CA1264500A - N-substituted-amido-amino acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds of the formula wherein R and R9 are independently hydroxy, lower alkoxy, lower alkenoxy, di(lower alkyl)amino-lower alkoxy, hydroxy-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryloxyl-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, hydroxyamino, or aryl-lower alkylamino, R1, R2, R3, R4, R5, R7, and R8 are independently alkyl, alkenyl or alkynyl containing up to 20 carbon atoms, aryl or aryl-lower alkyl containing up to 12 carbon atoms, heterocyclic or heterocyclic-lower alkyl containing up to 12 carbon atoms, or cycloalkyl or cycloalkyl alkyl containing up to 20 carbon atoms.
R6 is heterocyclic or heterocyclic alkyl;
R2 and R3 taken together with the carbon and nitrogen to which they are respectively attached and R3 and R5 taken together with the nitrogen and carbon to which they are respectively attached form an N-heterocycle containing from 3 to 5 carbon atoms or 2 to 4 carbon atoms and a sulfur atom, and wherein said alkyl, alkenyl, and alkynyl groups can be substituted with hydroxy, lower alkoxy, thio, lower alkylmercapto, amino, lower alklamino, di(lower alkyl) amino, halogen, and nitro;
and salts thereof, especially salts with pharmaceutically acceptable acids and bases.
The compounds possess hypertensive and antitensin convert-ing enzyme inhibitory activity.

Description

~037 . L _ 1 N-Substitut~cl-~m.ido-~mino ~clcls 'rhis invention rela-tes to new chemic~l compounds having valuable pharrnaceutical activity. It ~articularly relates to comounds possessing hypertensive and angiotensin 5 convertin enzyme inhibitory activity and having the structure Rl R4 R7 ROC ~ N ~ ~-N ~ CORg 10 wherein R and Rg are independently hydroxy, lower alkoxv, lower alkenoxy, di (lower alkyl) amino-lower alkoxy, hydroxy-lower alkoxy, aeylamino-lower alkoxy, aeyloxy~lower alkoxy, aryloxy, aryloxyl-lower alkoxy, amino, lower 15 alkylamino, di-lower alkylamino, hydroxyamino, or aryl-lower alkylamino;
Rl, R2, R3, R4, Rs~ ~7, and R8 are independently hydrogen, alkyl, alkenyl or alkynyl containing up to 20 earbon a-toms, aryl or aryl-lower alkyl containing up to 12 20 carbon atoms, heterocyclic or heterocyelie-lower alkyl having from 6 to 12 carbon atoms or cycloalkyl or cyeloall~;~J1 alkyl containing up to 20 carbon a-toms;
R6 is heteroeyelie and heteroeyelie lower alkyl;
R2 and R3 taken together with the carbon and 25 nitrogen to whi.eh they are respectively attached and ~3 and R5 taken togcther with the nitrogen and carbon to which they are respectively attaehed form an N-heterocycle containing from 3 to 5 carbon atoms or 2 to 4 carbon ato~s and a sulfur atom; and 3 Salts thereof, especially pharmaceutieally aeeeptable salts with aeids or bases.

:~ ' 5(30 1 The alky:L groups per se ox when present as substituents are prefer~bly lower alkyl containiny from 1 to 6 carbon atoms and may be strai~h-t chain or branched.
These groups include methyl, ehtyl, propyl, iso-propyl, 5 ~utyl, isobutyl, amyl, hexyl and the like.
The alkenyl and alkynyl groups per se or when present as substituents preferably contain from 2 to 6 carbon atoms and may be straight chain or branched~ These groups include vinyl, propenyl, allyl, isopropenyl, ethynyl and 10 the like.
The alkyl, alkenyl, and;alkynyl groups may carry substituents such as hydroxy, lower alkoxy, thio, lower alkylmercapto, amino, lower alkylamino, di ~lower alkyl~
amino, halogen, and nitro.
The aralkyl and heterocyclic-alkyl groups include benzyl, phenethyl, naphythylmethyl, indolylethyl, indanylmethyl, indanylethyl and the like.
The heterocyclic groups include saturated, partially saturated, and aromatic ring systems containing one or more 20 atoms other than carbon, as well as heterocyclic lower alkyl.
These heterocyclic groups include pyrrole, pyrroline, pyrrolidine, pyridine, dihydropyridine, piperidine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, furan, furfuryl, thiophene, benzimidazole, thiazole, 25 thiazoline, thiazolidine, indole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, and the like.
The heterocyclic groups may carry one or more substituents such as lower alkyl, lower alkenyl, lower alkynyl, hydroxy~ lower alkoxy, amino, lower alkylamino, 30 di (lower alkyl) amino, thiol, lower alkylmercapto, hydroxy-lower alkyl, amino-lower alkyl, thio-lower alkyl, nitro, ~2~5C~

l h~]ogell, trir:lalo:ro~ thyl, m~tl~ n~ lioxy, ur~ido, or guanidino.
The acyl groups are preEerably lo\-~r alkanoyl con-taining from l to 6 carbon atoms and ben~vl.
The halo~en group may be fluorine, clllorine, bromine and iodine.
Sui-table acid addition salts may be formed from inorganic acids such as hydrochloric, sulfurie and phosphoric, and organic acids such as acetic, lactic, citric, malic, lO maleic, fumaric, succinic, benzoic, hydroxybenæoie, amino-benzoic, nieoti.nic, benzenesulfonic and the like.
Suitable basie salts may include the salts of alkali and alkali earth metals sueh as sodium, li-thium, potassium, magnesium and ealcium, as well as iron and salts 15 of ammonia and amines, and quaternary ammonium salts.
Preferred eompounds of -the present invention are those having the formula:
Rl R4 R7 ROC ~ ~ R ~ ~ I R~

In addition, another preferred eompound is that of -the formula:

Rl R4 R7 ROC ~ R5 ~-N ~ I CORg 3o herei.n Rg is hydroxy, R2, R3, R4, R7, and R8 are hydrogen, R6 is pyrrolidine, R is ethoxy, and Rl is phenethyl, and salts thereof with pharmaeeutieally aeeeptable aeids and bases.

~3 5~
- 3.1 -The compounds of the present invention may contain one (1) or more asymme-tric carbon atoms and may exist in recemic and op-ticaLly ac-tive forms. All of these for~s are contemplated -to be within the scope of the present inventiorl.
The compounds of tne presen-t invention are prepared by amide-forming reaction of a compound of the formula ' R~- NH - C - CORg II
R~
with an acylating deri vati~re of an acid of the formula:
,Rl R4 ROC - C - N - C - COOIi III

to give the desired compound.

1 ~. arl ~L-terna~i~,e ~roach, a dipep-tide Or the structure R4 ~ ~7 ~ ~I R ~ COR9 ~7 R5 P~8 is reacted with an ~keto-acid or ester of the structure ROC - C - Rl O V

to form the corresPonding imine and the imine is reduced to give a compound of formulaI in which R2 and R3 are each H.
As a further reaction, the present new compounds can be prepared by reaction of a compound of -the formula:

ROC~ VI

with an ~-halo compound of the formula ,R7 Hal- C - CORg VII

25 by cle~vage of hydrogen halide.
The aforementioned condensation reaction to form imines with subsequent hydrogenation can be conveniently carried out in a single reaction zone by the expediency of mixing the ~-keto acid or derivative with the reactive 30 compound of formula IV under hydrogenation conditions. For practical purposes, the aforesaid reactants can be hydro-genated over noble metal catalyst such as palladium, 1'~6~50~

r~latin~ml, rilodium, ruthcnium, and -the like ancl -the two stayes occur under such conditions -to produce the desired end-product.
As in any oryanic reaction solvents can be employed 5 such as methanol, ethanol, propanol, acetone, tetrahydro-furan, dioxane, dimethylforrnamide, diethylacetamide, and the like. The reaction is normally effected at or near ro~m temperature, although tempera-tures from 0C up to the reflux temperature of the reaction mixture can be 10 employed.
In the above sequence of reactions, R - Rg are the same as described above and Hal is halogen.

Preferably, R and Rg are hydrogen or lower a]kyl, 15 R2, R5, R7 and R8 are hydrogen, Rl and ~4 are lower alkyl, R3 is hydrogen, and R6 is indole or thienyl.
The amide forminy conditions referred to herein involve the use of known derivatives of the described acids, such as the acyl halides, anhydrides, mixed anhydrides, 20 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 25 at room temperature or at elevated temperature. The use of elevated temperature is for convenience in that it permits somewhat shortened reaction periods. Temperatures ranginy from 0C. up to the reflux temperature of the reaction system can be used. As a further convenience the amide 30 forming reaction can be effected in the presence of a base such as tertiary organic amines, e.g., trimethylamine, l pyridille, picoline~ alld the like, particularly where hydrogen halide is ~ormed by the amide-forming reactiorl, e.g., acyl halide 2nd amino compound. Of course, in those reactions where hydrogen halide is produced, any of 5 commonly used hydrogen halide acceptors can also be used.
In the condensation of an alpha haloacid deriva-tive of formula V~I herein, similar reaction conditions, solvents and hydrogen halide acceptros can be used as for amide formation.
Various substituents on the present new compounds e.g., as defined for R8, 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 15 by nitration of the aromatic ring and the nitro group converted to other groups, such as amino by reduction, and halo by diazotization of the amino groups and replacement of the diazo group. Other reactions can be effected on the formed amide prod~ct. Amino groups can be alkylated to 20 form mono and dialkylamino groups, mercapto and hydroxy groups can be alkylated to form corresponding ethers.
Thus, substitution ox alteration reactions can be employed to provide a variety of substituents throughout~:
the molecule of the final products. Of course, reactive 25 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 3 compounds can be formed using standard procedures. Often, they are formed ln situ during the preparation of the present ~26~

-L new amido ~mino acids.
The present compounds obviously exist in stereo-isomeric forms an~ the products obtained thus can be mi~tures of the isomers~ which can be resolvec'. Alternatively, 5 b)~ selection o~ s~ecific isomers as starting compounds, the preferred stereoisomer can be produced. Therefore, the preferred forms, where each as~mmetric center (chairal center) is S-configuration, are preferably prepared by the stereospecific route rather than attempting resolution 10 of mixtures of isomers. The corounds 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.
EXAMPLE I
~. t-Butyl N-[2-(3-Indolyethyl)] -Glycinate Tryptamine hydrochloride (100 g, 624 mmols) was added to a mixture of acetonitrile (1 1) and concentrated ammonium hydroxide (48.8 ml.). Tert-butylbromoacetate (101 g, 518 mmols) in acetonitrile was added dropwise over one hour. The reaction was allowed to stir over-25 nig~t at room temperature. The solvent was evaporated and the residue was portioned between ethyl acetate and aqueous ammonium hydroxide. The layers were separa-ted and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated.
30 The crude product was crystallized from n-hexane/ether to give tan crystals (118 g, 83%), m.p. 88-90C.

