JPS5920324A - Polysilsesquioxane - Google Patents

Abstract

PURPOSE:A polysilsesquioxane of a powerful anticanceric effect useful as an anticanceric drug, prepared by, for example, a method comprising effecting the dehydration condensation of gamma-aminopropylpolysilsesquioxane with a specified carbonyl compound. CONSTITUTION:gamma-Aminopropylpolysilsesquioxane is reacted with a carbonyl compound of formula I [wherein R is H or alkyl, and X is cyano, carbamide, carboxyl, ester, or bis(haloalkyl)-amino], e.g., p-cyanobenzaldehyde, or p-carboxybenzaldehyde, so as to effect the reaction according to the reaction formula II. The produced polysilsesquoxane having structural units of formula IIIshows an excellent anticanceric effect, and is administered to a patient orally, parenterally, or topically. Its effective dose is usually 800-0.002mg/kg/day.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [where R is a hydrogen atom or an alkyl group; ) A type of group selected from the group consisting of amino groups.

Conventionally, some polysilsesquioxanes (where R is 1
The repeating unit is silsesquioxane (representing a valent organic group), and the model is RRR 111 10-8i-0-8i-○-8i - 111 000 111 -O-8i-0- 8i-0-8i- + 1 1 RR It is known to be a polymer compound generally having a ladder-like or cage-like skeleton structure, and is used as a water repellent agent.
It is widely used as an ITL lubricant, a catalyst, a synthetic intermediate for organosilicon compounds, etc.

On the other hand, as an organosilicon compound having a carbon-nitrogen double bond, in Patent Application Publication No. 36-9421, the general formula is a hydrogen atom, a hydrocarbon group, or a nitro group.

is a hydrocarbon group substituted with hydroxy, alkoxy, or halogen atom, a is an integer of at least 3, 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 0-81 group) are known, and the use of these compounds as filtering agents, ultraviolet absorbers, cranes, and coloring agents has been proposed. ing.

The present inventor has synthesized various polysilsesquioxanes and conducted various studies on their physiological activities. As a result, the following general formula [where R is a hydrogen atom or an alkyl group;
X is a type of group selected from the group consisting of ■cyano group, ■carbamide group, ■carboxyl group and its salt type group, ■ester group, and ■bis(haloalkyl)amino group]. The present inventors have discovered that the novel polysilsesquioxane has excellent physiological activity, particularly anticancer activity, and have completed the present invention.

That is, the present invention is based on the general formula [where R is a hydrogen atom or an alkyl group; The present invention provides a novel polysilsesquioxane consisting of a structural unit represented by the following 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, and in the above general formula,
The alkyl group of R or the aliphatic saturated hydrocarbon residue of the ester group represented by group, methoxycarbonyl group, ethoxycarbonyl group.

Propoxycarbonyl group, butoxycarbonyl group, etc. are most preferably used because of their advantages in terms of manufacturing process. In addition, the salt-type group of the carboxyl group represented by NaΦ
), potassium (K”), lithium (LiΦ), and other alkali metals; magnesium e (1/2uy), calcium (1/2Ca2Φ)
Alkaline earth metals such as, etc. are most preferably used.

Furthermore, the bis(haloalkyl)amine group represented by X in the above general formula is generally represented by Used without limitation, n is still 1~
An integer of 4 is most preferably used.

The polysilsesquioxane represented by the above general formula is amorphous white, pale yellow, yellow, or orange-yellow.

It is obtained as a solid polymer exhibiting an orange or brown color, and is often crushed and handled as a powder, but depending on the type of substituent R or X in the above general formula, it may be obtained as a viscous substance. . The polysilsesquioxane is modeled to be a three-dimensional cage-like polymer as described above, and is usually ligroin or cyclobenmene.

Virtually insoluble in hexane and benzene.

It is often sparingly soluble in toluene, chloroform, carbon tetrachloride, etc. On the other hand, it is soluble in alcohol, and is often soluble in polar nonaqueous solvents such as formamide, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoamide, and its solubility decreases particularly when heated. There is a tendency for the number to increase significantly. Many substances are sparingly soluble in water, and are therefore relatively stable in water, but in acidic or alkaline aqueous solutions, stability varies depending on the concentration and temperature, but in general carbon-nitrogen double The bond undergoes hydrolysis and decomposes into γ-aminopropylpolysilsesquioxane and the corresponding carbonyl compound (eg, substituted benzaldehyde or substituted acetaldehyde). 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 a structural unit represented by the above general formula. In particular, elemental analysis and infrared absorption spectrometry are extremely effective methods. That is, for the synthesized polysilsesquioxane, the weight percent of the elements of carbon, hydrogen, nitrogen, silicon (and, if the molecule contains a rogen atom, the rogen atom) is determined, and further recognized The sum of the weight percent of each element 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 types of characteristic chemical bonds and functional groups present within the polysilsesquioxane molecule. Generally the polysilsesquioxane is 16
From the fact that it exhibits characteristic infrared absorption based on -C=N bonds in the vicinity of 90cIn-1 to 1620cnj-1, and from the elemental analysis results, the polysilsesquioxane is usually in the -hydro-oro form in the solid state. Sometimes exists in dihydrated form, anhydrous 1
It is known that it rarely exists in the form of 0.

The method for producing the polysilsesquioxane used in the present invention is not particularly limited, and any method may be used to produce the polysilsesquioxane. General: As shown in the general reaction formula below, γ
-Aminopropylpolysilsesquioxane easily synthesized by dehydration condensation using the general formula [where R is a hydrogen atom or an alkyl group; The polysilsesquioxane of the present invention represented by the above general formula is a new compound, and the present inventors When the polysilsesquioxane was subjected to a physiological activity test, it was confirmed that it has a particularly remarkable anticancer effect. That is, since the polysilsesquioxane exhibits an extremely strong anticancer effect, the polysilsesquioxane having the above-mentioned structural unit can be used as an anticancer agent for the prevention, treatment, or treatment of various cancers.

Therefore, the anticancer agent of the present invention can be administered to a patient either orally, parenterally (for example, intraperitoneally, intrarectally), or locally, and in that case, the effective dose of polysilsesquioxane, which is the active ingredient, can be administered to a patient. is the age of the patient to be treated.

Although it varies depending on body weight, severity of symptoms, type of i, etc., it is generally a o O ~ 0.002 my/Ky/day.

Preferably, the amount may be 500 to 0.01 inches/Kg/day. The daily dose can be administered only once a day or divided into several times (3 to 5 times) a day. Also,
It goes without saying that the above-mentioned dosage is merely a guideline, and it is possible to administer doses beyond 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 sugar-coated tablets, powder packets, granules, syrups, capsules, etc. 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 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 to 6% by weight.
The concentration can be about 0% 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. , Manninto, Suf 71J 7f
li -v Cnesium, liquid paraffin, calcium carbonate.

Hydrogen carbonate) IJum, etc., 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: Capsule 4.5 parts by weight of lactose is added to 0.6 parts by weight of magnesium stearate and mixed with stirring to make the mixture uniform.Furthermore, 5 parts by weight of lactose and 10 parts by weight of crystalline cellulose are added and mixed. 20 parts by weight of polysilsesquioxane, which has been previously pulverized, 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 stearyl alcohol 10 parts by weight, liquid paraffin 20 parts by weight
After heating and dissolving 160 parts by weight of vaseline at 80°C, 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 3: Tablet After 25 parts by weight of polysilsesquioxane and 20 parts by weight of mannitol are thoroughly mixed and ground, 4.7 parts by weight of potato starch is 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 0.3 parts by weight of magnesium stearate,
It may be smoothed and compressed using a tablet machine in a conventional manner to form uncoated tablets of an appropriate size.

Examples of the production of polysilsesquioxane used as an active ingredient in the anticancer agent of the present invention, as well as pharmacological activity testing methods and their results are shown below. However, the present invention is not limited to the following reference examples and examples.

Example 1 When acetic acid (8,12r) was added to γ-aminopropyl polysilsesquioxane monohydrate (3,5Of), it generated heat and a white powder was obtained. Furthermore, benzene (
After adding p-cyanobenzaldehyde (6,00f) purified by distillation, the mixture was heated under reflux for 4 hours to terminate the reaction while performing azeotropic dehydration. After the reaction, the solvent remaining after the reaction is separated from the white solid produced by decanting, and further benzene 30n17! was added, heated to reflux, and then decanted again to remove the solvent. The residue was vacuum dried on an oil bath at 80°C to obtain 6.17f of white solid. Elemental analysis revealed C54, 31%, H5,
01%, N11.69N, C11Hl
l Calculated value for N20t, ssi・H20(241,33) C54,74X, H5,43%, N11.6
It was in good agreement with 1%. Furthermore, when an infrared absorption spectrum was measured, the infrared absorption spectrum shown in FIG. 1 was obtained. As is clear from Figure 1, the 1690c characteristic of the aldehyde group characteristic of the raw material p-cyanobenzaldehyde
Absorption of rn was not observed at all, from 3650 to 3100 cm
Broad absorption based on hydration water, absorption based on cyano group at 2225crn, absorption based on CH=N bond at 16406n, and strong 5i-0 from 1.240 to 900m-'
It showed absorption based on binding. The above results revealed that the isolated product was a ship base compound obtained by a dehydration condensation reaction, that is, p-cyanobenzylidene r-aminopropyl polysilsesquioxane.

