KR20130035540A - Glycosylated taxel compounds derivatives - Google Patents

Abstract

The present invention relates to a technique of attaching a sugar to a taxel compound structure to form a taxel compound derivative having a novel structure, and a glycosylated derivative synthesized by the technique, wherein water solubility is improved up to 25 times or more, and the linker or sugar chain is decomposed in vivo. The anticancer function of the taxel compound can be exerted.

Description

Glycosylated Taxel compounds derivatives

The present invention relates to a technique of attaching a sugar to a taxel compound structure to form a taxel compound derivative having a novel structure, and a glycosylated derivative synthesized by the technique, wherein water solubility is improved up to 25 times or more, and the linker or sugar chain is decomposed in vivo. To maintain or improve the anticancer capacity of the Taxel compound.

About 70% of the leading drugs currently being developed are estimated to be derived from natural products, the majority of which are sugar modified (Poiter, P. Actual. Chim. 11: 9, 1999).

The attachment of sugars has a great effect on the regulation of the absorption, distribution, metabolism or excretion of the drug. Depending on the type and number of sugars, the affinity for the target can also vary greatly.

Docetaxel (docetaxel, used herein as "DTX") is an anticancer agent that acts on breast cancer, ovarian cancer, non-small cell lung cancer, etc., and is a semisynthetic compound by chemically binding side branches to taxol skeletons extracted from yeast. Docetaxel is produced by Sanofi-Aventis under the trade name Taxtere and is sold worldwide. The world market is about $ 2 billion, and the market of paclitaxel is about $ 1.3 billion.

Docetaxel differs from paclitaxel in two respects in chemical properties. Paclitaxel has an acetate ester at the carbon position 10, while docetaxel has a hydroxyl group and a quaternary butyl-substituted group is substituted on the side of phenylpropionate. . The water solubility of docetaxel is somewhat higher than that of paclitaxel due to the hydroxyl group at the carbon 10 position. Therefore, the development of prodrugs with increased water solubility is expected to be very marketable. The domestic market of Docetaxel was KRW 35 billion in 2007, and the market is growing rapidly.

Docetaxel, an anticancer agent, has low water solubility due to its structural properties. Therefore, in order to achieve sufficient efficacy in the body, an excessive amount of drug must be administered, so side effects follow. Alternatively, special delivery systems may be introduced to improve docetaxel solubility.

In addition, docetaxel has a problem in that an effective concentration capable of reaching a cancer-generating site or an organ transplantation site and exerting a drug because the drug introduced into the body circulates the whole body through the blood flow is very low.

In order to remedy this problem, studies have attempted to combine a structure that can impart water solubility to poorly soluble drugs to improve water solubility or to combine targeting materials capable of inducing the drug to the site of disease occurrence. It is becoming.

The present invention is intended to combine sugar structures, such as glucose and sialic acid, which can increase the water solubility for the purpose of improving the water solubility of the anti-cancer drug Taxel, a poorly soluble substance. It is intended to be produced in the form of prodrugs that are separated from the taxel and can take full advantage of the pharmacological properties of the original drug, Taxel.

Therefore, an object of this invention is to provide the method of improving the solubility of a taxel compound.

It is also an object of the present invention to provide a taxel compound derivative having high solubility and having similar or higher bioavailability as the taxel compound in vivo.

The present inventors have improved the solubility of the taxel compound and studied derivatives having similar or high bioavailability with the taxel compound, and modified the sugar to synthesize a taxel compound glycosylated derivative having a novel structure.

The present invention provides saccharified derivatives of taxel compounds having high solubility and various physiological activities, and more particularly, water solubility is improved, thereby providing a saccharified compound saccharified derivative having excellent body dynamics and safety. In addition, the present invention utilizes a method of incorporating a linker between the taxel compound and the sugar to overcome steric hindrance that interferes with attaching the sugar to the taxel compound.

Samples used in the present invention are taxel compounds, specifically docetaxel, paclitaxel and the like, more preferably docetaxel. The functional group for modifying the sugar in the taxel compound may include a hydroxyl group, a methyl group, preferably a hydroxyl group. For example, docetaxel may be a hydroxyl group at a 2-position, a 7-position, or a 10-position, and may be all three positions, or one of the three regions. Preferably it is a hydroxyl group in 2-position. In the present invention, a linker may be used to link sugars, and the linker may be linked using an ester or amide bond, and may be a formyl group, an acetyl group, or propionyl as a functional group. ), Butyl, acryl, ethylsuccinyl, succinyl, aminohexyl, etc. may be attached, preferably succinyl Can be used alone. The sugars to be attached may be monosaccharides, disaccharides, trisaccharides and polysaccharides, and the number of sugars to be attached is preferably 1-5. Each sugar may contain an ordinary sugar such as aldose or ketose, which is C3-C7. There is no particular limitation on the type of sugar, and preferably, the monosaccharide is glucose, galactose, fructose, fucose, mannose, rhamnose, galactosamine, glucosamine, N-acetylgalactosamine, N-acetylglucosamine, vancosamine, Epi-vancosamine, glucuronic acid, sialic acid, deoxyglucose, deoxygalactose, and more preferably glucose, monosaccharides, lactose, trisaccharides, sialylactose can be selected. .

As a method of attaching sugar, sugar may be attached to a linker and then a taxel compound such as docetaxel may be attached, or a linker may be attached to a taxel compound and a sugar may be attached to the linker. The linker-sugar complex may extend to disaccharides, trisaccharides after attaching monosaccharides to the linker, or to trisaccharides after attaching disaccharides to linkers. At this time, expansion to disaccharide and trisaccharide can be carried out by chemical reaction or enzymatic reaction. Examples of enzymatic reactions include galactosyltransferase for the transformation from glucose to lactose and sialyltransferase for the conversion from lactose to sialyllactose.

Hereinafter, some specific examples of the taxel glycated derivatives of the present invention will be described.

The present invention provides a taxel glycosylated derivative compound represented by the formula (I) made from a taxel compound as a raw material, a pharmaceutically acceptable salt thereof or solvate thereof.

(Wherein R1 is an acetyl group or H, R2 is a phenyl group or t-butyloxy group, R is a C1-C12 acid ester-bonded, or a C1-C12 acid is linked to an ester-linked linker of C3-C7 Sugars containing 1 to 5 aldose or ketose sugar chains)

In addition, the present invention provides a compound of (1) to (4) which is a compound having a linker attached thereto or a compound having a sugar moiety attached to the linker in addition to R of a taxel compound skeleton having the structure of Formula (I).

To illustrate a specific compound of the present invention, R1 is an acetyl group or H, R2 is a phenyl group or t-butyloxy group, and R is as follows.

(화합물 1);R =

(Compound 1);

(화합물 2);R =

(Compound 2);

(화합물 3);

(Compound 3);

(화합물 4).
R =

(Compound 4).

The present invention also provides an anticancer prodrug comprising the taxel derivative, a pharmaceutically acceptable salt thereof or a solvate thereof.

Moreover, this invention also provides the process shown to the following (5)-(9) by the manufacturing method of the compound illustrated to said (1)-(4).

(5) the following steps:

A step of introducing succinyl group into 1-OH position using glucose as a raw material and protecting group into other -OH group.

(R3 and R4 may be the same or different, and is a protecting group of the OH group in a conventional chemical synthesis that can be easily dissociated by treatment with an acid or a base, and converted to H, preferably MMTr (Monomethoxytrityl) or TMS Tetramethylsilane group, more preferably R3 and R4 are benzyl groups).

(6) the following steps:

Process of making compound 2 by adding compound 5 produced by process (5) to a taxel compound, and then removing R3 and R4 which are -OH protecting groups.

(In this case, when R1 is H, it may be a protecting group of a conventional chemical synthetic OH group which can be easily dissociated by treatment with an acid or a base and transformed into H, preferably Troc (2,2,2-Trichloroethyl chlorofomate). R3 and R4 may be the same as or different from each other, and may be a protecting group of a conventional chemical synthetic OH group which may be easily dissociated by treatment with an acid or a base, and may be transformed into H.