-I E. -t-~utyl l~-(l-(~S) -Carbethoxyeth~ L-Alanyl-N-[2-(3-Indolyl,ethyl)l-Glycinate ... .
N-(l-(S)-Carbethoxyethyl)-L-alanine (3.7 g, 0.02mol) and 1,1'-carbonyldiimidazole (3.6 g, 0.022 mol~ were added 5 to dry tetrahydrofuran (30 ml.). The resulting mixture was refluxed under ni-trogen for thirty minutes. To the resulting solution was added t-butyl N-[2-(3-Indolyethyl)]-glycinate (5.5 g, 0.02 mol) in tetrahydrofuran (15 ml).
The resulting mixture was refluxed for two and a half hours.
lO The solvent was evaporated and the residue was dissolved'in chloroform. The chloroform was washed twice with water, dried over magnesium sulfate, filtered, and evaporated.
The crude product was chromatographed on silica-gel (CHCL3) to give the pure product (8 g, 83~) as a light auburn oil.
15 The product was characterized as its hydrochloride salt;
m.p. 140,~C.

A. Benzyl 2-Bromopropionate

2-Bromopropionic acid (750 g, 4.90 moles) and 20 benxyl alcohol (600 g, 3.55 moles) were dissolved in meth~lene chloride (1500 ml). To the resulting solution, was added concetrated sulfuric acid (10 ml). The resulting solution was heated to a gentle reflux for two days, water separating during this time. Wa~er (,500 ml) was added and the layers ~5 were separated. The methylene chloriae was washed with saturated sodium bicarbonate and the layers were separated.
The organic layer was washed with water, dried over magnesium sul~ate, filtered and evaporated to give a colorless oil which was vacuum distilled to give the

3 pure product as a colorless oil ~742 g, 86o).

~2~i00 _9_ . B _ ~] N-(~ S)~Lt _~vcali~on~1-3-Me-thYlbutyl)-L-Alanvl-N-~2-~3-Indolvl~thyl)]-GlvcLna~e N-(l-(S)-Ethoxycarbonyl-3-methylbutyl)-L-alanine t2.31 g, 0.01 mol) and l,l'-carbonyldiimidazole (2.3 g, 0~0142 mol) were added to dry tetrahydrofuran ~0 ml).
The resulting mixture was refluxed for fifteen minutes.
To the resultiny solution was added portionwise benzyl N-t2-illc'olv~et}lyl)-glycinate (3.08 g, 0.01 mole) dissolved in THF (15 ml). The resulting solution was reflu~ed for 10 two and a half hours. The solvent was evaporated and the residue was-dissolved in e-ther. The ether was washed three times with water. The ether was dried over magnesium sulfate, filtered, and evaporated to give the crude produc-t.
The crude product was chromatographed on silica-gel (ether) 15 to give the pure product (3.8 g, 72%) as a light-colored oil which was a misture of diastereomers.
EX~MPLE 3 A. t-Butyl N-Carbobenzyloxy-(J~Valyl)-N-~2-(3-Indolylethyl?]-Glycinate t-Butyl N-12-indolylethyl)-~lycinate (12.0 g, 43.8 mmols) was dissolved in methylene chloride (400 ml) and the solution was cooled in an ice bath. Dicyclohexyl-carbondiimide (8.2 g, 39.8 mmols) in a small amount of methylene chloride was added. N-carbobenzyloxy-L-valine 25 (10 g, 39.8 mmols) in a small amount of methylene chloride was add-eddropW~. N-carbobenzyloxy-L-valine (10 g, 39.8 mmols) in a small amount of methylene chloride was added dropwise.
The reaction was stirred with external cooling for 15 minutes and then at room temperature overnight. Precipitated 30 dicyclohexylurea was filtered and washed with a small amount of methylene chloride. The filtrate was evaporated ~Z~S1130 1 ~nd ether was a~ld~d to th~ residue to preclpi-tate rnore ~icyclohexylurea. The dicyclohe~ylurea wa.s flltered ~nd the filtrate was evaporated to afford the crude product as a tan gum. The crude product was purified by HPLC
5 using ethyl acetate/methylene chloride (10:90) as eluent to give the pure product as a light tan powder (23.8 g, 91.2%) ;'. N-Carbobenzyloxy-(L-Valyl)-N-[2-(3-Indolylethyl)]-Glycine t-Butyl N-carbobenzyloxy(~J-valyl)-N-[2-(3~indolylethyl)~-lO glycinate (22.5 g, 44.3 mmols) was dissolved in anisole(47.9 g, 443.2 mmols) and then trifluoroacetic acid (101.1 g, 886.5 mmols) was added. The resulting solution was stirred for three hours at room tempera-ture. Trifluoroacetic acid was removed at 30C under vacuum. The dark brown oil was 15 dissolved in ether and the organic extract was washed twice with water and dried over magnesium sulfate. The ether was filtered and evaporated to afford the crude product as a dark oil. The crude product was purified by ~PLC eluting with acetic acid/ethyl acetate/n-hexane (2 39:59) to afford the pure product as a pale yellow powder (11.1 g).

