JPH08143566A - Quinazoline derivative and medicine composition containing the same - Google Patents

Abstract

PURPOSE: To obtain a quinazoline derivative useful as a preventive and a therapeutic agent for diabetic complication such as cataract, having both blood sugar level depressing and inhibitory action on aldose reductase, essentially comprising quinazolineacetic acid in a base structure. CONSTITUTION: This derivative is shown by formula I [R<3> and R<4> are H, a halogen, a lower alkyl, a lower alkoxy or a haloalkyl; R<1> and R<2> are exclusively R<5> -COOR<6> (R<5> is a 1-3C alkylene; R<6> is H or a 1-8C lower alkyl) or a group of formula II (A is methylene or a bifunctional group of formula III; R is a heterocyclic ring containing a weakly acidic hydrogen, preferably 2,4- dioxothiazolidin-5-yl)methyl] such as 3- 4-[(2,4-dioxothiazolidin-5-yl) methyl]benzyl}-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-acetic acid. The derivative is preferably obtained through a reaction between a compound of formula IV and a compound of formula V under basic conditions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a quinazoline derivative and a pharmaceutical composition containing the same. More specifically, a novel quinazoline derivative having both a hypoglycemic action and an aldose reductase inhibitory action, and a medicament containing the same for preventing and treating various complications in diabetes such as diabetic cataract, retinopathy, neuropathy, and renal disorder. It relates to a composition.

[0002]

2. Description of the Related Art As a therapeutic drug for diabetes,
Insulin preparations have been known and used since early times. Since then, various biguanide compounds and sulfonylurea compounds have been developed and used as oral hypoglycemic agents. However, these compounds have problems. That is, the insulin preparation is currently used as an injection, and although it has been alleviated, the inconvenience at the time of its use is a great burden to the patient. Further, oral hypoglycemic agents have side effects such as lactic acidosis and severe hypoglycemia, have low toxicity, and development of an effective antidiabetic drug is desired. As prior art relating to hypoglycemic agents, USP 4572912, USP 46
No. 45617 and USP46887777 are known.

In recent years, attention has been paid to the accumulation and increase of sorbitol in tissues as a pathogenic mechanism of diabetic complications, and a compound that inhibits the activity of aldose reductase (AR), which is an enzyme that reduces aldoses such as glucose and converts them into sorbitol. Has been suggested in the literature to be useful in the treatment of cataracts, retinopathy, neuropathy, and renal disorders [K. Et Gaby, N. Spack, N. Lu et al., Metabolism (KHGabbay, N.Spack, N .Loo, et al., Metabolis
m), 28 (Suppl.1); 471-476 (1979), Dei Dvornik, N. Simardeau de Cuesne, M. Kurami et al., Science (D.Dvornik, N.Simard-Duq).
uesne, M.Krami, et al., Science), 182; 1146.
-1148 (1973), Jay Et Kinoshita,
Dei Dvornik, M Kurami and others, Bio Kimika.
Biophysical. Actor (JHKinosita, D.Dvornik, MK
rami, et al., Biochem. Biophys. Acta), 158; 472.
-475 (1968)]. Based on these facts, the development of aldose reductase (AR) inhibitors is in progress. Prior art relating to aldose reductase inhibitors includes USP 4734419 and European Patent 4710.
No. 9 is known. However, the AR inhibitor is only a symptomatic therapeutic agent for diabetic complications, and is considered to have a low therapeutic effect on diabetes itself.

[0004]

Therefore, at present, a hypoglycemic agent is required for the fundamental treatment of diabetes, and in addition, diabetic complications, and further development of a hypoglycemic agent having an AR inhibitory action is desired. There is.

[0005]

In view of the above situation, the present inventors have conducted diligent research to develop a hypoglycemic agent having an aldose reductase inhibitory action, and as a result, the quinazoline derivative of the present invention satisfies the above requirements. Therefore, the present invention has been completed. The present invention is as follows.

(1) Of quinazoline derivatives represented by the general formula (I), and their metal salts, addition salts, hydrates, solvates, hydrates of metal salts, solvates of metal salts and addition salts. Hydrate, solvate of addition salt.

[0007]

[Chemical 7]

[In the formula (I), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -C.
OOR ⁶ (in the formula, R ⁵ represents an alkylene group having 1 to 3 carbon atoms, R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms), or general formula (II) or (II
It is a group represented by I). ]

[0009]

Embedded image

[In the formula (II), A is a methylene group, a divalent group represented by the formula (IV), a divalent group represented by the formula (V), or a divalent group represented by the formula (VI). It is a valent group, and T represents a heterocycle having weakly acidic hydrogen. ]

[0011]

[Chemical 9]

[In the formula (III), m represents an integer of 1 to 7, B represents a divalent group represented by the formula (IV), and T represents a heterocyclic ring having weakly acidic hydrogen. ]

[0013]

[Chemical 10]

[In the formula (IV), --CH ₂ --group and --NHS
The bonding positional relationship of the O ₂ − group on the aromatic ring is 1,2-, 1,3
-Or 1,4-. ]

[0015]

[Chemical 11]

[In the formula (V), --CH ₂ --group and --CH ₂ CH ₂
The bonding positions on the aromatic ring of the -group are 1,2-, 1,3-,
Or 1,4-. ]

[0017]

[Chemical 12]

[In the formula (VI), --CH ₂ --group and --CH ₂ CH
The bonding positional relationship on the ₂ -group aromatic ring is 1,2-, 1,3
-Or 1,4-. ]

(2) T in the general formula (II) is 2,4
A diazothiazolidin-5-yl group and A is methylene, and the quinazoline derivative according to the above (1) and a metal salt, addition salt, hydrate, solvate or hydrate of a metal salt thereof, Solvates of metal salts, hydrates of addition salts, solvates of addition salts. (3) The quinazoline derivative according to the above (1), wherein T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and A is a group represented by the general formula (IV). And its metal salts, addition salts, hydrates, solvates, hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts.

(4) T in the general formula (II) is 2,4
-A dioxothiazolidin-5-yl group, wherein A is a group represented by the general formula (V), and the quinazoline derivative according to the above (1), and a metal salt, addition salt, hydrate or solvate thereof. , Hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts. (5) The quinazoline derivative according to the above (1), wherein T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group and A is a group represented by the general formula (VI). And its metal salts, addition salts, hydrates, solvates, hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts.

(6) T in the general formula (III) is 2,4
-Dioxothiazolidin-5-yl group, and B is a group represented by the general formula (IV), and the quinazoline derivative according to the above (1), and a metal salt, addition salt, hydrate or solvate thereof. , Hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts. (7) A pharmaceutical composition containing the quinazoline derivative according to (1) above.

(8) A pharmaceutical composition containing the quinazoline derivative described in (2) above. (9) A pharmaceutical composition containing the quinazoline derivative according to (3) above. (10) A pharmaceutical composition containing the quinazoline derivative according to (4) above. (11) A pharmaceutical composition containing the quinazoline derivative according to (5) above. (12) A pharmaceutical composition containing the quinazoline derivative according to (6).

The quinazoline acetic acid derivative of the present invention represented by the general formula (I) is a compound having a novel structure in which a quinazoline acetic acid moiety is essential as a basic structure. In the definition of the general formula (I), examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom, and examples of the lower alkyl group include a straight chain having 1 to 8 carbon atoms,
Branched or cyclic alkyl groups are preferred, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Examples include isopentyl, hexyl and octyl.
Examples of the lower alkoxy group include those in which the above lower alkyl group and an oxygen atom are bonded. Examples of the haloalkyl group include chloromethyl, 2,2-dichloroethyl, trifluoromethyl and the like. Further, in the definitions of the general formulas (II) and (III), examples of the heterocycle include a 2,4-dioxothiazolin-5-yl group.

Suitable salts of the quinazoline acetic acid derivative of the present invention represented by the general formula (I) are, for example, lithium,
Examples thereof include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and addition salts with organic bases such as triethylamine and pyridine.

The method for producing the quinazoline acetic acid derivative of the present invention represented by the general formula (I) will be described in detail below. (Production method 1) In the general formula (I), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively-.
R ⁵ —COOR ⁶ [In the formula, R ⁵ represents an alkylene group having 1 to 3 carbon atoms, and R ⁶ is a hydrogen atom or 1 to 8 carbon atoms.
Is a lower alkyl group. ] Or in the formula, A is a methylene group and T is a general formula (II) showing a 2,4-dioxothiazolidin-5-yl group, the production method of the quinazoline acetic acid derivative of the present invention is as follows. That is, the general formula (VI
The compound represented by the general formula (IX) or (X) is obtained by reacting the compound represented by I) with the compound represented by the general formula (VIII) under basic conditions.

[0026]

[Chemical 13]

[In the formula (VII), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ⁷ and R ⁸ are exclusively -R ^5-.
COOR ⁶ (in the formula, R ⁵ represents an alkylene group having 1 to 3 carbon atoms, and R ⁶ represents a lower alkyl group having 1 to 8 carbon atoms) or hydrogen. ]

[0028]

Embedded image

[In the formula (VIII), X represents a halogen atom such as chlorine, bromine or iodine. ]

[0030]

[Chemical 15]

[0031]

Embedded image

[In the formulas (IX) and (X), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ⁵ has 1 to 3 carbon atoms.
And an R ⁶ is a lower alkyl group having 1 to 8 carbon atoms. ]

Examples of the base at this time include alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal hydrogen carbonates such as, trialkylamines such as triethylamine and diisopropylethylamine, pyridine compounds such as pyridine, lutidine, picoline, and 4-dimethylaminopyridine, and the like, and sodium hydride is preferably used. The above reactions are usually carried out in various solvents such as dichloromethane, pyridine, N, N
-In conventional solvents or mixtures thereof which do not adversely influence the reaction, such as dimethylformamide, tetrahydrofuran, acetone, dimethylsulfoxide and the like. Particularly preferred solvents include N, N-dimethylformamide. The reaction temperature is usually in the range of cooling to heating. For example, when sodium hydride is used as the base, the reaction temperature is preferably 0 ° C to room temperature.

As another method for producing the compound represented by the general formula (IX) or (X), general formula (XI) or (XI
The compound represented by I) can be prepared by a known method [JP-A-62-9].
6476 and the Journal of Medicinal Chemistry, 34.
Vol. 1492-1503, 1991], ie 1,
It can also be prepared by ring closure with 1'-carbonyldiimidazole, phosgene and the like.

[0035]

[Chemical 17]

[0036]

Embedded image

[In the formulas (XI) and (XII), R ³ , R ⁴ , R ⁵
And R ⁶ have the same meanings as in formulas (IX) and (X). ]

Next, the product represented by the general formula (IX) or (X) is reduced to obtain the compound represented by the general formula (XIII) or (XIV).

[0039]

[Chemical 19]

[0040]

Embedded image

[In the formulas (XIII) and (XIV), R ³ , R ⁴ ,
R ⁵ and R ⁶ have the same meanings as shown in formulas (IX) and (X). ]

As the method of the reduction reaction, catalytic reduction, reduction with zinc-acetic acid, iron-acetic acid, tin (II) chloride and the like can be mentioned, preferably catalytic reduction or tin (II) chloride.
Is used. Examples of the catalyst for catalytic reduction include palladium-carbon, Raney nickel, platinum oxide and the like, but palladium-carbon is preferred. Hydrogen pressure is 1 atm to 5
The pressure is 0 atm, but preferably 1 atm to 5 atm.
Examples of the solvent include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, organic acids such as acetic acid, and a mixture of these. The reaction temperature is usually from room temperature to under heating. For example, when tetrahydrofuran-methanol is used as the solvent, room temperature is preferable under normal pressure. The solvent for the reduction with tin (II) chloride is usually ethanol, and the reaction temperature is room temperature to the reflux temperature.

The compound represented by the above-mentioned general formula (XIII) or (XIV) is represented by the general formula (XV) or (XVI) by performing recrystallization or column chromatography and then performing a mail vinelation reaction. This produces a compound. Reactions include, for example, USP 4461902 and the Journal of Medicinal Chemistry.
edicinal Chemistry), 32, 421-428, 19
It is carried out according to the method described in 1989 or the like. That is, the Mailbain allation reaction is usually acetone, water or alcohols such as methanol or ethanol, preferably acetone or a mixture of acetone and water as a solvent, after diazotization by a conventional method, in the presence of an acid, acrylic acid esters, This is then done by adding a catalytic amount of cuprous salt.

