JPH08143568A - Pyridopyrimidine derivative and medicine composition containing the same - Google Patents

Abstract

PURPOSE: To obtain a pyridopyrimidine 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, shown by a specific formula. CONSTITUTION: This derivative is shown by formula I [any one of A<1> to A<4> is exclusively N group and the other three are CH groups; X is H, a halogen, a lower alkyl, a lower alkoxy or a haloalkyl; R<1> and R<2> are exclusively R<3> - COOR<4> (R<3> is a 1-3C alkylene; R<4> is H or a 1-8C alkyl) or a group of formula II (B is methylene or a group of formula III; T is a weakly acidic hydrogen- containing heterocyclic ring)] such as 1- 4-[(2,4-dioxothiazolidin-5-yl) methyl]benzyl}-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3 d]pyrimidin-3-acetic acid ethyl ester. For example, 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 novel pyridopyrimidine derivative and a pharmaceutical composition containing the same. More specifically, a pyridopyrimidine 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 during its use is a great burden on 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. Prior arts related to hypoglycemic agents include USP4572912 and USP4645.
Nos. 617 and USP46877777 are known.

In recent years, accumulation and increase of sorbitol in tissues have attracted attention as a pathogenic mechanism of diabetic complications, and a compound that inhibits the activity of aldose reductase, which is an enzyme that reduces aldose such as glucose and converts it into sorbitol, is a cataract. , It has been suggested in the literature that it is useful for the treatment of retinopathy, neuropathy, and renal disorder [Kay Et Gaby, N Spak, S Lou et al., Metabolism
(KHGabbay, N.Spack, N.Loo, et al.Metabolism), 28 (Su
ppl.1), 471-476, 1979, D.Dvornik, N.Simard-Dequesne, M.Krami, et al.Scien.
ce), 182, 1146-1148, 1973, Jay H. Kinoshita, Dei Dvornik, M. Kurami et al., Bio Kimika. Biophysical. Actor (JH Kinoshita, D.Dvorn
ik, M.Krami, et al.Biochem.Boiphys.Acta), 158, 475-4
75, 1968]. Based on these facts, the development of aldose reductase (AR) inhibitors is in progress. As prior art relating to AR inhibitors, USP 4734419 is known.
Nos., EP 47109, and WO9212979 are known.

However, the AR inhibitor is a symptomatic therapeutic agent for diabetic complications, and is considered to have a low therapeutic effect on diabetes itself.

[0005]

Therefore, a hypoglycemic agent is necessary 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. .

[0006]

Means for Solving the Problems The inventors of the present invention, as a result of continuing diligent research in view of such circumstances, have found that a novel pyridopyrimidine derivative satisfies the demand,
The present invention has been completed. The present invention described above is as follows.

(1) Pyridopyrimidine derivatives represented by the general formula (I), and their metal salts, addition salts, hydrates, solvates, hydrates of metal salts, solvates of metal salts, Hydrates of addition salts, solvates of addition salts.

[0008]

Embedded image

[In the formula (I), any one of A ¹ , A ² , A ³ , and A ⁴ is a --N = group, and the other three are --CH.
= Indicates a group. X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a haloalkyl group. R ¹ and R ² are exclusively —R ³ —COOR ⁴ (R ³ is an alkylene group having 1 to 3 carbon atoms, R ⁴ is hydrogen or a lower alkyl group having 1 to 8 carbon atoms), or It is a group represented by the general formula (II) or (III). ]

[0010]

[Chemical 6]

[In the formula (II), B represents a methylene group or a divalent group represented by the formula (IV), and T represents a heterocyclic group having weakly acidic hydrogen. ]

[0012]

[Chemical 7]

[In the formula (III), m represents an integer of 1 to 8, Q represents a divalent group represented by the formula (IV), and T represents a heterocyclic group having weakly acidic hydrogen. ]

[0014]

Embedded image

[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-. ]

(2) T in the general formula (II) is 2,4-
A pyridopyrimidine derivative according to (1) above, which is a dioxothiazolidin-5-yl group and B is a methylene group, 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) T in the general formula (II) is 2,4-
The pyridopyrimidine derivative according to the above (1), which is a dioxothiazolidin-5-yl group, and B is a group represented by the general formula (IV), and a metal salt, addition salt, hydrate or solvent thereof. Solvates, hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts.

(4) T in the general formula (III) is 2,4-
A pyridopyrimidine derivative according to the above (1), which is a dioxothiazolidin-5-yl group, and Q is a group represented by the general formula (IV), and a metal salt, addition salt, hydrate or solvent thereof. Solvates, hydrates of metal salts, solvates of metal salts, hydrates of addition salts, solvates of addition salts.

(5) The pyridopyrimidine derivative according to the above (1) and a metal salt, addition salt, hydrate, solvate, hydrate of metal salt, solvate or addition salt of metal salt thereof. And a solvate of an addition salt thereof.

(6) The pyridopyrimidine derivative according to the above (2) and a metal salt, addition salt, hydrate, solvate, hydrate of metal salt, solvate or addition salt of metal salt thereof. And a solvate of an addition salt thereof.

(7) The pyridopyrimidine derivative according to (3) above, and its metal salts, addition salts, hydrates, solvates, hydrates of metal salts, solvates of metal salts, addition salts. And a solvate of an addition salt thereof.

(8) The pyridopyrimidine derivative according to the above (4) and a metal salt, addition salt, hydrate, solvate, hydrate of metal salt, solvate or addition salt of metal salt thereof. And a solvate of an addition salt thereof.

In the pyridopyrimidine derivative of the general formula (I) of the present invention, examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom, and the lower alkyl group is a straight chain having 1 to 8 carbon atoms. , A branched or cyclic alkyl group is preferable, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
Examples thereof include ter-butyl, pentyl, 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. Further, in the general formulas (II) and (III), examples of the heterocycle include a 2,4-dioxothiazolin-5-yl group.

Suitable salts of the pyridopyrimidine derivative represented by the general formula (I) include salts with alkali metals such as lithium, sodium and potassium, calcium,
Examples thereof include salts with alkaline earth metals such as magnesium and addition salts with organic bases such as triethylamine and pyridine.

Next, the method for producing the pyridopyrimidine 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), A ¹ , A ² , A ³ , and A ⁴
, Any one of the three exclusively represents a -N = group, and the other three are -C
H = group, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a haloalkyl group, R ¹ and R ² are exclusively -R ³ -COOR ⁴ [wherein R
³ represents an alkylene group having 1 to ³ carbon atoms, and R ⁴ represents hydrogen or a lower alkyl group having 1 to 8 carbon atoms. ] Or a general formula (II) [in the formula (II), B is a methylene group, T
Represents a 2,4-dioxothiazolidin-5-yl group. ] The manufacturing method of the pyridopyrimidine derivative of this invention when it is these is as follows.

That is, when a compound represented by the following general formula (V) and a compound represented by the following general formula (VI) are reacted under basic conditions, the following general formula (VII) or (VIII) ) The compound represented by this is obtained.

[0027]

[Chemical 9]

[In the formula (V), any one of A ¹ , A ² , A ³ and A ⁴ represents a --N = group exclusively, and the other three represent a --CH = group. X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a haloalkyl group.
R ⁵ and R ⁶ are exclusively —R ³ —COOR ⁴ (R ³ is 1 carbon atom
Or an alkylene group having 3, R ⁴ represents a lower alkyl group having 1 to 8 carbon atoms. ) Or hydrogen. ]

[0029]

[Chemical 10]

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

[Chemical 11]

[0031]

[Chemical 12]

[In the formulas (VII) and (VIII), A ¹ , A ² ,
A ^3, A ⁴ is any one who showed exclusively -N = group and the other three parties indicates -CH = group, X is a hydrogen atom, a halogen atom,
A lower alkyl group, a lower alkoxy group, or a haloalkyl group is shown. R ³ represents an alkylene group having 1 to ³ carbon atoms, and R ⁴ represents 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 hydrogen carbonate. Examples thereof include alkali metal hydrogencarbonates such as potassium, trialkylamines such as triethylamine and diisopropylethylamine, pyridine compounds such as pyridine, lutidine, picoline, and 4-dimethylaminopyridine, and sodium hydride is preferably used.

The above reaction is usually carried out in various solvents such as dichloromethane, pyridine, N, N-dimethylformamide, tetrahydrofuran, acetone, dimethylsulfoxide and the like, conventional solvents or mixtures thereof which do not adversely influence the reaction. Be seen. 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 compounds represented by the general formulas (VII) and (VIII), there are known methods [JP-A-62-96476 and Journal of Medicinal Chemistr.
y), Vol. 34, 1492-1503, 1991], the compound represented by the general formula (IX) or (X) may be treated with a carbonylating agent. As the carbonylating agent at this time, 1,1′-carbonyldiimidazole,
Examples include phosgene and bis (trichloromethyl) carbonate, and preferably 1,1′-carbonyldiimidazole is used. The above reaction is preferably carried out without a solvent, but a conventional solvent which does not adversely influence the reaction, such as chloroform or dimethylformamide, can be used. The reaction temperature is usually under heating. For example, when it is performed without a solvent, 130 ° C is preferable.

