JPH04253981A - Rhizoxin derivative - Google Patents

Abstract

PURPOSE:To provide a new rhizoxin derivative having excellent carcinostatic action, free from toxicity and useful as a treating agent for cancer. CONSTITUTION:The compound of formula I (R<1> is H or 1-20C aliphatic acyl), e.g. 5b-O-seco-5b,7-dihydroxyrhizoxin. The compound can be produced by reacting the carbonyl group of a rhizoxin of formula II [R' is H or CH3(CH2)14 CO] with a hydride reagent such as sodium borohydride in a solvent such as methanol or reducing the carbonyl group in the presence of a Pd/C catalyst in an organic solvent such as methanol at ordinary temperature by catalytic reduction. The compound is administered at a rate of 0.01-1,000mg/kg weight per day.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to novel rhizoxin derivatives having excellent anticancer activity.

0002

[Prior Art] Rhizoxin and its derivatives are known to have anticancer effects (Japanese Patent Application Laid-Open No. 1987-87
reference).

0003

[Problems to be Solved by the Invention] As a result of intensive research efforts, the present inventors have discovered that a new rhizoxin derivative has excellent anticancer activity, and have completed the present invention.

0004

[Means for Solving the Problem] The novel rhizoxin derivative of the present invention has the general formula

[0005]

[C4]

[0006], general formula

[0007]

[C5]

or the general formula

[0009]

[C6]

It is a rhizoxin derivative represented by:

The above formulas (I), (II) and (III)
In the formula (II), R1 represents a hydrogen atom or an aliphatic acyl group having 1 to 20 carbon atoms, and R2 represents a hydrogen atom or a hydroxyl group. Examples of the aliphatic acyl group for R1 include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,
Nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl,
tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, Octadecylcarbonyl, 1-
Mention may be made of methylheptadecylcarbonyl, nonadecylcarbonyl, eicosylcarbonyl and heneicosylcarbonyl.

Specific compounds having formula (I) include those shown in Table 1.

[0013]

[C7]

Specific compounds having formula (II) are shown in Table 2.
I can list the following.

[0015]

[Chemical formula 8]

[0016] Specific compounds having the formula (III) include those shown in Table 3.

[0017]

[Chemical formula 9]

Among the above-mentioned exemplified compounds, preferred compounds include 1
, 2, 5, 9, 11, 12, 13, 14, 25, 26,
Compounds 31, 32, 35 and 39 may be mentioned. Among the above exemplary compounds, more preferable compounds include 1, 9, 11, 12, 17, 18, 25, 26, 3
1 and 39 may be mentioned.

The novel rhizoxin derivative of the present invention can be produced by the method described below. Note that compound (2) can be produced by a known method (see Japanese Patent Application Laid-Open No. 63-246380).

[0020]

[Chemical formula 10]

(i) Carbonyl group reduction step (first and fourth steps)
Process) ■Reaction using zinc in ammonium chloride/water-methanol or water-hydrochloric acid-acetone ■Alkali metal borohydride such as sodium borohydride, lithium borohydride, lithium aluminum hydride , aluminum hydride compounds such as lithium triethoxide aluminum hydride, hydride reagents such as sodium tellurium hydride, alcohols such as methanol, ethanol, ethers, ethers such as tetrahydrofuran, or mixtures of the above. Reactions carried out in solvents - Using catalysts such as palladium on carbon, platinum, or Raney nickel, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and acetic acid. Catalytic reduction reaction at room temperature in a mixed solvent of fatty acids or these organic solvents and water ■Lewis acids such as aluminum chloride, tin tetrachloride, titanium tetrachloride and hydrogenated triethylsilane, hydrogenated triphenylsilane Reactions carried out using silyl hydrides such as tributyltin hydride, triphenyltin hydride, dibutyltin hydride using radical initiators such as azobisisobutyronitrile and triphenylboron as catalysts. This is accomplished in a conventional manner by a reaction of reduction with a radical reducing agent such as tin.

