NO178546B - Analogous method for the preparation of therapeutically active ACE inhibitors with nootropic effect - Google Patents

Analogous method for the preparation of therapeutically active ACE inhibitors with nootropic effect Download PDF

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NO178546B
NO178546B NO871282A NO871282A NO178546B NO 178546 B NO178546 B NO 178546B NO 871282 A NO871282 A NO 871282A NO 871282 A NO871282 A NO 871282A NO 178546 B NO178546 B NO 178546B
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compounds
carboxylic acid
alanyl
phenylpropyl
formula
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NO871282A
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Norwegian (no)
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NO871282D0 (en
NO871282L (en
NO178546C (en
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Franz Hock
Josef Scholtholt
Hansjorg Urbach
Rainer Henning
Ulrich Lerch
Wolf-Ulrich Nickel
Wolfgang Ruger
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Hoechst Ag
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Publication of NO178546C publication Critical patent/NO178546C/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
    • C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

The invention relates to novel compounds having a nootropic activity, the use of ACE inhibitors as medicaments having nootropic activity, agents containing them, and their use in the treatment and prophylaxis of cognitive malfunctions.

Description

Oppfinnelsen vedrører en analogifremgangsmåte for fremstilling av terapeutisk aktive angiotensin-converting-enzym-inhibitorer (ACE-inhibitorer), eller deres fysiologisk tålbare salter med nootrop (kognitiv friksjonsforbedrende) virkning. The invention relates to an analogue method for the production of therapeutically active angiotensin-converting-enzyme inhibitors (ACE inhibitors), or their physiologically tolerable salts with a nootropic (cognitive friction-improving) effect.

Foreliggende oppfinnelse angår således en analogifremgangsmåte for fremstilling av ACE-hemmere med nootrop virkning eller deres fysiologisk godtagbare salter med formel (II): The present invention thus relates to an analogue method for the production of ACE inhibitors with nootropic action or their physiologically acceptable salts with formula (II):

der: there:

n =1 eller 2, n = 1 or 2,

R = fenyl, R = phenyl,

r<1> = forgrenet eller uforgrenet lavere alkyl som eventuelt r<1> = branched or unbranched lower alkyl as appropriate

kan være substituert med fenyl, may be substituted with phenyl,

R^ og r<3> er ute eller forskjellige og betyr hydrogen, R^ and r<3> are out or different and mean hydrogen,

en alifatisk rest med 1 til 21 C-atomer, difenyllavere-alkyl, benzhydril, mentyl eller benzyl, an aliphatic radical of 1 to 21 C atoms, diphenyl lower alkyl, benzhydryl, menthyl or benzyl,

R<4> og R<5> danner sammen med de bærende atomene et ringsystem fra rekken oktahydroindol, oktahydrocyklopenta[b]pyrrol, R<4> and R<5> together with the supporting atoms form a ring system from the series octahydroindole, octahydrocyclopenta[b]pyrrole,

eller spiro[(bicyklo[2.2.2]oktan)-2,3'pyrrolidin], kjennetegnet ved at man omsetter deres fragmenter i et egnet oppløsningsmiddel eventuelt i nærvær av en base og/eller et koblingshjelpemiddel, reduserer eventuelt intermediært dannede umettede forbindelser, som Schiffske baser, forestrer eventuelle forbindelser med formel II med frie karboksylgrupper og overfører eventuelt de oppnådde forbindelsene eventuelt til deres fysiologisk godtagbare salter, or spiro[(bicyclo[2.2.2]octane)-2,3'pyrrolidine], characterized by reacting their fragments in a suitable solvent optionally in the presence of a base and/or a coupling aid, optionally reducing intermediately formed unsaturated compounds, as Schiff bases, esterify any compounds of formula II with free carboxyl groups and optionally transfer the obtained compounds to their physiologically acceptable salts,

bortsett fra forbindelser der R, R<1>, R<4>, R<5> og n er som definert over og except for compounds where R, R<1>, R<4>, R<5> and n are as defined above and

R<2> og R<3> er like eller forskjellige og begge har en av de følgende betydninger: R<2> and R<3> are the same or different and both have one of the following meanings:

hydrogen, alkyl med 1-6 C-atomer eller benzyl. hydrogen, alkyl with 1-6 C atoms or benzyl.

Oppfinnelsen angår også fremstilling av 2-[N-(lS)-etoksy-karbonyl-3-fenylpropyl)-S-alanyl]-cis, endo-2-azabicy-klo[3.3.0]oktan-3-S-karboksylsyreoctadesylester i fri form eller i saltform, kjennetegnet ved at man utgår fra tilsvarende utgangsmaterialer. The invention also relates to the preparation of 2-[N-(1S)-ethoxy-carbonyl-3-phenylpropyl)-S-alanyl]-cis, endo-2-azabicy-chloro[3.3.0]octane-3-S-carboxylic acid octadecyl ester in free form or in salt form, characterized by starting from corresponding starting materials.

Oppfinnelsen angår også fremstilling av l-[N-(IS)dodecykloksykarbonyl-3-fenylpropyl)-S-alanyl]-2S,3aR,7aR-oktahydroindol-2-karboksylsyre i fri form eller i saltform, kjennetegnet ved at man utgår fra tilsvarende utgangsmaterialer . The invention also relates to the preparation of 1-[N-(IS)dodecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-2S,3aR,7aR-octahydroindole-2-carboxylic acid in free form or in salt form, characterized by starting from corresponding starting materials.

