JPH0224265B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel bicyclic compounds useful as pharmaceuticals. Conventionally, various amino acid derivatives (e.g., JP-A-52-116457, JP-A-Sho 52-116457,
No. 52-136117, JP-A No. 12372-1983, JP-A-55-
38382 and JP-A-55-81845), the compound of the present invention has a different skeleton from any of these known compounds, and has excellent angiotensin-converting enzyme inhibitory activity and antihypertensive activity. That is, the present invention is based on the formula [In the formula, R ¹ and R ² are the same or different, hydrogen,
hydroxyl group or lower alkoxy group, R ³ is a lower alkyl group, R ⁴ is hydrogen, lower alkyl group, amino lower alkyl group or acylamino lower alkyl group, m and n mean 1 or 2] compounds and formulas [In the formula, R ⁵ is hydrogen, a lower alkyl group, or a phenyl lower alkyl group optionally substituted with a halogen, a lower alkyl group, or a hydroxyl group,
R ⁶ represents a hydroxyl group, a lower alkoxy group, an amino group, or a lower alkylamino group] is condensed by a catalytic reduction reaction or a reduction reaction with a metal hydride compound in the presence of a molecular sieve, and the resulting formula is A formula characterized by subjecting a compound represented by [wherein all symbols have the same meanings as above] to a hydrolysis reaction The present invention relates to a method for producing a bicyclic compound represented by the formula [wherein all symbols have the same meanings as above] or a salt thereof. Regarding the above formula, examples of the lower alkoxy group represented by R ¹ and R ² include lower alkoxy groups having about 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and isopropoxy groups; R ¹ and R ² may form a lower (C _1-4 )alkylenedioxy group such as a methylenedioxy group or an ethylenedioxy group. Examples of the lower alkyl group represented by R ³ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group,
Examples include alkyl groups having about 1 to 4 carbon atoms such as tert-butyl group. The lower alkyl group represented by R ⁴ is the same lower alkyl group as represented by R ³ , and the amino lower alkyl group is, for example, an aminomethyl group, a 1-
Straight chain or branched amino lower alkyl groups having about 1 to 4 carbon atoms, such as aminoethyl group, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, 3-amino-2-methylpropyl group, etc. but,
Examples of the acylamino lower alkyl group include the amino group in the above amino lower alkyl group.
Acyl groups derived from carboxylic acids or carbonates such as C _2-4 alkanoyl groups (e.g., acetyl, propionyl), benzoyl groups, C _2-4 alkoxycarbonyl groups (e.g., ethoxycarbonyl), benzyloxycarbonyl groups, etc. Examples include the following groups. The lower alkyl group represented by R ⁵ is the same lower alkyl group as represented by R ³ , and the phenyl lower alkyl group is, for example, benzyl group, phenethyl group, 3-phenylpropyl group, α-methylbenzyl group, α - Phenyl lower (C _1-4 ) alkyl groups having about 7 to 10 carbon atoms such as ethylbenzyl group, α-methylphenethyl group, β-methylphenethyl group, and β-ethylphenethyl group, and the phenyl group in the phenyl lower alkyl group is substituted with a halogen (e.g., fluorine, chlorine, bromine, iodine), a lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.), or a hydroxyl group. good. Examples of such substituted phenyl lower alkyl groups include 2-(4-chlorophenyl)ethyl group, 2-(4-hydroxyphenyl)ethyl group, 2-(p-tolyl)ethyl group, 4-ethylbenzyl group, Examples include 4-chlorobenzyl group. Examples of the lower alkoxy group represented by R ⁶ include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group,
Lower alkoxy groups having about 1 to 4 carbon atoms such as sec-butoxy group and tert-butoxy group, examples of lower alkylamino groups include methylamino group, ethylamino group, propylamino group, butylamino group, dimethylamino group, Examples include mono- or di-lower (C _1-4 ) alkylamino groups such as diethylamino groups. Among these compounds (), R ¹ and R ² are hydrogen, R ⁴ is a lower (C _1-4 ) alkyl group or amino lower (C 1-4 ) alkyl group, R ⁵ is a phenethyl group, and R ⁶ is a lower (C _1-4 ) alkyl group. _1-4 ) Desirably, a compound of 1 is used as an alkoxy group or a hydroxyl group, m and n. Examples of salts of compound () include hydrochloride,
Inorganic acid salts such as hydrobromide, sulfate, nitrate, phosphate, organic salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate acid salt,
Examples include metal salts such as sodium salts, potassium salts, calcium salts, and aluminum salts, and salts with bases such as triethylamine salts, guanidine salts, ammonium salts, hydrazine salts, quinine salts, and cinchonine salts. Examples of catalytic reduction reactions when condensing compounds () and () include platinum, palladium,
Catalytic reduction reactions using metals such as Raney nickel and rhodium or their mixtures with arbitrary carriers as catalysts, and ring element reactions using metal hydride compounds include lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, and hydrogen. Examples include reduction reactions using metal hydride compounds such as sodium borohydride and sodium cyanoborohydride. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether,
dioxane, methylene chloride, chloroform,
(benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide, etc.) in the presence of a molecular sieve, and the reaction temperature varies depending on the reduction method, but generally ranges from -20℃ to ++
About 100°C is preferable. Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased pressure or reduced pressure if necessary. Compound () can be produced by hydrolyzing compound (') obtained by the condensation reaction under the above reductive conditions. When R ⁶ is a hydroxyl group in compound (), compound () can also be produced by hydrolysis of the corresponding ester compound or catalytic reduction of benzyl ester. Compounds () and (′) are separated from the reaction mixture by conventional separation and purification methods such as extraction, concentration, neutralization,
It can be isolated by using means such as filtration, recrystallization, column chromatography, and thin layer chromatography. Compound () may exist in 2 to 8 stereoisomers depending on the presence or absence of substituents represented by R ⁴ and R ⁵ . Both of these individual isomers and mixtures thereof are naturally included within the scope of the present invention, and these isomers can also be produced individually if desired. For example, by carrying out the above reaction using a single isomer of the starting compound (), a single optical isomer of the compound () can be obtained, or the product can be a mixture of two or more isomers. In the case of It can also be separated into each isomer by a method of forming a salt with dehydroabiethylamine (such as dehydroabiethylamine), various chromatography, fractional recrystallization, and other separation means. In formula (), when R ⁴ and R ⁵ represent a group other than hydrogen, each S-coordination isomer generally exhibits more preferable physiological activity than the corresponding R-coordination compound. The compound of the present invention, that is, the bicyclic compound represented by formula () and its salt, can be used in animals, especially mammals (e.g., humans, dogs, cats, rabbits, guinea pigs,
It exhibits angiotensin-converting enzyme inhibitory effect, bradykinin-degrading enzyme (kininase) inhibitory effect, and enkephalinase inhibitory effect against rats).
For example, it is useful as a diagnostic, preventive or therapeutic agent for hypertension, or as an analgesic or analgesic enhancer. The compound of the present invention has low toxicity, good absorption even when administered orally, and excellent stability. Therefore, when used as the above-mentioned medicine, it can be used by itself or with appropriate pharmaceutically acceptable carriers, excipients, and diluents. It can be mixed and safely administered orally or parenterally as a pharmaceutical composition such as powder, granules, tablets, capsules, or injections. The dosage varies depending on the condition of the target disease and the route of administration, but for example, when administered to adult patients for the purpose of treating hypertension,
For oral administration, a single dose is usually about 0.02 to 20 mg/Kg, especially about 0.2 to 2 mg/Kg, and for intravenous administration, a single dose is preferably about 0.002 to 0.2 mg/Kg, especially about 0.02 to 0.2 mg/Kg. The dosage of 1 depending on the symptoms.
It is desirable to administer the drug about 2 to 5 times a day. The starting compound () of the present invention can be easily produced, for example, by the method shown in the following reaction formula. [In the formula, R ¹ , R ² , R ³ , R ⁴ , m, and n have the same meanings as above, and Cbz represents a benzyloxycarbonyl group] A more detailed explanation of the method for producing () shown in the above reaction formula Then, first () →
The reaction of () produces a Schiff base by reacting () and () in an appropriate solvent,
This is then carried out by subjecting it to a reduction reaction. Examples of solvents include methanol, ethanol,
Organic solvents such as dioxane, methylene chloride, chloroform, benzene, and toluene are used, and the reaction is usually carried out at a temperature range of about -10°C to +150°C. At this time, catalysts such as sulfuric acid and p-toluenesulfonic acid, dehydrating agents such as anhydrous sodium sulfate, anhydrous magnesium sulfate, and calcium chloride may be added to the reaction solution in order to facilitate the reaction. can. It is also possible to carry out the reaction advantageously by attaching a water separator to the reaction. The obtained Schiff base is used as a reaction solution, or after being isolated by a conventional method, it is added to a solvent again and subjected to a reduction reaction. Examples of the reduction method include catalytic reduction using platinum, palladium-carbon or the like as a catalyst, or a method using a reducing agent such as sodium borohydride or sodium cyanoborohydride. Furthermore, it is also possible to allow these reducing agents to coexist in the reaction solution of () and () from the beginning, so that Schiff base generation and reduction can proceed simultaneously. ()
→The reaction () is carried out by reacting () with () or a reactive derivative at its carboxyl group. Examples of reactive derivatives at the carboxyl group of the compound () include acid halides such as acid chloride and acid bromide;
An acid anhydride obtained by dehydrating one molecule of water from two molecules of (), a mixed anhydride in which the hydrogen of the carboxyl group in () is replaced with, for example, an ethoxycarbonyl group, isobutyloxycarbonyl group, benzyloxycarbonyl group, etc. , for example 1-
Examples include derivatives such as active esters of () derived from hydroxybenzotriazole, N-hydroxyphthalimide, N-hydroxysuccinimide, and the like. The reaction is generally carried out in a suitable solvent, and any solvent can be used as long as it does not inhibit the reaction. When () is used as it is without converting it into a reactive derivative, it is advantageous to carry out the reaction in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. When using an acid halide as a reactive derivative, the reaction can also be carried out in the presence of a base such as pyridine, picoline, triethylamine, sodium hydroxide, sodium bicarbonate, or sodium carbonate. The reaction temperature is usually about -
The reaction is carried out at a temperature of about 20°C to +150°C, and in most cases the reaction proceeds satisfactorily even at room temperature. The reaction ()→() is an N-protecting group elimination reaction by catalytic reduction. This catalytic reduction reaction can be carried out using water or e.g. methanol, ethanol, dioxane,
The reaction is carried out in an organic solvent such as tetrahydrofuran or acetic acid, or a mixed solvent thereof, in the presence of a suitable catalyst such as platinum, palladium on carbon, or Raney nickel. This reaction is carried out at normal pressure or at 150Kg/cm ²
The reaction is carried out at temperatures ranging from room temperature to 150° C. under pressure up to a certain degree, but the reaction generally proceeds sufficiently at room temperature. The present invention will be explained in more detail below using Reference Examples, Examples, Experimental Examples, and Preparation Examples, but the scope of the present invention is not limited thereto. Reference example 1 Dissolve 40 g of 2-indanone in 300 ml of methanol, and dissolve 78 g of glycine tert-butyl ester phosphite.
After adding g and 150 ml of water, 23 g of sodium cyanoborohydride was added over 15 minutes while stirring under water cooling, and the mixture was further stirred at room temperature for 4 hours. 20 to the reaction solution
Add 400 ml of % phosphoric acid little by little over 1 hour, then add 200 ml of water, stir for 30 minutes, extract with 800 ml of ethyl ether, adjust the aqueous layer to pH 10 with 20% sodium hydroxide, and add chloroform (500 ml in total) 4 times. Extract. After drying the extract over anhydrous sodium sulfate, it was distilled off under reduced pressure, and the resulting oil was diluted with ethanol.
Add 50ml and then 150ml of water and cool. The precipitated crystals were collected by filtration and recrystallized twice from aqueous ethanol, resulting in (indan-2-yl)glycine tert-
47 g of butyl ester can be obtained as colorless prismatic crystals with a melting point of 54-55°C. Reference example 2 21.8 g of N-carbobenzoxy-L-alanine and 12.3 ml of triethylamine were dissolved in tetrahydrofuran.
Dissolve in 200 ml and add 8.5 g of ethyl chlorocarbonate dropwise while stirring at -15°C. After stirring for 15 minutes after dropping, 22 g of (indan-2-yl)glycine tert-butyl ester was dissolved in 100 ml of chloroform and added dropwise at -10°C or lower. After stirring at room temperature for 1 hour, the reaction solution was poured into 500 ml of water, and the chloroform layer was separated and evaporated. Dilute the residue with 300ml of ethyl acetate
twice with 50 ml of 1N sodium hydroxide aqueous solution, once with 50 ml of water, then 20% phosphoric acid aqueous solution.
Wash twice with 50 ml each and once with 50 ml of water, dry over anhydrous magnesium sulfate, and distill off to obtain N-carbobenzoxy-L-alanyl-N-.
35 g of (indan-2-yl)glycine tert-butyl ester are obtained as an oil. This was dissolved in 300 ml of methanol, 7 g of oxalic acid and 3.5 g of 10% palladium on carbon (water content 50%) were added, and catalytic reduction was carried out at room temperature and pressure. After the reaction, the catalyst was filtered off, the filtrate was distilled off under reduced pressure, and 500 ml of ethyl ether was added to the residue.
Add and cool. When the precipitated crystals are collected by filtration and dried, L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate is obtained.
Obtain 21.8g. Melting point 138-141℃. [α] ²² _D +20.4° (c=1, methanol). Reference example 3 7 g of N-(indan-2-yl)glycine tert-butyl ester and N-(carbobenzoxy)-
By reacting and treating 8.5 g of L-leucine in the same manner as in Reference Example 2, 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester oxalate was obtained as a colorless amorphous powder. obtained as. Reference example 4 8.2 g of N-(indan-2-yl)glycine tert-butyl ester and 13 g of N-tert-butoxycarbonyl-N-carbobenzoxy-L-lysine
When reacted in the same manner as in Reference Example 2, 〓―tert―
Butoxycarbonyl-N〓-carbobenzoxy-
14g of L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
can get. NMR (CDCl ₃ ) δ: 1.40, 1.45 (18H), 5.05 (2H),
7.0-7.3 (9H). IR spectrum ν ^neat _nax cm ^-1 : 1700, 1640. [α] ²⁴ _D −14.3° (c=0.9, methanol). Reference Example 5 N〓-tert-butoxycarbonyl-N〓-carbobenzoxy-L-lysyl-N obtained in Reference Example 4
-(indan-2-yl)glycine tert-butyl ester 5g IN hydrogen chloride-ethyl acetate solution 100%
ml and leave at room temperature for 6 hours. Add 500 ml of petroleum ether to the reaction solution to separate the precipitated oil. The solution layer is concentrated under reduced pressure and subjected to the same hydrogen chloride treatment again. The combined oils obtained are dissolved in 100 ml of ethyl acetate and washed with 100 ml of 1N aqueous sodium hydroxide solution and water. The organic layer was dried over anhydrous magnesium sulfate, 1 g of oxalic acid was added, and the mixture was distilled off under reduced pressure. When a mixture of ether and petroleum ether is added, N〓-carbobenzoxy-L-lysyl-
2.4 g of N-(indan-2-yl)glycine tert-butyl ester oxalate is obtained as a colorless powder. Elemental analysis value: C ₂₉ H ₃₉ N ₃ O ₅・C ₂ H ₂ O ₄・H ₂ O Calculated value: C 60.28 H 7.02 N 6.80 Actual value: C 59.83 H 7.01 N 6.41 [α] ^23.5 _D = +17. 5° (c=1, methanol). Reference example 6 5,6-dimethoxy-1-indanamine hydrochloride
11 g was suspended in 200 ml of methyl ethyl ketone, 6.9 g of potassium carbonate, 2.0 g of potassium iodide and 8.2 g of chloroacetic acid tert-butyl ester were added, and the mixture was refluxed for 8 hours. The reaction solution is added to 500 ml of water, extracted with 200 ml of ethyl acetate, washed with water, dried, and then ethyl acetate is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-acetone (7:3) to obtain 6.0 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as an oil. . When this was dissolved in 50 ml of ethyl ether, 2.0 g of oxalic acid was added, and the mixture was left at room temperature, 7.3 g of N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate was obtained as a colorless needle. Obtained as crystals. Melting point 158-160℃. Reference example 7 N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate 7
g and N-carbobenzoxy-L-alanine 4.8g
By reacting and treating in the same manner as in Reference Example 2, 4 g of L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester oxalate was obtained as a colorless amorphous powder. can get. Reference example 8 3-phenylpropionic acid ethyl ester 143
A mixture of 234 g of ethyl oxalate and 154 ml of a 28% sodium ethoxide ethanol solution is heated on a water bath at a bath temperature of 60-70° C. for 1.5 hours while distilling off the ethanol under reduced pressure. Add 1.3 of 15V/V% sulfuric acid to the resulting red syrupy substance, boil and reflux with stirring for 15 hours, then separate the precipitated oil, neutralize with 10% sodium hydroxide, and extract with ethyl acetate. The aqueous layer is made acidic with dilute sulfuric acid, and the precipitated oil is extracted with ethyl acetate, washed with water, dried, and then evaporated under reduced pressure to obtain 130 g of 2-oxo-4-phenylbutyric acid as an oily substance. Reference Example 9 Add 130 g of 2-oxo-4-phenylbutyric acid to a mixture of 650 ml of ethanol and 13 ml of concentrated sulfuric acid, and boil and reflux for 5 hours. After concentrating the reaction solution to about half the volume, add water
Dilute with 500 ml, collect the separated oil, and extract the aqueous layer with ethyl acetate. The extract and oil are combined, dried, and distilled off under reduced pressure, and the residue is distilled off under reduced pressure. boiling point
113 g of ethyl 2-oxo-4-phenylbutyrate are obtained as a colorless oil at 135-141° C./3 mm Hg. Reference Examples 10 to 16 By the same operations as in Reference Examples 8 and 9, the compounds shown in Table 1 are obtained from the corresponding starting compounds.

[Table] Reference example 17 Veratrumaldehyde 99.6g, malonic acid 124.8g
g, 7.5 ml of piperidine was added to a solution of 240 ml of pyridine, heated at 80 to 85°C for 1 hour, and then further heated to 110 ml of pyridine.
Incubate at ~115°C for 3 hours. After cooling, pour the reaction solution into a large amount of water and filter the precipitated crystals. This crystal is dissolved in a dilute aqueous sodium hydroxide solution and then acidified with hydrochloric acid to obtain 70 g of needle-shaped crystals of 3,4-dimethoxycinnamic acid. Melting point 182-3℃. Genuine crystal 35g
Dissolve in 500 ml of ethanol to saturate with hydrogen chloride gas and leave overnight at room temperature. The crystals obtained by distilling off the ethanol are dissolved in ethyl acetate and washed with dilute aqueous sodium hydrogen carbonate solution and water. After drying, the crystals obtained by distilling off the ethyl acetate are recrystallized from ethanol to obtain 65 g of scaly crystals of ethyl 3,4-dimethoxycinnamate. Melting point 53-55℃. Book crystal 34
Dissolve g in 300 ml of ethanol, add 10 g of 5% palladium on carbon, and stir in a hydrogen stream at room temperature. After 3 hours, the catalyst is filtered off and the filtrate is concentrated to obtain 34 g of ethyl 3,4-dimethoxyphenylpropionate as an oil. Genuine oil 34.1
g, a solution of 43 g of diethyl oxalate, and a solution of 43 g of diethyl oxalate,
Add 3.8 g to a sodium ethoxide solution prepared from 150 ml of ethanol at 60°C while stirring. After the addition is complete, stir at 70-75°C for another 3 hours. Ethanol is distilled off under reduced pressure, 200 ml of water is added to the residue, and the portion to be extracted with ethyl acetate is removed. The aqueous layer is made acidic with hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and concentrated to obtain 27 g of ethyl 2-oxo-3-ethoxycarbonyl-4-(3,4-dimethoxyphenyl)butyrate as an oil. Dissolve 26g of this oil in 80ml of dimethyl sulfoxide and 8ml of water, and add salt.
Add 6.3g and stir at 120℃ for 2 hours. After cooling,
Add a large amount of water and extract with ethyl acetate. washing with water,
After drying, the crystals obtained by concentration are recrystallized from ether to give ethyl 2-oxo-4-(3,4
-Columnar crystals of dimethoxyphenyl)butyrate 15
get g. Melting point 85-87℃. Reference Example 18 In the same manner as Reference Example 17, ethyl 4-(p-benzyloxyphenyl) was prepared from the corresponding raw material compound.
-2-oxobutyrate is obtained as a yellow oil. Nuclear magnetic resonance (NMR) spectrum ( _CDCl3 ) δ:
1.3 (t, 3H), 2.7-3.3 (m, 4H), 4.3 (q,
2H), 5.0 (s, 2H), 6.7-7.4 (m, 9H). However, s is a singlet, d is a doublet, t is a triplet,
q means a quartet, m means a multiplet, and ph means a phenyl group (the same applies to the following Reference Examples and Examples). Reference example 19 9g of 2-oxo-4-phenylbutyric acid was added to benzene.
Dissolve in 100ml and add 10g of phosphorus pentachloride little by little while cooling on ice. After stirring at room temperature for 1 hour, a solution of 10 g of butylamine dissolved in 20 ml of tetrahydrofuran was added dropwise to the benzene solution. After dropping, stir at room temperature for 30 minutes, add the reaction solution to 100 ml of ice water,
Extract with ethyl acetate. After washing the extract with water and drying,
Ethyl acetate is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-acetone (7:3) to obtain 6.0 g of N-butyl-2-oxo-4-phenylbutyramide as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ: 0.90 (3H, m,
CH ₃ ), 1.20-1.50 (4H, m), 2.70-3.40 (5H,
m), 7.20 (5H, s, Ph). Example 1 21 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate was dissolved in 200 ml of ethanol, 4.1 g of sodium acetate,
After sequentially adding 10 ml of acetic acid, 25 g of ethyl 2-oxo-4-phenylbutyrate and 25 g of Molecular Sieve 3A, 30 g of Raney nickel suspended in 100 ml of ethanol was added together with ethanol and catalytic reduction was carried out at room temperature and pressure. After hydrogen absorption has ceased, the supernatant is decanted and the precipitate is washed with ethanol two to three times, combined with the washings, and concentrated under reduced pressure. The residue is dissolved in 500 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution and filtered with 30 g of diatomaceous earth. The ethyl acetate layer was separated from the filtrate, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2- Glycine tert-butyl ester 24g
is obtained as a pale yellow candy-like substance. IR spectrum ν ^Neat _Max cm ^-1 = 1730 (ester), 1640
(amide) NMR spectrum (CDCl ₃ ) δ=1.27 (3H, t,
CH ₃ ), 1.40 (9H, s, CH ₃ ×3), 1.8-2.2
(3H, m, CH ₃ ), 2.6―4.5 (10H, m), 3.8―
3.9 (2H, m, CH ₂ ), 4.2 (2H, q, CH ₂ ), 4.9
(1H, t, CH), 7.1-7.4 (9H, m, Ph). Example 2 N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl- obtained in Example 1
N-(indan-2-yl)glycine tert-butyl ester was subjected to column chromatography on 700 g of silica gel, followed by benzene, benzene-acetone (10:1 to 4:1), and then methanol-benzene (1:9). Each fraction was further subjected to column chromatography on 400 g of silica gel and purified by the same procedure as described above. From the first fraction, N-[1-(R)-ethoxycarbonyl-3 -phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine
2 g of tert-butyl ester are obtained as a colorless candy. [α] ²² _D −16.4° (c=1, methanol). On the other hand, from the later fraction, N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine
16.5 g of tert-butyl ester are obtained as a colorless candy. [α] ²² _D −12.6° (c=1, methanol). The 1R and NMR spectra of both are the same as those of the compound of Example 1. Example 3 N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine obtained in Example 2
Dissolve 5 g of tert-butyl ester in 5 ml of acetic acid,
Add 20ml of 25% hydrobromic acid acetic acid solution to this solution.