[0036]

[Chemical 13]

[0037]

Embedded image

[In the formulas (IX) and (X), A ¹ , A ² , A ³ ,
A ⁴ , X, R ³ and R ⁴ have the same meanings as in formulas (VII) and (VIII). ]

Next, the product represented by the general formula (VII) or (VIII) is reduced to obtain the compound represented by the general formula (XI) or (XII).

[0040]

[Chemical 15]

[0041]

Embedded image

[In the formulas (XI) and (XII), A ¹ , A ² ,
A ³ , A ⁴ , X, R ³ and R ⁴ are represented by the general formulas (VII) and (VII
It has the same meaning as I). ]

Examples of the reduction reaction include catalytic reduction, reduction with zinc-acetic acid, iron-acetic acid, tin (II) chloride, etc., 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 thereof. 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 general formula (XI) or (XII) is represented by the general formula (XIII) or (XIV) by performing recrystallization or column chromatography and then performing a mail vinelation reaction. Produce a compound that
Reactions are eg USP 4461902 and journals
Journal of Medicin
al Chemistry), 32, 421-428, 1989 and the like. That is, the Mailbain allation reaction is usually acetone, water or alcohols such as methanol and ethanol, preferably acetone or a mixture of acetone and water as a solvent, after diazotization by a conventional method,
It is carried out by adding acrylic acid esters in the presence of an acid, followed by a catalytic amount of cuprous salt.

[0045]

[Chemical 17]

[0046]

Embedded image

[In the formulas (XIII) and (XIV), A ¹ , A ² ,
A ³ , A ⁴ , X, R ³ and R ⁴ have the same meanings as in formulas (VII) and (VIII), R ⁷ represents a methyl group or an ethyl group, and Z represents a halogen atom such as chlorine or bromine. Indicates. ]

Next, these compounds are reacted with thiourea in the presence of sodium acetate to give the following formula (XV) or (XVI)
By synthesizing the compound represented by the formula (1) and further hydrolyzing the compound with an acid or, if necessary, further hydrolyzing the ester under a basic condition to obtain the desired general formula (XVII) as shown below. Alternatively, the compound represented by (XVIII) is obtained.

[0049]

[Chemical 19]

[0050]

Embedded image [In the formulas (XV) and (XVI), A ¹ , A ² , A ³ , A ⁴ , X,
R ³ and R ⁴ have the same meanings as shown in the general formulas (VII) and (VIII). ]

[0051]

[Chemical 21]

[0052]

[Chemical formula 22]

[In the formulas (XVII) and (XVIII), A ¹ ,
A ² , A ³ , A ⁴ , X and R ³ are represented by the general formulas (VII) and (VII
It has the same meaning as in (I) and R ⁴ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. ]

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 (XVII) or (XVII
In formula (I), R ⁴ is a hydrogen atom or a lower alkyl group depending on the alcohol used, in general formula (XVII) or (XV
A compound of formula III) is obtained. Therefore, the general formula (XVI
When a compound in which R ⁴ is a hydrogen atom is required in I) or (XVIII), sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, preferably sodium hydroxide is used as a base, and water is used as a solvent. The hydrolysis is carried out in conventional solvents or mixtures thereof which do not adversely influence the reaction, such as acetone, dioxane, methanol, ethanol, tetrahydrofuran and the like.

(Production Method 2) In the general formula (I), A ¹ , A
² , any one of A ³ , A ⁴ exclusively represents a -N = group,
The other three are -CH = groups, X is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, R ¹ and R ² are exclusively -R ³ -COOR.
⁴ [wherein R 3 represents an alkylene group having 1 to 3 carbon atoms,
R ⁴ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. ] Or general formula (II) [wherein B represents a divalent group represented by general formula (IV), and T represents a 2,4-dioxothiazolidin-5-yl group. ] The manufacturing method of the compound of this invention when is is as follows.

That is, when the compound represented by the general formula (XI) or (XII) in the production method 1 and the compound represented by the general formula (XIX) are reacted under a basic condition, the compound represented by the general formula (XX) or A compound represented by (XXI) is obtained.

[0057]

[Chemical formula 23]

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

[0059]

[Chemical formula 24]

[0060]

[Chemical 25]

[In the formulas (XX) and (XXI), A ¹ , A ² ,
A ³ , A ⁴ , X, R ³ and R ⁴ are represented by the general formulas (VII) and (VII
It has the same meaning as I). ]

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 obtained compound is subjected to acid hydrolysis or, if necessary, further subjected to ester hydrolysis under basic conditions to give the desired compound represented by the general formula (XXII) or (XXIII) as shown below. obtain.

[0064]

[Chemical formula 26]

[0065]

[Chemical 27]

[In the formulas (XXII) and (XXIII), A ¹ ,
A ² , A ³ , A ⁴ , X and R ³ are represented by the general formulas (VII) and (VII
It has the same meaning as in (I) and R ⁴ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. ]

In the general formula (I), A ¹ , A ² , A ³ ,
Any one of A ⁴ represents a -N = group exclusively, the other three represent a -CH = group, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a haloalkyl group, R ¹ and R ² are exclusively -R ³ -COOR ⁴ [wherein R 1
³ represents an alkylene group having 1 to 3 carbon atoms, and R ⁴ represents a hydrogen atom or a lower alkyl group having 1 to 8 carbon atoms. ] Or a general formula (II) [wherein B is a general formula (I
V) is a divalent group represented by —CH ₂ — and —NHS
The bonding positional relationship of the O ₂ − group on the aromatic ring is 1,4-, and T
Represents a 2,4-dioxothiazolidin-5-yl group. The compound represented by the formula [XI] or (XII) in the production method 1 is a known substance [Journal of Medicinal Chemistry].
(Journal of Medicinal Chemistry), Volume 35, 1853-1864,
1992]], or by further hydrolyzing the ester under basic conditions, if necessary.

[0068]

[Chemical 28]

As the base at this time, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, trialkylamines such as triethylamine and diisopropylethylamine,
Pyridine compounds such as pyridine, lutidine, 4-dimethylaminopyridine and the like can be mentioned, but diisopropylethylamine is preferable.

The reaction solvent is a conventional solvent which does not adversely influence the reaction such as N, N-dimethylformamide, dichloromethane, chloroform, acetone and the like, or a mixture thereof, preferably dichloromethane is used. The reaction temperature is in the range of 0 ° C to warming, preferably 0 ° C to room temperature.

The pyridopyrididine derivative of the present invention obtained by the above-mentioned production method is isolated by a conventional method such as extraction, precipitation, fractionation chromatography, fractional crystallization and recrystallization.
It can be purified. Further, the compound represented by the general formula (V) used as the starting material in the production method 1 is
It can be synthesized by Method 1, Method 2 or Method 3 described below.

(Method 1) In the general formula (V), A ¹ , A
⁴ is exclusively -N = group or -CH = group, A ^2, A ³ a is -CH = group, R ⁵ is -R ³ -COOR ⁴ (R ³ is an alkylene group having 1 to 3 carbon atoms R ⁴ represents a lower alkyl group having 1 to 8 carbon atoms), and R ⁶ is hydrogen, the synthetic method of the compound is as follows.

By reacting the compound represented by the general formula (XXV) with the compound represented by the general formula (XXVI) under basic conditions, the compound represented by the general formula (XXVII) is obtained.

[0074]

[Chemical 29]

[In the formula (XXV), A ¹ and A ⁴ are exclusively
N = group or -CH = group, X is a general formula (V)
Has the same meaning as shown in. ]

[0076]

Embedded image

[In the formula (XXVI), R ³ represents an alkylene group having 1 to 3 carbon atoms, and R ⁴ represents a lower alkyl group having 1 to 8 carbon atoms. ]

[0078]

[Chemical 31]

[In the formula (XXVII), A ¹ , A ⁴ , X, R ³ and R ⁴ have the same meanings as shown in the general formula (XXV) and the general formula (XXVI). ]

Examples of the base at this time include trialkylamines such as triethylamine and diisopropylethylamine, and pyridine compounds such as pyridine, lutidine, picoline and 4-dimethylaminopyridine, and triethylamine is preferably used.

The reaction solvent is dichloromethane, toluene,
It is carried out in a conventional solvent which does not adversely influence the reaction, such as pyridine, N, N-dimethylformamide, tetrahydrofuran, acetone or the like, or a mixture thereof, preferably toluene or N, N-dimethylformamide. The reaction temperature is usually in the range of cooling to reflux.

Next, the compound represented by the general formula (XXVII) is reacted with a carbonylating agent according to the method described in the production method 1 to obtain the compound represented by the general formula (V).

(Method 2) In the general formula (V), A ¹ , A
⁴ is exclusively -N = group or -CH = group or an A ^2, A ³ is -CH = group, R ⁵ is hydrogen, R ⁶ is -R ³ -COOR ⁴
(Where R ³ represents an alkylene group having 1 to ³ carbon atoms and R ⁴ represents a lower alkyl group having 1 to 8 carbon atoms), the synthetic method of the compound is as follows.

