JPS625433B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound hexahydro-6-oxo-pyrimidine-4-carboxylic acid derivative and its salt, which has angiotensin-converting enzyme inhibitory action and is useful as an antihypertensive agent.

The compound of the present invention is represented by the following general formula.

general formula [In the formula, R ₁ represents lower alkyl, lower alkylthio lower alkyl, phenyl lower alkylthio lower alkyl, or phenyl lower alkyl group which may have a hydroxy group as a substituent,
R ₂ represents hydrogen, lower alkyl, or phenyl lower alkyl group, and R ₃ represents hydrogen or lower alkyl group. ] Among the compounds represented by the general formula (1), R ₁ and R ₂
Examples of the lower alkyl group in R ₃ include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc., and examples of the lower alkylthio lower alkyl group include methylthiomethyl, 1-(methylthio)ethyl, 2 -(Methylthio)ethyl, 3-(methylthio)propyl, 4-(methylthio)butyl, 5-(methylthio)pentyl, 6-(methylthio)hexyl, ethylthiomethyl, 1-(ethylthio)ethyl, 2
-(Ethylthio)ethyl, 3-(ethylthio)propyl, 6-(ethylthio)hexyl, 2-(propylthio)ethyl, 3-(propylthio)propyl, 2-(butylthio)ethyl, 4-(butylthio)butyl, 2- (pentylthio)ethyl, 1-
hexylthiomethyl, 2-(1-hexylthio)
Ethyl, 6-(1-hexylthio)hexyl, phenyl lower alkylthio Lower alkyl groups include benzylthiomethyl, 1-(benzylthio)
Ethyl, 2-(benzylthio)ethyl, 3-(benzylthio)propyl, 4-(benzylthio)butyl, 5-(benzylthio)pentyl, 6-(benzylthio)hexyl, 2-phenylethylthiomethyl, 1-(2- Phenylethylthio)ethyl, 2
-(2-phenylethylthio)ethyl, 3-(2-
Phenylethylthio)propyl, 4-(2-phenylethylthio)butyl, 6-(2-phenylethylthio)hexyl, 2-(3-phenylpropylthio)ethyl, 6-(3-phenyl) propylthio)hexyl, 4-phenylbutylthiomethyl,
2-(4-phenylbutylthio)ethyl, 3-(4
-Phenylbutylthio)propyl, 4-(4-phenylbutylthio)butyl, 2-(5-phenylpentylthio)ethyl, 5-(5-phenylpentylthio)pentyl, 6-phenylhexylthio Examples include methyl, 4-(6-phenylhexylthio)butyl, and 6-(6-phenylhexylthio)hexyl.

Examples of phenyl lower alkyl that may have a hydroxy group as a substituent include benzyl, 1-phenylethyl, 2-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 5
-phenylpentyl, 6-phenylhexyl, o
-Hydroxybenzyl, m-hydroxybenzyl, p-hydroxybenzyl, 3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl, 2-(p-hydroxyphenyl)ethyl,
2-(3,4-dihydroxyphenyl)ethyl,
4-(p-hydroxyphenyl)ethyl, 6-(p
-hydroxyphenyl)hexyl and the like.

Compound (1) of the present invention can easily form a salt by reacting with a pharmaceutically acceptable acidic compound. Examples of acidic compounds include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. I can list them.

In addition, the compound (1) of the present invention having an acidic group can easily form a salt by reacting with a pharmaceutically acceptable base. Examples of bases used here include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, and potassium bicarbonate, and organic bases such as morpholine, piperazine, piperidine, ethylamine, dimethylamine, triethylamine, and dicyclohexylamine. Bases can be mentioned.

The hexahydro-6-oxo-pyrimidine-4-carboxylic acid derivative represented by the general formula (1) of the present invention can be produced, for example, by the method shown below.

[In the formula, R ₁ is the same as above, R′ ₂ is lower alkyl,
or phenyl lower alkyl, R′ ₃ represents a lower alkyl group] In the method shown in Reaction Formula 1, a carboxylic acid represented by the general formula (2) and an amine represented by the formula (3) are bonded together through a normal amide bond. This is a method of reacting in a production reaction.

This reaction can be carried out by various reactions such as those described below.

(a) A method using a dehydration condensation reaction between carboxylic acid (2) and amine (3) in the presence of a condensing agent.

Specifically, the condensing agent used in this method includes N,N'-dicyclohexylcarbodiimide (DCC), DCC-N-hydroxysuccinimide, DCC-N-hydroxybenzotriazole, DCC-N-hydroxy-5- Examples include norbornene-2,3-dicarboximide, diphenylphosphoryl azide, diethylphosphorocyanidate, and the like. The reaction is generally carried out in a suitable solvent, and any known solvent can be used as long as it does not adversely affect the reaction. Specifically, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and esters such as methyl acetate and ethyl acetate. and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The amount of compound (3) to be used is at least equimolar, preferably 1 to 1.2 times the molar amount of compound (2). The condensing agent is preferably used in an amount of about 1 to 2 times, preferably 1 to 1.2 times, the amount of compound (2). The reaction is usually carried out at -20 to 30°C
The reaction time is about 3 to 24 hours, preferably at -10°C to room temperature.

(b) Mixed acid anhydride method, that is, a method in which carboxylic acid (2) is reacted with a haloformic acid alkyl ester to form a mixed acid anhydride, and then this is reacted with amine (3). (c) Active ester method, that is, carboxylic acid A method in which the acid (2) is an active ester such as p-nitrophenyl ester or N-hydroxysuccinimide ester, and the amine (3) is reacted with this (d) Carboxylic acid halide method, i.e., carboxylic acid
A method of reacting the halide compound of (2) with the amine (3) (e) Another method is to convert the carboxylic acid (2) into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and then react the amine (3) with the carboxylic acid anhydride. Among these methods, the compound (2) of the present invention can be obtained by a dehydration condensation reaction. Preferably, it is manufactured.

The compound of the present invention can also be produced by the following method.

[In the formula, R ₁ and R ₃ are the same as above, and R'' ₂ represents an α-phenyl lower alkyl group. The above reaction formula-2 is hydrogenated using a conventional catalyst such as palladium or palladium black. This can be done by a reductive method.

Hydrogenation using the above catalyst can be carried out in water, lower alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, aprotic polar solvents such as dimethylformamide and dimethylacetamide, and mixed solvents thereof. , for example, hydrogen pressure of 1 atm, 0~
The reaction can be carried out at 40°C and is generally completed in about 30 minutes to 12 hours.

[In the formula, R ₁ , R′ ₂ , and R′ ₃ are the same as above] Among the compounds (1) of the present invention, the compound of general formula (1 ^d ) in which R ₂ and R ₃ are hydrogen atoms can be dissolved in a suitable solvent. It is produced by hydrolyzing a compound of general formula (1 ^a ) in the presence of a basic compound. Examples of the basic compounds used include alkali metal hydroxides, alkali metal carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate;
Examples include inorganic basic compounds such as alkali metal hydrogen carbonates. Examples of the solvent include water, lower alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetonitrile, and mixed solvents thereof. The reaction is preferably carried out under an inert gas atmosphere such as argon or nitrogen. The reaction is usually 0~
Proceeds suitably at about 80°C, preferably at room temperature,
Generally, the reaction is completed in about 30 minutes to 12 hours. In this way, a compound of general formula (1 ^d ) is produced.

The compound of the present invention thus produced can be easily isolated and purified by conventional separation means. Examples of the separation means include a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, a partial thin layer chromatography, an ion exchange chromatography, a gel chromatography, and the like.

The compound of the present invention has optical isomers due to the presence of an asymmetric carbon, but the present invention includes all existing optical isomers.

The compound (1) of the present invention and its salts obtained by the above method have an angiotensin-converting enzyme inhibitory effect and are low in toxicity, so they are extremely useful as antihypertensive agents.

