FR2502149A1 - NOVEL AMINO AMINO ACIDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND PROCESS FOR THE PREPARATION OF SAID AMINO AMINO ACIDS - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF THE FORMULA: (CF DRAWING IN BOPI) THESE COMPOUNDS ARE SUITABLE FOR THE TREATMENT OF HYPERTENSION.

Description

- 1 - New amido-amino acids, pharmaceutical compositions

  container and process for preparing these amido amino acids.

  The invention relates to novel compounds having valuable pharmacological activity. In particular, it relates to compounds having antihypertensive activity and angiotensin converting enzyme inhibitory activity and responding to the COOR7 structure.

QPP (R8)

R1OOC N (CH2) m 1 2m 1

3 R4 R6 (I)

  in which R and R7 each represents a hydrogen atom, a lower alkyl group or a phenyl-lower alkyl group, R2, R3, R4, R5 and R6 each represent a hydrogen atom, an alkyl, alkenyl, alkynyl or aryl group; , aryl-fused cycloalkyl, aralkyl, cycloalkyl or heterocyclic and may be the same or different, each of R8 is alkyl, alkenyl, alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxyl,

  alkoxyl, mercapto, alkylmercapto, hydroxyalkyl, mercapto

  alkyl, a halogen atom, a haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamide, methylenedioxy or trifluoromethyl group, the R8 groups may be the same or different when there is more than one, m is an integer of O at 2 and m 'an integer from 1 to 3, with the proviso that when m is 0, m' is 2 or 3 and when m is other than 0, m 'is 1 or 2, - 2 -

n is an integer from 0 to 4.

  The invention also relates to the salts of these compounds, especially the salts formed with acids and bases

pharmaceutically acceptable.

  The alkyl groups present as such or included in aralkyl, alkoxyl, aminoalkyl, thioalkyl, haloalkyl and hydroxyalkyl groups are preferably lower alkyl groups containing 1 to 6 carbon atoms.

  and may be branched or straight chain.

  The alkenyl and alkynyl groups contain 2 to 6 carbon atoms and may be branched or straight chained. The alkyl, alkenyl and alkynyl groups may carry substituents such as hydroxyl, alkoxyl, halogen, amino, alkylamino,

mercapto and alkylmercapto.

  The cycloalkyl groups contain 3 to 7 carbon atoms. They include cycloalkyl-alkyl groups and cycloalkyl groups may carry substituents such as alkyl groups, halogens, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, amine,

  aminoalkyl, alkylamine, trifluoromethyl and nitro.

  The aryl groups may contain from 6 to 10 carbon atoms and include phenyl groups and naphthyl and β-naphthyl groups The aryl groups may contain substituents such as alkyl, hydroxyl, alkoxyl, hydroxyalkyl, mercapto, alkylmercapto, mercaptoalkyl, halogens, haloalkyl, amino, alkylamino, aminoalkyl, nitro,

  methylenedioxy, trifluoromethyl, ureido and guanidino.

  The fused aryl-cycloalkyl groups include phenyl rings fused with cycloalkyl rings containing from 3 to 7 carbon atoms.

  also fused aryl-cycloalkylalkyl groups.

  The heterocyclic group may be saturated, partially saturated or unsaturated and includes groups such as pyridine, piperidine, morpholine, pyrrole, pyrrolidine, thiomorpholine, quinoline, isoquinoline, tetrahydroquinoline, thiazolidine, thiazoline, thiazole, imidazolidine, imidazoline, imidazole, thiophene,

  tetrahydrothiophene, furyl, tetrahydrofuran and the like.

  These heterocyclic groups may also carry substituents, such as those indicated for the aryl groups above. The heterocyclic group comprises

  also heterocyclic-lower alkyl groups.

  Halogens include fluorine, chlorine,

bromine and iodine.

  Preferably, the group -COOR7 is attached to a

  carbon adjacent to the nitrogen of the ring system.

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

toluenesulfonic acid.

  Suitable base salts include alkali and alkaline earth salts such as lithium, sodium, potassium, magnesium and calcium salts, iron salts as well as ammonium and quaternary ammonium salts. It is understood that the compounds of the invention may contain one or more asymmetric carbon atoms and that the various racemic mixtures as well as the optically active individual compounds are considered

  as falling within the scope of the invention.

  The compounds of the invention can be prepared by an amide-forming reaction between an amino compound of the formula - (R) n) and an acylating derivative of the acid of the formula:

1 --- 11 - OH

1 ila I '

R10RC R4 C

R3 R R6 O

  Alternatively, compounds in which R 3 and R 4 are hydrogen can be easily prepared by treating a compound of formula II with a compound of formula

0 R

1a 1 C

0 / "4 COOH (IV)

  R6 under amide-forming conditions to obtain a compound of structure: o It

WE.

  R4 (V) by separating the carbobenzyloxyl group to obtain a free amine of structure: (IIz) (III) -5- COOR7H10 -INc) / (vII) (CH2 1HQ (RB) n

H 0 C -1. 'C (VI)

  ## STR2 ## and reacting the amine with a--keto acid or ester of formula I

R1OOC - C - R2 (VII)

  O and reducing the imine obtained to obtain a compound of formula I in which R3 and R4 are atoms

hydrogen.

  Compounds of formula VII may also be reacted with a halo acid or ester of formula R 1 ROCO-C-Hal (VIII)

1 I

R3

  to obtain compounds of formula I wherein R3 and R4 may be H or any of the substituents

  indicated in the definition of R3 and R4.

  In the sequence of reactions above, R1 to R8, m, m 'and n correspond to the definition given above.

and "Hal" is a halogen.

  Preferably, R 1, R 3, R 4, R 5, R 7 and R are hydrogen atoms, R 2 is a lower alkyl group or

  phenyl-lower alkyl and R6 lower alkyl.

  The amide-forming conditions mentioned herein include the use of known derivatives of the acids described, for example, acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyldiimidazoles and the like. We drive the - 6 -

  reactions in organic solvents such as acetonitrile

  trile, tetrahydrofuran, dioxane, acetic acid, methylene chloride, ethylene chloride and similar solvents. The amide formation reaction occurs at room temperature or elevated temperature. The use of a high temperature is a convenience in that it allows somewhat shorter reaction times. Temperatures ranging from 00C up to the reflux temperature of the reaction system can be used. It is also convenient to carry out the amide formation reaction in the presence of a base such as tertiary organic amines, for example trimethylamine, pyridine, picolines and the like, particularly when a hydrogen halide is formed by the amide formation reaction, for example between an acyl halide and an amine compound. Of course, in these reactions where a hydrogen halide is formed, it is also possible to use all the acceptors

  of hydrogen halide commonly used.

  In the condensation of a "halo acid derivative of formula VIII, reaction conditions, solvents and hydrogen halide acceptors similar to those used for

amide formation.

  Various substituents carried by the novel compounds, for example those of the definition of R8, may be present in the starting compounds or added after amide formation by known methods of substitution or conversion reactions. Thus, the nitro group can be added to the final product by nitrating the aromatic ring and converting the nitro group to other groups such as amino groups by reduction, and halogens by diazotizing the amino group and replacing the diazo group. Other reactions can be applied to the formed amide. Amino groups can be alkylated to form monoalkylamine and dialkylamine groups, mercapto and hydroxyl groups can be alkylated to form corresponding ethers. Thus, substitution or rearrangement reactions can be used to obtain various substituents throughout the molecule of the final products. Of course, the reactive groups, when present, must be protected by appropriate blocking groups during all the aforesaid reactions, particularly the condensation reactions used for

form the amide groups.

  The acid and base salts of the novel compounds according to the invention can be formed using conventional methods. Often they are formed in situ during

  the preparation of the amido-amino acids according to the invention.

  The present compounds obviously exist in stereoisomeric forms and the products obtained can

  therefore be mixtures of isomers that can be split.

  Alternatively, by selecting selected isomers as starting compounds, the preferred stereoisomer can be obtained. Therefore, the preferential forms in which each asymmetric center (center of chirality) has an S configuration instead of attempting the resolution of isomeric mixtures are preferably prepared by the stereospecific route. Compounds in which the S configuration exists at all asymmetric centers are the most active; those in which the R configuration exists have less activity and those where the two R and S configurations exist have an intermediate activity. The invention is further illustrated by the following examples. - 8 -

EXAMPLE 1

  A. 2- (N-benzyloxycarbonyl-L-alanyl) -L-, 12,3,4-tetrahydro-

  Methyl isoquinoline-3-carboxylate to a suspension of 10.0 g (43.9 mmol) of methyl L-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride and 10.4 g (46.6 g. mmol) of carbobenzyloxy-L-alanine in 150 ml of dry acetonitrile, 4.4 g (43.6 mmol) of triethylamine are added. Then add drop by drop,

  stirred, a solution of 9.2 g (44.6 mmol) of N, N-dicyclo

  hexylcarbodiimide in 5 ml of dry acetonitrile. The resulting slurry was stirred overnight at room temperature, filtered and concentrated in vacuo. The residue is redissolved in ether, washed successively with 1 N HCl, saturated NaHCO 3 and brine, dried over MgSO 4, filtered and concentrated to give 18.3 g (105%) of amide. gross than

  it is used without further purification.

  B. 2- (N-Benzyloxycarbonyl-L-alanyl) -L-1,2,3,4-tetra-

  hydroisoquinoline-3-carboxylic acid 8.0 g of the crude amide ester obtained according to A are dissolved in 25 ml of 1N NaOH / CH3OH. 5 ml of water are added. The resulting solution is stirred overnight at room temperature, then poured into 150 ml of water and extracted with ether. The aqueous layer is then acidified and extracted with CH 2 Cl 2. The extracts are dried over MgSO 4 and concentrated under a water pump vacuum to obtain 5.5 g of product. After prolonged concentration under an oil pump vacuum, a fragile foam is obtained.

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

quinoline-3-carboxylic acid

  To a solution of 4.8 g (12.5 mmol) of carbobenzene

  The crude zyloxycarboxylic acid in 7 ml of acetic acid is charged with 5 ml of saturated HBr in acetic acid. The solution is stirred at room temperature until all gas evolution has ceased (1 to 1.5 hours). A slow stream of air is passed through the solution to remove excess HBr and then 25 ml of ether is added to precipitate the product. The solid was washed with two more portions of ether and then dried in vacuo to give 2.2 g of a pale yellow, C-melting solid.

  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 benzyl

  pyruvic acid hydrate in 5 ml of saturated NaHCO3 is added

  0.307 g (0.93 mmol) of alanyl-1,2,3,4-tetrahydro-

  isoquinoline-3-carboxylic acid, followed by 0.238 g (3.79 mmol) of sodium cyanohydroborate. The solution is stirred overnight at room temperature and then transferred to a column containing 20 g of "Dowex 50X8". The column is eluted with 50% CH 3 OH and then with 3% NH 4 OH. The first fractions of ammonia containing the desired product are combined and freeze-dried to obtain 85 mg of product in the form of a white fluffy pointy powder.

melting from 97 to 101 C.

EXAMPLE 2

  A. 2- (N-carbobenzyloxy-L-valyl) -L-1,2,3,4-tetrahydroiso-

  guinoline-3-carboxylic acid methyl ester To a suspension of 4.4 g (19.3 mmol) of methyl L-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride in 50 ml of dry acetonitrile, 5.2 g (20.7 mmol) of Ncarbobenzyloxy-L-valine, 2.7 g (20.0 mmol) of 1-hydroxybenzotriazole and 2.1 g (20.7 mmol) of triethylamine are added. The resulting mixture was stirred at room temperature and a solution of 4.5 g (21.8 mmol) of dicyclohexylcarbodiimide in 10 mg of dry acetonitrile was slowly added. The mixture is stirred overnight at room temperature, then filtered and treated as in Example 1A. The final concentration gives

8.3 g (101%) of a thick oil.

- 10 -

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

  isoquinoline-3-carboxylic acid 4.5 g (106 mmol) of crude methyl ester prepared as above are treated with 10 ml of 10% NaOH and enough methanol (35 to 40 ml) to give a homogeneous solution. This solution is stirred at room temperature for 23 hours, then diluted with 100 ml of water and extracted with two 25 ml portions of ether. The aqueous fraction is then acidified and extracted with 4 portions of 10 ml of methylene chloride. The extracts are dried over MgSO 4 and concentrated to obtain

  3.8 g (9.3 mmol, 87% /) of homogeneous carboxylic acid.

EXAMPLE 3

  A. 2- (N-carbobenzyloxy-L-isoleucyl) -L-1,2,3,4-tetrahydrate

  hydroisoquinoline-3-carboxylic acid As described in Example 2A, 4.5 g

  (19.8 mmol) L-1,2,3,4-tetrahydroisoquinyl hydrochloride

  methyl lein-3-carboxylate, 5.3 g (20.0 mmol) of N-carbobenzyloxy-Lisoleucine, 2.7 g (20.0 mmol) of

  1,1-hydroxybenzotriazole and 2.1 g (20.7 mmol) of triethyl

  amine by 4.4 g (21.3 mmol) dicyclohexylcarbodiimide and then treated to obtain 7.8 g (90%) of crude methyl ester. It is dissolved in 30 ml of methanol and treated with 10 ml of 10% NaOH. The solution is stirred overnight at room temperature and then treated as described above to obtain 1.8 g (overall 21.4%) of the acid.

  desired in the form of a yellow oil.

EXAMPLE 4

  2- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] isoacidic acid

  Quinaldique A solution of benzyl 2- (N-carbobenzoxy-L-alanyl) -isoquinidate in ethanol is hydrogenated with palladium on carbon. The solution is filtered and treated with ethyl 2-oxo-4-phenylbutyrate, alkali and sodium cyanohydroborate as in

- he -

  Example 1D. The product is purified by chromatography

and lyophilization.

EXAMPLE 5

  2-N- (11-Carboxyethyl) -L-alanyl-isoquinaldic acid A solution of benzyl 2- (N-carbobenzoxy-L-alanyl) isoquinaldate and pyruvic acid is hydrogenated with palladium on carbon. We concentrate the solution

  filtered and purified as in Example 1D.

EXAMPLE 6

  A. 1- (N-carbobenzoxy-L-alanyl) -2-benzoxycarbonylindoline N, N'-dicyclohexylcarbodiimide is treated with

  solution of N-carbobenzyloxy-L-alanine and 2-benzyloxy-

  carbonylindoline in methylene chloride. Purify

  the product by chromatography on silica gel.

