JPH08269019A - Carboxyalkyl heterocyclic derivative - Google Patents

Abstract

PURPOSE: To obtain a new compound, having excellent inhibiting actions with high enzymic selectivity on aldose reductases participating in the production of sorbitol and useful as a preventing and therapeutic agent for diabetic complications. CONSTITUTION: A compound of the formula [two of Ra to Rc are 0 and the remaining one is S, a lower alkylene, etc.; X is benzyl, benzothiazolylmethyl, etc.; R is H or a lower alkyl; (n) is 1-3; Z is a direct bond (in this case, the heterocyclic ring is a 5-membered one) or a bond through one C atom (in this case, the heterocyclic ring is a 6-membered one)], e.g. 3-(3-nitrobenzyl)-5- methylidene-2,4-dioxoimidazolidine-1-acetic acid. This compound is obtained by reacting, e.g. an oxamic acid having a group corresponding to the substituent group X with glycine esterified with trimethylsilylethyl, etc., then refluxing the resultant product with sodium acetate in acetic anhydride and subsequently hydrolyzing the prepared product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carboxyalkyl heterocyclic derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.

[0002]

2. Description of the Related Art As intractable chronic diseases associated with diabetes, diabetic neuropathy, diabetic cataract and diabetic retinopathy,
Although diabetic microangiopathy such as diabetic nephropathy and diabetic skin disorder are known, the involvement of the polyol metabolism system can be mentioned as a cause of these diabetic complications.

That is, when diabetes leads to a hyperglycemic state, glucose utilization via the polyol metabolic pathway is several times higher than in the normal state, and sorbitol production by aldose reductase is enhanced, so that peripheral nerves, retina, kidney, lens, It is considered that excessive accumulation of intracellular sorbitol occurs in arteries and the like, which causes cellular edema and dysfunction due to abnormal intracellular osmotic pressure. Therefore, inhibitors of aldose reductase are considered to be effective in the treatment and prevention of diabetic complications and are being studied.

[0004]

However, the conventional aldose reductase inhibitors have a problem that they also strongly inhibit enzymes not involved in the polyol metabolic pathway, such as aldehyde reductase.

[0007] Therefore, the present inventors have studied an inhibitor having a high enzyme selectivity for aldose reductase involved in the production of sorbitol for the purpose of treating and preventing the above-mentioned diabetic complications. Invention The present invention was completed by finding that the carboxyalkyl heterocyclic derivative has an excellent inhibitory action with high enzyme selectivity for aldose reductase.

[0006]

The object of the present invention is to provide a novel carboxyalkyl heterocyclic derivative having a high enzyme selectivity for aldose reductase and an excellent inhibitory action, a pharmaceutically acceptable salt thereof, and It is intended to provide a therapeutic agent for diabetic complications, which comprises a compound as an active ingredient.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The carboxyalkyl heterocyclic derivative of the present invention is a compound represented by the following general formula (A).

[Chemical 4] [In the formula, two of R _a , R _b and R _c represent oxygen,
The other one represents a combination of sulfur, a lower alkylene group, unsubstituted or hydrogen and a hydroxyl group, and X is substituted with a benzyl group, a nitro group and / or a halogen which may be substituted with a nitro group and / or a halogen. Optionally a benzothiazolylmethyl group, a nitro group and / or a naphthylmethyl group optionally substituted with halogen, R represents hydrogen or a lower alkyl group, and n represents an integer of 1 to 3,
Z represents a direct bond (in this case, the heterocycle represents a 5-membered ring) or a bond via one carbon atom (in this case, the heterocycle represents a 6-membered ring). ]

More specifically, the dioxoimidazolidine derivative represented by the following general formula (I) and the general formula (II)
Is a dioxopyrimidine derivative represented by

Embedded image In the above general formula (I), _{two of} R ₁ , R ₂ and R ₃ represent oxygen, and the other one is sulfur, a lower alkylene group, preferably 1 to 3 carbon atoms such as methylene, ethylene and propylene. , An alkylene group, particularly preferably a methylene group, unsubstituted (bonding two hydrogens) or a combination of hydrogen and a hydroxyl group. In addition, R ₄ and R _{5 in the} general formula (II)
One is oxygen and the other one is unsubstituted.

In the general formula (I) or (II), X is a nitro group and / or a benzyl group which may be substituted with halogen such as fluorine, chlorine, bromine and iodine, a nitro group and / or fluorine, chlorine, Represents a benzothiazolylmethyl group optionally substituted with halogen such as bromine and iodine, a nitro group and / or a naphthylmethyl group optionally substituted with halogen such as fluorine, chlorine, bromine and iodine, and R is Hydrogen or a lower alkyl group, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, te
represents an alkyl group having 1 to 4 carbon atoms such as rt-butyl,
n is an integer of 1 to 3, and preferably n is 1.
Two broken lines in the general formula (II) are R ₄ and R ₅
The oxygen-substituted side of is a single bond, and the remaining one is a double bond.

The carboxyalkyl heterocyclic derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the above general formula, for example, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium. Examples thereof include salts with metals or metals such as aluminum, or salts with bases such as ammonia and organic amines.

These salts can be prepared from the free carboxyalkylheterocyclic derivative of the present invention or converted into each other by a known method. Further, when the substance of the present invention has stereoisomers such as cis-trans isomers, optical isomers and conformational isomers, the present invention includes any of them.

The carboxyalkyl heterocyclic derivative of the present invention can be produced, for example, by the following method. (1) In the case of a dioxoimidazolidine derivative in which R ₃ of the general formula (I) is a methylene group, first, oxamic acid having a group corresponding to the substituent X is reacted with glycine esterified with trimethylsilylethyl or the like. , X-substituted-oxamide acetate ester form is obtained. This is refluxed with sodium acetate or the like in acetic anhydride to obtain an ester of 3-X-substituted-2-methylidene-4,5-dioxoimidazolidine-1-carboxylic acid, and then an ester such as trimethylsilylethyl. The compound of the present invention in which R is hydrogen can be produced by hydrolysis.

(2) In the case of a dioxoimidazolidine derivative in which R ₃ of the general formula (I) is sulfur, thiourea having a carboxyalkyl group esterified with a group corresponding to the substituent X is converted to oxalyl. 3 by reacting with chloride
The ester of the present invention of -X-substituted-4,5-dioxo-2-thioxoimidazolidine-1-carboxylic acid can be produced. This ester form can be obtained by the usual hydrolysis to obtain the compound of the present invention in which R is hydrogen.

(3) In the case of the dioxoimidazolidine derivative in which R ₁ of the general formula (I) is unsubstituted, first, the substituent X
X-substituted -N, N'- by reacting an aminoacetate having a group corresponding to
Bis (alkoxycarbonylalkyl) urea is obtained. This is refluxed in a mixed solvent of acetic acid and concentrated hydrochloric acid to produce 1-X-substituted-2,4-dioxoimidazolidine-3-carboxylic acids.

(4) In the case of the dioxoimidazolidine derivative in which R ₂ of the general formula (I) is unsubstituted, 2,4-dioxoimidazolidine-1-carboxylic acid alkyl ester and halogen, hydroxyl group, lower alkyl -SO ₂ -O- group or optionally substituted with a lower alkyl group phenyl -S
The ester compound of the present invention can be obtained by reacting the substituent X compound bonded to the O ₂ —O— group and introducing the substituent X into the dioxoimidazolidine skeleton. Similar to the above, this ester can be subjected to ordinary hydrolysis to produce the compound of the present invention in which R is hydrogen.