When the hexahydro-6-oxo-pyrimidine-4-carboxylic acid derivatives and salts thereof of the present invention are used as antihypertensive agents, they are administered to humans and animals as they are or as active ingredients together with a conventional pharmaceutical carrier. be able to. In this case, the administration route and dosage unit form are not particularly limited, and can be administered orally or parenterally, for example, as oral preparations such as tablets, granules, and oral solutions, or parenteral preparations such as injections. The dosage of the active ingredient is appropriately determined depending on the route of administration, dosage unit form, desired pharmacological effect, and the like. Generally, the dose of the active ingredient per kg of body weight per day may be about 0.1 to 50 mg, and this can be administered in one to three divided doses a day. Further, the amount of active ingredient incorporated in a unit form is suitably about 1 to 500 mg. The above-mentioned dosage unit form can be easily manufactured according to conventional methods, and the carriers that can be used at that time may also be conventional ones. For example, tablets contain active ingredients such as gelatin, starch, lactose, magnesium stearate,
It is shaped by mixing with excipients such as talcum and gum arabic. Capsules are prepared by mixing the active ingredient with an active pharmaceutical filler or diluent and filling the mixture into hard gelatin capsules, soft capsules, and the like. Furthermore, drugs for parenteral administration such as injections are manufactured by dissolving or suspending the active ingredient in a sterilized liquid carrier. Preferred carriers are water or saline.

The present invention will be explained in more detail below by giving examples of the compounds of the present invention.

Example 1 ( ^4S )-3-[( ^2RS )-[[( ^1S )-1-methoxycarbonyl-2-phenylethyl]amino]-
1-oxo-propyl]-hexahydro-6-
Preparation of oxo-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[( ^1S )-1-methoxycarbonyl-2-phenylethyl]-alanine 3.2g, ( ^4S )-
Dissolve 2 g of hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester in 70 ml of dimethylformamide, add 2.3 g of diethylphosphorocyanidate (DEPC) under stirring under ice cooling, and add 1.9 ml of triethylamine and 10 ml of dimethylformamide.
The solution was gradually added dropwise. After stirring for 30 minutes under ice cooling, the mixture was further stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, evaporation under reduced pressure was performed, and the residue was purified by silica gel column chromatography (solvent: chloroform:methanol = 10:1), and further recrystallized from isopropanol-isopropyl ether.
3.2 g of the target product was obtained at 100.5°C.

[α] ²¹ . ⁵ _D = -40.6° (C = 1.0, methanol) Example 2 ( ^4S )-3-[( ^2RS )-2-[[( ^1S )-1-benzyloxycarbonyl-2-phenylethyl]
Production of amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[(1 ^S )-1-benzyloxycarbonyl-2-phenylethyl]-alanine 3.5g,
(4 ^S )-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester 1.8 g,
It was prepared in the same manner as in Example 1 using 2.0 g of DEPC and 1.7 ml of triethylamine, and recrystallized from isopropanol-isopropyl ether.
1.4 g of the target compound was obtained at 127°C.

[α] ²⁵ . ⁵ _D = -36.1° (C = 1.1, methanol) Example 3 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-carboxy-2-phenylethyl]amino]-1 −
Preparation of ( ^4S )-3-[( ^2RS )-2 obtained in Example 2
-[[(1 ^S )-1-benzyloxycarbonyl-2
-Phenylethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester (1.1 g) was dissolved in a mixed solvent of 20 ml of methanol and 20 ml of water, and the mixture was heated with palladium black as a catalyst at room temperature and normal pressure. Catalytic reduction was carried out using After 2 hours, the catalyst was removed and the liquid was distilled off under reduced pressure. The residue was recrystallized from water-methanol,
600 mg of the target compound with a mp of 147-149°C was obtained.

[α] ²⁹ _D = -38.0° (C = 0.8, water) Example 4 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-carboxy-2-phenylethyl]amino ]-1-
Preparation of ( ^4S )-3-[( ^2RS )-2 obtained in Example 1
-[[( ^1S )-1-methoxycarbonyl-2-phenylethyl]amino]-1-oxo-propyl]-
Hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester 500 mg methanol 4 ml
2.7 ml of 1 ^N-NaOH was added to the solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in a small amount of water and applied to Amberlite CG-120 Type 1 (H ⁺ ). After thorough washing with water, the product was eluted with a 3% aqueous pyridine solution, and the product fraction was lyophilized. Furthermore, it was applied to a Sephadex LH-20 column (3 x 125 cm) and eluted with water. The product fractions were collected and lyophilized to obtain 340 mg of the desired product.

[α] ²⁸ _D = −28.8° (C = 1.2, water) 'H-NMR (D ₂ O): δ value 1.46 (3 ^H , d), 2.6 to 3.0 (2 ^H , m), 3.29
(2 ^H , d), 7.40 (5 ^H , S) Elemental analysis (as C ₇ H ₂₁ N ₃ O ₆ ) C H N Calculated value (%) 56.19 5.83 11.57 Actual value (%) 55.90 5.94 11.81 Example 5 ( 4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-ethoxycarbonyl-2-(p-hydroxyphenyl)ethyl]amino]-1-oxo-propyl]-hexahydro-6 Preparation of -oxy-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[( ^1S )-1-ethoxycarbonyl-2-(p-hydroxyphenyl)ethyl]-alanine 3.0g, ( ^4S ) -hexahydro-6-oxo-
Pyrimidine-4-carboxylic acid methyl ester
It was prepared in the same manner as in Example 1 using 1.7 g, DEPC 2.0 g, and triethylamine 1.6 ml, and recrystallized from isopropanol-isopropyl ether.
1.5 g of the target compound with a temperature of mp.131-135°C was obtained.

[α] ²⁶ _D = −38.5° (C = 0.8, methanol) Example 6 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-benzyloxycarbonyl-2-( Preparation of p-hydroxyphenyl)ethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[(1 ^S )-1-benzyloxy Carbonyl-2-(p-hydroxyphenyl)ethyl]-alanine 3.9 g, ( ^4S )-hexahydro-6-
It was prepared in the same manner as in Example 1 using 1.9 g of oxo-pyrimidine-4-carboxylic acid methyl ester, 2.0 g of DEPC, and 1.7 ml of triethylamine to obtain 1.3 g of the target compound.

[α] ²⁴ . ⁵ _D = -41.1° (C = 1.0, methanol) 'H-NMR (CDCl ₃ ); δ value 2.6-3.1 (4 ^H , m), 3.69 (3 ^H , S), 5.11
(2 ^H , S), 6.6-7.2 (4 ^H , ABq), 7.32 (5
^H , S) Elemental analysis (as C ₁₅ EH ₂₉ N ₃ O ₇ ) C H N Calculated value (%) 62.10 6.05 8.69 Actual value (%) 61.81 6.24 8.80 Example 7 (4 ^S )-3- [(2 ^RS )-2-[[(1 ^S )-carboxy-2-(p-hydroxyphenyl)ethyl]
Production of amino]-1-oxopropyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester ( ^4S )-3-[( ^2RS )-2 obtained in Example 6
-[[(1 ^S )-1-benzyloxycarbonyl-2
-(p-hydroxyphenyl)ethyl]amino]-
1-oxo-propyl]-hexahydro-6-oxopyrimidine-4-carboxylic acid methyl ester
600 mg, prepared in the same manner as in Example 3 using palladium black, recrystallized from methanol,
360 mg of the target compound with mp.173-175°C was obtained.

[α] ²⁸ . ⁵ _D = -32.8° (C = 0.9, water) Example 8 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-carboxy-2-(p-hydroxyphenyl ) Preparation of ethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid ( ^4S )-3-[( ^2RS )-2 obtained in Example 5
-[[(1 ^S )-1-ethoxycarbonyl-2-(p-
hydroxyphenyl)ethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-
Pyrimidine-4-carboxylic acid methyl ester 600
It was prepared in the same manner as in Example 4 using 4.6 ml of 1 ^N -NaOH and 350 mg of the target compound.

[α] ²⁷ _D = −23.2° (C = 0.5, water) 'H-NMR (D ₂ O); δ value 1.45 (3 ^H , d), 2.7 to 3.0 (2 ^H , m), 3.27
(2 ^H , d), 6.7-7.4 (4 ^H , ABq) Elemental analysis value (as C ₇ H ₂₁ N ₃ O ₇ H ₂ O) C H N Calculated value (%) 51.38 5.83 10.58 Actual value (%) 51.65 5.76 10.77 Example 9 ( ^4S )-3-[( ^2RS )-2-[[( ^1S )-1-ethoxycarbonyl-3-methylthiopropyl]amino]-1-oxo-propyl]hexahydro-6 -Production of oxo-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[( ^1S )-1-ethoxycarbonyl-3-methylthiopropyl]-alanine 3g, (4
^S )-hexahydro-6-oxo-pyrimidine-4
-carboxylic acid methyl ester 1.9g, DEPC2.2g,
It was prepared in the same manner as in Example 1 using 1.8 ml of triethylamine to obtain 1.8 g of the target compound.

[α] ²² _D = -52.9° (C = 0.9, ethanol) 'H-NMR (CDCl ₃ ); δ value 1.27 (3 ^H , t), 1.32 (3 ^H , d), 2.08 (3 ^H ,
S), 3.77 (3 ^H , S), 4.17 (2 ^H , q) Elemental analysis (as C ₁₆ H ₂₇ N ₃ O ₆ S) C H N Calculated value (%) 50.37 6.99 10.79 Actual value (%) 50.44 7.19 11.07 Example 10 ( ^4S )-3-[( ^2RS )-2-[[( ^1S )-1-carboxy-3-methylthiopropyl]amino]-
Preparation of 1-oxo-propyl]hexahydro-6-oxo-pyrimidine-4-carboxylic acid ( ^4S )-3-[( ^2RS )-2 obtained in Example 9
-[[( ^1S )-1-ethoxycarbonyl-3-methylthiopropyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-
700 mg of 4-carboxylic acid methyl ester, 1 ^N −
It was prepared in the same manner as in Example 4 using 4.0 ml of NaOH to obtain 500 mg of the target compound.

[α] ²⁸ _D = -54.0° (C = 0.6, water) 'H-NMR (D ₂ O); δ value 1.55 (3 ^H , d), 2.13 (3 ^H , S), 2.68 (2 ^H ,
t), 2.8-3.1 (2 ^H , m) Elemental analysis (as C ₁₃ H ₂₁ N ₃ O ₆ S) C H N Calculated value (%) 44.94 6.09 12.10 Actual value (%) 44.67 6.29 12.21 Example 11 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^R )-1-benzyloxycarbonyl-2-benzylthioethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine- Production of 4-carboxylic acid methyl ester (RS)-N-[1( ^R )-1-benzyloxycarbonyl-2-benzylthioethyl]-alanine
3g, ( ^4S )-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester 1.5g,
It was prepared in the same manner as in Example 1 using 1.4 g of DEPC and 1.2 ml of triethylamine to obtain 1.0 g of the target compound.

[α] ²⁷ _D = -50.1° (C = 0.9, methanol) 'H-NMR (CDCl ₃ ); δ value 1.18, 1.26 (total 3 ^H , each d), 3.68, 3.71 (2 ^H ,
S, 3 ^H , S), 5.12 (2 ^H , S), 7.24 (5 ^H ,
S), 7.32 (5 ^H , S) Elemental analysis (as C ₂₆ H ₃₁ N ₃ O ₆ S) C H N Calculated value (%) 50.68 6.27 8.17 Actual value (%) 50.53 6.30 8.41 Example 12 (4 ^S ) -3-[(2 ^RS )-2-[[(1 ^R )-1-carboxy-2-benzylthioethyl]amino]-
1-oxo-propyl]-hexahydro-6-
Preparation of oxo-pyrimidine-4-carboxylic acid ( ^4S )-3-[( ^2RS )-2 obtained in Example 11
-[[(1 ^R )-1-benzyloxycarbonyl-2
-benzylthioethyl]amino]-1-oxo-
[propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester 700 mg, 1 ^N
It was prepared in the same manner as in Example 4 using 3.1 ml of -NaOH to obtain 300 mg of the target compound.

[α] ²⁶ _D = −24.1° (C = 0.7, water) 'H-NMR (D ₂ O); δ value 1.48, 1.56 (total 3 ^H , each d), 2.8 to 3.1 (2 ^H ,
m), 3.06 (2 ^H , d), 3.83 (2 ^H , S) 7.40
(5 ^H , S) Elemental analysis (as C ₁₈ H ₂₃ N ₃ O ₆ S) C H N Calculated value (%) 52.80 5.66 10.26 Actual value (%) 52.96 5.57 10.49 Example 13 (4 ^S )-3- [ (2 ^RS )-2-[[(1 ^S )-1-benzyloxycarbonylethyl]amino]-1-
Preparation of (RS)-N-[(1 ^S )-1-benzyloxycarbonylethyl]-alanine 3 g, (4 ^S )-hexahydro It was prepared in the same manner as in Example 1 using 2.1 g of -6-oxo-pyrimidine-4-carboxylic acid methyl ester, 2.1 g of DEPC, and 1.8 ml of triethylamine to obtain 2.3 g of the target compound.

