JPH0144194B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention is based on the general formula (However, X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ) and an anticancer agent containing the silatrane compound as an active ingredient. (Prior art) Regarding organosilicon compounds, research has been carried out on their synthesis and physiological activities, and it is known that a specific group of organosilicon compounds has excellent physiological activities such as anticancer activity and antibacterial activity. . Among organosilicon compounds, a compound called silatran, represented by the following formula, has been found to have various physiological activities such as antibacterial/antifungal, insecticidal, rodenticidal, hair growth promoting, and antitumor intestinal effects. It is. (However, R represents a substituted or unsubstituted alkyl group, alkoxy group, or phenyl group.) Furthermore, Rugewicz et al. synthesized a silatrane derivative represented by the following formula and measured its anticancer activity against several types of mouse cancer cells. As a result, they reported that it was slightly effective only against Ehrlichi cancer [Izv.Akad.
Nauk.Latv.SSR, 338 (1978)]. (However, X is Cl, OH, OCH ₃ , NO ₂ , N
(C ₂ H ₅ ) ₂ is shown. ) (Problems to be Solved by the Invention) However, the effects of these compounds as anticancer agents are still insufficient, and there is a desire to search for compounds with even better anticancer effects. (Means and Effects for Solving the Problems) Over the years, the present inventor has synthesized many novel organosilicon compounds and continued research on various physiologically active effects of the organosilicon compounds. As a result, the present inventor succeeded in synthesizing a group of silatrane compounds having specific substituents on the aromatic ring, and discovered that this group of compounds exhibits an unparalleled and significant anticancer activity. have been completed and proposed here. That is, the present invention provides the following general formula (1) (However, X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ) and an anticancer agent containing the silatrane compound as an active ingredient. In the present invention, the type of group substituted on the benzene ring of the silatrane compound is, as described above, a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group. is important. The effects of the present invention cannot be obtained with chlorine atoms and fluorine atoms, which are the same halogen atoms as the above-mentioned bromine atoms and iodine atoms. For example, as is clear from the comparative examples described below, the anticancer effect of the compound having a chlorine atom as a substituent is extremely inferior to that of the silatrane compound of the present invention having a bromine atom or an iodine atom as a substituent. It has become a thing. From these facts, it is considered that the anticancer effect of the silatrane compound of the present invention is largely based on the type substituted on the benzene ring. In the above general formula (1), the number of carbon atoms in the alkylthio group represented by X is not particularly limited, but from the viewpoint of the anticancer effect described below, those having 1 to 4 carbon atoms are preferred. Specific examples of such groups include a merthio group, an ethylthio group, a propylthio group, a butylthio group, and the like. In addition, the number of carbon atoms in the alkoxycarbonyl group represented by X in the above general formula (1) is not particularly limited, but
Again, from the viewpoint of anticancer effect, those having 1 to 4 carbon atoms are preferable. Examples of such groups include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, and the like. Furthermore, in the general formula (1), the haloalkyl group of the bis(haloalkyl)amino group represented by X is,
The number of carbon atoms is not particularly limited, but in this case as well, those having 1 to 4 carbon atoms are preferred from the viewpoint of anticancer effect. Furthermore, each of fluorine, chlorine, bromine, and iodine atoms can be used as a halogen atom as a substituent of an alkyl group. Further, in the general formula (1), the alkyl group represented by R is not particularly limited in the number of carbon atoms, but from the viewpoint of easy availability of raw materials, the number of carbon atoms is preferably 1 to 4. Specific examples of such alkyl groups include methyl, ethyl, propyl, and butyl groups. Furthermore, in the general formula (1), n may be an integer of 1 or more. However, due to the ease of obtaining raw materials,
It is preferred that n is an integer of 1 to 4, particularly 1, 3 or 4. The silatrane compound of the present invention is in most cases a crystalline solid having a certain melting point at room temperature and normal pressure, and in rare cases is a viscous substance. The fact that the silatrane compound has the chemical structure represented by the general formula (1) can generally be confirmed and fixed by the following methods (a) to (d). (b) By measuring the infrared absorption spectrum (IR), it is possible to confirm the characteristic chemical bonds and types of functional groups that exist within the silatrane compound molecule. For example, the silatrane compound
Absorption based on CH bonds near 3000 to 2800 cm ^-1
Absorption based on CR=N bond is shown at 1650 to 1620 cm ^-1 . Furthermore, the substituent X in the silatrane compound
1710cm ^-1 if is an alkoxycarbonyl group
There is a strong absorption near the carbonyl bond of the ester group. (b) By measuring the mass spectrum (MS) and calculating the composition formula corresponding to each observed peak (generally a number expressed as m/e, which is the molecular weight m of the ion divided by the number of charges e), It is possible to estimate the binding mode and ultimately the molecular weight of the sample subjected to measurement. In other words, the sample subjected to measurement is expressed by the general formula (However, X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, and R
is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ), the molecular ion peak (M), which generally corresponds to the molecular weight, is M − where C ₆ H ₄ X is desorbed from the molecular ion peak.
A peak corresponding to C ₆ H ₄ X and a strong peak corresponding to N(CH ₂ CH ₂ O) ₃ Si appear at m/e174. (c) ¹³ C− nuclear magnetic resonance spectrum ( ¹³ C−
By measuring NMR), it is possible to know the number of carbon atoms, the arrangement of carbon chains, and the bonding mode of carbon atoms in the silatrane compound subjected to measurement. That is, in ¹³ C-NMR (tetramethylsilane standard), six unique peaks were observed regardless of the substituent X in the above general formula,
Generally, the approximate value (δ, ppm) of the chemical shift of each peak can be assigned as follows when n=3. Further, the shift value of each peak of the six carbon atoms constituting the aromatic ring in the above general formula varies depending on the type of substituent X, but is generally observed to be 110 to 150 ppm. Furthermore, when the substituent X is a group containing a carbon atom, such as an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, it is natural that peaks corresponding to each carbon atom will be observed at specific positions. be. (d) Determine the weight percent of each of carbon, hydrogen, nitrogen, and silicon (and halogen and sulfur if it contains halogen and sulfur) by elemental analysis, and then calculate the sum of the weight percent of each recognized element from 100. By subtracting, the weight percent of oxygen can be calculated and therefore the compositional formula of the silatrane compound can be determined. The properties of the silatrane compound of the present invention vary depending on the type of substituent X in the general formula, but generally, at room temperature and normal pressure, it is white, pale yellow, pale brown, yellow, orange-yellow, orange, It is a red or deep red crystalline solid, but it may also be viscous. The silatrane compound can be used in chlorinated solvents such as chloroform and methylene chloride, methanol,
It is relatively soluble in alcoholic solvents such as ethanol, polar non-aqueous solvents such as N,N-dimethylformamide and dimethyl sulfoxide, and soluble in benzene, toluene, tetrahydrofuran, dioxane, etc., and is soluble in hexane, ether, ligroin, etc. It is sparingly soluble in water and insoluble in water. The method for producing the silatrane compound of the present invention is not particularly limited, and any method may be used. A typical manufacturing method that is generally suitably employed will be described below. That is, the general formula (However, X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more, By reacting the trialkoxysilane represented by (R' is an alkyl group) with triethanol, the desired silatrane compound of the present invention can be obtained in a good yield. The above reaction formula is as follows. The trialkoxysilane represented by the above formula is not limited to its manufacturing method, and those obtained by known manufacturing methods can be used without particular restriction. Specific examples of the alkyl group represented by R′ in the general formula include methyl group,
Ethyl group, n-propyl group, iso-propyl group,
Examples include n-butyl group. Further, it is preferable to use a catalyst in the above reaction. The catalyst is not particularly limited and can be used as long as it cleaves the alkoxy group bonded to silicon to carry out the exchange reaction with triethanolamine, but potassium hydroxide, lithium hydroxide, and sodium hydroxide can be used. A small amount of a basic compound represented by an alkali metal hydroxide such as alkali metal hydroxide is often effective, so it is suitable. Representative examples of the above reactions will be described in detail in the Examples below. Although the reaction can be carried out without a solvent, it is generally carried out in the presence of a solvent. The solvent is not particularly limited and can be used as long as it does not react with the raw materials, products or catalyst, and generally alcoholic solvents such as ethanol, methanol, isopropyl alcohol, dimethoxyethane, dioxane, acetonitrile, etc. Preferably used. The reaction conditions are not particularly limited, but are generally 0 to 200°C, preferably 20 to 150°C.
It is sufficient to select a temperature range of several minutes to several days, usually 5 minutes to 50 hours, at a temperature of .degree. Further, since the reaction proceeds sufficiently under atmospheric pressure, it is usually sufficient to carry out the reaction at normal pressure, but it is also possible to carry out the reaction under increased pressure or reduced pressure if necessary. The silatrane compound of the present invention can also be obtained in good yield by reacting an aminoalkyl silatrane with a substituted benzoyl compound. The reaction formula is shown below. Representative examples of the above reactions will be described in detail in the Examples below, but the reactions are generally carried out in the presence of a solvent. The solvent is not particularly limited and can be used as long as it does not react with the raw materials or products, and generally includes benzene, toluene, ethanol, propanol, acetonitrile, N,N-
Dimethylformamide, chloroform, tetrahydrofuran, dioxane, dimethoxyethane and the like are preferably used. Further, the reaction conditions are not particularly limited, but are generally conducted at a temperature of 0 to 200°C, preferably 20 to 150°C, for several minutes to several days.
It is sufficient to select a time in the range of 10 minutes to 50 hours. In addition, this reaction is a so-called dehydration reaction, and as water is produced as the reaction progresses, benzene, chloroform, and ethanol, which have the property of being azeotropic with water, are used as solvents, and the reaction solution is heated to reflux, and the produced water is shared. It is convenient for the reaction to proceed efficiently to use a means of boiling and removing it from the system, or to use a dehydrating agent or a dehydrating catalyst as necessary. The silatrane compound of the present invention can usually be obtained in good yield by using each raw material in an equimolar ratio according to any of the above-mentioned reaction formulas. When the silatrane compound precipitates as crystals after completion of the reaction, it can be obtained in extremely pure form by filtering the crystals. Further, if the silatrane compound remains dissolved in the solution even after the completion of the reaction, it can be obtained by removing volatile components such as the solvent by means such as atmospheric distillation, reduced pressure distillation, vacuum distillation, etc. The silatrane compound thus obtained is generally a pure product, but if it is necessary to obtain a silatrane compound of even higher purity, purification methods such as recrystallization and reprecipitation may be used. The silatrane compound of the present invention has remarkable physiological activity, and exhibits particularly excellent anticancer activity. For example, it exhibits extremely strong anticancer effects against Ehrlichi condensate carcinoma in mice, Walker carcinoma sarcoma 256 ascites carcinoma in rats, and 388 leukemia in mice. Because of these effects, the silatrane compound of the present invention can be suitably used for the purpose of preventing, treating, or treating various cancers. As is clear from the comparative examples described below, the silatrane compound of the present invention has significantly higher anticancer activity than the silatrane derivative synthesized by Lukewicz et al. mentioned above. Although such high anticancer activity is due to the silatrane structure of the silatrane compound, it is also thought to be largely due to the type of substituents substituted on the aromatic ring. The silatrane compound of the present invention can be used in any known manner as an anticancer agent. Typical examples of the use form include administration to a patient either orally, parenterally (eg, intramuscularly, intravenously, subcutaneously, intraperitoneally, rectally), or locally. The effective dose of the silatran compound, which is the active ingredient, is determined by the age, weight, severity of symptoms, and age of the patient to whom it is administered.
It varies depending on the type of cancer, etc., but in general, 200~
It can be 0.002 mg/Kg/day, preferably 50-0.02 mg/Kg/day. The daily dose can be administered only once a day or divided into several times (3 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 active ingredient, the silatrane compound can be formulated into various dosage forms depending on the desired administration method (oral, parenteral, or topical). For example, for oral administration, it can be formulated into tablets, pills, dressings, powder sachets, granules, syrups, capsules, etc. For parenteral administration, it can be formulated into solutions, suspensions, suppositories, etc. For topical administration, it can be formulated into ointments, plasters, creams, and the like. 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: Injection Aseptically dispense into vials containing a predetermined amount of silatrane compound and seal to remove moisture and bacteria. Lidocaine 0.5% before use
An injection may be prepared by adding a predetermined amount of physiological saline containing the following. Formulation example 2: 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 parts by weight of crystalline cellulose are added and mixed. 20 parts by weight of the silatrane compound 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 3: 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 at 80°C, 0.5 parts by weight of cholesterol and 10 parts by weight of the silatrane compound previously pulverized were thoroughly added. It is advisable to add the mixture while stirring, stir well, and then leave it at room temperature to obtain an appropriate hardness. Formulation Example 4: Tablets After thoroughly mixing and pulverizing 25 parts by weight of silatrane compound and 20 parts by weight of mannitrate, 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. The particles may then be mixed with 0.3 parts by weight of magnesium stearate, smoothed, and compressed into tablets of appropriate size using a tablet machine in a conventional manner. The silatrane compound used as an active ingredient in the anticancer agent of the present invention, its production example, pharmacological activity test method and its results are shown below. However, the present invention is not limited thereto. Example 1 N-(P-ethoxycarbonylphenylmethylidene)-γ-aminopropyltriethoxysilane (9.75 g), triethanolamine (3.81 g), potassium hydroxide (0.30 g) and ethanol (30 g)
ml) was heated under reflux for 3 hours, then Example 1
The product was post-treated in the same manner as above and recrystallized from ethanol to obtain white crystals (5.09 g) with a melting point of 131.5-133.5°C. When the infrared absorption spectrum of the product was measured, the spectrum shown in Figure 1 was obtained, with absorption based on the carbonyl bond of COOC ₂ H ₅ groups at 1710 cm ^-1 and CH= at 1640 cm ^-1 .
It showed absorption based on N bonds. Its elemental analysis value is
C56.93%, H7.18%, N7.00%.
C ₁₉ H ₂₈ N ₂ O ₅ Si (C 58.13%, H 7.19%, which is the calculated value for the composition formula 392.52)
- Peak corresponding to H, M - at m/e243
Peak corresponding to C ₆ H ₄ COOC ₂ H ₅ , m/e174N
A peak corresponding to (CH ₂ CH ₂ O) ₃ Si was shown. Furthermore, as a result of ¹³ C-NMR measurement, each peak observed was assigned as follows (chemical shift value δ,
ppm. From the above results, the white crystals obtained are N-(P
-ethoxycarbonylphenylmethylidene) -γ
-Aminopropylsilatrane. The yield was 50.7%. Example 2 N-[P-bis(β-chloroethyl)aminophenylmethylidene]-γ-aminopropyltriethoxysilane (7.04 g), triethanolamine (2.68 g), potassium hydroxide (0.80 g)) ethanol (20 ml) was heated under reflux for 40 minutes and then left in a cool place to obtain pale yellow crystals (6.04 g) with a melting point of 146.5-148.5°C. When the infrared absorption spectrum of the product was measured, the spectrum shown in Figure 2 was obtained, and the infrared absorption spectrum at 1625 cm ^-1 was obtained.
It showed absorption based on CH=N bond. Its elemental analysis values are C51.95%, H6.66%, N8.86%,
The calculated values for the composition formula C ₂₀ H ₃₁ N ₃ O ₃ Cl ₂ Si (460.47) were in good agreement with C52.16%, H6.79%, and N9.13%. In addition, when the mass spectrum was measured, peaks corresponding to M at m/e461 and 459,
m/e219 and 217