(5) In the case of a dioxoimidazolidene derivative in which R ₁ of the general formula (I) is a methylene group, alkyl isocyanatocarboxylate is reacted with 2-X-substituted methyl-amino-3-hydroxypropionate. Then, by treating with an alkali such as potassium hydroxide or sodium hydroxide in a solvent of water or alcohol, 1-X substitution-5-
Methylidene-2,4-dioxoimidazolidine-3-carboxylic acids can be prepared.

(6) In the case of a dioxoimidazolidine derivative in which R ₂ of the general formula (I) is a methylene group, 3-X-substituted-5-benzylthiooxymethylimidazolidine-2,
Treatment of 4-dione with sodium hydride followed by reaction with alkyl halide carboxylate to give 3-X substituted-5-
Methylidene-2,4-dioxoimidazolidine-1-carboxylate alkyls can be prepared. Similar to the above, this ester can be subjected to ordinary hydrolysis to produce the compound of the present invention in which R is hydrogen.

(7) In the case of a dioxoimidazolidine derivative in which R ₁ of the general formula (I) is hydrogen or a hydroxyl group, first, N—X substituted urea is reacted with 2-benzyloxy-2-hydroxyacetate benzyl. To give 5-hydroxy-1-X-substituted-2,4-dioxoimidazolidine. Then, an alkyl halide carboxylate is reacted to give 5-hydroxy-1-X-substituted-2,4-dioxoimidazolidine-3-
Alkyl carboxylates can be prepared. This ester form can be converted to the compound of the present invention in which R is hydrogen by ordinary hydrolysis as described above.

(8) In the case of a dioxoimidazolidine derivative in which R ₂ of the general formula (I) is hydrogen and a hydroxyl group, N-
Reacting alkyl carbamoylaminocarboxylate with benzyl 2-benzyloxy-2-hydroxyacetate to give 5
-Hydroxy-2,4-dioxoimidazolidine-1-
After obtaining the alkyl carboxylate, a substituent X compound bonded to a phenyl-SO ₂ —O— group which may be substituted with a halogen, a hydroxyl group, a lower alkyl-SO ₂ —O— group or a lower alkyl group is reacted. The ester of the present invention can be obtained by introducing the substituent X into the dioxoimidazolidine skeleton. Similar to the above, this ester can be subjected to ordinary hydrolysis to produce the compound of the present invention in which R is hydrogen.

(9) In the case of the dioxopyrimidine derivative in which R _{5 in the} general formula (II) is unsubstituted, alkyl 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-carboxylate is used. after treatment with sodium hydride, halogen, hydroxyl, lower alkyl -SO ₂ -O- group or a lower alkyl phenyl which may be substituted with a group -SO ₂ -
By reacting the substituent X compound bonded to the O-group and introducing the substituent X into the dioxopyrimidine skeleton, 3-
X-substituted-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-carboxylate alkyls can be obtained. This ester form can be converted into the compound of the present invention in which R is hydrogen by ordinary hydrolysis.

(10) In the case of the dioxopyrimidine derivative of the general formula (II) in which R ₄ is unsubstituted, 3-X-substituted-uracil is treated with sodium hydride and then reacted with an alkyl halide carboxylate. , 1-X-substituted-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-3
-Alkyl carboxylates can be obtained. Similar to the above, this ester can be subjected to ordinary hydrolysis to produce the compound of the present invention in which R is hydrogen.

The compound of the present invention can be made into a medicine by combining with a suitable medicinal carrier or diluent, and can be formulated by any ordinary method. It can be solid, semi-solid for oral or parenteral administration, It can be formulated in liquid or gas dosage forms. In formulating, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention can be used alone or in an appropriate combination, or a combination with another pharmaceutically active ingredient. It may be.

As an oral administration agent, as it is or together with a suitable additive such as lactose, mannitol, corn starch, potato starch and the like conventional excipients, crystalline cellulose, cellulose derivative, gum arabic, corn starch, gelatin, etc. Binders, corn starch, potato starch, disintegrating agents such as potassium carboxymethyl cellulose, talc, lubricants such as magnesium stearate, other extenders, wetting agents, buffers, preservatives, perfumes and the like are appropriately combined. It can be tablets, powders, granules or capsules.

Further, the compound of the present invention may be mixed with various bases such as oleaginous bases such as cacao butter, emulsion bases or water-soluble bases such as macrogol, hydrophilic bases and the like to form suppositories. Good.

As the injection, an aqueous solvent or a non-aqueous solvent,
For example, it may be a solution or suspension of distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol or the like.

For use as an inhalant or an aerosol, the compound of the present invention is in the form of a solution, suspension or fine powder,
Fill in aerosol containers with a gas or liquid propellant and, if desired, conventional auxiliaries such as wetting or dispersing agents. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer.

For formulation as an eye drop, a solution or suspension can be prepared by using an aqueous solvent such as sterilized purified water or physiological saline or a non-aqueous solvent for injection, which is commonly used for preservation. Agents, preservatives, bactericides and the like can be added as appropriate.

Further, depending on the type of disease, it is possible to formulate into a dosage form other than the above which is most suitable for the treatment, such as an ointment or a poultice.

Although the desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period and the like, in order to obtain the desired effect, generally 10 to 10 days of the compound of the present invention are administered to an adult. Oral administration can be performed at 3,000 mg, preferably 20 to 1,500 mg. In the case of parenteral administration (for example, injection), the daily dose is preferably at a dose level of 3 to 1/10 of the above dose.

[0030]

EXAMPLE The produced compound of the present invention was purified by a conventional means such as distillation, chromatography, recrystallization and the like, and identified by elemental analysis, melting point measurement, IR, NMR, MS and the like. An example of a method for producing the compound of the present invention will be shown below by Examples.

Example 1. (1) 6.96 g of N- (3-nitrobenzyl) oxamic acid, 6.8 g of glycine 2- (trimethylsilyl)
A reaction mixture consisting of 150 mL of methylene chloride solution containing ethyl ester and 0.1 g of 4-N, N′-dimethylaminopyridine was treated at 0 ° C. with 8.62 g of water-soluble carbodiimide hydrochloride. After stirring at room temperature for 20 hours, it was poured into water and extracted several times with methylene chloride. The extracts were combined, washed with saturated saline, dried over sodium sulfate, and then concentrated. After purified by silica gel column, recrystallized from ethyl acetate-acetone mixed solvent to give 4.41
g of N-2- (trimethylsilyl) ethyl-N '-(3
-Nitrobenzyl) oxamide acetate was obtained.

(2) 4.90 g of the above product and 3.3
5 g of sodium acetate was refluxed in acetic anhydride for 2 days.
The reaction mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate three times. The extracts were combined, washed with a saturated sodium hydrogen carbonate solution and a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column and then recrystallized from a mixed solvent of ethyl acetate-acetone to give 2.19 g of 2- (trimethylsilyl) ethyl 3- (3-nitrobenzyl) -2-methylidene-.
4,5-Dioxoxoimidazolidine-1-acetate was obtained.

