KR890001146B1 - Amido-amino acids and preparation method there of - Google Patents

Abstract

Amino acid-substituted tetrahydroisoquinoline derivs. (I)[R1, R7=H, alkyl, phenylalkyl; R2-6=H, (un)substd. alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl; R8=alkyl, NO2, amino, OH, halo, CF3, etc.; m=0-2, m'=1-3, n=0-4 and their salts, useful as antihypertensives, were prepd.. Thus, Me L-1,2,3,4-tetrahydro- 3isoquinolinecarboxylate HCL salts were acetylated with PhCH2O2CAla- OH, and the product was deprotected and then treated with Ph CH2CH2COCO2H followed by redn. with NaBH3CN to give N-(1-carboxy3- phenylpropyl)alanyl-1,3,3,4-tetrahydroisoquinolin-3-carboxylic acid.

Description

Amido-amino acids and methods for their preparation

The present invention relates to a novel compound of the general formula (I) and salts thereof, in particular a salt with pharmaceutically acceptable acids and bases, having antihypertensive action and angiotensin converting enzyme inhibitory action.

Wherein R ₁ and R ₇ are each hydrogen, lower alkyl or phenyl lower alkyl; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ may be the same or different and each is hydrogen, alkyl, alkenyl, alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl, and heterocyclic ego ; R ₈ is alkyl, alkenyl, alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercapnoalkyl, halogen, haloalkyl, aminoalkyl When alkylaminoalkyl, dialkyl aminoalkyl, sulfonamido, methylene dioxy and trifluorobetayl and one or more R ₈ groups are present they may be the same or different; m is an integer from 0 to 2; m 'is an integer of 1 to 3; However, when m is 0, m 'is 2 or 3, and if m is not 0, m' is 1 or 2, and n is an integer of 0-4.

The alkyl group in alkyl, aralkyl, alkoxy aminoalkyl, thioalkyl, haloalkyl, hydroxyalkyl is preferably lower alkyl having 1 to 6 carbon atoms and may be jack or branched.

Alkenyl and alkynyl groups contain 2 to 6 carbon atoms and may be straight and branched chains.

Alkyl, alkenyl, alkynyl groups may have substituents such as hydroxy, alkoxy, halo, amino, alkyl amino, mercapto and alkyl mercapto.

Cycloalkyl groups contain 3 to 7 carbons, which include cycloalkyl-alkyl. The cycloalkyl group may have substituents such as alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, alkylamino, trifluoromethyl, nitro and the like.

Aryl groups contain 6 to 10 carbons and include phenyl and α- and β-naphthyl. Aryl groups are alkyl, hydroxy, alkoxy, hydroxyalkyl, mercapto, alkyl mercapto, mercaptoalkyl, halo, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylene dioxy, trifluoromethyl, urea And substituents such as guanidino.

Fused aryl-cycloalkyl includes a phenyl ring fused to a cycloalkyl ring having 3 to 7 carbon atoms. This group also includes fused aryl-cycloalkyl-alkyl.

Heterocyclic groups may be saturated, partially saturated or unsaturated, including those pyridine, piperidine, morpholine, pyrrole, pyrrolidine, thiomorpholine, quinoline, isoquinoline, tetrahydroquinoline, thiazoli Dine, taazoline, thiazole, imidazolidine, imidazoline, imidazole, thiophene, tetrahydrothiophene, furyl, tetrahydrofuran and the like. These heterocyclic groups may have substituents mentioned in the above aryl groups. This heterocyclic group also includes heterocyclic lower alkyl.

Halo group refers to fluorine, chlorine, bromine and iodine. Preferably, the -COOR ₇ group is linked to a carbon adjacent to the nitrogen in the ring.

Suitable acid addition salts include inorganic acid salts such as hydrochloride, phosphate, sulfate, etc .; Organic sulfonic acids and phosphates such as toluenesulfonic acid and organic carboxylates such as acetates, maleates, maleates, fumarates, succinates, citrates, lactates, benzoates, hydroxy benzoates, aminobenzoates and nicotinates Phonic acid is included.

Suitable basic salts include ammonium and quaternary ammonium salts as well as alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium, and iron.

The compounds according to the invention may have one or more absent carbon atoms and each optically active compound as well as several racemic mixtures is part of the invention.

The compounds according to the invention are prepared by reacting an amine of formula (2) with an acylated derivative of formula (III) acid to form an amide.

