JP2012116821A - Paclitaxel derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a paclitaxel derivative which not only exhibits high water solubility but also retains an outstanding anti-cancer activity, and to provide a medicine formed of the paclitaxel derivative and an anticancer agent including the paclitaxel derivative.SOLUTION: The paclitaxel derivative is represented by general formula (I) (in formula, X represents a linker group, Y represents a bonding group for bonding 2pieces of glycerol derivative group to X, and n represents an integer of 1 or more).

Description

  The present invention relates to a paclitaxel derivative, a pharmaceutical comprising the paclitaxel derivative, and an anticancer agent containing the paclitaxel derivative.

  As a cause of death in Japan, infections such as tuberculosis and pneumonia that frequently occurred from the Meiji period to the early Showa era decreased rapidly after the Second World War, and lifestyle-related diseases such as heart disease and cerebrovascular disease seem to occupy the top place. Became. Furthermore, cancer has become the leading cause of death since 1981, and the number of deaths due to cancer in 2007 was 336,468, with 266.9 deaths for a population of 100,000. It accounts for 4%. The number of cancer deaths by region is 1st: lung, 2nd: stomach, 3rd: liver, 4th: colon, 5th: spleen.

  Among these, the morbidity and mortality of lung cancer both begin to increase in the late 40s and become higher as the age increases. In addition, there is no significant difference between the morbidity and mortality of lung cancer, which indicates that the survival rate of lung cancer patients is low. Lung cancer is roughly classified into two types, non-small cell lung cancer and small cell lung cancer, and non-small cell lung cancer is further classified into adenocarcinoma, squamous cell carcinoma, large cell carcinoma and the like. Adenocarcinoma occurs most frequently in Japan, accounting for 40% of male lung cancer and more than 70% of female lung cancer. The next most squamous cell carcinoma accounts for 40% of male lung cancer and 15% of female lung cancer. Large cell carcinoma is generally fast growing and often already progresses when diagnosed with lung cancer. As chemotherapy for these non-small cell lung cancers, the combination of cisplatin and other anticancer agents is strongly recommended. Examples of the anticancer agent used in combination with cisplatin include paclitaxel, irinotecan hydrochloride, vinorelbine, gemcitabine, docetaxel and the like.

  Paclitaxel is a typical anticancer agent that has a microtubule polymerization-promoting action. Since its launch in 1993, paclitaxel has various ovarian cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer, Kaposi sarcoma, and non-small cell lung cancer. Has been used for various tumors.

  However, a drawback of paclitaxel is that it is sparingly soluble in water. As a result, in the formulation process, surfactants such as polyoxyethylene castor oil and ethanol must be used for solubilization, but these cause problems of hypersensitivity and pain. . In particular, polyoxyethylene castor oil has been reported to induce anaphylactic shock, and it has been instructed to use steroid drug dexamethasone sodium phosphate and antiallergic drug diphenhydramine hydrochloride. However, side effects caused by these drugs are also a concern.

  Therefore, a technique for improving the water solubility of paclitaxel has been demanded. For example, Non-Patent Document 1 discloses a polymer micelle preparation in which paclitaxel is coated with an outer shell containing a hydrophilic polyethylene glycol (PEG). Non-Patent Document 2 describes an example in which paclitaxel is modified with polyvinyl alcohol (PVA).

  However, a DDS preparation using a polymer carrier such as PEG has problems that the anticancer activity and immunogenicity are changed, and uptake of paclitaxel into cells by endocytosis is limited. In addition, when paclitaxel is modified with a polymer such as PVA, the activity on the active site is inhibited and the activity is remarkably reduced, or the molecular weight of PVA ranges from several times to several tens of times that of paclitaxel. In order to make it act, there exists a problem that a dosage increases extremely.

  By the way, the present inventors have developed a glycerol derivative group that effectively improves the water solubility of a compound (Patent Documents 1 to 3).

International Publication No. 2004/029018 Pamphlet International Publication No. 2005/023844 Pamphlet International Publication No. 2008/093655 Pamphlet

Yong Woo Cho et al., Journal of Controlled Release, 97, pp.249-257 (2004) Atsufumi KAKINOKI et al., Biol. Pharm. Bull. , 31 (5), pp.963-969 (2008)

  As described above, the present inventors have synthesized various derivatives of paclitaxel under the circumstances that the technology for improving the water solubility of paclitaxel has been desired. As a result, even when the same substituent was introduced, it was experimentally clarified that not only the water solubility differs depending on the substitution position, but also the anticancer activity itself differs.

  Thus, the problem to be solved by the present invention is that paclitaxel derivatives not only exhibit high water solubility but also maintain excellent anticancer activity, a medicament comprising the paclitaxel derivative, and an anticancer agent comprising the paclitaxel derivative Is to provide.

  The inventors of the present invention have made extensive studies to solve the above problems. As a result, it was found that paclitaxel derivatives in which a glycerol derivative group was introduced into the amino group at the 3-position were not only highly water-soluble compared to other derivatives, but also had excellent anticancer activity. completed.

  The paclitaxel derivative according to the present invention is represented by the following general formula (I).

[Wherein X is a C _1-6 alkylene group; amino group (—NH— etc.), ether group (—O—), thioether group (—S—), carbonyl group (> C═O), thionyl group ( > C = S), ester group (—C (═O) O— or —OC (═O) —), amide group (—C (═O) NH— or —NHC (═O) —), urea group A C _2-6 alkylene group containing one or more groups selected from the group consisting of (—NHC (═O) NH—) and a thiourea group (—NHC (═S) NH—); an amino group, an ether group , A thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, and a C _1-6 alkylene group having one group selected from the group consisting of a thiourea group at one end; or a carbonyl group, thionyl Group, ester group, amide group, urea group and thiourea A C _1-6 alkylene group having two groups at both ends selected from the group consisting of groups;
Y represents a linking group for linking 2 ^n-1 glycerol derivative groups to X;
n represents an integer of 1 or more]

In the present invention, the “C _1-6 alkylene group” refers to a linear or branched divalent hydrocarbon group having 1 to 6 carbon atoms. Examples include a methylene group, an ethylene group, a propylene group, a methylpropylene group, a dimethylpropylene group, a butylene group, a methylbutylene group, a dimethylbutylene group, a pentylene group, and a hexylene group, and preferably a C _2-4 alkylene group. It is.

The “amino group” includes an —NR— group (where R is a C _1-6 alkyl group) in addition to an —NH— group. Here, the “C _1-6 alkyl group” refers to a linear or branched monovalent hydrocarbon group having 1 to 6 carbon atoms. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group, an isobutyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group can be exemplified. _{A 1-4} alkyl group is preferable, a C _1-2 alkyl group is more preferable, and a methyl group is more preferable.

X is a linker group that links the amino group at the 3-position of paclitaxel and a group Y for linking the glycerol derivative group, and facilitates introduction of the glycerol derivative group into paclitaxel. Since it does not impair the anticancer activity, it has the effect of keeping the distance between the two moderate. However, it is not included in the range when an unstable structure such as —O—O— is generated due to the amino group at position 3 of paclitaxel or Y. The C _2-6 alkylene group containing an amino group or the like is a hydrocarbon group having at least both ends having a hydrocarbon group and having one or more amino groups or the like inside, and X contains a carbonyl group or the like. The carbon number is not included in the carbon number of the alkylene group.

Y is a bonding group for bonding 2 ^n-1 glycerol derivative groups to the linker group X. More specifically, when n is 1, that is, there is only one glycerol derivative group to be introduced, Y may be a single bond.

  When n is 2 or more, Y must bind the linker group X and a plurality of glycerol derivative groups. In this case, Y preferably has a serial branched structure in which a plurality of glycerol derivative groups are bonded together by the following structure (II), and a plurality of the following structures are bonded by the same structure.

[Wherein Y ¹ represents a single bond, a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, an ester group or an amide group; Y ² represents —CH <or —N <. And Y ³ and Y ⁴ each independently represent a single bond, a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, an ester group or an amide group]

  In the case where Y has a divergent branched structure in which a plurality of structures (II) are bonded, the paclitaxel derivative of the present invention has two or more glycerol derivative groups, and thus has high water solubility and is derived from paclitaxel. The activity is at least retained because the moiety is not covered by glycerol derivative groups. The branched structure here refers to, for example, the following dendrimer-type structure in which the structure (II) is linked in a branched manner.

  The following structure can be illustrated as specific structure (II).

  When a plurality of structures (II) are included in Y, the structures (II) may be the same as or different from each other. However, the plurality of structures (II) are preferably the same as each other from the viewpoint of ease of synthesis.

  For example, when n is 3, that is, the number of glycerol derivative groups is 4, examples of the structure of Y include the following.

  n is preferably 2 or more and 5 or less. When n is 2 or more, that is, when the number of glycerol derivative groups is 2 or more, the water solubility of the paclitaxel derivative is sufficiently increased. On the other hand, if n is too large, that is, if the number of glycerol derivative groups is too large, the molecular weight of the paclitaxel derivative and the overall structure may become too large, which may adversely affect anticancer activity and the like. n is more preferably 4 or less, and even more preferably 3 or less.

In the paclitaxel derivative, X is a C _2-4 alkylene group having two groups at both ends selected from the group consisting of a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, and a thiourea group; Is preferably a divergent branched structure in which the above structure (II) or a plurality of structures (II) are bonded; and n is preferably 2 or 3. The excellent water solubility and anticancer activity of such paclitaxel derivatives have been experimentally proven in the examples described later.

  The medicament according to the present invention comprises the paclitaxel derivative. The anticancer agent according to the present invention is characterized by containing the paclitaxel derivative.

  Since the paclitaxel derivative according to the present invention exhibits excellent water solubility, it can be formulated using water as a solvent compared to paclitaxel having low solubility in water, and a safer formulation can be prepared. In addition, since the glycerol derivative group introduced into the paclitaxel derivative according to the present invention has a relatively low molecular weight and a large number of hydroxyl groups, the water solubility can be enhanced without adversely affecting the anticancer activity of paclitaxel. Furthermore, the paclitaxel derivative of the present invention, according to the experimental findings by the present inventors, has a weak in vitro anticancer activity compared to other derivatives, but has a remarkable in vivo anticancer activity. It is excellent. Therefore, the paclitaxel derivative according to the present invention is extremely useful industrially as an active ingredient of medicines and further anticancer agents.

FIG. 1 is a graph for comparing the solubility in water of a paclitaxel derivative according to the present invention, paclitaxel and other paclitaxel derivatives. FIG. 2 is a graph for comparing the solubility in 1-octanol of a paclitaxel derivative according to the present invention, paclitaxel and other paclitaxel derivatives. FIG. 3 is a graph for comparing the anticancer activity of a paclitaxel derivative according to the present invention, paclitaxel and other paclitaxel derivatives.

  The paclitaxel derivative according to the present invention can be synthesized, for example, according to the following scheme.

  The raw material compound (III) is a known compound and can be produced according to the method described in WO 96/23780.

  Z of the raw material compound (IV) is a group for bonding the end portion of X which is bonded to the amino group of the raw material compound (III). For example, in the case where the end of X that is bonded to the amino group of the raw material compound (III) is an alkyl group, Z can be a halogen group. Further, when the end of X that is bonded to the amino group of the raw material compound (III) is a carbonyl group, the carbonyl group and Z, that is, —C (═O) —Z is succinimide, phthalic acid Active imides such as imide, N-hydroxysuccinimide, and 5-norbornene-2,3-dicarboximide; active esters such as p-nitrophenyl ester; and acid halides such as acid chloride.

  The raw material compound (IV) can be obtained by, for example, using a method described in an academic paper by the present inventors (NEMOTO H et al., Synlett, pp. 2091-2095 (2007)) or a method according to the method in the glycerol derivative group. The compound can be synthesized by synthesizing a compound in which two hydroxyl groups are protected as 1,3-dioxane, and a plurality of the glycerol groups are bonded by Y, and by combining X with a conventional method, followed by deprotection.

  What is necessary is just to determine suitably the reaction conditions of raw material compound (III) and raw material compound (IV) mainly according to Z. For example, when the —C (═O) —Z group is an active imide group, the paclitaxel derivative (I) can be obtained simply by reacting the raw material compound (III) and the raw material compound (IV) in a solvent.

  The solvent that can be used in this reaction is not particularly limited as long as it can appropriately dissolve the raw material compound (III) and the raw material compound (IV) and does not inhibit the reaction. For example, diethyl ether, tetrahydrofuran, 1,4- Examples include ether solvents such as dioxane; alcohol solvents such as methanol and ethanol; amide solvents such as dimethylformamide and dimethylacetamide; halogenated hydrocarbon solvents such as methylene chloride and chloroform.

  In addition, an additive such as 1-hydroxybenzotriazole, which is often used in an amide bond forming reaction and suppresses racemization, may be used.

  The reaction is preferably performed in an atmosphere of an inert gas such as argon gas or nitrogen gas.

  What is necessary is just to set reaction temperature and reaction time suitably. For example, it can be set to 10 ° C. or more and 50 ° C. or less and about 10 hours or more and 60 hours or less. The specific reaction time can be determined by a preliminary experiment or until the consumption of the raw material compound can be confirmed by TLC or the like.

  After the reaction, general post-treatment can be performed. For example, an organic solvent immiscible with water, such as ethyl acetate and chloroform, and an aqueous solution of copper sulfate that can move impurities to the aqueous phase are separated into the reaction mixture, and the obtained organic phase is washed. dry. The paclitaxel derivative (I) can be obtained by purifying the residue obtained by distilling off the solvent under reduced pressure by silica gel column chromatography or the like.

  The paclitaxel derivative according to the present invention exhibits the same anticancer activity as paclitaxel and is less toxic to the living body than paclitaxel. Therefore, the paclitaxel derivative of the present invention can be used as an anticancer agent.

  Examples of cancer to be treated include lung cancer such as non-small cell lung cancer, ovarian cancer, breast cancer, stomach cancer, endometrial cancer, head and neck cancer, and Kaposi sarcoma.

  The dosage form of the anticancer agent of the present invention is not particularly limited, and for example, it may be an injection, tablet, pill, powder, granule, syrup, liquid, suspension, emulsion, granule, capsule. Can do. Preparation of each preparation may be performed by a conventional method corresponding to each preparation. In addition, since the paclitaxel derivative based on this invention can melt | dissolve in water, since aqueous solution, such as a buffer solution, or water itself can be used as a solvent, formulation preparation is safer and simple. In addition, since it is not necessary to use an organic solvent or a surfactant or the amount of use thereof can be reduced, the preparation itself is safe.

  The dose of the paclitaxel derivative according to the present invention can be adjusted as appropriate depending on the severity of the disease, the sex and age of the patient, the dosage form, the administration method, etc. What is necessary is just to administer about 1000 mg or less. In addition, the number of administrations may be adjusted in the same manner, but it can usually be 1 to 3 times per day.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.

