JP3156026B2 - 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 and R ² are the same or different and each represents a lower alkoxy group or a phenyl group;
CO -, - CS- or -SO ₂ - indicates, B represents a heterocyclic group selected from the following (a) ~ (h).

(A) As a substituent, a lower alkyl group, a carbamoyl group, a nitro group, a halogen-substituted lower alkyl group,
A pyridine ring group having one or two groups selected from a cyano group and a lower alkanoyloxy group and which may be further substituted with a halogen atom; (b) a lower alkyl group, a halogen atom, and a halogen-substituted lower alkyl group A pyridine 1-oxide ring group which may have 1 to 2 groups selected from a group selected from a group and a cyano group; and (c) as a substituent, 1 to 2 groups selected from a lower alkyl group, a halogen atom and a lower alkylthio group. A pyrimidine ring group having (d) a pyrazine ring group which may have one or two halogen atoms as a substituent; (e) a phenyl group, a halophenyl group, a lower alkoxyphenyl group, a lower alkylphenyl group, a thienyl group, Having 1 to 2 groups selected from a phenylsulfonyl group and a hydroxyl group, or A lower alkyl group as isoxazole Hajime Tamaki (f) substituent having a group, a phenyl group, a cyano group, a phenyl-lower alkyl group, a carbamoyl group, 1 group selected from a halophenyl group and a thiocyanate group
A pyrazole or 3-pyrazolone ring group having three (g) a quinoline or a quinoline 1-oxide ring group which may be substituted by a lower alkyl group or a halogen atom; and (h) one or two lower alkyl groups. 1, which is replaced
8-Naphthyridine ring group] Specific examples of the groups represented by the general formula (1) include the following groups.

That is, examples of the lower alkyl group include straight-chain or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

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

Examples of the halogen-substituted lower alkyl group include, for example, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl, and tridecafluorohexyl.

The lower alkanoyloxy group includes, for example, acetoxy, propionyloxy, butyryloxy,
Examples include valeryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy groups and the like.

Examples of the lower alkylthio group include a methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio group and the like.

Examples of the halophenyl group include 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-iodophenyl, 3-iodophenyl, and 2-iodophenyl. , 4-fluorophenyl, 3-
Examples include fluorophenyl and 2-fluorophenyl groups.

As the lower alkoxyphenyl group, for example, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl
Examples include methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, and the like.

The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The lower alkylphenyl group includes, for example, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-pentylphenyl,
A hexylphenyl group can be exemplified.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
Examples thereof include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and 6-phenylhexyl group.

The thienyl group includes 2-thienyl and 3-thienyl groups.

Examples of the pyridine ring group shown as (a) include 3-carbamoylpyridine, 3-nitropyridine, 3-trifluoromethylpyridine, 3-cyanopyridine, 3-methylpyridine, and 3-bromo-5-tripyridine. Fluoromethylpyridine, 3-chloro-5-trifluoromethylpyridine, 3-bromo-5-methylpyridine, 3
-Bromo-2-methylpyridine, 3-chloro-5-methylpyridine, 2-acetoxy-3-trifluoromethylpyridine ring group and the like.

The pyridine 1-oxide ring group shown in the above (b) includes, in addition to pyridine 1-oxide,
For example, 3-bromopyridine 1-oxide, 3-cyanopyridine 1-oxide, 3-bromo-2-methylpyridine 1-oxide, 3-trifluoromethylpyridine 1-oxide, 3-bromo-5-methylpyridine 1-oxide
An oxide ring group etc. can be illustrated.

Examples of the pyrimidine ring group represented by (c) include 4-methylpyrimidine, 5-bromopyrimidine, 4-chloro-2-methylthiopyrimidine, 4,6
-Dimethylpyrimidine, 4,6-dichloropyrimidine ring group and the like.

The pyrazine ring group represented by the above (d) includes, in addition to pyrazine, for example, 2-bromopyrazine,
-Chloropyrazine, 2,6-dibromopyrazine ring group and the like.

Examples of the isoxazole ring group represented by (e) include, in addition to isoxazole, 3-phenylisoxazole, 3- (4-chlorophenyl)
Isoxazole, 3- (4-methoxyphenyl) isoxazole, 3- (4-methylphenyl) isoxazole, 3- (4-methylphenyl) -4-phenylsulfonylisoxazole, 3- (2-thienyl) isoxazole , 5-hydroxyisoxazole, 4-
A bromo-5-methylisoxazole ring group can be exemplified.

Examples of the pyrazole or 3-pyrazolone ring group represented by (f) include, in addition to pyrazole and 3-pyrazolone, 3-methylpyrazole, 4-cyanopyrazole, 1-phenylpyrazole, 1-methyl-3- Phenylpyrazole, 1,3-diphenylpyrazole, 3,4-diphenylpyrazole, 3-phenyl-
4-benzylpyrazole, 1-carbamoyl-3-phenylpyrazole, 1- (4-chlorophenyl) -3-phenylpyrazole, 3- (4-chlorophenyl) -1-
Examples thereof include methylpyrazole, 1-methyl-3-phenyl-4-thiocyanatopyrazole, 1-methyl-5-phenylpyrazole, and 1,5-dimethyl-2-phenyl-3-pyrazolone ring group.

The quinoline or quinoline 1-oxide ring group represented by the above (g) includes, in addition to quinoline and quinoline 1-oxide, for example, 2-methylquinoline, 3-methylquinoline, 4-methylquinoline, 2-ethylquinoline , 2-bromoquinoline, 3-bromoquinoline, 4-bromoquinoline, 2-chloroquinoline, 2-methylquinoline 1-oxide, 3-methylquinoline 1
-Oxide, 4-methylquinoline 1-oxide, 2-
Ethylquinoline 1-oxide, 2-bromoquinoline
1-oxide, 3-bromoquinoline 1-oxide, 4
-Bromoquinoline 1-oxide, 2-chloroquinoline 1-oxide ring group and the like.

Examples of the 1,8-naphthyridine ring group shown in the above (h) include, for example, 2,4-dimethyl-1,8-naphthyridine, 2,4-diethyl-1,8-naphthyridine, 2-methyl-1, 8-naphthyridine, 4-methyl-
Examples thereof include a 1,8-naphthyridine ring group.

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 therapeutic agent for high cholesterol. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as bloodemia, hypertriglyceridemia, hyperphospholipidemia, and hyperfree fatty acidemia, and for the treatment and prevention of diabetes. Further, the phosphonic acid diester derivative of the present invention also has a therapeutic action for improving cachexia such as cancer cachexia and infectious cachexia, and a therapeutic and preventive action for cataracts. It is also useful as an agent or an agent for preventing and treating cataracts.

Hereinafter, the method for producing the phosphonic acid diester derivative represented by the general formula (1) of the present invention will be described in detail. The derivative can be produced by various methods. Specific examples are shown in the following reaction process formulas.

[0029]

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Wherein R ¹ and R ² are as defined above. -A '
- is -CO- or -SO ₂ - and, X represents a halogen atom, respectively, B 'is the (a), (c), (d),
A heterocyclic group selected from (e), (f), (g) and (h) (however, in the case of (g), a quinoline 1-oxide ring group which may be substituted by a lower alkyl group or a halogen atom) Excluding). According to the method shown in Reaction Scheme 1, compound (2) and acid halide (3)
Is reacted in an inert solvent in the presence of a deoxidizing agent to give the present compound (1a). In the above, as the inert solvent, generally known various ones,
For example, benzene, toluene, xylene, aromatic or aliphatic hydrocarbons such as petroleum ether, diethyl ether,
1,2-dimethoxyethane, tetrahydrofuran (TH
F) Use of chain or cyclic ethers such as 1,4-dioxane, ketones such as acetone, methyl ethyl ketone and acetophenone, and halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane. it can.

As the deoxidizing agent, any of various known deoxidizing agents which do not adversely affect the reaction can be used. Specific examples thereof preferably include tertiary amines such as triethylamine, pyridine and 4-dimethylaminopyridine.

