DK157881B - METHOD OF ANALOGUE FOR THE PREPARATION OF 3-AMINO- (1) BENZAZEPIN-2-ON-1-ALKANIC ACIDS OR DERIVATIVES THEREOF OR STEREOISOMERS OR SALTS THEREOF - Google Patents

Description

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Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 3-amino[ 1 ]benzazepin-2-on-l-alkansyrer eller derivater deraf med den almene 5 formel /^° 1¾ CO-Ϊ^ hvori betyder hydrogen, C(1-4)-alkyl eller phenyl- substitueret C(1-4)-alkyl, R2 betyder hydrogen eller C( 1-4)-alkyl, og Rg og R7 hver for sig betyder hydroxy, 10 C(l-4)-alkoxy eller phenylsubstitueret C(l-4)-alkoxy, eller stereoisomerer eller salte deraf.The present invention relates to an analogous process for the preparation of novel 3-amino [1] benzazepin-2-one-1-alkanoic acids or derivatives thereof having the general formula / + 1 ° CO-Ϊ wherein hydrogen, C (1- 4) -alkyl or phenyl-substituted C 1 -C 4 -alkyl, R 2 is hydrogen or C 1 -C 4 -alkyl, and R 9 and R 7 are each hydroxy, 10 C (1-4) -alkoxy or phenyl-substituted C (1-4) alkoxy, or stereoisomers or salts thereof.

Opfindelsen er baseret på erkendelsen af, at 3-amino[ 1 ]-benzazepin-2-on-l-alkansyrer og derivater deraf med formlen (I) udgør en hidtil ukendt type stærkt virksomme 15 inhibitorer for det angiotensin-omdannende enzym (ACE).The invention is based on the recognition that 3-amino [1] -benzazepine-2-one-1-alkanoic acids and derivatives thereof of formula (I) constitute a novel type of highly active inhibitor of the angiotensin converting enzyme (ACE) .

De ovenfor anførte egenskaber gør de omhandlede 3-amino-[ 1 ]-benzazepin-2-on-l-alkansyrer og deres derivater, stereoisomerer og salte særligt værdifulde til enkeltvis eller kombineret indgift til pattedyr og mennesker, f.eks.The above properties make the 3-amino [1] -benzazepin-2-one-1-alkanoic acids and their derivatives, stereoisomers and salts particularly valuable for single or combined administration to mammals and humans, e.g.

20 til behandling af eller forebyggelse af sygdomme, som har relation til hæmningen af det angiotensin-omdannende enzym, f.eks. cardiovaskulære forstyrrelser, såsom højt blodtryk, og cardiale tilstande, såsom kongestiv hjerteinsufficiens.20 for the treatment or prevention of diseases related to the inhibition of the angiotensin-converting enzyme, e.g. cardiovascular disorders, such as high blood pressure, and cardiac conditions, such as congestive heart failure.

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22

Det er kendt, at visse N-carboxymethyl-dipeptider er inhibitorer for det angiotensin-omdannende enzym, jf. Nature, vol. 288, 280 (1980). De omhandlede 3-amino[ 1 ]-5 benzazepin-2-on-l-alkansyrer med formlen (I) adskiller sig strukturmæssigt væsentligt fra de kendte N-carboxymethyl-dipeptider.It is known that certain N-carboxymethyl dipeptides are inhibitors of the angiotensin-converting enzyme, cf. Nature, Vol. 288, 280 (1980). The present 3-amino [1] -5 benzazepin-2-one-1-alkanoic acids of formula (I) differ substantially structurally from the known N-carboxymethyl dipeptides.

Saltene af forbindelserne med formlen I er afledt af forbindelser, som har saltdannende egenskaber, og er 10 fortrinsvis farmaceutisk acceptable salte.The salts of the compounds of formula I are derived from compounds which have salt-forming properties and are preferably pharmaceutically acceptable salts.

Fremstillingen af derivater af de omhandlede forbindelser, som udgør forstadier for de virksomme forbindelser, f.eks. farmaceutisk acceptable estere af de omhandlede monoeller dicarboxylsyrer, som ved solvolyse eller under 15 fysiologiske betingelser kan omdannes til de tilsvarende carboxylsyrer, f.eks. de ovenfor nævnte estere, udgør et særligt aspekt af opfindelsen.The preparation of derivatives of the subject compounds, which constitute precursors of the active compounds, e.g. pharmaceutically acceptable esters of the subject mono or dicarboxylic acids which can be converted to the corresponding carboxylic acids by solvolysis or under physiological conditions, e.g. the esters mentioned above constitute a particular aspect of the invention.

Disse estere er fortrinsvis f.eks. ligekædede eller forgrenede, usubstituerede eller på passende måde 20 substituerede lavalkylestere, såsom benzylestere.These esters are preferably e.g. straight-chain or branched, unsubstituted or suitably substituted lower alkyl esters, such as benzyl esters.

Værdifulde forbindelser er især sådanne med formlen I, hvori betyder hydrogen, methyl, ethyl, isopropyl eller phenyl-(methyl, ethyl, propyl), R2 betyder hydrogen eller methyl, og Rg og Ry hver for sig betyder hydroxy, ethoxy, 25 methoxy eller benzyloxy, og deres farmaceutisk acceptable salte.In particular, valuable compounds are those of formula I wherein hydrogen, methyl, ethyl, isopropyl or phenyl (methyl, ethyl, propyl), R 2 represents hydrogen or methyl, and R 9 and R 1 are each hydroxy, ethoxy, methoxy or benzyloxy, and their pharmaceutically acceptable salts.

Helt specielt værdifulde forbindelser er sådanne med formlen 3Particularly valuable compounds are those of formula 3

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\ /A»' O\ / A »'O

V NH-CH (IA) S^N_y v«; I o ch2 -co-r ' hvori n er et helt tal på 1-4, og Rg og R7 hver for sig betyder hydroxy, lavalkoxy med højst 4 carbonatomer eller 5 benzyloxy, og farmaceutisk acceptable salte deraf.V NH-CH (IA) S ^ N_y v «; In o ch 2 -co-r 'wherein n is an integer of 1-4 and Rg and R7 are respectively hydroxy, lower alkoxy having not more than 4 carbon atoms or 5 benzyloxy, and pharmaceutically acceptable salts thereof.

Særligt værdifulde forbindelser er forbindelser med formlen IA, hvor CnH2n betyder ethylen, og Rg og R7 hver for sig betyder hydroxy eller lavalkoxy med højst 4 carbonatomer, og deres farmaceutisk acceptable salte.Particularly valuable compounds are compounds of formula IA wherein CnH2n represents ethylene and Rg and R7 each represent hydroxy or lower alkoxy having a maximum of 4 carbon atoms and their pharmaceutically acceptable salts.

10 Fremgangsmåden ifølge opfindelsen omfatter også fremstillingen af de stereoisomerer af forbindelserne med formlen I. Et antal racemater kan fremstilles, når f.eks. i formlen I mindst én af grupperne R^ og R2 er forskellig fra hydrogen.The process of the invention also comprises the preparation of the stereoisomers of the compounds of formula I. A number of racemates may be prepared when e.g. in formula I at least one of the groups R 1 and R 2 is different from hydrogen.

15 De enkelte enantiomerer af disse racemater kan isoleres. Bestemte specifikke eksempler på disse isomerer foretrækkes som inhibitorer for det angiotensin-omdannende enzym.The individual enantiomers of these racemates can be isolated. Specific specific examples of these isomers are preferred as inhibitors of the angiotensin converting enzyme.

Særligt udmærkede forbindelser er sådanne med formlenParticularly excellent compounds are those of the formula

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4 io ch2 -co-r'^ hvor S angiver chiraliteten, n^ er et helt tal på 1-4, og Rg og R7 hver for sig betyder hydroxy, lavalkoxy med højst 5 4 carbonatomer eller benzyloxy, og deres farmaceutisk acceptable salte.Where S represents the chirality, n ^ is an integer of 1-4, and R 9 and R 7 each represent hydroxy, lower alkoxy of not more than 5 4 carbon atoms or benzyloxy, and their pharmaceutically acceptable salts.

De her anvendte almene definitioner har i forbindelse med den foreliggende opfindelse følgende betydninger.For the purposes of the present invention, the general definitions used herein have the following meanings.

Phenyllavalkyl betyder fortrinsvis benzyl, 1- eller 10 2-phenethyl, 1-, 2- eller 3-phenylpropyl eller 1-, 2-, 3-eller 4-phenylbutyl, hvori phenylringen er usubstitueret.Phenyllavalkyl preferably means benzyl, 1- or 2-phenethyl, 1-, 2- or 3-phenylpropyl or 1-, 2-, 3-or 4-phenylbutyl wherein the phenyl ring is unsubstituted.

Ved udtrykket “lav" skal der ovenfor og i det følgende· i forbindelse med organiske grupper eller forbindelser forstås sådanne med højst 7, fortrinsvis højst 4, fordel-15 agtigt 1 eller 2 carbonatomer.By the term "low", above and hereinafter, in the context of organic groups or compounds, are meant those having at most 7, preferably at most 4, preferably 1 or 2 carbon atoms.

En lavalkylgruppe indeholder fortrinsvis 1-4 carbonatomer og betyder f.eks. ethyl, propyl, butyl eller fordelagtigt methyl.A lower alkyl group preferably contains from 1 to 4 carbon atoms and means e.g. ethyl, propyl, butyl or advantageously methyl.

En lavalkoxygruppe indeholder fortrinsvis 1-4 carbonatomer 20 og er eksempelvis methoxy, propoxy, isopropoxy eller fordelagtigt ethoxy.A lower alkoxy group preferably contains 1-4 carbon atoms 20 and is, for example, methoxy, propoxy, isopropoxy or advantageously ethoxy.

Phenyllavalkoxy betyder fordelagtigt f.eks. benzyloxy.Phenyllavalkoxy advantageously means e.g. -benzyloxy.

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5 I de omhandlede forbindelser kan den ene eller, begge carboxylgrupperne i dicarboxylsyrerne, dvs. forbindelserne med formlen I, hvori Rg og R7 betyder hydroxy, foreligge i 5 form af funktionelle derivater som estere. Disse funktionelle derivater er fortrinsvis mono- eller bis-lavalkyl-estrene, f.eks. methyl-, ethyl-, n- eller i-propyl- eller butylestrene eller benzylestrene. Stærkt foretrukne funktionelle derivater af monoestrene med formlen I, f.eks.In the compounds of the present invention, one or both carboxyl groups of the dicarboxylic acids, i. the compounds of formula I wherein R 9 and R 7 represent hydroxy are in the form of functional derivatives such as esters. These functional derivatives are preferably the mono- or bis-lower alkyl esters, e.g. the methyl, ethyl, n or i-propyl or butyl esters or benzyl esters. Highly preferred functional derivatives of the monoesters of formula I, e.g.

10 sådanne, hvori en af grupperne Rg og R7 betyder hydroxy, og den anden betyder lavalkoxy.10, wherein one of the groups Rg and R7 is hydroxy and the other is lower alkoxy.

Farmaceutisk acceptable salte er fortrinsvis metal- eller ammoniumsalte af forbindelserne med formlen I, hvori CORg og/eller COR7 betyder carboxy, især alkalimetal- eller 15 jordalkalimetalsalte, f.eks. natrium-, kalium-, magnesiumeller calciumsaltet, eller fordelagtigt let krystalliserende ammoniumsalte afledt af ammoniak eller organiske aminer, såsom mono-, di- eller trilav(alkyl-, cycloalkyl eller hydroxyalkyl)aminer, lavalkylendiaminer eller lav-20 (hydroxyalkyl eller aralkyl)alkylammoniumbaser, f.eks. methylamin, diethylamin, triethylamin, dicyclohexylamin, triethanolamin, ethylendiamin, tris-(hydroxymethyl)amino-methan eller benzyltrimethylammoniumhydroxid.Pharmaceutically acceptable salts are preferably metal or ammonium salts of the compounds of formula I wherein CORg and / or COR7 means carboxy, especially alkali metal or alkaline earth metal salts, e.g. the sodium, potassium, magnesium or calcium salt, or advantageously light crystallizing ammonium salts derived from ammonia or organic amines such as mono-, di- or trilaw (alkyl, cycloalkyl or hydroxyalkyl) amines, low alkylene diamines or low-hydroxyalkyl or aralkyl) alkylammonium bases , eg. methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris- (hydroxymethyl) amino-methane or benzyltrimethylammonium hydroxide.

Forbindelserne med formlen I danner endvidere syre-25 additionssalte, fortrinsvis sådanne med terapeutisk acceptable uorganiske eller organiske syrer, såsom stærke mineralsyrer, f.eks. hydrogenhalogenidsyrer, f.eks. hydrogenchlorid- eller hydrogenbromidsyre, svovlsyre, phosphorsyre, salpetersyre eller perchlorsyre, aliphatiske 30 eller aromatiske carboxyl- eller sulfonsyrer, f.eks. myresyre, eddikesyre, propionsyre, ravsyre, glycolsyre, mælkesyre, æblesyre, vinsyre, gluconsyre, citronsyre, ascorbinsyre, maleinsyre, fumarsyre, hydroxymaleinsyre, pyrodruesyre, phenyleddikesyre, benzoesyre, 4-aminobenzoe-35 syre, anthranilsyre, 4-hydroxybenzoesyre, salicylsyre, 4-The compounds of formula I further form acid addition salts, preferably those with therapeutically acceptable inorganic or organic acids, such as strong mineral acids, e.g. hydrogen halide acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, nitric or perchloric acid, aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, 4-aminobenzoic acid, -

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6 aminosalicylsyre, pamoesyre, nicotinsyre, methansulfon-syre, ethansulfonsyre, hydroxyethansulfonsyre, benzen- sulfonsyre, p-toluensulfonsyre, naphthalensulfonsyre, 5 sulfanilsyre eller cyclohexylsulfaminsyre.6 amino salicylic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid.

Forbindelserne med formlen I har værdifulde farmakologiske egenskaber, bl.a. som følge af deres hæmmende virkning på sekretionen af angiotensin II. Denne virkning fremkaldes ved selektiv hæmning af enzymet, som i pattedyr omdanner 10 angiotensinet. Forbindelserne med formlen I er derfor anvendelige til behandling af sygdomme, som reagerer på hæmningen af enzymet, der omdanner angiotensinet i pattedyr og mennesker.The compounds of formula I have valuable pharmacological properties, e.g. due to their inhibitory effect on the secretion of angiotensin II. This effect is elicited by selective inhibition of the enzyme which in mammals converts the angiotensin. Therefore, the compounds of formula I are useful in the treatment of diseases which respond to the inhibition of the enzyme which converts the angiotensin into mammals and humans.

De omhandlede forbindelser udviser i første række hypo-15 tensive/antihypertensive virkninger og påvirker hjertefunktionen. Disse egenskaber kan påvises ved hjælp af in vivo- eller in vitro-dyreforsøg, fortrinsvis med pattedyr, f.eks. rotter, katte, hunde eller isolerede organer fra disse dyr, som forsøgsobjekter. Dyrene kan enten være 20 normotensive eller hypertensive, f.eks. genetisk spontant f hypertensive rotter, eller renalt hypertensive rotter eller hunde, samt hunde, hvis natrium er fjernet. Forsøgsdyrene kan indgives forbindelserne enteralt eller parenteralt, fortrinsvis oralt eller intravenøst,’ f.eks.The compounds of the invention primarily exhibit hypotensive / antihypertensive effects and affect cardiac function. These properties can be demonstrated by in vivo or in vitro animal studies, preferably with mammals, e.g. rats, cats, dogs, or isolated organs from these animals as experimental objects. The animals may be either normotensive or hypertensive, e.g. genetically spontaneous hypertensive rats, or renally hypertensive rats or dogs, as well as dogs whose sodium is removed. The test animals may be administered the compounds enterally or parenterally, preferably orally or intravenously, e.g.

25 ved hjælp af gelatinekapsler eller i form af stivelsesholdige suspensioner eller vandige opløsninger. Den anvendte dosis kan ligge i et område fra mellem ca. 0,01 og 100 mg/kg/dag, fortrinsvis mellem ca. 0,05 og 50 mg/kg/ dag, især mellem ca. 0,1 og 25 mg/kg/dag.25 by gelatin capsules or in the form of starchy suspensions or aqueous solutions. The dose used may be in a range of from about. 0.01 to 100 mg / kg / day, preferably between ca. 0.05 to 50 mg / kg / day, especially between ca. 0.1 and 25 mg / kg / day.

30 Den blodtrykssænkende virkning in vivo registreres enten direkte med et kateter, som er indført i forsøgsdyrets femorale arterie, eller indirekte ved hjælp af sphygmo-manometri med rottehalen og et overføringsinstrument. Blodtrykket bestemmes i mm Hg før og efter indgivelsen af 35 den virksomme forbindelse.The in vivo blood pressure lowering effect is recorded either directly with a catheter inserted into the femoral artery of the test animal or indirectly by rat tail sphygmometry and a transfer instrument. Blood pressure is determined in mm Hg before and after administration of the active compound.

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Således kan de antihypertensive virkninger påvises i spontant hypertensive rotter ved indirekte måling af det systoliske blodtryk. Ikke-narkotiserede rotter anbringes 5 enkeltvis i bure, som begrænser deres bevægelse, i et let opvarmet kammer. En puls-sensor anbringes inden i en oppustelig manchet på hver enkelt rottes hale. Manchetten oppustes, således at den slutter til halearterien. Trykket i manchetten formindskes kontinuerligt, og det systoliske 10 tryk svarer til det tryk i manchetten, ved hvilket pulsbølgerne atter optræder. Efter registreringen af kontrolværdier for blodtrykket og hjertefrekvensen indgives forsøgsforbindelserne peroralt én gang daglig i fire på hinanden følgende dage. Yderligere blodtryksmålinger 15 foretages sædvanligvis efter 2,0, 4,0 og 23,5 timer efter hver dagsdosis. Værdierne sammenlignes med værdier opnået med rotter, som kun er behandlet med bærestoffet.Thus, the antihypertensive effects can be detected in spontaneously hypertensive rats by indirectly measuring systolic blood pressure. Non-narcotic rats are placed individually in cages which restrict their movement in a slightly heated chamber. A heart rate sensor is placed inside an inflatable cuff on the tail of each rat. The cuff is inflated to end 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 again occur. After recording blood pressure and heart rate control values, test compounds are administered orally once daily for four consecutive days. Additional blood pressure measurements are usually taken at 2.0, 4.0 and 23.5 hours after each daily dose. The values are compared with values obtained with rats treated with the carrier only.

Til illustration af de omhandlede forbindelsers anti-hypertensive virkning anføres virkningen af den "højere-20 smeltende" l-carboxymethyl-3-(l-ethoxycarbonyl-3-phenyl-propylamino)-2,3,4,5-tetrahydro-lH-[ 1 ]benzazepin-2-on ifølge eksempel 1: Ved en dosis på 3 mg/kg p.o. opnås en gennemsnitlig blodtrykssænkning på 40 mm Hg. Målingerne er foretaget 2 og 4 timer efter indgivelsen i de sidste to 25 dage. Den tilsvarende S,S-enantiomere forbindelse ifølge eksempel 12 bevirker en blodtrykssænkning på 30 mm Hg ved en peroral dosis på 1 mg/kg.To illustrate the anti-hypertensive effect of the compounds of the invention, the effect of the "higher-melting" 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1 [1] benzazepin-2-one according to Example 1: At a dose of 3 mg / kg po an average blood pressure drop of 40 mm Hg is achieved. The measurements were made 2 and 4 hours after the administration for the last two 25 days. The corresponding S, S enantiomeric compound of Example 12 causes a blood pressure drop of 30 mm Hg at an oral dose of 1 mg / kg.

De omhandlede forbindelser fremkalder efter intravenøs eller oral indgift også på normotensive rotter en hæmmende 30 virkning mod den af angiotensin I fremkaldte blodtryksforhøjelse. Angiotensin I hydrolyseres af det nævnte omdannelsesenzym til det stærkt blodtryksforhøjende stof angiotensin II. Hæmningen af det nævnte enzym blokerer dannelsen af angiotensin II ud fra angiotensin I. På denne 35 måde afsvækkes den af angiotensin I fremkaldte blodtryksforhøjelse.The compounds of this invention, following intravenous or oral administration, also exert an inhibitory effect on the blood pressure induced by angiotensin I in normotensive rats. Angiotensin I is hydrolyzed by the aforementioned conversion enzyme to the high blood pressure enhancer angiotensin II. The inhibition of said enzyme blocks the formation of angiotensin II from angiotensin I. In this way, the increase in blood pressure induced by angiotensin I is attenuated.

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Den tilsvarende in vivo-test med de intravenøst indgivne forbindelser gennemføres med normotensive hanrotter, som er narkotiseret med natriumsaltet af 5-ethyl-5-(1-methyl-5 propyl)-2-thiobarbitursyre. En femoral arterie og en vene i benet forsynet begge med en kanyle til den direkte måling af blodtrykket og til den intravenøse indgift af angiotensin I og forsøgsforbindelsen. Efter stabilisering af det basale blodtryk bestemmes trykændringen efter tre 10 intravenøse indgivelser af 333 ng/kg angiotensin I med 5 minutters mellemrum. Sådanne trykændringer bestemmes atter efter henholdsvis 5, 10, 15, 30 og 60 minutter efter intravenøs indgift af forsøgsforbindelsen. De sidstnævnte trykændringer sammenlignes med begyndelsesværdierne.The corresponding in vivo test with the intravenously administered compounds is performed with normotensive male rats anesthetized with the sodium salt of 5-ethyl-5- (1-methyl-5-propyl) -2-thiobarbituric acid. A femoral artery and a vein in the leg both provide a cannula for the direct measurement of blood pressure and for the intravenous administration of angiotensin I and the test compound. After stabilizing basal blood pressure, the pressure change is determined after three 10 intravenous administrations of 333 ng / kg angiotensin I at 5 minute intervals. Such pressure changes are determined again after 5, 10, 15, 30 and 60 minutes, respectively, after intravenous administration of the test compound. The latter pressure changes are compared with the initial values.

15 Enhver konstateret formindskelse af blodtrykspåvirkningen refererer til hæmningen af enzymet, som omdanner angiotensin I. Til illustration af de omhandlede forbindelsers virkning kan nævnes, at den "højeresmeltende" 1-carboxy-methyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-20 tetrahydro-lH-[ 1 ]benzazepin-2-on ifølge eksempel 1 og den tilsvarende S,S-enantiomere forbindelse ifølge eksempel 12 fuldstændigt hæmmer blodtryksforhøjelsen efter angiotensin I-påvirkning i 30 minutter efter intravenøs indgift af en dosis på 1 mg/kg pr. stof.Any decrease in blood pressure effect refers to the inhibition of the enzyme which converts angiotensin I. By way of illustration of the effect of the compounds of this invention, it can be mentioned that the "high-melting" 1-carboxy-methyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) - 2,3,4,5-20 tetrahydro-1H- [1] benzazepin-2-one of Example 1 and the corresponding S, S enantiomeric compound of Example 12 completely inhibit the blood pressure increase after angiotensin I effect for 30 minutes after intravenous administration. of a dose of 1 mg / kg per day. fabric.

25 In vitro-hæmningen af enzymet, som omdanner angiotensinet, kan ved de omhandlede forbindelser påvises analogt med fremgangsmåden ifølge Biochim. Biophys. Acta 293, 451 (1973). Ifølge denne fremgangsmåde opløses forsøgsforbindelserne i en omtrentlig millimolær koncentration i 30 phosphatpuffer. Til 100 mikroliter af opløsninger af forsøgsforbindelsen i phosphatpuffer, som man fortynder til den ønskede koncentration, sættes først 100 mikroliter 5 millimolær hippurylhistidyl-leucin i phosphatpuffer og derpå 50 μΐ af det angiotensin-omdannende enzym. Dette 35 enzym fremstilles af lunger fra voksne hankaniner i tris-puffer, som indeholder kalium- og magnesiumchlorid ogThe in vitro inhibition of the enzyme which converts the angiotensin can be detected by the compounds of this invention analogously to the method of Biochim. Biophys. Acta 293, 451 (1973). According to this method, the test compounds are dissolved in an approximate millimolar concentration in 30 phosphate buffer. To 100 microliters of solutions of the test compound in phosphate buffer diluted to the desired concentration, first add 100 microliters of 5 millimolar hippurylhistidyl-leucine in phosphate buffer and then 50 μΐ of the angiotensin converting enzyme. This enzyme is made from adult male rabbits in tris buffer containing potassium and magnesium chloride and

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9 tillige rørsukker. Opløsningerne inkuberes i 30 minutter ved 37°C, og den fortsatte reaktion afbrydes ved tilsætning af 0,75 ml 0,5 N vandig natriumhydroxidopløsning.9 also cane sugar. The solutions are incubated for 30 minutes at 37 ° C and the continued reaction quenched by the addition of 0.75 ml of 0.5 N aqueous sodium hydroxide solution.

5 Derpå tilsættes ved stuetemperatur 100 mikroliter af en 0,2%’s opløsning af o-phthalaldehyd i methanol og efter 10 minutters forløb 100 mikroliter 6 N saltsyre. Disse prøver sammenlignes i et spektrofotometer ved 360 nm med vand, og deres optiske tæthed bestemmes. Disse værdier 10 tilpasses en standardkurve ved hjælp af en omdannelsesfaktor, hvorved man får den i løbet af den nævnte inkubationstid på 30 minutter dannede histidyl-leucin-mængde i nanomol. Til bestemmelse af ICgg-værdien afbildes resultaterne grafisk mod koncentrationen af den virksomme 15 forbindelse. ICsg-værdien betyder den koncentration af virksom forbindelse, som bevirker halvdelen af aktiviteten af en kontrolprøve, der ikke indeholder noget virksomt stof. Til illustration af de omhandlede forbindelsers virkning kan nævnes, at den "højeresmeltende" l-carboxy-20 methyl-3-(1-carboxy-3-phenylpropylamino )-2,3,4,5-1etrahydro-1Η-[ 1 ]benzazepin-2-on ifølge eksempel 9 og den tilsvarende S,S-enantiomere forbindelse ifølge eksempel 18 har en ICso-værdi på henholdsvis 5,2 x ΙΟ-9 M og 1,7 x 10“9 M.Then, at room temperature, 100 microliters of a 0.2% solution of o-phthalaldehyde in methanol are added and after 10 minutes 100 microliters of 6N hydrochloric acid are added. These samples are compared in a spectrophotometer at 360 nm with water and their optical density determined. These values 10 are adjusted to a standard curve by a conversion factor to give the histidyl-leucine amount of nanomole produced during the said 30-minute incubation time. To determine the ICgg value, the results are plotted graphically against the concentration of the active compound. The ICsg value means the concentration of active compound which causes half the activity of a control sample containing no active substance. To illustrate the effect of the compounds of the invention, the "high melting" 1-carboxy-methyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-1etrahydro-1 [1-] benzazepine is mentioned. -2-on of Example 9 and the corresponding S, S-enantiomeric compound of Example 18 have an IC 50 value of 5.2 x ΙΟ-9 M and 1.7 x 10

Den tilsvarende "laveresmeltende" l-carboxymethyl-3-(l-25 carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[ 1 ]benz-azepin-2-on ifølge eksempel 8 har en ICsg-værdi på 5,8 x 10”8 M.The corresponding "lower melting" 1-carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one of Example 8 has an IC value of 5.8 x 10 ”8 M.

Enzymet, som omdanner angiotensin, deltager ikke blot i omdannelsen af angiotensin I til angiotensin II, men det 30 spiller også en rolle ved reguleringen af bradyquinin- og aldosteron-koncentrationerne. De omhandlede forbindelsers virkning på disse faktorer kan også bidrage til deres antihypertensive og hjertevirksomme egenskaber.The enzyme that converts angiotensin not only participates in the conversion of angiotensin I to angiotensin II, but it also plays a role in the regulation of bradyquinine and aldosterone concentrations. The effect of the compounds of the present invention on these factors may also contribute to their antihypertensive and cardiac properties.

Som følge af de ovenfor nævnte fordelagtige egenskaber er 35 de omhandlede forbindelser særdeles værdifulde som specifikke terapeutiske midler til pattedyr og mennesker.Because of the advantageous properties mentioned above, the compounds of the invention are extremely valuable as specific mammal and human therapeutic agents.

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10 I overensstemmelse hermed er de omhandlede forbindelser værdifulde antihypertensive midler, især til formindskelse af højt blodtryk (uden hensyntagen til etiologien) 5 og/eller ved hjertesygdomme, såsom hjerteinsufficiens, og/eller andre tilstande, der har forbindelse med ødemer eller ascites.Accordingly, the compounds of the invention are valuable antihypertensive agents, especially for lowering hypertension (without regard to etiology) and / or in heart disease such as heart failure, and / or other conditions associated with edema or ascites.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man 10 a) i en forbindelse med formlen oc^ ^-CH-COELy hvori R2 og R7 har de ovenfor anførte betydninger, indfører gruppen -CH(Ri)C0Rg ved alkylering med en forbindelse med formlen Ri-CH(Z)-C0Rg (Illa), hvori Z betyder en 15 reaktiv forestret hydroxygruppe, og Ri og Rg har de ovenfor angivne betydninger, eller med en forbindelse med formlen R^CO-CORg (IV), hvori Ri og Rg har de ovenfor angivne betydninger, i nærværelse af et reduktionsmiddel, eventuelt under midlertidig beskyttelse af eventuelle 20 hydroxygrupper, som kan forekomme i en vilkårlig af grupperne Rg og R7, eller b) alkylerer en forbindelse med formlenThe process of the invention is characterized in that by a) in a compound of the formula oc-CH-COELy wherein R 2 and R 7 have the above meanings, the group -CH (R 1) C0 R 9 is introduced by alkylation with a compound of the formula R 1 -CH (Z) -COrg (IIIa) wherein Z represents a reactive esterified hydroxy group and R 1 and R 5 have the above meanings, or with a compound of the formula R 1 CO-COR 6 (IV) wherein R 1 and R g have the above meanings, in the presence of a reducing agent, optionally under the temporary protection of any 20 hydroxy groups which may occur in any of the groups Rg and R7, or b) alkylate a compound of the formula

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1111

-v H-v H

L jl / t'“~?H'RL (V)L jl / t '“~? H'RL (V)

—/ I- / I

H ft 0°R6 hvori og Rg har de ovenfor angivne betydninger, med en forbindelse med formlen R2~CH(Z)-COR7 (IIIB), hvori Z 5 betyder en reaktiv forestret hydroxygruppe, og R2 og R7 har de ovenfor angivne betydninger, idet man eventuelt midlertidigt beskytter eventuelle hydroxygrupper, som kan forekomme i en vilkårlig af grupperne Rg og R7, eller c) kondenserer en forbindelse med formlen C jj^ /~x · μ i o R2-CH-COR7 hvori Y betyder oxo eller en reaktiv forestret hydroxygruppe Z sammen med hydrogen, og R2 og R7 har de ovenfor angivne betydninger, med en amin med formlenH ft 0 ° R6 wherein and Rg have the above meanings, with a compound of the formula R2 ~ CH (Z) -COR7 (IIIB) wherein Z5 is a reactive esterified hydroxy group and R2 and R7 have the meanings given above, optionally temporarily protecting any hydroxy groups which may be present in any of the groups Rg and R7, or c) condensing a compound of the formula C jj ^ · x · μ io R2-CH-COR7 wherein Y means oxo or a reactive esterified hydroxy group Z together with hydrogen and R 2 and R 7 have the above meanings, with an amine of the formula

HH

H-N-CH-R1 (VII) CORr b 15 hvori Rj[ og Rg har de ovenfor angivne betydninger, idet kondensationen gennemføres i nærværelse af et reduktions-H-N-CH-R1 (VII) CORr b 15 wherein R 1 and R 5 have the above meanings, the condensation being carried out in the presence of a reducing agent.

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12 middel, når Y betyder oxo, eller d) i en forbindelse med formlen ητΛ xri /~N\ ^12 when Y is oxo, or d) in a compound of the formula ητΛ xri / ~ N \

AA

R2 R" hvori R^ og R2 har de ovenfor angivne betydninger, et af symbolerne R' og R" betyder cyan, og det andet betyder ligeledes cyan eller CORg eller COR7 som defineret ovenfor, underkaster cyangruppen eller -grupperne en ^0 solvolyse eller e) cycliserer en forbindelse med formlenR 2 R "wherein R 1 and R 2 have the meanings given above, one of the symbols R 1 and R" means cyan, and the other also means cyan or COR 6 or COR 7 as defined above, the cyano group or groups subject to a ) cycles a compound of formula

HH

(IX) NH COOH CORg R2-CH-COR7 hvori Rj_, R2, Rø og R7 har de ovenfor angivne betydninger, eller en ester deraf, 15 og, om ønsket, omdanner en dannet forbindelse med formlen I som defineret ovenfor til en anden forbindelse med formlen I omfattet af den ovenfor anførte definition og/eller, om ønsket, omdanner en dannet forbindelse med formlen I som defineret ovenfor med saltdannende egen-20 skaber til et salt deraf eller frigør en fri forbindelse(IX) NH COOH CORg R2-CH-COR7 wherein R R, R₂, Rø and R7 have the meanings given above, or an ester thereof, and, if desired, convert a formed compound of formula I as defined above to another compound of formula I encompassed by the above definition and / or, if desired, converting a compound of formula I as defined above with salt-forming properties into a salt thereof or releasing a free compound

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13 med formlen I fra et sådant salt og/eller opkoncentrerer en optisk isomer, som har en specifik konfiguration med hensyn til i det mindste ét chiralitetscentrum, fra en 5 blanding af de stereoisomere former af en dannet forbindelse med formlen I.13 of formula I from such a salt and / or concentrates an optical isomer having a specific configuration with respect to at least one center of chirality, from a mixture of the stereoisomeric forms of a compound of formula I formed.

Alkyleringen ifølge fremgangsmåderne a) og b), som tjener til indføring af grupperne -CH(Ri)CORg eller -CH(R2)C0R7, gennemføres på sædvanlig måde, fordelagtigt ved omsætning 10 af et tilsvarende udgangsmateriale med formlen II eller V med et alkyleringsmiddel med formlen (IIIA) eller (HIB), hvori Z betyder en reaktionsdygtig forestret hydroxyl-gruppe, såsom en med en stærk organisk syre, f.eks. med en aliphatisk eller aromatisk sulfonsyre, såsom en 15 lavalkansulfonsyre, især methansulfonsyre, trifluormethan-sulfonsyre, især benzensulfonsyre, p-toluensulfonsyre, p-brombenzensulfonsyre og p-nitrobenzensulfonsyre, eller med en stærk uorganisk syre, såsom især svovlsyre, eller med en hydrogenhalogenidsyre, såsom hydrogenchloridsyre, 20 eller mest foretrukket hydrogeniodidsyre eller hydrogen-bromidsyre, forestret hydroxylgruppe. Alkyleringen gennemføres under sædvanlige generelle betingelser ved temperaturer i området fra ca. 0°C op til reaktionsblandingens kogetemperatur, fortrinsvis ved temperaturer 25 mellem stuetemperatur og ca. 100°C. Omsætningen gennemføres fordelagtigt i nærværelse af et opløsningsmiddel, som er indifferent over for reaktanterne, f.eks. i nærværelse af en chloreret lavalkan, f.eks. chloroform eller methylenchlorid, en acyclisk eller cyclisk ether, 30 f.eks. diethylether, 1,2-dimethoxyethan, dioxan eller tetrahydrofuran, og især en tertiær amid med lav molekylvægt, f.eks. N,N-dimethylformamid, N,N-dimethyl-acetamid, N-methylpyrrolidon, N-ethylpiperidon og hexamethylphosphorsyre-trisamid. Det er fordelagtigt at 35 binde den under reaktionen frigjorte stærke syre HZ ved tilsætning af et syrebindende middel, såsom fortrinsvis enThe alkylation according to processes a) and b) which serves to introduce the groups -CH (R 1) COR 6 or -CH (R 2) C0 R 7 is carried out in the usual manner, advantageously by reacting 10 of a corresponding starting material of formula II or V with an alkylating agent of formula (IIIA) or (HIB) wherein Z represents a reactively esterified hydroxyl group such as one having a strong organic acid, e.g. with an aliphatic or aromatic sulfonic acid such as a low alkanesulfonic acid, especially methanesulfonic acid, trifluoromethanesulfonic acid, especially benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzene sulfonic acid, p-nitrobenzenesulfonic acid, or with a strong inorganic acid such as sulfuric acid, especially sulfuric acid, such as hydrogen chloride acid, or most preferably hydrogen iodide acid or hydrogen bromic acid esterified hydroxyl group. The alkylation is carried out under the usual general conditions at temperatures in the range of approx. 0 ° C up to the boiling temperature of the reaction mixture, preferably at temperatures between room temperature and ca. 100 ° C. The reaction is advantageously carried out in the presence of a solvent which is inert to the reactants, e.g. in the presence of a chlorinated low alkane, e.g. chloroform or methylene chloride, an acyclic or cyclic ether, e.g. diethyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, and especially a low molecular weight tertiary amide, e.g. N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone and hexamethylphosphoric acid trisamide. It is advantageous to bind the strong acid HZ released during the reaction by the addition of an acid binding agent such as preferably a

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14 uorganisk syrebinder, f.eks. et alkalimetal-hydrogen-carbonat, -carbonat eller -hydroxid, et organisk kvater-nært ammoniumsalt, f.eks. et tetrabutylammoniumsalt, eller 5 en organisk tertiær base, såsom triethylamin, N-ethylpiperidin, pyridin eller quinolin.14 inorganic acid binders, e.g. an alkali metal hydrogen carbonate, carbonate or hydroxide, an organic quaternary ammonium salt, e.g. a tetrabutylammonium salt, or an organic tertiary base such as triethylamine, N-ethylpiperidine, pyridine or quinoline.

Ved fremgangsmåde a) kan alkyleringen også gennemføres under i og for sig kendte betingelser for en reducerende alkylering. Ved gennemførelse af alkyleringen omsættes en 10 forbindelse med den almene formel (IV) med den bicycliske udgangsforbindelse med formlen II og samtidigt eller i et efterfølgende trin med et reduktionsmiddel. Som reduktionsmidler, der kan anvendes samtidig med alkylerings-midlet, kan nævnes myresyre og komplekse metalhydrider, 15 såsom natriumcyanoborhydrid. Blandt de reduktionsmidler, der overvejende anvendes i et særskilt efterfølgende trin, dvs. reduktion af en tidligere dannet imin (schiffbase) kan nævnes diboran og komplekse metalhydrider, såsom natriumborhydrid og natriumcyanoborhydrid, som fordel-20 agtigt sættes til den primære reaktionsblanding uden isolering af mellemproduktet, f.eks. en imin. I dette tilfælde gennemføres alkyleringen fordelagtigt i et over for reduktionsmidlet indifferent organisk opløsningsmiddel, såsom i en aliphatisk eller cyclisk ether, f.eks.In process a) the alkylation can also be carried out under conditions known per se for reducing alkylation. In carrying out the alkylation, a compound of general formula (IV) is reacted with the bicyclic starting compound of formula II and simultaneously or in a subsequent step with a reducing agent. As reducing agents which can be used in conjunction with the alkylating agent may be mentioned formic acid and complex metal hydrides, such as sodium cyanoborohydride. Among the reducing agents used predominantly in a separate subsequent step, viz. reduction of a previously formed imine (schiff base) may be mentioned diborane and complex metal hydrides, such as sodium borohydride and sodium cyanoborohydride, which are advantageously added to the primary reaction mixture without isolation of the intermediate, e.g. and imin. In this case, the alkylation is advantageously carried out in an inert organic solvent, such as in an aliphatic or cyclic ether, e.g.

25 diethylether, diisopropylether, 1,2-dimethoxyethan, dioxan eller tetrahydrofuran, eller i en aliphatisk alkohol, som methanol, ethanol, isopropanol, glycol, glycolmonomethyl-ether, diethylenglycol, fortrinsvis ved temperaturer på fra ca. 0 til ca. 80°C. Et væsentligt reduktionsmiddel, 30 der kan anvendes både samtidigt med og i et senere trin, er dog hydrogen, især katalytisk aktiveret hydrogen. Som katalysatorer anvendes sådanne, der sædvanligvis anvendes som hydrogeneringskatalysatorer, dvs. fortrinsvis sådanne valgt blandt ædelmetallerne, f.eks. palladium, platin og 35 rhodium, på en bærer, f.eks. calciumcarbonat, aluminium-Diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or in an aliphatic alcohol such as methanol, ethanol, isopropanol, glycol, glycol monomethyl ether, diethylene glycol, preferably at temperatures of from ca. 0 to approx. 80 ° C. However, a major reducing agent that can be used both simultaneously and in a later step is hydrogen, especially catalytically activated hydrogen. Catalysts used are those commonly used as hydrogenation catalysts, i.e. preferably those selected from the precious metals, e.g. palladium, platinum and 35 rhodium, on a carrier, e.g. calcium carbonate, aluminum

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15 oxid eller bariumsulfat, i findispers suspension uden bærer eller i form af komplekser i homogen fase. Også findispergerede overgangsmetaller, f.eks. Raney-metaller, 5 især Raney-nikkel, er særdeles velegnede katalysatorer til den reducerende alkylering. De specifikke reaktionsbetingelser afhænger i stor udstrækning af den pågældende hydrogeneringskatalysator og dens nøjagtige aktivitet og afviger ikke fra de almindeligvis til hydrogeneringer 10 anvendte. Temperaturer i området fra stuetemperatur op til ca. 150°C og hydrogentryk i området for atmosfæretryk op til ca. 300 atmosfærer kan anvendes som ved de kendte standardfremgangsmåder. Foruden de ovenfor i forbindelse med hydridreduktionen anførte indifferente opløsnings-15 midler kan også anvendes lavmolekylære amider, især tertiære amider, såsom N,N-dimethylformamid, N,N-dimethyl-acetamid, N-methylpyrrolidon, N-ethylpiperidon og hexa-methylphosphorsyre-trisamid, endvidere også formamid og acetamid. Der skal træffes særlige foranstaltninger ved 20 udgangsforbindelserne med formlen II, som indeholder en let reducerbar funktionel gruppe. Til opretholdelse af denne gruppe er det nødvendigt at anvende selektive reduktionsbetingelser, f.eks. de kendte reduktionsbetingelser, eller når der ønskes eller kræves en samtidig 25 reduktion af disse grupper, anvendes tilsvarende energi-holdige reagenser og/eller betingelser.15 oxide or barium sulphate, in fine dispersant suspension without carrier or in the form of homogeneous phase complexes. Also, finely dispersed transition metals, e.g. Raney metals, especially Raney nickel, are particularly suitable catalysts for the reducing alkylation. The specific reaction conditions depend to a large extent on the hydrogenation catalyst concerned and its exact activity and do not differ from those commonly used for hydrogenations 10. Temperatures in the range from room temperature up to approx. 150 ° C and hydrogen pressure in the range of atmospheric pressure up to approx. 300 atmospheres can be used as per the known standard methods. In addition to the inert solvents listed above in connection with the hydride reduction, low molecular weight amides, especially tertiary amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpiperidone, and hexamethylphosphoric acid can also be used. trisamide, also formamide and acetamide. Special measures must be taken at the starting compounds of formula II, which contain a readily reducible functional group. To maintain this group, it is necessary to use selective reduction conditions, e.g. the known reduction conditions, or when a simultaneous reduction of these groups is desired or required, corresponding energy-containing reagents and / or conditions are used.

De ovenfor anførte, i forvejen dannede iminer fremstilles fortrinsvis ved kondensation af en amin med formlen II med en forbindelse med formlen IV i et indifferent opløsnings-30 middel, f.eks. toluen eller methylenchlorid, i første række i nærværelse af dehydratiseringskatalysatorer, f.eks. bortrifluorid-etherat, p-toluensulfonsyre eller molekylsigter.The aforementioned imines mentioned above are preferably prepared by condensing an amine of formula II with a compound of formula IV in an inert solvent, e.g. toluene or methylene chloride, primarily in the presence of dehydration catalysts, e.g. boron trifluoride etherate, p-toluenesulfonic acid or molecular sieves.

Fremgangsmåde b) gennemføres fortrinsvis i nærværelse af 35 meget stærke baser, såsom alkalimetalhydrider, f.eks. na-Process b) is preferably carried out in the presence of very strong bases such as alkali metal hydrides, e.g. reach-

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16 triura- eller kaliumhydrid, alkalimetalalkoholater, f.eks. natriummethylat eller -ethylat eller kalium-tert-butylat, eller alkalimetalamider, f.eks. lithiumdiisopropylamid, 5 idet der fortrinsvis anvendes de foran anførte ethere og amider som opløsningsmidler.16 triura or potassium hydride, alkali metal alcoholates, e.g. sodium methylate or ethylate or potassium tert-butylate, or alkali metal amides, e.g. lithium diisopropylamide, preferably using the aforementioned ethers and amides as solvents.

Til den fakultative midlertidige beskyttelse af hydroxy-grupperne kan der med fordel anvendes beskyttelsesgrupper, som kan fraspaltes ved reduktion, jf. Houben-Weyl: 10 Methoden der organischen Chemie, 4. udgave, bind 15/ I og II, samt tillige grupper, som kan fjernes ved acidolyse, såsom 2-tetrahydropyranyl, tert-butoxycarbonyl og tert-butyl. Foretrukne hydroxybeskyttelsesgrupper, som kan fraspaltes ved reduktion, er eksempelvis benzylgrupper, 15 som kan være substituerede i den aromatiske del med halogen, lavalkyl, lavalkoxy og/eller nitro, især 4-nitrobenzylgrupper. Det er også muligt at anvende acylgrupper, som kan fraspaltes under svagt basiske betingelser, såsom formyl eller trifluoracetyl.For the optional temporary protection of the hydroxy groups, protecting groups which can be split by reduction can advantageously be used, cf. Houben-Weyl: 10 The Method of Organic Chemistry, 4th edition, volumes 15 / I and II, as well as other groups which may be removed by acidolysis such as 2-tetrahydropyranyl, tert-butoxycarbonyl and tert-butyl. Preferred hydroxy protecting groups which can be cleaved off by reduction are, for example, benzyl groups which may be substituted in the aromatic moiety by halogen, lower alkyl, lower alkoxy and / or nitro, especially 4-nitrobenzyl groups. It is also possible to use acyl groups which can be cleaved off under slightly basic conditions such as formyl or trifluoroacetyl.

20 Den efterfølgende fraspaltning af beskyttelsesgrupperne afhænger af deres natur og gennemføres i hvert enkelt tilfælde under anvendelse af i og for sig kendte fremgangsmåder, idet der tages hensyn til de generelle · egenskaber ved den dannede forbindelse.The subsequent cleavage of the protecting groups depends on their nature and is carried out in each case using methods known per se, taking into account the general characteristics of the compound formed.

25 Grupperne, som kan fraspaltes ved reduktion, især sådanne, som indeholder halogenerede lavalkylgrupper, f.eks. 2,2,2-trichlorethylgrupper, isonicotylgrupper, f.eks. iso-nicotinyloxycarbonyl, og især substituerede benzyl-grupper, først og fremmest 4-nitrobenzylgrupper af enhver 30 art, fraspaltes fortrinsvis ved reduktion med zink, sædvanligvis i nærværelse af en syre, fortrinsvis eddikesyre, og med eller uden tilsætning af et indifferentThe groups which can be cleaved off by reduction, especially those containing halogenated lower alkyl groups, e.g. 2,2,2-trichloroethyl groups, isonicotyl groups, e.g. iso-nicotinyloxycarbonyl, and especially substituted benzyl groups, primarily 4-nitrobenzyl groups of any kind, are preferably cleaved by reduction with zinc, usually in the presence of an acid, preferably acetic acid, and with or without the addition of an inert

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17 organisk opløsningsmiddel, almindeligvis ved stuetemperatur. Fraspaltningen af en beskyttelsesgruppe ved sur hydrolyse (acidolyse) gennemføres i tilfældet med grupper 5 af tert-butyl-typen ved hjælp af hydrogenchlorid, hydrogenfluorid eller trifluoreddikesyre og i tilfælde af syrefølsomme beskyttelsesgrupper hovedsagelig ved hjælp af de lavere aliphatiske carboxylsyrer, såsom myresyre og/eller eddikesyre, i nærværelse af vand og eventuelt en 10 polyhalogeneret lavalkanol eller lavalkanon, såsom 1,1,1,3,3,3-hexaflourpropan-2-ol eller hexafluoracetone.17 organic solvent, usually at room temperature. The cleavage of a protecting group by acid hydrolysis (acidolysis) is carried out in the case of groups 5 of the tert-butyl type by means of hydrogen chloride, hydrogen fluoride or trifluoroacetic acid and in the case of acid-sensitive protecting groups mainly by the lower aliphatic carboxylic acids, such as formic acid and / or acetic acid, in the presence of water and optionally a polyhalogenated low alkanol or low alkanone such as 1,1,1,3,3,3-hexaflourpropan-2-ol or hexafluoroacetone.

På denne måde er det eksempelvis muligt at spalte en N-tritylgruppe ved hjælp af en organisk syre, såsom myresyre, eddikesyre, chloreddikesyre eller trifluor-15 eddikesyre, i vandigt eller absolut trifluorethanol som opløsningsmiddel, jf. DE-offentliggørelsesskrift nr. 2.346.147, eller med vandig eddikesyre, at fraspalte tert-butoxycarbonylgruppen ved hjælp af trifluoreddikesyre eller hydrogenchloridsyre og at fjerne 2-(p-biphenylyl)-20 isopropoxycarbonylgruppen ved hjælp af vandig eddikesyre eller eksempelvis ved hjælp af en blanding af iseddike, myresyre (koncentration på 82,8%) og vand (7:1:2) eller ifølge fremgangsmåden beskrevet i DE-offentliggørelsesskrift nr. 2.346.147. Ø-Silylethylestergrupperne fra-25 spaltes fortrinsvis ved hjælp af fluorldionafgivende reagenser, f.eks. fluorider af kvaternære organiske baser, såsom tetraethylammoniumfluorid.In this way, for example, it is possible to decompose an N-trityl group by means of an organic acid, such as formic acid, acetic acid, chloroacetic acid or trifluoroacetic acid, in aqueous or absolute trifluoroethanol as a solvent, cf. DE Publication No. 2,346,147 , or with aqueous acetic acid, decomposing the tert-butoxycarbonyl group by trifluoroacetic acid or hydrochloric acid and removing the 2- (p-biphenylyl) -20 isopropoxycarbonyl group by aqueous acetic acid or, for example, by a mixture of glacial acetic acid, formic acid (concentration of 82 , 8%) and water (7: 1: 2) or according to the method described in DE Publication No. 2,346,147. The β-silylethyl ester groups are preferably cleaved by fluoride dione releasing reagents, e.g. fluorides of quaternary organic bases such as tetraethylammonium fluoride.

De af de omhandlede forbindelser, som indeholder basiske grupper, fås afhængigt af isoleringsmåden i form af baser 30 eller syreadditionssalte. Tilsvarende kan forbindelser med sure grupper også fås i form af salte. Enhver form kan på kendt måde omdannes til den anden. Baserne kan fås ud fra syreadditionssaltene på i og for sig kendt måde. Ud fra baserne er det videre muligt at danne syreadditionssalte, 35 især terapeutisk anvendelige syreadditionssalte, vedThe compounds of the present invention which contain basic groups are obtained depending on the mode of isolation in the form of bases 30 or acid addition salts. Similarly, compounds with acidic groups can also be obtained in the form of salts. Any form can, in a known way, be transformed into the other. The bases can be obtained from the acid addition salts in a manner known per se. Furthermore, from the bases it is possible to form acid addition salts, especially therapeutically useful acid addition salts, by

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18 omsætning med syrer, f.eks. med syrer af typen, som danner de ovenfor anførte salte. Syrerne og saltene står også i et lignende forhold til hinanden. Forbindelser, som 5 indeholder såvel en fri carboxygruppe som en basisk gruppe, kan foreligge i form af indre salte, og disse kan eksempelvis fås ved, at man indstiller på det isoelek-triske punkt.18 reaction with acids, e.g. with acids of the type which form the salts listed above. The acids and salts are also in a similar relationship to each other. Compounds containing both a free carboxy group and a basic group can be in the form of internal salts, and these can be obtained, for example, by adjusting at the isoelectric point.

Udgangsforbindelserne med formlerne IIIA, HIB og IV, dvs.The starting compounds of formulas IIIA, HIB and IV, ie.

10 alkyleringsmidlerne, er kendte forbindelser eller kan fremstilles på enkel måde ved anvendelse af gængse syntesefremgangsmåder, når der er tale om hidtil ukendte forbindelser.The alkylating agents, are known compounds or can be prepared in a simple manner using conventional synthetic methods in the case of novel compounds.

Udgangsforbindelserne med formlerne II og V kan også 15 fremstilles ved anvendelse af kendte syntesefremgangsmåder, fordelagtigt på den måde, som er beskrevet i det følgende for specifikke mellemprodukter.The starting compounds of formulas II and V can also be prepared using known synthetic methods, advantageously in the manner described below for specific intermediates.

Fremgangsmåde c), som også er en alkyleringsfremgangsmåde, gennemføres efter de samme almene principper og ved 20 anvendelse af samme eksperimentelle betingelser som for de ovenfor anførte fremgangsmåder a) og b), således som det detaljeret er beskrevet ovenfor for omsætningen med et alkyleringsmiddel med formlen IIIA, HIB eller IV, nemlig den substitutive alkylering eller den reduktive alkyle-25 ring. Udgangsmaterialerne med formlen VI kan- fremstilles under anvendelse af kendte fremgangsmåder, f.eks. som beskrevet detaljeret i det følgende. Aminerne med formlen VII er kendte forbindelser eller kan fremstilles på enkel måde ved hjælp af gængse syntesefremgangsmåder, når de er 30 hidtil ukendte forbindelser.Process c), which is also an alkylation process, is carried out according to the same general principles and using the same experimental conditions as for the above processes a) and b) as described in detail above for the reaction with an alkylating agent of the formula IIIA, HIB or IV, namely the substitutive alkylation or the reductive alkylation. The starting materials of formula VI can be prepared using known methods, e.g. as described in detail below. The amines of formula VII are known compounds or can be prepared simply by conventional synthetic methods when they are novel compounds.

Fremgangsmåde d) gennemføres også på sædvanlig måde under anvendelse af de gængse solvolysebetingelser, som anvendes ved omdannelse af cyanider (nitriler) til frie carboxylsyrer eller deres salte eller estere.Process d) is also carried out in the usual manner using the usual solvolysis conditions used in the conversion of cyanides (nitriles) to free carboxylic acids or their salts or esters.

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1919

Ved omdannelsen til en fri syre gennemføres hydrolysen fordelagtigt i vand i et indifferent organisk opløsningsmiddel, som er i det mindste delvis blandbart med vand, 5 såsom ethere, f.eks. diethyl- og diisopropylether, 1,2-di-methoxyethan eller især dioxan eller tetrahydrofuran, eller lavere alkanoler, f.eks. methanol, ethanol, isopropyl alkohol, butylalkoholer, og især tert-butylalkohol, hvor der i sidstnævnte tilfælde kræves en større mængde 10 vand for at forhindre en alkoholyse. Hydrolysen kan katalyseres såvel med stærke syrer, især uorganiske syrer, såsom svovlsyre, eller fortrinsvis hydrogenhalogenidsyrer, f.eks. hydrogenbromidsyre eller først og fremmest hydrogenchloridsyre, som med baser, især uorganiske baser, 15 såsom hydroxider og carbonater af alkalimetaller, f.eks. natrium- og kaliumhydroxid. Baserne anvendes sædvanligvis i mindst støkiometriske mængder, hvorved carboxylsyre-saltene dannes som primære produkter. Til opnåelse af de bedste resultater anvendes de sure katalysatorer fordel-20 agtigt i form af en fortyndet vandig opløsning. Slutprodukterne med formlen I med en forestret carboxylgruppe -CORg og/eller -COR7 kan fremstilles ved, at man gennemfører solvolysen af nitrilet med den tilsvarende alkohol (alkoholyse) i nærværelse af en katalytisk mængde vandfri 25 stærk syre, fordelagtigt gasformigt hydrogenchlorid. Sædvanligvis anvendes et overskud af alkohol som opløsningsmiddel, men der kan dog tilsættes indifferente organiske opløsningsmidler, såsom acycliske og cycliske ethere, især de ovenfor anførte, og/eller halogenerede 30 lavalkaner, især chloroform og dichlormethan. Gennemføres alkoholysen under strenge vandfri betingelser, skal det primært dannede produkt (imidoester) hydrolyseres, fordelagtigt ved tilsætning af vand til reaktionsblandingen. Når alkoholysen på den anden side gennemføres i nærværelse af 35 en omtrentlig støkiometrisk mængde vand, opnås den ønskede ester direkte.In the conversion to a free acid, the hydrolysis is advantageously carried out in water in an inert organic solvent which is at least partially miscible with water, such as ethers, e.g. diethyl and diisopropyl ether, 1,2-dimethoxyethane or especially dioxane or tetrahydrofuran, or lower alkanols, e.g. methanol, ethanol, isopropyl alcohol, butyl alcohols, and especially tert-butyl alcohol, where in the latter case a greater amount of water is required to prevent an alcoholysis. The hydrolysis can be catalyzed as well with strong acids, especially inorganic acids such as sulfuric acid, or preferably hydrogen halide acids, e.g. hydrobromic acid or, first of all, hydrochloric acid, as with bases, especially inorganic bases, such as hydroxides and carbonates of alkali metals, e.g. sodium and potassium hydroxide. The bases are usually used in at least stoichiometric amounts, whereby the carboxylic acid salts are formed as primary products. For best results, the acidic catalysts are advantageously used in the form of a dilute aqueous solution. The final products of Formula I with an esterified carboxyl group -CORg and / or -COR7 can be prepared by carrying out the solubility of the nitrile with the corresponding alcohol (alcoholysis) in the presence of a catalytic amount of anhydrous strong acid, advantageous gaseous hydrogen chloride. Generally, an excess of alcohol is used as a solvent, but inert organic solvents such as acyclic and cyclic ethers, especially the above listed and / or halogenated lower alkanes, especially chloroform and dichloromethane, may be added. If the alcoholysis is carried out under strict anhydrous conditions, the primarily formed product (imidoester) must be hydrolyzed, advantageously by adding water to the reaction mixture. On the other hand, when the alcoholysis is carried out in the presence of an approximate stoichiometric amount of water, the desired ester is obtained directly.

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2020

Udgangsmaterialerne med formlen VIII kan fremstilles på i og for sig kendt måde, f.eks. ved kondensation analogt med kondensationen ifølge fremgangsmåde c), hvorved et 5 udgangsmateriale med den ovenfor anførte formel VI omsættes med en amin med formlen H2N-<pH-R1 (VII')The starting materials of formula VIII can be prepared in a manner known per se, e.g. by condensation analogous to the condensation of process c), wherein a starting material of the above formula VI is reacted with an amine of the formula H2N- <pH-R1 (VII ')

CNCN

hvori Rj har den ovenfor angivne betydning, og som svarer til den ovenfor definerede amin med formlen VII. Også 10 fremgangsmåde a) og b) kan på analog måde anvendes til fremstilling af nitriler med formlen VIII.wherein R 1 is as defined above and corresponds to the above defined amine of formula VII. Processes a) and b) can also be used in an analogous manner for the preparation of nitriles of formula VIII.

Cycliseringen ifølge fremgangsmåde e) kan også gennemføres på kendt måde, f.eks. ved dehydratisering. Særligt anvendelige fremgangsmåder til dette formål er udviklet i 15 forbindelse med dannelsen af amidbindingen i peptider, hvilket er beskrevet i litteraturen, f.eks. Houben-Weyl, bind 15/1 og bind 15/11, som anført ovenfor. Ifølge en foretrukken udførelsesform inaktiveres aminogruppen, som skal cycliseres, ved protonering, dvs. i form af et 20 syreadditionssalt, og carboxylgruppen omdannes til en aktiveret ester, f.eks. en sådan med 2,4,5-trichlorphenol, pentachlorphenol, pentafluorphenol, 2-nitrophenol eller især 4-nitrophenol, eller med en N-hydroxyforbindelse, såsom N-hydroxysuccinimid, 1-hydroxybenztriazol eller 25 N-hydroxypiperidin, eller eventuelt med et N,N'-disubsti-tueret isourinstof, såsom især N,N’-dicyclohexyliso-urinstof, eller et analogt almindeligt kendt aktiveringsmiddel. Cycliseringen gennemføres på den måde, at man gør reaktionsmediet basisk, fortrinsvis ved tilsætning af en 30 organisk base, f.eks. et kvaternært ammoniumsalt eller især en tertiær amin, såsom triethylamin, N-ethylmorpholin eller N-methylpiperidin, for at reaktivere aminogruppen, som skal cycliseres, ved omdannelse til den ikke-The cyclization according to process e) can also be carried out in known manner, e.g. by dehydration. Particularly useful methods for this purpose have been developed in connection with the formation of the amide bond in peptides, which is described in the literature, e.g. Houben-Weyl, Volume 15/1 and Volume 15/11, as set forth above. In a preferred embodiment, the amino group to be cyclized is inactivated by protonation, i.e. in the form of an acid addition salt and the carboxyl group is converted to an activated ester, e.g. one with 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol or especially 4-nitrophenol, or with an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenztriazole or N-hydroxypiperidine, or optionally with an N , N'-disubstituted isourine, such as, in particular, N, N'-dicyclohexylisourea, or an analogous commonly known activating agent. The cyclization is carried out by basing the reaction medium, preferably by the addition of an organic base, e.g. a quaternary ammonium salt or especially a tertiary amine such as triethylamine, N-ethylmorpholine or N-methylpiperidine to reactivate the amino group to be cyclized by conversion to the non-amine.

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21 protonerede form. Reaktionstemperaturen ligger sædvanligvis fra -20 til 50°C, fortrinsvis omkring stuetemperatur, og der anvendes gængse opløsningsmidler, f.eks. dioxan, 5 tetrahydrofuran, acetonitril, pyridin, dimethylformamid, dimethylacetamid, dimethylsulfoxid, N-methylpyrrolidon, hexamethylphosphorsyre-trisamid, samt chloroform og methylenchlorid og blandinger deraf. Ved en særlig udførelsesform for fremgangsmåden kan carboxygruppen 10 aktiveres direkte in situ ved omsætning af den frie syre med et carbodiimid, såsom N,N'-dicyclohexylcarbodiimid, eventuelt under tilsætning af N-hydroxysuccinimid, et usubstitueret eller eksempelvis halogen-, methyl- eller methoxy-substitueret 1-hydroxybenztriazol eller 4-hydroxy-15 benzo-1,2,3-tr±azin-3-oxid eller N-hydroxy-5-norbornen- 2,3-dicarboximid, eller N,N1-carbonyldiimidazol.21 protonated form. The reaction temperature is usually from -20 to 50 ° C, preferably about room temperature, and common solvents, e.g. dioxane, tetrahydrofuran, acetonitrile, pyridine, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, hexamethylphosphoric acid trisamide, as well as chloroform and methylene chloride and mixtures thereof. In a particular embodiment of the process, the carboxy group 10 can be activated directly in situ by reacting the free acid with a carbodiimide such as N, N'-dicyclohexylcarbodiimide, optionally with the addition of N-hydroxysuccinimide, an unsubstituted or, for example, halogen, methyl or methoxy. -substituted 1-hydroxybenztriazole or 4-hydroxy-benzo-1,2,3-triazine-3-oxide or N-hydroxy-5-norbornene-2,3-dicarboximide, or N, N1-carbonyldiimidazole.

Udgangsmaterialerne med formlen IX kan også fremstilles på i og for sig kendt måde, f.eks. som illustreret i det efterfølgende ved hjælp af specifikke eksempler.The starting materials of formula IX may also be prepared in a manner known per se, e.g. as illustrated below using specific examples.

20 Ved gennemførelsen af den eventuelle omdannelse af et fremstillet slutprodukt med formlen I til en anden forbindelse med den almene formel I foretages de i det følgende anførte omdannelser. En fri hydroxyl- eller carboxylgruppe frigøres fra den forestrede form ved 25 hydrolyse eller hydrogenolyse og/eller en fri carboxylgruppe forestres.In carrying out the possible conversion of a manufactured final product of formula I to another compound of general formula I, the conversions set forth below are made. A free hydroxyl or carboxyl group is released from the esterified form by hydrolysis or hydrogenolysis and / or a free carboxyl group is esterified.

Alle disse eventuelle omdannelser gennemføres under anvendelse af velkendte fremgangsmåder. Forestrede hydroxylgrupper frigøres især under anvendelse af de 30 ovenfor i forbindelse med fraspaltningen af hydroxyl-beskyttelsesgrupper detaljeret beskrevne fremgangsmåder.All of these possible conversions are accomplished using well known methods. In particular, esterified hydroxyl groups are released using the methods described above in connection with the cleavage of hydroxyl protecting groups in detail.

Til forestring kan en carboxylgruppe omsættes direkte med en diazoalkan, især diazomethan, eller med en tilsvarendeFor esterification, a carboxyl group can be reacted directly with a diazoalkane, especially diazomethane, or with a corresponding

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22 alkohol i nærværelse af en stærkt sur katalysator, f.eks. svovlsyre eller en organisk sulfonsyre, og/eller et dehydratiseringsmiddel, f.eks. dicyclohexylcarbodiimid.22 alcohol in the presence of a highly acidic catalyst, e.g. sulfuric acid or an organic sulfonic acid, and / or a dehydrating agent, e.g. dicyclohexylcarbodiimide.

5 Eventuelt kan carboxylgruppen omdannes til et reaktivt derivat deraf, f.eks. en i forbindelse med fremgangsmåde e) anført aktiv ester, eller til et blandet anhydrid, f.eks. et syrehalogenid, især et syrechlorid, eller et anhydrid med trifluoreddikesyre, og dette aktiverede 10 mellemprodukt omsættes med den ønskede alkohol.Optionally, the carboxyl group may be converted to a reactive derivative thereof, e.g. an active ester listed in process e), or to a mixed anhydride, e.g. an acid halide, especially an acid chloride, or an anhydride with trifluoroacetic acid, and this activated intermediate is reacted with the desired alcohol.

Den frie carboxylgruppe kan frigøres fra en forestret carboxylgruppe på sædvanlig måde, især ved basekatalyseret hydrolyse. Særlig interessse har dog fremgangsmåder, som selektivt kan frigøre en speciel carboxylgruppe defineret 15 ved symbolerne -CORg og -COR7. I et sådant tilfælde kan der gøres brug af en egnet kombination af estergrupper, der er kendt for at være carboxylbeskyttelsesgrupper og i stort antal er udviklet specielt til syntesen af peptider, jf. Houben-Weyl, bind 15/1 og bind 15/11, jf. ovenfor.The free carboxyl group can be released from an esterified carboxyl group in the usual manner, especially by base catalyzed hydrolysis. However, particular interest has methods that can selectively release a particular carboxyl group defined by the symbols -CORg and -COR7. In such a case, a suitable combination of ester groups known to be carboxyl protecting groups and in large numbers developed specifically for the synthesis of peptides can be used, cf. Houben-Weyl, Vol. 15/1 and Vol. 15/11. see above.