(3) 20 mL of 0.76 g of the above product
Was dissolved in a mixed solvent of tetrahydrofuran and 10 mL of hexane, 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added at room temperature, and the mixture was vigorously stirred for 2.5 hours. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate and then concentrated. Recrystallized from ethanol to give 3- (3-nitrobenzyl) -2-methylidene-4,
5-Dioxoimidazolidine-1-acetic acid [Compound 1] was obtained. Melting point: 160.0-160.5 ° C MS (EI, 70eV): 305 (M +, 30), 288 (32), 176 (30), 136 (10
0), 100 (45), 90 (91), 89 (65), 54 (56) IR (KBr): 3020 (OH), 1740 (C = O), 1684 (C = O), 1533 (N
O ₂ ), 1437, 1348 (NO ₂ ), 1192 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.10 (s, 2H, NCH ₂ CO), 4.47 (s, 1H, C
H ₂ =), 4.52 (s, 1H, CH ₂ =), 4.70 (d, J = 16.2Hz, 1H, CH ₂ Ar),
4.80 (d, J = 16.2Hz, 1H, CH ₂ Ar), 7.65 (dd, J = 12.3,8.4Hz, 1
H, Ar), 7.83 (d, J = 12.3Hz, 1H, Ar), 8.16 (d, J = 8.4Hz, 1H, A
r), 8.24 (s, 1H, Ar), 12.96 (brs, 1H, OH) Elemental analysis (C ₁₃ H ₁₁ N ₃ O ₆ 0.9H ₂ O): Calculated value (C = 48.57, H = 4.0
1, N = 13.07), measured value (C = 48.84, H = 3.92, N = 12.77)

Embodiment 2 FIG. (1) 3.0 g of N- (ethoxycarbonylmethyl)-
To N '-(3-nitrobenzyl) urea, add 30 mL of 1,
5.0 g of Lawesson's reagent dissolved in 4-dioxane was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was extracted several times with ethyl acetate, the extracts were combined and washed with saturated saline,
It was dried over sodium sulfate and concentrated. The residue was purified by silica gel column to obtain 2.5 g of N- (ethoxycarbonylmethyl) -N '-(3-nitrobenzyl) thiourea.

(2) 2.5 g of the above product was dissolved in 10 mL of methylene chloride, and this was added dropwise to 10 mL of methylene chloride solution containing 1.0 mL of oxalyl chloride at room temperature. The reaction mixture was stirred at room temperature for 8 hours and then concentrated under reduced pressure. Purify with silica gel column to
(3-Nitrobenzyl) -4,5-dioxo-2-thioxoimidazolidine-1-ethyl acetate was obtained.

(3) The above product was refluxed in a mixed solvent of 4.5 mL of acetic acid and 1.5 mL of hydrochloric acid for 1 hour and then concentrated. 4.5 mL acetic acid and 1.5 mL hydrochloric acid were added to the residue and refluxed for 1 hour. After concentration, the residue was recrystallized from a mixed solvent of ethanol-hexane to give 0.23 g of 3- (3
-Nitrobenzyl) -4,5-dioxo-2-thioxoimidazolidine-1-acetic acid [Compound 2] was obtained. Melting point: 188.0-188.5 ° C MS (EI, 70eV): 323 (M +, 67), 177 (55), 161 (63), 136 (9
0), 90 (100) IR (KBr): 3000 (OH), 1784 (C = O), 1722 (C = O), 1531 (N
O ₂ ), 1435 (C = S), 1346 (NO ₂ ), 1113 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.56 (s, 2H, NCH ₂ CO), 5.20 (s, 2H,
CH ₂ Ar), 7.65 (dd, J = 8.0,7.3Hz, 1H, Ar), 7.83 (d, J = 7.7H
z, 1H, Ar), 8.16 (d, J = 8.0Hz, 1H, Ar), 8.26 (s, 1H, Ar), 1
3.38 (brs, 1H, OH) Elemental analysis (C ₁₂ H ₉ N ₃ O ₆ S): Calculated value (C = 44.58, H = 2.81, N = 1
3.00), measured value (C = 44.55, H = 2.98, N = 12.79)

Example 3. (1) 50 mL of an ether solution in which 5.3 g of N-benzylaminoacetate was dissolved was added to a 50 mL ether solution containing 3.4 mL of ethylisocyanate acetate at room temperature and vigorously stirred for 14 hours. After the reaction mixture was concentrated, it was purified by a silica gel column and 5.5 g of N-
Benzyl-N, N'-bis (ethoxycarbonylmethyl) urea was obtained. Melting point: 64.0-65.0 ° C

(2) A mixture of 1.7 g of the above product dissolved in 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid was refluxed for 4 hours. After the solvent was distilled off, 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid were further added, and the mixture was stirred for 2 hours. After concentrating and washing well with water, it was recrystallized from ethanol to obtain 1.2 g of 1-benzyl-2,4-dioxoimidazolidine-3-acetic acid [compound 3]. Melting point: 139.5-141.0 ℃ MS (EI, 70eV): 248 (M +, 27), 202 (24), 189 (11), 132 (3
4), 118 (39), 91 (100), 65 (32) IR (KBr): 2940 (OH), 1759 (C = O), 1749 (C = O), 1684 (C =
O), 1470, 1207, 752, 702 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 3.99 (s, 2H, NCH ₂ CO), 4.11 (s, 2H, NCH
₂ CO), 4.53 (s, 2H, CH ₂ Ar), 7.20-7.40 (m, 5H, Ar), 13.15
(brs, 1H, OH) Elemental analysis (C ₁₂ H ₁₂ N ₂ O ₄ ): Calculated value (C = 58.06, H = 4.87, N = 1
1.28), measured value (C = 57.54, H = 5.00, N = 11.02)

(3) Using N- (3-nitrobenzyl) aminoacetate as a starting material, in the same manner as above,
1- (3-Nitrobenzyl) -2,4-dioxoimidazolidine-3-acetic acid [Compound 4] was obtained. Melting point: 168.0-170.0 ° C MS (EI, 70eV): 293 (M +, 6), 276 (85), 246 (20), 163 (24),
147 (31), 136 (97), 90 (100), 56 (55), 42 (88) IR (KBr): 3100 (OH), 1774 (C = O), 1745 (C = O), 1714 ( C =
O), 1533 (NO ₂ ), 1469, 1359 (NO ₂ ), 1238, 1151, 752, 7
00 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.08 (s, 2H, NCH ₂ CO), 4.12 (s, 2H, N
CH ₂ CO), 4.68 (s, 2H, CH ₂ Ar), 7.67 (dd, J = 8.6,7.7Hz, 1H, A
r), 7.76 (d, J = 7.7Hz, 1H, Ar), 8.16 (s, 1H, Ar), 8.17 (d, J
= 8.6Hz, 1H, Ar), 13.20 (brs, 1H, OH) Elemental analysis (C ₁₂ H ₁₁ N ₃ O ₆ ): Calculated value (C = 49.15, H = 3.78, N = 1)
4.33), measured value (C = 49.02, H = 3.84, N = 14.13)

Example 4. (1) 24.0 mL of concentrated hydrochloric acid was slowly added dropwise to a 350 ml aqueous solution containing 27.5 g of iminodiacetic acid diethyl ester and 23.3 g of potassium cyanate. After stirring at room temperature for 18 hours, the mixture was concentrated under reduced pressure. The residue was extracted several times with ethyl acetate, the extracts were combined and dried over sodium sulfate. After concentration, recrystallize from ethanol and
1.1 g of 2,4-dioxoimidazolidine-1-ethyl acetate was obtained as white crystals.

