JPH07188269A - Phoshonate diester derivative - Google Patents

Abstract

PURPOSE:To provide a phosphonate diester derivative represented by a specific formula, having an excellent lipid-lowering action and an excellent blood sugar- lowering action, and useful as a hyperlipemia-treating agent or diabete-treating agent. CONSTITUTION:This derivative is expressed by formula I (R<1>, R<2> are lower alkoxy, phenyl; A is CO, CS, SO3; B is heterocyclic ring, such as pyridine ring, which may have one or two of a lower alkyl, a carbamoyl, a nitro, a halogenated lower alkyl, a cyano, and a lower alkanoyloxy as substituents and further be substituted with one or more of halogen atoms), e.g. diisopropyl 4-[N-(5-cyano-2-pyridine)carbamoyl]benzylphosphonate. The production of the derivative of formula I is preferably performed in the presence of an acid- removing agent such as triethylamine in an inert solvent such as benzene as shown in the reaction formula II.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel phosphonic acid diester derivative.

[0002]

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

[0003]

DISCLOSURE OF THE INVENTION The present invention aims to provide a compound useful as a pharmaceutical 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]

[Chemical 2]

[In the formula, R ¹ and R ² are the same or different and each represents a lower alkoxy group or a phenyl group, and -A- represents a 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 1 to 2 groups selected from a cyano group and a lower alkanoyloxy group and optionally further substituted with a halogen atom (b) a lower alkyl group, a halogen atom, a halogen-substituted lower alkyl as a substituent A pyridine 1-oxide ring group which may have 1 or 2 groups selected from a group and a cyano group (c) 1 or 2 groups selected from a lower alkyl group, a halogen atom and a lower alkylthio group as a substituent. A pyrimidine ring group having (d) a pyrazine ring group which may have 1 or 2 halogen atoms as a substituent (e) A phenyl group, a halophenyl group, a lower alkoxyphenyl group, a lower alkylphenyl group, a thienyl group as a substituent, It has 1 to 2 groups selected from a phenylsulfonyl group and a hydroxyl group, or a halogen atom and a lower alkyl group. 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 which may have three (g) a lower alkyl group or a quinoline or quinoline 1-oxide ring group which may be substituted with a halogen atom (h) one or two lower alkyl groups Replaced by 1,
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 linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

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

Examples of halogen-substituted lower alkyl groups include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl groups.

Examples of the lower alkanoyloxy group include acetoxy, propionyloxy, butyryloxy,
Examples thereof include valeryloxy, pivaloyloxy, hexanoyloxy and heptanoyloxy groups.

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

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 thereof include fluorophenyl and 2-fluorophenyl groups.

Examples of the lower alkoxyphenyl group include 4-methoxyphenyl, 3-methoxyphenyl and 2-methoxyphenyl.
Examples thereof include methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl groups.

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

Examples of the lower alkylphenyl group include 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-pentylphenyl, 4-
A hexyl phenyl group etc. can be illustrated.

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 groups.

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

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

As the pyridine 1-oxide ring group shown as the above (b), 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-
An oxide ring group etc. can be illustrated.

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

As the pyrazine ring group shown as the above (d), in addition to pyrazine, for example, 2-bromopyrazine, 2
Examples include -chloropyrazine and 2,6-dibromopyrazine ring groups.

The isoxazole ring group represented by the above (e) includes, for example, 3-phenylisoxazole and 3- (4-chlorophenyl) in addition to isoxazole.
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 etc. can be illustrated.

The pyrazole or 3-pyrazolone ring group shown as (f) above includes, for example, 3-methylpyrazole, 4-cyanopyrazole, 1-phenylpyrazole, 1-methyl-3-, in addition to pyrazole and 3-pyrazolone. 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 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, for example, 2-methylquinoline, 3-methylquinoline, 4-methylquinoline, 2-ethylquinoline in addition to quinoline and quinoline 1-oxide. , 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
Examples thereof include -bromoquinoline 1-oxide and 2-chloroquinoline 1-oxide ring groups.

Examples of the 1,8-naphthyridine ring group shown as (h) above include 2,4-dimethyl-1,8-naphthyridine, 2,4-diethyl-1,8-naphthyridine, 2-methyl-1, 8-naphthyridine, 4-methyl-
Examples include 1,8-naphthyridine ring group and the like.

