JP3489012B2 - Phosphonic acid diester derivatives - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel phosphonic acid diester derivative. [0002] The phosphonic acid diester derivative of the present invention is a novel compound which has not been described in any literature. [0003] The object of the present invention is to provide compounds useful as pharmaceuticals as described below. According to the present invention, there is provided a phosphonic acid diester derivative represented by the following general formula (1). [0005] [Wherein R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkoxycarbonyl group, a phenylsulfonyl group, , N-di-lower alkylcarbamoyl group, nitro group, cyano group, phenyl-lower alkoxy group, phenyl group or halogen atom, and R ³ represents lower alkyl group. Specific examples of the groups in the general formula (1) include the following groups. That is, as the lower alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl,
Examples thereof include linear or branched lower alkyl groups such as isobutyl, tert-butyl, pentyl, and hexyl groups. The lower alkoxy group includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Examples of the halogen-substituted lower alkyl group include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl. Examples of the lower alkanoyl group include acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like. The lower alkoxycarbonyl group includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like. Examples of the lower alkylamino group include a methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino group and the like. Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and the like. The halogen atom includes a fluorine atom, a chlorine atom,
Bromine atoms and iodine atoms are included. The phosphonic acid diester derivative of the present invention represented by the above general formula (1) has an excellent lipid-lowering effect and hypoglycemic effect, and is used as a therapeutic agent for hyperlipidemia or diabetes as a high-cholesterol agent. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as bloodemia, hypertriglyceridemia, hyperphospholipidemia, and high free fatty acidemia, and for the treatment and prevention of diabetes. Hereinafter, the method for producing the phosphonic acid diester derivative of the present invention will be described in detail. The compound can be produced by various methods. Specific examples are shown in the following reaction process formulas. Embedded image Wherein R ¹ , R ² and R ³ are as defined above.
X represents a halogen atom. According to the method shown in the reaction step formula-1, the compound (1) is obtained by reacting the compound (2) with the acid halide (3) in an inert solvent in the presence of a deoxidizing agent. be able to. In the above, examples of the inert solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, petroleum ether, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF),
Chain or cyclic ethers such as 4-dioxane, ketones such as acetone, methyl ethyl ketone and acetophenone, dichloromethane, chloroform, carbon tetrachloride, 1,
Examples thereof include halogenated hydrocarbons such as 2-dichloroethane. Preferred examples of the deoxidizing agent include tertiary amines such as triethylamine, pyridine and 4-dimethylaminopyridine. The proportion of the compound (2) and the acid halide (3) used in the above reaction is not particularly limited, but it is usually preferable that the latter is generally in an equimolar amount to a small excess with respect to the former. The deoxidizing agent is usually preferably used in an equimolar amount to an excess amount based on the acid halide. The reaction proceeds under cooling, at room temperature, or under heating, but is preferably performed under a temperature condition of usually 0 ° C. to the reflux temperature of the solvent, and generally about 0.5 to 10
It ends in about an hour. Embedded image Wherein R ¹ , R ² and R ³ are as defined above. According to the method shown in the reaction step formula-2, the compound (1) is obtained by reacting the compound (2) with the compound (4) in an inert solvent in the presence of a condensing agent. Can be. As the inert solvent used in this reaction, any of known aprotic solvents may be used, and for example, N, N-dimethylformamide (DMF) and the like are particularly preferable. Examples of the condensing agent include N, N-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole, N-hydroxysuccinimide, diethyl phosphate cyanide, diphenyl phosphate azide and the like. It is particularly advantageous to use cyanide phosphate with triethylamine. Compound (2) and compound (4) in the above
The use ratio is not particularly limited and can be appropriately selected from a wide range, but usually the latter is equimolar to small excess with respect to the former,
It is preferable to use about equimolar amounts. The condensing agent is preferably used in an equimolar amount to an excess amount, preferably a small excess amount, based on the compound (4). The reaction is carried out under cooling to about room temperature, usually for about 0.5 to 2 hours. The target compound in each of the above steps can be easily isolated and purified by ordinary separation means. Examples of such means include adsorption chromatography, preparative thin-layer chromatography, solvent extraction, and recrystallization. EXAMPLES In order to explain the present invention in more detail, examples of the production of the compounds of the present invention will be given as examples. Example 1 Diethyl 4- [N- (2-ethyl-4-
Preparation of thiocyanatophenyl) carbamoyl] benzylphosphonate 5.3 g of 2-ethyl-4-thiocyanatoaniline and 20 ml of pyridine are dissolved in 20 ml of dry dichloromethane, and 4-[(( A solution of 8.7 g of [diethoxyphosphoryl) methyl] benzoyl chloride in 20 ml of dry dichloromethane was slowly added dropwise.
After stirring at room temperature for 10 hours, 100 ml of a 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with 100 ml of water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluted with chloroform: ethyl acetate = 1: 1), and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give the title 9.2 g of colorless crystals of the compound were obtained. Table 1 shows the structure and physical properties of the obtained compound. Examples 2 to 19 The compounds shown in Table 1 were prepared in the same manner as in Example 1. Table 1 shows the structure and physical properties of each compound. [Table 1] [Table 2]

Continuation of front page (56) References JP-A-63-264421 (JP, A) JP-A-5-170653 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 9 / 40 A61K 31/66 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] [Claim 1] The general formula: [Wherein R ¹ and R ² are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkyl group, a lower alkanoyl group, a benzoyl group, a lower alkoxycarbonyl group, a phenylsulfonyl group, an N, N-
Di-lower alkylcarbamoyl, nitro, cyano,
It represents a phenyl lower alkoxy group, a phenyl group or a halogen atom, and R ³ represents a lower alkyl group. A phosphonic acid diester derivative represented by the formula: