KR20030068955A - New self-immolating linker and its preparation method, water-soluble prodrug compound comprising residue of paclitaxel or derivatives thereof using the same, its preparation method, and pharmaceutical composition comprising the same - Google Patents

Abstract

PURPOSE: A novel self-immolating linker compound, its preparation method, a water-soluble prodrug compound containing paclitaxel or its derivative moiety, its preparation method and a pharmaceutical composition containing the prodrug compound as an effective ingredient are provided, to enable the prodrug compound having an excellent solubility in water to be produced massively and easily with an improved yield by employing the self-immolating linker compound. CONSTITUTION: The self-immolating linker compound is self-immolated in a water-soluble polymer and is represented by the formula 2, wherein R' is H or an alkyl group of C1-C5; X is a halogen atom; m is an integer of 1-3; and n is an integer of 10-460. The water-soluble prodrug compound is represented by the formula 1, wherein D is the paclitaxel having OH at the 2' or 7-position or its derivative moiety; R' is H or an alkyl group of C1-C5; X is a halogen atom; m is an integer of 1-3; and n is an integer of 10-460.

Description

New intermediate binder (SEELF-IMMOLATIINL LINNEWER) compound and its preparation method, water-soluble prodrug compound comprising residues of paclitaxel or derivatives thereof, preparation method thereof and pharmaceutical composition comprising the same as an active ingredient {NEW SELF-IMMOLATING LINKER AND ITS PREPARATION METHOD, WATER-SOLUBLE PRODRUG COMPOUND COMPRISING RESIDUE OF PACLITAXEL OR DERIVATIVES THEREOF USING THE SAME, ITS PREPARATION METHOD, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

The present invention relates to a self-immolating linker compound and a preparation method thereof, a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient. In detail, a novel self-immolating linker compound and a method for preparing the same, a process for producing a high yield of water-soluble prodrug compound with a simple process using a spontaneously degradable intermediate, and paclitaxel using the same It relates to a water-soluble prodrug compound comprising a residue of a derivative, a preparation method thereof, 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 have shown 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. Nos. 5,614,549, 5,880,131, 5,965,566), and Desai (Vivorx, Inc.). Water-soluble prodrugs have been synthesized using polyethylene glycol (PEG) (US Pat. No. 5,648,506). Chun Li (PG-TXL Company) et al. Synthesizes 2'-succinyl-paclitaxel by reacting paclitaxel with succinic anhydride and adds methoxypolyoxyethyleneamine (methoxypolyoxyethylene amine) was combined to synthesize a water-soluble prodrug (US Pat. No. 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.

There is also a method of preparing a water soluble prodrug compound using a compound of 18-crown-6. However, the compound of 18-crown-6 is expensive and difficult to commercially mass-produce. Moreover, when the crown compound is used, the reaction time is considerably long, and the yield is very low.

The present invention has been made to solve the problems of the prior art, it is an object to provide a new self-immolating linker compound capable of spontaneous decomposition between water-soluble polymers.

Another object of the present invention is to provide a method for preparing the intermediate binder compound.

Another object of the present invention is a water-soluble prodrug compound comprising residues of paclitaxel or derivatives thereof which have improved yield and maximized bioavailability by increasing the rate of hydrolysis of the prodrug by enzymes in vivo using the intermediate binder compound. To provide.

Another object of the present invention is to provide a method for preparing the water-soluble prodrug compound which is easy to manufacture and commercially available in mass production.

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

In order to achieve the above object, the present invention provides a self-immolating linker compound represented by the following formula (2).

[Formula 2]

Wherein R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460.

In another aspect, the present invention is to prepare a compound of the formula (3) by reacting a polyethylene glycol derivative of formula (5) with a compound of the formula (4) in the presence of an organic solvent and a base, and halogenating the compound of the formula (3)

It provides a method for producing an intermediate conjugate (self-immolating linker) compound represented by the formula (2) comprising a.

[Formula 3]

[Formula 4]

[Formula 5]

Wherein R is an alkyl or alkoxy group having 1 to 7 carbon atoms; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460.

The present invention also provides a water-soluble prodrug compound represented by the following formula (1) comprising a residue of paclitaxel or a derivative thereof.

[Formula 1]

Where

D is a residue of paclitaxel or a derivative thereof having hydroxy at the 2 'or 7 position; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460.

In addition, the present invention is represented by the formula (1) comprising a residue of paclitaxel or derivatives thereof comprising the step of reacting paclitaxel or a derivative thereof with a self-immolating linker compound of Formula 2 under a base and an organic solvent Provided are methods for preparing a water soluble prodrug compound.