20 Grupper, som er egnede til den selektive fraspaltning under frigørelse af carboxylgruppen, er estere, der f.eks. er afledt af alkoholer, som giver ved acidolyse fraspaltelige grupper, såsom cyanomethylalkohol, benzoylmethyl-alkohol eller tert-butylalkohol, dog især alkoholer, som 25 fører til grupper, der kan fraspaltes ved reduktion, såsom 2,2,2-trichlorethanol, benzylalkohol og især 4-nitro-benzylalkohol eller eventuelt isonicotinylalkohol. En særligt foretrukket gruppe substituerede alkanoler er ethyl alkohol er, som i /3-stillingen indeholder en trisub-30 stitueret silylgruppe, såsom triphenylsilyl, dimethyl-butylsilyl eller især trimethylsilyl. Som beskrevet i f.eks. belgisk patentskrift nr. 851.576 er disse alkoholer særligt egnede til selektiv fjernelse, da de tilsvarende /3-silylethylestere, f.eks. /3-( trimethylsilyl)- 35 ethylesteren, har stabilitet som almindelige alkylestere,Groups suitable for the selective cleavage during release of the carboxyl group are esters which e.g. are derived from alcohols which give by acidolysis cleavable groups such as cyanomethyl alcohol, benzoylmethyl alcohol or tert-butyl alcohol, but in particular alcohols which lead to groups which can be cleaved off by reduction, such as 2,2,2-trichloroethanol, benzyl alcohol and especially 4-nitrobenzyl alcohol or optionally isonicotinyl alcohol. A particularly preferred group of substituted alkanols is ethyl alcohol, which at the β-position contains a trisubstituted silyl group such as triphenylsilyl, dimethylbutylsilyl or especially trimethylsilyl. As described in e.g. Belgian Patent No. 851,576, these alcohols are particularly suitable for selective removal, since the corresponding β-silylethyl esters, e.g. / 3- (trimethylsilyl) - the ethyl ester, has stability as ordinary alkyl esters,

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23 men dog kan fraspaltes selektivt under milde betingelser ved indvirkning af fluoridioner under bibeholdelse af andre forestrede carboxylgrupper, f.eks. alkoxycarbonyl-5 grupper.23, however, can be selectively cleaved under mild conditions by the action of fluoride ions while retaining other esterified carboxyl groups, e.g. alkoxycarbonyl groups.

Fraspaltningen af de forestrende grupper afhænger af de pågældende gruppers natur og gennemføres i hvert enkelt tilfælde på i og for sig kendt måde, idet man tager hensyn til de øvrige gruppers egenskaber. Grupperne, som kan 10 fraspaltes ved reduktion, især sådanne, som indeholder halogenerede lavalkylgrupper, f.eks. 2,2,2-trichlorethyl-grupper, isonicotinylgrupper, f.eks. isonicotinyloxy- carbonyl, og eventuelt substituerede benzylgrupper, først og fremmest 4-nitrobenzylgrupper af enhver art, fraspaltes 15 fortrinsvis ved reduktion med zink, sædvanligvis i nærværelse af en syre, fortrinsvis eddikesyre, og med eller uden tilsætning af et indifferent organisk opløsningsmiddel, sædvanligvis ved stuetemperatur, og grupper af benzyl-typen, især usubstituerede benzylestere, fjernes 20 også ved anvendelse af hydrogeno lyseteknik, som denne sædvanligvis anvendes for benzylgrupper.The cleavage of the esterifying groups depends on the nature of the groups concerned and is carried out in each case in a manner known per se, taking into account the characteristics of the other groups. The groups which can be cleaved off by reduction, especially those containing halogenated lower alkyl groups, e.g. 2,2,2-trichloroethyl groups, isonicotinyl groups, e.g. isonicotinyloxycarbonyl, and optionally substituted benzyl groups, first and foremost 4-nitrobenzyl groups of any kind, are preferably cleaved by reduction with zinc, usually in the presence of an acid, preferably acetic acid, and with or without the addition of an inert organic solvent, usually room temperature, and benzyl-type groups, especially unsubstituted benzyl esters, are also removed by using hydrogeno light technique, which is usually used for benzyl groups.

Spaltningen af en estergruppe ved sur hydrolyse (acido-lyse) kan især i tilfælde af grupper af typen tert-butyl gennemføres ved anvendelse af hydrogenchlorid, hydrogen-25 fluorid eller trifluoreddikesyre. Ø-Silylethylester-grupperne fraspaltes fortrinsvis ved hjælp af fluorid-iondannende reagenser, f.eks. fluorider af kvaternære organiske baser, såsom tetraethylammoniumfluorid. Estergrupper, som er ustabile over for baser, kan fjernes for-30 sigtigt ved hurtig indvirkning af en vandig natriumeller kaliumhydrogencarbonatopløsning eller fortrinsvis ved indvirkning af vandig ammoniak i et organisk opløsnings- middel, sædvanligvis ved stuetemperatur. Estergrupperne fraspaltes fortrinsvis under de i 35 eksemplerne anførte reaktionsbetingelser eller under analoge betingelser.The cleavage of an ester group by acid hydrolysis (acidolysis) can be carried out, especially in the case of groups of the tert-butyl type, using hydrogen chloride, hydrogen fluoride or trifluoroacetic acid. The iso-silyl ethyl ester groups are preferably cleaved by fluoride ion forming reagents, e.g. fluorides of quaternary organic bases such as tetraethylammonium fluoride. Ester groups which are unstable to bases can be carefully removed by the rapid action of an aqueous sodium or potassium hydrogen carbonate solution or preferably by the action of aqueous ammonia in an organic solvent, usually at room temperature. The ester groups are preferably cleaved under the reaction conditions set forth in the Examples or under analogous conditions.

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2424

En egnet kombination af estergrupper kan vælges ved det tidligere syntesetrin eller gennem et passende valg af udgangsmateriale og reaktanter, idet der f.eks. ved 5 fremgangsmåde a) indføres en selektivt fraspaltelig estergruppe med en carboxylgruppe, som frigøres i det sidste trin.A suitable combination of ester groups can be selected by the previous synthesis step or by a suitable choice of starting material and reactants, e.g. by process a) a selectively cleavable ester group is introduced with a carboxyl group which is released in the final step.

Forbindelserne med formlen I fremstilles med fordel ifølge reaktionsrækken 1, hvorved der anvendes et hensigtsmæssigt 10 udvalg af udgangsmaterialer og mellemprodukter, og omfatter følgende trin: a) Kondensation ved basiske katalysebetingelser af en forbindelse med formlen σ 15 hvori Rg betyder amino, azido eller acylamino, f.eks. lavalkanoylamino eller -alkoxycarbonylamino, med en forbindelse med formlen R2 - CH - COR7 (HIB) hvori R2 betyder hydrogen eller lavalkyl, Z betyder 20 reaktivt forestret hydroxy, og R7 betyder hydroxy, lavalkoxy eller phenyllavalkoxy, b) eventuelt reduktion, hydrogenolyse eller hydrolyse af det dannede mellemprodukt til fremstilling af en forbindelse med formlenThe compounds of formula I are advantageously prepared according to reaction series 1, using an appropriate selection of starting materials and intermediates, and comprising the following steps: a) Condensation under basic catalysis conditions of a compound of formula σ wherein Rg represents amino, azido or acylamino; eg. lower alkanoylamino or alkoxycarbonylamino, with a compound of formula R 2 - CH - COR 7 (HIB) wherein R 2 represents hydrogen or lower alkyl, Z represents reactively esterified hydroxy, and R 7 represents hydroxy, low alkoxy or phenyllaalkoxy, b) optionally reducing, hydrogenolysis or hydrolysis of the intermediate formed to produce a compound of the formula

DK 157881 BDK 157881 B

25 OCJk (,°OCJk (, °

Rj-CH-COI^ hvori B-2 og R7 har de i forbindelse med formlen HIB anførte betydninger, 5 c) kondensation af en forbindelse med den ovenfor anførte formel II under betingelserne for en reducerende alkyle-ring med en forbindelse med formlen 0R 2 -CH-CO 1 wherein B-2 and R 7 have the meanings set forth in the formula HIB, c) condensation of a compound of the above formula II under the conditions of a reducing alkyl ring with a compound of the formula 0

Ri - C - COR6 (IV) hvori Ri betyder hydrogen, lavalkyl eller phenyllavalkyl, 10 og Rg betyder hydroxy eller phenyllavalkoxy, eller kondensation under alkyleringsbetingelser af en forbindelse med den ovenfor anførte forbindelse med formlen II med en forbindelse med formlenR 1 - C - COR 6 (IV) wherein R 1 is hydrogen, lower alkyl or phenyllavalkyl, and R 9 is hydroxy or phenyllavalkoxy, or condensation under alkylation conditions of a compound of the above formula II with a compound of the formula

Ri - CH - CORg (IIIA)Ri - CH - CORg (IIIA)

ZZ

15 hvori Ri og Rg har de i forbindelse med formlen IV anførte betydninger, og Z betyder reaktionsdygtigt forestret hydroxy, d) eventuelt hydrolyse af det dannede produkt eller omdannelse af det dannede produkt til et derivat, 20 e) omdannelse af en vilkårlig dannet forbindelse med formlen I til en anden omhandlet forbindelse.Wherein R 1 and R 5 have the meanings set forth in Formula IV and Z is reactively esterified hydroxy, d) optionally hydrolysis of the formed product or conversion of the formed product into a derivative, e) conversion of any formed compound with formula I for another compound.

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2626

Forbindelserne med formlen XI fremstilles ud fra de tilsvarende eventuelt til derivater omdannede 2,3,4,5-tetrahydro-lH-[ 1 ]benzazepin-2-oner [J.Chem.Soc. 1937, 456, 5 GB-PS 1.359.285 og Liebigs Annalen der Chemie, 574, 171 (1951)]. Hidtil ukendte udgangs-tetrahydro-[ 1 ]benz-azepin-2-oner, som er omdannet til egnede derivater, fremstilles med fordel ved Beckmann-omlejring af de tilsvarende derivater af naphthalen-l-oner under 10 anvendelse af i og for sig kendte fremgangsmåder og som beskrevet i forbindelse med den foreliggende opfindelse.The compounds of formula XI are prepared from the corresponding optionally converted to derivatives 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-ones [J.Chem.Soc. 1937, 456, 5 GB-PS 1,359,285 and Liebigs Annalen der Chemie, 574, 171 (1951)]. Novel starting tetrahydro- [1] benz-azepin-2-ones converted to suitable derivatives are advantageously prepared by Beckmann rearrangement of the corresponding derivatives of naphthalene-1-ones using 10 known per se. methods and as described in connection with the present invention.

Tetrahydro-[ 1 ]benzazepin-2-onerne omdannes til 3-halogen-, f.eks. 3-chlor-2,3,4,5-tetrahydro-lH-[ 1 ]benzazepin-2-on, under de her beskrevne betingelser, f.eks. ved behandling 15 med phosphorpentachlorid og efterfølgende hydrogenering. Substitutionen af disse halogenderivater med et metalazid, f.eks. natriumazid, og eventuel reduktion eller substitution med ammoniak og eventuel acylering fører til forbindelser med formlen XI.The tetrahydro- [1] benzazepin-2-ones are converted to 3-halo-, e.g. 3-chloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, under the conditions described herein, e.g. by treatment with phosphorus pentachloride and subsequent hydrogenation. The substitution of these halogen derivatives with a metal azide, e.g. sodium azide, and any reduction or substitution with ammonia and optional acylation leads to compounds of formula XI.

20 Eventuelt fremstilles forbindelserne med formlen XI, hvori Rg betyder amino eller acylamino, ved reduktion og cyclisering af den eventuelt til et derivat omdannede 4-(o-nitrophenyl)-2-aminosmørsyre og eventuelt efter følgende N-acylering.Optionally, the compounds of formula XI, wherein Rg is amino or acylamino, are prepared by reduction and cyclization of the 4- (o-nitrophenyl) -2-aminobutyric acid optionally converted and optionally following N-acylation.

25 Ved en anden fremgangsmåde til fremstilling af de omhandlede optisk aktive forbindelser anvendes den naturlige aminosyre tryptophan som udgangsmateriale. Nærmere betegnet omdannes L-4-(o-aminophenyl)-4-oxo-2-aminosmør-syre [ L-kynurenin, J.Am.Chem.Soc. 76, 1708 (1954), afledt 30 af L-tryptophan ] til et optisk aktivt udgangsmateriale med formlen XI, hvori Rg betyder acylamino, f.eks. (S)-tert-butyloxycarbonylamino, f.eks. som beskrevet i Australian Journal of Chemistry 33, 633-40 (1980). Lactam-alkylerin-In another method of preparing the optically active compounds of this invention, the natural amino acid tryptophan is used as the starting material. More specifically, L-4- (o-aminophenyl) -4-oxo-2-aminobutyric acid is converted [L-kynurenine, J.Am.Chem.Soc. 76, 1708 (1954), derived from L-tryptophan] to an optically active starting material of formula XI wherein R 9 is acylamino, e.g. (S) -tert-butyloxycarbonylamino, e.g. as described in the Australian Journal of Chemistry 33, 633-40 (1980). Lactam alkylerin-

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27 gen af en forbindelse med formlen XI med en reaktant med formlen HIB, som er velkendt fra teknikkens stade, gennemføres fortrinsvis i nærværelse af baser, såsom 5 alkalimetalhydrider, f.eks. natrium- eller kaliumhydrid, alkalimetalalkoholater, f.eks. kalium-tert-butylat eller natriummethylat, organometalforbindelser, f.eks. lithium-diisopropylamid, eller under betingelser for faseovergangskatalyse, f.eks. i nærværelse af et tetrabutyl-10 ammoniumsalt, fortrinsvis i et opløsningsmiddel, f.eks. tetrahydrofuran eller dimethylformamid, ved en temperatur på fortrinsvis mellem ca. 0 og ca. 75°C.27 gene of a compound of formula XI having a reactant of formula HIB 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 alcoholates, e.g. potassium tert-butylate or sodium methylate, organometallic compounds, e.g. lithium diisopropylamide, or under conditions of phase transition catalysis, e.g. in the presence of a tetrabutyl-ammonium salt, preferably in a solvent, e.g. tetrahydrofuran or dimethylformamide, at a temperature of preferably between ca. 0 and approx. 75 ° C.

Kondensationen af mellemprodukterne med formlen II med de kendte ce-ketosyrederivater med formlen IV, jf. Chem.Ber.The condensation of the intermediates of formula II with the known ce-ketoacid derivatives of formula IV, cf. Chem.Ber.

15 31, 551, 3133, ved reducerende N-alkylering gennemføres under anvendelse af kendte betingelser, f.eks. ved katalytisk hydrogenering med hydrogen i nærværelse af platin-, palladium- eller nikkel-katalysatorer eller med kemiske reduktionsmidler, såsom simple eller komplekse 20 letmetalhydrider, fordelagtigt et alkalimetalcyanobor-hydrid, såsom natriumcyanoborhydrid. Den reducerende aminering med et alkalimetalcyanoborhydrid gennemføres fortrinsvis i et indifferent opløsningsmiddel, f.eks. methanol eller acetonitril, fordelagtigt i nærværelse af 25 en syre, f.eks. hydrogenchloridsyre eller eddikesyre, ved en temperatur mellem ca. 0 og ca. 50°C, fortrinsvis ved stuetemperatur.15, 551, 3133, by reducing N-alkylation is carried out using known conditions, e.g. by catalytic hydrogenation with hydrogen in the presence of platinum, palladium or nickel catalysts, or with chemical reducing agents such as simple or complex light metal hydrides, advantageously an alkali metal cyanoborohydride such as sodium cyanoborohydride. The reducing 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 ca. 0 and approx. 50 ° C, preferably at room temperature.

Alkyleringen af mellemproduktaminerne med formlen II med en reaktant med formlen IIIA, der er kendt fra teknikken, 30 gennemføres med eller uden basiske katalysatorer, såsom triethylamin eller kaliumcarbonat, i et indifferent opløsningsmiddel.The alkylation of the intermediate product amines of formula II with a reactant of formula IIIA known in the art is carried out with or without basic catalysts, such as triethylamine or potassium carbonate, in an inert solvent.

Forbindelserne med formlen I kan også fremstilles ved anvendelse af reaktionsrækken 2 og 3.The compounds of formula I can also be prepared using reaction series 2 and 3.

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2828

Reaktionsrække 2 omfatter følgende trin: a) Kondensation under betingelserne for en reducerende alkylering af en forbindelse med formlen /V—\ I >~NH <XI1> rl-r o med en forbindelse med formlen 0Reaction row 2 comprises the following steps: a) Condensation under the conditions for reducing alkylation of a compound of formula / V - \ NH> XI1> rl-r o with a compound of formula 0

Ri - C - CO - Rg (IV) hvori Ri og Rg har de ovenfor ved reaktionsrække 1 anførte betydninger, eller under alkyleringsbetingelser med en 10 forbindelse med formlenR 1 - C - CO - R 9 (IV) wherein R 1 and R 9 have the meanings given above in reaction series 1, or under alkylation conditions having a compound of formula

Ri - JH - CORg (IIIA) hvori Ri, Rg og Z har de ovenfor ved reaktionsrække 1 angivne betydninger, til dannelse af en forbindelse med formlenR 1 - J H - COR 6 (IIIA) wherein R 1, R 9 and Z have the meanings given above in reaction row 1 to form a compound of formula

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2929

—\ H- \ H

Γ II /-» — (V) ål °°R6 hvori Ri og Rg har de ovenfor angivne betydninger, b) kondensation under betingelser for en basisk katalyse 5 af en fremstillet forbindelse med formlen V med en forbindelse med formlen R2 - - COR7 (HIB) hvori R2, R7 og Z har de ovenfor ved reaktionsrække 1 angivne betydninger, 10 c) eventuelt hydrolyse af det dannede produkt eller omdannelse af det dannede produkt til et derivat, d) eventuelt omdannelse af en vilkårlig fremstillet forbindelse med formlen I til en anden omhandlet forbindelse.Γ II / - »- (V) e ° ° R6 wherein R 1 and R g have the meanings given above, (b) condensation under conditions for a basic catalysis 5 of a prepared compound of formula V with a compound of formula R2 - - COR7 ( HIB) wherein R 2, R 7 and Z have the meanings given by reaction row 1, c) optionally hydrolysis of the formed product or conversion of the formed product into a derivative, d) optionally converting any prepared compound of formula I other related compound.

15 Reaktionsrækken 3 omfatter følgende trin: a) Kondensation af en forbindelse med formlen l1 h2n - CH - CORg (VII) hvori Ri betyder hydrogen, lavalkyl eller aryl, phenyl-lavalkyl, og Rg betyder hydroxy, lavalkoxy eller phenyl-20 lavalkoxy med en forbindelse med formlenThe reaction series 3 comprises the following steps: a) Condensation of a compound of formula IIh2n - CH - CORg (VII) wherein R 1 is hydrogen, lower alkyl or aryl, phenyl low alkyl, and R g represents hydroxy, low alkoxy or phenyl-low alkoxy with a compound of the formula

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3030

I OIN ISLAND

R2-CH-COR7 hvori R2 betyder hydrogen eller lavalkyl, Ry betyder hydroxy, lavalkoxy eller phenyllavalkoxy, og Y betyder 5 oxo, under betingelser for en reducerende N-alkylering eller kondensation af en forbindelse med formlen VII med en forbindelse med den ovenfor anførte formel VI, hvori Y betyder hydrogen og en reaktiv forestret hydroxygruppe, b) eventuelt hydrolyse eller derivatisering af det dannede 10 produkt, c) eventuelt omdannelse af en vilkårlig fremstillet forbindelse med formlen I til en anden omhandlet forbindelse.R 2 is hydrogen or lower alkyl, R 1 is hydroxy, lower alkoxy or phenyllavalkoxy, and Y is 5 oxo, under conditions of a reducing N-alkylation or condensation of a compound of formula VII with a compound of the above formula VI, wherein Y represents hydrogen and a reactive esterified hydroxy group, b) optionally hydrolysis or derivatization of the resulting product, c) optionally converting any prepared compound of formula I into another object compound.

Ved de ovenfor beskrevne reaktionsrækker 2 og 3 gennem-15 føres trinnene med lactamalkylering, reducerende N-alkylering og alkylering af aminer fordelagtigt under de for fremgangsmåde 1 beskrevne betingelser.In the reaction series 2 and 3 described above, the steps of lactamalkylation, reducing N-alkylation and alkylation of amines are advantageously carried out under the conditions described for process 1.

Ved de her beskrevne reaktionsrækker 1, 2 og 3 kan reaktanterne f.eks. med formlerne IIIA, HIB og VII 20 erstattes med de tilsvarende nitriler, f.eks. R2CH(Z)CN, RlCH(Z)CN henholdsvis NH2CH(R^)CN. De således fremstillede nitriler kan under anvendelse af gængse fremgangsmåder omdannes til de tilsvarende carboxylsyrer eller estere med formlen I.In the reaction series 1, 2 and 3 described herein, the reactants can e.g. with formulas IIIA, HIB and VII 20 are replaced by the corresponding nitriles, e.g. R2CH (Z) CN, R1CH (Z) CN and NH2CH (R4) CN, respectively. The nitriles thus prepared can be converted to the corresponding carboxylic acids or esters of formula I. using conventional methods.

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3131

Udgangsmaterialerne med formlen VII er aminosyrer og derivater, som er kendte forbindelser. Det skal bemærkes, at de optisk aktive omhandlede forbindelser kan fremstil-5 les ud fra en optisk aktiv forbindelse med formlen VII, f.eks. ud fra L-a-aminophenylsmørsyre, L-phenylalanin og derivater deraf.The starting materials of formula VII are amino acids and derivatives which are known compounds. It should be noted that the optically active compounds can be prepared from an optically active compound of formula VII, e.g. from L-α-aminophenylbutyric acid, L-phenylalanine and derivatives thereof.

I tilfælde af reaktanterne med formlerne IIIA, HIB, IV og VII, hvori R7 eller Rg betyder hydroxy, kan et egnet 10 carboxylatsalt fremstilles, fortrinsvis in situ, før kondensationen med de ovenfor anførte ønskede mellemprodukter.In the case of the reactants of formulas IIIA, HIB, IV and VII, wherein R7 or Rg represents hydroxy, a suitable carboxylate salt may be prepared, preferably in situ, before condensation with the desired intermediates listed above.

Visse af de ved de ovenfor beskrevne fremgangsmåder anvendte betegnelser har de i det følgende definerede 15 betydninger.Certain of the terms used in the methods described above have the meanings defined hereinafter.

En reaktionsdygtig forestret hydroxygruppe betyder en sådan, som er forestret med en stærk uorganisk eller organisk syre, først og fremmest en hydrogenhalogenidsyre, f.eks. hydrogenchloridsyre, hydrogenbromidsyre eller 20 hydrogeniodidsyre, en aliphatisk eller aromatisk sulfon-syre, f.eks. methansulfonsyre eller p-toluensulfonsyre.A reactive esterified hydroxy group means one which is esterified with a strong inorganic or organic acid, first of all a hydrogen halide acid, e.g. hydrochloric acid, hydrogen bromic acid or hydrogen iodide acid, an aliphatic or aromatic sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid.

De fakultative trin ved en reduktion, hydrogenolyse, hydrolyse eller en omdannelse til et derivat af udgangsprodukterne for den omhandlede fremgangsmåde og omdan-25 nelsen af en dannet forbindelse til en anden omhandlet forbindelse gennemføres under anvendelse af i og for sig kendte fremgangsmåder, som anskueliggøres i nærværende beskrivelse.The optional steps of a reduction, hydrogenolysis, hydrolysis or conversion to a derivative of the starting products of the present process and the conversion of a formed compound to another of the present compound are carried out using methods known per se which are illustrated in this description.

Omdannelsen af forbindelser med formlen I, hvori Rg 30 og/eller R7 betyder lavalkoxy eller phenyllavalkoxy til forbindelser med formlen I, hvori Rg og/eller R7 betyder hydroxy, gennemføres fordelagtigt ved hydrolyse med uor-The conversion of compounds of formula I wherein Rg 30 and / or R7 is lower alkoxy or phenylalloalkoxy to compounds of formula I wherein Rg and / or R7 is hydroxy is advantageously carried out by hydrolysis by

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32 ganiske syrer, såsom hydrogenhalogenidsyrer eller svovlsyre, eller med vandige baser, fortrinsvis alkalimetal-hydroxider, såsom lithium- eller natriumhydroxid.32 acidic acids, such as hydrogen halide or sulfuric acid, or with aqueous bases, preferably alkali metal hydroxides such as lithium or sodium hydroxide.

5 Den selektive omdannelse af forbindelser med formlen I, hvori Rg og/eller R7 betyder α-phenyllavalkoxy, f.eks.The selective conversion of compounds of formula I wherein R 9 and / or R 7 is α-phenyllavalkoxy, e.g.

VV

benzyloxy, til forbindelser med formlen I, hvori Rø og/eller R7 betyder hydroxy, gennemføres fordelagtigt ved hydrogenolyse under anvendelse af hydrogen i nærværelse af 10 en katalysator, f.eks. palladium.benzyloxy, for compounds of formula I wherein R0 and / or R7 is hydroxy, are advantageously carried out by hydrogenolysis using hydrogen in the presence of a catalyst, e.g. palladium.

Forbindelserne med formlen I, hvori hverken Rg eller R7 betyder hydroxy, kan omdannes til monocarboxylsyrer med formlen I, hvori en af grupperne Rg og R7 betyder hydroxy.The compounds of formula I wherein neither Rg nor R7 are hydroxy may be converted to monocarboxylic acids of formula I wherein one of the groups Rg and R7 represents hydroxy.

En sådan omdannelse gennemføres ved selektive hydrolytiske 15 eller hydrogenolytiske fremgangsmåder, som er kendte fremgangsmåder, der afhænger af den kemiske karakter af Rø- °9i R7~substituenterne.Such conversion is accomplished by selective hydrolytic or hydrogenolytic processes, which are known processes which depend on the chemical nature of the R0 9 R7 substituents.

De frie carboxylsyrer med formlen I, hvori Rg og/eller R7 betyder hydroxy, eller salte deraf kan forestres med 20 egnede kendte alkoholer eller derivater deraf til dannelse af de tilsvarende mono- eller diestere, nemlig forbindelser med formlen I, hvori Rg og/eller R7 betyder lavalkoxy eller phenyllavalkoxy.The free carboxylic acids of formula I wherein R 9 and / or R 7 are hydroxy or salts thereof may be esterified with 20 suitable known alcohols or derivatives thereof to form the corresponding mono- or diesters, namely compounds of formula I wherein R 9 and / or R7 is lower alkoxy or phenyllavalkoxy.

De ovenfor beskrevne reaktioner gennemføres under 25 anvendelse af standardfremgangsmåder i nærværelse eller fraværelse af fortyndingsmidler, fortrinsvis sådanne, som er indifferente over for reagenserne og er opløsningsmidler derfor, af katalysatorer, kondensationsmidler eller de andre midler og/eller indifferente atmosfærer, ved lave 30 temperaturer, stuetemperatur eller forhøjede temperaturer, fortrinsvis ved kogepunktet for det anvendte opløsningsmiddel, ved atmosfæretryk eller overtryk.The reactions described above are carried out using standard procedures in the presence or absence of diluents, preferably those which are inert to the reagents and are therefore solvents, of catalysts, condensing agents or the other agents and / or inert atmospheres, at low temperatures. room temperature or elevated temperatures, preferably at the boiling point of the solvent used, at atmospheric or overpressure.

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3333

Opfindelsen omfatter desuden sådanne udførelsesformer for fremgangsmåden, ved hvilken et på et vilkårligt trin af denne fremstillet mellemprodukt anvendes som udgangs-5 materiale ved gennemførelsen af de resterende trin, eller fremgangsmåden afbrydes på et vilkårligt trin, eller udgangsmaterialerne dannes under reaktionsbetingelserne, eller reaktionskomponenterne anvendes i form af salte deraf eller optisk rene antipoder. Ved disse reaktioner 10 skal der hovedsagelig anvendes sådanne udgangsmaterialer, som fører til dannelse af de ovenfor anførte forbindelser, som er karakteriseret som særligt værdifulde.The invention further encompasses such embodiments of the process in which any intermediate produced from this intermediate is used as the starting material in carrying out the remaining steps, or the process is interrupted at any stage, or the starting materials are formed under the reaction conditions or the reaction components are used in the reaction. form of salts thereof or optically pure antibodies. In these reactions 10, such starting materials are mainly used which lead to the formation of the above-mentioned compounds, which are characterized as particularly valuable.

Afhængigt af valget af udgangsmaterialer og fremgangsmåder kan de omhandlede forbindelser foreligge i form af en af 15 de mulige isomerer eller i blandinger deraf, f.eks. afhængigt af antallet af asymmetriske carbonatomer, som rene optiske isomerer, såsom antipoderne, eller som blandinger af optiske isomerer, såsom racematerne, eller som blandinger af diastereoisomerer.Depending on the choice of starting materials and methods, the subject compounds may be in the form of one of the possible isomers or in mixtures thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, such as the antipodes, or as mixtures of optical isomers, such as the racemates, or as mixtures of diastereoisomers.

20 Fremstillede diastereoisomerblåndinger og racematblandinger kan adskilles på kendt måde i de rene isomerer, diastereoisomerer eller racemater på grundlag af bestanddelenes fysisk-kemiske forskelle, f.eks. ved kromatografi og/eller fraktioneret krystallisation.Prepared diastereoisomer mixtures and racemate mixtures can be separated in known manner into the pure isomers, diastereoisomers or racemates on the basis of the physicochemical differences of the constituents, e.g. by chromatography and / or fractional crystallization.

25 De dannede racemater kan endvidere adskilles i de optiske antipoder på i og for sig kendt måde, f.eks. ved omkrystallisation fra et optisk aktivt opløsningsmiddel, ved hjælp af mikroorganismer eller ved omsætning af et surt slutprodukt med en optisk aktiv base, som danner salte med 30 den racemiske syre, og adskillelse af de på denne måde dannede salte, f.eks. på grundlag af forskelle i opløseligheder, i de diastereoisomerer, hvorfra antipoderne kan frigøres ved indvirkning af egnede midler. Basiske racemiske produkter kan ligeledes adskilles i antipoderne,Furthermore, the racemates formed can be separated into the optical antipodes in a manner known per se, e.g. by recrystallization from an optically active solvent, by microorganisms, or by reacting an acidic final product with an optically active base which forms salts with the racemic acid, and separating the salts thus formed, e.g. on the basis of differences in solubility, in the diastereoisomers from which the antipodes can be released by the action of suitable agents. Basic racemic products can also be separated into the antipodes,

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34 f.eks. ved adskillelse af de diastereoisomere salte, f.eks. ved fraktioneret krystallisation af d- eller i-tartraterne. Racemiske mellemprodukter eller udgangs-5 materialer kan adskilles på lignende måde.34 e.g. by separating the diastereoisomeric salts, e.g. by fractional crystallization of the d or i tartrates. Racemic intermediates or starting materials can be similarly separated.

Hensigtsmæssigt isoleres den mest aktive af de to antipoder.Conveniently, the most active of the two antipodes is isolated.

Endelig fås de omhandlede forbindelser enten i fri form eller i form af deres salte. En dannet base kan omdannes 10 til det tilsvarende syreadditionssalt, fortrinsvis under anvendelse af en farmaceutisk acceptabel syre eller et anionbytterpræparat, eller dannede salte kan omdannes til de tilsvarende frie baser, f.eks. under anvendelse af en stærkere base, såsom et metal- eller ammoniumhydroxid, 15 eller et basisk salt, f.eks. et alkalimetalhydroxid eller alkalimetalcarbonat, eller en kationbytter. En forbindelse med formlen I, hvori CORg og/eller COR7 betyder carboxy, kan således også omdannes til de tilsvarende metal- eller ammoniumsalte. Disse eller andre salte, f.eks. picraterne, 20 kan også anvendes til rensning af fremstillede baser. Baserne omdannes til saltene, saltene isoleres, og baserne frigøres fra saltene. Som følge af det snævre slægtskab mellem de frie forbindelser og forbindelserne i form af deres salte skal der altid, når der henvises til en 25 forbindelse, også forstås det tilsvarende salt, forudsat, at det er muligt eller regnet under de givne omstændigheder .Finally, the compounds of the present invention are obtained either in free form or in the form of their salts. A formed base can be converted to the corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or anion exchange preparation, or formed salts can be converted to the corresponding free bases, e.g. using a stronger base such as a metal or ammonium hydroxide, or a basic salt, e.g. an alkali metal hydroxide or alkali metal carbonate, or a cation exchanger. Thus, a compound of formula I wherein CORg and / or COR7 means carboxy can also be converted to the corresponding metal or ammonium salts. These or other salts, e.g. the picrates, 20 can also be used to purify prepared bases. The bases are converted to the salts, the salts are isolated and the bases released from the salts. Due to the close relationship between the free compounds and the compounds in the form of their salts, when referring to a compound, the corresponding salt should always also be understood, provided that it is possible or calculated under the given circumstances.