The ratio of the compound (2) and the acid halide (3) used in the above reaction is not particularly limited, but it is usually preferable to use the latter in an equimolar amount to a small excess with respect to the former. The deoxidizing agent is preferably used usually in an equimolar amount to an excess amount with respect to the acid halide (3). The reaction proceeds under cooling, at room temperature, or under heating, but is preferably performed under a temperature condition of generally 0 ° C. to the reflux temperature of the solvent, and is generally completed in about 0.5 to 10 hours. .

[0033]

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Wherein R ¹ , R ² , A ′ and B ′ are the same as above. According to the method shown in the reaction step formula-2, the compound (1a) of the present invention is obtained by reacting the compound (2) with the compound (4) in an inert solvent in the presence of a condensing agent. Can be.

In the above, the inert solvent may be any of known aprotic solvents, particularly, for example, N, N
-Dimethylformamide (DMF) is preferred. Also,
Examples of the condensing agent include various known agents, for example, N, N-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole, N-hydroxysuccinimide, diethyl phosphate cyanide, diphenyl phosphate azide and the like. Of these, cyanide diethyl phosphate is
It is particularly advantageous to use this with triethylamine. The use ratio of the compound (2) and the compound (4) in the above is not particularly limited and can be appropriately selected from a wide range.
Usually, the latter is used in an equimolar amount to a small excess amount, preferably about an equimolar amount, relative to the former. The condensing agent is used in an equimolar amount to an excess amount, preferably a small excess amount, relative to the compound (4). The reaction may be carried out under cooling to a temperature around room temperature, usually taking about 0.5 to 2 hours.

[0036]

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Wherein R ¹ and R ² are as defined above. R ′ and R ″ are the same or different and each represent a hydrogen atom, a lower alkyl group,
It represents a halogen atom, a halogen-substituted lower alkyl group or a cyano group. ]

[0038]

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Wherein R ¹ and R ² are the same as above. Ra represents ^a hydrogen atom, a lower alkyl group or a halogen atom. ]
As shown in the reaction process formulas -3a and -3b, the corresponding target compounds (1b) and (1d) can be obtained by oxidizing the compound (5) and the compound (1c), respectively.

In each of the above oxidation reactions, for example, lower alcohols such as methanol, ethanol and t-butanol, halogenated hydrocarbons such as dichloromethane and chloroform, and other suitable inert solvents such as acetic acid and a mixed solution of methanol and water. In which the compound (5) or the compound (1c) is treated with an oxidizing agent. Examples of the oxidizing agent include aqueous hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, t-butyl hydroperoxide and the like, which are usually used for compound (5) and compound (1c). It is preferable to use a molar amount to an excess amount. The reaction is usually completed at about 0 ° C. to room temperature for about 0.5 to 10 hours.

The starting compounds (5) and (1c) in the above can be obtained, for example, in the same manner as in the methods shown in the above reaction schemes -1 and -2.

[0042]

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Wherein R ^1, R ² and B are as defined above. The conversion reaction of the compound (1e) shown in the above reaction formula 4 into the compound (1f) is carried out by treating the compound (1e) with diphosphorus pentasulfide in an aprotic solvent. Examples of the aprotic solvent include pyridine,
Examples include tertiary amines such as triethylamine and N, N-dimethylaniline, aromatic hydrocarbons such as benzene, toluene and xylene, and acetonitrile. Among them, a mixed solvent of benzene and pyridine is preferable.
The amount of diphosphorus pentasulfide to be used is not particularly limited and can be appropriately selected from a wide range, but is usually about equimolar amount to excess amount, preferably about 1.5 to 2.5 times the molar amount of compound (1e). Good to do. The reaction is completed usually at room temperature to the reflux temperature of the solvent, preferably at about 70 to 90 ° C. for about 2 to 10 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.

