JPS59170123A - Polysilsesquioxane - Google Patents

Abstract

PURPOSE:A novel polysilsesquioxane useful as a carcinostatic agent, containing a specific structural unit. CONSTITUTION:The desired polysilsesquioxane having a structural unit shown by the formula I . It can be prepared by condensing a gamma-aminopropylpolysilsesquioxane shown by the formula II with a dihydroxybenzaldehyde shown by the formula III through dehydration. Preferably 500-0.01mg/kg/day of it is applied (parenterally) orally to the affected part.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a polysilsesquioxane having a structural unit represented by the general formula % and an anticancer agent containing the polysilsesquioxane as an active ingredient.

(However, Rtj: monovalent organic group) is a repeating unit of silsesquioxane, and the model is a polymer compound generally having a ladder-like or cage-like skeleton structure shown by the following formula. are known and are widely used as water repellent agents, lubricants, catalysts, synthetic intermediates for organosilicon compounds, etc.

On the other hand, as an organosilicon compound having a carbon-nitrogen double bond, the general formula R R1>C-N(CH2)aSi= (where R and R' are each Hydrogen atom, hydrocarbon group, or nitro.

A hydrocarbon group substituted with hydroxy, alkoxy, or a halogen atom, where a is an integer of at least 6, and the unsaturation measure of the silicon atom represented by Si- is alkyl, allyl, alkoxy, hydroxy or −
Alkoxysilane derivatives and polysiloxane derivatives (bonded to the 0-8i group) are known, and the use of these compounds as filtering agents, ultraviolet absorbers, and scissoring agents has been proposed. .

The present inventor has synthesized various polysilsesquioxanes and conducted various studies on their physiological activities. As a result, we established a method for producing a new polysilsesquioxane having a structural unit represented by the general formula n, and the new polysilsesquioxane has excellent physiological activity, especially anticancer activity. This discovery led to the completion of the present invention.

That is, the present invention provides a novel polysilsesquioxane consisting of a structural unit represented by the general formula, and an anticancer agent containing the polysilsesquioxane as an active ingredient.

The polysilsesquioxane of the present invention is a novel compound having a structural unit represented by the above general formula. The polysilsesquioxane is obtained as an amorphous solid polymer exhibiting colors such as white, pale yellow, yellow, ffl yellow, orange, brown, etc.
It is often crushed and handled as powder. Furthermore, the polysilsesquioxane is assumed to be a three-dimensional cage-like polymer as described above, and is usually ligroin, cyclopentane, or hexane.

Almost insoluble in benzene, toluene, chloroform, carbon tetramide, etc. On the other hand, it is sparingly soluble in polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and tetraglyme, but in the case of these solvents, heating significantly increases the solubility. It is also sparingly soluble in water, so it is relatively stable in water; however, in acidic or alkaline aqueous solutions, stability varies depending on the concentration and temperature, but in general, carbon-nitrogen double bonds are resistant to hydrolysis. and hydrolyzed into r-aminopropylpolysilsesquioxane and dihydroxybenzaldehyde. The hydrolysis tends to become more severe as the concentration of acid or base increases and as the temperature rises.

It can generally be confirmed by chemical analysis and instrumental analysis that the polysilsesquioxane has a chemical structure having the structural unit represented by the above general formula. In particular, elemental analysis and infrared absorption spectrometry are extremely effective methods. That is, the weight percent of the elements of carbon, hydrogen, nitrogen, and silicon (and halogen atoms if the molecule contains halogen atoms) in the synthesized polysilsesquioxane.
Find - Furthermore, the sum of the weight percent of each element obtained by recognition + f't is 1
By subtracting it from 00, the weight percent of the oxygen element can be calculated, and the compositional formula of the polysilsesquioxane sample can be determined. Furthermore, by measuring the infrared absorption spectrum of the sample, it is possible to confirm the characteristic chemical bonds and types of functional groups present within the polysilsesquioxane molecule. Generally the polysilsesquioxane is 16
It was found that the polysilsesquioxane exhibits a characteristic infrared absorption based on the -C=N bond in the vicinity of 90tMJ to 1620c7n, and furthermore, the elemental analysis results show that in the solid state, the polysilsesquioxane is usually in the hydrated form, and sometimes in the dihydrate form. Exists in hydrated form (7, very few exist in anhydrous form.

The method for producing polysilsesquioxane used in the present invention is not particularly limited, and polysilsesquioxane obtained by any production method may be used.In general, as shown in the general reaction formula below, r-
Aminopropyl polysilsesquioxant general formula 0
H 8-Zen Shichi 7, o, o, 1. . It can be easily synthesized by dehydration condensation with 67daldehyde.

01.5sicHzcH2cH2NH2+ 0-CH-
! :fr0”-81,5sicH2cH2cH2N-C
H40H Dihydroxybenzaldehyde, which is the raw material here, has the following six types of isomers.

The molar ratio of the aminopropyl polysilsesquioxanes and the dihydroxybenzaldehyde during the reaction is not particularly limited, but in consideration of recovery of unreacted materials, the molar ratio should be 1:1 or more. Roxybenzaldehyde may be removed by washing with a solvent such as benzene after the reaction.

In addition, the above reaction generally uses a reaction solvent.
For example, benzene, toluene.

Water azeotropic solvents such as chloroform and ethanol can be suitably used. Although the reaction temperature can be varied over a wide range of, for example, 0 to 150C or higher, it is generally preferable to carry out the reaction at the boiling point temperature of the solvent. The reaction time varies depending on the reaction temperature, but generally it can be carried out within a few minutes to several days.

In order to promote the dehydration condensation reaction of the above reaction, a method of adding an acid such as acetic acid or @acid to the reaction system is often suitably employed.

Since the polysilsesquioxane obtained by the present invention is a Schiff base compound of dihydroxybenzaldehyde and r-aminopropyl polysilsesquioxane, two of the polysilsesquioxanes produced by this method are The substitution positions of the hydroxyl groups correspond to the substitution positions of two hydroxyl groups in dihydroxybenzaldehyde, which is a raw material.

The above fact can be confirmed from the fact that when dihydroxybenzylidene polysilsesquioxane is hydrolyzed to produce dihydroxybenzaldehyde, the product is exactly the same compound as the raw material dihydroxybenzaldehyde. - That is, the polysilsesquioxane obtained by the present invention has 2,3-dihydroxy form; 2,4-dihydroxy form; 2,5-dihydroxy form; 2,6-dihydroxy form, depending on the position of the two hydroxyl groups. :3,4-dihydroxy form:
There are six isomers of the 6,5-dihydroxy form.

The polysilsesquioxane is a new compound, and when the present inventor conducted a physiological activity test on the polysilsesquioxane, it was confirmed that the polysilsesquioxane has a particularly remarkable anticancer effect. That is, since the polysilsesquioxane exhibits an extremely strong anticancer effect, the polysilsesquioxane having one of the above structural units can be used as an anticancer agent for the prevention, treatment, or treatment of MS.

Generally, there is no essential difference in the anticancer effect of the polysilsesquioxane, whether it has less than one hydration water or even more than one hydration water. .

The anticancer agent of the present invention can be administered to patients orally, parenterally (for example, intraperitoneally, intrarectally), or locally, and in this case, the effective administration of polysilsesquioxane, which is the active ingredient, The age and weight of the patient to be administered.

It varies depending on the type of SI, A, etc. of the symptoms, but in general, 8
00-0.002 mV/KW/day, preferably 500
~0.01■/Kq/day. Part 1
The daily dosage can be administered only once a day or divided into several times (6 to 5 times) a day. It goes without saying that the above-mentioned dosage is merely a guideline, and it is possible to administer doses exceeding the above-mentioned range at the discretion of the treating physician.

When administering the above active ingredient, the above polysilsesquioxane should be administered according to the desired administration method (oral, parenteral or topical).
Depending on the situation, it can be formulated into various dosage forms.

For example, tablets, pills for oral administration.

It can be formulated into dosage forms such as sugar-coated tablets, powder sachets, granules, syrups, and capsules, and for parenteral administration,
It can be formulated into dosage forms such as suspensions and herbal medicines, and furthermore, for topical administration, it can be formulated into dosage forms such as ointments, plasters, and creams.

