JPH03101680A - Z-rhizoxin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is H or acyl expressed by the formula R1CO; R1 is alkyl; A is single bond or O). USE:An antitumor agent. PREPARATION:A compound expressed by formula II is brought into contact with a carboxylic acid (reactive derivative) having the formula R1COOH, as necessary, in the presence of a condensing agent (e.g. dicyclohexylcarbodiimide).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel zoxin derivative, a method for producing the same, and an antitumor agent using the same as an effective ingredient.

Rhizoxin itself is known to have the following structural formula.The present inventors continued research to improve the antitumor effect of rhizoxin in vivo, and as a result, a novel Z
- Discovered a rhizoxin derivative and perfected the present invention.

The novel Z-rhizoxin derivative of the present invention has the formula 1111 (wherein R represents a hydrogen atom or an acyl group represented by R or Co. A represents a single bond or an oxygen atom), a pharmacologically acceptable salt thereof, or a closed ring lactone thereof.

In the general formula (r), R is a hydrogen atom or l? ，
It represents an acyl group represented by Co, and R1 represents a linear or branched alkyl group.

Examples of such R include methyl, ethyl, n-propyl, 1-methylethyl, n-7'thyl, 1-methylpropyl, 2-methylpropyl, 1.1-dimethylethyl, n-pentyl, 3-Methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylbubutyl, n-hexyl, 1-methylpentyl, 2-methylbentyl, 3-
Methylpentyl, 4-methylpentyl, n-heptyl,
l-Methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, n-octyl, 2-methylheptyl, 6-methylheptyl, 2-ethylhexyl, 2-ethyl-3-methylpentyl, 3-ethyl -2
-methylpentyl, n-nonyl, 2-methyloctyl,
7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl, 2-ethyl-1-methylhexyl, n-decyl, 2-methylnonyl, 8-methylnonyl, 5-ethyloctyl, 3-ethyl-2 -Methylheptyl, 3,3-diethylhexyl, n-undecyl, 2-
Methyldecyl, 9-methyldecyl, 4-ethylnonyl,
3.5-dimethylnonyl, 3-probyloctyl, 5-
Ethyl-4-methyloctyl, n-dodecyl, 1-methylundecyl, 10-methylundecyl, 3-ethyldecyl, 5-probylnonyl, 3.5-diethyloctyl, n-tridecyl, I1-methyldodecyl, 7-ethyl undecyl, 4-propyldecyl, 5-ethyl-3-
Methyldecyl, 3-pentyloctyl, n-tetradecyl, 12-methyltridecyl, 8-ethyldodecyl, 6
-probylundecyl, 4-butyldecyl, 2-pentylnonyl, n-pentadecyl, l3-methyltetradecyl, 10-ethyltridecyl, 7-probildodecyl,
5-ethyl-3-methyldodecyl, 4-pentyldecyl, n-hexadecyl, 14-methylbentadecyl, 6-
Ethyltetradecyl, 4-probyltridecyl, 2-butyldodecyl, n-hebutadecyl, 15-methylhexadecyl, 7-ethylpentadecyl, 3-probyltetradecyl, 5-bentodecyl, n-occudecyl, 1
6-methylhebutadecyl, 5-propylbentadecyl,
n-nonadecyl, 17-methyloctadecyl, 4-ethylhebutadecyl, icosyl, 18-methylnonadecyl, 3-ethyloctadecyl, henicosyl, docosinyl,
Examples include tricosinyl, tetracosinyl, and pentacosinyl. Among these alkyl groups, straight chain or branched chain alkyl groups having 2 to 20 carbon atoms are preferred. Particularly preferably 3 to 1 carbon atoms
It is a straight-chain or branched-chain alkyl group having 7, preferably 7 to 16 atoms.

The pharmaceutically acceptable salt of the compound having the general formula (I) of the present invention is, for example, a metal salt, an ano acid salt or an amine salt. Examples of metal salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts. Among them, alkali metal salts, alkaline earth metal salts and aluminum salts are preferred, and sodium salts, potassium salts, calcium salts and aluminum salts are most preferred. Preferred amino acid salts include basic amino acids such as arginine, lysine, histidine, α,γ-diagonobutyric acid, and ornithine. Suitable examples of Adan salts include t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkyl ester, and D-glucosamine.

