JP3489009B2 - 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 , R ² and R ³ are the same or different and are each a hydrogen atom, a lower alkyl group, a lower alkoxy group,
R ⁴ represents a hydrogen atom or a hydroxyl group; R ⁵ represents a lower alkyl group; Specific examples of the respective groups of the general formula (1) include the following groups. That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like. Examples of the phenyl lower alkoxy group include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, and 6-phenylhexyloxy. The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The phosphonic acid diester derivative of the present invention represented by the general formula (1) has an excellent lipid-lowering effect and hypoglycemic effect, and is useful as a therapeutic agent for hyperlipidemia or cataract. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as cholesterolemia, hypertriglyceridemia, hyperphospholipidemia, and high free fatty acidemia, and for the treatment and prevention of diabetes. Hereinafter, the phosphonic acid diester derivative represented by the above general formula (1) of the present invention can be produced by various methods. Specific examples thereof are shown in the following reaction scheme. [0013] Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above. X represents a halogen atom. The reaction between the compound (2) and the acid halide (3) shown in the above reaction scheme 1 is carried out by using dichloromethane, chloroform,
1,2-dichloroethane, tetrahydrofuran (TH
It is carried out in an inert solvent such as F) in the presence of a deoxidizing agent such as pyridine, collidine, lutidine, N, N-dimethylaniline, triethylamine and the like. The amount of the acid halide (3) to be used is preferably approximately equimolar to the compound (2), and an excess of the deoxidizing agent is generally used. The reaction is carried out at a temperature of 0 ° C. to room temperature for 1 to 12 hours. Subsequently, the compound (1a) of the present invention can be obtained by subjecting the resulting ester (4) to a rearrangement reaction. The rearrangement reaction is carried out by treating the ester (4) with 1 to 3 equivalents of a base in a solvent such as pyridine, collidine or lutidine. The base is preferably an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The reaction temperature may be in the range of room temperature to 100 ° C., and the reaction time may be about 0.5 to 4 hours. Embedded image Wherein R ¹ , R ² , R ³ , R ⁵ and X are as defined above. R and R 'are the same or different and represent a lower alkyl group. The reaction between the acid halide (3) and the amine (5) shown in the above reaction process formula-2 is carried out in an inert solvent in the presence of a deoxidizing agent. In the above, as the inert solvent, for example, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, petroleum ether and the like, and linear or aliphatic hydrocarbons such as diethyl ether, 1,2-dimethoxyethane, THF, and 1,4-dioxane Examples thereof include cyclic ethers, ketones such as acetone, methyl ethyl ketone, and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Preferred examples of the deoxidizing agent include tertiary amines such as triethylamine, pyridine and 4-dimethylaminopyridine. In the above reaction, the amine (5) is replaced with an acid halide (3)
It is preferable to use an equimolar amount to a small excess amount, and the deoxidizing agent is generally used in an equimolar amount to an excess amount. The reaction is
Usually, the reaction is completed in about 0.5 to 10 hours in the range of 0 ° C. to the reflux temperature of the solvent. The resulting amide (6) can be converted to the compound (1b) of the present invention by reacting the amide (6) with an acetophenone derivative (7) in the presence of a base. Examples of the base include hydrocarbon lithium salts such as n-butyllithium and phenyllithium, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. These are based on the acetophenone derivative (7). It is preferable to use a molar amount to a small excess amount.
The reaction is carried out in an inert solvent such as THF and diethyl ether.
The process is completed under a temperature condition of −78 ° C. to room temperature in about 5 to 15 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, recrystallization, and solvent extraction. 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 below as examples. Example 1 Preparation of diethyl 4- [3- (5-fluoro-2-hydroxyphenyl) -1,3-dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
Dissolve 19.0 g of chloride in 65 ml of dry dichloromethane, and add 5′-fluoro-2 ′
-Hydroxyacetophenone 10 g pyridine (65 m
l) The solution was slowly added dropwise. After stirring at room temperature for 10 hours, 100 ml of water was injected and extracted with chloroform. The chloroform layer was washed with 100% 10% hydrochloric acid and 100 ml of water.
After successively washing with water, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. Next, the residue was dissolved in 65 ml of pyridine, 5.4 g of potassium hydroxide was added, and the mixture was stirred at 50 ° C. for 2 hours. After completion of the reaction, 200 ml of 10% hydrochloric acid was injected to make the mixture acidic, and extracted with chloroform. The chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-n-hexane to give 15.7 g of the target compound as yellow crystals.
Got. Table 1 shows the structure and physical properties of the obtained compound. Examples 2 to 11 In the same manner as in Example 1, the compounds shown in Table 1 were synthesized. Table 1 also shows the structure and physical properties of the obtained compound. Example 12 Diethyl 4- [3- (4-chlorophenyl) -1.3
Preparation of -dioxopropyl] benzylphosphonate 4-[(diethoxyphosphoryl) methyl] benzoyl
74.4 g of chloride are dissolved in 250 ml of dry dichloromethane, and under ice-cooling and stirring, 500 ml of pyridine of 25 g of N, O-dimethylhydroxylamine hydrochloride is added to this solution.
The solution was slowly added dropwise. After stirring at room temperature for 2 hours, 200 ml of water was added to the reaction mixture, and extracted with chloroform. The chloroform layer was washed with 200 ml of a saturated aqueous solution of sodium hydrogen carbonate, 200 ml of 10% hydrochloric acid, and 200 ml of saturated saline.
The mixture was washed successively with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 48 g of a crude oily diethyl 4-[(N-methoxy-N-methyl) carbamoyl] benzylphosphonate. ¹ H-NMR [δ: ppm (CDC
l ₃ )] 1.24 (t, J = 7.1, 6H), 3.19 (d, J
= 21.9, 2H), 3.36 (s, 3H), 3.54
(S, 3H), 4.0-4.1 (m, 4H), 7.35
(Dd, J = 7.9, 2.1, 2H), 7.65 (d,
J = 7.9, 2H). Next, 4'-chloroacetophenone 3.9
g was dissolved in 25 ml of anhydrous THF, and 19 ml of a 1.55 Mn-butyllithium hexane solution was slowly dropped into this solution with cooling and stirring at -78 ° C. 1 at -78 ° C
After stirring for hours, subsequently 7.9 g of the compound obtained above
Was slowly added dropwise at −78 ° C., and the mixture was gradually returned to room temperature and stirred at room temperature for 12 hours. 50 ml of 10% hydrochloric acid was added to the reaction mixture,
Extracted with chloroform. The chloroform layer was washed with 100 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 1:
Purified in 1) and recrystallized from diethyl ether,
500 mg of colorless crystals of the target compound were obtained. Table 1 also shows the structure and physical properties of the obtained compound. [Table 1]

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Chieko Nawa 4-4, Higashimae, Higashi, Minamihama, Naruto-shi, Tokushima Pref. (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 , R ² and R ³ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group or a halogen atom, R ⁴ is a hydrogen atom or a hydroxyl group, and R ⁵ is Each represents a lower alkyl group. A phosphonic acid diester derivative represented by the formula: