JP2709677B2 - Phosphonic acid diester derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel phosphonic acid diester derivatives.

[0002]

2. Description of the Related Art The phosphonic acid diester derivative of the present invention is a novel compound which has not been described in any literature.

[0003]

SUMMARY OF THE INVENTION The object of the present invention is to provide compounds useful as pharmaceuticals as described below.

[0004]

According to the present invention, there is provided a phosphonic acid diester derivative represented by the following general formula (1).

[0005]

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[Wherein, R ¹ represents a hydrogen atom, an amino group, a phenylamino group, a lower alkoxycarbonylamino group, a hydroxyl group or a lower alkoxy group, and R ² represents a lower alkyl group, a phenyl group, a hydroxyamino group or a lower alkoxy group. An amino group, R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom, and R ⁵ represents a lower alkyl group. Specific examples of the respective groups in 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.

The lower alkoxycarbonylamino group includes, for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino and the like.

The lower alkoxy group includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

The lower alkoxyamino group includes, for example, methoxyamino, ethoxyamino, propoxyamino,
Butoxyamino, pentyloxyamino, hexyloxyamino 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 a preventive and therapeutic effect on cataract, and is used as a therapeutic agent for hyperlipidemia or cataract. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as hypercholesterolemia, hypertriglyceridemia, hyperphospholipidemia, and high free fatty acidemia, and for the treatment and prevention of cataract.

Hereinafter, the method for producing the phosphonic acid diester derivative represented by the above general formula (1) of the present invention will be described in detail with reference to the following reaction process.

[0014]

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Wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined above. R ^2a represents a lower alkyl group or a phenyl group. As shown in the above reaction scheme 1, by reacting the compound (2) with the compound (3), the compound of the present invention (1
a) can be obtained. The reaction is carried out in an inert solvent such as benzene, xylene or toluene in the presence of an organic acid such as acetic acid or propionic acid in a molar amount of 1.2 to 1.5 times the amount of compound (3) based on compound (2). This is performed using The reaction is carried out under a temperature condition of about the boiling point of the solvent for 1 to 10 hours.

[0016]

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Wherein R ³ , R ⁴ and R ⁵ are as defined above. R ^2b represents a hydroxyamino group or a lower alkoxyamino group. As shown in the above reaction scheme-2, the compound of the present invention (1) is reacted with the compound (4) and the compound (5).
b) can be manufactured. The reaction is carried out in a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, pyridine, 2,6-lutidine, N,
Compound (4) in the presence of a base such as N-dimethylaniline
The reaction is carried out using 1.2 to 1.5 times the molar amount of compound (5). The reaction is carried out at a temperature of about the boiling point of the solvent.
It takes 10 hours.

The compounds (2) and (4) used as starting materials in the above reaction schemes -1 and -2 can be produced, for example, by the method described in JP-A-61-151199.

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.

The phosphonic acid diester derivative of the present invention represented by the general formula (1) naturally includes syn- and anti-isomers. These isomers can be separated by a conventional separation method.

[0021]

EXAMPLES In order to explain the present invention in more detail,
Production examples of the compound of the present invention will be described as examples.

[0022]

Example 1 Preparation of diethyl 4-{[2- (1-hydrazonoethyl) phenyl] carbamoyl} benzylphosphonate 6.5 g of diethyl 4-[(2-acetylphenyl) carbamoyl] benzylphosphonate and hydrazine monohydrate 1.0 g of the hydrate was suspended in 100 ml of benzene, 1 ml of acetic acid was added thereto, and the mixture was heated under reflux for 5 hours. 70 ml of water was added to the reaction mixture, extracted with chloroform, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-diethyl ether-n-hexane to obtain 3.0 g of the target compound as colorless crystals. Table 1 shows the structure and physical properties of the obtained compound.

[0023]

Examples 2 to 15 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.

[0024]

Example 16 Diethyl 4-{[4-bromo-2-
Preparation of (N ¹ -methoxycarbamimidyl) phenyl] carbamoyl｝ benzylphosphonate diethyl 4-[(4-bromo-2-cyanophenyl)
Carbamoyl] benzylphosphonate 4.5 g and O-methylhydroxylamine hydrochloride 1.3 g in ethanol 6
5 ml, and 10 ml of pyridine is added thereto.
Heated to reflux for an hour. 100 ml of water was added to the reaction mixture, extracted with chloroform, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from chloroform-diethyl ether to obtain 3.1 g of the target compound as colorless crystals. Table 1 also shows the structure and physical properties of the obtained compound.

[0025]

Example 17 In the same manner as in Example 16, the compounds shown in Table 1 were synthesized. Table 1 also shows the structure and physical properties of the obtained compound.

[0026]

[Table 1]

[0027]

[Table 2]

Claims (1)

(57) [Claims] 1. A compound of the general formula Wherein R ¹ is a hydrogen atom, an amino group, a phenylamino group, a lower alkoxycarbonylamino group, a hydroxyl group or a lower alkoxy group, and R ² is a lower alkyl group, a phenyl group, a hydroxyamino group or a lower alkoxyamino group. , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom,
R ⁵ represents a lower alkyl group. A phosphonic acid diester derivative represented by the formula: