mixture was stirred for 30 minutes and then the acetonitrile was removed by distillation under reduced pressure. The obtained residue was dissolved in 30 ml of diethyl ether, washed with saturated sodium bicarbonate solution and distilled water, and then treated with anhydrous magnesium sulfate to remove the contained water, followed by drying under reduced pressure to obtain 1.9 g (95%) of the product. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.39-4.33 (m, mPEG), 5.75 (s, 2H)

Experimental Example 1

(Prodrug Solubility Experiment)

The prodrug compounds prepared by the methods of Examples 1 and 2 above were dissolved in 1 ml of distilled water, and dissolved by increasing the amount of the prodrug compounds. The prodrug compound addition amount which shows fluidity and the measured value is 0.5 or less was made into solubility. The results are shown in Table 1 below.

Dissolution Example 1 400 mg or more Example 2 400 mg or more

As can be seen in Table 1, the prodrug compounds of Examples 1 and 2 showed solubility in water of 400 mg or more, indicating very good solubility.

Experimental Example 2

(Measurement of half-life of prodrug hydrolysis)

10 ml of lett plasma were placed in a 37 ° C. water bath, and then dissolved in a prodrug compound (0.5 mg of paclitaxel) prepared according to the method of Example 1 or 2. 100 μl of the solution was taken for each hour, followed by mixing into a tube containing 200 μl of acetonitrile. The supernatant was separated by centrifugation at 11,000 rpm for 5 minutes and 200 μl of the supernatant was analyzed by HPLC.

In addition, the hydrolysis half-life of the prodrug was measured using human plasma, PBS buffer and distilled water instead of lett plasma.

T _1/2 hydrolysis PBS buffer (pH 7.4) Let plasma (pH 7.3) Human plasma (pH 6.8) Distilled water (pH6.0) Example 1 > 1 hour <10 minutes <10 minutes > 1 hour Example 2 > 1 hour <10 minutes <10 minutes > 1 hour

As shown in Table 2, the prodrug compounds prepared by the methods of Examples 1 and 2 showed a hydrolysis half-life within 2 minutes in lett plasma, and a very short half-life of about 3 minutes in human plasma. It was found to have. On the other hand, non-enzymatic hydrolysis rates in phosphate buffer (PBS) and distilled water were more than 26 hours and more than 200 hours.

In order to determine the conversion rate of the prodrug compound prepared by the method of Examples 1 and 2 to paclitaxel over time, the concentration of prodrug and the concentration of paclitaxel in the sample were measured to determine the valence of paclitaxel over time. Decomposition results are shown in Tables 3 and 4, respectively. In addition, the linear graph of this result is shown in FIG. 1 and FIG. 2, respectively.

Hour, minute 0 One 2 3 4 5 7 10 Prodrug Content,% 100 61 39 26 15 8 3 0

Hour, minute 0 One 2 3 4 5 7 10 Prodrug Content,% 100 65 45 30 19 12 4 0

As shown in Tables 1, 2 and FIGS. 1 and 2 above, the prodrug compounds of Examples 1 and 2 were converted to at least 50% paclitaxel within about 2 minutes and to 100% paclitaxel within 10 minutes.

As described in detail above, the water-soluble prodrug compound of the present invention has a rapid and easy hydrolysis of the prodrug in vivo, so that the conversion to paclitaxel or a derivative thereof having physiological activity is very fast, and the half-life of the hydrolysis is short. It is easy to formulate and has excellent solubility in water so that pharmaceutical compositions containing the same can be used as useful anticancer agents.

Claims (9)

A water-soluble prodrug compound represented by the following formula (1) comprising a residue of paclitaxel or a derivative thereof: [Formula 1] Where R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A) [Formula a] Where D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; And X is O, S or N. The water-soluble prodrug compound according to claim 1, wherein the paclitaxel derivative is dodetaxel. The water-soluble prodrug compound according to claim 1, wherein R in Chemical Formula 1 is polyethylene glycol having a molecular weight of 500 to 50,000. A method for preparing a water-soluble prodrug compound represented by the following Chemical Formula 1, comprising a residue of paclitaxel or a derivative thereof prepared by etherification of paclitaxel or a derivative thereof in the presence of a base and a solvent: [Formula 1] [Formula 2] Where R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A) [Formula a] D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N and Y is a suitable leaving group such as halogen. Method for preparing a water-soluble prodrug compound represented by the formula (1) prepared by reacting a compound of the formula (3) in the presence of a base and a solvent with a water-soluble polyethylene glycol derivative of the formula (2) and deprotection group reaction: [Formula 1] [Formula 2] [Formula 3] Where R ₁ is C ₆ H ₆ ; R ₂ is CH ₃ CO or H; Pt is a silyl protecting group; R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A) [Formula a] Where D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N and Y is a suitable leaving group such as halogen. The method for preparing a water-soluble prodrug compound according to claim 4 or 5, wherein the polyethylene glycol derivative compound of Formula 2 is prepared by reacting a compound of Formula 4 with a compound of Formula 5. [Formula 4] [Formula 5] In the above formula, R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of the formula (a), [Formula a] D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; X is O, S or N; Y is a suitable leaving group such as halogen. The method of claim 5, wherein the compound of Formula 3 is prepared by reacting paclitaxel or a derivative thereof with a silylating agent. A pharmaceutical composition comprising, as an active ingredient, a water-soluble prodrug compound represented by the following Chemical Formula 1 comprising a residue of paclitaxel or a derivative thereof: [Formula 1] Where R is a polyethylene glycol in which a hydroxyl group at the end is substituted with R ″, wherein R ″ is an alkyl group having 1 to 5 carbon atoms, or a group having a structure of Formula (A) [Formula a] Where D is a residue of paclitaxel or a derivative thereof; R 'is hydrogen or an alkyl group having 1 to 3 carbon atoms; And X is O, S or N. The pharmaceutical composition of claim 8, wherein the paclitaxel derivative is dodetaxel.