  Example 1-1: Synthesis of 4- (1,3-bis (2-phenyl-1,3-dioxan-5-yloxy) propan-2-yloxy) -4-oxobutanoic acid (1)

  Glycerol derivative (2) (Nemoto, H, et al., Synlett, 2007, pp. 2091-2095) (1.23 g, 2.95 mmol) was dissolved in methylene chloride (10 mL), and further dimethylaminopyridine (0.04 g, 0.04 g). 29 mmol), triethylamine (0.84 mL, 5.99 mmol) and succinic anhydride (0.33 g, 3.29 mmol) were added and stirred at room temperature under an argon atmosphere. After 16 hours, the disappearance of the glycerol derivative (2) was confirmed by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: ethyl acetate) gave the target compound (1) (1.27 g) as a white solid in an isolated yield of 84%.

FT-IR (neat): 2863, 1735, 1453, 1392, 1344, 1238, 1215, 1155, 1091, 1009, 982, 915, 759, 700 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.52-7.47 (m, 4H), 7.39-7.31 (m, 6H), 5.53 (s, 2H), 5.23 (quintet, J = 5.0 Hz, 1H), 4.39-4.32 (m, 4H), 4.04-3.98 (m, 4H), 3.86-3.74 (m, 4H), 3.33 (quintet, J = 1.5Hz, 2H), 2.68-2.63 (m, 2H), 2.59- 2.54 (m, 2H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 176.7 (C), 171.7 (C), 138.0 (C × 2), 128.8 (CH × 2), 128.1 (CH × 4), 126.0 (CH × 4) , 101.0 (CH x 2), 71.8 (CH), 70.9 (CH x 2), 68.8 (CH ₂ x 2), 68.4 (CH ₂ x 2), 66.4 (CH ₂ x 2), 29.0 (CH ₂ ), 28.6 (CH ₂ );
HRMS (ESI-TOF) m / z calcd for C ₂₇ H ₃₂ O ₁₀ Na [M + Na] ⁺ 539.1893, found 539.1901

  Example 1-2: Synthesis of 1,3-bis (2-phenyl-1,3-dioxan-5-yloxy) propan-2-yl 2,5-dioxopyrrolidin-1-yl succinate (3)

  The butanoic acid compound (1) obtained in Example 1-1 (0.10 g, 0.20 mmol) was dissolved in methylene chloride (2 mL), and N-hydroxysuccinimide (0.047 g, 0.40 mmol) and 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.077 g, 0.40 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 16 hours, the disappearance of the butanoic acid compound (1) was confirmed by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (ethyl acetate / hexane = 2/1) gave colorless amorphous target compound (3) (0.089 g, 0.14 mmol) in an isolated yield of 72%.

FT-IR (neat): 2860, 1815, 1784, 1740, 1454, 1390, 1239, 1206, 1153, 1091, 1011, 915, 845, 800, 732, 701, 648 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.52-7.46 (m, 4H), 7.39-7.31 (m, 6H), 5.48 (s, 2H), 5.25 (quintet, J = 5.2 Hz, 1H), 4.35-4.26 (m, 4H), 4.00-3.94 (m, 4H), 3.86-3.76 (m, 4H), 3.36 (quintet, J = 1.5Hz, 2H), 2.91 (t, J = 6.8Hz, 2H) , 2.80 (s, 2H), 2.76 (t, J = 6.6Hz, 2H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 170.5 (C), 168.9 (C × 2), 167.7 (C), 138.1 (C × 2), 128.8 (CH × 2), 128.1 (CH × 4) , 126.0 (CH x 4), 100.9 (CH x 2), 72.0 (CH), 70.8 (CH x 2), 68.8 (CH ₂ x 2), 68.3 (CH ₂ x 2), 66.3 (CH ₂ x 2) , 28.5 (CH ₂ ), 25.9 (CH ₂ ), 25.2 (CH ₂ × 2);
HRMS (ESI-TOF) m / z calcd for C ₃₁ H ₃₅ NO ₁₂ Na [M + Na] ⁺ 636.2057, found 636.2040

  Example 1-3 Synthesis of 1,3-bis (1,3-dihydroxypropan-2-yloxy) propan-2-yl 2,5-dioxopyrrolidin-1-yl succinate (4)

  Compound (3) of Example 1-2 (0.040 g, 0.065 mmol) was dissolved in ethanol (2 mL), palladium hydroxide (0.010 g, 7.1 μmol) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere. did. After 7 hours, the disappearance of the compound (3) and the intermediate was confirmed by TLC, and then palladium was filtered off to obtain an oily target compound (4) (0.019 g). It used for next reaction, without carrying out silica gel column purification.

  Example 1-4

  A de-N-benzoyl derivative of paclitaxel (known compound) (0.014 g, 0.018 mmol) was dissolved in tetrahydrofuran (0.3 mL), and the glycerol derivative (4) of Example 1-3 above (0.012 g, 0.027 mmol) was dissolved. ), 1-hydroxybenzotriazole (0.0006 g, 0.0036 mmol) and dimethylaniline (0.0023 mL, 0.018 mmol) were added and stirred at room temperature under an argon atmosphere. After 48 hours, the disappearance of the glycerol derivative (4) was confirmed by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. The product was purified by silica gel column chromatography (eluent: methanol / chloroform = 1/8) to obtain a paclitaxel derivative according to the present invention as a white solid in an isolated yield of 73%.

FT-IR (neat): 3385, 2926, 2348, 2251, 1723, 1662, 1539, 1452, 1373, 1243, 1177, 1110, 1071, 1026, 979, 909, 854, 776, 731, 647 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.11 (d, J = 7.7 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.46 -7.37 (m, 4H), 7.28 (t, J = 6.8Hz, 1H), 6.47 (s, 1H), 6.16 (t, J = 8.9Hz, 1H), 5.66 (d, J = 7.1Hz, 1H) , 5.45 (d, J = 4.1Hz, 1H), 5.06 (t, J = 4.9Hz, 1H), 4.99 (d, J = 9.4Hz, 1H), 4.59 (q, J = 4.4Hz, 1H), 4.32 (Dd, J = 10.6, 6.8Hz, 1H), 4.19 (s, 2H), 3.82 (d, J = 7.0Hz, 1H), 3.78-3.47 (m, 13H), 3.31 (s, 4H), 2.61 ( t, J = 14.0Hz, 4H), 2.51-2.42 (m, 1H), 2.34 (s, 3H), 2.25 (dd, J = 15.4, 9.4Hz, 1H), 2.18 (s, 3H), 2.04 (dd , J = 15.4, 9.4Hz, 1H), 1.93 (s, 3H), 1.85-1.76 (m, 1H), 1.66 (s, 3H), 1.19 (s, 4H), 1.17 (s, 3H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 205.4 (C), 174.6 (C), 174.3 (C), 174.2 (C), 172.1 (C), 171.5 (C), 167.8 (C), 142.3 ( C), 140.2 (C), 135.0 (C), 134.8 (CH), 131.5 (C), 131.3 (CH x 2), 129.9 (CH x 2), 129.8 (CH x 2), 129.0 (CH), 128.6 (CH x 2), 85.9 (CH), 83.2 (CH x 2), 82.4 (C), 79.1 (C), 77.5 (CH ₂ ) 76.9 (CH), 76.3 (CH), 74.9 (CH), 73.9 ( CH), 72.5 (CH), 72.4 (CH), 69.6 (CH ₂ × 2), 62.5 (CH ₂ × 4), 59.3 (C), 57.0 (CH), 47.9 (CH), 44.6 (C), 37.5 (CH ₂ ), 36.6 (CH ₂ ), 31.3 (CH ₂ ), 30.5 (CH ₂ ), 27.0 (CH ₃ ), 23.2 (CH ₃ ), 22.3 (CH ₃ ), 20.8 (CH ₃ ), 14.7 (CH _{3), 10.4 (CH 3)} ;
HRMS (ESI-TOF) m / z calcd for C ₅₃ H ₆₉ NO ₂₂ Na [M + Na] ⁺ 1094.4209, found 1094.4219