(ii) Ether ring formation step (second step) The reagent used in this step is not particularly limited as long as it does not affect other structural parts, but preferably triphenylphosphine and the like are used. A phosphorus compound and diethyl azodicarboxylate are used in combination. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
Mention may be made of ethers such as dimethoxyethane and pyridine. The reaction temperature is 10°C to 180°C, preferably 20°C to 80°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 0.5 to 4 hours.

(iii) Step of converting a carbonyl group into a thiocarbonyl group (third step) The reagent used in this step is usually not particularly limited as long as it can convert an oxygen atom into a sulfur atom. Preferably, phosphorus pentasulfide, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-
Mention may be made of phosphorus sulfide compounds such as 2,4-disulfide. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, Mention may be made of halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and pyridine. The reaction temperature is 10°C to 180°C,
Preferably the temperature is 20°C to 80°C. The reaction time varies mainly depending on the reaction temperature, the raw material compound, or the type of solvent used, but is usually 0.5 to 4 hours.

The above target compound can be collected, separated and purified by appropriately combining various methods. For example, pour the reaction solution into water to make it slightly acidic, add a solvent that is immiscible with water, such as benzene, ether, ethyl acetate, etc. If there are any insoluble materials, remove them by filtration as appropriate, and after separating the extract,
Obtained by distilling off the solvent. The target compound thus obtained may be further treated with activated carbon, if necessary.
This is carried out by adsorption using various carriers such as silica gel, ion exchange chromatography, reverse phase chromatography, gel filtration using a Sephadex column, or recrystallization using water or an organic solvent such as ether, ethyl acetate, or chloroform.

[0025]

EFFECTS OF THE INVENTION The novel rhizoxin derivatives of the present invention have excellent anticancer activity and are nontoxic, so they are useful as therapeutic agents for cancer. Compounds (I), (II) of the present invention
Examples of the administration form of (III) include oral administration in tablets, capsules, granules, powders, syrups, etc., and parenteral administration in injections, suppositories, etc. These formulations include excipients, binders,
It is manufactured by a well-known method using additives such as a disintegrant, a lubricant, a stabilizer, and a flavoring agent. The dosage varies depending on symptoms, age, etc., but is 0.01-1000mg/kg per day.
The body weight can be administered to adults usually once a day or in several divided doses.

[0026] The present invention will be explained in more detail below with reference to Examples.

[0027]

Examples (Example 1) 5b-O-Seco-5b,7-dihydroxyrhizoxin 200 mg of rhizoxin was dissolved in ethanol, 100 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off and 40 ml of saturated brine was added.
was added and extracted with ethyl acetate. After drying the solution over anhydrous sodium sulfate, it was distilled off, and the residue was purified by silica gel chromatography to obtain 193 mg of the target compound. 1H-NMR spectrum (CDCl3) δpp
m: 1.02 (3H, d), 1.22 (3H, d),
1.36 (3H, s), 1.63-1.75 (3H
, m), 1.82 (3H, s), 1.85-2.0
2 (2H, m), 2.07-2.15 (2H, m),
2.14 (3H, s), 2.25-2.35 (2H
, m), 2.47 (3H, s), 3.00 (1H,
d), 3.04 (1H, d), 3.13 (1H, d
), 3.14 (3H, s), 3.23 (1H, d)
, 3.16 (1H, d), 3.38 (1H, m),
3.75 (2H, m), 4.69 (1H, m),
5.21 (1H, dd), 5.64 (1H, dd),
6.08 (1H, d), 6.26 (1H, s), 6
．． 37 (1H, d), 6.58 (1H, dd), 7
．． 51 (1H, s).

(Example 2) 5b-O-Seco-5b,7-
Dihydroxy-13-O-palmitoylrizoxine 13
Using 500 mg of -O-palmitoylrizoxine, the reaction and treatment were carried out in the same manner as in Example 1, and the target compound 485
mg was obtained.

