NZ200047A - Amido-amino acids,their preparation and pharmaceutical compositions containing them - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £00047 200047 Pripr:.

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$$ F*--l« ???$ Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "AMIDO-AMINO ACIDS" i/WE USV PHARMACEUTICAL CORPORATION, a corporation organized and existing under the laws of the State of Delaware, located at 1 Scarsdale Road, Tuckahoe, New York, U.S.A hereby declare the invention, for which-l/we pray that a patfexit may be granted to we/us, and the method by which it is to be performed, to be particularly described in and by the following statement (followed by page I A.) - 1A -AMIDO-AMINO ACIDS This invention relates to new compounds having valuable pharmacological activity. It particularly relates to compounds having antihypertensive and angio-5 tensin converting enzyme inhibitory activity and the structure COOR r]ooc 1 1 MAR 1985 // (Ri»> 8'n wherein Rj and R^ are hydrogen, lower alkyl or phenyl lower alkyl, R.

R. and R,. are independently hydrogen, 2' ~3' r'A' "5 "6 lower alkyl, lower alkenyl, lower alkynyl, aryl, fused arylcycloalkyl, 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, hydroxy-alkyl, halo, mercapto, alkylmercapto, mercaptoalkyl, halo-alkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, and trifluoromethyl; each Rg is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, trifluoromethyl and may be the same or different; or, when two adjacent Rg groups are present, methylenedioxy. wherein the alkyl groups in alkyl per se, aralkyl, alkoxy, aminoalkyl, thioalkyl, haloalkyl and hydroxyalkyl contain from 1-6 carbon atoms; the alkenyl and alkynyl groups contain 2-6 carbon atoms; the aryl groups contain from 6-10 carbon atoms; and the cycloalkyl groups contain from 3-7 carbon atoms; 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 pharmac'eutically acceptable salts with an acid or a base. 20004 1 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 15 nitro.

The aryl groups may have from 6 to 10 carbons and include phenyl and - and f) -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. 25 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 30 imidazole, thiophene, tetrahydrothiophene, furyl, tetra-hydrofuran, and the like. These heterocyclic groups may 1 also carry substituents as described for the aryl groups above. The heterocyclic group also includes heterocyclic lower alkyl. 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 10 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 as lithium, sodium, potassium, magnesium and calcium and iron, as well as ammonium and quaternary ammonium salts. 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. prepared by amide forming reaction of an amine compound of the formula The halo groups include fluorine, chlorine, bromine It is to be understood that the compounds of the The compounds of the present invention may be II 200047 1 with an acylating derivative of the acid of the formula: -2 5 1,000 N 'X^SS' I C II R3 R4 R6 0 OH III Alternatively, the compounds in which and are hydrogen may be readily prepared by treating a compound of formula II with a compound of the formula C00H IV under amide-forming conditions to form a compound of the structure C00R-5 0 II -C. *5 O X J | C (CH2)m I *6 r4 n V splitting off the carbobenzyloxy group to give a free amine of the structure 2000 coor7 *5 H ku rr(,,)" [nt (ch2)m\/ *6 VI R4 and reacting the amine with an Q -keto acid or ester of the formula R,00C - C - R9 II o VII and reducing the resulting imine to give a compound of formula I wherein R^ and R^ are hydrogen.

Compounds of formula VI can also be reacted 20 with and -halo acid or ester of the formula R- R,00C - C - Hal I R3 VIII to give compounds of formula I wherein R^ and R^ can be H or any of the other substituents descriptive of the said R3 and R4.

In the above sequence of reactions R^ to Rg, m, m' 30 and n are as hereinbefore defined and Hal is halogen.