(2) A solution of 815 mg of the above product in 30 mL of dimethylformamide was added dropwise to a solution of 221 mg of sodium hydride suspended in 20 mL of dimethylformamide at 0 ° C or lower. After stirring for another hour under the same temperature condition, a dimethylformamide solution (30 m) containing 1.3 g of 3-nitrobenzyl bromide.
L) was added dropwise at 0 ° C. After stirring for 2 hours, the reaction mixture was added to ice-cooled 2N hydrochloric acid with vigorous stirring. The obtained reaction mixture was extracted several times with ethyl acetate, the extract was washed with saturated saline and then concentrated to obtain a residue. This was purified with a silica gel column to give 1.32 g of 3- (3-
Nitrobenzyl) -2,4-dioxoimidazolidine-
1-Ethyl acetate was obtained.

(3) 1.7 g of the above product was refluxed in a mixed solvent of 12 mL of acetic acid and 4 mL of concentrated hydrochloric acid for 1 hour. After distilling off the solvent, another 12 mL acetic acid and 4 mL
Of concentrated hydrochloric acid was added, and the mixture was refluxed for 1 hour. Pour this into a mixed solution of ethyl acetate and 10% sodium hydroxide,
After extracting several times with 10% sodium hydroxide, this aqueous extract layer was back-extracted several times with ethyl acetate. The extracts were combined, dried over sodium sulfate, concentrated, and recrystallized from ethanol to give 350 mg of 3- (3-nitrobenzyl) -2,4-dioxoimidazolidine-1-acetic acid [compound 6]. Obtained. Melting point: 165.0-166.0 ° C MS (EI, 70eV): 277 (M-OH +, 8), 276 (21), 248 (67), 232 (4
5), 219 (23), 161 (66), 136 (59), 91 (100), 89 (86), 77
(63) IR (KBr): 2990 (OH), 1789 (C = O), 1732 (C = O), 1686 (C =
O), 1525 (NO ₂ ), 1464, 1351 (NO ₂ ), 1217, 949, 756 cm
^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.08 (s, 2H, NCH ₂ CO), 4.10 (s, 2H, N
CH ₂ CO), 4.73 (s, 2H, CH ₂ Ar), 7.65 (dd, J = 7.9,7.4Hz, 1H, A
r), 7.74 (d, J = 7.9Hz, 1H, Ar), 8.14 (s, 1H, Ar), 8.16 (d, J
= 7.4Hz, 1H, Ar), 13.09 (brs, 1H, OH) Elemental analysis (C ₁₂ H ₁₁ N ₃ O ₆ ): Calculated value (C = 49.15, H = 3.78, N = 1)
4.33), measured value (C = 48.82, H = 3.83, N = 14.14)

(4) 2,4-dioxoimidazolidine-
1-ethyl acetate was reacted with benzyl bromide, 4-bromobenzyl bromide, 2-bromomethyl-4-chlorobenzothiazole, 2-bromomethyl-5-chlorobenzothiazole, 2-bromomethyl-1-bromonaphthalene in the same manner as above. Performed, 3-benzyl-2,4-dioxoimidazolidine-1-ethyl acetate, 3- (4-bromobenzyl) -2,4-dioxoimidazolidine-1-
Ethyl acetate, 3- [2- (4-chlorobenzothiazolyl) methyl] -2,4-dioxoimidazolidine-1-
Ethyl acetate, 3- [2- (5-chlorobenzothiazolyl) methyl] -2,4-dioxoimidazolidine-1-
Ethyl acetate and 3- [2- (1-bromonaphthyl) methyl] -2,4-dioxoimidazolidine-1-ethyl acetate were obtained. Then, similar acid hydrolysis is carried out to give 3-benzyl-2,4-dioxoimidazolidine-1-acetic acid [compound 5], 3- (4-bromobenzyl) -2,4-dioxoimidazolidine-1. -Acetic acid [compound 7], 3- [2
-(4-Chlorobenzothiazolyl) methyl] -2,4-
Dioxoimidazolidine-1-acetic acid [compound 9], 3-
[2- (5-chlorobenzothiazolyl) methyl] -2,
4-Dioxoimidazolidine-1-acetic acid [Compound 1
0], 3- [2- (1-bromonaphthyl) methyl]-
2,4-Dioxoimidazolidine-1-acetic acid [Compound 1
1] was obtained.

[Compound 5] Melting point: 169.5-170.5 ° C. MS (EI, 70 eV): 248 (M +, 30), 208 (18), 132 (15), 104 (1
9), 91 (100), 42 (78) IR (KBr): 3030 (OH), 1765 (C = O), 1718 (C = O), 1670, 12
07, 1153, 957, 764, 700 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.07 (s, 4H, NCH ₂ CO), 4.57 (s, 2H, C
H ₂ Ar), 7.20-7.40 (m, 1H, Ar), 13.25 (brs, 1H, OH) Elemental analysis (C ₁₂ H ₁₂ N ₂ O ₄ ): Calculated value (C = 58.06, H = 4.87, N = 1
1.28), measured value (C = 58.02, H = 4.73, N = 11.32)

[Compound 7] Melting point: 139.0-140.0 ° C. MS (EI, 70 eV): 328 (M +, ⁸¹ Br, 18), 326 (M +, ⁷⁹ Br, 20), 171
(38), 169 (40), 132 (26), 42 (100) IR (KBr): 3100 (OH), 1774 (C = O), 1732 (C = O), 1705 (C =
O), 1471, 1406, 1244, 1203, 760 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.07 (s, 2H, NCH ₂ CO), 4.55 (s, 2H, C
H ₂ Ar), 7.23 (d, J = 8.3Hz, 2H, Ar), 7.53 (d, J = 8.3Hz, 2H, A
r), 13.00 (brs, 1H, OH) Elemental analysis (C ₁₂ H ₁₁ BrN ₂ O ₄ ): Calculated value (C = 44.06, H = 3.39, N =
8.56), measured value (C = 43.96, H = 3.45, N = 8.49)

[Compound 9] Melting point: 114.0-115.0 ° C. (decomposition) MS (EI, 70eV) m / z: 341 (M +, ³⁷ Cl, 14), 339 (M +, ³⁵ Cl, 38),
224 (19), 169 (24), 42 (100) IR (KBr): 3283 (NH), 3281 (NH), 1662 (C = O), 1397, 103
4 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.12 (s, 2H, CH ₂ CO), 4.18 (s, 2H, CH
₂ CO), 5.08 (s, 2H, CH ₂ Ar), 7.45 (dd, J = 8.2,7.6Hz, 1H, Ar
H), 7.63 (dd, J = 7.6,1.2Hz, 1H, ArH), 8.08 (dd, J = 8.2,1.2
Hz, 1H, ArH) Elemental analysis (C ₁₃ H ₁₀ ClN ₃ O ₄ S): Calculated value (C = 45.96, H = 2.97, N =
12.37), measured value (C = 45.96, H = 2.93, N = 12.59)

