JPH0326215B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, n represents an integer of 1 or 2, B represents a hydrogen atom or a methyl group, Ar represents an unsubstituted or benzene ring having a substituent X, and the substituent X is a halogen atom, a hydroxyl group, an alkyl group, Alkoxy group, nitro group, cyano group, carbamide group, carboxyl group, salt type group of carboxyl group, ester group, di(alkyl)amino group, bis(haloalkyl)amino group, sulfonic acid group, and salt type of sulfonic acid group The present invention provides a polysilsesquioxane having a molecular weight of 750 to 6,100 and having a structural unit represented by the following group, and an anticancer agent containing the polysilsesquioxane as an active ingredient. . Traditionally, some polysilsesquioxanes are

[Formula] Further abbreviated as O _1.5 SiR (however, R represents a monovalent organic group), the repeating unit is silsesquioxane, and the model is as follows: It is generally known to be a polymer compound having a ladder-like or cage-like skeleton structure, and is widely used as a water repellent agent, a 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 Japanese Patent Publication No. 36-9421, the general formula:

[Formula] (However, R ¹ and R ² are each a hydrogen atom, a hydrocarbon group, or a hydrocarbon group substituted with a nitro, hydroxy, alkoxy, or halogen atom, and a is an integer of at least 3. ,
Alkoxysilane derivatives and polysiloxane derivatives in which the unsaturated valence of the silicon atom represented by Si≡ is bonded to alkyl, allyl, alkoxy, hydroxy or -O-Si≡ group are known, A filtering agent for the compound;
It has been proposed to be used as an ultraviolet absorber and a scissoring agent. The present inventor has synthesized various polysilsesquioxanes and conducted various studies on their physiological activities. As a result, the following general formula (However, R' is a hydrogen atom or an alkyl group, and Y
is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an alkyl group, a cyano group, a carbamide group, a carboxyl group, an ester group, a bis(haloalkyl)amino group, and the like. It has been discovered that polysilsesquioxane having a structural unit represented by ) has excellent physiological activity, particularly anticancer activity, and has already been proposed. The inventor of the present invention is interested in the physiological activity of polysilsesquioxane compounds, and as a result of further intensive research, the following general formula: (In the formula, n represents an integer of 1 or 2, B represents a hydrogen atom or a methyl group, Ar represents an unsubstituted or benzene ring having a substituent X, and the substituent X is a halogen atom, a hydroxyl group, an alkyl group, Alkoxy group, nitro group, cyano group, carbamide group, carboxyl group, salt type group of carboxyl group, ester group, di(alkyl)amino group, bis(haloalkyl)amino group, sulfonic acid group, and salt type of sulfonic acid group We succeeded in producing a new polysilsesquioxane with a molecular weight of 750 to 6,100, which has a structural unit represented by We have confirmed that it is effective as an anticancer drug and have decided to offer it here. The polysilsesquioxane of the present invention may have a structure represented by the above general formula. The most characteristic structure is the propyl group bonded to the silicon atom.
NHCH ₂ CH ₂ − or −NHCH ₂ CH ₂ NHCH ₂ CH ₂ −
, and this terminal CH ₂ - group has -N=
C-Ar or

[Formula] is connected. Physiologically active - (NHCH ₂ CH ₂ -) _o (n
is an integer of 1 or 2)

[Formula] (B is H or -CH ₃ and Be represents a benzene ring)
Polysilsesquioxane having a group attached to it has meaning, and the effect of physiological activity depending on whether or not the benzene ring has a substituent or the type of substituent is generally the effect of the above group. It is extremely small compared to . Furthermore, the polysilsesquioxane of the present invention is a new compound having a structural unit represented by the above general formula, in which Ar represents a benzene ring that is unsubstituted or has a substituent X, and is listed as the substituent X. The aliphatic saturated hydrocarbon residues, which are alkyl groups constituting alkoxy groups, alkyl groups constituting ester groups, and alkyl groups constituting dialkylamino groups, can be used without particular limitation. Generally, those having 1 to 4 carbon atoms, such as methyl group, ethyl group, propyl group, butyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc., are the most preferred because of their advantages in manufacturing process. Preferably used. In addition, the base salt type group of the carboxyl group represented by the substituent X is generally represented by COO M, and M is not particularly limited, but is generally ammonium (NH ₄ ); sodium (Na 2 ). , potassium (K), lithium (Li
); alkali metals such as magnesium (1/2Mg ²
), alkaline earth metals such as calcium (1/2Ca ² ), etc. are most preferably used. Further, as the halogen atom listed as the substituent X, chlorine, bromine, iodine, and fluorine atoms can be used without particular limitation. Furthermore, the bis(haloalkyl)amino group represented by the substituent X is generally [Z
(CH ₂ ) _n ] ₂ N, the halogen atom represented by Z may be chlorine, bromine, iodine, or fluorine without limitation, and m is an integer from 1 to 4. Most preferably used. The polysilsesquioxane represented by the above general formula is amorphous white, pale yellow, yellow, orange-yellow, orange,
It is obtained as a solid polymer exhibiting a brown color, etc., 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 also be obtained as a viscous substance. . The polysilsesquioxane usually exists as a 3- to 15-mer of the above-mentioned structural units, and is presumed to be a three-dimensional cage-like polymer as described above based on the model of mainly 7- to 8-mers, and usually contains water and ligroin. It is almost insoluble in , cyclopentane, and hexane, and is often sparingly soluble in benzene, 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 especially when heated. There is a marked tendency to increase. In addition, it is stable in water because it is insoluble in most cases, but its stability in acidic or alkaline aqueous solutions varies depending on its concentration and temperature. Generally, the C=N bond undergoes hydrolysis, resulting in aminopropyl polysilsesquioxanes and corresponding carbonyl compounds (such as substituted benzaldehyde or substituted furfural).
Decompose into. 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, 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 the sum of the weight percent of each recognized element.
By subtracting it from 100, 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 has a temperature of 1690 cm ^-1 ~
Around 1620cm ^-1

[Formula] It is found that the polysilsesquioxane exhibits a characteristic infrared absorption based on the bond, and the elemental analysis results show that the polysilsesquioxane usually exists in a monohydrated form, sometimes in a dihydrated form in a solid state, It is known that it rarely exists in anhydrous form. 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. Generally, as shown in the general reaction formula below, aminopropyl polysilsesquioxanes and the general formula

It can be easily synthesized by dehydrating and condensing a carbonyl compound represented by the formula. (However, n represents an integer of 1 or 2, B represents a hydrogen atom or a methyl group, Ar represents an unsubstituted or benzene ring having a substituent X, and the substituent X is a halogen atom, hydroxyl group, alkyl group, alkoxy group, nitro group, cyano group, carbamide group, carboxyl group, salt type group of carboxyl group, ester group, di(alkyl)amino group, bis(haloalkyl)amino group, sulfonic acid group, and salt type group of sulfonic acid group (a group selected from the group consisting of It is preferable to use the carbonyl compound in excess at a ratio of 1:1 or more. Unreacted carbonyl compounds may be removed by distillation after the reaction and washing with a solvent such as hexane. In addition, it is generally preferable to use a reaction solvent in the above reaction, and for example, solvents that are azeotropic with water such as benzene, toluene, chloroform, and ethanol can be suitably used. Although the reaction temperature can be varied over a wide range of, for example, 0 to 150°C or higher, it is generally preferable to carry out the reaction at the boiling point temperature of the solvent. Although the reaction time varies depending on the reaction temperature, it can generally be selected from several minutes to several days. In order to promote the dehydration condensation reaction of the above reaction, a means of adding an acid such as acetic acid or formic acid to the reaction system is often suitably employed. The polysilsesquioxane of the present invention represented by the above general formula is a new compound, and when the present inventor conducted a physiological activity test on the polysilsesquioxane, it was confirmed that the polysilsesquioxane has particularly remarkable anticancer activity. . That is, since the polysilsesquioxane exhibits an extremely strong anticancer effect, the polysilsesquioxane having the above 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 patients orally, parenterally (for example, intramuscularly, intravenously, subcutaneously, intraperitoneally, rectally), or locally, and the active ingredients The effective dosage of polysilsesquioxane varies depending on the age, weight, severity of symptoms, type of cancer, etc. of the patient to whom it is administered, but is generally 800 to 1 mg/Kg/day, preferably
It can be 500-10 mg/Kg/day. The daily dosage is only once a day or several times a day (3 to 5 times a day).
It can be administered in divided doses. 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 active ingredient, the polysilsesquioxane can be formulated into various dosage forms depending on the desired administration method (oral, parenteral, or topical), and parenteral administration For local administration, it can be formulated into dosage forms such as suspensions and suppositories, 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 it is generally about 0.05 to 90% by weight, preferably 1 to 60% by weight. be able to. As excipients that can be used in the above formulation, any excipient commonly used in the field can be used, and for solid form formulations, for example, lactose,
Examples include sucrose, starch, glycine, microcrystalline cellulose, mannitrate, magnesium stearate, liquid paraffin, calcium carbonate, sodium hydrogen carbonate, etc. For liquid form preparations,
For example, physiological saline, surfactant solution, glucose solution,
Examples include alcohols and esters. Specific examples of such formulations are as follows. Formulation Example 1: Capsule 0.6 parts by weight of magnesium stearate and 4.5 parts by weight of lactose
Add parts by weight and stir and mix 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 had been previously pulverized, was added to this mixture.
A prepared powder is obtained by mixing again. Capsules may be produced by filling this powder into cegelatine capsules using a capsule filling machine. Formulation Example 2: Ointment After heating and dissolving 10 parts by weight of stearyl alcohol, 20 parts by weight of liquid paraffin, and 160 parts by weight of petrolatum, 0.5 parts by weight of cholesterol and 10 parts by weight of polysilsesquioxane, which had been pulverized in advance, were added. It is preferable to add the mixture with good stirring, and after further stirring, leave it at room temperature to obtain an appropriate hardness. Formulation Example 3: Tablet 25 parts by weight of polysilsesquioxane and mannite
After thoroughly mixing and pulverizing 20 parts by weight, 4.7 parts by weight of potato starch was added as 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 may be mixed with 0.3 parts by weight of magnesium stearate, smoothed, and compressed using a tablet machine in a conventional manner to form uncoated tablets of an appropriate size. Examples of the synthesis of the polysilsesquioxane of the present invention and examples of its efficacy in anticancer activity tests are shown below. However, the present invention is not limited to the following examples. Example 1 γ-(2-aminoethyl)aminopropylpolysilsesquioxane (4.50g), acetic acid (10.76g),
Azeotropic dehydration was carried out by heating and refluxing a mixture of p-bromobenzaldehyde (6.50 g) and benzene (40 ml) on an oil bath for 5 hours. After the volatile components were distilled off under reduced pressure, 9.25 g of a yellowish brown solid was obtained by vacuum drying. Elemental analysis performed
The values _are C42.92%, H6.01%, _{N7.98 %} , Si8.01%, and the calculated values for _{C12H16N2O1.5BrSi}・_H2O (338.30) are C42.60% and H5. 37%, N8.28%, Si8.30%
matched. Furthermore, when the infrared absorption spectrum was measured, the infrared absorption spectrum shown in FIG. 1 was obtained. As is clear from FIG. 1, there was an absorption based on hydration water near 3400 cm ^-1 , an absorption based on CH=N bond at 1640 cm ^-1 , and a strong absorption based on Si-O between 1240 and 890 cm ^-1 . From the above results, the isolated product is N-(p-bromobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane obtained by the dehydration condensation reaction and represented by the following formula. It became clear. The molecular weight of the product was determined to be 2570 by vapor pressure osmometry (tetrahydrofuran solution). Example 2 γ-(2-aminoethyl)aminopropylpolysilsesquioxane (4.28g), acetic acid (9.64g),
A mixture of p-fluorobenzaldehyde (3.72 g) and benzene (80 ml) was heated under reflux to perform azeotropic dehydration for 5 hours. The reaction mixture was evaporated to dryness and dried under vacuum to obtain a dark brown viscous substance (9.08 g).
Elemental analysis revealed C51.39%, H6.15%,
Showing values of N9.58% and Si9.56%, C ₁₂ H ₁₆ N ₂ O _1.5
Calculated value C51.96% for FSi・H ₂ O (277.38),
It matched with H6.54%, N10.10%, and Si10.13%. The infrared absorption spectrum is as shown in Figure 2, and is 3400
Absorption based on hydration water near cm ^-1 , CH at 1640 cm ^-1
= Absorption based on N bonds, Si-O from 1220 to 850 cm ^-1
It showed absorption based on binding. From the above results, it became clear that the isolated product was N-(p-fluorobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane represented by the following formula. The molecular weight of the product was measured in the same manner as in Example 1 and was found to be 1,660. Example 3 γ-(2-aminoethyl)aminopropylpolysilsesquioxane (4.28g), p-cyanobenzaldehyde (3.35g), anhydrous benzene (80ml)
The mixture was heated under reflux for 5 hours to perform azeotropic dehydration, and then filtered under suction to obtain a bright yellow sandy solid (6.84 g). When elemental analysis was measured
The values are C55.52%, _H6.10 %, _N13.86 %, _Si9.53 %, and the calculated values for _{C13H16N3O1.5Si}・_H2O (284.39) are C54.90% and H6. 38%, N14.78%, Si9.88
% matched. The infrared absorption spectrum is as shown in Figure 3, with absorption based on hydration water near 3300 cm ^-1 , absorption based on CH bonds at 2930, 2880, and 2800 cm ^-1 , and absorption based on CH=N bonds at 1640 cm ^-1 . Absorption, 1250
Absorption based on Si-O bonds was observed at ~880 cm ^-1 .
The above results revealed that the isolated product was N-(p-cyanobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane represented by the following formula. The molecular weight of the product was measured in the same manner as in Example 1 and was found to be 3320. Example 4 A mixture of γ-(2-aminoethyl)aminopropyl polysilsesquioxane (4.28 g), p-carboxybenzaldehyde (3.90 g), acetic acid (9.62 g), and benzene (80 ml) was heated under reflux for 2 days. The mixture was subjected to azeotropic dehydration, followed by suction filtration to obtain an orange sandy solid (8.55 g). Elemental analysis showed values _of C51.46%, H5.98%, _N8.97 %, _Si9.54 %, and the calculated value C51 for _{C13H17N2O3.5Si}・_H2O (303.40) .46%, H6.31%, N9.24%,
It matched with Si9.26%. The infrared absorption spectrum is the fourth
As shown in the figure, there is a wide range of absorption based on hydration water and OH bonds of carboxyl groups at 3700 to 2100 cm ^-1 , absorption based on C=O bonds of carboxyl groups at 1695 cm ^-1 , and absorption based on CH=N bonds at 1635 cm ^-1 . Absorption based on
Absorption based on Si-O bonds was observed at 1180 to 900 cm ^-1 . From the above results, the product is N
It was revealed that it was -(p-carboxybenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane. The molecular weight of the product was measured in the same manner as in Example 1 and found to be 2,800. Example 5 γ-[2-(ethylenediamino)ethyl]aminopropylpolysilsesquioxane (monohydrate;
A mixture of 4.50 g), acetic acid (11.68 g), and p-bromobenzaldehyde (4.60 g) was heated under reflux for 1 day to perform azeotropic dehydration, and the volatile components were distilled off under reduced pressure, followed by vacuum drying to obtain a brown viscous substance ( 7.89g) was obtained. The viscous material solidified after being left for several days. Elemental analysis measured C43.90%, H6.53%,
Showing values of N10.59% and Si7.08%, C ₁₄ H ₂₃ N ₃ O _2.5
Calculated value C44.09% for BrSi・H ₂ O (381.36),
It matched with H6.08%, N11.02%, and Si7.37%. Measurement of the infrared absorption spectrum showed absorption based on hydration water at around 3400 cm ^-1 , absorption based on CH=N bond at 1640 cm ^-1 , and absorption based on Si-O bond at 1220 to 890 cm ^-1 . From the above results, the product is N-(p-bromobenzylidene)γ-
It became clear that it was [2-(ethylenediamino)ethyl]aminopropyl polysilsesquioxane. The molecular weight of the product was measured in the same manner as in Example 1 and found to be 5,570. Example 6 The polysilsesquioxanes listed in Table 1 were synthesized by methods similar to those detailed in Examples 1 to 5. In Table 1, characteristic absorption values and elemental analysis results in the infrared absorption spectrum (IR) of each synthesized polysilsesquioxane compound are also abbreviated. In this example, No. 2 and
The molecular weight of No. 8 polysilsesquioxane was measured in the same manner as in Example 1, and was found to be 2680 and 2420, respectively.
It was hot.