The phosphonic acid diester derivative of the present invention represented by the above general formula (1) has an excellent lipid-lowering action and hypoglycemic action, and is used as a therapeutic agent for hyperlipidemia and diabetes, high cholesterol. It is useful for the treatment and prevention of various diseases (hyperlipidemia) such as blood sugar, hypertriglyceridemia, hyperphospholipidemia, and hyperlipidemia, and also for the treatment and prevention of diabetes. Furthermore, the phosphonate diester derivative of the present invention also has an effect of improving and treating cachexia such as cancer cachexia and infectious cachexia, and the treatment and prevention of cataract. It is also useful as an agent and a preventive and therapeutic agent for cataract.

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 below. The derivative can be produced by various methods. Specific examples thereof are shown in the following reaction process formulas.

[0029]

[Chemical 3]

[Wherein R ¹ and R ² are the same as defined above]. -A '
− Represents —CO— or —SO ₂ —, X represents a halogen atom, and B ′ represents the above (a), (c), (d),
A heterocyclic group selected from (e), (f), (g) and (h) (provided that (g) is a lower alkyl group or a quinoline 1-oxide ring group which may be substituted with a halogen atom). (Except). According to the method shown in the reaction process formula-1, the compound (2) and the acid halide (3)
The compound (1a) of the present invention can be obtained by reacting with and in the presence of a deoxidizing agent in an inert solvent. In the above, as the inert solvent, generally known various ones,
For example, aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, petroleum ether, diethyl ether,
1,2-dimethoxyethane, tetrahydrofuran (TH
F), chain or cyclic ethers such as 1,4-dioxane, ketones such as acetone, methyl ethyl ketone and acetophenone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. it can.

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

The ratio of the compound (2) to 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 amount 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 it is usually carried out under temperature conditions in the range of 0 ° C. to the reflux temperature of the solvent, and generally completed in about 0.5 to 10 hours. .

[0033]

[Chemical 4]

[Wherein R ¹ , R ² , A'and B'are the same as defined above. According to the method represented by the reaction formula-2, the compound (2) and the compound (4) are reacted in the presence of a condensing agent in an inert solvent to obtain the compound (1a) of the present invention. You can

In the above, the inert solvent may be any known aprotic solvent, for example, N, N.
-Dimethylformamide (DMF) is preferred. Also,
Examples of the condensing agent include various known compounds such as N, N-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole, N-hydroxysuccinimide, diethylphosphoric acid cyanide, and diphenylphosphoric acid azide. Among them, diethyl phosphate cyanide is
It is particularly advantageous to use this with triethylamine. The ratio of the compound (2) to the compound (4) used 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 in an equimolar amount with respect to the former. Further, it is desirable that 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 can be carried out under temperature conditions of under cooling to around room temperature, usually for about 0.5 to 2 hours.

[0036]

[Chemical 5]

[In the formula, R ¹ and R ² are the same as defined above. R'and R "are the same or different and each is a hydrogen atom, a lower alkyl group,
A halogen atom, a halogen-substituted lower alkyl group or a cyano group is shown. ]

[0038]

[Chemical 6]

[Wherein R ¹ and R ² are the same as defined 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, 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 methanol-water mixture are used. In, the compound (5) or the compound (1c) is treated with an oxidizing agent. Examples of the oxidizing agent include hydrogen peroxide solution, peracetic acid, m-chloroperbenzoic acid, t-butyl hydroperoxide and the like. For example, for compound (5) and compound (1c), etc. It is preferable to use a molar amount to an excess amount. The reaction is usually completed at a temperature of 0 ° C. to room temperature for about 0.5 to 10 hours.

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

[0042]

[Chemical 7]

[Wherein R ¹ and R ² and B are the same as defined above]. The conversion reaction of the compound (1e) shown in the above reaction process formula-4 to the compound (1f) is performed by treating the compound (1e) with diphosphorus pentasulfide in an aprotic solvent. Examples of the aprotic solvent include pyridine,
Examples thereof include tertiary amines such as triethylamine and N, N-dimethylaniline, aromatic hydrocarbons such as benzene, toluene and xylene, acetonitrile and the like, and among them, it is preferable to use a mixed solvent of benzene and pyridine.
The amount of diphosphorus pentasulfide used is not particularly limited and can be appropriately selected from a wide range, but is usually equimolar amount to excess amount, preferably about 1.5 to 2.5 times molar amount relative to compound (1e). Good to do. The reaction is usually completed at room temperature to the reflux temperature of the solvent, preferably 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 a conventional separation means. Examples of such means include adsorption chromatography, preparative thin layer chromatography, recrystallization, solvent extraction and the like.