Preferably, the water-soluble prodrug compound is a compound of Formula 1a, which may be prepared by reacting paclitaxel or a derivative thereof having a 2′-hydroxy protecting group with a compound of Formula 2 and deprotecting.

[Formula 1a]

Wherein R ', m and n are as defined above, respectively.

In addition, the water-soluble prodrug compound is a compound of Formula 1b, which may be prepared by directly reacting paclitaxel or a derivative thereof with a self-immolating linker compound of Formula 2 in the presence of a base and an organic solvent.

[Formula 1b]

Wherein R ', m, and n are as defined above, respectively.

In another aspect, the present invention provides a pharmaceutical composition comprising a water-soluble prodrug compound represented by the formula (1) comprising a residue of paclitaxel or a derivative thereof as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel self-immolating linker capable of spontaneously degrading between paclitaxel and a water-soluble polymer, a method for preparing the same, and a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof, and a method for preparing the same. It is to provide a pharmaceutical composition comprising.

According to the present invention, a water-soluble prodrug compound comprising a residue of paclitaxel or a derivative thereof, which has improved manufacturing process and commercial yield can be combined with paclitaxel and a water-soluble polymer, and a pharmaceutical composition comprising the same can be provided. have.

Referring to the preparation method of the water-soluble prodrug compound of Formula 1 of the present invention in more detail as follows.

The water-soluble prodrug compound of Chemical Formula 1 of the present invention was prepared by introducing a new self-immolating linker of Chemical Formula 2, which can be spontaneously decomposed between paclitaxel and the water-soluble polymer, and then bonded to the water-soluble polymer.

[Formula 2]

Wherein R ', X, m and n are as defined above, respectively.

The self-immolating linker compound of Chemical Formula 2 is prepared by reacting a polyethylene glycol derivative of Chemical Formula 5 with a compound of Chemical Formula 4 in the presence of an organic solvent and a base to produce a compound of Chemical Formula 3, and then halogenating the compound. It is prepared to include.

[Formula 3]

[Formula 4]

[Formula 5]

Wherein R, R ', X, m and n are as defined above, respectively.

The compound of Formula 3 is prepared by the reaction in the solvent of benzene, toluene, or chlorobenzene by introducing a new intermediate binder. In this case, the amount of the compound of Formula 4 is preferably used in 1 to 3 equivalents based on 1 equivalent of the compound of Formula 5. If the amount of the compound of Formula 4 is less than 1 equivalent, the reaction is not completed. If it exceeds 3 equivalents, an undesirable side reaction may occur, which is not preferable. As the bases, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. may be used, and the amount thereof is preferably 1 to 5 equivalents based on 1 equivalent of the compound of Formula 5.

In addition, a solvent such as chloroform, methylene chloride or carbon tetrachloride may be used as the solvent used in the halogenation reaction. As the halogenating agent, thionyl chloride (SOCl ₂ ), postincrebromide, and the like may be used. Preferably, thionyl chloride is used. The amount of the halogenating agent is preferably used in 1 to 3 equivalents based on 1 equivalent of the compound of Formula 3.

For example, the reaction scheme for preparing the intermediate binder compound of Chemical Formula 2 according to the present invention is shown in Scheme 1 below.

Scheme 1

Wherein R ', m and n are as defined above, respectively.

In addition, the present invention prepares a water-soluble prodrug compound of formula (I) comprising paclitaxel or a residue thereof using the intermediate binder compound of formula (II) prepared above.

The present invention may be prepared by reacting paclitaxel or a derivative thereof with an intermediate binder compound of Formula 2 to produce a water-soluble prodrug compound of Formula 1. In this case, the water-soluble prodrug compound of Formula 1a or Formula 1b may be prepared according to protection of the hydroxyl group at the 2 ′ position or the 7 position of paclitaxel or a derivative thereof.

[Formula 1a]

[Formula 1b]

Wherein R ', m and n are as defined above, respectively.

The present invention is prepared by reacting paclitaxel or a derivative thereof with a silylating agent to prepare a compound protecting a 2′-hydroxy group, and reacting it with an intermediate binder compound of Formula 2 in the presence of a base and a solvent to prepare the compound of Formula 1a. Can be.

In addition, the compound of Formula 1b may be prepared by directly reacting paclitaxel or a derivative thereof with a compound of Formula 2 in the presence of an organic solvent and a base.

At this time, a solvent such as chloroform, methylene chloride, carbon tetrachloride and the like may be used, and as the base, N, N-diisopropyl ethylamine, triethylamine or pyridine may be used. The amount of the compound of Formula 2 is preferably 1 to 3 equivalents based on 1 equivalent of paclitaxel or a derivative thereof. It is preferable that the usage-amount of the said base is 1-3 equivalents with respect to 1 equivalent of paclitaxel or its derivative (s).

In the present invention, the derivative of paclitaxel of the prodrug compound is preferably dodetaxel.

For example, the reaction scheme of preparing the water-soluble prodrug compound of Chemical Formula 1 according to the present invention is shown in Scheme 2 and Scheme 3.

Scheme 2

Scheme 3

Wherein R ', m and n are each as defined above and Pt is a silyl protecting group.

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, the water-soluble prodrug compound of the formula (1) of the present invention can be used as an active ingredient in the pharmaceutical composition used for breast cancer, ovarian cancer, lung cancer and Kaposi tumor chiyoyo purposes. 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 Monomethoxy Polyethylene Glycol-5000-Succinylmethyl Ethyl Carbonate

Monomethoxy polyethyleneglycol-5000-succinic acid (5 g, 1 mmole) was dissolved in 100 ml of benzene and azeotropic reflux for 10 hours to remove moisture. Tert-butylchloromethyl carbonate (0.166 g, 1.2 mmole) and 1 M potassium tert-butoxide (1.2 mL, 1.2 mmole) were added thereto, the mixture was cooled to reflux for 1 hour, and then stirred at room temperature for 18 hours. Insolubles in this mixture were removed by filtration through celite and the solvent was removed by distillation under reduced pressure. The obtained residue was recrystallized with a mixed solvent of methylene chloride and isopropyl ether to obtain 4.73 g (yield: 92.2%) of monomethoxy polyethylene glycol-5000-succinylmethyl ethyl carbonate. ¹³ C NMR (75 MHz, CDCl ₃ ): δ 170.9 (C = O), 152.1 (OC (= 0) -O), 77.1 ((CH ₃ ) ₃ -C)

Example 2

(Synthesis of Monomethoxy Polyethylene Glycol-5000-Succinylmethyloxycarbonylchloride)

Monomethoxy polyethyleneglycol-5000-succinylmethyl tert-butyl carbonate (5.1 g, 1 mmole) was dissolved in 100 ml of methylene chloride and the reaction temperature was lowered to 0 ° C. under ice cooling. A solution of 0.24 (2 mmole) of thionyl chloride diluted in 10 mL of methylene chlorite was slowly added to the reaction solution so that the reaction temperature did not exceed 5 ° C. The reaction was terminated after stirring at the same temperature for 5 hours. The reaction product was distilled under reduced pressure to remove residual thionyl chloride and the reaction solvent and dried under reduced pressure to obtain 5.0 g (yield: 98.2%) of monomethoxy polyethylene glycol-5000-succinylmethyloxycarbonyl chloride.

Example 3

(Synthesis of 7-monomethoxypolyethylene glycol 5000-succinyloxymethyloxycarbonyl-2'-tert-butyldimethylsilyl paclitaxel)

968 mg (1 mmole) of 2'-tert-butyl dimethyl silyl paclitaxel and 7.65 g (1.5 mmole) of monomethoxypolyethylene glycol 5000-succinyloxymethyloxycarbonylchloride were dissolved in 50 mL of methylene chloride. After cooling the reaction temperature to 0 ° C. under ice-cooling, 0.119 g (1.5 mmole) of pyridine was diluted in 5 mL of methylene chloride and slowly added dropwise thereto. Stirred at the same temperature for 1 hour and stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was washed twice with 5% aqueous hydrochloric acid solution and once with saturated NaHCO ₃ solution. After drying over anhydrous magnesium sulfate and distillation under reduced pressure, 5.4 g (yield: 89.6%) of 7-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-2'-tert-butyl dimethylsilyl paclitaxel was obtained. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.97 (d, 1H, J = 6.47 Hz, OCOOC H ₂ Cl), 5.51 (d, 1H, J = 6.40 Hz, OCOOC H ₂ Cl), 3.92 (d, 1H , J = 6.77 Hz, 7-H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 154.83 (O C OOCH ₂ Cl)

Example 4

(Synthesis of 7-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-paclitaxel)

6.0 g (1 mmole) of 7-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-2'-tert-butyl dimethylsilyl paclitaxel was dissolved in 10 mL of acetonitrile. 10 mL of 1% hydrofluoric acid dissolved in acetonitrile was mixed into the solution. The mixture was stirred for 30 minutes and then the acetonitrile was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of diethyl ether, washed with saturated sodium bicarbonate solution and distilled water, and treated with anhydrous magnesium sulfate to remove the contained water, and then dried under reduced pressure to obtain a solid. The solid was obtained by preparative high performance chromatography (Prep. HPLC) to obtain 5.91 g (yield: 98.5%) of pure 7-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-paclitaxel. ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.39-3.38 (m, mPEG), 5.88 (d, 1H, J = 5.85 Hz, OCOOC H ₂ O), 5.71 (d, 1H, J = 5.85 Hz, OCOOC H ₂ O)