  B. 1- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyll-2-car-

  boxyindoline is hydrogenated by means of palladium on charcoal

  solution of 1- (N-carbobenzyloxy-L-alanyl) -2-benzyloxycar-

  bonyl-indoline in ethanol. To the filtered solution is added 2-oxo-4-phenylbutyrate ethyl, an alkali and

  sodium cyanohydroborate as in Example 1D.

  The product is purified by chromatography and lyophilization.

EXAMPLE 7

  1- (N- (1-carboxyethyl) -L-alanyl) -2-carboxyindoline A palladium-on-carbon

  solution of 1- (N-carbobenzyloxy-L-alanyl) -2-benzyloxycar-

  bonylindoline in ethanol. To the filtered solution,

  add ethyl pyruvate, alkali and cyanohydride

  sodium borate. The product is purified by chromatography

and lyophilization.

EXAMPLE 8

  l-benzyloxycarbonyl-2- (N-carbobenzyloxy-L-alanine) -5H-1,2,3,4

  tetrahydro-2-benzazepine is treated with N, N'-dicyclohexylcarbodiimide

  solution of N-carbobenzyloxy-L-alanine and 1-benzyloxy-

- 12 -

  carbonyl-5H-1,2,3,4-tetrahydro-2-benzazepine in methylene chloride, as in Example 3Ao Purify

  the final product by chromatography on silica gel.

EXAMPLE 9

  1-Carboxy-2-N- (1-carboxy-3-phenylpropyl) -L-alanyl-5H-1,2,3,4-tetrahydro-2-benzazepine Hydrogen by means of palladium on carbon is

  solution of 1-benzyloxycarbonyl-2- (N-carbobenzyloxy-L-)

  alanyl) -5H-1,2,3,4-tetrahydro-2-benzazepine. The filtered solution is treated with alkali, sodium cyanohydroborate and 2-oxo-4-phenylbutyric acid, as in

  Example 1D. The product is purified by chromatography.

EXAMPLE 10

  1-carboxy-2- [N- (1-carboxy-3-methylbutyl) -L-alanyll -5H-1,2,3,4-

  tetrahydro-2-benzazepine is hydrogenated with palladium on carbon a

  solution of 1-benzyloxycarbonyl-2- (N-carbobenzyloxy-alanyl) -

  H-1,2,3,4-tetrahydro-2-benzazepine. We treat the solution

  filtered by 2-oxo-4-methylpentanoic acid, cyano-

  sodium hydroborate and an alkali as in Example 1D. Chromatography and lyophilization give the

pure product.

EXAMPLE 11

  2- [1- (1- (1-Carbethoxy-3-phenylpropyl) -L-alanyl] -6,7-methyl-2-aminobutyric acid;

  lenedioxy-l, 2,3,4-tetrahydroisoquinolin-3-carboxylic acid

  By the method of Example 1A, the 6,7-methyl

  methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate with carbobenzyloxy-L-analine using dicyclohexylcarbodiimide in acetonitrile. The crude neutral product is then hydrolyzed with two equivalents of NaOH in 80% CH 3 OH to obtain the desired carboxylic acid. The carbobenzyloxy-dipeptide above is deprotected according to the method of Example 1C at an initial reaction temperature of 0 ° C. 0.675 g (1.81 mmol) of this is added.

2 50 2 1 4 9

- 13 -

  dipeptide to a solution of 1.47 g (7.13 mmol) of 2-oxo-4-

  ethyl phenylbutyrate in 25 ml of ethanol. The pH is adjusted to 6.80 with ethanolic NaOH and 0.35 g (5057 mmol) of sodium cyanohydroborate is added. After stirring for 24 hours at room temperature, 0.70 g of ester and 0.2 g of NaBH 3 CN are added again and stirring is continued for a further 48 hours. The mixture is transferred to a column of "Dowex 5OX8" and the

  column with 50% C2H5OH, 1% NH4OH and 3% NH4OH.

  Fractions containing the desired product are pooled and

  lyophilized to obtain 0.347 g of the diastereomeric mixture.

EXAMPLE 12

  2- (N- [1-carbethoxy-1- (2-indanyl) -methyl] -L-alanyl) -6-

  chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Similarly, the appropriate dipeptide is prepared

  starting from 6-chloro-1,2,4-tetrahydroisoquinoline-3-

  methyl carboxylate and carbobenzyloxy-L-alanine by coupling with dicyclohexylcarbodiimide, followed by

  by saponification and cleavage using HBr / CH3COOH.

  0.427 g (1.17 mmol) of the dipeptide was alkylated in the manner described above with 1.5 g (6.87 mmol) of ethyl 2-oxindane-2-acetate and 0.32 g (5%). 09 mmol) of NaBH 3 CN at pH 6.75 After 24 hours, a second portion of 0.85 g of the ketoester and 0.2 g of NaBH 3 CN are added, followed by stirring for 40 hours.

  ion exchange then gives 0.183 g of the desired product.

EXAMPLE 13

  2- (N- [1-carbethoxy-3- (2-pyridyl) propyl] -L-valyl) -6-

  methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid The initial dipeptide is prepared as indicated above,

  starting from 6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-

  methyl carboxylate and carbobenzyloxy-L-valine.

  Copulation with dicyclohexylcarbodiimide using hydroxybenzotriazole, followed by saponification and

  deblocking as above, gives the dipeptide salt.

- 14 -

  Reductive alkylation with ethyl 2-oxo-4- (2-pyridyl) -butyrate in the presence of sodium cyanohydroborate under normal conditions gives the crude monoester. It is

  purified by ion exchange chromatography and freeze-drying.

  as before, to obtain a mixture of

  diastereomers of the desired product.

EXAMPLE 14

  2- (N- [1-carbethoxy-3- (4-methoxyphenyl) propyl] -I-isoacidic acid

  leucyl) -6,7-dimethoxy-1,2,3g4-tetrahydroisoquinolin-3-

  The initial dipeptide is prepared starting from

  carbobenzyloxy-L-isoleucine and 6,7-dimethoxy-1,2,3,4-

  Methyl tetrahydroisoquinoline-3-carboxylate

  using hydroxybenzotriazole and dicyclohexylcarbonyl

  diimide as previously described. Saponification and deprotection as above then give the-hydrobromide

of dipeptide.

  Treatment with ethyl 2-oxo-4- (4-methoxyphenyl) -butyrate and sodium cyanohydroborate under normal conditions above gives the reducing alkylation product. It is purified as before to obtain

  the title compound as a diastereoisomeric mixture.

EXAMPLE 15

  2- (N- [1-carbethoxy-3- (4-chlorophenyl) -L-alanyl] -7-

  methoxy-1,2,3,4-tetrahydro-5H-benz c] azepine-3-carboxylic acid

  By acylating 1,2,3,4-tetrahydro-5H-benz [c] azepine-3-

  methyl carboxylate with carbobenzyloxy-L-alanine, with dicyclohexylcarbodiimide as copulation reagent

  as in Example 1A, the protected dipeptide is obtained.

  Saponification and deblocking then give the dipeptide

free as indicated above.

  Alkylation on N with 2-oxo-4- (4-chlorophenyl) -

  ethyl butyrate and sodium cyanohydroborate as in Example 12 gives a mixture containing the desired product. It is isolated by exchange chromatography

- 15 -

  of ions and lyophilization, as indicated above.

EXAMPLE 16

  2- (N- [1-carbethoxy-3- (4-pyridyl) propyl] -L-alanyl acid

  1,2,3,4-tetrahydro-5H-benzrc) azepine-3-carboxylic acid The initial dipeptide is prepared starting from

  carbobenzyloxy-L-alanine and 1,2,3,4-tetrahydro-5H-

  Methyl benz [c] azepine-3-carboxylate according to the general procedure of Example 1. Reductive alkylation, as described above, using ethyl 2-oxo-4- (4-pyridyl) -butyrate and sodium cyanohydroborate, gives the

  crude peptide alkylated on N. The purification by chromatogra-

  ion exchange and lyophilization gives the state

  pure the title compound as a mixture of diastereo-

isomèreso

EXAMPLE 17

  2- (N- [1-carbethoxy-3- (3-trifluoromethylphenyl) propyl] acid

  L-valyl) -7,8-methylenedioxy-l, 2,3,4-tetrahydro-5H-benz [c] Aze

pine-3-carboxylic acid

  By acylating 7,8-methylenedioxy-1,2,3,4-tetrahydro-

  Methyl 5H-benz [c] azepine-3-carboxylate by carbobenzene

  zyloxy-L-valine, using hydroxybenzotriazole and dicyclohexylcarbodiimide according to Example 2A, the protected dipeptide is obtained. It is then saponified and treated

  by HBr / acetic acid to obtain the desired peptide.

  By treating the dipeptide with 2-oxo-4- (3-trifluoro-

  methylphenyl) -butyrate ethyl and sodium cyanohydroborate at pH 6.55 according to Example 12, the product is obtained on N. The ion exchange chromatography and lyophilization give the pure compound in form

mixture of diastereomers.

EXAMPLE 18

  The stereospecific synthesis of the S-configuration compounds is carried out by the following method:

- 16 -

  A. 2- [N- (1-carbethoxy-3-phenylpropyl) -alanyl] -1,2,3,4-

  Benzyl tetrahydroisoquinoline-3-carboxylate

  To a suspension of 2.60 g (9.31 mmol) of (S, S) -N-

  (1-carbethoxy-3-phenylpropyl) -alanine in 20 ml of dry tetrahydrofuran is added 1.51 g (9.3 mmol) of 1,4-carbonyldiimidazole. When a clear solution is obtained (5 to 10 minutes), the mixture is cooled to 0.degree.

  3.12 g (7.44 mmol) of (S) -1,2,3,4-monotartrate are added.

  benzyl tetrahydroisoquinoline-3-carboxylate The mixture was stirred overnight at room temperature, then concentrated in vacuo and redissolved in ether. The solution is washed with saturated NaHCO 3 solution and water and concentrated to give 2.2 g (56%) of the desired amide which is used without

other purification.

  CIMS: 529 (n = 1), 234, 91 (chemical ionization mass spectrometry)

  NMR: 7.3; 5.1; 3.15; 2.8; 1.2 to 1.5.

  B. 2- [N- (1-Carbethoxy-3-phenylpropyl) -hydrochloride

  alanyl -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

* To a solution of 2.10 g (3.97 mmol) of (S, S, S) -2fN-

  (1-carbethoxy-3-phenylpropyl) -alanyl -1,2,3,4-tetrahydro-

  benzyl isoquinoline-3-carboxylate in 20 ml of ethanol, 0.2 g of 10% palladium

  coal. The mixture is stirred under about 2.03 bar of hydro-

  gene until absorption ceases. The mixture is filtered and concentrated in vacuo and partitioned between ether and 2N HCl. The aqueous solution is lyophilized and the resulting powder is washed with ether to obtain 0.70 g.

  (37%) of product, mp 101-105 C.

0 [O] d-10.9 (H 2 O)

CIMS 421 (M + 1-H 2 O)

  EIMS 421, 316, 270 (Electron Impact Mass Spectrography). Calcd for C25H31N2O5HCl-H2O: C 60.91 H 6.74 N 5.18 Found: C 61.16 H 6.47 N 5.48

- 17 -

  Following the methods of the above examples, the following compounds are further prepared:

  2-CN- (1-ethoxycarbonyl-3-methylbutyl) -L-alanyl) -

  isoquinaldique, 2- (CN- (1-ethoxycarbonyl-4-methylhexyl) -L-alanyl) isoquinidic acid,

  2-CN- (1-ethoxycarbonyl-5-methylhexyl) -L-alanyl) -

  isoquinaldique, 2-CN- (1,3-dicarboxypropyl) -L-alanyl) -isoquinidic acid,

  2-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl) -6-

hydroxy-isoquinaldic acid, 2- (N- (1-ethoxycarbonyl-5-methylhexyl) -L-valyl) -iso-

quinaldic,

  2-CN- (1,3-dicarboxypropyl) -L-alanyl) -6-methoxy-isoacidic acid

quinaldic,

  2- CN- (1-ethoxycarbonylhexyl-L-valyl) -8-methyl-isoacidic acid

quinaldic,

  2-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-phenyl-

alanyl) -6-chloro-isoquinaldique,

  2-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-histidyl acid)

8-hydroxy-isoquinaldique,

  1-CN- (1-ethoxycarbonyl-3-methylbutyl) -L-alanyl) -2-carboxy-

indoline

  1-CN- (l-ethoxycarbonyl-3-phenylpropyl) -L-phenylalanyl) -2-

  carboxyindoline, 1-CN- (1-ethoxycarbonylhexyl) -L-alanyl) -2carboxyindoline,

  1-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl) -2-

carboxy-5,6-dimethylindoline,

  1-CN- (l-ethoxycarbonyl-3-phenylpropyl) -L-valyl) -2-carboxy-

indoline

  1-CN- (1,3-dicarboxypropyl) -L-alanyl) -2-carboxy-5,6-dimethyl-

indoline

  l-CN- (1,3-dicarboxypropyl) -L-histidyl) -2-carboxy-4-chloro-

indoline

2502 1 49

- 18 -

  1- CN- (1-6-methoxycarbonylhexyl) -L-valyl) -2-carboxy-4-methoxy-

indoline

  1- CN- (1-ethoxycarbonylheptyl) -L-phenylalanyl) -2-carboxy-

  6-methylindoline, 1-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl) -2-carboxy-3-hydroxymethyl-5,6-dimethylindoline,

  1-carboxy-2-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl) -

  H-1,2,3,4-tetrahydro-2-benzazepine,

  1-carboxy-2-CN- (1-ethoxycarbonyl-3-methylbutyl-L-histidyl)

  5H-1,2,3,4-tetrahydro-2-benzazepine

  1-carboxy-2-CN- (1-ethoxycarbonyl-4-methylpentyl) -L-phenyl-

  alanyl -5H-1,2,3,4-tetrahydro-2-benzazepine,

  1-carboxy-2-CN- (1,3-dicarboxypropyl) -L-alanyl) -7,8-dimethyl-

  H-1,2,3,4-tetrahydro-2-benzazepine,

  1-Carboxy-2- (N- (1-ethoxycarbonyl-3-phenylpropyl) -isoleucyl)

  6-chloro-1,2,3,4-tetrahydro-2-benzaz6pine,

  1-carboxy-2-CN- (1-ethoxycarbonylhexyl) -L-valyl3-6-methoxy-

  7-methyl-1,2,3,4-t6trahydro-2-benzazepine,

  1-carboxy-2-CN- (1-ethoxycarbonyl-3-phenylpropyl) -L-histi

  dyl-6-chloro-1,2,3,4-tetrahydro-2-benzazepine,

  1-carboxy-2-CN- (1-carboxy-2-phenylthioethyl) -L-alanyl) -7

  methyl-5H-1,2,3,4-tetrahydro-2-benzazepine,

  1-carboxy-2-CN- (1-ethoxycarbonyl-3-p-chlorophénylpropyl) -

  L-valylD-7,8-dimethyl-5H-1,2,3,4-tetrahydro-2-benzazepine,

  1-carboxy-2-CN- (1-carboxy-2- (3-indolyl) ethyl) -L-valyld

  H-1,2,3,4-tetrahydro-2-benzazepine,

  2- (N-1 (1-carbethoxy-3- (4-chlorophenyl) propyl) -L-

  leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2 - (<N-1 (1-carbethoxy-3- (3-trifluoromethylphenyl) pro

  pyl) -L-valyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-2- (3-methoxyphenyl) ethyl) -L-

  methionyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N- (1-carbethoxy-3- (4-pyridyl) propyl) -L-alanyl) -

  2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

- 19 -

  2- (N-1 (1-carbethoxy-3- (4-methoxyphenyl) propyl) -L-

  lysyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3-pyridyl) propyl) -L-leucyl acid)

  1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N- (1-carbethoxy-2- (2-thienyl) ethyl) -L-arginyl) 1,2,304-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (methylthio) propyl) -L-iso acid

  leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3-thienyl) propyl) -L-valyl) -

  1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-2-phenylethyl) -L-lysyl) -1,2,3,4-

  tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-2- (phenoxy) ethyl) -L-lysyl acid -

  1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (2-furyl) propyl) -L-valyl) -

  1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3,4-methylenedioxyphenyl) -

  propyl) -L-alanyl) -1,2,3,4-tetrahydroisoquinoline-3-carbo-

xylique0

  2- (N-1 (1-carbethoxy-3- (3-chlorophenyl) propyl) -L-

  phenylalanyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (2-methoxyphenyl) propyl) -L-

  tyrosyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-2- (benzofuran-3-yl) ethyl) -L-

  leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (4-methoxyphenyl) propyl) -L-

  alanyl) -6-chloro-1,2,3,4-tetrahydroisoquinoline-3-carbo-

xylique,

  2- (N-1 (1-carbethoxy-3- (phenoxy) propyl) -L-arginyl acid)

  6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carbo-

xylique,

  2- (N-1 (1-carbethoxy-2- (indol-3-yl) ethyl) -L-leucyl acid)

  6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (4-methoxyphenyl) propyl) -L-

  leucyl) -5H-1,2,3,4-tetrahydrobenz [c] azepine-3-carboxylic acid,

- 20 -

  2- (N-1 (1-carbethoxy-3- (3-pyridyl) propyl) -L-methionyl acid)

  H-1,2,3,4-tetrahydrobenz [d] azepine-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (methylthio) propyl) -L-leucyl acid)

  H-1,1,3,4-tetrahydrobenz Ec] azepine-3-carboxylic acid, 2- (N1- (1-carboxy-2- (4-imidazolyl) ethyl) -L-valyl) -7-methoxy-5H-1, 2,3,4tétrahydrobenz [c] azepine-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3-methoxyphenyl) propyl) -L-

  lysyl) -6,7-methylenedioxy-5H-1,2,3,4-tetrahydrobenz [c] aze

pine-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3-chlorophenyl) propyl) -L-

  histidyl) -5H-1,2,3,4-tetrahydrobenz [c] azepine-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-3- (3-thienyl) propyl) -L-arginyl acid)

  7-methoxy-5H-12,3,4-tetrahydrobenz [c azepine-3-carboxylic acid,

  2- (N-1 (1-carbethoxy-2-phenylethyl) -L-trisosyl) -7-

  SH-chloro-1,2,3,4-tetrahydrobenz [ciazépine-3-carboxylic acid,

  N- (1-carboxy-2-indanylmethyl) -alanyl-1,2,3,4-tetraacetate

  hydroisoquinoléine-3-carboxylic acid. The compounds of the invention have demonstrated potent activity (in the range of I50 = 0.02 to 0.20 pmol) in the inhibition of angiotensin converting enzyme (ACEI activity) when The compounds of the invention have also demonstrated an I50 of about 1 to 2 mg / kg per os in the inhibition of angiotensin I injected in the rat. As a result, they are very

  useful in the treatment of hypertension.