By reacting the compound represented by the general formula (XXV) with the compound represented by the general formula (XXVIII) under basic conditions, the compound represented by the general formula (XXIX) is obtained.

[0085]

Embedded image

[In the formula (XXVIII), L represents a halogen atom such as chlorine, bromine or iodine, and R ³ and R ⁴ are represented by the general formula (XX
VI) has the same meaning. ]

[0087]

[Chemical 33]

[In the formula (XXIX), A ¹ , A ⁴ , X, R ³ and R ⁴ have the same meanings as in the general formula (XXV) and the general formula (XXVI). ]

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 alkali metal hydrogen carbonates such as sodium hydrogen carbonate. Examples thereof include salts, trialkylamines such as triethylamine and diisopropylethylamine, pyridine compounds such as pyridine, lutidine, picoline and 4-dimethylaminopyridine, and sodium hydride is preferably used.

The reaction solvent is dichloromethane, pyridine,
N, N-dimethylformamide, tetrahydrofuran,
The reaction is carried out in a conventional solvent which does not adversely influence the reaction such as acetone or a mixture thereof, and a particularly preferable solvent is N, N-dimethylformamide. The reaction temperature is in the range of cooling to heating, and preferably 0 ° C. to room temperature.

Further, according to Method 1, the compound represented by the general formula (XXIX) is ring-opened with concentrated aqueous ammonia, and the compound of the general formula (XX
The compound represented by the general formula (V) is obtained by treating the compound represented by X) with a carbonylating agent.

[0092]

Embedded image

[In the formula (XXX), A ¹ , A ⁴ , X, R ³ and R
⁴ has the same meaning as in general formula (XXV) and general formula (XXVI). ]

The compound represented by the general formula (XXV) is a known substance, or a known method [Synthesis (Sy
nthesis), 972, 1982].

(Method 3) In the general formula (V), A ¹ , A
² , any one of A ³ , A ⁴ exclusively represents a -N = group,
Other tripartite represents a -CH = group, R ⁵ is -R ³ -COOR
⁴ (R ³ represents an alkylene group having 1 to ³ carbon atoms, R ⁴ represents a lower alkyl group having 1 to 8 carbon atoms), and when R ⁶ is hydrogen, it is represented by the general formula (V). Compound is WO9
It can be produced according to the method described in No. 222979.

That is, a compound represented by the general formula (XXXI) is represented by the general formula (XXXII) [in the formula (XXXII), R ⁴ has the same meaning as shown in the general formula (V). ] It can synthesize | combine by condensing with the ester of the isocyanate acetic acid represented by these, and making it the compound represented by General formula (XXXIII), and treating with concentrated ammonia water.

[0097]

Embedded image

[In the formula (XXXI), R ⁸ represents a methyl group or an ethyl group. A ¹ , A ² , A ³ , A ⁴ and X have the same meanings as shown in formula (V). ]

[0099]

Embedded image

[In the formula (XXXII), R ⁴ has the same meaning as in the general formula (V). ]

[0101]

Embedded image

[In the formula (XXXIII), A ¹ , A ² , A ³ , A ⁴ ,
X, R ⁴ and R ⁸ have the same meanings as shown in the general formula (V) and the general formula (XXXI). ]

The compound represented by the general formula (XXXI) is a known substance, or a known method [Journal
Of Chemical Society (C) (Journal of C
Chemical Society (C)), 1816-1821, 1966].

The pyridopyrimidine derivative of the present invention has excellent hypoglycemic action and AR inhibitory action, and is effective in the prevention and treatment of 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. The dosage form includes oral preparations such as tablets, powders, granules, capsules, emulsions, suspensions,
Syrup, suppository as parenteral preparation, injection, drip,
It can be an external preparation or the like.

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.
It can be administered at a rate of 01 mg / kg to 200 mg / kg, preferably 0.05 mg / kg to 50 mg / kg, and more preferably 0.1 to 10 mg / kg, 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 and the like are used. As the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl starch, polyvinyl pyrrolidone, etc. are 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 with reference to the following examples, but the present invention is not limited thereto. The physical properties of the compounds described in the Examples are Hitachi R-1200 based on proton nuclear magnetic resonance spectrum (NMR).
(60MHz), Varian Unity 400 (4
00MHz) and infrared spectrum (IR) by Jeol
IR-810, melting point (mp) is Yawa B
It measured using Y-10.

Example 1 1- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Acetic acid ethyl ester (XXXIV) and 1- {4-
[(2,4-Dioxothiazolidin-5-yl) methyi
Lu] benzyl} -2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-3-acetic acid (X
XXV) Synthesis method A. 1,2-dihydro-2,4-dioxopyrido [2,3
-D] -3,1-oxazine and 1,2-dihydro-2,
4-dioxopyrido [3,2-d] -3,1-oxazine
Synthesis method of 2,3-pyridinedicarboxylic acid anhydride (31.6 g, 0.
21 mol) in a chloroform suspension (140 ml, ethanol free) was added to trimethylsilyl azide (29.5 ml, 0.1 ml).
22 mol) was added and carefully heated until the reaction started. 1 more after the first rapid nitrogen evolution subsided
The mixture was heated under reflux for an hour. Ethanol (12.4 ml, 0.21 mol) was added to the reaction mixture under ice-cooling, and the mixture was further stirred for 15 minutes, and the deposited precipitate was collected by filtration and dried. The precipitate was heated and refluxed in acetonitrile (180 ml) for 1 hour, and the precipitate was collected by filtration to obtain the desired 1,2-dihydro-2,4-dioxopyrido [2,3-d] -3,1. -Oxazine and 1,2-dihydro-2,4-dioxopyrido [3,2-d] -3,1-oxazine (milky white powder, 2
8.4 g, 82%) was obtained as a mixture. 1,2-dihydro-2,4-dioxopyrido [2,3-d] -3,1
The production ratio of -oxazine and 1,2-dihydro-2,4-dioxopyrido [3,2-d] -3,1-oxazine is 4
It was 4: 1 from 00 MHz NMR.

B. N- (3-aminopicolinoyl) green
Syn ethyl ester and N- (2-aminonicotino
Il) Glycine ethyl ester synthesis method 1,2-dihydro-2,4-dioxopyrido [2,3-
d] -3,1-oxazine and 1,2-dihydro-2,4
-Mixture of dioxopyrido [3,2-d] -3,1-oxazine (12.0 g, 73.1 mmol), glycine ethyl ester hydrochloride (10.2 g, 73.1 mmol), triethylamine (22.4 ml, 160) A toluene suspension (200 ml) of 0.9 mmol) was heated under reflux for 6 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the target N- (3-aminopicolinoyl) glycine ethyl ester (pale yellow oil, 2.4 g, 15) was obtained from the fraction eluted with n-hexane-ethyl acetate (3: 1). %)
From the fraction eluted with n-hexane-ethyl acetate (1: 2) to obtain the desired N- (2-aminonicotinoyl) glycine
Ethyl ester (pale yellow solid, 7.6 g, 48%) was obtained.

C. 2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-3-acetic acid
Method for synthesizing ethyl ester N- (2-aminonicotinoyl) glycine Ethyl ester (6.9 g, 30.9 mmol), 1,1′-carbonyldiimidazole (10.0 g, 61.8 mmol) melted at 130 ° C. And stirred for another 30 minutes. The reaction solution was cooled and the resulting solid was added with ethanol, washed and collected by filtration to obtain the desired 2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-. Acetic acid ethyl ester (white powder, 7.4 g, 96%) was obtained.

D. 1- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Method for the synthesis of pyrimidine-3-acetic acid ethyl ester Sodium hydride washed with n-hexane (60 in mineral oil
%, 0.41 g, 10.3 mmol) 2,4-dioxo-1, in a suspension of N, N-dimethylformamide (30 ml).
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (2.6 g, 10.3 mmo
l) was added little by little under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and then 4-nitrobenzyl bromide (2.5 g, 11.3 mm).
ol) in N, N-dimethylformamide solution (15 ml) was added dropwise under ice cooling, and the mixture was further stirred at room temperature overnight. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography. The target 1- (4-nitrobenzyl)-was obtained from the fraction eluted with n-hexane-ethyl acetate (5: 1).
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (pale yellow solid, 3.6 g, 90%) was obtained.

E. 1- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Synthesis of ethyl pyrimidine-3-acetic acid 1- (4-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (7.2 g, 18.7 mmo
l) 10% Palladium-carbon (0.72 g) was suspended in a tetrahydrofuran-methanol mixed solution (1: 1, 60 ml), and the mixture was stirred overnight at room temperature under a hydrogen stream. After filtering the reaction solution, the solvent is distilled off under reduced pressure to obtain the desired 1- (4-
Aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (pale yellow amorphous, 6.5 g, 9
8%).