【table】

【table】

[Table] Example 7 N-(p-bromobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane obtained in Example 1 was mixed with surfactant Tween 80.
A sample solution containing a specified amount of sample in addition to physiological saline containing . The sample solution was added to CDF ₁ mouse (male) having 5 x ¹⁰⁶ Ehrlichi cancer cells.
0.5 ml each was continuously injected intraperitoneally to 6 animals for 9 days. From the results of the survival effect over 60 days, the mean survival days (MST) was determined, and T/C% was calculated by comparing it with the mean survival days of the control group (30 animals). That is, the average survival days for test subjects (T) and controls (C)
It was calculated using T/C x 100 (%). As a result, when the dose was 200mg/Kg, 6 mice
The number of survivors among them is 4, and their MST is
It was over 45.0 days. In contrast, the control group
MST was 16.4 days. Therefore, the dose of N-(p-bromobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane 200
T/C% in mg/Kg is calculated to be 274 or more,
It has been revealed that it exhibits remarkable anticancer activity against Ehrlichi's cancer. Example 8 The N-(p-bromobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane obtained in Example 1 was mixed with the surfactant Tween 80.
A suspension containing a specified amount of the sample in addition to physiological saline was prepared. The sample solution was intraperitoneally injected for 5 consecutive days into 6 male Sprague-Dawley rats having 1 x 10 ⁵ Walker Carcinosarcoma 256 cancer cells in the peritoneal cavity for 1 month. The life-prolonging effect was investigated over time. The results are shown in Table 2.

[Table] Example 9 Using the N-(p-fluorobenzylidene)γ-(2-aminoethyl)aminopropylpolysilsesquioxane obtained in Example 2, the Ehrlitsu ascites of mice was treated in the same manner as in Example 7. Tested against cancer. The results are shown in Table 3.

[Table] Example 10 Using each of the polysilsesquioxanes obtained in Examples 3 to 6, a test against Ehrlichi's ascites carcinoma in mice was conducted in the same manner as in Example 7. The results are listed in Table 4.

【table】

【table】 [Brief explanation of drawings]

Figures 1, 2, 3, 4, and 5 of the attached drawings show the measurement results of infrared absorption spectra of the compounds obtained in Examples 1, 2, 3, and 4, respectively. be.

Claims (1)

[Claims] 1 General formula, (In the formula, n represents an integer of 1 or 2, B represents a hydrogen atom or a methyl group, Ar represents an unsubstituted or benzene ring having a substituent X, and the substituent X is a halogen atom, a hydroxyl group, an alkyl group, Alkoxy group, nitro group, cyano group, carbamide group, carboxyl group, salt type group of carboxyl group, ester group, di(alkyl)amino group, bis(haloalkyl)amino group, sulfonic acid group, and salt type of sulfonic acid group A polysilsesquioxane having a molecular weight of 750 to 6,100 and having a structural unit represented by (a group selected from the group consisting of groups).