Example 5

(Synthesis of 2′-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-paclitaxel)

854 mg (1 mmole) of paclitaxel and 7.65 g (1.5 mmole) of 7-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonylchloride were dissolved in 50 mL of methylene chloride. Dilute in 5 mL of methylene chloride under ice-cooling and slowly add dropwise. Stirred at the same temperature for 1 hour and stirred at room temperature for 12 hours. Upon completion of the reaction, the mixture was washed twice with 5 aqueous hydrochloric acid solution and once with saturated NaHCO ₃ solution. It was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain a solid. The solid was purified by preparative high performance chromatography (Prep. HPLC) to obtain 5.5 g (yield: 91.7%) of pure 2'-monomethoxypolyethyleneglycol 5000-succinyloxymethyloxycarbonyl-paclitaxel. MS (MALDI) / TOF) m / z 5996 (ave. M. Wt.); ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.22-3.37 (m, mPEG), 5.77 (m, 2H, OCOOC H ₂ O), 5.46 (s, 1H, 2′-H)

As described in detail above, according to the present invention, the water-soluble prodrug compound can be mass-produced in a large amount by using a water-soluble polymer and a spontaneously decomposable intermediate binder compound, which is easy to manufacture and economical. In addition, 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 its derivatives having a physiological activity is very fast and very soluble in water, the drug comprising the same The composition can be used as a useful anticancer agent.

Claims (11)

Self-immolating linker compound represented by the following formula (2) capable of spontaneous decomposition with a water-soluble polymer: [Formula 2] Wherein R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460. Reacting a polyethylene glycol derivative of Formula 5 with a compound of Formula 4 in the presence of an organic solvent and a base to prepare a compound of Formula 3, and halogenating the compound of Formula 3 Method for preparing a self-immolating linker compound represented by the following formula (2) comprising: [Formula 2] [Formula 3] [Formula 4] [Formula 5] Wherein R is an alkyl or alkoxy group having 1 to 7 carbon atoms; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460. A water-soluble prodrug compound represented by the following formula (1) comprising a residue of paclitaxel or a derivative thereof: [Formula 1] Where D is a residue of paclitaxel or a derivative thereof having hydroxy at the 2 'or 7 position; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460. The water-soluble prodrug compound of claim 3, wherein the prodrug compound is a compound of Formula 1a: [Formula 1a] The water-soluble prodrug compound of claim 3, wherein the prodrug compound is a compound of Formula 1b: [Formula 1b] The water-soluble prodrug compound according to claim 3, wherein the paclitaxel derivative is dodetaxel. Reacting paclitaxel or a derivative thereof with a self-immolating linker compound represented by the following Chemical Formula 2 under a base and an organic solvent: Method for preparing a water-soluble prodrug compound represented by the formula (1) comprising a residue of paclitaxel or a derivative thereof comprising: [Formula 1] [Formula 2] Where D is a residue of paclitaxel or a derivative thereof having hydroxy at the 2 'or 7 position; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460. The method of claim 7, wherein the water-soluble prodrug compound is a water-soluble prodrug compound of Formula 1a, wherein the water-soluble prodrug compound of Formula 1a is paclitaxel or a derivative thereof having a 2'-hydroxy protecting group and the compound of Formula 2 Method for preparing a water-soluble prodrug compound which is prepared by reacting and deprotecting: [Formula 1a] Where R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; m is an integer from 1 to 3; n is an integer from 10 to 460. The method according to claim 7, wherein the water-soluble prodrug compound is a compound of Formula 1b, wherein the compound of Formula 1b is paclitaxel or derivatives thereof in the presence of a base and an organic solvent and the self-immolating linker compound of Formula 2 Method for preparing a water-soluble prodrug compound that is prepared by direct reaction: [Formula 1b] Where R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; m is an integer from 1 to 3; n is an integer from 10 to 460. 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 D is a residue of paclitaxel or a derivative thereof having hydroxy at the 2 'or 7 position; R 'is hydrogen or an alkyl group having 1 to 5 carbon atoms; X is a halogen atom; m is an integer from 1 to 3; n is an integer from 10 to 460. The pharmaceutical composition of claim 10, wherein the paclitaxel derivative is dodetaxel.