After shaking for 10 minutes, 300 ml of ethyl ether was added and the precipitated crystals were collected by filtration, resulting in N-[1-(S)
-Ethoxycarbonyl-3-phenylpropyl]
5 g of -L-alanyl-N-(indan-2-yl)glycine hydrobromide are obtained as colorless powder crystals. Melting point 180-183℃. [α] ²⁰ _D +15.6° (c=1.4, methanol). Example 4 N-[1-(R)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine obtained in Example 2
By treating the tert-butyl ester in the same manner as in Example 3, N-[1-(R)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl ) Glycine hydrobromide can be obtained as colorless powder crystals. Melting point 150-155℃. [α] ²⁰ _D −20.2° (c=1, methanol). Example 5 N-[1-
(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrobromide (16.2 g) in ethyl acetate.
Add to a mixture of 500 ml, 33 g of sodium hydrogen carbonate, and 500 ml of water and stir to dissolve. Add 1N hydrochloric acid to pH
4, the ethyl acetate layer was separated, washed with water, dried, added with 20 ml of 7N ethanolic hydrochloric acid, concentrated under reduced pressure, added 250 ml of ethyl ether and 250 ml of petroleum ether to the residue, and collected the precipitated crystals by filtration. N
11 g of -[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride is obtained as colorless powdery crystals. Recrystallize this product from a mixture of acetone and 1N hydrochloric acid to obtain colorless plate-like crystals. Melting point 166-170
°C (decomposition). [α] ²² _D +18.5° (c=1, methanol). IR spectrum ν ^Nujol _Max cm ^-1 : 1740 (COOC ₂ H ₅ ), 1705
(COOH), 1640 (CO-N) Example 6 4.1 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate was dissolved in 40 ml of ethanol, 0.85 g of sodium acetate,
After adding 2 ml of acetic acid, 5 g of propyl 2-oxo-4-phenylbutyrate, and 5 g of molecular sieve 3A, 6 g of Raney nickel suspended in 20 ml of ethanol was added, and catalytic reduction was carried out at room temperature and pressure. After hydrogen absorption has stopped, the supernatant liquid is collected by decanting,
The precipitate is washed 2 to 3 times with ethanol, combined with the washing liquid, and evaporated under reduced pressure. The residue was shaken with 100 ml of ethyl acetate and an aqueous sodium bicarbonate solution, filtered with 10 g of diatomaceous earth, and the ethyl acetate layer of the filtrate was separated, washed with water, dried, and distilled off to give N-(1-propoxycarbonyl-3 -Phenylpropyl)-L
-Alanyl-N-(indan-2-yl)glycine tert-butyl ester is obtained as a pale yellow candy-like substance. 3 ml of acetic acid and 12 ml of 25% acetic hydrobromic acid were added to this, and the mixture was allowed to react for 15 minutes while stirring occasionally. Then, 150 ml of ethyl ether was added and the precipitated crystals were collected by filtration.N-(1-propoxycarbonyl- 3-phenylpropyl)-L-alanyl-
3.4 g of N-(indan-2-yl)glycine hydrobromide are obtained as colorless powder crystals. Add this to a mixture of 70 ml of water and 70 ml of ethyl acetate, stir, neutralize with sodium hydrocarbon, adjust the pH to 3-4 with 10% hydrochloric acid, separate the ethyl acetate layer, dry over anhydrous magnesium sulfate, and add ethanolic hydrochloric acid. Add to make acidic. The solvent was distilled off, 150 ml of ethyl ether was added to the residue, the mixture was left to stand for 10 minutes, and the precipitated crystals were collected by filtration to give N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-
N-(indan-2-yl)glycine hydrochloride 1.7
g is obtained. Melting point: 147-150℃ (decomposition). IR spectrum ν ^Nujol _Max cm ^-1 = 1740 (ester), 1710
(COOH), 1640 (CO-N). Example 7 Propyl 2-oxo-4- in Example 6
By carrying out the same reaction procedure as in Example 6 using butyl 2-oxo-4-phenylbutyrate instead of phenylbutyrate, N-(1-butoxycarbonyl-3-phenylpropyl)-L
-Alanyl-N-(indan-2-yl)glycine hydrochloride can be obtained. Melting point 154-156℃
(Disassembly). IR spectrum ν ^Nujol _Max cm ^-1 = 1740 (ester), 1700
(COOH), 1640 (CON). Example 8 Propyl 2-oxo-4- in Example 6
Isopropyl instead of phenylbutyrate 2-
By carrying out the same reaction procedure as in Example 6 using oxo-4-phenylbutyrate, N-
(1-isopropoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2
-yl)glycine hydrochloride can be obtained. Melting point: 150-153℃ (decomposition). Example 9 Propyl 2-oxo-4- in Example 6
Example 6 using isobutyl 2-oxo-4-phenylbutyrate instead of phenylbutyrate
By performing the same reaction operation, N-(1
-isobutoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride can be obtained. land melting point
148-149℃ (decomposition). Example 10 Propyl 2-oxo-4- in Example 6
N-
(1-methoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride can be obtained. Colorless needles. Melting point: 163-165℃ (decomposition). IR spectrum ν ^Nujol _Max cm ^-1 = 1750 (COOCH ₃ ), 1705
(COOH), 1640 (CO-N). Example 11 Propyl 2-oxo-4- in Example 6
Ethyl 4-(4-
N-[1-ethoxycarbonyl-3-(4-
chlorophenyl)propyl]-L-alanyl-N
-(Indan-2-yl)glycine hydrochloride can be obtained. Melting point: 163-168℃ (decomposition). [α] ²³ _D +28.1° (c=1, methanol). IR spectrum ν ^Nujol _Max cm ^-1 = 1740, 1710, 1640 Example 12 Propyl 2-oxo-4- in Example 6
N-
[1-Ethoxycarbonyl-3-(p-tolyl)
propyl]-L-alanyl-N-(indane-2
-yl)glycine hydrochloride is obtained. Melting point 160-
163℃ (decomposition). [α] ²³ _D +22.2° (c=1, methanol). IR spectrum ν ^Nujol _Max cm ^-1 = 1740, 1710, 1640. Example 13 L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate 3 g,
0.75 g of sodium acetate, 1.5 g of acetic acid, 5 g of molecular sieve 3A and 5 g of ethyl 4-(4-benzyloxyphenyl)-2-oxobutyrate.
was added to 100 ml of ethanol, and a catalytic reduction reaction was carried out using Raney nickel as a catalyst. Once hydrogen absorption has stopped, the catalyst is removed and a catalytic reduction reaction is carried out using palladium on carbon as a catalyst. When the catalyst was filtered off and distilled off under reduced pressure, N-[1-ethoxycarbonyl-3-(p-hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester was obtained as an oil. Obtained as an object. This product was treated with N-[1-ethoxycarbonyl-3-(4
-Hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine hydrobromide, which is further converted into hydrochloride by the same procedure as in Example 5, resulting in N-[ 0.65 g of 1-ethoxycarbonyl-3-(4-hydroxyphenyl)propyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride is obtained as colorless crystals. Melting point: 126-130℃ (decomposition). [α] ²⁴ _D +17.7° (c=1, methanol). Mass spectrum m/e: 450 (M ⁺ -HCl-H ₂ O),
405, 335, 334, 331, 330, 284, 215, 214,
169, 168, 133, 129, 120, 117, 116, 107. Example 14 N-(1-(S)-ethoxycarbonyl-3-
Dissolve 1.2 g of L-alanyl-N-(indan-2-yl)glycine hydrochloride in 30 ml of methanol, add 5 ml of 2N aqueous sodium hydroxide solution, and stir overnight at room temperature. Concentrate the reaction solution under reduced pressure, add 30 ml of water, and adjust the pH to 5~ with dilute hydrochloric acid.
The oil liberated upon adjustment to 6 is extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying, the solvent was distilled off under reduced pressure. Add 5 ml of methanol to the residue, dissolve it, and leave to stand to form crystals of N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine.
Obtain 0.6g. Melting point 140-142℃. [α] ²² _D +26° (c=0.6, 1% HCl). Example 15 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester was added to 50 g of ethanol.
ml, 3.5 g of ethyl 2-oxo-4-phenylbutyrate, 1.5 g of sodium acetate, 3.5 g of acetic acid.
g, 7.0 g of Molecular Sieve 3A, and 5.0 g of Raney Nickel were added, and catalytic reduction was performed at room temperature and pressure.
After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off, the filtrate is concentrated under reduced pressure, and 100 ml of water is added to the residue.
Add 2g of sodium hydrogen carbonate and add ethyl acetate.
Extract with 200ml. After washing with water and drying, ethyl acetate is distilled off under reduced pressure, and 20 ml of acetic acid and 5 ml of 25% hydrobromic acid-acetic acid solution are added to the residue. After stirring for 10 minutes at room temperature, 100 ml of ethyl ether was added and the precipitated oil was separated and washed with ethyl ether to give N.
-(1-ethoxycarbonyl-3-phenylpropyl)-L-leucyl-N-(indan-2-yl)glycine hydrobromide is obtained. Water this product
Suspend in 10 ml, make alkaline by adding sodium hydrogen carbonate, and extract insoluble matter with ethyl ether. Adjust the aqueous layer to PH4.0 with 10% hydrochloric acid, and add 200 ml of ethyl acetate.
After extracting with ml, washing with water and drying with magnesium sulfate,
Add 1 ml of ethanolic hydrochloric acid and distill off the ethyl acetate under reduced pressure. 200ml of ethyl ether to the residue
is added and allowed to stand at room temperature to obtain 0.8 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-leucyl-N-(indan-2-yl)glycine hydrochloride as a colorless amorphous powder. NMR spectrum (d ₆ -DMSO) δ: 0.93 (6H,
d, J=3Hz, CH( _CH3 ) ₂ ), 1.30(3H,t,
J = 7Hz, CH ₃ ), 2.90-3.20 (4H, m, CH ₂ ),
3.90 (2H, s, CH ₂ ), 4.00-4.35 (3H, m),
7.20 (4H, s, Ph), 7.30 (5H, s, Ph). Mass spectrum m/e: 476, 431, 361, 315,
171. Example 16 N〓-carbobenzoxy-L-lysyl-N-
Dissolve 3.5 g of (indan-2-yl)glycine tert-butyl ester oxalate in 20 ml of methanol, add 1 g of sodium acetate, 1.2 g of acetic acid, 8 g of molecular sieve and ethyl 2-oxo-4-phenylbutyrate. Add 15g. Add 3.3 g of sodium cyanoborohydride to this mixture while stirring.
A solution of 30 ml of methanol was added dropwise over 2 hours. After completing the dropping, add 3 g of sodium cyanoborohydride.
Add and stir for 3 hours. Add 200 ml of 2.5% phosphoric acid aqueous solution to the reaction solution, and extract twice with 200 ml of ethyl acetate. The extracted solution is washed with 0.5N aqueous sodium hydroxide and water, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oil was separated and purified using silica gel column chromatography (acetone:benzene = 1:12 to 1:5). From the first fraction, N〓-[1-(R )-ethoxycarbonyl-3-phenylpropyl]-N〓-carbobenzoxy-L-lysyl-N-(indan-
2-yl)glycine tert-butyl ester is obtained as an oil. Yield 1.1g Elemental analysis value C ₄₁ H ₅₃ N ₃ O ₇ Calculated value C70.36 H7.63 N6.00 Actual measurement C69.89 H7.64 N5.76 [α] ²⁴ _D = -4.5° (c = 1 , methanol) From the second fraction, N〓-{1-(S)-ethoxycarbonyl-3-phenylpropyl}-N〓-carbobenzoxy-L-lysyl-N-(indan-2-yl)
1 g of glycine tert-butyl ester is obtained as an oil. Elemental analysis value C ₄₁ H ₅₃ N ₃ O ₇ Calculated value C70.36 H7.63 N6.00 Actual value C70.28 H7.51 N5.93 [α] ²⁴ _D = -8.2° (c = 1, methanol) IR spectrum ν ^neat _nax cm ^-1 : 3300 (NH), 1720 (C=
0), 1630 (C=0) Example 17 N〓-[1-(R)-ethoxycarbonyl-3
-Phenylpropyl]-N-carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester (1 g) was dissolved in 2 ml of acetic acid, and 8 ml of a 25% hydrobromic acid-acetic acid solution was added. In addition, 30
Leave at room temperature for a minute. Add 200 ml of ether and 100 ml of petroleum ether to the reaction solution, and filter the precipitated crystals. This was recrystallized from a mixture of methanol and ethyl ether and N〓-[1-(R)-ethoxycarbonyl-3-phenylpropyl]-L-lysyl-
0.8 g of N-(indan-2-yl)glycine dihydrobromide is obtained. Melting point 128-133℃ (decomposition) [α] ²⁴ _D = -11.6゜ (c = 1, methanol) Example 18 By the same operation as Example 17, N〓-[1-
(S)-ethoxycarbonyl-3-phenylpropyl]-N〓-carbobenzoxy-L-lysyl-
N-(indan-2-yl)glycine tert-butyl ester 0.9g to N〓-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-
Lysyl-N-(indan-2-yl)glycine
0.6 g of dihydrobromide is obtained. Melting point 160-165
°C (decomposition) [α] ²⁴ _D +18.0° (c=1, methanol) Example 19 L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate 2.0 g and N- By reacting 4.0 g of butyl-2-oxo-4-phenylbutyramide in the same manner as in Example 1, N-(butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2 -yl)glycine tert-butyl ester 0.5
g is obtained as a colorless oil. NMR spectrum (CDCl ₃ ) δ: 1.90 (3H, m,
CH ₃ ), 1.40-1.55 (16H, m), 2.60-3.49 (8H,
m, CH ₂ ), 3.70-3.95 (2H, m), 7.20 (4H,
s, Ph), 7.30 (5H, s, Ph). Example 20 N-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester 0.5
By reacting g in the same manner as in Example 3, N
-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2
Colorless amorphous powder of glycine hydrobromide
Obtain 0.5g. NMR spectrum (d ₆ - DMSO) δ: 0.8 - 1.0
(3H, m, CH ₃ ), 1.2-1.55 (7H, m, CH ₃ +
CH ₂ ×2), 1.90-2.55 (2H, m, CH ₂ ), 2.40
-2.60 (2H, m, CH ₂ ), 2.95 - 3.30 (6H, m,
CH ₂ ), 4.80-5.0 (1H, m, CH), 7.10-7.30
(9H, m, Ph). Example 21 Dissolve 4.0 g of L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester in 80 ml of ethanol, add 0.77 g of sodium acetate, 4.0 g of acetic acid, and ethyl 2-oxo-
When 4.0 g of 4-phenylbutyrate, 12 g of Molecular Sieve 3A and 6.0 g of Raney nickel were added and reacted and treated in the same manner as in Example 1, N-
2.0 g of (1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester are obtained as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ: 1.20-1.50 (15H,
m, CH ₃ ×5), 1.90-2.20 (3H, m, CH ₂ ),
2.50 (2H, s, CH ₂ ), 2.60-2.95 (4H, m,
CH ₂ ), 3.80 (3H, s, OCH ₃ ), 3.90 (3H, s,
OCH ₃ ), 4.20 (2H, q, J = 7.0Hz, CH ₂ ),
5.40-5.60 (1H, m, CH), 6.80-6.90 (2H,
m, Ph), 7.25 (5H, s, Ph). Mass spectrum m/e = 568 (M ⁺ ), 495, 361,
308, 234. Example 22 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester was dissolved in 10 ml of acetic acid, 2 ml of 25% hydrobromic acid acetic acid solution was added dropwise under ice cooling. After standing at room temperature for 5 minutes, 50 ml of ethyl ether was added to the reaction solution, and the precipitated amorphous powder was collected by filtration. Add this to water 10
ml and made alkaline with sodium bicarbonate. Insoluble materials were removed by extraction with ethyl ether. The aqueous layer was adjusted to pH 4.0 with 10% hydrochloric acid and extracted with 100 ml of chloroform. After washing the extract with water and drying,
Add 1 ml of 20% ethanolic hydrochloric acid and distill off the chloroform under reduced pressure. After dissolving the residue in 2 ml of ethanol, adding 20 ml of ethyl ether and filtering off the precipitated colorless amorphous powder, N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5, 6-dimethoxyindan-1-
0.2 g of glycine hydrochloride is obtained. NMR spectrum (d ₆ -DMSO) δ: 1.25 (3H,
t, J = 8Hz, CH ₃ ), 1.40 (3H, d, J = 4.5
Hz, CH ₃ ), 3.75 (3H, s, OCH ₃ ), 3.80 (3H,
s, OCH ₃ ), 6.80 (1H, s, Ph), 6.90 (1H,
s, Ph), 7.25 (5H, s, Ph). Experimental Example 1 Angiotensin converting enzyme (ACE) inhibition experiment using the compound of the present invention [Experimental method] Cushman et al.'s method (Biochemical
The experiment was conducted using a method modified from Pharmacology, Vol. 20, p. 1637, 1971). That is, based on the inhibition rate of hippuric acid production when the compound of the present invention is added to the amount of hippuric acid produced by ACE using hyperlyl-L-histidyl-L-leucine (HHL) as a substrate,
The ACE inhibitory effect was determined. ACE100μ (protein concentration
A solution of the compound of the present invention dissolved in 0.02 to 0.5% dimethyl sulfoxide in 100 mM potassium phosphate buffer (pH 8.3, containing 300 mM sodium chloride) was added to 100 μl of 20 mg/ml, 1.25 mM MHHL. As a control, a potassium phosphate buffer containing dimethyl sulfoxide at the same concentration as the sample solution was placed. After heating this solution at 37°C for 1 hour, 150μ of 1N hydrochloric acid was added to stop the reaction, and 1ml of ethyl acetate was added.
Centrifugation was performed at 3000 rpm for 10 minutes. Ethyl acetate layer 0.5
ml was taken and dried under nitrogen gas at below 50°C, 5 ml of 1M saline was added to the residue, mixed well, and the mixture was colorimetrically determined at a wavelength of 228 nm. [Experimental Results] The experimental results for the compounds of Examples 6, 7, 8, and 14 were as shown in Table 2.

[Table] Experimental Example 2 Effect of the compound of the present invention on the pressor effect of angiotensin [Experimental method] Breeding with ad libitum access to food and water, weight 250-350
G male rats (Sprague-Dawley) were used. The day before the experiment, pentobarbital sodium (50
After the rats were anesthetized by intraperitoneal injection of 50 mg/Kg), polyethylene tubes were inserted and fixed into the femoral artery for blood pressure measurement and the femoral vein for injecting angiotensin and angiotensin. After recording the mean blood pressure during the control period on the day of the experiment using an electric sphygmomanometer (Nihon Kohden, MP-4T), 300 ng/Kg of angiotensin and then 100 ng/Kg of angiotensin were injected into the femoral vein to assess its pressor effect. Examined. Next, 13.8 μM/
Kg was orally administered as an aqueous solution or gum arabic suspension, and angiotensin and angiotensin were repeatedly injected 20, 60, and 120 minutes after administration to monitor the pressor response. In calculating the inhibition rate for the pressor effect of angiotensin, the inhibition rate was corrected based on the temporal variation of the pressor response of angiotensin. [Experimental Results] Table 3 shows the experimental results for the compounds of Examples 6 and 8.
It was as shown in.

[Table] Preparation Example When the compound of the present invention () is used as a therapeutic agent for hypertension, it can be used, for example, in the following formulation. 1 Tablet (1) N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride 10g (2) Lactose 90g (3) Corn starch 29g (4) ) Magnesium stearate 1g 1000 tablets 130g (1), (2) and 17g corn starch are mixed together and granulated with a pace made from 7g corn starch, 5g corn starch and (4) are added to the granules, Compress the mixture with a compression tablet machine to obtain tablets with a diameter of 7 mm containing (1) 10 mg per tablet.
Manufacture 1000 pieces. 2 Capsules (1) N-(1-butoxycarbonyl-2-phenylethyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride 10g (2) Lactose 135g (3) Cellulose fine powder 70g (4) ) Magnesium stearate 5g 1000 capsules 220g Mix all ingredients and gelatin capsule No. 3 (No. 9)
(Revised Japanese Pharmacopoeia) to produce 1000 capsules containing (1) 10 mg per capsule. 3 Injection (1) N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine sodium salt 10g (2) Sodium chloride 9g (3) Chlorobutanol 5g Dissolve all ingredients in 1000ml of distilled water and prepare a brown ampoule.
Dispense 1 ml each into 1000 pieces, replace with nitrogen gas, and seal. The entire process is performed under sterile conditions.

Claims (1)

[Claims] 1 formula [In the formula, R ¹ and R ² are the same or different, hydrogen,
hydroxyl group or lower alkoxy group, R ³ is a lower alkyl group, R ⁴ is hydrogen, lower alkyl group, amino lower alkyl group or acylamino lower alkyl group, m and n mean 1 or 2] compounds and formulas [In the formula, R ⁵ is hydrogen, a lower alkyl group, or a phenyl lower alkyl group optionally substituted with a halogen, a lower alkyl group, or a hydroxyl group,
R ⁶ represents a hydroxyl group, a lower alkoxy group, an amino group, or a lower alkylamino group] is condensed by a catalytic reduction reaction or a reduction reaction with a metal hydride compound in the presence of a molecular sieve, and the resulting formula is A formula characterized by subjecting a compound represented by [wherein all symbols have the same meanings as above] to a hydrolysis reaction A method for producing a bicyclic compound represented by the formula [wherein all symbols have the same meanings as above] or a salt thereof.