  Comparative Example 1-1

  Paclitaxel (0.070 g, 0.082 mmol) was dissolved in methylene chloride (1 mL), butanoic acid compound (1) (0.051 g, 0.098 mmol) obtained in Example 1-1 above, dimethylaminopyridine (0. 012 g, 0.098 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.019 g, 0.098 mmol) were added and stirred at room temperature under an argon atmosphere. After confirming the disappearance of paclitaxel by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/2) gave quantitatively the target compound (5) (0.102 g, 0.075 mmol) as a white solid in a yield of 92%. .

FT-IR (neat): 3502, 3065, 2975, 2250, 1732, 1660, 1603, 1580, 1522, 1488, 1453, 1372, 1240, 1153, 1093, 1016, 948, 912, 846, 799, 731, 648 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.15 (d, J = 7.4 Hz, 2H), 7.81 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.56 -7.31 (dd, J = 9.6, 5.9Hz, 20H), 7.17 (q, J = 9.1Hz, 1H), 6.31 (s, 1H), 6.23 (t, J = 8.8Hz, 1H), 5.98 (dd, J = 9.0, 3.2Hz, 1H), 5.69 (d, J = 7.0Hz, 1H), 5.51 (s, 1H), 5.48 (s, 2H), 5.15 (quintet, J = 4.9Hz, 1H), 4.97 ( d, J = 8.7Hz, 1H), 4.45 (m, 1H), 4.35-4.19 (m, 6H), 4.00-3.86 (m, 5H), 3.85-3.68 (m, 6H), 3.32 (s, 1H) , 3.27 (s, 1H), 2.73 (m, 2H), 2.65 (m, 2H), 2.56 (m, 1H), 2.45 (s, 3H), 2.34 (dd, J = 15.3, 9.3Hz, 1H), 2.22 (s, 3H), 2.19-2.11 (m, 1H), 1.94 (s, 3H), 1.91 (m, 1H), 1.69 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H) ;
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 203.6 (C), 171.6 (C), 171.0 (C), 170.9 (C), 169.7 (C), 167.8 (C), 167.0 (C), 166.8 ( C), 142.6 (C), 138.0 (C), 137.9 (C), 136.8 (C), 133.5 (CH), 133.4 (C), 132.6 (C), 131.8 (CH), 130.1 (CH x 2), 129.0 (C), 128.9 (CH x 2), 128.7 (CH x 2), 128.6 (CH), 128.5 (CH x 2), 128.3 (CH), 128.0 (CH x 5), 127.1 (CH x 2), 126.5 (CH x 2), 125.9 (CH x 4), 100.9 (CH x 2), 84.3 (CH), 80.8 (C), 78.9 (C), 76.2 (CH ₂ ), 75.4 (CH), 74.9 (CH ), 74.2 (CH), 71.9 (CH × 2), 71.6 (CH), 71.0 (CH), 70.8 (CH), 68.9 (CH ₂ ), 68.8 (CH ₂ ), 68.4 (CH ₂ ), 68.3 (CH ₂ ), 66.3 (CH ₂ ), 66.1 (CH ₂ ), 58.3 (C), 52.7 (CH), 45.4 (CH), 43.0 (C), 35.4 (CH ₂ × 2), 29.1 (CH ₂ ), 28.9 (CH ₂ ), 26.6 (CH ₃ ), 22.5 (CH ₃ ), 22.0 (CH ₃ ), 20.7 (CH ₃ ), 14.6 (CH ₃ ), 9.4 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₇₄ H ₈₁ NO ₂₃ Na [M + Na] ⁺ 1374.5097, found 1374.5150

  Comparative Example 1-2

  The compound (5) (0.10 g, 0.075 mmol) obtained in Comparative Example 1-1 was dissolved in methanol (1 mL), palladium hydroxide (0.020 g, 0.014 mmol) was added, and room temperature was obtained under a hydrogen atmosphere. Stir with. After 15 hours, the disappearance of compound (3) and the intermediate was confirmed by TLC, and then palladium was filtered off. After removing the solvent, the residue was purified by silica gel column chromatography (eluent: methanol / chloroform = 1/9) to obtain the target compound in a yield of 82%.

FT-IR (neat): 3447, 2937, 1734, 1647, 1540, 1490, 1373, 1243, 1153, 1070, 909, 731 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.16 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.54 -7.49 (m, J = 9.6, 5.9Hz, 3H), 7.45-7.38 (m, J = 3.0Hz, 6H), 7.37-7.32 (m, 1H), 6.32 (s, 1H), 6.21 (t, J = 8.9Hz, 1H), 5.96 (dd, J = 9.2, 3.4Hz, 1H), 5.69 (d, J = 6.6Hz, 1H), 5.49 (d, J = 3.6Hz, 1H), 5.04 (quint, J = 5.2Hz, 1H), 4.97 (dd, J = 9.6, 1.5Hz, 1H), 4.43-4.41 (m, 1H), 4.31 (d, J = 8.4Hz, 1H), 4.21 (d, J = 8.6Hz , 1H), 3.81-3.56 (m, 14H), 3.49-3.41 (m, 2H), 2.86-2.61 (m, 6H), 2.57-2.50 (m, 1H), 2.45 (s, 3H), 2.35 (dd , J = 15.5, 9.4Hz, 1H), 2.23 (s, 3H), 2.17-2.11 (m, 1H), 1.93 (s, 3H), 1.91-1.89 (m, 1H), 1.69 (s, 3H), 1.26 (s, 1H), 1.23 (s, 4H), 1.15 (s, 3H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 203 (C), 171.6 (C), 171.4 (C), 171.0 (C), 169.9 (C), 168.1 (C), 167.3 (C), 166.7 (C), 142.0 (C), 136.7 (C), 133.5 (C), 132.8 (C), 131.8 (CH), 130.1 (CH x 2), 129.1 (C), 128.9 (CH x 2), 128.6 ( CH × 2), 128.5 (CH × 3), 128.4 (CH), 127.2 (CH × 2), 126.6 (CH × 2), 84.3 (CH), 81.0 (CH × 2, C), 78.8 (C), 76.3 (CH ₂ ), 75.5 (CH), 74.8 (CH), 74.4 (CH), 72.1 (CH), 71.9 (CH), 71.6 (CH), 67.8 (CH ₂ ), 67.7 (CH ₂ ), 61.9 ( CH ₂ ), 61.8 (CH ₂ × 2), 61.7 (CH ₂ ), 58.2 (C), 52.8 (CH), 45.7 (CH), 43.1 (C), 35.7 (CH ₂ ), 35.3 (CH ₂ ), 29.1 (CH ₂ ), 28.8 (CH ₂ ), 26.5 (CH ₃ ), 22.5 (CH ₃ ), 21.9 (CH ₃ ), 20.8 (CH ₃ ), 14.6 (CH ₃ ), 9.6 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₆₀ H ₇₃ NO ₂₃ Na [M + Na] ⁺ 1198.4471, found 1198.4474

  Comparative Example 2-1

  A silyl ether derivative of paclitaxel (known compound; Pharmaceutical Research, 2008, 25, pp.194-206) (0.054 g, 0.055 mmol) was dissolved in methylene chloride (2 mL), and the butane obtained in Example 1-1 above was dissolved. Acid compound (1) (0.043 g, 0.083 mmol), dimethylaminopyridinium paratoluenesulfonate (0.033 g, 0.11 mmol) and diisopropylcarbodiimide (0.035 mL, 0.22 mmol) were added, and an argon atmosphere was added. And stirred at room temperature. After confirming the disappearance of the paclitaxel derivative by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) yielded 93% of the desired compound (6) (0.076 g, 0.051 mmol) as a white solid in an isolated yield of 81%. %.

FT-IR (neat): 3440, 2930, 1735, 1662, 1484, 1452, 1372, 1240, 1154, 1094, 1018, 982, 838, 757, 699 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.14 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.55 -7.30 (m, 20H), 7.09 (d, J = 8.9Hz, 1H), 6.29-6.21 (m, 2H), 5.77-5.69 (m, 2H), 5.61 (dd, J = 10.6, 7.1Hz, 1H ), 5.49 (s, 2H), 5.21 (quintet, J = 5.0Hz, 1H), 4.97 (d, J = 9.0Hz, 1H), 4.67 (d, J = 2.0, 1H), 4.35-4.28 (m, 5H), 4.21 (d, J = 8.5Hz, 1H), 3.99-3.95 (m, 5H), 3.84-3.77 (m, 4H), 3.40-3.36 (m, 2H), 2.77-2.55 (m, 8H) , 2.46-2.37 (m, 1H), 2.20-2.11 (m, 4H), 1.97 (s, 3H), 1.90-1.85 (m, 1H), 1.81 (s, 3H), 1.20 (s, 3H), 1.16 (S, 3H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 201.9 (C), 172.1 (C), 171.4 (C × 2), 169.8 (C), 169.0 (C), 167.0 (C), 166.8 (C ), 140.5 (C), 138.1 (C x 3), 134.0 (C), 133.6 (CH), 132.6 (CH), 131.7 (CH), 130.1 (CH x 2), 129.0 (C), 128.7 (CH x 2), 128.6 (CH x 4), 128.0 (CH x 5), 127.9 (CH), 126.9 (CH x 2), 126.3 (CH x 2), 126.0 (CH x 5), 100.9 (CH x 2) 83.8 (CH), 80.8 (C), 78.4 (C), 76.1 (CH ₂ ), 75.0 (CH), 74.9 (CH), 74.3 (CH), 71.7 (CH), 71.3 (CH), 71.1 (CH), 70.9 (CH), 70.8 (CH), 68.9 (CH ₂ × 2), 68.4 (CH ₂ ), 68.3 (CH ₂ ), 66.3 (CH ₂ × 2), 55.7 (C), 55.4 (CH), 46.6 ( CH), 43.1 (C), 35.3 (CH ₂ ), 33.0 (CH ₂ ), 28.8 (CH ₂ ), 28.7 (CH ₂ ), 26.1 (CH ₃ ), 25.2 (CH ₃ × 3), 22.7 (CH ₃ ), 21.1 (CH ₃ ), 20.4 (CH ₃ ), 17.8 (C), 14.3 (CH ₃ ), 10.6 (CH ₃ ), -5.53 (CH ₃ ), -6.16 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₈₀ H ₉₅ NO ₂₃ SiNa ([M + Na] ⁺ ): 1488.5962. Found: 1488.5955

  Comparative Example 2-2

  Compound (6) (0.076 g, 0.051 mmol) obtained in Comparative Example 2-1 was dissolved in tetrahydrofuran (1 mL), hydrogen fluoride pyridine (0.5 mL) and pyridine (1.5 mL) were added, and argon was added. Stir at room temperature under atmosphere. After confirming the disappearance of compound (6) by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) gave the target compound (7) (0.066 g, 0.049 mmol) as a white solid in a yield of 95%.

FT-IR (neat): 3438, 3014, 1733, 1652, 1602, 1581, 1486, 1452, 1238, 845, 755, 667 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.12 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.53 -7.31 (m, 20H), 7.07 (d, J = 8.9Hz, 1H), 6.20-6.13 (m, 2H), 5.80 (dd, J = 9.0, 3.2Hz, 1H), 5.67 (d, J = 6.9 Hz, 1H), 5.56 (dd, J = 10.4, 7.3Hz, 1H), 5.50 (s, 1H), 5.49 (s, 1H), 5.19 (quintet, J = 5.0Hz, 1H), 4.92 (d, J = 9.0Hz, 1H), 4.79 (dd, J = 4.7, 2.5Hz, 1H), 4.35-4.26 (m, 6H), 4.18 (d, J = 8.5Hz, 1H), 4.00-3.93 (m, 4H) , 3.91 (d, J = 6.8Hz, 1H), 3.85-3.76 (m, 4H), 3.62 (d, J = 4.8Hz, 1H), 3.41-3.36 (m, 2H), 2.74-2.53 (m, 5H ), 2.37 (s, 3H), 2.32 (dd, J = 8.9, 3.3Hz, 1H), 2.15 (s, 3H), 1.86-1.78 (m, 7H), 1.20 (s, 3H), 1.16 (s, 3H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 201.8 (C), 172.4 (C), 172.2 (C), 171.4 (C), 170.3 (C), 169.0 (C), 167.1 (C), 166.8 (C), 140.3 (C), 138.1 (C x 2), 138.0 (C), 133.7 (CH), 133.6 (C), 132.8 (C), 131.8 (CH), 130.1 (CH x 2), 129.0 ( C), 128.8 (CH x 2), 128.7 (CH x 2), 128.6 (CH x 3), 128.1 (CH x 5), 127.0 (CH x 4), 126.0 (CH x 5), 100.9 (CH x 2) ) 83.7 (CH), 80.8 (C), 78.2 (C), 76.2 (CH ₂ ), 75.1 (CH), 74.1 (CH), 73.0 (CH), 71.8 (CH), 71.7 (CH), 71.4 (CH ), 70.9 (CH x 2), 68.9 (CH ₂ x 2), 68.4 (CH ₂ x 2), 66.3 (CH ₂ x 2), 55.9 (C), 54.7 (CH), 46.7 (CH), 43.0 ( C), 35.3 (CH ₂ ), 33.0 (CH ₂ ), 28.8 (CH ₂ × 2) 26.2 (CH ₃ ), 22.3 (CH ₃ ), 20.6 (CH ₃ ), 20.5 (CH ₃ ), 14.3 (CH ₃ ), 10.5 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₇₄ H ₈₁ NO ₂₃ Na [M + Na] ⁺ 1374.5097, found 1374.5088

  Comparative Example 2-3

  Compound (7) (0.21 g, 0.15 mmol) obtained in Comparative Example 2-2 was dissolved in methanol (2 mL), palladium hydroxide (0.010 g, 0.071 mmol) was added, and the mixture was added at room temperature under a hydrogen atmosphere. Stir with. After 7 hours, the disappearance of compound (7) and the intermediate was confirmed by TLC, and then palladium was filtered off. After removing the solvent, the residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 8/1) to obtain the target compound (0.16 g, 0.13 mmol) as a white solid in an isolated yield of 88%.

