NO820903L - PROCEDURE FOR THE PREPARATION OF AMIDO-AMINO ACIDS. - Google Patents

Description

The present invention relates to new compounds

with valuable pharmacological activity. The invention relates in particular to compounds with antihypertensive and angiotensin-converting enzyme inhibitory activity and the structure

in which R 1 and R? each is hydrogen, lower alkyl or phenyl lower alkyl; R 2 , B , R 4 ' R 5 ° 9 R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl, heterocyclic group, and may be the same or different; each Rg is alkyl, alkenyl, alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, methylenedioxy and trifluoromethyl, and where more than an Rg group, the groups can be the same or different; m is an integer from 0 to 2; and m<1> is an integer from 1 to 3, provided that when m is 0, m<1> is 2 or 3 and when little m is different from 0, m' is 1 or 2; n is an integer from 0 to 4; and salts thereof, especially salts with pharmaceutically acceptable acids and bases.

The alkyl groups in alkyl per se, aralkyl, alkoxy, aminoalkyl, thioalkyl, haloalkyl and hydroxyalkyl are preferably lower alkyl containing 1 to 6 carbon atoms and may be branched or straight chain.

The alkenyl and alkynyl groups contain from 2 to 6 carbon atoms and may be branched or straight chain.

Alkyl, alkenyl and alkynyl groups can carry substituents such as hydroxy, alkoxy, halo, amino, acylamino, mercapto and alkylmercapto.

The cycloalkyl groups contain from 3 to 7 carbon atoms. Such cycloalkyl groups include cycloalkyl-

the alkyl and cycloalkyl groups may carry substituents such as alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, alkylamino, trifluoromethyl, and nitro.

The aryl groups can have from 6 to 10 carbon atoms and include phenyl and a- and g-naphthyl. The aryl groups can contain substituents such as alkyl, hydroxy, alkoxy, hydroxyalkyl, mercapto, alkylmercapto, mercaptoalkyl. halo, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, trifluoromethyl, ureido, and guanidino.

Condensed aryl-cycloalkyl comprises phenyl rings fused to cycloalkyl rings with from 3 to 7 carbon atoms. These groups also include fused aryl-cycloalkyl-alkyl.

The heterocyclic group may be saturated, partially saturated or unsaturated and includes such groups as pyridine, piperdine, morpholine, pyrrole, pyrrolidine, thiomorpholine, quinoline, isoquinoline, tetrahydroquinoline, thiazolidine, thiazoline, thiazole, imidazolidine, imidazoline, imidazole, thiophene, tetrahydrothiophene, furyl, tetrahydrofuran and the like. These heterocyclic groups can also carry substituents as described for the aryl groups. The heterocyclic group also includes heterocyclic lower alkyl.

The halogen groups include fluorine, chlorine, bromine and iodine.

Preferably, the -COOR^ group is attached to a carbon atom adjacent to the nitrogen in the ring system.

Suitable acid addition salts include inorganic salts such as hydrochloride, phosphate and sulfate; organic carboxylates such as acetate, malate, maleate, furmarate, succinate, citrate, lactate, benzoate, hydroxybenzoate, aminobenzoate, nicotinate and the like, and organic sulfone and phosphonic acids such as toluenesulfonic acid.

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

It should be understood that the compounds produced according to the invention may have one or more asymmetric carbon atoms, and the various racemic mixtures as well as the individual optically active compounds are considered to fall within the scope of the invention.

The compounds can be prepared by amide-forming reaction of an amine compound of formula

with an acylation derivative of an acid of formula Alternatively, the compounds in which R 3 and R 3 are hydrogen can be readily prepared by treating a compound of formula II with a compound of formula under amide-forming conditions, forming a compound of formula after which the carbobenzyloxy group is split off to form a free amine of formula and the amine is reacted with an α-keto acid or ester of formula whereupon the resulting imine is reduced to form a compound of formula I where R 3 and R 3 are hydrogen. Compounds of formula VI can also be reacted with an α-halo acid or ester of formula

forming compounds of formula I where R^ and R^ may be H or any of the other substituents descriptive of R^ and R^.

In the above-mentioned reaction sequence is to Rg,

m, m' and n as previously defined and Hal is halogen.

Preferably, R 1 , R 1 , R 1 , R 1 - and R 7 and R 8 are hydrogen. R 2 is lower alkyl or phenyl-lower alkyl, R 2 is lower alkyl.

The amide-forming conditions indicated here include the use of known derivatives of the described acids, such as acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles and the like. The reactions are carried out in organic solvents such as acetonitrile, tetrahydrofuran, dioxane, acetic acid, methylene chloride, ethylene chloride and similar solvents. The amide-forming reaction will take place at room temperature or at elevated temperature. The use of an elevated temperature is appropriate in that it enables a somewhat shorter reaction period. Temperatures varying from 0 up to the reaction system's reflux temperature can be used. Further expediently, the amide-forming reaction can be carried out in the presence of a base such as tertiary organic amines, for example trimethylamine, pyridine, picoline and the like, especially where hydrogen halide is formed by the amide-forming reaction, for example acyl halide and amino bond.

In the reactions where hydrogen halide is formed, any of the commonly used hydrogen halide acceptors can of course also be used.

In the condensation of alpha halo acid derivative of

formula VIII, similar reaction conditions, solvents and hydrogen halide acceptors can be used as for the amide formation.

Different substituents on the new compounds, for example as defined for Rg, can be present in the starting compounds or added after the formation of the amide products by known substitution methods or conversion reactions. Thus, the nitro group can be added to the final product by nitration of the aromatic ring and the nitro group can be converted into other groups such as amino by reduction, and halo by diazotization of the amino group and displacement of the diazo group. Other reactions can be carried out on the amide product formed. Amino groups can be alkylated to form mono and dialkylamino groups, mercapto and hydroxy groups can be alkylated to form the corresponding ethers. Thus, substitution or conversion reactions can be used to provide a multitude of substituents on the molecule in the final products. Where reactive groups are present, these must of course be protected with suitable blocking groups during any of the above-mentioned reactions, in particular the condensation reactions during formation of the amide bonds.

The acid and base salts of the new compounds can

formed according to standard procedures. These are often formed in situ during the production of the new amido-amino acids.

The new compounds exist in stereoisomers

forms and the products obtained can thus be mixtures of the isomers, which can be dissolved. By choosing specific isomers as starting compounds, the preferred stereoisomers can alternatively be prepared. The preferred forms where each asymmetric center (chiral center) is S-configuration are therefore preferably produced stereospecifically instead of the mixture of isomers being dissolved. The compounds in which the S configuration exists at all asymmetric centers

are most active; those in which the R configuration exists are less active and those in which both R and S configurations exist have an intermediate activity.

The invention is further illustrated in the following examples.

Example 1

A. 2-( N- Benzyloxycarbonyl- L- alanyl)- L- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid methyl ester

To a suspension of 10.0 g (43.9 mmol) L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride and 10.4 g (46.6 mmol) carbobenzyloxy-L-alanine in 150 ml dry

to acetonitrile was added 4.4 g (43.6 mmol) of triethylamine.

A solution of 9.2 g (44.6 mmol) of N,N-dicyclohexylcarbodiimide

in 5 ml of dry acetonitrile was then added dropwise with stirring. The resulting slurry was stirred overnight at room temperature, filtered and concentrated in vacuo. The residue was redissolved in ether, washed successively with 1N HCl, saturated NaHCO 3 and brine, dried over MgSP 2 /filtered and concentrated to give 18.3 g (105%) of crude amide which was used without further purification.

B 2-( N- Benzyloxycarbonyl- L- alanyl)- L- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid

8.0 g of the crude amide ester from A was dissolved in 25 ml of 1N NaOH/MeOH. To this was added 5 ml of water. The resulting solution was stirred overnight at room temperature, then poured into 150 mL of water and extracted with ether. The aqueous layer was then acidified and extracted with CH 2 Cl 2 . The extracts were dried over MgSO 4 and concentrated under suction to give 5.5 g of product. After prolonged concentration under oil pump vacuum, a fragile foam was obtained.

C. 2- L- Alanyl- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid hydrobromide

To a solution of 4.8 g (12.5 mmol) of impure carbobenzyloxycarboxylic acid in 7 ml of acetic acid was added 5 ml of saturated HBr in acetic acid. The solution was stirred at room temperature until all gas evolution had stopped (1-1.5 hours). A slow stream of air was passed through the solution to remove excess HBr, then 25 mL of ether was added to precipitate the product. The solid was washed with additional portions of ether, then dried in vacuo to give 2.2 g of a light yellow solid, mp 180°C.

D. N-(1- Carboxy- 3- phenylpropyl) alanyl- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid

To a solution of 1.3 g (6.63 mmol) of benzylpyruvic acid hydrate in 5 mL of saturated NaHCO 3 was added 0.307 g (0.93 mmol) of alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid followed by 0.238 g (3.79 mmol) of sodium cyanoborohydride. The solution was stirred overnight at room temperature and then transferred to a column of 20 g of Dowex 50X8. The column was eluted with 50% MeOH, then 3% NH 3 OH. The first ammonia fractions containing the desired product were combined and lyophilized to give 85 mg of product as a fluffy white powder with a melting point of 97-101°C.

Example 2

A. 2-( N- Carbobenzyloxy- L- valyl)- L- 1, 2, 3, 4- tetrahydroisoquinoline-3- carboxylic acid methyl ester

5.2 g (20.7 mmol) of N-carbobenzyloxy- L-valine; 2.7 g (20.0 mmol) of 1-hydroxybenzotriazole and 2.1 g (20.7 mmol) of triethylamine. The resulting mixture was stirred at room temperature and a solution of 4.5 g (21.8 mmol) of dicyclohexylcarbodiimide in 10 ml of dry acetonitrile was added slowly. The mixture was stirred overnight at room temperature, then filtered and worked up as described in Example 1 A. Final concentration gave 8.3 g (101%) of a thick oil.

B. 2-( N- Carbobenzyloxy- L- valyl)- L- 1, 2, 3, 4- tetrahydroisoquinoline-3- carboxylic acid

4.5 g (106 mmol) of crude methyl ester prepared according to the above procedure was treated with 10 ml of 10% NaOH and sufficient methanol (35-40 ml) to give a homogeneous solution. This solution was stirred at room temperature for 32 hours, then diluted with 100 ml of water and extracted with two 25 ml portions of ether. The aqueous fraction was then acidified and extracted with four 10 mL portions

methylene chloride. The extracts were dried over MgSO 4 and concentrated to give 3.8 g (9.3 mmol, 87%) of homogeneous carboxylic acid.

Example 3

A. 2-( N- Carbobenzyloxy- L- isoleucyl)- L- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid

4.5 g (19.8 mmol) L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride, 5.3 g (20.0 mmol) N-carbobenzyloxy-L-isoleucine, 2.7 g (20.0 mmol) 1-hydroxybentriazole and 2.1 g (20.7 mmol) triethylamine were treated

as described in Example 2A with 4.4 g (21.3 mmol) of dicyclohexyl-cabodiimide and was then worked up to give 7.8 g (90%) of impure methyl ester. This was dissolved in 30 ml of methanol and treated with 10 ml of 10% NaOH. The solution was stirred overnight at room temperature, then worked up as previously described to give 1.8 g (21.4% total yield) of the desired acid as a yellow oil.

Example 4

2- [ n-( 1- Ethoxycarbonyl- 3- phenylpropyl)- L- alanyl - isoquinaldic acid

An ethanolic solution of benzyl 2-(N-carbobenzoxy-L-alanyl)-isoquinaldate was hydrogenated with palladium on carbon. The solution was filtered and treated with ethyl 2-oxo-4-phenyl-butyric acid, alkali and sodium cyanoborohydride as described in Example 1D. The product was purified by chromatography and lyophilization.

Example 5

2-N-(1-Carboxyethyl)-L-alanyl- isoquinaldic acid

An ethanolic solution of benzyl 2-(N-carbobenzoxy-L-alanyl)-isoquinaldate and pyruvic acid was hydrogenated with palladium on carbon. The filtered solution was concentrated and purified as described in Example 1D.

Example 6

A. 1-(N-Carbobenzoxy-L-alanyl)-2-benzoxycarbonylindoline

A methylene chloride solution of N-carbobenzyloxy-L-alanine and 2-benzyloxycarbonyl-indoline was treated with N,N<1->dicyclohexylcarbodiimide. Purification of the product was carried out by chromatography on silica gel.

B. 1-[n-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-carboxy-indoline

An ethanolic solution of 1-(N-carbobenzyloxy-L-alanyl)-2-benzyloxycarbonyl-indoline was hydrogenated with palladium on carbon. To the filtered solution were added ethyl 2-oxo-4-phenyl-butyric acid, alkali and sodium cyanoborohydride as described in example 1D. The product was purified by chromatography and lyophilization.

Example 7

1 -[ n-(1- Carboxyethyl)- L- alanyl]- 2- carboxy- indoline

An ethanolic solution of 1-(N-carbobenzyloxy-L-alanyl)-2-benzyloxycarbonyl-indoline was hydrogenated with palladium on carbon. To the filtered solution were added ethyl pyruvate, alkali and sodium cyanoborohydride. The product was purified by chromatography and lyophilization.

Example 8

1- Benzyloxycarbonyl- 2-( N- carbobenzyloxy- L- alanine)- 5H- 1, 2, 3, 4-tetrahydro- 2- benzazepine

A methylene chloride solution of N-carbobenzyloxy-L-alanine and 1-benzyloxycarbonyl-5H-1,2,3,4-tetrahydro-2-benzazepine was treated with N,N<1->dicyclohexylcarbociimide as described in Example 3A. Purification of the final product was carried out by silica gel chromatography.

Example 9

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

An ethanolic solution of 1-benzyloxycarbonyl-2-(N-carbobenzyloxy-L-alanyl)-5H-1,2,3,4-tetrahydro-2-benzazepine was hydrogenated with palladium on carbon. The filtered solution was treated with alkali, sodium cyanoborohydride and 2-oxo-4-phenylbutyric acid as described in Example 1D. The product was purified by chromatography.

Example 10

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

An ethanolic solution of 1-benzyloxycarbonyl-2-(n-carbobenzyloxy-alanyl)-5H-1,2,3,4-tetrahydro-2-benzazepine was hydrogenated with palladium on carbon. The filtered solution was treated with 2-oxo-4-methylpentanoic acid, sodium cyanoborohydride and alkali as described in Example 1D. Chromatography and lyophilization gave the pure product.

Example 11

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

By the procedure described in example 1A

6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester was coupled with carbobenzyloxy-L-alanine using dicyclohexylcarbodiimide in acetonitrile. The crude neutral product was then hydrolyzed with two equivalents of NaOH in 80% MeOH to form the desired carboxylic acid.

The carbobenzyloxy dipeptide obtained above was deprotected following a procedure described in Example 1C with an initial reaction temperature of 0°C. 0.675 g (1.81 mmol) of this dipeptide was added to a solution of 1.47 g (7.13 mmol) ethyl 2-oxo-4-phenylbutyrate in 25 ml of EtOH.

The pH was adjusted to 6.80 with ethanolic NaOH and 0.35 g

(5.57 mmol) of sodium cyanoborohydride was added. After stirring for 24 hours at room temperature, an additional 0.70 g of ester and 0.2 g of NaBH^CN were added, and stirring was continued for a further•48 hours. The reaction mixture was transferred to a column of Dowex 50X8 and the column was eluted with 50% EtOH, H 2 O, 1% NH 2 OH, and 3% NH 2 OH. Fractions containing the desired product were combined and lyophilized to yield 0.347 g of the diastereomeric mixture.

Example 12

2-( N-( 1- Carboethoxy- 1-( 2- indanyl) methyl)- L- alanyl)- 6- chloro-1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid

In a similar manner, the appropriate dipeptide was prepared from 6-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-alanine by DCC coupling followed by saponification and cleavage with HBr/OHAc.

0.427 g (1.17 mmol) of the dipeptide obtained above was alkylated as previously described with 1.5 g (6.87 mmol) ethyl α-oxindane-2-acetate and 0.32 g (5.09 mmol) NaBH^ CN at pH 6.75. After 24 hours, a second 0.85 gram portion of the keto ester and 0.2 g of NaBH 2 CN were added. The reaction mixture was then stirred for 40 hours. Ion exchange chromatography then gave 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- tetrahydroisoquinoline- 3- carboxylic acid

The starting dipeptide was prepared from 6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-valine. Hydroxybenzotriazole-mediated DCC coupling, followed by saponification•and deblocking as previously described, afforded the dipeptide salt. Reductive alkylation with ethyl 2-oxo-4-(2-pyridyl)butyrate in the presence of sodium cyanoborohydride under standard conditions afforded the impure monoester. This was purified by ion exchange chromatography and lyophilization as previously described, forming a mixture of diastereomers of the desired product.

Example 14

2-( N- 1- carboethoxy- 3-( 4- methoxyphenyl) propyl)- L- isoleucyl)-6, 7- dimethoxy- 1, 2, 3, 4- tetrahydroisoquinoline- 3- carboxylic acid

The starting dipeptide was prepared from carbobenzyloxy-L-isoleucine and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester using hydroxybenzotriazole and DCC as previously described. Saponification and deprotection as previously indicated then gave the dipeptide hydrobromimide.

Treatment with ethyl 2-oxo-4-(4-methoxyphenyl)butyrate

and sodium cyanoborohydride under standard conditions gave the reductive alkylation product. This was purified as previously described to give the title compound as a diastereomer mixture.

Example 15

2-( N-( 1- carboethoxy- 3-( 4- chlorophenyl)- L- alanyl)- 7- methoxy- 1, 2, 3, 4- tetrahydro- 5H- benz [ c3 azepine- 3- carboxylic acid

Acylation of 1,2,3,4-tetrahydro-5H-benz[c]azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-alanine using DCC as coupling reagent as described in Example 1A gave the most protected dipeptide. Saponification and deblocking then gave the free dipeptide as previously described.

N-alkylation with ethyl 2-oxo-4-(4-chlorophenyl)butyrate

and sodium cyanoborohydride as described in Example 12 gave a mixture containing the desired product. This was isolated by ion exchange chromatography and lyophilization as previously described.

Example 16

2-( N-( 1- Carboethoxy- 3-( 4- pyridyl) propyl)- L- alanyl)- 1, 2, 3, 4-tetrahydro- 5H- benz [c] azepine- 3- carboxylic acid

The starting dipeptide was prepared from carbobenzyloxy-L-alanine and 1,2,3,4-tetrahydro-5H-benz [c],azepine-3-carboxylic acid methyl ester following the general procedure described in Example 1. Reductive alkylation as previously described , using ethyl 2-oxo-4-(4-pyridyl)-butyrate and sodium cyanoborohydride gave impure N-alkylated peptide. Purification by ion exchange chromatography and lyophilization afforded the pure title compound as a mixture of diastereomers.

Example 17

2-( N- 1 -( carboethoxy- 3-( 3- trifluoromethylphenyl) propyl)- L- valyl)-7, 8- methylenedioxy- 1, 2, 3, 4- tetrahydro- 5H- benz[ cjazepin- 3- carboxylic acid

Acylation of 7,8-methylenedioxy-1,2,3,4-tetrahydro-5H-benz[c]azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-valine using hydroxybenzotriazole and DCC as described in Example 2A gave the protected dipeptide . This was then saponified and treated with HBr/HOAc to form the desired peptide.

Treatment of the dipeptide with ethyl 2-oxo-4-(3-trifluoromethylphenyl)butyrate and sodium cyanoborohydride at pH 6.55 as described in Example 12 gave the N-alkylated product. Ion exchange chromatography and lyophilization gave the pure compound as a mixture of diastereomers.

Example 18

Stereospecific synthesis of compounds with S configuration is carried out according to the following procedure.

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

To a suspension of 2.60 g (9.31 mmol) (S,S)-N-(1-carboethoxy-3-phenylpropyl)alanine in 20 ml dry THF was added 1.51 g (9.3 mmol) 1 ,1<1->carbonyldimidazole. When a clear solution was obtained (5-10 min.), the reaction mixture was cooled to 0°C and 3.12 g (7.44 mmol) of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester monotartrate was added. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and redissolved in ether.

The ether solution was washed with saturated NaHCO 3 solution and water,

and was concentrated to give 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, 1.2-1.5

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

To a solution of 2.10 g (3.97 mmol) (S,S,S)-2-(N-(1-carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4-tetrahydroisoquinoline-3 -carboxylic acid benzyl ester in 20 ml of ethanol was added to 0.2 g of 10% Pd/C catalyst. The mixture was shaken for approx. 2 atm. hydrogen until uptake decreased. The reaction mixture was filtered and concentrated in vacuo, then partitioned between ether and 2N HCl. The aqueous solution was lyophilized and the resulting powder washed with ether to give 0.70 g (37%) of product, mp 101-105°C.

Calculated for C25H3^2°5•HC1'H2° C 60'91 H 6.74 N 5.18 Found C 61.16 H 6.47 N 5.48

By following the procedures described above, the following additional compounds were prepared: 2-[N-1-Ethoxycarbonyl-3-methylbutyl)-L-alanyl]-isoquinolinic acid 2- [N-1-Ethoxycarbonyl-4-methylhexyl)-L-alanyl]-isoquinolinic acid 2 -[N-1-Ethoxycarbonyl-5-methylhexyl)-L-alanyl]-isoquinolinic acid 2-[N-1,3-Dicarboxypropyl)-L-alanyl]-isoquinolinic acid 2-[N-1-Ethoxycarbonyl-3-phenylpropyl')-L-alanyl] -6-hydroxy-isoquinolinic acid

2- [N-1-Ethoxycarbonyl-5-methylhexyl)-L-valyl]-isoquinolinic acid 2- [N-1,3-Dicarboxypropyl)-L-alanyl]-6-methoxy- isoquinolinic acid 2-[N-1-Ethoxycarbonylhexyl-L-valyl]- 8-methyl-isoquiholinyl 2-[N-1-Ethoxycarbonyl-3-phenylpropyl)-L-phenylalanyl]-6-chloro-isoquinolinic acid

2- [N-1-Ethoxycarbonyl-3-phenylpropyl)-L-histidyl]-8-hydroxy-isoquinolinic acid

1-[N-(1-Ethoxycarbonyl-3-methylbutyl)-L-alanyl]-2-carboxy-indoline

1- [N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-phenylalanyl]-2-carboxy-indoline

1-[N-(1-Ethoxycarbonylhexyl)-L-alanyl]-2-carboxyindoline 1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-carboxy-5,6-dimethylindoline

1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-valyl]-2-carboxy-indoline

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

1-[N-(1,3-Dicarboxypropyl)-L-histidyl]-2-carboxy-4-<k>lo<r>~indoline

1-[N-(1-Ethoxycarbonylhexyl)-L-valyl]-2-carboxy-4-methoxy-indoline

1-[N-(1-Ethoxycarbonylheptyl)-L-phenylalanyl]-2-carboxy-6-methyl]-indoline

1-[N-(1-Ethoxycarbonyl-3-phenylpropyl)-L-valyl]-2-carboxy-3- hydroxymethyl-5,6-dimethylindoline

l-Carboxy-2-[N-(1-ethoxycarbonyl-3-phenylpropyl)-L-valyl]-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-( l-ethoxycarbonyl-3-methylbutyl-L-histidyl]-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2- [N-(l-ethoxycarbonyl-4-methylpentyl)-L- f .enylalanyl]-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1,3-dicarboxypropyl)-L-alanyl]-7,8-dimethyl-5H-1 ,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2- [N-(l-ethoxycarbonyl-3 - f.enylpropyl) isoleucyl] - 6-chloro -1,2,3,4-tetrahydro-2 -benzazepine l-Carboxy-2-[N-(1-ethoxycarbonylhexyl)-L-valyl]-6-methoxy-7-methyl-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[ N-(1-ethoxycarbonyl-3-phenylpropyl)-L-histidyl]-6-chloro-1,2,3,4-tetrahydro-2-benzazepine V-Carboxy-2-jN-(1-carboxy-2- phenylthioethyl)-L-alanyl)]-7-methyl-5H-1,2,3,4-tetrahydro-2-benzazepine

1-Carboxy-2 [n-(1-ethoxycarbonyl-3-p-chlorophenylpropyl)-L-valylJ-7,8-dimethyl-5H-1,2,3,4-tetrahydro-2-benzazepine 1-Carboxy-2 [n-(1-carboxy-2-(3-indolyl)ethyl]-L-valyl]-5H-1,2,3,4-tetrahydro-2-benzazepine

2-(N-1(1-Carboethoxy-3-(4-chlorophenyl)propyl)-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(3-trifluoromethylphenyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-1 (1-Carboethoxy- 2-(3-Methoxyphenyl)ethyl)-L-methionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(4-pyridyl)propyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-lysyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(3-pyridyl)propyl)-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-(1-Carboethoxy-2-(2-thienyl)ethyl)-L-Arginyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(methylthio)propyl)-L-isoleucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(3-thienyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-2-phenylethyl)-L-lysyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-2-(phenoxy)ethyl)-L-lysyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(2-furyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(3,4-methylenedioxy-phenyl)propyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-1( 1-Carboethoxy-3-(3-chlorophenyl)propyl)-L-phenylalanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(2-methoxyphenyl)propyl)-L-tyrosyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-2-(benzofuran-3-yl)ethyl)-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1(1-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-alanyl)-6-chloro-1,2,3,4-tetrahydroisoquinoline-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-leucyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2-(N-1 (1-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-leucyl)-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-leucyl)-5H-1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid

2 - (N-1(1 -Carboethoxy-2-(4-imidazolyl)ethyl)-L-valyl)-7-methoxy-5H-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-tetrahydrobenz[cjazepine-3-carboxylic acid 2 -(N-1(1-Carboethoxy-3-(3-chlorophenyl)propyl)-L-histidyl)-5H-1,2,3,4-tetrahydrobenz [c]azepine-3-carboxylic acid

2-(N-1(1-Carboethoxy-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-tryosyl)-7-chloro-5H-1,2,3,4-tetrahydrobenz [c]azepine-3-carboxylic acid

N-(1-Carboxy-2-indanylmethyl)-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The compounds produced according to the invention have

showed strong activity (in the order of I^q of 0.02 to 0.20 micromoles) in inhibiting angiotensin-converting enzyme (ACEI activity) when these were tested by the method described in Science 196, 441-4 (1977). The compounds prepared according to the invention have also exhibited a 1,-q of 1 to 2 mg/kg p.o. by inhibition of infused angiotensins I in rats. As such, these compounds will be very useful in the treatment of hypertension.

The compounds can be administered orally or parenterally in the treatment of hypertension, and the person skilled in the art will determine the amount to be administered in each case. Suitable dosage forms include tablets, capsules, elixirs and injectable solutions.

Claims (10)

1. Process for the preparation of therapeutically active compounds of formula wherein R 1 and R 7 are hydrogen, lower alkyl or phenyl lower alkyl, R 2 , R 1 , R 2 , R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused aryl-cycloalkyl, aralkyl . , halo, mercapto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy and trifluoromethyl; each Rg is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamide, methylenedioxy, or trifluoromethyl, m is an integer from 0 to 2; m' is an integer from 1 to 3, provided that when little m is 0 little m' is 2 or 3 and when m is different from 0 little m<1>1 or 2; n" is an integer from 0 to 4, and salts thereof, in particular pharmaceutically acceptable salts with an acid or a base, characterized in that a) a compound of formula is reacted under amide-forming conditions with an acylating derivative of an acid of formula III or Formula IV or b) that a compound of formula VI is reacted with a -keto acid or ester of formula VII whereupon the resulting imine is reduced, or c) that a compound of formula VI is reacted with a -halo acid or ester of formula VIII and optionally, that a compound obtained is subjected to substitution or transformation reactions to introduce different substituents into the compound; and optionally that a compound obtained is converted into a pharmaceutically acceptable salt with an acid or base. 2. Method according to claim 1, characterized in that the COOR7 substituent is bound to a carbon atom adjacent to the ring nitrogen atom. 3. Process according to claim 1 or 2, characterized in that R 7 is hydrogen. 4. Process according to claims 1-3, characterized in that R.j is ethyl or hydrogen. 5. Process according to claims 1-4, characterized in that R2 is phenyl-lower alkyl. 6. Method according to claim 5, characterized in that R2 is phenethyl. 7. Process according to claims 1-6, characterized in that Rg is methyl. 8. Process according to claims 1-6, characterized in that Rg is isopropyl. 9. Process according to claims 1-6, characterized in that Rg is isobutyl. 10. Process according to claims 1-5, characterized in that R2 is phenethyl and Rg is methyl.