[0044]

[Chemical 21]

[0045]

[Chemical formula 22]

[In the formulas (XV) and (XVI), R ³ , R ⁴ , R ⁵
And R ⁶ have the same meanings as in formulas (IX) and (X), R ⁷ represents a methyl group or an ethyl group, and Y represents a halogen atom such as chlorine or bromine. ]

Next, these compounds are reacted with thiourea in the presence of sodium acetate to give the following formula (XVII) or (XV
III) and then further hydrolyze these compounds with an acid or, if necessary, further hydrolyze the ester under basic conditions to obtain the desired compound of the general formula (XIX ) Or (XX) is obtained.

[0048]

[Chemical formula 23]

[0049]

[Chemical formula 24]

[In the formulas (XVII) and (XVIII), R ³ ,
R ⁴ , R ⁵ and R ⁶ have the same meanings as in formulas (IX) and (X). ]

[0051]

[Chemical 25]

[0052]

[Chemical formula 26]

[In the formulas (XIX) and (XX), R ³ , R ⁴ and R ⁵ have the same meanings as in the general formulas (IX) and (X), and R ⁶ is a hydrogen atom or a carbon number 1 8 to 8 lower alkyl groups are shown. ]

Suitable acids for the acid hydrolysis reaction are formic acid,
Organic acids such as acetic acid and mineral acids such as sulfuric acid and hydrochloric acid are mentioned, and hydrochloric acid is most preferably used. Examples of the reaction solvent include alcohols such as ethanol and methanol, water, sulfolane, and a mixture thereof, but a mixed solvent of water and alcohols is preferably used. At this time, the general formula (XIX) or (X
X), wherein R ⁶ is a hydrogen atom or a lower alkyl group depending on the alcohol used (XIX) or (X
X) is obtained. Therefore, when a compound in which R ⁶ is a hydrogen atom in the general formula (XIX) or (XX) is required, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, preferably sodium hydroxide is used as a base, The hydrolysis is carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dioxane, methanol, ethanol, tetrahydrofuran, etc. or a mixture thereof as a solvent.

The compound represented by the general formula (VII) and the compound represented by the general formula (IX) are known substances,
Alternatively, known methods [US Pat. No. 4,734,419 and Journal of Medicinal Chemistry (Journal of M
edicinal Chemistry), 34, 1492-1503.
1991] and can be easily manufactured.

(Production Method 2) R ³ and R in the general formula (I)
⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -C00R ⁶ [wherein R ⁵ has 1 to 3 carbon atoms; Represents an alkylene group, and R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. Or a quinazoline of the present invention wherein A is a divalent group represented by the general formula (IV) and T is a general formula (II) showing a 2,4-dioxothiazolidin-5-yl group. The method for producing the derivative is as follows. That is, when the compound represented by the general formula (XIII) or (XIV) and the compound represented by the general formula (XXI) in the production method 1 are reacted under basic conditions, the compound represented by the general formula (XXII) or (XXIII) ) The compound represented by this is obtained.

[0057]

[Chemical 27]

[In the formula (XXI), Z represents a halogen atom such as chlorine, bromine or iodine. ]

[0059]

[Chemical 28]

[0060]

[Chemical 29]

[In the formulas (XXII) and (XXIII), R ³ ,
R ⁴ , R ⁵ and R ⁶ have the same meanings as in formulas (IX) and (X). ]

Examples of the base at this time include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, trialkylamines such as triethylamine and diisopropylethylamine, pyridine, lutidine, and the like. Examples thereof include pyridine compounds such as 4-dimethylaminopyridine. Preferably diisopropylethylamine is used. The reaction solvent is, for example, dichloromethane, chloroform, pyridine,
It is carried out in a conventional solvent which does not adversely influence the reaction such as N, N-dimethylformamide and the like, and preferably dichloromethane is used. The reaction temperature is 0 ° C. to reflux, preferably 0 ° C. to room temperature.

Next, these nitro compounds are reduced according to the method described in the production method 1, and are successively subjected to a mailbain arylation reaction and a cyclization reaction using thiourea. The compound obtained is subjected to acid hydrolysis or, if necessary, further subjected to ester hydrolysis under basic conditions to obtain the desired compound (XXIV) or (XXV) represented by the general formula shown below. .

[0064]

Embedded image

[0065]

[Chemical 31]

[In the formulas (XXIV) and (XXV), R ³ , R ⁴ ,
R ⁵ and R ⁶ have the same meanings as shown in formula (I). ]

In the general formula (I), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively
—R ⁵ —COOR ⁶ [In the formula, R ⁵ represents an alkylene group having 1 to 3 carbon atoms, and R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. ], Or A in the formula is a divalent group represented by the general formula (IV), a —CH ₂ — group,
The compound in the case where the bonding positional relationship of the NHSO ₂ — group on the aromatic ring is 1,4- and T is the general formula (II) showing a 2,4-dioxothiazolidin-5-yl group is produced. The compound represented by the general formula (XIII) or (XIV) in Example 1 is a known substance [Journal of Medicinal].
Chemistry (Journal of Medicinal Chemistry), 3
5 vol., 1853-1864, 1992], or the compound (XXVI) is reacted under a basic condition or, if necessary, further hydrolyzed with an ester under a basic condition.

[0068]

Embedded image

Examples of the base at this time include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, triethylamine, and the like.
Examples include trialkylamines such as diisopropylethylamine and pyridine compounds such as pyridine, lutidine, and 4-dimethylaminopyridine, but diisopropylethylamine is preferable. The reaction solvent is
It is carried out in a conventional solvent or a mixture thereof which does not adversely influence the reaction, such as N, N-dimethylformamide, dichloromethane, chloroform, acetone and the like, preferably dichloromethane. The reaction temperature is in the range of 0 ° C to warming, preferably 0 ° C to room temperature.

(Production Method 3) In the general formula (I), R ³ , R
⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -COOR ⁶ [wherein R ⁵ has 1 to 3 carbon atoms; Represents an alkylene group, and R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. Or a quinazoline of the present invention wherein A is a divalent group represented by the general formula (VI) and T is a general formula (II) showing a 2,4-dioxothiazolidin-5-yl group. The method for producing the derivative is as shown below. That is, the compound represented by the general formula (VII) in the production method 1 and the general formula (XXVI
When the compound represented by I) is reacted under basic conditions, the compound represented by the general formula (XXVIII) or (XXIX) is obtained.

[0071]

[Chemical 33]

[In the formula (XXVII), Q represents a halogen atom such as chlorine, bromine or iodine. ]

[0073]

Embedded image

[0074]

Embedded image

[In the formulas (XXVIII) and (XXIX), R ³ ,
R ⁴ , R ⁵ and R ⁶ have the same meanings as in formulas (IX) and (X). ]

Examples of the base at this time include alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. Alkali metal hydrogen carbonate such as trialkylamine such as triethylamine, pyridine, lutidine, 4-
Pyridine compounds such as dimethylaminopyridine can be mentioned, but sodium hydride is preferably used. The reaction solvent is a conventional solvent which does not influence the reaction, such as N, N-dimethylformamide, dichloromethane, acetone, or a mixture thereof, and preferably N, N-dimethylformamide is used. The reaction temperature is in the range of 0 ° C. to heating. Preferably, when sodium hydride is used as the base, the temperature is 0 ° C to room temperature.

Next, these nitro compounds are reduced with tin (II) chloride according to the method described in the production method 1, and further subjected to merbaine arylation reaction and cyclization with thiourea in order. The obtained compound is subjected to acid hydrolysis or, if necessary, further subjected to ester hydrolysis under basic conditions to obtain the desired compound represented by the general formula (XXX) or (XXXI) as shown below.

[0078]

Embedded image

[0079]

Embedded image

[In the formulas (XXX) and (XXXI), R ³ , R ⁴ ,
R ⁵ and R ⁶ have the same meanings as shown in formula (I). ]

(Production Method 4) In the general formula (I), R ³ , R
⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -COOR ⁶ [wherein R ⁵ has 1 to 3 carbon atoms; Represents an alkylene group, and R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. Or a quinazoline of the present invention wherein A is a divalent group represented by the general formula (V) and T is a general formula (II) showing a 2,4-dioxothiazolidin-5-yl group. The method for producing the derivative is as follows. That is, the compound represented by the general formula (XXVIII) or (XXIX) in the production method 3 is catalytically reduced to give the general formula (XXXI
A compound represented by I) or (XXXIII) is obtained. As the catalyst, preferably palladium-carbon is used, as a solvent, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, organic acids such as acetic acid, hydrochloric acid,
It is carried out in a mineral acid such as sulfuric acid or a mixture thereof, and preferably tetrahydrofuran is used. The reaction temperature is from room temperature to under heating, usually room temperature is preferable, and the hydrogen pressure is 1 atm to 50 atm, preferably 1 atm to 5 atm.

[0082]

[Chemical 38]

[0083]

[Chemical Formula 39]

[In the formulas (XXXII) and (XXXIII), R ³ , R
⁴ , R ⁵ and R ⁶ have the same meanings as in formulas (IX) and (X). ]

The general formula (XXXI
The compound represented by I) or (XXXIII) is subjected to a melbaine arylation reaction and a cyclization reaction using thiourea according to the method described in the production method 1. The resulting compound is subjected to acid hydrolysis or, if necessary, further subjected to ester hydrolysis under basic conditions to obtain the desired compound represented by the general formula (XXXIV) or (XXXV) as shown below. .

[0086]

[Chemical 40]

[0087]

Embedded image

[In the formulas (XXXIV) and (XXXV), R ³ ,
R ⁴ , R ⁵ and R ⁶ have the same meanings as in formula (I). ]

(Production Method 5) In the general formula (I), R ³ , R
⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -C00R ⁶ [wherein R ⁵ has 1 to 3 carbon atoms; Represents an alkylene group, R ⁶ is hydrogen or has 1 carbon atom
8 to 8 lower alkyl groups are shown. ] Or in the formula, m represents an integer of 1 to 7, B is a divalent group represented by the formula (IV), and T is 2,4-dioxothiazolidine-5-
The production method of the quinazoline derivative of the present invention in the case of the general formula (III) showing an yl group is as follows. That is, the compound represented by the general formula (VII) in the production method 1 is represented by the general formula (XXX
The compound represented by the formula (VI) is reacted under basic conditions to obtain the compound represented by the general formula (XXXVII) or (XXXVIII).

[0090]

Embedded image

[In the formula (XXXVI), L represents a halogen atom such as chlorine, bromine or iodine, and n represents an integer of 1 to 6. ]

[0092]

[Chemical 43]

[0093]

[Chemical 44]

[In the formulas (XXXVII) and (XXXVIII), n represents an integer of 1 to 6, and R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as in formulas (IX) and (X). Is. ]

Examples of the base at this time include alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Examples thereof include alkali metal hydrogen carbonates, trialkylamines such as triethylamine and diisopropylethylamine, and pyridine compounds such as pyridine, lutidine, and 4-dimethylaminopyridine, but sodium hydride is preferably used. The reaction solvent is a conventional solvent which does not adversely influence the reaction such as N, N-dimethylformamide, dichloromethane, chloroform, acetone or the like, or a mixture thereof, preferably when sodium hydride is used as a base. N, N-dimethylformamide is suitable. The reaction temperature is 0 ° C to the temperature under which the reaction is carried out, preferably 0 ° C to room temperature. Next, the obtained product is reduced to obtain a compound represented by the general formula (XXXIX) or (XXXX).

[0096]

Embedded image

[0097]

Embedded image

[In the formulas (XXXIX) and (XXXX), n represents an integer of 1 to 6, and R ³ , R ⁴ , R ⁵ and R ⁶ are represented by the general formula (I
X) and (X) have the same meanings. ]

Examples of the reduction reaction method include catalytic reduction, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, and electrolysis. In catalytic reduction, Raney cobalt, Raney nickel, palladium carbon,
Examples thereof include platinum oxide and rhodium-alumina, and Raney nickel is preferably used. The reaction solvent may be methanol, ethanol or the like, but ethanol is preferably used when Raney / nickel is used as the reducing agent. At this time, it is more preferable to saturate ammonia with ethanol. The reaction temperature is from room temperature to heating, and the hydrogen pressure is 1 atm to 50 atm, preferably 1 atm to 5 atm at room temperature. Then, the same step as the reaction using the compound (XXI) or compound (XXVI) in the production method 2 is performed to obtain the desired compound represented by the general formula (XXXXI) or (XXXXII).

[0100]

[Chemical 47]

[0101]

Embedded image

[In the formulas (XXXXI) and (XXXXII), n is 1
Or an integer of 6, R ^3, R ⁴ and R ⁵ of the general formula (IX)
And (X) have the same meanings, and R ⁶ represents hydrogen or a lower alkyl group having 1 to 8 carbon atoms. ]

The quinazoline derivative of the present invention obtained by the above-mentioned production method can be isolated and purified by a conventional method such as extraction, precipitation, fractionation chromatography, fractionation, crystallization and recrystallization.

The compound of the present invention has excellent hypoglycemic action and aldose reductase inhibitory action, and is effective in preventing and treating diabetic complications. When the compound of the present invention is administered to humans for the purpose of preventing and treating diabetic complications, it is used as a solid preparation, a semisolid preparation or a liquid preparation together with an organic or inorganic auxiliary component suitable for internal, external or topical administration. It can be administered orally or parenterally. As the dosage form, oral preparations such as tablets, powders, granules, capsules, emulsions, suspensions, syrups, and parenteral preparations such as suppositories, injections, drops, and external preparations can be used.

The dose varies significantly depending on the degree of symptoms, the age of the patient, the progress of the disease, etc., but is usually 0.
01 mg / kg to 200 mg / kg, preferably 0.05 mg / k
g to 50 mg / kg, more preferably 0.1 to 10 mg / kg
Can be administered once or several times a day.

For formulation, a usual formulation carrier is used, and this can be done by a conventional method in the art. That is, in the case of producing an oral solid preparation, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the main drug, and then the tablet is prepared according to a conventional method. , Powders, granules, capsules, coated preparations, etc. As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, etc. are used. As the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth,
Gelatin, shellac, hydroxypropyl starch,
Polyvinylpyrrolidone or the like is used. Examples of the disintegrant include starch, agar, powdered gelatin, crystalline cellulose,
Calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like are used. As the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil and the like are used. As the colorant, those permitted to be added to pharmaceuticals are used. As a flavoring agent and a flavoring agent,
For example, cocoa powder, peppermint oil, peppermint brain, dragon brain, aromatic acid,
For example, cinnamon powder is used. These tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating may be applied. When preparing an injection, if necessary, a pH adjusting agent, a buffer, a stabilizer, a solubilizer, etc. are added to the main ingredient, and subcutaneously, intramuscularly,
Intravenous injection.

[0107]

The present invention will be described in more detail below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited thereto. The proton nuclear magnetic resonance spectra ( ¹ HNMR) of the compounds described in the examples are Hitachi R-
1200 (60MHz) and Varian Unity
Infrared spectrum (I
R) was measured using Jeol IR-810.

Reference Example 1 2,4-dioxo-2H-3,1-benzoxazine-1
Synthesis of (4H) -ethyl acetate Sodium hydride washed with n-hexane (60 in mineral oil
%, 29.4 g) of N, N-dimethylformamide (80
(0 ml) solution was added with isatoic anhydride (100 g) at 0 ° C. and stirred for 30 minutes. Ethyl bromoacetate (8
1.6 ml) was added dropwise at 0 ° C., the mixture was stirred at room temperature overnight, ice water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a residue, which was recrystallized from ethyl acetate to give the desired 2,4-dioxo-2H-3,1. -Benzoxazine-1 (4H) -ethyl acetate (white solid, 105.
9 g) was obtained.

Reference Example 2 [N- (2-carbamoylphenyl) amino] ethyl acetate
Synthesis of Le 2,4-dioxo-2H-3,1-benzoxazine -1
To a solution of (4H) -ethyl acetate (1.0 g) in N, N-dimethylformamide (8 ml) was added dropwise 28% ammonia (1.7 ml) under ice cooling. After stirring at 5 ° C for 30 minutes, 1
N-hydrochloric acid (40 ml) was added and the precipitated crystals were washed successively with water and diethyl ether, and the desired ethyl [N- (2-carbamoylphenyl) amino] acetate (white solid, 0.71) was obtained.
g) was obtained.

Reference Example 3 2,4-dioxo-1,2,3,4-tetrahydroquinazoli
Synthesis of N -1-ethyl acetate A mixture of ethyl [N- (2-carbamoylphenyl) amino] ethyl acetate (0.61 g) and 1,1′-carbonyldiimidazole (0.89 g) was stirred at 130 ° C. for 40 minutes. . The solid obtained by cooling to room temperature was washed with ethanol and the desired 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (white solid, 0.55
g) was obtained.

Reference Example 4 4-[(2,4-dioxothiazolidin-5-yl) me
Synthesis of tyl ] benzenesulfonyl chloride To chlorosulfonic acid (155.8 ml), 5-benzylthiazolidine-2,4-dione (60.43 g) was added little by little at 0 ° C, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was added dropwise to ice water and extracted with methylene chloride. The methylene chloride layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (methylene chloride), followed by methylene chloride-
Recrystallization from n-hexane yielded the desired 4-[(2,4-
Dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride (white powder, 53.28 g, mp. 13
9-141 ° C) was obtained.

Example 1 3- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate (XXXXII
I) and 3- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzyl} -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-1-acetic acid (XXXXI
Synthesis of V) ({2- [N- (4-nitrobenzyl) carbamoyl
Synthesis of ethyl]] phenyl} amino) acetate 2,4-dioxo-2H-3,1-benzoxazine-1
A suspension of (4H) -ethyl acetate (60.0 g), 4-nitrobenzylamine monohydrochloride (45.4 g) and triethylamine (73.8 ml) in toluene (700 ml) was added 10 times.
The mixture was stirred at 0 ° C for 2.5 hours. After cooling to room temperature and filtering impurities, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed successively with 1N hydrochloric acid and saturated brine. The residue obtained by drying over anhydrous sodium sulfate and evaporating the solvent was recrystallized from ethyl acetate-n-hexane to obtain the desired ({2- [N- (4-nitrobenzyl) carbamoyl] phenyl} amino) ethyl acetate. (Yellow solid, 78.01 g) was obtained.

3- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 1-ethyl acetate ({2- [N- (4-nitrobenzyl) carbamoyl]]
Ethyl phenyl} aminoacetate (77.98g) and 1,
A mixture of 1'-carbonyldiimidazole (70.76g) was heated at 130 ° C for 2 hours. The solid obtained by cooling to room temperature was washed with ethanol and the target 3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (light brown solid , 6
0.0 g) was obtained.

3- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline
Synthesis of -1-ethyl acetate 3- (4-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-1-ethyl acetate (60.0 g) was dissolved in a mixed solvent of tetrahydrofuran (1000 ml) and ethanol (500 ml), 10% palladium carbon (6.0 g) was added, and room temperature, hydrogen atmosphere After stirring under below overnight, the reaction solution was filtered through Celite. The residue obtained by concentrating the filtrate is recrystallized from chloroform-n-hexane to give the desired 3- (4-aminobenzyl)-
Obtained 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (pale yellow solid, 53.2 g).

3-{[4- (1-ethoxycarbonyl
Lumethyl-2,4-dioxo-1,2,3,4-tetrahydr
Roquinazolin-3-yl) methyl] phenyl} -2-bu
Synthesis of ethyl lomopropionate 3- (4-aminobenzyl) -2,4-dioxo-1,
To a solution of 2,3,4-tetrahydroquinazoline-1-ethyl acetate (2.30 g) in acetone (35 ml) was added 49% hydrogen bromide (2.20 ml) at 5 ° C or lower, and sodium nitrite (0.50 g) was added. An aqueous solution (3.5 ml) was added dropwise and the mixture was stirred at 5 ° C for 30 minutes. Ethyl acrylate (4.30 ml) was added and copper (I) oxide (90 mg) was added in small amounts at 30 ° C. After the generation of nitrogen was completed, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a residue, which was subjected to silica gel column chromatography (ethyl acetate). -N-
Hexane) to give the desired 3-{[4- (1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-
Ethyl tetrahydroquinazolin-3-yl) methyl] phenyl} -2-bromopropionate (2.36 g) was obtained as a yellow oil.

3- {4-[(2-imidazolidine-
4-on-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-1-
Synthesis of ethyl acetate 3-{[4- (1-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Ethyl (25 ml) suspension of ethyl 3-yl) methyl] phenyl} -2-bromopropionate (2.30 g), thiourea (0.37 g) and sodium acetate (0.40 g) was stirred under reflux for 6 hours. did. The residue obtained by distilling off the solvent is dissolved in chloroform and the insoluble matter is filtered off, and the residue obtained by distilling off the solvent is subjected to silica gel column chromatography (chloroform-methanol) to give the desired 3- {. 4-[(2-imidazolidin-4-one-5-
Iyl) methyl] benzyl} -2,4-dioxo-1,2,
Obtained 3,4-tetrahydroquinazoline-1-ethyl acetate (dark solid, 1.0 g).

3- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-1-
Ethyl acetate and 3- {4-[(2,4-dioxothiazo
Lysin-5-yl) methyl] benzyl} -2,4-dio
Xo-1,2,3,4-tetrahydroquinazoline-1-vinegar
Synthesis of acid 3- {4-[(2-imidazolidin-4-on-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate (1.0
The 2N hydrochloric acid suspension of g) was stirred under reflux for 1 hour. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a residue, which was subjected to silica gel column chromatography (chloroform-methanol). The target 3- {4-[(2,4-dioxothiazolidine-5-
Iyl) methyl] benzyl} -2,4-dioxo-1,2,
3,4-Tetrahydroquinazoline-1-ethyl acetate (XXX
XIII) (white amorphous, 180 mg) and 3- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXIV) (white amorphous, 270 mg) was obtained. It was Also 3- {4-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (XXXXIII) 180 mg was added to tetrahydrofuran-methanol (1: 1 (v / v) 2m
l) It was dissolved in a mixed solvent, 2N aqueous sodium hydroxide solution (0.35 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hr.
The mixture was acidified with 6N hydrochloric acid under ice cooling, and the precipitated solid was subjected to silica gel column chromatography (chloroform-methanol) to target 3- {4-[(2,4-dioxothiazolidin-5-yl) methyl]. Benzyl} -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
1-Acetic acid (XXXXIV) (white amorphous, 100 mg) was obtained. The structural formula and physical property values of this compound are shown below.

[0118]

Embedded image

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.22 (3H, t, J = 7.0Hz), 2.6
9-3.60 (2H, m), 4.13 (2H, q, J =
7.0 Hz), 4.34 (1H, dd, J = 4.0 and 1
0.0Hz), 4.75 (2H, s), 5.12 (2H,
s), 6.68-8.05 (8H, m)

[0120]

[Chemical 51]

NMR (60 MHz, CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 2.75-3.65 (2H,
m), 4.63 (1H, dd, J = 4.6 and 9.6H)
z), 4.87 (2H, s), 5.19 (2H, s), 7.
02-8.35 (8H, m) IR (Nujol); ν (cm ^-1 ) 3475, 312
5, 1733, 1690, 1650, 1630, 160
5

Example 2 3- {3-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate (XXXX
V) and 3- {3-[(2,4-dioxothiazolidine-
5-yl) methyl] benzyl} -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-1-acetic acid (XXXXV
Synthesis of I) ({2- [N- (3-nitrobenzyl) carbamoyl
[Luphenyl] amino) ethyl acetate 2,4-dioxo-2H-in the same manner as in Example 1 reaction.
The objective is to react 3,1-benzoxazine-1 (4H) -ethyl acetate with 3-nitrobenzylamine monohydrochloride ({2- [N- (3-nitrobenzyl) carbamoyl] phenyl} amino). Obtained ethyl acetate.

3- (3-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 1-ethyl acetate In the same manner as in Example 1, the reaction was performed by reacting ethyl ({2- [N- (3-nitrobenzyl) carbamoyl] phenyl} amino) acetate with 1,1′-carbonyldiimidazole. 3- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained. 3- (3-aminobenzyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-1-ethyl acetate
Synthesis of Example 1 In the same manner as in the reaction of Example 1, 3- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was hydrogenated with 10% palladium on carbon. , The desired 3- (3-aminobenzyl)-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained.

