IE53076B1 - Amido-amino acids - Google Patents

Abstract

Compounds of the formula wherein R1 and R2 are hydrogen, lower alkyl or phenyl lower alkyl, R2, R3, R4, R5 and R6 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused aryl-cycloalkyl, aralkyl, cycloalkyl, heterocyclic, substituted lower alkyl, lower alkenyl, and lower alkynyl groups wherein the substituent is hydroxy, alkoxy, halo, amino, alkylamino, mercapto and alkylmercapto groups, and substituted cycloalkyl, aryl and heterocyclic groups in which the substituent is alkyl, hydroxy, alkoxy, hydroxyalkyl, halo, mercapto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, and trifluoromethyl; each R8 is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalky, sulfonamido, methylenedioxy, or trifluoromethyl, m is an integer from 0 to 2 inclusive; m' is an integer from 1 to 3 inclusive, provided that when m is 0, m' is 2 or 3 and, when m is other than 0, m' is 1 or 2; n is an integer from 0 to 4 inclusive, and salts thereof, especially pharmaceutically acceptable salts with an acid or a base.

Description

This invention relates to new compounds having valuable pharmacological activity. It particularly relates to compounds having antihypertensive and angiotensin converting enzyme inhibitory activity and the structure wherein and R? are hydrogen, lower alkyl or phenyl lower alkyl, R2 , R3 , R4 , R& and Rg are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fus.ed arylcycloalkyl, aralkyl, cycloalkyl, heterocyclic, substituted lower alkyl, lower alkenyl, or lower alkynyl groups wherein the substituent is hydroxy, alkoxy, halo, amino, alkylamino, mercapto or alkylmercapto groups, or substituted cycloalkyl, aryl or heterocyclic groups in which the substituent is alkyl, hydroxy, alkoxy, hydroxyalkyl, halo, mercapto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, or 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, sulfonamido, methylenedioxy, or trifluoromethyl, m is an integer from 0 to 2 inclusive; m' is an integer from 1 to 3 inclusive, provided -3m is 0, m' is 2 or 3 and, when m is other than 0, m' is 1 or 2; and with the further provisos that when m' is 1 and m is 0, Ri, R2, R4, R5 and R7 are hydrogen, and R3 and Rg are independently lower alkyl or aralkyl or cycloalkyl or heterocyclic or aryl or substituted cycloalkyl or substituted aryl or fused arylcycloalkyl containing up to 10 carbon atoms, then COOR7 is not in the 2-position; or when m and m' are each 1, R2, R4, R5, R7 and Rg are hydrogen, R·] is hydrogen or alkyl and R3 and Rg are alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic or heterocyclicalkyl, substitued aryl or substituted cycloalkyl or fused aryl cycloalkyl containing up to 10 carbon atoms or a salt thereof, then COOR7 is not in the 3-position; and n is an integer from 0 to 4 inclusive, and salts thereof, espeically pharmaceutically aceptable salts with an acid or a base. -3a(A) Preferred embodiments of the invention provides β compound of the formula wherein R , R2, Rg, R^, R&, Rg, Ry, Rg, and n are as defined above; (B) Compounds wherein the COQR? substituent is attached to a carbon adjacent to the ring nitrogen; (C) Compounds wherein-R? is hydrogen; (D) Compounds wherein is ethyl or hydrogen; (E) Compounds wherein Rg is phenyl-lower alkyl, e.g. phenethyl; (F) Compounds wherein Rg is methyl; (G) Compounds wherein Rg is isopropyl; (H) Compounds wherein Rg is isobutyl; and (I) Compounds wherein Rg is phenethyl and Rg is methyl. - 4 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.

The alkyl, alkenyl, and alkynyl groups may carry substituents such as hydroxy, alkoxy, halo, amino, alkylamino, mercapto and alkylmercapto.

The cycloalkyl groups contain from 3 to. 7 carbon atoms. Such cycloalkyl groups include cycloalkyl-alkyl and the cycloalkyl groups may carry substituents such as alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, aminoalkyl, alkylamino, trifluoromethyl, and nitro.

The aryl groups may have from 6 to 10 carbons and include phenyl and ©4. - and -naphthyl. The aryl groups may contain substituents such as alkyl, hydroxy, alkoxy, hydroxyalkyl, mercapto, alkylmercapto, mercaptoalkyl, halo, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, trifluoromethyl, ureido, and guanidino.

