JPS6055031A - Polysilsesquioxane - Google Patents

Abstract

NEW MATERIAL:A polysilsesquioxane of formula I (wherein X is H, a halogen, OH, or an alkyl, y is a sulfonic acid group or its salt group). EXAMPLE:2-Sulfobenzylidene-gamma-aminopropylpolysilsesquioxane. USE:Carcinostatic agent. PREPARATION:A calcinostatic agent comprising a polysilsesquioxane is obtained by reacting a gamma-aminopropylpolysilsesquioxane with an excess of a substituted benzaldehyde compound at 0-150 deg.C in a solvent azeotropically distillable with water, such as benzene, toluene, or chloroform. This carcinostatic agent is given to a patient orally, parenterally, or topically one - five times a day in a dose of 0.002-800mg/kg/day.

Description

[Detailed description of the invention] The present invention is based on the general formula (However, LX is a hydrogen atom,...Ugen atom, hydroxyl group.

The present invention provides a polysilsesquioxane having a structural unit represented by an alkyl group (J), a sulfonic acid group or a salt type group thereof, and an anticancer agent containing the polysilsesquioxane as an active ingredient. be.

Conventionally, some polysilsesquioxane d2, 0H05S
The silsesquioxane represented by +IR (where 1 to R represents a monovalent organic group) is made into 11 repeating units, and is generally represented by the following formula %. It is known to be a polymer compound having a skeletal 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 carbon-nitrogen=heavy bond, Japanese Patent Publication No. 36-9421 R+.

In the general formula R2,C=N(CH2)aSi: (
However, R1 and R2B are each a hydrogen atom or a hydrocarbon group.

Or nitro, hydroxy, alkoxy.

or a hydrocarbon group substituted with a halogen atom (1), a is an integer of at least 3 (2), and the unsaturated bond of the silicon atom represented by si= is alkyl, allyl, alkoxy, hydroxy Alternatively, alkoxysilane derivatives and polysiloxane derivatives represented by (10-8i = group) are known, and these compounds can be used as filtering agents, ultraviolet absorbers, and scissoring agents. Proposed.

The present inventor has synthesized various polysilsesquioxanes and
Various studies have been conducted on their physiological activities. As a result, the following general formula (where R' is a hydrogen atom or an alkyl group, Z is a hydrogen atom,...a rogen 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) diamino group, etc. ) It has been found that polysilsesquioxane having the structural unit represented by Te has excellent physiological activity, particularly anticancer activity, and proposals 1 to 1 have already been made.

As a result of further intensive research into the physiological activity of polysilsesquioxane compounds, the present inventors found the following general formula (with the proviso that a hydrogen atom) and a rhodan atom. We succeeded in creating a new polysilsesquioxane having a structural unit represented by a hydroxyl group or an alkyl group, and a sulfonic acid group or its salt type group. It has been confirmed that the drug has excellent properties and is effective as an anticancer drug, and has been offered here.

That is, the present invention provides a novel structure having a structural unit represented by the general formula (where X is a hydrogen atom, ... a rodan atom, a hydroxyl group or an alkyl group), and Y is a sulfonic acid group or a salt type group thereof. The present invention provides a polysilsesquioxane 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. In the general formula,
The aliphatic saturated hydrocarbon residue which is an alkyl group listed as substituent X can be used without particular limitation. In general, those having 1 to 4 carbon atoms, ie, methyl group, ethyl group, propyl group, butyl group, etc., are most preferably used because of their advantages in fJiJ method. Moreover, the substituents X and I-
As mentioned above, chlorine, bromine, iodine and fluorine atoms can be used without particular limitation.

Furthermore, in the general formula, the substituent Y is a sulfonic acid group or a salt type group thereof. As is clear from the Examples described below, the -5o5θ functional group is effective for physiological activity (ε), and the type of cation that binds to the nucleus θ does not have much influence. Therefore, when the cation that binds to mosquito θ is expressed as -803M, for example, M is not particularly limited, and hydrogen atoms, ammonium, or metals are selected. The metal is not particularly limited, and includes, for example, Group 1, Group Ⅰ, and Group ① of the periodic table.

The metal may be appropriately selected from metals such as group (Ⅰ) and group (Ⅰ) metals.

Specific examples of typical metals that are generally widely used include ammonium (N (4); sodium rN
aΦ), potassium (K■), lithium (T, 1■), etc.; magnesium- (1/2 My20), calcium (1/2Ca2■)
) and the like are most preferably used.

The polysilsesquioxane represented by the above general formula is obtained as an amorphous solid polymer exhibiting a color such as white, pale yellow, pale orange-yellow, or light brown, and is often crushed and handled as a powder. Depending on the type of substituent X in the general formula, it may be obtained as a viscous substance. The polysilsesquioxane is modeled as described above (estimated to be a three-dimensional cage polymer, and usually contains ligroin, cyclopentane, hexane, or benzene.

It is often almost insoluble in toluene, chloroform, carbon tetrachloride, etc. On the other hand, it is often soluble in polar nonaqueous solvents such as formamide, N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphomide, and in alcohol, and its solubility increases particularly when heated. A trend can be seen.

It is also relatively stable in aqueous solutions near neutrality. On the other hand, in acidic or alkaline aqueous solutions, the stability varies depending on the concentration and temperature, but in general K C=
The N-bond undergoes hydrolysis and decomposes into r-aminopropylpolysilsesquioxane and the corresponding substituted benzaldehyde. 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 general formula. In particular, elemental analysis and infrared absorption spectrometry are extremely effective methods. IJII The synthesized nuclear polysilsesquioxane contains carbon, hydrogen, nitrogen, and silicon.

By calculating the weight percent of the element sulfur (and the halogen atom if it contains a halogen atom in the quadruplets), and further subtracting the sum of the recognized weight percent of each element from 100.I)
, the weight X of the oxygen element is calculated17, and the compositional formula of the polysilsesquioxane can be determined by test pricking. Furthermore, by measuring the infrared absorption spectrum of the limb 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 diameter of 1690 cm-' to 16
From the fact that it exhibits a characteristic infrared absorption based on C=N bonds near 40 m-1, and from the results of elemental analysis, the polysilsesquioxane is normally in the hydrated or dihydrated form in the solid state. It is known that it is rare to exist in an anhydrated form.

The method for producing the polysilsesquioxane used in the present invention is not particularly limited, and any production method may be used. Generally, as shown in the general reaction formula below, r-
Aminopropyl polysilsesquioxant general formula o =
[ζ] can be easily synthesized by dehydrating and condensing a substituted benzaldehyde compound represented by CH-Qf, Y.

O,,5SJ,CH2ClI2yenJ2NF12)-r
) -cH-αX (I former 7x hydrogen atom, halogen atom, hydroxyl group.

The molar ratio of the aminopropyl polysilsesquioxane and the carbonyl compound during the reaction is particularly limited, and there are no critical considerations. It is preferable to use the carbonyl compound in excess at a ratio of 1:1 or more, taking into consideration the recovery of unreacted materials. So I2
Unreacted carbonyl compounds are removed by distillation after the reaction 1. , you can remove it by washing with a solvent such as hexane.

In addition, it is generally preferable to use a reaction solvent in the above reaction, such as benzene or toluene.

Solvents that are azeotropic with water, such as chloroform and ethanol, can be suitably used. The reaction temperature is, for example, 0 to 150°C or the layer is J? Although it can be carried out over a wide range of temperatures, it is generally preferable to carry out 1C 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 preferably employed.

The bo-1-nosilsesquioxane of the present invention represented by the above general formula is a new compound ζJ, and when the present inventor conducted a physiological activity test on the polysilsesquioxane, it was found that the polysilsesquioxane has particularly remarkable anticancer activity. confirmed. 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.

However, the anticancer agent of the present invention can be administered to patients either orally, parenterally (for example, intraperitoneally, intrarectally) or locally in the ridge, and the active ingredient in this case, polysilsesquidone, can be administered to patients. The effective administration of oxane varies depending on the age and weight of the patient to whom it is administered, the severity of symptoms, the type of cancer, etc., but it is generally 800 to 0.002 ■/Kf/day, preferably 1
．． 〈 can be set to 500 to 0.01 ■/'b7 days. The dosage of said 1 [" is only once a day or several times a day (
It can be administered in divided doses (3 to 5 times). It goes without saying that the above-mentioned dosage is merely a guideline, and it is possible to administer doses beyond the stated range at the discretion of the treating physician.

When administering the above-mentioned active ingredient, the vorisilsesgioxane can be formulated into various dosage forms depending on the desired administration method (oral, parenteral, or topical).

For example, tablets, pills for oral administration.

It can be formulated into dosage forms such as sugar-coated tablets, powder sachets, granules, syrups, capsules, etc. It can also be formulated into dosage forms such as parenteral "one dose per administration", suspensions, and crude drugs. 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 formulations, any excipient commonly used in the field of medicine and limbs can be used.For solid form formulations, for example, lactose, sucrose, starch, glycine, , crystalline cellulose, mannitol, magnesium stearate, liquid paraffin, calcium carbonate.

Sodium bicarbonate and the like, and for liquid form preparations, for example 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 had been pulverized in advance, was added to this mixture and mixed again.
) Obtain the prepared powder. Capsules may be produced by filling this powder into gelatin capsules using a capsule filling machine.

Formulation Example 2: Softener 101 parts of stearyl alcohol, 20 parts of liquid halafin, and 160 parts by weight of petrolatum were dissolved by heating at 80°C, followed by 0.5 parts by weight of cholesterol and 1 part by weight of previously finely powdered polysilane. Add 10 parts by weight of lusesquioxane with good stirring, and after further stirring, leave to stand at room temperature to obtain a softener with a suitable hardness of 12.

Formulation Example 3: Tablets 25 parts by weight of polysilsesquioxane and 20 parts by weight of mannitol are thoroughly mixed and pulverized in a bale, then 4.7 parts by weight of potato starch is added as a glue 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 sterophosphate,
Smooth it and use the usual method to cut it into a tablet.
It can be compressed into plain 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 γ-minobrovir polysilsesquiogysan monohydrate (2,75f), sodium 2-formylbenzenesulfonate (5,20f').

A mixture of benzene (1()Omj), N,N-dimethylformamide (311 m/) and acetic acid (3-) was added to 11
[By heating under reflux for 0 hour] the reaction was carried out while performing azeotropic dehydration. After the reaction solution was cooled, it was suction filtered and thoroughly washed with benzene to obtain a colored powder. Elemental analysis revealed C35.39, TT 4.85%,
It shows a value of H4, 63%, f31B, 6ON, and Co.

Hr+N04,5s8JNa-2F(20(336,
39) Calculated value for (” 55.70%, H4,4
9%, H4, 16%, 3J8.35~ (agreed).

The infrared absorption spectrum shown in Figure 1 was obtained by measuring the red IAgL absorption spectrum of Sarashi C.

As is clear from the comparison with Figure 2, which is the infrared absorption spectrum of sodium 2-formylbenzenesulfonate (raw material)), the 1690 on = No sharp absorptions were observed, a broad absorption based on hydration at 3700 to 3100 on-1, a rather broad absorption based on the CFl2N bond at 1660 on-', and a broad absorption based on the CFL2N bond at 1660 on-'
00c+++-' shows absorption based on a strong 81-O bond. From the above two results, it was revealed that the isolated product was a Schiff base compound obtained by a dehydration condensation reaction, that is, a sodium salt of 2-sulfobenzylidene-r-aminobrobylborisilsesgioxane.

Example 2 r-Aminopropylborisilsesgioxane monohydrate (2,569), sodium 4-formylbenzenesulfonate (4A6f).

A mixture of benzene (100m), N,N-dimethylformamide (30d), and acetic acid (3,26m) was added to
Azeotropic dehydration was performed by heating under reflux for 0 hours, and the reaction solution was cooled and filtered with suction to obtain a pale yellow powder ('7.23
f) was obtained.

Elemental analysis showed c 35.26%.

T (4,59%, N 4.26%, Si 8.4
It shows a value of B'9, and C1(IHHNO4,58Si
Calculated value C for Na + 2H20 (336,39)
35,70%.

) T4.49%, H4.1<S, 818.35%. Furthermore, when an infrared absorption spectrum was measured, the infrared absorption spectrum shown in FIG. 3 was obtained. Third
Clear from the figure r) Kanasama K, 3700~S 100cm-'
Broad absorption based on water of hydration, slightly broader absorption at 169 ntyn-' C) Absorption based on T=N bond activity, 1280-9
Absorption based on the 81-0 bond was shown at 00FM. The above results revealed that the isolated product was the sodium salt of 4-sulfobenzylidene-r-aminobrobylborisilsesgioxane.

Example 3 The sodium salt of 2-sulfobenzylidene-r-aminobrobyl polysilsesquioxane obtained in Example 1 was added to physiological saline containing surfactant Tween 80 to prepare a sample solution containing a specified amount of sample. I was the assistant producer. The sample solution was converted to r-
--CDF with 5×1n' Luritzhi cancer cells.

1. Continuously administered 0.5 me intraperitoneally to 6 mice (female) for 9 days. Ta. Based on the results of the 4JE survival effect of 450 KJ-), the mean survival days (MST) was determined and
T/C was calculated by comparing with the average survival days of 0 animals). That is, the average survival days were calculated for the test subject (T'l) and the control subject (C) using T/CX100 (%).As a result, when the dose was 200 my/Ko, the survival time among the 6 mice The number is 3 and its MST is 45
．． It was 0 days or more. In contrast, the MAT of the control group was 1
It was 5.6 days. Therefore, 2-sulfobenzylidene-γ
The T/c% of the sodium salt of -aminopropylpolysilsesquioxane at a dosage of 200q/Kf was calculated to be 288 or more, and it was revealed that it exhibits remarkable anticancer activity against Ehrlich's carcinoma.

Example 4 The sodium salt of 4-sulfobenzylidene-γ-aminopropyl polysilsesquioxane obtained in Example 2 was added to physiological saline containing surfactant Tween 80 to prepare a sample solution containing a specified amount of sample. Created. For the sample solution,
An anticancer activity test against Ehrlich's carcinoma was conducted in the same manner as in Example 6. As a result, the dose was 100+v/We
In this case, the number of surviving mice out of 6 mice is 6 ζ
), its MST is 45.0 days or more I), T/C%1
It was calculated to be 286 or higher, and it was revealed that it showed remarkable anticancer activity against Ehrlich's cancer.

Example 5 2-sulfobenzylidene-γ-ryeε obtained in Example 1
A sample solution containing a specified number of samples was prepared by adding the sodium salt of nobrobilvolisilsesquioxane to a physiological saline solution containing the surfactant Tween 80. Inject the carcass sample solution into the peritoneal cavity of 1x Walker carcinoma sarcoma 256M cells.
Intraperitoneal injection of -r was administered to 6 male Sbrag-Dawley rats having 105 cells for 5 consecutive days, and the survival effect was investigated over a period of 12.1 months. - As a result, the dosage was set to 400Iv/Kf, 20 Q1Ny/J, 10
Cape 0/Kf 1. *In case, rat l-survivor I out of 6 rats]
The MST was 30 days or more in all cases. In contrast, the MST of the control group was 863 days. Therefore, the T/C was calculated to be 361 or more at all doses, and it was revealed that it exhibited extremely significant anticancer activity against 256 Walker cardiac sarcoma cancers.

Example 6 The sodium salt of 4-sulfobenzylidene-r-aminopropylpolysilsesquioxane obtained in Example 2 was tested against Walker Cardinosarcoma 256 cancer in the same manner as in Example 5. dosage 20
0■/ The number of survivors out of 6 rats in Ky is 3
The MS'I' was 30.08 or higher.

Therefore, the T/C% was calculated to be 361 or more, and it was revealed that the drug exhibited remarkable anticancer activity against Walker Cardiosarcoma 256 cancer.

Example 7 1. Same as Example 1 and Nuke 2. A mild polysilsesquioxane was synthesized. Example 3 and rffltjlHc+ were tested on Ehrlich's ascites carcinoma of Theaus using the polysil-1-skioxane. The results for Sonera are shown in Table 1.

[Brief explanation of the drawing]

Figure 1 of the attached drawings shows the red light 1 absorption spectrum of the dihydrate of the tutolium salt of 2-sulfobenzylidene-r--rminopropylpolysilsesquinone obtained in Example 1, and Figure 2 Figure 6 is a chart of the infrared absorption spectrum of sodium 2-formylbenzenesulfonate, and Figure 6 is a chart of the infrared absorption spectrum of the dihydrate of the thorium salt of 4-sulfobenzylidene-r-aminoprobylborisilsesquioxane. .Patent applicant: Tokuyama Ata Co., Ltd.

Claims (2)

[Claims] (1) A polysilsesquioxane having a structural unit represented by the general formula (1) where xH is a hydrogen atom, a halogen atom, a hydroxyl group or an alkyl group, and Y is a sulfonic acid group or a salt type group thereof. (2) A polysilsesquioxane having a structural unit represented by the general formula (where X is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group), a sulfonic acid group from Company Y or a salt-type group thereof) Anticancer drug as an active ingredient.