The concentration of the active ingredient in itc in these preparations is not particularly limited and can vary widely depending on the dosage form, but is generally 0.05 to 90% by weight, preferably 1% by weight.
The concentration can be approximately 60% by weight.

As excipients that can be used in the above preparations, any excipients commonly used in the field can be used; for solid form preparations, for example, lactose, sucrose, starch, glycine, crystalline cellulose, etc. , mannitol, magnesium stearate, liquid paraffin, calcium carbonate.

and, for liquid form preparations, for example physiological saline.

Examples include surfactant liquid, glucose liquid, alcohol, and esters.

Specific examples of such formulations are as follows. Formulation Example 1: Capsules 4.5 parts by weight of lactose was added to 0.6 parts by weight of magnesium stearate and mixed by stirring to make it homogeneous, and further 5 parts by weight of lactose was added. part and 10 parts by weight of crystalline cellulose and mix. 20 parts by weight of polysilsesquioxane, which has been pulverized in advance, is added to this mixture and mixed again to obtain a prepared powder. Capsules may be produced by filling this powder into gelatin capsules using a capsule filling machine.

Formulation Example 2: Ointment 10 parts by weight of stearyl alcohol, 2 parts by weight of liquid paraffin
After heating and dissolving 0 parts by weight and 160 parts by weight of petrolatum at 80C, 0.5 parts by weight of cholesterol and 10 parts by weight of polysilsesquioxane, which had been pulverized in advance, were added with thorough stirring, and further stirring was performed. Afterwards, it is best to leave it at room temperature and adjust it to an appropriate hardness to obtain a softener.

Formulation Example 6: Tablet After 25 parts by weight of polysilsesquioxane and 20 parts by weight of mannitol were thoroughly mixed and ground, 4.7 parts by weight of potato starch was added as a starch paste and granulated.

The particles are passed through a 60-mesh sieve, dried to a predetermined weight, and passed through a 16-mesh sieve. Next, the particles are mixed with 0.6 parts by weight of magnesium stearate phosphate, smoothed, and compressed using a tablet molding machine in a conventional manner to form uncoated tablets of an appropriate size. An example of the production of polysilsesquioxane used as an active ingredient in the anticancer agent of the invention, as well as a pharmacological activity test method and its results are shown. However, the present invention is not limited to the following reference examples and examples.

Example 1 When acetic acid (8,12f) was added to r-aminopropylpolysilsesquioxane-1 aqueous phase (3,50t), heat was generated and a white powder was obtained. Furthermore, benzene (
After adding 50 mg) and 38,4-dihydroxybenzaldehyde (6,002), the reaction was terminated while performing azeotropic dehydration by heating under reflux for 4 hours.

The solvent remaining in the reaction wave was separated from the solid produced by decanting, and 60% of benzene was added, heated to reflux, and then decanted again to remove the solvent. The residue was vacuum dried on an oil bath at 80C to obtain a brown solid of 6.17f.

Elemental analysis showed c 48.45%, H 5.7
6%, N5.55%, Cl0H12NO
Theoretical value for 5, ssi -E (20 (248, 32) 04 B, 57%, H5, 68%, N 5.64
% was in good agreement.

Furthermore, when the infrared absorption spectrum was measured, no absorption at 1650 m-1, which is characteristic of the aldehyde group characteristic of the raw material 6,4-dihydroxybenzaldehyde, was observed, and a wide absorption range from 3650 to 5100 cm-1 due to hydration water was observed. , 1640CrnKCH=N bond-based absorption and 1240-900 Rho 1 showed absorption based on strong 51-0 bond.

Furthermore, a portion of this white solid was taken out and subjected to a hydrolysis reaction. First, 1.22 g of a white solid was taken and stirred in 100 g of a 1N-NaOH aqueous solution at room temperature for 16 hours, resulting in a homogeneous solution. This solution was adjusted to pH 2 with hydrochloric acid, extracted four times with 50 ml of diethyl ether, the ether extracted layer was collected, and the ether was removed to obtain a 0.51 f solid. 1H-NMR spectrum of this
Mass spectrometry spectrum.

The infrared absorption spectrum and elemental analysis values were consistent with those of 5,4-dihydroxybenzaldehyde.

From the above results, it is clear that the isolated product is a Schiff base compound obtained by a dehydration condensation reaction, that is, 6,4-dihydroxybenzylidene r'-aminopropyl polysilsesquioxane monohydrate. Ta.

Example 2 2001'V of 6,4-dihydroxybenzylidene r-aminopropyl polysilsesquioxane monohydrate obtained in Example 1 was taken out and added to Kore'&1'200.
L TE3 Thus 1
85 ~ solids were obtained.

Elemental analysis of this material revealed that it was C52, 10%, H5
, 21X, N6.10X7 shows 6 values, Cl0H12
NO5,5Si (230,30) Theoretical value C for K”
52.15%, H5, 25%, N6.08X.

Furthermore, in the infrared absorption spectrum of this product, the absorption based on hydration water that was observed in the 3,4-dihydroxybenzylidene r-aminopropyl polysilsesquioxane monohydrate obtained in Example 1 was no longer observed. Other than that, they were exactly the same.

From these experimental facts, it became clear that this product was 6,4-dihydroxybenzylidene γ-aminopropyl polysilsesquioxane.

Example 3 A mixture of 6.00 f of r-aminopropylpolysilsesquioxane 1 aqueous phase, 40 d of acetic acid, 40 me of N,N-dimethylformamide, and 122 t of 5,4-dihydroxybenzaldehyde. Heated under reflux for 4 hours and reacted. The volatile components were removed from the mixture by distillation and washed five times with 50 ml of diethyl ether to give a reddish-orange solid.
o o r was obtained. Add this to 10 methanol
ml 10 times, N,N-dimethylformamide 10 m
5,4-
A dihydroxybenzylidene r-aminopropyl polysilsesquioxane 1 aqueous phase was obtained.

Example 4 6,4-dihydroxybenzylidene γ- obtained in Example 3
Aminopropylpolysilsesquioxane 1 aqueous phase
5, physiological saline solutions containing the surfactant Tween 80 at various concentrations were prepared. Add this sample solution to 5 m and weigh 20 m,
A test was conducted for 20 days by intraperitoneally injecting 15 CDF mice (male) before and after, and the acute toxicity value (LDsu
) was determined by the method of Litchfield and Wilkokun, and the LD5) value was >2512η/Kf.

Example 6. Example 3 except that 4-dihydroxybenzaldehyde was changed to the dihydroxybenzaldehyde shown in Table 1.
By performing the same operation as above, various dihydroxybenzylidene r-aminopropyl polysilsesquioxane monohydrates were obtained. Various dihydroxybenzaldehydes were recovered by subjecting these polysilsesquioxanes to the same hydrolysis reaction as shown in Example 1. These results are shown in Table 1.

Example 6 6,4-dihydroxybenzylidene r-aminopropyl polysilsesquioxane 1 aqueous phase obtained in Example 3 and Example 4 and 2,5-dihydroxybenzylidene r-aminopropyl polysil Sesquioxane monohydrate was tested for anticancer activity against Ehrlich ascites carcinoma in mice. That is, injections of various concentrations of the polysilsesquioxane prepared by the method described in Example 5 were intraperitoneally administered at a dose of 0.5 me into six Swiss mice (male) containing 5 x 106 Ehrlich cancer cells. Continuous injections were administered for 9 days. From the results of the survival effect over 60 days, the mean survival time (MST) was calculated, and the control group (60 animals)
T/C(X) was calculated by comparing with the average survival number of days.

That is, the average survival days t was determined for the test subject (T) and the control subject (C), and calculated as T/CX100 (%). Low value is 6
The number of days when the fourth animal died among the animals tested was taken as the average survival period,
It is determined by dividing this by the average survival days similarly determined from control subjects and multiplying the value by 100. Note that Table 2 lists accurate values calculated using a computer. Although 30 mice were used as a control group, the average value for 6 mice is shown in the table.

Example 7 For the various polysilsesquioxanes obtained in Examples 2 and 4, the anticancer activity T/c (%) against Ehrlich ascites carcinoma was measured using the same experimental procedure as in Example 6. These results are shown in Table 3.

Claims (2)

[Claims] (1), general formula ) Polysilsesquioxane having a structural unit represented by (2) Anticancer agent containing polysilsesquioxane as an active ingredient having a structural unit represented by the general formula