The fused aryl-cycloalkyl comprise phenyl rings fused to cycloalkyl rings having 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, 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 - 5 also carry substituents as described for the aryl groups above. The heterocyclic group also includes heterocyclic lower alkyl.

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

Preferably, the -COOR? group 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 basic salts include alkali and alkaline earth metal salts such lithium, sodium, potassium, magnesium and calcium and iron, as well as ammonium and quarternary ammonium salts.

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

The compounds of the present invention may be prepared by amide forming reaction of an amine compound of the formula S3076 - 6 with an acylating derivative of the acid of the formula: *2 □ ^OOC N .OH R.

C' II R6 0 III Alternatively, the comoounds in which R^ and R^ are hydrogen may be readily prepared by treating a compound of formula II with a compound of the formula SNR4 COOH IV under amide-forming conditions to form a compound of the structure ir I r4 <R8>n splitting off the carbobenzyloxy group to give a free amine of the structure and the reacting formula R.OOC -C-R, II VII and reducing the resulting imine to give a compound of formula I wherein Rg and R4 are hydrogen.

Compounds of formula VI can also be reacted with an Λ -halo acid or ester of the formula R-jOOC VIII to give compounds of formula I wherein Rg and R4 can be H or any of the other substituents descriptive of the said R, and R.. 4 In the above sequence of reactions R^ to Rg, m, m* and n are as hereinbefore defined and Hal is halogen.

Preferably, R^, Rg, R4, Rg and R? and Rg are hydrogen. R2 is lower alkyl or phenyl-lower alkyl, Rg is lower alkyl. - 8 The amide forming conditions referred to herein involve the use of known derivatives of the described acids, such as the acyl halides, anhydrides, mixed anhydrides, lower alkyl esters, carbodiimides, carbonyl diimidazoles, and the like. The reactions are carried out in organic solvents such as acetonitrile, tetrahydrofuran, dioxane, acetic acid, methylene chloride, ethylene chloride and similar such solvents. The amide forming reaction will occur at room temperature or at elevated temperature. The use of elevated temperature is for convenience in that it permits somewhat shortened reaction periods. Temperatures ranging from 0°C. up to the reflux temperature of the reaction system can be used. As a further convenience the amide forming reaction can be effected in the presence of a base such as tertiary organic amines, e.g., trimethylamine,pyridine,picolines and the like, particularly where hydrogen halide is formed by the amideforming reaction, e.g., acyl halide and amino compound.

Of course, in those reactions where hydrogen halide is produced, any of the commonly used hydrogen halide acceptors can also be used.

Xn the condensation of an alpha haloacid derivative of formula VIII herein, similar reaction conditions, solvents and hydrogen halide acceptors can be used as for amide formation.

Various substituents on the present new compounds, e.g., as defined for Kg,can be present in the starting compounds or added after formation of the amide products by the known methods of substitution or conversion reactions. Thus, the nitro group can be added to the final product by nitration of the aromatic ring and - 9 the nitro group converted to other groups, such as amino by reduction, and halo by diazotization of the amino group and replacement of the diazo group. Other reactions can be effected on the formed amide product.

Amino groups can be alkylated to form mono and dialkylamino groups, mercapto and hydroxy groups can be alkyxated to form corresponding ethers. Thus, substitution or alteration reactions can be employed to provide a variety of substituents throughout the molecule of the final products. Of course, reactive groups where present should be protected by suitable blocking groups during any of the aforesaid reactions particularly the condensation reactions to form the amide linkages.

The acid and base salts of the present new compounds can be formed using standard procedures. Often, they are formed in situ during the preparation of the present new amido amino acids.

The present compounds obviously exist in stereoisomeric forms and the products obtained thus can be mixtures of the isomers, which can be resolved. Alternatively, by selection of specific isomers as starting compounds, the preferred stereoisomer can be produced. Therefore, the preferred forms, where each asymmetric center (chairal center) is S-configuration, are preferably prepared by the stereospecific route rather than attempting resolution of mixtures of isomers.

The compounds in which the S-configuration exists at all asymmetric centers are the most active; those in which the R-configuration exists are of less activity; and those where both R- and S-configurations exist are of intermediate activity.

The invention is further illustrated by the following examples. - 10 The following Examples 1 to 3, 9 .to 12 and (marked · below with an asterisk) illustrate the production of compounds outside the scope of the invention, and are provided to illOstrate procedures that may be used in the. production of compounds according to the invention. DOWEY is a Registered Trade Mark.