The ring-closed lactone form of the compound having the general formula (1) above refers to a compound in which formula (1) is represented by the following ring-closed structure 2.

(In the formula, R and A have the same meanings as defined above.) Examples of the carboxylic acid having the general formula (1) obtained by the present invention, a pharmacologically acceptable salt thereof, or a closed ring lactone thereof are as follows. Examples include the compounds described in . However, hereinafter, Z-rhizoxin has the general formula (n)
Among these, R represents an isomer of rhizoxin, in which R is a hydrogen atom and A is an oxygen atom.

1. Z-rizoxin butanoic acid ester 5b-carboxylic acid 2. 2-Rizoxine bencitrate 5b-carboxylic acid 3.2-Rizoxine-3-methylbutanoate 5
b-carboxylic acid 4.2-rizoxine hexanoate 5b-carboxylic acid 5.2-rizoxine-3,3-dimethylbutanoate 5b=carboxylic acid 6.2-rizoxine hexanoate 5b-carboxylic acid 7 .2-Rizoxin-5-methylhexanoic acid ester
5b-carboxylic acid8. Z-rhizoxin-4-methylhexanoic acid ester
5b-carboxylic acid 9. 2-Rizoxine octanoate 5b-carboxylic acid 10. 2-Rizoxine-6-methylhebutanoate 5b-monocarboxylic acid 11. 2-Rizoxine-4-ethylhexanoate 5b-carboxylic acid 12, Z-rizoxine nonanoate 5b-carboxylic acid 13. Z-Rhizoxin-4-ethyl-3-methylhexanoate 5b-carboxylic acid 14, Z-Rhizoxin-7-methyloctanoate 5b-carboxylic acid 15. 2-Rizoxine decanoate 5b-carboxylic acid 16.2-Rizoxine-8-methylnonylate
5b-carboxylic acid 17.2-rizoxine-5-ethyloctanoate 5b-carboxylic acid 18.2-rizoxine undecanoate 5b-carboxylic acid 19.2-rizoxine-9-methyldecanoate
5b monocarboxylic acid 20.2-rizoxine-6-ethylnonanoate ester
5b-carboxylic acid 21.2-rizoxine dodecanoic acid ester 5b-carboxylic acid 22. Z-Rizoxin-10-methylundecanoic acid ester 5b-carboxylic acid 23. Z-Rizoxin-6-ethyl-5-methylnonanoate 5b-carboxylic acid 24.2-Rizoxine tridecanoate 5b-carboxylic acid 25.2-Rizoxin-11-methyldodecanoate 5b-carboxylic acid 26.2- Rhizoxin-4,6-diethylnonanoate 5b-carboxylic acid 27.2-Rizoxinetetradecanoate 5b-carboxylic acid 28.2-Rizoxin-8-ethyldodecanoate 5b-carboxylic acid 29.2-Rizoxinepentadecane Acid ester 5b monocarboxylic acid 30.2-rizoxine-9-ethyltridecanoate 5b monocarboxylic acid 31.2-rizoxine hexadecanoate 5b-carboxylic acid 32.2-rizoxine-8-propyltridecanoate ester 5b-carboxylic acid 33. 2-Rizoxine heptadecanoate 5b monocarboxylic acid 34. 2-Rizoxine-7-ethylbentadecanoate 5b monocarboxylic acid 35. 2-Rizoxine octadecanoate 5b-carboxylic acid 36. 2-Rizoxine-8-ethylhexadecanoic acid ester 5b monocarboxylic acid 37. Z-Rizoxin nonadecanoate 5b monocarboxylic acid 38. 2-Rizoxin icosanoate 5b carboxylic acid 39. 2-Rizoxin-2-enehebutanoate 5b-carboxylic acid 40. 2-Rizoxin-2-ene-octanoic acid ester 5b-carboxylic acid 41.2-rizoxin-2-ene nonanoic acid ester
5b-carboxylic acid 42.2-rizoxin-2-ene-7-methyloctanoate 5b-carboxylic acid 43.2-rizoxin-2-ene-decanoate ester
5b-carboxylic acid 44.2-rizoxin-2-en-8-methylnonanoate 5b-carboxylic acid 45.2-rizoxin-2-ene-undecanoate 5b-carboxylic acid 46.2-rizoxin-2-ene-9-methyldecanoate 5b-monocarboxylic acid 47.2-rizoxin-2-endodecanoic acid ester 5b-carboxylic acid 48.2-rizoxin-2-endodecanoic acid ester 5b-carboxylic acid and their pharmacologically acceptable salts and closed ring lactones thereof.

The carboxylic acid having the general formula (1), its pharmacologically acceptable salt, or its ring-closed lactone has various geometric isomers depending on the arrangement of substituents. Furthermore, various optical isomers also exist due to the presence of asymmetric carbon atoms. In the general formula (I), these isomers and mixtures of these isomers are all represented by a single formula. Therefore, the present invention includes all of these isomers and mixtures of these isomers. Compound (1)
is approved by method A or method B described below.

Method A 2 Among the target compounds of the present invention, the ring-closed lactone (the above general formula (■)) is a compound having the formula (wherein A has the same meaning as described above), and is converted into a compound having the formula R, COOH ( IV
) (wherein R has the same meaning as defined above) or a reactive derivative thereof. This reaction can be carried out by conventional acylation reaction means. When the carboxylic acid having the general formula (■) is used in free form, a suitable condensing agent is used.

Examples of the condensing agent include dehydrating agents such as dicyclohexylcarbodiimide and carbonyldiξdazole.

When a reactive derivative of a carboxylic acid having the general formula (IV) is used, examples thereof include acid halides or acid anhydrides such as acid chloride and acid bromide.

If acid halides are used, this is advantageously carried out in an inert organic solvent in the presence of an acid binder. Examples of solvents include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and trichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; dimethyl Fatty acid dialkylamides such as formamide and dimethylacetate; nitriles such as acetonitrile; ketones such as acetone; dimethyl sulfoxide; and pyridine. Examples of acid binders include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylane, pyridine, 4-dimethylaminopyridine, Organic bases such as 1-methylimidazole are preferably used. The reaction is usually carried out at -10 to 130°C.

When using an acid anhydride, in the presence of an inert organic solvent,
Alternatively, it is carried out using an excess of acid anhydride in the absence of an inert organic solvent. As the solvent, aromatic hydrocarbons such as benzene, toluene, and xylene; dioxane; ethers such as tetrahydrofuran, diethylene glycol, and dimethyl ether are preferably used. The reaction is usually carried out at room temperature to 160°C.

Production method B: The target compound of the present invention has the formula OCH3 (wherein, R represents a hydrogen atom or an acyl group represented by RICO. R represents a linear or branched alkyl group. A represents a single It can be obtained by dissolving a rhizoxin derivative consisting of a carboxylic acid having a bond or an oxygen atom (representing a bond or an oxygen atom) or a ring-closed lactone thereof in an organic solvent and irradiating the solution with light. Examples of organic solvents used include benzene,
Aromatic hydrocarbons such as toluene and xylene; Norogenated aliphatic hydrocarbons such as chloroform, dichloromethane and trichloroethane; Ethers such as dimethyl ether, tetrahydrofuran and dioxane; Dimethylformamide and dimethylacetamide Aliphatic dialkyladands; nitriles such as acetonitrile; ketones such as acetone; dimethyl sulfoxide; pyridine; alcohols such as ethanol are preferably used.

The reaction is usually carried out at -10 to 100'C. The light irradiation is performed by irradiating natural sunlight or light in the ultraviolet and visible regions for several hours, and the reaction after irradiation is treated according to a conventional method to obtain compound (r).

Next, among the objective compounds of the present invention, a pharmacologically acceptable salt of a carboxylic acid having the general formula (1) is prepared by reacting the ring-closed lactone form of the objective compound (general formula (■)) with a base. obtained by letting All of the methods are conventional methods, such as the following methods.