[Formula] Peak corresponding to m/e174 N(CH ₂ CH ₂ O) ₃ Si
The peak corresponding to Furthermore, ¹³ C−
As a result of NMR measurement, the observed peaks were assigned as follows (chemical shift value δ, ppm). From the above results, the pale yellow crystals obtained are N-
It was revealed that it was [P-bis(β-chloroethyl)aminophenylmethylidene]-γ-aminopropylsilatrane. The yield was 79.5%. Example 3 γ-aminopropyl silatrane (4.65 g) P-
Ethoxycarbonylbenzaldehyde (3.56g),
A mixture of benzene (70 ml) was heated under reflux for 3 hours, and the resulting water was removed by azeotrope while reacting to give the same N-(P-ethoxycarbonyl phenyl methane) product as obtained in Example 1. Liden)-γ-aminopropylsilatrane (3.08 g) was obtained. Example 4 N-[P-bis(β-chloroethyl)aminophenylmethylidene]-γ-aminopropyltrimethoxysilane (5.03 g), triethanolamine (1.84 g), lithium hydroxide (0.3 g), methanol (20 ml) was reacted in the same manner as in Example 2 to produce the same N
-[P-bis(β-chloroethyl)aminophenylmethylidene]-γ-aminopropylsilatoran (4.56 g) was obtained. Example 5 A silatrane compound represented by the following general formula was synthesized by a method similar to that described in Example 1 or 3. Structure of silatran compound. The physical property values, instrumental analysis results, yield, and reaction mixture composition are shown in Table 1. In addition, when mass spectra of the compounds shown in Table 1 were measured, all compounds had a molecular ion peak (M ) corresponding to the molecular weight and a silatraanyl group at m/e174, that is, N(CH ₂ CH ₂ O) ₃ Si A peak corresponding to was observed.

【table】

[Table] Example 6 The silatrane compound represented by the following general formula obtained in Examples 1 to 5 was added to physiological saline containing the surfactant Tween 80 to create a suspension containing a specified amount of the sample. Using this sample solution, the anticancer activity against Ehrrich's ascites carcinoma in mice was tested. That is, the sample solution was mixed with 5 Ehrlichi cancer cells.
Six Swiss mice (male) containing ×10 ⁶ cells were continuously injected intraperitoneally in 0.5 ml doses for 9 days. Part 60
The mean survival days (MST) was determined from the results of the survival effect over 55 days or 55 days, 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 were determined for the test subject (T) and the control subject (C), and calculated as T/C x 100 (%). The approximate value is determined by taking the number of days when the fourth animal among the six test animals 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. The results are shown in Table 2. However, although 30 mice were used as a control group, the average value for 6 mice is shown in the table.

【table】

[Table] Example 7 A sample solution was prepared by suspending a specified amount of the silatrane compound represented by the following general formula obtained in Examples 1 to 5 in physiological saline containing surfactant Tween 80. This sample solution was injected intraperitoneally for 5 consecutive days into 6 Sprague-Dawley rats (female) having 1 x 10 ⁵ Walker Carcinosarcoma 256 cancer cells in their peritoneal cavities for 2 months. The life-prolonging effect was investigated. The results are shown in Table 3.

[Table] Example 8 The N-[P-bis(β-chloroethyl)aminophenylmethylidene]-γ-aminopropylsilatorane synthesized in Example 2 was mixed with the surfactant Tween 80.
A sample solution containing a specified amount of sample in addition to physiological saline containing . The test sample solution was continuously injected into six CDF ₁ mice (male) containing 1×10 ⁶ P388 lympholeukemia cancer cells in 0.5 ml portions intraperitoneally for 9 days. According to a 30-day survival test, T/C (%) was 128 at a dose of 50 mg/Kg.
At a dose of 2 mg/Kg, the T/C (%) value was 157. Example 9 A silatrane compound represented by the following general formula was synthesized by a method similar to that described in Example 1,
The anticancer activity against Ehrlichi's dehydration carcinoma in mice was tested in the same manner as in Example 6. The compositional formula and elemental analysis values of the compound, as well as the anticancer activity test results are listed in Table 4. In addition, when the mass spectra of the compounds listed in Table 4 were measured,
For all compounds, the molecular ion peak (M ) corresponding to the molecular weight and the silatraanyl group at m/e174,
That is, a peak corresponding to N(CH ₂ CH ₂ O) ₃ Si was observed, and when the infrared absorption spectrum was further measured, a peak corresponding to N(CH 2 CH 2 O) 3 ^Si was observed.
Absorption based on CH=N bonds was observed.

【table】

【table】

[Table] Comparative Example A silatran compound represented by the following general formula was tested for anticancer activity against Ehritz's ascites carcinoma in mice in exactly the same manner as in Example 6. The results are shown in Table 5.

【table】

【table】 [Brief explanation of drawings]

FIG. 1 of the accompanying drawings shows the measurement results of the infrared absorption spectrum of the compound obtained in Example 1, and FIG. 2 shows the measurement results of the infrared absorption spectrum of the compound obtained in Example 2.

Claims (1)

[Claims] 1. General formula (However, X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, or a bis(haloalkyl)amino group, R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ) is a silatrane compound. 2 General formula (However, X is a bromine atom, an iodine atom, a cyano group,
It is an alkylthio group, an alkoxycarbonyl group or a bis(haloalkyl)amino group, R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ) An anticancer drug containing a silatrane compound as an active ingredient.