  The compounds can be administered orally or parenterally in the treatment of hypertension and it comes in the professional judgment and skill

  the practitioner to determine the quantity to be administered.

  Suitable dosage forms include tablets,

  capsules, elixirs and injectables.

- 21 -

Claims (22)

  1. A compound corresponding to the formula: COOR7 CH2) R2R5R (R8) n ROOC "N (CH) R3 R6   R4 wherein: R1 and R7 are hydrogen, lower alkyl or phenyl-lower alkyl, R2, R3, R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl; fused aryl, aryl, cycloalkyl, aralkyl, cycloalkyl, heterocyclic, or lower alkyl, lower alkenyl or lower alkynyl groups substituted by a hydroxyl, alkoxyl, halogen, amino, alkylamino, mercapto, or alkylmarceptop group or groups cycloalkylo-aryl or heterocyclic group bearing as substituent an alkyl, hydroxyl, alkoxyl or hydroxyalkyl group;   halogen, a mercapto group, alkylmercapto, mercapto   alkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy or trifluoromethyl, each R8 is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxyl, alkoxyl, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, a halogen, a group   haloalkyl, aminoalkyl, alkylaminoalkyl, dialkyl-   aminoalkyl, sulfonamide, methylenedioxy or trifluoromethyl, m is an integer from 0 to 2 inclusive, m 'is an integer from 1 to 3 inclusive, with the proviso that when m is 0, m' is 2 or 3 and when m is is other than O, m 'is 1 or 2, - 22 -   n is an integer from 0 to 4 inclusive, as well as salts of these compounds, especially pharmaceutically acceptable salts formed with an acid or a base.   2.- compound corresponding to the formula: COOR7 R1 C (R8) n ROOC N R3 J R6 R4   wherein: R 1, R 3, R 4, R 6, R 5, R 5, R 6, R 7, R 8 and the definition given in claim 1, and salts thereof, especially pharmaceutically acceptable salts formed with an acid or a base.   3 - Compound according to one of claims 1 and 2,   characterized in that the COOR7 substituent is   attached to a carbon adjacent to the nitrogen of the nucleus.   4. A compound according to one of claims 1 to 3,   characterized in that R7 is a hydrogen atom.   5. Compound according to one of claims 1 to 4,   characterized in that R1 is an ethyl group or a hydrogen atom.   6 - Compound according to one of claims 1 to 5,   characterized by the fact that R2 is a phenyl group lower alkyl.   7. A compound according to claim 6, characterized   in that R2 is a phenethyl group.   8. A compound according to one of claims 1 to 7,   characterized in that R6 is a methyl group.   9. A compound according to one of claims 1 to 7,   characterized in that R6 is an isopropyl group. - 23 -   10. A compound according to one of claims 1 to 7,   characterized in that R6 is an isobutyl group.   11. A compound according to one of claims 1 to 4,   characterized in that R2 is phenethyl and R6 is methyl. 12. A pharmaceutical composition for the treatment of hypertension, characterized in that it comprises an effective amount of a compound according to one of Claims 1 to 11.   13. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of the following formula is reacted under amide-forming conditions: R700C (.CH) S M   (CH) m on an acylating derivative of an acid of formula: ## STR2 ## R3 0R R3 R4 R6 or of formula: O O R5   It is possible to react with a compound of the formula: ## STR2 ## - 24 -   COOR 7 H C N 8n H / {1 /, (CH 2) m t 8 (VI) N C R 6 R4   on a "- ketoacid or ester of formula: ROOC - C - R II (VII)   o and that the imine obtained is reduced, or that a compound of formula (VI) is reacted with a "-halogenoacid or ester of formula: R 2 R 100 C - Hal (VIII) i I R 3 and that, optionally, by substitution or conversion reactions, various substituents are introduced into the products and that, optionally, salts are formed, especially pharmaceutically acceptable salts with an acid or a base.   14. A process according to claim 13, characterized in that the substituent COOR7 is attached to a   carbon adjacent to the nucleus nitrogen.   15.- Method according to one of claims 13 or 14,   characterized in that R7 is a hydrogen atom.   16.- Method according to one of claims 13 to 15,   characterized in that R1 is an ethyl group or a hydrogen atom.   17.- Method according to one of claims 13 to 16,   characterized in that R2 is a phenylalkyl group inferior. f - 25 -   18. A process according to claim 17, characterized   in that R2 is a phenethyl group.   19.- Method according to one of claims 13 to 18,   characterized in that R6 is a methyl group.   20.- Method according to one of claims 13 to 18,   characterized in that R6 is an isopropyl group   21.- Method according to one of claims 13 to 18,   characterized in that R6 is an isobutyl group.   22 - Method according to one of claims 13 to 17,   characterized by the fact that R2 is a phenethyl group and R6 is methyl.