3-{[3- (1-ethoxycarbonyl
Lumethyl-2,4-dioxo-1,2,3,4-tetrahydr
Roquinazolin-3-yl) methyl] phenyl} -2-bu
Synthesis of ethyl lomopropionate Example 1 Using ethyl 3- (3-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate in a similar manner to the reaction 3 -{[3
-(1-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)
Methyl] phenyl} -2-bromopropionate ethyl was obtained. 3- {3-[(2-imidazolidin-4-one-5
-Yl) methyl] benzyl} -2,4-dioxo-1,
Of 2,3,4-tetrahydroquinazoline-1-ethyl acetate
Synthetic Example 1 In the same manner as in the reaction, 3-{[3- (1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl) methyl] phenyl} -2-bromopropionate ethyl is reacted with thiourea to obtain the desired 3- {3-[(2-imidazolidine-
4-on-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-
Obtained ethyl acetate.

3- {3-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-1-
Ethyl acetate and 3- {3-[(2,4-dioxothiazo
Lydin-5-yl) methyl] benzyl} -2,4-dio
Xo-1,2,3,4-tetrahydroquinazoline-1-vinegar
Synthesis of acid 3- {3-[(2-imidazolidin-4-on-5-yl) methyl] benzyl} -in the same manner as in the reaction of Example 1.
The target 3- {3-[(2,4-dioxothiazolidin-5-yl) is obtained by hydrolyzing 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate with 2N hydrochloric acid. Methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate (XXXX
V) (white amorphous) and 3- {3-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl}-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXVI) (white amorphous) was obtained. Also, in the same manner as in the reaction of Example 1, 3- {3-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (XXXXV) was hydrolyzed with 2N sodium hydroxide aqueous solution to obtain the purpose. Yes 3- {3-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXVI) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0126]

Embedded image

NMR (60 MHz, CDCl ₃ , CD ₃ O
D, TMS); δ (ppm) 1.28 (3H, t, J = 7)
Hz), 2.62-3.80 (2H, m), 4.23 (2
H, q, J = 7Hz), 4.45 (1H, m), 4.90
(2H, s), 5.23 (2H, s), 6.90-8.4
0 (8H, m) IR (CHCl ₃ ); ν (cm ⁻¹ ) 3375, 175
0, 1730, 1700, 1655, 1610

[0128]

Embedded image

NMR (60 MHz, CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 2.77-3.65 (2H,
m), 4.67 (1H, dd, J = 4 and 10Hz),
4.88 (2H, s), 5.20 (2H, s), 7.00
-8.25 (8H, m) IR ( CHCl 3); ν (cm -1) 3500,317
5, 1770, 1755, 1690, 1640, 161
0

(Example 3) 1- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-3-ethyl acetate (XXXXVI
I) and 1- {4-[(2,4-dioxothiazolidine
-5-yl) methyl] benzyl} -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-3-acetic acid (XXX
XVIII) Synthesis N- (2-aminobenzoyl) glycine ethyl ether
Synthesis of Stell 13 suspensions of isatoic anhydride (11.93 g), glycine ethyl ester hydrochloride (10.21 g), and triethylamine (22.40 ml) in toluene (200 ml) were added.
Stir at 0 ° C. for 3.5 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline. The residue obtained by drying over anhydrous magnesium sulfate and distilling off the solvent was recrystallized from ethyl acetate-n-hexane to obtain the desired N
-(2-Aminobenzoyl) glycine ethyl ester (pale yellow solid, 12.38 g) was obtained. 2,4-dioxo-1,2,3,4-tetrahydro
Synthesis of quinazoline-3-ethyl acetate In the same manner as in Example 1, the reaction was carried out by reacting N- (2-aminobenzoyl) glycine ethyl ester with 1,1'-carbonyldiimidazole, which was the target 2,4-dioxo-.
Obtained 1,2,3,4-tetrahydroquinazoline-3-ethyl acetate.

1- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 3-ethyl acetate Sodium hydride washed with n-hexane (60 in mineral oil
%, 0.35 g) of N, N-dimethylformamide (15
ml), 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate (2.0 g) was added at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-nitrobenzyl bromide (1.92 g) in N, N-dimethylformamide (5 ml) was added dropwise to this mixture at 0 ° C., the mixture was stirred at room temperature for 1 hr, ice water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a residue, which was recrystallized from ethyl acetate-n-hexane to obtain the desired 1- (4-nitrobenzyl) -2. , 4-Dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate (pale yellow solid, 2.12 g)
I got 1- (4-aminobenzyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-3-ethyl acetate
Synthesis of 1- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate was hydrogenated with 10% palladium on carbon in the same manner as in the reaction of Example 1. , The desired 1- (4-aminobenzyl)-
Obtained 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate as a yellow solid.

3-{[4- (3-ethoxycarbonyl
Lumethyl-2,4-dioxo-1,2,3,4-tetrahydr
Roquinazolin-1-yl) methyl] phenyl} -2-bu
Synthesis of ethyl lomopropionate Example 1 Using ethyl 1- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate in a similar manner to the reaction 3 -{[4
-(3-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)
Ethyl methyl] phenyl} -2-bromopropionate was obtained as a yellow oil. 1- {4-[(2-imidazolidin-4-one-5
-Yl) methyl] benzyl} -2,4-dioxo-1,
Of 2,3,4-tetrahydroquinazoline-3-ethyl acetate
Synthesis Example 1 In the same manner as in the reaction, 3-{[4- (3-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-1-yl) methyl] phenyl} -2-bromopropionate ethyl is reacted with thiourea to obtain 1- {4-[(2-imidazolidine-
4-on-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Ethyl acetate was obtained as a white powder.

1- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-3-
Ethyl acetate and 1- {4-[(2,4-dioxothiazo
Lydin-5-yl) methyl] benzyl} -2,4-dio
Xo-1,2,3,4-tetrahydroquinazoline-3-vinegar
Synthesis of acid 1- {4-[(2-imidazolidin-4-on-5-yl) methyl] benzyl} -in the same manner as in the reaction of Example 1.
The target 1- {4-[(2,4-dioxothiazolidin-5-yl) is obtained by hydrolyzing 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate with 2N hydrochloric acid. Methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-3-ethyl acetate (XXXXVI
I) (white amorphous) and 1- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl}-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-3-acetic acid (XXXXVIII) (white amorphous) was obtained. In addition, 1- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate (XXXXVII) was added to 2
1-by hydrolyzing with an aqueous solution of sodium hydroxide N
{4-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzyl} -2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline-3-acetic acid (XXXXVIII) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0134]

[Chemical 54]

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.30 (3H, t, J = 7Hz), 3.07
(1H, dd, J = 9 and 14Hz), 3.54 (1
H, dd, J = 4 and 14 Hz), 4.26 (2H,
q, J = 7 Hz), 4.50 (1H, dd, J = 4 and
9Hz), 4.91 (2H, s), 5.38 (2H, s),
7.05-8.35 (8H, ArH) IR ( CHCl 3); ν (cm -1) 1760,171
0, 1660

[0136]

[Chemical 55]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.08 (1H, dd,
J = 9.7 and 14.1 Hz), 3.47 (1 H, dd,
J = 3.8 and 14.1 Hz), 3.47 (1 H, dd,
J = 3.8 and 14.1 Hz), 4.43 (1 H, dd,
J = 3.8 and 9.7 Hz), 4.85 (1H, d, J =
16.5Hz), 4.89 (1H, d, J = 16.5Hz),
5.36 (2H, s), 7.09-8.24 (8H, Ar
H) IR (KBr); ν (cm ^-1 ) 1750, 1700, ¹
660

Example 4 1- {3-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-3-ethyl acetate (XXXXI
X) and 1- {3-[(2,4-dioxothiazolidine-
5-yl) methyl] benzyl} -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-3-acetic acid (XXXX
Synthesis of X) 1- (3-nitrobenzyl) -2,4-dioxo-
Synthesis of 2H-3,1-benzoxazine Sodium hydride washed with n-hexane (60 in mineral oil
%, 1.47 g) of N, N-dimethylformamide (40
ml) suspension was added with isatoic anhydride (5.0 g) at 0 ° C. and stirred at room temperature for 30 minutes. A solution of 4-nitrobenzyl bromide (7.95 g) in N, N-dimethylformamide (20 ml) was added to this solution at 0 ° C., the mixture was stirred overnight at room temperature, ice water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue, which was recrystallized from methanol-chloroform to obtain the desired 1- (3-nitrobenzyl)- 2,4-Dioxo-2H-3,1-benzoxazine (white solid, 5.90 g) was obtained.

N- (3-nitrobenzyl) -2-ca
Synthesis of luvamoylaniline 1- (3-nitrobenzyl) -2,4-dioxo-2H
To a solution of -3,1-benzoxazine (5.89 g) in N, N-dimethylformamide (50 ml) was added dropwise 25% ammonia (10 ml) under ice cooling, and the mixture was stirred for 1 hour. 1N Hydrochloric acid was added dropwise to acidify the reaction solution, and the precipitated crystals were collected by filtration to obtain the desired N- (3-nitrobenzyl) -2-carbamoylaniline (pale yellow solid, 5.62 g). This product was used for the next reaction without purification. 1- (3-nitrobenzyl) -2,4-dioxo-
Synthesis of 1,2,3,4-tetrahydroquinazoline Example 1 In the same manner as the reaction, N- (3-nitrobenzyl) -2-carbamoylaniline and 1,1′-carbonyldiimidazole were reacted to form 1- (3-Nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline was obtained.

1- (3-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 3-ethyl acetate Sodium hydride washed with n-hexane (60 in mineral oil
%, 0.85 g) of N, N-dimethylformamide (50
ml) suspension in 1- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (5.1
0 g) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Ethyl bromoacetate (2.30 ml) was added dropwise to this solution at 0 ° C,
Stir overnight at room temperature. Ice water was added, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography to obtain the desired 1- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate. (Yellow solid, 4.80 g) was obtained. 1- (3-aminobenzyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-3-ethyl acetate
Synthesis of 1- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate was hydrogenated with 10% palladium on carbon in a similar manner to the reaction of Example 1. The desired 1- (3-aminobenzyl) -2,
4-Dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate was obtained.

3-{[3- (3-ethoxycarbonyl
Lumethyl-2,4-dioxo-1,2,3,4-tetrahydr
Roquinazolin-1-yl) methyl] phenyl} -2-bu
Synthesis of ethyl lomopropionate Example 1 Using ethyl 1- (3-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate in a similar manner to the reaction 3 -{[3
-(3-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)
Ethyl methyl] phenyl} -2-bromopropionate was obtained as a yellow oil. 1- {3-[(2-imidazolin-4-one-5-
Iyl) methyl] benzyl} -2,4-dioxo-1,2,
Combination of 3,4-tetrahydroquinazoline-3-ethyl acetate
In the same manner as in the reaction of Synthesis Example 1, 3-{[3- (3-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-1-yl) methyl] phenyl} -2-bromopropionate ethyl is reacted with thiourea to obtain 1- {3-[(2-imidazoline-4-
On-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate was obtained.

