JPH0120129B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel antitumor agent. Although various compounds have been used as antitumor agents, there are few that are satisfactory in terms of efficacy and side effects, and there is a demand for the development of better antitumor agents. Recently, benzaldehyde has attracted attention as an antitumor agent having a specific action (see Japanese Patent Publication No. 54-962), but benzaldehyde has the disadvantage of being easily oxidized and difficult to formulate into formulations. The present inventors have conducted intensive research to develop a novel antitumor agent, and have discovered that a benzylidene compound of polyhydric alcohol has an excellent antitumor effect. The present invention is based on this knowledge, and the general formula (In the formula, X ¹ and X ³ are single bonds or hydrogen atoms, individual
X ² is a single bond and/or a hydrogen atom, R is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, m is an integer of 1 to 4, and n is an integer of 1 to 3. ) is an antitumor agent containing the compound represented by the following as an active ingredient. Examples of the linear or branched alkyl group having 1 to 6 carbon atoms for R in this formula include a methyl group, _an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. R is preferably a hydrogen atom or a lower alkyl group, particularly a methyl group. Compounds of formula (In the formula, m has the above meaning) A compound represented by the general formula (In the formula, R has the above-mentioned meaning) It can be produced by reacting with a compound represented by
Publications No. 14758 and Journal of American Chemical Society Vol. 50, p. 2237
(see 1928). As compounds of the formula, sugar alcohols of triose, tetrose, pentose and hexose are used, which may be in the D, L or meso form. For example, sorbitol, mannitol, iditol, talitol, dulcitol, allitol, arabitol, xylitol,
Examples include adonitol, erythritol, and glycerin. Examples of compounds of the formula include benzaldehyde, tolualdehyde, ethylbenzaldehyde,
Propylbenzaldehyde, butylbenzaldehyde, pentylbenzaldehyde, hexylbenzaldehyde and the like are used, with benzaldehyde or tolualdehyde being preferred. The compound of the formula contains 1 mole of tri- to hexavalent sugar alcohol (compound) and 1 to 3 benzaldehydes of the formula.
A condensation product with molar X ¹ in the formula,
At least two of X ² and X ³ are each (In the formula, R has the above-mentioned meaning) represents a single bond with a benzylidene group, and the remainder are hydrogen atoms. In this case, the radicals of the formula a are usually connected via two adjacent carbon atoms or one carbon atom of the sugar alcohol.
It is bonded in the form of a bridge with hydroxyl groups on carbon atoms.
In other words, the relationship between m and n in the formula is that when m = 1, n = 1, and when m = 2 and 3, n =
1 or 2, and when m=4, n=1, 2 or 3. Examples of the compounds of the formula include the following.

[Table] le

[Table] The compound of the formula is used as a gel for organic liquids, such as solid toiletries, adhesives, solid alcohol fuel, etc., and as a thickener for paints, inks, polymers, etc., but it is not used as a medicine. Its activity has not been reported so far, and it has not been put to practical use. The present inventors have demonstrated that the compound of the formula has a remarkable suppressive effect on subcutaneously transplanted Ehritzhi carcinoma tumors, which are widely recognized as a model for transplanted tumors, and has low toxicity, making it useful as an antitumor agent for humans and animals. I found that. Although the mechanism of action of the compound of the formula has not yet been clarified, it is easily hydrolyzed in acidic solutions with a pH of 4 or less, and the compound of the formula, i.e., benzaldehyde or alkyl-substituted benzaldehyde, and the sugar alcohol of the formula, such as sorbitol, xylitol, glycerin, etc. It is presumed that the former exhibits antitumor activity. Although one or more compounds of the formula may be used as they are as the antitumor agent of the present invention, they are usually mixed with ordinary organic or inorganic solid or liquid excipients, adjuvants, inclusion agents, etc. It is preferable to use it in the form of a preparation suitable for oral and parenteral administration. Suitable excipients are, for example, water, gelatin, lactose, starch, cellulose calcium glycolate, microcrystalline cellulose, stearyl alcohol, magnesium stearate, talc, vegetable oil, benzyl alcohol, propylene glycol, gum, polyalkylene glycol, white These include petroleum, jelly, and cholesterol. Examples of auxiliary agents used include preservatives, wetting agents, emulsifiers, solubility promoters, salts for adjusting osmotic pressure, buffers, binders, suspending and dispersing agents, and the like. As the inclusion agent, for example, cyclodextrin is used. Examples of the formulation include powders, granules, capsules, pills, tablets, sugar-coated tablets, injections, suppositories, and ointments, and dosage forms suitable for oral administration are preferred. These preparations can be manufactured by conventional methods. When using the antitumor agent of the present invention for treatment, the dosage of the active ingredient is generally 0.5 per adult per day.
~6000mg. The antitumor agent of the present invention can also be used in animals, and the dose at that time is adjusted as appropriate depending on body weight and other factors. The acute toxicity LD50 value of the compounds of the present invention is
8000 by oral administration in ~25g male mice.
It was more than mg/Kg. An example of producing a compound of the formula is shown below. Reference Example 1 64 g of 70% sorbitol aqueous solution, 53 g of benzaldehyde and 6 g of 50% sulfuric acid were placed in a container equipped with a cooler with a decanter, a thermometer, a gas inlet and a stirrer.
Add 500 ml of cyclohexane-dimethyl sulfoxide (100:3) to a four-necked flask, purify the system with nitrogen gas, and heat to 70-80°C with stirring to remove water in the mixture and condensation products. The reaction is carried out while water is removed from the system by azeotropy using a decanter. In a reaction time of 3 hours, an approximately 1:1 mixture of 2,4-monobenzylidene sorbitol and 1,3,2,4-dibenzylidene sorbitol is produced. A solution of 5.1 g of caustic potassium dissolved in 100 ml of water was added to this, stirred at room temperature for 1.5 hours to neutralize, and then added water.
Add 100 ml and heat under reflux to transfer monobenzylidene sorbitol to the aqueous layer. The upper cyclohexane layer and the lower aqueous layer are separated, and when the aqueous layer is allowed to cool to room temperature, monobenzylidene sorbitol is precipitated. Separately, after washing with methanol and drying, 32g of 2,4-monobenzylidene sorbitol
is obtained. Melting point: 270-271℃ Elemental analysis value: C H Actual value (%) 57.80 6.86 Theoretical value (%) 57.77 6.71 On the other hand, when 500 ml of water was added to the cyclohexane layer and heated to distill off the cyclohexane and collect it, dibenzylidene An aqueous slurry of sorbitol remains. When this is centrifuged, washed with water and dried,
1,3,2,4-dibenzylidene sorbitol 36
g is obtained. Melting point: 226.5-227.5℃ Elemental analysis: C H Actual value (%) 67.12 6.32 Theoretical value (%) 67.03 6.19 Reference example 2 70% sorbitol aqueous solution 35g, benzaldehyde 43g, concentrated sulfuric acid 0.47g and cyclohexane 526ml
When the reaction is carried out for about 7.5 hours in the same manner as in Reference Example 1, 51.2 g of 1,3,2,4,5,6-tribenzylidene sorbitol is obtained. Melting point: 203-204℃ Elemental analysis value: C H Actual value (%) 72.43 5.80 Theoretical value (%) 72.48 5.82 Reference example 3 Powdered xylitol 151g, benzaldehyde 212
When reacting for 5 hours in the same manner as in Reference Example 1 using 3 g of 50% sulfuric acid and 1.3 g of cyclohexane-dimethylformamide (100:3), 1.3,
290 g of 2,4-dibenzylidenekylitol are obtained. Melting point: 187-188°C Elemental analysis: C H Actual value (%) 69.75 5.79 Theoretical value (%) 69.72 5.81 Reference example 4 Glycerin 92g, m-tolualdehyde 120g,
1g paratoluenesulfonic acid and 200ml toluene
When the reaction is carried out at 120° C. for 4 hours in the same manner as in Reference Example 1, 120 g of 1,2-mono-(m-methylbenzylidene)-glycerol is obtained. Boiling point: 133-134℃/2mmHg Reference example 5 Benzaldehyde instead of tolualdehyde
Using 106 g and operating in the same manner as in Reference Example 4, 1,2-monobenzylidene glycerol
111g is obtained. Boiling point: 130-132℃/2mmHg Reference Example 6 Using m-tolualdehyde instead of benzaldehyde and operating in the same manner as Reference Example 1, 2.4
-Mono-(m-methylbenzylidene)-sorbitol is obtained. Melting point: 148-150°C Elemental analysis: C H Actual value (%) 59.13 7.10 Theoretical value (%) 59.15 7.04 Example (tablet) 2500 g of the compound of the formula, 1375 g of lactose, 775 g of microcrystalline cellulose, and calcium cellulose glycolate
After sieving 375g using a 16-mesh sieve and mixing it uniformly, it was put into a kneading machine, and to this was added 3% hydroxypropyl cellulose solution (in a mixture of isopropyl alcohol and water = 3:7). Practice. The mixture was granulated using an extrusion granulator and heated to 40°C.
Dry with air for 8 hours. Next, after sizing the granules to a range of 16 to 60 meshes, the granules were mixed with 0.3% magnesium stearate and compressed into tablets.
The tablets are 200 mg. Test example (antitumor activity) Using 10 5-week-old ICR/JCL female mice in each group, 2 × 10 ⁶ Ehritzch carcinoma ascites cells were used.
mice/mouse were implanted subcutaneously. Starting the day after tumor implantation, the test compound was orally administered once a day for 24 days. The dose of the test compound was as shown in Table 1, and the concentration of each compound was adjusted with physiological saline so that the dose was 0.2 ml/mouse. The tumor was excised on the 25th day after tumor implantation, its weight was measured, and the inhibition rate was calculated using the following formula. Inhibition rate (%) = non-administration group weight - administration group weight / non-administration group weight x 100 The results obtained are shown in Table 1.

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Claims (1)

[Claims] 1. General formula (In the formula, X ¹ and X ³ are single bonds or hydrogen atoms, individual
X ² is a single bond and/or a hydrogen atom, R is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, m is an integer of 1 to 4, and n is an integer of 1 to 3 ) An antitumor agent containing a compound represented by the following as an active ingredient.