Example 2 γ-aminopropyl polysilsesquioxane (4,5O
acetic acid (a, o or >) was added to f), then benzene (60d) and p-carboxybenzaldehyde (5,50r) were added and heated under reflux for 5 hours to terminate the reaction while performing azeotropic dehydration.Reaction Once finished, remove the solution portion by decanting and add more benzene (
The solution portion was removed by adding 50 rnl), heating, cooling, and decanting again. After repeating the tilting operation two more times, the residue was vacuum dried to give a pale yellow powder (10,
339). When elemental analysis was performed, C50,
63%.

H6,32X, N5.39N, CHH12
NOs, 58 Co. Calculated value for H20 (260,33) C50,755X, H6,92%, N5.38%
It matched well. Furthermore, when an infrared absorption spectrum was measured, the infrared absorption spectrum shown in FIG. 2 was obtained. As is clear from FIG. 2, there is a wide absorption range from 3600 to 2000 an=2950 based on hydration water and the OH bond of the carboxyl group.

2920.2850(7) has absorption based on OH bond, 1
A slightly broad absorption based on the carbonyl bond of the carboxyl group was observed at 680 crn, an absorption based on the CH=N bond at 1635 cm, and a broad absorption based on the 81-0 bond between 1220 and 900 crn. The above results revealed that the isolated product was a Schiff base compound obtained by a dehydration condensation reaction, that is, p-carboxybenzylidene γ-aminopropyl polysilsesquioxane.

Example 3 γ-Aminopropylpolysilsesquioxane (5,0O
r) In acetic acid (16,95f), benzene (40m/)
, and p-bis(β-chloroethyl)aminobenzaldehyde was heated under reflux for 4 hours to perform azeotropic dehydration and terminate the reaction. Volatile components were removed using an evaporator, and the residue was vacuum-dried to obtain a hygroscopic orange-red solid (17.79 t). Elemental analysis showed C46.88%, H5.96%, N7.5
1X, Si8.02N, C+4H+pN2
Calculated value for 0+, 5Ct2Si・H20(356,33) c47.19X, H5,94%, N 7.
865X and Si 7.88N.

Furthermore, its infrared absorption spectrum is as shown in Figure 6, with a broad absorption based on hydration water at 6650 to 2300 ctn, an absorption based on OH bond at 2920 an', and an absorption based on OH bonds at 166 to 2300 ctn.
Absorption based on CH=N bond in 0on=, 1210-90
A wide range of absorption based on 81-0 bonds was observed in 0 Rust-1.

The above results revealed that the isolated product was a Schiff base compound produced by a dehydration condensation reaction, that is, p-bis(β-chloroethyl)aminobenzylidene r-aminopropylpolysilsesquioxane.

Example 4 p-carboxybenzylidene γ-aminopropyl polysilsesquioxane (4,65f) obtained in Example 2
was heated and dissolved in N,N-dimethylformamide (500 wt), and then cooled to room temperature. After passing dry ammonia gas through the magnetically stirred leg solution for 3 hours, the solvent was distilled off under reduced pressure to obtain a white solid. As a result of elemental analysis of the product, the compositional formula of the product was C11H15N2
It became clear that it corresponds to 0!1.5 Si.H2O (277,56). Furthermore, when we measured the infrared absorption spectrum, we found a wide absorption range of 3650 to 2200σ, 1
Broad absorption based on carboxylate ions from 660 to 1560 crn', 5i-0 from 1230 to 900 m
Broad absorption due to bonding was observed. The above results revealed that the isolated product was an ammonium salt of p-carboxybenzylidene γ-aminopropyl polysilsesquioxane represented by the following formula.

Example 5 p-carboxybenzylidene r-aminopropyl polysilsesquioxane (5,02f) obtained in Example 2
was suspended in ethanol (200+xl) and sodium ethylate was added in small portions with stirring until equivalent weight was reached. After the addition, the reaction mixture was stirred and heated to 50° C. for 4 hours, and then the volatile components were distilled off. A sodium salt of p-carboxybenzylidene γ-aminopropyl polysilsesquioxane was obtained.

Example 6 The polysilsesquioxanes listed in Table 1 were synthesized by methods similar to those described in detail in Examples 1-3. Table 1 also abbreviates the aspects of each synthesized polysilsesquioxane compound, characteristic absorption values in infrared absorption spectra, and elemental analysis results, as well as the reaction raw material composition, reaction conditions, and reaction treatment conditions used. .

Example 7 The p-cyanobenzylidene γ-aminopropyl polysilsesquioxane obtained in Example 1 was mixed with 6 types including the surfactant Tween 80 (2000~/Kp, 1585/Kp).
g, 1259WJI! /ni9, 1000~/scent, 79
4■/Kr and 661K/Ky> were prepared. Using this sample solution, CDF mice (male) weighing around 209 kg were tested.
A 20-day test was conducted by intraperitoneally injecting the drug into 15 animals.
The acute toxicity value (LDso) was determined by the method of Lynchfield and Wilkokun. LD5. value is 1
It was 375tmy/Ky.

Example 8 The p-cyanobenzylidene γ-aminopropyl polysilsesquioxane obtained in Example 1, the p-carboxybenzylidene γ-aminopropyl polysilsesquioxane obtained in Example 2, and the p-cyanobenzylidene γ-aminopropyl polysilsesquioxane obtained in Example 6. The obtained p-bis(β-chloroethyl)aminobenzylidene r-aminopropyl polysilsesquioxane was used to test its anticancer activity against Ehrlich's ascites carcinoma in mice. That is, an injection prepared by preparing the polysilsesquioxane by the method described in Example 7 above was administered to 5 x 1 Ehrlich cancer cells.
0' intraperitoneally into 6 Swiss mice (male).
A dose of 5 mt was administered by continuous injection for 9 days. From the results of the survival effect over 60 days, the mean survival days (MST) was determined, and T/C(X) was calculated by comparing it with the mean survival days of the control group (30 animals). That is, the average survival days were determined for the test subject (T) and the control subject (C), and T/CX 10
0 (X).

The approximate value is determined by taking the number of days in which the fourth animal among the six test subjects died as the average number of days of survival, dividing this by the average number of days of survival similarly determined from the control subjects, and multiplying the value by 100. In addition, in Examples (Table 2), accurate values calculated using a computer are listed. Although 60 mice were used as a control group, the average value for 6 mice is shown in the table.

Example 9 An experiment on Ehrlich's ascites carcinoma in mice was conducted in the same manner as in Example 8 using each of the polysilsesquioxanes listed in Table 3. The results are listed in Table 3.

Example 10 The p-cyanobenzylidene γ-aminopropyl polysilsesquioxane obtained in Example 1 was suspended in a physiological saline (0.85%) solution containing the surfactant Ly-780. Furthermore, a sample solution was prepared for p-carboxybenzylidene γ-aminobrobilbolysilsesquioxane obtained in Example 2 by dissolving it in physiological saline. Inject this sample solution into the abdominal cavity with a walker.
Intraperitoneal injections were administered to 6 Sprague-Dawley rats (female) having 1×105 Cardiosarcoma 256 cancer cells for 12 consecutive days for 58 days, and the survival effect was investigated over a period of 2 months. The results are shown in Table 4.

Example 11 The p-bis(β-chloroethyl)aminobenzylidene r-aminopropyl polysilsesquioxane obtained in Example 3 was added to physiological saline containing the surfactant Tween 80, and a suspension containing a specified amount of the sample was prepared. A suspension was created. The sample liquid,
P 3881j C with 106 lymphoid leukemia cancer cells
0.5me each into the peritoneal cavity of 6 DFI mice (male)
Continuous injections were administered for days. From the results of the survival effect over 60 days, the mean survival time (MST) was calculated, and the control group (30
T/c% by comparing with the average survival days of
Calculate '#:,. As a result, administration-R100ray/
T/C(X) in Ky is 163. Dosage 50! IV
/Kg, T/C (%) was 121.

[Brief explanation of the drawing]

Figure 1 of the attached drawings shows the measurement results of the infrared absorption spectrum of the polysilsesquioxane obtained in Example 1, and Figure 2 shows the infrared absorption spectrum of the polysilsesquioxane obtained in Example 2. Figure 6 shows the measurement results of the infrared absorption spectrum of the polysilsesquioxane obtained in Example 6. Patent applicant Tokuyama Soda Co., Ltd.

Claims (2)

[Claims] (1) General formula [where R is a hydrogen atom or an alkyl group; A polysilsesquioxane having a structural unit represented by: (2) General formula [where R is a hydrogen atom or an alkyl group; An anticancer agent containing polysilsesquioxane as an active ingredient, which has a structural unit represented by: