CA1218993A - 3-amino-1-benzazepin-2-one-1-alkanoic acids - Google Patents

Abstract

4-14336/CGC 949/4/+

3-Amino-1-benzazepin-2-one-1-alkanoic acids Abstract of the disclosure The invention concerns angiotensin-converting enzyme inhibitor compounds of the formula (I) wherein RA and RB are radicals of the formula and , respectively, in which R0 is carboxy or a functionally modified carboxy; R1 is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, acylamino lower alkyl, mono- or di- lower alkylamino lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, esterified carboxy lower alkyl, carbamoyl lower alkyl, N-substituted carbamoyl lower alkyl, hydroxy lower alkyl, etherified or acylated hydroxy lower alkyl, aryloxy lower alkyl, aryl-(thio-, sulfinyl-, or sulfonyl-) lower alkyl, aryl-N-lower alkylamino lower alkyl, or arylamino lower alkyl; R2 is hydrogen or lower alkyl; R3 and R4, each independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R3 and R4 taken together represent lower alkylenedioxy; R5 is hydrogen or lower alkyl; and X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro; with the proviso, that, if R1 represents hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, X is acylated hydroxy together with one hydrogen; and salts thereof.

They are prepared, for example, by reducing a starting material corresponding to formula I, which contains a double bond located at the carbon atom in 3-position.

Description

4-14336/CGC 949/4/+

3-Amino-l-benzazepin-2-one-1-alkanoic acids . . . _ _ _ ~ _ This invention concerns novel 3-amino-1-benzazepin-2-one-l-alkanoic acids of the general formula R ~ ~ O
~ \ / \ R
o ~ N - RA (I) o ~/\ /
R ^ N~
R O
wherein R and R are radicals of the formula Rl R2 -1H - R and -CH - R , respectively, ;n which R is carboxy or a functionally modified carboxy; R is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, acylamino lower alkyl, mono- or di- lower alkylamino lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, esterified carboxy lower alkyl, carbamoyl lower alkyl, N-substituted carbamoyl lower alkyl, hydroxy lower allcyl, etherified or acylated hydroxy lower alkyl, aryloxy lower alkyl, aryl-~thio-, sulfinyl-, or sul~onyl-) lower alkyl, aryl-N-lower alkylamino lower alkyl, or arylamino lower alkyl; R is hydrogen or lower alkyl; R3 and R4, eash independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R and R taken together represent lower alkylenedioxy; R is hydrogen or lower alkyl; and X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6l7l8l9-tetrahydroi with the proviso, that, if R represents hydrogen, lower alkyl, amino lower alkyll aryl, aryl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl, X is acylated hydroxy together with one hydrogen; salts, especially pharmaceutically acceptable salts thereof; stereoisomers of all these compounds;
processes for their manufacture, pharmaceutical preparations containing these compounds and their therapeutic application.

The functionally modified carboxyl group in the meaning of the symbol R is e.g. an esterified carboxyl group or a carbamoyl group optionally substituted on the nitrogen atom. More specifically one or both of R independently represent carboxy, esterified carboxy, carbamoyl or substituted carbamoyl.

A group R is represented by GOR in radical R and represented by COR in radical R .

A carboxyl group R is represented by COR6 wherein R6 is hydroxy or COR wherein R is hydroxy.

~n esterified carboxyl group R is especially one in which the esterifying radical represents optionally substituted lower alkyl or optionally substituted phthalidyl and is represented by COR or COR
wherein one or both of R and R represent lower alkoxy, optionally substituted by amino, mono- or di-lower alkylamino, carboxy, e.g. in the ~-position, lower alkoxycarbonyl, e.g. in the ~-position, aryl, hydroxy, lower alkanoyloxy, lower alkoxy, bicycloalkoxycarbonyl;
3-phthalidoxy or (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy.

An optionally N-substituted carbamoyl group R is especially one which is represented by COR or COR wherein one or both of R and R7 represent amino; lower alkylamino; di-lower alkylamino; di-lower alkylamino in which both alkyl groups are linked by a carbon to carbon bond and together with the amino nitrogen form a 5-, 6- or 7-membered heterocyclic ring, e.g. pyrrolidino, piperidino, or perhydroazepino; (amino or acylamino)-substituted lower alkylamino;
a-(carboxy or lower alkoxycarbonyl)-substituted lower alkylamino;
aryl substituted lower alkylamino in which aryl is preferably phenyl or indolyl and which can be substituted on the a-carbon by carboxy or lower alkoxycarbonyl.

Furthermore, the terms esterified carboxy and N-substituted carbamoyl, as such appear in esterified carboxy lower alkyl and N-substituted carbamoyl lower alkyl within the definition of Rl, may have any of the meanings cited above for said terms.

The general definitions used herein have the following meanings within the scope of the present invention.

The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms.

A lower alkyl group contains 1-7 carbon atoms, preferably 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantage-ously methyl.

Aryl represents a carbocyclic or heterocyclic aromatic radical preferably being phenyl, unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; indolyl, advantageously 3-indolyl; or indolyl, advantageously 3-indolyl substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl respectively.

The term cycloalkyl represents a saturated cyclic hydrocarbon radical which preferably contains 3 to 8 carbons and is, for example, cyclopentyl or cyclohexyl.

The term aryl lower alkyl represents preferably benzyl, 1- or

2-phenylethyl, 1-, 2- or 3-phenylpropyl, 1-, 2-, 3- or 4-phenyl-butyl, wherein the phenyl ring is unsubstituted or mono- or di-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkylene-dioxy, lower alkanoyloxy, halogen or trifluoromethyl; also indolyl-methyl advantageously 3-indolylmethyl, 1- or 2-indolylethyl advantageously 2-(3-indolyl)ethyl.

The term cycloalkyl lower alkyl represents preferably 1 or 2-(cyclo-pentyl or cyclohexyl)ethyl, 1-, 2- or 3-(cyclopentyl or cyclo-hexyl)propyl, or 1~, 2-, 3- or 4-(cyclopentyl or cyclohexyl)-butyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantage-ously ethoxy.

A mono- lower alkylamino group preferably contains 1-4 carbon atoms in the alkyl portion and is for example N-methylamino, N-propylamino or advantageously N-ethylamino. A di- lower alkylamino group preferably contains 1-4 carbon atoms in each lower alkyl portion and represents, for example, N,N-dimethylaminol N-methyl-N-ethylamino and advantageously N,N-diethylamino.

Lower alkylthio lower alkyl represents preferably (methyl, ethyl or propyl)-thio~(methyl, ethyl, propyl or butyl), advantageously 2-(methylthio)ethyl.

Lower alkanoyloxy represents preferably acetoxy, propionyloxy or pivaloyloxy.

Alkylenedioxy represents pre~erably ethylenedioxy, and advantage-ously methylenedioxy.

Aryl lower alkoxy represents advantageously e.g. benzyloxy, benzyl-oxy substituted by methyl, methoxy or chloro, and pyridylmethoxy.

Carboxy lower alkoxy represents advantageously e.g. l-carboxyethoxy.

Lower alkoxycarbonyl lower alkoxy represents advantageously e.g.
l-(ethoxycarbonyl)ethoxy.

Amino lower alkoxyl mono- lower alkylamino lower alkoxy, di- lower alkylamino lower alkoxy advantageously represent respectively e.g.
amiDoethoxy, ethylaminoethoxy, diethylaminoethoxy.

Lower alkanoyloxyalkoxy represents advantageously e.g. pivaloyloxy-methoxy.

Bicycloalkyloxycarbonyl- lower alkoxy preferably represents bicyclo-~2,2,1]heptyloxycarbonyl- lower alkoxy unsubstituted or substituted by lower alkyl, advantageously bicyclo~2,2,1]heptyloxycarbonyl-methoxy, e.g. bornyloxycarbonyl-methoxy.

Amino lower alkyl and ~-amino lower alkyl represent preferably amino (ethyl, propyl or butyl) and ~-amino (ethyl, propyl or butyl) respectively.

Halogen preferably represents chlorine, b~lt may also be bromine, fluorine or iodine.

Acylated hydroxy represerlts preferably lower alkanoyloxy, e.g.
acetyloxy, benzoyloxy, benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy, e.g. methyl, chloro or methoxy respectively, or nicotinoyloxy.

Etherified hydroxy represents preferably lower alkoxy e.g. methoxy, ethoxy or t-butoxy, or benzyloxy.

Aryloxy represents preferably phenoxy or phenoxy substituted by lower alkyl, lower alkoxy or halogen, e.g. methyl~ methoxy or chloro respectively.

Arylthio represents preferably phenylthio or phenylthio substituted by lower alkyl, lower alkoxy or halogen, e.g. methyl, methoxy or chloro respectively.

Arylsulfinyl and -sulfonyl represents preferably phenylsulfinyl or -sulfonyl substituted by lower alkyl, lower alkoxy or halogen, e.g.
methyl, methoxy or chloro respectively.

Arylamino represents preferably anilino; aryl-N- lower alkylamino represents preferably N-methylanilino.

Acylamino lower alkyl and ~-acylamino lower alkyl represent prefer-ably acylamino(ethyl, propyl or butyl) and ~-acylamino(ethyl, propyl or butyl) respectively.

Acylamino represents lower alkanoylamino, lower alkoxycarbonylamino, cycloalkylcarbonylamino, cycloalkyloxycarbonylamino, cycloalkyl lower alkoxycarbonylamino; also aryl lower alkanoylamino, aryl lower alkoxycarbonylamino, arylsulfonamido in which aryl preferably represents phenyl or phenyl substituted by preferably lower alkyl, lower alkoxy or halogen; also aroylamino in which aroyl preferably represents benzoyl, or benzoyl substituted by preferably lower alkyl, lower alkoxy or halogen, or nicotinoyl.

Aryl lower alkoxycarbonylamino represents preferably arylmethoxy-carbonylamino, advantageously benzyloxycarbonylamino (also called carbobenzyloxyamino), benzyloxycarbonylamino substituted on the phenyl ring by lower alkyl, lower alkoxy or halogen, e.g. methyl, methoxy or chloro respectively, or pyridylmethoxycarbonylamino.

The salts of the compounds oE formula I are derived from those compounds which have salt forming properties and are preferably pharmaceutically acceptable salts.

Pharmaceutically acceptable salts are preferably metal or ammonium salts of said compounds of formula I wherein R represents carboxy or of formula IA wherein COR6 and/or CoR7 represent carboxy, more particularly alkali or alkaline earth metal salts, e.g., the sodium, potassium, magnesium or calcium salt; or advantageously easily crystallizing ammonium salts derived from ammonia or organic amines, such as mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl)-amines, lower alkylenediamines or (lower hydroxyalkyl or aralkyl)-alkylammonium bases, e.g., methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxy-methyl)aminomethane or benzyltrimethylammoniumhydroxide. Said compounds of formula I form acid addition salts, which are prefer-ably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example hydrohalic, e.g. hydro-chloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, aceticl propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, hydroxy-maleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic;
methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzene-sulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid.

The compounds of formula I exhibit valuable pharmacological proper-ties, e.g. cardiovascular effects, by inter alia inhibiting the release of Angiotensin II through selective inhibition of angiotensin-converting enzyme in mammals. The compounds are thus useful for treating diseases responsive to angiotensin-converting enzyme inhibition in mammals including man.

The compounds of this invention exhibit primarily hypotensive/-antihypertensive and cardiac effects inter alia due to their angiotensin-converting enzyme inhibitory activity. These properties are demonstrable by in vivo or in vitro tests, using advantageously mammals, e.g., rats, cats, dogs or isolated organs thereof, as test objects. The animals may either be normotensive or hypertensive e.g., genetically spontaneous hypertensive rats, or renal hyper-tensive rats and dogs, and sodium-depleted dogs. The compounds can be applied to the test animals enterally or parenterally, advantage-ously orally or intravenously, for example within gelatin capsules or in the form of starchy suspensions or aqueous solutions. The applied dosage may range between about 0.01 and 100 mg/lcg/day, preferably between about 0.05 and 50 mg/kg/day, advantageously between about 0.1 and 25 mg/kg/day.

The in vivo lowering effect on the blood pressure is recorded, either directly by means of a catheter, placed in the test animal's femoral artery, or indirectly by sphygmomanometry at the rat's tail or a transducer. The blood pressure is recorded in mm Hg prior to and after dosing.

Thus the antihypertensive effects are demonstrable in spontaneously hypertensive rats by indirect measurement of systolic pressure.
~onscious rats are placed individually in restraint cages within a gently warmed chamber. A pulse sensor is placed distal to an inflatable occlusive cuff on each rat's tail. The cuff is periodi-cally inflated to occlude the tail artery. The pressure in the cuff is continously reduced and the systolic pressure corresponds to the pressure in the cuff, at which the pulse waves reappear. After obtaining control values of blood pressure and heart rate, test compounds are administered orally once daily for 4 consecutive days.
Additional blood pressure measurements are usually made at 2.0, 4.0 and 23.5 hours after each daily dosing, and responses are compared to those of rats dosed with the treatment vehicle.

The compounds of this invention when administered intravenously or orally also exhibit an inhibitory effect against the Angiotensin I
induced pressor response of normotensive rats. Angiotensin I is hydrolyzed by the action of said converting enzyme to the potent pressor substance Angiotensin II. The inhibition of said enzyme prevents the generation of Angiotensin II from I. In this manner the increase of blood pressure provoked by Angiotensin I is attenuated.

The corresponding _ vivo test is performed with male, normotensive rats, which are anesthetized with sodium 5-ethyl-5-(1-methylpropyl)-2-thiobarbiturate. A femoral artery and saphenous vein are cannulated respectively for direct blood pressure measurement and the i.v. administration of Angiotensin I and a compound of this invention. After the basal blood pressure is stabilized, pressor responses to 3 challenges of 333 ng/kg Angiotensin I i.v., at 5 minute intervals, are obtained. Such pressure responses are usually again obtained at 5, 10, 15, 30 and 60 minutes after i.v. administration or l, 2, 3 and 4 hours after p.o. administration of the compound to be tested, and compared with the initial responses. Any observed decrease of said pressor response caused by the compounds of the invention is an indication of Angiotensin I converting enzyme inhibition.

The in vitro inhibition of the angiotensin-converting enzyme by the compounds of this invention can be demonstrated by a method analo-gous to that given in Biochim. Biophys. Acta 293, 451 (1973).
According to this method, said compounds are dissolved at about 1 mM
concentration in phosphate buffer. To lO0 microliters of solutions of the test compound in phosphate buffer, diluted to the desired concentration, are added lO0 microliters of 5 mM hippuryl-histidyl-leucine in phosphate buffer, followed by 50 microliters of the angiotensin-converting enzyme preparation (from lungs of adult male rabbits) in Tris buffer, containing potassium and magnesium chloride, as well as sucrose. Said solutions are incubated at 37C
for 30 minutes and combined with 0.75 ml of 0.6 N aqueous sodium hydroxide to stop further reaction. Then 100 microliters of a 0.2 solution of o-phthalaldehyde in methanol are added at room tempera-ture, and 10 minutes later 100 microliters of 6N hydrochloric acid.
These samples are read against water in a spectrophotometer set at 360 nm, and the optical densities thereof estimated. They are corrected for the standard curve via a conversion factor expressing nanomoles of hystidyl-leucine formed during said 30 minute incuba-tion period. The results are piotted against drug concentration to dertermine the IC50, i.e., the drug concentration which gives half the activity of the control sample containing no drug.

Angiotensin-converting enzyme not only participates in the conversion of Angiotensin I to Angiotensin II, but also plays a role in the control of bradykinin and aldosterone levels. The effect of the compounds of this invention on these factors may also contribute to the antihypertensive and cardiac effects of the compounds of this invention.

The aforementioned advantageous properties render the compounds of this invention of great value as specific therapeutic agents for mammals including man.

Accordingly, the compounds of this invention are valuable anti-hypertensive agents, especially useful for ameliorating hypertension (regardless of etiology) and/or cardiac conditions, such as congestive heart failure, and/or other edemic or ascitic diseases.
They are also useful in the preparation of other valuable products, especially of corresponding pharmaceutical compositions.

According to the present invention one or both of the carboxyl groups of the dicarboxylic acids, i.e. compounds of formula IA, IB
or IC wherein R and R are hydroxy, may be functionali2ed as esters or amides. These functional derivatives are preferably the mono or bis lower alkyl esters, e.g. methyl, ethyl, n- or i-propyl, butyl or benzyl esters; the mono or bis-amides, the mono- or di-N-alkylated amides, e.g. mono- or diethylamides; the mono or di-substitued lower alkyl esters, e.g. the ~-(amino, mono- or dimethylamino, carboxy or carbethoxy)-(ethyl, propyl or butyl) esters. Highly preferred func-tional derivatives are the mono esters of formula IA, e.g. wherein one of R and R represents hydroxy and the other represents lower alkoxy.
--Any prodrug derivatives of compounds of this invention e.g. any pharmaceutically acceptable esters and amides of the mono- or di~carboxylic acids of this invention that may be convertible by solvolysis or under physiological conditions to the said carboxylic acids e.g. esters and amides cited above, represent a particular object of the invention.

Said esters are preferably, e.g, the straight chain or branched lower alkyl esters unsubstituted or suitably substituted such as the pivaloyloxymethyl, bornyloxycarbonylmethyl, benzyl, pyridylmethyl, a-carboxyethyl or suitably esterified a-carboxyethyl esters, and the like.

Said amides are preferably e.g. simple primary and secondary amides and amides derived from the amino acids or derivatives thereof, such as the amides derived from alanine, phenylalanine and the like.

More particularly, the invention relates to compounds of formula IA

\ / \ I ~
N - CH (IA) ~ / \ / COR6 R o N - o R -CHCOR
wherein the carbocyclic ring may also be hexahydro; R is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, cycloalkyl, cycloalkyl lower alkyl, acylamino lower alkyl, mono- or di- lower alkylamino lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, esterified carboxy lower alkyl, carbamoyl lower alkyl, N-substituted carbamoyl lower alkyl, hydroxy lower alkyl, etherified or acylated hydroxy lower alkyl, aryloxy lower alkyl, arylthio lower alkyl, aryl-N- lower alkylamino lower alkyl, or arylamino lower alkyl; R and R represent hydrogen or lower alkyl; R and R
represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxyl halogen, trifluoromethyl; or R3 and R4 taken together represent lower alkylenedioxy; X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy group and one hydrogen with the proviso given abovej R~ and R7 independently represent hydroxy, amino, mono- or di- lower alkylamino, lower alkoxy, aryl lower alkoxy, lower alkanoyloxymethoxy, (amino, mono- or di-lower alkyl-amino, carboxy, or lower alkoxycarbonyl) lower alkoxy; or the pharmaceutically acceptable salts thereof.

A more specific embodiment of this invention relates to compounds of formula IA wherein R is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, cycloalkyl lower alkyl; and wherein within the above definitions aryl represents phenyl unsubstituted or mono-or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogen or trifluoromethyl; and cyclo alkyl contains 3 to 8 carbons; X and R to R are as defined above with the proviso given above; or the pharmaceutically acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

A further embodiment of this invention relates to compounds of formula IA wherein R is aryl lower alkyl where aryl represents indolyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, hydroxy lower alkyl, lower alkylthio lower alkyl, acylamino lower allcyl; aryloxy lower alkyl or arylthio lower alkyl; X and R to R
are as defined above with the proviso given above; or the pharma-ceutically acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

Preferred embodiments of this invention relate to compounds of formula IA wherein R is hydrogen, lower alkyl, amino lower alkyl, acylamino lower alkyl, aryl lower alkyl where aryl represents phenyl unsubstituted or mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or trifluoromethyl; R and R4 are hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; or R3 and R4 taken together represent alkylenedioxy; R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl lower alkoxy, lower alkoxycarbonyl lower alkoxy, R2l R5 and X are as defined above with the proviso given above; or pharmaceutically acceptable salts thereof, or said compounds wherein the carbocyclic ring is hexahydro.

Especially preferred are compounds of formula IA, wherein R is hydrogen, lower alkyl, amino lower alkyl, aryl lower alkoxycarbonyl-amino lower alkyl or aryl lower alkyl where aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; R and R are hydrogen or lower alkyl; R3 and R4 are hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoromethyl; or R and R taken together represent lower alkylenedioxy; X represents oxo, two hydrogens, or one hydroxy or lower alkanoyloxy and one hydrogen with the above proviso in modified form depending on the meaning of X; R and R
independently represent hydroxy, amino, lower alkoxy, phenyl lower alkoxy, lower alkoxycarbonyl lower alkoxy; or pharmaceutically acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

Particularly preferred are compounds of formula IA wherein R is hydrogen, lower alkyl, ~-amino lower alkyl, ~-arylmethoxycarbonyl-amino lower alkyl, aryl lower alkyl where aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; R and R are ilydrogen or lower alkyl; R is hydrogen; R is hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoromethyl; X represents oxo, two hydrogens, or one hydroxy or lower alkanoyloxy and one hydrogen with the above proviso in modified form depending on the meaning of X; R and R independently represent hydroxy, amino, lower alkoxyl phenyl lower alkoxy, lower alkoxycarbonyl lower alkoxy; or pharma-ceutically acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

Especially preferred are compounds of formula IA wherein R is hydrogen, methyl, ethyl, isopropyl, ~-aminopropyl, ~-aminobutyl, ~-(benzyloxycarbonylamino)propyl, ~-(benzyloxycarbonylamino)butyl, aryl-(methyl, ethyl, propyl) where aryl represents phenyl unsub-stituted or substituted by one methyl, hydroxy, methoxy1 methylene-dioxy, acetoxy, chloro or trifluoromethyl group; R and R are hydrogen or methyl; R3 and R4 represent hydrogen, methoxy, methyl, chloro or trifluoromethyl; X represents oxo, two hydrogens, or one hydroxy or one acetoxy and one hydrogen with the above proviso in modified form depending on the meaning of X, R6 and R7 independently represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxy-carbonylmethoxy or pivaloyloxymethoxy; or pharmaceutically accept-able salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

Very much preferred are colnpounds of formula IB
o ~ H C H R8 ! ~ \ I , n 2n -N - CH (IB) '~ / \ / COR6 N---a / ~
7 o wherein n represents an integer from 1 to 4; R is benzyloxy-carbonylamino; R and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or pharmaceuti-cally acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

Especially preferred are compounds of formula IB wherein C H2 represents ethylene, n-propylene or n-butylenel R8 represents benzyloxycarbonylamino; R and R independently represent hydroxy ~ ?3 or lower alkoxy with up to 4 carbon atoms; or pharmaceutically acceptable salts thereof; or said compounds wherein the carbocyclic ring is hexahydro.

The present invention also relates to the stereoisomers of compounds of formula I. A number of racemates are obtainable when, e.g. in formula IA at least one of R and R is not hydrogen and/or X
represents H(OH) or H(acylated OH). Furthermore, the compounds of the invention in which the carbocyclic ring is hexahydro may also exist as the isomers with either a cis or trans ring junction.

The individual enantiomers of said racemates may in turn be ob-tained. Certain specific said isomers are preferred as angiotensin-converting enzyme inhibitors.

Preferred are said compounds in which the asymmetric ring carbon (position 3) bearing the substituted amino group is of the (S)-con-figuration. Further preferred are said componds in which the side chain asymmetric carbon atom bearing the COR group is of the (S)-configuration.

Outstanding are compounds of formula IC

o ~"
! ~ \ H / n 2n S o-~ _ CH (IC) / \ / CCR
2~

C1~2COR

wherein S represents the chirality, n represents an integer from 1 to 4; R8 is benzyloxycarbonylamino; R and R independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or pharmaceutically acceptable salts thereof.

~7~ c~ ~

The compounds of formula I acccording to the invention can be prepared in a manner which is known per se, in that7 e.g.

a) in a compound of the formula R~ o ! c ~-NH-R (II)

3~ / \ /
R o N---~
R O
in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, R , R , R4 and R5 have the meanings given hereinabove, R is introduced by alkylation with a compound of the formula RA z (IIIA) wherein Z is a reactive esterified hydroxyl group and R has the meanings given hereinabove or with a compound of the formula R -CO-R (IV) wherein R and R have meanings given hereinabove, in the presence oE a reducing agent with temporary protection oE any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups, which may be present in any one of the residues X, R , R
and R , and/or in the alkylating agent, or b) a compound of the formula R ~ ~ R5 o ~ I ~A' (V) ~, 0 ~/\ /
R ~ N~
/ ~
H O
in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, R3, R4 and R5 have the meanings given hereinabove and R is hydrogen or RA as defined hereinabove, is alkylated with a compound of the formula RB z (IIIB) wherein Z is a reactive esterified hydroxyl group and R has the meanings given hereinabove, while protecting temporarily any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups which may be present in any one of the residues X, R , R , R
and R , or c) a compound oE the formula X

R4 o oh~\! \
¦ ¦¦ =Y (VI) o ~ /
3~
R ~ N------o B/

in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein Y is oxo or dichloro or a reactive esterified hydroxyl group Z together with hydrogen, and X, RB, R
and R4 have the meanings given hereinabove, is condensed with an amine of the formula R -NH-R (VII) wherein R and R have the meanings given hereinabove, with the proviso that when Y is oxo, or dichloro, the condensation is carried out in the presence of a reducing agent and with a temporary protection of the oxo group which may be present as the substituent X, or d) in a compound of the forrnula

4 \\
\ / \ RS R1 CH (VIII) ~ / ; / R
R o N~
2 o" ~

in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X and R to R have the meanings given hereinabove, one of the symbols R and R is cyano and the other one is cyano or R as defined hereinabove, the cyano group(s) is (are) subject to solvolysis, or ~ % ~ 3 e) a compound of the formula 4 \\
~ \ / \ /R
! ¦¦ CH-N (IX) 3~ R
R o NH COOH
RB

in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, RA, R , R , R and R5 have the meanings given hereinabove, or an ester thereof, is cyclised, or f) a compound which is structurally identical with a compound of formula I specified above, except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group R , is treated with a reducing agent in order to saturate this double bond, or g) in order to produce a compound of formula I as specified herein-above, in which X i~s oxo, condensing a compound of the formula R4 o ~
1l (x) 3~ / \ /
R o N------4 B/

R O
in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein R , R and R have the meanings given hereinabove, with an amine of the formula R -NH-R (VII) wherein RA and R5 have the meaning given hereinabove, and, if desired, a resulting compound oE formula I is converted into another compound of formula I, and/or if desired, a resulting compound of formula I having salt-forming properties is converted into a salt thereof or a resulting salt into another salt or a free compound is liberated from such a salt, and/or if so required, an optical isomer which has a specific configuration with respect to at least one center of chirality is enriched from a mixture of stereoisomeric forms of a resulting compound of formula I.

A reactive esterified hydroxyl group Z is such as a hydroxyl group esterified with a strong organic acid, e.g. an aliphatic or aromatic sulfonic acid (such as a lower alkanesulfonic acid, especially methanesulfonic, trifluoromethanesulfonic acid, especially benzene-sulfonic, p-toluenesulfonic, p-bromobenzenesulfonic and p-nitro-benzenesulfonic acid) or with a strong inorganic acid, such as, especially, sulfuric acid, or a hydrohalic acid, such as hydro-chloric or, most preferably, hydroiodic or hydro~romic acicl.

Any substitutive alkylation according to the present invention is carried out under conventional general conditions at temperatures ranging between about 0C up to the boiling temperature of the reaction mixture, preferably at temperatures between room tempera-ture to about 100C. The reaction takes place advantageously in the presence of a solvent which is inert with respect to the reactants, such as a chlorinated lower alkane (e.g. chloroform or methylene chloride), an acyclic or cyclic ether (e.g. diethyl ether, 1,2-di-methoxyethane, dioxane or tetrahydrofuran) and, in particular, a lower molecular weight tertiary amide (e.g. N,N-dirnethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric acid triamide). Advantageously, the strong acid HZ liberated during the reaction is bound by the addition of an acid-binding agent, such as, preferably, an inorganic acid-scavenger such as an alkali metal bicarbonate, carbonate or hydroxide, an organic quaternary ammonium salt (e.g. a tetrabutylammonium salt) or an organic tertiary base, such as triethylamine, ~-ethylpiperidine, pyridine or quinoline.

An alkylation according to the present invention can also be carried out unter the conditions of reductive alkylation in the manner generally known and used in the art. In carrying out that alkylation the starting materials are, simultaneously or in a subsequent step, reacted with a reducing agent. Among reducing agents which are used simultaneously with the alkylating agent, mention should be made of formic acid and complex metal hydrides such as sodium cyanoboro-hydride; among reducing agents used predominantly in a separate subsequent operation i.e. reduction of a preformed imine (Schiff's base), mention should be made of diborane and complex metal hydrides, such as, sodium borohydride, sodium cyanoborohydride which are added advantageously to the primary reaction mixture without isolating an intermediate, e.g. the imine. In this case, the alkylation is carried out advantageously in an organic solvent inert to the reducing agent, such as in an aliphatic or cyclic ether (such as diethyl ether, diisopropyl ether, l,2-dimethoxyethane~ dioxane or tetrahydrofuran) or an aliphatic alcohol (such as methanol, ethanol, isopropyl alcohol, glycol, glycol monomethyl ether or diethylene-glycole), preferably at about 0-80C. A principal reducing agent, however, which can be used both simultaneously and subsequently, is hydrogen, especially catalytically activated hydrogen. The catalysts are those conventionally used as hydrogenation catalysts, i.e.
preferably those of the class of precious metals (such as palladium, platinum and rhodium) on a carrier (such as calcium carbonate, aluminium oxide or barium sulfate), in a finely dispersed suspension without carrier or, in form of complexes, in a homogeneous phase.
Also, finely dispersed transition metals such as Raney metals, especially Raney nickel, are very suitable catalysts for the reductive alkylation. The specific reaction conditions depend, to a large extent, on the particular hydrogenation catalyst and its precise activity, and do not differ from those generally known for hydrogenation. Temperatures ranging from room temperature to about C~=~3 150 C, and pressures of hydrogen ranging from atmospheric pressure to about 300 atmospheres are applicable according to the standard procedures of the art. In addition to the inert solvents which were mentioned above in connection with the hydride reduction, low molecular weight amides, especially tertiary amides (such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone, hexamethylphosphoric acid triamide), and also formamide and acetamide can be used as suitable solvents. Special measures have to be taken with starting materials which have an easily reducible functional group, such as the 5-oxo group; in order to preserve these groups, selective reduction conditions, as known in the prior art, have to be applied, or, if a simultaneous reduction of these groups is desired or required, vigorous reagents and/or conditions are employed accordingly.

The preformed imines referred to above are preferably prepared by condensing corresponding starting materials in an inert solvent, e.g. toluene or methylene chloride, advantageously in the presence of a dehydrating catalyst, e.g. boron trifluoride etherate, p-toluenesulfonic acid or molecular sieves.

In the case of reactants of e.g. formulae IIIA, IIIB, IV and Vll that contain a free carboxylic group R , an appropriate carboxylate salt is prepared, preferably in situ, before condensation with the desired intermediates cited hereinafter in detail.

In any of the alkylation processes, primary and secondary amino groups in starting materials, except for the amino group to be alkylated, must be in a temporarily protected form during the alkylation. Suitable protecting groups, as well as procedures for their introduction and removal are well known in the art, being elaborated in great detail in particular as general methods for the synthesis of peptides, cf. Houben-Weyl: Methoden der Organischen Chemie; 4th edition, vol. 15/I and II, E. Wunsch (editor): Synthese von Peptiden (Georg Thieme Verlag, Stuttgart; 1974~. The narrower selection of the protecting groups depends on the specific purpose, it being necessary to take into account in particular the specific properties of the particular starting materials and the reaction conditions of the specific process. In the case of several func-tional groups to be protected, advantageous combinations can be selected. Preferably, for example, similar or, even better, identi-cal amino protecting groups, are used both in the radicals R and in the radical R and are simultaneously removed following alkylation.

Suitable as amino-protecting groups are especially amino-protecting groups that can be removed by reduction, for example especially those of the benzyloxycarbonyl type in which the benzyloxycarbonyl group may be substituted in the aromatic moiety by halogen atoms, lower alkoxy groups and/or lower alkyl radicals and, especially, by nitro groups, such as the p-chloro- and p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-methylbenzyloxycarbonyl and, especially, p-nitrobenzyloxycarbonyl group, or alternatively the isonicotinyloxycarbonyl group. An advantageous amino-protecting group is an ethoxycarbonyl group which carries in the ~-position a silyl group substituted by three hydrocarbon radicals,such as triphenylsilyl, dimethyl-tert.-butylsilyl or, especially, tri-methylsilyl. A ~-(trihydrocarbylsilyl)-ethoxycarbonyl group of this type, such as a ~-ttri-lower alkylsilyl)-ethoxycarbonyl group, for example, especially ~-(trimethylsilyl)-ethoxycarbonyl, forms with the amino group to be protected a corresponding ~-trihydrocarbyl-silylethoxycarbonylamino group (for example the ~-trimethylsilyl-ethoxycarbonylamino group), which may be removed under very specific, very mild conditions by the action of fluoride ions.

It is also possible to use groups that can be removed by acidolysis, such as the tert-butoxycarbonyl groups and analogous groups, as well as those of the aralkyl type, such as benzhydryl, di-(~-methoxy)-benzhydryl and triphenylmethyl (trityl), or certain aralkoxycarbonyl groups of the 2-(p-biphenylyl)-2-propoxycarbonyl type, which are described in Swiss Patent Specification No. 509 266. It should be noted that protecting groups derived from esters of carbonic acids are in most cases also removable by basic hydrolysis.

- ~4 -For the optional temporary protection of hydroxy groups, protecting groups may be used advantageously that can be removed by reduction, _ . the above-cited text (Houben-Weyl), and also groups that can be removed by acidolysis, such as 2-tetrahydropyranyl, tert-butoxy-carbonyl and tert-butyl. Preferred hydroxy~protecting groups that can be removed by reduction are, for example, benzyl groups that may be substituted in the aromatic moiety by halogen, lower alkyl, lower alkoxy and/or, especially, nitro, especially the 4-nitrobenzyl group. It is also possible to use acyl groups that can be removed under weakly basic conditions, such as formyl or trifluoroacetyl.

~or the optional protection of oxo groups, these are preferably protected as ketals, especially as ketals derived from lower alkanols, such as methanol or ethanol, or advantageously of ethylene glycol, or as corresponding thioketals preferably those of 1,2-ethanedithiol. All these groups can liberate oxo groups under the conditions indicated further below.

The subsequent removal of protecting groups in accordance with the invention depends on their nature and is carried out in each case in a conventional manner known per se taking into considerat;on the general properties of the derived product. If the protecting groups for amino, hydroxy and oxo have been so selected that they can be removed under similar conditions (especially preferred here are the groups removable by acidolysis or, for amino and hydroxy, by reduction, that have already been given special mention), then all of these protecting groups are advantageously removed in a single operation; in speciaL cases, however, it is possible to use diffe-rent types of groups and remove each of them individually.

The groups that can be removed by reduction, especially those that contain halogenated lower alkyl radicals (for example 2,2,2-tri-chloroethyl radicals), isonicotinyl radicals (for example iso-nicotinyloxycarbonyl) and, especially, substituted benzyl radicals, especially 4-nitrobenzyl radicals of any kind, are preferably removed by zinc reduction, usually in the presence of an ac;d, preferably acetic acid, and with or without the addition of an inert organic solvent, usually at room temperature. The removal of a protecting group by acid hydrolysis ~acidolysis) is carried out in the case of groups of the tert-butyl type by means of hydrogen chloride, hydrogen fluoride or trifluoroacetic acid, and in the case of acid-sensitive protecting groups chiefly by means of a lower aliphatic carboxylic acid, such as formic acid and/or acetic acid, in the presence of water and, optionally, a polyhalogenated lower alkanol or lower alkanone, such as 1,1,1,3,3,3-hexafluoropropan-2-ol or hexafluoroacetone. In this manner, it is possible, for example, for an N-trityl group to be removed by an organic acid, such as formic acid, acetic acid, chloroacetic acid or trifluoroacetic acid, in aqueous or absolute trifluoroethanol as solvent (cf. German Offenlegungsschrift 2 346 147) or by aqueous acetic acid; for the tert-butoxycarbonyl group to be removed by trifluoro-acetic acid or hydrochloric acid; and for the 2-(p-biphenylyl)-isopropoxycarbonyl group to be removed by aqueous acetic acid or, for example, by a mixture of glacial acetic acid, formic acid (82.8 ~ strenght) and water (7:1:2) or in accordance with the process in DE-OS 2 346 147. The ~-silylethyl ester groups are preferably removed by fluoride ion-yielding reagents, for example fluorides of quaternary organic bases, such as tetraethylammonium fluoride.

Ketalized and thioketalized oxo groups are converted into free oxo groups by acidolysis with usual strong inorganic acids, or with oxalic ac;d, in the presence of water, the latter ones advantage-ously by treatment with a sulfur-binding agent, e.g. a mercury II -salt and/or cadmium carbonate. Protecting groups that are unstable to basic conditions, for example formyl, trifluoroacetyl and carbonic acid ester groups, can be carefully removed by the action of an aqueous sodium or potassium bicarbonate or carbonate solution, or, also, aqueous ammonia, in an organic solvent, usually at room - 2~ -temperature The protecting groups are preferably removed under the reaction conditions of the examples, or under analogous conditions.

Process a) Condensation of amines of formula II with the known x-ketoacid derivatives oE formula IV (e.g.Chem. Ber. 3l, 551,3133) by reductive N-alkylation is carried out under conditions known to the art, e.g. by catalytic hydrogenation with hydrogen in the presence of platinum, palladium or nickel catalysts or with chemical reducing agents such as simple or complex light metal hydrides, advantageously an alkali metal cyanoborohydride such as sodium cyanoborohydride. The reductive amination with an alkali metal cyanoborohydride is preferably carried out in an inert solvent, e.g.
methanol or acetonitrile, advantageously in the presence of an acid, e.g. hydrochloric acid or acetic acid at a temperature between about 0 and 50C, preferably room temperature.

Alkylation o~ amines of formula II with a reastant of formula IIIA, well known to the art, is carried out with or without basic catalysts such as triethylamine or potassium carbonate in an inert solvent.

The starting materials of formula IIIA and IV are known or, if they are unknown, can be simply obtained by conventional synthetic processes. The starting materials of formula II can be obtained by conventional synthetic processes, and advantageously in the manner which is described in more detail and exemplified for specific intermediates hereinafter.

Compounds of formula II can be obtained by condensing under conditions of basic catalysis, a compound of the formula 3 \\

¦ ¦l o -R (XI) 4~ / \ /
R ~ N-~-r \~
H O
or a hexahydro derivative thereof wherein R and R4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R and R4 taken together represent lower alkylenedioxy; X represents two hydrogens, one hydrogen and one etherified or esterified hydroxy, oxo or oxo protected in form of a ketal or thioketal and R9 is amino, lower alkylamino, azido or acylamino, e.g. lower alkanoylamino or alkyloxycarbonylamino with a compound of the formula R2 _ CH - COR (III'B) 1.

wherein R represents hydrogen or lower alkyl; R represents hydroxy, di- lower alkylamino, lower alkoxy, aryl lower alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl lower alkoxy and Z
represents reactive esterified hydroxy; and optionally reducing, hydrogenolyzing, hydrolyzing or alkylating the resulting inter-mediate.

Compounds of formula XI are obtained Erom the corresponding opt;onally substituted and/or derivatized 2,3,4,5-tetrahydro-lH-l-benzazepin-2-ones [J. Chem. ~oc. 1937, 456; British patent 1~359l235, Liebig's Ann. Chem. 5741 171 (1951~1 Novel appropriately derivatized starting l-benzazepin-2-ones are advantageously prepared by Beckmann rearrangement of the correspondingly derivatized naphthalen-l-ones using procedures known to the art and exemplified herein.

Said tetrallydro-l-benzazepin-2--ones are converted to the 3-halo-, e.g. 3-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one under conditions exemplified herein, e.g. by treatment with phosphorus pentachloride followed by hydrogenation. Substitution of said halo derivative with a metal azide, e.g. sodium azide and optional reduction, or substitution with arnmonia or a lower alkylamine and optional acylation, yields compounds of formula XI.

Alternatively, compounds of formula XI wherein R9 represents amino, alkylamino or acylamino are obtained by reduction and cyclization of the appropriately substituted and/ or derivatized 4-(2-nitro-phenyl)-2-aminobutyric acid and optional subsequent N-alkylation or N-acylation.

An alternate synthesis for the optically active compounds of this invention starts with the natural amino acid tryptophane.
Specifically L-4-(2-aminophenyl)-4-oxo-2-aminobutyric acid (L-kynurenine, J. Am. Chem. Soc. 76, 1708 (1954), derived from L-tryptophane) is converted to an optically active starting material of formula XI wherein R is acylamino, e.g. 3-(S)-t-butyloxy-carbonylamino-2,3,4,5-tetrahydro-lH-l-benæazepine-2,5-dione as described in the Australian Journal of Chemistry 33, 633-40 (1980).
The lactam alkylation of a compound of formula XI with a reactant of formula IIIB, well known in the art, is preferably carried out in the presence of bases such as alkali metal hydrides, e.g. sodium or potassium hydride, alkali metal alkoxides, e.g. potassium t-butoxide or sodium methoxide, organo-metallic reagents, e.g. lithium diiso-propylamide or under conditions of phase transfer catalysis e.g. in the presence of a tetrabutylammonium salt, preferably in a solvent e.g. tetrahydrofuran, dimethylformamide, at a temperature preferably between about 0 and 75 C.

Process b) is carried out in a conventional manner under the conditions of substituitve alkylation as described hereinbefore and is preferably carried out in the presence of very strong bases, such as alkali metal hydrides (e.g. sodium or potassium hydride), alkoxides (e.g. sodium methoxide or ethoxide, potassium tert-butoxide) or amides (e.g. lithium diisopropylamide), whereby ethers and amides mentioned above are preferred as solvents. In a special modification of process b), starting materials are used in which R is hydrogen, and at least two equivalents of the reactant IIIB
is employed. In the resulting product, both RA and RB are identical and within the scope of the meanings of R .

The starting materials of formula IIIB are known or, if they are unknown, can be simply obtained by conventional synthetic processes.
The starting materials of formula V can be obtained by conventional syntlletic processes, and advantageously in the manner which is described in more detail and exemplified for specific intermediates hereinafter.

Compounds of formula V can be obtained by condensing under conditions of reductive alkylation a compound of the formula R ~ ~ R5 ! 1I N-H (XII) 3~ / \ /
R o N~
H O
or a hexahydro derivative thereof wherein R , R and X have meanings as ~ef;ned for formula XI; and R is hydrogen or lower alkyl, with a compound of the formula IV' o Rl _ C - COR (IV') wherein Rl and R have meanings as previously defined, or under alkylation conditions with a compound of formula III'A

Rl _ CH - COR6 (III'A) I
z wherein R , R and z have meanings as previously defined.

Process c), also being an alkylation reaction is performed according to the same general considerations and under the same experimental conditions as described in detail above (substitutive alkylation or reductive alkylation). Starting materials of formula VI can be obtained by conventional processes known per se, e.g. in the manner described more specifically hereinafter.

The starting materials of formula VII or VII' represent amino acids and derivatives well known to the art or synthesized by methods well-known to the art. It is noteworthy that the optically active compounds of this invention may be synthesized starting with an optically active compound of formula VII or VII', e.g. L-~-amino-phenylbutyric acid ! L-phenylalanine, L-tryptophane, L-methionine, L-aspartic acid, L-threonine, L-glutamic acid, L-lysine, L-ornithine or derivatives thereof.

Process d) is also carried out in a conventional manner under the general conditions of solvolysis, which are known to convert cyanides (nitriles) into free ca~boxylic acids or their salts, esters or amides. For conversion into a free acid, hydrolysis with water is carried out advantageously in an inert organic solvent wh;ch is at least partially miscible with water, such as an ether (e.g. diethyl or diisopropyl ether, 1,2-dimethoxyethane or, especially dioxane or tetrahydrofuran) or a lower alkanol (e.g.
methanol, ethanol, isopropyl alcohol, a butyl alcohol, especially tert-butyl alcohol), a larger amount of water being required in the latter cases in order to prevent alcoholysis. The hydrolysis can be catalysed both by strong acids, especially inorganic acids such as sulfuric acid or, preferably hydrohalic acids (e.g. hydrobromic or, as a first choice, hydrochloric acid), or by bases, especially inorganic bases such as hydroxides and carbonates of allcali metals, 63~3 e.g. sodium and potassium hydrox;de. The bases are usually employed in at least stoichiometric quantities giving rise to carboxylic acid salts as primary products. The acidic catalysts are advantageously applied as dilute aqueous solution for the best result. Final products of formula I, in which R represents an esterified carboxyl group, can be obtained by carrying out the solvolysis of the nitrile with the corresponding alcohol (alcoholysis) in the presence of a catalytic amount of an anhydrous strong acid, advantageously gaseous hydrogen chloride. Usually, excess alcohol is used as solvent;
however, inert organic solvents can be added, such as acyclic and cyclic ethers (especially these mentioned above), and/or halogenated lower alkanes (especially chloroform and dichloromethane). If the alcoholysis is carried out under strictly anhydrous conditions, the primary product (imido ester) is to be hydrolyzed, advantageously by adding water to the reaction mixture; otherwise, by carrying out the alcoholysis in the presence of an approximately stoichiometric equivalent of water, the desired ester is obtained directly. In order to obtain a corresponding amide (i.e. a compound of formula I, wherein R is carbamoyl), a corresponding nitrile of formula VIII
can preferably be subjected to alkaLine hydrolysis in the presence of hydrogen peroxide.

The starting materials of formula VIII can be obtained by conven-tional methods known per se, e.g. by a condensation analogous to that of process c) in which a starting material of the formula VI is treated with an amine of the formula R
S
R -NH -CU -CN (VII') wherein R and R have the meanings given hereinabove. Also, processes a) and b) can analogously be used for the preparation of the nitriles of formula VIII.

The cyclization according to process variant e) can also be carried out in the manner known per se, e.g. by dehydration. Especially useful general methods for this purpose are those developed in connection with the formation of the amide bond in peptides, as reviewed in compilative works, e.g. Houben-Weyl1 Volumes 15/I and 15/II as cited hereinabove. According to one preferred modiEication, the amino group to be cyclized is rendered inactive by protonation (i.e. in the form of an acid addition salt), and the carboxyl group is converted into an activated ester, such as tllat with 2,4,5-tri-chlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or, especially, 4-nitrophenol, or with an N-hydroxy compound, such as N-hydroxysuccinimide, l-hydroxybenætriazole or N-hydroxy-piperidine, or alternatively with an N7N'-disubstituted isourea, such as, especially, N,N'-dicyclohexylisourea, or a similar generally known activating agent. The cyclization is effected by basification preferably by the addition of an organic base, for example a quaternary ammonium salt, or especially a tertiary amine, such as triethylamine, N-ethylmorpholine or N-methylpiperidine, in order to reactivate the amino group to be cyclized by converting it into the unprotonated formO The reaction temperature is usually from -20 to +50C, preferably approximately at room temperature, and customary solvents are usedt for example, dioxan, tetrahydrofuran, acetonitrile, pyridine, dimethylfonnamide~ dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoric acid triamide, as well as chloroform and methylene chloride, and expedient mixtures thereof. In a special variant of the process, the carboxy group can be directly activated in situ by the action of the free acid wit7h a carbodiimide, such as N,N'-dicyclohexylcarbodiimide (optionally with the addition of N-hydroxysuccinimide, an unsubsti-tuted or, for example, halogen-, methyl- or methoxy-substituted l-hydroxybenztriazole or 4-hydroxybenzo-l,2,3-triazine-3-oxide or N-hydroxy-5-norbornene-2,3-dicarboximide), or with N,N'-carbonyl-diimidazole.

Starting materials of formula IX can be obtained according to general methods known per se, e.g. as discussed in more specific examples hereinafter.

Also, reduction according to process f) can be carried out in a manner generally known per se for saturation of such double bonds.
More specifically, the double bond in the unsaturated starting materials corresponding to formula I can be located between C-3 and C-4 or between C-3 and the adjacent nitrogen atom, or between the nitrogen atom and the adjacent carbon atom within the group RA. The saturation of the double bond is advantageously carried out by catalytic hydrogenation, e.g. under the preferred conditions discussed in detail hereinbefore, and also by metal reduction, such as zinc reduction in neutral or acidic medium, or, especially in the case of the C-N double bond, by diborane or complex hydrides such as sodium borohydride, as mentioned hereinbefore. The unsaturated starting materials for this process are obtained according to known general methods, e.g. those discussed in processes a) and c) and/or in a more specific form hereinafter.

The condensation according to process g) is carried out unter conventional general conditions at temperatures ranging between about 0C and 100C in a solvent which is inert to the reactants, e.g. methylene chloride, l,2-dimethoxyethane, N,N-dimethylformamide, optionally in the presence of a base, e.g. a tertiary amine such as triethylamine or an alkali metal hydride such as sodium hydride.

In performing the optional interconversions of a resulting Einal product of formula I into another compound of formula I, trans-Eormations such as the following are carried out. an amino group is alkylated, and/or an oxo group, especially that of the symbol X, is converted into hydroxyl (plus hydrogen) or into two hydrogens by reduction and/or hydroxyl is converted into oxo by oxidation or into hydrogen by reduction, and/or a free hydroxyl or carboxyl group is liberated from its esterified form by hydrolysis or hydrogenolysis and/or a hydroxyl or amino group is acylated and/or a free carboxyl is esterified, and/or the aromatic carbocyclic ring in formula I is hydrogenated to the hexahydro or the ~,7,8,9-tetrahydro form, and/or - 3~ -the hexahydro carbocyclic ring is dehydrogenated eo 6,7,8,9-tetra-hydro or to the aromatic carbocyclic ring. All these optional inter-conversions are carried out by well-known conventional methods.

A lower alkyl group as represented by R5 can be introduced into the final product of formula I, wherein R5 is hydrogen, by an alkylation reaction, using any of the modifications discussed in detail hereinabove. Both substitutive and reductive alkylation can be employed, the former with alkyl halides, the latter with lower aliphatic aldehydes and ketones and e.g. catalytically activated hydrogen or, in the case of formaldehyde~ advantageously with formic acid as the reducing agent. By the substitutive alkylation, lower alkyl groups can also be introduced into a carbamoyl group repre-sented by symbol R .

Compounds of formula I or IA, and intermediates therefor, wherein X
represents oxo may be converted to the corresponding compounds wherein X represents one hydrogen and one hydroxy by reduction, e.g.
by catalytic hydrogenation, e.g. with hydrogen in the presence of a platinum catalyst, or with a metal hydride reducing agent such as an alkali metal borohydride (e.g. sodium borohyride), or according to the method of Meerwein-Ponndorf, or a modification thereof using an alkanol, especially isopropyl alcohol, as both solvent and reducing agent and a metal alkoxide, preferably one corresponding to the reducing alcohol, such as aluminium isopropoxide, as a catalyst. The reduction of the oxo group to two hydrogens can advantageously be accomplished e.g. by treatment with amalgamated zinc and hydro-cllloric acid, or by Raney nickel desulfurization of a correspvnding dithioketal. Resulting compounds wherein X represents one hydrogen and one hydroxy may be converted to compounds wherein X represents two hydrogens, e.g. by catalytic hydrogenation of the adduct of a carbodiimide, e.g. the adduct formed by condensation of a compound wherein X represents one hydrogen and one hydroxy with dicyclo-hexylcarbodiimide in the presence of cuprous chloride according to the general method described in Chem. Ber. 107, 1353 (1974).

Alternatively, the compounds wllerein X represents one hydrogen and one hydroxy may be first converted to the corresponding compounds wherein X represents one hydrogen and one acylated hydroxy (or acyloxy e.g. acetoxy) and subsequently reduced, e.g. by catalytic hydrogenation in the presence of a palladium catalyst, to compounds wherein X represents two hydrogens. The oxidation oE hydroxyl to oxo can be preferably carried out with a derivative of hexavalent chromium such as chromic acid or its salts, with a permanganate salt (especially potassium permanganate) or under the conditions of the Oppenauer oxidation, with acetone or cyclohexanone as oxidant and aluminium isopropoxide as catalyst. Esterified hydroxyl groups are liberated in particular by methods discussed in detail hereinabove ;n connection with removing hydroxyl-protecting groups; the acylation of hydroxyl groups is carried out in the usual way, preferably using a corresponding acid anhydride or halide.

The aromatic carbocyclic ring in compounds of formula I or in intermediates for the preparation of compounds of formula I is converted to the hexahydro form by e.g. hydrogenation at atmospheric or higher pressure in the presence of a catalyst (such as platinum or rhodium) at room or elevated temperature in a polar solvent such as ethanol.

Compounds of formula I or IA wherein R represents amino lower alkyl may be converted to compounds wherein R represents acylamino lower alkyl, or vice versa, by methods well-known in the art and described hereinabove in connect;on with protecting groups.

Free carboxylic acids of formula I or IA wherein R and/or R7 represent hydroxy or salts thereof may be esterified with the appropriate alcohols or reactive derivatives thereof well known to the art or with a diazoalkane, especially diazomethane to give the corresponding mono-or bis-ester, namely compoùnds of formula I or IA
wherein R and/or R is lower alkoxy, aryl lower alkoxy, lower alkanoyloxymethoxy, or lower alkoxycarbonyl lower alkoxy. Alter-natively, the carboxyl group can be converted into a reactive derivative thereof, such as an active ester such as that with 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or, especially, 4-nitrophenol, or with an N-hydroxy compound, such as N-hydroxysuccinimide, l-hydroxybenætriazole or N-hydroxypiperidine, or alternatively with an N,N'-disubstituted isourea, such as, especially, N,N'-dicyclohexylisourea or into a mixed anhydride, e.g. with an acid halide (i.e., especially an acid chloride) and this activated intermediate reacted with the desired alcohol. Furthermore the free carboxylic acids may be converted via reactive intermediates to mono- or bis-amides of formula I wherein R and/or R7 represents amino, mono- or di-lower alkylamino.

The free carboxyl group can be liberated from an esterified carboxyl in a manner generally known, especially by base-catalyzed hydro-lysis. Of special interest, however, are methods capable of selectively liberating one particular carboxyl group represented by the symbols -COR6 and -COR . In such a case, use can be made of a proper combination of ester groups known in the art especially as carboxyl-protecting groups and developed in a great variety in particular for the synthesis of peptides, cf. Houben~Weyl, Volumes 15/I and 15/II as cited hereinabove. Radicals suitable for selective removal with liberation of the carboxyl are esters derived, for example, from alcohols that yield radicals that can be removed by acidolysis, such as cyanomethyl alcohol, benzoylmethyl alcohol or tert-butyl alcohol, but especially alcohols that yield radicals which can be removed by reduction, such as 2,2,2-trichloroethanol, benzyl alcohol, and especially ~-nitrobenzyl alcohol, or alter-natively isooicotinyl alcohol. An especially advantageous class of substituted alkanols are ethyl alcohols which carry in the ~-position a tri-substituted silyl group, such as triphenylsilyl, dimethyl-tert-butylsilyl orl especially, trimethylsilyl. As is described, for example, in Belgian Patent No. 851,576, these alcohols are particularly suitable for selective removal because the corresponding ~-silylethyl esters, for example ~-(trimethylsilyl)-ethyl esters, have the stability of customary alkyl esters but can : .

be selectively removed under mild conditions by the action of fluoride ions while retaining other esterified carboxyl groups, for example alkoxycarbonyl groups.

The removal of esterifying groups depends on their nature and is carried out in each case in a conventional manner known per se taking into consideration the properties of the other radicals involved. The groups that can be removed by reduction, especially those that contain halogenated lower alkyl radicals (for example 2,2,2-trichloroethyl radicals), isonicotinyl radicals (for exanple isonicotinyloxycarbonyl) and optionally substituted benzyl radicals, especially 4-nitrobenzyl radicals of any kind, are preferably removed by zinc reduction, usually in the presence of an acid, preferably acetic acid, and with or without the addition of an inert organic solvent, usually at room temperature, those of the benzyl-type, especially unsubstituted benzyl esters, also by hydrogenolysis techniques conventionally used for benzyl groups, e.g. using hydrogen in the presence of a catalystl e.g. palladium.

Conversion of compounds of formula I or IA wherein R and/or R is lower alkoxy, aryl lower alkoxy, amino, mono- or di-(lower alkyl)-amino to compounds of formula I or IA wherein R and/or R repre-sents hydroxy is advantageously carried out by hydrolysis with inorganic acids such as hydrohalic acids, trifluoro acetic acid or ~ulfuric acid. The ~-silylethyl ester groups are preferably removed by Eluoride-ion-yielding reagents, for example fluorides of quaternary organic bases, such as tetraethylammonium fluoride.
Groups COR and/or COR that are base-unstable can be carefully removed by the rapid action of an aqueous sodium or potassium bicarbonate solution or, preferably, aqueous ammonia in an organic solvent, usually at room temperature and/or with aqueous alkalies preerably alkali metal hydroxides such as l;thium or sodium hydroxide. The ester groups are preferably removed under the reaction conditions of the examples, or under analogous conditions.

A proper combination of the ester groups can be chosen in the earlier stages of the synthesis, or by a proper choice of starting materials and reactants, e.g. a selectively removable ester group being introduced with a carboxyl which is to be liberated in the last stage.

Compounds of formula I or IA wherein R6 and/or R7 is lower alkoxy may be amidized with ammonia, mono- or di-lower alkylamines to yield compounds of formula I or IA wherein R6 and/or R represents unsubstituted, mono- or di-lower alkylamino.

Compounds of formula I or IA wherein neither R nor R represents hydroxy may be converted to monocarboxylic acids of formula I or IA
wherein one of R and R7 is hydroxy. Such conversion is carried out by selective hydrolytic or hydrogenolytic procedures well known to the art and based on the chemical character of the R and R
substituents.

The above mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmos-pheres, at low temperatures, room temperature or elevated tempera-tures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or the process is discontinued at any stage the-reof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes. Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially useful.

The invention also relates to novel starting materials and processes for their manufacture.

~epending on the choice of starting materials and methods~ the new compounds may be in the form of one of the possible isomers or mixtures thereoE, for example, depending on the number oE asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of optical isomers such as racemates or mixtures of diastereoisomers.

Resulting mixtures of diastereoisomers and mixtures of racemates can be separated on the basis of the physicochemical differences oE the constituents, in known manner, into the pure isomers, diastereo-isomers or racemates, for example by chromatography and/or fractional crystallisation.

Resulting racemates can furthermore be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically act;ve solvent, by means of microorganisms or by reacting an acidic end product with an optically active base that forms salts with the racemic acid, and separating the salts obtained in this manner, Eor example on the basis of their different solubilities, into the diastereoisomers, from which the antipodes can be liberated by the action of suitable agents. Basic racemic products can l;kewise be resolved ;nto the antipodes, for example, by separation of d;astereomeric salts thereof, e.g. by the fractional crystall;za-tion of d- or l-tartrates. Any racem;c intermediates or starting materials can likewise be resolved.

Advantageously, the more active oE the two antipodes is isolated.

Finally, the compounds of the invention are either obtained in the free formi or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutically acceptable acid or anion exchange preparationl or resulting salts can be converted into the corresponding free bases, .:

YP3~

for example, with the use of a stronger base, such as a metal or a~nonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of formula I wherein R represents carboxy or of formula IA wherein COR6 and/or CoR7 represent carboxy can thus also be converted into the corresponding metal or ammonium salts. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are sepflrated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds, including the;r salts, can also be obtained ;n the form of their hydrates, or include other solvents used for the crystallization.

The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, for the treatment or prevention of diseases responsive to inhibition of angiotensin-converting en2yme, e.g. cardiovascular diseases such as hypertension and congestive heart failure comprising an effective amount of a pharmacologically active compound of formula I, or pharmaceutically acceptable salts thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture oE pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
Pre~erred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose sucrose, mannitol, sorbitol, cellulose and/or glycine, b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol, for tablets also c) binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and~or polyvinylpyrrolidone, if desired, d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or sus-pensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compos;tions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75 ~, preferably about 1 to 50 ~, of the active ingredient. A unit dosage for a mammal of about 50 to 70 kg may contain between about lO to 200 mg of the active ingredient.

Tlle following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 and lO0 mm~lg.

In the case of compounds of formula I or IA wherein more than one asymmetric center exists the resulting diastereoisomeric compounds are clenoted as ~, B, etc., in the said examples. The respective diastereoisomeric compounds are characterized by physical proper-ties, e.g. melting point or specific rotation.

In the case of compounds of formula I or IA wherein X is two hydrogens and an asymmetric center exists in the side chain at the carbon atom bearing the nitrogen atom, the symbols A and B have been assigned as follows to the respective isomers on the basis of their 8~3 relative migration on chromatograpl~y. On the basis of nigration on thin-layer chromatography and norlnal phase high pressure liquid chromatography employ;ng silica gel as the stationary phase, the fast mo~ing isomer is called isomer A and the slow moving isomer is called isomer B. On the basis of migration on reverse phase high pressure liquid chromatography the slow moving isomer is called isomer A and the fast moving isomer is called isomer B.

Example 1

5-Acetoxy-l-carboxymethyl-3-(S)-(l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-1~-1-benzazepin-2-one hydrochloride A solution of 5-acetoxy-3-(S)-amino-l-carboxymethyl-2,3,4,5-tetra-hydro-lH-l-benzazepin-2-one trifluoroacetate (4 g) and ethyl benzyl-pyruvate (6.1 g) in methanol (30 ml) and acetic acid (30 ml) is stirred at room temperature for 1 hour. A solution of sodium cyanoborohydride (0.75 g) in methanol (10 ml) is then added dropwise during 7 hours. The reaction mixture is stirred for an additional 18 hours at room temperature. Concentrated hydrochloric acid (4 ml) is added and stirring continued for an additional 1 hour.The solvents are removed under reduced pressure and the residue partitioned between ice/water (200 ml) and ether (50 ml). The p~l is adjusted to 9.3 with 40 ~ aqueous sodium hydroxide, and the ether layer discarded. The pH of the aqueous solution is adjusted to 4.3 w;th concentrated hydrochloric acid, and the solution is extracted with ethyl acetate (3 x 50 ml). The combined ethyl acetate solutions are dried over sodium sulfate and evaporated under reduced pressure.
The residue is boiled with ethyl acetate (50 ml), cooled to room temperature, and filtered to give the title acetoxy compound, mp.
215-217.

The starting material is prepared as follows: A solution of 3-(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-11~-1-benzazepin-2-one (5 g3 in trifluoroacetic acid (60 ml) is stirred at roorn temperature for 1 hour under a nitrogen atmospllere. The solvent is removed under reduced pressure and the residue washed with ether to give the acetoxy-amino acid trifluoroacetate, used witllout further puriE;cation in the next step of the synthesis.

~xample 2: a) A solution of l-ethoxycarbonylmethyl-2,3,4,5-tetra-_ _ _ _ hydro-lH-l-benzazepin-2,3-dione (5.0 g), S-benzyl-L-cysteine ethyl ester (4.4 g) and dibutyltin dichloride (380 mg) in chloroform (250 ml) is refluxed for 18 hours using a water separator. The solvent is removed under reduced pressure to give the crude imine. This substance is dissolved in methanol (250 ml) and sodium cyanoboro-hydride (1.4 g) and glacial acetic acid (45 ml) are added. The reaction mixture is stirred at room teperature for 18 hours under a dry nitrogen atmosphere. Concentrated hydrochloric acid (15 ml) is added and the reaction mixture stirred at room temperature for 30 minutes. The solvents are removed under reduced pressure and the residue is partitioned between dilute aqueous ammonia (500 ml) and ether (300 ml). The aqueous phase is extracted with additional ether (2xlS0 ml) and the combined ether solutions are washed with saturated sodium chloride (200 ml), 2N hydrochloric acid (200 ml), and saturated sodium chloride (200 ml). The etller solution is dried over sodium sulfate and the solvent removed under reduced pressure to give the crude product as a mixture of isomers. This material is puriEied by flash chromatography using ethyl acetate/toluene (1:4) to give l-etlloxycarbonylmethyl-3-~1-ethoxycarbonyl-2-benzylthio-(lR)-ethylamino]-2,3,4,5-tetrahydro-lH-1-(3R,S)-benzazepin-2-one (as a mixture oE R,R and R,S isomers).

The -ketolactam starting material may be prepared as follows:

3-azido-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (5.0 kg) is added portionwise under nitrogen to potassium tert-butoxide (3.03 kg) in dry tetrahydrofuran (50 liters) at such a rate that the temperature is maintained below 5, and the reaction mixture is stirred for 1 hour after the addition is completed. A solution of ethyl bromoacetate (4.38 kg) in tetrahydrofuran (5 liters) is then added slowly so as to maintain the temperature below 5. The reaction mixture is tllen stored at room temperature overnight.
Filteraid (1.5 kg of Hiflo) is added, and the reaction mixture is f;ltered. The fil~er cake is washed with tetrahydrofuran and the combined tetrahydrofuran solution is evaporated to dryness to give 3-azido-l-ethoxycarbonylmethyl-2l3~4~5-tetrahydro-lH-l-benzazepin 2-one which is used without further purification in the next step.
The reaction mixture of 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (13.93 kg) and 5 ,~ palladium on carbon (1.3 kg) in anhydrous ethanol (57 liters) is hydrogenated under 3 atmospheres pressure of hydrogen Eor 5 hours. The pressure reactor is vented at hourly intervals to remove the accumulated nitrogen. The catalyst is removed by filtration and washed with ethyl alcohol. The solution is evaporated to dryness to give 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one.

t-Butyl nitrite (31 ml) is added with stirring to a solution of 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benxazepin-2-one (55 g) in chloroform (1000 ml) and acetic acid (2.8 ml). The reaction mixture is refluxed under nitrogen for 3.5 hours, and tllen cooled to 0. While stirring is maintained, m-chloroperbenzoic acid (43.5 g) is added in five portions during 0.5 hour. The reaction mixture is allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture is washed with saturated a(lueous sodium bicarbonate (500 ml), concentrated aqueous ammonia (?x250 ml), and saturated brine (250 ml). The organic solution is dried over sodium sulfate, treated witll charcoal~ and evaporated und~r reduced pressure to give an oil which is triturated with ether to give l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepill-2,3-dione, m.p. 112-114.

b) Similarly prepared is l-etlloxycarbonylmethyl-3-[1-ethoxycarbonyl-2-phenethylthio-(lR)-ethylamino]-2,3,4,5-tetrahydro-lH-1-(3R,S)-benza~epin-2-one starting with (S)-S-phenethylcysteine (U.S. Patent 3,950,542).

c) Similarly prepared is l-ethoxycarbonylmethyl-3-[1-ethoxycarbonyl-2-phenylthio-(lR)-ethylamino~-2,3~4,5-tetrahydro-lH-l-benzazepin-2 one from (S)-S-phenylcysteine CS.H. Zbarsky and L. Young, J. Biol.
Chem. 151, 211 (1943)].

d) Similarly prepared is l-ethoxycarbonylmethyl-3-[1-ethoxycarbonyl-3-methylthio-(lS)-propylamino]-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one from L-methionine ethyl ester.

e) Similarly prepared is l-ethoxycarbonylmeth-yl-3-~1-ethoxycarbonyl-2-benzyloxy-(lS)-ethylamino~-2,3,4,5-tetrahydro-lH-1-(3S,R)-benz-azepin-2-one from 0-benzyl-L-serine.

Example 3: a) Aqueous sodium hydroxide (2N; 4.8 ml, 2.1 mole _ _ _ _ equivalents) is added to a solution of l-ethoxycarbonylmethyl-3-[I-ethoxycarbonyl-2-benzylthio-(lR)-ethylamino]-2,3,4,5-tetrahydro-lll-l-benzazepin-2-one (2.1 g) in methanol (30 ml) and the solution is stirred at room temperature for 18 hour~s. .he solvents are removed under reduced pressure, and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase is extracted with ethyl acetate (2x50 ml) and then acidified to pH 3 with concentrated hydrochloric acid. An oil separates. Rthyl acetate (50 ml) is added and the mixture is stirred at room temperature for 30 minutes to yield 1-carbo~ymethyl-3-[1-carboxy-2-benzylthio-(lR)-ethylamino]~2,3,4,5-tetrahydro-lH-1-(3S)-benzazepin-2-one as a crystalline solid, m.p. 213-215 with decomposition, C~]D = -207.2 (C = 1.0, DMF).

b) Similarly prepared is l-carboxymethyl-3-~1-carboxy-2-phenyl-ethylthio-(l~)-ethylamino]-2,3,4,5-tetrahydro-lH-1-(3S)-benzazepin-2-one, m.p. 197-199 with decomposition and ~a]D = -46.1 (c = 0.83, DMF) .

c) Similarly prepared is l-carboxymethyl-3-[1-carboxy-2-phenylthio-(lR)-ethylam;no~-2,3,4,5-tetrahydro-lH-1-(3S)-benzazepin-2-one, m.p. 206-208 with decoTnposition, [~]~ = -110.8 (c = 0.72, ~MF).

d) Similarly prepared is l-carboxymethyl-3-[1-carboxy-3-methylthio-(IS)-propylamino]-2,3,4,5-tetrahydro-lU-1-(3S)-benzaæepin-2-one, m.p. 236, [a]D = -lS9 (c = 1.1, ethanol).

e) Similarly prepared is l-carboxymethyl-3-[1-carboxy-2-benzyloxy-(lS)-ethylamino~-2,3,4,5-tetrahydro-lH-1-(3S,R)-benzazepin-2-one hydrochloridel m.p. 68-70 with decomposition, [~]D = 42 (c = 1, methanol).

~xample 4: a) Aqueous potassium hydroxide (2N; 1 ml, 0.95 mole equivalent) is added to a solution of l-ethoxycarbonylmethyl-3-[l-ethoxycarbonyl-2-benzylthio-(lR)-ethylamino~-213l4,5-tetrahydro-111-1-(3R,S)-benzazepin-2-one (1.0 g) in ethanol (30 ml) and the reaction mixture is stirred at room temperature for 18 hours. The solvents are removed under reduced pressure and water (30 ml) is added to the residue. Tlle solution is extracted with ether (2x30 ml) and the aqueous phase acidiEied with concentrated hydrochloric acid and extracted with ethyl acetate (3x20 ml). The combined ethyl acetate solutions are dried over magnesium sulfate, evaporated, and the residue is redissolved in dicl-loromethane (35 ml). ~lis solution is saturated with dry hydrogen chloride gas, and the solvent removed under reduced pressure. The residue is triturated with ether to give l-carboxymethyl-3-[1-ethoxycarbonyl-2-benzylthio-(lR)-ethylamino]-2,3,415-tetrahydro-11-1-1-(3RIS)-benzazepin-2-one hydrochloride, m.p.I83-1~35 ~ [~D = -13.2 (c = 1.1, ethanol), as a mixture of two diastereoisomers.

b) Similarly, hydrolysis of l-ethoxycarbonylmethyl-3-~1-ethoxy-carbonyl-2-phenylthio-(lR)-ethylamino~-2,3,4,5-tetrahydro-lll-1-(3R,S)-benzazepin-2-one yields 1-carboxymethyl-3-[1-ethoxy-carbonyl-2-phenylthio-(lR)-ethylamino~-2l3~4l5-tetrahydro-lH
(3S)-benzazepin-2-one hydrochloride, m.p. 120-126 with decomposition and ~]D = 58.5 (c = 0.81, ethanol).

c) Similarly, l-carboxymethyl-3-[1-ethoxycarbonyl-3-methylthio-(lS)-propylamino]-2,3,4,5-tetrahydro-1~ (3S)-benzazepin-2-one hydrochloride, mOp. 196-197 is obtained by hydrolysis of l-ethoxy-carbonylmethyl-3-[1-ethoxycarbonyl-3-methylthio-(lS)-propylamino]-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one.

d) Similarly prepared is l-carboxymethyl-3-~1-ethoxycarbonyl-2-benzyloxy-(lS)-ethylamino]-2,3,4,5-tetrahydro-lH-1-(3R,S)-benz-azepin-2-one hydrochloride, m.p. 198~201, [~]D = 3 (c ~ 1, methanol).

Example 5: Using procedures similar to the ones described in the previous examples with N-(s)-benzoyl-L-lysine as the starting material, l-carboxymethyl-3-[1-ethoxycarbonyl-5-benzoylamino-(lS)-pentylamino]-2,3,4,5-tetrahydro-lU-1-(3S)-benzazepin-2-one hydro-chloride, m.p. 107-109U~ [~]D = ~30 (c = 1, methanol) is prepared.

~xample 6: The following compounds of formula IA, wherein X
represents two hydrogens; R to R represent llydrogen; R is hydroxy or ethoxy; and R7 is hydroxy, may be prepared essentially according to the procedures illustrated in the previous examples, advantageously as the S,S isomers thereof.

Compound R Deriva ives 6a ethoxycarbonylmethyl 6b methylthioethyl 6c 4-benzoylaminobutyl 6d 4-(benzyloxycarbonylamino)- hexahydro butyl 6e phenoxyethyl 6f phenylthioethyl 6g hydroxymethyl Starting Materials Eor 6a - L-aspartic acid diethyl ester 6b - Methionin ethyl ester 6c - N-benzoyl-L-lysine ethyl ester 6d - L-N-benzyloxycarbonyl-L-lysine ethyl ester 6e - ethyl 4-phenoxy-2-aminobutyrate 6f - ethyl 4-phenylthio-2-aminobutyrate 6g - L-Serine ethyl ester Example 7: a) To a solution of 3-~(5-benzyloxycarbonylamino-1-methoxycarbonyl)-pentylamino~-l-ethoxycarbonylmetllyl-2,3,4,5-tetra-hydro-l~l-lbenzazepin-2-one (lsomer A: 1.5 g) in methanol (60 ml) at 0 is added 5~ aqueous sodium hydroxide (5 ml), and the reaction mixture is stirred at room temperature for 18 hours. The solution is acidi~ied with 2 N hydrocllloric acid and evaporated to dryness.
Etllanol (25 mL) is added and the solution evaporated to dryness. The resulting white solid is stirred with methylene chloride (30 ml), and the remaining solid filtered off. This material is stirred with methylene chloride (30 ml), and filtered. The combined methylene chloride solutions are evaporated and the resulting solid triturated with ether and Eiltered to give 3-L(5-benzyloxycarbonylamino-1-carboxy)-pentylamino]-l-carboxymethyl-2,3,4,5-tetrahydro-1 benzazepin-2-one hydrochloride (Isomer A), m.p. 123-126, ~]r = loS (c = 1, methanol) b~ Sl~ilarly~ 3-~(5-benzyloxycarbonyla~ino-1-methoxyo~rbonyl~-pentylamlno~ ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1~
benzazepln-2-one ~I~o~er B~ y~elds 3-f(5-benzyloxyca~bonylamin3-1-carboxy~-pentylamino]~1-carboxy~ethyl-2j3,4,5-tetrahydro-1H~1-ben~azepin-2-one bydrochlorlde ~I~o~er B~, ~.p. 107^110, f~ln ~ -88 (c ~ 1.26, mathanol), asslgnad ths S,S ~tereochemi3try.

The startlng material i8 prepared as followa:
A solution of 3-amino-1-ethoxycarbonyl~thyl-2,3,4,5-tetrahydro-lH-l-benza2epin-2-one 18 ~), acetic acld (0.4 ml), ~nd t-butyl nitrite (4.5 ml) in chlorofor~ ~160 ~1) i8 refluxed for 2 hours and cooled to roo~ temp0r~ture. ~-Chloroperbenzoic acld ~6.0 g~ i5 added in portlons with stirrln~, and stirring ls maintainad for an additional 30 ~inute3. The solutlon i8 washed wlth ~aturat~d aqueous aodlu~
bicarbonate (100 ~l~, 2N hydrochlorlc acid (50 ml) and water (50 ml), and dried over ~agns~iu~ 0ulfate. The solvene 18 re~oved under reduced p~es~ure and the re3idue trlturated wlth ethyl acetate~potroleum ether (bp 60-80) to give the ~-~etolactam as a y~llow solld (m.p. lO8-110, used withnut fur~her purification in the next st~p), na~ely 1-Qtbo~ycarbonylmethyl-2,3,4,5-tetrahydro-1H-1-banzazepin-2,3-dione.

To a solutlon of l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benza~epin-2,3-dione (11 g~, ~-E-benzyloxycarbonyllyalne oetbyl ~ter hydrochlorid0 ~14 g3, triethylaminc (6 ml~, and dibutyltln di-chlorid~ (0.~ g~ in methylone chloride (600 ~l), 4 A molecular sieve~ (50 8~) are added. The reaction ~lxtura i8 stirred and refluxed for 40 hour~ After cooling to room temperature~ ths reactiDn ~ixturc i9 f~lt~red through c~lite~ and the solYent removed under red~cod pr~sure. ~h~ resid~e i~ di~solved in ~thanol (750 ml) and acetlc acid ~28 ~l)o After 5 minuteA, sodium cyanoboro-hydride (0.3~ added and the reaction ~ixture i8 ~tirr~d at room te~perature for 72 hDur~, then acidified by the addltio~ of conce~trat~d hydrochloric acid (1~ ~l). The ~olution i~ svaporated to dryness to give an oil which is separat~d by Elash chromatograpny using ethyl acetate/toluene (9:1) as the solvent system. Two discrete fractions are obtained; namely a) 3-[(5-benzyloxycarbonylamino-1-methoxycarbonyl)-pentylamino~
ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (Isomer A); Rf = 0.7, NMR (CDC13) 1.47 (m,5H), 3.16 (m,4H).
b) 3-~(5-benzyloxycarbonylamino-1-methoxycarbonyl)-pentylamino]-1-ethoxycarbonylmethyl-2,314,5-tetrahydro-lH-l-benzazepin-2-one (Isomer B); Rf = 0.6, NMR (CDC13) 1.30 (m,5H), 3.06 (m,4H).

Example 8: A solution of 3-[(5-benzyloxycarbonylamino-1-methoxy-carbonyl)-(lS)-pentylamino]-l-ethoxycarbonylmethyl-2,3,4,5-tetra-hydro-11~-1-(3S)-benzazepin-2-one (Isomer B, 22.6 g) and lN sodium hydroxide (84 ml) in methanol (580 ml) is stirred under nitrogen at room temperature for 19 hours. The solution is concentrated and the residue is partitioned between water (300 ml) and ether (300 ml).
The organic layer is separated and the aqueous layer is washed once more with ether (300 ml). The aqueous layer is then acid;fied to pH 2.0 with concentrated hydrochloric acid whereupon the product slowly crystallizes. The resulting solid is collected by vacuum filtration, washed well with water, and dried to give 3-C(5-benzyl-oxycarbonylamino-l-carboxy)-(lS)-pentylamino]-l-carboxymethyl-2,3,4,5-tetrahydro-lH-1-(3S)-benzazepin-2-one, m.p. 216-218 dec.

~xalllple 9: ~ry hydrogen chloride gas is bubbled through a solution of 3-r(5-benzyloxycarbonylamino-1-t-butyloxycarbonyl)-(lS)-pentylaminol-I-ethoxycarbonylmethyl-2,3,4j5~tetrahydro-1~1-1-(3S)-benzazepin-2-one (2.8 g) in ethyl acetate (150 ml) until TLC analysis indicates that no starting material has remained. The solvent is removed under reduced pressure and the residue triturated with ether to give 3-[(5-benzyloxycarbonylamino-1-carboxy)-(lS)-pentylamino~ ethoxy-carbonylmethyl-2,3,4,5-tetra'nydro-lH-1-(3S)-benzazepin-2-one hydrochloride, m.p. 124-126 with decomposition, [~D= ~ (c = 1, methanol).

The starting material is prepared as follows:
The starting 3-[(5-benzyloxycarbonylaminv-1-t-butyloxycarbonyl)~
(ls)-pentylamino~-l-ethoxycarbonylmethyl-2t3l~l5-tetrahydro-l~
(3S)-benzazepin-2-one is prepared essentially according to the methvd in example 7 by condensation of l-ethoxycarbonylmethyl-2,3~4~5-tetrahydro-lH-l-benzazepin-2~3-dione and N-e-benzyloxy-carbonyllysine t-butyl ester.

The starting l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benz-azepin--2,3-dione may also be prepared as follows:

3-Azido-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one (5.0 kg) is added portionwise under nitrogen to potassium tert-butoxide (3.03 kg) in dry tetrahydrofuran (50 liters) at such a rate that the temperature is maintained below 5, and the reaction mixture is stirred for 1 hour after the addition is completed. A solution of ethyl bromo-acetate (4.38 kg) in tetrahydrofuran (5 liters) is then added slowly so as to maintain the cemperature below 5. The reaction m;xture is then stored at room temperature overnight. Filteraid (1.5 kg of lliflo) is added, and the reactioll mixture is filtered. The filter cake is washed with tetrahydrofuran and the combined tetrahydrofuran solution is evaporated to dryness to give 3-azido-1-ethoxycarbonyl-methyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one which is used without Eurther purification in the next step.

The reaction mixture of 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH~ benzazepin-2-one (13.98 kg) and 5 ~ palladium on carbon (1.3 kg) in anhydrous ethanol (57 liters) is hydrogenated under 3 atmospheres pLessure oE hydrogen for 5 llours. The pressure reactor is vented at hourly intervals to remove the accumulated nitrogen. The catalyst is removed by filtration and washed with ethanol. The solution is evaporated to dryness to give 3-amino-1-ethoxycarbonylmethyl-2~3i4l5-tetrallydro-lH-l-benzazepin-2-one.

t--Butyl nitrite (31 rnl) is added with stirring to a solution of 3~amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH--l-bellzazepin-2-one (55 g) in chloroform (1000 ml) and acetic acid (2.8 ml). The reaction mixture is refluxed under nitrogen for 3.5 hoursl and then cooled to 0. While stirring is maintained, m-chloroperbenzoic acid (43.5 g) is added in five portions during 0.5 hour. The reaction mixture is allowed to warm to room temperature and stirred for an additional 1.5 hours. The reaction mixture is washed with saturated aqueous sodium bicarbonate (500 ml), concentrated aqueous ammonia (2x250 ml), and saturated brine (250 ml). The organic solution is dried over sodium sulfate, treated with charcoal, and evaporated under reduced pressure to give an oil which is triturated with ether to give l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2,3-dione, m.p. 112-114~.

Example 10: 3-~(5-benzyloxycarbonylamino-1-methoxycarbonyl)-(lS)-pentylamino]-l-benzyloxycarbonylmetllyl-2,3,4,5-tetrahydro-lH-l-(3S)-benzazepin-2-one hydrochloride, m.p. 61-63, [~]D ~ ~53 (c = L, methanol), is prepared according to the previous examples by condensation of N-c-benzyloxycarbonyllysine methyl ester and l-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-l-benzazepin-2,3--dione, m.p. 106~108. The ct-ketolactarn is prepared using methodology previously described by oxidation of 3-amino-1-benzyloxycarbonyl-rnethyl-2,3,4,5-tetrahydro-111-1-benzazepin-2-one.

T;.xarnple 11: The following procedure is used for selective hydrolysisof some 3-~(5-benzyloxycarbonylamino)-pentylamino~-diesters to the corresponding l-carboxymethyl compounds:

The diester is dissolved in ethanol and treated with one-molar equivalent of aqueous potassium hydroxide, and the reaction mixture is stirred at room temperature for l hour. The solvents are removed under reduced pressure and water is added to the residue. I~e aqueous solution is washed with ether, acidified with hydrocllloric acid to liberate the free amino acid which is isolated by extraction and converted to the hydrocllloride salt.

The follow;ng compounds are prepared:
a) 3-~(5-benzyloxycarbonylamino-1-methoxycarbonyl)-(lS)-pentyl-amino]-l-carboxymethyl-2,3,4,5-tetrahydro-lH-1-(3S)-benzazepine-2-one hydrochloride, m.p. 102-104, ~a]D = -116 (c = 1, methanol) by hydrolysis of the corresponding l-ethoxycarbonylmethyl derivative;

b) 3-[(5-benzyloxycarbonylamino-1-ethoxycarbonyl)-(lS)-pentyl-amino~ carboxymethyl-2,3,4,5-tetrahydro-lH-1-(3S)-benzazepin-2-one hydrochloride, m.p. 104-106, [a]D = -113 (c = 1, methanol) by hydrolysis of the corresponding l-ethoxycarbonylmethyl derivative.

Example 12: Preparation of 10,000 tablets each containing 10 mg of the active ingredient of Example 1:

_ormula:
5-Acetoxy-l-carboxymethyl-3-(S)-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one hydrochloride100,00 g Lactose 1157,00 g Corn starch 75,00 g Polyethylene glycol 6,000 75,00 g Talcum powder 75,00 g Magnesium stearate 18,00 g puriEied water ~.s.

Procedure:
All the powders are passed through a screen with openings of 0.6 mm.
Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other hal~
of the starch is suspended in 40 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35 , broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with

6.4 mm diameter, uppers bisected.

Claims (16)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the manufacture of 3-amino-1-benzazepin-2-one-1-alkanoic acids of the general formula (I) wherein RA and RB are rad1cals of the formula and , respectively, in which R0 is carboxy or a functionally modified carboxy; R1 is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl lower alkyl, acylamino lower alkyl, mono- or di- lower alkylamino lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, esterified carboxy lower alkyl, carba-moyl lower alkyl, N-substituted carbamoyl lower alkyl, hydroxy lower alkyl, etherified or acylated hydroxy lower alkyl, aryloxy lower alkyl, aryl-(thio-, sulfinyl-, or sulfonyl-) lower alkyl, aryl-N-lower alkylamino lower alkyl, or arylamino lower alkyl; where aryl represents phenyl, unsubstituted or mono- or di-substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, halogan or trifluoromethyl; indolyl or indolyl, substituted by lower alkyl, lower alkoxy, lower alkylenedioxy, lower alkanoyl-oxy, hydroxy, halogen or trifluoromethyl; or pyridyl; where acyl is selected from lower alkanoyl, lower alkoxycarbonyl, C3-8-cycloalkyl-carbonyl, C3-8-cycloalkyloxycarbonyl, C3-8-cycloalkyl lower alkoxy-carbonyl; also aryl lower alkanoyl, aryl lower alkoxycarbonyl, arylsulfonyl in which aryl represents phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen; also benzoyl, or benzoyl substituted by lower alkyl, lower alkoxy or halogen, or nicotinoyl;

where esterified carboxy is lower alkoxycarbonyl, unsubstituted or substituted by amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl, aryl, hydroxy, lower alkanoyloxy, lower alkoxy, bicycloalkoxycarbonyl; or is 3-phthalidoxycarbonyl or (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxycarbonyl; where N-substituted carbamoyl lower alkyl is substituted on the nitrogen by lower alkyl; di-lower alkyl; di-lower alkyl in which both alkyl groups are linked by a carbon to carbon bond and together with the amino nitrogen form a 5-, 6- or 7-membered heterocyclic ring; ( smino or acylamino)-substituted lower alkyl; .alpha.-(carboxy or lower alkoxy-carbonyl)-substituted lower alkyl; aryl substituted lower alkyl ln which aryl is phenyl or indolyl and which can be substituted on the .alpha.-carbon by carboxy or lower alkoxycarbonyl; where etherified hydroxy is lower alkoxy or benzyloxy; and where acylated hydroxy is lower alkanoyloxy, benzoyloxy, benzoyloxy substituted on the phenyl ring by lower alkyl, halogen or lower alkoxy, or nicotinoyloxy; R2 is hydrogen or lower alkyl; R3 and R4, each independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R3 and R4 taken together represent lower alkylenedioxy; R5 is hydrogen or lower alkyl; and X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro; with the proviso, that, if R1 represents hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, C3-8-cycloalkyl, or C3-8-cycloalkyl lower alkyl, X is acylated hydroxy together with one hydrogen; salts, and stereoisomers of all these compounds, which consists in that a) in a compound of the formula (II) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, RB, R3, R4 and R5 have the meanings given hereinabove, RA is introduced by alkylation with a compound of the formula RA - Z (IIIA) wherein Z is a reactive esterified hydroxyl group and RA has the meanings given hereinabove or with a compound of the formula R1-CO-R0 (IV) wherein R1 ant R0 have meanings given hereinabove, in the presence of a reducing agent with temporary protection of any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups, which may be present in any one of the residues X, RB, R3 and R4, and/or in the alkylating agent, or b) a compound of the formula (V) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, R3, R4 and R5 have the meanings given hereinabove and RA' is hydrogen or RA as defined hereinabove, is alkylated with a compound of the formula RB - Z (IIIB) wherein Z is a reactive esterified hydroxyl group and RB has the meanings given hereinabove, while protecting temporarily any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo groups which may be present in any one of the residues X, RA, RB, R3 and R4, or c) a compound af the formula (VI) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein Y is oxo or dichloro or a reactive esteri-fied hydroxyl group Z together with hydrogen, and X, RB, R3 and R4 have the meanings given hereinabove, is condensed with an amine of the formula RA-NH-R5 (VII) wherein RA and R5 have the meanings given hereinabove, with the proviso that when Y is oxo, or dichloro, the condensation is carried out in the presence of a reducing agent and with a temporary protection of the oxo group which may be present as the substituent X, or d) in a compound of the formula (VIII) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X and R1 to R5 have the meanings given hereinabove, one of the symbols R0' and R0" is cyano and the other one is cyano or R0 as defined hereinabove, the cyano group(s) is (are) subject to solvolysis, or e) a compound of the formula (IX) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X, RA, RB, R3, R4 and R5 have the meanings given hereinabove, or an ester thereof, is cyclised, or f) a compound which is structurally identical with a compound of formula I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, is treated with a reducing agent in order to saturate this double bond, or g) in order to produce a compound of formula I as specified herein-above, in which X is oxo, condensing a compound of the formula (X) in which the carbocyclic ring may also be hexahydro or 6,7,8.9-tetrahydro, and wherein RB, R3 and R4 have the meanings given hereinabove, with an amine of the formula RA-NH-R5 (VII) wherein RA and R5 have the meaning given hereinabove, and, if desired, a resulting compound of formula I is converted into another compound of formula I, and/or if desired, a resulting compound of formula I having salt-forming properties is converted into a salt thereof or a resulting salt into another salt or a free compound is liberated from such a salt, and/or if so required, an optical isomer which has a specific configuration with respect to at least one center of chirality is enriched from a mixture of stereoisomeric forms of a resulting compound of formula I.

2. A process as claimed in claim 1, characterisd in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein the carbocyclic ring may also be hexahydro; R1 is hydrogen, lower alkyl, amino lower alkyl, aryl, aryl lower alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl lower alkyl, acylamino lower alkyl, mono- or di-lower alkylamino lower alkyl, lower alkylthio lower alkyl, carboxy lower alkyl, esterified carboxy lower alkyl, carba-moyl lower alkyl, N-substituted carbamoyl lower alkyl, hydroxy lower alkyl, etherified or acylated hydroxy lower alkyl, aryloxy lower alkyl, arylthio lower alkyl, aryl-N- lower alkylamino lower alkyl, or arylamino lower alkyl; R2 and R5 represent hydrogen or lower alkyl; R3 and R4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl; or R3 and R4 taken together represent lower alkylenedioxy; X represents oxo, two hydrogens, or one hydroxy or acylated hydroxy group and one hydro-gen, with the proviso given in claim 1; R6 and R7 independently represent hydroxy, amino, mono- or di lower alkylamino, lower alkoxy, aryl lower alkoxy, lower alkanoyloxymethoxy, (amino, mono-or di-lower alkylamino, carboxy, or lower alkoxycarbonyl) lower alkoxy; or a salt thereof is selected as a starting material, wherein aryl, acyl, esterified carboxy, N-substituted carbamoyl lower alkyl, etherified and acylated hydroxy, Z, RA', Y, R0' and R0"
have the meaning given in claim 1, so as to produce a compound of the formula IA

(IA), wherein R1 to R7 and X have the meanings given above, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

3. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R1 is hydrogen, lower alkyl, amino lower alkyl, aryl lower alkoxycarbonylamino lower alkyl or aryl lower alkyl where aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or trifluoromethyl; R2 and R5 are hydrogen or lower alkyl; R3 and R4 are hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoro-methyl; or R3 and R4 taken together represent lower alkylenedioxy; X
represents oxo, two hydrogens, or one hydroxy or lower alkanoyloxy and one hydrogen with the proviso of claim 1 in modified form depending on the meaning of X; R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl lower alkoxy, lower alkoxycar-bonyl lower alkoxy; or said compounds wherein the carbocyclic ring is hexahydro or a salt thereof is selected as a starting material, wherein 2, RA', Y, R0' and R0" have the meaning given in claim 1, so as to produce a compound of the formula IA, wherein R1 to R7 and X have the meanings given above, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

4. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R1 is hydrogen, lower alkyl, .omega.-amino lower alkyl, .omega.-arylmethoxycarbonylamino lower alkyl, aryl lower alkyl, where aryl represents phenyl unsubstituted or mono-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen or tri-fluoromethyl; R2 and R5 are hydrogen or lower alkyl; R3 is hydrogen;
R4 is hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoro-methyl; X represents oxo, two hydrogens, or one hydroxy or lower alkanoyloxy and one hydrogen with ththe proviso of claim 1 in modified form depending on the meaning of X; R6 and R7 independently repre-sent hydroxy, amino, lower alkoxy, phenyl lower alkoxy, lower alkoxycarbonyl lower alkoxy; or said compounds wherein the carbocyc-lic ring is hexahydro or a salt thereof is selected as a starting material, wherein Z, RA', Y, R0' and R0" have the meanings given in claim 1, so as to produce a compound of the formula IA, wherein R1 to R7 and X have the meanings given above, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

5. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R1 is hydrogen, methyl, ethyl, isopropyl, .omega.-amino-propyl, .omega.-aminobutyl, .omega.-(benzyloxycarbonylamino)propyl, .omega.-(benzyloxy-carbonylamino)butyl, aryl-(methyl, ethyl, propyl) where aryl represents phenyl unsubstituted or substituted by one methyl, hydroxy, methoxy, methylenedioxy, acetoxy,chloro or trifluromethyl group; R2 and R5 are hydrogen or methyl; R3 and R4 represent hydrogen, methoxy, methyl, chloro or trifluoromethyl; X represents oxo, two hydrogens, or one hydroxy or one acetoxy and one hydrogen with the proviso of claim 1 in modified form depending on the meaning of X, R6 and R7 independently represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonylmethoxy or pivaloyloxy-methoxy; or said compounds wherein the carbocyclic ring is hexahydro or a salt thereof is selected as a starting material, wherein Z, RA', Y, R0' and R0" have the meanings given in claim 1, so as to produce a compound of the formula IA, wherein R1 to R7 and X have the meanings given above, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

6. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R2, R3, R4 and R5 are hydrogen, R1 is represented by CnH2nR8, wherein n represents an integer from 1 to 4; R8 is benzyloxycarbonylamino; X represents two hydrogens, R6 and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or said compounds wherein the carbocyclic ring is hexahydro or a salt thereof is selected as a starting material, wherein Z, RA', Y R0' and R0" have the meaning given in claim 1 so as to produce a compound of the formula IB

(IB), wherein n, R6, R7 and R8 have the meanings given above, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

7. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R2, R3, R4 and R5 are hydrogen, R1 is represented by CnH2nR8, wherein n represent an integer from 1 to 4; R8 is benzyloxycarbonylamino; X represents two hydrogens, R6 and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, amino; or said compounds wherein the carbocyclic ring is hexahydro or a salt thereof is selected as a starting material, wherein Z, RA', Y, R0' and R0'' have the meanings given in claim 1, so as to produce a compound of the formula IC

(IC), wherein n, R6, R7 and R8 have the meanings given above, and S
represents the chirality, by enriching the optical isomer of formu-la IC from a mixture of stereoisomeric forms of a resulting compound of formula IB shown in claim 6 or by using starting materials of the formula II, IIIA, V, IIIB, VII, VIII or IX wherein the desired S-configuration is already present, or a pharmaceutically acceptable salt of such a compound having salt forming properties.

8. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formu-la I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB is CHR2COR7, wherein R1 is 2-phenylethyl, R2 to R5 are hydrogen, R6 is ethoxy, R7 is hydroxy and X is acetoxy and one hydrogen or a salt thereof is selected as a starting material, wherein Z, RA', Y, R0' and R0" have the meanings given in claim 1, so as to produce 5-acetoxy-1-carboxymethyl-3-(S)-(1-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one or a pharmaceuti-cally acceptable salt thereof.

9. A process as claimed in claim 1 comprising alkylating 5-acetoxy-3-(S)-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one trifluoroacetate with ethyl benzyl pyruvate in the presence of sodium cyanoborohydride so as to produce 5-acetoxy-1-carboxymethyl-3-(S)-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one or a pharmaceutically acceptable salt thereof.

10. A process as claimed in claim 1, characterised in that a compound of formulae II and IIIA or IV, V and IIIB, VI and VII, VIII, IX, a compound which is structurally identical with a compound of formula I except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon atom within the group RA, or of formula X, wherein RA is CHR1COR6 and RB
is CHR2COR7, wherein R1 is 4-benzyloxycarbonylaminobutyl, R2 to R5 are hydrogen, R6 and R7 are hydroxy and X is two hydrogens or a salt thereof is selected as a starting material, wherein Z, RA', Y, R0' and R0" have the meanings given in claim 1, so as to produce 3-[(5-benzyloxycarbonylamino-1-carboxy)-pentylamino]-1-carboxy-methyl-2,3,4,5-tetrahydro-1E-1-benzazepin-2-one or a pharmaceuti-cally acceptable salt thereof.

11. A process as claimed in claim 1 comprising alkylating N-.epsilon.-benzyl-oxycarbonyllyaine methyl ester hydrochloride with 1-ethoxycarbonyl-methyl-2,3,4,5-tetrahydro-1H-benzazepin-2,3-dione in the presence of dibutyltin dichloride followed by saponification of the ethoxy-carbonyl and methoxycarbonyl group with aqueous sodium hydroxide so as to produce 3-[(5-benzyloxycarbonylamino-1-carboxy)-pentylamino]-1-carboxymethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one or a pharmaceutically acceptable salt thereof.

12. A compound of the formula I or IA shown in claims 1 to 3, in which formulae all the symbols have the meanings given in claims 1 to 3, salts and stereoisomers of all these compounds whenever prepared or produced by the process of manufacture claimed in claims 1 to 3 or by any process which is an obvious chemical equivalent thereof.

13. A compound of the formula IA or IB shown in claims 4 to 6, in which formulae all the symbols have the meanings given in claims 4 to 6, salts and stereoisomers of all these compounds whenever prepared or produced by the process of manufacture claimed in claims 4 to 6 or by any process which is an obvious chemical equivalent thereof.

14. A compound of the formula IC shown in claim 7, in which formula all the symbols have the meanings given in claim 7, salts and stereoisomers of all these compounds whenever prepared or produced by the process of manufacture claimed in claim 7 or by any process which is an obvious chemical equivalent thereof.

15. 5-acetoxy-1-carboxymethyl-3-(S)-(1-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one or a pharmaceuti-cally acceptable salt thereof whenever prepared or produced by the process of manufacture claimed in claims 8 and 9 or by any process which is an obvious chemical equivalent thereof.

16. 3-[(5-benzyloxycarbonylamino-1-carboxy)-pentylamino]-1-carboxy-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one or a pharmaceuti-cally acceptable salt thereof whenever prepared or produced by the process of manufacture claimed in claims 10 ant 11 or by any process which is an obvious chemical equivalent thereof.