[Compound 10] Melting point: 228.0-229.0 ° C. MS (EI, 70 eV) m / z: 341 (M +, ³⁷ Cl, 17), 339 (M +, ³⁵ Cl, 43),
224 (23), 169 (24), 42 (100) IR (KBr): 3300 (OH), 1772, 1713 (C = O), 1458, 1206, 1
137 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.12 (s, 2H, CH ₂ CO), 4.17 (s, 2H, CH
₂ CO), 5.05 (s, 2H, CH ₂ Ar), 7.51 (d, J = 8.2Hz, 1H, ArH), 8.
08 (s, 1H, ArH), 8.13 (d, J = 8.2Hz, 1H, ArH), 13.05 (brs, 1
(H, COOH) Elemental analysis (C ₁₃ H ₁₀ ClN ₃ O ₄ S 2H ₂ O): Calculated value (C = 45.47, H =
3.05, N = 12.23), measured value (C = 45.70, H = 3.01, N = 11.86)

[Compound 11] Melting point: 81.0-82.0 ° C. (decomposition) MS (EI, 70 eV) m / z: 378 (M +, ⁸¹ Br, 2.8), 376 (M +, ⁷⁹ Br, 2.
8), 297 (100), 182 (25), 139 (22), 42 (73) IR (KBr): 3300 (OH), 1766, 1714 (C = O), 1464, 1246, 76
1 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.12 (s, 2H, CH ₂ CO), 4.18 (s, 2H, CH
₂ CO), 4.88 (s, 2H, CH ₂ Ar), 7.32 (d, J = 8.4Hz, 1H, ArH), 7.
63 (dd, J = 8.4,8.4Hz, 1H, ArH), 7.71 (dd, J = 8.4,8.4Hz, 1H,
ArH), 7.97 (d, J = 8.4Hz, 1H, ArH), 7.99 (d, J = 8.4Hz, 1H, Ar
H), 8.24 (d, J = 8.4Hz, 1H, ArH), 13.07 (brs, 1H, COOH) Elemental analysis (C ₁₆ H ₁₃ BrN ₂ O ₄ ): Calculated value (C = 50.95, H = 3.47, N =
7.43), measured value (C = 50.92, H = 3.54, N = 7.44)

Example 5. (1) To a tetrahydrofuran solution (30 mL) of 5.13 g of 3-nitro-4-chlorobenzyl alcohol, 4.70 g of 2,4-dioxoimidazolidine-1-ethyl acetate and 8.68 g of triphenylphosphine, 5.
A solution of 30 mL of tetrahydrofuran containing 2 mL of diethyl azodicarboxylate was added at 0 ° C. The reaction mixture was poured into water and extracted several times with ethyl acetate. The extracts were combined, washed with saturated brine, dried over sodium sulfate, and concentrated. After purified by silica gel column, recrystallized from ethanol-water mixed solvent to give 7.01 g of 3-
(3-Nitro-4-chlorobenzyl) -2,4-dioxoimidazolidine-1-ethyl acetate was obtained.

(2) The above product was subjected to acid hydrolysis in the same manner as in Example 4 (3) to give 1.42 g of 3- (3-nitro-4-chlorobenzyl) -2,4-dioxoimidazo. Lysine-1-acetic acid [Compound 8] was obtained. Melting point: 167.0-168.5 ℃ MS (EI, 70eV): 327 (M +, 1.6), 310 (13), 195 (15), 170 (1
3), 42 (100) IR (KBr): 3160 (OH), 1749 (C = O), 1707 (C = O), 1531 (N
O ₂ ), 1477, 1336 (NO ₂ ), 1053, 756 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.08 (s, 2H, NCH ₂ CO), 4.10 (s, 2H, N
CH ₂ CO), 4.69 (s, 2H, CH ₂ Ar), 7.60 (d, J = 8.4Hz, 1H, Ar),
7.76 (d, J = 8.4Hz, 1H, Ar), 7.97 (s, 1H, Ar), 13.08 (brs, 1
(H, OH) Elemental analysis (C ₁₂ H ₁₀ ClN ₃ O ₆ ): Calculated value (C = 43.99, H = 3.08, N =
12.82), measured value (C = 43.99, H = 3.22, N = 12.50)

Example 6. (1) Add 1.9 mL of ethyl isocyanatoacetate to 3.4
An ether solution containing 6 g of methyl 2- (3-nitrobenzyl) amino-3-hydroxypropionate (50 m
L) at room temperature and stirred vigorously for 7 hours. The deposited precipitate was collected by filtration, washed with ether, and recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 4.15 g of N- (3-nitrobenzyl) -N-[(1-methoxycarbonyl-2-
(Hydroxy) ethyl] -N′-ethoxycarbonylmethylurea was obtained as white crystals.

(2) To a water-ethanol mixed solution in which 0.38 g of potassium hydroxide was dissolved, 2.53 g of the above product was added at 0 ° C. After stirring at room temperature for 24 hours, it was washed with ethyl acetate three times. It was acidified with concentrated hydrochloric acid and the aqueous layer was back extracted with ethyl acetate. The extract was concentrated and then purified with a silica gel column to obtain 0.10 g of 1- (3-nitrobenzyl) -5-methylidene-2,4-dioxoimidazolidine-3-acetic acid [compound 12]. . Melting point: 169.0-171.0 ℃ IR (KBr): 3000 (OH), 1738 (C = O), 1718 (C = O), 1662 (C =
O), 1527 (NO ₂ ), 1452, 1439, 1354 (NO ₂ ), 1250 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.24 (s, 2H, NCH ₂ CO), 5.01 (s, 2H, C
H ₂ Ar), 5.15 (d, J = 2.6Hz, 1H, CH ₂ =), 5.35 (d, J = 2.6Hz, 1H,
CH ₂ =), 7.66 (dd, J = 8.1,7.7Hz, 1H, Ar), 7.75 (d, J = 7.7Hz,
1H, Ar), 8.17 (d, J = 8.1Hz, 1H, Ar), 8.20 (s, 1H, Ar), 13.3
2 (brs, 1H, OH) Elemental analysis (C ₁₃ H ₁₁ N ₃ O ₆ ): Calculated value (C = 51.95, H = 3.63, N = 1
3.77), measured value (C = 50.95, H = 3.61, N = 13.70)

Example 7. (1) 1.12 in 4.0 g of 3- (3-nitrobenzyl) -5-benzylthiooxymethylimidazolidine-2,4-dione in dimethylformamide (50 mL).
To a dimethylformamide solution (10 mL) in which g of sodium hydride was suspended was added dropwise at 0 ° C or lower. After stirring for another hour under the same temperature conditions, a dimethylformamide solution (40 mL) containing 2.7 mL of ethyl bromoacetate was added dropwise at 0 ° C. After stirring for 2.5 hours, the reaction mixture was added to ice-cooled 2N hydrochloric acid with vigorous stirring. Then, extract with ethyl acetate several times, and extract with saturated saline.
After washing twice, it was dried over sodium sulfate and concentrated. After purification by silica gel column, recrystallization from ethanol gave 0.69 g of 3- (3-nitrobenzyl) -5-methylidene-2,4-dioxoimidazolidine-1-ethyl acetate.

(2) Add 241 to a mixed solution of methanol and water.
mg of the above product and 50.3 mg of potassium hydroxide were suspended and stirred vigorously for 24 hours. The pH of the reaction mixture was adjusted to about 4 with 2N hydrochloric acid, concentrated, and then extracted several times with ethyl acetate. The extract was dried over sodium sulfate, concentrated, washed with chloroform, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to obtain 106 mg of 3- (3-nitrobenzyl) -5-methylidene-2,4-dioxoimidazolidine-1-acetic acid [Compound 13]. IR (KBr): 3000, 1781 (C = O), 1714 (C = O), 1664 (C = O), 1
527 (NO ₂ ), 1450, 1444,1351 (NO ₂ ) cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.40 (s, 2H, NCH ₂ CO), 4.84 (s, 2H, C
H ₂ Ar), 5.17 (d, J = 1.9Hz, 1H, CH ₂ =), 5.36 (d, J = 1.9Hz, 1H,
CH ₂ =), 7.66 (dd, J = 7.6,7.6Hz, 1H, Ar), 7.73 (d, J = 7.6Hz,
1H, Ar), 8.14 (s, 1H, Ar), 8.16 (d, J = 7.6Hz, 1H, Ar)

Example 8. (1) Add 78 g of N- (3-nitrobenzyl) urea to 50
Dissolve in 0 mL of 80% acetic acid and add 120 g of benzyl 2-benzyloxy-2-hydroxyacetate at 80 ° C.
Stir for hours. After concentrating under reduced pressure, the solvent was distilled off by azeotropic distillation with toluene. It was purified by a silica gel column and recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 49 g of 5-hydroxy-1- (3-nitrobenzyl) -2,4-dioxoimidazolidine.

(2) 12.5 g of the above product and 10 g of potassium hydrogen carbonate were suspended in 150 mL of acetone, and 9
mL of t-butyl bromoacetate was added, and the mixture was refluxed for 8 hours with stirring. The filtrate from which the insoluble matter was removed by filtration was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the residue obtained by distilling off ethyl acetate was purified by a silica gel column to give 12.4 g of 5
-Hydroxy-1- (3-nitrobenzyl) -2,4-
Dioxoimidazolidine-3-t-butyl acetate was obtained.

(3) 3.6 g of the above product was added to 4N hydrochloric acid-
It was dissolved in a mixed solvent of dioxane and stirred at room temperature for 6 hours. The reaction solution was concentrated to dryness under reduced pressure, and chloroform was added to the residue to stimulate and solidify it. The crystals were collected by filtration, washed with chloroform, and dried to give 0.8 g of 5-hydroxy-1- (3-nitrobenzyl) -2,4-dioxoimidazolidine-3-acetic acid [compound 14] as amorphous crystals. Got as. Melting point: 123.0-125.0 ℃ MS (SIMS, glycerol) m / z: 310 [M + H] ⁺ IR (KBr): 1782, 1718, 1529, 1466, 1352, 1236 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.09 (d, J = 17.6Hz, 2H, CH ₂ CO ₂ ), 4.
13 (d, J = 17.6Hz, 2H, CH ₂ CO ₂ ), 4.58 (d, J = 16.2Hz, 2H, Ar-CH
₂ ), 4.68 (d, J = 16.2Hz, 2H, Ar-CH ₂ ), 5.28 (s, 1H, CH), 7.3
6 (brs, 1H, OH), 7.65 (dd, J = 8.1,7.7Hz, 1H, Ar-H-5), 7.79
(d, J = 7.7Hz, 1H, Ar-H-6), 8.14 (d, J = 8.1Hz, 1H, Ar-H-4),
8.20 (s, 1H, Ar-H-2), 13.13 (brs, 1H, COOH) Elemental analysis (C ₁₂ H ₁₁ N ₃ O ₇ ): Calculated value (C = 46.61, H = 3.58, N = 1)
3.59), measured value (C = 46.35, H = 3.60, N = 13.72)

Example 9. (1) Example 8 using ethyl N-carbamoylaminoacetate
It was reacted with benzyl 2-benzyloxy-2-hydroxyacetate in the same manner as in (1) to obtain 5-hydroxy-2,4-dioxoimidazolidine-1-ethyl acetate.

(2) The above product and 3-nitrobenzyl bromide were subjected to the same condensation reaction as in Example 8 (2) to give 5
-Hydroxy-3- (3-nitrobenzyl) -2,4-
Obtained dioxoimidazolidine-1-ethyl acetate.

(3) 15 g of the above product was suspended in a mixed solvent of acetic acid-hydrochloric acid and refluxed for 2 hours while stirring. After concentration under reduced pressure, ether-chloroform was added to stimulate and solidify. The crystals were washed with ether and recrystallized from a mixed solvent of ethanol-water to give 8.1 g of 5-hydroxy-3- (3-nitrobenzyl) -2,4-dioxoimidazolidine-1-acetic acid [compound 15]. Got Melting point: 153.0-155.0 ℃ MS (SIMS, glycerol) m / z: 310 [M + H] ⁺ IR (KBr): 3533, 3494, 3431, 1776, 1735, 1713, 1527,
1468, 1350, 1238 cm ^-11 H-NMR (DMSO-d ₆ ) δ: 3.90 (d, J
= 18.0Hz, 2H, CH ₂ CO ₂ ), 4.16 (d, J = 18.0Hz, 2H, CH ₂ CO ₂ ), 4.
73 (d, J = 15.6Hz, 2H, Ar-CH ₂ ), 4.78 (d, J = 15.6Hz, 2H, Ar-CH
₂ ), 5.24 (s, 1H, CH), 7.20 (brs, 1H, OH), 7.66 (ddd, J = 8.
0,7.6,1.0Hz, 1H, AH-5), 7.76 (d, J = 7.6Hz, 1H, Ar-H-6),
8.15-8.17 (m, 2H, Ar-H-2, Ar-H-4), 13.00 (brs, 1H, COOH) Elemental analysis (C ₁₂ H ₁₁ N ₃ O ₇ ): Calculated value (C = 46.61, H = 3.58, N = 1
3.59), measured value (C = 46.88, H = 3.72, N = 13.81)

Example 10. (1) 10.02 g uracil, 3.3 mL ethyl bromoacetate, 13.85 g potassium carbonate and 4.52 g
The dimethylsulfoxide solution (150 mL) containing sodium iodide in (1) was stirred at 90 ° C. for 6 hours. The reaction mixture was poured into water and extracted with chloroform. The extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. This was poured into saturated saline solution, extracted with ethyl acetate, and the extract was dried over sodium sulfate. After concentration, it was recrystallized from ethyl acetate to give 2.30 g of 2,4-dioxo-1,
2,3,4-Tetrahydropyrimidine-1-ethyl acetate was obtained.

(2) The above product was dissolved in 40 mL of dimethyl sulfoxide, and this was dissolved in 0.58 g of sodium hydride in a dimethylformamide solution (30 mL).
Was added dropwise at 0 ° C or lower. After stirring for another 1.5 hours,
3.42 g dissolved in 70 mL of dimethyl sulfoxide
Of 3-nitrobenzyl bromide was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours, poured into water, and extracted several times with ethyl acetate. The extracts were combined, washed with a saturated saline solution, dried and then concentrated. Purified by silica gel column, recrystallized from ethanol and 1.86 g of 3- (3-
Nitrobenzyl) -2,4-dioxo-1,2,3,4
-Tetrahydropyrimidine-1-ethyl acetate was obtained.

