JP3533542B2 - Phosphonic acid diester derivatives - Google Patents

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 4]

[Wherein R ¹ , R ² , R ³ and R ⁶ are the same or different and each is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a lower alkoxy group, a cyano group, a phenylsulfonylamino group or a benzoylamino group. Group, an amino group or a halogen-substituted lower alkyl group, R ⁴ is a phenyl group,
Lower alkyl group, phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, lower alkenyl group, carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxy lower alkyl group, lower alkynyl group, benzoyl A lower alkyl group, an amino group, a di-lower alkanoylamino group, a benzylideneamino group which may have a lower alkoxy group on the phenyl ring or a pyridylmethylideneamino group, R ⁵ is a lower alkyl group, and R ⁷ is a lower alkoxy group. , A hydroxyl group, a phenyl group, a phenyl lower alkoxy group or a phenyl lower alkylamino group which may have a halogen atom on the phenyl ring, X ¹ and X ² each represent an oxygen atom or a sulfur atom, and A represents an oxygen atom or a single atom. Bond, and Z is lower alkyle The group, respectively. Specific examples of the groups defined in the general formula (1) include the following groups.

That is, examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom, and examples of the lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyl. Examples of the lower alkyl group such as an oxy group include a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group and the like.

As the phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring,
For example, benzyl, α-phenethyl, β-phenethyl, 1
-Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-bromobenzyl, 3
-Bromobenzyl, 4-bromobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-iodobenzyl,
2-bromo-4-fluorobenzyl, 2-fluoro-4
-Bromobenzyl, 2-chloro-4-fluorobenzyl, 2-fluoro-4-chlorobenzyl, 2-bromo-
4-chlorobenzyl, 2-chloro-4-bromobenzyl, 2-iodo-4-bromobenzyl, 3-chloro-5
-Bromobenzyl, 3-bromo-5-fluorobenzyl, 3-chloro-5-fluorobenzyl, 3-iodo-
Examples include 5-bromobenzyl and 3-chloro-5-iodobenzyl groups.

Examples of the lower alkenyl group include vinyl, 1-methylvinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,
Examples thereof include 2-dimethylvinyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl groups.

Examples of the carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6 Examples thereof include a carboxyhexyl group.

Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, tert-butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl,
1-methoxycarbonylethyl, 2-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl, 3-ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-ethoxycarbonylpentyl, 6
Examples include -ethoxycarbonylhexyl group.

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

As the lower alkoxy lower alkyl group,
For example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl,
Examples thereof include 6-methoxyhexyl group.

Examples of the lower alkynyl group include ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl,
A 5-hexynyl group etc. can be illustrated.

Examples of the benzoyl lower alkyl group include benzoylmethyl, 2-benzoylethyl, 3-benzoylpropyl, 4-benzoylbutyl, 5-benzoylpentyl and 6-benzoylhexyl groups.

Examples of the di-lower alkanoylamino group include diacetylamino, dipropionylamino, dibutyrylamino, divalerylamino, dihexanoylamino and diheptanoylamino groups.

As the benzylideneamino group which may have a lower alkoxy group on the phenyl ring, in addition to an unsubstituted benzylideneamino group, for example, 4-methoxybenzylideneamino, 3-methoxybenzylideneamino, 2
-Methoxybenzylidene amino, 4-ethoxy benzylidene amino, 4-propoxy benzylidene amino, etc. can be illustrated.

The pyridylmethylideneamino group includes 2-pyridylmethylideneamino, 3-pyridylmethylideneamino and 4-pyridylmethylideneamino groups.

Examples of the phenyl lower alkoxy group which may have a halogen atom on the phenyl ring include, for example, benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy and 6-phenylhexyl. Examples thereof include oxy, 4-chlorobenzyloxy, 3-chlorobenzyloxy, 2-chlorobenzyloxy and 4-bromobenzyloxy groups.

As the phenyl lower alkylamino group,
For example, benzylamino, 2-phenylethylamino, 3
Examples include -phenylpropylamino, 4-phenylbutylamino, 5-phenylpentylamino and 6-phenylhexylamino groups.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene groups.

The phosphonic acid diester derivative of the present invention represented by the above general formula (1) has excellent lipid lowering action, hypotensive action and hypoglycemic action, and is a therapeutic agent for hyperlipidemia and therapeutic agent for hypertension. , As a therapeutic agent for diabetes, for treating and preventing various diseases (hyperlipidemia) such as hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, hyperphospholipidemia and hyperlipidemia, hypertension It is useful for the treatment and prevention of diabetes mellitus, and for the treatment and prevention of diabetes, respectively.

As an example of the derivative of the present invention represented by the above general formula (1), in the formula, R ¹ , R ² , R ³ and R ^{6 are represented.}
Are the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group or a halogen-substituted lower alkyl group, and R ⁴ is a phenyl group, a lower alkyl group or phenyl which may have a halogen atom as a substituent on the phenyl ring. A lower alkyl group, a lower alkenyl group, a carboxy lower alkyl group or a lower alkoxycarbonyl lower alkyl group, R ⁵ is a lower alkyl group, R ⁷ is the same as an OR ⁵ group, A is a single bond, and Z is a methylene group. , X ¹ and X ² each represent an oxygen atom or a sulfur atom.

Representative examples of the derivative of the present invention which are useful in the field of pharmaceuticals, particularly for the treatment and prevention of diabetes, and for the treatment and prevention of hyperlipidemia, include those represented by the following general formula (1 '). It can be illustrated.

[0025]

[Chemical 5]

[Wherein R ^{1 ′} is a hydrogen atom or a halogen atom, R ^{2 ′} is a hydrogen atom, a lower alkyl group, a halogen atom,
A nitro group or a lower alkoxy group, R ^3'is a hydrogen atom, a halogen atom, a nitro group, a halogen-substituted lower alkyl group,
A cyano group, a phenylsulfonylamino group, a benzoylamino group, an amino group or a lower alkoxy group, R ^{4 ′} represents a phenyl group, a lower alkyl group, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, Lower alkenyl group, carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxy lower alkyl group, lower alkynyl group, benzoyl lower alkyl group, amino group, dilower alkanoylamino group,
A benzylideneamino group or a pyridylmethylideneamino group which may have a lower alkoxy group on the phenyl ring, R ^{5 ′} is a lower alkyl group, R ^{6 ′} is a hydrogen atom, a lower alkoxy group or a halogen atom, and R ^{7 ′} Is a lower alkoxy group, a hydroxyl group, a phenyl group, a phenyl lower alkoxy group which may have a halogen atom on the phenyl ring or a phenyl lower alkylamino group, and X ^{1 ′} and X ^{2 ′} are an oxygen atom or a sulfur atom, respectively. A'represents an oxygen atom or a single bond, Z'represents an ethylene group when A'is an oxygen atom, and a methylene group when A'is a single bond. Among the derivatives represented by the above general formula (1 ′), those particularly represented by the following general formula (1 ″) can be exemplified.