[0045]

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

[0046]

Example 1 Production of diisopropyl 4- [N- (5-cyano-2-pyridyl) carbamoyl] benzylphosphonate 3.1 g of 2-amino-5-cyanopyridine hydrochloride and 20 ml of pyridine were dissolved in 20 ml of dry dichloromethane. Then, a solution of 6.4 g of 4-[(diethoxyphosphoryl) methyl] benzoyl chloride in 10 ml of dry dichloromethane was slowly added dropwise to the mixture under ice-cooling and stirring. 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 50 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 compound. 5.1 g of colorless crystals were obtained. The structure and physical properties of the obtained compound
It is shown in the table.

[0047]

Examples 2 to 57 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. For oily compounds, ¹
The H-NMR spectrum data is described.

[0048]

Example 58 Production of 2- {4-[(diisopropoxyphosphoryl) methyl] benzoyl} amino-5-cyanopyridine 1-oxide 1.5 g of the compound obtained in Example 1 was dissolved in 20 ml of dry dichlorometha. While stirring at room temperature, 1.0 g of m-chloroperbenzoic acid was added to this solution. After stirring at room temperature for 8 hours, a 10% aqueous sodium hydrogen carbonate solution was added to the reaction mixture.
Then, the resulting mixture was extracted with chloroform. The chloroform layer was washed with 50 ml of water and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol = 40: 40).
1 and eluted with 1).
Recrystallized from hexane, colorless crystals of the title compound 0.7
g was obtained. Table 1 shows the structure and physical properties of the obtained compound.

[0049]

Examples 59 to 67 In the same manner as in Example 58, the compounds shown in Table 1 were synthesized. Table 1 also shows the structure and physical properties of the obtained compound.

[0050]

Working Example 68 Diethyl 4- [N- (1-methyl-
Production of 3-phenylpyrazol-5-yl) thiocarbamoyl] benzylphosphonate 1.7 g of the compound obtained in Example 32 and 1.8 g of diphosphorus pentasulfide were added to 20 ml of dehydrated pyridine and 20 m of dehydrated benzene.
The mixture was suspended in 1 l of a mixed solvent, and heated under reflux with stirring for 8 hours. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 40: 1).
And the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 0.4 g of yellow crystals of the title compound.
Table 1 shows the structure and physical properties of the obtained compound.

[0051]

[Table 1]

[0052]

[Table 2]

[0053]

[Table 3]

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 27/12 A61P 27/12 35/00 35/00 (72) Inventor: Kazuhiko Tsuda 127, Kokuwajima-shi Maehama, Fuyo-cho, Naruto-shi, Tokushima ) Inventor Kazuhiko Tsutsumi 428-7 Tenjin, Kamisuke Town, Tokushima City, Tokushima Prefecture (72) Inventor, Yasuhide Inoue 11-54, Benzaitenten Hama, Naruto City, Tokushima Prefecture (56) References JP-A-3-109393 (JP, A) WO 93/23409 (WO, A1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 9/58 C07F 9/6503 C07F 9/60 C07F 9/6509 C07F 9/6512 C07F 9/653 C07F 9/6561 A61K 31/665-31/675 A61K 31/66 A61P 3/06 A61P 3/10 A61P 27/12 A61P 35/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [Wherein, R ¹ and R ² are the same or different and represent a lower alkoxy group or a phenyl group, and -A- is a group -CO-, -CS
Or -SO _2- , and B represents (a) one or two groups selected from a lower alkyl group, a carbamoyl group, a nitro group, a halogen-substituted lower alkyl group, a cyano group and a lower alkanoyloxy group as a substituent; A pyridine ring group which may be further substituted with a halogen atom, and (b) having one or two substituents selected from a lower alkyl group, a halogen atom, a halogen-substituted lower alkyl group and a cyano group. Having from 1 to 3 groups selected from lower alkyl groups, phenyl groups, cyano groups, phenyl lower alkyl groups, carbamoyl groups, halophenyl groups and thiocyanate groups as pyridine 1-oxide ring groups or (c) substituents Represents a pyrazole or 3-pyrazolone ring group. A phosphonic acid diester derivative represented by the formula: