JPH0680067B2 - Cilatran compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention provides a silatrane compound having a specific structure and an anticancer agent containing the silatrane compound as an active ingredient.

(Prior Art) With regard to organosilicon compounds, research has been conducted repeatedly on synthesis and physiological activity, and it is known that a specific organosilicon compound group has excellent physiological activity such as antitumor activity and antibacterial activity. .

Among the organosilicon compounds, a compound called silatrane represented by the following formula has been found to have various physiological activities such as antibacterial / antifungal action, insecticidal action, rodenticidal action, hair growth promoting action, and antitumor intestinal action. Has been.

(However, R represents a substituted or unsubstituted alkyl group, an alkoxy group, or a phenyl group.) Furthermore, Lukevitch et al. Synthesize a silatrane derivative represented by the following formula and measure the antitumor activity against several mouse cancer cells. As a result, it has been reported that it has a slight effect only on Ehrlich cancer (Izv.Akad.Nauk.Latv.SSR.) 338 (197).
8)].

(Wherein, X is Cl, OH, OCH _3, showing the _{NO 2, N (C 2 H} 5) 2.) ( Problems to be Solved by the Invention) However, the effect of the anticancer agent for these compounds, yet There has been a demand for a compound that is insufficient and has an excellent anticancer effect.

(Means and Effects for Solving Problems) For many years, the present inventor has synthesized many novel organosilicon compounds and has continued research on various physiologically active actions of the organosilicon compounds.

As a result, the present inventor succeeded in synthesizing a group of silatrane compounds having a group represented by —NHCH ₂ CH ₂ — in the skeleton and having a specific substituent on the aromatic ring, and the compound group was The inventors have found that they express a remarkable antitumor activity, have completed the present invention, and have proposed the present invention.

That is, the present invention provides the following general formula (1) [However, X is a halogen atom, a cyano group, a hydroxy group,
A nitro group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, a bis (haloalkyl) amino group,
R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ] The silatrane compound shown by these and the anticancer agent which uses this silatrane compound as an active ingredient.

In the present invention, the type of the group substituted on the benzene ring of the silatrane compound is a halogen atom, a cyano group, a hydroxy group, a nitro group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, or a bis (haloalkyl) group as described above. It is important that it is an amino group, and in addition to that, it is important to contain a group called —NHCH ₂ CH ₂ — in the main chain. The antitumor effect of the silatrane compound of the present invention is considered to be largely due to the type of the group substituted on the benzene ring and the presence of the —NHCH ₂ CH ₂ — group in the main chain. Because.

As the halogen atom represented by X in the above general formula (1), each atom of fluorine, chlorine, bromine and iodine can be used.

In the general formula (1), the number of carbon atoms of the alkoxy group represented by X, the alkylthio group and the alkyl group constituting the alkoxycarbonyl group is not particularly limited, but the number of carbon atoms is 1 to 1 from the viewpoint of the anticancer effect described later. 4 is preferable.
Specific examples of such groups include, for example, methoxy group, ethoxy group, propoxy group, butoxy group; methylthio group, ethylthio group, propylthio group, butylthio group;
Examples thereof include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group and the like.

Further, in the general formula (1), the haloalkyl group of the bis (haloalkyl) amino group represented by X is not particularly limited in the number of carbons, but in this case, the number of carbons is also 1 to 4 from the viewpoint of anticancer effect. Are preferred. The halogen atom which is a substituent of the alkyl group includes fluorine, chlorine,
Each atom of bromine and iodine can be used.

Further, in the general formula (1), the alkyl group represented by R is not particularly limited in carbon number, but preferably has 1 to 4 carbon atoms from the viewpoint of easy availability of raw materials. Specific examples of such an alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group.

Further, in the general formula (1), n may be an integer of 1 or more. However, since the raw materials are easily available, n is 1 to 4
Is preferably an integer of 1, 3, or 4, in particular.

The silatrane compound of the present invention is a crystalline solid having a constant melting point in most cases at room temperature and atmospheric pressure, and is rarely a viscous substance.

The fact that the silatrane compound has the chemical structure represented by the general formula (1) can be generally confirmed and identified by the following means (a) to (e).

(A) By measuring the infrared absorption spectrum (IR), it is possible to confirm the types of characteristic chemical bonds and functional groups present in the silatrane compound molecule. For example,
The silatrane compounds absorption based on NH bond around 3400~3200cm ^-1, absorption based on the CH bond in the vicinity of 3000~2800cm ^-1,
Absorption based on CR = N bond is shown at 1650 to 1610 cm ^-1 . Substituent X of the silatrane compound exhibits a strong absorption based on the carbonyl bond of the ester group near 1710 cm ^-1 in the case of alkoxycarbonyl groups, the absorption around 2250 cm ^-1 in the case substituent X is a cyano group Indicates.

(B) Measure each mass spectrum (MS) and observe each
(Generally, the molecular weight m of the ion is divided by the charge number e, m /
to calculate the composition formula corresponding to the number represented by e)
Therefore, the binding mode of the sample used for measurement and ultimately
The molecular weight of can be estimated. That is, it was subjected to measurement
Samples with general formulaWhen represented by, the molecular weight depends on the types of R and X.
Molecular ion peak (M ) May be indicated
However, generally from the molecular ion peak at m / e 245Appears.

(C) ¹³ by measuring the C- nuclear magnetic resonance spectrum ⁽¹³ C-NMR), the number of carbon atoms of the silatrane compound was subjected to the measurement, the mode of arrangement of the carbon chain, to know the binding mode of carbon atoms I can. That is, in ¹³ C-NMR (based on tetramethylsilane), a unique peak based on each ¹³ C is observed depending on the types of the substituents X and R in the above general formula and the value of n. For example, X is Br, R is H,
¹³ C-NMR was measured in a deuterated chloroform solvent for the silatrane compound in which n was 3, and the analysis result was as follows (chemical shift value: δ, pp.
m).

(D) by measuring the ¹ H- nuclear magnetic resonance spectra ⁽¹ H-NMR), the number of carbon atoms of the silatrane compound was subjected to the measurement, it is possible to know the bonding mode of hydrogen atoms.
That is, in ¹ H-NMR (tetramethylsilane standard),
Depending on the types of R and X in the general formula (1) and the value of n, a unique peak based on each ¹ H is observed.

(E) Obtaining each weight% of carbon, hydrogen, nitrogen, silicon (halogen and sulfur when halogen and sulfur are further included) by elemental analysis, and then subtracting the total weight% of each recognized element from 100 By weight of oxygen
Can be calculated, and thus the composition formula of the silatrane compound can be determined.

Although the properties of the silatrane compound of the present invention are slightly different depending on the kind of the substituent X in the above general formula, it is generally white, pale yellow, pale brown, yellow, orange yellow, orange, red, at normal temperature and pressure. Although it is a deep red crystalline solid, it may be a viscous substance. The silatrane compound is relatively well soluble in a chlorine-based solvent such as chloroform and methylene chloride, an alcohol-based solvent such as methanol and ethanol, a polar non-aqueous solvent such as N, N-dimethylformamide and dimethyl sulfoxide, and benzene, toluene, It is soluble in tetrahydrofuran, dioxane, etc., sparingly soluble in hexane, ether, ligroin, 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 adopted will be described below. That is, the general formula [However, X is a halogen atom, a cyano group, a hydroxy group,
A nitro group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, a bis (haloalkyl) amino group,
R is a hydrogen atom or an alkyl group, n is an integer of 1 or more, and R'is an alkyl group. ] The target silatrane compound of the present invention can be obtained in good yield by reacting a trialkoxysilane represented by the following with triethanol. The above reaction formula is shown below.

The trialkoxysilane represented by the above formula is not limited to its production method, and those obtained by known production methods can be used without particular limitation. Specific examples of the alkyl group represented by R'in the general formula include methyl group, ethyl group, n-propyl group, iso
Examples include -propyl group and n-butyl group. A catalyst is preferably used in the above reaction. The catalyst can be used without particular limitation as long as it can cut an alkoxy group bonded to silicon to cause an exchange reaction with triethanolamine, and potassium hydroxide, lithium hydroxide, sodium hydroxide can be used. Basic compounds represented by alkali metal hydroxides such as ## STR3 ## are preferable because they are often effective even in a small amount. A typical example of the above reaction will be described in detail in Examples described later. The reaction can be carried out without a solvent, but it is generally carried out in the presence of a solvent. The solvent can be used without particular limitation as long as it is a solvent that does not react with raw materials, products or catalysts, and generally, alcohol solvents such as ethanol, methanol and isopropyl alcohol, cimethoxyethane, dioxane, acetonitrile and the like. Is preferably used. The reaction conditions are not particularly limited, but generally 0 to 200 ° C, preferably 20 to 150 ° C.
It is sufficient to select the temperature within the range of several minutes to several days, and usually within the range of 5 minutes to 50 hours. The reaction pressure is usually atmospheric pressure because the reaction proceeds sufficiently under atmospheric pressure, and may be carried out under pressure or under reduced pressure as 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.

A typical example of the above reaction will be described in detail in Examples described later, but the reaction is generally performed in the presence of a solvent. The solvent can be used without particular limitation as long as it is a solvent that does not react with raw materials or products, and is generally benzene, toluene, ethanol, propanol, acetonitrile, N, N-dimethylformamide, chloroform, tetrahydrofuran, dioxane, Dimethoxyethane and the like are preferably used. The reaction conditions are not particularly limited, but generally 0 to 200 ° C, preferably 20 to 150 ° C.
It is sufficient to select at a temperature of ℃ for several minutes to several days, usually 10 minutes to 50 hours. The reaction is a so-called dehydration reaction, and water is produced as the reaction progresses. Therefore, benzene, chloroform, ethanol, etc., which have an azeotropic property with water, are used as a solvent, and the reaction solution is heated under reflux to produce water. It is convenient to use a means for azeotropically removing azeotropically to the outside of the system, or to use a dehydrating agent or a dehydrating catalyst, if necessary, in order to allow the reaction to proceed efficiently.

The silatran compound of the present invention is usually obtained in good yield by using each raw material at an equimolar ratio according to any of the above reaction formulas. When the silatran compound precipitates as crystals after completion of the reaction, it can be obtained as an extremely pure product by filtering the crystals. Further, when the silatrane compound is dissolved in the solution even after the completion of the reaction, it can be obtained by removing volatile components such as a solvent by means such as atmospheric distillation, reduced pressure distillation and vacuum distillation. The silatran compound thus obtained is generally a pure product, but if a highly pure silatran compound is required to be obtained, a purification means such as recrystallization or reprecipitation can be used.

The silatrane compound of the present invention has remarkably excellent physiological activity and exerts an excellent anticancer activity. For example, it exerts an extremely potent anti-cancer effect against Ehrlich's ascites tumor in mice, Walker Carcinosarcoma 256 ascites tumor in rats, and P388 leukemia in mice. From these effects, the silatrane compound of the present invention can be suitably used for the purpose of preventing, treating or treating various cancers. Many of the silatran compounds of the present invention exhibit high antitumor activity, as is clear from the examples described later.
The antitumor activity of the silatrane compound varies depending on the types of R and X in the general formula (1) and the value of n, but generally n is 3, R is a hydrogen atom or a methyl group. , X is a bromine atom, an iodine atom, a cyano group, an alkylthio group, an alkoxycarbonyl group, and a bis (haloalkyl) amino group tend to show strong activity. Preferred examples of the alkoxycarbonyl group include a methoxycarbonyl group and an ethoxycarbonyl group, preferred examples of the alkylthio group include a methylthio group and an ethylthio group, and a preferred example of the bis (halalkyl) amino group. Examples include a bis (chloroethyl) amino group, a bis (bromoethyl) amino group and a bis (iodoethyl) amino group.

When the silatrane compound of the present invention is used as an anticancer agent, any known form can be used. A typical example of the use form is oral,
It can be given to patients either parenterally (eg intramuscularly, intravenously, subcutaneously, intraperitoneally, intrarectally) or topically. The effective dose of the silatrane compound, which is the active ingredient at that time, varies depending on the age, weight, weight of symptoms, type of cancer, etc. of the patient to be administered, but is generally 200 to 0.0
It can be 02 mg / Kg / day, preferably 50 to 0.02 mg / Kg / day. The daily dose can be administered only once a day or divided into several times a day (3 to 5 times). Further, it goes without saying that the above-mentioned dose is merely a guideline, and it is possible to administer over the above-mentioned range depending on the judgment of the treating doctor.

Upon administration of 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 a dosage form such as tablets, pills, dragee tablets, powder sachets, granules, syrups, capsules, etc., and for parenteral administration, a solution or suspension, a suppository. And the like.

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

As the excipient that can be used in the above-mentioned formulation, any of those commonly used in the art can be used. For the solid-form formulation, for example, lactose, sucrose, starch, glycine, crystalline cellulose can be used. , Mannitol, magnesium stearate, liquid paraffin, calcium carbonate, sodium hydrogencarbonate, etc. For liquid form preparations, for example, physiological saline, surfactant solution, glucose solution, alcohol, esters, etc. Is mentioned.

The specific examples of such preparations are as follows.

Formulation Example 1: Injectable Aseptically dispensed into vials to contain the predetermined amount of silatrane compound and sealed to remove water and bacteria. Before use, a prescribed amount of physiological saline containing lidocaine 0.5% may be added to obtain an injection.

Formulation Example 2: Capsules 45 parts by weight of lactose was added to 0.6 parts by weight of magnesium stearate, and the mixture was stirred and mixed to make uniform.
1 part by weight and 10 parts by weight of crystalline cellulose are added and mixed. To this mixture, 20 parts by weight of a finely powdered silatrane compound was added, and the mixture was mixed again to obtain a prepared powder. Capsules may be manufactured by filling gelatin capsules with this powder using a capsule filling machine.

Formulation Example 3: Tablets 25 parts by weight of silatrane compound and 20 parts by weight of mannitol were thoroughly mixed and pulverized, and then potato starch 4.7 as starch paste was prepared.
Add parts by weight to granulate. The particles are passed through a 60 mesh screen, dried to a specified weight and screened through a 16 mesh screen. Next, the particles were treated with magnesium stearate
It may be mixed with 3 parts by weight, smoothed, and compressed by a tablet molding machine by a conventional method to give tablets of an appropriate size.

The silatrane compound of the present invention, production examples thereof, and bioactivity test examples are shown below. However, the present invention is not limited to these.

Example 1 A mixture of γ- (2-aminoethyl) -aminopropylsilatrane (4.04 g), p-bromobenzaldehyde (2.72 g) and benzene (50 ml) was heated under reflux for 1 hour to produce water by azeotropic dehydration. To react. Volatile components were removed by vacuum distillation, and the residue was recrystallized from ethanol to give a white solid (5.16 g) with a melting point of 118-120 ° C. When the infrared absorption spectrum of the product was measured, a spectrum as shown in FIG. 1 was obtained, showing a wide absorption at 3430 cm ⁻¹ based on the NH bond, 1640 cm.
^-1 showed absorption based on CH = N bond. Its elemental analysis values C49.05%, H6.50%, N9.58% , Br17.89%, calcd for a _{Si6.57% C 18 H 28 N 3} O 3 BrSi (442.43) a composition formula Consistent with C48.86%, H6.38%, N9.50%, Br18.06%, Si6.35%. Moreover, when the mass spectrum was measured, m / e245
To Corresponding to the peak, at m / e 174 The peak corresponding to Then, ¹³ C-NMR was measured, and a spectrum as shown in Fig. 2 was obtained. The results of analyzing the spectrum were assigned as follows.

Furthermore, ¹ H-NMR of the compound was measured in deuterated chloroform on the basis of tetramethylsilane.
The spectrum unique to the silatrane compound as shown in the figure was shown.

From the above results, the obtained product is N represented by the following formula.
It was revealed to be-(p-bromophenylmethylidene) -γ- (2-aminoethyl) -aminopropylsilatrane. The yield was 79.3%.

The compound No. of the compound is designated as No. 1.

Example 2 N- (p-bromophenylmethylidene) -in the formula below
γ- (2-aminoethyl) -aminopropyltrimethoxysilane (3.89 g) and triethanolamine (1.49 g) were added to ethanol (50 m) in the presence of potassium hydroxide (0.18 g).
l) was reacted in.

The reaction mixture was treated in the same manner as in Example 1 to give the same N- (p-bromophenylmethylidene) -γ- (2-aminoethyl) -aminopropylsilatran as the product obtained in Example 1. (2.65 g) was obtained.

Example 3 A mixture of γ- (2-aminoethyl) -aminopropylsilatrane (3.23 g), p-bis (β-chloroethyl) aminobenzaldehyde (2.88 g) and benzene (70 ml) was added to 2 parts.
The mixture was heated under reflux for a reaction to give an orange solid (5.18 g) having a melting point of 102 to 105 ° C. When the infrared absorption spectrum of the product was measured, a spectrum as shown in FIG. 4 was obtained, showing a wide absorption at 3310 cm ⁻¹ based on the NH bond, 1640 cm.
^-1 showed absorption based on CH = N bond. Its elemental analysis values C52.73%, H7.39%, N10.89% , for Cl14.26%, a _{Si5.77% C 22 H 36 N 4} O 3 Cl 2 Si (503.54) a composition formula Calculated values are C52.47%, H7.21%, N11.13%, Cl14.08%, Si5.
Well matched with 58%. In addition, the mass spectrum was measured and found to be m / e 245. Corresponding to the peak, at m / e 174 The peak corresponding to The product obtained from the above results was N- [p-bis (β-chloroethyl) aminophenylmethylidene] -γ- (2-aminoethyl) -aminopropylsilatrane represented by the following formula. confirmed. The yield was 87.9%.

The compound No. of this compound is designated as No. 2.

Example 4 γ- (2-aminoethyl) -aminopropyl silatrane
(4.03g), p-nitrobenzaldehyde (2.21g), Tor
A mixture of ene (40 ml) is heated to reflux for 30 minutes to react,
An orange-red viscous substance (4.65 g) was obtained. Infrared absorption spectrum of the product
When measuring the vector, 3325 cm^-1Based on NH bond
Wide absorption, 1640 cm^-1Shows absorption based on CH = N bond
It was Its elemental analysis values are C53.24%, H6.74%, N13.74%, Si7.
10% and C₁₈H₂₈N_FourO_FiveFor the composition formula Si (408.52)
Calculated values of C52.92%, H6.91%, N13.72%, Si6.88%
Matched Also, when the mass spectrum was measured, m /
The molecular ion peak corresponding to the molecular weight at e408 (M ), M / e
To 245Peak at m / e 174The peak corresponding to Obtained from the above results
The product is represented by the following formula: N- (p-nitrophenylene
Tylidene) -γ- (2-aminoethyl) -aminopropyi
It was confirmed to be Luciratran. Yield is 78.0%
It was.