F. 1- [4- (2-bromo-2-etoki
Cycarbonylethyl) benzyl] -2,4-dioxo-
1,2,3,4-tetrahydropyrido [2,3-d] pyrimy
Synthetic Method of Zin-3-acetic Acid Ethyl Ester 1- (4-aminobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (3.9 g, 11.1 mmo
l) acetone solution (15 ml) in distilled water (3 ml), 47
After adding% hydrogen bromide (3.9 ml, 33.4 mmol), 5 ° C
Sodium nitrite (0.84g, 12.2mmol) below
Was added dropwise (1.5 ml) and the mixture was stirred for 30 minutes. Further, ethyl acrylate (7.2 ml, 66.7 mmol) was added, and the reaction solution was brought to 40 ° C., and then copper (I) oxide (0.16) was added.
g, 1.1 mmol) was added in small portions. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, and the target 1- [4- (2-bromo-2-ethoxy) was obtained from the n-hexane-ethyl acetate (7: 1) elution fraction. Carbonylethyl) benzyl] -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (pale yellow amorphous,
4.4 g, 76%) was obtained.

G. 1- {4-[(2-imino-4-oxy
Sothiazolidin-5-yl) methyl] benzyl} -2,
4-dioxo-1,2,3,4-tetrahydropyrido [2,
Synthesis of 3-d] pyrimidine-3-acetic acid ethyl ester
Method 1- [4- (2-Bromo-2-ethoxycarbonylethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid
Ethyl ester (4.3 g, 8.4 mmol), thiourea (0.70 g, 9.2 mmol), sodium acetate (0.76)
An ethanol solution (50 ml) of g, 9.2 mmol) was heated under reflux overnight. The reaction mixture was cooled with ice water and the precipitate was collected by filtration to give the desired 1- {4-[(2-imino-4-oxothiazolidin-5-yl) methyl] benzyl} -2,4.
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
Obtained -d] pyrimidine-3-acetic acid ethyl ester (white powder, 3.9 g, quantitative).

H. 1- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-acetic acid ethyl ester and 1-
{4-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzyl} -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-3-vinegar
Method for synthesizing acid 1- {4-[(2-imino-4-oxothiazolidine-
5-yl) methyl] benzyl} -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (2.7 g, 5.8 mmo
l) 2N hydrochloric acid (29 ml) in ethanol (40 ml)
After heating under reflux for 8 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the target 1- {4-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester (XXXIV) (milky white Amorphous, 1.4g, 52
%) From the fraction eluted with 1% methanol-chloroform to give the desired 1- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-
1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid (XXXV) (white solid, 0.9 g, 36
%) Was obtained.

Further, 1- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4-
Dioxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-acetic acid ethyl ester (XXXIV)
(1.4 g, 2.9 mmol), a 2N aqueous sodium hydroxide solution (7.2 ml) in a tetrahydrofuran-methanol mixed solution (1: 1, 20 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the target 1- {4-[(2,4
-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid (XXXV) (white solid, 1.0 g, 76%) was obtained. NMR and IR data for this product support structures (XXXIV) and (XXXV) of the formula

[0117]

[Chemical 38]

400 MHz NMR (CDCl ₃ , TMS);
δ (ppm) 1.29 (3H, t, J = 7.1Hz), 3.0
9 (1H, dd, J = 9.8, 14.1Hz), 3.49
(1H, dd, J = 3.8, 14.1Hz), 4.24 (2
H, q, J = 7.1Hz), 4.48 (1H, dd, J =
3.8, 9.8Hz), 4.83 (2H, s), 5.55 (2
H, s), 7.16 (2H, d, J = 8.2Hz), 7.2
4 (1H, dd, J = 4.8, 7.7Hz), 7.44
(2H, d, J = 8.2Hz), 8.48 (1H, dd, J
= 1.8, 7.7 Hz), 8.69 (1H, dd, J = 1.
8,4.8 Hz) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1760,171
0,1670

[0119]

[Chemical Formula 39]

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.04 (1H, dd, J
= 9.9, 14.1 Hz), 3.48 (1H, dd, J = 3.
8, 14.1Hz), 4.42 (1H, dd, J = 3.8,
9.9Hz), 4.80 (2H, s), 5.52 (2H,
s), 7.16 (2H, d, J = 8.1Hz), 7.24
(1H, dd, J = 4.8, 7.7Hz), 7.42 (2
H, d, J = 8.1Hz), 8.47 (1H, dd, J =
2.0, 7.7 Hz), 8.80 (1H, dd, J = 2.0,
4.8 Hz), 11.06 (1H, brs) IR (KBr); ν (cm ^-1 ) 1750, 1700, ¹
670

Example 2 1- {3-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Acetic acid ethyl ester (XXXVI) and 1- {3-
[(2,4-Dioxothiazolidin-5-yl) methyi
Lu] benzyl} -2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-3-acetic acid (X
XXVII) Synthesis method A. 1- (3-nitrobenzyl) -2,4-dioxo-
1,2,3,4-tetrahydropyrido [2,3-d] pyrimy
Synthetic Method of Zin-3-acetic Acid Ethyl Ester By a method similar to that in Example 1 · D, 2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3] obtained in Example 1 · C was obtained. -D] pyrimidine-3-acetic acid ethyl ester was reacted with 3-nitrobenzyl bromide to obtain the desired 1- (3-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was obtained.

B. 1- (3-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Synthesis method of pyrimidine-3-acetic acid ethyl ester 1- (3-Nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido was prepared in the same manner as in Example 1E. [2,3-d] Pyrimidine-3-acetic acid ethyl ester was reduced with 10% palladium-carbon to give the desired 1- (3-aminobenzyl) -2,4-dioxo-1,2,3, 4-Tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was obtained.

C. 1- [3- (2-bromo-2-etoki
Cycarbonylethyl) benzyl] -2,4-dioxo-
1,2,3,4-tetrahydropyrido [2,3-d] pyrimy
Synthetic Method of Zin-3-acetic Acid Ethyl Ester By the same method as in Example 1 · F, 1- (3-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2, 3-d] pyrimidine-3-acetic acid ethyl ester is reacted with ethyl acrylate to obtain the desired 1-
[3- (2-bromo-2-ethoxycarbonylethyl)
Benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was obtained.

D. 1- {3-[(2-imino-4-oxy
Sothiazolidin-5-yl) methyl] benzyl} -2,
4-dioxo-1,2,3,4-tetrahydropyrido [2,
Synthesis of 3-d] pyrimidine-3-acetic acid ethyl ester
By the same method as the law in Example 1 · G, 1- [3- ( 2- bromo-2-ethoxycarbonylethyl) benzyl] -
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester is reacted with thiourea to obtain the desired 1- {3-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was obtained.

E. 1- {3-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-acetic acid ethyl ester and 1-
{3-[(2,4-dioxothiazolidin-5-yl)
Methyl] benzyl} -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-3-vinegar
Acid Synthesis Method 1- {3-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was hydrolyzed with 2N hydrochloric acid to give the desired 1- {. 3-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Acetic acid ethyl ester (XXXVI) and 1- {3-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid (X
XXVII) was obtained. In addition, 1- {3-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] pyrimidine-3-acetic acid ethyl ester (XXXV
I) is hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 1- {3-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1, 2,3,4-Tetrahydropyrido [2,3-d]
Pyrimidine-3-acetic acid (XXXVII) was obtained. NM of this thing
R and IR data are represented by the structures (XXXVI) and (XXXVI)
Support I).

[0126]

[Chemical 40]

60 MHz NMR (CDCl ₃ , TMS); δ
(Ppm) 1.29 (3H, t, J = 7Hz), 3.00
3.60 (2H, m), 4.25 (2H, q, J = 7H
z), 4.51 (1H, dd, J = 4, 9Hz), 4.85
(2H, s), 5.57 (2H, s), 7.05 to 8.8
5 (7H, ArH)

[0128]

Embedded image

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.05 (1H, dd, J
= 9.9, 14.1 Hz), 3.48 (1H, dd, J = 3.
8, 14.1Hz), 4.43 (1H, dd, J = 3.8,
9.9Hz), 4.81 (2H, s), 5.55 (2H,
s), 7.11 (1H, d, J = 7.7Hz), 7.24
(1H, dd, J = 4.8, 7.9Hz), 7.24 (1
H, t, J = 7.7Hz), 7.33 (1H, s), 7.3
9 (1H, d, J = 7.7Hz), 8.47 (1H, dd,
J = 1.8, 7.9 Hz), 8.69 (1H, dd, J = 1.
8,4.8 Hz) IR (KBr); ν (cm ^-1 ) 175
0,1700,1650

(Example 3) 1- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [3,2-d] pyrimidine-3
-Synthesis of acetic acid (XXXVIII) A. 2,4-dioxo-1,2,3,4-tetrahydropyr
De [3,2-d] pyrimidine-3-acetic acid ethyl ester
In the same manner as in Example 1 · C, N- (3-aminopicolinoyl) glycine ethyl ester obtained in Example 1 · B was reacted with 1,1′-carbonyldiimidazole,
The target 2,4-dioxo-1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester was obtained.

B. 1- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [3,2
-D] Method for synthesizing pyrimidine-3-acetic acid ethyl ester By the same method as in Example 1 · D, 2,4-dioxo-
1,2,3,4-Tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester was reacted with 4-nitrobenzyl bromide to give the desired 1- (4-nitrobenzyl) -2,4 -Dioxo-1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester was obtained.

C. 1- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [3,2
-D] Synthesis of ethyl pyrimidine-3-acetic acid 1- (4-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester (1.7 g, 4.4 mmo
l), tin (II) chloride dihydrate (4.0g, 17.5mmo
An ethanol solution (17 ml) of 1) was heated under reflux for 1 hour and a half. The reaction mixture was adjusted to pH 9 with 1N aqueous sodium hydroxide solution, extracted twice with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure to obtain the desired 1
-(4-aminobenzyl) -2,4-dioxo-1,2,
3,4-Tetrahydropyrido [3,2-d] pyrimidine-
3-Acetic acid ethyl ester (yellow solid, 1.4 g, 88
%) Was obtained.

D. 1- [4- (2-bromo-2-etoki
Cycarbonylethyl) benzyl] -2,4-dioxo-
1,2,3,4-tetrahydropyrido [3,2-d] pyrimi
Synthetic Method of Zin-3-acetic Acid Ethyl Ester By the same method as in Example 1 · F, 1- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 2-d] pyrimidine-3-acetic acid ethyl ester was subjected to a Mailbain reaction to give the desired 1- [4
-(2-Bromo-2-ethoxycarbonylethyl) benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester was obtained.

E. 1- {4-[(2-imino-4-oxy
Sothiazolidin-5-yl) methyl] benzyl} -2,
4-dioxo-1,2,3,4-tetrahydropyrido [3,
Synthesis of 2-d] pyrimidine-3-acetic acid ethyl ester
By the same method as the law in Example 1 · G, 1- [4- ( 2- bromo-2-ethoxycarbonylethyl) benzyl] -
2,4-Dioxo-1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester is reacted with thiourea to obtain the desired 1- {4-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester was obtained.

F. 1- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydropyrido [3,2-
d] Synthesis method of pyrimidine-3-acetic acid 1- {4-[(2-imino-4-oxothiazolidine-
5-yl) methyl] benzyl} -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [3,2-d] pyrimidine-3-acetic acid ethyl ester (0.91 g, 2.0 mmo
(1) was heated and refluxed in 2N hydrochloric acid (20 ml) for 2 hours and a half, water and ethyl acetate were added, and the deposited precipitate was collected by filtration. The residue was recrystallized from ethanol-n-hexane to give the desired 1- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2, 3,4-Tetrahydropyrido [3,2-d]
Pyrimidine-3-acetic acid (XXXVIII) (white crystals, 0.62)
g, 72%, mp 207-209 ° C). The NMR and IR data for this product support the structure of formula (XXXVIII):

[0136]

Embedded image

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.10 (1H, dd, J
= 9.5, 14.1 Hz), 3.46 (1H, dd, J = 3.
8, 14.1Hz), 4.44 (1H, dd, J = 3.8,
9.5Hz), 4.89 (1H, d, J = 16.2Hz), 4.
93 (1H, d, J = 16.2Hz), 5.36 (2H,
s), 7.22 (4H, s), 7.51 (2H, d, J =
2.7 Hz), 8.61 (1 H, t, J = 2.7 Hz) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660

Example 4 1- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [3,4-d] pyrimidine-3
-Synthesis of acetic acid (XXXIX) A. 2,4-dioxo-1,2,3,4-tetrahydropyr
De [3,4-d] pyrimidine-3-acetic acid ethyl ester
Synthesis 3-Amino isonicotinic acid methyl ester le (2.8
g, 18.5 mmol) and isocyanoacetic acid ethyl ester (2.6 ml, 23.2 mmol) were heated to 50 ° C. until homogeneous and heated for a further 15 minutes. After cooling the reaction solution, anhydrous ethanol (35 ml) and concentrated aqueous ammonia (11 ml) were added, and the mixture was stirred at 50 ° C. for 6 hours. The reaction mixture was adjusted to pH 1 with 1N hydrochloric acid and the precipitate was collected by filtration to obtain the desired 2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3- Acetic acid ethyl ester (pale yellow powder, 4.1 g, 89%) was obtained.

B. 1- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [3,4
-D] Method for synthesizing pyrimidine-3-acetic acid ethyl ester By the same method as in Example 1 · D, 2,4-dioxo-
1,2,3,4-Tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester was reacted with 4-nitrobenzyl bromide to give the desired 1- (4-nitrobenzyl) -2,4 -Dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester was obtained.

C. 1- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [3,4
-D] Synthesis method of pyrimidine-3-acetic acid ethyl ester 1- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido was prepared by the same method as in Example 3C. [3,4-d] Pyrimidine-3-acetic acid ethyl ester was reduced with tin (II) chloride dihydrate to give the desired 1- (4-aminobenzyl) -2,4-dioxo-1. Obtained 2,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester.

D. 1- [4- (2-bromo-2-etoki
Cycarbonylethyl) benzyl] -2,4-dioxo-
1,2,3,4-tetrahydropyrido [3,4-d] pyrimi
Synthetic Method of Zin-3-acetic Acid Ethyl Ester By the same method as in Example 1 · F, 1- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [3, 4-d] pyrimidine-3-acetic acid ethyl ester is reacted with ethyl acrylate to obtain the desired 1-
[4- (2-bromo-2-ethoxycarbonylethyl)
Benzyl] -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester was obtained.

E. 1- {4-[(2-imino-4-oxy
Sothiazolidin-5-yl) methyl] benzyl} -2,
4-dioxo-1,2,3,4-tetrahydropyrido [3,
Synthesis of 4-d] pyrimidine-3-acetic acid ethyl ester
By the same method as the law in Example 1 · G, 1- [4- ( 2- bromo-2-ethoxycarbonylethyl) benzyl] -
2,4-Dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester was reacted with thiourea to obtain the desired 1- {4-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester was obtained.

F. 1- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydropyrido [3,4-
d] Method for synthesizing pyrimidine-3-acetic acid 1- {4-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid ethyl ester is treated with 2N hydrochloric acid to give the desired 1- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [3,4-d] pyrimidine-3-acetic acid (X
XXIX) (mp 161-164 ° C) was obtained. NM of this thing
The R and IR data support the structure of formula (XXXIX):

[0144]

[Chemical 43]

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.07 (1H, dd, J
= 9.9, 14.1 Hz), 3.49 (1H, dd, J = 3.
8, 14.1 Hz), 4.43 (1H, dd, J = 3.8, 9.
9Hz), 4.86 (2H, s), 5.39 (1H, d, J
= 16.5Hz), 5.44 (1H, d, J = 16.5H
z), 7.22 (2H, d, J = 8.2Hz), 7.27 (2
H, d, J = 8.2 Hz), 8.00 (1H, d, J = 4.
7Hz), 8.51 (1H, d, J = 4.7Hz), 8.65
(1H, s), 11.55 (1H, brs) IR (KBr); ν (cm ⁻¹ ) 1750,1700,1
680

Example 5 1- {4-[(2,4-dioxothiazolidin-5-i
Ru) methyl] benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Propionic acid ethyl ester (XXXX) and 1- {4
-[(2,4-Dioxothiazolidin-5-yl) methyl
Lu] benzyl} -2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-3-propyi
Synthesis of propionic acid (XXXXI) A. N- (3-aminopicolinoyl) -β-alanine
Ethyl ester and N- (2-aminonicotinoyl)
Synthesis Method of -β-Alanine Ethyl Ester By a method similar to that in Example 1 · B, 1,2-dihydro-2,4-dioxopyrido [2,3-obtained in Example 1 · A] was obtained.
d] -3,1-oxazine and 1,2-dihydro-2,4
Reaction of a mixture of -dioxopyrido [3,2-d] -3,1-oxazine with β-alanine ethyl ester / hydrochloride to give the desired N- (3-aminopicolinoyl) -β
-Alanine ethyl ester and N- (2-aminonicotinoyl) -β-alanine ethyl ester were obtained.

B. 2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-3-propyi
Method for synthesizing ononic acid ethyl ester By the same method as in Example 1 · C, N- (2-aminonicotinoyl) -β-alanine ethyl ester and 1,1 ′ were prepared.
-Carbonyldiimidazole was reacted to obtain the target 2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester.

C. 1- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] pyrimidine-3-propionic acid ethyl ester
Synthesis of 2,4-dioxo- by the same method as in Example 1D.
1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester was reacted with 4-nitrobenzyl bromide to give the desired 1- (4-nitrobenzyl) -2, 4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester was obtained.

D. 1- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] pyrimidine-3-propionic acid ethyl ester
By the same method as Synthesis Example 1 · E of 1- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine -3 -Propionic acid ethyl ester was reduced with 10% palladium-carbon to give the desired 1- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Pyrimidine-3-propionic acid ethyl ester was obtained.

E. 1- [4- (2-bromo-2-etoki
Cycarbonylethyl) benzyl] -2,4-dioxo-
1,2,3,4-tetrahydropyrido [2,3-d] pyrimy
Synthetic Method of Zin-3-propionic Acid Ethyl Ester By the same method as in Example 1 · F, 1- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2 , 3-d] Pyrimidine-3-propionic acid ethyl ester was reacted with ethyl acrylate to give the desired 1- [4- (2-bromo-2-ethoxycarbonylethyl) benzyl] -2,4-dioxo-1. , 2,3,4
-Tetrahydropyrido [2,3-d] pyrimidine-3-
Propionic acid ethyl ester was obtained.

F. 1- {4-[(2-imino-4-oxy
Sothiazolidin-5-yl) methyl] benzyl} -2,
4-dioxo-1,2,3,4-tetrahydropyrido [2,
3-d] pyrimidine-3-propionic acid ethyl ester
By the same method as Synthesis Example 1 · G Le, 1- [4- (2-bromo-2-ethoxycarbonylethyl) benzyl] -
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester is reacted with thiourea to give the desired 1- {4-
[(2-Imino-4-oxothiazolidin-5-yl)
Methyl] benzyl} -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester was obtained.

G. 1- {4-[(2,4-dioxothia
Zolidine-5-yl) methyl] benzyl} -2,4-di
Oxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-propionic acid ethyl ester
And 1- {4-[(2,4-dioxothiazolidine-5-
Iyl) methyl] benzyl} -2,4-dioxo-1,2,
3,4-Tetrahydropyrido [2,3-d] pyrimidine-
Synthesis Method of 3-Propionic Acid 1- {4-[(2-
Imino-4-oxothiazolidin-5-yl) methyl]
Benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester was hydrolyzed with 2N hydrochloric acid to give the desired 1- {4-[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-
1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ethyl ester (XXXX) and 1- {4-[(2,4-dioxothiazolidin-5-yl) methyl ] Benzyl} -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Propionic acid (XXXXI) was obtained. Also, 1- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionate ethyl The ester (XXXX) is hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 1- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzyl} -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-propionic acid ( XXXXI) was obtained. The NMR and IR data for this product support the structures (XXXX) and (XXXXI) of the formula:

[0153]

[Chemical 44]

60 MHz NMR (CDCl ₃ , TMS);
δ (ppm) 1.22 (3H, t, J = 7Hz), 2.72
(2H, t, J = 7Hz), 3.00 to 3.75 (2H,
m), 4.14 (2H, q, J = 7Hz), 4.42 (2
H, t, J = 7 Hz), 4.50 (1H, dd, J = 5)
10Hz), 5.56 (2H, s), 7.11-8.77
(7H, ArH) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1760,171
0,1670

[0155]

Embedded image

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 2.70 (2H, t, J =
7.5 Hz), 3.05 (1H, dd, J = 9.9, 14.1H
z), 3.48 (1H, dd, J = 3.8, 14.1Hz),
4.38 (2H, t, J = 7.5Hz), 4.43 (1H,
dd, J = 3.8, 9.9 Hz), 5.53 (2H, s),
7.16 (2H, d, J = 8.2Hz), 7.22 (1H,
dd, J = 4.8, 7.7 Hz), 7.44 (2H, d, J
= 8.2 Hz), 8.45 (1H, dd, J = 1.8, 7.
7 Hz), 8.67 (1 H, dd, J = 1.8, 4.8 Hz) IR (KBr); ν (cm ^-1 ) 1750, 1700, ¹
650

Example 6 3- (4- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Lido [2,3-d] pyrimidine-1-acetic acid ethyl ester
Ter. (XXXXII) Synthesis Method A. 1,2-dihydro-2,4-dioxopyrido [2,3
-D] -3,1-oxazine-1-acetic acid ethyl ester
Synthesis washed sodium hydride in n- hexane Le (in mineral oil 60
%, 0.75 g, 18.6 mmol) in a suspension of N, N-dimethylformamide (30 ml) obtained in Example 1 · A 1,
2-dihydro-2,4-dioxopyrido [2,3-d]-
A mixture of 3,1-oxazine and 1,2-dihydro-2,4-dioxopyrido [3,2-d] -3,1-oxazine (2.8 g, 16.9 mmol) was added little by little under ice cooling, and the mixture was cooled to room temperature. After stirring for 30 minutes at room temperature, a solution of bromoacetic acid ethyl ester (2.1 ml, 18.6 mmol) in N, N-dimethylformamide (10 ml) was added dropwise under ice cooling, and the mixture was further stirred for 1.5 hours. The reaction solution was poured into ice water and the deposited precipitate was collected by filtration. The residue was dissolved in ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired 1,2-dihydro-2,4-dioxopyrido [2,3-d] -3,1-
Oxazine-1-acetic acid ethyl ester (pink solid, 1.
6 g, 37%) was obtained.

B. 2- (N-ethoxycarbonylmethyl)
) Amino-N '-(4-nitrobenzyl) nicotinic acid
Synthesis of amides 1,2-dihydro-2,4-dioxopyrido [2,3-
d] -3,1-Oxazine-1-acetic acid ethyl ester (1.3 g, 5.4 mmol), 4-nitrobenzylamine.
A suspension of the hydrochloride (1.0 g, 5.4 mmol), triethylamine (1.6 ml, 11.8 mmol) in N, N-dimethylformamide (20 ml) was stirred at 60 ° C. for 2 hours. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the obtained residue is recrystallized from ethyl acetate-n-hexane to give the desired 2- (N-ethoxycarbonylmethyl) amino-N '-(4-nitrobenzyl).
Nicotinic acid amide (pale yellow crystals, 1.7 g, 86%) was obtained.

C. 3- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Method for synthesizing pyrimidine-1-acetic acid ethyl ester 2- (N-ethoxycarbonylmethyl) amino-N'-
(4-Nitrobenzyl) nicotinic acid amide (1.7 g,
4.6 mmol), 1,1'-carbonyldiimidazole (3.
8 g, 23.2 mmol) was melted at 130 ° C., and the mixture was further stirred for 1.5 hours. The reaction solution was cooled and the resulting solid was washed by adding ethanol and collected by filtration to obtain the desired 3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2 , 3-d] Pyrimidine-1-acetic acid ethyl ester (milky white solid, 1.1 g, 61%) was obtained.

D. 3- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
Synthesis of 3 -d] pyrimidine-1-acetic acid ethyl ester 3- (4-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester (1.1 g, 2.8 mmo
l) 10% palladium-carbon (0.11 g) in tetrahydrofuran-methanol mixed solution (1: 1, 20 mml)
And was stirred overnight at room temperature under a hydrogen stream. After filtering the reaction solution, the solvent is distilled off under reduced pressure to obtain the desired 3- (4
-Aminobenzyl) -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester (milky white solid, 0.8 g, 83%)
I got

E. 3- (4- {4-[(2,4-dioki
Sothiazolidin-5-yl) methyl] benzenesulfone
Amido} benzyl) -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-1-vinegar
Synthesis of acid ethyl ester 3- (4-aminobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester (0.83 g, 2.3 mmo
l) in dichloromethane solution (10 ml) under ice cooling.
[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride (0.72 g, 2.3
mmol), and then diisopropylethylamine (0.49 ml, 2.8 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was subjected to silica gel column chromatography,
The target 3- (4- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo was obtained from the fraction eluted with 0.5% methanol-chloroform. -1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester (XXXXII) (pale yellow amorphous, 0.65 g,
45%). The NMR of this product is represented by the structure (XX
XXII).

[0162]

Embedded image

60 MHz NMR (CDCl ₃ , TMS); δ
(Ppm) 1.28 (3H, t, J = 7Hz), 2.95 ~
3.55 (2H, m), 4.24 (2H, q, J = 7H
z), 4.55 (1H, t, J = 6Hz), 4.90 (1
H, d, J = 14 Hz), 5.14 (2H, s), 5.40
(1H, d, J = 14Hz), 6.80-8.70 (11
H, ArH)

Example 7 3- (4- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Of Lido [2,3-d] pyrimidine-1-acetic acid (XXXXIII)
Synthesis method 3- (4- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) obtained in Example 6E-2,4-dioxo-1,2 , 3,4
-Tetrahydropyrido [2,3-d] pyrimidine-1-
Acetic acid ethyl ester (0.61 g, 0.98 mmol), 2
A tetrahydrofuran-methanol mixed solution (1: 1, 6 ml) of an aqueous solution of N sodium hydroxide (2.5 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography, and the desired 3- (4- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide} is obtained from the fraction eluted with 1% methanol-chloroform. Benzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid (XXXXIII)
(White amorphous, 0.52 g, 89%) was obtained. The NMR and IR data of this product are shown in the structure (XXXXII
Support I).

[0165]

[Chemical 47]

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.22 (1H, dd, J
= 8.2, 14.1 Hz), 3.37 (1H, dd, J = 4.
0, 14.1Hz), 4.47 (1H, dd, J = 4.0,
8.2Hz), 5.06 (1H, d, J = 14.1Hz), 5.
08 (2H, s), 5.22 (1H, d, J = 14.1H
z), 7.00 (2H, d, J = 8.4Hz), 7.22 (1
H, dd, J = 4.8, 7.7 Hz), 7.25 (2H,
d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4H)
z), 7.67 (2H, d, J = 8.4Hz), 8.44 (1
H, dd, J = 1.9, 7.7 Hz), 8.61 (1 H, d
d, J = 1.9, 4.8 Hz), 9.02 (1 H, s) IR (KBr); ν (cm ⁻¹ ) 1750, 1700, ¹
660, 1160

(Example 8) 3- (4- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Lido [2,3-d] pyrimidine-1-acetic acid ter-bu
Method for the synthesis of chill ester (XXXXIV) A. 1,2-dihydro-2,4-dioxopyrido [2,3
-D] -3,1-oxazine-1-acetic acid ter-butyl
By the same method as Synthesis Example 6 · A of glycol ester, obtained in Example 1 · A 1,2-dihydro-2,4-Okisohi ° dichloride [2,3-d] -3,1-
A mixture of oxazine and 1,2-dihydro-2,4-dioxopyrido [3,2-d] -3,1-oxazine was reacted with bromoacetic acid ter-butyl ester to give the desired 1,2-dihydro-2, 4-dioxopyrido [2,3-
d] -3,1-Oxazine-1-acetic acid ter-butyl ester was obtained.

B. 2- (N-ter-butoxycarbonyl
Rumethyl) aminonicotinic acid amide 1,2-dihydro-2,4-dioxopyrido [2,3-
d] -3,1-Oxazine-1-acetic acid ter-butyl ester (8.0 g, 28.8 mol) in N, N-dimethylformamide solution (50 ml) was added concentrated aqueous ammonia (13.7 m).
l) was added dropwise under ice cooling, and the mixture was further stirred for 3 hours. The reaction mixture was adjusted to pH 8 with 1N hydrochloric acid, and the deposited precipitate was collected by filtration to give the desired 2- (N-ter-butoxycarbonylmethyl) aminonicotinic acid amide (pink powder, 6.1
g, 84%).

C. 2,4-dioxo-1,2,3,4-teto
Lahydropyrido [2,3-d] pyrimidine-1-acetic acid
Synthesis method of ter-butyl ester By the same method as in Example 1 · C, 2- (N-ter-
Butoxycarbonylmethyl) aminonicotinic acid amide (6.0 g, 24.0 mmol) is reacted with 1,1′-carbonyldiimidazole (7.8 g, 48.0 mmol) to give the desired 2,4-dioxo-1, 2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ter-butyl ester was obtained.

D. 3- (4-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] pyrimidine-1-acetic acid ter-butyl ester
Synthesis of 2,4-dioxo- by the same method as in Example 1D.
1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ter-butyl ester is reacted with 4-nitrobenzyl bromide to give the desired 3- (4-nitrobenzyl) -2. , 4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid
ter-Butyl ester was obtained.

E. 3- (4-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] pyrimidine-1-acetic acid ter-butyl ester
Synthesis method of 3- (4-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-1 by the same method as in Example 1 · E. -Acetic acid ter-
The butyl ester was reduced with 10% palladium-carbon to give the desired 3- (4-aminobenzyl) -2,4-
Dioxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-1-acetic acid ter-butyl ester was obtained.

F. 3- (4- {4-[(2,4-dioki
Sothiazolidin-5-yl) methyl] benzenesulfone
Amido} benzyl) -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-1-vinegar
Synthesis of acid ter-butyl ester By the same method as in Example 6 · E, 3- (4-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3- d] pyrimidine-1-acetic acid ter-
Butyl ester is reacted with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride to give the desired 3- (4- {4-[(2,4-
Dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo-1,2,
3,4-Tetrahydropyrido [2,3-d] pyrimidine-
1-Acetic acid ter-butyl ester (XXXXIV) was obtained.
The NMR and IR data of this product are shown by the structure (XXXXI
V) support.

[0173]

Embedded image

400 MHz NMR (CDCl ₃ , TMS);
δ (ppm) 1.49 (9H, s), 3.09 (1H, d
d, J = 4.7, 14.2 Hz), 3.51 (1H, dd,
J = 4.7, 14.2Hz), 4.57 (1H, dd, J =
4.7, 4.7Hz), 4.91 (1H, d, J = 14.2H)
z), 5.01 (1H, d, J = 16.8Hz), 5.08
(1H, d, J = 16.8Hz), 5.43 (1H, d, J
= 14.2Hz), 6.42 (1H, s), 6.86 (2
H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.
4Hz), 7.26 (1H, dd, J = 4.8, 7.9H
z), 7.29 (2H, d, J = 8.4Hz), 7.54 (2
H, d, J = 8.4 Hz), 8.51 (1H, dd, J =
1.8, 7.9 Hz), 8.63 (1H, dd, J = 1.
8,4.8 Hz) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1740,171
0,1660,1160

Example 9 3- (3- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydr
Lopyrido [2,3-d] pyrimidine-1-ethyl acetate
Synthesis of ester (XXXXV) A. 2- (N-ethoxycarbonylmethyl) amino-
Synthesis of N '-(3-nitrobenzyl) nicotinic acid amide
By the same method as the law Example 6 · B, obtained in Example 6 · A 1,2-dihydro-2,4 Jiokisopirido [2,3
-D] -3,1-Oxazine-1-acetic acid ethyl ester was reacted with 3-nitrobenzylamine · hydrochloride to give the desired 2- (N-ethoxycarbonylmethyl) amino-N ′-(3-nitrobenzyl ) Nicotinic acid amide was obtained.

B. 3- (3-nitrobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Method for synthesizing pyrimidine-1-acetic acid ethyl ester 2- (N-ethoxycarbonylmethyl) amino-N '-(3-nitrobenzyl) nicotinic acid amide and 1,2) were prepared by the same method as in Example 6C. By reacting 1'-carbonyldiimidazole, the target 3- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-1- Acetic acid ethyl ester was obtained.

C. 3- (3-aminobenzyl) -2,4
-Dioxo-1,2,3,4-tetrahydropyrido [2,3
-D] Synthesis method of pyrimidine-1-acetic acid ethyl ester 3- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido was prepared in the same manner as in Example 6D. Reduction of [2,3-d] pyrimidine-1-acetic acid ethyl ester (1.1 g, 2.8 mmol) to give the desired 3
-(3-aminobenzyl) -2,4-dioxo-1,2,
3,4-Tetrahydropyrido [2,3-d] pyrimidine-
1-Acetic acid ethyl ester was obtained.

D. 3- (3- {4-[(2,4-dioki
Sothiazolidin-5-yl) methyl] benzenesulfone
Amido} benzyl) -2,4-dioxo-1,2,3,4-
Tetrahydropyrido [2,3-d] pyrimidine-1-vinegar
Synthesis of acid ethyl ester 3- (3-aminobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] was prepared in the same manner as in Example 6E. Pyrimidine-1-acetic acid ethyl ester and 4-[(2,4-dioxothiazolidine-5-
3- (3- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo -1,2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester (XXXXV) was obtained. The NMR data for this product supports the structure of the formula (XXXXV):

[0179]

[Chemical 49]

60 MHz NMR (CDCl ₃ , TMS); δ
(Ppm) 1.26 (3H, t, J = 7Hz), 3.30
(2H, d, J = 6Hz), 4.23 (2H, q, J = 7H
z), 4.54 (1H, t, J = 6Hz), 5.09 (2
H, s), 5.14 (2H, s), 6.90-8.70
(11H, ArH)

(Example 10) 3- (3- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Of Lido [2,3-d] pyrimidine-1-acetic acid (XXXXVI)
Synthetic Method By a method similar to that in Example 7, 3-
(3- {4-[(2,4-dioxothiazolidine-5-
Il) methyl] benzenesulfonamide} benzyl)-
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid ethyl ester is hydrolyzed to give the desired 3- (3- {4-[(2 , 4
-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrido [2,3-d] pyrimidine-1-acetic acid (XXXXVI) was obtained. NMR and I of this product
The R data supports the structure of the formula (XXXXVI):

[0182]

Embedded image

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.19 (1H, dd, J
= 8.4, 14.1 Hz), 3.38 (1H, dd, J = 4.
0, 14.1Hz), 4.46 (1H, dd, J = 4.0,
8.4Hz), 5.12 (2H, d, J = 16.6Hz), 5.
13 (2H, d, J = 16.6Hz), 7.00 (1H,
s), 7.10 to 7.18 (3H, m), 7.23 (1
H, dd, J = 4.8, 7.8 Hz), 7.25 (2H,
d, J = 8.4Hz), 7.69 (2H, d, J = 8.4H)
z), 8.20 (1H, s), 8.44 (1H, dd, J
= 1.8, 7.8 Hz), 8.62 (1H, dd, J = 1.
8,4.8 Hz) IR (KBr); ν (cm ^-1 ) 1750, 1700, ¹
670, 1160

(Example 11) 1- (4- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Lido [2,3-d] pyrimidine-3-acetic acid ethyl ester
Synthesis of ter (XXXXVII) 1-E obtained in Example 1E by the method of Example 6E
(4-aminobenzyl) -2,4-dioxo-1,2,3,
4-Tetrahydropyrido [2,3-d] pyrimidine-3
-Acetic acid ethyl ester was reacted with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride to give the desired 1- (4- {4-
[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-acetic acid ethyl ester (XXXXVI
I) got. The NMR and IR data for this product support the structure of the formula (XXXXVII):

[0185]

[Chemical 51]