The metal salt of carboxylic acid can be obtained by contacting the hydroxide, carbonate, etc. of the metal with the ring-closed lactone in an aqueous solvent. Examples of aqueous solvents used include water; alcohols such as methanol and ethanol; ethers such as dimethoxyethane and dioxane; and organic solvents such as acetone, n-hexane, ethyl acetate, dimethylformamide, dimethylsulfoxide, and pyridine. A mixed solvent with water is preferred. Particularly suitable is a mixed solvent of a hydrophilic organic solvent and water. The reaction is normally suitably carried out at around room temperature, but may be carried out under heating if necessary.

The amine salt of carboxylic acid can be obtained by contacting the amine with the ring-closed lactone in an aqueous solvent. Examples of the aqueous solvent used include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; mixed solvents of nitriles such as acetonitrile and water; however, hydrous acetone is preferable. be. The reaction is usually preferably carried out at pH 7 to 8.5 and below room temperature, particularly at 5 to 10"C. The reaction is completed instantaneously. Alternatively, for example, the carboxylic acid metal salt obtained above is dissolved in an aqueous solvent, and then It can also be obtained by adding a mineral acid salt (for example, hydrochloride) of the desired amine under the above conditions and carrying out a salt exchange reaction.

The amino acid salt of carboxylic acid can be obtained by contacting the amino acid with the ring-closed lactone in an aqueous solvent.

Examples of the aqueous solvent used include water, alcohols such as methanol and ethanol, and mixed solvents of water and ethers such as tetrahydrofuran. The reaction is usually carried out under heating, preferably around 50 to 60°C.

Next, among the target compounds of the present invention, the carboxylic acid having the general formula (I) is a carboxylic acid having the general formula (I) among the target compounds.
It is obtained by contacting a pharmacologically acceptable salt of a carboxylic acid having 1) with an acid. The method is a conventional method, for example the following method. That is, the obtained pharmacologically acceptable salt of the carboxylic acid having the general formula (I) is preferably dissolved in a solvent such as methanol, acetone, dimethylformamide, or dimethyl sulfoxide, and an equivalent to a slight excess of the acid is dissolved. obtained by adding The acid used is not limited to organic acids or mineral acids as long as it does not affect the target compound; for example, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. are preferably used.

The target compound thus obtained can be collected, separated, and purified by appropriately combining various methods. For example, pour the reaction solution into water, use a solvent that is immiscible with water,
For example, extract with benzene, ether, ethyl acetate, etc.
It is obtained by distilling off the solvent from the extract. If necessary, the target compound thus obtained may be further processed by adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or by gel analysis using a Sephadefex column, /lFA, ether, ethyl acetate, chloroform, etc. This is done by recrystallization using an organic solvent.

The rhizoxin derivative of the present invention is derived from P388 transplanted into mice.
It showed strong antitumor effects against cells. Therefore, the lyzoxin derivatives of the present invention can be used as antitumor agents for these neoplastic diseases in warm-blooded animals including humans. The administration forms include intravenous injection, subcutaneous injection, intramuscular injection, parenteral administration such as suppositories, tablets, etc.
Oral administration methods include capsules, powders, and granules.

The dosage for adults varies depending on the target disease, route of administration, number of administrations, period, etc., but usually 1 to 100 mg per day is administered once or in divided doses.

It may also be used in combination with other anticancer drugs, such as nitrosourea drugs such as ACNU and BCNU, cisplatin, 5-FU, daunomycin, adriamycin, mitomycin C, or etoboside. Additionally, rhizoxin derivatives can be prepared for administration in any conventional manner. Therefore, the present invention also includes preparations and compositions containing zoxin derivatives that are suitable as pharmaceuticals. Compositions for injection may be presented in unit-dose ampoules or in multi-dose containers. The compositions may contain additives such as suspending, stabilizing, and dispersing agents and are usually redissolved in a suitable solvent, e.g. a sterile, pyrogen-free aqueous medium, before use. It may be. Such a formulation is prepared, for example, by dissolving the zoxin derivative in acetone, dispensing it into vials, adding water, and freeze-drying. Furthermore, oral compositions are provided in the form of tablets, capsules, powders, granules, syrups, etc. containing an appropriate amount of the zoxin derivative for administration.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Z-Rysoxin 1g of z-Rysoxin in 5ml of acetonitrile? The mixture was dissolved and irradiated with ultraviolet autofade meter at room temperature for 150 minutes at a distance of 25 cm. After the irradiation, the product was loaded onto a DS (octadecylsilane)-based preparative reverse phase chromatography column and eluted with 100% acetonitrile as a solvent to obtain a crude product of Z-rhizoxin. This was subjected to column chromatography again under the same conditions to obtain the target product in a yield of 6.
Obtained in %.