(3) 1.60 g of the above product, 6 mL of acetic acid and 2 mL of hydrochloric acid were mixed and refluxed for 2 hours. After concentration, the mixture was refluxed with 6 mL of acetic acid and 2 mL of hydrochloric acid for 2 hours. The solvent was distilled off, the residue was washed with water, and recrystallized from ethanol to give 1.39 g of 3- (3-nitrobenzyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1. -Acetic acid [compound 16] was obtained as white crystals. Melting point: 161.0-161.5 ° C MS (EI, 70eV): 305 (M +, 47), 288 (40), 161 (48), 128 (1
9), 82 (100) IR (KBr): 2980 (OH), 1734 (C = O), 1703 (C = O), 1637, 160
1, 1537 (NO ₂ ), 1470, 1350 (NO ₂ ), 1238, 1200 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.50 (s, 2H, NCH ₂ CO), 5.10 (s, 2H , C
H ₂ Ar), 5.83 (d, J = 7.9Hz, 1H, COCH = C), 7.62 (dd, J = 7.9,7.
9Hz, 1H, Ar), 7.72 (d, J = 7.7Hz, 1H, Ar), 7.73 (d, J = 7.9Hz,
1H, COC = CH), 8.12 (s, 1H, Ar), 8.13 (d, J = 7.9Hz, 1H, Ar),
13.20 (brs, 1H, OH) Elemental analysis (C ₁₃ H ₁₁ N ₃ O ₆ ): Calculated value (C = 5
1.15, H = 3.63, N = 13.77), measured value (C = 50.95, H = 3.83, N = 13.7
6)

(4) In the same manner, 3- (3-chloro-4-)
Nitrobenzyl) -2,4-dioxo-1,2,3,4
-Tetrahydropyrimidine-1-ethyl acetate, 3- [2
-(4-Chlorobenzothiazolyl) methyl] -2,4-
Dioxo-1,2,3,4-tetrahydropyrimidine-
1-ethyl acetate, 3- [2- (5-chlorobenzothiazolyl) methyl] -2,4-dioxo-1,2,3,4-
Tetrahydropyrimidine-1-ethyl acetate, 3- [2-
(1-Bromonaphthyl) methyl] -2,4-dioxo-
1,2,3,4-Tetrahydropyrimidine-1-ethyl acetate was produced and then acid-hydrolyzed to give 3- (3-chloro-
4-nitrobenzyl) -2,4-dioxo-1,2,
3,4-Tetrahydropyrimidine-1-acetic acid [Compound 1
7], 3- [2- (4-chlorobenzothiazolyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-acetic acid [Compound 18], 3- [2-
(5-Chlorobenzothiazolyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1
-Acetic acid [compound 19], 3- [2- (1-bromonaphthyl) methyl] -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-1-acetic acid [compound 20] were obtained as white crystals. It was

[Compound 17] Melting point: 184.0-185.0 ° C. MS (EI, 70 eV) m / z: 341 (M +, ³⁷ Cl, 8.7), 339 (M +, ³⁵ Cl, 2)
6), 324 (14), 332 (38), 195 (43), 82 (100) IR (KBr): 1735 (C = O), 1706 (C = O), 1662, 1658, 1553 (N
O ₂ ), 1461, 1349 (NO ₂ ), 770 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.48 (s, 2H, NCH ₂ CO ₂ ), 5.05 (s, 2H,
CH ₂ Ar), 5.82 (d, J = 8.0Hz, 1H, CH =), 7.57 (dd, J = 8.2,1.6H
z, 1H, ArH), 7.73 (d, J = 8.2Hz, 1H, ArH), 7.74 (d, J = 8.0Hz,
1H, CH =), 7.93 (d, J = 1.6Hz, 1H, ArH), 13.20 (brs, 1H, COO
H) Elemental analysis (C ₁₃ H ₁₀ ClN ₃ O ₆ ): Calculated value (C = 45.97, H = 2.97, N =
12.37), measured value (C = 46.17, H = 2.82, N = 12.43)

[Compound 18] Melting point: 184.0-185.0 ° C. (decomposition) MS (EI, 70 eV) m / z: 353 (M +, ³⁷ Cl, 27), 351 (M +, ³⁵ Cl, 73),
224 (73), 196 (23), 169 (78), 128 (69), 82 (100) IR (KBr): 3300 (OH), 1729, 1705 (C = O), 1661 (C = O), 144
7, 1107 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.53 (s, 2H, NCH ₂ CO ₂ ), 5.43 (s, 2H,
CH ₂ Ar), 5.92 (d, J = 8.0Hz, 1H, CH =), 7.45 (dd, J = 7.8,7.6H
z, 1H, ArH), 7.62 (d, J = 7.8Hz, 1H, ArH), 7.81 (d, J = 8.0Hz,
1H, CH =), 8.05 (d, J = 7.6Hz, 1H, ArH), 13.20 (brs, 1H, COO
H) Elemental analysis (C ₁₄ H ₁₀ ClN ₃ O ₄ S): Calculated value (C = 47.80, H = 2.86, N =
11.95), measured value (C = 48.21, H = 2.79, N = 11.88)

[Compound 19] Melting point: 208.0-209.0 ° C MS (EI, 70 eV) m / z: 353 (M +, ³⁷ Cl, 34), 351 (M +, ³⁵ Cl, 75),
224 (91), 196 (30), 169 (100), 128 (57), 82 (98) IR (KBr): 1716 (C = O), 1685 (C = O), 1453, 1362 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.53 (s, 2H, NCH ₂ CO ₂ ), 5.41 (s, 2H,
CH ₂ Ar), 5.88 (d, J = 7.8Hz, 1H, CH =), 7.49 (dd, J = 8.6,2.0H
z, 1H, ArH), 7.79 (d, J = 7.8Hz, 1H, CH =), 8.05 (d, J = 2.0Hz,
1H, ArH), 8.10 (d, J = 8.6Hz, 1H, ArH) Elemental analysis (C ₁₄ H ₁₀ ClN ₃ O ₄ S): Calculated value (C = 47.80, H = 2.86, N =
11.95), measured value (C = 47.94, H = 3.01, N = 11.83)

[Compound 20] Melting point: 208.0-209.0 ° C MS (EI, 70eV) m / z: 309 (M + -Br, 100), 219 (10), 182 (55) IR (KBr): 3452 (OH) , 1739, 1705 (C = O), 1658 (C = O), 145
5, 1199 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.53 (s, 2H, NCH ₂ CO ₂ ), 5.24 (s, 2H,
CH ₂ Ar), 5.90 (d, J = 7.8Hz, 1H, CH =), 7.00 (d, J = 7.8Hz, 1H,
ArH), 7.61 (dd, J = 8.6,8.6Hz, 1H, ArH), 7.71 (dd, J = 8.4,
8.4Hz, 1H, ArH), 7.84 (d, J = 7.8Hz, 1H, CH =), 7.91 (d, J = 8.
4Hz, 1H, ArH), 7.97 (d, J = 7.8Hz, 1H, ArH), 8.24 (d, J = 8.4H
z, 1H, ArH), 13.25 (brs, 1H, COOH) Elemental analysis (C ₁₇ H ₁₃ BrN ₂ O ₄ 1EtOH): Calculated value (C = 52.46, H =
3.48, N = 7.11), measured value (C = 52.75, H = 3.84, N = 6.77)

