JPS59181297A - Alpha,alpha-trehalose-6,6'-(medium chain) fatty acid diester and antitumor agent containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (n is 6-10). EXAMPLE:6,6'-Di-O-decanoyl-alpha,alpha-trehalose. USE:An antitumor agent having extremely low toxicity. PREPARATION:For example, alpha,alpha-trehalose of formula II is converted to 2,3,2', 3'-tetra-O-benzyl-alpha,alpha-trehalose of formula III, which is made to react with preferably 1.8-2.4 times mole of a medium chain fatty acid (or its active derivative) of formula IV in the presence of an acid acceptor such as pyridine, triethylamine, etc. The resultant novel intermediate, 2,3,2',3'-tetra-O-benzyl-alpha,alpha-trehalose- 6,6'-(medium chain) fatty acid diester of formula V is reduced and debenzylated to obtain the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel α,α-tre/.lose-6,6'-medium chain fatty acid diester and an anti-Scancer agent containing the same as an active ingredient.

α,α-trehalose is a type of so-called disaccharide composed of two molecules of glucose, and is a compound widely distributed in nature. Various derivatives of this compound have also been synthesized,
Its pharmacological activity has been investigated. For example, it has been reported that mixtures of various diesters with different fatty acid bonding positions have antitumor effects.

The present inventors synthesized various 6,6'-fatty acid diesters of α,α-trehalose and investigated their pharmacological effects, and found that the following formula (1) (where n is an integer from 6 to 10) It was discovered that α,α-trehalose-6,6'-medium chain fatty acid diester represented by the following formula has an excellent antitumor effect and is useful as a pharmaceutical, and the present invention was completed.

That is, an object of the present invention is to provide a novel α,α-trehalose-6,6'-medium chain fatty acid diester represented by formula (1).

Further, another object of the present invention is α represented by the formula (I)″′,
An object of the present invention is to provide an antitumor agent containing α-trehalone 6,6'-medium chain fatty acid zoester as an active ingredient.

The α,α-trehalose-6,6'-medium chain fatty acid diester (hereinafter simply referred to as trehalose medium chain fatty acid diester) (I) of the present invention can be prepared, for example, according to the following reaction formula.
-Trehalose (...) 2, 3, 2', 3'-
Tetra-0-benzo-α,α-trehalose (Ml)
and then reacted with medium chain fatty acid (1■) or its active derivative to form a novel intermediate 2,3.2',3'-
Tetra-0-benzo-α, α-trehalose-6,6
It is produced by obtaining a '-medium chain fatty acid diester (■) and further reducing it using a reduction catalyst and depenfluidizing it.

(II) (1) (V) (In the formula, B+a represents a benzyl group, and n has the meaning described above.) In the above method, 2, 3 represented by formula (III)
, 2', 3'-tetra-0-benzo-α.

α-trehalose is prepared by reacting benzaldehyde with trehalose expressed by formula 9 (If) in a conventional manner.
6.4', 6'-C〇-Benz'J Te:y-α,α
- Trehalose and then benzyl chloride at 2.3
．． It can be obtained by converting it into a 2',3'-tetra-0-bensyl compound and further reacting with an acid.

In addition, the reaction between the compound (lit) and the medium-chain fatty acid (IV) or its active derivative follows general esterification reaction conditions. ), preferably 1,8
This is carried out by reacting medium-chain fatty acids (■) or their active derivatives in a proportion of ~2.4 moles.

This reaction is carried out in the presence or absence of a solvent and under water cooling at ~30°C.
It is preferable to do this for 1 to 24 hours.

Examples of the solvent used here include methylene chloride,
Examples include chloroform, benzene, toluene, ether, tetrahydrone, dioxane and the like.

The reductive debensylation reaction of the compound (V) thus obtained is preferably carried out in an amount of 0.5 to 1 mol per mol of compound (V).
This is carried out by catalytic reduction using 0 mol of reduction catalyst in a suitable solvent.

Examples of the reduction catalyst include Noq Lazoum Black, No9 Lazoum Carbon, and Raney Nicke.

Further, examples of the solvent used here include alcohols such as methanol, ethanol, and isoteronoQ-nol; halodane compounds such as chloroform and methylene chloride; and mixed solvents thereof.

Next, Treno Rose medium chain fatty acid diester of the present invention (
1) shows the pharmacological action.

(1) Cell-killing effect of Tolenolose medium-chain fatty acid diester: Using Leukemia L-5178Y cells,
The number of cells was 105/- in RPM11640 medium containing % tallow serum, and the sample was added to this medium at a predetermined concentration. 48 in a 5% CO2 incubator at 37°C
After culturing for an hour, the number of viable cells was counted under a microscope, the proliferation rate was determined by comparing with the control group, and plotted on log probability paper.
From the obtained straight line, 9 ICBo value was determined. Sample concentrations were 25.50, 100, 200 and 400 μf/-.

The results are shown in Table 1.