MS spectrum m/e 625: (M''')U
V Shek}/I/ (CH:+CN)A-(g) :2
30 (sh), 311.3 (3.56X10'
) NMR (CDC 1 3) spectrum: δ (pp
m) Signal pattern Number of protons
j hanging IXO. 82 d. t
I H-4(α
)0.95 dt 1
tl-6(α)1.02
d3
}1-16a1.19 d
3 H-8a1.42
s 3
H-12a1.83 brs
3 H-18a1.
89-1.96 m2
L6(β), H-14(β)2.02
s 3
H-22a2.27-2.45 m
32. 48 s 32.
74 dd 12. 97
d l2.74
dd 12.97 d
l3.03brd 1H
-8, H-4 (β), H-16 H- 26a H-5a (β) H-2 H-5a (β) H-2 H-13 3,13 3,17 3.25 3,30 3 .87 4.56 5.36 5.61 6.06 6,20 6.58 7.45 H-11 17-OCR. H-3 H-17 }1-7 H-15 H-10 8-9 H-23 H-19 H-20 H-25 Example 2 Z-Rizoxin palmitate ester Rhizoxin palmitate Ig was added to 5 mj? It was dissolved in acetonitrile and irradiated with ultraviolet autofade meter at room temperature for 150 minutes at a distance of 25 cm. After the irradiation was completed, the same treatment as in Example 1 was carried out to obtain the desired product in a yield of 12%.

MS spectrum m/e: 863 (M”) UV spectrum ((JI3CN) A na (ε): 234.
7 (1.22xlO'), 311.6 (3.58x
lO') NMR (CDC 1 z>spectrum: δ
(ppm) Signal pattern Number of protons: 0
．． 85-0.90 m 20
．． 88t 30
．． 97 d 31.
21 d 31.2
6-1.40 (m)-(s) 241.4
6s 31.70
quintet 21.82
brs 3 Attribution H-4 (α), H-6 (α) H-16 H-16a H-8a H-4 to 15 12a H-3 H-18a 3.30 3.91 4.29 4. 68 5.32 5.65 6.13 6.29 6.64 7.15 7.77 H-3 H-7 H-13 H-15 H-10 H-9 H-23 H-19 H-20 H -21 H-25 2.00 s 3H-22a 2.43 2,74 2,96 3.16 3,18 3.24 dd d d d H-26a H-5a (β) H-2 17-OCR, H-11 ■-17 Water-boiled people, eight people, three people, three K, paddy company 8-Unshi Shouten Ohno

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or an acyl group represented by R_1CO. R_1 is a linear or branched alkyl group , A represents a single bond or an oxygen atom), a pharmacologically acceptable salt thereof, or a closed ring lactone derivative thereof. 2. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom or an acyl group represented by R_1CO. R_1 represents a linear or branched alkyl group. An antitumor agent containing as an active ingredient a Z-rhizoxin derivative consisting of a carboxylic acid having a bond or an oxygen atom, a pharmacologically acceptable salt thereof, or a closed ring lactone thereof. 3. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents a single bond or an oxygen atom). Method 4 for producing Z-rhizoxin derivatives having the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. etc.▼ (In the formula, R represents a hydrogen atom or an acyl group represented by R_1CO. R_1 represents a linear or branched alkyl group. A represents a single bond or an oxygen atom.) There are formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by irradiating light on a rhizoxin derivative consisting of a carboxylic acid, its pharmacologically acceptable salt, or its ring-closed lactone. (In the formula, R and A are as described above. )
A method for producing a Z-rhizoxin derivative comprising a carboxylic acid having the following, a pharmacologically acceptable salt thereof, or a closed ring lactone thereof.