EXAMPLE 1» A. 2-(N-Benzyloxycarbonyl-L-alanyl) -L-l, 2,3,4-tetrahydroisoquinollne-3-carboxyllc acid methyl ester To a suspension of 10.0 g (43.9 mmols) of L-l,2,3,4tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride and 10.4 g (46.6 mmols) of carbobenzyloxy-L-alanine in 150 ml dry acetonitrile was added 4..4 g (43.6 mmols) of triethylamine. A solution of 9.2 g (44.6 mmol) of N,N-dicyclohexylcarbodiimide in 5 ml 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 IN HCl, sat. NaHC0g , and brine, dried over MgS04 , filtered, and concentrated to give 18.3 g (10556) of crude amide which was used without further purification.

B. 2- (N-Benzyloxycarbonyl—L—alanyl)-L-l, 2,3,4-tetrahydroisoquinoline-3-carboxyllc acid 8.0 g of the crude amide ester from A was dissolved in 25 ml IN NaOH/MeOH. To this was added 5 ml water. The resulting solution was stirred overnight at room temperature, then poured into 150 ml water and extracted with ether. . The aqueous layer was then acidified and extracted with CHgClg. The extracts were dried over MgSO^ and concentrated at aspirator pressure to give 5.5 g of product. After prolonged concentration at oil pump vacuum there was obtained a brittle foam. - 11 c. 2-L-Alanyl-I,2,3,4-tetrahydroisoauinoline-3-carboxylic acid hydrobromide To a solution of 4.8 (12.5 mmol) crude carbobenzyloxycarboxylic acid in 7 nil acetic acid was added 5 ml of saturated HBr in acetic acid. The solution was stirred at room temperature until all gas evolution had ceased (1-1.5 hr). A slow stream of air was passed through the solution to remove excess HBr, then 25 ml ether was added to precipitate the product. The solid was washed with two further portions of ether, then dried in vacuo to give 2.2 g of pale yellow solid, m.p. 180°.

D. N-(l-Carboxy-3-phenylpropyl)alanyl-1,2,3,4-tetrahydroisoguinoline-3-carboxylic acid To a solution of 1.3 g (6.63 mmol) of benzylpyruvic acid hydrate in 5 ml, sat. NaHCOg 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 then transferred to a column holding 20 g of Dowex 50X8. The column was eluted with 50% MeOH, then 3% NH^OH. The first ammonia fractions, containing the desired product, were combined and lyophilized to give 85 mg of product as a fluffy white powder, m 97-101°. - 12 EXAMPLE 2 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 mmols) of L-l,2,3,4tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride in 50 ml dry acetonitrile were added 5.2 g (20.7 mmols) N-carbobenzyloxy-L-valine, 2.7 g (20.0 mmols) 1-hydroxybenzotriazole and 2.1 g (20.7 mmols) triethylamine. The resulting mixture was stirred at room temperature and a solution of 4.5 g (21.8 mmols) of dicyclohexylcarbodiimide in 10 ml dry acetonitrile was added slowly. The mixture was stirred overnight at room temperature, then filtered and worked up as described in Example IA. Final concentration gave 8.3 g (101%) of a thick oil.

B. 2-(N-Carbobenzyloxy-L-Valyl)-L-l,2,3,4-tetrahydroi5oquinoline-3-carboxylic acid 4.5 g (106 mmols) of crude methyl ester prepared according to the above procedure was treated with 10 ml 10% NaOH and sufficient methanol (35-40 ml) to produce a homogeneous solution. This solution was stirred at room temperature for 23 hrs., then diluted with 100 ml water and extracted with two 25 ml portions ether. The aqueous fraction was then acidified and extracted with four 10 ml portions methylene chloride. The extracts were dried over MgSO^ and concentrated to give 3.8 g (9.3 mmols, 87%) of homogeneous carboxylic acid.

