JPH0223538B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 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, Japanese Patent Publication No. 12372, No. 1983, Japanese Patent Publication No. 1987-1237-
No. 38382, JP-A-55-81845, etc.), but the compound of the present invention has a different skeleton from any of these known compounds and has excellent angiotensin-converting enzyme inhibitory and antihypertensive effects. . That is, the present invention is based on the formula [In the formula, R ¹ and R ² are the same and represent hydrogen or a lower alkoxy group, R ³ is a lower alkyl group, and R ⁴
is an amino lower alkyl group acylated with a lower alkyl group or a benzyloxycarbonyl group,
R ⁵ represents a phenyl lower alkyl group which may be substituted with a hydroxyl group, R ⁶ represents a lower alkoxy group or a lower alkylamino group] or a salt thereof. Regarding the above formula (), examples of lower alkoxy groups represented by R ¹ and R ² include methoxy group,
Examples include lower alkoxy groups having about 1 to 4 carbon atoms such as ethoxy group, propoxy group, butoxy group, and isopropoxy 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. Examples of the lower alkyl group represented by R ⁴ include the same lower alkyl groups as those represented by R ³ . Examples of the amino lower alkyl group of the amino lower alkyl group acylated with a benzyloxycarbonyl group include an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 3-aminopropyl group, a 4-aminobutyl group, and a 3-aminobutyl group. Examples include linear or branched amino lower alkyl groups having about 1 to 4 carbon atoms, such as -amino-2-methylpropyl group. Examples of the phenyl lower alkyl group represented by R ⁵ include benzyl group, phenethyl group, 3-phenylpropyl group, α-methylbenzyl group, α-ethylbenzyl group, α-methylphenethyl group, β-
Examples include phenyl lower (C _1-4 ) alkyl groups having about 7 to 10 carbon atoms such as methylphenethyl group and β-ethylphenethyl group, and the phenyl group in the phenyl lower alkyl group may be substituted with, for example, a hydroxyl group. . Examples of such substituted phenyl lower alkyl groups include, for example, 2-(4-hydroxyphenyl)ethyl groups. 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, lower alkylamino groups such as methylamino group, ethylamino group, propylamino group, butylamino group, dimethylamino group, Examples include mono- or di-lower ( _C1-4 ) 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, and R ⁵
A compound in which R 6 is a phenethyl group and R ⁶ is a lower (C _1-4 ) alkoxy group is desirable. 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. The compound of the present invention () has the formula [In the formula, each symbol has the same meaning as above] and the formula It can be produced by subjecting a compound represented by the formula [wherein R ⁵ and R ⁶ have the same meanings as above] to a condensation reaction under reductive conditions. The reductive conditions include, for example, catalytic reduction using metals such as platinum, palladium, Raney nickel, rhodium, and mixtures thereof with arbitrary carriers as catalysts, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, Reduction with metal hydride compounds such as sodium borohydride and sodium cyanoborohydride,
Reduction of metallic sodium, metallic magnesium, etc. with alcohols, metals such as iron, zinc, etc. and hydrochloric acid,
Examples of reaction conditions include reduction with an acid such as acetic acid, electrolytic reduction, and reduction with a reductase.
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.), and the reaction temperature varies depending on the reduction method, but is generally -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 () is also the formula [In the formula, Z represents a protecting group that can be removed by hydrolysis or catalytic reduction, and the other symbols have the same meanings as above] Produced by subjecting the compound to hydrolysis or catalytic reduction reaction You can also do that. In parentheses, all kinds of acyl groups and trityl groups can be used as the protecting group shown by Z that can be removed by hydrolysis, but especially benzyloxycarbonyl group, tert-butoxycarbonyl group, trifluoroacetyl group, trityl group, etc. It is advantageous if the reaction is carried out under relatively mild reaction conditions. Examples of the protective group represented by Z which can be removed by catalytic reduction include benzyl group, diphenylmethyl group, and benzyloxycarbonyl group. The hydrolysis reaction in this method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, pyridine, acetic acid, acetone, methylene chloride, or a mixed solvent thereof. Hydrohydric acid, hydriodic acid, hydrofluoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.) or bases (e.g., sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate) , sodium acetate, triethylamine, etc.). The reaction temperature is usually in the range of -10 to +150°C. The catalytic reduction reaction in this method is carried out in water or an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran, or a mixed solvent thereof, in the presence of a suitable catalyst such as platinum, palladium-carbon, or the like. This reaction is carried out at normal pressure or under pressure up to about 150 kg/ ^cm2 , at room temperature or at 150 ℃.
The reaction is carried out at a temperature of °C, but the reaction generally proceeds satisfactorily at room temperature and pressure. Compound () also has the formula [In the formula, R ⁵ and R ⁶ have the same meanings as above, and X is a halogen or a group represented by the formula R ⁷ SO ₂ -O- (R ⁷ represents a lower alkyl group, phenyl group, or p-tolyl group) It can also be produced by reacting a compound represented by The reaction proceeds by maintaining both in a suitable solvent at a temperature range of about -10 to +150°C. At this time, a base such as potassium carbonate, sodium hydroxide, sodium bicarbonate, pyridine, triethylamine, etc. may be present in the reaction system as a deoxidizing agent for the purpose of accelerating the reaction rate. The object compound () of the present invention thus obtained can be separated and purified from the reaction mixture using conventional separation and purification methods, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. It can then be isolated. Compound () may have stereoisomers, but both these individual isomers and mixtures thereof are naturally included in the scope of the present invention, and these isomers can be produced individually if desired. can. For example, a single optical isomer of () can be obtained by carrying out the above reaction using a single isomer of the starting compound () or (), or a product with two or more types can be obtained. In the case of isomer mixtures, this can be separated using conventional separation methods, such as optically active acids (e.g. camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.), optically active bases (e.g. cinchonine, cinchonidine, quinine, quinidine, α-methyl It is also possible to separate the isomers into their respective isomers by a method of forming a salt with benzylamine, dehydroabiethylamine, etc.) or by separation means such as various chromatography and fractional recrystallization. In R ⁴ and R ⁵ , each S-coordination isomer generally exhibits more favorable 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, enkephalinase inhibitory effect, etc. 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. By hydrolysis of the compound (), it can be used as a diagnostic, preventive or therapeutic agent for hypertension, or as an analgesic.
It is also possible to obtain compounds that are more desirable as analgesic effect enhancers, ie, compounds in which R ³ is hydrogen in formula (). 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 have the same meanings as above,
Cbz represents a benzyloxycarbonyl group] To explain in more detail the method for producing () shown in the above reaction formula, 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 to +150°C.
At this time, in order to advance the reaction advantageously, a catalyst such as sulfuric acid or p-toluenesulfonic acid,
For example, a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, etc. can also be added to the reaction solution. 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 a catalyst such as platinum or palladium-carbon, 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 compound () include acid halides such as acid chloride and acid bromide;
Acid anhydrides obtained by dehydrating one molecule of water from two molecules, mixed anhydrides in which the hydrogen of the carboxyl group in () is replaced with, for example, an ethoxycarbonyl group, isobutyloxycarbonyl group, benzyloxycarbonyl group, etc. Examples include derivatives such as active esters of () derived from 1-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 dicyclohexycarbodiimide or carbonyldiimidazole. Further, when an acid halide is used as a reactive derivative, the reaction can be carried out in the presence of a base such as pyridine, picoline, triethylamine, sodium hydroxide, sodium bicarbonate, or sodium carbonate. Reaction temperature is usually about -20℃
The reaction is carried out at temperatures ranging from ~+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. The catalytic reduction reaction is carried out in water or an organic solvent such as methanol, ethanol, dioxane, tetrahydrofuran, 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 a pressure of up to about 150 kg/cm ² and at a temperature of normal temperature to 150°C, but the reaction generally proceeds satisfactorily at normal temperature. The present invention will be explained in more detail below using Reference Examples, Examples, and Experimental 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. to the reaction solution
Add 400 ml of 20% 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).
Extract 4 times. The extract was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. To the resulting oil, 50 ml of ethanol and then 150 ml of water were added and cooled. 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. 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. The residue was dissolved in 300 ml of ethyl acetate, twice with 50 ml of 1N aqueous sodium hydroxide solution, once with 50 ml of water, then 50 ml of 20% phosphoric acid solution.
Washed twice with 50 ml of water and once with 50 ml of water, dried over anhydrous magnesium sulfate, and distilled off to give N-carbobenzoxy-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester. 35 g 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 removed by filtration, the filtrate was distilled off under reduced pressure, and 500 ml of ethyl ether was added to the residue, followed by cooling. The precipitated crystals were collected by filtration and dried to yield 21.8 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate.
get. Melting point 138-141℃. [α] ²² _D +20.4° (c=1, methanol). Reference example 3 8.2 g of N-(indan-2-yl)glycine tert-butyl ester and 13 g of N-tert-butoxycarbonyl-N-carbobenzoxy-L-lysine
When reacting in the same manner as in Reference Example 2, N〓−tert
-Butoxycarbonyl-N〓-carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil 14
g can be obtained. 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 4 5 g of N-tert-butoxycarbonyl-N-carbobenzoxy-L-lysyl-(indan-2-yl)glycine tert-butyl ester obtained in Reference Example 3 was added to 100 ml of a 1N hydrogen chloride-ethyl acetate solution. Dissolve in 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 resulting oil was combined with ethyl acetate.
Dissolve in 100ml 1N sodium hydroxide aqueous solution 100%
ml and wash with 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,
2.4 g of N-carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester sulfate 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; H7.02; N6.80 Actual value: C 59.83, H7.01; N6.41 [α] ^23.5 _D +17.5° (c=1, methanol). Reference example 5 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 iodine 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 dissolved in colorless needles. Obtained as crystals. Melting point 158-160℃. Reference example 6 N-(5,6-dimethoxyindan-1-yl)
By reacting and treating 7 g of glycine tert-butyl ester oxalate and 4.8 g of N-carbobenzoxy-L-alanine in the same manner as in Reference Example 2, L
4 g of -alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester sulfate are obtained as a colorless amorphous powder. Reference example 7 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 8 130 g of 2-oxo-4-phenylbutyric acid is added to a mixture of 650 ml of ethanol and 13 ml of concentrated sulfuric acid, and the mixture is boiled and refluxed 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 DEG-141 DEG C./3 mm Hg. Reference Example 9 By the same operation as Reference Examples 7 and 8, the boiling point
Propyl 2-oxo-4 at 105-118℃/1mmHg
- phenyl butyrate is obtained. Reference example 10 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-like crystals of 3,4-dimethoxycinnamic acid. Melting point 182-3℃. Genuine crystal 35g
Dissolve in 500 ml of ethanol, saturate with hydrogen chloride gas, and leave at room temperature overnight. 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
Dissolve 34g in 300ml of ethanol and add 5% to this solution.
Add 10g of 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
Add a solution of 34.1 g and 43 g of diethyl oxalate to a sodium ethoxide solution prepared from 3.8 g of sodium metal and 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 was washed with water, dried, and concentrated to give 2-oxo-ethoxycarbonyl-4-(3,4-dimethoxyphenyl) as an oil.
Obtain 27 g of ethyl butyrate. Dissolve 26 g of this oil in 80 ml of dimethyl sulfoxide and 8 ml of water, and dissolve 6.3 g of salt.
Add g and stir at 120℃ for 2 hours. After cooling, add a large amount of water and extract with ethyl acetate. After washing with water, drying, and concentrating, the crystals obtained are recrystallized from ether. Ethyl 2-oxo-4-(3,4-
15g columnar crystals of dimethoxyphenyl)butyrate
get. Melting point 85-87℃ Reference Example 11 Ethyl 4-(p-benzyloxyphenyl)-
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 12 9 g 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-phenylbutide amide 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, followed by catalytic reduction 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 then evaporated under reduced pressure to give N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-
24 g of 2-yl)glycine tert-butyl ester are obtained as a pale yellow candy. 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 using 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-N -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 tert
-16.5 g of butyl ester are obtained as a colorless candy. [α] ²² _D −12.6° (c=1, methanol). The IR and NMR spectra of both are the same as those of the compound of Example 1. Reference Example 13 N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine tert obtained in Example 2
- 5 g of butyl ester was dissolved in 5 ml of acetic acid, 20 ml of 25% hydrobromic acid and acetic acid solution was added to this solution, and the mixture was shaken for 10 minutes. 300 ml of ethyl ether was added and the precipitated crystals were collected by filtration. 1-(S)-Ethoxycarbonyl-3-phenylpropyl]-L
5 g of -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). Reference Example 14 N-[1-(R)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine tert obtained in Example 2
-Butyl ester was reacted in the same manner as in Reference Example 13 to produce 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). Reference Example 15 N-[1-
(S)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)
16.2 g of glycine hydrobromide, 500 ml of ethyl acetate,
Add to a mixture of 33 g of sodium hydrogen carbonate and 500 ml of water and stir to dissolve. After adjusting the pH to 4 by adding 1N hydrochloric acid, the ethyl acetate layer was separated, washed with water, dried,
Add 20ml of 7N ethanolic hydrochloric acid and concentrate under reduced pressure.
Add 250 ml of ethyl ether and 250 ml of petroleum ether to the residue.
ml and filtered the precipitated crystals, N-[1
11 g of -(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(indan-2-yl)glycine hydrochloride are obtained as colorless powder crystals. Recrystallize this product from a mixture of acetone and 1N hydrochloric acid to obtain colorless plate-like crystals. Melting point 166-170℃ (decomposition). [α] ²² _D +18.5° (c=1, methanol). IR spectrum ν ^nujol _nax cm ^-1 : 1740 (COOC ₂ H ₅ ),
1705 (COOH), 1640 (CO-N). Example 3 ()L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate 4.1
Dissolve g in 40 ml of ethanol, add sodium acetate
0.85g, acetic acid 2ml, propyl 2-oxo-4-phenylbutyrate 5g, molecular sieve
After adding 5 g of 3A, 6 g of Raney nickel was suspended in 20 ml of ethanol, and catalytic reduction was carried out at room temperature and pressure. After hydrogen absorption has stopped, the supernatant liquid is collected by decanting, and the precipitate is washed with ethanol two to three times, 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.
-(1-Propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester is obtained as a pale yellow candy-like substance. () Add 3 ml of acetic acid and 12 ml of 25% acetic hydrobromic acid to the substance obtained above,
After reacting for 15 minutes with occasional stirring, 150 ml of ethyl ether was added and the precipitated crystals were collected by filtration to give N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-
3.4 g of 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 hydrogen carbonate, 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, left for 10 minutes, and the precipitated crystals were collected by filtration.
N-(1-propoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-
1.7 g of glycine hydrochloride are obtained. Melting point 147
−150℃ (decomposition). IR spectrum ν ^nujol _nax cm ^-1 = 1740 (ester), 1710
(COOH), 1640 (CO-N). Example 4 ()L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate 3
g, sodium acetate 0.75 g, acetic acid 1.5 g, molecular sieve 3A 5 g and ethyl 4-(4-benzyloxyphenyl)-2-oxobutyrate 5 g
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. The catalyst was filtered off and evaporated under reduced pressure to give N-[1-ethoxycarbonyl-3-(p-hydroxyphenyl)propyl].
-L-alanyl-N-(indan-2-yl)glycine tert-butyl ester is obtained as an oil. (ii) The oil obtained above was subjected to the same reaction procedure as in Reference Example 13 to obtain N-[1-ethoxycarbonyl-3-(4-hydroxyphenyl)propyl].
-L-alanyl-N-(indan-2-yl)glycine hydrobromide, and further converted to hydrochloride by the same operation as in Reference Example 15, N-[1
0.65 g of -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. Reference Example 16 Dissolve 1.2 g of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrochloride in 30 ml of methanol, and dissolve 2N- Add 5 ml of sodium hydroxide aqueous solution and stir overnight at room temperature. The reaction solution is concentrated under reduced pressure, 30 ml of water is added, and the pH is adjusted to 5-6 with dilute hydrochloric acid. The oily substance liberated 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 let it stand to form N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-N.
-0.6 g of crystals of (indan-2-yl)glycine are obtained. Melting point 140-142℃. [α] ²² _D +26° (c=0.6, 1% HCl). Example 5 3.5 g of N-carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester sulfate was dissolved in 20 ml of methanol.
Add 1 g of sodium acetate, 1.2 g of acetic acid, 8 g of molecular sieves and 15 g of ethyl 2-oxo-4-phenibutyrate. While stirring, a solution of 3.3 g of sodium cyanoborohydride in 30 ml of methanol was added dropwise to this mixed solution over 2 hours. After the addition was completed, 3 g of sodium cyanoborohydride was further added and stirred 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 Calculated value as ₇ C70.36; H7.63; N6.00 Actual value 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 Calculated value as N ₃ O ₇ C 70.36; H7.63; N6.00 Actual value C 70.28; 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). Reference example 17 N〓-[1-(R)-ethoxycarbonyl-3-phenylpropyl]-N〓-carbobenzoxy-L-
Lysyl-N-(indan-2-yl)glycine
Dissolve 1 g of tert-butyl ester in 2 ml of acetic acid,
Add 8 ml of 25% hydrobromic acid-acetic acid solution and leave at room temperature for 30 minutes. 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 to obtain N〓-[1-(R)-ethoxycarbonyl-
3-phenylpropyl]-L-lysyl-N-(indan-2-yl)glycine dihydrobromide 0.8
get g. Melting point: 128-133°C (decomposition) [α] ²⁴ _D -11.6° (c=1, methanol). Reference example 18 By the same operation as reference example 17, N〓-[1-(S)
-ethoxycarbonyl-3-phenylpropyl]
-N〓-Carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester 0.9 g to N〓-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L -lysyl-N-(indan-2-yl)glycyl dihydrobromide
0.6g is obtained. Melting point 160-165°C (decomposition) [α] ²⁴ _D +18.0° (c=1, methanol). Example 6 2.0 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate and N
By reacting 4.0 g of -butyl-2-oxo-4-phenylbutyramide in the same manner as in Example 1, N-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-( Indan-2-yl)glycine tert-butyl ester 0.5g
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). Reference example 19 N-(1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-
By reacting 0.5 g of 2-yl)glycine tert-butyl ester in the same manner as in Reference Example 13, N-
Colorless amorphous powder of (1-butylaminocarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)glycine hydrobromide 0.5
get g. NMR spectrum ( _d6 -DMSO) δ: 0.8-1.0
(3H, m, CH ₃ ), 1.2−1.55 (7H, m,
CH ₃ + CH ₂ × 2), 1.90−2.25 (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 7 L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester
Dissolve 4.0g in 80ml of ethanol, 0.77g of sodium acetate, 4.0g of acetic acid, ethyl 2-oxo-4-
Phenylbutyrate 4.0g, molecular sieve
By adding 12 g of 3A and 6.0 g of Raney nickel and reacting and treating in the same manner as in Example 1, N-(1-ethoxycarbonyl-3-phenylpropyl)-L
-Alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester 2.0g
is obtained as a pale yellow oil. NMR spectrum ( _CDCl3 ) 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. Reference Example 20 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, 25 on ice
Add 2 ml of % hydrobromic acid acetic acid solution dropwise. After leaving it at room temperature for 5 minutes, add 50 ml of ethyl ether to the reaction solution.
The precipitated amorphous powder is collected by filtration. Dissolve this in 10ml of water, make alkaline with sodium bicarbonate,
After removing insoluble matter by extraction with ethyl ether,
Adjust the aqueous layer to PH4.0 with 10% hydrochloric acid and chloroform.
Extract with 100ml. After washing the extract with water and drying, 20%
Add 1 ml of ethanolic hydrochloric acid and distill off the chloroform under reduced pressure. After dissolving the residue in 2 ml of ethanol, 20 ml of ethyl ether was added and the precipitated colorless amorphous powder was collected by filtration to give N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5, 6-dimethoxyindan-1-yl)
0.2 g of glycine hydrochloride is obtained. NMR spectrum ( _d6 -DMSO) δ: 1.25 (3H,
t, J = 8Hz, CH ₃ ), 1.40 (3H, d, J
=4.5Hz, 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 1 converting enzyme (ACE) inhibition experiment [Experimental method] Cushman et al.'s method (Biochemical
The experiment was conducted using a method modified from Pharmacology, Vol. 20, p. 1637, 1971). In other words, from the inhibition rate of hippuric acid production when the compound is added to the amount of hippuric acid produced by ACE using hipuryl-L-histidyl-L-leucine (HHL) as a substrate, ACE
asked for restraint. ACE100μl (protein concentration 20mg/ml),
100μl of 1.25mMHHL with 0.02-0.5% dimethyl sulfoxide 100mM potassium phosphate buffer (PH8.3,
A solution of the compound dissolved in a solution (containing 300 mM NaCl) was added. 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, 150 μl of 1N hydrochloric acid was added to stop the reaction.
1 ml of ethyl acetate was added and centrifuged at 3000 rpm for 10 minutes. 0.5 ml of the ethyl acetate layer was taken and dried under nitrogen gas at a temperature 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 ml. [Experimental Results] The experimental results for the compounds of Example 3(ii) and Reference Example 16 were as shown in Table 1.

〔experimental method〕

Breeding with free 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 2 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 of the compound was orally administered as an aqueous solution or gum arabic suspension, and angiotensin was repeatedly injected 20, 60, and 120 minutes after administration to monitor the pressor response. In calculating the inhibition rate for the pressor action of angiotensin, the inhibition rate was corrected based on the temporal variation of the angiotensin pressor response. [Experimental Results] The experimental results regarding the compound of Example 3(ii) were as shown in Table 2.

【table】

Claims (1)

[Claims] 1 formula [In the formula, R ¹ and R ² are the same and represent hydrogen or a lower alkoxy group, R ³ is a lower alkyl group, and R ⁴
is an amino lower alkyl group acylated with a lower alkyl group or a benzyloxycarbonyl group,
A bicyclic compound or a salt thereof, wherein R ⁵ represents a phenyl lower alkyl group which may be substituted with a hydroxyl group, and R ⁶ represents a lower alkoxy group or a lower alkylamino group.