1- {3-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-3-
Ethyl acetate and 1- {3-[(2,4-dioxothiazo
Lydin-5-yl) methyl] benzyl} -2,4-dio
Xo-1,2,3,4-tetrahydroquinazoline-3-vinegar
Synthesis of acid 1- {3-[(2-imidazolin-4-on-5-yl) methyl] benzyl} -in the same manner as in the reaction of Example 1.
The target 1- {3-[(2,4-dioxothiazolidin-5-yl) is obtained by hydrolyzing 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate with 2N hydrochloric acid. Methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-3-ethyl acetate (XXXXI
X) (white amorphous) and 1- {3-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl}-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-3-acetic acid (XXXXX) (white amorphous) was obtained.
In addition, 1- {3-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-ethyl acetate (XXXXIX) was hydrolyzed with 2N sodium hydroxide aqueous solution to obtain the purpose. Do 1- {3-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetic acid (XXXXX) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0143]

[Chemical 56]

NMR (60 MHz, CDCl ₃ , CD ₃ O
D, TMS); δ (ppm) 1.30 (3H, t, J =
7.0Hz), 2.78-3.70 (2H, m), 4.28
(2H, q, J = 7.0Hz), 4.53 (1H, dd, J
= 4.0 and 9.0 Hz), 4.91 (2H, s), 5.4
1 (2H, s), 6.95-7.83 (7H, m), 8.
23 (1H, dd, J = 1.6 and 7.0 Hz) IR (CHCl ₃ ); ν (cm ⁻¹ ) 3380, 175
5, 1715, 1710, 1670, 1610

[0145]

[Chemical 57]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.08 (1H, dd,
J = 9.5 and 14.1 Hz), 3.41 (1H, dd,
J = 4.0 and 14.1 Hz), 4.46 (1 H, dd,
J = 4.0 and 9.5 Hz), 4.88 (2H, s), 5.
34 (2H, s), 7.02-7.12 (3H, m),
7.18 (1H, t, J = 7.8Hz), 7.22 (1H,
t, J = 7.8Hz), 7.25 (1H, t, J = 8.0H
z), 7.56 (1H, dd, J = 1.6 and 8.0H
z), 8.19 (1H, dd, J = 1.6 and 8.0 Hz) IR (Nujol); ν (cm ⁻¹ ) 3460, 312
0, 1750, 1700, 1655, 1650, 161
0

Example 5 N- {4-[(1-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-3-yl) me
Cyl] phenyl} -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
Synthesis of XXXI) 3- (4-aminobenzyl) synthesized in the reaction of Example 1
To a solution of 2,2-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (1.19 g) in methylene chloride (15 ml) was added 4-[(2,4-dioxothiazolidin-5-yl). ) Methyl] benzenesulfonyl chloride (0.86g) in methylene chloride (5ml) was added at 0 ° C, then N, N-diisopropylethylamine (0.63g).
ml) was added dropwise. After stirring overnight at room temperature, the reaction solution was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (ethyl acetate-n-hexane) to obtain the desired N- {4-[(1-ethoxycarbonylmethyl-2,
4-dioxo-1,2,3,4-quinazolin-3-yl)
Methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXI) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0148]

Embedded image

NMR (400 MHz, CDCl3, TM
S); δ (ppm) 1.29 (3H, t, J = 1.2H
z), 3.10 (1H, dd, J = 4.2 and 13.9H)
z), 3.48 (1H, dd, J = 5.1 and 13.9H)
z), 4.27 (2H, q, J = 7.2Hz), 4.40 (1
H, dd, J = 4.2 and 5.1 Hz), 4.91 (1
H, d, J = 18Hz), 4.92 (1H, d, J = 14H)
z), 4.99 (1H, d, J = 18Hz), 5.45 (1
H, d, J = 14 Hz), 6.65 (1H, brs), 6.
84-8.29 (12H, ArH) IR (KBr); ν (cm ^-1 ) 1750, 1700, ¹
650, 1330, 1160

(Example 6) N- {4-[(1-carboxymethyl-2,4-dioki)
So-1,2,3,4-quinazolin-3-yl) methyl] fu
Phenyl} -4-[(2,4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (XXXXXII)
Synthesis of N- synthesized in Example 5 in the same manner as in the reaction of Example 1.
{4-[(1-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidine-5- (Il) methyl] benzenesulfonamide (XXXX
XII) is hydrolyzed with 2N sodium hydroxide to give the desired N- {4-[(1-carboxymethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (XXXXXII)
(Pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0151]

Embedded image

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.21 (1H, dd,
J = 8.2 and 14.1 Hz), 3.71 (1 H, dd,
J = 4.0 and 14.1), 4.46 (1H, dd, J
= 4.0 and 8.2), 4.84 (2H, d, J = 16.
6Hz), 4.89 (1H, d, J = 16.6Hz), 5.0
8 (1H, d, J = 14.1Hz), 5.24 (1H, d,
J = 14.1Hz), 6.99-7.80 (12H, Ar
H), 8.21 (1H, dd, J = 1.4 and 7.8H
z), 9.06 (1H, s) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660, 1330, 1160

Example 7 N- {3-[(1-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-3-yl) me
Cyl] phenyl} -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
Synthesis of XXXIII) was carried out in the same manner as in Example 5 by the reaction of Example 2 3-
(3-aminobenzyl) -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate and 4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride was reacted with the target N- {3-[(1-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XX
XXXIII) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0154]

Embedded image

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.25 (3H, t, J = 7Hz), 3.22
-3.32 (2H, m), 4.24 (2H, q, J = 7H
z), 4.37-4.61 (1H, m), 4.88 (2H,
s), 5.15 (2H, s), 6.02-8.29 (14
H, m) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
650, 1330, 1160

(Example 8) N- {3-[(1-carboxymethyl-2,4-dioxy)
So-1,2,3,4-quinazolin-3-yl) methyl] fu
Phenyl} -4-[(2,4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (XXXXXIV)
Synthesis of N- synthesized in Example 7 in the same manner as in the reaction of Example 1.
{3-[(1-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidine-5- 2) Nyl) methyl] benzenesulfonamide
Target N- {3- by hydrolyzing with sodium hydroxide
[(1-Carboxymethyl-2,4-dioxo-1,2,
3,4-Quinazolin-3-yl) methyl] phenyl}-
4-[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXIV) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0157]

[Chemical formula 61]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.11 (1H, dd,
J = 9 and 14Hz), 3.39 (1H, dd, J = 4)
and 14.0 Hz), 4.42 (1H, dd, J = 4a)
nd9Hz), 4.88 (2H, s), 5.16 (2H,
s), 7.05-7.32 (8H, m), 7.64-7.7
2 (3H, m), 8.21 (1H, dd, J = 2 and
8Hz), 8.83 (1H, s), 11.22 (1H, br
s) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
650, 1330, 1160

Example 9 N- {4-[(3-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-1-yl) me
Cyl] phenyl} -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
XXXV) was synthesized in the same manner as in Example 5 in the reaction of Example 3 1-
(4-aminobenzyl) -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate and 4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride was reacted to obtain the desired N- {4-[(3-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-1-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XX
XXXV) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0160]

Embedded image

NMR (60 MHz, CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 1.25 (3H, t, J =
7Hz), 2.92-3.55 (2H, m), 4.18
(2H, q, J = 7Hz), 4.28-4.60 (1H,
m), 4.83 (2H, s), 5.22 (2H, s),
6.63-8.30 (12H, m) IR (CHCl ₃ ); ν (cm ⁻¹ ) 3350, 320
0, 1750, 1710, 1690, 1655, 161
0, 1330, 1155

(Example 10) N- {4-[(3-carboxymethyl-2,4-dioki)
So-1,2,3,4-quinazolin-1-yl) methyl] fu
Phenyl} -4-[(2,4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (XXXXXVI)
Of N- synthesized in Example 9 in the same manner as in the reaction of Example 1.
{4-[(3-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-1-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidine-5- 2) Nyl) methyl] benzenesulfonamide
Hydrolyze with sodium hydroxide to obtain the desired N- {4-
[(3-Carboxymethyl-2,4-dioxo-1,2,
3,4-Quinazolin-1-yl) methyl] phenyl}-
4-[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXVI) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0163]

[Chemical formula 63]

NMR (60 MHz, CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 2.76-3.73 (2H,
m), 4.63 (2H, s), 4.82 (1H, dd, J
= 4 and 9 Hz), 5.25 (2H, s), 6.80-
8.25 (12H, ArH) IR (Nujol); ν (cm ^-1 ) 3425, 320
0, 3025, 1745, 1695, 1690, 165
0, 1610, 1330, 1150

Example 11 N- {3-[(3-ethoxycarbonylmethyl-2,4
-Dioxo-1,2,3,4-quinazolin-1-yl) me
Cyl] phenyl} -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
Synthesis of XXXVII)
(3-aminobenzyl) -2,4-dioxo-1,2,3,
4-quinazoline-3-ethyl acetate and 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride are reacted to obtain the desired N- {3-[(3
-Ethoxycarbonylmethyl-2,4-dioxo-1,
2,3,4-quinazolin-1-yl) methyl] phenyl}
-4-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzenesulfonamide (XXXXXVII) (pale yellow amorphous) was obtained. The structural formula and physical property values of this product are shown below.

[0166]

[Chemical 64]

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.28 (3H, t, J = 7Hz), 3.05
-3.90 (2H, m), 4.24 (2H, q, J = 7H
z), 4.30-4.65 (1H, m), 4.85 (2H,
s), 5.25 (2H, s), 6.70-8.35 (12
H, m) IR (CHCl ₃ ); ν (cm ⁻¹ ) 3350, 320
0, 1750, 1710, 1700, 1650, 161
0, 1330, 1155

(Example 12) N- {3-[(3-carboxymethyl-2,4-dioxy)
So-1,2,3,4-quinazolin-1-yl) methyl] fu
Phenyl} -4-[(2,4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (XXXXXVII
N) synthesized in Example 11 in the same manner as in the reaction of Synthesis Example 1 of I).
-{3-[(3-ethoxycarbonylmethyl-2,4-
Dioxo-1,2,3,4-quinazolin-1-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide was added to 2N
Target N- {3- by hydrolyzing with sodium hydroxide
[(3-Carboxymethyl-2,4-dioxo-1,2,
3,4-Quinazolin-1-yl) methyl] phenyl}-
4-[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXVIII) (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0169]

Embedded image

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.13 (1H, dd,
J = 9.2 and 14.1 Hz), 3.43 (1 H, dd,
J = 4.0 and 14.1 Hz), 4.44 (1H, dd,
J = 4.0 and 9.2 Hz), 4.85 (2H, s), 5.
26 (2H, s), 6.95 (1H, t, J = 7.5H
z), 6.97 (1H, s), 7.03 (1H, d, J =
8.4Hz), 7.06 (2H, d, J = 8.4Hz), 7.1
4 (1H, d, J = 7.8Hz), 7.16-7.22 (3
H, m), 7.24 (1H, t, J = 7.1Hz), 7.5
4 (1H, dd, J = 1.7 and 7.1 Hz), 7.64
(2H, d, J = 8.4Hz), 8.22 (1H, dd, J
= 1.7 and 7.8 Hz), 9.25 (1H, s), 11.
45 (1H, s) IR (Nujol); ν (cm ⁻¹ ) 3470, 320
0, 3000, 1745, 1700, 1650, 164
0, 1600, 1330, 1150

Example 13 N- {4-[(1-tert-butoxycarbonylmethyl-
2,4-dioxo-1,2,3,4-quinazolin-3-i
Lu) methyl] phenyl} -4-[(2,4-dioxothio)
Azolidin-5-yl) methyl] benzenesulfonami
Synthesis of dox (XXXXXIX) 2,4-dioxo-2H-3,1-benzoxazine
Synthesis of -1 (4H) -tert-butyl acetate In the same manner as in Reference Example 1, isatoic anhydride and bromoacetic acid tert.
-Butyl ester was reacted to obtain the target 2,4-dioxo-2H-3,1-benzoxazine-1 (4H) -acetate tert-butyl as white crystals.

({2- [N- (4-nitrobenzyl
Ru) carbamoyl] phenyl} amino) acetic acid tert-butyl
Synthesis of 2,4-dioxo-2H-in the same manner as in the reaction of Example 1.
3,1-benzoxazine-1 (4H) -acetic acid tert-
The objective tert-butyl ({2- [N- (4-nitrobenzyl) carbamoyl] phenyl} amino) acetate was obtained by reacting butyl with 4-nitrobenzylamine monohydrochloride. 3- (4-nitrobenzyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-1-acetic acid ter
Synthesis of t-butyl ({2- [N- (4-nitrobenzyl) carbamoyl] phenyl} amino) acetic acid te in the same manner as in the reaction of Example 1.
Reaction of rt-butyl with 1,1'-carbonyldiimidazole to obtain the desired 3- (4-nitrobenzyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-1
-Tert-butyl acetate was obtained.

3- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 1-tert-butyl acetate 3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-tert-butyl acetate 10- Hydrogenation with% palladium on carbon gave the desired 3- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-tert-butyl acetate. N- {4-[(1-tert-butoxycarbonylmethyl
Le-2,4-dioxo-1,2,3,4-quinazoline-3-
Iyl) methyl] phenyl} -4-[(2,4-dioxo
Thiazolidin-5-yl) methyl] benzenesulfon
Synthesis of amide In the same manner as in Example 5, 3- (4-aminobenzyl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid tert-butyl and 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride were reacted with the purpose of N- {4-[(1-te
rt-butoxycarbonylmethyl-2,4-dioxo-1,
2,3,4-quinazolin-3-yl) methyl] phenyl}
-4-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzenesulfonamide (XXXXXIX) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0174]

[Chemical formula 66]

NMR (400 MHz, CDCl ₃ , TM
S); δ (ppm) 1.47 (9H, s), 3.11 (1
H, dd, J = 4.2 and 13.9 Hz), 3.47 (1
H, dd, J = 5.3 and 13.9 Hz), 4.56 (1
H, dd, J = 4.2 and 5.3 Hz), 4.81 (1
H, d, J = 17.7 Hz), 4.88 (1H, d, J = 1)
7.7 Hz), 4.93 (1H, d, J = 14.3 Hz), 5.
43 (1H, d, J = 14.4 Hz), 6.72-6.78
(1H, m), 6.86 (2H, d, J = 8.4Hz),
6.99 (1H, d, J = 8.4Hz), 7.18 (2H,
d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4H)
z), 7.31 (2H, t, J = 7.7Hz), 7.54 (2
H, d, J = 8.4 Hz), 7.67 (1H, dd, J =
1.6 and 7.3 Hz), 7.69 (1H, dd, J = 1.
6 and 7.3 Hz, 8.26 (1H, dd, J = 1.4)
and 7.7 Hz), 9.58 (1 H, s) IR (Nujol); ν (cm ^-1 ) 3550, 320
0, 1740, 1700, 1660, 1650, 161
0, 1330, 1155

Example 14 N- {4-[(6-chloro-1-ethoxycarbonylme
Chill-2,4-dioxo-1,2,3,4-quinazoline-3
-Yl) methyl] phenyl} -4-[(2,4-dioki
Sothiazolidin-5-yl) methyl] benzenesulfone
Synthesis of amides (XXXXXX) 6-chloro-2,4-dioxo-2H-3,1-ben
Synthesis of zooxazine-1 (4H) -ethyl acetate In the same manner as in Reference Example 1, 5-chloroisatoic anhydride was reacted with ethyl bromoacetate to obtain the desired 6-chloro-2,4.
-Dioxo-2H-3,1-benzoxazine-1 (4
H) -ethyl acetate was obtained.

({6-chloro-2- [N- (4-ni
Trobenzyl) carbamoyl] phenyl} amino) acetic acid
Synthesis of ethyl 6-chloro-2,4-dioxo-2H-3,1-benzoxazine-1 (4H) -in the same manner as in the reaction of Example 1.
Ethyl acetate was reacted with 4-nitrobenzylamine · hydrochloride to obtain the desired ethyl ({6-chloro-2- [N- (4-nitrobenzyl) carbamoyl] phenyl} amino) acetate. 3- (4-nitrobenzyl) -6-chloro-2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 1-ethyl acetate ({6-chloro-2- [N
3- (4-Nitrobenzyl) carbamoyl] phenyl} amino) ethyl acetate is reacted with 1,1′-carbonyldiimidazole to obtain the target 3- (4-nitrobenzyl) -6.
-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained as a milky white solid.

3- (4-aminobenzyl) -6-qua
Lolo-2,4-dioxo-1,2,3,4-tetrahydroxy
Synthesis of nazoline-1-ethyl acetate In the same manner as in the reaction of Example 1, 3- (4-nitrobenzyl) -6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate Is hydrogenated with 10% palladium on carbon to give the desired 3- (4-aminobenzyl) -6-chloro-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline-1-ethyl acetate was obtained as a milky white solid. N- {4-[(6-chloro-1-ethoxycarbonyl
Lumethyl-2,4-dioxo-1,2,3,4-quinazoline
-3-yl) methyl] phenyl} -4-[(2,4-di
Oxothiazolidin-5-yl) methyl] benzenesul
Synthesis of phonamide 3- (4-aminobenzyl) -6 in the same manner as in Example 5.
-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate reacted with 4-[(2,4-dioxothiazolin-5-yl) methyl] benzenesulfonyl chloride N- {4-[(6-chloro-1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2, 4-dioxothiazolidine-5
-Yl) methyl] benzenesulfonamide (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0179]

Embedded image

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.27 (3H, t, J = 7Hz), 2.95
-3.70 (2H, m), 4.23 (2H, q, J = 7H
z), 4.47 (1H, dd, J = 4 and 9Hz), 4.
87 (2H, s), 5.25 (2H, s), 6.75-
8.20 (11H, ArH) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1750, 170
0, 1660, 1350, 1160

Example 15 N- {4-[(6-chloro-1-carboxymethyl-
2,4-dioxo-1,2,3,4-quinazolin-3-i
Lu) methyl] phenyl} -4-[(2,4-dioxothio)
Azolidin-5-yl) methyl] benzenesulfonami
Synthesis of N- (XXXXXXI) N-synthesized in Example 14 in the same manner as in Example 1 reaction.
{4-[(6-Chloro-1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxo Thiazolidin-5-yl) methyl] benzenesulfonamide is hydrolyzed with 2N sodium hydroxide to give the desired N-
{4-[(6-chloro-1-carboxymethyl-2,4
-Dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XX
XXXXI) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0182]

[Chemical 68]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.19 (1H, dd,
J = 8.6 and 14.1 Hz), 3.40 (1 H, dd,
J = 4.0 and 14.1 Hz), 4.46 (1 H, dd,
J = 4.0 and 8.6 Hz), 4.84 (2H, s), 5.
08 (1H, d, J = 14.1Hz), 5.20 (1H,
d, J = 14.1 Hz), 6.99-7.70 (11H, A
rH), 8.16 (1H, d, J = 2.6 Hz), 9.31
(1H, s) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660, 1330, 1160

Example 16 N- {4-[(7-chloro-1-ethoxycarbonylme
Chill-2,4-dioxo-1,2,3,4-quinazoline-3
-Yl) methyl] phenyl} -4-[(2,4-dioki
Sothiazolidin-5-yl) methyl] benzenesulfone
Synthesis of amide (XXXXXXII) Synthesis of 4-chloro-2-nitrobenzoyl chloride 4-Chloro-2-nitrobenzoic acid (10 g) was dissolved in thionyl chloride (14.5 ml) and stirred under reflux for 1.5 hours. Thionyl chloride was distilled off under reduced pressure to obtain the desired 4-
Obtained chloro-2-nitrobenzoyl chloride. This product was used for the next reaction without purification. Synthesis of 4-chloro-2-nitrobenzamide 10% reaction solution was added to 28% ammonia (25 ml) under ice cooling.
4-Chloro-2-nitrobenzoyl chloride was added keeping the temperature below ℃. After stirring at room temperature for 1 hour, the insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain the desired 4-chloro-2-
Obtained nitrobenzamide. This product was used for the next reaction without purification.

2-Amino-4-chlorobenzamide
Synthesis of 4-chloro-2-nitrobenzamide (1.0 g) was dissolved in ethanol (20 ml), and a solution of tin (II) chloride dihydrate (4.5 g) in ethanol (10 ml) was added dropwise.
After stirring under reflux for 4.5 hours, the solvent was evaporated and the resulting residue was added with water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was subjected to silica gel column chromatography (chloroform-methanol) to obtain the desired 2-amino-4-chlorobenzamide (0.68 g) as a pale yellow solid. [N- (4-chloro-2-carbamoylphenyl)
Synthesis of amino] ethyl acetate 2-amino-4-chlorobenzamide (3.82 g),
Ethyl bromoacetate (2.98 ml) and potassium carbonate (7.7
A solution of 9 g) of N, N-dimethylformamide (15 ml) was stirred at 80 ° C for 5.5 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 2N hydrochloric acid, water and saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (chloroform-methanol) to give the desired product [N-
Ethyl (4-chloro-2-carbamoylphenyl) amino] acetate (3.11 g) was obtained.

7-chloro-2,4-dioxo-1,
Of 2,3,4-tetrahydroquinazoline-1-ethyl acetate
Synthesis Example 1 [N- (4-chloro-2-
Carbamoylphenyl) amino] ethyl acetate and 1,1′-
Targeted 7- by reacting with carbonyldiimidazole
Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained. 3- (4-nitrobenzyl) -7-chloro-2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 1-ethyl acetate In the same manner as in Example 3, the reaction was conducted by reacting 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate with 4-nitrobenzyl chloride. 3- (4-nitrobenzyl) -7-chloro-2,
4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained.

3- (4-aminobenzyl) -7-ku
Lolo-2,4-dioxo-1,2,3,4-tetrahydroxy
Synthesis of nazoline-1-ethyl acetate 3- (4-nitrobenzyl) -7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-
Ethyl acetate (1.81 g) was dissolved in ethanol (20 ml) and tin (II) chloride dihydrate (2.46 g) was added under ice cooling.
Of ethanol (10 ml) was added dropwise. After stirring under reflux for 5 hours, the solvent was distilled off, water was added to the residue, the mixture was neutralized with sodium hydrogen carbonate under ice cooling, ethyl acetate was added, and the insoluble matter was collected by filtration. Was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography (chloroform-methanol) to give the desired 3
There was obtained-(4-aminobenzyl) -7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (yellow solid, 1.22 g).

N- {4-[(7-chloro-1-eth
Xycarbonylmethyl -2,4-dioxo-1,2,3,4
-Quinazolin-3-yl) methyl] phenyl} -4-
[(2,4-Dioxothiazolidin-5-yl) methyi
Synthesis of 3- [4-aminobenzyl) -7 in the same manner as in Example 5.
-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate reacted with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride N- {4-[(7-
Chloro-1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl]
Phenyl} -4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide (XXXXXXI
I) (pale yellow amorphous) was obtained. The structural formula and physical property values of this product are shown below.

[0189]

[Chemical 69]

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.27 (3H, t, J = 7Hz), 2.95
-3.70 (2H, m), 4.23 (2H, q, J = 7H
z), 4.47 (1H, dd, J = 4 and 9Hz), 4.
87 (2H, s), 5.25 (2H, s), 6.75 ~
8.20 (11H, ArH)

Example 17 N- {4-[(7-chloro-1-carboxymethyl-
2,4-dioxo-1,2,3,4-quinazolin-3-i
Lu) methyl] phenyl} -4-[(2,4-dioxothio)
Azolidin-5-yl) methyl] benzenesulfonami
Synthesis of Example (XXXXXXIII) N-synthesized in Example 16 in the same manner as in the reaction of Example 1.
{4-[(7-Chloro-1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxo Thiazolidin-5-yl) methyl] benzenesulfonamide is hydrolyzed with 2N sodium hydroxide to give the desired N-
{4-[(7-chloro-1-carboxymethyl-2,4
-Dioxo-1,2,3,4-quinazolin-3-yl) methyl] phenyl} -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (white amorphous) was obtained. . The structural formula and physical property values of this product are shown below.

[0192]

Embedded image

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 3.19 (1H, dd,
J = 8.6 and 14.1 Hz), 3.40 (1 H, dd,
J = 4.0 and 14.1 Hz), 4.46 (1 H, dd,
J = 4.0 and 8.6 Hz), 4.84 (2H, s), 5.
08 (1H, d, J = 14.1Hz), 5.20 (1H,
d, J = 14.1 Hz), 6.99-7.70 (11H, A
rH), 8.16 (1H, d, J = 2.56Hz), 9.3
1 (1H, s) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660, 1320, 1160

(Example 18) 3- (4-{[4- (2,4-dioxothiazolidine-
5-yl) methyl] styryl} benzyl) -2,4-di
Oxo-1,2,3,4-tetrahydroquinazoline-1-
Ethyl acetate (XXXXXXIV) and 3- (4-{[4- (2,
4-dioxothiazolidin-5-yl) methyl] stilly
Ru} benzyl) -2,4-dioxo-1,2,3,4-teto
Synthesis of lahydroquinazoline-1-acetic acid (XXXXXXV) Synthesis of diethyl 4-nitrobenzylphosphonate 4-nitrobenzyl bromide (10 g) and triethyl phosphite (9.0 ml) were stirred at 130 ° C. for 3 hours and then released. It was cooled, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the desired diethyl 4-nitrobenzylphosphonate. This product was used for the next reaction without purification. 4-methoxycarbonyl-4'-nitrostilbene
Synthesis of Diethyl 4-nitrobenzylphosphonate (30 ml) in dimethylformamide (7.3 g) was added dropwise to a dimethylformamide (25 ml) solution under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was recrystallized from ethyl acetate-n-hexane to obtain the desired 4-methoxycarbonyl-4′-nitrostilbene (4.6 g).