→

(R1 is an acetyl group or H, and R2 is a phenyl group (for paclitaxel) or t-butyloxy group (for docetaxel))

(7) the following process:

A step of synthesizing compound 3 by enzymatic method using galactosyltransferase of compound (2) prepared in step (6) above.

                           Compound 2

(R1 is an acetyl group or H, and R2 is a phenyl group (for paclitaxel) or t-butyloxy (for docetaxel))

(8) the following process:

Synthesizing Compound 4 by transferring sialic acid to Compound 3 prepared by the above step (7) by enzymatic method using sialyltransferase.

                  Compound 3

(R1 is an acetyl group or H and R2 is a phenyl group (for paclitaxel) or t-butyloxy (for docetaxel)

(9) the following steps:

The process of ester-bonding dicarboxylate to an OH group to a taxel compound.

X may be added to the taxel compound to provide a linker capable of ester linkage to the hydroxyl group. X is dicarboxylic acid or its anhydride, salts or solvates thereof, preferably oxalic acid, malonic acid, succinic acid, glutaric acid, Adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid (dodecanedioic acid), phthalic acid, isophthalic acid, terephthalic acid, maleic acid, maleic acid, fumaric acid, glutaconic acid, chromatic acid, traumatic acid ), Which is selected from muconic acid, and more preferably malonic acid, succinic acid, maleic acid, phthalic acid, glutaric acid, Adipic acid, pimelic acid, Mar acid (fumaric acid) or it is one selected from the group consisting of as its anhydride.

Wherein R1 is an acetyl group or H and R2 is a phenyl group (for paclitaxel) or t-butyloxy group (for docetaxel), and when R1 is H, it can be easily dissociated by treatment of acid or base to be transformed to H May be a protecting group of a conventional chemical synthetic OH group, preferably Troc, X is a diacetic acid group of C2-C12, preferably succinic anhydride)

The taxel glycated derivatives according to the present invention have improved water solubility up to 25 times or more, and the linker or sugar chain is degraded in vivo to maintain or improve the anticancer ability of the taxel compound.

1 shows the results of water solubility test of docetaxel and docetaxel glycosylated derivative compounds.
2A shows the results of rat in vivo conversion and pharmacokinetic evaluation of docetaxel glycosylated derivatives DTX-M2'-LS-Glc.
Figure 2b is the result of rat in vivo conversion and pharmacokinetic evaluation test of docetaxel glycosylated derivative DTX-M2'-LS-Lac.
Figure 2c is the result of rat in vivo conversion and pharmacokinetic evaluation test of docetaxel glycosylated derivative DTX-M2'-LS-SL.
Figure 2d is the result of rat in vivo conversion and pharmacokinetic evaluation test of docetaxel glycosylated derivative DTX-M2'-LS.

Hereinafter, the configuration of the present invention through examples and test examples in more detail.

However, it is apparent to those skilled in the art that the present invention is not limited to the scope of the Examples and Test Examples. The examples described specifically describe the preparation of saccharified derivatives of docetaxel (DTX) in the taxel compounds, but it is apparent to those skilled in the art that other taxel compounds may be prepared in the same manner. Do.

In the examples, the following abbreviations are used.

DTX: Docetaxel

MMTr-Cl; Monomethoxytrityl chloride

MC; Methylene Chloride

TEA; Triethylamine

DMAP; 4-Dimethylaminopyridine

TMS; Tetramethylsilane

CMP; Cytidine 5 'monophosphate

DCC; N, N-dicyclohexylcarbodiimide

Et3N; Triethylamine

Hex; Hexane

EA; Ethylacetate

Troc; 2,2,2-Trichloroethyl chlorofomate

MeOH: Methanol

EtOH: Ethanol

The structures, names, and molecular weights of the compounds 1 to 4 of the present invention are shown in Table 1.

Example rescue designation mass
(MW) Measured value One

DTX-M2'-LS
(One) C ₄₇ H ₅₇ NO _17
907.97
929
[M + Na] ⁺ 2

DTX-M2'-LS-Glc
(2) C ₅₃ H ₆₇ NO ₂₂
1070.
11 1092.2
[M + Na] ⁺ 3

DTX-M2'-LS-Lac
(3) C ₅₉ H ₇₇ NO ₂₇
1232.
25 1254.5
[M + Na] ⁺ 4

DTX-M2'-LS-SL
(4) C ₇₀ H ₉₄ N ₂ O ₃₅
1523.
51 1521.3
[M-2H] ^2-

Example 1, Example 2, Example 3, and Example 4 exemplify methods for producing the compound by one method for producing these compounds. Compounds 1 to 4 may be prepared by other methods in addition to the methods of Examples 1 to 4 will be apparent to those skilled in the art.

≪ Example 1 >

Example 1 is a description of the preparation of compound 1.

First Step: Intermediate Compound 27,10- ditroc - DTX Synthesis of

1 g of 7,10-ditroc-DTX was dissolved in 10 ml of anhydrous methylene chloride, and 0.24 ml of triethyleneamine was added thereto and stirred. 21 mg of DMAP and 95 mg of succinic anhydride were added and stirred for 1 hour. After confirming the thin layer chromatography with MC: MeOH (95: 5), the reaction solution was washed with 0.5 M citric acid solution. After filling the silica column with MC, MC: MeOH (98: 2) (95: 5) mixture solution was developed in order to obtain 1.16 g of the intermediate of Compound 1 (107%).

Second Step: Compound (1) DTX - M2 ' - LS  (2 DTX ) Synthesis of

1.16 g of 2-succinyl 7,10-ditroc-DTX of the first step was added to 12 ml of MeOH: acetic acid (9: 1), and the inlet was closed with a rubber stopper, and stirred for about 15 minutes at room temperature to be sufficiently dissolved. 580mg of powdered zinc was added and stirred at room temperature for 1 hour. When the reaction was completed by thin layer chromatography analysis, Celite was placed on the glass filter, zinc was filtered off, and the filtrate was concentrated using a rotary evaporator. After dissolving with 200 ml of ethyl acetate, 200 ml of distilled water was added and the ethyl acetate layer was concentrated. The silica column was packed with methylene chloride (MC) and then developed with MC: MeOH (95: 5) to obtain 0.68 g of Compound (1) DTX-M2'-LS (80%).

<Example 2>

Example 2 is a description of the preparation of compound 2. The following steps will be explained separately.

First Step: Intermediate Compounds 2,3,4,6- Tetra  Benzyl-1-o- methyl  Synthesis of Glucose

Methyl glucose (50 g), powdered KOH (250 g), and dioxane (dioxane) (184 ml) were added thereto, followed by stirring. Benzyl chloride (84 ml) was added slowly while raising the temperature from room temperature to 120 ° C. for 40 minutes in an oil bath. Benzyl chloride (166ml) was slowly added while refluxing for 1 hour 30 minutes. After filtration, the filtrate was concentrated at a temperature of 30 ~ 70 ℃ using an evaporator. Normal hexane (n-Hexane): EtOAc was sequentially developed in a silica column (12 × 42 cm) to 15: 1, 4: 1, 2: 1 to give 146 g of an oily intermediate compound (101.4%).

Second Step: Intermediate Compounds 2,3,4,6- Tetra  Benzyl Glucose Synthesis

146 g of the oily intermediate compound obtained in the first step was dissolved in 1029 ml of acetic acid and 485 ml of 2M H ₂ SO ₄ . It stirred for 3 hours at 110-120 degreeC in the oil bath. The reaction vessel was removed from the oil bath and stirred at room temperature for 3 hours. As the temperature lowered, the compound precipitated. 764 ml of water was added thereto, and the reaction solution was filtered, and the filtered precipitate was dissolved in methylene chloride and washed with water. The organic layer was concentrated to give 121 g intermediate compound (85.2%).

Third Step: Intermediate Compound 2,3,4,6- Tetra  Benzyl 1-O- Succinyl  Glucose synthesis

121 g of the second step was dissolved in 1200 ml of methylene chloride anhydride. 45.3 g of dried triethyleneamine, 5.47 g of DMAP, and 24.6 g of succinic anhydride were added thereto, followed by stirring at room temperature for 1 hour 30 minutes. The reaction solution was washed with 0.5M citric acid and the organic layer was concentrated. A silica column (12 × 42 cm) was developed sequentially with methylene chloride: MeOH 50: 1, 30: 1 to give 75.5 g of compound 5 (52.8%).

Fourth Step: Intermediate Compound 2′-Glucose (2,3,4,6- Tetra  Benzyl) -7,10- ditroc Synthesis of DTX

5.10 g of 7,10-Ditrox-DTX was added to the round flask, and the mouth was closed with a rubber stopper, and 60 ml of anhydrous methylene chloride was added thereto. 0.7 g of 4-dimethylaminopyridine and 1.2 g of N, N-dicyclohexylcarbodiimide were added thereto, and the resultant was sufficiently dissolved by stirring at room temperature for about 15 minutes. 4.5 g of 2,3,4,6-tetra benzyl 1-O-succinyl glucose was added thereto, followed by stirring at room temperature for 1 to 2 hours. After confirming the reaction termination by thin layer chromatography analysis, the precipitate was filtered off. 190 ml of methylene chloride was added to the reaction solution, and the mixture was partitioned into 250 ml of 10% citric acid aqueous solution. The methylene chloride layer (lower layer solution) was separated and concentrated. After filling with a silica column (5 × 23 cm), it was developed with a solvent of n-Hex: EA (4: 1 ~ 2: 1) to give 6.95 g of intermediate compound (82.5%).

Fifth Process: Compound 2 DTX - M2 ' - LS - Glc Synthesis of

1) In a round flask, add 6 ml of 2'-glucose (2,3,4,6-tetrabenzyl) -7,10-ditroc-DTX) in the fourth step, MeOH: acetic acid (9: 1), and add 70 ml of inlet. After sealing with a rubber stopper, the solution was sufficiently dissolved by stirring at room temperature for about 15 minutes. 3.5 g of powdered zinc was added and stirred at room temperature for 1 to 2 hours. When the reaction was completed by thin layer chromatography analysis, a celite was placed on the glass filter, zinc was filtered off, and the filtrate was concentrated using a rotary evaporator. After dissolving with 500 ml of methylene chloride, 500 ml of distilled water was added, and the methylene chloride layer (lower layer solution) was concentrated. The silica column (5 × 20 cm) was packed with methylene chloride and then developed with methylene chloride: MeOH (98: 2) to give 4.3 g of intermediate compound (77%).

2) 6.6 g of 2'-glucose (Bn) -DTX) and 100 ml of MeOH were added to a round flask and stirred until it was sufficiently dissolved. 70 ml of 50% acetic acid was added slowly with stirring. 6.6 g of palladium on activated carbon of 10% by weight was added. Stirring at room temperature overnight while slowly adding hydrogen gas. After completion of the reaction by analysis by thin layer chromatography (developing solvent methylene chloride: MeOH 5: 1), a celite was placed on a glass filter and the reaction solution was filtered and concentrated by a rotary evaporator. The silica column (8 × 24 cm) was packed with methylene chloride and then developed with methylene chloride: MeOH (10: 1) and (5: 1) to give 2.2 g of compound 2 (53%). Prep LC purification was performed to increase the purity.

<Example 3>

Example 3 is a description regarding the preparation of compound 3.

Compound (2), DTX-M2 'using beta1,4-galactosyltransferase (LgtB) to transfer galactose to glucose position 4 of DTX-M2'-LS-Glc -LS-Lac was synthesized.

4.4 g of MgCl ₂ 6H ₂ O, 13 g of UDP-D-galactose and Tris HCl buffer (pH 7.5) were added to 25-50 mM. 4.8 g of the reaction starting material, DTX-M2'-LS-Glc, was dissolved in 0.2 L of DMSO and slowly mixed into the reactor. After adjusting the volume to 1.1 L with distilled water, beta 1,4-galactosyltransferase was added to initiate the reaction. The reaction conditions were maintained at pH 6.5 and 37 ℃, and the degree of conversion was confirmed through HPLC analysis to terminate the reaction at a conversion rate of about 90%.

