NL8201066A - AMIDO-AMINO ACIDS. - Google Patents

Description

VO 3195

Ami do-amino acids and.

The invention relates to new compounds with valuable pharmacological activity. In particular, it concerns compounds with antihypertensive and inhibitory activities on angiotensin converting enzyme. These compounds correspond to the formula 1 of the formula sheet, wherein R 1 and hydrogen, alkyl or phenylalkyl,

Rg, Rl, Rl, Rl and Rg represent hydrogen, alkyl, alkenyl, alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl and a hetero ring and may be the same or different; Each Rg is alkyl, alkenyl, alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, mercanto, alkyl mercapto, hydroxyalkyl, mercaptoalkyl, halo, haloalkyl, aminoalkyl, alkylaminoalkyl, di-alkylaminoalkyl, sulfonamido, methylenedioxy and trifluorom when there is more than one Rg group, these groups may be the same or different; m is 0, 1 or 2; and a 'is 1,2 or 3 provided that if m = 0, m' is 2 or 3, and if m is not 0, m 'is 1 or 2;

n is 0 - U

And the salts thereof, especially salts with pharmaceutically suitable acids or bases.

The alkyl groups at alkyl itself, aralkyl, alkoxy, aminoalkyl, thioalkyl, haloalkyl and hydroxyalkyl preferably have 1-6 carbon atoms and can be straight or branched.

The alkenyl and alkynyl groups have 2-6 carbon atoms and can be straight or branched.

The alkyl, alkenyl and alkynyl groups may further substituent and carry such as hydroxyl, alkoxy, halogen, amino, alkylamino, mer-capto and alkyl mercapto.

The cycloalkyl groups have 3-7 carbon atoms. Such 8201066-2-1 cycloalkyl groups also include cycloalkylalkyl groups, and the cycloalkyl groups may further carry substituents such as alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, amino, aminoalkyl, alkyl-amino, trifluoromethyl and nitro.

The aryl groups can have 6-10 carbon atoms and include phenyl as well as ai and / - naphthyl. The aryl groups may also contain substituents such as alkyl, hydroxyl, alkoxy, hydroxyalkyl, mercapto, alkyl mercapto, mercaptoalkyl, halogen, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, trifluoromethyl, ureido and guanidino. The fused aryl cycloalkyl groups include phenyl rings fused with cycloalkyl rings of 3-7 carbon atoms. These groups also include fused aryl cycloalkyl alkyl.

The hetero rings may be saturated, partially unsaturated or unsaturated and include such groups as pyridine, piperidine, morpholine, pyrrole, pyrrolidine, thiomorpholine, quinoline, isoquinoline, tetrahydroquinoline, thiazolidine, thiazoline, thiazole, imidazolidine, imidazoline, imidazoline, imidazoline , furyl, tetrahydrofuran and the like. These heterocyclic groups can also contain substituents as described for the aryl groups. The heterocyclic groups can also include heterocyclic alkyl.

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

Preferably, the CQR5 group is attached to a carbon atom in addition to a nitrogen atom of the ring system.

Suitable acid addition salts include inorganic salts such as hydrochlorides, phosphates and sulfates; but also organic carboxylates, such as acetates, malates, maleates, fumarates, succinates, citrates, lactates, benzoates, hydroxybenzoates, amino benzoates, nicotinates and the like, as well as salts of organic sulfonic and phosphonic acids such as toluenesulfonic acid.

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

The subject compounds may contain one or more asymmetric carbon atoms in which case the various racemic mixtures 35 as well as the individual optically active compounds are included in the invention.

The present compounds can be prepared by an amide-forming reaction of an amine compound of the formula II with an acylating derivative of a 2 hour of the formula III.

Also, the compounds wherein R 8 and R 8 are hydrogen can be readily prepared by treating a compound of formula 2 with a compound of formula k under amide-forming conditions to form a compound of formula 5; cleavage of the carbobenzyloxy group then yields a free amine of the formula 6 and a reaction of this amine with a cc-keto acid or ester of the formula 7 and reduction of the obtained imine leads to a compound of the formula 1, in which Rg and R ^ propose hydrogen *

Compounds of the formula 6 can also be reacted with an α-β-haloacid or ester of the formula 8 into compounds of the formula 1, wherein Rg and R1 are hydrogen or one of the other substituents described at Rg and R1 introduce.

In the above reactions, R 1 - Rg, m, m 'and n have the meanings indicated above while Hal represents halogen.

Preferably R 1, R 8, R 1, R 1, and R 1 and R 1 are all hydrogen.

Rg is alkyl or phenylalkyl, Rg is preferably alkyl.