4-hydroxymethyl-4′-nitro
Synthesis of stilbene 4-methoxycarbonyl-4'-nitrostilbene (4.
Diisobutylaluminum hydride (1.5M toluene solution, 30 ml) was added dropwise to a solution of 55 g) in toluene (200 ml) and tetrahydrofuran (200 ml) at -70 ° C. After stirring overnight at room temperature, methanol is added to decompose excess diisobutylaluminum hydride and further 2
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (ethyl acetate-n-hexane) to give the desired 4- Hydroxymethyl-4′-nitrostilbene (4.3 g) was obtained. Synthesis of 4- chloromethyl-4'-nitrostilbene 4-hydroxymethyl-4'-nitrostilbene (4.3
g) was dissolved in N, N-dimethylformamide (50 ml), and lithium chloride (0.86 g) was added under ice-cooling, and 2,
4,6-collidine (3.4 ml) was added dropwise. Further, mesyl chloride (1.6 ml) was added dropwise, and the mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate-n-hexane). Objective 4
-Chloromethyl-4'-nitrostilbene (4.2g) was obtained.

3- [4- (4-nitrostyryl) be
]]-2,4-Dioxo-1,2,3,4-tetrahydr
Synthesis of Roquinazoline-1-ethyl acetate 2,4-Dioxo-1,2 ,
3,4-Tetrahydroquinazoline-1-ethyl acetate and 4
3- [4- (4-nitrostyryl) benzyl] to be reacted with -chloromethyl-4'-nitrostilbene
-2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained. 3- [4- (4-aminostyryl) benzyl]-
2,4-dioxo-1,2,3,4-tetrahydroquinazoli
Synthesis of 3--1-ethyl acetate 3- [4- (4-nitrostyryl) benzyl] -2,4-dioxo-1,2,3,4 in a similar manner to the reaction of Example 16.
-Tetrahydroquinazoline-1-ethyl acetate was reduced with tin (II) chloride dihydrate to give the desired 3- [4- (4-
Aminostyryl) benzyl] -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-1-ethyl acetate was obtained.

3- (4-{[4- (1-ethoxyca
Lubonyl-2,4-dioxo-1,2,3,4-tetrahydr
Roquinazolin-3-yl) methyl] styryl} phenyl
Synthesis of ethyl) -2-bromopropionate 3- [4- (4-aminostyryl) benzyl] -2,4-dioxo-1,2,3,4-
Using tetrahydroquinazoline-1-ethyl acetate, the target 3- (4-{[4- (1-ethoxycarbonyl-
Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) methyl] styryl} phenyl) -2-bromopropionate was obtained as a yellow oil. 3- (4-{[4- (2-imidazolin-4-one
-5-yl) methyl] styryl} benzyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-1
-Synthesis of ethyl acetate In the same manner as in the reaction of Example 1, 3- (4-{[4- (1-
Ethoxycarbonyl-2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl) methyl] styryl} phenyl) -2-bromopropionate ethyl and thiourea are reacted to obtain the desired 3- (4-{[4- (2-imidazolin-4-one-5-yl ) Methyl] styryl}
Benzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was obtained as a light brown solid.

3- (4-{[4- (2,4-dioki
Sothiazolidin-5-yl) methyl] styryl} benzi
Le) -2,4-dioxo-1,2,3,4-tetrahydroxy
Nazolin-1-ethyl acetate and 3- (4-{[4-
(2,4-Dioxothiazolidin-5-yl) methyl]
Styryl} benzyl) -2,4-dioxo-1,2,3,4
Synthesis of -tetrahydroquinazoline-1-acetic acid 3- (4-{[4- (2-
Imidazoline-4-on-5-yl) methyl] styryl} benzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate is hydrolyzed with 2N hydrochloric acid to give the desired 3- (4-{[4- (2,4-Dioxothiazolidin-5-yl) methyl] styryl} benzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (XXXXXXIV ) (White amorphous) and 3- (4-{[4- (2,4-dioxothiazolidin-5-yl) methyl] styryl} benzyl)-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXXXV) (white amorphous) was obtained. Also, in the same manner as in the reaction of Example 1, 3- (4-{[4-
(2,4-Dioxothiazolidin-5-yl) methyl]
Styryl} benzyl) -2,4-dioxo-1,2,3,4
-Tetrahydroquinazoline-1-ethyl acetate (XXXXXXI
V) is hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 3- (4-{[4- (2,4-dioxothiazolidin-5-yl) methyl] styryl} benzyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
1-Acetic acid (XXXXXXV) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0199]

Embedded image

NMR (60 MHz, CDCl ₃ , CD ₃ 0
D, TMS); δ (ppm) 1.27 (3H, t, J = 7)
Hz), 2.70-3.53 (2H, m), 4.23 (2
H, q, J = 7Hz), 4.50 (1H, dd, J = 4a
nd12Hz), 4.90 (2H, s), 5.27 (2H,
s), 6.73-7.90 (13H, m), 8.26 (1
H, dd, J = 8 and 1.6Hz)

[0201]

Embedded image

NMR (400 MHz, DMSO-d ₆ , TM
S); δ (ppm) 3.10-3.23 (1H, m), 3.
35-3.45 (1H, m), 4.90 (2H, s),
4.82-5.05 (1H, m), 5.10 (2H,
s), 6.79 (1H, d, J = 16Hz), 7.26-
7.36 (5H, m), 7.40 (1H, d, J = 8.6H
z), 7.54 (1H, d, J = 16Hz), 7.56 (2
H, d, J = 8.2 Hz), 7.63 (2H, d, J = 8.
2Hz), 7.77 (1H, t, J = 8.6Hz), 8.12
(1H, d, J = 7.8Hz), 10.18 (1H, s),
11.95-12.20 (1H, brs) IR (Nujol); ν (cm ^-1 ) 3475, 315
0, 1760, 1740, 1700, 1680, 165
0,1610

(Example 19) 3- [4- (4- {2- [4- (2,4-dioxothia
Zolidine-5-yl) methyl] phenyl} ethyl) ben
Zil] -2,4-dioxo-1,2,3,4-tetrahydro
Quinazoline-1-ethyl acetate (XXXXXXVI) and 3- [4
-(4- {2- [4- (2,4-dioxothiazolidine
-5-yl) methyl] phenyl} ethyl) benzyl]-
2,4-dioxo-1,2,3,4-tetrahydroquinazoli
Synthesis of benzene-1-acetic acid (XXXXXXVII) 3- {4- [2- (4-aminophenyl) ethyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahi
Synthesis of Droquinazoline-1-ethyl acetate 3- [4- (4-nitrostyryl) benzyl] -2,4-dioxo-1,2,3,4-synthesized by the reaction of Example 18
Tetrahydroquinazoline-1-ethyl acetate (1.0 g)
10% Palladium on carbon (0.1 g) was added to a tetrahydrofuran (30 ml) solution of, and the mixture was stirred overnight in an autoclave under a hydrogen atmosphere (hydrogen pressure 5 kg / cm ² ) at room temperature. After filtration and removal of palladium carbon, the solvent of the obtained filtrate is distilled off and the resulting residue is subjected to silica gel column chromatography (ethyl acetate-n-hexane) to give the desired 3-
{4- [2- (4-Aminophenyl) ethyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (0.85 g) was obtained.

3- (4- {2- [4- (1-etoki
Cycarbonyl-2,4-dioxo-1,2,3,4-tetra
Hydroquinazolin-3-yl) methyl] phenyl} ethyl
Synthesis of ethyl phenyl-2-bromopropionate 3- {4- [2- (4-aminophenyl) ethyl] benzyl} -2,4-dioxo-1,2,3 in the same manner as in Example 1 reaction The target 3- (4- {2- [4- (1-ethoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3 was obtained by using 1,4-tetrahydroquinazoline-1-ethyl acetate. -Yl) methyl] phenyl}
Ethyl) ethyl phenyl-2-bromopropionate was obtained as a yellow oil. 3- [4- (4- {2- [4- (2-imidazoline
-4-on-5-yl) methyl] phenyl} ethyl)
]]-2,4-Dioxo-1,2,3,4-tetrahydr
Synthesis of roquinazoline-1-ethyl acetate 3- (4- {2- [4-
(1-Ethoxycarbonyl-2,4-dioxo-1,2,
3,4-Tetrahydroquinazolin-3-yl) methyl]
Styryl} phenyl) -2-bromopropionate ethyl and thiourea are reacted to obtain the desired 3- [4- (4- {2
-[4- (2-Imidazolin-4-one-5-yl) methyl] phenyl} ethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate is light brown Obtained as a solid.

3- [4- (4- {2- [4- (2,
4-dioxothiazolidin-5-yl) methyl] phenyl
Ru} ethyl) benzyl] -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline-1-ethyl acetate and 3-
[4- (4- {2- [4- (2,4-dioxothiazoli
Zin-5-yl) methyl] phenyl} ethyl) benz
]]-2,4-Dioxo-1,2,3,4-tetrahydroxy
Synthesis of nazoline-1-acetic acid 3- [4- (4- {2-
[4- (2-Imidazolin-4-on-5-yl) methyl] phenyl} ethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate with 2N hydrochloric acid The desired 3- [4- (4
-{2- [4- (2,4-dioxothiazolidine-5-
Iyl) methyl] phenyl} ethyl) benzyl] -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline-
1-ethyl acetate (XXXXXXVI) (white amorphous) and 3- [4- (4- {2- [4- (2,4-dioxothiazolidin-5-yl) methyl] phenyl} ethyl) benzyl] -2, 4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXXXVII) (white amorphous) was obtained. Further, in the same manner as in the reaction of Example 1, 3- [4
-(4- {2- [4- (2,4-dioxothiazolidin-5-yl) methyl] phenyl} ethyl) benzyl]-
2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (XXXXXXVI) is hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 3- [4- (4- {2
-[4- (2,4-dioxothiazolidin-5-yl)
Methyl] phenyl} ethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetic acid (XXXXXXVII) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0206]

Embedded image

NMR (60 MHz, CDCl ₃ , TMS);
δ (ppm) 1.27 (3H, t, J = 8Hz), 2.07
(2H, s), 2.85 (2H, s), 2.95-3.4
8 (2H, m), 4.23 (2H, q, J = 8Hz), 4.
32-4.65 (1H, m), 4.90 (2H, s),
5.20 (2H, d, J = 6Hz), 6.75-7.82
(11H, m), 8.25 (1H, d, J = 8Hz), 8.
45-9.00 (1H, br)

[0208]

[Chemical 74]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 2.53-2.67 (2
H, m), 2.92-3.12 (3H, m), 3.47
(1H, dd, J = 4 and 14Hz), 4.43 (1
H, dd, J = 4 and 9 Hz), 4.87 (2H,
s), 5.23 (2H, s), 7.04 (1H, d, J =
8Hz), 7.08-7.22 (4H, m), 7.25 (1
H, t, J = 8Hz), 7.64 (1H, t, J = 8H
z), 8.21 (1H, d, J = 8Hz), 8.48-8.7
0 (1H, brs), 11.5 (1H, s) IR (Nujol); ν (cm ^-1 ) 3360, 324
0, 1760, 1740, 1700, 1670, 165
0

(Example 20) N- [4- (1-ethoxycarbonylmethyl-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-3
-Yl) butyl] -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
XXXXVIII) Synthesis 3- (3-cyanopropyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline-1-ethyl acetate
Washed sodium hydride in Synthesis n- hexane Le (in mineral oil 60
%, 0.97 g) of N, N-dimethylformamide (40
ml), a solution of 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate in N, N-dimethylformamide (20 ml) was added dropwise to the suspension under ice cooling and the mixture was stirred at room temperature for 3 times.
Stir for 0 minutes. A solution of 4-bromobutyronitrile (2.98 g) in N, N-dimethylformamide (10 ml) was added dropwise to this reaction solution under ice cooling, and the mixture was stirred at room temperature for 5 hours. Water was added, the mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (ethyl acetate-n-hexane). Objective 3-
(3-Cyanopropyl) -2,4-dioxo-1,2,3,
4-Tetrahydroquinazoline 1-ethyl acetate (white powder, 4.50 g) was obtained.