Preferably, R^, R3, R^, R,. and R? and Rg are hydroge R2 is lower alkyl or phenyl-lower alkyl, Rg is lower alkyl. 2 00047 t_ The amide forming conditions referred to herein in volve 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 5 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 10 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 15 of a base such as tertiary organic amines, e.g., tri-methylamine,pyridine,picolines and the like, particularly where hydrogen halide is formed by the amide-forming reaction, e.g., acyl halide and amino compound. Of course, in those reactions where hydrogen halide 20 is produced, any of the commonly used hydrogen halide acceptors can also be used.

In the condensation of an alpha haloacid derivative of formula VIII herein, similar reaction conditions, solvents and hydrogen halide acceptors can be used 25 as for amide formation.

Various substituents on the present new compounds, e.g., as defined for Rg,can be present in the starting compounds or added after formation of the amide products by the known methods of substitution or conversion 30 reactions. Thus, the nitro group can be added to the final product by nitration of the aromatic ring and 4vu\)-i7 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 alkylated 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 com- J pounds can be formed using standard procedures. Often, they axe formed in situ during the preparation of the present new amido amino acids.

The present compounds obviously exist in stereo-isomeric 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 (chiral 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. 200047 1 EXAMPLE 1 a. 2-(N-Benzyloxycarbonyl-l-alanyl)-l-l,2,3, 4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester To a suspension of 10.0 g (43.9 mmols) of L-l,2,3,4-5 tetrahydroisoquinoline-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 aceto-10 nitrile 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 HC1, sat. NaHC03, and brine, dried over MgS04, filtered, 15 and concentrated to give 18.3 g (105%) of crude amide which was used without further purification.

B. 2-(N-Benzyloxycarbonyl-L-alanyl)-L-l,2,3,4-tetrahydro isoquinoline-3-carboxylic 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 ageuous layer was then acidified and extracted with 25 CH2C12. 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. *uOQ D. N-(l-Carboxy-3-phenylpropyl)alanyl-1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid ^ To a solution of 1.3 g (6.63 mmol) of benzyl- pyruvic acid hydrate in 5 ml. sat. NaHCO^ was added 0.307 g (0.93 mmol) of alanyl-1,2,3,4-tetrahydroiso-quinoline-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. (Dowex is a registered Trade Mark.) The column was eluted with 50% MeOH, then 3% NH4OH. 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°. 2 0 0 0 4 7. 1 EXAMPLE 2 A. 2-(N-Carbobenzyloxy-L-valyl)-L-l,2,3,4-tetrahydroiso-quinoline-3-carboxylic acid methyl ester To a suspension of 4.4 g (19.3 mmols) of L-l,2,3,4-5 tetrahydroisoquinoline-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) triethyl-amine. The resulting mixture was stirred at room tempera-10 ture and a solution of 4.5 g (21.8 mmols) of dicyclo-hexylcarbodiimide 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 lA. Final concentration gave 8.3 g (101%) of 15 a thick oil.

B. 2-(N-Carbobenzyloxy-L-Valyl)-L-l,2,3,4-tetrahydro-isoqulnoline-3-carboxylic acid 4.5 g (106 mmols) of crude methyl ester prepared 20 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 2 3 hrs., then diluted with 100 ml water and extracted with two 25 ml portions ether. The aqueous 25 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. 200047 EXAMPLE 3 1 A. 2-(N-Carbobenzyloxy-L-isoleucyl)-L-l,2,3,4-tetra-hydroisoquinoline-3-carboxylic Acid 4.5 g (19.8 mmols) of L-l,2,3,4-tetrahydroiso-quinoline-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) dicyclohexyl-^ carbodiimide, 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.