S3076 - 13 EXAMPLE 3 A. 2-(N-Carbobenzyloxy-L-isoleucyl)-L-l,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid 4.5 g (19.8 mmols) of L-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride, .3 g (20.0 mmols) of N-carbobenzyloxy-L-isoleucine, 2.7 g (20.0 mmols) 1-hydroxybentriazole, and 2.1 g (20.7 mmols) triethylamine were treated as described for example 2A with 4.4 g (21.3 mmols) dicyclohexylcarbodiimide, then worked up to give 7.8 g (90%) of crude methyl ester. This was dissolved in 30 ml methanol and treated with 10 ml 10% NaOH. The solution was stirred overnight at room temperature, then worked up as previously described to give 1.8 g (21.4% overall) of the desired acid as a yellow oil. - 14 EXAMPLE 4 2- Ν-(1-Ethoxycarbonyl-3-phcnylpropyl)-L-alanyl -1,2,3,4tetrahydrolsoqulnoline-l-carboxyllc acid An ethanolic solution of benzyl 2-(N-carbobenzoxyL-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 in Example ID. The product is purified by chromatography and lyophilization.

EXAMPLE 5 2-N-(1-Carboxyethyl)-L-alanyl-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid An ethanolic solution of benzyl 2-(N-carbobenzoxyL-alanyl)-isoquinaldate and pyruvic acid was hydrogenated with palladium on carbon. The filtered solution was concentrated and purified as in Example ID. - 15 EXAMPLE 6 1- Benzyloxycarbonyl-2-(N-carbobenzyloxy-L-alanine)5H-1,2,3,4 -tetrahvdro -2-benzazepine A methylene chloride solution of N-carbobenzyloxy -L-alanine and l-benzyloxycarbonyl-5H-l,2,3,4-tetrahydro2- benzazepine was treated with Ν,Ν'-dicyclohexylcarbodiimide as in example 3A. Purification of the final product was accomplished by silica gel chromatography. - 16 EXAMPLE 7 l-Carboxy-2-N-(l-carboxy-3-phenylpropyl)-L-alanyl-5H-l, 2,3,4-tetrahydro-2-benzazepine An ethanolic eolution of l-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 in example ID. The product was purified by chromatography. - 17 EXAMPLE 8 1-Carboxy-2-[N-(l-carboxv-3-methylbutyl)-L-alanyl]-5H-1, 2,3,4-tetrahydro-2-benzazepine An ethanolic solution of l-benzyloxycarbonyl-2(n-carbobenzyloxy-alanyl)-5H-1,2,3,4-tetrahydro-2benzazepine was hydrogenated with palladium on carbon. The filtered solution was treated with 2-oxo-4-methylpentanoic acid, sodium cyanoborohydride and alkali as in example ID. Chromotography and lyophilization provided the pure product. - 18 EXAMPLE 9* 2-(N-(l-Carboethoxy-3-Phenylpropyl)-L-Alanyl)-6,7Methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-Carboxylic Acid By the procedure in example IA, 6,7-methylenedioxyl,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 give the desired carboxylic acid.

The above carbobenzyloxy-dipeptide was deprotected according to the procedure in example 1C with an initial reaction temperature of 0eC. 0.675 g (1.81 mmol) of this dipeptide was added to a solution of 1.47 g (7.13 mmol) of ethyl 2-oxo-4-phenylbutyrate in 25 ml 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 a further 0.70g of ester and 0.2 g of NaBHjCN were added and the stirring continued an additional 48 hours. The reaction mixture was transferred to a column of Dowex 50X8 and the column eluted with 50% EtOH, HjO, 1% NH^OH, and 3% NH^OH. Fractions containing the desired product were combined and lyophilized to give 0.347 g of the diastereomeric mixture. - 19 EXAMPLE 10* 2-(N-(1-Carboethoxy-l-(2-indanyl)methyl)-L-alanyl)-6chloro-1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid In a similar manner the appropriate dipeptide was prepared from 6-chloro-l,2,3,4 - tetrahydroisoguinoline-3carboxylic acid methyl ester and carbobenzyloxy-L-alanine by DCC coupling followed by saponification and cleavage with HBr/HOAc.

The above dipeptide (0.427 g, 1.17 mmol) was alkylated as described above by 1.5 g (6.87 mmol) of ethyl d -oxindane-2-acetate and 0.32 g (5.09 mmol) of NaBH^CN at pH 6.75. After 24 hours a second 0.85 portion of the keto ester and 0.2 g NaBH^CN were added. The reaction was then stirred for 40 hours. Ion exchange chromatography then gave 0.183 g of desired product. - 20 EXAMPLE 11* 2-(N-(l-Carboethoxy-3- (2-Pyridyl)propyl)L-valyl)-6methoxy-1,2,3,4-tetrahydroiBoquinoline-3-carboxylic acid The starting dipeptide was prepared as indicated above from 6-methoxy-l,2,3,4-tetrahydroieoguinoline-3carboxylic acid methyl ester and carbobenzyloxy-L-valine. Hydroxybenzotriazole-mediated DCC coupling, followed by saponification and deblocking as before, gave the dipeptide salt. Reductive alkylation with ethyl 2-oxo4-(2-pyridyl)butyrate in the presence of sodium cyanoborohydride under standard conditions gave the crude monoester. This was purified by ion exchange chromatography and lyophilization as before to give a mixture of diastereomers of the desired product.