[α] ²⁷ _D = -55.0° (C = 1.1, methanol) 'H-NMR (CDCl ₃ ); δ value 1.24 (3 ^H , d), 1.32 (3 ^H , d), 2.76 (2 ^H ,
d), 3.74 (3 ^H , S) 5.14 (2 ^H , S), 7.34
(5 ^H , S) Elemental analysis (as C ₁₉ H ₂₅ N ₃ O ₆ ) C H N Calculated value (%) 58.30 6.44 10.74 Actual value (%) 58.36 6.51 10.98 Example 14 (4 ^S )-3- [( Preparation of ^2RS )-2-[[( ^1S )-1-carboxyethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester Obtained in Example 13 (4 ^S ) −3 − [(2 ^RS ) −2
-[[( ^1S )-1-benzyloxycarbonylethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester (1.2 g) and palladium black were used in Example 3. It was prepared in the same manner as above and recrystallized from water-methanol-isopropyl ether, mp.138-141℃.
720 mg of the target compound was obtained.

[α] ²⁶ . ⁵ _D = -68.1° (C = 0.8, water) Example 15 (4 ^S )-3-[(2 ^RS )-2-[[(1 ^S )-1-ethoxycarbonylethyl]amino]-1-oxo -Propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid methyl ester (RS)-N-[( ^1S )-1-ethoxycarbonylethyl]-alanine 3g, ( ^4S )-hexahydro-
2.5 g of 6-oxo-pyrimidine-4-carboxylic acid methyl ester, 2.9 g of DEPC, 2.5 g of triethylamine
ml was prepared in the same manner as in Example 1 to obtain 1.0 g of the target compound.

[α] ²⁴ _D = -55.1° (C = 1.1, ethanol) 'H-NMR (CDCl ₃ ); δ value 1.28 (3 ^H , t), 1.28 (2 ^H , d), 1.30 (2 ^H ,
d), 2.79 (2 ^H , d), 3.76 (3 ^H , S) 4.16
(2 ^H , q) Elemental analysis (as C ₁₄ H ₂₃ N ₃ O ₆ ) C H N Calculated value (%) 51.05 7.04 12.76 Actual value (%) 51.28 7.18 13.06 Example 16 (4 ^S ) -3- [( Preparation of ^2RS )-2-[[( ^1S )-1-carboxyethyl]amino]-1-oxo-propyl]-hexahydro-6-oxo-pyrimidine-4-carboxylic acid (obtained in Example 15) 4 ^S ) −3 − [(2 ^RS ) −2
-[[( ^1S )-1-ethoxycarbonylethyl]amino]-1-oxo-propyl]-hexahydro-
Prepared in the same manner as in Example 4 using 800 mg of 6-oxo-pyrimidine-4-carboxylic acid methyl ester and 4.8 ml of 1 ^N -NaOH to obtain 440 mg of the target compound.
I got it.

[α] ²⁶ _D = -44.6° (C = 0.8, water) 'H-NMR (D ₂ O); δ value 1.53 (3 ^H , d), 1.56 (3 ^H , d), 2.8 ~ 3.1
(2 ^H , m) Elemental analysis (as C ₁₁ H ₁₇ N ₃ O ₆・H ₂ O) C H N Calculated value (%) 43.27 6.27 13.77 Actual value (%) 43.37 6.23 13.96

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents lower alkyl, lower alkylthio lower alkyl, phenyl lower alkylthio lower alkyl, or phenyl lower alkyl group which may have a hydroxy group as a substituent,
R ₂ represents hydrogen, lower alkyl or phenyl lower alkyl group, and R ₃ represents hydrogen or lower alkyl group. ] A hexahydro-6-oxo-pyrimidine-4-carboxylic acid derivative and a salt thereof.