Example 11. (1) 100 mL of a hexamethyldisilazane solution containing 5.29 g of uracil and 12.0 mL of chlorotrimethylsilane was refluxed for 2 hours. The transparent reaction solution was concentrated under reduced pressure, 14.0 g of 3-nitrobenzyl bromide and 1.11 g of tetrabutylammonium iodide in methylene chloride solution (100 mL) were added, and the mixture was stirred at room temperature for 4 days. The reaction solution was poured into water, and the precipitated crystals were collected by filtration, washed with water and ethyl acetate, dried, and then dried.
60 g of 3- (3-nitrobenzyl) uracil was obtained.

(2) 5.91 g of the above product was added to 100 m
A solution of dimethyl sulfoxide (2,1) dissolved in L of dimethyl sulfoxide and suspended with 1.21 g of sodium hydride (2
0 mL) at 0 ° C. and then stirred for 3 hours. A dimethyl sulfoxide solution (20 mL) containing 2.7 mL of ethyl bromoacetate was added dropwise to this reaction mixture, and the mixture was stirred for 2.5 hours and then poured into water. The product was purified on a silica gel column and recrystallized from ethanol to give 3.15 g of 1- (3-nitrobenzyl) -2,4-dioxo-1,
2,3,4-Tetrahydropyrimidine-3-ethyl acetate was obtained.

(3) 2.29 g of the above product was used in Example 8
Acid hydrolysis was performed in the same manner as in (3), and 1.82 g of 1-
(3-nitrobenzyl) -2,4-dioxo-1,2,
3,4-Tetrahydropyrimidine-3-acetic acid [Compound 2
1] was obtained. Melting point: 200.0-201.5 ° C MS (EI, 70eV): 305 (M +, 47), 287 (26), 203 (74), 187 (7
0), 136 (94), 90 (100) IR (KBr): 2900 (OH), 1741 (C = O), 1705 (C = O), 1637, 160
8, 1524 (NO ₂ ), 1463, 1350 (NO ₂ ), 920, 771 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 4.46 (s, 2H, NCH ₂ CO), 5.10 (s, 2H , C
H ₂ Ar), 5.86 (d, J = 7.9Hz, 1H, COCH = C), 7.68 (dd, J = 8.5,7.
5Hz, 1H, Ar), 7.78 (d, J = 7.7Hz, 1H, Ar), 8.00 (d, J = 7.9Hz,
1H, COC = CH), 8.18 (d, J = 8.1Hz, 1H, Ar), 8.22 (s, 1H, Ar),
12.99 (brs, 1H, OH)

[0072]

The pharmacological action of the compound of the present invention will be described below. (1) Aldose Reductase Inhibitory Action The aldose reductase inhibitory action of the compound of the present invention was examined using aldose reductase prepared from rat lens. That is, a test drug was added to a reaction system consisting of a phosphate buffer solution, NADPH and aldose reductase, and the stability of the absorbance was confirmed for several minutes, and then glyceraldehyde was added to the reaction system.
The ability of the test drug to inhibit aldose reductase was measured by measuring the decrease in absorbance at 40 nm with time.

Table 1 shows an example of the results. In addition, the inhibition rate for aldose reductase in the table is the test drug concentration of 1 × 1.
It is a value at 0 ^-7 M.

[Table 1]

[0074]

As is clear from the above pharmacological test results, the carboxyalkyl heterocyclic derivative of the present invention exhibits an excellent aldose reductase inhibitory action, has low toxicity, and is extremely useful as a drug for diabetic complications. It is a thing. That is, diabetic neuropathy due to excessive accumulation of intracellular sorbitol, diabetic cataract or diabetic retinopathy, diabetic nephropathy, various diabetic microangiopathy such as diabetic microangiopathy such as diabetic skin disorder, treatment, prevention It is useful as a drug for

The inhibitory effect of the compound of the present invention on aldehyde reductase in rat kidney was measured at a test drug concentration of 1 × 10 ^-4 M, but almost no inhibition was observed. As described above, the compound of the present invention having a high enzyme selectivity for aldose reductase involved in the production of sorbitol which induces diabetic complications, has low toxicity and high safety, and thus chronic chronic administration requiring long-term administration. It is particularly advantageous for the treatment of diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 233/72 C07D 233/72 239/54 239/66 239/66 417/06 233 417/06 233 C07D 239/55 // (C07D 417/06 233: 96 277: 64) (72) Inventor Yasuhiro Nagaki 442-1, Kawakitayama, Kinashi, Kato-gun, Hyogo Prefecture

Claims (6)

[Reference number] PC-249 [Claims] 1. A carboxyalkyl heterocyclic derivative represented by the general formula (A) and a pharmaceutically acceptable salt thereof. Embedded image [In the formula, two of R _a , R _b and R _c represent oxygen,
The other one represents a combination of sulfur, a lower alkylene group, unsubstituted or hydrogen and a hydroxyl group, and X is substituted with a benzyl group, a nitro group and / or a halogen which may be substituted with a nitro group and / or a halogen. Optionally a benzothiazolylmethyl group, a nitro group and / or a naphthylmethyl group optionally substituted with halogen, R represents hydrogen or a lower alkyl group, and n represents an integer of 1 to 3,
Z represents a direct bond (in this case, the heterocycle represents a 5-membered ring) or a bond via one carbon atom (in this case, the heterocycle represents a 6-membered ring). ] 2. The compound according to claim 1, wherein Z is a direct bond. 3. The compound according to claim 2, which is represented by the general formula (I). Embedded image [In the formula, _{two of} R ₁ , R ₂ and R ₃ represent oxygen,
The other one represents a combination of sulfur, a lower alkylene group, unsubstituted or hydrogen and a hydroxyl group, and X is substituted with a benzyl group, a nitro group and / or a halogen which may be substituted with a nitro group and / or a halogen. Optionally represents a benzothiazolylmethyl group, a nitro group and / or a naphthylmethyl group optionally substituted with halogen, R represents hydrogen or a lower alkyl group, and n is an integer of 1 to 3. ] 4. The compound according to claim 1, wherein Z is a bond through one carbon atom. 5. The compound according to claim 4, which is represented by the general formula (II). Embedded image [In the formula, one of R ₄ and R ₅ represents oxygen and the other one represents unsubstituted, and X represents a benzyl group optionally substituted with a nitro group and / or a halogen, a nitro group and / or a halogen substituted. A benzothiazolylmethyl group which may be substituted, a nitro group and / or a naphthylmethyl group which may be substituted with halogen, R represents hydrogen or a lower alkyl group, n is 1 to 3, and One broken line represents a single bond on the oxygen-substituted side of R ₄ and R ₅ , and the other one represents a double bond. ] 6. A therapeutic agent for diabetic complications, which comprises as an active ingredient at least one of the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable salt thereof.