400 MHz NMR (CDCl ₃ , TMS);
δ (ppm) 1.29 (3H, t, J = 7.1Hz), 3.1
6 (1H, dd, J = 4.2, 13.9Hz), 3.46
(1H, dd, J = 5.5, 13.9Hz), 4.24 (2
H, q, J = 7.1Hz), 4.56 (1H, dd, J =
4.2, 5.5Hz), 4.85 (2H, s), 5.23 (1
H, d, J = 14.7Hz), 5.75 (1H, d, J = 1)
4.7Hz), 6.48 (1H, s), 6.87 (2H,
d, J = 8.4Hz), 7.21 (2H, d, J = 8.4H)
z), 7.25 (2H, d, J = 8.4Hz), 7.29 (1
H, dd, J = 4.8, 7.7 Hz), 7.58 (2H,
d, J = 8.4 Hz), 8.51 (1H, dd, J = 1.
8, 7.7 Hz), 8.71 (1H, dd, J = 1.8, 4.
8 Hz) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1760, 171
0,1670,1160

Example 12 1- (4- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Lido [2,3-d] pyrimidine-3-acetic acid (XXXXVIII)
By the same method as Synthesis Example 7 was obtained in Example 11 1-
(4- {4-[(2,4-dioxothiazolidine-5-
Il) methyl] benzenesulfonamide} benzyl)-
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 1- ( 4- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide}
Benzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid (XXXXV
III). NMR and IR data for this product support the structure of the formula (XXXXVIII):

[0188]

Embedded image

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.18 (1H, dd, J
= 8.8, 14.1 Hz), 3.42 (1 H, dd, J = 4.
0, 14.1Hz), 4.46 (1H, dd, J = 4.0,
8.8Hz), 4.78 (2H, s), 5.40 (1H,
d, J = 14.5 Hz), 5.51 (1H, d, J = 14.4.
5Hz), 7.04 (2H, d, J = 8.6Hz), 7.23
(1H, dd, J = 4.8, 7.9Hz), 7.25 (2
H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.
6Hz), 7.69 (2H, d, J = 8.4Hz), 8.45
(1H, dd, J = 2.0, 7.9Hz), 8.65 (1
H, dd, J = 2.0,4.8 Hz) IR (KBr); ν (cm ⁻¹ ) 1750,1700,1
670, 1160

Example 13 1- (3- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Lido [2,3-d] pyrimidine-3-acetic acid ethyl ester
Synthesis method of ter (XXXXIX) 1- (3-aminobenzyl) -2,4-dioxo-1, obtained in Example 2 · B was prepared by the same method as in Example 6 · E.
Reaction of 2,3,4-tetrahydropyrido [2,3-d] pyrimidin-3-acetic acid ethyl ester with 4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonyl chloride 1- (3- {4
-[(2,4-Dioxothiazolidin-5-yl) methyl] benzenesulfonamide} benzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-
d] Pyrimidine-3-acetic acid ethyl ester (XXXXIX)
I got NMR and IR data for this product support the structure of the formula (XXXXXIX):

[0191]

Embedded image

60 MHz NMR (CDCl ₃ , TMS); δ
(Ppm) 1.27 (3H, t, J = 7Hz), 3.30
(2H, d, J = 6Hz), 4.23 (2H, q, J = 7H
z), 4.53 (1H, t, J = 6Hz), 4.82 (2
H, s), 5.46 (2H, s), 6.95-8.75
(11H, ArH), 9.00 (1H, brs) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1760, 171
0,1670,1160

Example 14 1- (3- {4-[(2,4-dioxothiazolidine-
5-yl) methyl] benzenesulfonamide} benz
) -2,4-Dioxo-1,2,3,4-tetrahydropi
Combination of Lido [2,3-d] pyrimidine-3-acetic acid (XXXXX)
In the same manner as in Production Example 7, 1-obtained in Example 13
(3- {4-[(2,4-dioxothiazolidine-5-
Il) methyl] benzenesulfonamide} benzyl)-
2,4-Dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid ethyl ester was hydrolyzed with 2N aqueous sodium hydroxide solution to give the desired 1- ( 3- {4-[(2,4-dioxothiazolidin-5-yl) methyl] benzenesulfonamide}
Benzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine-3-acetic acid (XXXX
X). NMR and IR data for this product support the structure of the formula (XXXXX):

[0194]

[Chemical 54]

400 MHz NMR (CDCl ₃ , DMSO-
d ₆ , TMS); δ (ppm) 3.13 (1H, dd, J
= 9.3, 14.1 Hz), 3.45 (1H, dd, J = 3.
8, 14.1Hz), 4.45 (1H, dd, J = 3.8,
9.3 Hz), 4.79 (2H, s), 5.46 (2H,
s), 7.01 to 7.16 (4H, m), 7.22 (2
H, d, J = 8.6 Hz), 7.23 (1H, dd, J =
4.8, 7.9Hz), 7.68 (2H, d, J = 8.6H
z), 8.46 (1H, dd, J = 2.0, 7.9Hz),
8.64 (1H, dd, J = 2.0, 4.8Hz), 8.92
(1H, s), 11.33 (1H, brs) IR (CHCl ₃ ); ν (cm ⁻¹ ) 1750,170
0,1660,1160

(Test Example) Next, the results of a pharmacological test showing the effectiveness of the pyridopyrimidine derivative of the present invention will be described. Similar effects were also observed for the pyridopyrimidine derivatives of the present invention, which are not exemplified in this test example.

(1) For the hypoglycemic effect experiment, KK / Ta Jcl male mice of 13 to 20 weeks of age 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 cage, and the pyridopyrimidine derivative of the present invention was orally administered twice a day at a dose of 100 mg / kg. 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.

[0198]

[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, 19
65 years] and adjusted aldose reductase. Measurement of aldose reductase activity was performed by Dufran.
e) et al. [Biochemical Medicine (Biochem.m
ed.), 32, 99-105, 1984]. Ie 10
0 mM lithium sulfate, 0.03 mM NADPH (reduced nicotinamide adenine dinucleotide phosphate)
And 135 mM sodium-potassium-adjusted to contain 0.1 mM DL-glyceraldehyde as substrate
To 400 μl of a phosphate buffer (pH 7.0), 50 μl of the above aldose reductase and 50 μl of the pyridopyrimidine derivative of the present invention (dissolved in ethanol) at various concentrations were added,
The reaction was carried out at 30 ° C for 30 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 (nicotinamide adenine dinucleotide) produced by the above reaction. Phosphate) is converted to a fluorescent substance, and 60
The fluorescence intensity was measured after a minute. Fluorescence intensity is M at room temperature
The measurement was performed using a TP-100F corona microplate reader (Corona Electric Co., Ltd.) under the conditions of an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm. Further, the fluorescence intensity measured by the same reaction 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 are shown in Table 1.

[0201]

[Table 1]

(Acute toxicity) Using an ICR male mouse (5-week life), an acute toxicity test by oral administration was conducted.
The LD ₅₀ values of the pyridopyrimidine derivatives of the present invention were all 300 mg / kg or more, confirming high safety.

[0203]

INDUSTRIAL APPLICABILITY The novel pyridopyrimidine derivative represented by the general formula (I) of the present invention has both hypoglycemic action and AR inhibitory action, and a pharmaceutical composition containing it has, for example, cataract, neurosis, It is effective as a drug for the prevention and therapeutic treatment of various complications of diabetes such as retinopathy and renal disorder.

Claims (8)

[Claims] 1. A pyridopyrimidine derivative represented by the general formula (I). Embedded image [In the formula (I), any one of A ¹ , A ² , A ³ , and A ⁴ represents a —N = group exclusively, and the other three represent a —CH = group. X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a haloalkyl group. R ¹ and R ² are exclusively —R ³ —COOR ⁴ (R ³ is an alkylene group having 1 to ³ carbon atoms, R ⁴ is hydrogen or a lower alkyl group having 1 to 8 carbon atoms), or general It is a group represented by formula (II) or (III). ] [Chemical 2] [In the formula (II), B represents a methylene group or a divalent group represented by the formula (IV), and T represents a heterocyclic group having weakly acidic hydrogen. ] [Chemical 3] [In the formula (III), m represents an integer of 1 to 8, and Q represents the formula (I
V) is a divalent group represented by V), and T is a heterocyclic group 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-. ] 2. The pyridopyrimidine derivative according to claim 1, wherein T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and B is a methylene group. 3. T in the general formula (II) is a 2,4-dioxothiazolidin-5-yl group, and B is the general formula (IV).
The pyridopyrimidine derivative according to claim 1, which is a group represented by: 4. T in the general formula (III) is a 2,4-dioxothiazolidin-5-yl group, and Q is the general formula (IV).
The pyridopyrimidine derivative according to claim 1, which is a group represented by: 5. A pharmaceutical composition comprising the pyridopyrimidine derivative according to claim 1. 6. A pharmaceutical composition comprising the pyridopyrimidine derivative according to claim 2. 7. A pharmaceutical composition comprising the pyridopyrimidine derivative according to claim 3. 8. A pharmaceutical composition comprising the pyridopyrimidine derivative according to claim 4.