O ' 1 ' t~*j i EXAMPLE 4 2-[N-- (l-ethoxycarbohyl-3-phenypropyl)-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid An ethanolic solution of benzyl 2-(N-carbobenzoxy-5 L-alanyl)-isoquinaldate was hydrogenated with palladium on carbon. The solution was filtered and treated with ethyl 2-oxo-4-phenyl-butyric acid, alkali and sodium cyanoborohydride as in example ID. The product is purified by chromatography and lyophilization. r EXAMPLE 5 1 2-N-(1-Carboxyethyl)-L-alanyl-1,2,3,4-tetrahydroiso-quino1ino-l-carboxylie acid An ethanolic solution of benzyl 2-(N-carbobenzoxy-L-alanyl)-isoquinaldate and pyruvic acid was hydrogenated 5 with palladium on carbon. The filtered solution was concentrated and purified as in example ID. 200047 1 EXAMPLE 6 A. 1-(N-Carbobenzoxy-L-alanyl)-2-benzoxycarboriyliridoline A methylene chloride solution of N-carbobenzyloxy-L-alanine and 2-benzyloxycarbonyl-indoline was treated 5 with N,N'-dicyclohexylcarbodiimide. Purification of the product was accomplished by chromatography on silica gel.

B. 1-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-carboxy-indoline An ethanolic solution of 1-(N-carbobenzyloxy-L- alanyl)-2-benzyloxycarbonyl-indoline was hydrogenated with palladium on carbon. To the filtered solution was added ethyl 2-oxo-4-phenylbutyric acid, alkali and sodium cyanoborohydride as in example ID. The pro-15 duct was purified by chromatography and lyophilization. 2 0004 7 1 EXAMPLE 7 1-[N-(1-Carboxyethyl)-L-alanyl]-2-carboxy-indoline An ethanolic solution of 1-(N-carbobenzyloxy-L-alanyl)-2-benzyloxycarbonyl-indoline was hydrogenated with c palladium on carbon. To the filtered solution was added ethyl pyruvate, alkali and sodium cyanoborohydride. The product was purified by chromatography and lyophilization. 2 00047 1 EXAMPLE 8 1-Benzyloxycarbonyl-2-(N-carbobenzyloxy-L-alanine)-5H-1,2,3,4 -tetrahydro -2-benzazepine A methylene chloride solution of N-carbobenzyloxy 5 -L-alanine and l-benzyloxycarbonyl-5H-l,2,3,4-tetrahydro- 2-benzazepine was treated with N,N'-dicyclohexylcarbodiimide as in example 3A. Purification of the final product was accomplished by silica gel chromatography. 200047 1 EXAMPLE 9 l-Carboxy-2-N-(l-carboxy-3-phenvlpropyl)-L-alanyl-5H-l, 2,3,4-tetrahydro-2-benzazepine An ethanolic solution of l-benzyloxycarbonyl-2-5 (N-carbobenzyloxy-L-alanyl)-5H-1,2,3,4-tetrahydro-2-benza-zepine was hydrogenated with palladium on carbon. The filtered solution was treated with alkali, sodium cyano-borohydride and 2-oxo-4-pnenylbutyric acid as in example ID. The product was purified by chromatography. *00047 1 EXAMPLE 10 l-Carboxy-2-[N-(l-carboxy-3-methylbutyl)-L-alanyl]-5H-1, 2 ,3,4-tetrahydro-2-benzazepine An ethanolic solution of l-benzyloxycarbonyl-2-5 (N-carbobenzyloxy-alanyl)-5H-1,2,3,4-tetrahydro-2-benzazepine was hydrogenated with palladium on carbon. The filtered solution was treated with 2-oxo-4-methyl-pentanoic acid, sodium cyanoborohydride and alkali as in example ID. Chromotography and lyophilization 10 provided the pure product. 2 0 00 4 7 1 EXAMPLE 11 2-(N-(l-Carboethoxy-3-Phenylpropyl)-L-Alanyl)-6,7-Methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-Carboxylic Acid By the procedure in example 1A, 6,7-methylenedioxy- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester was coupled with carbobenzyloxy-L-alanine using dicyclo-hexylcarbodiimide in acetonitrile. The crude neutral product was then hydrolyzed with two equivalents of NaOH 10 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 0°C. 0.675 g (1.81 mmol) of this dipeptide was added to a solution of 1.47 g (7.13 mmol) of 15 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 NaBH^CN were added and the stirring continued 20 an additional 48 hours. The reaction mixture was transferred to a column of Dowex 50X8 and the column eluted with 50% EtOH, H20, 1% NH4OH, and 3% NH^OH. Fractions containing the desired product were combined and lyophilized to give 0.347 g of the diastereomeric mixture. 