EXAMPLE 12* 2-(N-(l-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-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester using hydroxybenzotriazole and DCC as previously described. Saponification and deprotection as before then gave the dipeptide hydrobromide.

Treatment with ethyl 2-oxo-4-(4-methoxyphenyl) butyrate and sodium cyanoborohydride under the above standard conditions gave the reductive alkylation protuct. This was purified as before to give the title compound as a diastereomeric mixture. - 22 EXAMPLE 13 2-(N-(l-Carboethoxy-3-(4-chlorophenyl)propyl-L-alanyl)-7methoxy-1,2,3, 4-tetrahydro-5H-benz[c]azepine-3-carboxylic acid Acylation of 1,2,3,4-tetrahydro-5H-benz[c]azepine-3carboxylic acid methyl ester with carbobenzyloxy-L-alanine using DCC as coupling reagent as in example 1A gave the 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 in example 10 gave a mixture containing the desired product. This was isolated by ion exchange chromotography and lyophilization as previously described.

B3076 - 23 EXAMPLE 14 2-(N-(l-Carboetho;:y-3-(4-pyridyl)propyl)-L-alanyl)1,2,3,4-tetrahydro-5H-benz[c]azepine-3-earboxylic acid The starting dipeptide was prepared from carbobenzyloxy-L-alanine and l,2,3,4-tetrahydro-5H-benz[c] azepine-3-carboxylic acid methyl ester according to the general procedure of example 1. Reductive alkylation as described previously, using ethyl 2-oxo-4-(4-pyridyl) butyrate and sodium cyanoborohydride, gave crude Nalkylated peptide. Purification by ion exchange chromatography and lyophilization gave the pure title compound as a mixture of diastereomers. - 24 EXAMPLE 15 2- (N-l-(Carboethoxy-3-(3-trifluoromethylphenyl)propyl -L-valyl)-7,8-methylenedioxy-l,2,3,4-tetrahydro-5H-benz (c]azepine-3-carboxyllc acid Acylation of 7,8-methylenedioxy-l,2,3,4-tetrahydro-5H-benz[c] azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-valine using hydroxybenzotriazole and DCC according to example 2A gave the protected dipeptide. This was sequentially saponified and treated with HBr/HOAc to give the desired peptide.

Treatment of the dipeptide with ethyl 2-oxo-4-(3trifluoromethylphenyl)butyrate and sodium cyanoborohydride at pH 6.55 according to example 10 gave the N-alkylated product. Ion exchange chromatography and lyophilization gave the pure compound as a mixture of diastereomers. - 25 EXAMPLE 16* Stereospecific synthesis of the S-configuration compounds is accomplished by the following procedure.

A. 2-(N-(l-Carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4tetrahydroisoguinoline-3-carboxylic acid benzyl ester To a suspension of 2.60 g (9.31 mmol) of (S,S)-N(l-carboethoxy-3-phenylpropyl)alanine in 20 ml dry THF was added 1.51 g (9.3 mmol) of 1,1'-carbonyldimidazole. When a clear solution was obtained (5-10 min.,, the reaction mixture was cooled to 0’ and 3.12 g (7.44 mmol) of (S)-l,2,3,4-tetrahydroisoguinoline-3-carboxylic acid benzyl ester monotartrate was added. The reaction mixture was allowed to stir at room temperature overnight, then concentrated in vacuo and redissolved in ether. The ether solution was washed with saturated NaHCOj solution and water and concentrated to give 2.2 g (56%) of the desired amide, which was used without further purification C1MS: 529 (n=l), 234, 91 NMR: 7.3, 5.1, 3.15, 2.8, 1.2-1.5 B. 2-(N-(l-Carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid hydrochloride To a solution of 2.10 g (3.97 mmol) of (S,S,S)-2(N- (1-carboethoxy—3-phenylpropyl)alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester in 20 ml ethanol was added 0.2 g 10% Pd/C catalyst. The mixture was shaken under ca. 2 atm. hydrogen until uptake ceased. The reaction mixture was filtered and concentrated in vacuo, then partitioned between ether and 2N HC1. The aqueous solution was lyophilized and the - 26 resulting powder washed with ether to give 0.70 g (37%, of product, m. 101-105°. le*]d -10.9’ (H20) CIMS 421 (M+1-H2O) EIMS 421, 316, 270 Calc, for C25H31N2O5.HC1.H2O C 60.91 H 6.74 N 5.18 Found C 61.16 H 6.47 N 5.48 S3076 27. Following the procedures of the above Examples, the following additional compounds were prepared: 2-[N-(l-Ethoxycarbonyl-3-methylbutyl)-L-alanylJ -1,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-4-methylhexyl)-L-alanyl 1 -1,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-5-methylhexyl)-L-alanyl3-1,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l„3-Dlcarboxypropyl)-L-alanyl3-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-[N-CL-Ethoxycarbonyl“3-phenylpropyi.)-I,-alanyl3-6-Jiydroxy1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-CN-( l-Ethoxycarbonyl-5-methylhexyl)-L-valyl 3-1,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-[n-( 1,3-Dicarboxypropyl)-L-alanyl 3 -6-methoxy-1,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-Cn-( 1-Ethoxycarbonylhexyl-L-valyl3 -8-methyl-l,2,3,4tetrahydroisoquinoline-l-carboxylic acid 2-£N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-phenylalanyl3-6chloro-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-Q}-(l-Ethoxycarbonyl-3-phenylpropyl)-L-histidyl3-8hydroxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid - 28 l-Carboxy-2-[Ν-(l-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-benza'zepine l-Carboxy-2-[N-(l-ethoxycarbonyl-4-methylpentyl,-L-phenylalanyl)-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1,3-dicarboxypropyl)-L-alanyl]-7,8-dimethyl5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1-ethoxyearbony1-3-phenylpropyl)isoleucyl]6-chloro-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1-ethoxycarbonylhexyl)-L-valyl)-6-methoxy-7methyl-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-ethoxycarbonyl-3-phenylpropyl)-L-histidyl]6-chloro-l, 2,3,4-tetr.ahydro-2-benzazepine l-Carboxy-2-[N-(l-carboxy-2-phenylthioethyl)-L-alanyl]-7methyl-5H-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-ethoxycarbonyl-3-p-chlorophenylpropyl)-Lvalyl]-7,8-dimethyl-5H-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-carboxy-2-(3-indolyl)ethyl]-L-valyl]5H-1,2,3,4-tetrahydro-2-benzazepine - 29 2- (N-l(l-Carboethoxy-3-(methylthio)propyl)-L-leucyl)-5H1,2,3,4-tetrahydrobenz[cJazepine-3-carboxylic acid 2- (N-l(l-Carboethoxy-2-(4-imidazolyl)ethyl)-L-valyl)-7methoxy-5H-l,2,3,4-tetrahydrobenz(cJ azepine-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(3-methoxyphenyl)propyl)-L-lysyl)6,7-methylenedioxy-5H-l,2,3,4-tetrahydrobenzIc]azepine-3carboxylic acid 2- (N-l (l-Carboethoxy-3-(3-ohlorophenyl)propyl)-L-histidyl) 5H-1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylie acid 2- (N-l(l-Carboethoxy-3-(3-thienyl)propyl)-L-arginyl)-7methoxy-5H-l,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 2- (N-l(l-Carboethoxy-2-phenylethyl)-L-tryosyl)-7-chloro5H-1,2,3,4-tetrahydrobenztc]azepine-3-carboxylie acid .

The compounds of the present invention have demonstrated potent activity (of the order of Ι^θ of 0.02 to 0.20 micromols) in inhibiting the angiotensin converting enzyme (ACEI activity) when tested by the method described in Science 196, 441-4 (1977). The compounds of the present invention have also demonstrated an of about 1 to 2 mg/kg p.o. in inhibiting infused angiotensin I in rats. As such, these would be very useful in the treatment of hypertension.

The compounds may be administered orally or parenterally in the treatment of hypertension, and it will be within the professional judgment and skill of the practioner to determine the amount to be administered. Suitable dosage forms include tablets, capsules, elixirs and injectables.

Claims (24)

CLAIMS:

1. A compound of the formula wherein and R^ are hydrogen, lower alkyl or phenyl lower alkyl, r 2 , Rj, R 4 , R 5 and Rg are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused arylcycloalkyl, aralkyl, cycloalkyl, heterocyclic, substituted lower alkyl, lower alkenyl, or lower alkynyl groups wherein the substituent is hydroxy, alkoxy, halo, amino, alkylamino, mercapto or alkylmercapto groups, or substituted cycloalkyl, aryl or heterocyclic groups in which the substituent is alkyl, hydroxy, alkoxy, hydroxyalkyl, halo, mercapto, alkylmercapto, mercaptoalkyl, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, or 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, sulfonamido, methylenedioxy, or trifluoromethyl, m is an integer from 0 to

2. Inclusive; m'is an integer from 1 to 3 inclusive, provided that when -31m is 0, n' is 2 or 3 and, when m is other than 0, m' is 1 or 2; and with the further provisos that when m' is 1 and m is 0, R·], R2, R4, R5 and R7 are hydrogen, and R3 and Rg 5 are independently lower alkyl or aralkyl or cycloaikyl or heterocyclic or aryl or substituted cycloaikyl or substituted aryl or fused arylcycloalkyl containing up to 10 carbon atoms, then COOR7 is not in the 2-position; or when m and m' are each 1, R2, R4, R5, R7 and Rg are 10 hydrogen, R-] is hydrogen or alkyl and R3 and Rg are alkyl, cycloaikyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic or heterocyclicalkyl, substitued aryl or substituted cycloaikyl or fused aryl cycloaikyl containing up to 10 carbon atoms or a salt thereof, then COOR7 is not in the 15 3-position; and n is an integer from 0 to 4 inclusive, and salts thereof, espeically pharmaceutically aceptable salts with an acid or a base. -31a2. A compound of the formula R-jOOC (Rg) n Β n wherein R^ , Rg , Rg . R^ , Rj , Rg , Ry , Rg , and n are as defined in Claim 1 and salts thereof, especially pharmaceutically acceptable salts with an acid or 5 a base.

3. A compound according to Claim 1, wherein the COORy substituent is attached to a carbon adjacent to the ring nitrogen.

4. A compound according to any of Claims 1-3, wherein Ry is hydrogen.

5. A compound according to any of Claims 1-4, wherein R^ is ethyl or hydrogen.

6. A compound according to any of Claims 1-5, wherein Rg is phenyl-lower alkyl. 15

7. A compound according to Claim 6, wherein Rg is phenethyl.

8. A compound according to any of Claims 1-7, wherein R, is methyl, b - 32 1

9. A compound according to any of Claim 1-7, wherein Rg is isopropyl.

10. A compound according to any of Claims 1-7, wherein Rg is isobutyl. 5

11. A compound according to any of Claims 1-4, wherein R^ is phenethyl and Rg is methyl.

12. A pharmaceutical composition for treatment of high blood pressure which comprises an antihypertensively effective amount of a compound according 10 to any of Claims 1-11.

13. The process of preparing a compound of formula I herein which comprises reacting under amide-forming conditions a compound of formula II herein with an acylating derivative of an acid of formula III or formula IV herein; 15 or reacting a compound of formula VI herein with an P^-keto acid or ester of formula VII herein and reducing the resulting imine; or reacting a compound a compound of formula VI herein with an -halo acid or ester of formula VIII herein; and 20 optionally by substitution or conversion reactions introducing various susbstituents into the said products; and optionally forming salts thereof, especially pharmaceutically acceptable salts with an acid or.a base.

14. A process according to Claim 13, wherein 25 the COOR.? substituent is attached to a carbon adjacent to the ring nitrogen.

15. A process according to any of Claims 13 or 14, wherein R ? is hydrogen.

16. A process according to any of Claims 13-15, 30 wherein R^ is ethyl or hydrogen.

17. A process according to any of Claims 13-16, wherein R 2 is phenyl-lower alkyl. - 33 1

18. A process according to Claim 17, wherein B 2 is phenethyl.

19. A process according to any of Claims 13-18, wherein R g is methyl. 5

20. A process according to any of Claims 13-18, wherein R g is isopropyl.

21. A process according to any of Claims 13-18, wherein R g is isobutyl.

22. A process according to any of Claims 13-17, 10 wherein Rg is phenethyl and R g is methyl.

23. A pharmaceutical composition according to Claim 12 and substantially as hereinbefore described.

24. A process according to Claim 13 and substantially as hereinbefore described with reference to 15 any of Examples 4 to 8 and 13 to 15.