The reaction solution (4.8 g, volume about 1.1 L) was partitioned twice into equal amounts of ethyleneamine to recover DTX-M2'-LS-Lac present in the reaction solution and concentrated. The silica column (7 × 23 cm) was filled with methylene chloride and developed with methylene chloride: MeOH (10: 1), (8: 1), (5: 1) to form white form of DTX-M2'-LS-Lac, compound 3 2.17 g (40%) was obtained.

<Example 4>

Example 4 is a description of the preparation of compound 4.

Compound 3 prepared in Example 3, ie, alpha 2,3-sialyltransferase (SialT), which transfers sialic acid to galactose of DTX-M2'-LS-Lac Thus, DTX-M2'-LS-SL, which is Compound 4, to which sialic acid was added, was synthesized from the DTX-M2'-LS-Lac and the CMP-sialic acid precursor.

9.84 g of MgCl ₂ 6H ₂ O, 45.7 g of CMP-sialic acid and Tris HCl buffer (pH 7.5) were added to 25-50 mM. Approximately 21 g of the reaction starting material, DTX-M2'-LS-Lac, was dissolved in 0.6 L of DMSO well and placed in a reactor to adjust the volume to 2.46 L with distilled water. Alpha 2,3-sialyltransferase was added to the opaque reaction solution to start the reaction, and the reaction proceeded at room temperature. PH 8.2 was maintained, and the degree of conversion was confirmed by HPLC analysis. When the conversion was about 90%, the same amount of MeOH was added to terminate the reaction. The reaction solution was centrifuged and filtered to remove the precipitate, and the upper layer was concentrated. During the concentration process, the same amount of MeOH was added to remove precipitates and concentrated using a rotary evaporator. The silica column (8x40 cm) was packed with methylene chloride and developed with MC: MeOH (8: 1), (5: 1), (3: 1), (1: 1) to give a white DTX-M2'-LS-SL 10.2g of compound 3 was obtained (40%).

In order to increase the purity was further purified using Prep-HPLC. In addition, the purification was performed with a change in time with a buffer (A), purified water; (B), acetonitrile in a reverse phase column (50 x 500 mm) for high purity purification. Drying under reduced pressure drying and lyophilization was performed for final recovery.

Analysis Example 1 Analysis of Solubility of Docetaxel Derivatives

For solubility measurements and comparisons in aqueous solutions of docetaxel derivatives, calibration curves were prepared for region (A) of HPLC (UV) to weight of docetaxel standard and confirmed relative water solubility. Each sample was dissolved in a certain amount of distilled water in a supersaturated state and left for 30 minutes in a constant temperature water bath at 37 ° C. The supernatant was analyzed by HPLC analysis to obtain an area (A) of the peak appearing at a UV wavelength of 260 nm. The amount of the compound was obtained. As a result, when comparing docetaxel solubility to 1, Compound 1 (DTX-M2'-LS) was 1.03, Compound 2 (DTX-M2'-LS-Glc) was 3.06, and Compound 3 (DTX-M2'-LS-Lac). ), Solubility was 5.39, and compound 4 (DTX-M2'-LS-SL) was 25.49.

Analysis Example 2 In Vitro Conversion and Pharmacokinetic Evaluation of Docetaxel

end. In rats  Compound 2 ( DTX - M2 ' - LS - Glc )of Pharmacokinetics

Plasma over time of DTX-M2'-LS-Glc and docetaxel for 24 hours after intravenous or oral single administration (6.22 mg / kg, n = 3) of DTX-M2'-LS-Glc to male SD rats The pharmacokinetic parameters were determined by measuring the change in concentration and performing a non-compartmental analysis of the experimental results.

The intravenous administration of DTX-M2'-LS-Glc at a dose of 6.22 mg / kg disappeared very rapidly in the body and was not detected beyond the quantitative limit in plasma 30 minutes after administration. Docetaxel, on the other hand, was continuously detected from 5 minutes to 24 hours of total time, with the highest plasma concentration at the first sampling time point, followed by a pattern of multi-exponential decay. It is believed that the conversion of prodrugs to docetaxel is completed very quickly in the body as it decreases. In addition, changes in plasma concentration over time of docetaxel produced after administration of DTX-M2'-LS-Glc are assumed to follow elimination rate-limited metabolite kinetics.

There was not enough plasma concentration data for DTX-M2'-LS-Glc to obtain the pharmacokinetic parameters of the prodrug itself. The apparent terminal half-life of the resulting docetaxel was approximately similar to that when docetaxel itself was administered at 11.9 hours.

Changes in plasma concentrations of docetaxel produced after intravenous administration of DTX-M2'-LS-Glc showed a generally similar trend over the entire time compared to the results obtained after intravenous administration of docetaxel itself, resulting in terminal half-life. ) Were generally similar. As a result, the bioavailability (BA) was 124%, indicating that the administered prodrug was converted to docetaxel almost quantitatively in the body.

I. In rats  Compound 3 ( DTX - M2 ' - LS - Lac )of Pharmacokinetics

Plasma concentrations of DTX-M2'-LS-Lac and docetaxel over 24 hours after single injection of DTX-M2'-LS-Lac into male SD rats intravenously (7.63 mg / kg, n = 3). Pharmacokinetic parameters were obtained by measuring changes and performing noncompartmental analysis of the experimental results.

When intravenous DTX-M2'-LS-Lac was administered at a dose of 7.63 mg / kg, the concentration was detected above the quantitative limit in plasma up to 2 hours after administration, and the change in plasma concentration over time was multi-compartmental disposition. ) Is shown. Docetaxel was continuously detected in plasma from 5 minutes after the initial sampling and showed a characteristic of multi-exponential decay almost parallel to DTX-M2'-LS-Lac. Thus, DTX-M2'-LS-Lac appears to be rapidly converted to docetaxel upon intravenous administration, and the plasma kinetics of the resulting docetaxel is found to be dependent on the change in concentration of DTX-M2'-LS-Lac. It appears to be characterized by the formation rate-limited metabolite kinetics.

DTX-M2'-LS-Lac showed a systemic clearance of 1.4 l / hr / kg, which is significantly lower than docetaxel. Steady-state volume of distribution is 0.3 l / kg, which is significantly lower than total body water, making it difficult to distribute outside of blood vessels. It seems to be due to the increase. The apparent terminal half-life was 0.2 hours for prodrug DTX-M2'-LS-Lac and the resulting docetaxel was relatively short at 2.4 hours.

Plasma concentrations of docetaxel produced after administration of DTX-M2'-LS-Lac were significantly decreased from 30 minutes after administration, compared with the results obtained after intravenous administration of docetaxel itself. As a result, the bioavailability (BA) was as low as 48%, indicating that the administered prodrug DTX-M2'-LS-Lac could not be converted quantitatively into docetaxel in the body.

All. In rats  Compound 4 ( DTX - M2 ' - LS - SL )of Pharmacokinetics

Changes in plasma concentrations with time of DTX-M2'-LS-SL and docetaxel for 24 hours after a single intravenous injection of DTX-M2'-LS-SL in male SD rats (9.43 mg / kg, n = 3) Pharmacokinetic parameters were determined by non-compartmental analysis of experimental results.

Plasma concentration changes of docetaxel produced after intravenous administration of DTX-M2'-LS-SL showed a tendency to decrease significantly after 2 hours of administration compared to the results obtained after intravenous administration of docetaxel itself. As a result, the bioavailability (BA) was as low as 53%.

la. In rats  Compound 1 ( DTX - M2 ' - LS )of Pharmacokinetics

Plasma concentration change over time of DTX-M2'-LS and docetaxel for 24 hours after a single intravenous injection of DTX-M2'-LS into male SD rats (5.62 mg / kg, n = 3), Pharmacokinetic parameters were obtained by noncompartmental analysis of the experimental results.

When intravenously administered DTX-M2'-LS at a dose of 5.62 mg / kg, it was detected at a concentration above the quantitative limit in plasma up to 1 hour after administration. Docetaxel was consistently detected at concentrations above the limit in plasma from 5 minutes to 8 hours at the time of initial sampling.

DTX-M2'-LS showed a systematic removal rate of 3.2 l / hr / kg, which was lower than docetaxel but higher than prodrug with sugar moiety. The steady-state volume of distribution was 0.5 l / kg, similar to the total body fluid. The apparent terminal half-life was short for 0.1 h for prodrug DTX-M2'-LS but relatively longer for docetaxel produced for 6.6 h.

Plasma concentrations of docetaxel produced after administration of DTX-M2'-LS were significantly higher up to 1 hour after administration compared to the results obtained after intravenous administration of docetaxel itself, but thereafter showed a similar tendency in the whole time. The bioavailability (BA) was 240%, more than twice the theoretically possible figure.

Claims (10)

Taxel derivatives, pharmaceutically acceptable salts or solvates thereof, prepared from taxel and represented by the following formula (1).
&Lt; Formula 1 >

(Wherein R1 is an acetyl group or H, R2 is a phenyl group or t-butyloxy group, R is a C1-C12 acid ester-bonded, or a C1-C12 acid is linked to an ester-linked linker of C3-C7 Sugars containing 1 to 5 aldose or ketose sugar chains)
The method of claim 1,
Said taxel is a docetaxel or paclitaxel, a taxel derivative, a pharmaceutically acceptable salt or solvate thereof.
The method of claim 1,
The linker may be a formyl group, an acetyl group, a propionyl group, a butyl group, an acryl group, an ethylsuccinyl group, a succinyl group, or Taxel derivatives, pharmaceutically acceptable salts or solvates thereof, characterized in that they comprise aminohexyl groups.
The method of claim 1,
The sugars are glucose, galactose, fructose, fucose, mannose, rhamnose, galactosamine, glucosamine, N-acetylgalactosamine, N-acetylglucosamine, vancosamine, epi-vancosamine, glucuronic acid, sialic A taxel derivative, a pharmaceutically acceptable salt thereof, or a solvate thereof, characterized in that the monosaccharide, disaccharide, or polysaccharide is at least one selected from the group of monosaccharides including acid, deoxyglucose and deoxygalactose.
The method of claim 1,
In the taxel derivative, R ₁ is an acetyl group or H, R ₂ is a phenyl group or t-butyloxy group, R is
(1) R =

,
(2) R =

,
(3) R =

And
(4) R =

Taxel derivatives, pharmaceutically acceptable salts thereof or solvates thereof, characterized in that one selected.
An anticancer prodrug comprising the taxel derivative of any one of claims 1-5, a pharmaceutically acceptable salt thereof or a solvate thereof.
(a) introducing succinyl group into 1-OH position using glucose as a raw material and introducing a protecting group to other -OH groups;

(R3 and R4 may be the same or different, and is a protecting group of the OH group in a conventional chemical synthesis that can be easily dissociated by treatment with an acid or a base, and converted to H, preferably MMTr (Monomethoxytrityl) or TMS (Tetramethylsilane) group, more preferably R3 and R4 are benzyl groups)
(b) adding the compound 5 to the taxel compound, and then removing R 3 and R 4, which are -OH protecting groups, to form Compound 2 represented by the following Formula 2; a taxel derivative, a pharmaceutically acceptable salt thereof, or a solvent thereof How to manufacture a cargo.
(2)

(In Formula 2, R ₁ is an acetyl group or H, R ₂ is a phenyl group or t-butyloxy group)
A method for preparing a taxel derivative represented by Formula 3 below, a pharmaceutically acceptable salt thereof, or a solvate thereof using UDP-D-galactose and galactosyl transferase in Compound 2 represented by Formula 2.
(3)

(In Formula 3, R ₁ is an acetyl group or H, R ₂ is a phenyl group or t-butyloxy group)
A method of preparing a taxel derivative represented by the following formula (4), a pharmaceutically acceptable salt thereof, or a solvate thereof using sialic acid and sialyl transferase in the compound 3 represented by the formula (3) of claim 8.
&Lt; Formula 4 >

(In Formula 4, R ₁ is an acetyl group or H, R ₂ is a phenyl group or t-butyloxy group)
A process for esterifying a dicarboxylate to a 2-position hydroxyl group of a taxel compound to prepare a taxel derivative represented by the following formula (5), a pharmaceutically acceptable salt thereof, or a solvate thereof.
&Lt; Formula 5 >

(In Formula 5, R ₁ is an acetyl group or H, R ₂ is a phenyl group or t-butyloxy group)

Images