3- (4-aminobutyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-1
-Synthesis of ethyl acetate 3- (3-cyanopropyl) -2,4-dioxo-1,
2,3,4-Tetrahydroquinazoline-1-ethyl acetate (4.50 g) was added to ammonia saturated ethanol (30 ml).
Raney nickel W-2 (0.5 g) was added, and the mixture was stirred overnight in an autoclave under a hydrogen atmosphere (hydrogen pressure 5 kg / cm ² ) at room temperature. The catalyst is removed and washed with ethanol, the solvent is distilled off, and the target 3- (4-aminobutyl) -2,
4-Dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate (2.73 g) was obtained. This compound was used in the next reaction without purification. N- [4- (1-ethoxycarbonylmethyl-2,
4-dioxo-1,2,3,4-tetrahydroquinazoline
-3-yl) butyl] -4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzenesulfonamide
In the same manner as in Synthesis Example 5 of 3- (4-aminobutyl) -2,
4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was reacted with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride to obtain the desired N- [ 4- (1-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) butyl] -4-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXXVIII) (white amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0212]

[Chemical 75]

NMR (400 MHz, CDCl ₃ , TM
S); δ (ppm) 1.29 (3H, t, J = 8Hz),
1.35-1.60 (4H, m), 3.02-3.07 (2
H, m), 3.36 (1H, dd, J = 6 and 15H
z), 3.42 (1H, dd, J = 7 and 15Hz),
3.91-4.03 (2H, m), 4.17 (2H, q,
J = 8 Hz), 4.59 (1H, dd, J = 6 and
7), 4.78 (1H, t, J = 6Hz), 4.86 (1
H, d, J = 18Hz), 4.91 (1H, d, J = 18H)
z), 6.96-8.24 (8H, ArH)

(Example 21) N- [4- (1-carboxymethyl-2,4-dioxo)
-1,2,3,4-tetrahydroquinazoline-3-i
Ru) butyl] -4-[(2,4-dioxothiazolidine
-5-yl) methyl] benzenesulfonamide (XXXXXX
Synthesis of IX) N- [4- (1-ethoxycarbonylmethyl-2,4) synthesized by the reaction of Example 20 in the same manner as the reaction of Example 1.
-Dioxo-1,2,3,4-tetrahydroquinazoline-
3-yl) butyl] -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide is hydrolyzed with 2N sodium hydroxide to give the desired N- [4
-(1-carboxymethyl-2,4-dioxo-1,2,
3,4-Tetrahydroquinazolin-3-yl) butyl]
-4-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzenesulfonamide (pale yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0215]

[Chemical 76]

NMR (400 MHz, CDCl ₃ , DMSO
-D ₆ , TMS); δ (ppm) 1.50-1.56 (2
H, m), 1.64-1.69 (2H, m), 2.90-
2.95 (2H, m), 3.18 (1H, dd, J = 9.
5 and 14.1 Hz), 3.52 (1 H, dd, J = 3.
8 and 14.1 Hz), 4.00-4.04 (2H,
m), 4.50 (1H, dd, J = 3.8 and 9.5H)
z), 4.86 (2H, s), 6.58 (1H, t, J =
6Hz), 7.05 (1H, d, J = 8.2Hz), 7.24
-7.28 (1H, m), 7.36-7.39 (2H,
m), 7.63-7.68 (1H, m), 7.79-7.8
2 (2H, m), 8.18-8.20 (1H, m) IR (KBr); ν (cm ⁻¹ ) 1750, 1700,
1650, 1330, 1160

(Example 22) N- [2- (1-ethoxycarbonylmethyl-2,4-)
Dioxo-1,2,3,4-tetrahydroquinazoline-3
-Yl) ethyl] -4-[(2,4-dioxothiazolyl
Zin-5-yl) methyl] benzenesulfonamide (XX
XXXXX) 3-cyanomethyl-2,4-dioxo-1,2,3,4
Synthesis of -tetrahydroquinazoline-1-ethyl acetate 2,4-dioxo-1, in the same manner as in the reaction of Example 20.
Ethyl 2,3,4-tetrahydroquinazoline-1-ethyl acetate was reacted with chloroacetonitrile to obtain the target 3-cyanomethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate. .

3- (2-aminoethyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-1
-Synthesis of ethyl acetate 3-cyanomethyl-2, in the same manner as in Example 20 reaction
4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate was reduced with Raney nickel W-2 to give the desired 3- (2-aminoethyl) -2,4-dioxo-
1,2,3,4-Tetrahydroquinazoline-1-ethyl acetate was obtained. This compound was used in the next reaction without purification. N- [2- (1-ethoxycarbonylmethyl-2,
4-dioxo-1,2,3,4-tetrahydroquinazoline
-3-yl) ethyl] -4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzenesulfonamide
In the same manner as in Synthesis Example 5 of 3- (4-aminoethyl) -2,
4-dioxo-1,2,3,4-tetrahydroquinazoline-1-ethyl acetate is reacted with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride to give the desired N- [ 2- (1-Ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) ethyl] -4-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXXX) was obtained. The structural formula and physical property values of this compound are shown below.

[0219]

Embedded image

NMR (400 MHz, CDCl ₃ , TM
S); δ (ppm) 1.33 (3H, t, J = 8Hz),
3.13 (1H, dd, J = 8 and 14Hz), 3.34
(1H, dd, J = 4 and 14Hz), 3.35-3.3
9 (2H, m), 4.07-4.20 (2H, m), 4.
28 (2H, q, J = 8Hz), 4.46 (1H, dd,
J = 4 and 8Hz), 4.82 (1H, d, J = 20H
z), 4.89 (1H, d, J = 20Hz), 4.34 (1
H, t, J = 7 Hz), 6.95-8.17 (8H, m)

(Example 23) N- [2- (1-carboxymethyl-2,4-dioxo)
-1,2,3,4-tetrahydroquinazolin-3-yl)
Ethyl] -4-[(2,4-dioxothiazolidine 5-
Of (yl) methyl] benzenesulfonamide (XXXXXXXI)
Synthesis Example 22 N- [2- (1-ethoxycarbonylmethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) ethyl] -4- synthesized in the reaction
[(2,4-Dioxothiazolidin-5-yl) methyl]
Benzenesulfonamide is hydrolyzed with 2N sodium hydroxide to obtain the desired N- [2- (1-carboxymethyl-
2,4-Dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) ethyl] -4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide (XXXXXXXI) (pale) Yellow amorphous) was obtained. The structural formula and physical property values of this compound are shown below.

[0222]

Embedded image

NMR (400 MHz, CDCl ₃ , DMSO
−d ₆ , TMS); δ (ppm) 3.02 (1H, dd,
J = 9.3 and 14.2 Hz), 3.29-3.35 (2
H, m), 3.36 (1H, dd, J = 3.9 and 1)
4.2Hz), 4.16-4.19 (2H, m), 4.39
(1H, dd, J = 3.9 and 9.3 Hz), 4.83
(2H, s), 6.31 (1H, t, J = 5.6Hz),
7.04 (1H, d, J = 8.4 Hz), 7.19-8.12.
(7H, m), 11.4-11.7 (1H, br) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660, 1330, 1160

(Test Example) Next, the results of a pharmacological test showing the effectiveness of the compound of the present invention represented by the general formula (I) will be described. Similar effects can be obtained for the compounds of the present invention not exemplified here. Was recognized. (1) For the hypoglycemic effect experiment, 13 to 20-week-old male KK / Ta Jcl mice were used as one group of 4 to 5 mice. Three days before the start of the test, heparin blood was collected from the orbital venous plexus (30 μl) and the blood glucose level was determined by the glucose oxidase method. Blood sugar level is 350 ~
Individuals of 400 mg / dl or more were selected and divided into groups so that the average blood glucose levels in each group were equal. Each mouse was placed in an individual gauge and the drug was orally administered at a dose of 100 mg / kg twice a day. Blood was collected 3 hours after the administration on the 4th day, and the blood glucose level of the solvent control group was set to 100, and the blood glucose lowering rate (shown in the following numerical formula 1) was calculated. The results are shown in Table 1.

[0225]

[Equation 1]

(2) Aldose reductase inhibitory activity
(ARI activity) A 5-week-old male Wistar rat was killed under ether anesthesia and the lens was immediately removed. From the lens to the method of Hayman et al. [Journal of Biological Chemistry (J. Biol. Chem.),
240, 877-882 (1965)], and aldose reductase was prepared. The aldose reductase activity is measured by the method of Dufran et al. [Biochemical Medicine (Biochem.me.
d. ), 32, 99-105 (1984)]. That is, 100 mM lithium sulfate, 0.03 mM NADPH
(Reduced nicotinamide adenine dinucleotide
Phosphate) and 400 μl of 135 mM sodium-potassium-phosphate buffer (pH 7.0) adjusted to contain 0.1 mM DL-glyceraldehyde as a substrate, 50 μl of the above-mentioned aldose reductase and 50 μl of various concentrations of sample (dissolved in ethanol). In addition, 3 at 30 ℃
The reaction was allowed for 0 minutes.

Next, 0.15 ml of 0.5N hydrochloric acid was added to stop the reaction, and 0.5 ml of 6N sodium hydroxide containing 10 mM imidazole was added to give NADP (oxidized nicotinamide adenine) produced by the above reaction.
Dinucleotide phosphate) was converted into a fluorescent substance, and its fluorescence intensity was measured after 60 minutes. The fluorescence intensity is
Excitation wavelength of 360 nm using MTP-100F Corona Microplate Reader (Corona Electric Co., Ltd.) at room temperature,
The measurement was carried out under the condition of a fluorescent wavelength of 460 nm. Further, the fluorescence intensity measured by reacting in the same manner as above except that ethanol was added instead of the sample was used as a control value. The aldose-reductase inhibitory activity of the sample was determined as the concentration required to inhibit the aldose reductase activity by 50% (50% inhibitory concentration; IC ₅₀ ) from the decrease in fluorescence intensity. The results of aldose reductase inhibitory activity are shown in Table 1.

[0228]

[Table 1]

(Acute toxicity) An acute toxicity test by oral administration was carried out using ICR male mice (5-week life).
The LD ₅₀ values of the quinazoline derivatives of the present invention are all 300
It was more than mg / kg, and high safety was confirmed.

[0230]

The novel quinazoline derivative represented by the general formula (I) of the present invention has both a hypoglycemic action and an aldose reductase inhibitory action, and a pharmaceutical composition containing this has, for example, It is useful as a drug for the prevention and therapeutic treatment of various complications in diabetes such as renal disorders.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/505 AED C07D 417/12 239 (72) Inventor Miyoshi Sugisaki 1500 Inoguchi, Nakai-cho, Ashigarakami-gun, Kanagawa Prefecture Terumo Corporation

Claims (12)

[Claims] 1. A quinazoline derivative represented by the general formula (I). Embedded image [In the formula (I), R ³ and R ⁴ represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, and R ¹ and R ² are exclusively -R ⁵ -COOR ⁶ (formula Wherein R ⁵ represents an alkylene group having 1 to 3 carbon atoms, R ⁶ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms), or a group represented by the general formula (II) or (III). Is. ] [Chemical 2] [In the formula (II), A is a methylene group, a divalent group represented by the formula (IV), a divalent group represented by the formula (V), or a divalent group represented by the formula (VI). And
T represents a heterocycle having weakly acidic hydrogen. ] [Chemical 3] [In the formula (III), m represents an integer of 1 to 7, and B represents the formula (I
V) is a divalent group, and T represents a heterocycle having weakly acidic hydrogen. ] [Chemical 4] [In the formula (IV), the bonding positional relationship between the —CH ₂ — group and the —NHSO ₂ — group on the aromatic ring is 1,2-, 1,3-, or 1,
4-. ] [Chemical 5] [In the formula (V), the bonding positional relationship between the —CH ₂ — group and the —CH ₂ CH ₂ — group on the aromatic ring is 1,2-, 1,3-, or 1,4.
− ] [Chemical 6] [In the formula (VI), the bonding positional relationship between the —CH ₂ — group and the —CH ₂ CH ₂ — group on the aromatic ring is 1,2-, 1,3-, or 1,
4-. ] 2. The quinazoline derivative according to claim 1, wherein T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group and A is methylene. 3. T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and A is the general formula (IV).
The quinazoline derivative according to claim 1, which is a group represented by: 4. T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and A is the general formula (V).
The quinazoline derivative according to claim 1, which is a group represented by: 5. T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and A is the general formula (VI).
The quinazoline derivative according to claim 1, which is a group represented by: 6. T in the general formula (III) is a 2,4-dioxothiazolidin-5-yl group, and B is the general formula (IV).
The quinazoline derivative according to claim 1, which is a group represented by: 7. A pharmaceutical composition containing the quinazoline derivative according to claim 1. 8. A pharmaceutical composition containing the quinazoline derivative according to claim 2. 9. A pharmaceutical composition containing the quinazoline derivative according to claim 3. 10. A pharmaceutical composition containing the quinazoline derivative according to claim 4. 11. A pharmaceutical composition containing the quinazoline derivative according to claim 5. 12. A pharmaceutical composition containing the quinazoline derivative according to claim 6.