[0027]

[Chemical 6]

[Wherein R ^{1 "} is a hydrogen atom or a halogen atom, R ^2" is a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group, and R ^{3 "} is a hydrogen atom, a halogen atom, A halogen-substituted lower alkyl group or a lower alkoxy group, R ^{4 "} is a lower alkyl group, a phenyl lower alkyl group, a lower alkynyl group, a pyridylmethylideneamino group or a lower alkenyl group, and R ^5" is a lower alkyl group,
R ^{7 ″} represents a lower alkoxy group, a phenyl group or a phenyl lower alkylamino group, respectively.] Preferred examples of the derivative represented by the general formula (1 ″) are as follows.

(A) R ^{1 "} is a hydrogen atom, R ^2" is a halogen atom, a nitro group or a lower alkoxy group, and R ^{3 "}
Is a hydrogen atom or a lower alkoxy group, R ^{4 "} is a lower alkyl group, a phenyl lower alkyl group or a lower alkenyl group, and R ^7" is a lower alkoxy group.

(B) R ^{2 "} is a hydrogen atom or a lower alkyl group, R ^3" is a hydrogen atom, a halogen-substituted lower alkyl group or a halogen atom, and R ^{4 "} is a lower alkyl group, a phenyl lower alkyl group, A derivative which is a lower alkynyl group or a pyridyl methylidene amino group.

(C) The derivative described in (b) above, wherein R ^{2 "} is a hydrogen atom and R ^3" is a hydrogen atom or a halogen atom.

(D) The derivative according to (c) above, wherein R ^{1 "} is a hydrogen atom, R ^3" is a halogen atom, and R ^{7 "} is a lower alkoxy group or a phenyl lower alkylamino group.

The derivative represented by the above (a) is particularly suitable as an active ingredient of a therapeutic and prophylactic agent for hyperlipidemia,
The derivatives represented by (b) to (d) are particularly suitable as an active ingredient of a diabetes treatment and prevention agent.

Among the derivatives of the present invention, the most preferable one is diethyl 4- (7-chloro-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate, diethyl 4- (7-bromo-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate and ethyl [4- (7-chloro-3-methyl-4 (3
H) -quinazolinon-2-yl) benzyl] -N-benzylamidophosphonate can be exemplified, among which diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphospho is included. Nart is preferred.

The phosphonic acid diester derivative represented by the general formula (1) of the present invention can be produced by various methods.
Hereinafter, a specific example thereof will be described with reference to reaction process formulas.

[0036]

[Chemical 7]

[In the formula, R ⁵ is the same as defined above. R ^1a , R ^2a ,
R ^3a and R ^6a are the same or different and each is a hydrogen atom, a halogen atom, a nitro group, a lower alkoxy group, a cyano group or a halogen-substituted lower alkyl group, and R ^4a is a phenyl group, a lower alkyl group or a substituent on the phenyl ring. A phenyl lower alkyl group which may have a halogen atom, a lower alkenyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkynyl group, a lower alkoxy lower alkyl group or a benzoyl lower alkyl group,
Y represents a halogen atom, and R ^7a represents the same group as OR ⁵ . ] 2- (Toluyl) -4 (3
H) -Quinazolinone derivative (2) is monohalogenated by benzoyl peroxide, α, α′-azobisisobutyronitrile (AIBN), tert-butyl in an inert solvent such as benzene or carbon tetrachloride. In the presence of a catalyst such as hydroperoxide, N-bromosuccinimide (NB
S), N-chlorosuccinimide (NCS), bromine or other halogenating agent. The amount of the halogenating agent used is usually an equimolar amount to about 1.1 with respect to the compound (2).
The reaction can be carried out under the conditions of about 50 ° C. to the reflux temperature of the solvent for about 1 to 20 hours in a double molar amount.

The reaction between the benzyl halide derivative (3) obtained above and the trialkyl phosphite (4) is carried out without solvent or in a solvent which does not adversely influence the reaction, for example, lower alcohols, aromatic or aliphatic carbonization. Hydrogen,
It is carried out in an inert solvent such as N, N-dimethylformamide (DMF), preferably without solvent. The amount of the trialkyl phosphite (4) used is preferably an equimolar amount to about 10 times the molar amount of the compound (3).
The reaction temperature is preferably about 130 to 180 ° C., and the reaction time is usually about 0.5 to 3 hours, varying depending on the kind of the benzyl halide derivative (3).

[0039]

[Chemical 8]

[In the formula, R ^4a , R ⁵ , R ^7a and Y are the same as defined above. R ^1b , R ^2b , R ^3b and R ^6b are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a lower alkoxy group, a cyano group or a halogen-substituted lower alkyl group. In the reaction process formula-2, the hydrolysis reaction of the nitrile compound (5) is carried out without solvent or in tetrahydrofuran (TH
F), hydrogen peroxide solution having a concentration of about 10 to 30% can be used in the presence of a base catalyst such as sodium hydroxide and potassium hydroxide in an inert solvent such as F), methanol and 1,4-dioxane. The amount of hydrogen peroxide used is usually compound (5)
It is generally an equimolar amount to about 10 times the molar amount, and the amount of the base catalyst used is generally an equimolar amount to a small excess amount with respect to the compound (5). It can take about 2 to 20 hours under temperature conditions.

The cyclization reaction of the obtained carbamoyl derivative (6) is carried out in an inert solvent such as lower alcohol or 1,4-dioxane in an amount of about 1 to 6 N of an alkali such as sodium hydroxide or potassium hydroxide. It can be carried out using an aqueous solution.
The alkali is preferably used in an equimolar amount to a small excess amount with respect to the compound (6), and the reaction can be carried out at room temperature to the reflux temperature of the solvent for about 1 to 10 hours.

The reaction of the obtained cyclized product (7) with the alkyl halide derivative (8) is carried out using THF, a lower alcohol,
It can be carried out in the presence of a base such as metallic sodium, sodium hydride or potassium tert-butoxide in an inert solvent such as 1,4-dioxane or DMF. The amount of the base used is an equimolar amount to a small excess amount with respect to the compound (7), the reaction temperature is preferably about 0 to 60 ° C., and the reaction is usually completed in about 0.5 to 10 hours. Inventive compound (1b)
Can be obtained. According to the above reaction, the compound (13P) may be obtained as a by-product.

The compound (5) used as a starting material in the above reaction scheme-2 is, for example, US Pat.
It can be obtained by the method described in the specification of No. 22780.

[0044]

[Chemical 9]

[Wherein R ^1b , R ^2b , R ^3b , R ^4a , R ⁵ ,
R ^6b and R ^7a are the same as above. ] As shown in Reaction Scheme-3, the compound of the present invention (1b)
Is Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,
4-disulfide], phosphorus pentasulfide, or the like can be converted to the compound (1c) and the compound (1d) by treating it with a sulfur-containing reagent. The conversion treatment is carried out by using a sulfur-containing reagent in an inert solvent such as benzene, toluene, xylene, or acetonitrile in an amount of about 2 times the amount of the compound (1b).
It can be carried out under the solvent reflux temperature conditions for about 2 to 10 hours.

Based on the above, the compound (1c) and the compound (1d) are obtained as a mixture, and these can be easily isolated by the usual separation and purification means described later.

[0047]

[Chemical 10]

[Wherein R ^1b , R ^2b , R ^3b , R ^4a , R ⁵ ,
R ^6b , A and Z are the same as above. R ^7b represents a lower alkoxy group, a phenyl group or a phenyl lower alkoxy group which may have a halogen atom on the phenyl ring. The azidation reaction of the 2-aminobenzoic acid derivative (9) shown in the reaction process formula-4 is carried out by using about 2 to about 2 such as hydrochloric acid and hydrobromic acid.
After reacting the derivative (9) with an equimolar amount to about 1.2 times the molar amount of nitrite such as sodium nitrite or potassium nitrite in an acidic aqueous solution of about 6N, reaction is formed. The reaction can be carried out by reacting an equimolar amount to an approximately 1.1-fold molar amount of an azide such as sodium azide or potassium azide. All of these reactions can be carried out under conditions of about 0 ° C. to room temperature for about 10 to 20 minutes.

The azide derivative (10) thus obtained is reacted with a chlorinating agent such as thionyl chloride or oxalyl chloride in the absence of solvent or in a solvent such as aromatic or aliphatic hydrocarbons or DMF, preferably in the absence of solvent. Acid chloride
An imide derivative (12) is obtained by reacting this with a benzylphosphonic acid derivative (11).

The reaction for obtaining the above acid chloride is carried out by using the compound (1
It can be carried out at a temperature of about 50 ° C. to about the reflux temperature of the solvent by using an equimolar amount to about 10 times the molar amount of 0), and the reaction time varies depending on the kind of the chlorinating agent. It is usually about 1 to 2 hours. The reaction between the obtained acid chloride and compound (11) can be carried out in the presence of a base such as triethylamine, pyridine or 4-dimethylaminopyridine in an inert solvent such as benzene, xylene or carbon tetrachloride. Compound (1
The amounts of 1) and the base used are approximately equimolar to about 1.2 times the molar amount of the compound (10), the reaction temperature is preferably room temperature to the reflux temperature of the solvent, and the reaction time is usually about It is about 2 to 20 hours.

The cyclization reaction of the imide derivative (12) obtained above is carried out in an inert gas atmosphere, for example, in a solvent that does not adversely affect the reaction of aromatic or aliphatic hydrocarbons or the like, with a trialkyl or triarylphosphine. In the presence of. The amount of trialkyl or triarylphosphine used is preferably an equimolar amount to about 1.1 times the molar amount of the compound (12), and the reaction temperature is preferably about 0 ° C to room temperature. Is usually about 0.5
It will be finished in about 3 hours.

[0052]

[Chemical 11]

[Wherein R ^1b , R ^2b , R ^3b , R ⁵ , R ^6b ,
R ^7b , A, Y and Z are the same as defined above. R ^4b is a phenyl group,
A lower alkyl group, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, a lower alkenyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkynyl group or a benzoyl lower alkyl group . In Reaction Scheme-5, the reaction between the 2-aminobenzoic acid derivative (9) and the acid halide (13) can be carried out in an inert solvent in the presence of a deoxidizing agent. Examples of the inert solvent include aromatic hydrocarbons or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ethers, ethers such as diethyl ether, ketones such as acetone, methyl ethyl ketone and acetophenone, dichloromethane, chloroform, and four. Halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane can be used. As the deoxidizing agent, amines such as triethylamine, N, N-diethylaniline, N-methylmorpholine, pyridine and 4-dimethylaminopyridine can be preferably used. The reaction is generally carried out under the temperature condition of 0 ° C. to room temperature in the range of 0.5 to 10
It may take about time. Further, if necessary, a haloformate ester such as methyl chloroformate and ethyl chloroformate, and an acid anhydride such as acetic anhydride and propionic anhydride or thionyl chloride are added to the reaction system, and in the presence of the above deoxidizing agent. It is also possible to carry out additional reaction at about 0 ° C to room temperature for about 0.5 to 10 hours. In the above, the acid halide (1 with respect to the 2-aminobenzoic acid derivative (9)
The use ratio of 3) is preferably an equimolar amount to a small excess amount when the above-mentioned additional reaction is carried out, and it is preferably about 2-2.2 times the molar amount when the additional reaction is not carried out. . In addition, the amount of the deoxidizing agent used is preferably a 2-fold molar amount to an excess amount with respect to the 2-aminobenzoic acid derivative (9) in any case.

Next, the compound (1
4) can be converted to the compound (16) by reacting it with an equimolar amount to an excess amount of the amine (15). The reaction can be carried out without solvent or in an inert solvent such as THF, methanol, 1,4-dioxane under the temperature conditions of 0 ° C. to room temperature and for 0.5 to 10 hours.

By subjecting the resulting compound (16) to a cyclization reaction, the compound (1f) of the present invention can be obtained. The cyclization reaction can be carried out in the presence of a silicon compound and a base in an inert solvent. Examples of the inert solvent include aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ether, ethers such as diethyl ether, halogenated carbonization such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Hydrogen or the like can be used. As the silicon compound, chlorotrimethylsilane, chlorotriethylsilane, chlorobutyldimethylsilane, chloroethyldimethylsilane and the like can be used. As the base, triethylamine, N, N-diethylaniline, N
Amines such as -methylmorpholine, pyridine and 4-dimethylaminopyridine can be preferably used. The silicon compound and the base are preferably used in equimolar amounts to excess amounts with respect to the compound (16), and the reaction is usually completed at room temperature to around reflux temperature in about 0.5 to 10 hours. .

[0056]

[Chemical 12]

[Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ⁵ ,
R ^6b , R ^7b , A, Y and Z are the same as defined above. In Reaction Scheme-6, the reaction of compound (17) with acid halide (13) can be carried out in an inert solvent in the presence of a deoxidizing agent. As the inert solvent, aromatic hydrocarbons or aliphatic hydrocarbons such as benzene, toluene, xylene and petroleum ethers and ethers such as diethyl ether,
Ketones such as acetone, methyl ethyl ketone, acetophenone, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane can be used. Further, as a deoxidizing agent, triethylamine,
Amines such as N, N-diethylaniline, N-methylmorpholine, pyridine and 4-dimethylaminopyridine can be preferably used. The amount of acid halide (13) used is
It is preferable that the equimolar amount to a small excess amount relative to the compound (17) and the use amount of the deoxidizing agent be an equimolar amount to an excessive amount relative to the compound (17). The reaction can be carried out generally under the temperature condition of 0 ° C. to room temperature for about 0.5 to 10 hours.

The obtained compound (16) has the following reaction process formula-
By the cyclization reaction shown in 5, the compound of the present invention (1f) can be converted.

[0059]

[Chemical 13]

[Wherein R ^1b , R ^2b , R ^3b , R ⁵ , R ^6b ,
R ^7b , A and Z are the same as above. ] As shown in Reaction Scheme-7, the compound (14) of the present invention is treated with hydrazine to give the compound (1g) of the present invention.
Can be obtained. The treatment reaction is solvent-free or TH
Triethylamine, N, N-dimethylaniline, N in an inert solvent such as F, methanol, 1,4-dioxane
It can be carried out in the presence of a base such as -methylmorpholine, pyridine or 4-dimethylaminopyridine. The amount of hydrazine used is an equimolar amount to 2 times the molar amount of the compound (14), and the amount of the base used is an equimolar amount to an excess amount of the compound (14). Generally, it can be performed at room temperature to around reflux temperature for about 2 to 20 hours.
The above compound (14) is an intermediate in Reaction Process Formula-5.

