GB2103614A - Benzazepin-2-ones - Google Patents

Description

1 GB 2 103 614 A 1

SPECIFICATION

Benzazepin-2-ones The present invention is based upon the discoverythat certain substituted 3-amino-[llbenzazepin-2-one-l- 5 alkanoic acids and derivatives represent a new class of potent angiotensin-converting enzyme (ACE) inhibitors.

The foregoing attributes render the 3-amino-[1 Jbenzazepin-2-ones of this invention particularly useful when administered, alone or in combination, to mammals, e.g. for the treatment or prevention of diseases jo responsive to inhibition of angiotensin converting enzyme e.g., cardiovascular disorders such as hypertension and cardiac conditions such as congestive heart failure.

This invention relates to novel 3-amino-[llbenzazepin-2-one-1 -alkanoic acids, and derivatives useful as angiotensin-converting enzyme inhibitors, processes for preparing same, pharmaceutical compositions comprising said compounds, and methods of treating diseases responsive to inhibition of angiotensin converting enzyme by administration of said compounds and compositions to mammals.

The compounds of the invention are characterized by the general formula 1 R4 6 X 1 3 N 20 8 1 R3 9 a i RA R 0 25 wherein RA and RB are radicals of the formula R2 -CH and -CH respectively, R.

R.

in which, R, is carboxy or a functionally modified carboxy; R, is hydrogen, lower alkyl, amino(lower) alkyl.

ary], aryl (lower) alkyl. cycloalkyl or cycloalkyl (lower) alky]; R2 is hydrogen or lower alkyl; R3 and R4, each 35 independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethy], or R3 and R4 taken together represent lower alkylenedioxy; R5 is hydrogen or lower alky], and X represents oxo, two hydrogens, or one hydroxy togetherwith one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro; and salts and complexes thereof.

The functionally modified carboxyl group in the meaning of the symbol R. is e.g. an esterified carboxyl 40 group or a carbamoyl group optionally substituted on the nitrogen atom.

More specifically one or both of R. represented by COR6 in radical RA and represented by COR7 in radical RB independently represent carboxy, esterified carboxy, carbamoyl or substituted carbamoyl.

The salts and complexes of the compounds of formula 1 are derived from those compounds which have salt forming properties and are preferably pharmaceutical ly acceptable salts and complexes.

A carboxyl group R,, is represented by COR6 (in radical RA) wherein R6 is hydroxy or COR7 (in radical RB) wherein R7 is hydroxy.

An 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 the partial formula -COR6 (in radical RA) or the partial formula -COR7 (in radical RB), wherein one or both of R6 and R7 represents lower 50 alkoxy; (amino, mono- or di-lower alkylamino)-substituted lower alkoxy; carboxy-substituted lower alkoxy, e.g. a-carboxy substituted lower alkoxy; lower alkoxycarbonyi-substituted lower alkoxy, e.g. a-lower alkoxycarbonyi-substituted lower alkoxy; aryl-substituted lower alkoxy, e. g. optionally substituted benzy loxy or pyridyimethoxy; (hydroxy, lower alkanoyloxy or lower alkoxy) substituted lower alkoxy, e.g.

pivaloyloxymethoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)substituted lower alkoxymethoxy; bicycloalkoxycarbonyi-substituted lower alkoxy, e.g. bicyclo [2,2,1 lheptyloxycarbonyi-substituted lower alkoxy, especially bicyclo[2,2,1,Iheptyloxycarbonyi-substituted methoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy.

An optionally N-substituted carbamoyl group R, is especially one which is represented bythe partial formula -COR6 (in radical RA) orthe partial formula -COR7 (in radical R13), wherein one or both of R6 and R7 60 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 alkoxycarbonyi)-substituted lower alkylamino; aryl substituted lower alkylamino in which aryl is preferably phenyl or indolyl and which can be substituted on the a-carbon atom 65 2 GB 2 103 614 A 2 by carboxy or lower alkoxycarbonyl.

Any prodrug derivatives of compounds of this invention e.g. any pharmaceutical ly acceptable esters and amides of the mono- or dicarboxylic 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 5 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 pivaloyloxymethy], bornyloxyca rbonyl methyl, benzyi, pyridyimethyi, (xcarboxyethyl 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 am ides derived from alanine, phenylalanine and the like. 10 More particularly, the invention relates to compounds of formula IA R4 X N-CH-Rl N -R5 1 c 0 R3 1 0 CH R2 CD-R7 OA) wherein R, is hydrogen, lower alky], amino(lower)alkyl, ary], aryi- (iower)alkyi, cycloalkyl(lower)alkyl, R2 and R5 represent hydrogen or lower alkyl, R3 and R4 represent hydrogen, lower alky], lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluormethyl; or R3 and R4 taken together represent lower alkylendioxy, X 25 represents oxo, two hydrogens or one hydroxy group and one hydrogen, R6 and R7 independently represent hydroxy, amino, mono- or di-(lower)aikylamino, lower alkoxy, aryl(lower)alkoxy, lowr alkanoyloxymethoxy, (amino, mono- or di-lower alkylamino, carboxy, or lower alkoxycarbonyl)- 1ower alkoxy; or the pharmaceutic ally acceptable salts or complexes thereof.

Preferred embodiments of this invention relate to compounds of formula IA, wherein R, is hydrogen, lower alkyl, amino(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 trifluoromethy], R2 and R5 are hydrogen or lower alkyl, R3 and R4 are hydrogen, lower alkoxy, lower alkyl, halogen ortrifluoromethyl; or R3 and R4 taken together represent alkylenedioxy, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower) alkoxy, lower alkoxycarbonyl(iower)alkoxy, or pharmaceutical ly acceptable salts thereof.

Very useful are compounds of formula [A, wherein R, is hydrogen, lower alkyl, w-amino(lower)aikyi, aryl(lower)alkyl where aryl represents phenyl unsubstituted or mono- substituted by lower alkyl, hydroxy; lower alkoxy, lower alkanoyloxy, halogen ortrifluoromethyl, R2 and R5 are hydrogen or lower alkyl, R3 and R4 40 are hydrogen, lower alkoxy, lower alkyl, halogen, or trifluoromethyl; or R3 and R4 taken together represent lower alkylendioxy, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl(iower)alkoxy, lower alkoxycarbonyi(iower) alkoxy, or pharmaceutically acceptable salts thereof.

Particularly useful are compounds of formula IA wherein R, is hydrogen, lower alkyl, w-amino(lower)aikyi, aryl(lower) alkyl, R2 and R5 are hydrogen or lower alky], R3 is hydrogen, R4 is hydrogen, lower alkoxy, lower alky], halogen, or trifluoromethyl, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower) alkoxy, lower alkoxycarbonyl (lower)alkoxy, or pharmaceutically acceptable salts thereof.

Especially useful are compounds of formula IA wherein R, is hydrogen, methyl, ethyl, isopropyl, 50 (o-aminopropyi, w-aminobutyl, aryl(methyl, ethyl, propyl) where aryl represents phenyl unsubsituted or substituted by one methyl, hydroxy, methoxy, methylenedioxy, acetyloxy, chloro or trifluoromethyl group, R2 and R5 are hydrogen or methyl, R3 and R4 represents hydrogen, methoxy, methyl, chloro or trifluoromethyl, X represents oxo, one hydroxy and one hydrogen or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonyimethoxyor pivaloyloxymethoxy; or 55 pharmaceutically acceptable salts thereof. Exceedingly useful are compounds of formula IB ,CnH2n-R8 N NH-CH 1-1 CO-R6 0 -R CH2-CO 7 (1 B) 3 GB 2 103 614 A 3 wherein n represents an integerfrom 1 to 4, R8 is hydrogen, phenyl unsubstituted or monosubstituted by lower alky], lower alkoxy, lower alkanoyloxy, halogen, hydroxy, ortrifluoromethyl, R6 and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, or amino, or pharmaceutical ly acceptable salts thereon.

Especially valuable are compounds of formula IB, wheren CnH2n represents ethylene, R8 represents phenyl 5 or phenyl mono-substituted by lower alkoxy with up to 4 carbon atoms, lower alkyl with up to 4 carbon atoms, halogen or trifluoromethyl, R6 and R7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms, or pharmaceutical ly acceptable salts thereof.

The present invention also relates to the stereoisomers of compounds of formula 1. A number of racemates are obtainable when, e.g. in formula IA at least one of R, and R2 is not hydrogen and/or X represents H(OH).10 The individual enantiomers of said racemates may in turn be obtained. Certain specific said isomers are preferred as angiotensin-converting enzyme inhibitors.

Outstanding are compounds of formula]C (sj,,-CnH2r-R8 15 (S) NH-CH OC) --C 0 -R, CH2-CO-R7 wherein S represents the chirality, n represents an integerfrom 1 to 4, R8 is hydrogen, phenyl unsubstituted or monosubstituted by lower alky], lower alkoxy, lower alkanoyloxy, halogen, hydroxy, ortrifluoromethyl, R6 and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy or amino, or 25 pharmaceutically acceptable salts thereof.

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

Aryl represents a carbocyclic or heterocyclic aromatic radical preferably being phenyl, unsubstituted or mono or di-substituted by lower alky], lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, hydroxy, 30 halogen ortrifluoromethyl.

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

The term aryl(lower)alkyl represents preferably benzyi, 1- or 2phenylethyl, 1-, 2- or 3-phenylpropyl 1-, 2-, 3- or 4-phenylbutyl, wherein the phenyl ring is unsubstituted or mono- or di-substituted by lower alkyl, 35 hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen or trifl uoro methyl.

The term cycloalkyl(lower)alkyl represents preferably 1- or 2(cyclopentyl or cyclohexyl)ethyl, 1-, 2- or 3-(cyclopentyl or cyclohexyl) propyl, or 1-, 2-,3- or 4-(cyclopentyl or cyclohexyi)-buty].

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 40 or two carbon atoms.

A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propy], butyl or advantageously methyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantageously ethoxy. A mono-flower)alkylamino group preferably contains 1-4 45 carbon atoms in the alkyl portion and is for example N-methylamino, N- propylamino or advantageously Wethylamino. A di-(iower)aikylamino group preferably contains 1-4 carbon atoms in each lower alkyl portion and represents, for example, N,N-dimethylarnino, N-methyi-N- ethylamino and advantageously N,N-cliethylarnino.

Lower alkanoyloxy represents preferably acetoxy, propionyloxy or pivaloyloxy.

Alkylenedioxy represents preferably ethylenedioxy, and advantageously methylenedioxy.

Aryl lower alkoxy represents advantageously e.g. benzyloxy, benzyloxy substituted by methyl, methoxy or chloro, and pyridyimetboxy.

Carboxy lower alkoxy represents advantageously e.g. 1-carboxyethoxy.

Lower alkoxycarbonyl lower alkoxy represents advantageously e.g. 1(ethoxycarbonyi)ethoxy.

Arnino(lower)alkoxy, mono-(iower)aikylamino lower alkoxy, di-(lower) alkylamino lower alkoxy advan tageously represent respectively e.g. aminoethoxy, ethyl am inoethoxy, cliethylaminoethoxy.

Lower alkanoyloxymethoxy represents advantageously e.g. pivaloyloxymethoxy.

Bicycloalkyioxycarbonyi-(iower)aikoxy preferably represents bicyclo[2,2, 11 Iheptyloxycarbonyl (lower)aikoxy unsubstituted or substituted by lower alkyl advantageously bornyloxycarbonyimethoxy. 60 Arnino(lower)aikyl and (9-amino(lower)aikyl represent preferably amino(ethyi, propyl or butyl) and w-amino(ethy], propyl or butyl) respectively.

Halogen preferably represents chlorine, but may also be bromine, fluorine or iodine.

According to the present invention one or both of the carboxyl groups of the dicarboxylic acids, i.e.

compounds of formula IA or IB wherein R6 and R7 are hydroxy, may befunctionalized as esters or amides. 65 4 GB 2 103 614 A 4 These functional derivatives are preferably the mono or bis lower alkyl esters e.g. methy, ethyl, n- or i-propyl, butyl or benzyl esters; the mono- or bis-amides, the mono- or di Walkylated amides, e.g. mono- or diethylamides; the mono or bis substituted lower alkyl esters, e.g. the o)-(amino, mono- or dimethylamino, carboxy or carbethoxy) -(ethyl, propyl or butyl) esters. Highly preferred functional derivatives are the mono esters of formula IA, e.g. wherein one of R6 and R7 represents hydroxy and the other represents lower alkoxy.

Pharmaceutical ly acceptable salts are preferably metal or ammonium salts of said compound of formula 1 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-(hydroxymethyi)aminomethane or benzy[trimethylammonium hydroxide. Said compounds of Formula 1 form acid addition salts, which are preferably such of therapeutically acceptable inorganic or organic acids, such as strong mineral acids, for example, hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic 15 carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluene-sulfonic, naphthalenesuifonic, sulfanilic or cyclohexyisulfamic acid.

The compounds of formula 1 exhibit valuable pharmacological properties, e. g. cardiovascular effects, by interalia inhibiting the release of Angiotensin 11 through selective inhibition of angiotensin-converting enzyme in mammals. The compounds are thus useful for treating diseases responsive to angiotensinconverting enzyme inhibition in mammals including man.

The compounds of this invention exhibit primarily hypotensive/a nti hypertensive and cardiac effects. 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 hypertensive rats and dogs, and sodium- depleted dogs. The compounds can be applied to the test animals enterally or parenterally, advantageously 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/kg/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 and a transducer. The blood pressure is recorded prior to and after dosing in mm Hg.

Thus the anti hypertensive effects are demonstrable in spontaneously hypertensive rats by indirect measurement of systolic pressure. Conscious rats are placed individually in restraint cages within a gently warmed chamber. A pulse sensor is placed distal to an inflatable occulsive cuff on each rat's tail. The cuff is periodically inflated to occlude the tail artery. The pressure in the cuff is continuously reduced and the systolic pressure corresponds to the pressure in the cuff, at which the pulse waves reappear. After obtaining 40 control values of blood presure 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.

As an illustration of the invention, the anti hypertensive effect of the higher melting- 1-carboxymethyl-3- (1 -ethoxyca rbonyl-3-phenyl propyla m i no)-2,3,4,5-tetra hydro- 1 H-[ 11 benzazepi n-2-one of example 1 is reported: at a dose of 3 mg/kg p.o. it lowers blood pressure by 40 mm Hg as the average effect measured at 2 and 4 hours after the last two daily closings. The corresponding S,S enantiomer of example 12 at a dose of 1 mg/kg p.o. lowers blood pressure by 30 m m Hg.

The compounds of this invention when administered intravenously or orally also exhibit an inhibitory effect against the Angiotensin 1 induced pressor response of normotensive rats. Angiotensin 1 is hydrolyzed 50 by the reaction of said converting enzyme to the potent pressor substance Angiotensin 11. The inhibition of said enzyme presents the generation of Angiotensin 11 from Angiotensin 1. In this manner the increase of blood pressure provoked by Angiotensin 1 is attenuated.

The corresponding in vivo testfor intravenously administered compounds is performed with male, normotensive rats, which are anesthetized with sodium 5-ethyl -5-(1 - methyl pro pyl)-2-th io ba rbitu rate. A femoral artery and saphenous vein are cannulated respectively for direct blood pressure measurement and the im. administration of Angiotensin 1 and a compound of this invention. After the basal blood pressure is stabilized, pressor responses to 3 challenges of 333 ng/kg Angiotensin 1 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 of the compound to be tested, and compared with the initial responses. Any observed decrease of said pressor response is an indication of Angiotensin 1 converting enzyme inhibition. Illustrative of this invention, the "higher melting" 1 -ca rboxym ethyl -3-(11 -eth oxyca rbo nyl -3-p henyl pro pyl am in o)2,3,4,5tetrahydro-1 H[llbenzazepin-2- one of example 1 and the corresponding S,S enantiomer of example 12 completely inhibit the pressor response following Angiotensin 1 challenge through 30 minutes after administration of either of the said compounds at a dose of 1 mg/kg i.v..

GB 2 103 614 A 5 The in vitro inhibition of the angiotensin-converting enzyme by the compounds of this invention can be demonstrated by a method analogous to Biochim. Biophys. Acta 293,451 (1973). According to this method, said compounds are dissolved at about 1 mM concentration in phosphate buffer. To 100 microiiters of solutions of the test compound in phosphate buffer, diluted to the desired concentration, are added 100 microliters of 5 mM hippuryi-histidyi-ieucine 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 37'C for 30 minutes and combined with 0.75 mi 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 temperature, and 10 minutes later 100 microliters of 6N hydrochloric acid. These samples are read against water in a spectrophotometer set at 360 10 nm, and the optical densities thereof estimated. They are corrected for the standard curve via conversion factor expressing nanomoles of histidylleucine formed during said 30 minute incubation period. The results are plotted against drug concentration to determine the IC50, i.e., the drug concentration which gives half the activity of the control sample containing no drug. Illustrative of the invention, the "higher melting" 1-carboxymethyi-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H[1]b enzazepin-2-oneof example15 9 and the corresponding S,S enantiomer of example 19 show an 1C50 of 5.2 x 1 0-9M and 1.7 X 10-9M respectively. The corresponding '1ower melting1-carboxymethyi-3-(1-carboxy-3-phenylpropylamino)2,3,4,5-tetrahydro-1 H[1 Ibenzazepin-2-one of example 8 shows an [C50 of 5.8 x 1 0-11M.

Angiotensin-converting enzyme not only participates in the conversion of Angiotensin 1 to Angiotensin 11, but also plays a role in the control of bradykinin and aidosterone levels. The effect of the compounds of this 20 invention on these factors may also contribute to the anti hypertensive and cardiac effects of these new compounds.

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, andlor other edemic or ascitic diseases. They are also useful intermediates in the preparation of other valuable products, especially of corresponding pharmaceutical compositions.

The compounds of formula 1 according to the invention can be prepared in a manner which is known per se, in that, e.g. a) in a compound of the formula R X NH-RS R3 0 R a (11) 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 hereinbefore, RA is introduced by alkylation with a compound of the formula RA - Z (11 IA) wh e rei n Z is a reactive esterified hyd roxy 1 g ro u p a n d RA h as th e mea n i n g s g ive n h erei n befo re, o r with a compound of the formula R, - CO - R.

OV) wherein R, and R. have the meanings given hereinabove, in the presence of a reducing agent, with a 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 substituents X, RA, RB, R,, R3, R4 and R5 or b) a compound of the formula R4 X R , 5 N 1.1 1 N R RO H ,7 0 (V) 6 GB 2 103 614 A 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 6 % - Z (I1IB) 5 wherein Z is a reactive esterified hydroxyl group and RE3 has the meanings given herenabove, 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, R13, R3, R4 and R5, or 10 c) a compound of the formula 174 X 1 Y p, R3 1 0 RB (V1) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein Y is oxo or a reactive 20 esterified 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 MO wherein RA and R5 have the meanings given hereinabove, with the proviso that in the case Y is oxo, 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 30 R4 X 1 --- R1 (V111) N-CH ON R 35 R, 0 CH R 2 Ro 40 in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X and R, to R5 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) subjected to solvolysis, or 45 e) a compound of formula R 0 4 R N 5 NH 00 0 Hco H RA R3 1 RB OX) in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein X, RA, RB, R:3, R4 and 55 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 1 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 RA, is treated with a reducing agent in order to saturate this double bond, or g) in order to produce a compound of formula] as specified hereinabove, in which Xis oxo, condensing a 60 compound of the formula 7 GB 2 103 614 A 7 D 0 4 1 (X) OC > 5 R3 1 0 RB in which the carbocyclic ring may also be hexahydro or6,7,8,9-tetrahydro, and wherein RB, R3 and R4 have 10 the meanings given hereinabove, with an amine of the formula RA NH - Rs (V11) wherein RA and Rr, have the meaning given hereinabove, and h) if desired, a resulting compound of formula[ as specified above is converted into another compound of formula 1 within its above-specified scope and/or i) if desired, a resulting compound of formula[ as specified above and having salt-forming properties is converted into a salt thereof or a free compound is liberated from such a salt, and/or D if desired, a resulting compound of formula 1 as specified above and having complex-forming properties 20 is converted into a complex thereof, andlor k) 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 formulaL The alkylation according to processes a) and b), which serves for introduction of residues RA and RB, respectively, is carried out in a conventional manner, advantageously by treating a corresponding starting 25 material of formulae 11 and V, respectively, with an alkylating agent of the formula RA-Z (IIIA) or RB-Z 01113), respectively, wherein RA or RB have the meanings given hereinabove and Z is a reactive esterified hydroxyl group, such as a hydroxyl group esterified with a strong organic acid, e. g. an aliphatic or aromatic sulfonic acid (such as a lower alkane sulfonic acid, especially methane sulfonic, trifluoromethanesulfonic acid, especially benzenesulfonic, p-toiuenesuifonic, p-bromobenzenesulfonic and p-nitrobenzenesulfonic acid) or 30 with a strong inorganic acid, such as, especially, sulfuric acid, or a hydrohalic acid, such as hydrochloric or, most preferably, hydriodic or hydrobromic acid. The alkylation is carried out under conventional general conditions at temperatures ranging between about O'C up to the boiling temperature ofthe reaction mixture, preferably at temperatures between room temperature to about 1 OWC. The reacton takes place advantageously in the presence of a solvent which is inert with respect to the reactants, such as chlorinated 35 lower alkane (e.g.chloroform or methylene chloride), an acyclic or cyclic ether (e.g. diethyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran) and, in particular, a low-molecular weight tertiary amide (e.g. N,N-dimethylformarnide, N,N-dimethylacetamide, N-methylpyrrolidone, Wethylpiperidone and hex amethylphosphoric 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 40 alkali metal bicarbonate, carbonate or hydroxide, an organic quaternary ammonium salt (e.g. a tetrabutylammonium salt) or an organic tertiary base, such as triethylamine. Wethylpiperidine, pyridine or quinoline.

