JPH09110865A - Taxol derivative - Google Patents

Abstract

(57) [Summary] (1) The following general formula (1): [In the formula, X is a single bond, an alkylene group having 1 to 6 carbon atoms or a group -CO-Y-R (where Y is a single bond, -O-, -N).
H- or -S-, and R represents an alkylene group having 1 to 6 carbon atoms or a phenylene group.]] Or a salt thereof. [Effect] It has good water solubility and high antitumor activity.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has good water solubility,
The present invention relates to a taxol derivative having high antitumor activity and an antitumor agent containing the same.

[0002]

2. Description of the Related Art Taxol is a Taxus.
brevifolia) bark, a diterpenoid extracted from the bark, and first isolated and structurally determined by Wani et al. in 1971 (J. Am. Chem. So.
c. , 1971, 93, 2325). This product has been reported to show high efficacy against ovarian cancer and breast cancer (Ann. Int. Med., 111, 273, 19).
89).

However, since taxol is a poorly water-soluble compound, it is necessary to use a special solvent to prescribe it as an injectable drug, which makes it difficult to prepare an injectable drug and causes side effects due to the solvent. Was there. For this reason,
In recent years, water-soluble derivatives of taxol have been actively developed (Nicolaou, et al., Nature.
e, 364, 464, 1993), but no satisfactory derivative has been found yet.

[0004]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a novel taxol derivative having improved water solubility and high antitumor activity.

[0005]

DISCLOSURE OF THE INVENTION In view of such circumstances, the present inventor has conducted diligent research, and as a result, a novel compound in which a piperidinopiperidine derivative is bonded to a hydroxyl group of taxol has good water solubility and is taxol. More antitumor activity,
They have found that they are useful as antitumor agents and completed the present invention.

That is, the present invention provides the following general formula (1):

[0007]

Embedded image

[In the formula, X is a single bond, an alkylene group having 1 to 6 carbon atoms or a group -CO-Y-R- (where Y represents a single bond, -O-, -NH- or -S-. Shown, R is 1 carbon
~ 6 represents an alkylene group or a phenylene group)
The present invention provides a taxol derivative represented by or a salt thereof. Further, the present invention provides an antitumor agent comprising the taxol derivative (1) or a salt thereof as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The taxol derivative of the present invention is represented by the above general formula (1), and in the formula, the alkylene group having 1 to 6 carbon atoms represented by X or R is a straight chain or Examples of the branched alkylene group include alkylene groups having 1 to 3 carbon atoms, and specific examples thereof include a methylene group, an ethylene group, a propylene group, and a trimethylene group. The bonding position of the phenylene group represented by R may be ortho, meta, or para. Particularly preferred groups of X, a single _{bond, - (CH 2) 3 -} , -
_{COOCH 2 -, - CO (CH} 2) 2 -, - CONHCH 2
And -COO-phenylene-.

The salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, but mineral salts such as hydrochlorides, sulfates and nitrates, acetates, succinates and fumaric acid. Examples thereof include organic acid salts such as salts. In addition, the compound (1) of the present invention or a salt thereof may exist as a solvate represented by a hydrate.

The taxol derivative (1) of the present invention can be produced, for example, by reacting taxol (2) with a piperidinopiperidine derivative (3) or a carboxylic acid reactive derivative thereof according to the following reaction formula. .

[0012]

Embedded image

[Wherein X is the same as above]

Examples of the carboxylic acid-reactive derivative of piperidinopiperidine include acid halides and mixed acid anhydrides. When the piperidinopiperidine derivative (3) is directly reacted, a suitable condensing agent (for example, dicyclohexyldiimide, diisopropylcarbodiimide,
Such as N-ethyl-N'-3-dimethylaminopropylcarbodiimide, benzotriazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphide salt, diphenylphosphoryl azide, 1,1'-carbonylbis-1H-imidazole It is preferable to carry out the condensation reaction in the presence. The condensation reaction is carried out by using a base such as dimethylaminopyridine in a suitable solvent (eg, toluene, ether, dioxane, tetrahydrofuran (THF), methylene chloride, chloroform, dichloromethane, N, N-dimethylformamide (DMF), pyridine, etc.). It is preferably carried out in the presence and at room temperature.

Since the taxol derivative (1) of the present invention has high solubility in water, it can be made into a pharmaceutical preparation such as an injection without using a special solvent. As a pharmaceutical formulation,
Injectables such as intravenous injections and intramuscular injections are preferable, but in addition to injections, inhalants, liquids such as syrups or emulsions, solid preparations such as tablets, capsules or granules, or external preparations such as ointments and suppositories And so on. In addition, these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants, if necessary. Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cacao butter, magnesium stearate or talc.

The dose of the compound of the present invention when used as an antitumor agent varies depending on the administration method, the age and weight of the patient, the condition of the patient, etc., but is 0.1 to 10 mg per day for adults.
/ Kg body weight is preferable, and this may be administered in several divided doses per day.

[0017]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of 2 '-(4-piperidinopiperidinecarbonyl) taxol: (1) 4-piperidinopiperidine (6 g) was dissolved in benzene (300 ml), and phosgene dimer (5 ml) of benzene was dissolved. The solution (100 ml) was slowly added dropwise at room temperature to 30
Stirred for minutes. The precipitate was collected by filtration and extracted with methylene chloride. The organic layer was washed with potassium carbonate solution, dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography [chloroform-acetone (5
0: 1)] and the eluted TLC single spot fractions were combined to give 5.1 g (60% yield) of 4-piperidinopiperidine carbonyl chloride. (2) Taxol (340 mg, 0.4 mmol) and 4-piperidinopiperidine carbonyl chloride (140 mg, 0.
6 mmol) was dissolved in pyridine (20 ml), dimethylaminopyridine (hereinafter abbreviated as DMAP) (40 mg) was added, and the mixture was stirred at room temperature for 65 hours. A saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1), and the eluting TLC single spot fractions were combined and reduced under reduced pressure. After concentration to dryness, 130 mg (yield 31%) of the title compound was obtained.

Mp: 165-166 ° C IR (KBr, cm ^-1 ): 1715, 1653

¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, J = 7.8Hz, 2H, Ar
H), 7.76 (bs, 2H, ArH), 7.62 (t, J = 7.1Hz, 1H, ArH), 7.52
(m, 3H, ArH), 7.40 (m, 6H, ArH), 7.29 (m, 1H, ArH), 7.08 (d,
_{J = 8.8Hz, 1H, C 3} '-NH), 6.26 (s, 1H, C 10 -H), 6.20 (bt, J = 9.
6Hz, 1H, C ₁₃ -H), 5.85 (dd, J = 8.8,2.6Hz, 1H, C ₃ ^' -H), 5.65
(d, J = 7.1Hz, 1H, C ₂ -H), 5.48 (d, J = 5.1Hz, 1H, C ₂ ^' -H), 4.95
(d, J = 8.3Hz, 1H, C ₅ -H), 4.42 (bs, C ₇ -H), 4.29 (d, J = 8.5H
z, 1H, C ₂₀ -H), 4.17 (d, J = 8.4Hz, 1H, C ₂₀ -H), 4.22-4.12 (b
s, 2H), 3.77 (d, J = 6.6Hz, 1H, C ₃ -H), 2.95-2.63 (bs, 8H),
2.38 (s, 3H, C ₄ -OAc), 2.23 (s, 3H, C ₁₀ -OAc), 2.10-1.35 (m, 1
0H), 1.89 (bs, 3H, C ₁₈ -Me), 1.66 (s, 3H, C ₁₉ -Me), 1.34-1.
08 (m, 2H), 1.22 (s, 3H), 1.12 (s, 3H).

Mass (SIMS): 1048 (M + H) ⁺ .

Example 2 Synthesis of 2 '-[(4-piperidinopiperidinecarbonyloxy) acetyl] taxol: (1) 4-piperidinopiperidinecarbonyl chloride (920 mg, 4 mmol) and ethyl glycolate (1250)
mg, 12 mmol) was dissolved in methylene chloride (40 ml), triethylamine (2.55 ml, 20 mmol) and dimethylaminopyridine (100 mg) were added, and the mixture was stirred at room temperature for 47 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (chloroform), and the eluting TLC single spot fractions were combined to obtain 620 mg of an ethyl ester (yield 52%). A 1N sodium hydroxide solution (2 ml) was added to this ester form (600 mg, 2 mmol), and the mixture was stirred at room temperature for 24 hours. A 1N hydrochloric acid solution (2 ml) was added to the reaction solution, which was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (50% methanol-chloroform) and eluted by TLC.
Single spot fractions were combined to give 500 mg of 4-piperidinopiperidinecarbonyloxyacetic acid (yield 92%). (2) Taxol (260 mg, 0.3 mmol) and 4-piperidinopiperidine carbonyloxyacetic acid (243 mg,
0.9 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and dicyclohexyldiimide (hereinafter abbreviated as DCC) (12)
4 mg, 0.6 mmol) and DMAP (30 mg) were added, and the mixture was stirred at room temperature for 62 hours. The precipitate in the reaction mixture was filtered off, saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography (chloroform: methanol = 9:
Purification according to 1) and eluting TLC single spot fractions were combined and concentrated under reduced pressure to dryness to obtain 140 mg of the title compound (yield 42%).

Mp: 133-135 ° C IR (KBr, cm ^-1 ): 1711, 1655

¹ H-NMR (CDCl ₃ ) δ: 8.13 (d, J = 7.0Hz, 2H, Ar
H), 7.76 (d, J = 11.3Hz, 2H, ArH), 7.63-7.31 (m, 11H, ArH),
6.96 (bs, 1H, C ₃ ^' -NH), 6.28 (s, 1H, C ₁₀ -H), 6.23 (t, J = 8.5
Hz, 1H, C ₁₃ -H), 5.95 (br-d, J = 5.8Hz, 1H, C ₃ ^' -H), 5.67 (d, J
= 7.3Hz, 1H, C ₂ -H), 5.54 (bs, 1H, C ₂ ^' -H), 4.96 (d, J = 7.6H
z, 1H, C ₅ -H), 4.70 (s, 2H, -CH _2- ), 4.43 (bs, 1H, C ₇ -H), 4.3
0 (d, J = 8.2Hz, 1H, C ₂₀ -H), 4.19 (d, J = 8.0Hz, 1H, C ₂₀ -H), 4.
18-4.15 (m, 2H), 3.80 (d, J = 7.1Hz, 1H, C ₃ -H), 2.95-2.03
(m, 10H), 2.41 (s, 3H, C ₄ -OAc), 2.22 (s, 3H, C ₁₀ -OAc), 1.9
8-1.52 (m, 8H), 1.92 (s, 3H, C ₁₈ -Me), 1.67 (s, 3H, C ₁₉ -M
e), 1.50-1.35 (m, 2H), 1.22 (s, 3H), 1.12 (s, 3H).

Mass (SIMS): 1106 (M + H) ⁺ .

Example 3 2 '-[4- (4-piperidinopiperidine) butyryl]
Synthesis of taxol: (1) 4-piperidinopiperidine (3.3 g, 20 mmo
l) and 4-bromobutyric acid ethyl ester (5.0 g, 26 mmol) were added to dimethylformamide (50
ml), sodium iodide (330 mg) was added, and the mixture was stirred at room temperature for 72 hours. The reaction solution was concentrated to dryness under reduced pressure,
The residue was purified by silica gel chromatography (10% chloroform-methanol), and the eluted TLC single spot fractions were combined to give 4.8 g of ethyl ester.
(Yield 85%) was obtained. This ester form (3g, 10mm
1N sodium hydroxide solution (11 ml) was added to
Stir at room temperature for 48 hours. After adding 1N hydrochloric acid solution (11 ml) to the reaction solution, the mixture was concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (50% methanol-chloroform), and the eluting TLC single spot fractions were combined. Thus, 2.3 g (yield 85%) of 4- (4-piperidinopiperidine) butyric acid was obtained. (2) Taxol (100 mg, 0.11 mmol) and 4-
(4-piperidinopiperidine) butyric acid (107 mg,
0.4 mmol) was dissolved in CH ₂ Cl ₂ (20 ml) and DCC was added.
(87 mg, 0.4 mmol) and DMAP (10 mg) were added, and the mixture was stirred at room temperature for 60 hours. The precipitate in the reaction mixture was filtered off, and the filtrate was saturated aqueous sodium hydrogen carbonate solution (100 ml).
Was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the residue was chromatographed on silica gel (chloroform: methanol =
9: 1), and the eluted TLC single spot fractions were combined and concentrated to dryness under reduced pressure to give 100 mg of the title compound.
(Yield 78%) was obtained.

Mp: 167-171 ° C (dec.) IR (KBr, cm ^-1 ): 1731, 1720, 1662.

¹ H-NMR (CDCl ₃ ) δ: 8.09 (d, J = 8.0Hz, 2H, Ar
H), 7.80 (d, J = 7.8Hz, 2H, ArH), 7.16-7.33 (m, 11H, ArH),
7.17 (t, J = 7.7Hz, 1H, C 3 '-NH), 6.24 (s, 1H, C 10 -H), 6.01
(t, J = 8.5Hz, 1H, C ₁₃ -H), 5.87 (dd, J = 9.0,6.5Hz, 1H, C ₃ ^' -
H), 5.60 (d, J = 7.0Hz, 1H, C ₂ -H), 5.51 (d, J = 5.8Hz, 1H, C ₂ ^' -
H), 4.93 (d, J = 9.5Hz, 1H, C ₅ -H), 4.39 (dd, J = 10.5,7.0Hz, 1
H, C ₇ -H), 4.26 (d, J = 8.3Hz, 1H, C ₂₀ -H), 4.14 (d, J = 8.5Hz, 1
H, C ₂₀ -H), 3.71 (d, J = 6.8Hz, 1H, C ₃ -H), 3.06-2.04 (m, 11
H), 2.45 (s, 3H, C ₄ -OAc), 2.18 (s, 3H, C ₁₀ -OAc), 2.04-1.4
2 (m, 19H), 1.85 (s, 3H, C ₁₈ -Me), 1.62 (s, 3H, C ₁₉ -Me), 1.2
2 (s, 3H), 1.16 (s, 3H).

Mass (SIMS): 1090 (M + H) ⁺ .

Example 4 Synthesis of 2 '-[(4-piperidinopiperidinecarbamido) acetyl] taxol: (1) 4-piperidinopiperidine carbonyl chloride (920 mg, 4 mmol) and glycine ethyl hydrochloride (2780)
mg, 20 mmol) was dissolved in methylene chloride (80 ml), triethylamine (5.1 ml, 40 mmol) and dimethylaminopyridine (100 mg) were added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (chloroform), and the eluted TLC single spot fractions were combined to obtain 950 mg of ethyl ester (yield 80%). A 1N sodium hydroxide solution (2 ml) was added to this ester compound (600 mg, 2 mmol), and the mixture was stirred at room temperature for 36 hours. A 1N hydrochloric acid solution (2 ml) was added to the reaction solution, which was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (50% methanol-chloroform) and eluted by TLC.
The single spot fractions were combined to give 510 mg (94% yield) of 4-piperidinopiperidinecarbamidoacetic acid. (2) Taxol (38 mg, 0.044 mmol) and 4-piperidinopiperidinecarbamidoacetic acid (40 mg, 0.15
mmol) in CH ₂ Cl ₂ (15 ml) and DCC (30 ml)
mg, 0.15 mmol) and DMAP (4.5 mg) were added, and the mixture was stirred at room temperature for 60 hours. The precipitate in the reaction mixture was filtered off,
A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography (chloroform: methanol = 9:
Purified by 1), the eluted TLC single spot fractions were combined and concentrated to dryness under reduced pressure to give 48 mg of the title compound (yield 9
6%) was obtained.

Mp: 205-209 ° C (dec.) IR (KBr, cm ^-1 ): 1740, 1710, 1639.

¹ H-NMR (CDCl ₃ ) δ: 8.11 (d, J = 7.8Hz, 2H, Ar
H), 7.81 (d, J = 7.8Hz, 2H, ArH), 7.62-7.38 (m, 11H, ArH),
7.27 (bs, 1H, C ₃ ^' -NH), 6.29 (s, 1H, C ₁₀ -H), 6.16 (t, J = 7.0H
z, 1H, C ₁₃ -H), 5.92 (dd, J = 8.5,4.1Hz, 1H, C ₃ ^' -H), 5.66 (d,
J = 7.1Hz, 1H, C ₂ -H), 5.52 (d, J = 4.1Hz, 1H, C ₂ ^' -H), 4.95 (d,
J = 9.5Hz, 1H, C ₅ -H), 4.39 (dd, J = 10.7,6.8Hz, 1H, C ₇ -H), 4.
29 (d, J = 8.2Hz, 1H, C ₂₀ -H), 4.18 (d, J = 8.4Hz, 1H, C ₂₀ -H),
3.76 (d, J = 7.1Hz, 1H, C ₃ -H), 2.80-2.44 (m, 11H), 2.39 (s,
3H, C ₄ -OAc), 2.21 (s, 3H, C ₁₀ -OAc), 2.00-1.55 (m, 8H),
1.89 (s, 3H, C ₁₈ -Me), 1.67 (s, 3H, C ₁₉ -Me), 1.47 (m, 2H),
1.20 (s, 3H), 1.13 (s, 3H).

Mass (SIMS): 1105 (M + H) ⁺ .

Example 5 Synthesis of 2 '-[4- (4-piperidinopiperidinecarbonyloxy) benzoyl] taxol: (1) 4-piperidinopiperidinecarbonyl chloride (920 mg, 4 mmol) and p-hydroxybenzoic acid. Ethyl (3320 mg, 20 mmol) was dissolved in methylene chloride (50 ml), triethylamine (5.5 ml, 40 mmol) was added, and the mixture was stirred at room temperature for 50 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (chloroform), and the eluted TLC single spot fractions were combined to give 1340 mg of ethyl ester (yield 93
%). This ester (1000mg, 2.77mm
ol) was dissolved in a mixture of ethanol-water (1: 1) (25 ml), and lithium hydroxide monohydrate (204 mg, 2.78 mmo).
l) was added and the mixture was stirred at room temperature for 36 hours. A 1N hydrochloric acid solution (2.78 ml) was added to the reaction solution, which was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (40% methanol-chloroform) and eluted by TLC.
The single spot fractions were combined and 380 mg of p- (4-piperidinopiperidinecarbonyloxy) benzoic acid (yield 4
2%). (2) Taxol (30 mg, 0.035 mmol) and p-
(4-Piperidinopiperidinecarbonyloxy) benzoic acid (53 mg, 0.16 mmol) was dissolved in CH ₂ Cl ₂ (10 ml), and DCC (30 mg, 0.15 mmol) and DMAP were added.
(4.5 mg) was added and the mixture was stirred at room temperature for 60 hours. The precipitate in the reaction mixture was filtered off, saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) and eluted TL.
The C single spot fractions were combined and concentrated to dryness under reduced pressure to obtain 39 mg (yield 95%) of the title compound.

Mp: 175-177 ° C (dec.) IR (KBr, cm ^-1 ): 1715, 1664.

¹ H-NMR (CDCl ₃ ) δ: 8.12 (d, J = 8.3Hz, 2H, Ar
H), 8.00 (d, J = 8.7Hz, 2H, ArH), 7.76 (d, J = 8.3Hz, 2H, ArH),
7.62-7.20 (m, 13H, ArH) , 7.05 (d, J = 9.0Hz, 1H, C 3 '-NH),
6.29 (s, 1H, C ₁₀ -H), 6.25 (t, J = 7.0Hz, 1H, C ₁₃ -H), 6.03 (m,
^{_{1H, C 3 '-H),}} 5.66 (m, 2H, C 2 -H and C 2' -H), 4.96 (d, J = 9.7H
_{z, 1H, C 5 -H)} , 4.45 (m, 1H, C 7 -H), 4.30 (d, J = 8.5Hz, 1H, C 20 -
H), 4.19 (d, J = 8.5Hz, 1H, C ₂₀ -H), 3.81 (d, J = 7.1Hz, 1H, C _3-
H), 3.01 (br-t, 1H), 2.85 (br-t, 1H), 2.62-2.42 (m, 7H),
2.43 (s, 3H, C ₄ -OAc), 2.31 (m, 1H), 2.22 (s, 3H, C ₁₀ -OAc),
2.11 (m, 1H), 2.00 (s, 3H, C ₁₈ -Me), 1.64 (s, 3H, C ₁₉ -Me),
1.63-1.40 (m, 10H), 1.22 (s, 3H), 1.13 (s, 3H).

Mass (SIMS): 1168 (M + H) ⁺ .

Example 6 2 '-[3- (4-piperidinopiperidinecarbonyl)
Synthesis of propionyl] taxol: (1) 4-piperidinopiperidine (3.3 g, 20 mmo
l) and ethylsuccinic acid monochloride (3.9 g, 24 mmo)
l) was dissolved in dimethylformamide (50 ml), sodium iodide (330 mg) was added, and the mixture was stirred at room temperature for 72 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was chromatographed on silica gel (10% chloroform-methanol).
The TLC single-spot fractions that had been purified by and were eluted were combined to obtain 5 g of ethyl ester (yield 85%). This ester form (1 g, 3.3 mmol) was dissolved in an ethanol-water (1: 1) mixture (30 ml), and lithium hydroxide 1
Add hydrate (282 mg, 3.78 mmol) and add 2 at 70 ° C.
It was stirred for 036 hours. 1N hydrochloric acid solution (3.
(78 ml) and then concentrated to dryness under reduced pressure, the residue was purified by silica gel chromatography (50% methanol-chloroform), and the eluted TLC single-spot fractions were combined and combined with 3- (4-pyrone). 500 mg (yield 55%) of peridinopiperidinecarbonyl) propanoic acid was obtained. (2) Taxol (38 mg, 0.044 mmol) and 3-
Dissolve (4-piperidinopiperidinecarbonyl) propanoic acid (24 mg, 0.088 mmol) in CH ₂ Cl ₂ (10 ml) and add DCC (18 mg, 0.088 mmol) and DMAP.
(4.5 mg) was added and the mixture was stirred at room temperature for 60 hours. The precipitate in the reaction mixture was filtered off, saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 9: 1) and eluted TL.
The C single spot fractions were combined and concentrated to dryness under reduced pressure to obtain 30 mg of the title compound (yield 63%).

Mp: 142-143 ° C IR (KBr, cm ^-1 ): 1741, 1725, 1631

¹ H-NMR (CDCl ₃ ) δ: 8.12 (d, J = 8.3Hz, 2H, Ar
H), 7.81-7.30 (m, 13H, ArH), 7.25 (m, 1H, C ₃ ^' -NH), 6.28
(s, 1H, C ₁₀ -H), 6.19 (t, J = 7.0Hz, 1H, C ₁₃ -H), 5.89 (m, 1H, C
^{_{3 '-H), 5.67 (d}} , J = 7.0Hz, 1H, C 2 -H), 5.47 (d, J = 4.2Hz, 1H, C
^{_{2 '-H), 4.96 (d}} , J = 9.0Hz, 1H, C 5 -H), 4.60 (d, J = 13Hz, 1H),
4.43 (m, 1H, C ₇ -H), 4.30 (d, J = 8.3Hz, 1H, C ₂₀ -H), 4.19 (d, J
= 8.3Hz, 1H, C ₂₀ -H), 3.84 (d, J = 13Hz, 1H), 3.79 (d, J = 6.8H
z, 1H, C ₃ -H), 2.99 (m, 1H), 2.79 (m, 2H), 2.78-2.39 (m, 9
H), 2.40 (s, 3H, C ₄ -OAc), 2.31 (m, 1H), 2.22 (s, 3H, C ₁₀ -OA
c), 2.11 (m, 1H), 1.91 (s, 3H, C ₁₈ -Me), 1.90-1.40 (m, 8H),
1.67 (s, 3H, C ₁₉ -Me), 1.22 (s, 3H), 1.13 (s, 3H).

Mass (SIMS): 1104 (M + H) ⁺ .

Example 7 Synthesis of 2 '-[3- (4-piperidinopiperidinecarbonyloxy) benzoyl] taxol: (1) 4-piperidinopiperidinecarbonyl chloride (2.3 g, 10 mmol) and m-hydroxy. Ethyl benzoate (3320 mg, 20 mmol) was added to methylene chloride (50 ml).
Was dissolved in, triethylamine (5.5 ml, 40 mmol) was added, and the mixture was stirred with heating under reflux for 50 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography (4
% Methanol-chloroform), and the eluted TLC single spot fractions were combined to obtain 1820 mg (55%) of an ethyl ester form. This ester form (170
0 mg, 4.75 mmol) was dissolved in an ethanol-water (1: 1) mixture (30 ml), and lithium hydroxide (349 mg, 4.3 mg) was added.
76 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After adding 1N hydrochloric acid solution (4.76 ml) to the reaction solution, the mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography (40%).
(Methanol-chloroform) and elute T
The LC single spot fractions were combined to give 970 mg of m- (4-piperidinopiperidinecarbonyloxy) benzoic acid (63% yield). (2) Taxol (30 mg, 0.035 mmol) and m-
(4-Piperidinopiperidinecarbonyloxy) benzoic acid (53 mg, 0.16 mmol) was dissolved in CH ₂ Cl ₂ (10 ml), and DCC (30 mg, 0.15 mmol) and DMAP were added.
(5 mg) was added, and the mixture was stirred at room temperature for 60 hours. The precipitate in the reaction mixture was filtered off, saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the filtrate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure,
The residue was chromatographed on silica gel (chloroform:
Purification by methanol = 9: 1), the elution TLC single spot fractions were combined and concentrated under reduced pressure to dryness to obtain 20 mg (yield 49%) of the title compound.

Mp: 165-167 ° C IR (KBr, cm ^-1 ): 1724, 1651

¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, J = 8.3 Hz, 2 H, Ar
H), 7.83-7.76 (m, 4H, ArH), 7.64-7.60 (m, 1H, ArH), 7.53-
7.29 (m, 12H, ArH) , 7.18 (br, 1H, C 3 '-NH), 6.29 (s, 1H, C 10 -
H), 6.22 (t, J = 10.2Hz, 1H, C ₁₃ -H), 6.03 (m, 1H, C ₃ ^' -H),
5.68 (m, 2H, C ₂ -H and C ₂ ^' -H), 4.96 (d, J = 9.0Hz, 1H, C _5-
H), 4.45 (m, 1H, C ₇ -H), 4.30 (d, J = 8.3Hz, 1H, C ₂₀ -H), 4.18
(d, J = 8.3Hz, 1H, C ₂₀ -H), 3.80 (d, J = 6.8Hz, 1H, C ₃ -H), 2.98
(br-t, 1H), 2.83 (br-t, 1H), 2.64-2.50 (m, 7H), 2.42 (s, 3
H, C ₄ -OAc), 2.29 (m, 1H), 2.22 (s, 3H, C ₁₀ -OAc), 2.09 (m, 1
H), 1.94 (s, 3H, C ₁₈ -Me), 1.67 (s, 3H, C ₁₉ -Me), 1.62-1.4
4 (m, 10H), 1.22 (s, 3H), 1.13 (s, 3H).

Mass (SIMS): 1168 (M + H) ⁺ .

Example 8 Preparation Method of Hydrochloride: To the compounds obtained in Examples 1 to 7, 1.1 molar equivalent of 0.02N hydrochloric acid aqueous solution was added,
After dissolving the sample, it was freeze-dried to obtain the hydrochloride.

Test Example 1 Measurement of Antitumor Activity The compounds of the present invention were tested for antitumor effect as follows. Mouse leukemia L1210 cells and human leukemia R
The effects on PMI-8402 cells are shown below. Test method: Target is mouse leukemia cell line (L1210)
And human T-cell lymphoblastic leukemia cell line (RPM
I-8402), RP 5 × 10 ⁵ cells / ml of each cell
MI-1640 and 10-15% (15% in human cells)
Fetal bovine serum (Gibco) culture medium at 5% CO ₂
Cultivated under the condition of 7 ℃, and added various concentrations (10,1,0.1μg / ml) of the test substance to the culture solution, and in the case of mouse leukemia cells, killed every 10 hours for 3 days. The number of dead cells was calculated every 24 hours for human leukemia cells for 6 days, and after 3 days for mouse leukemia and for human leukemia cells, the percentage of dead cells 6 days after the start of the test was compared with the initial cells. It was defined as the cell killing effect of the substance. For the determination of dead cells, the in vitro anticancer drug action prediction test developed by Koguro (Jpn. J. Cancer Res., 76:
131-141, 1985). The above experimental results are shown in Tables 1 and 2.

[0048]

[Table 1]

[0049]

[Table 2]

Test Example 2 Solubility Measurement: The compounds of the present invention were tested for solubility in water as follows. Test method: 5 mg of the compound of Example 4 was weighed, purified water was added, and the mixture was shaken for 24 hours, and the solubility was calculated from the amount determined when the compound was visually dissolved. The results are shown below. Example 4: 0.25 mg / ml Taxol: 0.03 mg / ml

[0051]

INDUSTRIAL APPLICABILITY The novel taxol derivative of the present invention has good water solubility and high antitumor activity, and is therefore useful as an antitumor agent.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Atsuhiro Abe 1-1-19 Higashishimbashi, Minato-ku, Tokyo Yakult Honsha Co., Ltd. (72) Inventor Seigo Sawada 1-1-1 Higashishimbashi, Minato-ku, Tokyo No. 19 Stock Company Yakult Head Office

Claims (2)

[Claims] 1. The following general formula (1): [In the formula, X is a single bond, an alkylene group having 1 to 6 carbon atoms or a group -CO-Y-R- (where Y is a single bond, -O-,-
Represents NH- or -S-, and R represents an alkylene group having 1 to 6 carbon atoms or a phenylene group.]] Or a salt thereof. 2. An antitumor agent comprising the taxol derivative or its salt according to claim 1 as an active ingredient.