In contrast, compounds of formula (I) wherein R ₃ and R ₄ are hydrogen are treated with compounds of formula (IV) under amide forming conditions to obtain compounds of formula (V). Thereafter, the carbobenzyloxyl group is decomposed to obtain a free amine of the general formula (VI), and the amine is reacted with an α-kato acid or an ester of the general formula (VII) to obtain an imine, followed by reduction of the obtained imine. Can be.

Reacting a compound of formula (VI) with an α-halo acid or ester of formula (VIII) so that R ₃ and R ₄ are hydrogen or other substituents mentioned in R ₃ and R ₄ above ) Can be prepared.

(Ⅷ)

(Ⅷ)

Wherein R ₁ to R ₈ , m, m ', and n are as mentioned above and Hal is halogen.

Preferably R ₄ , R ₃ , R ₄ , R ₅ , and R ₇ and R ₈ are hydrogen. R ₂ is lower alkyl or phenyl lower alkyl and R ₆ is lower alkyl.

In the reaction for forming the amide, known acid derivatives such as acyl halide, anhydride, mixed anhydride, lower alkyl ester, and carbodiamide carbonyl diimidazole are used. The reaction is carried out in organic solvents such as acetonitrile, tetra hydrofuran, dioxane, acetic acid, methylene chloride, ethylene chloride and similar solvents. The amide formation reaction is carried out at room temperature or at elevated temperature. The reaction can be carried out at elevated temperature and the reaction time can be shortened slightly. Temperatures in the range of 0 ° C. to the reflux temperature of the reaction system can be used. More conveniently, the reaction is preferably carried out in the presence of a base such as a higher organic amine such as trimethylamine, pyridine, picoline, and the like, especially when hydrogen halides are formed by amidation reactions such as acyl halides and amino compounds, for example. Even more so. Of course, in such reactions where hydrogen halide is produced, hydrogen halide acceptors can usually be used.

In the condensation reaction of the α-halo acid derivative of the general formula (III), reaction conditions similar to those of the amide formation reaction, a solvent, and a hydrogen halide acceptor can be used.

Several substituents (eg R ₈ ) present in the novel compounds of the present invention can be added by known substitutions or conversion reactions present in the starting compounds or after the amide product is formed. Thus, the nitro group can be added to the final product by nitration of the aromatic ring and this nitro group can be converted to another group such as amino by reduction, diazotized the amino group and then substituted with the diazo group to halo. have. Other reactions can also be applied to the amide product. The amino groups can be alkylated to form mono and dialkylamino groups and the mercapto and hydroxy groups can be alkylated to form the corresponding ethers. Other substitutions can be used to change the substituents of the final product. Of course, the reactive groups present must protect suitable protecting groups during the reaction, especially during the condensation reaction to form amide bonds.

Acid and basic salts of the compounds of the present invention can be formed according to standard methods. These are usually produced in situ during the overproduction of the novel amido amino acids of the present invention.

Since the compounds of the present invention exist as geometric isomers, the product obtained can be a mixture of isomers and they can be separated. Alternatively, specific isomers can be selected as starting materials to obtain the desired geometric isomers. When each member center (chiral center) is an S-array, it is preferable to select and react geometric starting materials rather than to separate isomeric mixtures. In all absent centers, compounds present as S-arrays are most active. In the case of a compound having an R-configuration, the activity is inferior, and in the case of a compound having both an R-configuration and an S-configuration, the effect is intermediate.

The invention is explained in more detail in the following examples.

Example 1

A.2- (N-benzyloxycarbonyl-L-alanyl) -L-1,2,3,4-retrahydro isoquinoline-3-carboxylic acid methyl ester

150 ml containing 10.0 g (43.9 mmol) of L-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester hydrochloride and 10.4 g (46.6 mmol) of carbobenzyloxy-L-alanine 4.4 g (43.6 mmol) triethylamine are added to anhydrous acetonitrile suspension. 5 ml of anhydrous acetonitrile solution containing 9.2 g (44.6 mmol) of N, N-dicyclohexylcarbodiimide is added dropwise with stirring. The resulting slurry was stirred overnight at room temperature, filtered and concentrated in vacuo. The residue is redissolved in ether, washed sequentially with 1N hydrochloric acid, saturated hydrocarbon sodium, brine, dried over magnesium sulfate, filtered and concentrated to yield 18.3 g (105%) of crude amide. It is used for the next reaction without further purification.

B.2- (N-benzoyloxycarbonyl-L-alanyl) -L 1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

8.0 g of the crude amide ester obtained in A is dissolved in 25 ml of 1N sodium hydroxide / methanol. 5 ml of water is added thereto. The resulting solution is stirred overnight at room temperature and then poured into 150 ml of water and extracted with ether. The aqueous layer is acidified and extracted with CH ₂ Cl ₂ . The extract is dried over magnesium sulfate and concentrated at aspirator pressure to give 5.5 g of product. Concentration over an extended period of time under an oil pump vacuum yields a brittle foamy material.

C.2-r-alanyl-1,2,3,4tetrahydro isoquinoline-3-carboxylic acid hydrobromide

To 7 ml of acetic acid solution containing 4.8 g (12.5 mmol) of crude carbobenzyloxy carboxylic acid is added saturated HBr in 5 ml of acetic acid. The solution is stirred at room temperature until stopped by gas repellent (1 to 1.5 hours). The air is passed slowly through the solution to remove excess HBr and then 25 ml of ether is added to precipitate the product. This solid is washed twice more with ether and dried in vacuo to yield 2.2 g of a pale yellow solid. Melting Point 180 ℃

D.N- (1-carboxy-3-phenylpropyl) alanyl-1,2,3,4-tetra-hydro isoquinoline-3-carboxylic acid

0.307 g (0.93 mmol) of alanyl-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid in 5 ml saturated sodium bicarbonate solution containing 1.3 g (6.63 mmol) benzylpyruvic acid hydrate. 0.238 g (3.79 mmol) of sodium cyanoborohydride are added. The solution is stirred overnight at room temperature and then placed in 20 g of Doex 50 × 8 column and eluted with 50% methanol and then with 3% ammonium hydroxide solution. The ammonia fraction contains the desired product, which is collected and lyophilized to yield 85 mg of fluffy white powder. Melting Point 97-101 ° C

Example 2

A. 2- (N-carbenzyloxy-L-valine) -L-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester

5.2 g (20.7 mmol) of N-carbo in 50 ml of anhydrous acetonitrile suspension containing 4.4 g (19.3 mmol) of L-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl esterhydrochloride Benzyloxy-L-valine, 2.7 g (20.0 mmol) 1-hydroxybenzotriazole and 2.1 g (20.7 mmol) triethylamine are added. The resulting mixture is stirred at room temperature and 10 ml of anhydrous acetonitrile solution containing 4.5 g (21.8 mmol) of dicyclohexyl carbodiimide is slowly added. The mixture is stirred overnight at room temperature and then filtered and worked up as in Example 1A. Final concentration yields 8.3 g (101%) of thick oil.

b. 2- (N-carbenzyloxy-L-valyl) -L-1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid

4.5 g (106 mmol) of the crude methyl ester prepared according to the above process is treated with 10 ml of 10% sodium hydroxide and musilim methanol (35-40 ml) to obtain a homogeneous solution. The solution is stirred at room temperature for 23 hours, diluted with 100 ml of water and then extracted twice with 25 ml of ether each. The aqueous layer is acidified and extracted four times with 10 ml of methylene chloride each time. The extract was dried over magnesium sulfate and concentrated to yield 3.8 g (9.3 mmol, 87%) of homogeneous carboxylic acid.

Example 3

A. 2- (N-carbenzyloxy-L-iso-yl) -L-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid

4.5 g (19.8 mmol) of L-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester hydrochloride, 5.3 g (20.0 mmol) of N-carbenzyloxy-L-isoleucine, 2.7 g (20.0 mmol) of 1-hydroxybentriazole, and 2.1 g (20.7 mmol) of triethylamine after treatment with 4.4 g (21.3 mmol) of dicyclohexyl carbodiimide as described in Example 2A. Treatment yields 7.8 g (90%) of crude methyl ester. It is dissolved in 30 ml of methanol and treated with 10 ml of 10% sodium hydroxide. The solution is stirred overnight at room temperature and worked up as above to give 1.8 g (21.4%) of the desired acid as a yellow oil.

Example 4

2-N-[(1-ethoxycarbonyl-3-petylpropyl) -L-alanyl] -isoquinalic acid

An ethanol solution of benzyl 2- (N-carbenzoxy-L-alanyl) isoquinaldate is hydrogenated at pd / c. This solution is filtered and treated with ethyl 2-oxo-4-phenyl-butyric acid, alkyli and sodium cyanoborohydride as in Example 1D. The product is purified by chromatography and lyophilization.

Example 5

2-N- (1-carboxylethyl) -L-alanyl-isoquinalic acid

An ethanolic solution of benzyl2- (N-carbenzoxy-L-alanyl) -isoquinaldate and pyruvic acid is hydrogenated at pd / c. The filtrate is concentrated and purified as in Example 1D.

Example 6

A.1- (N-Carbenzoxy-L-alanyl) -2-benzoxy carbonyl indolin

A methylene chloride solution of N-carbenzyloxy-L-alanine and 2-benzyloxycarbonyl-indolin is treated with N, N'-dicyclo hexylcarbodiimide. Purification of the product is carried out by chromatography on silica gel.

B.1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] -2-carboxy-indolin

An ethanol solution of 1- (N-carbenzyloxy-L-alanyl) -2-benzyloxycarbonyl-indolin is hydrogenated at pd / c. To the filtered solution is added ethyl 2-oxo-4-phenyl butyric acid, alkyli and sodium cyanoborohydride as in Example 1D. The product is purified by chromatography and freezing conditions.

Example 7

1- [N- (1carboxyethyl) -L-alanyl] -2-carboxy-indolin

The ethanol solution of 1- (N-carbenzyloxy-L-alanyl) -2-benzyloxycarbonyl-indolin is hydrogenated at pd / c. Ethyl pyruvate, alkali and sodium cyanoborohydride are added to the filtered solution. The product is purified by chromatography and lyophilization.

Example 8

1-benzyloxycarbonyl-2- (N-carbenzyloxy-L-alanine) -5-1,2,3,4-tetrahydro-2-benzazine

A methylene chloride solution of N-carbenzyloxy-L-alanyl and 1-benzyloxycarbonyl-5H-1,2,3,4-tetrahydro-2-benzazin was prepared in N, N as in Example 3A. Treatment with '-dicyclohexyl carbodiimide and purification of the final product by silica gel chromatography.

Example 9

1-carboxy-2-N- (1-carboxy-3-phenylpropyl) -L-alanyl-5H-1,2,3,4-tetrahydro-2-benzazine

Hydrogenation of an ethanol solution of 1-benzyloxycarbonyl-2- (N-carbenzyloxy-L-alanyl) -5H-1,2,3,4-tetrahydro-2-benzazine to pd / c Let's do it. The solution is filtered and treated with alkali, sodium cyanoborohydride and 2-oxo-4-phenyl butyric acid as in Example 1D. The product is purified by chromatography.

Example 10

1-carboxy-2- [N- (1-carboxy-3-methylbutyl) -L-alanyl] -5H-1,2,3,4-tetrahydro-2-benzazine

An ethanol solution of 1-benzyloxycarbonyl-2- (N-carbenzyloxy-alanyl) -5-1,2,3,4-tetrahydro-2-benzazine is hydrogenated at pd / c. The solution is filtered and treated with 2-oxo-4-methylpentanoic acid, sodium cyanoborohydride, alkali as in Example 1D. Chromatography and lyophilization yields a pure product.

Example 11

2- (N- (1-Carboethoxy-3-phenylpropyl) -L-alanyl-6,7-methylenedioxy-1,2, 3,4-tetrahydro isoquinoline-3-carboxylic acid

6,7-methyleneoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester according to the method of Example 1A using dicyclohexylcarbodiimide in acetonitrile with carbobenzyloxy- Coupling with L-alanine. The neutral crude product is hydrolyzed with 2 equivalents sodium hydroxide in 80% methanol to afford the desired carboxylic acid.

The carbobenzyloxy-dipeptide was deprotected according to the method of Example 1C at an initial reaction temperature of 0 ° C. 0.675 g (1.81 mmol) of the dipeptide is added to 25 mL of ethanol solution containing 1.47 g (7.13 mmol) of ethyl2-oxo-4-phenylbutyrate. Ethanol sodium hydroxide was added to adjust pH to 6.80, followed by 0.35 g (5.57 mmol) of sodium cyanoborohydride. After stirring for 24 hours at room temperature, 0.70 g of ester and 0.2 g of NaBH ₃ CN are further added and further stirred for 48 hours. The reaction mixture is placed in a 50x8 column of Doxes and eluted with 50% ethanol, water, 1% ammonium hydroxide and 3% ammonium hydroxide. The fractions containing the desired product are collected and lyophilized to yield 0.347 g of diastereomer mixture.

Example 12

2- (N- (1-Carboethoxy-1- (2-indanyl) -menyl) -L-alanyl) -6-chloro-1,2, 3,4-tetrahydro isoquinoline-3-carboxylic acid

In a similar manner, 6-chloro-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methylester and carbobenzyloxy-L-alanyl are DCC coupled and then saponified and digested with HBr / HOAc Prepare dipeptides.

The dipeptide (0.472 g, 1.17 mmol) is alkylated with 1.5 g (6.8 mmol) ethylα-oxindane-2-acetate and 0.32 g (5.09 mmol) NaBH ₃ CN at pH6.75 as above. After 24 h, 0.85 parts of keto ester and 0.2 g of NaBH ₃ CN are added. The reaction is stirred for 40 hours. Ion exchange chromatography gives 0.183 g of the desired product.

Example 13

2- (N- (1-Carboethoxy-3- (2-pyridyl) propyl) L-valyl) -6-methoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

The starting material dipentide is prepared from 6-methoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-valine as mentioned above. Dipeptide salts are prepared by hydroxybenzotriazole-mediated DCC coupling followed by saponification and deprotection. Under standard conditions, reductive alkylation with ethyl 2-oxo-4- (2-pyridyl) butyrate in the presence of sodium cyanoborohydride yields a crude monoester. Purification by ion exchange chromatography and lyophilization as described above gives a diastereomer mixture of the desired product.

Example 14

2- [N- (1-carboethoxy-3- (4-methoxyphenyl) prolyl) -L-isoroyl) 6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline 3-carboxylic acid

Starting dipeptides were described above using hydroxybenzotriazole and DCC from carbobenzyloxy-L-isoleucine and 6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid methyl ester Prepare as described.

Treatment with ethyl 2-oxo-4- (4-methoxyphenyl) butyrate and sodium cyanoborohydride under standard conditions yields a reductive alkylation product. Purification as above affords the title compound as a geometric mixture.

Example 15

2- (N- (1-Carboethoxy-3- (4-chlorophenyl) -L-alanyl) -7-methoxy-1,2,3,4-tetrahydro-5H-benz [C] ase Fin-3-carboxylic acid

Acylation of 1,2,3,4-tetrahydro-5H-benzyl [C] azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-alanine using DCC as the coupling agent as in Example 1A This yields a protected dipeptide. Saturation and deprotection yield free dipeptides.

N-alkylation with ethyl 2-oxo-4- (4-chlorophenyl) butyrate and sodium cyano borohydride as in Example 12 yields a compound containing the desired product. It is isolated by lyophilization with ion exchange chromatography as described above.

Example 16

2- (N- (1-carboethoxy-3- (4-pyridyl) propyl) -L-alanine) -1,2,3,4-tetrahydro-5H-benz [C] azepine-3- Carboxylic acid

Starting dipeptides are prepared according to the process of Example 1 from carbobenzyloxy-L-alanine and 1,2,3,4-tetrahydro-5H-benz [C] azepine-3-carboxylic acid methyl ester. Reductive alkylation with ethyl 2-oxo-4 (4-pyridyl) butyrate and sodium cyanoborohydride as mentioned above yields a crude N-alkylated peptide. Purification by ion exchange chromatography and lyophilization affords the title compound as a diastereomer mixture.

Example 17

2- (N-1- (carboxyethoxy-3- (3-trifluoromethylphenyl) propyl-L-valyl) 7,8-methylenedioxy-1,2,3, -tetrahydro-5H-benz [ C] Azepine-3-carboxylic acid

According to Example 2A, 7,8-methylenedioxy-1,2,3,4-tetrahydro-5H-benz [C] azepine-3-carboxylic acid methyl ester and carbobenzyloxy-L-valine are hydroxy Acylation with benzotriazole and DCC yields a protected polypeptide. Name saponification and treatment with HBr / HOAc yields the desired peptide.

Treatment of this dipeptide with ethyl 2-oxo-4- (3-trifluoromethylphenyl) butyrate and sodium cyanoborohydride according to Example 12 at pH6.5 affords an N-alkylated product. Ion exchange chromatography and lyophilization give pure compounds as mixtures of diastereomers.

Example 18

The S-coordination compound is prepared by selective geometric isomer synthesis by the following process.

A.2- (N- (1-carboethoxy-3-phenylpropyl) alanyl) -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid benzyl ester

1.51 g (9.3 mmol) 1,1'- in 20 mL anhydrous THF suspension containing 2.60 g (9.31 mmol) of (S, S) -N- (1-carboethoxy-3-phenylpropyl) alanine. Carbonyldiimidazole is added. Once a clear solution was obtained (5-10 minutes), the reaction mixture was cooled to 0 ° C. and 3.12 g (7.44 mmol) of (S) -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid benzyl ester Monotartrate is added. The reaction mixture is stirred overnight at room temperature, then concentrated in vacuo and redissolved in ether. The ether solution was washed with saturated sodium bicarbonate solution and water and concentrated to yield 2.2 g (56%) of the desired amide, which was used without further purification.

CIMS: 529 (n = 1), 234,91

NMR: 7.3, 5.1, 3.15, 2.8, 1.2 to 1.5

B.2- (N- (1-carboethoxy-3-phenylpropyl) alanyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride

2.10 g (3.97 mmol) of (S, S, S) -2- (N- (1-carboethoxy-3-phenylpropyl) alanyl-1,2,3,4-tetrahydro-isoquinoline-3 0.2 g of 10% pd / d catalyst is added to a 20 ml ethanol solution containing carboxylic acid benzyl ester, the mixture is shaken at about 2 hydrogen pressure until the consumption of hydrogen is over and the reaction mixture filtered and vacuum It is partitioned between ether and 2N hydrochloric acid, the solution is lyophilized and the resulting powder is washed with ether to give 0.70 g (37%) of product.

[α] _d -10.9 ° (H ₂ O)

CIMS 421 (M + 1-H ₂ O)

EIMS 421,316,270

Elemental Analysis for C ₁₅ H ₃₁ N ₂ O ₅ ㆍ Hcl · H ₂ 0

Calculated value; C: 60.91, H: 6.74, N: 5.18 (%)

Found value; C: 61.16, H: 6.47, N: 5.48 (%)

The following compounds are prepared according to the process of the above examples:

2- [N- (1-ethoxycarbonyl-3-methylbutyl) -L-alanyl] -isoquinalic acid

2- [N- (1-ethoxycarbonyl-4-methylhexyl) -L-alanyl] -isoquinalic acid

2- [N- (1-ethoxycarbonyl-5-methylhexyl) -L-alanyl] -isoquinalic acid

2- [N- (1,3-dicarboxypropyl) -L-alanyl] -isoquinalic acid

2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] -6-hydroxy-isoquinalic acid

2- [N- (1-ethoxycarbonyl-5-methylhexyl) -L-baryl] -isoquinalic acid

2- [N- (1,3-Dicarboxypropyl) -L-alanyl] -6-methoxy-isoquinalic acid

2- [N- (1-ethoxycarbonylhexyl-L-baryl) -8-methyl-isoquinalic acid

2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-phenylalanyl] -6-chloro-isoquinalic acid

2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-histidyl] -8-hydroxy-isoquinalic acid

1- [N- (1-ethoxycarbonyl-3-methylbunyl) -L-alanyl] -2-carboxy-indolin

1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-phenylalanyl] -2-carboxy-indolin

1- [N- (1-ethoxycarbonylhexyl) -L-alanyl] -2-carboxyindolin

1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] -2-carboxy-5,6-dimethylindolin

1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl] -2-carboxy-indolin

1- [N- (1,3-dicarboxypropyl) -L-alanyl] -2-carboxy-5,6-dimethyl-indolin

1- [N- (1,3-dicarboxypropyl-L-histidyl] -2-carboxy-4-chloro-indolin

1- [N- (1-ethoxycarbonylhexyl) -L-valyl] -2-carboxy-4-methoxy-indolin

1- [N- (1-ethoxycarbonylheptyl) -L-phenylalanyl] -2-carboxy-6-methyl-indolin

1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-baryl] -2-carboxy-3-hydroxymethyl-5,6-dimethylindolin

1-carboxy-2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl] -5H-1,2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonyl-3-methylbutyl) -L-histidyl] -5H-1,2, 3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonyl-4-methylpentyl) -L-phenyl-alanyl] -5H-1,2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1,3-ticarboxypropyl) -L-alanyl] -7,8-dimethyl-5H-1, 2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonyl-3-phenylpropyl) isoloyyl] -6-chloro-1,2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonylhexyl) -L-valyl] -6-methoxy-7-methyl-1, 2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-histidyl] -6-chloro-1,2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-carboxy-2-phenylthioethyl) -L-alanyl] -7-methyl-5H-1,2,3,4-tetrahydro-2-benz azepine

1-carboxy-2- [N- (1-ethoxycarbonyl-3-P-chlorophenylpropyl) -L-valyl] 7,8-dimethyl-5H-1,2,3,4-tetrahydro-2 Benz Azepine

1-carboxy-2- [N- (1-carboxy-2- (3-indolyl) ethyl-L-baryl] -5H-1,2, 3,4-tetrahydro-2-benz azepine

2- [N-1 (1-Carboethoxy-3- (4-chlorophenyl) propyl) -L-royl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (3-trifluoromethylphenyl) propyl) -L-valyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-2- (3-methoxyphenyl) ethyl) -L-methylthio] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (4-pyridyl) propyl) -L-alanyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (4-methoxyphenyl) propyl) -L-lysyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (3-pyridyl) propyl) -L-royl]]-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N- (1-Carboethoxy-2- (2-thienyl) ethyl) -L-arginyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (methylthio) propyl) -L-isoroyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (3-thienyl) propyl) -L-valyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-2-phenylethyl) -L-lysyl] -1,2,3,4-tetrahydro isoquinoline-4-carboxylic acid

2- [N-1 (1-Carboethoxy-2- (phenoxy) ethyl) -L-lysyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (2-furyl) propyl) -L-valyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-carboethoxy-3- (3,4-fumethylenedioxy-phenyl) propyl] -L-alanyl-1,2,3,4-tetrahydro isoquinoline-3- Carboxylic acid

2- [N-1 (1-Carboethoxy-3- (3-chlorophenyl) propyl) -L-phenylalanyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (2-methoxyphenyl) propyl) -L-tyrosyl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-Carboethoxy-2- (benzofuran-3-yl) ethyl) -L-royl] -1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

2- [N-1 (1-carboethoxy-3- (4-methoxyphenyl) propyl) -L-alanyl) -6-chloro-1,2,3,4-tetrahydro isoquinoline-3- Carboxylic acid

2- [N-1 (1-carboethoxy-3- (phenoxy) propyl) -L-arginyl] -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3 Carboxylic acid

2- [N-1 (1-carboethoxy-2- (indol-3-yl) ethyl) -L-royl] -6-methoxy-1, 2,3,4-tetrahydroisoquinoline-3 Carboxylic acid

2- [N-1 (1-carboethoxy-3- (4-methoxyphenyl) propyl) -L-royl] -5H-1,2, 3,4-tetrahydrobenz [C] azepine- 3-carboxylic acid

2- [N-1 (1-carboethoxy-3- (3-pyridyl) propyl) -L-methionyl] -5H-1,2,3,4-tetrahydrobenz [C] azepine-3 Carboxylic acid

2- [N-1 (1-Carboethoxy-3- (methylthio) propyl) -L-royl] -5H-1,2,3,4-tetrahydro [C] azepine-3-carboxylic acid

2- [N-1 (1-carboethoxy-2- (4-imidazolyl) ethyl) -L-valyl] -7-methoxy-5 H-1,2,3,4-tetrahydrobenz [ C] Azepine-3-carboxylic acid

2- [N-1 (1-carboethoxy-3- (3-methoxyphenyl) propyl) -L-lysyl] -6,7-methylenedioxy-5H-1,2,3,4-tetrahydro Mercedes Benz [C] azepine-3-carboxylic acid

2- [N-1 (1-Carboethoxy-3- (3-chlorophenyl) propyl) -L-histidyl] -5H-1, 2,3,4-tetrahydrobenzezepine-3-carboxylic acid

2- [N-1 (1-carboxyethoxy-3- (3-thienyl) propyl) -L-arginyl] -7-methoxy-5H-1,2,3,4-tetrahydrobenz [C ] Azepine-3-carboxylic acid

2- [N-1 (1-carboethoxy-2-phenylethyl) -L-tyrosyl] -7-chloro-5H-1,2,3,4-tetrahydrobenz [C] azepine-3 Carboxylic acid

N- (1-carboxy-2-indanylmethyl) -alanyl-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid

The compounds according to the invention have an effective action (I 50: 0.02 to 0.20 micromolar) that inhibits angiotensin converting enzyme (ACEI activity) when tested by the method described in Science 196,441-4 (1977). Indicates. The compounds of the present invention also exhibit an I ₅₀ of 1-2 mg / kg (oral) in inhibiting angiotensin I in rats. Likewise they are very useful for the treatment of hypertension.

The compound may be administered orally or parenterally for the treatment of hypertension, and the dosage may be determined by a specialist or a skilled person. Suitable dosage forms include tablets, capsules, elixirs and injections.

Claims (24)

The compound of formula (II) is reacted with an acylated derivative of formula (III) or a compound of formula (VI) under amide forming conditions, or the compound of formula (VI) is reacting with an α-keto acid or an ester to obtain an imine and reducing the obtained imine, or reacting a compound of formula (VI) with an α-halo acid or ester of formula (VIII) A process for preparing a compound of I) and salts thereof, in particular pharmaceutically acceptable salts with acids or bases.

Wherein R ₁ and R ₇ are hydrogen, lower alkyl or phenyl lower alkyl; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl or heterocyclic, or A lower alkyl, lower alkenyl or lower alkynyl group substituted by a hydroxy, alkoxy, halo, amino, alkylamino, mercapto or alkyl mercapto group, or an alkyl, hydroxy, alkoxy, hydroxyalkyl, halo, mer A cycloalkyl, aryl or heterocyclic group substituted by capto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy or trifluoromethyl; Each R ₈ is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkyl mercapto, hydroxyalkyl, mercaptoalkyl, halogen, Haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylamitoalkyl, sulfonamido, methylenedioxy or trifluoromethyl; m is an integer from 0 to 2; m 'is an integer of 1 to 3, provided that m' is 2 or 3 when m is 0, m 'is 1 or 2 when m is not 0, n is an integer of 0 to 4, Hal Is halogen. The method of claim 1 wherein the COOR ₇ substituent is linked to a carbon atom adjacent to the nitrogen in the ring. The method of claim 1 or 2, wherein R ₇ is hydrogen. The method of claim 1 or 2, wherein R ₁ is ethyl or hydrogen. The method of claim 1 or 2, wherein R ₂ is phenyl-loweralkyl. The method of claim 1 or 2, wherein R ₂ is phenethyl. The method of claim 1 or 2, wherein R ₆ is methyl. The method of claim 1 or 2, wherein R ₆ is isopropyl. The method of claim 1 or 2, wherein R ₆ is isobutyl. The method of claim 1 or 2, wherein R ₂ is phenethyl and R ₆ is methyl. Compounds of the general formula (1) and salts thereof, in particular pharmaceutically acceptable salts with acids or bases.

Wherein R ₁ and R ₇ are hydrogen, lower alkyl or phenyl lower alkyl; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl or heterocyclic group, or A lower alkyl, lower alkenyl or lower alkynyl group substituted by hydroxy, alkoxy, halo, amino, alkylamino, mercapto or alkylmerkato group, or alkyl, hydroxy, alkoxy, hydroxy alkyl, halo, Mercapto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy or trifluoromethyl substituted cycloalkyl, aryl or heterocyclic group; Each R ₈ is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkyl mercapto, hydroxyalkyl, mercaptoalkyl, halogen, halo Alkyl, aminoalkyl, alkylaminoalkyl, dialkylamitoalkyl, sulfonamido, methylenedioxy or trifluoromethyl; m is an integer from 0 to 2; m 'is an integer of 1 to 3 except that m' is 2 or 3 when m is 0, m 'is 1 or 2 when m is not 0, and n is an integer of 0-4. A compound according to claim 11, and a salt thereof, in particular a pharmaceutically acceptable salt with an acid or a base.

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and n are as defined in claim 11. 13. The compound of claim 11 or 12, wherein the COOR ₇ substituent is linked to a carbon atom adjacent to the nitrogen in the ring. 13. The compound of claim 11 or 12, wherein R ₇ is hydrogen. The compound of claim 11 or 12, wherein R ₁ is ethyl or hydrogen. 13. The compound of claim 11 or 12, wherein R ₂ is phenyl-loweralkyl. 13. The compound of claim 11 or 12, wherein R ₂ is phenethyl. The compound of claim 11 or 12, wherein R ₆ is methyl. The compound of claim 11 or 12, wherein R ₆ is isopropyl. 13. The compound of claim 11 or 12, wherein R ₆ is isobutyl. 13. The compound of claim 11 or 12, wherein R ₂ is phenethyl and R ₆ is methyl. A pharmaceutical composition for the treatment of hypertension, characterized by containing an antihypertensive effective amount of the compound according to claim 11. The process according to claim 1, wherein the obtained compound of formula (I) is subsequently converted to another compound of formula (1) by substitution or conversion reaction. 2. Process according to claim 1, wherein the compound of general formula (I) obtained is subsequently converted to salts thereof, in particular salts with pharmaceutically acceptable acids or bases.