Benzyl N~ (S)-Ethoxycarbonyl-2-Phenylethyl)-L-Alanyl-N-[2(3-Indolylethyl)]-Glycinate [N-(~thyl 2-phenyl-1-(s)-~,ropiona-te]-L-alanine (2.65 g, 10.0 mmols) and l,l'-carbonyldiimidazole (2.0 g, 0.0123 mols) were added to dry tetrahydrofuran (40ml).
The resultiny mixture was refluxed for fifteen minutes under nitrogen. To the resulting solution was added 3O portionwise benzyl N-~2(3-Indolylethyl)]-glycinate (3.5 g, 11.4 mmols) in a small amount of TIIF (20 ml). The ~2~
--].1~

1 resultin~l so:lution was refluxed for three hours. rrhe solvent was evaporated and the residue was dissolve~ in ether. The ether was washed tl.~?ice with water, dried over magnesiu~
sulfate, filtered and evaporated to afford an auburn oil.
5 The crude product was chromatographed on silica-qel to afford the pure product as a yellow oil (4.5 g, 81~) which was a ~isture of diastereomers.

A. Ethyl N-Carbobenz~loxy (L-Phenylalanyl'-N-~2(3-Indolylethyl)]-Glycinate Ethyl N- I2- ( 3-indolylethyl)]-glycinate (17.3 g, 0.0703 mol) was dissolved in methylene chloride (400 ml) and the resulting solution was cooled in an ice bath.
Dicyclohexylcarbodii`mide ('16.0 g, 0.078 mol) in a small 15 amount of methylene chloride (25 ml) was added portionwise.
N-carbobenzyloxy--L-phenylalanine (21.04 g, 0.0703 mol) was added portionwise. The reaction was stirred with external cooling for fifteen minutes and then for two and a half hours at room temperature. Precipitated dicyclohexylurea 20 was filtered and washed with ether. The filtrate was evaporated. The residue was dissolved in ether and washed with 10% ~ICL, saturated NaHCO3, water and dried over magnesium sulfate. Filtration and evaporation of the solvent yave a tan viscous oil (33.7 g, 95~).
25 B. L-Phenylalanyl-N-12'(3-indolylethyl)~-Glycine N-Carbobenzyloxy-L-phenylalanyl-N-[2(3-indolyl-ethyl)]-glycine (1.3 g~ 0.0026 mol) was added to a saturated solution of anhydrous HBr in glacial acetic acid (20 ml) which had been chilled in an ice bath. The resulting 3 solution was stirred for fiteen minu,tes with external cooling and then for forty-five minutes at room temperature.

IL5~

l Mos~: oE the acetic acid was evaporatecl and ether was added to the resi.due to precipitate the hydrobromide of the product. The hydrobromide was filtered and washed with either to afford tan crystals (0.85 g, 70.8%); m.p. 140.

A. Ethyl N-carbobenzyloxy'-L-alanyl-N-(3-thienyl')g].ycinate A methylene chloride solution of N-carbobenzyloxy-L-alanine and ethyl (3-thienvl) glycinate was treated with N,N-dicyclobhexylcarbodiimide as in example 5A. The product lO was applied to silica-gel to afford ethyl N-carbobenzyloxy-L-alanyl-N-(3-thienyl) glycinate.
B. N-Carbobenzyloxy-L-'alanyl-N (3-thienyl) glycine .
Ain ethanolic solution of ethyl N-carbobenzyloxy-L-alanyl-N-(3-thienyl), g].ycinate was treated with two 15 equivalents of potassium hydroxide to yield N-carbobenzyloxy-L~alanyl-N-(3-thienyl) glycine.
C. L-alanyl-N~(3-thienyl)glycine In a ~anner described in example 5B, N-carbobenzyloxy-L-alanyl-N-(3-thienyl) glycine was treated with anhydrous 20 hydrogen bromide in acetic acid to yield the hydrobromide salt of L-alanyl-N-(3-thienyl) glycine.

N-(l-Carboxy-3-phenylpropyl)-L-alanyl-N-(3-thienyl)glycine 2-Oxo-4-phenylbutyric acid and L-alanyl-N-(3-thienyl)-glycine a.re condensed in the presence of sodium cyanoborohydride to yield N-tl-carboxy-3-phenylpropyl)-L-alanyl-N-(3-thienyl) glycine.
EXP.~PLE 8 30 A. N-Carbobenzyloxy~L-isoleucyl-N-(3-pyridyl) glycinine An ethanolic solution of ethyl N-carbobenzyloxy-L-isoleucyl-N~t3-pyridyl) glycinate was treated with potassium ] hydro~ldc to hield N-carbobenZyloxy-L-iSoleUcyl-N-(3-p~riclyl)-glycine.
B. Eth~l N-Carbobenzyloxy L-isoleucyl-N-(3-pyridyl) glycinate A methylene chloride solution of N-carbobenzyloxy-L-5 isoleucine and ethyl N-(3-pyridyl)-glycinate was treated with N,N-dicyclohexylcarbodiimide as in example 5A. Purification of the product was accomplished by chromatography on silica-gel.
C. L-Isoleucyl-N-(3-pyridyl)glycinate In a manner described in example 5B, N-carbobenzyloxy-L-isoleucyl-N-~3-pyridyl)-glycine was treated with ahydrous hydrogen bromide in acetic acid to yield L-isoleucyl-N-(3-pyridyl- glycine hydrobromide.

N-[l-(S)-Ethoxycarbonyl-3-methylbutyl]-L-isoleucyl-N-(3-pyridyl) glyclne Ethyl 4-methyl-2-oxopentanoate and L-isoleucyl-N-(3-pyridyl)-glycine were condensed in the presence of sodium cyanoborohydri~de to yield N-[l-(S)-ethoxycarbonyl-3-methyl-20butyl]-L-isoleucyl-N-(3-pyridyl) glycine.
E~AMPLE lQ
A. N-Carbobenzyloxy-L-leucyl-N-(2-ethylmorpholine)glycine An ethanolic solution of ethyl N-carbobenzyloxy-L-leucyl-N-(2-ethylmorpholine~ glycinate was treated with potassium hydroxide to yield N-carbobenzyloxy-L-leucyl-N-(2-ethylmorpholine)glycine.
B. Ethyl N-Carbobenzyloxy-I.-luecyl-N-(2-ethylmorpholine)glycine A methylene chloride solution of N-carbobenzyloxy-L
leucine and ethyl N-(2-ethylmorpholine) glycinate was treated with N,N-dicyclohexylcarbodiimide as in example 5A. The product was purified by chromatocrraphy (silica-gel) to 12~5~0 yield e-thyl N-carboben~yloxy-l,-leucyl-N-(2-ethylmorpholine) ~iycinate.

Ben~yl N-(l-(S)-ethox~carbonyl-2-phenylethyl) alanyl-N-(2-5benzothiaæo]e) glyclnate Benzyl N-~l-(S)-ethoxycarbonyl-~-plenylethyl]alanine and l,l-carbonyldiimidazole were added to dry tetrahydrofuran.
The result1ng mixtul-e was re~luxed for fi~teen minutes. To the resultinq solution was added portionwise benzyl N-(2-ben20thiozole)-glycinate. The resulting mixture was refluxed for three hours. The product was purified in a manner as described in example lB.
XAM~LE 12 15A. Benzyl N-rl-(S)-Ethoxycarbonylethyl]alanyl-N-(2-pyrimidyl) glycinate N-[l-(~)-Ethoxycarbonylethyl] alanine and 1,1'-carbonyldiimidazole were added to dry tetrahydrofuran. The xesulting mixture was refluxed for fifteen minutes. To 20 the resulting solution was added benzyl N-(2-pyrimidyl) glycinate. The resulting mixture was refluxed for three hours. The product was purified by HPLC chromatography to yield benzyl N-[l-(S) ethoxycarbonylethyl]-alanyl-N-(2-pyrimidyl) glycinate.
2~B. N-[l-(S)-Ethoxycarbonylethyl]alanyl-N-(2-pyrimidyl)glycine J
Ben~yl [N-l-(S)-ethoxycarbonylethyl]alanyl-N-(2-pyrimidyl) glycinate was dissolved in ethanol and 10~
Pd/c was added under r~itrogen. The reaction mixture was hydrogenated and purified to yield N-[l-(S)-ethoxycarbonyl-30ethyl]alanyl-N-(2-pyrimidyl)glycine.
By following the procedures in the above examples, the following additional compounds were prepared:

sn~

1 N-[l-(S)-Ethoxycarbonyl-2-phenyle-thyl]alanyl-N-(furfury:L) alvcin~
N-[l-(S)-Ethoxycarbonyl-3-methylbutyl]alanyl-N-(3-pyri~yl) glycine 5N-[l-(S)-Ethoxycarbonyl-3-pllenylpropyl]alanyl-N-(tetrahydro-furfuryl)-glycine N-[l-(S)-E-tho~ycarbonyl-2-methylthioethyl]alanyl-N-[l-methyl-3-(2-indolylethyl)~-glycine N-[l-Ethoxycarbonyl-4-methylpentyl]alanyl-N-(2-benzothiazole) alanine N-[l-(S)-Ethoxycarbonyl-3-phenylpropyl]alanyl-N-(2-ethylmo.rpholine) glycine N-[l-(S)-Ethoxycarbonyl-2-(3-indole!ethyl]alanyl-N-~(2-ethyl) pyrrolidine]glycine N- E 1- (s) -Ethoxycarbonylethyl]valyl-N-(5-indolyl)glycine N-(1,3-Dicarboxypropyl)leucyl-N-(1,4-benzodioxan-6-yl)glycine N-[l-(S)-Ethoxycarbonylethyl~isoleucyl-N-(5-benzofurfuryl)glycine N-~l-(S)-Carboxyethyl]alanyl-N-(3-thienyl)glycine N-~l-(S)-Carboxy-3-phenylpropyl]phenylalanyl-N-(3-thiazolyl) glycine N-[l-(S)-Ethoxycarbonyl-2-phenylethyl]alanyl-N-(2-thienyl)glycine 20N-(1,3-Diethoxycarbonylpropyl)-P-chlorophenylalanyl)-N'-(2-pyrimidyl)glycine N-(l-(S)-Carbox.y-3-methylbutyl)alanyl-N-(tetrahydrothiophene-l,l-dioxide-3yl)-lycine N-(l-(S)-Ethoxycarbonyl-3-phenylpropyl)valyl-N-(N-ethylpeperidine-3-yl)-lycine 25N-(l-(S)-CarboYy-2--phenylekhyl)-phenylalanyl-N'-(4-tetrahydro-thiopyranyl)-glycine The compounds bf the present invention have demonstrated potent activlty (of the order of Iso of 1.0 to 50.0 micromolsl in inhibiting the angiotensin converting 30enzyme ~ACEI activity) when tested by the method described in Science 196, 441-4 (1977). The compounds of the present ~2~ 0 invention have also demonstrated an ~50 o about 1 to 10 mg/kg P.O. in inhibiting infused angiotensin in rats. As such~ these would be very useful in the treatment of hypertension.
The compounds may be administered orally or 5parenterally 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.
A particularly effective compound is N-(l-carbethoxy-102-phenylethyl)-L-glycyl-N-[2-(3-indolylethy~]glycine and related compounds including the indolylethyl substituent on -the gl~,~cine nitrogen atom.

The following example illustrates stereospecific synthesis:
A. Tert-butyl N-(3-pyridylinethyl) glycinate hydrochloride Acetonitrile (300 ml) was added to 3-aminomethyl-pyridine (21.6 g, 0.2 mole) followed by the addition of 20water (20 ml) and concentrated ammonium hydroxide (20 ml).
To the resulting stirring solution tert-butyl bromoacetate (39 q, 0.2 mole) in acetonitrile (75 ml) was added dropwise at room temperature. The acetonitrile was evaporated on a rotary evaporator and then water was added to the residue 25and the product was extracted several times into methylene chloride. The combined methylene chloride extract was washed several times with water, dried over magnesium sulfate, filtered and concentrated to afford the crude product as a tan oil. The crude product was purified by silica-gel 3chromotography using methylene chloride as eluent. The desired product fractions were combined and concentrated ~2~4S~:)O

l:tO afford the clesired product as an orange oilO The hydrochlori~le was prepared using anhydrous hydrogen chloride in ether to afford tert-butyl N-(3-methylpyridine) glycinate hydrochloride as a colorless powder (30 Fg, 59%);
spr. P. 142i mass spectra (CI): 223 (m -~ 1, 100~)~
Ana]. calcd. for C12H18N2O2 10.83 Found: C, 55.11; H, 7.19; N! 10-50.

B. Tert-buytl M-~l-(s)-ethoxy carbonyl-3-phenylpropyl]-(s)~alanyl-N-(3'pyridylinethyl) glycinate hydrochloride To N-[l-(s)- ethoxy carbonyl-3-phenylpropyl-(S)-alanyl-N-carboxyanhydride (1~5 g, 4.92 mole) in methylene chloride (30 ml) was added tert~butyl N-(3-pyridylmethyl) glycinate (1.4 g, 6.3 mole). The resulting solution was stirred overnight at room temperature. The solvent was 20evaporated and the residue was chromatographed over silica-gel using methylene chloride as eluent. The desired product fractions were combined and concentrated to give pure tert-butyl N-[1-(S)-ethoxy carbonyl-3- phenylPropyl]-(S)-alanyl-N-(3-methylpyridine) glycinate hydrochloride 25as a light colored oil (1.3 g, 54%). The hydrochloride of the product was prepared usin~ anhydrous ether saturated with anhydrous hydrogen chloride to give a colorless solid which was ~iltered and washed with cold anhydrous ether^
~.P. 76; mass spectra (CI): 484.9 (m + 1, 100%); [ ]
30CHc13 = -~50.99; [ ]546CHc13 = 61.36; L ]436CHc13 = 109.64;
[ ]365CHCl3 = 178-26-Anal- calcd- for C27H37N35 2~cl C~ 54-~8; Hr 6-29; N~
7.09 Found: C, 54.59; H, CHcl; N. 7.32, ~2~ iO~
~,~

l C. N ~-(S)-Ethoxycarbonyl-3-phenylPropyl]-(S)- alanyl-N-(3-pyridylinethyl) glycine dihydrochloride To tert-butyl N-~l- (S)-ethoxy carbonyl-3-phenyl-propyl]-(s)-alanyl-N-(3-pyridylinethyl) glycinate (.6 g, 5 1.24 mmolesj was added P-dioxane (30 ml) which had been saturated with anhydrous hvdro~en chloride. The resulting ~olution was stirred for two and a half hours at room temperature and then the solvent was evaporated to afford the desired product as a colorless powder (0.495 g, 86%): M.P. 77;
lO [ l EtoM = ~14.04; mass spectra (CI): 410 (m + 1 - H2O, :100%).
Anal. calcd. for C23H29N3Os 2HCl-2H20 C~51.49; H~6.58;
N,7.83 Found: C, 51.28; H, 6.86; N, 7.32.

3o

Claims (55)

WE CLAIM:

1. Process for the preparation of compounds of the formula:

I

wherein R and R9 are independently hydroxy, lower alkoxy, lower alkenoxy, di(lower alkyl)amino-lower alkoxy, hydroxy-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryloxyl-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, hydroxyamino, or aryl-lower alkylamino, R1, R2, R3, R4, R5, R7, and R8 are independently H
alkyl, alkenyl or alkynyl containing up to 20 carbon atoms, aryl or aryl-lower alkyl containing up to 12 carbon atoms, heterocyclic or heterocyclic-lower alkyl containing up to 12 carbon atoms, or cycloalkyl or cycloalkyl alkyl containing up to 20 carbon atoms.
R6 is heterocyclic or heterocyclic alkyl;
R2 and R3 taken together with the carbon and nitrogen to which they are respectively attached and R3 and R5 taken together with the nitrogen and carbon to which they are respectively attached form an N-heterocycle containing from 3 to 5 carbon atoms or 2 to 4 carbon atoms and a sulfur atom, and wherein said alkyl, alkenyl, and alkynyl groups can be substituted with hydroxy, lower alkoxy, thio, lower alkylmercapto, amino, lower alklamino, di(lower alkyl) amino, halogen, and nitro;

aim 1 - continued comprising A. reacting under amide-forming conditions an amino compound of the formula II

wherein R6, R7, R8 and R9 are as defined above, with an acylating.
derivative of an acid of the formula III

wherein R, R1, R2, R3, R4 and R5 are as defined above;

B. reducing the corresponding imine; or C. reacting a compound of the formula VI

wherein R, R1, R2, R3, R4, R5 and R6 are as above defined, with a halo compound of the formula wherein R7, R8 and R9 are as above defined, and if desired, before forming a salt, reacting a product obtained to form a product (wherein the R groups are defined as above) wherein one or more R groups are converted from one value of the R groups to another value of the R groups, and converting a product obtained if desired into a salt thereof.

2. Process as in Claim 1 wherein R and R9 are independently hydroxy and lower alkoxy, R1 and R2 are independently hydrogen, lower alkyl, aryl- lower alkyl having from 7 to 12 carbon atoms, or heterocyclic- lower alkyl having from 6 to 12 carbon atoms, R3, R4, R5, R7 and R8 are hydrogen or lower alkyl, and R6 is heterocyclic or heterocyclic alkyl;

3. Process as in Claim 2, wherein R6 is pyrrole, pyrroline, pyrrolidine, pyridine, di-hydropyridine, piperidine, morpholine, thiamorpholine, imidazole, imidazoline imidazolidine, furan, furfuryl, thiophene, benzimidazole, thiazole, thiazoline, thiazolidine, indole, quinoline, iso-quinoline, tetrahydroquinoline, or tetrahydroisoquinoline.

4. Process as in Claim 3, wherein the heterocyclic groups have 1 or more substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)amino, thiol, lower alkylmercapto, hydroxy-lower alkyl, amino-lower-alkyl, thio-lower alkyl, nitro, halogen, trifluoromethyl, methylenedioxy, ureido or guanidino.

5. Process as in claim 1, wherein R1 is lower alkyl or phenyl-lower alkyl, R4 is lower alkyl, and R2, R3, R5, R7 and R8 are hydrogen.

6. Process as in claim 1, wherein R and R9 are hydroxy.

7. Process as in claim 1, wherein R is ethoxy and R9 is hydroxy.

8. Process as in claim 1, wherein R1 and R4 are each methyl.

9. Process as in claim 1, wherein R1 is benzyl or phenethyl and R4 is methyl.

10. Process as in claim 1, wherein R6 is indolyl-ethyl.

11. Process as in claim 1, wherein R1 is benzyl.

12. Process as in claim 1, wherein R1 is phenethyl.

13. Process as in claim 1, wherein R is ethoxy, R1 is phenethyl, R4 is methyl, R6 is 2-(3-indolylmethyl) and R9 is hydroxy.

14. Process as in claim 1, wherein R2, R3, R5, R7 and R8 are each hydrogen.

15. Process as in claim 1, wherein R is ethoxy, R1 is phenethyl, R4 is methyl, R6 is 3-pyridylmethyl and R9 is OH.

16. Process as in claim 15 wherein R2, R3, R5, R7 and R8 are each hydrogen.

17. Compounds of the formula wherein R and R9 are independently hydroxy, lower alkoxy, lower alkenoxy, di(lower alkyl)amino-lower alkoxy, hydroxy-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryloxyl-lower alkoxy, amino, lower alkylamino, di-lower alkylamino, hydroxyamino, or aryl-lower alkylamino, R1, R2, R3, R4, R5, R7, and R8 are independently H
alkyl, alkenyl or alkynyl containing up to 20 carbon atoms, aryl or aryl-lower alkyl containing up to 12 carbon atoms, heterocyclic or heterocyclic-lower alkyl containing up to 12 carbon atoms, or cycloalkyl or cycloalkyl alkyl containing up to 20 carbon atoms.
R6 is heterocyclic or heterocyclic alkyl, R2 and R3 taken together with the carbon and nitrogen to which they are respectively attached and R3 and R5 taken together with the nitrogen and carbon to which they are respectively attached form an N-heterocycle containing from 3 to 5 carbon atoms or 2 to 4 carbon atoms and a sulfur atom, and wherein said alkyl, alkenyl, and alkynyl groups can be substituted with hydroxy, lower alkoxy, thio, lower alkylmercapto, amino, lower alklamino, di(lower alkyl) amino, halogen, and nitro;
and salts and pharmaceutically acceptable acid and base salts thereof,

18. A compound of the formula wherein:
R and R9 are independently hydroxy and lower alkoxy, R1 and R2 are independently hydrogen, lower alkyl, aryl- lower alkyl having from 7 to 12 carbon atoms, or heterocyclic- lower alkyl having from 6 to 12 carbon atoms, R3, R4, R5, R7 and R8 are hydrogen or lower alkyl, and R6 is heterocyclic or heterocyclic alkyl; and salts thereof with pharmaceutically-acceptable acids and bases.

19. Compound according to claim 18 wherein R6 is pyrrole, pyrroline, pyrrolidine, pyridine, di-hydro-pyridine, piperidine, morpholine, thiamorpholine, imidazole, imidazoline, imidasolidine, furan, furfuryl, thiophene, benzimidazole, thiazole, thiazoline, thiazolidine, indole, quinoline, isoquinoline, tetrahydroquinoline, or tetra-hydroisoquinoline and pharmaceutically acceptable acid and base salts thereof.

20. Compound according to claim 19 wherein the heterocyclic groups have 1 or more substituents selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, amino, lower alkyl-amino, di(lower alkyl)amino, thiol, lower alkylmercapto, hydroxy-lower alkyl, amino-lower alkyl, thio-lower alkyl, nitro, halogen, trifluoromethyl, methylenedioxy, ureido or guanidino , and pharmaceutically acceptable acid and base salts thereof.

21. A compound according to claim 17, wherein R1 is lower alkyl or phenyl-lower alkyl, R4 is lower alkyl, and R2, R3, R5, R7 and R8 are hydrogen, and pharmaceutically acceptable acid and base salts thereof.

22. A compound according to claim 17, wherein R
and R9 are hydroxy and pharmaceutically acceptable acid and base salts thereof,

23. A compound according to claim 17, wherein R
is ethoxy and R9 is hydroxy, and pharmaceutically acceptable acid and base salts thereof.

24. A compound according to claim 17, wherein R1 and R4 are each methyl, and pharmaceutically acceptable acid and base salts thereof.

25. A compound according to claim 17, wherein R1 is benzyl or phenethyl and R4 is methyl, and pharmaceutically acceptable acid and base salts thereof.

26. A compound according to claim 17, wherein R6 is indolylethyl, and pharmaceutically acceptable acid and base salts thereof-

27. A compound according to claim 17, wherein R1 is benzyl, and pharmaceutically acceptable acid and base salts thereof.

28. A compound according to claim 17, wherein R1 is phenethyl,and pharmaceutically acceptable acid and base salts thereof.

29. A compound according to claim 17, wherein R
is ethoxy, R1 is phenethyl, R4 is methyl, R6 is 2-(3-indolyl-methyl) and R9 is hydroxy, and pharmaceutically acceptable acid and base salts thereof.

30. A compound according to claim 17, wherein R2, R3, R5, R7 and R8 are each hydrogen, and pharmaceutically acceptable acid and base salts thereof.

31. A compound according to claim 17, wherein R
is ethoxy, R1 is phenethyl, R4 is methyl, R6 is 3-pyridylmethyl and R9 is OH, and pharmaceutically acceptable acid and base salts thereof.

32. A compound according to claim 17, wherein R2, R3, R5, R7 and R9 are each hydrogen, and pharmaceutically acceptable acid and base salts thereof.

33. Process according to claim 1, wherein R2, R3, R5, R7 and R8 are each hydrogen, R1 is methyl, benzyl or phenethyl, R4 is methyl, R6 is indolylethyl, 2-(3-indolylmethyl) or 3-pyridyl-methyl, R9 is hydroxy, and R is hydroxy or ethoxy.

34. A compound according to claim 17, wherein R2, R3, R5, R7 and R8 are each hydrogen, R1 is methyl, benzyl or phenethyl, R4 is methyl, R6 is indolylethyl, 2(3-indolylmethyl) or 3-pyridyl-methyl, R9 is hydroxy, and R is hydroxy or ethoxy, and pharmaceutically acceptable acid and base salts.

35. Process according to claim 1 wherein R2, R3, R4, R7 and R8 are hydrogen, R9 is hydroxy, R is C2H5O, R1 is , R5 is -CH3, and R6 is or ,

36. Compound according to claim 17 wherein R2, R3, R4, R7 and R8 are hydrogen, R9 is hydroxy, R is C2H5O, R1 is , R5 is -CH3, and R6 is or and pharmaceutically acceptable acid and base salts thereof.

37. Process according to claim 1 wherein R2, R3, R4, R7, and R8 are hydrogen, R9 is hydroxy, R is C2H5O, R1 is C2H4, R5 is-(CH2)4NH2 and R6 is ,

38. Compound according to claim 17 wherein R2, R3, R4, R7, and R8 are hydrogen, R9 is hydroxy, R is C2H5O, R1 is C2H4, R5 is-(CH2)4NH2 and R6 is .
and pharmaceutically acceptable acid and base salts thereof.

39. Process according to claim 1 wherein R2, R3, R4, R7 and R8 are hydrogen, R9 is hydroxy, R5 is CH3, R1 is , R is C2H5O or HO, and R6 is .

40. Compound according to claim 17 wherein R2, R3, R4, R7 and R8 are hydrogen, R9 is hydroxy, R5 is CH3, R1 is , is C2H5O or HO, and R6 is .

and pharmaceutically acceptable acid and base salts thereof.

41. A pharmaceutical composition comprising a compound of claim 17, 18, or 19, together with a pharmaceutically acceptable carrier therefor.

42. A pharmaceutical composition comprising a compound of claim 20, 21 or 22, together with a pharmaceutically acceptable carrier therefor.

43. A pharmaceutical composition comprising a compound of claim 23, 24 or 25, together with a pharmaceutically acceptable carrier therefor.

44. A pharmaceutical composition comprising a compound of claim 26, 27 or 28, together with a pharmaceutically acceptable carrier therefor.

45. A pharmaceutical composition comprising a compound of claim 29, 30 or 31, together with a pharmaceutically acceptable carrier therefor.

46. A pharmaceutical composition comprising a compound of claim 32, 34 or 36, together with a pharmaceutically acceptable carrier therefor.

47. A pharmaceutical composition comprising a compound of claim 38 or 40 together with a pharmaceutically acceptable carrier therefor.

48. A compound of the formula:

wherein Rg is hydroxy, R2, R3, R4, R7, and R8 are hydrogen, R6 is pyrrolidine, R is ethoxy, and R1 is phenethyl, and salts thereof with pharmaceutically acceptable acids and bases.

49. Use of the compound of Claim 17, 18 or 19, as a hypertensive and angiotensin inhibitory agent.

50. Use of the compound of Claim 20, 21 or 22, as a hypertensive and angiotensin inhibitory agent.

51. Use of the compound of Claim 23, 24 or 25, as a hypertensive and angiotensin inhibitory agent.

52. Use of the compound of Claim 26, 27 or 28, as a hypertensive and angiotensin inhibitory agent.

53. Use of the compound of Claim 29, 30 or 31, as a hypertensive and angiotensin inhibitory agent.

54. Use of the compound of Claim 32, 34 or 36, as a hypertensive and angiotensin inhibitory agent.

55. Use of the compound of Claim 38, 40 or 48, as a hypertensive and angiotensin inhibitory agent.