[0061]

[Chemical 14]

[Wherein R ^1b , R ^2b , R ^3b , R ⁵ , R ^6b ,
R ^7b , A and Z are the same as above. ψ represents a phenyl group or a pyridyl group which may have a lower alkoxy group, and R ^4c represents a benzylideneamino group or a pyridylmethylideneamino group which may have a lower alkoxy group on the phenyl ring. ] As shown in reaction process formula-8, this invention compound (1g) is made to react with this invention compound (1g) and aldehyde (18).
h) can be obtained. The reaction is carried out without solvent or in an inert solvent such as THF, methanol and 1,4-dioxane in the presence of a trace amount of an acid catalyst such as concentrated hydrochloric acid, concentrated sulfuric acid and p-toluenesulfonic acid, and an equimolar amount to 1. It is carried out with approximately twice the molar amount of aldehyde (18). The reaction temperature is preferably room temperature to around the reflux temperature, and the reaction time is preferably about 2 to 30 hours.

[0063]

[Chemical 15]

[Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ⁵ ,
R ^6b , R ^7a , A and Z are the same as defined above. According to the method shown in Reaction Scheme-9, the compound (1i) is reacted with lithium halide such as lithium bromide, lithium chloride and lithium iodide, and in a post-treatment step, an aqueous mineral acid solution such as hydrochloric acid and sulfuric acid is used. By the treatment, the partially hydrolyzed target compound (1j) can be obtained. The reaction is
It can be carried out at room temperature to around reflux temperature for about 10 to 100 hours using a lithium halide in an amount of 5 times or more in an inert solvent such as acetonitrile or DMF.

[0065]

[Chemical 16]

[Wherein R ^1b , R ^2b , R ^3b , R ^4b , R ⁵ ,
R ^6b , A and Z are the same as above. R ^7c represents a phenyl lower alkylamino group or a phenyl lower alkoxy group which may have a halogen atom on the phenyl ring. According to Reaction Process Formula-10, compound (1k) can be obtained by halogenating compound (1j) and then reacting it with compound (19).

In the above halogenation reaction, a halogenating agent such as thionyl chloride or phosphorus pentachloride is used as a compound (1) in the absence of solvent or in an inert solvent such as dichloromethane, chloroform or DMF.
It can be carried out at room temperature to around the reflux temperature for about 0.5 to 2 hours, using an equimolar amount to 1.2 times the molar amount of j).

Next, the compound (19) and a base such as pyridine, triethylamine, diazabicyclo [5,4,0] undec-7-ene (DBU) were used as starting materials in the reaction solution obtained above. Equimolar amount to 1
The desired compound (1k) can be obtained by adding about 0-fold molar amount and reacting at 0 ° C. to room temperature for about 1 to 20 hours.

[0069]

[Chemical 17]

[Wherein R ^1b , R ^2b , R ^3b , R ⁵ , R ^6b ,
R ^7b , A and Z are the same as above. R ^4d represents a di-lower alkanoylamino group. ] As shown in Reaction Process Formula-11, a compound (1l) can be obtained by alkanoylating the compound (1g).
The reaction is solvent-free or pyridine, lutidine, DMF, D
It can be carried out using an alkanoylating agent in an inert solvent such as MA. As the alkanoylating agent, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic anhydride,
An acid anhydride such as heptanoic anhydride or an acid halide such as acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride or heptanoyl chloride can be used. It is usually preferable to use about 1 to 10 equivalents relative to the compound (1 g). The reaction is completed at room temperature to about 100 ° C. in about 3 to 30 hours.

[0071]

[Chemical 18]

[In the formula, R ⁵ , R ^7b , A and Z are the same as defined above. At least one of R ^1c , R ^2c , R ^3c and R ^6c is a nitro group, and the other is the same or different and represents a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group or a cyano group. , R ^4e is a phenyl group, a lower alkyl group, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy lower alkyl group or a benzoyl lower group. Indicates an alkyl group. R ^1d , R ^2d , R ^3d and R ^6d are
The same group as each group is shown except that the group corresponding to the nitro group among R ^1c , R ^2c , R ^3c and R ^6c is an amino group. ] As shown in Reaction Process Formula-12, compound (1n) can be obtained by catalytically reducing compound (1m). In the reaction, the compound (1m) was treated with palladium-carbon on an inert solvent such as methanol, ethanol, ethyl acetate,
It can be carried out by stirring with hydrogen gas at room temperature for about 10 minutes to 2 hours in the presence of a catalyst such as platinum oxide.

[0073]

[Chemical 19]

[Wherein R ^1d , R ^2d , R ^3d , R ⁵ , R ^6d ,
R ^7b , A and Z are the same as above. R ^4f represents a phenyl group, a lower alkyl group, a phenyl lower alkyl group which may have a halogen atom as a substituent on the phenyl ring, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy lower alkyl group or a benzoyl lower alkyl group,
R ^1e , R ^2e , R ^3e and R ^6e are R ^1d , R ^2d , R ^3d and R
^The same groups as those described above are shown, except that the group corresponding to the amino group in ^6d is a benzoylamino group or a phenylsulfonylamino group. As shown in Reaction Process Formula-13, the compound (1p) is obtained by reacting it with a benzenesulfonyl halide such as benzenesulfonyl chloride or a benzoyl halide such as benzoyl chloride in an inert solvent such as pyridine, lutidine, or triethylamine. Can be converted to the compound (1q). The amounts of benzenesulfonyl halide and benzoyl halide used in the reaction are the same as those of compound (1p).
The amount is preferably 1 to 3 times the molar amount, and the reaction can be carried out at a temperature of 0 ° C. to room temperature for about 30 minutes to 24 hours.

The target compound or the compound of the present invention obtained in each of the above steps can be easily isolated and purified by a conventional separation means. Examples of the means include adsorption chromatography, preparative thin layer chromatography, recrystallization,
Examples include solvent extraction and the like.

A pharmaceutical preparation containing the compound of the present invention as an active ingredient is usually put into practical use in the form of a general pharmaceutical preparation composition using a pharmaceutical carrier together with the active ingredient compound. As the pharmaceutical carrier, a filler, a bulking agent, a binder, a moisturizing agent, a disintegrating agent, a surface-active agent, which is usually used, depending on the use form of the pharmaceutical preparation,
Diluents and excipients such as lubricants can be exemplified, and these can be appropriately selected and used according to the dosage unit form of the obtained preparation.

As the dosage unit form of the above-mentioned pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, Capsules, suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned.

In the case of molding in the form of tablets, as the above-mentioned pharmaceutical carrier, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate, etc.,
Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, dried Starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate and other disintegrants, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, surfactants such as stearic acid monoglyceride, sucrose, stearin, cocoa butter, Disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, starch, etc. Moisturizers, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multi-layer tablets.

In the case of molding into a pill form, as a pharmaceutical carrier, for example, glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, disintegrating agents such as laminaran and agar can be used.

In the case of molding in the form of suppositories, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used as a pharmaceutical carrier.

Capsules are usually prepared by mixing the active ingredient compound of the present invention with various pharmaceutical carriers exemplified above and filling hard gelatin capsules, soft capsules and the like according to a conventional method.

Injections such as solutions, emulsions and suspensions containing the compound of the present invention are preferably sterilized and isotonic with blood. When molding into other forms, for example, water or ethyl may be used as a diluent. Alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. still,
In this case, a sufficient amount of salt, glucose, glycerin or the like to adjust the isotonic solution may be contained in the pharmaceutical agent, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. Good.

Furthermore, colorants, preservatives, perfumes, flavors, sweeteners and other pharmaceuticals may be incorporated into the above-mentioned various forms of pharmaceutical preparations, if necessary.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is determined according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered, and injections are intravenously administered alone or in a mixture with a normal replenishing solution such as glucose and amino acid. Independently, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered, and the suppository is intrarectally administered.

The amount of the active ingredient compound of the present invention represented by the general formula (1) to be contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected from a wide range. It is preferable that the content is about wt%. The dose of the pharmaceutical preparation is appropriately selected depending on its usage, patient's age, sex and other conditions, degree of disease, etc., but the amount of the compound of the present invention as an active ingredient is usually about 0 per 1 kg of body weight per day. The dosage is preferably about 0.05 to 100 mg, and the preparation can be administered 1 to 4 times per day.

[0086]

EXAMPLES In order to explain the present invention in more detail, production examples of the compound of the present invention will be given as examples, followed by pharmacological test examples conducted on the compound of the present invention and formulation examples using the compound of the present invention.

[0087]

Example 1 Diethyl 4- (3-phenyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate Preparation 2- (4-Methylphenyl) -3-phenyl-4 (3
H) -quinazolinone 0.62 g, N-bromosuccinimide (NBS) 0.39 g and benzoyl peroxide 0.0
5 g was suspended in 20 ml of benzene and heated under reflux for 10 hours. 50 ml of water was added to the reaction mixture and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2- (4
-Bromomethylphenyl) -3-phenyl-4 (3H)
-Pale yellow crude crystals of quinazolinone were obtained.

The crude crystals were mixed with phosphorous acid triethyl ester 3
It was suspended in ml and heated with stirring at 150 ° C. for 1 hour. After distilling off excess triethyl phosphite under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 1), and the obtained crude crystals were regenerated from benzene-n-hexane. Crystallization gave 0.45 g of colorless crystals of the title compound.

Structure and physical properties of the obtained compound (melting point)
Is shown in Table 1.

[0090]

Example 2 Diethyl 4- (3-methyl-4 (3H)
Preparation of -quinazolinon-2-yl) benzylphosphonate Diethyl 4- [N- (2-cyanophenyl) carbamoyl] benzylphosphonate 1 in 100 ml THF.
1.2 g was melted and cooled with ice water. To this, a 50% solution of 30% hydrogen peroxide containing 1.2 g of sodium hydroxide was added dropwise, and after completion of the addition, the mixture was stirred at room temperature for 16 hours. 50 ml of saturated saline was added to the reaction mixture, extraction was performed with chloroform, the chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is ethanol 150
ml and 20 ml of 2N sodium hydroxide aqueous solution,
Stir for 6 hours at room temperature. Saturated saline solution 15 in the reaction mixture
After adding 0 ml and extracting with chloroform, the chloroform layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from methylene chloride-diethyl ether to give diethyl 4- (4-hydroxyquinazoline-
5.9 g of colorless crystals of 2-yl) benzylphosphonate were obtained.

In 100 ml of anhydrous methanol, 5.9 g of diethyl 4- (4-hydroxyquinazolin-2-yl) benzylphosphonate, 1.8 g of potassium tert-butoxide and 2.3 g of methyl iodide were suspended at 40 ° C.
The mixture was heated and stirred for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methylene chloride: methanol = 100: 1), and the obtained crude crystals were recrystallized from methylene chloride-n-hexane. Thus, 3.0 g of the title compound was obtained as colorless crystals.

Table 1 shows the structure and physical properties (melting point) of the obtained compound.

[0093]

Examples 3 to 23 In the same manner as in Example 2, the compounds shown in Table 1 were synthesized. The structure and physical properties (melting point) of the obtained compound are also shown in Table 1.

[0094]

Examples 24 and 25 Diethyl 4- (5-fluoro-3-methyl-4 (3H) -quinazolinon-2-yl)
Benzylthiophosphonate and diethyl 4- (5-fluoro-3-methyl-4 (3H) -quinazolinethione-
Preparation of 2-yl) benzylthiophosphonate 3.9 g of the compound obtained in Example 3 and Lawesson's reagent 4.
5 g was suspended in 50 ml of toluene and heated under reflux for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: methylene chloride).
It was recrystallized from diethyl ether-n-hexane.

Thus, from the later fractions, diethyl 4- (5
-Fluoro-3-methyl-4 (3H) -quinazolinone-
Pale yellow crystals of 2-yl) benzylthiophosphonate.
5 g was obtained (Example 24).

From the previous fraction, diethyl 4- (5-fluoro-3-methyl-4 (3H) -quinazolinethione-
2-yl) benzylthiophosphonate yellow crystals 0.8
g was obtained (Example 25).

Structure and physical properties of each compound obtained (melting point)
Is shown in Table 1.

[0098]

Example 26 Preparation of diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate 2-amino-4 in 60 ml concentrated hydrochloric acid and 60 ml distilled water.
-5.2 g of chlorobenzoic acid was suspended and cooled on ice. To this, 30 ml of a 1.1 M aqueous sodium nitrite solution was added dropwise. Further, a solution prepared by dissolving 2.0 g of sodium azide in 60 ml of a saturated aqueous solution of sodium acetate was added to the reaction mixture, and the brown precipitate thus deposited was collected by filtration to obtain 3.6 g of 2-azido-4-chlorobenzoic acid. .

2.0 g of 2-azido-4-chlorobenzoic acid was suspended in 11.9 g of thionyl chloride, and the suspension was stirred at 80 ° C. for 1 hour.
Heated to reflux for hours. After completion of the reaction, unreacted thionyl chloride was distilled off under reduced pressure. The residue was dissolved in 50 ml of benzene, 2.9 g of diethyl 4- (N-methylcarbamoyl) benzylphosphonate and 1.0 g of triethylamine were added, and the mixture was heated under reflux at 80 ° C. for 15 hours. After the reaction was completed, the precipitate was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent ... chloroform) and recrystallized from chloroform-n-hexane to obtain 1.2 g of colorless crystals of imide.

In 10 ml of xylene, 0.9 g of imide compound was added.
And 0.5 g of triphenylphosphine were dissolved, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to obtain 0.8 g of the desired product as colorless crystals. Table 1 shows the structure and physical properties (melting point) of the obtained compound.

[0101]

Examples 27 to 42 In the same manner as in Example 2, the compounds shown in Table 2 were synthesized. The structure and physical properties (melting point) of the obtained compound are also shown in Table 2.

[0102]

Examples 43 and 44 In the same manner as in Example 1, the compounds shown in Table 2 were synthesized. The structure and physical properties (melting point) of the obtained compound are also shown in Table 2.

[0103]

[Table 1]

[0104]

[Table 2]

[0105]

[Table 3]

[0106]

[Table 4]

[0107]

Example 45 Preparation of diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate (step 1) 4-diethoxyphosphorylmethylbenzoic acid 6
00 g of dichloromethane 250 ml and DMF 250 m
1 g, thionyl chloride (260 g) was added dropwise thereto,
The mixture was stirred at 40 ° C for 2 hours.

On the other hand, 188 g of 4-chloroanthranilic acid
Was dissolved in 1200 ml of pyridine, and the above reaction mixture solution was slowly added dropwise to this mixture under ice-cooling stirring. After stirring at room temperature for 20 hours, 1500 ml of distilled water was added to the reaction mixture.
Was added, and the deposited precipitate was collected by filtration, and diethyl 4- (7
233 g of -chloro-4H-1,3-benzoxazin-4-one-2-yl) benzylphosphonate were obtained.

The filtrate was washed successively with 3N aqueous hydrochloric acid solution and distilled water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure and recrystallized from dichloromethane-diethyl ether to obtain 102 g of the same compound as above. Obtained.

(Step 2) Compound 1 obtained in the above step 1
02 g was dissolved in 750 ml of THF, 58 ml of 40% methylamine aqueous solution was added, and the mixture was stirred for 1 hour at room temperature. Distilled water was added to the residue, and the deposited precipitate was collected by filtration and washed with diethyl ether.
4-{[7-chloro-2- (N-methylcarbamoyl)
Phenyl] carbamoyl} benzylphosphonate 98g
Got

(Step 3) 80 g of the compound obtained in Step 2
221 g of triethylamine and 2000 of dichloromethane
87 g of chlorotrimethylsilane was slowly added dropwise to the solution while stirring at room temperature with stirring. After the dropping, 40 ℃
The mixture was heated and stirred for 17 hours. After completion of the reaction, the reaction mixture was concentrated, 1N hydrochloric acid (1000 ml) was added to the residue, and the mixture was extracted with dichloromethane. After drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue for crystallization, and the crystals were collected by filtration. The crude crystals were recrystallized from ethanol-water to give the desired diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate 88.6 g.
Got

The compound thus obtained was identical with the compound prepared in Example 26 in melting point and ¹ H--N
Confirmed by MR spectral data.

[0113]

Examples 46 to 51 In the same manner as in Example 45, the compounds shown in Table 3 were synthesized. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0114]

Example 52 Preparation of diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate (step 1) 4-diethoxyphosphorylmethylbenzoic acid 2
7.2 g was suspended in 60 ml of dichloromethane and 2 ml of DMF, 13.1 g of thionyl chloride was added thereto, and the mixture was refluxed for 1 hour. After the reaction was completed, the reaction mixture was allowed to cool,
(N-methylcarbamoyl) -5-chloroaniline 1
8.5 g of pyridine 50 ml and dichloromethane 30 m
1 solution was slowly added dropwise to the solution under ice-cooling with stirring. After completion of the dropping, the mixture was stirred at room temperature for 48 hours, and water was added to the reaction mixture.
0 ml was added, and the precipitated crystals were collected by filtration, washed thoroughly with water and dried, and diethyl 4-{[7-chloro-2-
(N-methylcarbamoyl) phenyl] carbamoyl}
23.6 g of benzylphosphonate were obtained.

(Step 2) Using the compound obtained in Step 1 above, a reaction similar to Step 3 in Example 45 was carried out to obtain crystals of the target compound.

The melting point and ¹ H-NMR spectrum data confirmed that the compound thus obtained was the same as the compounds prepared in Example 26 and Example 45.

[0117]

Examples 53 to 56 In the same manner as in Example 52, the compounds shown in Table 3 were synthesized. The structure and physical properties (melting point) of the obtained compound are also shown in Table 3. The ¹ H-NMR spectrum data (δ: ppm) of the oily substance is shown.

[0118]

Example 57 Preparation of diethyl 4- (3-amino-7-chloro-4 (3H) -quinazolinon-2-yl) benzylphosphonate The compound 20. obtained in Step 1 of Example 45 in 200 ml of pyridine. 0 g and 2.5 g of hydrazine hydrate were suspended and refluxed for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane, and washed successively with 2N hydrochloric acid, distilled water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: dichloromethane:
The crystals obtained were purified by methanol = 50: 1) and further recrystallized from dichloromethane-diethyl ether to obtain 14.1 g of colorless crystals of the target compound.

Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0120]

Example 58 Diethyl 4- (3-N-benzylideneamino-7-chloro-4 (3H) -quinazolinone-2-
Ilyl) Production of benzylphosphonate 2.0 g of the compound obtained in Example 56, 1.0 g of benzaldehyde and a catalytic amount of concentrated hydrochloric acid were suspended in 50 ml of methanol and stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from dichloromethane-diethyl ether to give colorless crystals of the target compound 1.6.
g was obtained. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0121]

[Embodiments 59 and 60]
Each compound shown in the table was synthesized. The structures and physical properties (melting points) of the obtained compounds are also shown in Table 3.

[0122]

Example 61 Preparation of ethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate 70 g of the compound obtained in Example 26 was added to acetonitrile 8
It was dissolved in 00 ml, 118 g of lithium chloride was added, and the mixture was refluxed for 3 days. After the reaction was completed, the precipitate was collected by filtration and distilled water 2.5
It was dissolved in 1 and acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give 58 g of the target compound crystals. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0123]

Example 62 Ethyl [4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzyl]
Production of -N-benzylamide phosphonate 0.50 g of the compound obtained in Example 61, 1 ml of DMF
And 0.15 g of thionyl chloride in 10 ml of dichloromethane
And the mixture was refluxed for 3 hours. After completion of the reaction, the mixture was allowed to cool, and a solution of 0.14 g of benzylamine and 0.58 g of DBU in 10 ml of dichloromethane was added dropwise thereto, followed by stirring at room temperature for 18 hours. After the reaction, the organic layer was washed successively with diluted hydrochloric acid, distilled water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: dichloromethane: methanol = 30: The product was purified in 1) and recrystallized from ethyl acetate-n-hexane to obtain 0.28 g of colorless crystals of the target compound. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0124]

[Examples 63 and 64]
Each compound shown in the table was synthesized. The structures and physical properties (melting points) of the obtained compounds are also shown in Table 3. For the oily substance, ¹ H-NMR spectrum data (δ: pp
m) is shown.

[0125]

Example 65 Diethyl 4- (7-chloro-3-N,
N-diacetylamino-4 (3H) -quinazolinone-2
-Yl) Preparation of benzylphosphonate 3.0 g of the compound obtained in Example 57 and acetic anhydride 2.
2 g was suspended in 20 ml of pyridine and refluxed at room temperature for 18 hours. After the reaction, the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent ... dichloromethane: methanol = 50: 1) and further dichloromethane-
Recrystallization from n-hexane gave 2.3 g of colorless crystals of the target compound. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0126]

Example 66 Preparation of diethyl 4- (7-amino-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate 15.8 g of the compound obtained in Example 27 was dissolved in 450 ml of purified ethanol. 5% palladium-carbon 1.5g
Was added, and the mixture was stirred in hydrogen gas at room temperature for 30 minutes. After the reaction, palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure.
The residue is subjected to silica gel column chromatography (eluent ...
The product was purified with chloroform: methanol = 20: 1) and recrystallized from chloroform-diethyl ether to obtain 9.8 g of colorless crystals of the target compound. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0127]

Example 67 Diethyl 4- (3-methyl-7-phenylsulfonylamino-4 (3H) -quinazolinone-2
-Yl) Preparation of benzylphosphonate 1.5 g of the compound obtained in Example 66, 10 m of pyridine
0.57 ml of benzenesulfonyl chloride was added to the solution 1 at 0 ° C.
Dropped slowly down. The mixture was stirred at room temperature for 12 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was washed with diluted hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to obtain 1.75 g of colorless crystals of the target compound. Table 3 shows the structure and physical properties (melting point) of the obtained compound.

[0128]

Example 68 In the same manner as in Example 67, each compound shown in Table 3 was synthesized. The structures and physical properties (melting points) of the obtained compounds are also shown in Table 3.

[0129]

[Table 5]

[0130]

[Table 6]

[0131]

[Table 7]

[0132]

[Pharmacological Test Example 1] The high lipid preventive and therapeutic effects of the compound of the present invention in Triton-induced hyperlipidemia rats were examined by the method of Kuroda et al. [Biochem. Biophys. Acta., 489 , 119 (1977)].
The following tests were performed according to

[0133] That is, 6 to 7-week-old Wistar male rats (5 groups per group) (test group) were preliminarily dissolved in physiological saline, and Triton (Triton WR1339) 300 mg /
kg by tail vein administration and at the same time 100 mg / test compound
kg was orally administered in the form of suspension suspended in 0.5% sodium carboxymethyl cellulose (CMC-Na) solution.

As a control group, there was provided a group in which 5 rats of the same Triton-administered rat were orally administered with 0.5% CMC-Na aqueous solution alone.

Rats in each group mentioned above were treated with Triton.
4 hours later, blood was collected and plasma triglyceride (TG)
The amount was measured using Triglyceride G-Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).

Based on the above measured values in the control group,
From the measured values in the test group, the reduction rate (%) in plasma TG amount was calculated according to the following formula. In addition, all the test rats were fasted before the administration of Triton until the blood collection was completed, but water was freely taken.

Plasma TG reduction rate (%) = [1- (test group value) / (control group value)] × 100 The results are shown in Table 4 below.

[0138]

[Table 8]

From Table 4, all of the tested compounds of the present invention have a TG level lowering action, which indicates that they are effective for the prevention and treatment of hyperlipidemia.

[0140]

[Pharmacological Test Example 2] The hypoglycemic effect of the compound of the present invention in mice was tested as follows.

That is, a powdered feed (CFR-1: Oriental Yeast Co., Ltd.) was prepared by mixing 5 to 8 week-old KKAy male mice per group (test group) with the test compound at a concentration of 0.1% by weight. Manufactured) and water were freely ingested for 4 days. Blood was collected from the fundus on the 5th day, and the blood glucose level was measured using a glucose sensor (manufactured by Daikin Industries, Ltd.).

A group fed with a diet not mixed with a test compound was used as a control group, and the blood glucose lowering rate (%) was calculated from the measured value in the test group based on the measured value in the control group according to the following formula.

Blood glucose decrease rate (%) = [1- (test group value) /
(Control group value)] × 100 The obtained results are shown in Table 5 below.

[0144]

[Table 9]

From Table 5, it can be seen that the compound of the present invention has a hypoglycemic action and is effective in treating diabetes.

[0146]

[Pharmacological Test Example 3] The hypoglycemic effect of the compound of the present invention in rats was tested as follows.

That is, 1 of 6-week-old male Wistar rats
Dexamethasone (decadron S injection: manufactured by Banyu Pharmaceutical Co., Ltd.) 0.5 mg / kg was intraperitoneally administered once a day for 4 days to 5 animals (test group) in a group, and 100 mg of the test compound immediately after the administration.
/ Kg was dissolved in a 5% gum arabic solution and orally administered every day. After 4 hours from the administration of dexamethasone on the 4th day, decapitated blood was collected and centrifuged (3000 rpm, 4 ° C., 15 minutes), and the glucose level in the obtained serum was measured by glucose cII test Wako (manufactured by Wako Pure Chemical Industries, Ltd.). It was measured using. Rats were fed ad libitum and fasted 24 hours before blood collection.

As a control group, 5 was used instead of the test compound.
% Arabic gum solution was administered and a normal group was provided with only free feeding, the glucose level in serum was measured in the same manner, and the blood glucose was calculated from the value (average value) of each group. The rate of decrease was calculated by the following formula.

Blood glucose lowering rate (%) = [(control group value)-(test group value)] / [(control group value)-(normal group value)] × 100 The obtained results are shown in Table 6 below. Shown in.

[0150]

[Table 10]

From Table 6, it can be seen that the compound of the present invention has an excellent hypoglycemic action and is effective in treating diabetes.

[0152]

[Formulation Example 1] Preparation of tablets Using the compound obtained in Example 26 as an active ingredient, tablets (2000 tablets) each containing 250 mg thereof were prepared according to the following formulation.

Compound of the present invention obtained in Example 26 500 g Lactose (Japanese Pharmacopoeia) 67 g Corn starch (Japanese Pharmacopoeia) 33 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 25 g Methylcellulose (Japanese Pharmacopoeia) 12 g Magnesium stearate (Japanese Pharmacopoeia product) 3 g Total amount 640 g That is, according to the above formulation, the compound obtained in Example 26, lactose, corn starch and carboxymethyl cellulose calcium are thoroughly mixed, and the mixture is granulated using an aqueous solution of methyl cellulose, and sieved with 24 mesh. , And mixed with magnesium stearate and pressed into tablets to obtain target tablets.

[0154]

[Formulation Example 2] Preparation of capsules Using the compound obtained in Example 16 as the active ingredient, hard gelatin capsules (2000 tablets) containing 250 mg of each capsule were prepared according to the following formulation.

The compound of the present invention obtained in Example 16 500 g Crystalline cellulose (Japanese Pharmacopoeia) 60 g Corn starch (Japanese Pharmacopoeia) 34 g Talc (Japanese Pharmacopoeia) 4 g Magnesium stearate (Japanese Pharmacopoeia) 2 g Total amount 600 g That is, according to the above formulation, each component was finely powdered, mixed so as to form a uniform mixture, and then filled into a gelatin capsule for oral administration having a desired size to obtain a target capsule.

In addition to the compounds described in the above examples, typical compounds included in the present invention are shown below.