In process a), the alkylation can also be carried out under the conditions of reductive alkylation in the manner generally known and used in the art. In carrying out the alkylation, a compound of the general 45 formula R, CO - R,, OV) in which R, and R. have the meanings given hereinabove, is reacted with the starting bicyclic compound 11 50 and, simultaneously or in a subsequent step, 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 cyanoborohydride; among reducing agents used predominantly in a separate subsequent operation, i.e. reduction of a preformed imine (Schiffis base), mention should be made of diborane and complex metal hydrides, such as, sodium borohydride, sodium cya no borohyd ride 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, 1,2-dimethoxyethane, dioxane or tetrahydrofuran) or an aliphatic alcohol (such as methanol, ethanol, isopropyl alcohol, glycol, glycol monomethyl ether or diethyleneglycol), preferably at about W-80'C. A principal reducing agent, however, 60 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, 65 1 -- ' --kl; k ' ' 8 GB 2 103 614 A 8 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 differfrom those generally known for hydrogenation. Temperatures ranging from room temperature to about 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, also low- molecular weight amides, especially tertiary amides (such as N,N-dimethylformamide, N,N,-dimethylacetarnicle, N-methylpyrrolidone, N ethyl pi peridone, hexa methyl phosphoric acid triamide) but also formamide and acetamide can be used as suitable solvents. Special measures have to be taken with starting materials of formula 11 which have an easily reducible functional group, such as the 5-oxo group; in orderto pressure 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 an amine of formula 11 with a compound of formula IV in an inert solvent, e.g. toluene or methylene chloride, advantageously in the presence of a dehydrating catalyst, e.g. boron trifluoride etherate, ptoluenesulfonic acid or molecular 15 sieves.

Process b) 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 RA is hydrogen, and at 20 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 RB.

In any of the alkylation processes, primary and secondary amino groups in starting materials, exceptfor the secondary 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. 15/1 and 11, E. WOnsch (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 functional groups to be protected, advantageous combinations can be selected. Preferably, for example, similar or, even better, identical 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 35 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 thep-chloro- and p- bromobenzyloxycarbonyi,pmethoxybenzyl oxyca rbonyl, p-m ethyl benzyloxyca rbo nyl and, especially, p-nitrobenzyioxycarbonyl group, or alternatively the isonicotinyloxycarbonyl group. An advantageous amino-protecting group is an ethoxycarbonyl group which carries in the P-position a silyl group substituted by three hydrocarbon radicals, 40 such as triphenylsilyl, dimethyltert.butylsilyl or, especially, trimethylsilyl. A P-(trihydrocarbonylsilyl) ethoxycarbonyl group of this type, such as a P-(tri-lower alkylsiiyi)- ethoxycarbonyl group, for example, especially P-(tri methyl s i lyi)-eth oxyca rbo ny], forms with the amino group to be protected a corresponding 0-trihydrocarbyisilylethoxycarbonylamino group (for example the Ptrimethyisilylethoxycarbonylamino 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-(4-methoxy)-benzhydryl and triphenyimethyl (trityl), or certain aralkoxycarbonyl groups of the 2(p-biphenylyl)-2-propoxycarbonyI 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. 50 For the optional temporary protection of hydroxy groups, protecting groups may be used advantageously that can be removed by reduction, cf. the above-cited text (Houben-Weyl), and also groups that can be removed by acidolysis, such as 2-tetrahydropyranyl, tert-butoxycarbonyl and tert-buty]. 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 alky], lower alkoxy and/or, especially, nitro, especially the 55 4-nitrobenzyl group. It is also possible to use acyl groups that can be removed under weakly basic conditions, such as formyl or trifluoroacetyl.

For the optional protection of oxo groups. these are preferably protected as ketals, derived from lower alkanols, such as methanol or ethanol, or advantageously of ethylene glycol, or as corresponding thiolketals preferably those of 1,2-ethanedithiol. All these groups can liberate oxo groups under the conditions 60 indicated further below.

The subsequent removal of protecting groups in accordance with the invention depends on the nature and is carried out in each case in a conventional manner known persetaking into consideration the general properties of the derived product. If the protecting groups for amino, hydroxy and oxo hve been so selected that they can be removed under similar conditions (especially preferred here are the groups removable by 65 9 GB 2 103 614 A 9 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 differenttypes 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-trichlorethyl radicals), isonicotinyl radicals (for example isonicotinyloxycarbonyl) and, especially, 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. 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 10 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 Offen legungssch rift DT 2 346 147) or by aqueous acetic acid; for the 15 tert-butoxycarbonyl group to be removed by trifluoroacetic acid or hydrochloric acid; and for the 2-(p-biphenyiyi)-isopropoxycarbonyI group to be removed by aqueous acetic acid or, for example, by a mixture of glacial acetic acid, formic acid (82.8% strength) and water Q:1:2) or in accordance with the process in DT 2 346 147. The P-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, orwith oxalic acid, in the presence of water, the latter one advantageously by treatment with a sulfur-binding agent, e.g. a mercury 11 - 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, 25 aqueous ammonia, in an organic solvent, usually at room temperature. The protecting groups are preferably removed under the reaction conditions of the examples, or under analogous conditions.

Those of the end products according to the invention that contain basic groups are obtained, depending on the manner of isolation, in form of bases or acid addition salts; analogously, end products having acidic groups may also be obtained in the form of salts. Each form can be converted into the other in known manner. The bases can be obtained from the acid addition salts in a manner known perse. From the bases it is in turn possible to obtain acid addition salts, especially therapeutically useful acid addition salts, by reaction with acids, for example with acids of the type that form the abovementioned salts. Acids and their salts also stand in a similar relationship to one another. Compounds that have both a free carboxy group and a basic group may be in the form of inner salts and these are obtained, for example, by establishing the 35 isoelectric point.

The starting materials of formula IIIA, IIIB and W, that is to say the alkylating agents, are known or, if they are unknown, can be simply obtained by conventional synthetic processes.

The starting materials of formula 11 and V can be obtained by conventional synthetic processes, and advantageously in the manner which is described in more detail and exemplified for specific intermediates 40 hereinafter.

Process c), also being an alkylation reaction is performed according to the same general considerations and under the same experimental conditions as the above processes a) and b) as described in detail above for the treatment with an alkylating agent of formula IIIA, NIB or W (i.e. substitutive alkylation or reductive alkylation). Starting materials of formula VI can be obtained by conventional processes known per se, e.g. in 45 the manner described more specifically hereinafter. The amines of formula VII are known, or if unknown, they are easily accessible by conventional synthetic methods.

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 carboxylic acids ortheir salts, esters or imides. - For the conversion into a free acid, hydrolysis with water is carried out advantageously in an inert organic solvent 50 which is at least partially miscible with water, such as ethers (e.g. diethyl and diisopropyl ether, 1,2-dimethoxyethane or, especially dioxane ortetrahydrofurane) or lower alkanols (e.g. methanol, ethanol, isopropyl alcohol, butyl alcohols, 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 55 choice, hydrochloric acid), or by bases, especially inorganic bases such as hydroxides and carbonates of alkali metals, e.g. sodium and potassium hydroxide. 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 1, in which R.

represents an esterified carboxyl group, can be obtained by carrying out the solvolysis of the nitrile with the 60 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), andlor halogenated lower alkanes (especially chloroform and dichloromethane). If the aicoholysis is carried out under strictly anhydrous conditions, the primary product (imino ester) isto be hydrolyzed, advantageously 65 GB 2 103 614 A 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 1, wherein R. is carbamoyl), a corresponding nitrile of formula Vill can preferably be subjected to alkaline hydrolysis in the presence of hydrogen peroxide.

The starting materials of formula VIII can be obtained by conventional methods known per se, e.g. by a 5 condensation analogous to that of process c), in which a starting material of the above-defined formula Vi is treated with an amine of the formula R, IR,-NI-I-CH \ (VII1) CN wherein R, and R5 have the meanings given hereinabove, and which corresponds to the above-defined amine of formula VII. 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 perse, 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-Weyl, Volumes 15/1 20 and 15/2 as cited hereinabove. According to one preferred modification, 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 that with 2,4,5- trichlorophenol, pentach loro phenol, pentaf luorophenol, 2-nitrophenol or, especially, 4-nitrophenol, or with an N- hydroxy compound, such as N-hydroxysuccinimide, 1 -hydroxybenztriazole or Whydroxypiperidine, or alternatively with an N,W- 25 substituted 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 re-activate the amino group to be cyclized by converting it into the unprotonated form. The reaction temperature is usually from -20'to +50'C, preferably approximately at 30 room temperature, and customary solvents are used, for example, dioxan, tetrahydrofuran, acetonitrile, pyridine, dimethylformamicle, dimethylacetamide, dimethyl sulfoxide, Nmethylpyrrolidone, hexamethyl phosphoric acid triamide, as well as chloroform and methylene chloride, and expedient mixture thereof. In a special variant of the process, the carboxy group can be directly activated in situ by the action of the free acid with a carbodiimide, such as N,N'-dicyclohexylcarbodiimide (optionally with the addition of Nhydroxysuccinimide, an unsubstituted or, for example, halogen-, methyl- or methoxy-substituted 1 hydroxybenztriazole or 4-hydroxybenzo-1,2,3-triazine-3-oxide or N-hydroxy- 5-norbornene-2,3 dicarboximide), or with N,N'-carbonyidiimidazole. Starting materials of formula IX can be obtained according to general methods known perse, e.g. as discussed in more specific examples hereinafter.

Also, reduction according to process f) can be carried out in a manner generally known perse for saturation of such double bonds. More specifically, the double bond in the unsaturated starting materials corresponding to formula 1 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 a group RA. The saturation of the double bond is advantageously carried out by catalytic hydrogenation, e.g. underthe preferred conditions discussed in detail hereinbefore, and also be 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 variant 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 under conventional general conditions at 50 temperatures ranging between about O'C and 1 OWC in a solvent which is inert to the reactants, e.g.

methylene chloride, 1,2-dimethoxyethane, N,N-dimethy[formarnide 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 final product of formula 1, into another compound within the above-specified scope of formula 1, transformations such as the following are carried 55 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 1 is hydrogenated to hexahydro or 6,7,8,9-tetra hydro, and/or the hexahydro carbocyclic ring is dehydrogenated to the 6,7,8,9-tetrahydro or aromatic carbocyclic ring.

All these optional interconversions are carried out by well-known conventional methods. Bythe alkylation reaction, e.g. the lower alkyl as represented by R5 can be introduced into the final product of formula 1, wherein R5 is hydrogen, using any of the modifications discussed in detail in connection with process variant 65 11 GB 2 103 614 A 11 a). Both substitutive and reductive alkylation can be employed, the former with alkyl halides, the latter with lower aliphatic aldehydes and ketones and catalytically activated hydrogen or, in the case of formaldehyde, advantageously with formic acid as the reducing agent. By the substitutive alkylation, lower alkyls can also be introduced into an amino group which is a component of the carbamoyl group represented by symbol R,.

Also the reduction of the 5-oxo group to hydroxy is carried out in the usual manner, e.g. using a complex 5 metal hydride, especially a mild one, such as an alkali metal borohydride (e.g. sodium borohydride), 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 hydrochloric 10 acid, or by Raney-nickel desulfurization of a corresponding dithioketal. The oxidation of hydroxyl to form oxo can be preferably carried out with a derivative of hexavalent chromium such as chromic acid and 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 in connection with 15 removing hydroxyl-protecting groups; the acylation of both hydroxyl and amino groups is carried out in the usual way, preferably using a corresponding acid anhydride or halide. For esterification a carboxy group can be reacted directly with a diazoalkane, especially diazomethane, or with a corresponding alcohol in the presence of a strong acid catalyst (e.g. sulfuric acid or an organic sulfonic acid) and/or a dehydrating agent (e.g. dicyclohexylcarbodiimide). Alternatively, the carboxyl group can be converted into a reactive derivative 20 thereof, such as an active ester mentioned in connection with process e), or into a mixed anhydride, e.g. with an acid halide (i.e., especially acid chloride) or with trifluoroacetic acid, and this activated intermediate reacted with the desired alcohol.

The free carboxyl group can be liberated from an esterified carboxyl in a manner generally known, especially by base-catalyzed hydrolysis. Of special interest, however, are methods capable of selectively 25 liberating one particular carboxyl group represented by the symbols -COR6 and -COR7. 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 1511 and 15/2 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, benzoyimethyl alcohol or tert-butyl alcohol, but especially alcohols that yield radicals which can be removed by reduction, such as 2,2,2-trichloroethanol, benzy] alcohol, and especially 4-nitrobenzyl alcohol, or alternatively isonicotinyl alcohol. An especially advantageous class of substituted alkanols are ethyl alcohols which carry in the P-position a trisubstituted sily] group, such as triphenylsilyl, climethylbutylsilyl or, especially, trimethyisily]. As is described, for example, in Belgian Patent No. 851.576, 35 these alcohols are particularly suitable for selective removal because the corresponding P- silylethyl esters, for example P-(tri methyl si]yi)-ethyl ester, have the stability of customary alkyl esters but can selectively be removed under mild conditions by the action of fluoride ions to retain other esterified carboxyl groups, for example alkoxycarbonyl groups. 4o The removal of esterifying groups depends on their nature and is carried out in each case in a conventional 40 manner known perse 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 example isonicotinyloxycarbonyi) 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 45 inert organic solvent, usually at room temperature, those of the benzyi type, especially unsubstituted benzyl esters, also by hydrogenolysis techniques conventionally used for benzyl groups.

The removal of an ester group by acid hydrolysis (acidolysis) can be carried out especially in the case of groups of the tert-butyl type, by means of hydrogen chloride, hydrogen fluoride or trifluoroacetic acid. The P-silylethyl ester groups are preferably removed by fluoride-ion-yielding reagents, for example fluorides of 50 quaternary organic bases, such as tetraethylammonium fluoride. Ester groups 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. The ester groups are preferably removed under the reaction conditions of the examples, or under analgous 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. in process a), a selectively removable ester group being introduced with a carboxyl which is to be liberated in the last stage.

The compounds of formula 1 in general, and IA in particular, are prepared advantageously according to reaction sequence 1, which involves an advantageous selection of starting materials and intermediates, and 12 GB 2 103 614 A 12 comprises the following steps: a) condensing under conditions of basic catalysis, a compound of the formula R 1 X 3 R9 R H (X0 wherein R and R4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or R3' and R4taken together represent lower alkylendioxy, X' presents 2 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 15 compound of the formula R2' - CH - COR7' i L (11 IT) wherein R represents hydrogen orlower alkyl, Z represents reactively esterified hydroxy, and R represents hydroxy, di(lower) alkylamino, lower alkoxy, aryl(iower)alkoxy, lower alkanoyloxymethoxy or lower alkoxy- carbonyl(lower)alkoxy, b) optionally reducing, hydrogenolyzing, hydrolyzing or alkylating the resulting intermediate to obtain a compound of the formula ll' 1 25 4 NH OLN 30 1 3 1 0 CH R9 CO-% wherein R, R4, X' are as defined for formula M; R and W5 represent hydrogen or lower alkyl, 137' represents hydroxy, amino, monoor di(lower)aikylamino, lower alkoxy, aryi(lower)aikoxy, lower alkanoyloxymethoxy, di(lower alkylamino)lower alkoxy or lower alkoxycarbonyi(lower)aikoxy, c) condensing a compound of 40 formula ll' above under conditions of reductive alkylation with a compound of the formula IT 0 H Rl' - C - COR6 OT) wherein Ri is hydrogen, lower alkyl, acylated amino (lower) alkyl, aryl, aryl(lower)alkyl, cycloalkyi(iower)aikyl and R6 represents hydroxy, di(lower)aikylamino, lower alkoxy, aryl(lower) alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl(lower) alkoxy, or condensing under alkylation conditions a compound of formula IV above with a compound of the formula lIVA R11 - CH - COR 1 z (11 VA) wherein Ri'and W6 have meanings given above in formula 1W and Z represents reactively esterified hydrOxY, 55 d) optionally hydrolyzing or derivatizing the resulting product; e) converting any resulting compound of formula IA into another compound of the invention.

Compounds of formula Xl are obtained from the corresponding optionally substituted and/or derivatized 2,3,4,5-tetrahydro-1 H[1 Ibenzazepin-2ones (J. Chem. Soc. 1937,456; British patent 1,359,285; Liebigs's Annalen Chemie 574,171 (1951). Novel appropriately derivatized starting [1 Ibenzazepin-2-ones are advantageously prepared by Beckmann rearrangement of the correspondingly derivatized naphthalen-1 ones using procedures known to the art and exemplified herein.

Said tetrahydro-[1 Ibenzazepin-2-ones are converted to the 3-halo-, e.g. 3-chloro-2,3,4,5-tetrahydro1 H[1]benzazepin-2-one under conditions exemplified herein, e.g. by treatment with phosphorus pentachlor65 ide followed by hydrogenation. Substitution of said halo derivative with a metal azide, e.g. sodium axide and 65 13 GB 2 103 614 A 13 optional reduction, or substitution with ammonia or a lower alkylamine and optional acylation, yields compounds of formula Xl.

Alternatively, compounds of formula Xl wherein R9 represents amino, alkylamino or acylamino are obtained by reduction and cyclization of the appropriately substituted and/or derivatized 4-(o-nitrophenyl)-25 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 L4-(o-aminophenyi)-4-oxo-2-amino-butyric acid (L-kynurenine, J.Am.Chem. Soc. 76,1708 (1954), derived from L-tryptophane) is converted to an optionally active starting material of formula Xl wherein R9 is acylamino, e.g. 3-(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1 H[II]benzazepin2,5-clione as described in the Australian Journal of Chemistry 33,633-40 (1980). The lactam alkylation of a 10 compound of formula M with a reactant of formula 111'B, 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, organometallic reagents, e. g. lithium diisopropylamide 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 00 and 75'. 15 Condensation of intermediates of formula Wwith the known a-ketoacid derivatives of formula 1W (e.g.

Chem. Ber. 31, 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 cyan oborohyd ride 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 to 50', preferably room temperature.

Alkylation of intermediate amines of formula U'with a reactant of formula lIVA, well known to the art, is carried out with or without basic catalysts such as triethylamine or potassium carbonate in an inert solvent. 25 The compounds of formula 1 in general, and IA in particular. can also be prepared by sequences 2 and 3.

Sequence2 comprises the following steps: a) condensing under conditions of reductive alkylation a compound of the formula Ri' X ú 1 5 PN NH H (X11) wherein %, R4 and X' have meanings as defined for formula Xl, and RA is hydrogen or lower alkyl, with a 40 compound of the formula 1W 0 11 Ril - C - CO - RA OV1 45 wherein Ri and RA have meanings as previously defined, or under alkylation conditions with a compound of formula lIVA Ri - CH - COR6 50 1 4 wherein Ri, RA and Z have meanings as previously defined, to obtain a compound of the formula V' R X 1 R / N-CH PN R'H 0 (V1 CO-R 14 GB 2 103 614 A wherein Ri, RS, R4, R, % and X' have meanings as previously defined, b) condensing under conditions of basic catalysis a resulting compound of the formula Wwith a compound of the formula Ill'13 14 R2' - CH - COR,' (11 V13) 5 wherein R2' and R and Z have meanings as previously defined, c) optionally hydrolyzing or derivatizing the resulting product, d) optionally converting any resulting compound of formula 1 into another compound of 10 the invention.

Sequence3 comprises the following steps: a) condensing a compound of the formula V11' R9 IRY 1 1 15 HN - CH - COR9 (V111) wherein R7 is hydrogen, lower alkyl, acylated amino(lower)aiky], aryl, aryl(lower)alkyl, cycloalkyl(iower)alky]; R'5'represents hydrogen or lower alkyl; and %'represents hydroxy, di(lower)aikylamino, lower alkoxy, aryl(lower)alkoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl(iower)aikoxy, with a compound of 20 the formula W R a X 4,\ Y (V11) 25 0 CH 30 CO-R wherein R2represents hydrogen or lower alky], R3and R represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, trifluoromethyl or RS and R4"taken together represent lower alkylenedioxy; X' represents 2 hydogens, one hydrogen and one etherified or esterified hydroxy, oxo or oxo protected in the form of a ketal or thioketal; R7represents hydroxy, di(lower)alkylamino, lower alkoxy, aryi(lower)aikoxy, lower alkanoyloxymethoxy or lower alkoxycarbonyl(lower)alkoxy; and Y represents oxo or dichloro- under conditions of reductive Walkylation, or condensing a compound of formula VIVwith a compound of the formula Wwherein X' represents oxo, Y represents hydrogen and one reactively esterified or etherified 40 hydroxy, or with a 3,4-dehydro elimination product of said compound or with a 3,4-clehydro derivative of said compound; b) optionally reducing, hydrolyzing or derivatizing the resulting product; c) optionally converting any resulting compound into another compound of the invention.

In the preceding sequences 2 and 3 the steps of lactam alkylation, reductive N-alkylation and alkylation of amines are advantageously carried out under the conditions described for process 1.

In sequences 1, 2 and 3 described herein, reactants of e.g. formulae lIVA, Ill'B and VIV may be replaced with the corresponding nitriles, e.g. R2'ClA(Z)CN, R1'CH(Z)CN and R5NI- ICH(Ri)CIN respectively. The nitriles thus obtained may be converted to the carboxylic acids, esters and amides of formula 1 using methods well known to the art.

The starting materials of formula Vill' represent amino acids and derivatives well known to the art. It is 50 noteworthy that the optically active compounds of this invention may be synthesized starting with an optically active compound of formula VIV, e.g. L-a-aminopheny[butyric acid, IL-phenylalanine and derivatives thereof.

In the case of reactants of formula 111A Ill'13, 1W and V11'wherein R7, R6' or R9 represents hydroxy, an appropriate carboxylate salt is prepared, preferably in situ, before condensation with the described 55 intermediates cited above.

Certain terms used in the foregoing processes have the meanings as defined below.

A reactively esterified hydroxy represents such esterified by a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, an aliphatic or aromatic sulfonic acid, e.g.

methanesulfonic acid or p-toluenesulfonic acid.

Etherified hydroxy represents preferably lower alkoxy, e.g. methoxy, ethoxyort-butoxy.

The optional steps of reducing, hydrogenolyzing hydrolyzing or derivatizing the initial products of the aforesaid processes and the conversion of a resulting product into another compound of this invention are performed by chemical methodology known to the art and exemplified herein.

Compounds of formula 1 or IA wherein R6 and/or R7 is lower alkoxy may be amidized with ammonia, 65 is GB 2 103 614 A 15 mono- or di-(iower)aikylamines to yield compounds of formula 1 or]A wherein R6andlor R7 represents unsubstituted, mono- or di-(iower)aikylamino.

Conversion of compounds of formula 1 or IA wherein Re, and/or R7 is lower alkoxy, aryl(lower)alkoxy, amino, mono- or di-(iower)amino to compounds of formula 1 or IA wherein R6 and/or R7 represents hydroxy is advantageously carried out by hydrolysis with inorganic acids such as hydrohalic or sulfuric acid or with 5 aqueous alkalies preferably alkali metal hydroxides such as lithium or sodium hydroxide.

The selective conversion of compounds of formula 1 or]A wherein R6 and/or R7 represents a aryl(lower)alkoxy, e.g. benzyloxy to compounds of formula 1 or IA wherein R6 and/or R7 represents hydroxy is advantageously carried out by hydrogenolysis using hydrogen in the presence of a catalyst, e.g.

palladium.

Compounds of formula 1 or iA wherein neither R6 nor R7 represents hydroxy may be converted to monocarboxylic acids of formula 1 or IA wherein one of R6 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 R6 and R7 substituents.

Free carboxylic acids of formula 1 or IA wherein R6 and/or R7 represent hydroxy or salts thereof may be 15 esterified with the appropriate alcohols or reactive derivatives thereof well known to the art to give the corresponding mono- or bis-ester, namely compounds of formula 1 or IA wherein R6 and/or R7 is lower alkoxy, aryl(lower) alkoxy, lower alkanoyloxymethoxy, or lower alkoxycarbonyi(iower) alkoxy. Furthermore the free carboxylic acids may be converted via reactive intermediates to monoor bis-amides of formula 1 wherein R6 and/or R7 represents amino, mono- or di-(iower)aikylamino.

Compounds of formula 1 or IA, and intermediates therefor, e.g. of formulae X and W, wherein X or X' represents oxo may be converted to the corresponding compounds wherein X or 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 sodium borohydride. Resulting compounds wherein X or X' represents one hydrogen and one hydroxy may be converted to compounds 25 wherein X or 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 or X' represents one hydrogen and one hydroxy with dicyclohexylcarbodiimide in the presence of cuprous chloride according to the general method described in Chem. Ber., 107,1353 (1974).

Alternatively, the compounds wherein X and X' represents one hydrogen and one hydroxy may be first 30 converted to the corresponding compounds wherein X or X' represents one hydrogen and one acyloxy (e.g.

acetoxy) and subsequently reduced, e.g. by catalytic hydrogenation in the presence of a palladium catalyst, to compounds wherein X or X' represents two hydrogens.

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 35 said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, 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 40 process is discontinued at any stage thereof, 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 optionally 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 fortheir manufacture.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, depending on the number of 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 50 physicochemical differences of the constituents, in known manner, into the pure isomers, diastereoisomers 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 active solvent, by means of miroorganisms or by reacting an acidic end product with an optically active base that forms salts with the racemic acid, and separating the 55 salts obtained in this manner, for 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 poclucts can likewise be resolved into the antipodes, for example, by separation of diastereomeric salts thereof. e.g. by the fractional crystallization of d- or Martrates. Any racemic intermediates or starting materials can likewise be resolved.

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

Finally, the compounds of the invention are either obtained in the free form, or as a salt thereof any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a pharmaceutical ly acceptable acid or anion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example, with the use of a stronger base, such as a metal or ammonium 65 16 GB 2 103 614 A 16 hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation. A compound of formula 1 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 separated and the bases are liberated from the salts. In view of the close relationship 5 between the free compounds of 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 underthe circumstances.

The compounds, including their salts, can also be obtained in 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 enzyme, e.g. cardiovascular diseases such as hypertension and congestive heart failure comprising an effective amount of a pharmacological ly active compound of formula 1, or pharmaceutical ly acceptable salts thereof, alone or in combination with one or 15 more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose 20 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, methylcel 1 u lose, sodium ca rboxymethyl cell u lose andlor polyvinyl pyrrolidone, if desired, cl) 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 25 solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspension. 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 compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 30 0.1 to 75%. preferaby about 1 to 50%, of the active ingredient. A unit dosage for a mammal of about 50 to 70 kg may contain between about 10 to 200 mg of the active ingredient.

The following Examples are intended to illustrate the invention and are notto 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 35 between about 15 and 100 mmHg.

In the case of compounds of formula 1 or IA wherein more than one asymmetric center exists the resulting diastereoisomeric compounds are denoted as A, B. etc., in the said examples. The respective di astereoisomeric compounds are characterized by physical properties, e.g. melting point, relative migration on chromatography, infrared, or nuclear magnetic resonance spectral properties.

In the case of compounds of formula 1 or]A wherein X is H2 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 relative isomers on the basis of their relative migration on chromatography. On the basis of migration on thin-layer chromatography and normal phase high pressure liquid chromatography employing silica gel as the stationary phase, the fast moving isomer is called isomer 45 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

1Carboxymethyl-3(1ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro1H-[llbenzazepin-2-one (higher melting isomer) A solution of 3-am ino-1 -ca rboxym ethyl -2,3,4,5-tetra hyd ro- 1 H-[1 Ibenzazepin-2-one (10.0 g) and ethyl benzylpyruvate (26.4 9) in acetic acid (75 ml) and methanol (75 mi) is stirred at room temperature under nitrogen for 1 hour. Sodium cya no borohyd ride (3.4 g) in methanol (25 mi) is added dropwise over 4 hours. 55 The reaction mixture is stirred at room temperature for 24 hours. Concentrated hydrochloric acid (4 mi) is added dropwise, and the mixture stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness. The residue is partitioned between 150 mi of water and 50 mi of ether and adjusted to pH 9 and'40 % aqueous sodium hydroxide solution. The layers are separated and the ether layer is discarded. The aqueous layer is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with 3 X 75 mI of ethyl 60 acetate. The organic portions are dried (magnesium sulfate) and concentrated to dryness. Hydrogen chloride gas is bubbled into a solution of the crude product in 310 m] of methylene chloride for 5 minutes. The solution is evaporated and the residue is stirred in 225 m[ of ether. The produce is collected by filtration to give a 70:30 diastereomeric mixture as determined by high pressure liquid chromatography. The product is recrystallized from ethanol/ethyl acetate (1:3) to give 1-carboxymethyl-3- (1-ethoxycarbonyi-3- 17 GB 2 103 614 A 17 phenyl propylamino)-2,3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one hydrochloride melting at 246-248' (decomposition) and corresponding to the racemic isomer B. A solution of the above hydrochloride salt (0.9 g) and propylene oxide (10 mi) in ethanol (150 mi) is stirred under nitrogen for 18 hours. The solution is evaporated to dryness, and the residue is dissolved in 3 mi of ethanol. Ether (75 mi) is added, precipiatating a small quantity of the starting hydrochloride. The filtrate is evaporated to dryness and stirred with ether/petroleum ether W9). The solid is filtered off to give 1carboxymethy]-3-(1-ethoxycarbonyi-3-phenylpropylamino)-2,3,4,5-tetrahydro1 H-[llbenzazepin-2-one melting at 139-141', and being the higher melting racemic isomer B of the compound of formula IB wherein C^n is ethylene, R6 is ethoxy, R7 is hydroxy and R8 is phenyl.

Resolution under standard conditions with an optically active amine and separation of the diastereoisomeric salts yields pure enantiomer, e.g. 1carboxymethyl-3S-(1 S-ethoxycarbonyl-3phenyl propyla m in o)-2,3,4,5tetra hydro-1 H-[1]benzazepin-2-one of Example 12.

Using high pressure liquid chromatography on a reverse phase column (solvent system: methanol, water (31) containing 0.025 % acetic acid) isomer B is faster moving than lower melting racemic isomer A of Example 5.

The starting material, 3-amino-l-carboxymethy]-2,3,4,5-tetrahydro-1H[llbenzazepin-2-one is prepared as follows A mixture of 2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one (48.3 g, see Briggs et al., J. Chem. Soc. 1937,456), phosphorus pentachloride (188 g), and xylene (1300 mi) is heated with stirring under an atmosphere of nitrogen to 900 (oil bath temperature) during 30 min with pauses at 30' (to allow the phosphorus pentachloride to dissolve) and at 50'. There is a copious evolution of hydrogen chloride. The temperature is maintained at 90'for 30 minutes. The reaction mixture is filtered while hot to remove a small amount of suspended solid, and the filtrate is evaporated under reduced pressure until all the solvent is removed. The residue is added with stirring to saturated aqueous sodium carbonate (100 mi). The product is filtered after the solidification process is complete, then slurried in ethanol (150 mi), filtered, washed with ethanol (50 mi) 25 and ether (50 mi) and dried to give 3,3-dichloro-2,3,4,5-tetrahydro-1 H- [1 Ibenzazepin-2-one, m.p. 185-1870.

A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (20 g, 0.174 mol) and anhydrous sodium acetate (15.4 g, 0.188 mol) in glacial acetic acid (920 mi) is hydrogenated at atmospheric pressure using 5 % Pd-C (1.72 9) at catalyst until the uptake of hydrogen ceases. The catalyst is filtered off and the acetic acid evaporated under reduced pressure. The residue is equilibrated between 10 % NaHC03 (900 M1) 30 and dichloromethane (300 m]). The aqeuous layer (pH 8) is further extracted with dichloromethane (3 X 300 mi) and the combined organic solutions are dried over anhydrous sodium sulfate and evaporated to give 3-chloro-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p. 163-167'.

A solution of 3-chloro-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (15.9 g, 0.08 mol) and sodium azide (6.36 g, 0.10 mol) in dimethylsulfoxide (320 mi) is maintained at 80' under an atmosphere of nitrogen for 3 hours. 35 Atthis time, the M spectrum of an aliquot shows a strong peak at 2150 cm1 characteristic of the axide group. The reaction mixture is poured into 1000 mi of ice/water and the suspension is stirred for 30 min. The solid is filtered off, washed with water (250 m]) and dried to give 3azido-2,3,4,5-tetrahydro-1 H [l Ibenzazepin-2-one, m.p. 142-145'.

A solution of 3-azido-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (8.7 g, 0.043 moll, in dry dimethylforma- 40 mide (75 mO is added during 30 min to a stirred suspension of sodium hydride [from 60 % mineral oil dispersion (1.9 g) washed with petroleum ether (3 x 150 mi)l in dry dimethylformamide (250 m[) maintained at 0'under a nitrogen atmosphere. Stirring is continued for an additional 1.5 hours, then benzy] bromoacetate (10.8 g; 0.047 mol) in dry dimethylformamide (75 m[) is added during 45 minutes, the temperature being maintained at 0'. The reaction mixture is then allowed to warm to room temperature while stirring for an additional 18 hours. The dimethylformamide is removed under reduced pressure and the residue partitioned between water (500 m]) and dichloromethane (500 mi). The aqueous phase is extracted with additional dichloromethane (3 x 500 mi). The combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure to give the crude ester-azide as an oil. This material is dissolved in toluene (500 mi) and silica gel (48 g) is added. Filtration and removal of the solvent 50 under reduced pressure gives 3-azido-l-benzyioxycarbonyimethyi-2,3,4,5- tetrahydro-1 H-[1 Ibenzazepin-2 one, as an oil, used withoutfurther purification in the next synthetic step.

A suspension of Raney nickel active catalyst in water (15 mi) is washed with ethanol (5 x 100 mi) and added to a mechanically stirred solution of 3-azido-l- benzyioxycarbonyimethy]-2,3,4,5-tetrahydro-1 H [llbenzazepin-2-one (5.0 g) in ethanol (300 m]), and the suspension is stirred for 18 hours at room temperature under nitrogen. The catalyst is filtered off and the solvent removed under reduced pressure.

The residue is dissolved in 2H hydrochloric acid (200 mi) and the solution extracted with ether (2 x 250 mi).

The aqueous solution is made basic (pH 9) with concentrated aqueous ammonia, and the solution extracted with ether (3 x 200 mO. The combined ether solutions are dried over sodium sulfate and evaporated under reduced pressure to give 3-amino-l-benzyioxycarbonyimethyi-2,3,4,5tetrahydro-1H-[llbenzazepin-2-one as 60 an oil, used without further purification for the next synthetic step.

3-Ami no-1 -benzyi oxyca rbo nyl m ethyl-2,3,4,5-tetra hydro- 1 H-[1 1 benzazepi n-2-one is also prepared as fol lows: A solution of 3-amino-2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one (5. 0 g, 0.028 mol), in dimethylforma mide (100 mi) is added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3 X 150 m])] in 18 GB 2 103 614 A 18 dimethylforma m ide (400 m[) to which tetrabutyla m moniu m bromide (10.0 g, 0.031 mol) has been added. The reaction mixture is maintained at 50'for 15 minutes, then a solution of benzyi bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 mi) is added. The reaction mixture is stirred for an additional 18 hours at 500, then cooled to room temperature, and the dimethylformamide removed under high vacuum. Theresidue is stirred with toluene/dichloromethane (1:1, 500 mi) to precipitate inorganic salts. After filtration, the solution is evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 0-15 % ethyl acetate in toluene gives 3-amino-l-benzyioxycarbonyimethyl-2, 3,4,5-tetrahydro-1 H [1 Ibenzazepin-2-one as a major product.

A solution of 3-amino-l-benzyioxycarbonyimethyi-2,3,4,5-tetrahydro-1 W[1]benzazepin-2-one (1.3 g) in ethanol (250 mi) is hydrogenated at room temperature and atmospheric pressure, using 10 % Pd-C (0.20 g) 10 as catalyst, until uptake of hydrogen ceases. The catalyst is filtered off and the solvent removed under reduced pressure to give a white foam (0.90 g). This material is triturated with ether to give 3-amino-l-carboxymethyl-2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one, m.p. 147-150'.

A solution of 3-azido-1 -benzy[oxycarbonyimethyl-2,3,4,5-tetrahydro-1 H[1 Ibenzazepin-2-one (14.0 g, 0.04 mol) in ethanol (300 mi) is hydrogenated for 25 hours at 3.1 at at room temperature using 5 % Pd-C (2.0 g) as 15 catalyst. The catalyst is filtered off and the solvent removed under reduced pressure. The residue is dissolved in water (500 mi) and the solution extracted with dichloromethane (2 x 400 mi). The aqueous solution is filtered, and evaporated under reduced pressure. Ethanol (50 mi) is added and the solution evaporated under reduced pressure. More ethanol (50 m[) is added, and the evaporation repeated. The residue is recrystallized from ethanol/ethyl acetate to give 3-amino-lcarboxymethyl-2,3,4,5-tetrahydro-1H- 20 [1]benzazepin-2-one, m.p. 147-150'.

EXAMPLE 2

1-Benzyloxycarbonylmethyl-3-(1-carboxy3-phenylpropylamino)2,3,4,5tetrahyd ro 1H[llbenzazepin-2-one Sodium cya noborohyd ride (0. 152 g, 0.0014 mol) is added to a solution of 1 -benzyl oxyca rbonyl methyl -3amino-2,3,4,5-tetrahydro-1 W[1 1 benzazepin-2-one (0.45 g, 0.0014 mol) and benzylpyruvic acid (0.48 g, 0.0028 mol) in methanol (35 mi). The reaction mixture is stirred at room temperature under nitrogen for 2 hours.

Additional benzylpyruvic acid (0.48 g, 0.0028 mol) is added, and the reaction mixture stirred for an additional 18 hours. Concentrated hydrochloric acid (0.5 mi) is added and the resulting solution stirred for 1 hour. The solvents are removed under reduced pressure and the residue is treated with dichloromethane (100 m]) to 30 precipitate sodium chloride. After filtration, the solvent is removed under reduced pressure and the residue chromatographed on silica gel (30 g). Elution with ethyl acetate/methanollacetic acid (90:10:0.2) gives 1 -benzy[oxycarbonyl methyl-3-(1 -ca rboxy-3-phenyl pro pyl a mi no)-2,3, 4,5-tetrahydro-1 W[11benzazepin-2-one as an oil; NIVIR(C13C13) 6 7.35 (m,14H), 5.1 0(s,2H), 4.60(m,2H), 3.00(m, 12H).

EXAMPLE 3 1-Benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3phenylpropylamino)-2,3,4,5-t etrahydro-1H[llbenzazepin-2-one Asolution of 1-benzy[oxycarbonyimethyi-3-(1-carboxy-3-phenylpropylamino)2,3,4,5-tetrahyd ro-1H- [1]benzazepin-2-one (0.364g, 0.00075 mol), sodium bicarbonate (0.190 g, 0. 0022 mol), and ethyl iodide (0.315 40 g, 0.002 mol) in dimethylacetamide (15 m]) is stirred at room temperature under nitrogen for 72 hours. The reaction mixture is filtered and evaporated under reduced pressure. Water (100 mi) is added, and the resulting solution extracted with dichloromethane (4 x 50 mi). The combined extracts are dried over sodium sulfate and the solvent removed under reduced pressure to give the diester as an oil. This material is separated by high pressure liquid chromatography into three fractions, using ethyl acetate/toluene (30:70) as 45 solvent. The first fraction yields isomer A of the title compound as an oil; the second fraction contains a mixture or isomers A and B and the third fraction yields isomer B of the title compound. Using high pressure liquid chromatography on a reverse phase column (solvent system: methanol, water (3: 1) containing 0.025 % acetic acid) isomer A moves more slowly than isomer B. EXAMPLE4 1-Carboxymethy-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydro- 1H-[llbenzazepin-2-one (higher melting isomer) A solution of 1 -benzyf oxyca rbo nyl methyl -3-(1 -eth oxyca rbo nyl -3- p h enyl pro pyl am in o)-2,3,4,5-tetra hyd ro- 1 H-[1 Ibenzazepin-2-one (isomer B of example 3, 0.9 g) in ethanol (150 m[) is hydrogenated at room temperature and atmospheric pressure, using 10 % palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen has ceased, the catalyst is filtered off, and the solvent removed under reduced pressure to give a solid. This material is triturated with ether (8 m[) to give the title compound melting at 138-140' and identical to the compound obtained in Example 1.

EXAMPLE 5 I-Carboxymethyl-3-(1-ethoxycarbonyl3phenylpropylamino)-2,3,4,5tetrahydro- 1H-[llbenzazepin-2-one (lower melting isomer) Asolution of 1 -benzyl oxyca rbo nyl methyl -3-(1 -eth oxyca rbo nyl-3- phenyl propyl am in o)-2,3,4,5-tetra hyd ro- 1 H-[1 Ibenzazepin-2-one (isomer A of example 3; 1.2 g) in ethanol (125 mi) is hydrogenated at room 19 GB 2 103 614 A 19 temperature and atmospheric pressure, using 10 % palladium on charcoal (0. 5 g) as catalyst. After uptake of hydrogen ceases, the catalyst is filtered off, and the solvent removed under reduced pressure to give a solid. This material is triturated with ether (8 mi) to give 1carboxymethy]-3-(1-ethoxycarbonyi-3phenyl propylamino)-2,3,4,5-tetrahydro1 H-[1 Ibenzazepin-2-one melting at 126-129', and being the lower 5 melting racemic isomer A.

Using high pressure liquid chromatography on a reverse phase column [solvent system: methanol, water (3:1) containing 0.025 % acetic acid] isomer A moves more slowly than higher melting racemic isomer B of Example 1.

EXAMPLE 6

1-Benzyloxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4, 5-t etrahydro- 1 [llbenzazepin-2-one A solution of 3-(11 -ethoxycarbonyi-3-phenylproplamino)-2,3,4,5- tetrahydro-1 H-[1 Ibenzazepin-2-one (5.0 g), in dry dimethylformamide (20 mi) is added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60 % mineral oil dispersion (0.6 g) by washing with petroleum ether (3 x 75 m])] 15 in dry dimethy[formamide (85 mi) to which tetrabutylammonium bromide (4.4 9) has been added. The reaction mixture is stirred at room temperature for 30 minutes, then a solution of benzyl bromoacetate (3.2 g) in dry dimethylformamide (10 mi) is added. The reaction mixture is stirred for an additional 30 minutes at room temperature. heated to 60', and maintained at that temperature for 18 hours. The reaction mixture is cooled to room temperature, and the solvent removed under high vacuum. Water (150 mi) is added, and the 20 resulting solution extracted with ethyl acetate (2 x 250 mi). The combined ethyl acetate extracts are washed with water (100 mi), dried over magnesium sulfate. and the solvent removed under reduced pressure to give a brown oil. This material is chromatographed on silica gel (150 g). Elution with toluenelethyl acetate (3: 1) first gives isomerA of 1-benzyioxycarbonyimethy]-3-(1-ethoxycarbonyl-3phenylpropylamino)-2,3,4,5- tetrahydro-1 W[1]benzazepin-2-one followed by isomer B. Isomer A and B are identical to compounds of 25 Example 3 as determined by high pressure liquid chromatography on a reverse phase column (solvent system: methanol, water (3: 1) containing 0.025 % acetic acid).

The starting material is prepared as follows:

A solution of diethyl acetamidomalonate (33.2 g) in ethanol (150 mi) is added to a solution of sodium ethoxide in ethanol [prepared from sodium (3.8 g) and ethanol (200 mi)l. The reaction mixture is stirred at 30 room temperature for 30 minutes and a solution of 2-nitrophenethyl bromide Q. Med. Chem. 20,1020 (1977), 40.0 g) in ethanol (100 mi) is added dropwise during 20 minutes. After addition is complete, the reaction mixture is refluxed for 18 hours. then cooled to room temperature and evaporated under reduced pressure.

The residue is dissolved in water (350 m[) and the solution extracted with ethyl acetate (2 X 350 mi). The combined ethyl acetate extracts are washed with water (200 m]) and dried over magnesium sulfate. Removal 35 of the solvent under reduced pressure gives diethyl 2-acetamido-2-(onitrophenethyi)-malonate as a low melting solid, used withoutfurther purification forthe next synthetic step.

A solution of diethyl 2-acetamido-2-(o-nitrophenethyi)-malonate (80 g) in 3N hydrochloric acid (900 m]) is refluxed for 12 hours. The solution is cooled and extracted with ethyl acetate (200 mi). The aqueous solution is filtered, and evaporated to dryness under reduced pressure. The residue is recrystallized from ethanollether to give 2-amino-4-(2nitrophenyi)butyric acid hydrochloride, m.p. 219-221' (decomposition).

A solution of 2-amino-4-(2-nitrophenyl)buryric acid hydrochloride (38.0 g) in 10 % ethanolic hydrogen chloride (1200 mi) is refluxed with stirring for 18 hours. The reaction mixture is evaporated to dryness under reduced pressure. water (250 mi) is added, and the aqueous solution made basic by the addition of 2N sodium hydroxide. The solution is extracted with dichloromethane (2 x 500 mi), and the combined dichloromethane solutions washed with water (2 X 150 mi), and dried over anhydrous magnesium sulfate.

Evaporation gives ethyl 2-amino-4-(2-nitrophenyl)butyrate, used without further purification forthe next synthetic step.

A solution of ethyl 2-amino-4-(2-nitrophenyi)butyrate (27 9) in ethanol (600 m]) is hydrogenated at room temperature and atmospheric pressure, using 10 % palladium on charcoal (2. 5 g) as catalyst, until hydrogen 50 uptake ceases. The catalyst is filtered off and evaporation to dryness gives ethyl 2-amino-4-(2 aminophenyl)butyrate used without purification for the next synthetic step.

A solution of ethyl 2-amino-4-(2-aminophenyi)butyrate (35.0 g) in methanol (100 m]) is added to a solution of sodium methoxide in methanol [prepared from sodium (1.0 g) and methanol (400 m])] with stirring, under a nitrogen atmosphere. The reaction mixture is refluxed for 65 hours and evaporated under reduced pressure. The residue is distributed between water (100 mi) and dichloromethane (400 mi). The aqueous solution is extracted with dichloromethane (400 mO, and the combined organic solutions washed with water (100 mi) and dried over magnesium sulfate. Evaporation to dryness and trituration with ether (250 m]) gives 3-amino-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p. 161-162'.

Alternatively, a solution of 2-amino-4-(2-nitrophenyl)-butyric acid hydrochloride (2.5 g) in water (200 mi) is 60 hydrogenated at room temperature and atmospheric pressure, using 10 % Pd- C (0.5 g) as catalyst. After uptake of hydrogen ceases, the catalyst is filtered off, and the filtrate evaporated to dryness. The residue is dissolved in water (50 m[) and the pH adjusted to 7 by the addition of 10 % sodium hydroxide. The solid is filtered off, washed with water, and dried to give 2-amino-4-(2- aminophenyl)butyric acid. A solution of the 2-amino-4-(2-aminophenyi)butyric acid (1.09), hexamethyldisilazane (5.4g), and chlorotrimethylsilane (0.165 GB 2 103 614 A g) in xylene (125 mi) is refluxed for 65 hours. The reaction mixture is cooled, poured into ethanol (200 m[) and evaporated under reduced pressure. Water (100 mi) is added, and the solution extracted with dichloromethane (2 x 125 mi). The combined dichloromethane solutions are washed with water (50 mi), dried over magnesium sulfate, and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1 H5 [1 Ibenzazepin-2-one as above.

3-Amino-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one is also prepared as follows:

To a solution of 3-azido-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (see Example 1) (27 g) in ethanol (3500 mi) while stirring at room temperature under an atmosphere of nitrogen, a suspension of Raney nickel in water (50 mi, washed with 10 volumes of ethanol) is added. The mixture is stirred at room temperature for 2 hours when an additional 30 mi of Raney nickel suspension is added. After stirring for an additional 30 minutes, the catalyst is filtered off and the solvent removed under reduced pressure to give an oil which solidifies on addition of ether to give 3-amino-2,3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one, melting at 161-1620.

A solution of 3-amino-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (8.0 g) and benzylpyruvic acid (18.0 9) in methanol (450 mi) is stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride 15 (4.5 g) is added, and the resulting solution stirred at room temperature for 48 hours. Concentrated hydrochloric acid (7 m[) was added dropwise during 10 minutes and stirring is maintained for an additional 1 hour. The reaction mixture is evaporated to dryness, dichloromethane (150 mi) is added, and the mixture stirred for 30 minutes. The solid is filtered off, stirred with water (100 mO for 15 minutes, then filtered, washed with water (50 mi), and dried to give 3-(1 -carboxy-3phenylpropylamino)-2,3,4,5-tetrahydro-1 H- [1 Ibenzazepin-2-one, m.p. 173-175' as a mixture of isomers.

A solution of 3-0 -carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (6.0 g), sodium bicarbonate (4.0 g), and ethyl iodide (11.6 g) in dimethylacetamide (200 mi) is stirred at room temperature under nitrogen for 72 hours. The reaction mixture is filtered and evaporated under high vacuum. Water (250 mi) is added, and the resulting solution extracted with dichforomethane (2 x 400 m[). 25 The combined extracts are dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-(1-ethoxycarbonyi-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H[llbenzazepin -2-one as a mixture of isomers. NIVIR(CIDC13) 6 9.22(s, 1 H), 4.10(2 superimposed quartets, 21-1), 1.13(2 superimposed triplets, 3H).

EXAMPLE 7

1-Benzyloxycarbonylmethyl-3(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3 4,5-tetrahydro-1H [llbenzazepin-2-one A solution of 3-(1-benzyioxycarbonyi-3-phenylpropylamino)-2,3,4,5tetrahydro-1H-[1]benzaze pin-2-one (4.0 g) in dry climethylformamide is added under a nitrogen atmosphere to a stirred suspension of sodium hydride [from the 60 % mineral oil dispersion (0.42 g) washed with petroleum ether (3 x 80 mi)l in dry 35 dimethylformamicle (100 mi) at room temperature to which tetrabutylammonium bromide (3.1 g) has been added. Stirring is continued for an additional 30 minutes at room temperature, when a solution of benzyi bromoacetate (2.2 g) in dry dimethylformamide (10 mi) is added. After an additional 30 minutes at room temperature, the reaction mixture is heated to 50', and maintained at that temperature for 18 hours. The reaction mixture is cooled to room temperature, and the solvent removed under high vacuum. Water (150 40 mi) is added and the solution extracted with ethyl acetate (2 x 300 mi). The combined ethyl acetate solutions are washed with water (100 mi), dried over magnesium sulfate, and the solvent removed under reduced pressure to give a brown oil which is chromatographed on silica gel (250 g). Elution with toluene/ethyl acetate (1: 1, 600 mi) gives an oil, characterized as isomer A of the title compound; NIVIR (CIDC13) 6 5.12(s, 4H), 4.50(q, 2H). Elution with an additional 2000 mi of the solvent mixture gives an oil characterized as isomer B of 45 the title compound; N MR(CIDC13) 6 5.17(s, 2H), 5.03(d, 2H), 4.60(q, 21- 1).

The starting material is prepared as follows:

A solution of 3-(1 -carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1 H[1 Ibenzazepin-2-one (as described in Example 6,13.0 g), sodium bicarbonate (10.0 g), and benzyl bromide (19. 0 g) in dimethylacetamide (750 mi) is stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture is filtered 50 and evaporated under high vacuum. Water (150 mi) is added, and the resulting solution extracted with dichloromethane (2 x 400 m[). The combined extracts are washed with water (100 mi), dried over magnesium sulfate and evaporated under reduced pressure to give the crude benzyi ester. Recrystallization from ethyl acetate gives 3-(1 -benzyloxyca rbonyl-3-phenyl pro pyla mi no)-2,3,4,5tetra hyd ro-1 H-[1 Ibenzazepin- 2-one, m.p. 139-141'.

EXAMPLE 8

1-Carboxymethyl-3-(1carboxy-3phenylpropyjamino)2,3,4,5-tetrahydro-1H-[llb enzazepin2-one (lower melting isomer) Asoltuion of 1-benzyioxycarbonyimethyi-3-(1-benzyioxycarbony]-3phenylpropylamino)-2,3,4, 5- tetrahydro-1 H-[1 Ibenzazepin-2-one (isomer A of example 7, 2.7 g) in ethanol (800 mi) is hydrogenated at room temperature and atmospheric pressure, using 10 % palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen has terminated, the catalyst is filtered off, and the solvent removed under reduced pressure to give the title diacid, characterized as isomer A, m.p. 256- 259'.

The identical compound is obtained on hydrolysis of the compound of Example 5.

21 GB 2 103 614 A 21 EXAMPLE 9 I-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5- tetrahydro1H-[llbenzazepin-2-one (higher melting isomer) A solution of 1-benzyloxycarbonyimethyi-3-(1-benzyioxycarbonyl-3phenylpropyiamino)-2,3,4, 5- tetrahydro-1 H-[1 Ibenzazepin-2-one (isomer B of Example 7, 5.0 g) in ethanol (950 m[) is hydrogenated at room temperature and atmospheric pressure, using palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen has terminated, the catalyst is filtered off, and the solvent removed under reduced pressure to give the title diacid, characterized as isomer B, m.p. 280-282'.

The identical compound is obtained on hydrolysis of the compound of Example 1 (isomer B) or compound 10 of Example 10 (isomer B).

EXAMPLE 10

1-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetr ahydro-1H-[llbenzazepin-2one A solution of 3-(1 -ethoxyca rbonyi-3-phenyl pro pyl am i no)-2,3,4,5- tetra hydro-1 H-[1]benzazepin-2-one (see 15 Example 6,10 g) in dry dimethylformamide (10 mi) is added dropwise during 10 minutes to a stirred suspension of sodium hydride [from the 60 % mineral oil dispersion (0.36 g) washed with petroleum ether (3 x 75mffi in dry dimethylformamide (100 m]) at room temperature under nitrogen. Stirring is maintained for an additional 30 minutes, a solution of ethyl bromoacetate (1.4 g) in dimethy[formamide (15 m[) is added and the reaction mixture is maintained at 600 for 48 hours. After the reaction mixture is cooled to room temperature, the solvent is removed under high vacuum. Water (100 m]) is added, and the solution extracted with ethyl acetate (2 X 200 mi). The combined ethyl acetate solutions are washed with water (50 mi), dried over magnesium sulfate, and the solvent removed under reduced pressure to give a yellow oil (3.8 g). This material is chromatographed on silica gel (120 g). Elution with toluene/ethyl acetate (1:1; 250 m]) gives isomer A of the desired product. Elution with an additional 250 m[ of solvent mixture gives an oil which 25 contains mostly isomer B and some isomerA of the desired product as determined by analytical high pressure liquid chromatography (see Example 6). Elution with a further 250 mi of solvent mixture gives an oil which is essentially pure isomer B (slower moving). This material is dissolved in methanol (25 mi) and converted to the maleate salt by addition of an equimolar quantity of maleic acid in methanol. Evaporation of the solvent and recrystallization of the residue from methanol/ether yields pure isomer B of 1 ethoxyca rbonyl methyl-3-(1 -ethoxyca rbonyl-3-ph enyl pro pyla m i no)-2, 3,4,5-tetra hyd ro-1 H-[ 11 benzazepi n-2 one as the maleate salt melting at 114-116'.

EXAMPLE 11

1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro- 1H-[ljbenzazepin2-one A solution of 1 -benzyi oxyca rbo nyl methy-3-benzy] oxyca rbo nyl methyl a mi no-2,3,4,5-tetra hyd ro-1 H [1 Ibenzazepin-2-one (4.8 g; 0.01 mol) in ethanol (550 mi) is hydrogenated at room temperature and atmospheric pressure using 5 % Pd-C (0.85 g) as catalyst until uptake of hydrogen ceases. Water (300 mi) is added, the catalyst filtered off, and the solvent removed under reduced pressure. The residue is triturated with ether to give the title diacid, m.p. 232-236'.

The starting material is prepared as follows:

A solution of 3-amino-2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one (5.0 g, 0.028 mol) in dimethylformamide (100 mO is added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the % mineral oil dispersion (1.2 g) by washing with petroleum ether (3 x 150 mi)l in dimethylformamide (400 mi) to which tetrabutylammonium bromide (10.9 g, 0.031 mol) has been added. The reaction mixture is 45 maintained at 50'for 15 minutes, then a solution of benzyl bromoacetate (72. g, 0.031 mol) in dimethylformamide (25 mi) is added. The reaction mixture is stirred for an additional 18 hours at 500, then cooled to room temperature, and the dimethylformamide removed under high vacuum. The residue is stirred with tolueneldichloromethane (1: 1, 500 m]) to precipitate inorganic salts. After filtration, the solution is evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 50 0-15 % ethyl acetate in toluene gives 1 -benzy[oxycarbonyl methyl-3- benzyloxycarbonyl methyl am i no-2,3,4,5 tetrahydro-1 H-[llbenzazepin-2-one as the firstfraction. Further elution gives 3-benzyloxycarbonylamino 2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one, m.p. 124-127'and 3-amino-l- benzy[oxycarbonyimethyi-2,3,4,5- tetrahydro-1 H-[1 Ibenzazepin-2-one (see Example 1).

EXAMPLE 12

1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydr o- 1H-[llbenzazepin-2one 3(S)-Amino-1 -carboxymethyi-2,3,4,5-tetrahyd ro-1 H-[1 1 benzazepin-2-one when treated with ethyl benzyi pyruvate in the presence of sodium cyanoborohydride by the procedure described in Example 1 for the racemic compound gives after purification 1 -carboxymethyl-3S-(1 S- ethoxycarbonyl-3-phenyl propylamino)- 60 2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, as described below.

A solution of sodiu m hyroxide (2.1 g) in water (5 m]) is added to a solution of 3(S)-amino-1 - ethoxycarbonyimethyl-2,3,4,5-tetrahydro-1 H-[1 1 benzazepin-2-one (14.0 g) in methanol (150 mi) at room temperature, and the solution is stirred for two hours. The solvents are evaporated and the residue is thoroughly dried, then slurried with ether, to give 3(S)-amino-l- carboxymethy]-2,3,4,5-tetrahydro-1 H- 65 22 GB 2 103 614 A 22 [l l benzazepin-2-one sod iu m salt. This is used without further purification.

A solution of the above sod iu m sa It (12.9 g) and ethyl benzylpyruvate (31 g) in acetic acid (100 m l) and methanol (75 mi) is stirred at room temperature under a dry nitrogen atmosphere for one hour. A solution of sodium cyanoborohydride (3,8 g) in methanol (30 m[) is then added dropwise over a 4 hour period. The combined solutions are stirred overnight at room temperature. Concentrated hydrochloric acid (10 mi) is added dropwise and the mixture stirred at room temperature for 1 hour followed by the evaporation of solvents. The residue is partitioned between water (400 mi) and ether (100 mi) and the pH adjusted to 9.3 with 40 % sodium hydroxide. The layers are separated and the ether layer is discarded. The aqueous layer is adjusted to p11 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 100 mi). The organic phases are combined, dried (magnesium su [fate), and evaporated. Hydrogen chloride gas is bubbled 1 through a solution of the crude product in methylene chloride (150 mi) for 5 minutes. The solvent is evaporated and the resulting foam is dissolved in hot methyl ethyl ketone (100 m]). The solid which precipitated is collected by filtration to give a 95:5 diastereomeric mixture as determined by high pressure liquid chromatography. The product is recrystallized from 3- pentanone/methanol (10: 1) to give l carboxymethy]-3(S)-(1(S)-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahy dro-1H-[1]benzazepin-2-one 15 hydrochloride, m.p. 188-190', ICCID = -141.0' (c=0.9 in ethanol), of formula lla wherein C,H2n is ethylene, R6 is ethoxy, R7 is hydroxy and R13 is phenyl.

A solution of the above hydrochloride salt (0.035 g) and propylene oxide (0.5 mi) in ethanol (4 mi) is stirred under nitrogen overnight at room temperature. The solution is evaporated to dryness. Ether (2 mi) is added, and the solid filtered off to give 1 -ca rboxym ethyl -3S-0 S-ethoxyca rbo nyl -3-p he nyl pro pyl am i no)-2,3,4,5- 20 tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p. 148-149', ICCID = -159' (c = 1. 2 in ethanol).

The optically active starting material is prepared as indicated below.

a) A solution of 0.4 g of 3(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro1 H-[llbenzazepin-2,5-dione [prepared from L-kynurenine as described in Australian J. Chemistry Vol. 33, 633-40 (1980)1, and ethyl bromoacetate (0.23 g) in dry tetrahydrofuran (30 ml) is stirred at 0' under a dry nitrogen atmosphere.

Potassium t-butoxide (0.254 g) is added in one portion. After 1 hour at 0', an additional quantity of ethyl bromoacetate (0.23 g) is added and the reaction mixture is stirred at O'for a further 1 hour. Water (100 m]) is added and the mixture is extracted with ethyl acetate (2 x 50 m]). The combined ethyl acetate solutions are washed with water (100 mi) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives a yellow gum which on trituration with ether/petroleum ether (bp 30-60') gives 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyimethy]-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2,5-dione, m.p.

86-88', 1(X1D = -203' (c = 1 in climethylformamide).

A solution of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyimethyl-2,3,4,5tetrahydro-1 H-[llbenzazepin 2,5-clione (0.14 g) and sodium borohydride (7 mg) in ethanol (10 mO is stirred at room temperature for 18 hours. The ethanol is removed under reduced pressure, and the residue dissolved in dichloromethane (25 35 mi). The solution is extracted with 2N hydrochloric acid (2 x 20 mi) and saturated aqueous sodium chloride solution (20 mi), and dried over sodium sulfate. The solvent is removed under reduced pressure, and the residue triturated with ether to give 3(S)-t-butyloxycarbonylamino-1 - ethoxycarbonyimethyl-5-hydroxy2,3,4,5-tetrahydro-1 W[1]benzazepin-2-one, m.p. 167-169.5', 1a1D = -193' (c = 0.52 in climethylformamicle).

The substance is also obtained by hydrogenation of the benzazepin-2,5dione derivative with H2/Pt in 40 ethanol.

* A mixture of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyimethyi-5hydroxy-2,3,4,5-tetrah ydro-1 H [1 Ibenzazepin-2-one (0.076 g), dicyclohexylcarbodiimide (0.064 9) and cuprous chloride (7 mg) is heated at 60' under nitrogen for 32 hours. The reaction mixture is allowed to cool to room temperature. The residue is dissolved in methylene chloride (50 m[) and washed with dilute ammonium hydroxide (2 x 15 mi) followed 45 by water (20 mi). The organic phase is dried over sodium sulfate and evaporated to give a mixture of the desired adduct and excess dicyclohexylcarbodiimide.

This mixture (0.100 g) is dissolved in ethyl acetate (40 m[) and placed in a pressure bottle. 10 % Pd/C (0.010 g) is added and the mixture is hydrogenated at 3 atmospheres pressure and at 40'for 16 hours. The catalyst is filtered off and the filtrate evaporated. The residue is triturated with ether, and the ether solution evaporated to give 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyimethyl-2, 3,4,5-tetrahydro-1 H [1 lbenzazepin-2-one, m.p. 11 5-116.5o, MD = - 182' (c = 2.6 in dimethylformamicle).

b) Tartaric acid (12.6 g) and racemic3-amino-l-ethoxycarbonyimethyl-2,3,4, 5-tetrahydro-1H- [1 Ibenzazepin-2-one (22 g) are dissolved in hot ethanol (200 m]). This solution is cooled and allowed to stand overnight at room temperature. The solid which precipitates is collected by filtration and recrystallized twice 55 from ethanol (200 mi) to give 3(S)-amino-1 -eth oxyca rbo nyl methyl -2,3, 4,5-tetra hyd ro- 1 W[1 Ibenzazepin-2 one tartrate salt. This is dissolved in water (100 mi) and the pH adjusted to 9 with dilute ammonium hydroxide and extracted with methylene chloride (2 X 50 mi). The combined extracts are washed with water (75 mi), dried(magnesium sulfate) and evaporated to give 3(S)-amino-1 ethoxycarbonyimethyi-2,3,4,5 tetrahydro-1 W[1]benzazepin-2-one, m.p. 104-106', 10.1D = -285.5' (c = 0. 99 in ethanol).

c) Hydrogen chloride gas is bubbled through a solution of 3(S)-tbutyloxycarbonylamino-l ethoxycarbonylmethyi-2,3,4,5-tetrahydro-1H-[11benzazepin-2-one (under a) above, 0.225 9) in ethyl acetate (25 mi) for 45 minutes. Nitrogen is then bubbled through this solution for 30 minutes. The ethyl acetate is washed with water (30 m[) and 1 N hydrochloric acid (30 mi). The ethyl acetate layer is discarded and the aqueous phases are combined. The aqueous solution is adjusted to pH 9 with dilute ammonium hydroxide, 65 23 GB 2 103 614 A 23 extracted with ethyl acetate (3 x 50 m]); the organic phases are combined, dried (sodium sulfate) and evaporated to give 3(S)-amino-l-ethoxycarbonyimethyi-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p.

101-102', laID = -298' (c = 0.46 in ethanol).

Treatment with ethanedithiol/boron trifluoride etherate or trifluoroacetic acid/anisole to remove the protecting group yields 3(S)-amino-1 -ethoxycarbonyimethy]-2,3,4,5- tetrahydro-1 W[11benzazepin-2-one.

Alternately 3(S)-amino-1 -ethoxycarbonyimethy]-2,3,4,5-tetrahydro-1 W[1]benzazepin-2-one is also pre pared as follows:

d) A solution of 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyimethyi-5hydroxy-2,3,4,5-tetrah ydro-1 H [llbenzazepin-2-one (previously described, 1.0 g) in acetic anhydride (20 mi) is maintained at80'for3 hours.

The reaction mixture is cooled to room temperature and the solvents are removed under reduced pressure.

Ether (100 mi) is added, and the resulting solution washed with water (50 mi) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 5-acetoxy- 3(S)-t-butyloxycarbonylamino-1 ethoxycarbonyimethyi-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one as a pale yellow oil which is used without further purification.

A solution of 5-acetoxy-3(S)-t-butyloxycarbonylamino-lethoxycarbonyimethyi-2,3,4,5-tetrah ydro-1 H [1 Ibenzazepin-2-one (0.7 g) in ethanol (50 mi) is hydrogenated at 2.9 atmospheres for 24 hours at 70o using 10 % palladium on charcoal (0.5 g) as catalyst. The catalyst is filtered off and the solvent removed under reduced pressure to give 3(S)-t-butyloxycarbonylamino-l- ethoxycarbonyimethyi-2,3,4,5-tetrahydro-1 H [1 Ibenzazepin-2-one which, without further purification is converted to 3(S)-am ino-1 -ethoxyca rbonyl methyl 2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one by the procedure described above; M.P. 99-101', [U1D = -297' (c 20 = 1 in ethanol).

e) A solution of 3(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H[llbenzazepin-2,5-dione (12.5 9) pre pared from L-kynurenine as described in Australian J. Chemistry Vol. 33, 633-40 (1980), and t-butyl bromoacetate (10.1 g) in acetone (700 m]) is stirred at room temperature under a dry nitrogen atmosphere.

Potassium carbonate (12.5 g) is added in one portion and the resulting suspension is stirred at room temperature for 16 hours. The potassium salts are filtered off and the filtrate evaporated to dryness. The residue is partitioned between ethyl acetate (250 m]) and water (250 m[). The layers are separated and the organic phase is dried (sodium sulfate). The residue is triturated with petroleum ether (350 m]; bp 30-60') to give 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethyi-2,3,4,5tetrahydro-1 W[11benzazepin-2,5 dione, m.p. 75-77', IUID = -172' (c = 0.96 in dimethylformamide).

A solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethy]-2,3, 4,5-tetrahydro-1 H [1 Ibenzazepin-2,5-dione (8.0 g) in ethanol (500 mi) containing platinum oxide (800 mg) is hydrogenated at atmospheric pressure and at room temperature for two hours. The catalyst is filtered off and the filtrate evaporated to give 3(S)-t-butyloxycarbonylamino-l-tbutyloxycarbonyimethyi-5-hydroxy-2,3,4,5-te trahydro- 1 W[1]benzazepin-2-one, 1(X1D = -173o (c = 1.8 in dimethy[formamide).

A suspension of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethyl-5hydroxy-2,3,4,5-te trahydro- 1 H-[llbenzazepin-2-one (3.0 g), dicyclohexylcarbodiimide (5.0 g), and cuprous chloride (500 mg) is mechanically stirred and heated at 80'for 16 hours under a dry nitrogen atmosphere. The mixture is cooled, diluted with methylene chloride (100 mi), and filtered. The solids are discarded. The filtrate is washed with 7 % ammonium hydroxide (4 X 75 mi), followed by 1 x 100 mi with water and saturated aqueous sodium chloride solution (100 m]). The organic phase is dried (sodium sulfate) and evaporated to give a mixture of the desired adduct and excess dicyciohexylcarbodiimide.

This mixture (5.5 g) is dissolved in ethyl acetate (200 mi) and placed in a pressure bottle. 10 % Pd/C (3.0 g) is added and the mixture is hydrogenated at 3 atmospheres pressure and at 40'for 16 hours. The catalyst is filtered off and the filtrate evaporated. The residue is triturated with ether (75 mi) to give a white solid, 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethyi-2,3,4,5tetrahydro-1 H-[1]benzazepin-2-one, m.p.

145-147', laID = - 194' (c = 0.46 in dimethy[formamide).

A solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethyl-5hydroxy-2,3,4,5-te trahydro-1H- [1 Ibenzazepin-2-one (described above, 3.0 g) in acetic anhydride (50 m]) is heated at 80' under a dry nitrogen atmosphere for 2 hours. The acetic anhydride is evaporated. The residue is dissolved in ethyl acetate (75 mi) 50 and washed with saturated aqueous sodium bicarbonate solution (50 m]), water (50 mi), and saturated aqueous sodium chloride solution (50 mi). The organic phase is dried (sodium sulfate), evaporated, and the residue triturated with ether (50 m[) to give 3(S)-t- butyloxycarbonylamino-l-t-butyloxycarbonyimethy]-5acetoxy-2,3,4,5-tetrahydro-1 W[1]benzazepin-2-one, m.p. 164-166.5', laID = -169' (c = 0.36 in dimethylfor mamide).

A solution of 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyimethyi-5acetoxy-2,3,4,5-te trahydro-1 H [1]benzazepin-2-one (2.2 g) in ethanol (300 mi) containing 10 % Pd/C (2.0 g) is placed in a pressure bottle and hydrogenated at 3 atmospheres pressure and 70'for 3 days. The catalyst is filtered off and the filtrate evaporated to give 3(S)-t-butyloxycarbonylamino-l-tbutyloxycarbonyimethyi-2,3,4,5-tetrahydro-1 H- [Ilbenzazepin-2-one, m.p. 164-165', laID = -200.6' (c = 0.64 in dimethylformamide).

Hydrogen chloride gas is bubbled through a solution of 3(S)-tbutyloxycarbonylamino-l-tbutyloxycarbonyimethyi-2,3,4,5-tetrahydro-1 H[llbenzazepin-2-one (0.85 9) in ethyl acetate (40 m]) for 2 hours. Nitrogen is then bubbled through the solution for 0.5 hour. The ethyl acetate is evaporated and the white solid residue immediately dissolved in ethanol (40 m]). Propylene oxide (5 mi) is added and the mixture is stirred at room temperature for 16 hours. The white solid which precipitates is collected by 24 GB 2 103 614 A 24 filtration to give 3(S)-a m ino-l-carboxym ethyl -2,3,4,5-tetrahydro-1H- [l I benzazepin-2-one, m.p. 275-276', [a]D = -287' (c = 0.71, in 1 N hydrochloric acid) which is condensed with ethyl benzylpyruvate in the presence of sodium cyanoborohyd ride as described above.

EXAMPLE 13

1-Carboxymethyl-3-(1-carboxy-3-phenylpropylamino)-5-hydroxy-2,3,4,5tetrahyd ro- 1H-fllbenzazepin-2-one To a solution of 1 -benzyloxycarbonyl methyl-3-(1 -carboxy-3- phenylpropylamino)-2,5-dihydro-1 H[1 Ibenzazepin-2,5-dione (1.00 g) in glacial acetic acid (50 m]) is added platinum oxide (0.10 g). The resulting mixture contained in a pressure bottle is hydrogenated at 2.9 atmospheres for 5 hours. The catalyst is removed by filtration, the filtrate concentrated, and the resulting oil triturated with anhydrous ethanol. The 10 resulting solid is collected, dried, and suspended in water (10 mi). The suspension is stirred for 1.5 hours. The solid is collected and dried to give impure 1 -carboxymethyi-3-(1-carboxy-3-phenylpropylamino)-5hydroxy-2, 3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one melting with decomposition at 179'.

The starting material is prepared as follows:

Benzyl bromoacetate (9.16 g, 0.04 mole) is added dropwise to a mixture of 3-methoxy-2,5-dihydro-1 H- 15 [1]benzazepine-2,5-dione [8.13 g, 0.04 mol, prepared as described in the Canadian J. Chem., 52, 610 (1974)l powdered potassium hydroxide (2.24 g, 0.04 mole) and tetrabutylammonium bromide (1.29 g, 0.004 mol) in 1000 mi of acetonitrile with stirring at room temperature. Upon complete addition, the suspension is stirred at room temperature for 64 hours, filtered, and the filtrate concentrated under reduced pressure to give a partially crystalline oil. This oil is triturated with ether to give a solid which is suspended and stirred in ethyl 20 acetate (100 mi) for 1.5 hours. The insoluble material is filtered off and the filtrate concentrated to give the crude 1-benzyloxycarbonyimethyl-3-methoxy-2,5-dihydro-1 H-[11-benzazepin2,5-dione which is used direct ly in the next step.

To a 1.OM solution of potassium t-butoxide (0.64 g, 0.0057 mol) in tbutanol (5.7 ml), while stirring under nitrogen at room temperature is added (+)-homophenylaianine (1.02 g; 0. 0057 mol) in one portion. The 25 resulting suspension and t-butanol (4.3 m[) is heated until most of the suspended solid is dissolved. Upon cooling, a suspension is obtained. This suspension is added, in portions, via pipette to a refluxing solution of 1 -be nzyi oxyca rbo nyl methyl -3-m ethoxy-2,5-d i hyd ro- 1 H-[1 Ibenzazepin-2,5-dione (2.00 g) in t-butanol (40 m]) stirring under nitrogen over a period of 10 minutes. During the addition, a yellow precipitate forms. Upon complete addition, the resulting suspension is refluxed for 3 hours. The suspension is filtered, the resulting 30 gummy solid is washed with petroleum ether and dissolved in water (20 mi). The solution is filtered, acidified to pH 5 with 3N hydrochloric acid, the resulting crude 1 - benzyioxycarbonyimethyl-3-(1-carboxy-3phenyl propyla mino)-2,5-di hyd ro- 1 W[1 Ibenzazepin-2,5-dione is collected and used directly for the preparation of the title compound.

EXAMPLE 14 Analogous to the methods disclosed herein, thefollowing compounds of formula lAwherein X = H2, R2 and R5 = H, R6 = 0C2H5 and R7 = OH are prepared:

No. R, R, R, 40 1 C,H,Cl-1, H H 2 C,H5CH2CH2 7-OCH3 8-OCH3 45 3 C^CH2CH2 7-Cl H 4 C61-1,Cl-12CH2 8-CH, H 5 C^CH2CH2 8-OCH3 H 50 6 P-CIC61-14CH2CH2 H H 7 CH, H H 55 The starting substituted 2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-ones for compounds 2-5 are prepared as follows:

The 7-chloro-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p. 164-165', is prepared as described in British Patent 1,359,285.

The 8-m ethyl -2,3,4,5-tetra hyd ro- 1 W[1]benzazepin-2-one is prepared by the method of Huisgen, Liebigs 60 Ann. Chem. 574,171 (1951), m.p. 153-154'.

The 7,8 dimethoxy-2,3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one is prepared as follows:

A solution of 24 g of 6,7-dimethoxy-a-tetraline [Snider, T. et al, Org. Prep. Proced. Int., 5, 291 (1973)l in ethanol (300 mi) and water (60 m[) is treated at reflux for two hours with hydroxylamine hydrochloride (16 g) and sodium hydroxide (25 g) to form the oxime. The reaction mixture is poured into 500 mi of an ice/water 65 GB 2 103 614 A 25 mixture and extracted with 3 X 300 m] portions of dichloromethane. The combined extracts are washed with mi water, dried over anhydrous magnesium sulfate and evaporated to yield 25 g of the oxime, m.p.

154-1560.

The oxime is redissolved in 170 mi of dichloromethane and 170 mi of polyphosphate ester (Fieser and Fieser: Reagents for Organic Synthesis, Wiley N.Y. 1967, P. 892) was added. The reaction mixture is refluxed 5 for 18 hours. The dichloromethane layer is separated, treated with charcoal and dried over magnesium sulfate to yield the 7,8-dimethoxy-2,3,4,5-tetrahydro-1 H-[1]benzazepin-2- one, m.p. 153-156'.

The 8-methoxy-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one, m.p. 132-134' is similarly prepared from 7 methoxy-a-tetralone.

3-Amino-7-chloro-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one is synthesized as follows:

A solution of 3-amino-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (4.0 g), 2-t-butyloxycarbonyioxyimino-2 phenylacetonitrile (6.1 g) and triethylamine (5 m]) in water (20 mi) and dioxane (25 m]) is stirred at room temperature for 18 hours. The resulting solid is filtered off and washed with water. Recrystallization from ethyl acetate gives 3-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [llbenzazepin-2-one. m.p. 199-2010.

Chlorine gas is bubbled through a solution of 3-t-butyloxycarbonylamino-2, 3,4,5-tetrahydro-1 H [11benzazepin-2-one (1.5 g) in acetic acid (20 mi) for 10 minutes. The reaction mixture is stirred for an additional 10 minutes. The solid which precipitates is collected, suspended in water (30 mi) and aqueous ammonia is added until basic. Filtration gives 3-amino-7-chloro-2,3,4,5- tetrahydro-1H-[llbenzazepin-2-one, m.p. 170-171% EXAMPLE 15:

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

1-Carboxymethyi-3-(1-ethoxycarbonyi-3-phenylpropylamino)-2,3,4,5tetrahydro-l H-[1 Ibenzazepin-2-one Lactose Corn starch Polyethylene glycol 6,000 Talcum powder Magnesium stearate Purified water 100g 1,157 g 75g 75g 75g 189 q.s.

Procedure:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, 40 talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 mi of water and the suspension added to the boiling solution of the polyethylene glycol in mi 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. 45 EXAMPLE 16

Preparation of an injectable formulation containg 25 mg of the active ingredient of Example 1 per 5 m] of solution:

Formula:

1-Carboxymethy]-3-(1 -ethoxycarbony]-3-phenylpropylamino)-2,3,4,5tetrahydro-1 W[1 Ibenzazepin-2-one hydrochloride 25.0 g Propylparaben 1.0 g Water for injection q.s. 5000.0 m[ 60 Procedure:

The active ingredient and preservative are dissolved in 3500 mi of waterfor injection and the solution is diluted to 5000 mi. The solution is filtered through a sterile filter and filled into injection vials under sterile 65 conditions each vial containing 5 m] of the solution.

26 GB 2 103 614 A 26 EXAMPLE 17

Preparation of 10,000 capsules each containing 20 mg of the active ingredient of Example 9.

Formula:

1-Carboxymethyi-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H[llbenzazepin-2-one Lactose Talcum powder g 1,700 g g Procedure All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the talcum, then with the lactose until homogenous. No. 3 capsules 15 are filled with 200 mg; using a capsule filling machine. Analogously, tablets, injectable formulations or capsules are prepared from the remaining compounds of the invention, e.g., those illustrated by the Examples herein.

EXAMPLE 18

1-Carboxymethyl3S-(1R-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydr o- 1H-[llbenzazepin-2-one The methyl ethyl ketone f iltrate f rom the crystallization of 1 - carboxymethyl-3S-(1 S-ethoxycarbonyl-3 phenyl propyla m ino)-2,3,4,5-tetra hyd ro- 1 H-[1 Ibenzazepin-2-one hydrochloride in Example 12 is evaporated, and the residue tritutated with ethyl acetate (50 mi). The resulting solid is distributed between ethyl acetate (100 mO and water (100 mi), and adjusted to pH 4.3 with concentrated hydrochloric acid. The layers are 25 separated and the aqueous phase is extracted with ethyl acetate (2 x 100 mi). The combined ethyl acetate solutions are dried over sodium sulfate and the solvent removed under reduced pressure. The residue is separated into its components by high pressure liquid chromatography with a C18 reverse phase preparative column and using water/methanol Q:7) containing 0.05 % acetic acid as the solvent. An additional quantity of the S,S isomer of Example 12 is thus obtained, as well as the S,R isomer. The material corresponding to 30 the S,R isomer is dissolved in dichloromethane (75 m[), and hydrogen chloride gas bubbled in for five minutes. The solvent is evaporated under reduced pressure and the residue recrystallized from methyl ethyl ketone to give 1 -ca rboxym ethyl -3S-(1 R-ethoxycarbonyl-3phenylpropylamino)-2,3,4,5-tetrahydro-1 H [1 Ibenzazepin-2-one hydrochloride, m.p. 181-183', laID = -188' (c = 0.8 in ethanol).

EXAMPLE 19

1-Carboxymethyl-3S-(1Scarboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro- 1H[llbenzazepin-2-one A solution of sodium hydroxide (0.27 g) in water (2 m 1) is added to a solution of 1 -ca rboxym ethyl -21S-(11 S ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2on e hydrochloride (1 g) in methanol (10 mi). The reaction mixture is stirred for 18 hours at room temperature and the solvents removed 40 under reduced pressure. The residue is dissolved in water (25 mi), and the pH adjusted to 3 by the addition of 4N hydrochloric acid. The resulting solid is filtered off, washed with water, and dried to give 1 -ca rboxym ethyl -3S-(1 S-carboxy-3-phenylpropylamino)-2,3,4,5- tetrahydro-1 H-[1]benzazepin-2-one, m.p.

270-272', 1CLID = -200.5' (c = 1, in 3 % aqueous ammonia).

EXAMPLE 20

1-Ethoxycarbonylmethyl-3-((1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4, 5-t etrahydro- 1H [llbenzazepin-2-one A solution of 3-(1 -benzyioxycarbonyl-3-phenylpropylamino)-2,3,4,5- tetrahydro-1 H-[1]benzazepin-2-one (5.0 g) in dry climethylformamide is added under a nitrogen atmosphere to a stirred suspension of sodium 50 hydride [from the 60 % mineral oil dispersion (0.5 g) washed with petroleum ether (3 x 80 mi)l in dry climethylformamide (100 m]) at room temperature. Stirring is continued for an additional 30 minutes at room temperature, when a solution of ethyl bromoacetate (2.0 g) in dry dimethylformamide (10 m]) is added. After an additional 30 minutes at room temperature the reaction mixture is heated to 50', and maintained at that temperature for 18 hours. The reaction mixture is cooled to room temperature and the solvent removed 55 under high vacuum. Water (150 ml) is added and the solution extracted with ethyl acetate (2 X 300 m]). The combined ethyl acetate solutions are washed with water (100 m]), dried over magnesium sulfate, and the solvent removed under reduced pressure to give a brown oil which is chromatographed on silica gel (250 g).