Forbindelserne herunder deres salte kan også fås i form af hydrater eller omfatte andre til krystallisationen 30 anvendte opløsningsmidler.The compounds including their salts may also be obtained in the form of hydrates or include other solvents used for crystallization.

De farmaceutiske præparater er sådanne, der er egnede til enteral, såsom oral eller rektal, og parenteral indgift til pattedyr og mennesker, til behandling af sygdomme, derThe pharmaceutical compositions are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals and humans, for the treatment of diseases which

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35 reagerer på inhiberingen af det angiotensin-omdannende enzym, f.eks. af cardiovaskulære sygdomme, såsom hypertension, og af kongestiv hjerteinsufficiens, og omfatter 5 en virksom mængde af en farmakologisk aktiv forbindelse med formlen I eller et farmaceutisk acceptabelt salt deraf, alene eller i kombination med et eller flere farmaceutisk acceptable bærestoffer.35 responds to the inhibition of the angiotensin-converting enzyme, e.g. of cardiovascular diseases such as hypertension, and of congestive heart failure, and comprises an effective amount of a pharmacologically active compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers.

De farmakologisk virksomme forbindelser kan anvendes til 10 fremstilling af farmaceutiske præparater, som indeholder en virksom mængde af den farmakologiske forbindelse sammen med eller i blanding med strækkemidler eller bærestoffer, som er egnede til enteral eller parenteral indgift. Der foretrækkes tabletter og gelatinekapsler, som indeholder 15 den aktive bestanddel sammen med a) fortyndingsmidler, f.eks. lactose, dextrose, saccharose, mannitol, sorbitol, cellulose og/eller glycin, b) glittemidler, f.eks. siliciumdioxid, talkum, stearinsyre, magnesium- eller calciumstearat og/eller polyethylenglycol, til tabletter 20 tillige c) bindemidler, f.eks. magnesiumaluminiumsilicat, stivelsespasta, gelatine, tragant, methylcellulose, natriumcarboxymethylcellulose og/eller polyvinyl-pyrrolidon, eventuelt d) sønderdelings- eller disintegreringsmidler, f.eks. stivelsesarter, agar, alginsyre eller 25 natriumalginat, eller opskumningsblåndinger og/eller e) absorptionsmidler, farvemidler, smagsstoffer og sødemidler. Injektionspræparater er fortrinsvis vandige isotoniske opløsninger eller suspensioner, og suppositorier fremstilles fordelagtigt ud fra fedtemulsioner eller 30 -suspensioner. Disse præparater kan steriliseres og/eller indeholde hjælpestoffer, såsom konserveringsmidler, stabiliseringsmidler, fugtemidler eller emulgeringsmidler, opløsningsfremmende stoffer, salte til regulering af det osmotiske tryk og/eller puffere. Endvidere kan de også 35 indeholde andre terapeutisk værdifulde forbindelser. Disse præparater fremstilles under anvendelse af gængse blandings-, granulerings- eller overtrækningsmetoder ogThe pharmacologically active compounds may be used for the preparation of pharmaceutical compositions containing an effective amount of the pharmacological compound together with or in admixture with excipients or carriers suitable for enteral or parenteral administration. Tablets and gelatin capsules containing the active ingredient are preferred with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol, for tablets as well as c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, optionally d) decomposition or disintegrating agents, e.g. starches, agar, alginic acid or sodium alginate, or foaming mixtures and / or e) absorbents, colorants, flavors and sweeteners. Injection preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. These compositions may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solvents, osmotic pressure control salts and / or buffers. Furthermore, they may also contain other therapeutically valuable compounds. These compositions are prepared using conventional mixing, granulating or coating methods and

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36 indeholder fra ca. 0,1 til ca. 75%, fortrinsvis fra ca. 1 til ca. 50% virksom bestanddel. En enhedsdosis til et pattedyr med en legemsvægt på ca. 50-70 kg kan indeholde 5 mellem ca. 10 og ca. 200 mg virksom bestanddel.36 contains from ca. 0.1 to approx. 75%, preferably from approx. 1 to approx. 50% active ingredient. A unit dose for a mammal having a body weight of approx. 50-70 kg can contain 5 between approx. 10 and approx. 200 mg of active ingredient.

Fremgangsmåden ifølge opfindelsen belyses nærmere ved % hjælp af de følgende eksempler, hvori samtlige dele er på vægtbasis. Medmindre andet er indført, foretages samtlige inddampninger under formindsket tryk, fortrinsvis mellem 10 ca. 15 og ca. 100 mm Hg.The process according to the invention is further illustrated by the following examples, in which all parts are by weight. Unless otherwise introduced, all evaporation is carried out under reduced pressure, preferably between about 10%. 15 and approx. 100 mm Hg.

I tilfælde af forbindelser med formlen I, hvori der findes mere end et asymmetricentrum, betegnes de dannede diastereoisomere forbindelser som A, B osv. i de pågældende eksempler. De enkelte diastereoisomere 15 forbindelser karakteriseres ved hjælp af de fysiske egenskaber, f.eks. smeltepunktet, den relative vandring ved kromatografi samt de spektrale egenskaber ved infrarødt spektroskopi eller NMR-spektroskopi.In the case of compounds of formula I in which there is more than one center of asymmetry, the resulting diastereoisomeric compounds are designated as A, B, etc. in the examples in question. The individual diastereoisomeric compounds are characterized by their physical properties, e.g. melting point, relative migration by chromatography as well as the spectral properties of infrared spectroscopy or NMR spectroscopy.

I tilfælde af forbindelser med formlen I, hvori der fore-20 ligger et asymmetricentrum i sidekæden til carbonatomet, som bærer nitrogenatomet, tilordnes symbolerne A og B de pågældende isomerer på basis af deres relative vandring ved kromatografi på følgende måde. På basis af vandringen ved tyndtlagskromatografi og normalfasehøjtryksvæske-25 kromatografi under anvendelse af siliciumdioxidgel som stationær fase betegnes den hurtigt vandrende isomer som isomer A og den langsomt vandrende isomer som isomer B. På basis af vandringen ved højtryksvæskekromatografi med omvendt fase betegnes den langsomt vandrende isomer som 30 isomer A og den hurtigt vandrende isomer som isomer B.In the case of compounds of formula I in which there is an asymmetry center in the side chain of the carbon atom bearing the nitrogen atom, symbols A and B are assigned the isomers concerned on the basis of their relative migration by chromatography as follows. On the basis of the migration by thin-layer chromatography and normal-phase high-pressure liquid chromatography using silica gel as stationary phase, the rapidly migrating isomer is designated as isomer A and the slowly migrating isomer is isomer B. 30 isomer A and the rapidly migrating isomer as isomer B.

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Eksempel 1, l-Carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (Den højeresmel-tende Isomer) 5 En opløsning af 3-amino-l-carboxymethyl-2,3,4,5-tetrahydro-1H-[l]benzazepin-2-on (10,0 g) og benzylpyrodruesyre-ethyl-ester (26,4 g) omrøres i eddikesyre (75 ml) og methanol (75 ml) under nitrogen ved stuetemperatur i 1 time. Til reaktionsblandingen sættes derpå dråbevis natriumcyanborhydrid 10 (3,4 g) i methanol (25 ml) i løbet af 4 timer, og blandin gen omrøres ved stuetemperatur i 24 timer. Til blandingen sættes dråbevis koncentreret saltsyre (4 ml), * der omrøres i 1 time ved stuetemperatur og inddampes til tørhed. Remanensen fordeles mellem 150 ml vand og 50 ml 15 ether, og blandingen indstilles med 40%'s vandig natriumhydroxidopløsning på pH-værdien 9. Lagene adskilles, og etherlaget kastes bort. Det vandige lag indstilles på pH-værdien 4,3 med koncentreret saltsyre og ekstraheres med 3 x 75 ml ethylacetat. De organiske ekstrakter tørres over magnesium-20 sulfat .og inddampes til tørhed. Til opløsningen af råproduktet i 310 ml methylenchlorid ledes hydrogenchloridgas i 5 minutter. Opløsningen inddampes, og remanensen omrøres i 225 ml ether. Produktet frafiltreres. Der fås en 70:30 diastereomer blanding, bestemt ved højtryksvæskekromatogra-25 fi. Produktet omkrystalliseres af ethanol/ethylacetat (1:3).Example 1, 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (The High-melting Isomer) A solution of 3-Amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (10.0 g) and benzylpyruvic acid ethyl ester (26.4 g) are stirred in acetic acid ( 75 ml) and methanol (75 ml) under nitrogen at room temperature for 1 hour. To the reaction mixture is then added dropwise sodium cyanoborohydride 10 (3.4 g) in methanol (25 ml) over 4 hours and the mixture is stirred at room temperature for 24 hours. To the mixture is added dropwise concentrated hydrochloric acid (4 ml), which is stirred for 1 hour at room temperature and evaporated to dryness. The residue is partitioned between 150 ml of water and 50 ml of 15 ether and the mixture is adjusted with 40% aqueous sodium hydroxide solution to pH 9. 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 ml of ethyl acetate. The organic extracts are dried over magnesium sulfate and evaporated to dryness. To the solution of the crude product in 310 ml of methylene chloride is passed hydrogen chloride gas for 5 minutes. The solution is evaporated and the residue is stirred in 225 ml of ether. The product is filtered off. A 70:30 diastereomeric mixture is obtained, as determined by high pressure liquid chromatography. The product is recrystallized from ethanol / ethyl acetate (1: 3).

Man får l-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-hydrochlorid, som smelter ved 246-248°C (sønderdeling), og som svarer til den racemiske isomer B.There is obtained 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride, which melts at 246-248 ° C (decomposition) corresponding to the racemic isomer B.

30 En opløsning af det ovenfor fremstillede hydrochloridsalt (0,9 g) og propylenoxid (10 ml) i ethanol (150 ml) omrøres i 18 timer under nitrogen. Opløsningen inddampes til tørhed, og remanensen opløses i 3 ml ethanol. Der tilsættes ether (75 ml), hvorved der udfældes en mindre mængde af det oven-A solution of the above hydrochloride salt (0.9 g) and propylene oxide (10 ml) in ethanol (150 ml) is stirred for 18 hours under nitrogen. The solution is evaporated to dryness and the residue is dissolved in 3 ml of ethanol. Ether (75 ml) is added to precipitate a small amount of the above

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38 for anførte hydrochlorid. Filtratet inddampes til tørhed, omrøres med ether/petroleumsether (1:9), og det faste materiale frafiltreres. Man får l-carboxymethyl-3-(1-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-5 azepin-2-on, som smelter ved 139-141°C. Dette er den højere-smeltende racemiske isomer B af forbindelsen med formlen IB, ' hvori CnH2n er ethylen, Rg er ethoxy, er hydroxy, og Rg er phenyl.38 for listed hydrochloride. The filtrate is evaporated to dryness, stirred with ether / petroleum ether (1: 9) and the solid is filtered off. There is obtained 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-5-azepin-2-one, which melts at 139-141 ° C. This is the higher-melting racemic isomer B of the compound of formula IB wherein CnH2n is ethylene, Rg is ethoxy, is hydroxy, and Rg is phenyl.

Ved adskillelse med en optisk aktiv amin under sædvanlige 10 betingelser og adskillelse af de diastereomere salte fås de rene enantiomere, f.eks. l-carboxymethyl-3S-(lS-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on ifølge eksempel 12.By separation with an optically active amine under the usual conditions and separation of the diastereomeric salts, the pure enantiomers, e.g. 1-Carboxymethyl-3S- (1S-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one according to Example 12.

Ved anvendelse af højtryksvæskekromatografi (der i det føl-15 gende betegnes som hplcj på en søjle med omvendte faser (opløsningsmiddelsystem: methanol/vand (3:1), som indeholder 0,025% eddikesyre), vandrer isomeren B hurtigere end den laveresmeltende isomer A ifølge eksempel 5.Using high-pressure liquid chromatography (hereinafter referred to as hplcj on a reverse phase column (solvent system: methanol / water (3: 1) containing 0.025% acetic acid)), the isomer B migrates faster than the low-melting isomer A of Example 5.

Udgangsforbindelsen,dvs. 3-amino-l-carboxymethyl-2,3,4,5-20 tetrahydro-lH-[1]benzazepin-2-on fremstilles på følgende måde:The starting compound, ie. 3-Amino-1-carboxymethyl-2,3,4,5-20 tetrahydro-1H- [1] benzazepin-2-one is prepared as follows:

En blanding af 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (48,3 g, jfr. Briggs et al., J.Chem.Soc. 1937 456), phosphor-pentachlorid (188 g) og xylen (1300 ml) opvarmes i en nitro-25 genatmosfære under omrøring ved 90°C (oliebadtemperatur) i løbet af 30 minutter. Opvarmningen gennemføres med pauser ved 30°C (man lader phosphorpentachloridet gå i opløsning) og ved 50°C. Der indtræder en kraftig hydrogenchloridudvik-ling. Temperaturen holdes i 30 minutter ved 90°C. Reaktions-30 blandingen filtreres varmt under fjernelse af små mængder af' et suspenderet fast materiale, og filtratet inddampes til tørhed under formindsket tryk. Remanensen sættes under omrøring til en mættet vandig natriumcarbonatopløsning (100 ml). Når produktet er blevet fast, frafiltreres det,A mixture of 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (48.3 g, cf. Briggs et al., J. Chem. Soc. 1937,456), phosphorus pentachloride ( 188 g) and xylene (1300 ml) are heated in a nitrogen atmosphere with stirring at 90 ° C (oil bath temperature) over 30 minutes. The heating is carried out with breaks at 30 ° C (the phosphorus pentachloride is dissolved) and at 50 ° C. There is a strong development of hydrogen chloride. The temperature is kept at 90 ° C for 30 minutes. The reaction mixture is filtered hot to remove small amounts of a suspended solid and the filtrate is evaporated to dryness under reduced pressure. The residue is added with stirring to a saturated aqueous sodium carbonate solution (100 ml). Once the product is solid, it is filtered out,

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39 hvorefter det opslæmmes i ethanol (150 ml), vaskes med ethanol (50 ml) og ether (50 ml) og tørres. Man får 3,3-di-chlor-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on, som smelter ved 185-187°C.39 and then it is suspended in ethanol (150 ml), washed with ethanol (50 ml) and ether (50 ml) and dried. There is obtained 3,3-dichloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 185-187 ° C.

5 En opløsning af 3,3-dichlor-2,3,4,5-tetrahydro-lH-[l]benz-azepin-2-on (20 g, 0,174 mol) og vandfrit natriumacetat (15,4 g, 0,188 mol) i iseddike (920 ml) hydrogeneres ved atmosfæretryk med 5%'s palladium-på-kul-katalysator (1,72 g)f indtil hydrogenoptagelsen er ophørt. Katalysatoren frafil-10 treres, og eddikesyren fordampes under formindsket tryk.A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (20 g, 0.174 mole) and anhydrous sodium acetate (15.4 g, 0.188 mole) ) in glacial acetic acid (920 ml) is hydrogenated at atmospheric pressure with 5% palladium-on-carbon catalyst (1.72 g) f until hydrogen uptake has ceased. The catalyst is filtered off and the acetic acid is evaporated under reduced pressure.

Remanensen fordeles mellem 10%' s natriumhydrogencarbonatopløs-ning (900 ml) og dichlormethan (300 ml). Det vandige lag (pH-værdi 8) ektraheres yderligere med dichlormethan (3 x 300 ml). De sammenblandede ekstrakter tørres over vandfrit 15 natriumsulfat og inddampes. Man får 3-chlor-2,3,4,5-tetra-hydro-lH-[1]benzazepin-2-on, som smelter ved 163-167°C.The residue is partitioned between 10% sodium bicarbonate solution (900 ml) and dichloromethane (300 ml). The aqueous layer (pH 8) is further extracted with dichloromethane (3 x 300 ml). The combined extracts are dried over anhydrous sodium sulfate and evaporated. There is obtained 3-chloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 163-167 ° C.

En opløsning af 3-chlor-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (15,9 g, 0,08 mol) og natriumazid (6,36 g, 0,10 mol) i dimethylsulfoxid (320 ml) henstår under nitrogen i 3 timer 20 ved 80°C. På dette tidspunkt viser en prøve ved IR-spektro-skopi et kraftigt maximum ved 2150 cm 1, som er karakteristisk for azidgruppen. Reaktionsblandingen hældes i 1000 ml isvand, og suspensionen omrøres i 30 minutter. Det faste materiale frafiltreres, vaskes med vand (250 ml) og tørres.A solution of 3-chloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (15.9 g, 0.08 mol) and sodium azide (6.36 g, 0.10 mol) ) in dimethyl sulfoxide (320 ml) is left under nitrogen for 3 hours at 80 ° C. At this point, a sample by IR spectroscopy shows a strong maximum at 2150 cm 1, which is characteristic of the azide group. The reaction mixture is poured into 1000 ml of ice water and the suspension is stirred for 30 minutes. The solid material is filtered off, washed with water (250 ml) and dried.

25 Man får 3-azido-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, som smelter ved 142-145°C.There is obtained 3-azido-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 142-145 ° C.

En opløsning af 3-azido-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (8,7 g, 0,043 mol) i tørt dimethylformamid (75 ml) sættes i løbet af 30 minutter til en omrørt suspension af 30 natriumhydrid [fremstillet ud fra en 60%'s dispersion i mineralolie (1,9 g), vasket med petroleumsether (3 x 150 ml)] i tørt dimethylformamid (250 ml) ved 0°C under nitrogen. Omrøringen fortsættes i yderligere 1,5 timer, hvorpå der tilsættes bromeddikesyrebenzylester (10,8 g, 0,047 mol) 35 i tørt dimethylformamid (75 ml) i løbet af 45 minutter,A solution of 3-azido-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (8.7 g, 0.043 mol) in dry dimethylformamide (75 ml) is added over 30 minutes to a stirred suspension of 30 sodium hydride [prepared from a 60% dispersion in mineral oil (1.9 g), washed with petroleum ether (3 x 150 ml)] in dry dimethylformamide (250 ml) at 0 ° C under nitrogen. Stirring is continued for an additional 1.5 hours, then bromoacetic acid benzyl ester (10.8 g, 0.047 mol) is added in dry dimethylformamide (75 ml) over 45 minutes.

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40 idet temperaturen holdes ved 0°C. Reaktionsblandingen omrøres i yderligere 18 timer, hvorved den antager stuetemperatur. Dimethylformamidet fordampes under formindsket tryk, og remanensen fordeles mellem vand (500 ml) og dichlormethan 5 (500 ml). Den vandige fase ekstraheres med dichlormethan (3 x 500 ml). De sammenblandede ekstrakter tørres over natriumsulfat, og opløsningsmidlet fordampes under formindsket tryk. Man får det rå ester-azid i form af en olie. Denne opløses i toluen (500 ml), og der tilsættes silicagel (48 g).40 keeping the temperature at 0 ° C. The reaction mixture is stirred for an additional 18 hours, assuming room temperature. The dimethylformamide is evaporated under reduced pressure and the residue partitioned between water (500 ml) and dichloromethane 5 (500 ml). The aqueous phase is extracted with dichloromethane (3 x 500 ml). The mixed extracts are dried over sodium sulfate and the solvent is evaporated under reduced pressure. The crude ester azide is obtained in the form of an oil. This is dissolved in toluene (500 ml) and silica gel (48 g) is added.

10 Ved filtrering og fordampning af opløsningsmidlet under formindsket tryk fås 3-azido-l-benzyloxycarbonylmethy1-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on i form af en olie, som uden yderligere rensning anvendes i det efterfølgende syntesetrin.By filtration and evaporation of the solvent under reduced pressure, 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained in the form of an oil which is used without further purification. in the subsequent synthesis step.

En suspension af aktiv Raney-nikkel-katalysator i vand (15 ml) 15 vaskes med ethanol (5 x 100 ml) og sættes til en mekanisk omrørt opløsning af 3-azido-l-benzvloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (5,0 g) i ethanol (300 ml). Suspensionen omrøres i 18 timer under nitrogen ved stuetemperatur. Katalysatoren frafiltreres, og opløsningsmidlet for-20 dampes under formindsket tryk. Remanensen opløses i 2 N saltsyre (200 ml), og opløsningen ekstraheres med ether (2 x 250 ml). Den vandige opløsning gøres basisk med koncentreret vandig ammoniak (pH-værdi 9), og opløsningen ekstraheres med ether (3 x 200 ml). De sammenblandede etherekstrakter tørres over 25 natriumsulfat og inddampes under formindsket tryk. Man får 3-amino-l-benzyloxycarbonylmethy1-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on i form af en olie, som uden yderligere rensning anvendes i det efterfølgende syntesetrin.A suspension of active Raney nickel catalyst in water (15 ml) is washed with ethanol (5 x 100 ml) and added to a mechanically stirred solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro -1H- [1] benzazepin-2-one (5.0 g) in ethanol (300 ml). The suspension is stirred for 18 hours under nitrogen at room temperature. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is dissolved in 2N hydrochloric acid (200 ml) and the solution is extracted with ether (2 x 250 ml). The aqueous solution is made basic with concentrated aqueous ammonia (pH 9) and the solution is extracted with ether (3 x 200 ml). The mixed ether extracts are dried over 25% sodium sulfate and evaporated under reduced pressure. There is obtained 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one in the form of an oil which is used without further purification in the subsequent synthesis step.

3-Amino-l-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-30 [1]benzazepin-2-on fremstilles på følgende måde:3-Amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-30 [1] benzazepin-2-one is prepared as follows:

En opløsning af 3-amino-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-.on (5,0 g, 0,028 mol) i dimethylformamid (100 ml) sættes i en nitrogenatmosfære til en omrørt suspension af natrium-hydrid [fremstillet ud fra 60%'s dispersion i mineralolieA solution of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (5.0 g, 0.028 mol) in dimethylformamide (100 ml) is added to a stirred atmosphere in a nitrogen atmosphere. sodium hydride suspension [prepared from 60% dispersion in mineral oil

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41 (1,2 g) ved vaskning med petroleumsether (3 x 150 ml) i di-methylf ormamid (400 ml) , hvortil der er sat tetrabutyl-ammoniumbromid (10,0 g, 0,03l mol). Reaktionsblandingen holdes i 15 minutter ved 50°C, hvorpå der tilsættes en opløs-5 ning af bromeddikesyrebenzylester (7,2 g, 0,031 mol) i di-methylf ormamid (25 ml). Reaktionsblandingen omrøres i yderligere 18 timer ved 50°C, hvorefter den afkøles til stuetemperatur, og dimethylformamidet fordampes i højvakuum. Remanensen omrøres med toluen/dichlormethan (1:1, 500 ml), til 10 udfældning af uorganiske salte. Efter filtrering inddampes opløsningen under formindsket tryk, og remanensen kromatogra-feres på silicagel (200 g). Der elueres med 0-15% ethylacetat i toluen. Som hovedprodukt fås 3-amino-l-benzyloxycarbonyl-methyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on.41 (1.2 g) by washing with petroleum ether (3 x 150 ml) in dimethylformamide (400 ml) to which is added tetrabutylammonium bromide (10.0 g, 0.03 l mol). The reaction mixture is kept for 15 minutes at 50 ° C, then a solution of bromoacetic acid benzyl ester (7.2 g, 0.031 mol) in dimethylformamide (25 ml) is added. The reaction mixture is stirred for an additional 18 hours at 50 ° C, then cooled to room temperature and the dimethylformamide evaporated in high vacuum. The residue is stirred with toluene / dichloromethane (1: 1, 500 ml) to precipitate inorganic salts. After filtration, the solution is evaporated under reduced pressure and the residue is chromatographed on silica gel (200 g). Elute with 0-15% ethyl acetate in toluene. The main product is 3-amino-1-benzyloxycarbonyl-methyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

15 En opløsning af 3-amino-l-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (1,3 g) i ethanol (250 ml) hydrogeneres med 10%'s palladium-på-kul-katalysator (0,20 g) ved stuetemperatur og atmosfæretryk, indtil hydrogenoptagelsen er ophørt. Katalysatoren frafiltreres, og opløsningsmid-20 let fordampes under formindsket tryk. Der fås et hvidt skum (0,90 g).A solution of 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (1.3 g) in ethanol (250 ml) is hydrogenated with 10% palladium-on-carbon catalyst (0.20 g) at room temperature and atmospheric pressure until hydrogen uptake has ceased. The catalyst is filtered off and the solvent is evaporated under reduced pressure. A white foam (0.90 g) is obtained.

Dette tritureres med ether, hvorved man får 3-amino-l-carboxy-methyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, smp. 147-150°C.This is triturated with ether to give 3-amino-1-carboxy-methyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, m.p. 147-150 ° C.

25 En opløsning af 3-azido-l-benzyloxycarbonylmethyl-2,3,4,5- tetrahydro-lH-[l]benzazepin-2-on (14,0 g, 0,04 mol) i ethanol (300 ml) hydrogeneres i 25 timer ved 3,1 atmosfærer og stuetemperatur under anvendelse af 5%'s palladium-på-kul-katalysator (2,0 g). Katalysatoren frafiltreres, og opløsningsmid-30 let fordampes under formindsket tryk. Remanensen opløses i vand (500 ml), og opløsningen ekstraheres med dichlormethan (2 x 400 ml). Den vandige opløsning filtreres og inddampes under formindsket tryk. Remanensen opløses i ethanol (50 ml), og opløsningen inddampes under formindsket tryk. Remanensen 35 optages atter i ethanol (50 ml), og inddampningen gentages.A solution of 3-azido-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (14.0 g, 0.04 mol) in ethanol (300 mL) is hydrogenated for 25 hours at 3.1 atmospheres and room temperature using 5% palladium-on-carbon catalyst (2.0 g). The catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is dissolved in water (500 ml) and the solution is extracted with dichloromethane (2 x 400 ml). The aqueous solution is filtered and evaporated under reduced pressure. The residue is dissolved in ethanol (50 ml) and the solution is evaporated under reduced pressure. The residue 35 is taken up again in ethanol (50 ml) and the evaporation is repeated.

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Remanensen omkrystalliseres fra ethanol/ethylacetat. Man får 3-amino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on, som smelter ved 147-150°C.The residue is recrystallized from ethanol / ethyl acetate. There is obtained 3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 147-150 ° C.

Eksempel 2.Example 2.

5 l-Benzyloxycarbonylmethyl-3-(l-carboxy-3-phenylpropylamino)- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on.5-Benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

Natriumcyanborhydrid (0,152 g, 0,0014 mol) sættes til en opløsning af l-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetra-hydro-ΙΗ-[1]benzazepin-2-on (0,45 g, 0,0014 mol) og benzylpyrodrpe-10 syre-benzylester (0,48 g, 0,0028 mol) i methanol (35 ml). Reaktionsblandingen omrøres ved stuetemperatur i 2 timer i en nitrogenatmosfære. Til reaktionsblandingen sættes atter benzyl-pyrodruesyre-benzylester (0,48 g, 0,0028 mol), og der omrøres i yderligere 18 timer. Der tilsættes koncentreret salt-15 syre (0,5 ml), og den dannede opløsning omrøres i 1 time. Opløsningsmidlet fordampes under formindsket tryk, og remanensen behandles med dichlormethan (100 ml) til udfældning af natriumchloridet. Blandingen filtreres, opløsningsmidlet fordampes under formindsket tryk, og remanensen kromatogra-20 feres på silicagel (30 g). Der elueres med ethylacetat/me-thanol/eddikesyre (90:10:0,2). Man får 1-benzyloxycarbonyl-methyl-3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-on i form af en olie. NMR (CDCl^) δ 7,35 (m, 14H), 5,10 (s, 2H), 4,60 (m, 2H), 3,00 (m, 12H).Sodium cyanoborohydride (0.152 g, 0.0014 mol) is added to a solution of 1-benzyloxycarbonylmethyl-3-amino-2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one (0.45 g , 0.0014 mol) and benzylpyrodrpiperic acid benzyl ester (0.48 g, 0.0028 mol) in methanol (35 ml). The reaction mixture is stirred at room temperature for 2 hours in a nitrogen atmosphere. To the reaction mixture is added benzyl-pyruvic acid benzyl ester (0.48 g, 0.0028 mol) and stirred for an additional 18 hours. Concentrated hydrochloric acid (0.5 ml) is added and the resulting solution is stirred for 1 hour. The solvent is evaporated under reduced pressure and the residue is treated with dichloromethane (100 ml) to precipitate the sodium chloride. The mixture is filtered, the solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (30 g). Elute with ethyl acetate / methanol / acetic acid (90: 10: 0.2). 1-benzyloxycarbonyl-methyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained in the form of an oil. NMR (CDCl3) δ 7.35 (m, 14H), 5.10 (s, 2H), 4.60 (m, 2H), 3.00 (m, 12H).

25 Eksempel 3.Example 3.

l-Benzyloxycarbonylmethyl-3-(l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-onl-Benzyloxycarbonylmethyl-3- (l-ethoxycarbonyl-3-phenylpropyl-amino) -2,3,4,5-tetrahydro-LH [l] benzazepin-2-one

En opløsning af l-benzyloxycarbonylmethyl-3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on 30 (0,364 g, 0,00075 mol), natriumhydrogencarbonat (0,190 g, 0,0022 mol) og ethyliodid (0,315 g, 0,002 mol) i dimethyl-A solution of 1-benzyloxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (0.364 g, 0.00075 mol), sodium bicarbonate (0.190 g, 0.0022 mol) and ethyl iodide (0.315 g, 0.002 mol) in dimethyl

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43 acetamid (15 ml) omrøres under nitrogen ved stuetemperatur i 72 timer. Reaktionsblandingen filtreres, hvorefter den inddampes under formindsket tryk. Der tilsættes vand (100 ml), hvorpå den dannede opløsning ekstraheres med dichlormethan 5 (4 x 50 ml). De sammenblandede ekstrakter tørres over na triumsulfat, og opløsningsmidlet fordampes under formindsket tryk. Man får diesteren i form af en olie. Dette materiale adskilles ved hjælp af hplc. i 3. fraktioner, idet man som opløsningsmiddel anvender ethylacetat/toluen (30:70).43 acetamide (15 ml) is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is filtered and then evaporated under reduced pressure. Water (100 ml) is added and the resulting solution is extracted with dichloromethane 5 (4 x 50 ml). The mixed extracts are dried over sodium sulfate and the solvent is evaporated under reduced pressure. You get the diester in the form of an oil. This material is separated using hplc. in the 3rd fractions using ethyl acetate / toluene (30:70) as the solvent.

10 Den første fraktion giver isomeren A af den Ønskede forbindelse i form af en olie. Den anden fraktion indeholder en blanding af isomerene A og B, og den tredje fraktion giver isomeren B af den ønskede forbindelse. Anvender man hplc.på en søjle med omvendte faser [opløsningsmiddelsystem: 15 methanol/vand (3:1), indeholdende 0,025% eddikesyre], vandrer isomeren A langsommere end isomeren B.The first fraction gives the isomer A of the desired compound in the form of an oil. The second fraction contains a mixture of isomers A and B, and the third fraction gives the isomer B of the desired compound. If applied to a reverse phase column [solvent system: 15 methanol / water (3: 1) containing 0.025% acetic acid], the isomer A migrates more slowly than the isomer B.

Eksempel 4.Example 4

1- Carboxymethyl-3-(l-ethoxy-carbonyl-3-phenylpropylamino) - 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (Den højeresmelten- 20 de isomer)1- Carboxymethyl-3- (1-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (The high-melting isomer)

En opløsning af l-benzyloxycarbonylmethyl-3-(1-ethoxycarbo-nyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin- 2- on (isomeren B ifølge eksempel 3, 0,9 g) i ethanol (150 ml) hydrogeneres ved stuetemperatur og atmosfæretryk under an- 25 vendelse af 10%'s palladium-på-kul-katalysator (0,5 g). Efter endt hydrogenoptagelse frafiltreres katalysatoren, og opløsningsmidlet fordampes under formindsket tryk. Man får et fast materiale, som tritureres med ether (8 ml). Man får den ønskede forbindelse, som smelter ved 138-140°C, og som 30 er identisk med produktet ifølge eksempel 1.A solution of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (the isomer B of Example 3, 9 g) in ethanol (150 ml) is hydrogenated at room temperature and atmospheric pressure using 10% palladium-on-carbon catalyst (0.5 g). After hydrogen uptake is completed, the catalyst is filtered off and the solvent is evaporated under reduced pressure. A solid is obtained which is triturated with ether (8 ml). The desired compound is obtained which melts at 138-140 ° C and which is identical to the product of Example 1.

4444

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Eksempel 5.Example 5

l-Carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)- 2.3.4.5- tetrahydro-lH-[1]benzazepin-2-on(Den laveresmelten-de isomer) 5 En opløsning af l-benzyloxycarbonylmethyl-3-(1-ethoxycarbo-nyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzaze-pin-2-on (isomeren A ifølge eksempel 3, 1,2 g) i ethanol (125 ml) hydrogeneres ved stuetemperatur og atmosfæretryk med 10%'s palladium-på-kul-katalysator (0,5 g). Efter endt 10 hydrogenoptagelse frafiltreres katalysatoren, og opløsningsmidlet fordampes under formindsket tryk. Der fås et fast materiale, som tritureres med ether (8 ml). Man får 1-carb- oxymethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5- o tetrahydro-ΙΗ-[1]benzazepin-2-on, som smelter ved 126-129 C, 15 og som er den laveresmeltende racemiske isomer A.1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (The lower molten isomer) A solution of 1-benzyloxycarbonylmethyl-3- ( 1-Ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazpin-2-one (isomer A of Example 3, 1.2 g) in ethanol (125 ml ) is hydrogenated at room temperature and atmospheric pressure with 10% palladium-on-carbon catalyst (0.5 g). Upon completion of hydrogen uptake, the catalyst is filtered off and the solvent evaporated under reduced pressure. A solid is obtained which is triturated with ether (8 ml). There is obtained 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-o tetrahydro-ΙΗ- [1] benzazepin-2-one, which melts at 126-129 ° C. 15 and which is the low-melting racemic isomer A.