The amide-forming conditions include the use of known derivatives of the said acids, such as the acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyl dimidazoles and the like. The reactions are carried out in organic solvents such as acetonitrile, tetrahydrofuran, dioxane, acetic acid, methylene chloride, ethylene chloride and corresponding solvents. The amide-forming reaction takes place at room temperature or at an elevated temperature. The use of elevated temperatures improves the course and allows shorter reaction times.

Temperatures between 0 ° C and the boiling temperature of the reaction system are preferably used. Also, for a better progress, the amide-forming reaction can be carried out in the presence of a base, such as a tertiary organic amine, e.g. trimethylamine, pyridine, picoline and the like, especially when a hydrogen halide is formed during the amide-forming reaction, e.g. when using an 8201066 • £ - I; - acid halide and an amino compound. Of course, any conventional hydrogen halide acceptor can also be used in the reactions in which hydrogen balides are formed.

At the condensation of a cc. -haloic acid derivative of the formula 8, corresponding reaction conditions, solvents and hydrogen halide acceptors can be used as in the amide formation.

Various substituents on the present new compounds, e.g. as defined for Rg, may be present in the starting compounds or introduced after the formation of the amide products according to known substitution or conversion reactions. For example, the nitro group can be introduced into a final product by nitriding the aromatic ring, after which, if desired, this nitro group can be converted into other groups, e.g. by reduction in amino or by diazotizing the amino group and replacing the iaziaz group in halogen. Other reactions can be carried out with the amide product formed. Amino groups can be alkylated to mono- and dialkylamino groups, mercapto and hydroxyl groups can be alkylated to corresponding ethers. For example, substitution or change reactions can be used to form a series of substituents across the entire molecule of the final products. Obviously, any reactive groups present during these types of reactions must be temporarily protected by appropriate protecting groups, especially in condensation reactions to form the amide bonds.

The salts with acids and bases of the new compounds can be formed according to standard methods. Often these are already formed in situ during the preparation of the present amido amino acids.

The present compounds can, as is evident, occur in steroomeric forms, and the products thus obtained may be mixtures of isomers which can still be cleaved. Also, the preferred stereoisomers can be prepared by a selection of specific starting isomers. To this end, preferred terms where each asymmetric center (chiral center) has the S configuration were preferably prepared by a stereospecific route, rather than by attempting to cleave a mixture of isomers. The compounds 35 where an S configuration exists at all asymmetric centers are 8201066-5dr v the most active; which is in a K-configuration. occur are less active; and which are present as many R and S configurations have an intermediate activity.

The invention is further illustrated by the following examples.

Example I

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

To a suspension of 10.0 g (3 3.9 mmol) of L-1,2,3, ij-tetrahydro-10 isoquinoline-3-carboxylic acid methyl ester hydrochloride and 10, h g (6,6mmol)

O

carbobenzyloxy-L-alanine in 150 cur vessel-free acetonitrile added h, k g (3,6 3.6 mmol) triethylamine. A solution of 9.2 g {kb, 6

O

mmol) Ν, Ν-dicyclohexylcarbodiimide in 5 cm vessel-free acetonitrile, then added dropwise with stirring. The resulting suspension was stirred overnight at room temperature, filtered and concentrated in vacuo. The residue was redissolved in ether again, successively washed with 1 N hydrochloric acid, saturated NaHCO 2 solution and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated to 18.3 g (105%) of crude amide. used without further purification.

B. 2- (N-benzyloxycarbonyl-B-alanyl) -L-1,2,3, k-1-tetrahydric osinoquinoline-3-carboxylic acid.

8.0 g of the crude amide ester from A are dissolved in 3 ml of 3 N 1 NaOH / MeOH, to which an additional 5 cm more is added. The resulting solution was stirred overnight at room temperature, then poured 150 ml more and extracted with ether. The water layer was then acidified and extracted with CH 2 Clg. The extracts obtained were dried with magnesium sulfate and concentrated under reduced pressure to 5 g of product. After concentrating for a long time under an oil pump vacuum, a brittle foam was obtained.

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

To a solution of 4.3 g (12.5 mmol) of impure carbobenzyl-3 3. ...

oxycarboxylic acid in T cm acetic acid added 5 cm saturated HBr m acetic acid 35. This solution was stirred at room temperature until 8201066 + + - 6 gas no longer evolved (1 - 1 hour). A weak stream of air was then passed through the solution to remove excess HBr, then 25 cm. Of ether was added and the product precipitated therewith. The precipitate was washed with two further portions of ether, then dried in vacuo to 2.2 g of a pale yellow solid product, mp 180 ° C.

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

0.307 g (0.93 mmol) of alanyl-1,2,3,4-tetrahydroisoquinoline-3- was added to a solution of 1.3 g (6.63 mmol) of benzylpyruvic acid 10 hydrate in 5 cm saturated NaHCO 2 solution. carboxylic acid, followed by 0.238 g (3.79 mmol) of sodium cyanoborohydride. The solution was stirred at room temperature overnight, then transferred to a column with 20 g of Dowex 50X8. This column was eluted with 50% MeOH 15 and then with 3% ammonia. The first ammonia fractions with the desired product were combined and lyophilized to 85 mg of product in the form of a fluffy white powder, mp 97-101 ° C.

Example II

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

To a suspension of 4.4 g (19.3 mmol) of L-1,2,3,4-tetrahydro-3. . Isoquinoline-3-carboxylic acid methyl ester hydrochloride with 50 cm anhydrous acetonitrile were 5.2 g (20.7 mmol) N-carbobenzyloxy-N-valine, 2.7 g, (20.0 mmol) 1-hydroxybenzotriazole and 2.1 g ( 20.7 mmol) triethylamine 25. The resulting mixture was stirred at room temperature and a solution of 4.5 g (21.8 mmol) of dicyclohexylcarbodiimide in 10 3. . . .

cnr anhydrous acetonitrile added slowly. This mixture was stirred at room temperature overnight, then filtered and worked up as described in Example 1A. A final concentration of liver-the 8.3 g (101%) of a thick oil.

B. 2- (U-carbobenzylcxy-L-vinyl) -L-1,2,3,4-tetrahydrocosoquinoline-3-carboxylic acid.

4.5 g (106 mmol) of the crude methyl ester obtained according to

O

A, was treated with 10 cm 10% caustic soda and sufficient methanol

O

35 (35-40 cnr) to obtain a homogeneous solution. This solution 8201066 ♦ - 7 - •. 3 was stirred at room temperature for 23 hours, then diluted with 100 cm 3 of water and extracted with two 25 cm portions of ether. The water layer 3 was then acidified and extracted with 10 cm of methylene chloride four times. These extracts were dried with magnesium sulfate and concentrated to 3.8 g (9.3 mmol; 87%) of homogeneous carboxylic acid.

Example III

A. 2- (M-carbobenzyloxy-L-isoleucyl) -L-1,2,3,4-tetrahydroisoehinoline-3-carboxylic acid.

4.5 g (19.8 mmol) of L-1,2,3,4-tetrahydroisoquinoline-3-carbonone-10 acid methyl ester hydrochloride. 5.3 g (20.0 mmol) N-carbobenzyloxy-L-isoleucine, 2.7 g (20.0 mmol) 1-hydroxybenztriazole and 2.1 g (20.7 mmol) triethylamine were treated as described in Example II A with 4.4 g (21.3 mmol) of dicyclohexylearbodiimide; it was then worked up to 7.8 g (90%) of the crude methyl ester. This was dissolved in 30 cm 3 of methanol and treated with 10 cm 10 of sodium hydroxide solution. The resulting solution was stirred at room temperature overnight, then worked up as described previously to 1.8 g (21.4% total) of. the desired acid in the form of a yellow oil.

Example IV

2- / ~ N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl J-isochinaldic acid.

An ethanol solution of benzyl-2- (H-carbobenzoxy-L-anylyl) isochinaldate was hydrogenated with carbon on palladium. The solution was filtered and treated with ethyl 2-oxo-4-phenylbutyric acid, alkali and sodium cyanoborohydride as described in Example ID. The product obtained was purified by chromatography and lyophilization.

Example V

2-H- (1-carboxyethyl) -L-alanyl isochinaldine acid.

An ethanol solution of benzyl 2- (H-carbobenzoxy-L-alanyl) -30 isochinaldate and pyruvic acid was hydrogenated with palladium on carbon. The filtered solution was concentrated and purified as described in Example ID.

Example VI

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

A methylene chloride solution of β-carbobenzyloxy-L-alanine 8201066-8 and 2-benzyloxycarbonyl indoline was treated with TT, H'-dicyclohexylcarbodiimide. Purification of the product was performed by chromatography on silica gel.

B. 1-CTT- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl-7-2-arboxy-5 indoline.

An ethanol solution of 1- (N-carbobenzyloxy-L-alanyl) -2-benzyloxyearbonyl-indoline was hydrogenated with palladium on carbon. To the filtered solution was added ethyl 2-oxo-phenylbutyric acid, alkali and sodium cyanoborohydride as in Example ID. The product 10 was purified by chromatography and lyophilization.

Example VII 1- / TN- (1-carboxyethyl) -L-alanyl J7-2-carboxyindoline.

An ethanol solution of 1- (H-carbobenzyloxy-L-alanyl) -2-benzyl-oxycarbonyl-indoline was hydrogenated with palladium on carbon. Pyruvic acid ethyl ester, alkali and sodium cyanoborohydride were added to the filtered solution. The product was purified by chromatography and lyophilization.

Example VIII

1-benzyloxycarbony1-2- (N-carbobenzyloxy-L-alanine) -5H-1,2,3, k-tetra-2Q; hydro-2-benzazepine.

A methylene chloride solution of TT-carbobenzyloxy-L-alanine and 1-benzyloxycarbonyl-5H-1,2,3, k-tetrahydro-2-benzazepine was treated with Η, Ν'-dicyclohexylcarbodiimide according to Example III A. Purification of the final product was carried out by silica gel chromatography.

Example IX

1-carboxy-2-i- (1-carboxy-3-phenylpropyl) -L-alanyl-5H-1,2,3,1-tetrahydro-2-benzazepine.

An ethanol solution of 1-benzyloxycarbony1-2- (N-carbobenzyl-30-oxy-L-alanyl) -5H-1,2,3, tetrahydro-2-benzazepine was added with palladium

hydrogenated on carbon. After filtration, the solution was treated with alkali, sodium cyanoborohydride and 2-oxo-L-phenylbutyric acid as described in Example 1D. The product was purified by chromatography. Example X.

35 l-carboxy-2 - {_ H- (1-carboxy-3-methylbutyl) -L-alanyl J7-5H-1,2,3,1-tetra-8201066 r.

- 9 - hydro-2-benzazepine.

An ethanol solution of 1-benzyloxycarbony1-2- (N-carbobenzyl-oxy-alanyl) -5H-1,2,3,2-tetrahydro-2-benzazepine was generated with palladium, carbonated. After filtration, the solution was treated with 2-5 oxo-U-methylpentanoic acid, sodium cyanoborohydride and alkali as described in Example 1 D. Chromatography and lyophilization gave the pure final product.

Example XI

2 - (N - (1-carboethoxy-3-phenylpropyl) -L-alanyl) -6,7-methylenedioxy-10 1,2,3, + - et rahy dr o? Oquinoline-3-carboxylic acid.

Analogous Example IA was coupled with 6,7-methylenedioxy-1,2,3 Wt etrahydroisoquinoline-3-carboxylic acid methyl ester with carbobenzyloxy-L-alanine using dicyclohexylcarbodiimide in acetonitrile. The crude neutral product was then hydrolyzed with 2 equivalents of caustic soda in 2.0% methanol to yield the desired carboxylic acid.

This carbobenzyloxy dipeptide was screened analogously to Example I C at an initial reaction temperature of 0 ° G. 0.675 g (11.8 mmol) of this dipeptide was added to a solution

O

Dissolve 1.7 g (7.13 mmol) of ethyl 2-oxo-U-phenylbutyrate in 2 cm of ethanol. The pH was adjusted to 6.8 with ethanolic caustic soda and 0.35 g (5.57 mmol) of sodium cyanoborohydride was added. After stirring for 2 hours at room temperature, a further 0.70 g of ester and 0.2 g of NaBH 2 CN were added and stirring was continued for another 8 hours. The reaction mixture was then transferred to a column of Dowex 50X8 and this column eluted with 50% ethanol, H 2 O, 1% NH 2 OH and 3% NH 2 OH. Fractions of the desired product were combined and lyophilized to 0.3 ^ 7 g of the diastereomeric mixture.

Example XII

2- (N- (1-carboethoxy-1- (2-indanyl) methyl) -L-alanyl) -6-chloro-1,2,3,3-tetrahydroisquinoline-3-carboxylic acid.

Likewise, the appropriate dipeptide was prepared from 6-chloro-1,2,3-tetrahydroisoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-alanine by coupling via DCC followed by saponification and cleavage with HBr / acetic acid.

8201066 - 10 - •. v

The said dipeptide (0.27 g, 1.17 nmol) was alkylated as described above with 1.5 g (6.87 mmol) of ethyl c-oxydane-2-acetate and 0.32 g (5, 09 mmol) NaBH 2 CN "at pH 6.75. After 2 h, a second portion of 0.85 g of ketoester and 0.2 g of NaBH 2 CN was added. The mixture was then stirred for another 40 hours. Ion exchange chromatography then yielded 0.183 g desired product.

Example XIII

2- (N- (1-carboethoxy-3- (2-pyridyl) propyl) -L-valyl) -6-methoxy-1,2,3, b-tetrahydroisoquinoline-3-carboxylic acid.

The starting dipeptide was prepared as shown above from 6-methoxy-1,2,3,2-tetrahydrolsoquinoline -j-carboxylic acid methyl ester and carbobenzyloxy-L-valine using hydroxybenzothiazole and DCC, followed by saponification and deblocking as before displayed. The resulting dipeptide salt was then reductively alkylated with ethyl 2-oxo-U- (2-pyridyl) butyrate in the presence of sodium cyanoborohydride under standard conditions. The crude monoester obtained was purified by ion exchange chromatography and lyophilization as before to give a mixture of diastereomers of the desired product.

Example XIV

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

The starting dipeptide was prepared from carbobenzyloxy-L-iso-leucine and 6,7-dimethoxy-1,2,3,2-tetrahydroisoquinoline-3-carboxylic acid-25-methyl ester using hydroxybenzotriazole and DCC. Saponification and removal of the protecting groups gave the dipeptide hydrobromide.

Treatment with ethyl 2-oxo-U- (2-methoxyphenyl) butyrate and sodium cyanoborohydride under the standard conditions outlined above gave the alkylation product reductively. This was purified as shown above to yield the title compound in the form of a diastereomeric mixture.

Example XV

2- (N- (1-carboethoxy-3 - (^ - chlorophenyl) -L-alanyl) -7-methoxy-1,2,3,3-te-35 trahydro-5H-benz / C? C Jazepine-3 -carboxylic acid.

8201066 é .- - 11 -

Acylation of 132.3.sub.2t.sulfide (10-5H-benz / fc-7azepine-3-carboxylic acid methyl ester with carbobenzyloxy-3-alanine using DCC as coupling agent as in Example 1A) protected dipeptide Saponification and deblocking then yielded the free peptide as previously described.

N-alkylation with ethyl 2-oxo-+ (U-chlorophenyl) butyrate and sodium cyanoborohydride as in Example XII gave a mixture containing the desired product. This was isolated by ion exchange chromatography and lyophilization as previously described.

Example XVI

2- (N- (1-carboethoxy-3- (U-pyridyl) propyl) -L-alanyl) -1,2,3-, h-t etrahydro-5H-benzyl-jacepin-3-carboxylic acid.

The starting dipeptide was prepared from carbobenzyloxy-L-alanine and 1,2,3,1-etrahydro-5H-benzyl-azazepine-3-carboxylic acid methyl ester 15 according to the general procedure of Example 1. Reductive alkylation as previously described using ethyl 2-oxo - (- (pyridyl) butyrate and sodium cyanoborohydride gave the crude U-alkylated peptide. Purification by ion-exchange chromatography and lyophilization gave the pure title compound as a mixture of diastereomers.

Example XVII

2- (N-1- (carbonethoxy-3- (3-trifluoromethylphenyl) propyl-L-valyl) -7,8-methylenedioxy-1,2,3-tetrahydro-5H-benz 12c Jazepine-3-carboxylic acid.

Acylation of 7,8-methylenedioxy-1,2,3-tetrahydro-5H-benz-2 C 7azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-valine using hydroxybenztriazole and DCC according to Example II A provided the protected dipeptide. This was then saponified and treated with HBr / acetic acid to give the desired dipeptide. Treatment of this dipeptide with 2-oxo-i + - (3-trifluoromethylphenyl) butyrate and sodium cyanoborohydride at pH 6.55 according to Example XII gave the N-alkylated product.

Ion exchange chromatography and lyophilization provided the pure compound in the form of a diastereomeric mixture.

8201066 - «- 12 -

Example XVIII

Stereospecific synthesis of the S-configuration compounds was accomplished as follows: A. 2- (N- (1-carboethoxy-3-phenylpropyl) alanyl) -1,2,3,3-tetrahydroisoquinoline-3-carboxylic acid benzyl ester .

To a suspension of 2.60 g (9.31 mmol) (S, S) -W- (1-carboetho-

O

xy-3-phenylpropyl) alanine in 20 cnr anhydrous THF, 1.51 g (9.3 nmol) Ι, Ι'-earbonyldimidazole was added. When a clear solution was obtained (5-10 minutes), the reaction mixture was cooled to 0 ° C and 3.12 g (7.0 µmmol) (S) -1,2,3, H-tetrahydrolosoquinoline-3-carboxylic acid - benzyl ester monotartrate added. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and redissolved in ether. The resulting ether solution was washed with a saturated NaHCO 2 solution and water and concentrated to 2.2 g (56%) of the desired amide, which was used without further purification. CIMS: 529 (n = 1), 23b, 91 MR: 7.3, 5.1, 3.15, 2.8, 1.2-1.5.

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

20 To a solution of 2.10 g (3.97 mmol) (S, S, S) -2- (N- (1-carbonethoxy-3-phenylpropyl) alanyl) -1,2,3,2- tetrahydroisoquinoline-3-carbon-

O

acid benzyl ester in 20 cm3 of ethanol, 0.2 g of 10% Pd / C catalyst was added. The mixture was shaken under ca 2 at hydrogen until no more hydrogen was taken up. The reaction mixture was then filtered and concentrated in vacuo and partitioned between ether and 2N hydrochloric acid. The aqueous solution was lyophilized and the resulting powder washed with ether to produce 0.70 g (31%) of product, mp 101-105 ° C.

Jd -10.9 ° (H20) 30 CIMS 1 * 21 (M + 1-H20) EIMS b21,316,270 calculated for C ^ H ^ HgO ^ HCl.HgO: C 60.91, H 6jb, H 5.13 $; found: C 6.16, H 6.1 + 7, H 5, b8%.

Analogously to the previous examples, the following further 8201066 - 13 - * i compounds were still prepared: 2-fN-1-ethoxycarbonyl-3-methylbutyl) -L-alanyl J-isochinaldic acid 2-C Nl-ethoxycarbonyl-iMethylhexyl) -L- alanyl J-isochinaldic acid 2-C Nl-ethoxycarbonyl-5-methylhexyl) -L-alanyl J-isochinaldic acid 5 2-C Nl, 3-dicarboxypropyl) -IL-alanyl J-isochinaldic acid 2-C Nl-ethoxycarbonyl-3-phenylpropyl) -L-alanylJ-6-hydroxyis ohalinaldic acid 2 -C Nl-ethoxycarbonyl-5-methylhexyl) -L-valyl Jr-isochinaldinic acid 2-CN-1s 3-dicarboxypropyl) -L-alanyl J-6-methoxy-isochinaldic acid 10 2- / * N-ethoxycarbonylhexyl-L-valyl-7-8-with hyl-isochinaldic acid 2-C N-ethoxycarbonyl-3-phenylpropyl) -L-phenylalanyl J-6-chloroisochinaldinic acid 2-C Hl -ethoxycarbonyl-3-phenylpropyl) -L-histidyl J-8-hydroxyisochinaldinoic acid 15 ll I- (1-ethoxycarbonyl-3-methylbutyl) -L-alanylJ-2-carboxyindoline 1-CN- (1-ethoxycarbonyl-3- phenylpropyl) -L-phenylalany1 J-2-carboxyindo-line 1-C ΓΤ- (1-ethoxycarbonylhexyl) -L-alanyl J-2-carboxyindoline 1-C N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl J-2-carboxy-5, 6-dime-20 thylindoline 1-C N- (1-ethoxycarbonyl-3-phenylpropyl) ) -L-valyl J-2-carboxyindoline 1-C (1,3-dicarboxypropyl) -L-alanylJ-2-carboxy-5,6-dimethylindoline 1-JN- (1,3-dicarboxypropyl) -L-histidyl J -2-carboxy - ^ - chlorindoline 1-CN- (1-ethoxycarbonylhexyl) -L-valylJ-2-carboxy-U-methoxyindoline 25 1-CN- (1-ethoxycarbonylheptyl) -L-phenylalanylJ-2-carboxy-6- methyl indoline 1-CH- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl J-2-carboxy-3-hydroxy-methyl-5,6-dimethylindoline 1-carboxy-2-CN- (1-ethoxycarbonyl -3-phenylpropyl) -L-valylJ-5H-1,2,3, h-30 tetrahydro-2-benzazepine 1-carboxy-2-CN- (1-ethoxycarbonyl-3-methylbutyl-L-histidylJ-5H- 1.2 .3, -tetrahydro-2-benzazepine-1-carboxy-2-CN- (1-ethoxycarbonyl-1-methylpentyl) -L-phenylalanyl J-5I-1,2,3, tetrahydro-2-benzazepine-35-carboxy-2 -L N- (1,3-dicarboxypropyl) -L-alanyl J-7,8-dimethyl-5H- 8201066 \-1¾ - 1.2.3,--tetrahydro-2-benzazepine l-carboxy-2- / N- (1-ethoxycarb onyl-3-i'enylpropyl) isoleucyl 7-6-chloro-1.2.3, k-tetrahydro-2-benzazepine 1-carboxy-2-7 N- (1-ethoxycarbonylhexyl) -L-valyl-1-methoxy -T-methyl-5 1,2,3, U-tetrahydro-2-benzazepine 1-carboxy-2-7 N- (1-ethoxycarbonyl-3-phenylpropyl) -L-hi idyl 7-6-chloro-1.2 .3, Wtetrahydro-2-benzazepine 1-carboxy-2-ΖΓ N- (1-carboxy-2-phenylthioethyl) -L-alanyl-7-7-methyl-5H-1.2.3, ii-tetrah.ydro-2- benzazepine 10 l-carboxy-2-ΖΓN- (1-ethoxycarbonyl-3-p-chlorophenylpropyl) -L-valyl J-T, 8-dimethyl-5H-1,2,3, k-tetrahydro-2-benzazepine 1- carboxy-2- / TI- (l-carboxy-2- (3-indolyl) ethyl J-L-r & lyl 7-5H-1,2,3,1-tetrahydro-2-benzazepine 2- (N- (l-carboethoxy) -3- (U-chlorophenyl) propyl) -L-leucyl) -1,2,3,2- tetra-hydroisoquinoline-3-carboxylic acid 2- (N1- (1-carboethoxy-3- (3-trifluoromethylphenyl) propyl) -L-valyl) -1,2,3,3-tetrahydroisoquinoline-3-carboxylic acid 2- (N- (1- (1-carboethoxy-2- (3-methoxyphenyl) ethyl) -L-methionyl) - 1,2,3, U-tetrahydroisoquinoline-3-carboxylic acid 20 2- (Nl- (1-carboethoxy-3 - (^ - pyridyl) propyl) -L-alanyl) -1,2, 3 Λ-tetrahydroisoquinoline-3-carboxylic acid 2- (N1- (1-carboethoxy-3- (U-methoxyphenyl) propyl) -L-lysyl) -1,2,3 U-tetrahydroquinoline-3-carbonzTiur 2- (N1- (1-carbon-ethoxy-3- (3-pyridyl) propyl) -L-leucyl) -1,2,3, U-tetrahydro-driesoquinoline-3-carbonic acid 2- (N- ( 1-carboethoxy-2- (2-thienyl) ethyl) -L-arginyl) -1,2,3, H-tetrahydroisoquinoline-3-carboxylic acid 2- (N- (1-carboethoxy-3- (methylthio) propyl) ) -L-isoleucyl) -1,2,3, U-tetrahydroisoquinoline-3-carboxylic acid 2- (N1- (1-carboethoxy-3- (3-thienyl) propyl) -L-valyl) -1 , 2,3, U-tetrahydroisoquinoline-3-carboxylic acid 2- (N- (1-carboethoxy-2-phenylethyl) -L-lysyl) -1,2,3, U-tetrahydroisoquinoline-3-carboxylic acid 2 - (N1- (1-carboethoxy-2- (phenoxy) ethyl) -L-lysyl) -1,2,3, k-tetrahydroiso-35 quinoline-3-carboxylic acid 8201066-15- 2- (IT-1- ( 1-carboethoxy-3- (2-phryl) propyl) -L-valyl) -1,2,3,1-tetrahydroisoquinoline-3-carboxylic acid 2- (1-1- (1-carboethoxy-3- (3 , 1-methylenedioxy-: phenyl) propyl) -L-alanyl) - 1,2,3,1-t-etrahydroxosoquinoline-3-carboxylic acid 5 2- (TT-1- (1-carboethoxy-3) - (3-chlorophenyl) propyl) -L-phenylalanyl) -1,2,3,1-tetrahydroxosoquinoline-3-carboxylic acid 2- (Nl- (1-carboethoxy-3- (2-methoxyphenyl) propyl) -L-tyrosyl ) -1,2,3,1-tetrahydroxyquinoline-3-carboxylic acid 2- (Nl- (1-carboethoxy-2- (benzofuran-3-yl) ethyl) -L-leucyl) -1,2,3,1- 10-tetrahydroxyquinoline-3-carboxylic acid 2- (1-1- (1-carboethoxy-3- (1-methoxyphenyl) propyl) -L-alanyl) -6-chloro-1.2.3.1-tetrahydroxyquinoline-3-carboxylic acid 2- (Nl - (1-carboethoxy-3- (phenoxy) propyl) -L-arginyl) -6,7-methylenedioxy- 1.2.3.1-tetrahydroxyquinoline-3-carboxylic acid 15 2- (N- (1-carboethoxy-2- (indole) -3-yl) ethyl) -L-leucyl) -6-methoxy-1,2,3,1-tetrahydroxsodiololine-3-carboxylic acid.

2- (1-1- (1-carboethoxy-3- (1-methoxyphenyl) propyl) -L1 eucy 1) - 5H-1,2,3,1-tetrahydrobenz2C-Jazepine-3-carboxylic acid 2- (Nl - (1-carboethoxy-3- (3-pyridyl) propyl) -L-methionyl) -5H-1,2,3,1-20 tetrahydrobenzZ, c / azepine-3-carboxylic acid 2- (ΪΓ — 1— ( 1-carboethoxy-3- (methylthio) propyl) -L-leucyl) -5H-1,2,3,1-tetrahydrobenz / Γc-7acepine-3-carboxylic acid 2- (TT-1— (1-carboethoxy -2- (1-imidazolyl) ethyl) -L-valyl) -7-methoxy-5H- 1.2.3.1-tetrahydrobenz ƒ "c j7azepine-3-carboxylic acid 25 2- (N- (1-carboethoxy-3- (3 -methoxyphenyl) propyl) -L-lysyl) -6,7-methylenedioxy-5H-1,2,3,1-tetrahydrobenzazazepine-3-carboxylic acid 2- (IT-1- (1-carboethoxy- 3- (3-chlorophenyl) propyl) -L-histidyl) -5H-1,2,3,1-tetrahydrobenz Cc 7azepine-3-carboxylic acid 2- (TT-1— (1-carboethoxy-3- (3-thienyl) ) propyl) -L-ar ginyl) -7 -with hoxy- 5H-30 1,2,3,1-tetrahydrobenz [Jazepxne-3-carboxylic acid 2- (TT-1 - (1-carboethoxy-2-phenylethyl) -L-tyro syl) -7-chloro-5H-1,2,3,1-tetrahydrobenzyl Jazepine-3-carboxylic acid TT- (1-carboxy-2-xndanyimethyl) -alanyl-1,2,3, 1-tetrahydro xsoquinoline-3-carboxylic acid.

The present compounds have a strong activity (in 8201066 -lde order of 0.02-0.20 mmol) in inhibiting angiotensin converting enzyme (ACEI activity) in a study according to the method described in Science 196, UUl— h- (197T) · The present compounds were also found to have one of about 1-2 mg / kg orally when inhibiting infused angiotensin I in rats. As such, the present compounds are thus particularly useful in the treatment of hypertension.

The compounds can be administered by the oral or parenteral route to control high blood pressure and those skilled in the art will determine the most appropriate amount thereto. Suitable dosage forms include tablets, capsules, elixirs and injectable preparations.

8201066

Claims (17)

1. Compounds of formula 1 of the formula sheet, wherein R 1 and R 2 hydrogen, alkyl or phenylalkyl, Rg, R ^, R ^, R, - and Rg independently hydrogen, alkyl, alkenyl, alkynyl, aryl, fused arylcycloalkyl, aralkyl , cycloalkyl, a heterocycle, substituted alkyl, alkenyl and alkynyl, the substituent being hydroxyl, alkoxy, halogen, amino, alkyl-amino, mercapto and alkyl mercapto, and substituted cycloalkyl, aryl and heterocyclic groups forming the substituent by alkyl, hydroxyl, alkoxy, hydroxyalkyl, halogen, mercapto, alkylmer-capto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy and trifluoromethyl; any group of Rg alkyl, alkenyl, alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, mercapto, alkyl mercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, methylenedioxy or trifluorom; m 0, 1 or 2; m '1, 2 or 3, with the proviso that if m = 0, m' - 2 or 3 and if m is not equal to 0, m '1 or 2; n represent 0, 1, 2, 3 or b and their salts, in particular pharmaceutically suitable salts with an acid or a base. 2. A compound of the formula 9, wherein R 1, R 2 and n have the meanings indicated above, as well as the salts thereof, in particular the pharmaceutically suitable salts with an acid or a base. A compound according to claim 1 or 2, characterized in that the COORy substituent is attached to a carbon atom directly next to the ring nitrogen atom. h. Compound according to claims 1-3, characterized in that R1. 30 is hydrogen. Compound according to claims 1 - 1, characterized in that R is ethyl or hydrogen. 8201066 - 18 - 6. Compound according to claims 1-5 »characterized in that Rg is phenylalkyl. Compound according to claim 6, characterized in that Rg is phenyl. 8, A compound according to claims 1 to 7, characterized in that Rg is methyl. Compound according to claims 1-7, characterized in that Rg is isopropyl. 10. A compound according to claims 1-7, characterized in that Rg 10 is isobutyl. Compound according to claims 1 - characterized in that Rg is phenethyl and Rg is methyl. 12. Pharmaceutical preparation for the treatment of hypertension, characterized in that it contains an antihypertensive effective amount of a compound according to any one of claims 1-11. 13. A process for preparing a compound of the formula I, characterized in that a compound of the formula 2 is reacted with an acylating derivative of an acid of the formula 3 or the formula k under amide-forming conditions; or reacting a compound of the formula 6 with an o <-ketoic acid or ester of the formula 7 »and reducing the resulting imine; or reacting a compound of the formula VI with a -haloic acid or ester of the formula VIII and, if desired, introducing various substituents into the obtained substances by substitution or conversion reactions and, if desired, forming the salts thereof, in particular the pharmaceutically suitable salts with acids or bases. 1 ^. Process according to claim 13, characterized in that the COOR 1 substituent is attached to a carbon atom directly next to the ring nitrogen atom. 15. A method according to claims 13-1, wherein R 1 is hydrogen. 16, Process according to claims 13-15, characterized in that R 1 is ethyl or hydrogen. Process according to claims 13 - 16, characterized in that Rg is phenylalkyl. 18. Process according to claim 17, characterized in that Rg is phenylene-35. 8201066 - 19 - 19. Process according to claims 13-18, characterized in that R 6 is methyl. 20. Process according to claims 13-18, characterized in that R 2 is isopropyl. 21. Process according to claims 13-18, characterized in that Rg is isohutyl. Process according to claims 13-17, characterized in that R2 is phenethyl and Rg is methyl. 8201066