JPH0651711B2 - Phosphonic acid diester derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel phosphonic acid diester derivative.

2. Description of the Related Art The phosphonate diester derivative of the present invention is a novel compound that has not been published in the literature.

Problems to be Solved by the Invention An object of the present invention is to provide a compound useful as a medicine as described below.

Means for Solving the Problems According to the present invention, the general formula [Wherein, R ¹ and R ² are each a hydrogen atom, a substituent selected from a halogen atom, a hydroxyl group, a lower alkoxy group, an N, N-di-lower alkylamino group and an N, N-di-lower alkylamino lower alkoxy group. Or a phenyl lower alkyl group or a diphenyl lower alkyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring, or are bonded to each other. 1,2,3,4-tetrahydroquinolin-1-yl group with the nitrogen atom to which they are bonded, an indoline-1-yl group which may have a phenyl group at the 2-position or 3-position, the 2-position or Having a 2,3-dihydro-4H-1,4-benzoxazin-4-yl group that may have a phenyl group at the 3-position or a halogen atom on the benzene ring It shows a group which forms a certain phenothiazine-10-yl group. R ³ represents a lower alkyl group. A
Represents a methylene group or a sulfonyl group. ] The phosphonic acid diester derivative represented by these is provided.

Specific examples of the respective groups represented by the general formula (I) include the following respective groups.

Examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,
A hexyl group etc. can be illustrated.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and hexyloxy groups.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the N, N-di-lower alkylamino group include N,
N-dimethylamino, N, N-diethylamino, N, N
-Dipropylamino, N, N-dihexylamino, N-
Examples include methyl-N-ethylamino, N-methyl-N-butylamino, N-ethyl-N-hexylamino groups and the like.

Examples of the N, N-di-lower alkylamino-lower alkoxy group include (N, N-dimethylamino) methoxy and 1-
(N, N-dimethylamino) ethoxy, 2- (N, N-
Dimethylamino) ethoxy, 2- (N, N-diethylamino) ethoxy, 2- (N, N-dimethylamino) propoxy, 3- (N-methyl-N-ethylamino) butoxy, 6- (N, N-di). Examples include propylamino) hexyloxy group and the like.

Examples of the phenyl lower alkyl group include phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 3-phenylbutyl, 5-phenylpentyl and 6-phenylhexyl groups.

Examples of the diphenyl lower alkyl group include diphenylmethyl, 1,2-diphenylethyl, 2,2-diphenylethyl, 2,3-diphenylpropyl, 3,3-diphenylpropyl, 1-phenyl-1-methyl-2-phenyl. Examples thereof include ethyl, 4,4-diphenylbutyl, 2,5-diphenylpentyl and 6,6-diphenylhexyl groups.

1 as a substituent selected from a halogen atom, a hydroxyl group, a lower alkoxy group, an N, N-di-lower alkylamino group and an N, N-di-lower alkylamino-lower alkoxy group.
As the phenyl group which may have 3 to 3, in addition to the phenyl group, for example, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2,
4-dichlorophenyl, 2,3,4-trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4,6-trihydroxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2, 4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4
-Ethoxyphenyl, 4-t-butoxyphenyl, 4-
Hexyloxyphenyl, 2-dimethylaminophenyl, 4-dimethylaminophenyl, 2,5-bis (dimethylamino) phenyl, 2,4,6-tris (dimethylamino) phenyl, 4-diethylaminophenyl, 4-
(N-methyl-N-ethylamino) phenyl, 2- (2
-Dimethylaminoethoxy) phenyl, 2- (2-diethylaminoethoxy) phenyl, 3- (2-diethylaminoethoxy) phenyl, 4- (2-diethylaminoethoxy) phenyl, 2,5-bis (2-diethylaminoethoxy) phenyl, Examples include 2,4,6-tris (2-diethylaminoethoxy) phenyl and 2- {2- (N-methyl-N-ethylamino) ethoxy} phenyl groups.

1-3 lower alkoxy groups as substituents on the phenyl ring
Examples of the phenyl lower alkyl group which may have benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl, 2-phenylbutyl, 5-
Phenylpentyl, 6-phenylhexyl, 2-methoxybenzyl, 3,4-dimethoxybenzyl, 2- (3-
Methoxyphenyl) ethyl, 2- (4-methoxyphenyl) ethyl, 2- (2,3-dimethoxyphenyl) ethyl, 2- (3,4-dimethoxyphenyl) ethyl, 3-
Examples include (4-ethoxyphenyl) propyl and 6- (3,4-dimethoxyphenyl) hexyl groups.

The phosphonate diester derivative of the present invention represented by the general formula (I) has an excellent lipid-lowering effect, and is used as a therapeutic agent for hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperphospholipid. It is useful for treating and preventing various diseases (hyperlipidemia) such as blood sugar and hyperfree fatty acidemia.

Hereinafter, the method for producing the phosphonic acid diester derivative represented by the above general formula (I) of the present invention will be described in detail. The derivative can be produced by various methods. It is as shown in 1 to -5.

Reaction formula-1 Reaction formula-2 Reaction formula-3 Reaction formula-4 Reaction formula-5 [In the general formulas shown in the above reaction formulas -1 to -5, R ¹ , R ² ,
R ³ and A are the same as above. Y represents a halogen atom. According to the method shown in Reaction Scheme-1, the compound (Ia) of the present invention can be obtained by reacting the sulfonic acid halide derivative (II) with the amines (III).

The above reaction is generally carried out using a deoxidizing agent in a suitable solvent. As the deoxidizing agent used here, various known deoxidizing agents that do not adversely affect the reaction can be used.
Specific examples thereof include tertiary amines such as triethylamine, diethylaniline, N-methylmorpholine, pyridine, and 4-dimethylaminopyridine. As the solvent, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, chain or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran (THF) and 1,4-dioxane, acetone , Ketones such as methyl ethyl ketone and acetophenone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane.

The ratio of the sulfonic acid halide derivative (II) and the amines (III) used in the above reaction is not particularly limited,
Usually, it is preferable to use the former in an equimolar amount to an excessive amount relative to the latter. The deoxidizing agent is preferably used usually in an equimolar amount to a small excess amount with respect to the sulfonic acid halide derivative (II). The reaction proceeds under cooling, at room temperature, or under heating, but is usually carried out under the temperature condition of from around room temperature to the reflux temperature of the solvent, and is generally completed in about 0.5 to 15 hours.

According to the method shown in Reaction Scheme-2, the aldehyde derivative (I
The compound (Ib) of the present invention can be obtained by the reaction of V) with amines (IIIa).

The above reaction is carried out in a suitable protic solvent in the presence of a reducing agent. Here, as the reducing agent, various conventionally known ones can be widely used, and specific examples thereof include complex hydrogen compounds such as sodium borohydride and sodium cyanoborohydride, dimethylamino-borane complex, and trimethylamine- A borane complex etc. can be illustrated. Of these, the use of sodium cyanoborohydride is preferred.
As the solvent, for example, a mixed solvent of water, methanol, ethanol, acetic acid, and the like can be used.

The use ratio of the aldehyde derivative (IV) and the amines (IIIa) is not particularly limited, but it is usually preferable to use the former in an equimolar amount to an excess amount with respect to the latter. Further, the reducing agent is preferably used in an excess amount with respect to the aldehyde derivative (IV). The reaction proceeds under cooling, at room temperature, or under heating, but is usually performed under temperature conditions in the range of about room temperature to the reflux temperature of the solvent, and is generally completed in about 1 to 6 hours.

According to the method shown in Reaction Scheme-3, the compound (Ic) of the present invention can be obtained by the reaction between the benzyl halide derivative (V) and the amine (III).

The above reaction can generally be carried out using a deoxidizing agent in a suitable solvent. As the deoxidizing agent, heretofore known basic compounds can be widely used. Specific examples thereof include, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate,
Metal carbonates or hydrogen carbonates such as potassium carbonate, metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride and potassium hydride, sodium methoxide and potassium methoxide. Inorganic basic compounds such as metal alkoxides such as sodium ethoxide and potassium ethoxide can be exemplified. Among these, metal carbonates such as sodium carbonate and potassium carbonate are preferable.

Further, as the solvent, various ordinary ones, for example, diethyl ether, dimethoxyethane, THF, chain or cyclic ethers such as 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, acetonitrile, dimethylformamide, Any aprotic polar solvent such as dimethylacetamide, dimethylsulfoxide or hexamethylphosphoramide can be used, and among them, aprotic polar solvents such as dimethylformamide and acetonitrile are particularly preferable.

The ratio of the benzyl halide derivative (V) and the amines (III) to be used is not particularly limited, but it is usually preferable that the latter is equimolar to a small excess with respect to the former. The deoxidizing agent is preferably used in an equimolar amount to a small excess amount with respect to the amines (III).

The reaction proceeds either under cooling, at room temperature or under heating, but it is suitable to carry out the reaction under the temperature conditions of usually room temperature to the reflux temperature of the solvent, and generally the reaction is completed in about 4 to 20 hours.

According to the method shown in Reaction Scheme-4, the sulfonic acid derivative (V
The compound (Ia) of the present invention can be obtained by reacting I) with the amines (III).

The above reaction is generally carried out in a suitable solvent in the presence of a condensing agent. Here, as the condensing agent, various conventionally known ones can be used. Specific examples thereof include N, N′-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-hydroxysuccinimide, diethylphosphoric acid cyanide, diphenylphosphoric acid azide, and the like, and the diethylphosphoric acid cyanide is It is particularly advantageous to use with triethylamine. As the solvent, any known aprotic solvent can be used, but especially N, N-dimethylformamide (DM
F) is preferred.

The ratio of the sulfonic acid derivative (VI) and the amines (III) used in the above reaction is not particularly limited and can be appropriately selected from a wide range, but usually the latter is equimolar to excess amount, preferably equimolar to the former. It is good to set the amount. It is desirable that the condensing agent is used in an equimolar amount to an excess amount, preferably a small excess amount, with respect to the sulfonic acid derivative (VI). As the reaction temperature condition, a temperature from under ice cooling to around room temperature can be adopted, and the reaction is usually completed in about 0.5 to 2 hours.

According to the method shown in Reaction Scheme-5, the haloamide derivative (VI
The compound (I) of the present invention can be obtained by reacting I) with phosphite triesters (VIII).

The above-mentioned reaction is a suitable solvent which does not adversely influence the reaction, for example, lower alcohols, aromatic or aliphatic hydrocarbons,
Although it can be carried out in a solvent such as DMF, it is usually preferably carried out without a solvent.

In the reaction, the haloamide derivative (VII) and the phosphite triester (VIII) are usually used in an excess amount with respect to the former, and the reaction is usually about 130-
It is carried out at a temperature of 180 ° C., preferably about 140 to 150 ° C., and the reaction time is the phosphite triesters (VI
Although it depends on the type of II), it is generally about 0.5 to 3 hours.

The desired compound of the present invention obtained by the methods shown in the above Reaction Schemes -1 to -5 can be isolated from the reaction system and purified by a commonly used separation means. As the isolation and purification means, solvent extraction, distillation, recrystallization, column chromatography, preparative thin layer chromatography and the like can be adopted.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, production examples of the compound of the present invention will be given as Examples.

Example 1 2.55 g (20 mmol) of p-chloroaniline and 2.22 g (22 mmol) of triethylamine were dissolved in 40 m of dry dichloromethane, and 4-diethoxyphosphinoylmethylbenzene was added to this mixture under stirring with ice cooling. A solution of 6.53 g (20 mmol) of sulfonyl chloride in 10 m of dry dichloromethane was slowly added dropwise. After stirring at room temperature for 12 hours, 50 m of water was added to the reaction mixture, extracted with chloroform, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted with chloroform: ethyl acetate = 1: 1).
Then, it was recrystallized from benzene-n-hexane to obtain colorless crystals of 4-diethoxyphosphinoylmethyl-N- (4-chlorophenyl) benzenesulfonamide (3.30 g).

Melting point 145 to 146 ° C. Examples 2 to 12 In the same manner as in Example 1, each compound shown in Table 1 below was obtained.

The compound obtained in Example 1 is also shown in Table 1.

Further, among the compounds shown in Table 1, oily compounds (Example 6,
8, 9 and 10 compounds), their ¹ H-
NMR (CDC ₃ , internal standard: TMS) analysis result (δ
The value: ppm) is continuously shown in Table 2.

Example 13 0.56 g (6 mmol) of aniline in 10 m of methanol
While stirring at room temperature, a solution of 4-diethoxyphosphinoylmethylbenzaldehyde (1.54 g, 6 mmol) in methanol (10 m) was added at once to the solution, and the mixture was stirred at room temperature for 30 minutes. Then, under ice-cooling stirring, 0.75 g (12 mmol) of sodium cyanoborohydride was added to methanol 10
The solution dissolved in m was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. Then, 50 m of a 2N sodium hydroxide aqueous solution was added to the reaction mixture, and the mixture was extracted with chloroform. After drying over sodium sulfate and evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform: ethyl acetate =
Elution with 1: 1) gave 0.80 g of oily N- (4-diethoxyphosphinoylmethylbenzyl) aniline.

The ¹ H-NMR analysis result of this product is as shown in Table 4 below.

Examples 14 to 17 In the same manner as in Example 13, each compound shown in Table 3 below was obtained. In addition, Table 3 also shows the compounds obtained in Example 13 above.

Further, Table 1 shows the ¹ H-NMR analysis results of the obtained compounds.

Example 18 A suspension of 0.64 g (3 mmol) of N-benzyl-p-anisidine and 0.41 g (3 mmol) of anhydrous potassium carbonate in 20 m of acetonitrile was stirred at room temperature under stirring.
Diethoxyphosphinoylmethylbenzyl bromide 0.
A solution of 96 g (3 mmol) in 10 m of acetonitrile was added dropwise. After stirring for 12 hours at room temperature, 30 m of water was added to the reaction mixture, extracted with chloroform, dried over sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1).
Was eluted with water) to obtain 0.49 g of oily N-benzyl-N- (4-diethoxyphosphinoylmethylbenzyl) -p-anisidine.

The ¹ H-NMR analysis result of this product is as shown in Table 6 below.

Examples 19 to 25 In the same manner as in Example 18, each compound shown in Table 5 below was obtained. The compound obtained in Example 18 is also shown in Table 5.

The results of ¹ H-NMR analysis of the oily compound are shown in Table 6 below.

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Claims (1)

[Claims] 1. A general formula [Wherein, R ¹ and R ² are each a hydrogen atom, a substituent selected from a halogen atom, a hydroxyl group, a lower alkoxy group, an N, N-di-lower alkylamino group and an N, N-di-lower alkylamino lower alkoxy group. Or a phenyl lower alkyl group or a diphenyl lower alkyl group which may have 1 to 3 lower alkoxy groups as a substituent on the phenyl ring, or are bonded to each other. 1,2,3,4-tetrahydroquinolin-1-yl group with the nitrogen atom to which they are bonded, an indoline-1-yl group which may have a phenyl group at the 2-position or 3-position, the 2-position or Having a 2,3-dihydro-4H-1,4-benzoxazin-4-yl group that may have a phenyl group at the 3-position or a halogen atom on the benzene ring It shows a group which forms a certain phenothiazine-10-yl group. R ³ represents a lower alkyl group. A represents a methylene group or a sulfonyl group. ] The phosphonic acid diester derivative represented by these.