200047 1 EXAMPLE 12 2-(N-(1-Carboethoxy-l-(2-indanyl)methyl)-L-alanyl)-6-chloro-1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid In a similar manner the appropriate dipeptide was 5 prepared from 6-chloro-l,2,3,4 - tetrahydroisoquinoline-3-carboxylic 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 10 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 15 then gave 0.183 g of desired product. 2 000 47 1 EXAMPLE 13 2-(N-(l-Carboethoxy-3-(2-Pyridyl)propyl)L-valyl)-6-methoxy-1,2,3,4-tetrahydroisoguinoline-3-carboxylic acid The starting dipeptide was prepared as indicated 5 above from 6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-valine. Hydroxybenzotriazole-mediated DCC coupling, followed by saponification and deblocking as before, gave the dipeptide salt. Reductive alkylation with ethyl 2-oxo-10 4-(2-pyridyl)butyrate in the presence of sodium cyano-borohydride 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. 2 0 00 4 7 EXAMPLE 14 2-(N-(l-carboethoxy-3-(4-methoxyphenyl)propyl)-L-isoleucyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ^ The starting dipeptide was prepared from carbo- benzyloxy-L-isoleucine and 6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinoline-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 product. This was purified as before to give the title compound as a diastereomeric mixture. 2 00047 1 EXAMPLE 15 2-(N-(l-Carboethoxy-3-(4-chlorophenyl)-L-alanyl)-7-methoxy-1,2,3,4-tetrahydro-5H-benz[c]azepine-3-carboxylic acid Acylation of 1,2,3,4-tetrahydro-5H-benz[c]azepine-3- carboxylic acid methyl ester with carbobenzyloxy-L-alanine using DCC as coupling reagent as 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 12 gave a mixture containing the desired product. This was isolated by ion exchange chromotography and lyophilization as previously described. 2 0004 1 EXAMPLE 16 2-(N-(l-Carboethoxy-3-(4-pyridyl)propyl)-L-alanyl)-1,2,3,4-tetrahydro-5H-benz[c]azepine-3-carboxylic acid The starting dipeptide was prepared from carbo-5 benzyloxy-L-alanine and 1,2,3,4-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 N-10 alkylated peptide. Purification by ion exchange chromatography and lyophilization gave the pure title compound as a mixture of diastereomers. 2 0004 7 1 EXAMPLE 17 2-(N-l-(Carboethoxy-3-(3-trifluoromethylphenyl)propyl -L-valyl) -7 , 8-methylenedioxy.-l ,2,3, 4-tetrahydro-5H-benz [c]azepine-3-carboxylic acid 5 Acylation of 7,8-methylenedioxy-l,2,3,4-tetra- hydro-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 10 with HBr/HOAc to give the desired peptide.

Treatment of the dipeptide with ethyl 2-oxo-4-(3-trifluoromethylphenyl)butyrate and sodium cyanoborohydride at pH 6.55 according to example 12 gave the N-alkylated product. Ion exchange chromatography and lyophilization 15 gave the pure compound as a mixture of diastereomers. 2 0004 1 EXAMPLE 18 Stereospecific synthesis of the S-configuration compounds is accomplished by the following procedure.

A. 2-(N-(l-Carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4- tetrahydroisoquinoline-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 2 0 ml dry THF was added 1.51 g (9.3 mmol) of 1,11-carbonyldimidazole.

When a clear solution was obtained (5-10 min.), the 10 reaction mixture was cooled to 0° and 3.12 g (7.44 mmol) of (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester monotartrate was added. The reaction mixture was allowed to stir at room temperature overnight, then concentrated in vacuo and redissolved in 15 ether. The ether solution was washed with saturated NaHCO^ solution and water and concentrated to give 2.2 g (56%) of the desired amide, which was used without further purification CIMS: 529(n=l), 234, 91 20 NMR: 7.3, 5.1, 3.15, 2.8, 1.2-1.5 B. 2-(N-(l-Carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride To a solution of 2.10 g (3.97 mmol) of (S,S,S)-2-(N-(l-carboethoxy-3-phenylpropyl)alanyl)-1,2,3,4-tetra-25 hydroisoquinoline-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 30 HC1. The aqueous solution was lyophilized and the 2 000 1 resulting powder washed with ether to give 0.70 g (37%) of product, m. 101-105°. [ eC ]d -10.9° (H20) CIMS 421 (M+1-H20) EIMS 421, 316, 270 Calc. for C25H31N205.HC1.H20 C 60.91 H 6.74 N 5.18 Found C 61.16 H 6.47 N 5.48 Following the procedures of the above examples, the following additional compounds were prepared: 2-[N-(l-Ethoxycarbonyl-3-methylbutyl)-L-alanyl]-1,2,3,4- . tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-4-methylhexyl)-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-5-methylhexyl)-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-[N-(1,3-Dicarboxypropyl)-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-6-hydroxy- 1,2,3,4-tetrahydroisoguinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-5-methylhexyl)-L-valyl]-1,2,3,4- tetrahydroisoquinoline-l-carboxylic acid 2-[N-(1,3-Dicarboxypropyl)-L-alanyl]-6-methoxy-l,2,3,4- tetrahydroisoquinoline-l-carboxylic acid 2- [N- (l-Ethoxycarbonylhexyl)-L-valyl] -8-methyl-l ,2,3,4- tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-phenylalanyl]-6-chloro-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 2-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-histidyl]-8-hydroxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 1-[N-(l-Ethoxycarbonyl-3-methylbutyl)-L-alanyl]-2-carboxy-indoline 1-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-phenylalanyl]-2-carboxy-indoline 20 1-[N-(1-Ethoxycarbonylhexyl)-L-alanyl]-2-carboxyindoline 1-[N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-2-carboxy-5,6-dimethylindoline 1- [N-(l-Ethoxycarbonyl-3-phenylpropyl)-L-valyl]-2-carboxy-indoline l- [N-(1,3-Dicarboxypropyl)-L-alanyl]-2-carboxy-5,6-dimethylindoline 1- [N-(1,3-Dicarboxypropyl)-L-histidyl]-2-carboxy-4-chloro-indoline 1-[N-(1-Ethoxycarbonylhexyl)-L-valyl]-2-carboxy-4-methoxy-30 indoline 1-[N-(1-Ethoxycarbonylheptyl)-L-phenylalanyl]-2-carboxy-6-methyl-indoline £ut)047 l-Carboxy-2-[N-(l-ethoxycarbonyl-3-phenylpropyl)-L-valyl]-5H-1,2,3,4-tetrahydro-2-benzazepine 5 l-Carboxy-2-[N-(l-ethoxycarbonyl-3-methylbutyl-L-histidyl]-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-ethoxycarbonyl-4-methylpentyl)-L-phenylalanyl ]-5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1,3-dicarboxypropyl)-L-alanyl]-7,8-dimethyl-10 5H-1,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-ethoxycarbonyl-3-phenylpropyl)isoleucyl]-6-chloro-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(1-ethoxycarbonylhexyl)-L-valyl]-6-methoxy-7-methyl-1,2,3,4-tetrahydro-2-benzazepine 15 l-Carboxy-2-[N-(l-ethoxycarbonyl-3-phenylpropyl)-L-histidyl] -6-chloro-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-carboxy-2-phenylthioethyl)-L-alanyl]-7-methyl-5H-l,2,3,4-tetrahydro-2-benzazepine l-Carboxy-2-[N-(l-ethoxycarbonyl-3-p-chlorophenylpropyl)-L-20 valyl]-7,8-dimethyl-5H-l,2,3,4-tetrahydro-2-benzazepine 1-Carboxy-2-[N-(l-carboxy-2-(3-indolyl)ethyl]-L-valyl]-5H-1,2,3,4-tetrahydro-2-benzazepine 2-(N-l(l-Carboethoxy-3-(4-chlorophenyl)propyl)-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(3-trifluoromethylphenyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-2-(3-methoxyphenyl)ethyl)-L-methionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylie acid 2-(N-l(l-Carboethoxy-3-(4-pyridyl)propyl)-L-alanyl)-1,2,3,4-30 tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-lysyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 200 1 2-(N-l(l-Carboethoxy-3-(3-pyridyl)propyl)-L-leucyl)-1,2,3,4-tetrahydroisoguinoline-3-carboxylie acid 2-(N-(l-Carboethoxy-2-(2-thienyl)ethyl)-L-Arginyl)-1,2,3,4-tetrahydroisoguinoline-3-carboxylic acid 5 2-(N-l(l-Carboethoxy-3-(methylthio)propyl)-L-isoleucyl)-1,2,3,4-tetrahydroisoguinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(3-thienyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(1-Carboethoxy—2-phenylethyl)-L-lysyl)-1,2,3,4-tetra-10 hydroisoquinoline-3-carboxylic acid 2-(N-l(1-Carboethoxy-2-(phenoxy)ethyl)-L-lysyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(2-furyl)propyl)-L-valyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 15 2-(N-l(l-Carboethoxy-3-(3,4-methylenedioxy-phenyl)propyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(3-chlorophenyl)propyl)-L-phenylalanyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(2-methoxyphenyl)propyl)-L-tyrosyl)-20 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-2-(benzofuran-3-yl)ethyl)-L-leucyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-alanyl)-6-chloro-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 25 2-(N-l(l-Carboethoxy-3-(phenoxy)propyl)-L-arginyl)-6,7- methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-2-(indol-3-yl)ethyl)-L-leucyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(4-methoxyphenyl)propyl)-L-leucyl)-5H-30 1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 2-(N-l(l-Carboethoxy-3-(3-pyridyl)propyl)-L-methionyl)-5H-1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid <^'j00'i7 1. 1 2-(N-l(l-Carboethoxy-3-(methylthio)propyl)-L-leucyl)-5H-1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 2-(N-l(l-Carboethoxy-2-(4-imidazolyl)ethyl)-L-valyl)-7-methoxy-5H-l,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 5 2-(N-l(l-Carboethoxy-3-(3-methoxyphenyl)propyl)-L-lysyl)-6,7-methylenedioxy-5H-l,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 2. 2-(N-l(l-Carboethoxy- 3. 3-(3-chlorophenyl)propyl)-L-histidyl)-5H-1,2,3, 4. 4-tetrahydrobenz[c]azepine-3-carboxylic acid 10 2-(N-l(l-Carboethoxy-3-(3-thienyl)propyl)-L-arginyl)-7- methoxy-5H-l,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid 2-(N-l(l-Carboethoxy-2-phenylethyl)-L- tyrosy]) -7-chloro-5H-1,2,3,4-tetrahydrobenz[c]azepine-3-carboxylic acid N-(l-Carboxy-2-indanylmethyl)-alanyl-1,2,3,4-tetrahydroiso-15 quinoline-3-carboxylic acid The compounds of the present invention have demonstrated potent activity (of the order of 1,-q of 0.02 to 0.20 micromols) in inhibiting the angiotensin converting enzyme (ACEI activity) when tested by the method described in Science 196, 20 441-4 (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 25 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 (1)

1. WHAT WE CLAIM IS: - 32 - * V 0 V 'i;1. A compound of the formula lower alkyl,;R2' ^3' ^4' ^5 an<^ Rg are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused arylcycloalkyl, 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 Rg is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, trifluoromethyl and may be the same or different; or, when two adjacent Rg groups are present, methylenedioxy.;wherein the alkyl groups in alkyl per se, aralkyl, alkoxy, aminoalkyl,, thioalkyl, haloalkyl and hydroxyalkyl contain from 1-6 carbon atoms; the alkenyl and alkynyl groups contain 2-6 carbon atoms; the aryl groups contain from 6-10 carbon atoms; and the cycloalkyl groups contain from 3-7 carbon atoms;;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.;-33-;& kJ {J \ j f;2. A compound of the formula;COOR;10;R-i OOC;15;wherein;R^, R2, R^, R^, R^, Rg, R^, Rg, and n are as defined in Claim 1 and salts thereof, especially pharmaceutically acceptable salts with an acid or a base. 20 3. A compound according to Claim 1 or 2, 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 R^ is hydrogen.;25 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 R2 is phenyl-lower alkyl.;7. A compound according to Claim 6, wherein 30 R2 is phenethyl.;8. A compound according to any of Claims 1-7, wherein Rg is methyl.;35;IfjWARris:;-34-;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 anti-hypertensively 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 of formula VI herein with an OC -halo acid or ester of formula VIII herein; and;20 optionally by substitution or conversion reactions introducing various substituents into the said products; and optionally forming salts thereof, especially pharma-ceutically 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.;wherein R?;16.;30 wherein R^;17.;wherein R2;35;A process according to Claim 13 or 14, is hydrogen.;A process according to any of Claims 13-15, is ethyl or hydrogen.;A process according to any of Claims 13-16, is phenyl-lower alkyl.;f;OlMARl^;-3 5. 5-;*u0047 18. A process according to Claim 17, wherein R2 is phenethyl. 19. a process according to any of Claims 13-18, wherein Rg is methyl. 5 20. A process according to any of Claims 13-18, wherein Rg is isopropyl. 21. A process according to any of Claims 13-18, wherein Rg is isobutyl. 22. A process according to any of Claims 13-17, 10 wherein R2 is phenethyl and Rg is methyl. 23. A compound of formula I substantially as- specifically described herein with reference to any one of the Examples. 24. A pharmaceutical composition comprising a compound of Formula I substantially as specifically described herein with reference to any one of the Examples. 25. A process of preparing a compound of formula I substantially as specifically described herein with reference to any one of the Examples. wherein R^ and R? are hydrogen, lower alkyl oij phenyl lower alkyl, R2, R4' R5 an^ R6 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, fused arylcycloalkyl, 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; 26. a compound of the formula coor7 "36" 200047 each Rg is lower alkyl, lower alkenyl, lower alkynyl, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercapto-alkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, trifluoromethyl and may be the same or different; or, when two adjacent Rg groups are present, methvlenedioxy; wherein the alkyl groups in alkyl per se, aralkyl, alkoxy, aminoalkyl, thioalkyl, haloalkyl and hydroxyalkyl contain from 1-6 carbon atoms; the alkenyl and alkynyl groups contain 2-6 carbon atoms; the aryl groups contain from 6. 6-10 carbon atoms; and the cycloalkyl groups contain from 3-7 carbon atoms; COOR^ is attached at the 1-position on the isoqui-linoline ring; 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. 27. A pharmaceutical composition comprising a compound as claimed in claim 26 together with a pharmaceutically acceptable carrier therefor. H BURTON Commissioner of Patents BALDWIN, SON & CAREY Reference has been directed, in pursuance of section 14 of the Patents Act 1953, to specification No.193195. Reference has been directed, in pursuance of section 14 of the Patents Act 1953, to specification No.198542. attorneys for the applicants