Diisopropyl 4- (7-bromo-3)
-Methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate-ethylmethyl 4- (7-chloro-3-methyl-4)
(3H) -Quinazolinon-2-yl) benzylphosphonate / ethylisopropyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate / isopropylmethyl 4- (7-chloro) -3-Methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate methyl [4- (7-chloro-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzyl] -N-benzylamidophosphonate isopropyl [4- (7-chloro-3-methyl-4
(3H) -Quinazolinon-2-yl) benzyl] -N-
Benzylamidophosphonate methyl [4- (7-bromo-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzyl] -N-benzylamidophosphonate ethyl [4- (7-bromo-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzyl] -N-benzylamidophosphonate isopropyl [4- (7-bromo-3-methyl-4
(3H) -Quinazolinon-2-yl) benzyl] -N-
Benzylamidophosphonate diethyl 4- (5-bromo-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate diethyl 4- (5-iodo-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate dimethyl 4- (5-fluoro-3-methyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate diethyl 4- (5-fluoro-3-ethyl-4 (3
H) -Quinazolinon-2-yl) benzylphosphonate diisopropyl 4- (5-fluoro-3-methyl-
4 (3H) -quinazolinon-2-yl) benzylphosphonate.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Jun Kanya Tokai 22-7, Nakamura, Kitashima-cho, Itano-gun, Tokushima Prefecture 22-7 (72) Keigo Sato Keiho Sato, Matsushimo-machi, Itano-gun, Tokushima Prefecture 1 of 96 (56) Reference Documents JP-A-5-43589 (JP, A) JP-A-61-254524 (JP, A) JP-A-57-123170 (JP, A) International publication 95/00524 (WO, A1) International publication 95/06051 ( WO, A1) International Publication 93/23409 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07F 9/6512 A61K 31/675 A61P 3/06 A61P 3/10 A61P 9/12 CAPLUS (STN) REGISTRY (STN)

Claims (15)

(57) [Claims] 1. A general formula: [Wherein R ¹ , R ² , R ³ and R ⁶ are the same or different and each is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group,
A lower alkoxy group, a cyano group, a phenylsulfonylamino group, a benzoylamino group, an amino group or a halogen-substituted lower alkyl group, and R ⁴ may have a halogen atom as a substituent on the phenyl group, lower alkyl group or phenyl ring. Phenyl lower alkyl group, lower alkenyl group, carboxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxy lower alkyl group,
A lower alkynyl group, a benzoyl lower alkyl group, an amino group, a dilower alkanoylamino group, a benzylideneamino group or a pyridylmethylideneamino group which may have a lower alkoxy group on the phenyl ring, R ⁵ represents a lower alkyl group, R ⁷ is a lower alkoxy group, a hydroxyl group, a phenyl group, a phenyl lower alkoxy group which may have a halogen atom on the phenyl ring, or a phenyl lower alkylamino group, X ¹ and X ² are an oxygen atom or a sulfur atom, respectively. Represents an oxygen atom or a single bond, and Z represents a lower alkylene group. ] The phosphonic acid diester derivative represented by these. 2. A general formula: [Wherein R ^{1 ′} is a hydrogen atom or a halogen atom, R ^{2 ′} is a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group or a lower alkoxy group, and R ^{3 ′} is a hydrogen atom, a halogen atom,
A nitro group, a halogen-substituted lower alkyl group, a cyano group, phenylsulfonylamino group, a benzoylamino group, an amino group or a lower alkoxy group, R 4 ^'is a phenyl group, a lower alkyl group, a halogen atom as a substituent on the phenyl ring A phenyl lower alkyl group, a lower alkenyl group, a carboxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxy lower alkyl group, a lower alkynyl group, a benzoyl lower alkyl group which may have,
An amino group, a di-lower alkanoylamino group, a benzylideneamino group which may have a lower alkoxy group on the phenyl ring or a pyridylmethylideneamino group, R ^{5 ′} is a lower alkyl group, R ^{6 ′} is a hydrogen atom, a lower alkoxy group. group or halogen atom, R 7 ^'is a lower alkoxy group, a hydroxyl group, a phenyl group, a phenyl lower alkoxy group or a phenyl-lower alkylamino group which may have a halogen atom on the phenyl ring, X ^1' and X ^{2 '} Each represent an oxygen atom or a sulfur atom, A'represents an oxygen atom or a single bond, Z'represents an ethylene group when A'is an oxygen atom,
When A'is a single bond, it represents a methylene group. ] The phosphonic acid diester derivative of Claim 1 represented by these. 3. A general formula: [Wherein R ^{1 "} is a hydrogen atom or a halogen atom, R ^2" is a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a lower alkoxy group, and R ^{3 "} is a hydrogen atom, a halogen atom,
A halogen-substituted lower alkyl group or lower alkoxy group,
R ^{4 "} is a lower alkyl group, a phenyl lower alkyl group, a lower alkynyl group, a pyridylmethylideneamino group or a lower alkenyl group, R ^5" is a lower alkyl group, and R ^{7 "} is a lower alkoxy group, a phenyl group or a phenyl lower group. An alkylamino group is shown respectively.] The phosphonic acid diester derivative according to claim 1. 4. R ^{1 "} is a hydrogen atom, R ^2" is a halogen atom, a nitro group or a lower alkoxy group, R ^{3 "} is a hydrogen atom or a lower alkoxy group, and R ^4" is a lower alkyl group. The phosphonic acid diester derivative according to claim 3, wherein R ^{7 ″} is a lower alkoxy group, phenyl lower alkyl group or lower alkenyl group. 5. A therapeutic and prophylactic agent for hyperlipidemia, which comprises an effective amount of the phosphonic acid diester derivative according to any one of claims 1 to 4 together with a pharmaceutical carrier. 6. The therapeutic and prophylactic agent for hyperlipidemia according to claim 5, wherein the active ingredient is the phosphonic acid diester derivative according to claim 4. 7. R ^{2 "} is a hydrogen atom or a lower alkyl group, R ^3" is a hydrogen atom, a halogen-substituted lower alkyl group or a halogen atom, and R ^{4 "} is a lower alkyl group, a phenyl lower alkyl group, a lower group. The phosphonic acid diester derivative according to claim 3, which is an alkynyl group or a pyridyl methylidene amino group. 8. The phosphonic acid diester derivative according to claim 7, wherein R ^{2 "} is a hydrogen atom and R ^3" is a hydrogen atom or a halogen atom. 9. The phosphonate diester derivative according to claim 8, wherein R ^{1 "} is a hydrogen atom, R ^3" is a halogen atom, and R ^{7 "} is a lower alkoxy group or a phenyl lower alkylamino group. 10. Diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinone-2-yl) benzylphosphonate, diethyl 4- (7-bromo-3-methyl-4 (3H) -quinazolinone. -2-yl) benzylphosphonate and ethyl [4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzyl]
The phosphonic acid diester derivative according to claim 9, which is selected from -N-benzylamide phosphonate. 11. The phosphonic acid diester derivative according to claim 10, which is diethyl 4- (7-chloro-3-methyl-4 (3H) -quinazolinon-2-yl) benzylphosphonate. 12. A therapeutic and prophylactic agent for diabetes, which comprises an effective amount of the phosphonic acid diester derivative according to any one of claims 1 to 3 and 7 to 11 together with a pharmaceutical carrier. 13. The therapeutic and prophylactic agent for diabetes according to claim 12, wherein the active ingredient is the phosphonic acid diester derivative according to any one of claims 7 to 11. 14. The therapeutic and prophylactic agent for diabetes according to claim 13, wherein the active ingredient is the phosphonic acid diester derivative according to claim 10. 15. The therapeutic and prophylactic agent for diabetes according to claim 14, wherein the active ingredient is the phosphonic acid diester derivative according to claim 11.