[0045]

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

[0046]

Example 1 Preparation of diisopropyl 4- [N- (5-cyano-2-pyridyl) carbamoyl] benzylphosphonate 3.1 g of 2-amino-5-cyanopyridine hydrochloride and 20 ml of pyridine are dissolved in 20 ml of dry dichloromethane. Then, a solution of 4-[(diethoxyphosphoryl) methyl] benzoyl chloride (6.4 g) in dry dichloromethane (10 ml) was slowly added dropwise to the mixture under ice-cooling stirring. After stirring at room temperature for 10 hours, 100 ml of 10% hydrochloric acid aqueous 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 are
Shown in the table.

[0047]

Examples 2 to 57 In the same manner as in Example 1, each compound shown in Table 1 was synthesized. The structure and physical properties of the obtained compound are also shown in Table 1. For oily compounds, ¹
The 1 H-NMR spectrum data is described.

[0048]

Example 58 Preparation 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 dichlorometa. 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, the reaction mixture was added with 10% aqueous sodium hydrogencarbonate solution 50
ml was added and 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:
1), and the resulting crude crystals are ethyl acetate-n-
Recrystallize from hexane to give 0.7 colorless crystals of the title compound.
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. The structure and physical properties of the obtained compound are also shown in Table 1.

[0050]

Example 68 Diethyl 4- [N- (1-methyl-
Preparation of 3-phenylpyrazol-5-yl) thiocarbamoyl] benzylphosphonate 1.7 g of the compound obtained in Example 32 and 1.8 g of phosphorus pentasulfide were dehydrated with pyridine (20 ml) and dehydrated benzene (20 m).
It was suspended in 1 l of the mixed solvent and heated under reflux for 8 hours with stirring. After allowing to cool 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).
The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to obtain 0.4 g of the title compound as yellow crystals.
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]

Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 413/04 333 471/04 114 A C07F 9/60 9155-4H 9/6503 9155-4H 9/6509 Z 9155 −4H 9/6512 9155−4H 9/653 9155−4H 9/6561 Z 9155−4H // C07D 213/61 213/84 (72) Inventor, Yoshihiko Tsuda 127, Maebama, Kuwajima, Kureshima, Naraido, Tokushima Prefecture ( 72) Inventor Kazuhiko Tsutsumi, 428 Tenjin, Kamisukecho, Tokushima City, Tokushima Prefecture (72) Inventor Yasuhide Inoue 11-54 Hama 11-54, Benaiten, Senyo Town, Naruto City, Tokushima

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ and R ² are the same or different and each represents a lower alkoxy group or a phenyl group, and -A- represents a group -CO- or -C.
S- or -SO ₂ - indicates, B represents a heterocyclic group selected from the following (a) ~ (h). (A) a lower alkyl group as a substituent, a carbamoyl group,
A pyridine ring group having 1 to 2 groups selected from a nitro group, a halogen-substituted lower alkyl group, a cyano group and a lower alkanoyloxy group and which may be further substituted with a halogen atom (b) a lower alkyl group as a substituent group A pyridine 1-oxide ring group which may have 1 or 2 groups selected from a group, a halogen atom, a halogen-substituted lower alkyl group and a cyano group (c) a lower alkyl group, a halogen atom and a lower alkylthio group as a substituent Pyrimidine ring group having 1-2 selected groups (d) Pyrazine ring group which may have 1-2 halogen atoms as a substituent (e) Phenyl group, halophenyl group, lower alkoxyphenyl group as a substituent 1-2 of a group selected from a lower alkylphenyl group, a thienyl group, a phenylsulfonyl group and a hydroxyl group. Or an isoxazole ring group having a halogen atom and a lower alkyl group (f) a substituent selected from a lower alkyl group, a phenyl group, a cyano group, a phenyl lower alkyl group, a carbamoyl group, a halophenyl group and a thiocyanate group. 1 to
A pyrazole or 3-pyrazolone ring group which may have three (g) a lower alkyl group or a quinoline or quinoline 1-oxide ring group which may be substituted with a halogen atom (h) one or two lower alkyl groups Replaced by 1,
8-naphthyridine ring group].