(Example 3) 180 mg of 5b-desoxyrizoxine triol was mixed with methylene chloride-toluene (1:
2), 70 mg of triphenylphosphine and 70 μl of diethyl azodicarboxylate were added, and the mixture was stirred for 24 hours. After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 90 mg of the target product. 1H-NMR spectrum (CDCl3) δpp
m: 0.60 (1H, dd), 0.79 (1H, dd
), 1.00 (3H, d), 1.10 (3H, d)
, 1.42 (3H, s), 1.48-1.78 (4
H, m), 1.81 (3H, s), 1.85 (1H
, d), 2.02-2.38 (5H, m), 2.1
1 (3H, s), 2.44 (3H, s), 2.86 (
1H, dd), 2.93 (1H, d), 3.00 (1
H, br. s), 3.14 (3H, s), 3.18
-3.27 (2H, m), 3.40 (1H, t),
3.99 (1H, d), 4.60 (1H, d), 5
．． 27 (1H, dd), 5.60 (1H, dd),
6.05 (1H, d), 6.24 (1H, s), 6
．． 34 (1H, d), 6.55 (1H, dd), 7
．． 55 (1H, s).

(Example 4) 5b-desoxy-13-O
-Palmitoylrizoxine 13 Using 500 mg of O-palmitoylrizoxine, reaction and treatment were carried out in the same manner as in Example 1 to obtain the target compound 7.
0 mg was obtained. 1H-NMR spectrum (CDCl3) δpp
m: 0.59 (1H, dd), 0.77 (1H, dd
), 0.87 (3H, t), 1.08 (3H, d)
, 1.20 (3H, d), 1.20-1.40 (2
6H, m), 1.45 (3H, s), 1.51 (1
H, d), 1.60-1.70 (2H, m), 1.
80 (3H, s), 1.92-2.13 (3H, m)
, 2.13 (3H, s), 2.23 (1H, d),
2.36 (3H, m), 2.44 (3H, s),
2.88 (1H, t), 2.93 (1H, d), 3
．． 15 (3H, s), 3.16 (1H, d), 3.
24 (2H, m), 3.30 (1H, dd), 4.
01 (1H, d), 4.23 (1H, d), 4.6
8 (1H, d), 5.23 (1H, dd), 5.6
1 (1H, dd), 6.23 (1H, d), 6.2
6 (1H, s), 6.49 (1H, d), 6.57
(1H, dd), 7.51 (1H, s).

(Example 5) 5b-Hydroxyrhizoxin 65 mg of rhizoxin was dissolved in 1 ml of anhydrous methylene chloride, diisobutylaluminum hydride (1M hexane solution) was added at -78°C under an argon atmosphere, and the reaction temperature was maintained for 3 hours. The temperature was then raised to room temperature. After the reaction, methanol was added, water was added, and the mixture was extracted with ethyl acetate. The treatment was carried out in the same manner as in the examples to obtain 10 mg of the target compound. 1H-NMR spectrum (CDCl3) δpp
m: 0.5-0.9 (2H, m), 1.0 (3H, d
), 1.06 and 1.12 (3H, d and
d), 1.42 (3H, s), 1.62-1.9
2 (4H, m), 1.82 (3H, s), 2.05
-2.40 (7H, m), 2.13 (3H, s),
2.45 (3H, s), 2.93 (1H, d), 3
．． 03 (1H, m), 3.14 (3H, s), 3.
15-3.30 (3H, m), 3.51 (0.6H,
t), 4.11 (1H, dd), 4.60 (0.6H
, d), 4.73 (0.4H, d), 5.29 (2
H, m), 5.60 (1H, dd), 6.06 (1
H, d), 6.23 (1H, s), 6.35 (1H
, d), 6.57 (1H, dd), 7.50 (3H
,s).

Claims (3)

[Claims] [Claim 1] A rhizoxin derivative represented by the general formula [Formula 1] (wherein R1 represents a hydrogen atom or an aliphatic acyl group having 1 to 20 carbon atoms). [Claim 2] Rhizoxin derivatives represented by the general formula [Formula 2] (wherein R1 represents a hydrogen atom or an aliphatic acyl group having 1 to 20 carbon atoms, and R2 represents a hydrogen atom or a hydroxyl group) . 3. A rhizoxin derivative represented by the general formula: [Image Omitted] (wherein R1 represents a hydrogen atom or an aliphatic acyl group having 1 to 20 carbon atoms).