Ved anvendelse af hplc. på en søjle med omvendte faser [opløsningsmiddelsystem: methanol/vand (3:1), som indeholder 0,025% eddikesyre], vandrer isomeren A langsommere end den højeresmeltende racemiske isomer B ifølge eksempel 1.When using hplc. on a reversed-phase column [solvent system: methanol / water (3: 1) containing 0.025% acetic acid], the isomer A migrates slower than the high-melting racemic isomer B of Example 1.

25 Eksempel 6.Example 6

l-Benzyloxycarbonylmethyl-3-(l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-onl-Benzyloxycarbonylmethyl-3- (l-ethoxycarbonyl-3-phenylpropyl-amino) -2,3,4,5-tetrahydro-LH [l] benzazepin-2-one

En opløsning af 3-(1-ethoxycarbonyl-3-phenylpropylamino)- 2.3.4.5- tetrahydro-lH-[l]benzazepin-2-on (5,0 g) i tørt di-30 methylformamid (20 ml) sættes i en nitrogenatmosfære til en omrørt suspension af natriumhydrid [fremstillet ud fra en 60%'s dispersion i mineralolie (0,6 g), som vaskes med petro-leumsether (3 x 75 ml)] i tørt dimethylformamid (85 ml), som indeholder tetrabutylammoniumbromid (4,4 g). Reaktionsblan-35 dingen omrøres i 30 minutter ved stuetemperatur, hvorpå der tilsættes en opløsning af bromeddikesyrebenzylester (3,2 g) i tørt dimethylformamid (10 ml). Blandingen omrøres i yder-A solution of 3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (5.0 g) in dry dimethylformamide (20 ml) is added to a nitrogen atmosphere for a stirred suspension of sodium hydride [prepared from a 60% dispersion in mineral oil (0.6 g) washed with petroleum ether (3 x 75 ml)] in dry dimethylformamide (85 ml) containing tetrabutylammonium bromide (4.4 g). The reaction mixture is stirred for 30 minutes at room temperature, then a solution of bromoacetic acid benzyl ester (3.2 g) in dry dimethylformamide (10 ml) is added. The mixture is stirred in outer

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45 ligere 30 minutter ved stuetemperatur, opvarmes til 60°C og holdes ved denne temperatur i 18 timer. Reaktionsblandingen afkøles til stuetemperatur, og opløsningsmidlet fordampes i højvakuum. Der tilsættes vand (150 ml), og 5 den dannede opløsning ekstraheres med ethylacetat (2 x 250 ml). De sammenblandede ethylacetatekstrakter vaskes med vand (100 ml), tørres over magnesiumsulfat og inddampes under formindsket tryk. Der fås en brun olie, som kromato-graferes på silicagel (150 g) og elueres med toluen/ethyl-10 acetat (3:1). Man får først isomeren A af 1-benzyloxycarbo-nylmethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on. Derpå fremkommer isomeren B. Isomerene A og B er identiske med forbindelserne ifølge eksempel 3, bestemt ved hplc. på en søjle med omvendte fa-15 ser [opløsningsmiddelsystem: methanol/vand (3:1), indeholdende 0,025% eddikesyre].45 for 30 minutes at room temperature, heated to 60 ° C and kept at this temperature for 18 hours. The reaction mixture is cooled to room temperature and the solvent is evaporated in high vacuum. Water (150 ml) is added and the resulting solution is extracted with ethyl acetate (2 x 250 ml). The mixed ethyl acetate extracts are washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure. A brown oil is obtained which is chromatographed on silica gel (150 g) and eluted with toluene / ethyl acetate (3: 1). The isomer A of 1-benzyloxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is first obtained. Then the isomer B. The isomers A and B are identical to the compounds of Example 3, determined by hplc. on a reverse phase column [solvent system: methanol / water (3: 1) containing 0.025% acetic acid].

Udgangsforbindelsen fremstilles på følgende måde: En opløsning af acetamido-malonsyre-diethylester (33,2 g) i ethanol (150 ml) sættes til en opløsning af natriumethoxid 20 i ethanol [fremstillet ud fra natrium (3,8 g) og ethanol (200 ml)]. Reaktionsblandingen omrøres ved stuetemperatur i 30 minutter,, hvorpå der i løbet af 20 minutter dråbevis tilsættes en opløsning af 2~nitro-phenylethyl-bromid [J.Med. Chem. 20, 1020 (1977), 40,0 g] i ethanol (100 ml). Efter 25 endt tilsætning koges reaktionsblandingen i 18 timer under tilbagesvaling, hvorefter den afkøles til stuetemperatur og inddampes under formindsket tryk. Remanensen opløses i vand (350 ml), og opløsningen ekstraheres med ethylacetat (2 x 350 ml). De sammenblandede ethylacetatekstrakter va-30 skes med vand (200 ml) og tørres over magnesiumsulfat. Opløsningsmidlet fordampes under formindsket tryk. Man får 2-acetamido-2-(o-nitro-nhenylethyl)-malonsyre-diethylester som et lavtsmeltende fast materiale, som uden yderligere rensning anvendes i det efterfølgende syntesetrin.The starting compound is prepared as follows: A solution of acetamido-malonic acid diethyl ester (33.2 g) in ethanol (150 ml) is added to a solution of sodium ethoxide 20 in ethanol [prepared from sodium (3.8 g) and ethanol (200 ml)]. The reaction mixture is stirred at room temperature for 30 minutes, then a solution of 2 ~ nitro-phenylethyl bromide is added dropwise over 20 minutes [J.Med. Chem. 20, 1020 (1977), 40.0 g] in ethanol (100 ml). After the 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 ml) and the solution is extracted with ethyl acetate (2 x 350 ml). The mixed ethyl acetate extracts are washed with water (200 ml) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure. 2-acetamido-2- (o-nitro-nhenylethyl) -malonic acid diethyl ester is obtained as a low-melting solid which is used without further purification in the subsequent synthesis step.

35 En opløsning af 2-acetamido-2-(o-nitrophenylethyl)-malonsy-A solution of 2-acetamido-2- (o-nitrophenylethyl) -malonic acid

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46 re-diethylester (80 g) i 3 N saltsyre (900 ml) koges i 12 timer under tilbagesvaling. Opløsningen afkøles og ekstrahe-res med ethylacetat (200 ml). Den vandige opløsning filtreres og inddampes til tørhed under formindsket tryk. Rema-5 nensen omkrystalliseres fra ethano1/ether. Man får 2-amino- 4-(2-nitrophenyl)-smørsyre-hydrochlorid, som smelter ved 219-221°C (sønderdeling).46 diethyl ester (80 g) in 3 N hydrochloric acid (900 ml) is refluxed for 12 hours. The solution is cooled and extracted with ethyl acetate (200 ml). The aqueous solution is filtered and evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol / ether. 2-amino-4- (2-nitrophenyl) -butyric acid hydrochloride is obtained, which melts at 219-221 ° C (dec.).

En opløsning af 2-amino-4-(2-nitrophenyl)-smørsyre-hydrochlorid (38 g) i 10%'s ethanolisk saltsyre (1200 ml) koges 10 i 18 timer under tilbagesvaling. Reaktionsblandingen inddampes under formindsket tryk, der tilsættes vand (250 ml), og den vandige opløsning gøres basisk med 2 N natriumhydroxidopløsning. Opløsningen ekstraheres med dichlormethan (2 x 500 ml). De sammenblandede dichlormethanopløsninger vaskes 15 med vand (2 x 150 ml) og tørres over vandfrit natriumsulfat. Efter inddampning får man 2-amino-4-(2-nitrophenyl)-smørsy-re-ethylester, som uden yderligere rensning anvendes i det efterfølgende syntesetrin.A solution of 2-amino-4- (2-nitrophenyl) -butyric acid hydrochloride (38 g) in 10% ethanolic hydrochloric acid (1200 ml) is refluxed for 18 hours. The reaction mixture is evaporated under reduced pressure, water is added (250 ml) and the aqueous solution is basified with 2N sodium hydroxide solution. The solution is extracted with dichloromethane (2 x 500 ml). The mixed dichloromethane solutions are washed with water (2 x 150 ml) and dried over anhydrous sodium sulfate. After evaporation, 2-amino-4- (2-nitrophenyl) -butyric acid ethyl ester is obtained, which is used without further purification in the subsequent synthesis step.

En opløsning af 2-amino-4-(2-nitrophenyl)-smørsyre-ethyl-20 ester (27 g) i ethanol (600 ml) hydrogeneres ved stuetempere-tur og atmosfæretryk under anvendelse af 10%'s palladium-på-kul-katalysator (2,5 g), indtil hydrogenoptagelsen er afsluttet. Katalysatoren frafiltreres, og opløsningen inddampes til tørhed. Man får 2-amino-4-(2-aminophenyl)-smørsyre-ethyl-25 ester, som uden yderligere rensning anvendes i det efterfølgende syntesetrin.A solution of 2-amino-4- (2-nitrophenyl) -butyric acid ethyl ester (27 g) in ethanol (600 ml) is hydrogenated at room temperature and atmospheric pressure using 10% palladium-on-charcoal catalyst (2.5 g) until hydrogen uptake is completed. The catalyst is filtered off and the solution is evaporated to dryness. 2-amino-4- (2-aminophenyl) butyric acid ethyl ester is obtained, which is used without further purification in the subsequent synthesis step.

En opløsning af 2-amino-4-(2-aminophenyl)-smørsyre-ethylester (35,0 g) i methanol (100 ml) sættes under omrøring i en nitrogenatmosfære til en opløsning af natriummethoxid i methanol 30 [fremstillet ud fra natrium (1,0 g) og methanol (400 ml)]. Reaktionsblandingen koges i 65 timer under tilbagesvaling og inddampes under formindsket tryk. Remanensen fordeles mellem vand (100 ml) og dichlormethan (400 ml). Den vandige opløsning ekstraheres med dichlormethan (400 ml). De sammen-35 blandede organiske opløsninger vaskes med vand (100 ml) og 47A solution of 2-amino-4- (2-aminophenyl) -butyric acid ethyl ester (35.0 g) in methanol (100 ml) is added under stirring in a nitrogen atmosphere to a solution of sodium methoxide in methanol [prepared from sodium ( 1.0 g) and methanol (400 ml)]. The reaction mixture is refluxed for 65 hours and evaporated under reduced pressure. The residue is partitioned between water (100 ml) and dichloromethane (400 ml). The aqueous solution is extracted with dichloromethane (400 ml). The combined organic solutions are washed with water (100 ml) and 47

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tørres over magnesiumsulfat. Opløsningen inddampes til tørhed, og remanensen tritureres med ether (250 ml). Man får 3-amino-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, som smelter ved 161-162°C.dried over magnesium sulfate. The solution is evaporated to dryness and the residue is triturated with ether (250 ml). 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained, which melts at 161-162 ° C.

5 I andre tilfælde kan man gå frem på følgende måde: En opløsning af 2-amino-4-(2-nitrophenyl)-smørsyre-hydrochlorid (2,5 g) i vand (200 ml) hydrogeneres ved stuetemperatur og atmosfæretryk under anvendelse af 10%'s palladium-på-kul-ka-talysator. Efter endt hydrogenoptagelse frafiltreres kataly-10 satoren, og filtratet inddampes til .tørhed. Remanensen opløses i vand (50 ml), og opløsningen indstilles på pH-værdien 7 med 10%'s natriumhydroxidopløsning. Bundfaldet frafiltreres, vaskes med vand og tørres. Man får 2-amino-4-(2-aminophenyl)-smørsyre. En opløsning af 2-amino-4-(2-aminophenyl)-smør-15 syre (1,0 g), hexamethyldisilazan (5,4 g) og chlortrimethyl-silan (0,1 g) i xylen (125 mlXkoges i 65 timer under tilbagesvaling, Reaktionsblandingen afkøles, hældes i ethanol (200 ml) og inddampes under formindsket tryk. Der tilsættes vand (100 ml), og opløsningen ekstraheres med dichlormethan (2 x 20 125 ml). De sammenblandede dichlormethanopløsninger vaskes med vand (50 ml), tørres over magnesiumsulfat og inddampes under formindsket tryk. Man får 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-on, som er identisk med den ovenfor anførte forbindelse.In other cases, the following can be done: A solution of 2-amino-4- (2-nitrophenyl) -butyric acid hydrochloride (2.5 g) in water (200 ml) is hydrogenated at room temperature and atmospheric pressure using 10% palladium-on-coal catalyst. After hydrogen uptake is complete, the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in water (50 ml) and the solution is adjusted to pH 7 with 10% sodium hydroxide solution. The precipitate is filtered off, washed with water and dried. 2-amino-4- (2-aminophenyl) -butyric acid is obtained. A solution of 2-amino-4- (2-aminophenyl) -butyric acid (1.0 g), hexamethyldisilazane (5.4 g) and chlorotrimethylsilane (0.1 g) in xylene (125 ml) was boiled for 65 hours. The reaction mixture is cooled, poured into ethanol (200 ml) and evaporated under reduced pressure, water is added (100 ml) and the solution is extracted with dichloromethane (2 x 20 125 ml). The combined dichloromethane solutions are washed with water (50 ml). ), dried over magnesium sulfate and evaporated under reduced pressure to give 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which is identical to the above compound.

25 3-Amino-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on fremstilles også på følgende måde:3-Amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is also prepared as follows:

Til en opløsning af 3-azido-2,3,4,5-tetrahydro-lH-[l]benz-azepin-2-on (se eks. 1) (27 g) i ethanol (3500 ml)· sættes i en nitrogenatmosfære under omrøring ved stuetemperatur en 30 suspension af Raney-nikkel i vand (50 ml, vasket med 10 rumfangsdele ethanol). Blandingen omrøres ved stuetemperatur i 2 timer, hvorpå der tilsættes yderligere 30 ml Raney-nikkel -suspension. Blandingen omrøres i endnu 30 minutter, hvorefter katalysatoren frafiltreres, og opløsningsmidletTo a solution of 3-azido-2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one (see Example 1) (27 g) in ethanol (3500 ml) nitrogen atmosphere with stirring at room temperature a suspension of Raney nickel in water (50 ml, washed with 10 parts by volume ethanol). The mixture is stirred at room temperature for 2 hours, then an additional 30 ml of Raney-nickel suspension is added. The mixture is stirred for another 30 minutes, after which the catalyst is filtered off and the solvent

48 DK 157881 B48 DK 157881 B

fordampes under formindsket tryk. Der fås en olie, som størkner efter tilsætning af ether. Man får 3-amino-2,3,4,5-tetrahydro-ΙΗ-[l]benzazepin-2-on, som smelter ved 161-162°C.evaporates under reduced pressure. An oil is obtained which solidifies after the addition of ether. There is obtained 3-amino-2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one, which melts at 161-162 ° C.

En opløsning af 3-amino-2,3,4,5-tetrahydro-lH-[l]benzazepin-5 2-on (8,0 g) og benzylpyrodruesyre (18,0 g) i methanol (450 ml) omrøres -under nitrogen ved stuetemperatur i 30 minutter.A solution of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-5-2-one (8.0 g) and benzylpyruvic acid (18.0 g) in methanol (450 ml) is stirred - under nitrogen at room temperature for 30 minutes.

Der tilsættes natriumcyanborhydrid (4,5 g), og den dannede opløsning omrøres i 48 timer ved stuetemperatur. Til blandingen sættes dråbevis koncentreret saltsyre (7 ml) i lø-10 bet af 10 minutter, og der omrøres i yderligere 1 time.Sodium cyanoborohydride (4.5 g) is added and the resulting solution is stirred for 48 hours at room temperature. To the mixture is added dropwise concentrated hydrochloric acid (7 ml) over 10 minutes and stirred for an additional 1 hour.

Reaktionsblandingen inddampes til tørhed, hvorefter der tilsættes dichlormethan (150 ml), og blandingen omrøres i 30 minutter. Det faste materiale frafiltreres, omrøres med vand (100 ml) i 15 minutter, hvorpå der filtreres, vaskes med 15 vand (50 ml) og tørres. Man får 3-(l-carboxy-3-phenylpropyl-amino)-2,3,4,5~tetrahydro~lH-[l]benzazepin-2-on som en iso-merblanding. Smp. 173-175°C.The reaction mixture is evaporated to dryness, then dichloromethane (150 ml) is added and the mixture is stirred for 30 minutes. The solid is filtered off, stirred with water (100 ml) for 15 minutes, then filtered, washed with 15 water (50 ml) and dried. There is obtained 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one as an isomer mixture. Mp. 173-175 ° C.

En opløsning af 3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-{l]benzazepin-2-on (6,0 g), natriumhydrogen-20 carbonat (4,0 g) og ethyliodid (11,6 g) i dimethylacetamid (200 ml) omrøres ved stuetemperatur i 72 timer under nitrogen, hvorpå der filtreres og inddampes i højvakuum. Remanensen optages i vand (250 ml), og den fremkomne opløsning ekstrahe-res med dichlormethan (2 x 400 ml). De sammenblandede ekstrak-25 ter tørres over magnesiumsulfat, og opløsningsmidlet inddampes under formindsket tryk. Man får 3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on som en isomerblanding. NMR (CDC13) δ 9,22 (s, IH), 4,10 (2 overlejrede kvartetter, 2H), 1,13 (2 overlejrede tripletter, 30 3H) .A solution of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- {1] benzazepin-2-one (6.0 g), sodium hydrogen carbonate (4.0 g) and ethyl iodide (11.6 g) in dimethyl acetamide (200 ml) are stirred at room temperature for 72 hours under nitrogen, then filtered and evaporated in high vacuum. The residue is taken up in water (250 ml) and the resulting solution is extracted with dichloromethane (2 x 400 ml). The mixed extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There is obtained 3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one as an isomer mixture. NMR (CDCl3) δ 9.22 (s, 1H), 4.10 (2 superimposed quartets, 2H), 1.13 (2 superimposed triplets, 3H).

Eksempel 7.Example 7

l-Benzyloxycarbonylmethyl-3-(l-benzyloxycarbonyl-3-phenyl-propylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-onl-Benzyloxycarbonylmethyl-3- (l-benzyloxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [] benzazepin-2-one

En opløsning af 3-(l-benzyloxycarbonyl-3-phenylpropylamino)-A solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -

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49 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (4,0 g) i tørt di-methylformamid sættes under nitrogen ved stuetemperatur til en omrørt suspension af natriumhydrid [ud fra 60%'s dispersion i mineralolie (0,42 g), vasket med petroleumsether (3 5 x 80 ml)] i tørt dimethylformamid (100 ml), hvortil der er sat tetrabutylammoniumbromid (3,1 g). Blandingen henstår i yderligere 30 minutter ved stuetemperatur, hvorpå der tilsættes en opløsning af bromeddikesyrebenzylester (2,2 g) i tørt dimethylformamid (10 ml). Efter yderligere 30 minutter 10 ved stuetemperatur opvarmes reaktionsblandingen til 50°C, og denne temperatur opretholdes i 18 timer. Blandingen afkøles til stuetemperatur, og opløsningsmidlet fordampes i højvakuum. Remanensen optages i vand (150 ml), og opløsningen ekstraheres med ethylacetat (2 x 300 ml), De sammen-15 blandede ethylacetatopløsninger vaskes med vand (100 ml), tørres over magnesiumsulfat og inddampes under formindsket tryk. Der fås en brun olie, som kromatograferes på silica-gel (250 g). Der elueres med toluen/ethylacetat (1:1, 600 ml), hvorved man får en olie, som er isomeren A af den øn-20 skede forbindelse. NMR (CDC13) δ 5,12 (s, 4H), 4,50 (q, 2H). Elueringen med yderligere 2000 ml af opløsningsmiddelblandingen giver en olie, som er isomeren B af den ønskede forbindelse. NMR (CDC13) δ 5,17 (s, 2H), 5,03 (d, 2H), 4,60 (q, 2H).49 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (4.0 g) in dry dimethylformamide is added under nitrogen at room temperature to a stirred suspension of sodium hydride [from 60% dispersion in mineral oil (0.42 g), washed with petroleum ether (3.5 x 80 ml)] in dry dimethylformamide (100 ml), to which is added tetrabutylammonium bromide (3.1 g). The mixture is allowed to stand for another 30 minutes at room temperature, then a solution of bromoacetic acid benzyl ester (2.2 g) in dry dimethylformamide (10 ml) is added. After a further 30 minutes 10 at room temperature, the reaction mixture is heated to 50 ° C and this temperature is maintained for 18 hours. The mixture is cooled to room temperature and the solvent is evaporated in high vacuum. The residue is taken up in water (150 ml) and the solution is extracted with ethyl acetate (2 x 300 ml). The mixed ethyl acetate solutions are washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure. A brown oil is obtained which is chromatographed on silica gel (250 g). Elute with toluene / ethyl acetate (1: 1, 600 ml) to give an oil which is the isomer A of the desired compound. NMR (CDCl 3) δ 5.12 (s, 4H), 4.50 (q, 2H). The elution with an additional 2000 ml of the solvent mixture gives an oil which is the isomer B of the desired compound. NMR (CDCl 3) δ 5.17 (s, 2H), 5.03 (d, 2H), 4.60 (q, 2H).

25 Udgangsstoffet fremstilles på følgende måde: En opløsning af 3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (som beskrevet i eksempel 6, 13,0 g), natriumhydrogencarbonat (10,0 g) og benzylbromid (19,0 g) i dimethylacetamid (750 ml) omrøres ved stuetemperatur un-30 der nitrogen i 7,2 timer. Reaktionsblandingen filtreres og inddampes i højvakuum. Remanensen optages i vand (150 ml), og den dannede opløsning ekstraheres med dichlormethan (2 x 400 ml). De sammenblandede ekstrakter vaskes med vand (100 ml), tørres over magnesiumsulfat og inddampes under 35 formindsket tryk. Man får den rå benzylester, Ved omkrystallisation fra ethylacetat fås 3-(l-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on, som smelter ved 139-141°C.The starting material is prepared as follows: A solution of 3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (as described in Examples 6, 13 , 0 g), sodium bicarbonate (10.0 g) and benzyl bromide (19.0 g) in dimethylacetamide (750 ml) are stirred at room temperature under nitrogen for 7.2 hours. The reaction mixture is filtered and evaporated in high vacuum. The residue is taken up in water (150 ml) and the resulting solution is extracted with dichloromethane (2 x 400 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure. The crude benzyl ester is obtained. Recrystallization from ethyl acetate gives 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 139-141 ° C.

Eksempel 8.Example 8.

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l-Carboxymethyl-3-(l-carboxy-3-phenylpropylamino)-2 ,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (Den laveresmeltende Isomer)1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (The lower melting isomer)

En opløsning af l-benzyloxycarbonylmethyl-3-(1-benzyloxy-5 carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[ljbenz-azepin-2-on (isomeren A ifølge eksempel 7, 2,7 g) i ethanol (800 ml) hydrogeneres ved stuetemperatur og atmosfæretryk med 10%'s palladium-på-kul-katalysator (0,5 g). Efter endt hydrogenoptagelse frafiltreres katalysatoren, og opløsninqs-10 midlet fordampes under formindsket tryk. Man får disyren (den Ønskede forbindelse), som er isomeren A, Smp. 256-259°C,A solution of 1-benzyloxycarbonylmethyl-3- (1-benzyloxy-5-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1-benz-azepin-2-one (isomer A of Example 7, 2 7 g) in ethanol (800 ml) is hydrogenated at room temperature and atmospheric pressure with 10% palladium-on-carbon catalyst (0.5 g). Upon completion of hydrogen uptake, the catalyst is filtered off and the solvent evaporated under reduced pressure. One obtains the diacid (the desired compound), which is the isomer A, m.p. 256-259 ° C,

Den identiske forbindelse fås ved hydrolyse af forbindelsen ifølge eksempel 5.The identical compound is obtained by hydrolysis of the compound of Example 5.

Eksempel 9.Example 9

15 l-Carboxymethyl-3-(l-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (Den høieresmeltende isomer)1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (The high melting isomer)

En opløsning af l-benzyloxycarbonylmethyl-3-(1-benzyloxycarb-onyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on (isomeren B ifølge eksempel 7, 5,0 g) i ethanol 20 (950 ml) hydrogeneres ved stuetemperatur og atmosfæretryk med palladium-på-kul-katalysator (0,5 g), Efter afslutning af hydrogenoptagelsen frafiltreres katalysatoren, og opløsningsmidlet inddampes under formindsket tryk. Der fås den ovenfor anførte disyre (titelforbindelse), som er isomeren 25 B. Smp. 280-282°C.A solution of 1-benzyloxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one (the isomer B of Example 7, 5.0 g) in ethanol 20 (950 ml) is hydrogenated at room temperature and atmospheric pressure with palladium-on-carbon catalyst (0.5 g). After completion of hydrogen uptake, the catalyst is filtered off and the solvent is evaporated under reduced pressure. There is obtained the diacid (title compound), which is the isomer 25 B. Mp. 280-282 ° C.

Den identiske forbindelse fremstilles ved hydrolyse af forbindelsen ifølge eksempel 1 (isomer B) eller forbindelsen ifølge eksempel 10 (isomer B)The identical compound is prepared by hydrolysis of the compound of Example 1 (isomer B) or the compound of Example 10 (isomer B)

Eksempel 10.Example 10.

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l-Ethoxycarbonylmethyl-3- (l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4f5-tetrahydro-lH-[1]benzazepin-2-on1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4f-tetrahydro-1H- [1] benzazepin-2-one

En opløsning af 3-(l-ethoxycarbonyl-3-phenylpropylamino)-5 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (se eksempel 6, 3,0 g) i tørt dimethylformamid (10 ml) sættes dråbevis i løbet af 10 minutter til en omrørt suspension af natriumhydrid [ud fra 60%'s suspension i mineralolie (0,36 g), vasket med petroleumsether (3 x 75 ml)] i tørt .dimethylformamid (100 ml) 10 ved stuetemperatur i en nitrogenatmosfære. Blandingen omrøres i yderligere 30 minutter, hvorpå der tilsættes en opløsning af bromeddikesyreethylester (1,4 g) i dimethylformamid (15 ml), og blandingen holdes ved 60°C i 48 timer. Reaktionsblandingen afkøles til stuetemperatur, og opløsningsmidlet for-15 dampes i højvakuum. Til remanensen sættes vand (100 ml), og opløsningen ekstraheres med ethylacetat (2 x 200 ml). De sammenblandede ekstrakter vaskes med vand (50 ml), tørres over magnesiumsulfat, og opløsningsmidlet fordampes under formindsket tryk. Man får e.n gul olie (3,8 g) . Denne kromatogra-20 feres på silicagel (120 g) og elueres med toluen/ethylacetat (1:1, 250 ml). Man får isomer A af det ønskede produkt, Ved eluering med yderligere 250 ml af opløsningsmiddelblandingen fås en olie. Denne består hovedsagelig af isomeren B og en mindre mængde af isomeren A af det ønskede produkt, bestemt 25 ved analytisk hplc.(se eksempel 6). Ved eluering med yderligere 250 ml af opløsningsmiddelblandingen fås en olie, som i det væsentlige består af ren isomer B (den langsomt vandrende). Dette materiale opløses i methanol (25 ml) og omdannes ved tilsætning af den ækvivalente mængde maleinsy-30 re i methanol til maleatsaltet. Efter'inddampning af opløsningsmidlet og omkrystallisation af remanensen fra methan-ol/ether får man den rene isomer B af 1-ethoxycarbonylmethyl- 3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-on som maleatsalt, som smelter ved 114-35 116°C.A solution of 3- (1-ethoxycarbonyl-3-phenylpropylamino) -5 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (see Example 6, 3.0 g) in dry dimethylformamide ( 10 ml) is added dropwise over 10 minutes to a stirred suspension of sodium hydride [from 60% suspension in mineral oil (0.36 g), washed with petroleum ether (3 x 75 ml)] in dry dimethylformamide (100 ml 10 at room temperature in a nitrogen atmosphere. The mixture is stirred for a further 30 minutes, then a solution of bromoacetic acid ethyl ester (1.4 g) in dimethylformamide (15 ml) is added and the mixture is kept at 60 ° C for 48 hours. The reaction mixture is cooled to room temperature and the solvent is evaporated in high vacuum. To the residue is added water (100 ml) and the solution extracted with ethyl acetate (2 x 200 ml). The combined extracts are washed with water (50 ml), dried over magnesium sulfate and the solvent evaporated under reduced pressure. Yellow oil (3.8 g) is obtained. This is chromatographed on silica gel (120 g) and eluted with toluene / ethyl acetate (1: 1, 250 ml). Isomer A of the desired product is obtained. Eluting with an additional 250 ml of the solvent mixture gives an oil. This consists mainly of the isomer B and a minor amount of the isomer A of the desired product, determined by analytical hplc (see Example 6). By eluting with an additional 250 ml of the solvent mixture, an oil is obtained which consists essentially of pure isomer B (the slow-moving one). This material is dissolved in methanol (25 ml) and converted by adding the equivalent amount of maleic acid in methanol to the maleate salt. After evaporation of the solvent and recrystallization of the residue from methane-ol / ether, the pure isomer B of 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1 [1] benzazepin-2-one as maleate salt, melting at 114-35 116 ° C.

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Eksempel 11.Example 11.

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1- Carboxymethyl-3-carboxymethylamino-2 >3,4,5-tetrahydro-lH-[l]benzazepln-2-on1- Carboxymethyl-3-carboxymethylamino-2> 3,4,5-tetrahydro-1H- [1] benzazeplin-2-one

En opløsning af l-benzyloxycarbonylmethyl-3-benzyloxycarb-5 onylmethylamino-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (4,8 g, 0,01 mol) i ethanol (550 ml) hydrogeneres ved stuetemperatur og atmosfasretryk med 5%' s palladium-på-kul-katalysator (0,85 g), indtil hydrogenoptagelsen er ophørt.A solution of 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (4.8 g, 0.01 mole) in ethanol (550 ml ) is hydrogenated at room temperature and atmospheric pressure with 5% palladium-on-carbon catalyst (0.85 g) until hydrogen uptake has ceased.

Til blandingen sættes vand (300 ml), katalysatoren frafil-10 treres, og opløsningsmidlet fordampes under formindsket tryk. Remanensen tritureres med ether. Man får titelforbindelsen (disyren), som smelter ved 232-236°C.To the mixture is added water (300 ml), the catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is triturated with ether. The title compound (diacid) is obtained, which melts at 232-236 ° C.

Udgangsforbindelsen fremstilles på følgende måde: En opløsning af 3-amino-2,3,4,5-tetrahydro-lH-[l]benzazepin-15 2-on (5,0 g, 0,028 mol) i dimethylformamid (100 ml) sættes under nitrogen til en omrørt suspension af natriumhydrid [fremstillet ud fra en 60%'s suspension i mineralolie (1,2 g) ved vaskning med petroleumsether (3 x 150 ml)] i dimethylformamid (400 ml), hvortil der er sat tetramethylammonium-20 bromid (10,9 g,0,031 nol). Reaktionsblandingen holdes i 15 minutter ved 50°C, hvorpå der tilsættes en opløsning af bromeddikesyrebenzylester (7,2 g, 0,031 mol) i dimethylformamid (25 ml). Blandingen omrøres i yderligere 18 timer ved 50°C, hvorpå den afkøles til stuetemperatur, og 25 dimethylformamidet fordampes i højvakuum. Remanensen udrøres med toluen/dichlormethan (1:1, 500 ml) til udfældning af de uorganiske salte. Efter filtrering inddampes opløsningen under formindsket tryk. Remanensen kromatograferes på silicagel (200 ml) og elueres med 0-15% ethylacetat i 30 toluen. Man får l-benzyloxycarbonylmethyl-3-benzyloxycarb-onylmethylamino-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on som den første fraktion. Ved yderligere eluering fås 3-benzyloxyc^bonylmethylamino-2,3,4,5-tetrahydro-lH- [1 ] benzazepin- 2- on, smp. 124-127°C,og 3-amino-l-benzyloxycarbonylmethyl- 35 2,3,4,5-tetrahydro-lH-[1]-benzazepin-2-on (se eksempel 1).The starting compound is prepared as follows: A solution of 3-amino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (5.0 g, 0.028 mol) in dimethylformamide (100 ml) is added under nitrogen to a stirred suspension of sodium hydride [prepared from a 60% suspension in mineral oil (1.2 g) by washing with petroleum ether (3 x 150 ml)] in dimethylformamide (400 ml) to which tetramethylammonium is added. 20 bromide (10.9 g, 0.031 nol). The reaction mixture is kept at 50 ° C for 15 minutes, then a solution of bromoacetic acid benzyl ester (7.2 g, 0.031 mol) in dimethylformamide (25 ml) is added. The mixture is stirred for an additional 18 hours at 50 ° C, then cooled to room temperature and the dimethylformamide evaporated in high vacuum. The residue is stirred with toluene / dichloromethane (1: 1, 500 ml) to precipitate the inorganic salts. After filtration, the solution is evaporated under reduced pressure. The residue is chromatographed on silica gel (200 ml) and eluted with 0-15% ethyl acetate in toluene. 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained as the first fraction. Further elution gives 3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, m.p. 124-127 ° C and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] -benzazepin-2-one (see Example 1).

iin

Eksempel 12.Example 12.

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53 l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3/4,5-tetrahydro-lH-[1]benzazepin-2-on 3(S)-Amino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-[l]benz-5 azepin-2-on giver ved behandling med benzylpyrodruesyre-ethylester i nærværelse af natriumcyanborhydrid (som beskrevet i eksempel 1 for den racemiske forbindelse) og rensning l-carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on på følgende 10 måde: Λ53 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3 / 4,5-tetrahydro-1H- [1] benzazepin-2-one 3 (S) -Amino-1-carboxymethyl-2, 3,4,5-tetrahydro-1H- [1] benz-5-azepin-2-one gives by treatment with benzylpyruvic acid ethyl ester in the presence of sodium cyanoborohydride (as described in Example 1 for the racemic compound) and purification 1-carboxymethyl-3S - (1S-Ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one in the following manner: Λ

En opløsning af natriumhydroxid (2,1 g) i vand (5 ml) sættes til en opløsning af 3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (14,0 g) i methanol (150 ml) ved stuetemperatur, og opløsningen omrøres i 2 timer. Opløs-15 ningsmidlet fordampes, remanensen tørres omhyggeligt og op- slæmmes med ether. Man får 3(S)-amino-l-carboxymethyl-2,3,4,5-tetrahydro-ΙΗ-[l]benzazepin-2-on-natriumsalt, som anvendes uden yderligere rensning.A solution of sodium hydroxide (2.1 g) in water (5 ml) is added to a solution of 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2 -one (14.0 g) in methanol (150 ml) at room temperature and the solution stirred for 2 hours. The solvent is evaporated, the residue is carefully dried and slurried with ether. 3 (S) -amino-1-carboxymethyl-2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one sodium salt is obtained, which is used without further purification.

En opløsning af det ovenfor beskrevne natriumsalt (12,9 g) 20 og benzylpyrodruesyreethylester (31 g) i eddikesyre (100 ml) og methanol (75 ml) omrøres i 1 time i en tør nitrogenatmosfære ved stuetemperatur. Derpå tilsættes dråbevis en opløsning af natriumcyanborhydrid (3,8 g) i methanol (30 ml) i løbet af 4 timer. De sammenblandede opløsninger omrøres natten 25 over ved stuetemperatur, hvorpå der dråbevis tilsættes koncentreret saltsyre (10 ml). Blandingen omrøres i 1 time ved stuetemperatur og inddampes. Remanensen fordeles mellem vand (400 ml) og ether (100 ml), og pH-værdien indstilles på 9,3 med 40%'s natriumhydroxidopløsning. Lagene adskilles, 30 og etherlaget kastes bort. Det vandige lag indstilles med koncentreret saltsyre på pH-værdien 4,3 og ekstraheres med ethylacetat (3 x 100 ml). De organiske faser hældes sammen, tørres over magnesiumsulfat og inddampes. Det rå produkt opløses i methylenchlorid (150 ml), og hydrogenchloridgas le-A solution of the sodium salt (12.9 g) described above and benzylpyruvic acid ethyl ester (31 g) in acetic acid (100 ml) and methanol (75 ml) is stirred for 1 hour in a dry nitrogen atmosphere at room temperature. Then, a solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) is added dropwise over 4 hours. The mixed solutions are stirred overnight at room temperature, and then concentrated hydrochloric acid (10 ml) is added dropwise. The mixture is stirred for 1 hour at room temperature and evaporated. The residue is partitioned between water (400 ml) and ether (100 ml) and the pH is adjusted to 9.3 with 40% sodium hydroxide solution. The layers are separated, 30 and the ether layer discarded. The aqueous layer is adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 100 ml). The organic phases are combined, dried over magnesium sulfate and evaporated. The crude product is dissolved in methylene chloride (150 ml) and hydrogen chloride gas is dissolved.

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54 des i 5 minutter gennem opløsningen. Opløsningsmidlet fordampes, og det fremkomne skum opløses i varm methylethylketon (100 ml). Det udfældede bundfald frafiltreres. Der fås en 95:5 diastereomer blanding, bestemt ved hplc. Produktet om-5 krystalliseres fra 3-pentanon/methanol (10:1). Man får 1-carboxymethyl-3(S)-(1(S)-ethoxycarbonyl-3-phenylpropylamino)- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on-hydrochlorid, smp. 188-190°C, [α]D = -141,0° (c = 0,9 i ethanol) med formlen IA, hvori cnH2n betyder ethylen, R^ betyder ethoxy og R1^ be-10 tyder hydroxy.54 dec for 5 minutes through the solution. The solvent is evaporated and the resulting foam is dissolved in hot methyl ethyl ketone (100 ml). The precipitated precipitate is filtered off. A 95: 5 diastereomeric mixture is obtained, determined by hplc. The product is recrystallized from 3-pentanone / methanol (10: 1). There is obtained 1-carboxymethyl-3 (S) - (1 (S) -ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride, m.p. 188-190 ° C, [α] D = -141.0 ° (c = 0.9 in ethanol) of formula IA wherein cnH2n is ethylene, R4 is ethoxy and R1 is hydroxy.

En opløsning af det ovenfor fremstillede hydrochlorid . (0,035 g) og propylenoxid (0,5 ml) i ethanol (4 ml) omrøres under nitrogen ved stuetemperatur natten over. Opløsningen inddampes til tørhed, der tilsættes ether (2 ml), og bund-15 faldet frafiltreres. Man får l-carboxymethyl-3S-(lS-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on, som smelter ved 148-149°C. [a]^ = -159° (c = 1,2 i ethanol).A solution of the hydrochloride prepared above. (0.035 g) and propylene oxide (0.5 ml) in ethanol (4 ml) are stirred under nitrogen at room temperature overnight. The solution is evaporated to dryness, ether (2 ml) is added and the precipitate is filtered off. There is obtained 1-carboxymethyl-3S- (1S-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one, which melts at 148-149 ° C. [α] D = -159 ° (c = 1.2 in ethanol).

Det optisk aktive udgangsmateriale fremstilles på følgende 20 måde: a) En opløsning af 0,4 g 3(S)-t-butyloxycarbonylamino-2,3,4,5-tetrahydro-lH-[l]benzazepin-2,5-dion [fremstillet ud fra L-kynurenin ifølge Australian J. Chemistry, bind 33, 633-640 (1980)] og bromeddikesyreethylester (0,23 g) i tørt tetra-25 hydrofuran (30 ml) omrøres ved 0°C i en tør nitrogenatmosfære. Til blandingen sættes kalium-t-butoxid (0,254 g) i én portion, hvorefter den henstår i 1 time ved 0°C, hvorpå der tilsættes en yderligere portion bromeddikesyreethylester (0,23 g), og blandingen henstår i yderligere 1 time 30 ved 0°C. Til reaktionsblandingen sættes vand (100 ml), hvorpå der ekstraheres med ethylacetat (2 x 50 ml). De sammenblandede ekstrakter vaskes med vand (100 ml), tørres over magnesiumsulfat og inddampes under formindsket tryk.The optically active starting material is prepared as follows: a) A solution of 0.4 g of 3 (S) -t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione [prepared from L-kynurenine according to Australian J. Chemistry, Vol. 33, 633-640 (1980)] and bromoacetic acid ethyl ester (0.23 g) in dry tetrahydrofuran (30 ml) is stirred at 0 ° C in a dry nitrogen atmosphere. . To the mixture is added potassium t-butoxide (0.254 g) in one portion, then left for 1 hour at 0 ° C, then an additional portion of bromoacetic acid ethyl ester (0.23 g) is added and the mixture is left for an additional 1 hour at 0 ° C. To the reaction mixture is added water (100 ml) and then extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulfate and evaporated under reduced pressure.

Der fås et gult gummiagtigt materiale, som efter udrivning 35 med ether-petroleumsether (kogeinterval 30-60°C) giverA yellow rubbery material is obtained which after tearing 35 with ether-petroleum ether (boiling range 30-60 ° C) gives

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55 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2,5-dion, smp. 86-88°C. [α]β = -203° (c = 1 i dimethylformamid).3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione, m.p. 86-88 ° C. [α] β = -203 ° (c = 1 in dimethylformamide).

En opløsning af 3(S)-t-butyloxycarbonylamino-l-ethoxycarb-5 onylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2,5-dion (0,14 g) og natriumborhydrid (7 mg) i ethanol (10 ml) omrøres i 18 timer ved stuetemperatur. Ethanolet fordampes under formindsket tryk, og remanensen opløses i dichlor-methan (25 ml). Opløsningen ekstraheres med 2 N saltsyre 10 (2 x 20 ml) og med mættet vandig natriumchloridopløsning (20 ml), hvorefter den tørres over natriumsulfat. Opløsningsmidlet fordampes under formindsket tryk, og remanensen tritureres med ether. Man får 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-lH-15 [l]benzazepin-2-on, som smelter ved 167-169,5°C. [α]β = -193° (c =0,52 i dimethylformamid). Denne forbindelse fås også ved hydrogenering af benzazepin-2,5-dion-derivatet med H^/Pt i ethanol.A solution of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione (0.14 g) and sodium borohydride ( 7 mg) in ethanol (10 ml) is stirred for 18 hours at room temperature. The ethanol is evaporated under reduced pressure and the residue is dissolved in dichloromethane (25 ml). The solution is extracted with 2N hydrochloric acid 10 (2 x 20 mL) and with saturated aqueous sodium chloride solution (20 mL), then dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue triturated with ether. There is obtained 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-15 [1] benzazepin-2-one, which melts at 167-169.5 ° C. [α] β = -193 ° (c = 0.52 in dimethylformamide). This compound is also obtained by hydrogenation of the benzazepine-2,5-dione derivative with H 2 / Pt in ethanol.

En blanding af 3(S)-t-butyloxycarbonylamino-l-ethoxycarbonyl-20 methyl-5-hydroxy-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (0,076 g), dicyclohexylcarbodiimid (0,064 g) og kobber-I-chlorid (7 mg) opvarmes i en nitrogenatmosfære ved 60°C i 32 timer. Reaktionsblandingen henstår til afkøling til stuetemperatur. Remanensen opløses i methylenchlorid (50 ml), 25 hvorpå den først vaskes med fortyndet ammoniumhydroxidopløs-ning (2 x 15 ml) og derpå med vand (20 ml). Den organiske fase tørres over natriumsulfat og inddampes. Der fås en blanding af det ønskede addukt og af overskud af dicyclohexylcarbodiimid .A mixture of 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonyl-methyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (0.076 g), dicyclohexylcarbodiimide ( 0.064 g) and copper I chloride (7 mg) are heated in a nitrogen atmosphere at 60 ° C for 32 hours. The reaction mixture is allowed to cool to room temperature. The residue is dissolved in methylene chloride (50 ml), then washed first with dilute ammonium hydroxide solution (2 x 15 ml) and then with water (20 ml). The organic phase is dried over sodium sulfate and evaporated. A mixture is obtained of the desired adduct and of excess dicyclohexylcarbodiimide.

30 Sidstnævnte blanding (0,100 g) opløses i ethylacetat (40 ml), og opløsningen anbringes i-en trykbeholder. Der tilsættes 10%' s palladiiun-på-kul-katalysator (0,010 g), og blandin gen hydrogeneres i 16 timer ved 40°C og 3 atmosfærer.Katalysatoren frafiltreres, og filtratet inddampes. Remanensen 35 tritureres med ether, og etheropløsningen inddampes. ManThe latter mixture (0.100 g) is dissolved in ethyl acetate (40 ml) and the solution is placed in a pressure vessel. 10% palladium-on-carbon catalyst (0.010 g) is added and the mixture is hydrogenated for 16 hours at 40 ° C and 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. The residue is triturated with ether and the ether solution is evaporated. You

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56 får 3 (S) -t-butyloxycarbonylamino-l-ethoxycarbonylmethyl- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, smp. 115-116,5°C.56 gives 3 (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, m.p. 115-116.5 ° C.

[a]^ - -182° (c = 2,6 i dimethylformamid).[α] D -182 ° (c = 2.6 in dimethylformamide).

b) Vinsyre (12,6 g) og racemisk 3-amino-l-ethoxycarbonyl-5 methyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (22 g) opløses i varmt ethanol (200 ml). Denne opløsning afkøles, hvorpå den henstår natten over ved stuetemperatur. Det dannede bundfald frafiltreres og omkrystalliseres to gange fra ethanol (200 ml). Man får 3(S)-amino-l-ethoxycarbonylmethyl- 10 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on-tartratsaltet.b) Tartaric acid (12.6 g) and racemic 3-amino-1-ethoxycarbonyl-5-methyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (22 g) are dissolved in hot ethanol (200 ml). This solution is cooled and left to stand overnight at room temperature. The resulting precipitate is filtered off and recrystallized twice from ethanol (200 ml). The 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one tartrate salt is obtained.

Dette opløses i vand (100 ml), pH-værdien indstilles på 9 med fortyndet ammoniumhydroxidopløsning, og der ekstraheres med methylenchlorid (2 x 50 ml). De sammenblandede ekstrakter vaskes med vand (75 ml), tørres over magnesiumsulfat og 15 inddampes. Man får 3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, smp, 104-106°C. [α]β = -285,5° (c =0,99 i ethanol).This is dissolved in water (100 ml), the pH is adjusted to 9 with dilute ammonium hydroxide solution and extracted with methylene chloride (2 x 50 ml). The combined extracts are washed with water (75 ml), dried over magnesium sulfate and evaporated. There is obtained 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, mp, 104-106 ° C. [α] β = -285.5 ° (c = 0.99 in ethanol).

c) Til en opløsning af 3(S)-t-butyloxycarbonylamino-l-ethoxy-carbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepln-2-on [jf.c) To a solution of 3 (S) -t-butyloxycarbonylamino-1-ethoxy-carbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepln-2-one [cf.

20 ovenfor under a), 0,225 g] i ethylacetat (25 ml) ledes først hydrogenchloridgas i 45 minutter og derpå nitrogen i 30 minutter. Ethylacetatfasen vaskes med vand (30 ml) og 1 N saltsyre (30 ml). Ethylacetatlaget kastes bort, og de vandige faser hældes sammen. Den vandige opløsning indstilles 25 med fortyndet ammoniumhydroxidopløsning på pH-værdien 9 og ekstraheres med ethylacetat (3 x 50 ml). De organiske faser hældes sammen, tørres over natriumsulfat og inddampes.20 above under a), 0.225 g] in ethyl acetate (25 ml) is first passed hydrogen chloride gas for 45 minutes and then nitrogen for 30 minutes. The ethyl acetate phase is washed with water (30 ml) and 1N hydrochloric acid (30 ml). The ethyl acetate layer is discarded and the aqueous phases are combined. The aqueous solution is adjusted to 25 with dilute ammonium hydroxide solution at pH 9 and extracted with ethyl acetate (3 x 50 ml). The organic phases are combined, dried over sodium sulfate and evaporated.

Man får 3(S)-amino-l-ethoxycarbonylmethyl-2,3,4,5-tetra-hydro-lH-[1]benzazepin-2-on, smp. 101-102°C. [a]D = “298° 30 (c = 0,46 i ethanol).3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained, m.p. 101-102 ° C. [α] D = 298 ° (c = 0.46 in ethanol).

Beskyttelsesgruppen fraspaltes ved behandling med ethan-dithiol/bortrifluoridetherat eller med trifluoreddiksyre/ anisol. Man får 3 (S) -amino-l-ethoxycarbonylmethyl:—2,3,4,5-tetrahydro-lH- [1]benzazepin-2-on.The protecting group is cleaved by treatment with ethanedithiol / boron trifluoride etherate or with trifluoroacetic acid / anisole. There is obtained 3 (S) -amino-1-ethoxycarbonylmethyl: -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

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57 3(S)-Amino-l-ethoxycarbonylmethy1-2/3,4,5-tetrahydro-lH-[l]benzazepin-2-on fremstilles også på følgende måde: d) En opløsning af 3(S)-t-butyloxycarbonylamino-l-ethoxy-carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-lH-[l]benz-5 azepin-2-on (beskrevet ovenfor, 1,0 g) i eddikesyreanhydrid (20 ml) henstår i 3 timer ved 80°C. Reaktionsblandingen afkøles til stuetemperatur og inddampes under formindsket tryk. Til remanensen sættes ether (100 ml), den dannede opløsning vaskes med vand (500 ml) og tørres over magnesium-10 sulfat. Opløsningsmidlet fordampes under formindsket tryk.57 3 (S) -Amino-1-ethoxycarbonylmethyl-2 / 3,4,5-tetrahydro-1H- [1] benzazepin-2-one is also prepared as follows: d) A solution of 3 (S) -t- butyloxycarbonylamino-1-ethoxy-carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (described above, 1.0 g) in acetic anhydride (20 ml) let stand for 3 hours at 80 ° C. The reaction mixture is cooled to room temperature and evaporated under reduced pressure. To the residue is added ether (100 mL), the resulting solution washed with water (500 mL) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure.

Man får 5-acetoxy-3(S)-t-butyloxycarbonylamino-l-ethoxy-carbonylmethy1-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on som en bleg olie, som anvendes uden yderligere rensning.5-Acetoxy-3 (S) -t-butyloxycarbonylamino-1-ethoxy-carbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained as a pale oil which is used without further cleaning.

En opløsning af 5-acetoxy-3-(S)-t-butyloxycarbonylamino-1-15 ethoxycarbonylmethy1-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (0,7 g) i ethanol (50 ml) hydrogeneres i 24 timer ved 70°C og 2,9 atmosfærer med 10%'s palladium-på-kul-katalysa-tor (0,5 g).Katalysatoren frafiltreres, og opløsningsmidlet fordampes under formindsket tryk. Man får 3(S)-t-butyloxy-20 carbonylamino-l-ethoxycarbonylmethy1-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, som uden yderligere rensning omdannes analogt med den ovenfor beskrevne fremgangsmåde til 3(S)-amino-l-ethoxycarbonylmethy1-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on. Smp. 99-101°C, [a]D = -297° (c = 1 i ethanol).A solution of 5-acetoxy-3- (S) -t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (0.7 g) in ethanol (50 ml) is hydrogenated for 24 hours at 70 ° C and 2.9 atmospheres with 10% palladium-on-carbon catalyst (0.5 g). The catalyst is filtered off and the solvent is evaporated under reduced pressure. There is obtained 3 (S) -t-butyloxy-carbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which is converted without further purification by analogy to the procedure described above. to 3 (S) -amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one. Mp. 99-101 ° C, [α] D = -297 ° (c = 1 in ethanol).

25 e) En opløsning af 3(S)-t-butyloxycarbonylamino-2,3,4,5- tetrahydro-lH-[l]benzazepin-2,5-dion (12,5 g),fremstillet ud fra L-kynurenin som beskrevet i Australian J. Chemistry bind 33, 633-640 (1980), og bromeddikesyre-t-butylester (10,1 g) i acetone (700 ml) omrøres ved stuetemperatur i en 30 tør nitrogenatmosfære. Kaliumcarbonat (12,5 g) tilsættes i én portion, og den dannede suspension omrøres i 16 timer ved stuetemperatur. Kaliumsaltene frafiltreres, og filtratet inddampes til tørhed. Remanensen fordeles mellem ethyl-acetat (250 ml) og vand (250 ml). Lagene adskilles, og den 35 organiske fase tørres over natriumsulfat. Remanensen tritu- 58E) A solution of 3 (S) -t-butyloxycarbonylamino-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione (12.5 g), prepared from L-kynurenine as described in Australian J. Chemistry Vol. 33, 633-640 (1980), and bromoacetic acid t-butyl ester (10.1 g) in acetone (700 ml) is stirred at room temperature in a dry nitrogen atmosphere. Potassium carbonate (12.5 g) is added in one portion and the resulting suspension is stirred for 16 hours at room temperature. The potassium salts are filtered off and the filtrate is evaporated to dryness. The residue is partitioned between ethyl acetate (250 ml) and water (250 ml). The layers are separated and the organic phase is dried over sodium sulfate. The residue tritu- 58

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reres med petroleumsether (350 ml, kogeinterval 30-60°C).Stir with petroleum ether (350 ml, boiling range 30-60 ° C).

Man får 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyl-methyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2,5-dion. Smp.There is obtained 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione. Mp.

75-77°C. [α]β = ~172° (c = 0,96 i dimethylformamid).75-77 ° C. [α] β = ~ 172 ° (c = 0.96 in dimethylformamide).

5 En opløsning af 3(S)-t-butyloxycarbonylamino-l-t-butyloxy-carbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2,5-dion (8,0 g) i ethanol (500 ml) hydrogeneres med platinoxid (800 mg) i 2 timer ved atmosfæretryk og stuetemperatur. Katalysatoren frafiltreres, og filtratet inddampes. Man får 10 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-5- hydroxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, [α]β = -173° (c = 1,8 i dimethylformamid).A solution of 3 (S) -t-butyloxycarbonylamino-lt-butyloxy-carbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,5-dione (8.0 g) in ethanol ( 500 ml) is hydrogenated with platinum oxide (800 mg) for 2 hours at atmospheric pressure and room temperature. The catalyst is filtered off and the filtrate is evaporated. 3 (S) -t-butyloxycarbonylamino-1t-butyloxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, [α] β = -173 ° ( c = 1.8 in dimethylformamide).

En suspension af 3(S)-t-butyloxycarbonylamino-l-t-butyloxy-carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-lH-[1]benzazepin-15 2-on (3,0 g), dicyclohexylcarbodiimid (5,0 g) og kobber-I-chlorid (500 mg) omrøres mekanisk og opvarmes i en tør nitrogenatmosfære i 16 timer til 80°C. Blandingen afkøles, fortyndes med methylenchlorid (100 ml) og filtreres. Det faste materiale kastes bort. Filtratet vaskes med 7%'s 20 ammoniumhydroxidopløsning (4 x 75 ml), derpå med 1 x 100 ml vand og til sidst med mættet vandig natriumchloridopløs-ning (100 ml). Den organiske fase tørres over natriumsulfat og inddampes. Der .fås en blanding af det ønskede addukt og overskud af dicyclohexylcarbodiimid.A suspension of 3 (S) -t-butyloxycarbonylamino-1-butyloxy-carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (3.0 g), dicyclohexylcarbodiimide (5.0 g) and copper I chloride (500 mg) are mechanically stirred and heated in a dry nitrogen atmosphere for 16 hours to 80 ° C. The mixture is cooled, diluted with methylene chloride (100 ml) and filtered. The solid material is discarded. The filtrate is washed with 7% 20 ammonium hydroxide solution (4 x 75 ml), then with 1 x 100 ml water and finally with saturated aqueous sodium chloride solution (100 ml). The organic phase is dried over sodium sulfate and evaporated. A mixture of the desired adduct and excess dicyclohexylcarbodiimide is obtained.

25 Denne blanding (5,5 g) opløses i ethylacetat (200 ml), hvorpå opløsningen anbringes i en trykbeholder, der tilsættes 10%'s palladium-på-kul-katalysator (3,0 g), hvorefter der hydrogeneres i 16 timer ved 40°C og 3 atmosfærer.Katalysatoren frafiltreres, og filtratet inddampes. Remanensen tri-30 tureres med ether (75 ml). Der fås et hvidt fast materiale, som er 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonyl-methyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on. Smp. 145-147°C, [α]β = -194° (c = 0,46 i dimethylformamid).This mixture (5.5 g) is dissolved in ethyl acetate (200 ml) and the solution is placed in a pressure vessel which is added to 10% palladium-on-carbon catalyst (3.0 g) and then hydrogenated for 16 hours. at 40 ° C and 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. The residue is triturated with ether (75 mL). A white solid is obtained which is 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonyl-methyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one. Mp. 145-147 ° C, [α] β = -194 ° (c = 0.46 in dimethylformamide).

En opløsning af 3(S)-t-butyloxycarbonylamino-l-t-butyloxy-A solution of 3 (S) -t-butyloxycarbonylamino-1-t-butyloxy

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59 carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on (beskrevet ovenfor, 3,0 g) i eddikesyreanhydrid (50 ml) opvarmes i 2 timer i en tør nitrogenatmosfære til 80°C. Eddikesyreanhydridet fordampes, remanensen opløses i 5 ethylacetat (75 ml), og der vaskes med mættet vandig natrium-hydrogencarbonatopløsning (50 ml), vand (50 ml) og mættet vandig natriumchloridopløsning (50 ml). Den organiske fase tørres over natriumsulfat, inddampes, og remanensen tritu-reres med ether (50 ml). Man får 3(S)-t-butyloxycarbonyl-10 amino -1 - t-bulylDX^carbonylmethyl- 5—acetoxy-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on. Smp. 164-166,5°C, [a)D = -169° (c = 0,36 i dimethylformamid).59 carbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (described above, 3.0 g) in acetic anhydride (50 ml) is heated for 2 hours in a dry nitrogen atmosphere to 80 ° C. The acetic anhydride is evaporated, the residue is dissolved in ethyl acetate (75 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic phase is dried over sodium sulfate, evaporated and the residue is triturated with ether (50 ml). There is obtained 3 (S) -t-butyloxycarbonyl-amino-1-t-butylDX-carbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one. Mp. 164-166.5 ° C, [a) D = -169 ° (c = 0.36 in dimethylformamide).

En opløsning af 3(S)-t-butyloxycarbonylamino-l-t-butyloxy-carbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-lH-[1]benzazepin-15 2-on (2,2 g) i ethanol (300 ml) sættes til en trykbeholder sammen med 10%'s palladium-på-kul-katalysator. Blandingen hydrogeneres i 3 dage ved 70°C og 3 atmosfærer.Katalysatoren frafiltreres, og filtratet inddampes. Man får 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-20 tetrahydro-ΙΗ-[l]benzazepin-2-on. Smp. 164-165°C, [a]D = -200,6° (c =0,64 i dimethylformamid).A solution of 3 (S) -t-butyloxycarbonylamino-1-butyloxy-carbonylmethyl-5-acetoxy-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (2.2 g) in ethanol (300 ml) is added to a pressure vessel together with 10% palladium-on-carbon catalyst. The mixture is hydrogenated for 3 days at 70 ° C and 3 atmospheres. The catalyst is filtered off and the filtrate is evaporated. There is obtained 3 (S) -t-butyloxycarbonylamino-1-t-butyloxycarbonylmethyl-2,3,4,5-20 tetrahydro-ΙΗ- [1] benzazepin-2-one. Mp. 164-165 ° C, [α] D = -200.6 ° (c = 0.64 in dimethylformamide).

Gennem en opløsning af 3(S)-t-butyloxycarbonylamino-l-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (0,85 g) i ethylacetat (40 ml) ledes hydrogenchlorid-25 gas i 2 timer, hvorefter nitrogen gennemledes i 30 minutter. Ethylacetatet fordampes, og det som remanens fremkomne hvide materiale opløses straks i methanol (40 ml). Propylenoxid (5 ml) tilsættes, og blandingen omrøres i 16 timer ved stuetemperatur. Det som bundfald fremkomne hvide materiale fra-30 filtreres. Man får 3(S)-amino-l-carboxymethyl-2,3,4,5-tetra-hydro-ΙΗ-[l]benzazepin-2-on, smp. 275-276°C, [a]D = -287° (c = 0,71 i N saltsyre). Dette produkt kondenseres som beskrevet ovenfor med benzylpyrodruesyre-ethylester i nærværelse af natriumcyanborhydrid.Through a solution of 3 (S) -t-butyloxycarbonylamino-1t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (0.85 g) in ethyl acetate (40 ml) hydrogen chloride gas for 2 hours, then nitrogen is passed for 30 minutes. The ethyl acetate is evaporated and the white material obtained as the residue is dissolved immediately in methanol (40 ml). Propylene oxide (5 ml) is added and the mixture is stirred for 16 hours at room temperature. The precipitated white material is filtered off. 3 (S) -amino-1-carboxymethyl-2,3,4,5-tetrahydro-hydro- [1] benzazepin-2-one is obtained, m.p. 275-276 ° C, [α] D = -287 ° (c = 0.71 in N hydrochloric acid). This product is condensed as described above with benzylpyruvic acid ethyl ester in the presence of sodium cyanoborohydride.

Eksempel 13.Example 13

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Analogt med de ovenfor beskrevne fremgangsmåder fremstilles følgende forbindelser med fomlen I, hvori betyder H,By analogy to the methods described above, the following compounds are prepared by the formula I, wherein H

Rg betyder OC2H^, og R^ betyder OH:R 2 is OC 2 H 2 and R 2 is OH:

5 Nr. R-L5 No. R-L

1 c6h5ch2 2 CH31 c6h5ch2 2 CH3

Eksempel 14.Example 14.

Fremstilling af 10.000 tabletter med et indhold af 5 mg 10 virksom forbindelse ifølge eksempel 1 pr. tablet:Preparation of 10,000 tablets with a content of 5 mg of 10 active compound according to Example 1 per tablet:

Bestanddele l-Carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH[l]benzazepin-2-on 100 g Mælkesukker 1157 g 15 Majsstivelse 75 gIngredients 1-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H [1] benzazepin-2-one 100 g Milk sugar 1157 g Corn starch 75 g

Polyethylenglycol 6000 75 gPolyethylene Glycol 6000 75 g

Talkumpulver 75 gTalcum powder 75 g

Magnesiumstearat 18 gMagnesium stearate 18 g

Rent vand q.s.Pure water q.s.

20 Samtlige pulverformige bestanddele sigtes gennem en sigte med en maskevidde på 0,6 mm. Derpå blandes den virksomme forbindelse med mælkesukker, talkum, magnesiumstearat og med halvdelen af stivelsen i et egnet blandeapparatur.All powdered components are sieved through a sieve with a mesh width of 0.6 mm. Then the active compound is mixed with milk sugar, talc, magnesium stearate and with half of the starch in a suitable mixing apparatus.

Den anden halvdel af stivelsen suspenderes i 40 ml vand, 25 og suspensionen sættes til en kogende opløsning af poly-ethylenglycolen i 150 ml vand. Den fremkomne pasta sættes til pulverblandingen, og der granuleres eventuelt under tilsætning af yderligere vand. Granulatet tørres natten over ved 35°C, presses gennem en sigte med en maskevidde 30 på 1,2 mm og komprimeres til tabletter med delekærv og med en diameter på 6,4 mm.The other half of the starch is suspended in 40 ml of water, 25 and the suspension is added to a boiling solution of the polyethylene glycol in 150 ml of water. The resulting paste is added to the powder mixture and optionally granulated with the addition of additional water. The granulate is dried overnight at 35 ° C, pressed through a sieve with a mesh width of 1.2 mm, and compressed into tablets with split grooves and a diameter of 6.4 mm.

Eksempel 15.Example 15

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Injektionspræparat indeholdende 25 mg virksom forbindelse ifølge eksempel 1 i 5 ml opløsning:Injection preparation containing 25 mg of active compound of Example 1 in 5 ml of solution:

Bestanddele 5 l-Carboxymethyl-3-(l-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-hydrochlorid 25,0 gIngredients 5 l-Carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride 25.0 g

Propylparaben 1,0 gPropylparaben 1.0 g

Vand til injektion q.s. ad 5000,0 ml 10 Den virksomme forbindelse og konserveringsmidlet opløses i 3500 ml vand til injektion, og der fortyndes til 5000 ml. Opløsningen filtreres gennem et sterilfilter, hvorefter den under sterile betingelser fyldes i ampuller i en mængde på 5 ml pr. ampul.Water for injection q.s. ad 5000.0 ml 10 The active compound and preservative are dissolved in 3500 ml water for injection and diluted to 5000 ml. The solution is filtered through a sterile filter and then, under sterile conditions, is filled into ampoules at a rate of 5 ml per ml. ampoule.

15 Eksempel 16.Example 16.

Fremstilling af 10.000 kapsler med et indhold af 20 mg virksom forbindelse ifølge eksempel 9 pr. kapsel:Preparation of 10,000 capsules containing 20 mg of active compound of Example 9 per capsule:

Bestanddele l-Carboxymethyl-3-(l-carboxy-3-phenylpropylamino)-20 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on 200 g Mælkesukker 1700 gIngredients 1-Carboxymethyl-3- (1-carboxy-3-phenylpropylamino) -20 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one 200 g Milk sugar 1700 g

Talkumpulver 100 gTalcum powder 100 g

Samtlige pulverformige bestanddele sigtes gennem en si med en maskevidde på 0,6 mm. Derefter homogeniseres den virk-25 somme forbindelse først med talkum og derefter med mælkesukker i et egnet blandeapparatur. Blandingen fyldes i kapsler nr. 3 i en mængde på 200 mg pr. kapsel ved hjælp af en påfyldningsmaskine .All powdered components are screened through a screen having a mesh width of 0.6 mm. Thereafter, the active compound is first homogenized with talc and then with milk sugar in a suitable mixing apparatus. The mixture is filled into capsules # 3 at 200 mg / ml. capsule using a filling machine.

På tilsvarende måde fremstilles tabletter, injektionspræpa-30 rater eller kapsler indeholdende andre af de omhandlede for-Similarly, tablets, injection preparations or capsules containing other of the present invention are prepared.

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62 bindeiser, f.eks. sådanne, som er illustreret i de øvrige eksempler.62 binders, e.g. such as are illustrated in the other examples.

Eksempel 17.Example 17

l-Carboxymethyl-3S-(lR-ethoxycarbonyl-3-phenylpropylamino)-5 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on.1-Carboxymethyl-3S- (1R-ethoxycarbonyl-3-phenylpropylamino) -5,2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

Methylethylketonfiltratet fra krystallisationen af 1-carb-oxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-ΙΗ-[1]benzazepin-2-on-hydrochlorid i eksempel 12 inddampes, og remanensen tritureres med ethylacetat (50 ml).The methyl ethyl ketone filtrate from the crystallization of 1-carb-oxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one hydrochloride in Example 12 is evaporated and the residue is triturated with ethyl acetate (50 ml).

10 Det dannede faste materiale fordeles mellem ethylacetat (100 ml) og vand (100 ml), og pH-værdien indstilles på 4,3 med koncentreret saltsyre. Lagene adskilles, og den vandige fase ekstraheres med ethylacetat (2 x 100 ml). De sammen-blandede ethylacetatopløsninger tørres over natriumsulfat og 15 inddampes under formindsket tryk. Remanensen adskilles i komponenterne ved hjælp af hplc. under anvendelse af en C^g "Reverse Phase" præparativ søjle. Som opløsningsmiddel anvendes vand/methanol (3:7), som indeholder 0,05% eddikesyre. Således fremstilles en yderligere mængde af S,S-isomeren 20 ifølge eksempel 12 og tillige S,R-isomeren. Det til S,R-iso-meren svarende materiale opløses i dichlormethan (75 ml), og der ledes hydrogenchloridgas til opløsningen. Opløsningsmidlet inddampes under formindsket tryk, og remanensen omkrystalliseres fra methylethylketon. Man får l^c'arboxymethyl-3S-2 5 (lR-ethoxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro- lH-[l]benzazepin-2-on-hydrochlorid. Smp. 181-183°C, [a]D = -188° (c = 0,8 i ethanol).The solid formed is partitioned between ethyl acetate (100 ml) and water (100 ml) and the pH is adjusted to 4.3 with concentrated hydrochloric acid. The layers are separated and the aqueous phase is extracted with ethyl acetate (2 x 100 ml). The mixed ethyl acetate solutions are dried over sodium sulfate and evaporated under reduced pressure. The residue is separated into the components by hplc. using a C ^ g "Reverse Phase" preparative column. As solvent is water / methanol (3: 7) which contains 0.05% acetic acid. Thus, an additional amount of the S, S isomer 20 of Example 12 and also the S, R isomer is prepared. The material corresponding to the S, R isomer is dissolved in dichloromethane (75 ml) and hydrogen chloride gas is fed to the solution. The solvent is evaporated under reduced pressure and the residue is recrystallized from methyl ethyl ketone. 1'C'arboxymethyl-3S-2,5 (1R-ethoxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride is obtained. Mp 181-183 ° C, [α] D = -188 ° (c = 0.8 in ethanol).

Eksempel 18.Example 18.

l-Carboxymethyl-3S-(lS-carboxy-3-phenylpropylamino)-2,3,4,5-30 tetrahydro-lH-[1]benzazepin-2-on1-Carboxymethyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-30 tetrahydro-1H- [1] benzazepin-2-one

Til en opløsning af l-carboxymethyl-3S-(IS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-To a solution of 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one

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6363

hydrochloric! (1 g) i methanol (10 ml) sættes en opløsning af natriumhydroxid (0,27 g) i vand (2 ml). Reaktionsblandingen omrøres i 18 timer ved stuetemperatur, hvorpå den inddampes under formindsket tryk. Remanensen opløses i vand 5 (25 ml), hvorefter den indstilles på pH-værdien 3 med 4 Nhydrochloric! (1 g) in methanol (10 ml) is added a solution of sodium hydroxide (0.27 g) in water (2 ml). The reaction mixture is stirred for 18 hours at room temperature and then evaporated under reduced pressure. The residue is dissolved in water 5 (25 ml) and adjusted to pH 3 with 4 N

saltsyre. Det dannede bundfald frafiltreres, vaskes med vand og tørres. Man får l-carboxymethyl-3S-(lS-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on, som smelter ved 270-272°C. [a]D = -200,5° (c = 1 i 3%'s 10 vandig ammoniak).hydrochloric acid. The resulting precipitate is filtered off, washed with water and dried. There is obtained 1-carboxymethyl-3S- (1S-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which melts at 270-272 ° C. [α] D = -200.5 ° (c = 1 in 3% aqueous ammonia).

Eksempel 19.Example 19.

l-Ethoxycarbonylmethyl-3-(l-benzyloxycarhonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-onl-Ethoxycarbonylmethyl-3- (l-benzyloxycarhonyl-3-phenylpropyl-amino) -2,3,4,5-tetrahydro-LH [l] benzazepin-2-one

En opløsning af 3-(l-benzyloxycarbonyl-3-phenylpropylamino)-15 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (5,0 g) i tørt dimethylformamid sættes i en nitrogenatmosfære til en omrørt suspension af natriumhydrid [fremstillet ud fra 60%'s dispersion i mineralolie (0,5 g), vasket med petroleumsether (3 x 80 ml)] i tørt dimethylformamid (100 ml) ved stuetemperatur.A solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (5.0 g) in dry dimethylformamide is added in a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from 60% dispersion in mineral oil (0.5 g), washed with petroleum ether (3 x 80 ml)] in dry dimethylformamide (100 ml) at room temperature.

20 Blandingen omrøres i yderligere 30 minutter ved stuetemperatur, hvorpå der tilsættes en opløsning af bromeddikesyre-ethylester (2,0 g) i tørt dimethylformamid (10 ml). Reaktionsblandingen henstår i yderligere 30 minutter ved stuetemperatur, hvorpå den opvarmes til 50°C og henstår i 18 timer ved 25 denne temperatur. Blandingen afkøles til stuetemperatur, og opløsningen fordampes i højvakuum. Remanensen opløses i vand (150 ml), og opløsningen ekstraheres med ethylacetat (2 x 300 ml). De sammenblandede ekstrakter vaskes med vand (100 ml), tørres over magnesiumsulfat, og opløsningsmidlet fordampes un-30 der formindsket tryk. Man får en brun olie, som kromatogra-feres på silicagel (250 g) og elueres med toluen/ethylacetat (9:1, 600 ml). Man får en olie, som er isomer A af titelforbindelsen. Yderligere eluering med 1000 ml af opløsningsmiddelblandingen giver en olie, som er isomer B af titelforbin-35 delsen.The mixture is stirred for an additional 30 minutes at room temperature, then a solution of bromoacetic acid ethyl ester (2.0 g) in dry dimethylformamide (10 ml) is added. The reaction mixture is left for an additional 30 minutes at room temperature, then heated to 50 ° C and left for 18 hours at this temperature. The mixture is cooled to room temperature and the solution evaporated in high vacuum. The residue is dissolved in water (150 ml) and the solution is extracted with ethyl acetate (2 x 300 ml). The combined extracts are washed with water (100 ml), dried over magnesium sulfate and the solvent evaporated under reduced pressure. A brown oil is obtained which is chromatographed on silica gel (250 g) and eluted with toluene / ethyl acetate (9: 1, 600 ml). An oil is obtained which is isomer A of the title compound. Further elution with 1000 ml of the solvent mixture gives an oil which is isomer B of the title compound.

Eksempel 20,.Example 20

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l-Ethoxycarbonylmethyl-3-(l-carboxy-3-phenylpropylamino) - 2,3,4,5-tetraiiydro-lH- [ 1] benzazepin-2-on.1-Ethoxycarbonylmethyl-3- (1-carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

l-Ethoxycarbonylmethyl-3-(l-benzyloxycarbonyl-3-phenylpropyl-5 amino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (isomeren B ifølge eksempel 19, 1,1 g) i ethanol (150 ml) hydrogeneres ved stuetemperatur og atmosfæretryk med palladium-på-kul-katalysator (0,5 g). Efter endt hydrogenoptagelse frafiltre-res katalysatoren, og opløsningsmidlet fordampes under for-10 mindsket tryk. Der fås et halvfast materiale, som tritureres med ether (30 ml).. Man får isomer B af titelforbindelsen, smp. 17 5-177°C.1-Ethoxycarbonylmethyl-3- (1-benzyloxycarbonyl-3-phenylpropyl-5-amino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (the isomer B of Example 19, 1.1 g ) in ethanol (150 ml) is hydrogenated at room temperature and atmospheric pressure with palladium-on-carbon catalyst (0.5 g). Upon completion of hydrogen uptake, the catalyst is filtered off and the solvent is evaporated under reduced pressure. A semi-solid material is obtained which is triturated with ether (30 ml). Isomer B of the title compound is obtained, m.p. 17 5-177 ° C.

Eksempel 21.Example 21.

1-(1-Carboxyethyl)-3-(l-ethoxycarbonyl-3-phenylpropylamino) -15 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-hydrochlorid1- (1-Carboxyethyl) -3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride

En opløsning af 3-amino-l-(1-carboxyethyl)-2,3,4,5-tetra-hydro-ΙΗ-[l]benzazepin-2-on-hydrochlorid (3 g) og benzyl-pyrodruesyre-ethylester (6,5 g) i eddikesyre (30 ml) og methanol (30 ml) omrøres i 1 time ved stuetemperatur. Der 20 tilsættes natriumcyanborhydrid (0,8 g) i methanol (10 ml) i løbet af 4 timer. Reaktionsblandingen omrøres i 24 timer ved stuetemperatur, hvorpå der tilsættes koncentreret saltsyre (2 ml) og omrøres i 1 time. Opløsningsmidlet fordampes under formindsket tryk, og remanensen fordeles mellem 25 vand (50 ml) og ether (30 ml). pH-Værdien indstilles på 9,4, etherlaget isoleres og kastes bort. Den vandige opløsning indstilles på pH-værdien 4,3 og ekstraheres med ethyl-acetat (3 x 50 ml). De sammenblandede ekstrakter tørres over magnesiumsulfat, og opløsningsmidlet fordampes under 30 formindsket tryk. Til en opløsning af råproduktet i methylen-chlorid (10 ml) ledes hydrogenchloridgas 2 minutter, og opløsningen inddampes. Man får 1-(1-carboxyethyl)-3-(1-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on-hydrochlorid som en diastereomerblanding, smp.A solution of 3-amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one hydrochloride (3 g) and benzylpyruvic acid ethyl ester ( 6.5 g) in acetic acid (30 ml) and methanol (30 ml) are stirred for 1 hour at room temperature. Sodium cyanoborohydride (0.8 g) in methanol (10 ml) is added over 4 hours. The reaction mixture is stirred for 24 hours at room temperature, then concentrated hydrochloric acid (2 ml) is added and stirred for 1 hour. The solvent is evaporated under reduced pressure and the residue is partitioned between 25 water (50 ml) and ether (30 ml). The pH is adjusted to 9.4, the ether layer is isolated and discarded. The aqueous solution was adjusted to pH 4.3 and extracted with ethyl acetate (3 x 50 ml). The combined extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. To a solution of the crude product in methylene chloride (10 ml) is added hydrogen chloride gas for 2 minutes and the solution is evaporated. 1- (1-carboxyethyl) -3- (1-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride is obtained as a diastereomer mixture, m.p.

35 87-94°C.87-94 ° C.

Udgangsmaterialet fremstilles på følgende måde: 65The starting material is prepared as follows: 65

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3-Azido-2,3,4,5-tetrahyd.ro-IH- [1] benzazepin-2-on (fremstillet ifølge eksempel 1, 5 g) sættes i §n portion til en omrørt suspension af kaliumhydroxid (1,8 g) og tetrabutyl-5 ammoniumbromid (1,8 g) i tetrahydrofuran (50 ml) i en nitrogenatmosfære ved 0°C. Omrøringen fortsættes i 5 minutter, hvorpå der i løbet af 5 minutter tilsættes (R)-2-brompropi-onsyre-tert-butylester [J.P.Greenstein et al., J.Am.Chem.3-Azido-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (prepared according to Example 1.5 g) is added in one portion to a stirred suspension of potassium hydroxide (1.8 g) and tetrabutylammonium bromide (1.8 g) in tetrahydrofuran (50 ml) in a nitrogen atmosphere at 0 ° C. Stirring is continued for 5 minutes, followed by the addition of (R) -2-bromopropionic acid tert-butyl ester over 5 minutes [J.P.Greenstein et al., J.Am.Chem.

Soc. 7j5, 6054 (1954) , H.Niedrich og G.Koiler, J.Prakt.chem.Soc. 7j5, 6054 (1954), H. Niedrich and G. Koiler, J.Prakt.chem.

10 316, 729 (1974)] (5,2 g) i tetrahydrofuran (15 ml). Reak tionsblandingen henstår under omrøring i yderligere 2 timer til opvarmning til stuetemperatur. Reaktionsblandingen filtreres og inddampes under formindsket tryk. Remanensen fordeles mellem vand (50 ml) og ether (100 ml).10 316, 729 (1974)] (5.2 g) in tetrahydrofuran (15 ml). The reaction mixture is left stirring for a further 2 hours to warm to room temperature. The reaction mixture is filtered and evaporated under reduced pressure. The residue is partitioned between water (50 ml) and ether (100 ml).

15 Den organiske fase vaskes med 2 N saltsyre (10 ml), tørres over magnesiumsulfat, og opløsningsmidlet fordampes under formindsket tryk. Man får 3-azido-l-(1-tert-butyloxycarbonyl-ethyl)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on i form af en olie, som anvendes uden yderligere rensning.The organic phase is washed with 2N hydrochloric acid (10 mL), dried over magnesium sulfate and the solvent evaporated under reduced pressure. There is obtained 3-azido-1- (1-tert-butyloxycarbonyl-ethyl) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one in the form of an oil which is used without further purification.

20 En opløsning af 3-azido-l-(1-tert-butyloxycarbonylethyl)- 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (7 g) i ethanol (70 ml) hydrogeneres ved et tryk på 3 atmosfærer i 3 timer under anvendelse af 10%'s palladium-på-kul-katalysator (0,5 g). Katalysatoren frafiltreres, og ethanolet fordampes 25 under formindsket tryk. Man får 3-amino-l-(1-tert-butyloxy-carbonylethyl)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on i form af en olie. hplc. viser, at produktet er en ca. 1:1-diastereomerblanding. Dette materale anvendes uden yderligere rensning.A solution of 3-azido-1- (1-tert-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (7 g) in ethanol (70 ml) is hydrogenated a pressure of 3 atmospheres for 3 hours using 10% palladium-on-carbon catalyst (0.5 g). The catalyst is filtered off and the ethanol is evaporated under reduced pressure. 3-amino-1- (1-tert-butyloxy-carbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained as an oil. hplc. shows that the product is an approx. 1: 1 diastereomer mixture. This material is used without further purification.

30 En opløsning af den ovenfor beskrevne 3-amino-l-(1-tert- butyloxycarbonylethyl)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on (4,7 g) i trifluoreddikesyre (25 ml) omrøres i 1 time ved stuetemperatur. Trifluoreddikesyren fordampes underA solution of the above-described 3-amino-1- (1-tert-butyloxycarbonylethyl) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (4.7 g) in trifluoroacetic acid ( 25 ml) is stirred for 1 hour at room temperature. The trifluoroacetic acid is evaporated below

DK 157881 BDK 157881 B

66 formindsket tryk, og remanensen optages i ether (100 ml).66 reduced pressure and the residue was taken up in ether (100 ml).

Til opløsningen ledes hydrogenchloridgas, indtil der ikke længere dannes bundfald. Det faste materiale frafiltreres.Hydrochloride gas is fed to the solution until no precipitate is formed. The solid material is filtered off.

Man får 3-amino-l-(1-carboxyethyl)-2,3,4,5-tetrahydro-lH-5 [l]benzazepin-2-on-hydrochlorid, smp. 165-176°C. Hplc. viser, at produktet er en ca. l:-diastereomerblanding.There is obtained 3-amino-1- (1-carboxyethyl) -2,3,4,5-tetrahydro-1H-5 [1] benzazepin-2-one hydrochloride, m.p. 165-176 ° C. Hplc. shows that the product is an approx. L: -diastereomerblanding.

Eksempel 22.Example 22.

l-Ethoxycarbonylmethyl-3S-(lS-ethoxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on 10 En opløsning af 3S-amino-l-ethoxycarbonylmethyl-2,3,4,5-te-trahydro-ΙΗ-[1]benzazepin-2-on (1,5 g), 2-brom-4-phenylsmØr-syreethylester (1,6 g) og triethylamin (0,8 ml) i dimethyl-formamid (37 ml) omrøres under nitrogen i 18 timer ved 70°C. Dimethylformamidet fordampes derpå under formindsket tryk.1-Ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one A solution of 3S-amino-1-ethoxycarbonylmethyl 2,3,4,5-tetrahydro-ΙΗ- [1] benzazepin-2-one (1.5 g), 2-bromo-4-phenylbutyric acid ethyl ester (1.6 g) and triethylamine (0.8 in dimethylformamide (37 ml) is stirred under nitrogen for 18 hours at 70 ° C. The dimethylformamide is then evaporated under reduced pressure.

15 Remanensen optages i ethylacetat (70 ml), vaskes med vand (5 x 25 ml), tørres over magnesiumsulfat og inddampes. Produktblandingen adskilles ved hjælp af kromatografi på silicagel, idet der som opløsningsmiddel anvendes ethylacetat/hexan (40:60). Man får omtrent lige store mængder 1-ethoxycarbo-20 nylmethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on [NMR (CDC13): δ 4,52 (q, 2H)], den S,S,enantiomere af forbindelsen ifølge eksempel 10, og den diastereomere, l-ethoxycarbonylmethyl-3S-(lR-ethoxycar-bonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-25 azepin-2-on, NMR (CDC13): δ 4,50 (q, 2H).The residue is taken up in ethyl acetate (70 ml), washed with water (5 x 25 ml), dried over magnesium sulfate and evaporated. The product mixture is separated by chromatography on silica gel using ethyl acetate / hexane (40:60) as the solvent. Approximately equal amounts of 1-ethoxycarbonylmethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one are obtained [NMR (CDCl3) : δ 4.52 (q, 2H)], the S, S, enantiomer of the compound of Example 10, and the diastereomeric, 1-ethoxycarbonylmethyl-3S- (1R-ethoxycarbonyl-3-phenylpropylamino) -2,3, 4,5-tetrahydro-1H- [1] benz-azepin-2-one, NMR (CDCl3): δ 4.50 (q, 2H).

Tyndtlagskromatografi: (silicagel, ethylacetat/hexan = 40:60): (S,S)-isomeren har en Rf-værdi på 0,24, og (S,R)-isomeren har en Rf-værdi på 0,33.Thin layer chromatography: (silica gel, ethyl acetate / hexane = 40:60): The (S, S) isomer has an Rf of 0.24 and the (S, R) isomer has an Rf of 0.33.

Eksempel 23.Example 23

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67 l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2/3,4,5-tetrahydro-lH-[1]benzazepin-2-on67 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one

En 2 N kaliumhydroxidopløsning (0,26 ml) sættes dråbevis 5 til en opløsning af l-ethoxycarbonylmethyl-3S-(lS-ethoxy-carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on (0,25 g) i ethanol (5 ml) under omrøring ved stuetemperatur under nitrogen. Blandingen omrøres i 1 time, hvorefter ethanolet fordampes, og remanensen opløses i 10 vand (5 ml), indstilles på pH-værdien 2 med 2 N saltsyre og ekstraheres med ethylacetat (2 x 30 nil) .A 2N potassium hydroxide solution (0.26 ml) is added dropwise 5 to a solution of 1-ethoxycarbonylmethyl-3S- (1S-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one (0.25 g) in ethanol (5 ml) with stirring at room temperature under nitrogen. The mixture is stirred for 1 hour, then the ethanol is evaporated and the residue is dissolved in 10 water (5 ml), adjusted to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate (2 x 30 nil).

De sammenblandede ethylacetatopløsninger vaskes med mættet natriumhydroxidopløsning (5 ml), tørres over magnesiumsulfat og inddampes til tørhed. Man får l-carboxymethyl-3S-15 (lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[l]benzazepin-2-on, forbindelsen ifølge eksempel 12.The mixed ethyl acetate solutions are washed with saturated sodium hydroxide solution (5 ml), dried over magnesium sulfate and evaporated to dryness. There is obtained 1-carboxymethyl-3S-15 (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, the compound of Example 12.

Eksempel 2 4.Example 2 4.

l-Carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)- 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-hydrochlorid 20 3(S)-Amino-1-carboxymethyl-2,3,4,5-tetrahydro-lH-[1]benz- 25 azepin-2-on-natriumsalt (619 g) , som har en [ot]D -værdi på -304,4° (c = 1,08 i vand), benzylpyrodruesyreethylester (1960 g), vandfrit ethanol (5880 ml) og iseddike (5880 ml) blandes og omrøres i 1,5 timer ved 20-25°C. I løbet af 25 24 timer tilsættes langsomt og ensartet en opløsning af natriumcyanborhydrid (179 g) i vandfri ethylalkohol (2200 ml). Efter endt tilsætning omrøres reaktionsblandingen i 24 timer. Til reaktionsblandingen sættes 12 N saltsyre (500 ml), og opløsningsmidlet fordampes ved 35-40°C 30 og 3 mm Hg. Den tilbageblevne olie sættes til en blanding af is (3000 g), vand (3000 ml) og diethylether (3000 ml) , og blandingens pH-værdi indstilles på 9-9,5 med 10 N natrium-1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride 3 (S) -Amino-1-carboxymethyl 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one sodium salt (619 g) having a [ot] D value of -304.4 ° (c = 1, (8 g in water), benzylpyruvic acid ethyl ester (1960 g), anhydrous ethanol (5880 ml) and glacial acetic acid (5880 ml) are mixed and stirred for 1.5 hours at 20-25 ° C. Over 25 24 hours, slowly and uniformly a solution of sodium cyanoborohydride (179 g) in anhydrous ethyl alcohol (2200 ml) is added. After the addition is complete, the reaction mixture is stirred for 24 hours. To the reaction mixture is added 12N hydrochloric acid (500 ml) and the solvent is evaporated at 35-40 ° C 30 and 3 mm Hg. The residual oil is added to a mixture of ice (3000 g), water (3000 ml) and diethyl ether (3000 ml) and the pH of the mixture is adjusted to 9-9.5 with 10 N sodium chloride.

DK 157881 BDK 157881 B

68 hydroxidopløsning (1735 ml). Den vandige fase isoleres, og til etherfasen sættes yderligere 8000 ml ether, hvorved der opnås en yderligere produktmængde i form af en olie.68 hydroxide solution (1735 ml). The aqueous phase is isolated and to the ether phase is added an additional 8000 ml of ether, thereby obtaining an additional product amount in the form of an oil.

Det med ether ikke blandbare lag isoleres og forenes med 5 den vandige fase. Derpå vaskes etherekstrakten med vand (2 x 1000 ml), vaskevæsken sættes til den ovenfor beskrevne vand/olie-bestanddel, og blandingens pH-værdi indstilles på 4,25-4,35 med 12 N saltsyre (550-650 ml). Blandingen ekstraheres med ethylacetat (3 x 2000 ml). De sammenblan-10 dede ethylacetatekstrakter vaskes med vand (2000 ml) og tørres over vandfrit magnesiumsulfat (500 mg). Tørringsmidlet frafiltreres, og opløsningsmidlet fordampes omhyggeligt ved 40°C og 3 mm Hg. Den fremkomne olie opløses i ethylacetat (4500 ml), og der tilsættes 28%'s etherisk saltsyre (309 g) 15 under kraftig omrøring. Der tilsættes diethylether (1500 ml), og blandingen omrøres 1 time. Det faste materiale isoleres og vaskes med ethylacetat (2 x 500 ml) og diethylether (3 x 1000 ml). Ved tørring ved 50°C og 3 mm Hg fås det rå produkt, som består af ca. 65% af det ønskede 1-carboxy-20 methyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on, som er identisk med produktet ifølge eksempel 12. Dette konstateres ved hplc. under anvendelse af en C^g "Reverse Phase" præparativ søjle. Som opløsningsmiddel anvendes en blanding af methanol, 25 vand og eddikesyre (75:25:0,02).The ether immiscible layers are isolated and joined to the aqueous phase. Then, the ether extract is washed with water (2 x 1000 ml), the washing liquid is added to the water / oil component described above and the pH of the mixture is adjusted to 4.25-4.35 with 12 N hydrochloric acid (550-650 ml). The mixture is extracted with ethyl acetate (3 x 2000 ml). The combined ethyl acetate extracts are washed with water (2000 ml) and dried over anhydrous magnesium sulfate (500 mg). The desiccant is filtered off and the solvent is evaporated carefully at 40 ° C and 3 mm Hg. The resulting oil is dissolved in ethyl acetate (4500 ml) and 28% ethereal hydrochloric acid (309 g) is added with vigorous stirring. Diethyl ether (1500 ml) is added and the mixture is stirred for 1 hour. The solid is isolated and washed with ethyl acetate (2 x 500 ml) and diethyl ether (3 x 1000 ml). Drying at 50 ° C and 3 mm Hg gives the crude product, which consists of approx. 65% of the desired 1-carboxy-methyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one, which is identical to the product according to Example 12. This is found by hplc. using a C ^ g "Reverse Phase" preparative column. As a solvent, a mixture of methanol, water and acetic acid (75: 25: 0.02) is used.

Det ovenfor fremstillede råprodukt suspenderes i dichlor-methan (26900 ml), og der tilledes hydrogenchloridgas i en ensartet strøm. Efter 40 minutters forløb fås en opløsning. Derefter afbrydes tilførslen af gassen. Opløsningen filtre-30 res til fjernelse af spor af uopløseligt materiale, og der tilsættes diethylether (10750 ml).The crude product prepared above is suspended in dichloromethane (26900 ml) and hydrogen chloride gas is fed in a uniform stream. After 40 minutes, a solution is obtained. Then the gas supply is interrupted. The solution is filtered to remove traces of insoluble material and diethyl ether (10750 ml) is added.

Suspensionen omrøres natten over ved stuetemperatur, og det faste materiale frafiltreres. Dette vaskes med dichlor-methan (4 x 500 ml) og diethylether (3 x 1000 ml). Efter 35 tørring får man et rent produkt som hydrochloridsalt. Smp. 175-178°C.The suspension is stirred overnight at room temperature and the solid is filtered off. This is washed with dichloromethane (4 x 500 ml) and diethyl ether (3 x 1000 ml). After drying, a pure product such as hydrochloride salt is obtained. Mp. 175-178 ° C.

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6969

Til 1880 g af det ovenfor fremstillede hydrochloridsalt sættes dichlormethan (18000 ml). Suspensionen behandles atter med hydrogenchloridgas til dannelse af en opløsning.To 1880 g of the hydrochloride salt prepared above is added dichloromethane (18000 ml). The suspension is again treated with hydrogen chloride gas to form a solution.

Til opløsningen sættes diethylether (7200 ml) . Den fremkom-5 ne suspension omrøres i 3 timer og filtreres. Det faste materiale vaskes med dichlormethan (2 x 1000 ml) og diethy1-ether (2 x 1000 ml) og tørres. Man får produktet, som smelter ved 183-185°C. (Hplc. viser, at produktet indeholder 96%'s ren forbindelse).Diethyl ether (7200 ml) is added to the solution. The resulting suspension is stirred for 3 hours and filtered. The solid is washed with dichloromethane (2 x 1000 ml) and diethyl ether (2 x 1000 ml) and dried. The product is obtained which melts at 183-185 ° C. (Hplc. Shows that the product contains 96% pure compound).

10 Til 1280 g af det ovenfor fremstillede salt sættes chloroform (4000 ml), og blandingen koges i 10 minutter under tilbagesvaling. Opvarmningen afbrydes, blandingen omrøres i 4 timer og filtreres. Det faste materiale vaskes med chloroform (2 x 200 ml) og diethylether (3 x 500 ml), tørres og 15 sigtes. Man får l-carboxymethyl-3S-(lS-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on-hydrochlorid, som smelter ved 184-186°C. [a]^ = -139,26° (c = 0,92 i absolut ethanol). Produktet er identisk med hydrochloridsaltet ifølge eksempel 12.To 1280 g of the salt prepared above is added chloroform (4000 ml) and the mixture is refluxed for 10 minutes. The heating is stopped, the mixture is stirred for 4 hours and filtered. The solid is washed with chloroform (2 x 200 ml) and diethyl ether (3 x 500 ml), dried and sieved. There is obtained 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride, which melts at 184-186 ° C. [α] D = -139.26 ° (c = 0.92 in absolute ethanol). The product is identical to the hydrochloride salt of Example 12.

20 Eksempel 25.Example 25.

3-(l-Benzyloxycarbonyl-3-phenylpropylamino) -1-carboxymethyl- 2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on-hydrochlorid (isomer B)3- (1-Benzyloxycarbonyl-3-phenylpropylamino) -1-carboxymethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride (isomer B)

Til en opløsning af 3-(l-benzyloxycarbonyl-3-phenylpropyl-25 amino)-l-tert-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (4,0 g i ethylacetat (100 ml), ledes hydrogenchloridgas under omrøring ved 0°C i 20 minutter. Reaktionsblandingen inddampes under formindsket tryk, og det fremkomne faste materiale tritureres med ether 30 (50 ml). Det faste materiale frafiltreres, vaskes med ether (15 ml) og ethylacetat (15 ml), hvorpå det koges med ethylacetat (50 ml). Produktet omkrystalliseres fra methanol/ethyl-acetat. Man får den ønskede forbindelse, som smelter ved 197-199°C. (Isomer B).To a solution of 3- (1-benzyloxycarbonyl-3-phenylpropyl-amino) -1-tert-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (4.0 g ethyl acetate (100 ml), hydrogen chloride gas is passed under stirring at 0 ° C for 20 minutes, the reaction mixture is evaporated under reduced pressure and the resulting solid is triturated with ether 30 (50 ml). The solid is filtered off, washed with ether (15 ml). and ethyl acetate (15 ml), then boil with ethyl acetate (50 ml). The product is recrystallized from methanol / ethyl acetate to give the desired compound, which melts at 197-199 ° C (Isomer B).

Udgangsmaterialet fremstilles på følgende måde: 70The starting material is prepared as follows: 70

DK 157881 BDK 157881 B

Til en opløsning af 3-(l-benzyloxycarbonyl-3-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (3,0 g) og bromeddikesyre-tert-butylester (2,2 g) i tetrahydrofuran 5 (100 ml) sættes kalium-tert-butoxid (1,2 g) under tørt nitro gen og under omrøring ved stuetemperatur. Reaktionsblandingen omrøres i 20 timer ved stuetemperatur, hvorefter den hældes i vand (250 ml) og ekstraheres med dichlormethan (2 x 150 ml). De sammenblandede ekstrakter vaskes med vand 10 (100 ml) og tørres over magnesiumsulfat. Efter fordampning af opløsningsmidlet får man 3-(l-benzyloxycarbonyl-3-phenyl-propylamino)-l-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-on.To a solution of 3- (1-benzyloxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (3.0 g) and bromoacetic acid tert-butyl ester (2.2 g) in tetrahydrofuran 5 (100 ml) is added potassium tert-butoxide (1.2 g) under dry nitrogen and stirred at room temperature. The reaction mixture is stirred for 20 hours at room temperature, then poured into water (250 ml) and extracted with dichloromethane (2 x 150 ml). The combined extracts are washed with water 10 (100 ml) and dried over magnesium sulfate. After evaporation of the solvent, 3- (1-benzyloxycarbonyl-3-phenyl-propylamino) -1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained.

Eksempel 26.Example 26

15 l-Ethoxycarbonylmethyl-3-(l-ethoxycarbonyl-2-phenylpropyl-amino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-2-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one

Til en opløsning af natriummethoxid i methanol [fremstillet ud fra natrium (0,25 g) og methanol (50 ml)] sættes under omrøring i en nitrogenatmosfære en opløsning af 2-(l-ethoxy-. 20 carbonyl-3-phenylpropylamino)-4-[o-(ethoxycarbonylmethyl- amino) -phenyl] -smørsyreethylester (5,6 g) i methanol (100 ml). Reaktionsblandingen koges i 65 timer under tilbagesvaling, hvorpå den inddampes under formindsket tryk. Remanensen fordeles mellem vand (50 ml) og dichlormethan (200 ml). Den 25 vandige opløsning ekstraheres med dichlormethan (200 ml).To a solution of sodium methoxide in methanol [prepared from sodium (0.25 g) and methanol (50 ml)] is added, with stirring, in a nitrogen atmosphere a solution of 2- (1-ethoxy-20-carbonyl-3-phenylpropylamino) - 4- [o- (ethoxycarbonylmethylamino) -phenyl] -butyric acid ethyl ester (5.6 g) in methanol (100 ml). The reaction mixture is refluxed for 65 hours and then evaporated under reduced pressure. The residue is partitioned between water (50 ml) and dichloromethane (200 ml). The aqueous solution is extracted with dichloromethane (200 ml).

De sammenblandede organiske opløsninger vaskes med vand (50 ml) og tørres over kaliumcarbonat.The combined organic solutions are washed with water (50 ml) and dried over potassium carbonate.

Efter inddampning af opløsningsmidlet får man en blanding af isomer A og B af l-ethoxycarbonylmethyl-3-(1-ethoxy-30 carbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on, som adskilles ved kromatografi på silicagel og under anvendelse af fremgangsmåden ifølge eksempel 10 omdannes i de enkelte maleater.After evaporation of the solvent, a mixture of isomer A and B of 1-ethoxycarbonylmethyl-3- (1-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzene is obtained. azepin-2-one, which is separated by chromatography on silica gel and using the procedure of Example 10 is converted into the individual maleate.

Udgangsforbindelsen fremstilles på følgende måde:The starting compound is prepared as follows:

71 DK 157881 B71 DK 157881 B

Til en opløsning af 2-amino-4-(o-nitrophenyl)-smørsyre-ethylester (17,4 g) i 50%'s vandigt dioxan (130 ml) sættes triethylamin (10,5 g) og 2-(tert-butyloxycarbonyloxyimino)-5 2-phenylacetonitril (18,7 g). Reaktionsblandinge omrøres ved stuetemperatur i 4 timer, hvorpå den fortyndes med vand (300 ml). Blandingen ekstraheres med ether (2 x 150 ml), den vandige fase syrnes med iskold 2 N saltsyre og ekstraheres med ethylacetat (2 x 250 ml). Ethylacetatlagene hældes 10 sammen, vaskes med vand (150 ml) og tørres over natriumsulfat. Opløsningsmidlet fordampes under formindsket tryk.To a solution of 2-amino-4- (o-nitrophenyl) -butyric acid ethyl ester (17.4 g) in 50% aqueous dioxane (130 ml) is added triethylamine (10.5 g) and 2- (tert. butyloxycarbonyloxyimino) -2-phenylacetonitrile (18.7 g). The reaction mixture is stirred at room temperature for 4 hours, then diluted with water (300 ml). The mixture is extracted with ether (2 x 150 ml), the aqueous phase is acidified with ice-cold 2 N hydrochloric acid and extracted with ethyl acetate (2 x 250 ml). The ethyl acetate layers are poured together, washed with water (150 ml) and dried over sodium sulfate. The solvent is evaporated under reduced pressure.

Man får 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)-smør-syre-ethylester, som anvendes uden yderligere rensning.There is obtained 2-t-butyloxycarbonylamino-4- (o-nitrophenyl) butyric acid ethyl ester which is used without further purification.

En opløsning af 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)-15 smørsyre-ethylester (13,0 g) i ethanol (300 ml) hydrogeneres ved stuetemperatur og atmosfæretryk med 10%'s palladium-på-kul-katalysator (1 g), indtil hydrogenoptagelsen er ophørt. Katalysatoren frafiltreres, og opløsningsmidlet fordampes.A solution of 2-t-butyloxycarbonylamino-4- (o-nitrophenyl) -butyric acid ethyl ester (13.0 g) in ethanol (300 ml) is hydrogenated at room temperature and atmospheric pressure with 10% palladium-on-carbon catalyst (1 g) until hydrogen uptake has ceased. The catalyst is filtered off and the solvent is evaporated.

Man får 2-t-butyloxycarbonylamino-4-(o-aminophenyl)-smør-20 syre-ethylester, der anvendes uden yderligere rensning i det følgende trin.There is obtained 2-t-butyloxycarbonylamino-4- (o-aminophenyl) butyric acid ethyl ester which is used without further purification in the following step.

En opløsning af 2-t-butyloxycarbonylamino-4-(o-aminophenyl)-smørsyre-ethylester (10,0 g) og glyoxalsyre-ethylester (4,2 g) i ethanol (120 ml) hydrogeneres ved 80°C og et tryk 25 på 3 atmosfærer i 72 timer med 10%'s palladium-på-kul-ka-talysator. Reaktionsblandingen afkøles til stuetemperatur, og katalysatoren frafiltreres. Opløsningsmidlet fordampes under formindsket tryk, og remanensen fordeles mellem ethylacetat (150 ml) og vand (75 ml). Den organiske fase tørres 30 over natriumsulfat, og opløsningsmidlet fordampes under formindsket tryk. Man får 2-t-butyloxycarbonylamino-4-[o-(ethoxycarbonylmethylamino)-phenyl]-smøresyre-ethylester, der anvendes i det det efterfølgende trin uden yderligere rensning.A solution of 2-t-butyloxycarbonylamino-4- (o-aminophenyl) -butyric acid ethyl ester (10.0 g) and glyoxalic acid ethyl ester (4.2 g) in ethanol (120 ml) is hydrogenated at 80 ° C and a pressure 25 in 3 atmospheres for 72 hours with 10% palladium-on-carbon catalyst. The reaction mixture is cooled to room temperature and the catalyst is filtered off. The solvent is evaporated under reduced pressure and the residue partitioned between ethyl acetate (150 ml) and water (75 ml). The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. There is obtained 2-t-butyloxycarbonylamino-4- [o- (ethoxycarbonylmethylamino) -phenyl] -butyric acid ethyl ester which is used in the subsequent step without further purification.

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Hydrogenchloridgas ledes i 30 minutter ved stuetemperatur til en opløsning af 2-t-butyloxycarbonylamino-4-[o-(ethoxy-carbonylmethylamino)-phenyl]-smørsyre-ethylester (8,5 g) i ethylacetat (150 ml). Opløsningen inddampes under formind-5 sket tryk, og remanensen opløses i ethylacetat (100 ml). Opløsningen vaskes med vand (3 x 100 ml) og tørres over natriumsulfat. Opløsningsmidlet fordampes under formindsket tryk. Man får 2-amino-4-[o-(ethoxycarbonylmethylamino)-phenyl]-smørsyre-ethylester, der anvendes i det efterfølgen-10 de trin uden yderligere rensning.Hydrogen chloride gas is passed for 30 minutes at room temperature to a solution of 2-t-butyloxycarbonylamino-4- [o- (ethoxy-carbonylmethylamino) -phenyl] -butyric acid ethyl ester (8.5 g) in ethyl acetate (150 ml). The solution is evaporated under reduced pressure and the residue is dissolved in ethyl acetate (100 ml). The solution is washed with water (3 x 100 ml) and dried over sodium sulfate. The solvent is evaporated under reduced pressure. There is obtained 2-amino-4- [o- (ethoxycarbonylmethylamino) -phenyl] -butyric acid ethyl ester, which is used in the subsequent step without further purification.

En opløsning af 2-amino-4-[o-(ethoxycarbonylamino)-phenyl]-smørsyre-ethylester (4,7 g) og benzylpyrodruesyre-ethyl-ester (12,4 g) i eddikesyre (35 ml) og methanol (35 ml) omrøres under nitrogen i 1 time ved stuetemperatur. Natrium-15 cyanborhydrid (1,6 g) i methanol (15 ml)‘tilsættes dråbevis 1 løbet af 4 timer.Reaktionsblandingen omrøres i 24 timer ved stuetemperatur, der tilsættes dråbevis koncentreret saltsyre (2 ml) og omrøres i 1 time ved stuetemperatur. Blandingen inddampes til tørhed, remanensen fordeles mellem 20 vand (75 ml) og ether (75 ml), og pH-værdien indstilles på 2 med 6 N saltsyre. Lagene adskilles, og den vandige fase ekstraheres med ether (2 x 75 ml). Etherekstrakterne kastes bort, og den vandige fases pH-værdi indstilles på 9 med 40%'s natriumhydroxidopløsning, og der ekstraheres med ethylacetat 25 (3 x 50 ml). Ekstrakterne tørres over natriumsulfat og ind dampes under formindsket tryk. Man får 2-(1-ethoxycarbonyl- 3-phenylpropylamino)-4-[o-(ethoxycarbonylmethylamino)-phenyl]-smørsyre-ethylester, som anvendes direkte til fremstilling af slutproduktet.A solution of 2-amino-4- [o- (ethoxycarbonylamino) phenyl] butyric acid ethyl ester (4.7 g) and benzylpyruvic acid ethyl ester (12.4 g) in acetic acid (35 ml) and methanol (35 g) ml) is stirred under nitrogen for 1 hour at room temperature. Sodium 15 cyanoborohydride (1.6 g) in methanol (15 ml) is added dropwise over 4 hours. The reaction mixture is stirred for 24 hours at room temperature, is added dropwise concentrated hydrochloric acid (2 ml) and stirred for 1 hour at room temperature. The mixture is evaporated to dryness, the residue is partitioned between 20 water (75 ml) and ether (75 ml) and the pH is adjusted to 2 with 6 N hydrochloric acid. The layers are separated and the aqueous phase is extracted with ether (2 x 75 ml). The ether extracts are discarded and the pH of the aqueous phase is adjusted to 9 with 40% sodium hydroxide solution and extracted with ethyl acetate 25 (3 x 50 ml). The extracts are dried over sodium sulfate and evaporated under reduced pressure. There is obtained 2- (1-ethoxycarbonyl-3-phenylpropylamino) -4- [o- (ethoxycarbonylmethylamino) phenyl] butyric acid ethyl ester which is used directly to prepare the final product.

30 Eksempel 27.Example 27.

2-Amino-4-phenylsmørsyre-ethylester omsættes under betingelserne for den reducerende alkylering, som beskrevet i de ovenstående eksempler, med l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ-[l]benzazepin-2,3-dion. Man får 1-ethoxycarb-35 onylmethyl-3-(l-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on ifølge eksempel 10.2-Amino-4-phenylbutyric acid ethyl ester is reacted under the conditions of the reducing alkylation, as described in the above examples, with 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-ΙΗ- [1] benzazepine-2,3- dione. There is obtained 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one according to Example 10.

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Udgangsforbindelsen fremstilles på følgende måde: En opløsning af 3,3-dichlor-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (1,0 g, 4,32 mol) og bromeddikesyreethylester (0,51 ml) i tetrahydrofuran (30 ml) sættes dråbevis under omrøring i 5 løbet af 15 minutter til en opløsning af natriumhydrid (4,76 mmol) i tetrahydrofuran (20 ml) i en nitrogenatmosfære. Blandingen omrøres i yderligere 2 timer. Opløsningen spaltes ved tilsætning af mættet vandig ammoniumchloridop-løsning, og opløsningsmidlet fordampes under formindsket 10 tryk. Remanensen ekstraheres med ether (3 x 20 ml), de sammenblandede etheropløsninger vaskes med mættet vandig na-triumchloridopløsning (20 ml) og tørres over magnesiumsulfat. Opløsningsmidlet fordampes under formindsket tryk. Man får 3,3-dichlor-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-lH-15 [l]benzazepin-2-on. NMR (CDCl^): δ 1,27 (t, 3H), 3,22 (m, 4H), 4,25 (q, 2H), 4,65 (s, 2H) og 7,3 (m, 4H).The starting compound is prepared as follows: A solution of 3,3-dichloro-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (1.0 g, 4.32 mol) and bromoacetic acid ethyl ester (0 (51 ml) in tetrahydrofuran (30 ml) is added dropwise with stirring over 5 minutes to a solution of sodium hydride (4.76 mmol) in tetrahydrofuran (20 ml) in a nitrogen atmosphere. The mixture is stirred for a further 2 hours. The solution is decomposed by the addition of saturated aqueous ammonium chloride solution and the solvent is evaporated under reduced pressure. The residue is extracted with ether (3 x 20 ml), the combined ether solutions are washed with saturated aqueous sodium chloride solution (20 ml) and dried over magnesium sulfate. The solvent is evaporated under reduced pressure. There is obtained 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-15 [1] benzazepin-2-one. NMR (CDCl3): δ 1.27 (t, 3H), 3.22 (m, 4H), 4.25 (q, 2H), 4.65 (s, 2H) and 7.3 (m, 4H) ).

En blanding af morpholin (0,315 g, 3,6 mmol) og 3,3-dichlor- 1- ethoxyvarbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin- 2- on (0,5 g) omrøres under nitrogen ved 110°C i 18 timer.A mixture of morpholine (0.315 g, 3.6 mmol) and 3,3-dichloro-1-ethoxyvarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (0.5 g) Stir under nitrogen at 110 ° C for 18 hours.

20 Opløsningen fortyndes med chloroform til 10 ml og afkøles til 0°C. Der tilsættes 20%'s svovlsyre (1 ml), og opløsningen omrøres i 2 timer ved 0°C. Opløsningen ekstraheres med chloroform (2 x 20 ml), og ekstrakterne vaskes med 2 N salt-. . syre (2 x 10 ml) og mættet vandig natriumchloridopløsning 25 (5 ml). Opløsningen tørres over magnesiumsulfat og inddam- pesunder formindsket tryk. Man får 1-ethoxycarbonylmethyl- 2,3,4,5-tetrahydro-lH-[l]benzazepin-2,3-dion. NMR (CDCl^): δ 1,25 (t, 3H), 2,6 (m, 2H), 3,6 (m, 2H), 4,2 (q, 2H) og 7,3 (m, 4H).The solution is diluted with chloroform to 10 ml and cooled to 0 ° C. 20% sulfuric acid (1 ml) is added and the solution is stirred for 2 hours at 0 ° C. The solution is extracted with chloroform (2 x 20 ml) and the extracts are washed with 2N brine. . acid (2 x 10 ml) and saturated aqueous sodium chloride solution 25 (5 ml). The solution is dried over magnesium sulfate and evaporated under reduced pressure. 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepine-2,3-dione is obtained. NMR (CDCl3): δ 1.25 (t, 3H), 2.6 (m, 2H), 3.6 (m, 2H), 4.2 (q, 2H) and 7.3 (m, 4H) ).

30 Eksempel 28 .Example 28.

2-Amino-4-phenylsmørsyreethylester omsættes i nærværelse af kaliumcarbonat i methylenchlorid med 3-brom-1-ethoxy-carbonylmethyl-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on.2-Amino-4-phenylbutyric acid ethyl ester is reacted in the presence of potassium carbonate in methylene chloride with 3-bromo-1-ethoxy-carbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one.

Man får l-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phen-35 ylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on ifølge eksempel 10.There is obtained 1-ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenyl-propylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one according to Example 10.

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Udgangsmaterialet fremstilles på følgendemåde: Til en opløsning af 2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (2,5 g) i chloroform (30 ml) sættes protionsvis phosphorpentachlorid (3,2 g), idet temperaturen holdes ved 0-5°C. Efter endt til-5 sætning tilsættes dråbevis først iod (30 mg) og derpå brom (2,5 g) i løbet af 5 minutter. Blandingen koges derefter i 4 timer under tilbagesvaling. Chloroformopløsningen inddampes, og remanensen fordeles mellem isvand (30 ml) og di- chlormethan (75 ml). Den organiske fase tørres over mag-10 nesiumsulfat og inddampes under formindsket tryk. Den råremanens renses ved kromatografi på kiselgel, idet der elue-res med ether/hexan (7:3). Efter inddampning af de egnede fraktioner får man 3-brom-2,3,4,5-tetrahydro-lH-[l]benz-azepin-2-on, som smelter ved 146-148°C.The starting material is prepared as follows: To a solution of 2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (2.5 g) in chloroform (30 ml) is added by phosphorus pentachloride (3.2 g) , keeping the temperature at 0-5 ° C. After completion of the addition, iodine (30 mg) and then bromine (2.5 g) are 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 ml) and dichloromethane (75 ml). The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with ether / hexane (7: 3). Evaporation of the appropriate fractions gives 3-bromo-2,3,4,5-tetrahydro-1H- [1] benz-azepin-2-one, which melts at 146-148 ° C.

15 Til en omrørt suspension af kaliumhydroxid (90 mg) og tetra-butylammoniumbromid (40 mg) i tetrahydrofuran (10 ml) sættes 3-brom-2,3,4,5-tetrahydro-lH-[l]benzazepin-2-on (300 mg) i én portion i en nitrogenatmosfære ved 0°C. Omrøringen fortsættes i 5 minutter. Til blandingen sættes bromeddikesyre-20 ethylester (200 mg) i én portion, og blandingen henstår i 3 timer under omrøring til opvarmning til stuetemperatur. Tetrahydrofuranet fordampes under formindsket tryk, og remanensen fordeles mellem vand (5 ml) og ether (26 ml). Den organiske fase vaskes med 2 N saltsyre (5 ml), tørres over 25 magnesiumsulfat og inddampes under formindsket tryk. Man får 3-brom-l-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[l]benzazepin-2-on. Smp. 114-116°C.To a stirred suspension of potassium hydroxide (90 mg) and tetra-butylammonium bromide (40 mg) in tetrahydrofuran (10 ml) is added 3-bromo-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one (300 mg) in one portion in a nitrogen atmosphere at 0 ° C. Stirring is continued for 5 minutes. To the mixture is added bromoacetic acid ethyl ester (200 mg) in one portion, and the mixture is allowed to stir for 3 hours to warm to room temperature. The tetrahydrofuran is evaporated under reduced pressure and the residue partitioned between water (5 ml) and ether (26 ml). The organic phase is washed with 2N hydrochloric acid (5 ml), dried over 25 magnesium sulfate and evaporated under reduced pressure. There is obtained 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one. Mp. 114-116 ° C.

Eksempel 29.Example 29.

1-Ethoxycarbonylmethyl-3-(l-ethoxycarbonyl-3-phenylpropyl-30 amino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on1-Ethoxycarbonylmethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one

Ved behandling af 3-(l-carboxy-3-phenylpropylamino)-1-cyanmethyl-2,3,4,5-tetrahydro-IH-[1]benzazepin-2-on med en blanding af ethanol og ether (1:1), som er mættet medIn the treatment of 3- (1-carboxy-3-phenylpropylamino) -1-cyanomethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one with a mixture of ethanol and ether (1: 1) ), which is saturated with

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75 hydrogenchlorid, i 48 timer ved stuetemperatur får man efter oparbejdning l-ethoxycarbonylmethyl-3-(1-ethoxy-carbony1-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benzazepin-2-on, som er identisk med den ifølge eksem-5 pel 10 fremstillede forbindelse.75 hydrochloride, for 48 hours at room temperature, after working up 1-ethoxycarbonylmethyl-3- (1-ethoxy-carbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one , which is identical to the compound of Example 10.

Udgangsforbindelsen fremstilles på følgende måde: 3—(1— carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[1]benz-azepin-2-on alkyleres med bromacetonitril i dimethylformamid i nærværelse af natriumhydrid. Efter oparbejdning 10 får man 3-(l-carboxy-3-phenylpropylamino)-l-cyanmethyl~ 2,3,4,5-tetrahydro-lH-[l]benzazepin-'2-on, som anvendes direkte i det efterfølgende trin.The starting compound is prepared as follows: 3- (1- carboxy-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is alkylated with bromoacetonitrile in dimethylformamide in the presence of sodium hydride. After work-up 10, 3- (1-carboxy-3-phenylpropylamino) -1-cyanomethyl-2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is obtained, which is used directly in the subsequent step. .

Eksempel 3Q.Example 3Q.

Fremstilling af 10.000 tabletter indeholdende 10 mg virk- 15 som forbindelse ifølge eksempel 12 pr. tablet:Preparation of 10,000 tablets containing 10 mg of the compound of Example 12 per tablet:

Bestanddele l-Carboxymethyl-3S-(lS-ethoxycarbonyl- 3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-on 100 g 20 Mælkesukker 1157 gIngredients 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one 100 g Milk sugar 1157 g

Majsstivelse 75 gCorn starch 75 g

Polyethylenglycol 6000 75 gPolyethylene Glycol 6000 75 g

Talkumpulver 7 5 gTalcum powder 7 5 g

Magnesiumstearat 18 g 25 Rent vand q.s.Magnesium stearate 18 g 25 Pure water q.s.

Tabletterne fremstilles under anvendelse af samme fremgangsmåde som i eksempel 14.The tablets are prepared using the same procedure as in Example 14.

Eksempel 31.Example 31.

Fremstilling af 10.000 kapsler indeholdende 20 mg af hydro-30 chloridsaltet af forbindelsen ifølge eksempel 12 pr. kapsel:Preparation of 10,000 capsules containing 20 mg of the hydrochloride salt of the compound of Example 12 per ml. capsule:

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Bestanddele l-Carboxymethyl-3S-(lS-ethoxycarbonyl- 3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[l]benzazepin-2-on-hydrochlorid 200 g 5 Mælkepulver 1700 gIngredients 1-Carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one hydrochloride 200 g Milk powder 1700 g

Talkumpulver 100 gTalcum powder 100 g

Kapslerne fremstilles under anvendelse af den i eksempel 16 beskrevne fremgangsmåde.The capsules are prepared using the procedure described in Example 16.

De omhandlede forbindelsers kardiovaskulære farmakologi 10 Afprøvningen af forbindelsernes virkning er foretaget under anvendelse af fremgangsmåderne for bedømmelse af hæmningen af enzymet, som omdanner angiotensin [angiotensin converting enzyme = ACE]. Ved den biokemiske bedømmelse af in vitro ACE-hæmningen [ACE inhibition = ACEI] be-15 stemmes en forbindelses aktivitet i kaninlungevæv.Cardiovascular Pharmacology of the Compounds of the Invention 10 The efficacy of the compounds has been tested using the methods of assessing the inhibition of the enzyme which converts angiotensin [angiotensin converting enzyme = ACE]. The biochemical assessment of the in vitro ACE inhibition [ACE inhibition = ACEI] determines a compound's activity in rabbit lung tissue.

Ved in vivo-afprøvningsmetoden fremkaldes først en blodtryksforøgelse ved indgift af angiotensin I (AI) til forsøgsdyret. Derefter bestemmes de enkelte forbindelsers hæmning af denne blodtryksforøgelse.In the in vivo assay method, a blood pressure increase is first induced by the administration of angiotensin I (AI) to the test animal. Then, the inhibition of each compound is determined by this blood pressure increase.

20 I. Biokemisk testmetode20 I. Biochemical Test Method

Der anvendes et kaninlungevævspræparat [Das og Saffer, J. Biol. Chem. 250, 6762 (1975)] til bestemmelsen af ACE ved fremgangsmåden ifølge Cheung og Cushman [Cheung, og Cushman, Biochim. Biophys. Acta 293, 451 (1973)]. Ved den-25 ne metode foretages spektrofotometrisk bestemmelse af den mængde histidyl-leucin, som frigøres fra et syntetisk substrat i løbet af en inkubation på 30 minutter ved 37°C. IC^Q-værdien for ACE-hæmningen beregnes da grafisk. ICj-q-værdien er den koncentration (i mol) af forsøgsforbindel-30 sen, der formindsker den i fraværelse af forsøgsforbindelsen dannede mængde histidyl-leucin med 50%.A rabbit lung tissue preparation is used [Das and Saffer, J. Biol. Chem. 250, 6762 (1975)] for the determination of ACE by the method of Cheung and Cushman [Cheung, and Cushman, Biochim. Biophys. Acta 293, 451 (1973)]. In this method, spectrophotometric determination of the amount of histidyl-leucine released from a synthetic substrate over a 30 minute incubation at 37 ° C is made. The IC ^ Q value for the ACE inhibition is then calculated graphically. The ICj-q value is the concentration (in moles) of the test compound that reduces the amount of histidyl-leucine formed in the absence of the test compound by 50%.

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77 II. Metode til hæmning af den ved hjælp af angiotensin I (AI) fremkaldte blodtryksforhøjelse ved intravenøs indgift af forsøgsforbindelsen (% AI-hæmning)77 II. Method of inhibiting the blood pressure rise induced by angiotensin I (AI) by intravenous administration of the test compound (% AI inhibition)

Ved disse forsøg anbringes som beskrevet ovenfor et kate-5 ter i en femaralarterie og i en lægvene på rotten.In these experiments, as described above, a catheter is placed in a femoral artery and in a calf of the rat.

Arterietrykket registreres ved hjælp af arteriekateteret, medens angiotensin I (AI) og de enkelte forsøgsforbindelser injiceres gennem venekateteret. Hæmningen af den af angiotensin I fremkaldte blodtryksstigning udtrykkes ved 10 den procentvise formindskelse af den før behandlingen målte kontrolværdi for blodtryksstigningen og i tabellen anført som gennemsnitsværdien for hæmningen i løbet af 30 minutter efter indgivelsen af forsøgsforbindelsen.Arterial pressure is recorded by the artery catheter, while angiotensin I (AI) and the individual test compounds are injected through the venous catheter. The inhibition of the angiotensin I induced blood pressure rise is expressed by the 10 percent decrease in the pre-treatment control value of the blood pressure rise and listed in the table as the mean inhibition value over 30 minutes after administration of the test compound.

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Resultaterresults

Forbin- In vitro Hæmning af blodtryksforhøjelse fremdelse ACEI kaldt af angiotensin I (AI) ifølge --Combine - In vitro Inhibition of blood pressure elevation ACEI called angiotensin I (AI) according to -

5 eks. nr. IC5Q (M) i.v. dosis % AINo. 5 IC5Q (M) i.v. dose of AI

(mg/kg) hæmning 1 6 x 10“7 10 100 1,0 100 0,1 50 5 2 x 10-7 0,1 37 10 9 5 x 10-9 0,3 93 0,1 80 0,03 40 10 1 X 10"5 1,0 80(mg / kg) inhibition 1 6 x 10 “7 10 100 1.0 100 0.1 50 5 2 x 10-7 0.1 37 10 9 5 x 10-9 0.3 93 0.1 80 0.03 40 10 1 X 10 ”5 1.0 80

Maleat-15 salt 12 4 x 10-7 1,0 100 HCl-salt 0,3 95 0,1 82 0,06 74 20 0,03 29 18 2 x 10"9 0,1 93 0,06 84 0,03 70 0,02 69 25 0,01 28 0,007 14 25 1 x 10"7 0,1 92Maleate salt 12 4 x 10-7 1.0 100 HCl salt 0.3 95 0.1 82 0.06 74 20 0.03 29 18 2 x 10 "9 0.1 93 0.06 84 0, 03 70 0.02 69 25 0.01 28 0.007 14 25 1 x 10 ”7 0.1 92

Isomer B, HCl-saltIsomer B, HCl salt

Claims (7)

1. Analogifremgangsmåde til fremstilling af 3-amino- [ 1 ]benzazepin-2-on-l-alkansyrer eller derivater deraf med 5 den almene formel CQt; /^° R2 θ’"*? hvori Ri betyder hydrogen, C(l-4)-alkyl eller phenyl-substitueret C(l-4)-alkyl, R2 betyder hydrogen eller C( 1-4)-alkyl, og Rg og R7 hver for sig betyder hydroxy,An analogous process for the preparation of 3-amino- [1] benzazepine-2-one-1-alkanoic acids or derivatives thereof having the general formula CQt; Wherein R 1 is hydrogen, C 1 -C 4 alkyl or phenyl-substituted C 1 -C 4 alkyl, R 2 is hydrogen or C 1 -C 4 alkyl, and R 6 and R7 individually means hydroxy, 10 C(l-4)-alkoxy eller phenylsubstitueret C(l-4)-alkoxy, eller stereoisomerer eller salte deraf, kendetegnet ved, at man a) i en forbindelse med formlen ^NH2 (l° Rj-CH-COI^ 15 hvori R2 og R7 har de ovenfor anførte betydninger, indfører gruppen -CH(Ri)C0Rg ved alkylering med en forbin- DK 157881 B delse med formlen Ri-CH(Z)-CORg (Illa), hvori Z betyder en reaktiv forestret hydroxygruppe, og R^ og Rg har de ovenfor angivne betydninger, eller med en forbindelse med formlen R^-CO-CORg (IV), hvori R^ og Rg har de ovenfor 5 angivne betydninger, i nærværelse af et reduktionsmiddel, eventuelt under midlertidig beskyttelse af eventuelle hydroxygrupper, som kan forekomme i en vilkårlig af grupperne Rg og R7, eller b) alkylerer en forbindelse med formlen C s—\ ° I Vn- CH-R. (V) i ^ ål, «*6 hvori Ri og Rg har de ovenfor angivne betydninger, med en forbindelse med formlen R2~CH(Z)-COR7 (HIB), hvori Z betyder en reaktiv forestret hydroxygruppe, og R2 og R7 har de ovenfor angivne betydninger, idet man eventuelt 15 midlertidigt beskytter eventuelle hydroxygrupper, som kan forekomme i en vilkårlig af grupperne Rg og R7, eller c) kondenserer en forbindelse med formlen I o r2-ch-cor7 DK 157881 B hvori Y betyder oxo eller en reaktiv forestret hydroxy-gruppe Z sammen med hydrogen, og R2 og R7 har de ovenfor angivne betydninger, med en amin med formlen H H—N-CH—R. (VII) :l L COR, o 5 hvori Ri og Rg har de ovenfor angivne betydninger, idet kondensationen gennemføres i nærværelse af et reduktionsmiddel, når Y betyder oxo, eller d) i en forbindelse med formlen _ ._ H A / N-0? (VIII) pi . RfR- 10 hvori Ri og R2 har de ovenfor angivne betydninger, et af symbolerne R' og R" betyder cyan, og det andet betyder ligeledes cyan eller CORg eller COR7 som defineret ovenfor, underkaster cyangruppen eller -grupperne en solvolyse eller 15 e) cycliserer en forbindelse med formlen H Νχ| N-CH-R^ (IX) NH COOH C0Rg R2~CH-COR7 DK 157881B hvori R-l, B-2, Rg og R7 har de ovenfor angivne betydninger, eller en ester deraf, og, om ønsket, omdanner en dannet forbindelse med formlen 5 I som defineret ovenfor til en anden forbindelse med formlen I omfattet af den ovenfor anførte definition og/eller, om ønsket, omdanner en dannet forbindelse med formlen I som defineret ovenfor med saltdannende egenskaber til et salt deraf eller frigør en fri forbindelse 10 med formlen I fra et sådant salt og/eller opkoncentrerer en optisk isomer, som har en specifik konfiguration med hensyn til i det mindste ét chiralitetscentrum, fra en blanding af de stereoisomere former af en dannet forbindelse med formlen I.10 C (1-4) alkoxy or phenyl substituted C (1-4) alkoxy, or stereoisomers or salts thereof, characterized in that a) in a compound of the formula ^ NH 2 (1 R 2 -CH-CO 1 wherein R 2 and R 7 have the above meanings, the group -CH (R 1) C0 R 9 introduces by alkylation with a compound of the formula R 1 -CH (Z) -CORg (IIa), wherein Z represents a reactive esterified hydroxy group, and R 1 and R 9 have the meanings given above, or with a compound of the formula R 1 -CO-CORg (IV) wherein R 1 and R 5 have the meanings given above, in the presence of a reducing agent, optionally under temporary protection of any hydroxy groups which may be present in any of the groups Rg and R7, or b) alkylate a compound of formula C s - \ ° I Vn-CH-R. (V) in eel, 6 wherein R 1 and R 9 have the above meanings, with a compound of the formula R2 ~ CH (Z) -COR7 (HIB) wherein Z represents a reactive esterified hydroxy group and R 2 and R 7 have the meanings given above, optionally temporarily protecting any hydroxy groups which may be present in any of the groups Rg and R7, or c) condensing a compound of the formula I wherein R is oxo or a reactive esterified hydroxy group Z together with hydrogen, and R 2 and R 7 have the above meanings, with an amine of the formula HH-N-CH-R. (VII): 1 L COR, wherein R 1 and R g have the above meanings, the condensation being carried out in the presence of a reducing agent when Y is oxo, or d) in a compound of formula _ HA / N-0 ? (VIII) pi. RfR-10 wherein R 1 and R 2 have the above meanings, one of the symbols R 'and R "means cyan, and the other also means cyan or CORg or COR7 as defined above, the cyano group or groups undergoes a solvolysis or e) cycles a compound of the formula HΝχN-CH-R ^ (IX) NH COOH CO₂R₂ R2 ~ CH-COR7 DK 157881B wherein Rl, B-2, Rg and R7 have the above meanings, or an ester thereof, and, if as desired, transforms a compound of formula I as defined above into another compound of formula I encompassed by the above definition and / or, if desired, converts a compound of formula I as defined above with salt-forming properties into a salt thereof or liberating a free compound 10 of formula I from such a salt and / or concentrating an optical isomer having a specific configuration with respect to at least one chirality center from a mixture of the stereoisomeric forms of a compound formed e of formula I. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller en forbindelse med formlen λ" NH-CH (ΙΑ) \o-r; I O ch2 -co-r^ hvori n er 1-4, og Rg og R7 hver for sig betyder hydroxy, C(l-4)-alkoxy eller benzyloxy, eller farmaceutisk accep-20 table salte deraf.A process according to claim 1, characterized in that a compound of the formula λ "NH-CH (ΙΑ) \ or; IO ch 2 -co-r 2 wherein n is 1-4 and R hydroxy, C (1-4) alkoxy or benzyloxy, or pharmaceutically acceptable salts thereof. 3. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller l-carboxymethyl-3-(1-ethoxycarbonyl- 3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[ 1 ]benzazepin-2-on, eller stereoisomerer eller salte deraf. DK 157881 BProcess according to claim 1, characterized in that 1-carboxymethyl-3- (1-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is prepared, or stereoisomers or salts thereof. DK 157881 B 4. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller den ved 138-140°C smeltende racemiske forbindelse af den i krav 3 anførte forbindelse eller enantiomerer eller salte deraf.Process according to claim 1, characterized in that the racemic melting at 138-140 ° C of the compound of claim 3 or enantiomers or salts thereof is prepared. 5. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller den ved 126-129°C smeltende racemiske forbindelse af den i krav 3 anførte forbindelse eller enantiomerer eller salte deraf.Process according to claim 1, characterized in that the racemic-melting melting compound of the compound of claim 3 or enantiomers or salts thereof is prepared at 126-129 ° C. 6. Fremgangsmåde ifølge krav 1, kendetegnet ved, at 10 man fremstiller l-carboxymethyl-3S-(lS-ethoxycarbonyl- 3-phenylpropylamino)-2,3,4,5-tetrahydro-lH-[ 1 ]benzazepin-2-on eller salte deraf.Process according to claim 1, characterized in that 1-carboxymethyl-3S- (1S-ethoxycarbonyl-3-phenylpropylamino) -2,3,4,5-tetrahydro-1H- [1] benzazepin-2-one is prepared. or salts thereof. 7. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man fremstiller hydrochloridsaltet af den i krav 6 anførte 15 forbindelse.Process according to claim 1, characterized in that the hydrochloride salt of the compound of claim 6 is prepared.