FT-IR (neat): 3420, 2942, 2250, 1734, 1647, 1603, 1579, 1522, 1487, 1452, 1372, 1240, 1158, 1108, 1067, 979, 913, 846, 729 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.11 (d, J = 7.3 Hz, 2H), 7.79-7.76 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.53-7.46 ( m, 5H), 7.43-7.30 (m, 5H), 6.19-6.13 (m, 2H), 5.78 (dd, J = 8.7, 2.3Hz, 1H), 5.66 (d, J = 6.9Hz, 1H), 5.56 (Dd, J = 10.4, 7.2Hz, 1H), 5.11 (quint, J = 4.8Hz, 1H), 4.94 (d, J = 9.0Hz, 1H), 4.80 (dd, J = 5.3, 2.7Hz, 1H) , 4.31 (d, J = 8.5Hz, 1H), 4.18 (d, J = 8.5Hz, 1H), 4.10 (d, J = 1.2Hz, 1H), 3.88 (d, J = 6.8Hz, 1H), 3.84 -3.60 (m, 12H), 3.53-3.46 (m, 2H), 3.03-2.77 (m, 3H) 2.73-2.52 (m, 5H), 2.37 (s, 3H), 2.31 (d, J = 9.0Hz, 2H), 2.16 (s, 3H), 1.87-1.78 (m, 9H), 1.20 (s, 3H), 1.15 (s, 3H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 201.7 (C), 172.5 (C × 2), 172.3 (C), 171.7 (C), 170.5 (C), 169.1 (C), 167.4 (C), 166.5 (C), 140.5 (C), 138.0 (C), 133.6 (C, CH), 132.5 (C), 131.7 (CH), 130.0 (CH x 2), 128.9 (C), 128.7 (CH x 3) , 128.6 (CH), 128.5 (CH x 2), 127.9 (CH), 127.0 (CH x 2), 126.9 (CH x 2), 83.7 (CH), 81.0 (CH x 2), 80.8 (C), 78.2 (C), 76.2 (CH ₂ ), 75.2 (CH), 74.1 (CH), 72.9 (CH), 71.8 (CH), 71.6 (CH), 71.5 (CH), 67.9 (CH ₂ × 2), 61.7 ( CH ₂ ), 61.6 (CH ₂ × 2), 61.5 (CH ₂ ), 55.8 (C), 55.0 (CH), 46.9 (CH), 43.0 (C), 35.3 (CH ₂ ), 33.0 (CH ₂ ), 28.9 (CH ₂ × 2), 26.3 (CH ₃ ), 22.4 (CH ₃ ), 20.7 (CH ₃ ), 20.6 (CH ₃ ), 14.3 (CH ₃ ), 10.7 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₆₀ H ₇₃ NO ₂₃ Na [M + Na] ⁺ 1198.4471, found 1198.4467

  Example 2-1 Synthesis of 5,5 '-(2-azidopropane-1,3-diyl) bis (oxy) bis (2-phenyl-1,3-dioxane) (8)

  Glycerol derivative (2) (Nemoto, H, et al., Synlett, 2007, pp. 2091-2095) (1.0 g, 2.4 mmol) was dissolved in pyridine (6 mL) and tosyl chloride (0.69 g, 3.6 mmol) was dissolved. And dimethylaminopyridine (0.029 g, 0.24 mmol) were added, and the mixture was stirred at room temperature under an argon atmosphere. After 12 hours, the disappearance of the glycerol derivative (2) was confirmed by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and brine, and the organic layer was dried over anhydrous sodium sulfate. After sodium sulfate was filtered off, the solvent was removed to obtain an oil. The resulting oil was used in the next reaction without further purification.

  The oil was dissolved in N, N-dimethylformamide (20 mL), sodium azide (0.46 g, 7.2 mmol) was added, and the mixture was stirred at 100 ° C. under an argon atmosphere. Two hours later, the disappearance of the raw material was confirmed by TLC, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) gave the target compound (8) (0.89 g, 2.0 mmol) in an isolated yield of 84%.

FT-IR (neat): 2099, 1154, 1092, 1010, 699 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.52-7.47 (m, 4H), 7.39-7.31 (m, 6H), 5.52 (s, 2H), 4.38-4.31 (m, 4H), 4.04-3.98 (M, 4H), 3.85-3.75 (m, 5H), 5.15 (quintet, J = 1.6Hz, 2H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 138.0 (C × 2), 128.7 (CH × 2), 128.0 (CH × 4), 125.9 (CH × 4), 100.9 (CH × 2), 71.1 ( CH × 2), 68.5 (CH ₂ × 2), 68.3 (CH ₂ × 2), 67.5 (CH ₂ × 2), 60.0 (CH);
HRMS (ESI-TOF) m / z calcd for C ₂₃ H ₂₇ N ₃ O ₆ Na [M + Na] ⁺ 464.1798, found 464.1797

  Example 2-2: 2,5-dioxopyrrolidin-1-yl 5- (1,3-bis (2-phenyl-1,3-dioxan-5-yloxy) propan-2-ylamino) -5-oxo Synthesis of pentanoate (9)

  The azide compound (8) (1.0 g, 2.3 mmol) obtained in Example 2-1 was dissolved in tetrahydrofuran (20 mL), and lithium aluminum hydride (0.27 g, 7.0 mmol) was added and stirred. After confirming disappearance of the raw material by TLC, ethyl acetate and water were added to inactivate the reagent, followed by filtration. The filtrate was dried over anhydrous sodium sulfate and the solvent was removed.

  The residue (1.14 g) was dissolved in methylene chloride (15 mL), triethylamine (0.65 mL, 4.7 mmol) and glutaric anhydride (0.32 g, 2.8 mmol) were added, and the mixture was stirred at room temperature. After confirming disappearance of the raw material by TLC, an aqueous copper sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed.

  The residue (1.31 g) was dissolved in methylene chloride (15 mL) and N-hydroxysuccinimide (0.54 g, 4.7 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0. 89 g, 4.7 mmol) was added and stirred at 40 ° C. After confirming disappearance of the raw material by TLC, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3) afforded the white amorphous target compound (9) (1.0 g, 1.6 mmol) in an isolated yield of 69%. It was.

FT-IR (neat): 2866, 1783, 1738, 1661, 1530, 1454, 1388, 1209, 1154, 1091, 1010, 755, 701 cm ^-1 ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 7.50-7.44 (m, 4H), 7.39-7.32 (m, 6H), 6.79 (d, J = 8.4, 2H), 5.50 (s, 2H), 4.37-4.27 (m, 5H), 4.00-3.93 (m, 4H), 3.80-3.75 (m, 2H), 3.71-3.65 (m, 2H), 3.35 (s, 2H), 2.60 (t, J = 6.8 , 2H), 2.53 (s, 4H), 2.28 (t, J = 6.8, 2H), 2.06 (t, J = 6.8, 2H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 171.4 (C), 169.4 (C × 2), 168.2 (C), 138.1 (C × 2), 128.7 (C × 2), 128.0 (C × 4) , 125.8 (C x 2), 100.9 (CH x 2), 70.6 (CH x 2), 68.9 (CH ₂ x 2), 68.3 (CH ₂ x 2), 65.8 (CH ₂ x 2), 48.6 (CH) , 34.1 (CH ₂ ), 29.6 (CH ₂ ), 25.2 (CH ₂ × 2), 20.9 (CH ₂ );
HRMS (ESI-TOF) m / z calcd for C32H38N2O11Na [M + Na] ⁺ 649.2373, found 649.2350

  Example 2-3: 2,5-Dioxopyrrolidin-1-yl 5- (1,3-bis (1,3-dihydroxypropan-2-yloxy) propan-2-ylamino) -5-oxopentanoate Synthesis of (10)

  Glycerol derivative (9) obtained in Example 2-2 (0.097 g, 0.16 mmol) was dissolved in tetrahydrofuran (1 mL), palladium hydroxide (0.040 g, 0.28 mmol) was added, and under a hydrogen atmosphere, Stir at room temperature. Two hours later, after confirming disappearance of the glycerol derivative (9) and the intermediate by TLC, palladium was filtered off. It used for next reaction, without carrying out silica gel column purification.

  Example 2-4

  De-N-benzoyl derivative of paclitaxel (known compound) (0.014 g, 0.019 mmol) was dissolved in N, N-dimethylformamide (0.2 mL), and the glycerol derivative (10) obtained in Example 2-3 above (10) ( 0.077 mmol) was added, and the mixture was stirred at room temperature under an argon atmosphere. After 48 hours, the disappearance of the glycerol derivative (10) was confirmed by TLC, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and the organic layer was dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed. Purification by silica gel column chromatography (eluent: methanol / chloroform = 1/7) gave a paclitaxel derivative (0.014 g, 0.013 mmol) according to the present invention which is a colorless transparent oil with an isolated yield of 68%. It was.

FT-IR (neat): 3365, 2924, 2853, 1721, 1648, 1542, 1458, 1374, 1276, 1121, 1072, 977, 748, 708 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ , 400 MHz): δ = 8.13 (d, J = 7.3 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.48 -7.39 (m, 4H), 7.30 (t, J = 7.0Hz, 1H), 6.48 (s, 1H), 6.17 (t, J = 8.8Hz, 1H), 5.68 (d, J = 7.1Hz, 1H) , 5.48 (d, J = 4.5Hz, 1H), 5.01 (d, J = 9.4Hz, 1H), 4.61 (d, J = 4.6Hz, 1H), 4.35 (dd, J = 10.8, 6.65Hz, 1H) , 4.21 (s, 2H), 4.15 (dt, J = 10.3, 5.2Hz, 1H), 3.85 (d, J = 7.1Hz, 1H), 3.79-3.71 (m, 2H), 3.69-3.52 (m, 10H ), 3.46-3.38 (m, 2H), 3.34-3.31 (m, 1H), 2.53-2.42 (m, 1H), 2.37-2.21 (m, 8H), 2.20 (s, 3H), 2.08 (dd, J = 15.5, 9.0Hz, 1H), 1.95 (s, 3H), 1.91-1.77 (m, 3H), 1.68 (s, 3H), 1.22-1.16 (m, 6H);
¹³ C-NMR (CDCl ₃ , 75 MHz): δ = 205.1 (C), 175.4 (C), 175.2 (C), 174.5 (C), 171.8 (C), 171.3 (C), 167.6 (C), 142.1 ( C), 140.0 (C), 135.0 (C), 134.6 (CH), 131.3 (C), 131.1 (CH x 2), 129.7 (CH x 4), 128.9 (CH), 128.5 (CH x 2), 85.8 (CH), 83.1 (CH), 83.0 (CH), 82.3 (C), 79.0 (C), 77.5 (CH ₂ ) 76.8 (CH), 76.2 (CH), 74.7 (CH), 72.4 (CH), 72.3 (CH), 69.8 (CH ₂ × 2), 62.6 (CH ₂ ), 62.5 (CH ₂ ), 62.4 (CH ₂ × 2), 59.3 (C), 56.8 (CH), 51.0 (CH), 47.9 (CH ), 44.6 (C), 37.5 (CH ₂ ), 36.6 (CH ₂ ), 36.1 (CH ₂ ), 35.0 (CH ₂ ), 27.0 (CH ₃ ), 23.3 (CH ₂ ), 23.2 (CH ₃ ), 22.4 (CH ₃ ), 20.8 (CH ₃ ), 14.7 (CH ₃ ), 10.5 (CH ₃ );
HRMS (ESI-TOF) m / z calcd for C ₅₄ H ₇₂ N ₂ O ₂₁ Na [M + Na] ⁺ 1107.4525, found 1107.4520

  Example 3-1: 2,5-Dioxopyrrolidin-1-yl 5- (5,11-bis ((1,3-dihydroxypropan-2-yloxy) methyl) -1,15-dihydroxy-2,14 Synthesis of bis (hydroxymethyl) -3,6,10,13-tetraoxapentadecan-8-ylamino) -5-oxopentanoate (11)

  Glycerol derivative (known compound; SYNLETT, 2007, 13, pp.2091-2095) (0.028 g, 0.025 mmol) was dissolved in ethanol (2.5 mL), and palladium hydroxide (0.010 g, 0.071 mmol) was dissolved. In addition, the mixture was stirred at room temperature under a hydrogen atmosphere. Two hours later, the disappearance of the glycerol derivative and the intermediate was confirmed by TLC, and then palladium was filtered off to obtain the objective compound (11) (0.017 g) as a colorless transparent oil. It used for next reaction, without carrying out silica gel column purification.

  Example 3-2

De-N-benzoyl derivative of paclitaxel (known compound) (0.8 mg, 1 μmol) dissolved in N, N-dimethylformamide (0.1 mL), and glycerol derivative (11) (17 mg) obtained in Example 3-1 above. And stirred at room temperature under an argon atmosphere. After 40 hours, the disappearance of the glycerol derivative (11) was confirmed by TLC. Purification was performed by HPLC under the following conditions, and lyophilization was performed to obtain a paclitaxel derivative (1.2 mg, 0.9 μmol) according to the present invention as a white solid in an isolated yield of 81%.
HPLC conditions Column: Tosoh ODS80Ts 4.6 mm × 15 cm
Eluent: Acetonitrile / water = 1/9 (0 min) → 6/4 (20 min) linear change Flow rate: 0.8 mL / min Retention time: 18 min
HRMS (ESI-TOF) m / z calcd for C ₆₆ H ₉₆ N ₂ O ₂₉ Na [M + Na] ⁺ 1403.5996, found 1403.5996

Test Example 1 Measurement of water solubility (1) Preparation of calibration curve In addition to paclitaxel, the paclitaxel derivatives of Example 1 and Comparative Examples 1 and 2 were dissolved in ethanol in order to prepare a calibration curve, and the concentrations were 10 μM, 20 μM, and 40 μM. And an 80 μM solution was obtained. After adding an equal volume of 20 μM acetylsalicylic acid solution as an internal standard substance to each solution, the solution was filtered through a membrane filter (Millipore, Millex (registered trademark) -FG 0.2 μm), and 10 μL was injected into the HPLC system and measured. Went. The measurement conditions of HPLC are as follows.
Column: Nacalai _{Tesque, 5C 18 -AR-II, 4.6mm} × 100mm i. d.
Pump: JASCO, 880-PU type Detector: Hitachi, L-7400 type Data processor: Keyence, NR-2000 type Mobile phase: Acetonitrile / 2 mM phosphate buffer (pH 6.5) = 55/45
Flow rate: 1.1 mL / min
Measurement wavelength: 227nm

  Under the above HPLC conditions, paclitaxel was observed after 3 minutes and 13 seconds, the paclitaxel derivative of Example 1 was observed after 1 minute and 21 seconds, Comparative Example 1 was observed after 1 minute and 58 seconds, and Comparative Example 2 was observed after 2 minutes and 11 seconds. . The calibration curve was prepared by plotting the value obtained by dividing the peak height of each paclitaxel by the peak height of the internal standard on the vertical axis and the concentration of each paclitaxel on the horizontal axis. Both calibration curves were almost straight. The approximate expressions of paclitaxel, Example 1, Comparative Example 1, and Comparative Example 2 are y = 0.1771x, y = 0.0835x, y = 0.1667x, and y = 0.2086x, respectively, and the correlation coefficient is They were 0.991, 0.9971, 0.9934, and 0.9979, respectively.

(2) Measurement of distribution coefficient The experiment for determining the distribution coefficient was performed according to NITE (National Institute of Technology and Evaluation). Specifically, paclitaxel was dissolved in 1-octanol to obtain a 100 μM solution. To each solution, distilled water was added at a volume ratio of 1: 1. Each solution was shaken for 5 minutes at a rotation speed of 20 times / min using a shaker (manufactured by IWAKI), and then centrifuged at 2900 rpm for 20 minutes. After confirming that the two layers were completely separated, 150 μL samples were taken from the 1-octanol layer and the aqueous layer of each solution. The obtained sample was centrifuged to remove the solvent, and then dissolved in ethanol (150 μL). To the obtained solution, a 40 μM ethanol solution (150 μL) of acetylsalicylic acid was added as an internal standard substance. The obtained solution was filtered with a membrane filter (Millipore, Millex (registered trademark) -FG 0.2 μm), and then analyzed by HPLC shown in (1) above. Moreover, it analyzed similarly about the paclitaxel derivative of Example 1 and Comparative Examples 1-2. The measurement was performed 4 times or 5 times. Using the calibration curve prepared in (1) above, the concentration of paclitaxel or paclitaxel derivative in each solution was determined from the obtained measured values. Moreover, the significant difference test regarding the density | concentration in each layer of the paclitaxel derivative of Example 1 and the comparative examples 1-2 with respect to the case where a paclitaxel was used was performed by the Turkey test. Furthermore, the distribution coefficient was calculated | required by the following formula.
Distribution coefficient P = log ₁₀ Pow
Pow: Co / Cw
Co: Test substance concentration in 1-octanol layer (mol / L)
Cw: Test substance concentration in the water layer (mol / L)

  The concentration of paclitaxel or each paclitaxel derivative in the aqueous layer is shown in FIG. 1, and the same concentration in the 1-octanol layer is shown in FIG. In the figure, “*” indicates a case where there is a significant difference with a risk factor p <0.001. Table 1 shows the ratio of the partition coefficient to the concentration of paclitaxel or each paclitaxel derivative in the aqueous layer and 1-octanol layer.

  As shown in Table 1 and FIG. 1, the water-solubility of the paclitaxel derivative of the comparative example was hardly changed or not much changed with respect to paclitaxel. On the other hand, the paclitaxel derivative according to the present invention was significantly more soluble in water than other compounds. Further, as shown in FIG. 2, the paclitaxel derivative of the present invention maintains the property of being easily dissolved in an organic solvent. From the above results, it was demonstrated that the paclitaxel derivative according to the present invention is a compound that has acquired water solubility while retaining the property of being easily dissolved in an organic solvent.

Test Example 2 Anticancer Activity Test Lung adenocarcinoma cells (human A549 lung cells) 3 suspended in PBS in 37 6-week-old male nude mice (CLEA Japan, BALB / cAJc1-nu / nu mice) × 10 ⁶ cell / 200 μL was subcutaneously administered. The mice were divided into 7 control groups and 4 drug administration groups of 6 mice each. Separately, paclitaxel and the paclitaxel derivatives of Example 1 and Comparative Examples 1 and 2 were mixed with saline / polyoxyethylated castor oil (Cremophor EL) /ethanol=7.5/12.5/12.5. Dissolved in. One week after cancer cell ingestion, 200 μL of each solution was intraperitoneally administered to the drug administration group once so that the ratio of paclitaxel or paclitaxel derivative was 3.51 nmol / kg body weight. Mice were bred under a light / dark cycle of 22 ± 2 ° C. and 12 hours. The same amount of physiological saline was similarly administered to the control group. After 0 days, 4 days, 29 days, 35 days and 42 days after the start of administration, the tumor diameter was measured using a venier caliper, and the tumor volume and growth inhibition rate were calculated by the following formula.
Tumor volume ^{(mm 3) = ab 2/} 2 [a: Tumor length, b: width of tumor]
Growth inhibition rate (%) = [(1−average tumor volume in drug administration group) / (average tumor volume in control group)] × 100

  The mean value ± standard deviation (SD) was obtained from the obtained values, analyzed by two-sided ANOVA, and the significant difference of each group was determined by the Turkey test. The results are shown in FIG. Note that “**” in the figure indicates a case where there is a significant difference at a risk rate p <0.05.

  As shown in the results of FIG. 3, when the paclitaxel derivative according to the present invention was administered, after 35 days from the administration of the drug, no significant effect was observed with other drugs, compared to the control group. Tumor volume was significantly reduced. Moreover, the growth inhibition rate of lung adenocarcinoma cells after 42 days when the paclitaxel derivative according to the present invention was administered was 51%, which was significant with respect to the control group. Thus, the anticancer activity of the paclitaxel derivative according to the present invention has been proved by in vivo experiments.

  In the paclitaxel derivative administration group according to the present invention, there were no deaths throughout the experiment, whereas in the paclitaxel administration group, the number of surviving mice was 1 after 4 days from the start of administration, and the paclitaxel derivative administration of Comparative Example 1 was performed. In the group, the number of surviving mice became 2 after 7 days, making it impossible to continue the observation. The reason for this is not clear, but there are cerebral hemorrhages and sepsis, etc. that cannot be denied the causal relationship with the administration of paclitaxel in clinical trials. The death cases of the paclitaxel administration group and the derivative administration group of Comparative Example 1 are considered to be caused by the same cause.

Claims (6)

A paclitaxel derivative represented by the following general formula (I):
[Wherein X is a C _1-6 alkylene group; one or more groups selected from the group consisting of an amino group, an ether group, a thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, and a thiourea group. A C _2-6 alkylene group containing an amino group, an ether group, a thioether group, a carbonyl group, a thionyl group, an ester group, an amide group, a urea group, and a thiourea group. A C _1-6 alkylene group having a terminal; or a C _1-6 alkylene group having two groups selected from the group consisting of a carbonyl group, a thionyl group, an ester group, an amide group, a urea group and a thiourea group at both ends Indicates;
Y represents a linking group for linking 2 ^n-1 glycerol derivative groups to X;
n represents an integer of 1 or more] The paclitaxel according to claim 1, wherein X is a C _2-4 alkylene group having two groups at both ends selected from the group consisting of a carbonyl group, a thionyl group, an ester group, an amide group, a urea group and a thiourea group. Derivative. The paclitaxel derivative according to claim 1 or 2, wherein Y has a divergent branched structure in which the following structure (II) or a plurality of structures (II) are bonded.
[Wherein Y ¹ represents a single bond, a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, an ester group or an amide group; Y ² represents —CH <or —N <. And Y ³ and Y ⁴ each independently represent a single bond, a C _1-6 alkylene group, an amino group, an ether group, a thioether group, a carbonyl group, an ester group or an amide group]   The paclitaxel derivative according to any one of claims 1 to 3, wherein n is 2 or 3.   A pharmaceutical comprising the paclitaxel derivative according to any one of claims 1 to 4.   An anticancer agent comprising the paclitaxel derivative according to any one of claims 1 to 4.