The compound No. of this compound is designated as No. 3.

Example 5 The compounds obtained in Examples 1 to 4 were added to physiological saline containing the surfactant agent Tween 80 to prepare a suspension containing a specified amount of sample, and this sample solution was used to prepare a mouse. Was tested for antitumor activity against Ehrlich ascites cancer. That is, the test solution was intraperitoneally administered to 6 Swiss mice (female) having 1 × 10 ⁶ Ehrlich cancer cells by intraperitoneal injection of 0.5 ml each for 9 consecutive days. The number of days (MST) was calculated, and T / C (%) was calculated by comparing with the average survival time of the control group (30 animals). That is, the average survival time was calculated for the test body (T) and the control body (C),
Calculated as T / C x 100 (%). The approximate value is determined by taking the number of days when the 4th animal out of 6 test subjects died as the average number of days to survive, and dividing this by the average number of days to survive similarly determined from the control body, and then multiplying by 100. The results are shown in Table 1. However, although 30 mice were used as a control group, the average value of 6 mice is shown in the table.

From the above results, it was revealed that the compounds No. 1 to 3 synthesized in Examples 1 to 4, particularly the compounds No. 1 and 2 exhibited remarkable antitumor activity.

Example 6 A sample solution of the No. 1 compound was prepared in the same manner as in Example 5, and intraperitoneally Walker Carcinosarcoma 256 cancer cells 1
Six (10) Sprague Dawley rats (male) having × 10 ⁵ cells were intraperitoneally injected for 5 consecutive days, and the life-prolonging effect was examined for 1 month. As a result, the dose is 100m
Rats (6 g / Kg, 50 mg / Kg and 25 mg / Kg)
The number of surviving animals is 4 and 3, respectively, and the T / C (%) is 3
It was revealed that the compound of No. 1 having a level of 85 or more exhibited remarkable antitumor activity.

Example 7 A sample solution of the No. 2 compound was prepared in the same manner as in Example 5. The sample solution was intraperitoneally administered to 6 CDF ₁ mice (male) having 1 × 10 ⁶ P388 lymphocytic leukemia cancer cells by intraperitoneal injection in an amount of 0.5 ml for 9 consecutive days. A 30-day life-prolonging effect test showed that the T / C (%) was 15 at a dose of 50 mg / Kg.
1. T / C (%) was 167 at a dose of 25 mg / Kg.

Example 8 The following general formula was prepared by the same method as that described in Example 5.
A silatrane compound represented by
The anti-tumor activity of Ehrlich ascites tumor in mice
Tested. Composition formula and elemental analysis value of the compound, and
The results of the anticancer activity test are also shown in Table 2. In addition,
The mass spectra of the compounds listed in Table 2 were measured.
About all compoundsPeak corresponding to, (M ) And m / e 174 to cilatranil
Base, ieThe peak corresponding to
Was measured to be 1680 to 1610 for all compounds.
cm^-1Absorption based on CR = N bond was observed in.

[Brief description of drawings]

1 and 4 show Example 1 and Example 3, respectively.
The infrared absorption spectrum of the silatrane compound of the present invention obtained in 1. is shown. Further, FIG. 2 shows the ¹³ C-nuclear magnetic resonance spectrum of the silatrane compound obtained in Example 1, and FIG. 3 shows the ¹ H-nuclear magnetic resonance spectrum of the silatrane compound obtained in Example 1.

Claims (2)

[Claims] 1. A general formula [However, X is a halogen atom, a cyano group, a hydroxy group,
A nitro group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, a bis (haloalkyl) amino group,
R is a hydrogen atom or an alkyl group, and n is an integer of 1 or more. ] The silatran compound shown by these. 2. General formula [However, X is a halogen atom, a cyano group, a hydroxy group,
A nitro group, an alkoxy group, an alkylthio group, an alkoxycarbonyl group, 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 agent containing the silatrane compound shown by these as an active ingredient.