Elution with toluene/ethyl acetate (9: 1; 600 m[) gives an oil, characterized as isomer A of the title compound.

Elution with an additional 1000 mi of the solvent mixture gives an oil characterized as isomer B of the title 60 compound.

27 GB 2 103 614 A 27 EXAMPLE 21 1-Ethoxycarbonylmethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4, 5-tetrahydro- 1H-[llbenzazepin-2-one 1 -Ethoxycarbonyimethyi-3-(1 benzyloxyca rbonyl-3-phenyl pro pylam i no-2,3,4,5-tetra hydro-1 H[1]benzazepin-2-one (isomer B of Example 20, 1.1. 9) in ethanol (150 mi) is hydrogenated at room temperature and atmospheric pressure using palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen terminates, the catalyst is filtered off, and the solvent removed under reduced pressure to give a semi-solid. Trituration with ether (30 mi) yielded isomer B of the title compound m.p. 175-177% EXAMPLE 22 lo 1-Carboxymethyl-3-(1-ethoxycarbony-3-phenylpropylamino)-8-methoxy-2,3, 4,5-te trahydro- 1H[llbenzazepin-2-one(isomer 8) A solution of 3-amino-1 -carboxymethyi-8-methoxy-2,3,4,5-tetrahydro-1 H- [1 Ibenzazepi n-2-one (4.0 g) and ethyl benzylpyruvate (9.4 g) in a mixture of acetic acid (35 mi) and methanol (35 mi) is stirred for 1 hour. A solution of sodium cyanoborohydride (1.1 g) in methanol (50 m[) is then added slowly over the course of 5 is hours. After stirring an additional 16 hours, concentrated hydrochloric acid (4 mi) is added and stirring is continued for 1 hour. The solvents are removed at reduced pressure and the residue is partitioned between water (75 mO and ether (35 mi). The pH is adjusted to 9.4 and the ether layer is separated and discarded. The aqueous layer is acidified to pH 4.3 and extracted with ethyl acetate (3 X 50 m]). The combined ethyl acetate solutions are dried over magnesium sulfate and the solvent is removed at reduced pressure. Hydrogen chloride gas is bubbled into a solution of the crude product in methylene chloride (100 m]) for 5 minutes. The 20 solution is evaporated and the residue is stirred in ether (75 mi). The product is collected by filtration to give an approximately 70:30 diastereomeric mixture as determined by high pressure liquid chromatography.

The product is recrystallized from 3-pentanone to give 1 -carboxymethyi-8methoxy-3-(1 -ethoxycarbonyl 3-phenylpropyi-amino)-2,3,4,5-tetrahydro-1 W[1]benzazepin-2-one hydrochloride (isomer B) melting at 240 245' (decomposition).

The starting material is prepared as follows: A solution of 8-methoxy-2,3, 4,5-tetrahydro-1 W[1 Ibenzazepin 2-one (7.0 g, described in Example 14) and phosphorus pentachloride (30.0 g) in xylene (200 mi) is heated with stirring under an atmosphere of nitrogen to 90' (oil bath temperature) during 30 minutes with pauses at 300 and at 500. There is a copious evolution of hydrogen chloride gas. The temperature is maintained at 900 for 30 minutes. The reaction mixture is filtered while hot to remove a small amount of suspended solid, and 30 the filtrate is evaporated under reduced pressure until all the solvent is removed. The residue is added with stirring to saturated aqueous sodium carbonate (20 m[). The product is filtered afterthe solidification process is complete, slurried in ethanol (30 mi), washed with ethanol (10 m[) and ether (10 mi) and dried to give 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one, m.p. 148-150'.

A solution of 3,3-dichloro-8-methoxy-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (20g) and anhydrous 35 sodium acetate (13.2 g) in glacial acetic acid (250 mi) is hydrogenated at atmospheric pressure using 10 % Pd/C (1 g) as catalyst, until the uptake of hydrogen ceases. The catalyst is filtered off and the acetic acid is evaporated under reduced pressure. Water (100 mi) is added to the residue and the suspension stirred for 1 hour. The solid is filtered, washed with water (50 mi), and dried to give 3-chloro-8-methoxy-2,3,4,5 tetrahydro-l H-[1 Ibenzazepin-2-one m.p. 162-163'.

A solution of 3-chloro-8-methoxy-2,3,4,5-tetrahydro-1 W[11benzazepin-2one (12.5 9) and sodium azide (4.3 g) in dimethyisuifoxide (150 m[) is maintained at 80' under an atmosphere of nitrogen for 3 hours. The reaction mixture is poured into ice/water (300 m]) and the suspension is stirred for 30 minutes. The solid is filtered off, washed with water (50 m[) and dried to give 3-azido-8- methoxy-2,3,4,5-tetrahydro-1 H [l Ibenzazepin-2-one, m.p. 136-1380.

3-Azido-8-methoxy-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (5g) is added in one portion to a stirred suspension of potassium hydroxide (1.3 9) and tetrabutylammonium bromide (0.7 g) in tetrahydrofuran (50 m]) maintained at 0' under a nitrogen atmosphere. Stirring is continued for 5 minutes, then a solution of ethyl bromoacetate (3.6 g) in tetrahydrofuran (15 mi) is added during 5 minutes. The reaction mixture is allowed to warm to room temperature while stirring for an additional 2 hours. The reaction mixture is filtered 50 and the tetrahydrofuran is removed at reduced pressure. The residue is partitioned between water (50 m]) and ether (100 mi). The organic phase is washed with 2N hydrochloric acid (10 mi), dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-azido-l- ethoxycarbonyimethyi-8- methoxy-2,3,4,5-tetrahydro-1 H-[llbenzazepin-2-one, m.p. 90-91'.

A suspension of 3-azido-l-ethoxycarbonyimethyi-8-methoxy-2,3,4,5tetrahydro-1 H-[1]benzazepin-2-one 55 (13.8 g) in methanol (75 mi) is treated with a solution of sodium hydroxide (1.9 g) in water (75 mi). The reaction mixture is stirred at 40-45'for 2 hours. Water (100 mi) is added and the mixture is acidified with concentrated hydrochloric acid (10 mi) and extracted with methylene chloride (3 x 75 m[). The combined methylene chloride solutions are dried over magnesium sulfate and evaporated at reduced pressure to give 3-azido-l-carboxymethyi-8-methoxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2one, m.p. 145-147'. 60 A solution of 3-azido-l-carboxymethyi-8-methoxy-2,3,4,5-tetrahydro-1H[llbenzazepin-2-one (1 lg) in a mixture of ethanol (250 mO and water (50 m]) is hydrogenated for 3 hours at 3 atmospheres pressure and room temperature using 10 % Pd-C (0.5 g) as catalyst. 2N Hydrochloric acid (50 m]) is added, and the catalyst is filtered off. The solvent is removed at reduced pressure, and the residue dissolved in a mixture of water (50 mO and ethanol (50 mi). Propylene oxide (25 m]) is added and the mixture is stirred for 1 hour. The solvents 65 28 GB 2 103 614 A are removed under reduced pressure to give 3-amino-l-carboxymethyl-8methoxy-2,3,4,5-tetrahydro-1H[11benzazepin-2-one, m.p. >300'.

28 EXAMPLE 23

1-(1-Carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahyd ro- 1H-[llbenzazepin-2-one hydrochloride A solution of 3-amino-1 -(1 -carboxyethyi)-2,3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one hydrochloride (3 g) and ethyl benzy] pyruvate (6.5 g) in acetic acid (30 mi) and methanol (30 mi) is stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.8 g) in methanol (10 m 1) is added over 4 hours. The reaction mixture is stirred at room temperature for 24 hours. Concentrated hydrochloric acid (2 mi) is added and the mixture is 10 stirred for 1 hour. The solvents are removed at reduced pressure and the residue is partitioned between water (50 mi) and ether (30 mi). The pH is adjusted to 9.4, the ether layer is separated and discarded. The aqueous solution is adjusted to pH 4.3 and extracted with ethyl acetate (3 x 50 mi). The combined ethyl acetate solutions are dried over magnesium sulfate and the solvent removed under reduced pressure.

Hydrogen chloride is bubbled into a solution of the crude product in methylene chloride (10 mi) for 2 minutes. The solution is evaporated to give 1-(1-carboxyethyl)-3-(1- ethoxycarbonyi-3-phenylpropylamino)2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one hydrochloride, as a mixture of diastereomers, m.p. 87-94'.

The starting material is prepared as follows: 3-Azido-2,3,4,5-tetrahydro1 W[11benzazepin-2-one (as prepared in Example 1, 5 g) is added in one portion to a stirred suspension of potassium hydroxide (1.8 g) and tetrabutylammonium bromide (0.8 g) in tetrahydrofuran (50 m[) maintained at 0' under a nitrogen 20 atmosphere. Stirring is continued for 5 minutes, then (R)-t-butyl 2- bromopropionate [J.P. Greenstein et al., J.

Am. Chem. Soc. 76, 6054 (1954), H. Niedrich and G. Koller, J. Prakt. Chem. 316, 729 (1974)l (5.2 g) in tetrahydrofuran (15 m[) is added during 5 minutes. The reaction mixture is allowed to warm to room temperature while stirring for an additional 2 hours. The reaction mixture is filtered and the tetrahydrofuran removed at reduced pressure. The residue is partitioned between water (50 mi) and ether (100 mi). The organic phase is washed with 2N hydrochloric acid (10 mi), dried over manganese sulfate, and the solvent evaporated under reduced pressure to give 3-azido-1 -(1 -t- butyloxycarbonylethyl)-2,3,4,5-tetrahydro-1 H [1 Ibenzazepin-2-one as an oil that is used without further purification.

A solution of 3-azido-1 -(1 -t-butyloxycarbonylethyi)-2,3,4,5-tetrahydro1 H-[1 Ibenzazepin-2-one (7g) in etha nol (70 ml) is hydrogenated at 3 atmospheres pressure for 3 hours using 10 % Pd-C (0.5 g) as catalyst. The catalyst is removed by filtration and the ethanol removed under reduced pressure to give 3-amino-l-(1-t butyloxycarbonylethyi)-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one as an oil. High pressure liquid chroma tography (HPLC) indicates that theproduct is an approximately 1: 1 mixture of diastereomers. This material is used without further purification.

A solution of the above 3-amino-1 -0 -t-butyloxycarbonylethyl)-2,3,4,5tetrahydro-1 H-[1 Ibenzazepin-2-one 35 (4.7 g) in trifluoroacetic acid (25 mi) is stirred at room temperature for 1 hour. The trifluoroacetic acid is removed under reduced pressure and the residue dissolved in ether (100 mi). Hydrogen chloride gas is bubbled into the solution until precipitation ceases. The solid is collected by filtration to give 3-amino-1 -(1 -carboxyethyi)-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one hydrochloride, m.p. 165-176'. HPLC indicated that the product is an approximately 1: 1 mixture of diastereomers.

EXAMPLE 24

1-Ethoxycarbonylmethyl-3S-(1S-ethoxycarbonyl-3phenylpropylamino)-2,3,4,5te trahydro- W [llbenzazepin2-one A solution of 3S-am ino-1 -ethoxycarbonyl methyl -2,3,4,5-tetra hyd ro- 1 W[1 Ibenzazepin-2-one (1.5 g), ethyl 45 2-bromo-4-phenylbutyrate (1.6 g), and triethylamine (0.8 mi) in dimethylformamide (37 mi) is stirred under nitrogen for 18 hours at 70'. The dimethylformamide is then removed under reduced pressure. The residue is taken up in ethyl acetate (70 m[), washed with water (5 x 25 mi), dried over magnesium sulfate, and evaoprated. The product mixture is then separated on a silica gel chromatography system with ethyl acetate/hexane (40:60) as solvent to yield about equal quantities of 1ethoxycarbonylmethyl-3S-(1 S ethoxyca rbonyl-3-ph enyl pro pyl am i no)-2,3,4,5-tetra hyd ro-1 H-[1 Ibenzazepin-2-one [NIVIR (CIDC13) 64.52 (cl,2H)l the S,S enantiomer of the compound of Example 10 and its diastereomer, 1 -ethoxycarbonyl methyl 3S-(1 R-ethoxyca rbonyl-3-phenyl pro pyla m ino)-2,3,4,5-tetra hyd ro-1 W[1 Ibenzazepin-2-one; NMR (CIDC13):

64.50 (q, 2H). TILC: (silica gel, ethyl acetate/hexane 40:60): the (S,S) isomer has Rf=0.24 and the (S,R) isomer Rf=0.33.

EXAMPLE 25

1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5tetrahydr o- 1H-[llbenzazepin-2-one 2N Potassium hydroxide (0.26 m[) is added dropwise to a solution of 1 - ethoxycarbonyimethyi-3S-(1 S ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1 W[1 1 benzazepin2-one (0.25 9) in ethanol (5 m]), 60 while stirring at room temperature under a nitrogen atmosphere. After stirring for one hour the ethanol is evaporated and the residue is dissolved in water (5 mi), acidified with 2N hydrochloric acid to pH2 and extracted with ethyl acetate (2 x 30 mi). The combined ethyl acetate solutions are washed with saturated sodium chloride solution (5 mi), dried over magnesium sulfate and evaporated to dryness to yield 1 -ca rboxymethyl-3S-(1 S-etinoxyca rbonyl-3-phenyl pro pyla mi no)-2,3,4, 5-tetra hyd ro-1 W[1 1 benzazepi n-2-one,65 29 the compound of Example 12.

GB 2 103 614 A 29 EXAMPLE 26 1-Carboxymethyl-7-chloro-3-(1-ethoxycarbonyl-3phenylpropylamino)-2,3,4,5-te trahydro- 1H-fllbenzazepin5 2-one, isomer 8 Chlorine is bubbled through a solution of 1-carboxymethyi-3-(1ethoxycarbony]-3-phenylpropylamino)2,3,4,5-tetrahydro-l W[1 Ibenzazepin-2one(isomer B, 1.5 g) in acetic acid (25 mi), with stirring at room temperature. A white solid precipitates out; chlorine is bubbled through the reaction mixture until the reaction is complete. The solid is filtered off and separated by reverse phase HPLC using a C18 column and methanol/0.1 % aqueous ammonium carbonate (1: 1) as solvent. The appropriate fraction is dissolved in methanol/ethyl acetate (1: 1, 50 mi) and hydrogen chloride bubbled through the solution. The solution is evaporated, the residue is suspended in ether (100 mi) and the suspension is filtered to give 1 -carboxymethyi-7-chloro-3-(1 -ethoxyca rbony]-3phenyl pro pyl am i no)-2,3,4,5-tetra hyd ro-1 H-[1 Ibenzazepin2-one hydrochloride, m.p. 149-151'(isomer B).

EXAMPLE 27

1-Carboxymethyl-3S- 1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydro- 1H-[llbenzazepin-2-one hydrochloride 3(S)-Amino-l-carboxymethyi-2,3,4,5-tetrahydro-1 H-[1 lbenzazepin-2-one sodium salt (619 g) having ICCID 25= -304.40 (c=1.08 in water), ethyl benzylpyruvate (1960 g), anhydrous ethyl alcohol (5880 m]) and 20 glacial acetic acid (5880 mi) are combined and stirred at 20-25'for 1.5 hours. A solution of sodium cyanobrohydride (179 g) in anhydrous ethyl alcohol (2200 m[) is added at a constant slow rate over 24 hours.

After addition is complete, the reaction mixture is stirred for 24 hours. 12N Hydrochloric acid (500 mi) is added to the reaction mixture and the solvent is evaporated at 35-40'/3 mm Hq. The oil which remains is combined with ice (3000 g) water (3000 m]) and diethyl ether (3000 mi), and the pH of the mixture is adjusted 25 to 9-9.5 with 1ON sodium hydroxide solution (1735 m]). The aqueous portion is removed and an additional 8000 m] of diethyl ether is added to the ether portion to oil out additional product. The ether immiscible portion is removed and combined with the aqueous portion. The ether extract is then washed with water (2 x 1000 mO, the washes are incorporated with the aqueous/oil portions from above and the mixture is adjusted to pH 4.25-4.35 with 12N hydrochloric acid (550-650 mi). The mixture is extracted with ethyl acetate 30 (3x2000 m]), the combined ethyl acetate portions are washed with water (2000 m]) and dried with anhydrous magnesium sulfate (500 g). The drying agent is removed by filtration and the solvent is thoroughly removed by evaporation at 40'/3 mm Hq. The resulting oil is dissolved in ethyl acetate (4500 mi) and 28 % ethereal hydrogen chloride (309 g) was added with vigorous stirring. Diethyl ether (1500 mi) is added and the mixture is stirred for 1 hour. The solid is collected and is washed with ethyl acetate (2x500 m]) and diethyl ether 35 (3x1000 mi). Drying at 500/3 mm Hg affords crude product consisting of approximately 65 % of the desired 1 -ca rboxym ethyl-3S-(1 S-ethoxyca rbonyl-3-p henyl pro pyl am i no)-2,3, 4,5-tetra hyd ro- 1 W[11benzazepin-2-one, identical to the material of Example 12, as determined by reverse phase HPLC on a C18 column with a mixture of methanol, water, and acetic acid (75:25:0.02) as eluent.

Hydrogen chloride gas is added in a steady stream to a suspension of the above crude product in 40 dichloromethane (26900 mi). A solution is obtained after 40 minutes when the addition of the gas is stopped.

The solution is filtered to remove trace insolubles an diethyl ether (10750 mi) was added.

The suspension is stirred overnight at ambient temperature and the solid is collected by filtration and washed with dichloromethane (4 x 500 m[) and diethyl ether (3 X 1000 m]). Drying affords purer product as the hydrochloride salt, m.p. 175-178'.

1880 g of above hydrochloride salt is combined with dichloromethane (18000 mi). The suspension is again treated with hydrogen chloride gas to complete solution. Diethyl ether (7200 m[) is added. The suspension is stirred for 3 hours and filtered. The collected solid is washed with dichloromethane (2 x 1000 m[) and diethyl ether (2 X 1000 m]) and is dried to give product m.p 183-185' (HPLC indicated that the product was approximately 96 % pure).

1280 9 of the above salt is combined with chloroform (4000 m]) and the mixture is heated at reflux temperature for 10 minutes. Heating is discontinued and the mixture is stirred for 4 hours and filtered. The solid is washed with chloroform (2 x 200 m[) and diethyl ether (3 X 500 mi), dried and sieved to give 1-carboxymethyi-3S-(1 S-ethoxycarbonyl-3phenyl pro pyla mi no)-2,3,4,5-tetra hyd ro-1 H-[1 Ibenzazepin-2-one hydrochloride, m.p. 184-1860, [Cl]25 139 D.260 (c = 0.92, absolute ethanol), and identical to the hydrochloride salt of Example 12.

EXAMPLE 28 3-(1-benzyloxycarbonyl-3-phenylpropylaMino)- 1-carboxymethyl-2, 3,4,5-tetrahydro- 1H-[llbenzazepin-2-one 60 hydrochloride (Isomer B) Dry hydrogen chloride gas is bubbled through a solution of 3-(1benzyioxycarbonyi-3phenylpropylamino)-1 -t-butyloxycarbonyimethyi-2,3,4,5tetrahydro-1 W[1 Ibenzazepin-2-one (4.0 g, see Example 7) in ethyl acetate (100 mi) for 20 minutes while stirring at 0'. The reaction mixture is evaporated under reduced pressure and the resulting solid triturated with ether (50 mi). The solid is filtered off, washed with 65 ether (15 mi) and ethyl acetate (15 mi), and then boiled with ethyl acetate (50 mi). The product is GB 2 103 614 A recrystallized from methanol/ethyl acetate to give the title compound. m. p. 197-199' (isomer B).

The starting material is prepared as follows: Potassium t-butoxide (1.2 g) is added to a solution of 3-(1-benzyioxycarbonyi-3-phenylpropylamino)2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one (3.0 g) and t-butyl bromoacetate (2.2 g) in tetrahydrofuran (100 m[) stirring at room temperature under an atmosphere of dry nitrogen. The reaction mixture is stirred for 20 hours at room temperature, then poured into water (250 mi) and extracted with dichloromethane (2 x 150 m]). The combined dichloromethane solutions are washed with water (100 mi) and dried over magnesium sulfate. Evaporation of the solvent gives 3-0 benzyloxyca rbonyl-3-phenyl pro pyl am i no)-1 - t-b utyl oxyca rbo ny [m ethyl -2,3,4,5-tetra hyd ro- 1 W[11 Ibenzazepin2- one.

EXAMPLE 29

1Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetr ahydro- 1H[llbenzazepin-2 one A solution of ethyl 2-(1 -ethoxyca rbonyl-3-p henyl pro pyla mi n o)-4-[o- (ethoxycarbonyl methyla m ino) phenyl]-butyrate (5.6 g) in methanol (100 mi) is added to a solution of sodium methoxide in methanol [prepared from sodium (0.25 g) and methanol (50 m[)] with stirring under a nitrogen atmosphere. The reaction mixture is refluxed for 65 hours, then evaporated under reduced pressure. The residue is distributed between water (50 mi) and dichloromethane (200 mi). The aqueous solution is extracted with dichlor omethane (200 mi) and the combined organic solutions washed with water (50 ml) and dried over potassium carbonate. Evaporation of the solvent gives as a mixture of isomers A and B of 1-ethoxycarbonyimethyi-3-(1ethoxycarbony]-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[llbenzazepin-2on e, which is separated by chromatography on silica gel and converted to the individual maleate salts as described in Example 10.

The starting material is obtained as follows: To a solution of ethyl 2amino-4-(o-nitrophenyi)-butyrate (17.4 g) in 50 %aqueous dioxane (130 m[) is added triethyla mine (10.5 g) and 2- (tert-butyloxyca rbonyloxyimino) 2-phenylacetonitrile (18.7 g). The reaction mixture is stirred at room temperature for 4 hours and then diluted 25 with water (300 mi). The mixture is extracted with ether (2 x 150 m[), the aqueous phase acidified with ice-cold 2N hydrochloric acid and extracted with ethyl acetate (2 x 250 m[). The ethyl acetate layers are combined, washed with water (150 m]) and dried over sodium sulfate. The solvent is removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-(o-nitrophenyi)butyrate, used without further purifica- tion.

A solution of ethyl 2-t-butyloxycarbonylamino-4-(o-nitrophenyi)-butyrate (13.0 g) in ethanol (300 mi) is hydrogenated at room temperature and atmospheric pressure, using 10 % palladium on charcoal (1 g) as catalyst, until uptake ceases. The catalyst is filtered off. Evaporation of the solvent gives ethyl 2-t-butyloxycarbonylamino-4-(o-aminophenyl)-butyrate which is used without further purification forthe next step.

A solution of ethyl 2-t-butyloxycarbonylamino-4-(o-aminophenyi)-butyrate (10.0 g) and ethyl glyoxylate (4.2 g) in ethanol (120 m]) is hydrogenated at 80' and 3 atmospheres pressure for 72 hours using 10 % palladium on charcoal (3 g) as catalyst. The reaction mixture is cooled to room temperature and the catalyst filtered off. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate (150 m[) and water (75 mi). The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-[o-(ethoxycarbonyimethylamino)phenyl 1butyrate which is used without further purification for the next step.

Hydrogen chloride gas is bubbled through a solution of ethyl 2-tbutyloxycarbonylamino-4-[o(ethoxycarbonyimethylamino)-phenyll-butyrate (8. 5 g) in ethyl acetate (150 mi) for 30 minutes at room temperature. The solution is evaporated under reduced pressure and the residue dissolved in ethyl acetate (100 mi). The solution is washed with water (3 x 100 m]) and dried over sodium sulfate. The solvent is removed under reduced pressure to give ethyl 2-amino-4-[o- (ethoxycarbonyimethylamino)-phenyi]-butyrate used without further purification forthe next step.

A solution of ethyl 2-amino-4-[o-(ethoxycarbonyimethylamino)-phenyllbutyrate (4.7 g) and ethyl benzylpyruvate (12.4 g) in acetic acid (35 mi) and methanol (35 mi) is stirred at room temperature under 50 nitrogen for 1 hour. Sodium cyanoborohydride (1.6 g) in methanol (15 mi) is added dropwise over 4 hours.

The reaction mixture is stirred at room temperature for 24 hours. Concentrated hydrochloric acid (2 m]) is added dropwise, and the mixture stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness, and the residue partitioned between water (75 mi) and ether (75 m[) and adjusted to pH 2 with 6N hydrochloric acid. The layers are separated, and the aqueous phase extracted with ether (2 x 75 mi). The 55 ether extracts are discarded and the aqueous layer adjusted to pH 9 with 40 % sodium hydroxide, and extracted with ethyl acetate (3 x 50 mi). The ethyl acetate extracts are dried over sodium sulfate and the solvent removed under reduced pressure to give ethyl 2-(1 -ethoxycarbonyl3-phenylpropylamino)-4-(o- ethoxycarbonyl methyl am i no)-phenyl 1 butyrate which is used directly for preparing the final product above.

EXAMPLE 30

Ethyl 2-amino-4-pheny[butyrate is treated under conditions of reductive alkylation as described in the previous Examples with 1 -eth oxyca rbo nyl m ethyl-2,3,4,5-tetra hyd ro- 1 H-[ 1]be nzaze pi n-2,3-d i one to give 1-ethoxycarbonyimethyi-3-(1ethoxycarbonyi-3-phenylpropylamino)-2,3,4,5-tetr ahydro-1 H-[1 Ibenzazepin-2- one of Example 10.

31 GB 2 103 614 A 31 The starting material is prepared as follows: A solution of 3,3-dichloro- 2,3,4,5-tetrahydro-1 H[l Ibenzazepin-2-one (1.0 g, 4.32 mmol) and ethyl bromoacetate (0.51 mi) in tetrahydrofuran (30 m[) is added dropwise with stirring during 15 minutes to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 mi) at room temperature under a nitrogen atmosphere. Stirring is continued for an additional 2 hours. The solution is quenched by addition of saturated aqueous ammonium chloride and the solvents are removed under reduced pressure. The residue is extracted with ether (3 x 20 mi), the combined ether solutions washed with saturated aqueous sodium chloride solution (20 m]) and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives 3, 3-dichloro-l-ethoxycarbonyimethyi-2,3,4,5tetra hyd ro-1 H-[ 11 benzazepi n-2-one. NIVIR(CDC13): 81.27 (t,3H); 3.22 (m, 4H); 4.25 (q, 2H); 4.65 (s, 2H) and 7.3 (m, 4H).

A mixture of morpholine (0.315 m], 3.6 mmol) and 3,3-dichloro-lethoxycarbonyimethyl-2,3,4,5tetrahydro-l H-[1]benzazepin-2-one (0.5 g) is stirred under nitrogen at 1 10'for 18 hours. The solution is diluted to 10 mi with chloroform and cooled to 00. 20 % sulfuric acid (1 mi) is added and the solution stirred for 2 hours at 0'. The solution is extracted with chloroform (2 X 20 mi) and the extracts are washed with 2 N hydrochloric acid (2 X 10 mi) and saturated aqueous sodium chloride solution (5 m[). The solution is dried 15 over magnesium sulfate and evaporated under reduced pressure to yield 1- ethoxycarbonyimethy]-2,3,4,5tetrahydro-l H-[1]benzazepine-2,3-dione. NMR (C13C13): 81.25 (t,3H); 2.6 (m,2H); 3.6 (m,2H); 4.2 (q, 21-1) and 7.3 (m, 4H).

EXAMPLE 31 20

Ethyl 2-amino-4-phenylbutyrate is treated in the presence of potassium carbonate in methylene chloride with 3-bromo-l-ethoxycarbonyimethy]-2,3,4,5-tetrahydro-1 W[11benzazepin-2- one to give l ethoxycarbonyimethyi-3-(1-ethoxycarbony]-3-phenylpropylamino)-2,3,4,5tetrah ydro-1 H-[1 Ibenzazepin-2 one of Example 10.

The starting material is prepared as follows: To a solution of 2,3,4,5tetrahydro-1H-[llbenzazepin-2-one 25 (2.5 g) in chloroform (30 mi), phosphorous pentachloride (3.2 g) is added in portions, while maintaining the temperature at 0-5% When the addition is complete, iodine (30 mg) is added followed by bromine (2.5 g), which is added dropwise over 5 minutes. The mixture is then refluxed for 4 hours. The chloroform solution is evaporated and the residue is partitioned between ice-water (30 mi) and dichloromethane (75 m]). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue is 30 purified by chromatography over silica gel, eluting with ether and hexane Q:3). Concentration of the appropriate fractions yields 3-bromo-2,3,4,5-tetrahydro-1 H-[llbenzazepin- 2-one, m.p. 146-148o.

3-Bromo-2,3,4,5-tetrahydro-1 H-[1]benzazepin-2-one (300 mg) is added in one portion to a stirred suspension of potassium hydroxide (90 mg) and tetrabutylammonium bromide (40 mg) in tetrahydrofuran (10 mi) maintained at 0' under a nitrogen atmosphere. Stirring is continued for 5 minutes, then ethyl 35 bromoacetate (200 mg) is added in one portion. The reaction mixture is allowed to warm to room temperature while stirring for an additional 3 hours. The tetrahydrofuran is removed under reduced pressure and the residue partitioned between water (5 mi) and ether (25 m]). The organic phase is washed with 2N hydrochloric acid (5 mi), dried over magnesurn sulfate, and the solvent removed under reduced pressure to give 3-bromo-l-ethoxycarbonyimethyi-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin2-one, m.p. 114-116% 3,Chloro-l-ethoxycarbonyimethy-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2- one is similarly prepared.

A solution of 3-chloro-2,3,4,5-tetrahydro-1 W[1 Ibenzazepin-2-one (1.95 g) in dimethylformamide (10 mi) is added dropwise with stirring to a solution of potassium t-butoxide (1.12 g) in dimethylformamide (10 m[) at 5% The solution is stirred for an additional 15 minutes at 5', then ethyl bromoacetate (1.78 g) in dimethylformamide (5 m]) is added dropwise. Stirring is continued for an additonal 30 minutes at 5' and then 45 for 3 hours at room temperature. The reaction mixture is cooled to 10' and water (100 mi) is added. The solution is extracted with chloroform (100 mO and the chloroform solution washed with water (2 x 10 mi) and dried over sodium sulfate. The solvent is removed under reduced pressure to yield 3-chloro-l ethoxycarbonyimethy]-2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one;NMR(DMSOd6): 61.2(t,3H);2.65(m, 41-1); 4.15 (q, 2H); 2.6 (d,2H) and 7.3 (m).

EXAMPLE 32

1-carboxymethyl-3S-(1S-pivaloyloxymethoxycarbonyl-3-phenylpropylamino)-2, 3,4,5-tetrahydro- 1H [llbenzazepin-2-one 1 -Benzyioxycarbonyimethyi3S-(1 S-pivaloyloxymethoxycarbonyi-3-phenyi- propylamino)-2,3,4,5tetrahydro-l W[1 Ibenzazepin-2-one (3 9) is dissolved in ethanol (50 m]) and 10 % Pd-C (0.3 9) is added and the solution hydrogenated at 1 atmosphere pressure and room temperature for 2 hours. The reaction mixture is filtered and evaporated to yield 1-carboxymethy]-3S-(1 Spivaloyloxymethoxycarbonyl-3 phenyl propyla m ino)-2,3,4,5-tetra hyd ro-1 W[1 Ibenzazepin-2-one.

The starting material is prepared as follows: 1 -benzyioxycarbonyimethy]3S-(1 S-carboxy-3- 60 phenyl propylam ino)-2,3,4,5-tetra hyd ro-1 W[1 Ibenzazepin-2-one (5 g, Example 2) is dissolved in 2N potas sium hydroxide solution (5.15 m]) and the solution evaporated to dryness. lodomethyl pivalate (2.3 g) and dimethylformamide (50 mi) are added, and the reaction mixture is stirred at room temperature for 18 hours under a nitrogen atmosphere. The dimethylformamide is evaporated, the residue is taken up in ethyl acetate (100 m[) and washed with saturated sodium bicarbonate (3 x 25 m]), water (3 x 25 mi), and saturated sodium65 32 GB 2 103 614 A chloride (25 mi), and dried over magnesium sulfate. Evaporation gives 1benzyioxycarbonyimethyl-3S-(1Spivaloyl oxym ethoxyca rbonyl-3-phenyl pro pyla m i no)-2,3,4,5-tetra hyd ro-1 H-[ 11 benzazepin-2-one.

32 Similarly prepared are:

a) 1-carboxymethyl-3S-(1S-,(-bornyloxycarbonyimethoxycarbony]-3phenylpropyiami no)-2,3,4,5- 5 tetrahydro-l H-[1]benzazepin-2-one using e-bornyl iodoacetate as starting material.

b) 1-carboxymethyi-3S-(1S-P-methoxyethoxymethoxycarbony]-3phenylpropylamin)-2, 3,4,5-tetrahydro- 1H-[llbenzazepin-2-one using P-methoxyethoxymethyl chloride as starting material.

c) 1-carboxymethy]-3-S-[1S-(3-phthalidoxycarbonyl)-3-phenylpropylaminol-2, 3,4,5 -tetrahydro-1H- [l Ibenzazepin-2-one using 3-bromophthalide as starting material.

d) 1-carboxymethyl-3S-[1S-(3-pyridyimethoxycarbonyl)-3-phenylpropylaminol2,3,4,5-tetrahydro-1H- [l Ibenzazepin-2-one using 3-pyridyimethyl chloride as starting material.

EXAMPLE 33

1-Carboxymethyl-3S-(1-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5,5a,6,7,8, 9,9a-decahydro- W- 15 [llbenzazepin-2-one A solution of 3(S)-amino-l-carboxymethyl-2,3,4,5,5a,6,7,8,9,9a-decahydro1H-[llbenzazepin-2 -one sodium salt (0.6 g) and ethyl benzylpyruvate (1.5 g) in acetic acid (5 m[) and methanol (3 mi) is stirred at room temperature under an atmosphere of dry nitrogen for 1 hour. A solution of sodium cyanoborohydride (0.2 g) in methanol (2 m!) is then added over a 4 hour period. The reaction mixture is stirred at room temperature for 20 18 hours. Concentrated hydrochloric acid (0.5 mi) is added and the mixture stirred at room temperature for 1 hour. The solvents are removed under reduced pressure and the residue partitioned between water (20 mi) and ether (20 mi). The pH is adjusted to 9.3 with 40 % sodium hydroxide. The layers are separated and the ether layer discarded. The aqueous phase is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 25 m]). The extracts are dried over magnesium sulfate and the solvent removed under reduced pressure. Hydrogen chloride is bubbled into a solution of the residue in dichloromethane (70 m]) for 5 minutes. The solution is evaporated and the residue recrystallized from ethanol/ether to give 1-ca rboxym ethyl -3S(1-ethoxycarbony]-3-phenylpropylamino)-2,3,4,5,5a,6,7,8,9,9adecahydro-1 W[1]benzazepin-2-one-hydrochloride as a mixture of isomers.

The starting material is prepared as follows: A solution of 3(S)-tbutyloxycarbonylamino-l- eth oxyca rbo nyl methyl -2,3,4,5-tetra hyd ro- 1 W[1 Ibenzazepine-2,5- dione (3.6 g) in acetic acid (50 mi) is hydrogenated for 120 hours at 3 atmospheres pressure using platinum oxide (1.2 g) as catalyst. The catalyst is filtered off and the filtrate evaporated under reduced pressure. The residue is distributed between dichloromethane (200 mi) and saturated aqueous sodium bicarbonate (100 mi). The dichloromethane solution is washed with water (50 mi), dried over sodium sulfate and the solvent removed under reduced 35 pressure. The residue is chromatographed on silica gel eluting with 0-50 % ethyl acetate in toluene. The fraction eluting with 50 % ethyl acetate in toluene is collected to give 3(S)-t-butyloxycarbonylamino-l eth oxyca rbo nyl methyl -2,3,4,5,5a,6,7,8,9,9 a-d eca hyd ro- 1 W[1 lbenzazepin-2,5-dione used without further purification for the next synthetic step.

A solution of 3(S)-t-butyloxycarbonylamino-l-eth oxyca rbo nyl methyl -2, 3,4,5,5a,6,7,8,9,9a-deca hyd ro- 1W 40 [llbenzazepin-2,5-dione (2.7 g) and sodium borohydride (0.2 9) in ethanol (100 mi) is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure, and the residue dissolved in dichloromethane (100 m[). The solution is extracted with ice-cold 2N hydrochloric acid (2 x 50 mi) and saturated aqueous sodium chloride solution (50 mi) and dried over sodium sulfate. The solvent is removed under reduced pressure and the residue triturated with ether to give 3(S)- t-butyloxycarbonylamino-lethoxycarbonyimethyl-5-hydroxy-2,3,4,5,5a,6,7,8,9,9a-decahydro-1 W[1 Ibenzazepin-2-one.

A mixture of 3(S)-t-butyl oxyca rbo nyl am in o- 1 -eth oxyca rbo nyl methyl -5-hyd roxy-2,3,4,5,5a,6,7,8,9,9a decahydro-1 W[11benzazepin-2-one (2.1 g), dichlorohexylcarbodiimide (1.8 g) and cuprous chloride (0.2 g) is heated at 80' under nitrogen for 32 hours. The reaction mixture is cooled to room temperature, the residue is dissolved in methylene chloride (200 mi), washed with dilute ammonium hydroxide (2 x 50 mi) and water 50 (50 m[). The organic phase is dried over sodium sulfate and evaporated to give a mixture of the desired adduct and excess dicyclohexylcarbodiimide. This mixture is dissolved in ethyl acetate (100 mi) and placed in a pressure bottle 10 % Pd/C (0.4 g) is added and the mixture hydrogenated at 3 atmospheres pressure and 40'for 16 hours. The catalyst is filtered off and the filtrate is evaporated to give 3(S)-t butyloxycarbonylamino-1 -ethoxycarbonyimethyl-2,3,4,5,5a,6,7,8,9,9a- decahydro-1 H-[1 Ibenzazepin-2-one, 55 used without further purification for the next synthetic step.

Hydrogen chloride gas is bubbled through a solution of the above compound (1.1 g) in ethyl acetate (50 mi) for 45 minutes. The reaction mixture is evaporated under reduced pressure, the residue dissolved in ethyl acetate (50 mi) and washed with water (3 x 30 mi). The ethyl acetate solution is dried over sodium sulfate and the solvent removed under reduced pressure to give 3(S)-am i no-1 -ethoxycarbonyl methyl 2,3,4,5,5a,6,7,8,9,9a-decahydro-1 H-[1 Ibenzazepin-2-one, which is used without further purification forthe next step.

A solution of sodium hydroxide (0.1 g) in water (0.25 mi) is added to a solution of the above amine (o.6 g) in methanol (7.5 m]) at room temperature, and the solution is stirred for 2 hours. The solvents are evaporated and the residue thoroughly dried, then slurried with ether, to give the sodium salt of 3(S)-amino-l- 65 33 GB 2 103 614 A 33 carboxymethyi-2,3,4,5,5a,6,7,8,9,9a-decahydro-1 W[11benzazepin-2-one.

EXAMPLE 34

N-[1-(1-carboxymethyl)-2,3,4,5-tetrahydro-2-oxo- 1H-[llbenzazepin-3Sylamino)-3-phenylpropyl- 1-carbonyll5 L-phenylalanine.

L-Phenylalanine methyl ester hydrochloride is condensed with 1 benzyioxycarbonyimethyi-3S-(1 Scarboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1 H-[1 Ibenzazepin-2-one in methylene chloride in the presence of ll-Q-di methyl am i nop ro pyl)3-ethylcarbodi i m ide hydrochloride at room temperature to yield afterworkup the W[1-(1 -benzyioxycarbonyimethyi-2,3,4,5-tetrahydro-2-oxo1 H-[1]benzazepin-3S-yiamino)10 3-phenylpropyi-l-carbonyll-Lphenylaianine methyl ester.

Hydrogenation using 10 % Pd/C catalyst in ethanol gives N-[1-(1carboxymethyi-2,3,4,5-tetrhydro-2-oxo- 1 W[ 11 benzazepi n-3S-yl am i no)-3-p henyl pro pyi- 1 -ca rbo nyl I-L- phenyl al ani n e methyl ester.

Hydrolysis with dilute aqueous sodium hydroxide at room temperature for 18 hours yields the W[1 -(1-carboxymethy]-2,3,4,5-tetrahydro-2-oxo1 W[ 11 benzazepi n-3S-yla m i no)-3-ph enyl pro py]-1 -ca rbonyll15 Uphenylalanine.

EXAMPLE 35 1-Ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3phenylpropylamina)-2,3,4,5-tetr ahydro- 1H-Illbenzazepin-2one 20 Treatment of 3-(1 -carboxy-3-phenylpropylamino)-1 -cyanomethyi-2,3,4,5- tetrahydro-1 H-[1 Ibenzazepin-2- 20 one with ethanoi-ether (1: 1) saturated with hydrogen chloride at room temperature for 48 hours gives after workup 1-ethoxycarbonyimethy]-3-(1-ethoxycarbonyi-3phenylpropylamino)-2,3,4,5-tetr ahydro-1H[1 Ibenzazepin-2-one identical to the compound of Example 10. Thestarting material is prepared asfollows: &(1 -ca rboxy-3-phenyl p ropy] am i no)-2,3,4,5-tetra hyd ro-1 H[1]benzazepin-2-one is alkylated with bromoacetonitrile in dimethylformamide solution in the presence of 25 sodium hydride to yield after work-up, 3-(1-carboxy-3-phenylpropylamino)-1 -cyanomethyi-2,3,4, 5tetrahydro-l W[1]benzazepin-2-one, used directly in the next step.

EXAMPLE 36

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

Formula:

1-Carboxymethyi-3S-(1S-ethoxycarbony]-3-phenypropylamino)-2,3,4,5tetrahydro-l H11-[11benzazepin-2-one 100g 35 Lactose 1,157 g Corn starch75g 40 Polyethylene glycol 6,000 75g Talcum powder 75g Magnesium stearate 18g 45 Purified water q.s.

Procedure:

As described in Example 15.

34 GB 2 103 614 A 34 EXAMPLE 37

Preparation of 10,000 capsules each containing 20 mg of the hydrochloride salt of the active ingredient of Example 12.

Formula: 5 1-Carboxymethyi-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4, 5tetrahydro-1 W[1]benzazepin-2-one hydrochloride g Lactose 1,700 g Talcum powder g Procedure:

As described in Example 17.

Cardiovascularpharmacology of compounds of the invention Testing of compounds is carried out by methods of evaluation of the inhibition of the angiotensin converting enzyme (ACE). Biochemical assessment of in vitro ACE inhibition (ACE[) gauges the inhibition of peptidolytic activity of a compound in rabbit lung tissue. In in vivo studies angiotensin 1 (N) pressor 20 response inhibition of the compounds are conducted in rats.

In the in vivo test method an increase in the blood pressure is first caused by administration of angiotensin 1 (AI) to the test animal. The inhibitory action of the individual compounds on this increase in blood pressure is then determined.

Biochemical testing methodology A rabbit lung tissue preparation [Das and Saffer, J. Boil. Chem. 250: 6762, (1975)] was used for assessment of ACE by the method of Cheung and Cushman [Cheung and Cushman, Biochim. Biophys, Acta 293:451, (1973)1. This test system incorporates spectrophotometric evaluation of the amount of histidyl-leucine liberated from a synthetic substrate after 30 min. of 37'C incubation. 1C50 values for ACE inhibition were 30 determined graphically as the concentration of test drug required to reduce the amount of histidyl-leucine formed to 50% of that generated in the absence of the test compound.

Methodology of angiotensin 1 (AI) pressorresponse inhibition following intravenous administration of test 35 co mp o un ds (l/o A 1) In these studies catheters were placed in a femoral artery and a saphenous vein of anesthetized rats as described above. Arterial pressure was continuously recorded from the arterial catheter, while AI and the test compounds were injected through the venous catheter. AI pressor response inhibition was expressed as percent decrease of the response from pretreatment control values and tabulated as the average inhibition 40 recorded within 30 minutes after test drug administration.

GB 2 103 614 A 35 Results:

Angiotensin 1 pressor response inhibition in rats 5 Compound of in vitro i.v. Dose (mg/kg) % AI inhibition Example ACEI

1C50 (M) 1 6 x 10-7 10 100 10 1.0 100 0.1 50 15 2 X 10-7 0.1 37 9 5 X 10-9 0.3 93 0.1 80 20 0.03 40 1 X 10-5 1.0 80 25 Maleate Salt 12 4 x 10-7 1.0 100 30 HCI Salt 0.3 95 0.1 82 0.06 74 35 0.03 29 19 2 x 10-9 0.1 93 40 0.06 84 0.03 70 0.02 69 45 0.01 28 0.007 14 50 28 1 X 10-7 0.1 92 Isomer B, HCI Salt 36 GB 2 103 614 A

Claims (63)

1. A compound of the general formula 1 36 X R5 7 54 8 1 3 N _1 9a N 9 1 RA wherein RA and RB are radicals of the formula (1) -CH R, and -CH R2 respectively, R. R. 20 in which R,, is carboxy or a functionally modified carboxy; R, is hydrogen, lower alkyl, amino(lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl or cycloalkyl (lower) alkyl; R2 is hydrogen or lower alkyl; R3 and R4, each independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trif luoro methyl, or R3 and R4taken together represent lower alkylenedioxy; R5 is hydrogen or lower alkyl, and X represents oxo, two hydrogens, or one hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro; complexes thereof; and stereoisomers of all these compounds.

2. A compound of claim 1 wherein one or both of R. represented by COR6 in radical RA and represented by COR7 in radical RB independently represent carboxy, esterified carboxy, carbamoyl or substituted 30 carbamoyl.

3. A compound of claim 2 wherein one or both of R6 and R7 represent hydroxy; lower alkoxy; (amino, mono- or di-lower alkylamino)-substituted lower alkoxy; carboxy- substituted lower alkoxy; lower alkoxycar bonyl-substituted lower alkoxy; aryl-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxy; (hydroxy, lower alkanoyloxy or lower alkoxy)-substituted lower alkoxy- 35 methoxy; bicycloalkoxycarbonyi-subsituted lower alkoxy; 3-phthalidoxy; (lower alkyl, lower alkoxy, halo)-substituted 3-phthalidoxy; 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; (amino or acylamino)-substituted lower alkylamino; a-(carboxy or lower alkoxycarbonyi)-substituted lower alkylamino; aryl-substituted lower alkylamino which can be 40 substituted on the a-carbon by carboxy or lower alkoxycarbonyl.

4. A compound of the formula IA "4 45 (IA) N-CH-Rl 1 RP3 CO-R6 1 0 50 CH R2 CO-R7 wherein R, is hydrogen, lower alkyl, amino(lower)aikyi, aryl, aryl(lower)alkyl, cycloalkyi(lower)aikyi, R2 and 55 R5 represent hydrogen or lower alkyl, R3 and R4 represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluormethyl; or R3 and R4 taken together represent lower alkylendioxy, X represents oxo, two hydrogens of one hydroxy group and one hydrogen, 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)- 1ower alkoxy; or complexes 60 thereof.

5. A compound of the formula]A shown in claim 4, wherein R, is hydrogen, lower alkyl, amino(lower)al kyl, aryl(lower)alkyl where aryl represents phenyl unsubstituted or mono- or disubstituted by lower alkyl, hydroxy, lower alkoxy, lower alkylenedioxy, lower alkanoyloxy, halogen ortrifluoromethyl, R2 and R5 are hydrogen or lower alkyl, R3 and R4 are hydrogen, lower alkoxy, lower alkyl, halogen, ortrifluoromethy]; or R365 37 GB 2 103 614 A 37 and R4 taken together represent alkylenedioxy, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl(] ower)a 1 koxy, lower alkoxycarbonyi(iower)aikoxy.

6. A compound of the formula [A shown in claim 4, wherein R, is hydrogen, lower alkyl, 0) amino(lower)aikyi, aryl(lower)alkyl where aryl represents phenyl unsubstituted or mono-substitited by lower 5 alkyl, hydroxy; lower alkoxy, lower alkanoyloxy, halogen or trifl uoro methyl, R2 and R5 are hydrogen or lower alkyl, R3 and R4 are hydrogen, lower alkoxy, lower alky], halogen, or trifluoromethyi; or R3 and R4 taken together represent lower alkylendioxy, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl (lower)al koxy, lower alkoxycarbony l(lower)alkoxy.

7. A compound of the formula IA shown in claim 4, wherein R, is hydrogen, lower alkyl, co amino(lower)aikyi, aryi(iower)aikyi, R2 and Rr, are hydrogen or lower alkyl, R3 is hydrogen, R4 is hydrogen, lower alkoxy, lower alky], halogen, or trifluoromethyl, X represents oxo, one hydroxy and one hydrogen, or 2 hydrogens, R6 and R7 independently represent hydroxy, amino, lower alkoxy, phenyl(lower) alkoxy, lower alkoxycarbonyi(iower)aikoxy.

8. A compound of the formula IA shwon in Claim 4, wherein R, is hydrogen, methyl, ethyl, isopropyl, (9-aminopropyi, (o-aminobutyl, aryl(methyl, ethyl, propyl) where aryl represents phenyl unsubstituted or substituted by one methyl, hydroxy, methoxy, methylenedioxy, acetyloxy, chloro or trifluoromethyl group, R2 and R5 are hydrogen or methyl, R3 and R4 represents hydrogen, methoxy, methyl, chloro or trifluoromethyl, X represents oxo, one hydroxy and one hydrogen or 2 hydrogens, R6 and R7 independently 20 represent hydroxy, amino, ethoxy, methoxy, benzyloxy, ethoxycarbonyimethoxy or pivaloyloxy-methoxy.

9. A compound of the formula IB NH-CH An H2f-R8 (IB) 25 N CO-R6 o 1 0 CH2-CO-RI 7 30 wherein n represents an integer from 1 to 4, R8 is hydrogen, phenyl unsubstituted or monosubstituted by loweralkyl, loweralkoxy, lower alkanoyloxy, halogen, hydroxy, ortrifluoromethy], R6and R7independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy, or amino.

10. A compound of the formula IB shown in claim 9, wherein C,,1-12, represents ethylene, R8 represents 35 phenyl, or phenyl mono-substituted by lower alkoxy with up to 4 carbon atoms, lower alkyl with up to 4 carbon atoms, halogen ortrifluoromethyl, R6 and R7 independently represent hydroxy or lower alkoxy with up to 4 carbon atoms.

11. Acompound oftheformula 1Ashown in claim 4,whereinX = H2, R2and R5 =H, R6 = 0C21-15and R7 OH and the other symbols have the following meanings: 40 No. R, R3 R4 1 C61-1,CH2 H H 45 2 C6H5CH2CH2 7-OCH3 8-OCH3 3 C6H5CH2CH2 7-Cl H 4 C6H5CH2CH2 8-CH3 H 50 C61-1,CH2CH2 8-OCH3 H 6 p-CIC6H4CH2CH2 H H 7 CH3.1 H H

12. A compound of the formula IC 'k_k is),---"CnH2ri---R8 1 tS) -NH CH aN > 0 CH2-CO-R7 (IC) 38 GB 2 103 614 A 38 wherein S represents the chirality, n represents an integer from 1 to 4, R8 is hydrogen, phenyl unsubstituted or monosubstituted by lower alkyl, lower alkoxy, lower alkanoyloxy, halogen, hydroxy, or trifluoromethyl, R6 and R7 independently represent hydroxy, lower alkoxy of up to 4 carbon atoms, benzyloxy or amino, or pharmaceutical ly acceptable salts thereof.

13. 1-Carboxymethy]-3-(1-ethoxycarbonyi-3-phenylpropylamino)-2,3,4,5tetrahydro-1 H-[1]benzazepin-2- 5 one or stereoisomers thereof.

14. The higher melting racemic compound of the compound of claim 13 and an enantiomer thereof.

15. The lower melting racemic compound of the compound claimed in claim 13 and an enantiomer thereof.

16. 1 -Ca rboxym ethyl -3S-(1 S-ethoxyca rbo nyl -3-p h enyl pro pyl am in o)-2,3,4,5-tetra hyd ro- 1 H [1 Ibenzazepin-2-one.

17. 1-Benzyioxycarbonyimethyi-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5tetrahyd ro-1H- [llbenzazepin-2-one.

18. 1-Benzyloxycarbonyimethyi-3-(1-ethoxycarbonyi-3-phenyipropylamino)-2, 3,4,5-t etrahydro-1H- [1 Ibenzazepin-2-one.

19. 1-Benzy[oxycarbonylethyi-3-(1-benzyioxycarbonyi-3-phenyipropylamino)2,3,4,5 -tetrahydro-1H- [1 Ibenzazepin-2-one.

20. 1 -Carboxymethyl-3-(1 -ca rboxy-3-phenyl pro pyla mi no)-2,3,4,5tetra hyd ro-1 H-[1] benzazepin-2-one or stereoisomers thereof.

21. The lower melting racemic compound of the compound claimed in claim 20 or an enantiomer 20 thereof.

22. The higher melting racemic compound of the compound claimed in claim 20 oran enantiomer thereof.

23. The racemic isomer B of 1-ethoxycarbonylmethy]-3-(1-ethoxycarbonyi-3phenylpropylamino)- 2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one.

24. 1-Carboxymethylamino-2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one.

25. 1 -Ca rboxym ethyl -3-(] -ca rboxy-3-p he nyl pro pyl am in o)-5- hyd roxy-2,3,4,5-tetra hyd ro- 1 H[llbenzazepin-2-one.

26. 1-Carboxymethyl-3S-(1R-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5tetrahydr o-1H- [11benzazepin-2-one.

27. 1-Carboxymethyi-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5tetrahydro-1H-[l lbenzazepin-2-one.

28. 1-Ethoxycarbonyimethyi-3-(1-benzyioxycarbony]-3-phenylpropylamino)-2, 3,4,5-t etrahydro-1H[1]benzazepin-2-one.

29. The racemic isomer A of the compound claimed in claim 28.

30. The racemic isomer B of the compound claimed in claim 28.

31. 1-Ethoxycarbonyimethyl-3-(1-carboxy-3-phenylpropylamino)-2,3,4,5tetrahydro-1 H-[llbenzazepin-2- one or stereoisomers thereof.

32. The racemic isomer compound B of the compound claimed in claim 31.

33. The racem ic isom er corn pou n d of 1 -ca rboxym ethyl -3-0 ethoxyca rbonyl-3-phenyl pro pylamino)-8 methoxy-2,3,4,5-tetrahydro-1H-[llbenzazepin-2-one.

34. 1 -(1 -Ca rboxyethyl)-3-(1 -ethoxyca rbo nyl-3-phenyl pro pyla m i no)-2,3,4,5-tetrahydro-1 H-[1 1 benzazepin 2-on.

35. 1-Ethoxycarbonyimethyi-3S-(1S-ethoxycarbony]-3-phenylpropylamino-2,3, 4,5-tet rahydro-1H- [llbenzazepin-2-one.

36. 1-Ethoxycarbonyimethyl-3S-(1R-ethoxycarbonyl-3-phenylpropylamino)-2,3, 4,5-te trahydro-1H- 45 [llbenzazepin-2-one.

37. The racemic isomer compound B of 1-carboxymethyi-7-chloro-3-(1ethoxycarbonyl-3- phenyl propyla m i no)-2,3,4,5-tetrahyd ro-1 H-[1 Ibenzazepin-2-one.

38. 3-(1-Benzy[oxycarbonyi-3-phenylpropylamino)-1-carboxymethyl-2,3,4,5tetrahyd ro-1H- [1 Ibenzazepin-2-one or stereoisomers thereof,

39. 1-Carboxymethyi-3S-(1S-pivaloyloxymethoxycarbonyi-3phenylpropylamino)-2,3,4,5-tetrahydro-1H- [1 Ibenzazepin-2-one.

40. 1 -Ca rboxym ethyl -3S-(1 S-C-bo rnyl oxyca rbo nyl m eth oxyca rbo nyl-3-p henyl-p ro p 1 am i no)-2,3,4,5 tetrahydro-1 H-[1]benzazepin-2-one.

41. 1 -Ca rboxym ethyl -3S-(1 S-0-m ethoxyeth oxym eth oxyca rbo nyl-3-ph enyl pro pyl am i no)-2,3,4,5 tetrahydro-l H-[1 Ibenzazepin-2-one.

42. 1-Carboxymethyl-3-S-[1S-(3-phthalidoxycarbonyl)-3-phenyipropylamino]2,3,4,5 -tetrahydro-1H- [llbenzazepin-2-one.

43. 1-Carboxymethyi-3S-[1S-(3-pyridyimethoxycarbonyi)-3phenylpropylaminol-2,3,4,5-tetrahydro-1H- [llbenzazepin-2-one.

44. 1 -Ca rboxy methyl -3S-(1 -eth oxyca rbo nyl -3-p h enyl pro pyl am i no)-2,3,4,5,5a,6,7,8,9,9a-deca hyd ro- 1 H[llbenzazepin-2-one.

45. N-[1-(1-carboxymethyl)-2,3,4,5-tetrahydro-2-oxo-1H-[1lbenzazepin-3Syiamino) -3-phenylpropyi-lcarbonyll-L-phenyla la nine.

46. A salt of a compound having a salt forming group, as claimed in anyone of claims 4,6-9 and 11-25. 65 39 GB 2 103 614 A 39

47. A salt of a compound having a salt forming group, as claimed in anyone of claims 5, 10 and 26-32;

48. A salt of a compound having a salt forming group. as claimed in anyone of claims 1-3 and 33-45.

49. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in anyone of claims 4,6-9 and 11-25.

50. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in anyone 5 of claims 5, 10 and 26-32.

51. A pharmaceutically acceptable salt of a compound having a salt forming group, as claimed in anyone of claims 1-3 and 33-45.

52. A compound of formula] substantially as described with reference to any of Examples 1 to 35.

53. A pharmaceutical preparation comprising a compound claimed in anyone of claims 4,6-9,11-25 and 10 49, in admixture or conjunction with a pharmaceutically suitable carrier.

54. A pharmaceutical preparation comprising a compound claimed in anyone of claims 5,10,26-32 and 50 in admixture or conjunction with a pharmaceutical ly suitable carrier.

55. A pharmaceutical preparation comprising a compound claimed in anyone of claims 1-3,33-45 and 51 in admixture or conjunction with a pharmaceutically suitable carrier.

56. A pharmaceutical preparation according to claim 53,54 or 55 substantially as described with reference to Examples 36 or 37.

57. Process for the manufacture of 3-amino-M Ibenzazepin-2-one-1-alkanoic acids of the general formula] R4 p6 X 4 RS 20 7 5 1 3 N 8 9 9C7 R 1 A R3.9 1 0 25 R, wherein RA and RB are radicals of the formula -CH / R, and -CH / R2 respectively, R.

Ro in which R. is carboxy or a functionally modified carboxy; R, is hydrogen, lower alky], amino(lower) alkyl, aryll, aryl (lower) alkyl, cycloalkyl or cycloalkyl (lower) alkyl; R2 is hydrogen or lower alkyl; R3 and R4, each independently, represent hydrogen, lower alky], lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R3 and R4taken together represent lower alkylenedioxy; R5 is hydrogen or lower alkyl, 40 and X represents oxo, two hydrogens, or one hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro; salts, complexes and stereoisomers of all these compounds, which consists in that a) in a compound of the formula X 45 NH-R N 5 1 50 R, 1 0 R9 in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetra hydro, and wherein X, RB, R3, R4 and R5 have the meanings given hereinbefore, RA is introduced by alkylation with a compound of the formula 55 RA - Z (111M wherein Z is a reactive esterified hydroxyl group and RA has the meanings given hereinbefore, or with a compound of the formula 60 R, - CO - Ro OV) wherein R, and R. have the meanings given hereinabove, in the presence of a reducing agent, with a temporary protection of any primary and secondary amino groups and/or, optionally, hydroxyl and/or oxo 65 GB 2 103 614 A groups, which may be present in any one of the substitutents, X, RA, RB, R,, R3, R4 and R5 or b) a compound of the formula R4 X R N N N R' RIO, H A 3 0 (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 R, - Z (IIIB) wherein Z is a reactive esterified hydroxyl group and RI3 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, R4 and R5, or c) a compound of the formula X Ra 0 (V0 in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro and wherein Y is oxo or a reactive esterified 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 (V11) wherein RA and R5 have the meanings given hereinabove, with the proviso that in the case Y is oxo, the condensation is carried out in the presence of a reducing agent and with a temporary protection of the oxo group which maybe present as the substituent X, or cl) in a compound of the formula R X 1 5 RI N-CH R3 0 CH R2 R 0 -, 1 R in which the carbocyclic ring may also be hexahydro or 6,7,8,9-tetrahydro, and wherein X and R, to R5 have the meanings given hereinabove, one of the symbols R0' and ROZis cyano and the other one is cyano or R, as 55 defined hereinabove, the cyano group(s) is (are) subjected to solvolysis, or e) a compound of the formula R 0 4 R N 5 NH COOH RA R3 1 RB (V110 45 OX) 41 GB 2 103 614 A 41 in which the carbocyciic 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 1 specified above, except for having an additional double bond located at C-3, or between the nitrogen atom and the adjacent carbon 5 atom within the group RA, is treated with a reducing agent in order to saturate this double bond, or 9) in order to produce a compound of formula 1 as specified hereinabove, in which Xis oxo, condensing a compound of the formula R 0 4 N R3 0 RB (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 (V11) 20 wherein RA and R5 have the meaning given hereinabove, and h) if desired, a resulting compound of formula 1 as specified above is converted into another compound of formula 1 within its above-specified scope, and/or i) if desired, a resulting compound of formula 1 as specified above and having salt-forming properties is 25 converted into a salt thereof or a free compound is liberated from such a salt, andlor j) if desired, a resulting compound of formula 1 as specified above and having complex-forming properties is converted into a complex thereof, and/or k) 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 1 '

58. A process for the preparation of compounds substantially as described in anyone of Examples 1 to 14.

59. A process for the preparation of compounds substantially as described in anyone of Examples 18 to 21.

60. A process for the preparation of compounds substantially as described in anyone of Examples 22 to 35 35.

61. A compound of formula 1 when prepared according to a process of claim 57 or 58.

62. A compound of formula 1 when prepared according to a process of claim 57 or 59.

63.A compound of formula 1 when prepared according to a process of claim 57 or 60.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1983. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.