As shown in Table 1 above, trehalose medium chain fatty acid diester has antitumor activity.
It is significantly stronger than the corresponding compounds No. 22 to 22.

The toxicity of the trehalose medium chain fatty acid diester of the present invention is as follows:
For example, sucrose fatty acid esters, which are similar substances, are designated as food additives and are widely used as harmless surfactants in foods, medicines, cosmetics, etc., as evidenced by the fact that they are almost non-toxic. It is a safe compound.

In addition, the dosage forms for administering the compound of the present invention include various dosage forms depending on the dosage form, such as oral and parenteral dosage forms, such as oral dosage forms such as tablets, capsules, powders, granules, and liquid preparations; , intramuscular or intravenous injection, infusion mixture, or intravenous parenteral administration.

The above formulation can be performed by a method known per se. Namely, trehalose medium chain fatty acid diester tensin,
Excipients such as lactose and mannitol; Binders such as sodium carboxymethyl cellulose and hydroxyzorobyl cellulose; Disintegrants such as crystalline cellulose and calcium carboxymethyl cellulose; Lubricants such as talc and magnesium stearate; Light anhydrous silicic acid, etc. Tablets, capsules, powders, or granules can be produced by appropriately combining fluidity improvers and the like. In addition, solutions and injections are manufactured by dissolving trehalose medium-chain fatty acid diester in vegetable oil, etc. to make an oil-based injection, or by dissolving or suspending it in water, etc. using a conventional method to make a syrup, etc. be able to. Furthermore, in order to make it into a living substance, it can be produced by dispersing it in a commonly used base such as cacao butter, synthetic oil, etc. by a conventional method and then solidifying it.

The dosage of the trehalose medium-chain fatty acid diester of the present invention varies depending on the severity of the disease, but is usually 0.1 to 2 oOOsay/'i for oral administration in adults, and for parenteral administration. 0.05~1000ηlLy
It is preferable to administer once a day or in several divided doses.

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

Example 1 2.3.2',3'-tetra-O-benzo-α,α-
Trehalose 2.119 Nigirishin 20-ml and dichloromethane 20 ml were added and dissolved, and decanoyl chloride 1.26 F was added dropwise thereto under stirring at 0°C under water cooling. 30
After stirring for several minutes, the mixture was returned to room temperature and further stirred for 1 hour. The resulting reaction mixture was poured into ice water, extracted with chloroform, and then chloroform was distilled off under reduced pressure.

The residue was purified by silica alkali chromatography to give 2,3°2',3'-tetra-
0-Benzol-6.6'-C O-y' Kail-
2.799 α,α-trehalose (yield 92%) was obtained.

Example 2 7'c2,3.2',3'-tetra- obtained in Example 1
0-Pencil-6,6'-C〇-Decanoyru α,α
-r liverose 2.679 407! Q Radium Black 1.0 was dissolved in chloroform and added to this solution as a catalyst.
0f was added, hydrogen gas was introduced, and catalytic reduction was carried out for 1 hour.

The resulting reaction solution was filtered to remove the catalyst, and Solution F was concentrated to dryness under reduced pressure. The residue was recrystallized from inzolopanol to give 6,6'-cy0-decanoyl- as colorless needles.
1.06f of α,α-trehalose (yield 62%) was obtained.

Example 3 The compounds shown in Table 2 were obtained in the same manner as in Example 1. At the same time, the compound obtained in Example 1 is also shown in the table.

Thereafter, the compounds shown in Table 3 were obtained in the same manner as in Example 2. At the same time, the compound obtained in Example 2 is also shown in the table.

Below margin Example 5 tablet One tablet having the following ingredients and quantities was manufactured according to a conventional method.

Trehalose medium chain fatty acid diester 1001
n! (decanoate) D-mannitol 1501N
i Crystalline cellulose 50~
Denzon 28■
Carboxymethylcellulose calcium 1
6+v talc
4av magnesium stearate
2 ■ Total amount 35
0 da Example 6 Capsules Granules with the following ingredients and amounts were manufactured according to a conventional method, and 3
Filled into one capsule.

Crystalline Cellulose 17q Light Anhydrous Silicic Acid 7■Magnesium Stearate 1■Example 7 Injection One injection was prepared from the following ingredients and amounts in a conventional manner.

Make the total amount 1- with olive oil.

Example 8 The following components and amounts were melted and stirred using a conventional method for bio-double, and then molded and solidified to produce one bio-double.

Cocoa fat 1100η Total amount 1200+ Applicant Nisnis Pharmaceutical Co., Ltd. 1 Agent Patent attorney Yuki Kazo Patent attorney Kazumi Ono ＊″l.

)5. ...22.

Claims (1)

[Claims] 1. α,α-trehalose-6,6'-medium chain fatty acid diester represented by the following formula (1) (wherein n represents an integer of 6 to 10). 2. An antitumor agent containing α,α-trenorose-6,6′-medium chain fatty acid diester represented by the following formula (D (wherein n represents an integer of 6 to 10) as an active ingredient.