DE3209708A1 - PEPTIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new compounds having valuable pharmacological activity. In particular, it relates to Verbin Applications with antihypertensive effect and inhibitory effect on the angiotensin converting enzyme and with the structure

COOR

R10OC

< ^R 8> n

wherein R ₁ and R_ are each hydrogen, lower-alkyl or phenyl-lower-alkyl; Rp, R_, R., R ₁ . and R _{ß are} each hydrogen, alkyl, alkenyl, alkynyl, aryl, condensed aryl-cycloalkyl, aralkyl, cycloalkyl and heterocyclic and can be the same or different;

Rg in each case alkyl, alkenyl, akinyl, nitro, amino, alkylamino ,. Dialkylamino, hydroxy, alkoxy, mercapto, alky! Mercapto, hydroxyalkyl, mercaptoalkyl, halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, methylenedioxy and trifluoromethyl and, if more than one group R _{R is} present, the groups may be the same or different can;

m is an integer from 0 to 2; and m ^{1 is} an integer from 1 to 3 provided that when m is 0, m ^{1 is} 2 or 3, and when m is other than 0, m 'is 1 or 2;

η is an integer from 0 to 4;

and salts thereof, especially salts with pharmaceutically acceptable acids and bases.

The alkyl groups in alkyl per se, aralkyl, alkoxy, aminoalkyl,

Thioalkyl, haloalkyl and hydroxyalkyl are preferably lower-alkyl with 1 to 6 carbon atoms and can be branched or be straight chain.

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

The alkyl, alkenyl and alkynyl groups can have substituents such as hydroxy, alkoxy, halogen, amino, alkylamino, Mercapto and alkyl mercapto.

The cycloalkyl groups contain 3 to 7 carbon atoms. Such Cycloalkyl groups include cycloalkyl-alkyl, and the Cycloalkyl groups can carry substituents such as alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, amino, Aminoalkyl, alkylamino, trifluoromethyl and nitro.

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

The fused aryl-cycloalkyl includes phenyl rings attached to Cycloalkyl rings having 3 to 7 carbon atoms are fused. These groups also include fused aryl-cycloalkylalkyl.

The heterocyclic group can 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 can also carry substituents, as described above for the aryl groups. The hetero-

3203708

ι cyclic group also includes hetercyclic-lower-alkyl. The halogen groups include fluorine, chlorine, bromine and iodine.

The group -COOR- is preferably on a carbon atom bonded 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, pumarat, 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, potassium, sodium, magnesium and calcium and iron, as well as ammonium and quaternary ammonium salts.

It goes without saying that the compounds according to the invention are a or can have several asymmetric carbon atoms and the various racemic mixtures as well as the individual optically active compounds fall within the scope of the invention.

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

R ₇ OOC ρ

I - Γ oL (R ₈ )

HN XJ ^{ö n}

with an acylating derivative of the acid of formula 35

R ₁ OOC

3 L

320S708

A1

OH

III

Alternatively, the compounds wherein R ₃ and R _{4 are} hydrogen can be readily prepared by treating a compound of formula II with a compound of formula

COOH

IV

under amide-forming conditions to form a compound of the structure

COOR-;

Cleavage of the carbobenzyloxy group to form a free amine of the structure

- -er -

COOR ₇

< ^R 3> n

VI

and reaction of the amine with a C 1 -C 4 keto acid or a Ester of the formula

R ₁ OOC

I!

* "" Rr

VII

and reducing the resulting imine to form a compound of Formula I wherein R ₃ and R _{4 are} hydrogen.

The compounds of the formula VI can also be treated with an oC -halic acid or an ester of the formula

R ₁ OOC

C - shark

R-,

VIII

are reacted to form compounds of formula I wherein R ₃ and R ₄ can be H or any other substituents which R ₃ and R ₄ can represent.

In the following reaction sequence, R ₁ to R _g , m, m ¹ and η are

as defined above and Hai is halogen.

Preferably R ^, R ₃ , R ₄ , R ₅ and R_ and R _{g are} hydrogen. R "is lower-alkyl or phenyl-lower-alkyl, R _ß is lower-alkyl.

The amide-forming conditions mentioned here include the use of known derivatives of the acids described, such as the acyl halides, anhydrides, mixed anhydrides, lower-alkyl esters, carbodiimides, carbonyldiimidazoles and the like. The reactions are carried out in organic solvents such as acetonitrile, tetrahydrofuran, dioxane, Acetic acid, methylene chloride and ethylene chloride and like such solvents. The amide-forming reaction takes place at room temperature or at an elevated temperature. The use of an elevated temperature is expedient since it enables somewhat shorter reaction times. Temperatures in the range from ⁰ ° C. to the reflux temperature of the reaction system can be used. As a further facilitation, the amide-forming reaction can be carried out in the presence of a base such as tertiary organic amines, e.g. trimethylamine, pyridine, picolines and the like, especially when hydrogen halide is formed by the amide-forming reaction, e.g. acyl halide and amino compound. Of course, when hydrogen halide is generated, any of the commonly used hydrogen halide acceptors can be used in such reactions.

In the condensation of oC halogen acid derivatives of the above Formula VIII can have similar or identical reaction conditions, solvents and hydrogen halide acceptors, as used for amide formation.

Various substituents of the new compounds according to the invention, for example as _{defined for R ß} , can be present in the starting compounds or after formation of the amide

* ■ products are added or added according to known methods for substitution or conversion reactions »The nitro group can be added to the end product by nitration on the aromatic ring, and the nitro group can be converted into other groups, such as amino, by reduction and halogen by diazotizing the amino group and replacing the diazo group. Other reactions can be performed on the amide product formed. Amino groups can be alkylated to form mono- and dialkylamino groups, mercapto and hydroxy groups can be alkylated to form the corresponding ethers. Thus, substitution reactions or altering reactions can be used to provide different substituents in the molecule of the end products. Of course, reactive groups, if present, should be protected by suitable protecting or blocking groups during any of the above reactions, in particular the condensation reactions for the formation of the amide bonds.

® The acid and base salts of the new compounds according to the invention can be formed using conventional procedures. Often they are formed in situ during the preparation of the novel amidoamino acids according to the invention.

The compounds of the invention are evidently in stereoisomeric forms, and the products so obtained may be mixtures of the isomers which can be separated. Alternatively, the preferred stereoisomer can be generated by choosing the specific isomers as starting compounds

Become J50. Thus, the preferred forms in which each center of asymmetry (Chirialzentrum) has the S configuration, preferably produced in a stereospecific route instead of attempting to cleave the mixture of isomers. The connections in which the S configuration at all Centers of asymmetry are most active; those in which the R configuration is present are less active; and those

209708

where both the R and the S configurations are present, have an intermediate activity.

The following examples serve to further illustrate the invention.

example 1

A) 2- (N-Benzyloxycarbonyl-L-alanyI) -L-I, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester

To a suspension of 10.0 g (43.9 mmol) of L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester hydrochloride and 10.4 g (46.6 mmol) of carbobenzyloxy-L-alanine in 150 4.4 g (43.6 mmol) of triethylaitiin were added to ml of dry acetonitrile. A solution of 9.2 g (44.6 mmol) of Ν, Ν-dicyclohexylcarbodiimide in 5 ml of dry acetonitrile was then added dropwise with stirring. The resulting slurry was stirred at room temperature overnight, filtered and concentrated in vacuo. The residue was redissolved in ether, washed sequentially with In-HCl, saturated NaHCO _3, and brine, _{dried over MgSO 4} , filtered and concentrated to give 18.3 g (105%) of crude amide, which was used without further purification .

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

■:

8.0 g of the crude amide ester of A were dissolved in 25 ml of 1N NaOH / MeOH. 5 ml of water were added to this. The resulting solution was stirred at room temperature overnight, then poured into 150 ml of water and extracted with ether. The aqueous layer was then acidified and extracted _{with CH 3} Cl _2. The extracts were dried _{over MgSO 4}

and concentrated, at water pump pressure, to give 5.5 g of product. After concentrating for a long time in an oil pump vacuum a brittle foam was obtained.

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

To a solution of 4.8 g (12.5 mmol) of crude carbobenzyloxycarboxylic acid 5 ml of saturated HBr in acetic acid were added to 7 ml of acetic acid. The solution was at room temperature stirred until all gas evolution ceased (1 to 1.5 h) A slow stream of air was passed through the solution for removal Passed by excess HBr, and then 25 ml of ether were 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 solid with a melting point of 180 °.

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

To a solution of 1.3 g (6.63 mmol) of benzylpyruvic acid hydrate in 5 ml of saturated NaHCO ₃ , 0.307 g (0.93 mmol) of alanyl-1,2,3 ^ -tetrahydroisoquinoline-S-carboxylic acid, followed by 0.238 g ( 3.79 mmol) sodium cyanoborohydride, added. The solution was stirred at room temperature overnight and then transferred to a column with 20 g of Dowex 5OX8. The column was eluted with 50% MeOH and then with 3% NH ₄ OH. The first fractions of ammonia containing the desired product were combined and lyophilized to give 85 mg of product as a fluffy white powder, mp 97-101 °.

in the-

Example 2

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

To a suspension of 4.4 g (19.3 mmol) of L-1,2,3,4-tetrahydroisoquinoline-S-carboxylic acid methyl ester hydrochloride in 50 ml of dry acetonitrile were 5.2 g (20.7 mmol) of N-carbobenzyloxy-L-valine, 2.7 g (20.0 mmol) of 1-hydroxybenzotriazole and 2.1 g (20.7 mmol) of triethylamine added. The resulting mixture was stirred at room temperature, and a solution of 4.5 g (21.8 mmol) of dicyclohexylcarbodiimide in 10 ml of dry acetonitrile was slowly added. The mixture was over Stirred overnight at room temperature, then filtered and worked up as described in Example 1A. The final Concentration gave 8.3 g (101%) of a thick oil.

B) 2- (N-carbobenzyloxy-L-valy1) -L-1,2,3,4-tetrahydro-

isoquinoline-3-carboxylic acid

4.5 g (106 mmol) of crude methyl ester (prepared by the above procedure) was treated with 10 ml of 10% NaOH and sufficient methanol (35-40 ml) to form a homogeneous solution. This solution was stirred at room temperature for 23 h, then diluted with 100 ml of water and extracted with two 25 ml portions of ether. The aqueous fraction was then acidified and extracted with four 10 ml portions of methylene chloride. The extracts were _{dried over MgSO 4} and concentrated to give 3.8 g (9.3 mmol, 87%) of homogeneous carboxylic acid.

Al

Example 3

2- (N-carbonbenzyloxy-L-isoleucyl) -L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

4.5 g (19.8 mmol) L-1,2,3 ^ -Tetrahydroisoquinoline-S-carboxylic acid methyl ester hydrochloride, 5.3 g (20.0 mmol) of N-carbobenzyloxy-L-isoleucine, 2.7 g (20.0 mmol) of 1-hydroxybenzotriazole and 2.1 g (20.7 mmol) of triethylamine were, as described in Example 2A, with 4.4 g (21.3 mmol) of dicyclohexylcarbodiimide treated, then worked up to form 7.8 g (90%) of crude methyl ester. This was dissolved in 30 ml of methanol and treated with 10 ml of 10% NaOH. The solution was stirred overnight at room temperature and then as before

^ -5, as described above, worked up, with the formation of 1.8 g (21.4% total) of the desired acid as a yellow oil.

Example 4

2 ~ l N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl-isoquinaldic acid

An ethanolic solution of benzyl-2- (N-carbobenzoxy-L-alanyD-isochinaldate was hydrogenated with palladium on charcoal. The solution was filtered and treated with ethyl 2-oxo-4-phenylbutyric acid, Alkali and sodium cyanoborohydride treated as in Example 1D. The product was determined by chromatography and Lyophilize purified.

Example 5

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

An ethanolic solution of benzyl-2- (N-carbobenzoxy-L-alanyl) -isoquinaldate and pyruvic acid was mixed with palladium

hydrogenated on coal. The filtered solution was concentrated and purified as in Example 1D.

Example 6

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

A methylene chloride solution of N-carbobenzyloxy-L-alanine and

2-Benzyloxycarbonyl-indoline was _{treated with N 7} N ¹ -dicyclohexylcarbodiimide. The purification of the product was carried out by chromatography on silica gel. 15th

B) 1- / ~ N- (1-Ethoxycarbonyl-3-phenylpropyl) -L-alanyl_7-2-carboxy-indoline

An ethanolic solution of 1- (N-carbobenzyloxy-L-alanyl) -2-benzyloxycarbonyl-indoline was hydrogenated with palladium on carbon. Ethyl 2-oxo-4-phenyl butyric acid _7- alkali and sodium cyanoborohydride were added to the filtered solution as in Example 1D. The product was purified by chromatography and lyophilization.

Example 7

1- / N- (1-carboxyethyl) -L-alanyl_7-2-carboxy-indoline

An ethanolic solution of 1- (N-carbobenzyloxy-L-alanyl) 2-benzyloxycarbonyl-indoline was hydrogenated with palladium on charcoal. Ethyl pyruvate, Alkali and sodium cyanoborohydride added. The product was purified by chromatography and lyophilization.

Example 8

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

A methylene chloride solution of N-carbobenzyloxy-L-alanine and 1-benzyloxycarbonyl-SH-1, 2,3,4-tetrahydro-2-benzazepine was ^{treated with N, N 1} -dicyclohexylcarbodiimide as in Example 3A. The final product was purified by chromatography on silica gel.

Example9

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

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

Example ok

1-Carboxy-2- / ~ N- (1-carboxy-3-methylbutyl) -L-alanyl_7-5H-1,2,3,4-tetrahydro-2 * -benzazepine

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

- yr-

Example 11

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

Following the procedure of Example 1A, 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diethyl ester was obtained with carbobenzyloxy-L-alanine using dicyclohexylcarbodiimide coupled in acetonitrile. The crude neutral product was then treated with 2 equivalents of NaOH in 80% MeOH hydrolyzes to form the desired carboxylic acid.

The above carbobenzyloxydipeptide was unblocked according to the procedure of Example 1C at an original reaction ^{temperature of 0} ° C. 0.675 g (1.81 mmol) of this dipeptide were converted into a solution of 1.47 g (7.13 mmol) of ethyl-2 -oxo-4-phenylbutyrate in 25 ml EtOH added. 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 0.70 g of ester and 0.2 g of NaBH ₃ CN were added and stirring was continued for a further 48 hours. The reaction mixture was transferred to a Dowex 50X8 column and the column was eluted with 50% EtOH, H ₂ O, 1% NH ₄ OH, and 3% NH ₄ OH. Fractions containing the desired product were combined and lyophilized to give 0.347 g of the mixture of diastereomers.

Example 12

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

The corresponding dipeptide was prepared in the same way from 6-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester and carbobenzyloxy-L-alanine by DCC coupling, followed by saponification and splitting with HBr / HOAc.

0.427 g (1.17 mol) of the above dipeptide were added as described above with 1.5 g (6.87 mmol) of ethyl- ^c V-oxindane-2-acetate and 0.32 g (5.09 mmol) of NaBH ₃ CN alkylated at pH 6.75. After 24 hours, a second portion of 0.85 g of the keto ester and 0.2 g of NaBH ₃ CN were added. The reaction was then stirred for 40 hours. Ion exchange chromatography then gave 0.183 g of the desired product.

Example 13

2- (N-i-Carboethoxy-3- (2-pyridyl) -propyl) -L-valyl) -6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The starting dipeptide was prepared from 6-methoxy-1,2,3 ^ -tetrahydroisoquinoline-S-carboxylic acid methyl ester as indicated above and carbobenzyloxy-L-valine. Hydroxybenzotriazole-one Hydroxybenzotriazole-mediated DCC coupling, followed by saponification and deblocking, as before.

described above gave the dipeptide salt. Reductive alkylation with ethyl 2-oxo-4- (2-pyridyl) butyrate in the presence of sodium cyanoborohydride under standard conditions gave the crude monoester. This was purified by ion exchange chromatography and lyophilizing as described above to form a mixture of the diastereomers of the desired product.

Example 14

2- (N- (i-Carboethoxy-3- (4-methoxyphenyl) propyl) -L-isoleucyl) 6,7-diraethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

The starting dipeptide was prepared on carbobenzyloxy-L-isoleucine and 6,7-dimethoxy-i, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester using hydroxy-benzo-

triazole and DCC as described above. Obtained by saponification and removal of the protecting group as described above one the dipeptide hydrobromide.

By treating with ethyl 2-oxo-4- (4-methoxyphenyl) butyrate and sodium cyanoborohydride under the standard conditions above the reductive alkylation product was obtained. This was purified as above to give the Title compound as a mixture of diasters.

Example 15

2- (N- (i-Carboethoxy-3- (4-chlorophenyl) -L-alanyl) -7-15-methoxy-1,2,3,4-tetrahydro-5H-benz / ~ c-7azepine-3-carboxylic acid

The acylation of 1,2,3,4-tetrahydro-5H-benz / c_7azepine-3-carboxylic acid methyl ester with carbobenzyloxy-L-alanine using DCC as the coupling reagent as in Example 1A 20 the protected dipeptide. Saponification and deblocking gave the free dipeptide as described above.

N-alkylation with ethyl 2-oxo-4- (4-chlorophenyl) butyrate and sodium cyanoborohydride as in Example 12 gave a mixture 25 containing the desired product. This was done through ion exchange chromatographed and lyophilize as described above, isolated.

Example 16

2- (N- (i-Carboethoxy-3- (4-pyridyl) -propyl) -L-alanyl) -1,2,3,4-tetrahydro-5H-benz ^ c_ / azepine-3-carboxylic acid

35The starting dipeptide was prepared from carbobenzyloxy-L-alanine and 1,2,3,4-tetrahydro-5H-benz / c_7-azepin-3-carbon-

IH

acid methyl ester according to the general procedure of Example 1. The reductive alkylation as described above, using ethyl 2-oxo-4- (4-pyridyl) butyrate and sodium cyanoborohydride gave crude N-alkylated peptide.

Purification by ion exchange chromatography and lyophilization gave the pure title compound as a mixture of the diastereomers.

Example17

2- (N-1- (Carboethoxy-3- (3-trifluoromethylphenyl) -propyl-L-valyl) -7,8-methylenedioxy-1,2,3,4 ~ tetrahydro-5H-benz / c_7azepine-3-carboxylic acid

The acylation of 7,8-methylenedioxy-1,2,3,4-tetrahydro-5H-benz / c_7azepine-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 form of the desired peptide.

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

Example 18

The sterospecific synthesis of the compounds with the S configuration is achieved using the following procedure:

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

1.51 g (9.3 mmol) of 1, 1'-carbonyldimidazole added. 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) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester monotartrate were added. The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and redissolved in ether. The ether solution was washed with saturated NaHCO 3 solution and water and concentrated to give 2.2 g (56%) of the desired amide, the
was used without further purification.

CIMS: 529 (n-1), 234, 91

NMR: 7.3, 5.1, 3.15, 2.8, 1.2-1.5

B) 2- (N- (1-Carboethoxy-3-phenylpropyl) -alanyl) -1,2,3,4-

tetrahydroisoquinoline-S-carboxylic acid hydrochloride

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

(^) _Λ -10.9 ° (H ₉ O)

"ti

CIMS 421 ₂
EIMS 421, 316, 270

Analysis for C ₂₅ H ₃₁ N ₂ O ₅₂

Calculated: C 60.91, H 6.74, N 5.18 found: C 61.16, H 6.47, N 5.48

The following additional compounds were prepared according to the procedure of the preceding examples:

2- / ~ N-1-ethoxycarbonyl-3-methylbutyl) -L-alanyl_7-isoquinaldic acid,

2- / ~ N ~ 1-ethoxycarbonyl-4-methylhexyl) -L-alanyl_7-isoquinaldic acid,

2- / ~ N ~ 1-ethoxycarbonyl-5-methylhexyl) -L-alanyl_7-isoquinaldic acid,

2 ~ / ~ N-1,3-dicarboxypropyl) -L-alanyl_7-isoquinaldic acid, 2 ~ / ~ N ~ 1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl_7-6 ~ hydroxyisoquinaldic acid,

2- / ~ N-1-ethoxycarbonyl-5-methylhexyl) -L-valyl_7 ~ isoquinaldic acid,

2- / ~ N ~ 1, 3-dicarboxypropyl) -L-alanyl_7-6-methoxy-isoquinaldic acid,

2- / ~ N-1-ethoxycarbonyl-3-phenylpropyl) .L-phenylalanyl-7-6-chloroisoquinaldic acid

2- / ~ N-1-ethoxycarbonyl-3-phenylpropyl) -L-histidyl_7-8-hydroxyisoquinaldic acid

1- / ~ n- (1-ethoxycarbonyl-3-raethylbutyl) -L-alanyl_7-2-carboxyindoline,

1- / ~ N- (1-ethoxycarbonyl-3-phenylpropyl) -L-phenylalanyl_7-2-carboxy-indoline,

1- / Ä7- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl_7-2-carboxy-5,6-dimethylindoline,

1- / N- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl_ / - 2-carboxyindoline,

1209708

1- / 7 ^ - (1,3-dicarboxypropyl) -L-alanyl_7-2-carboxy-5,6-dimethylindoline,

1 - / "n- (1,3-dicarboxypropyl) -L-histidyl_7-2-carboxy-4-chloroindoline,
1 - ^ "n- (1-Ethoxycarbonylhexyl) -L-valyl_7-2-carboxy-4-methoxyindoline,

1- ^ ~ N- (1-ethoxycarbonylheptyl) -L-phenylalanyl_7-2-carboxy-6-methyl-indoline,

1- ^ ~ N- (1-ethoxycarbonyl-3-phenylpropyl) -L-valyl_7-2-carboxy- ^ 3-hydroxymethyl-5,6-dimethylindoline,

1-carboxy-2 - / "N- (1, -ethoxycarbonyl-3-phenylpropyl) -L-valyl_7-5H-1,2,3,4-tetrahydro-2-benzazepine,

1 -Carboxy-2- ₁ / ~ N- (1 -ethoxycarbonyl-3-methylbutyl-L-histidyl_7-

5H-1,2,3,4-tetrahydro-2-benzazepine,
¹ ^ ι -carboxy-2- / ~ N- (1-ethoxycarbonyl-4-methylpentyl) -L-phenylalanyl_7-5H-1 _/ 2,3,4-tetrahydro-2-benzazepine, 1-carboxy-2- / ~ N- (1,3-dicarboxypropyl) -L-alanyl_7 ~ 7,8-dimethyl-5H-1 ^, S ^ -tetrahydro ^ -benzazepine,

1-Carboxy-2- ^ ~ N- (1-ethoxycarbonyl-3-phenylpropyl) -isoleucyl_7 ~ 6-chloro-1,2,3,4-tetrahydro-2-benzazepine, 1-Carboxy-2- ^ ~ N- (1-ethoxycarbonylhexyl) -L-valyl_7-6-methoxy-7-methyl-1,2,3,4-tetrahydro-2-benzazepine, 1-carboxy-2- / ~ N- (1-ethoxycarbonyl-3-phenylpropyl) -L-histidyl_7-

6-chloro-1,2,3,4-tetrahydro-2-benzazepine, ² ^ 1-carboxy-2- / ~ N- (1-carboxy-2-phenylthioethy1) -L-alanyl_7-7-methyl-5H- 1,2,3,4-tetrahydro-2-benzazepine, 1-carboxy-2- / ~ N- (i-ethoxycarbonyl-3-p-chlorophenylpropyl) -L-valyl_7-7,8-dimethyl-5H-1, 2,3,4-tetrahydro-2-benzazepine, 1-carboxy-2- / ~ N- (1-carboxy-2- (3-indolyl) -ethyl-7-L-valyl-7-5H-1,2,3,4 -tetrahydro-2-benzazepine,

2- (N-1- d-Carboethoxy-3- (4-chlorophenyl) -propyl) -L-leucyl) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1-d-carboethoxy-3- (3-trifluoromethylphenyl) propyl) -L-valyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1-d-carboethoxy-2- (3-methoxyphenyl) -ethyl) -L-methionyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

P- [N-1-A * ". HoxycnrV) onylhexyl-L-valyl] -S-methyl- i soctr" raldi psMure ,

2- (N-1- (1-Carboethoxy-3- (4-pyridyl) -propyl) -L-alanyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (4-methoxyphenyl) propyl) -L-lysyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (3-pyridyl) -propyl) -L-leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-d-Carboethoxy-2- (2-thienyl) -ethyl) -L-arginyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

2- (N-1- (1-Carboethoxy-3- (methylthio) -propyl) -L-isoleucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (3-thienyl) -propyl) -L-valyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-2-phenylathy1) -L-lysyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

2- (N-1- (1-Carboethoxy-2- (phenoxy) -ethyl) -L-lysyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (2-furyl) -propyl) -L-valyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (3,4-methylenedioxy-phenyl) -propyl) -L-alanyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (3-chlorophenyl) propyl) -L-phenylalanyl) 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-3- (2-methoxyphenyl) propyl) -L-tyrosyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-2- (benzofuran-3-yl) -ethyl) -L-leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2- (N-1- (1-Carboethoxy-2- (benzofuran-3-yl) -ethyl) -L-leucyl) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

2- (N-1- (1-Carboethoxy-S- (4-methoxyphenyl) -propyl) -L-alanyl) - ^ ⁰ 6-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,

2- (N-1- (1-Carboethoxy-3- (phenoxy) propyl) -L-arginyl) -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid , 2- (N -1- (1-Carboethoxy-2- (indol-3-yl) -ethyl) -L-leucyl) -6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, ^ 5 2- (N -1- (1-Carboethoxy-3- (4-methoxyphenyl) -propyl) -L-leucyl) -5H-1,2,3,4-tetrahydrobenz / c_7azepine-3-carboxylic acid,

209708

1- [N- (I-ethoxycarbonylhexy1) -L-alany I] -P -carboxy indoline

2- (N-1- d-Carboethoxy-3- (3-pyridyl) -propyl) -L-methionyl) -5H-1,2,3,4-tetrahydrobenz / c_7azepine-3-carboxylic acid

-> 2- (N-1-d-Carboethoxy-3- (methylthio) -propyl) -L-leucyl) -5-H-1,2,3,4-tetrahydrobenz ^ c_ / azepine-3-carboxylic acid, 2- (N-d-carboethoxy-2- (4-imidazolyl) -ethyl) -L-valyl) -7-methoxy-5H-1,2,3,4-tetrahydrobenz ^ ~ C_7azepine-3-carboxylic acid,

2- (N-1-d-Carboethoxy-3- (3-methoxyphenyl) -prooyl) -L-lysyl) -in _ * _

^ 6,7-methylenedioxy-5H-1,2,3,4-tetrahydrobenz / c_ / azepine-3-carboxylic acid,

2- (N-1-d-Carboethoxy-3- (3-chlorophenyl) -propyl) -L-histidyl) -5H-1,2,3,4-tetrahydrobenz> / c_ / azepine-3-carboxylic acid 2- ( N-1- (1-Carboethoxy-3- (3-thienyl) -propyl) -L-arginTl) -7-methoxy-5H-1,2,3,4-tetrahydrobenz / c_7azepine-3-carboxylic acid, 2- ( N-1-d-carboethoxy-2-phenylethyl) -L-tryosyl) -7-chloro-5H-1,2,3,4-tetrahydrobenz / ~ c_7azepine-3-carboxylic acid, Nd-carboxy-2-indanylmethyl) - alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.
20th

The compounds of the invention exhibited potent activity (on the order of I ₅₀ from 0.02 to 0.20 micromoles) in inhibiting angiotensin converting enzyme (ACEI activity) when tested according to

^ 5 Method described in Science 196, 441-4 (1977). The compounds according to the invention also show an I ^ ₀ of about 1 to 2 mg / kg po in the inhibition of infused angiotensin I in rats. They are therefore very useful in the treatment of hypertension and high blood pressure.

The compounds can be administered orally or parenterally in the treatment of hypertension and it is within the range to determine the amount administered using the skill of the art. Suitable dosage forms include tablets, Capsules, elixirs and injectable forms.

Claims (22)

TE GRÜNECKER · DR. KlNKELDEY ■ DR. STOCKMAIR DR. SCHUMANN · JAKOS · DR. BEZOLD ■ MBSTER HILGERS-DR. MMR-PLATH USV PHARMACEUTICAL CORPORATION 1 Scarsdale Road Tuckahoe, New York USA P 17 102 Peptide derivatives, processes for their preparation and pharmaceuticals containing them Patent claims 1.1 Connection with the formula * «Β COOR R ₁ OOC where R- and R _{7 are} hydrogen, lower-alkyl or phenyl-lower-alkyl, R ₂ , R ₃ , R., R ₅ and R _{fi 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, halogen, amino, alkylamino, mercapto and alkyl mercapto groups, and substituted cycloalkyl, aryl and heterocyclic groups wherein the substituent is alkyl, hydroxy, alkoxy, hydroxyalkyl, halogen, mercapto , Alkylmercapto, mercaptoalky, haloalkyl, amino, alkylamino, aminoalkyl, nitro, methylenedioxy, and tri fluorine thy 1 is; Rg in each case lower-alkyl, lower-alkenyl, lower-alkynyl, Nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, mercapto, alkylmercapto, hydroxyalkyl, mercaptoalkyl, Halogen, haloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, Is sulfonamido, methylenedioxy or trifluoromethyl, m represents an integer from 0 to 2 inclusive; m ^{1 represents} an integer from 1 to 3 inclusive, O Γ * \ Ο H ^ O Ci zUd / Uo provided that when m is O, m ^{1 is} 2 or 3, and when m is different from O, m 'is 1 or 2; η represents an integer from 0 to 4 inclusive, and salts thereof, especially pharmaceutically acceptable salts with an acid or a base. 2. Compound of formula 20th RiOOC COOR- wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R _ß , R ₇ , Rg and η are as defined in claim and the salts thereof, in particular pharmaceutically acceptable salts with an acid or a base. 3 »Compound according to claim 1 or 2, wherein the substituent COOR ₇ on a
is bound. COOR ₇ on a carbon atom adjacent to the ring nitrogen 25th 4. A compound according to any one of claims 1 to 3, wherein is hydrogen. 5. A compound according to any one of claims 1 to 4, wherein R-ethyl or is hydrogen. 6. A compound according to any one of claims 1 to 5, wherein R _{3 is} phenyl-lower-alkyl. 7. A compound according to claim 6, wherein R- is phenethyl. vJ 8. A compound according to any one of claims 1 to 7, wherein R, Is methyl. 9. A compound according to any one of claims 1 to 7, wherein Rg Is isopropyl. 10. A compound according to any one of claims 1 to 7, wherein Rg Is isobutyl. ^ O 11. A compound according to any one of claims 1 to 4, wherein R _{2 is} phenethyl and R _{g is} methyl. 12. Pharmaceutical composition suitable for treatment from high blood pressure, containing an antihypertensive ■ •• 5 effective amount of a compound according to any one of the claims 1 to 11. 20th 13. A process for the preparation of a compound of the formula I according to any one of claims 1 to 11, characterized in that that under amide-forming conditions a compound of the formula II 25th R ₇ OOC with an acylating derivative of an acid of the formula III ^R 2 ^R 5 R ₁ OOC OH L ^R 6 ° III or formula IV COOH implements; or a compound of the formula VI IV 0S708 COOR with a © C keto acid or an ester of the formula VII R ₁ OOC - C - R ₂ 0 VII converts, and the resulting imine is reduced; or a compound of the formula VI (R ₈ ) _n VI with a c ^ halogen acid or an ester of the formula VIII ^R 2 R ₁ OOC - C - Hal ι I VIII R ₃ implements; and optionally introducing various substituents into the products by substitution or conversion reactions; and
15th optionally forming salts thereof, in particular pharmaceutically acceptable salts with an acid or a base. 14. The method according to claim 13, characterized in that the substituent COOR ₇ to a Koh.
is bound to the ring nitrogen. the substituent COOR _{7 is} adjacent to a carbon atom 15. The method according to any one of claims 13 or 14, characterized in that R _{7 is} hydrogen. 16. The method according to any one of claims 13 to 15, characterized in that R _{1 is} ethyl or hydrogen. 17. The method according to any one of claims 13 to 16, characterized 3209703 indicates that R _{2 is} phenyl-lower alkyl. 18. The method according to claim 17, characterized in that
R _{2 is} phenethyl. 19. The method according to any one of claims 13 to 18, characterized in, that Rg is methyl. 20. The method according to any one of claims 13 to 18, characterized in that that Rg is isopropyl. 21. The method according to any one of claims 13 to 18, characterized in, that Rg is isobutyl. 22. The method according to any one of claims 13 to 17, characterized in that R _{0 is} phenethyl and R is methyl. ^ 6