Oppfinnelsen angår også fremstilling av 2-[N-[(lS)etoksykar-bonyl-3-fenylpropyl )-L-alanyl]-(IS,3S,5S)-2-azabicyklo-[3.3.0]oktan-3-karboksylsyreoctade'sylester i fri form eller i saltform, kjennetegnet ved at man utgår fra tilsvarende utgangsmaterialer. The invention also relates to the preparation of 2-[N-[(1S)ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-(1S,3S,5S)-2-azabicyclo-[3.3.0]octane-3-carboxylic acid octade 'sylester in free form or in salt form, characterized by starting from corresponding starting materials.

Forbindelsene med formel I er hemstoffer av angiotensin-converting-enzymer (ACE) respektiv mellomprodukter ved fremstilling av slike hemstoffer. The compounds of formula I are inhibitors of angiotensin-converting enzymes (ACE) or intermediates in the production of such inhibitors.

Som salter av forbindelsene med formel II kommer det alt etter disse forbindelsers sure eller basiske natur på tale alkali- eller jordalkalisalt eller salter med fysiologisk tålbare aminer eller salter med uorganiske eller organiske syrer som for eksempel HC1, HBr, H2SO4, maleinsyre, fumar-syre, vinsyre, sitronsyre. Depending on the acidic or basic nature of these compounds, salts of the compounds of formula II include alkali or alkaline earth salts or salts with physiologically tolerable amines or salts with inorganic or organic acids such as HC1, HBr, H2SO4, maleic acid, fumaric acid , tartaric acid, citric acid.

Kapi11arstrukturen av hjernens blodkar adskiller seg fra de i andre områder av legemet. Hjernekapillarene er omgitt av et sjikt av endotelceller, som spesielt er snevert sammenknyttet med hverandre ("tight junctions"). Hjernekapillarer har dessuten meget mindre av de porer hvorigjennom andre blod-kapillarer i lavmolekylære stoffer kan tre inn eller ut i det omgivende vev. På denne måte får ved hjernekapillarer egenskapen av lipidoppløselighet en meget større betydning for fordelingen mellom blod og omgivende vev enn dette er tilfelle for resten av legemet. The capillary structure of the brain's blood vessels differs from those in other areas of the body. The brain capillaries are surrounded by a layer of endothelial cells, which are particularly tightly connected to each other ("tight junctions"). Brain capillaries also have much less of the pores through which other blood capillaries in low molecular weight substances can enter or leave the surrounding tissue. In this way, in the case of brain capillaries, the property of lipid solubility has a much greater importance for the distribution between blood and surrounding tissue than is the case for the rest of the body.

Det er derfor foretrukket forbindelser med formel II, hvori minst en av restene R, R<1>, R<2> og R<3> betyr en lipofil rest, som en langkjedet alifatisk, alisyklisk-alifatisk, arali-fatisk eller heteroaralifatisk rest, en tilstrekkelig stor alisyklisk rest, eller en tilsvarende substituert alisyklisk, aromatisk eller heteroaromatisk rest, eller inneholder en slik som delstruktur. Compounds of formula II are therefore preferred, in which at least one of the residues R, R<1>, R<2> and R<3> means a lipophilic residue, such as a long-chain aliphatic, alicyclic-aliphatic, araliphatic or heteroaraliphatic residue , a sufficiently large alicyclic residue, or a correspondingly substituted alicyclic, aromatic or heteroaromatic residue, or contains such as partial structure.

Forbindelser med formel II kan bli fremstilt ved at man eksempelvis omsetter forbindelser med formel V, med forbindelse med formel VI. Compounds of formula II can be prepared by, for example, reacting compounds of formula V with compounds of formula VI.

Omsetningen av disse forbindelser kan eksempelvis gjennom-føres analogt i kjente peptidkoblingsfremgangsmåter, i et egnet organisk oppløsningsmiddel som DMF, CH2CI2. DMA i nærvær av koblingshjelpemidler som karbodiimider (for eksempel dicykloheksylkarbodiimid), difenylfosforylasid, alkanfosforsyreanhydrider , dialkylfosfinsyreanhydrider eller N,N-succinimidylkarbonater i et oppløsningsmiddel som CH3CN. Aminogrupper i forbindelse med formel V kan aktiveres med tetraethyldidfosfit. Forbindelsene med formel VI kan overføres til aktivester (for eksempel med 1-hydroksy-benzotriasol), blandede anhydrider (for eksempel med klor-maursyreester), asider eller karbodiimidderivater og dermed aktiveres (sml. Schroder, Liibke, The Peptides, Bind 1, New York 1965, s.76-136). Reaksjonen gjennomføres fortrinnsvis mellom -20°C og reaksjonsblandingens kokepunkt. The reaction of these compounds can, for example, be carried out analogously to known peptide coupling methods, in a suitable organic solvent such as DMF, CH2Cl2. DMA in the presence of coupling aids such as carbodiimides (for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl carbonates in a solvent such as CH3CN. Amino groups in connection with formula V can be activated with tetraethyldiphosphite. The compounds of formula VI can be transferred to active esters (for example with 1-hydroxy-benzotriazole), mixed anhydrides (for example with chloroformic acid ester), azides or carbodiimide derivatives and thus activated (cf. Schroder, Liibke, The Peptides, Volume 1, New York 1965, pp.76-136). The reaction is preferably carried out between -20°C and the boiling point of the reaction mixture.

Likeledes lar det seg også omsette forbindelser med formel VII med forbindelser med formel VIII under dannelse av forbindelse med formel II. Likewise, it is also possible to react compounds of formula VII with compounds of formula VIII to form compounds of formula II.

hvori enten Y<1> betyr amino og Y<2> en avspaltbar gruppe, eller <yl> betyr en avspaltbar gruppe og Y<2> betyr amino. Egnede avspaltbare grupper er for eksempel Cl, Br, I, alkylsulfonyl-oksy eller arylsulfonyloksy. wherein either Y<1> means amino and Y<2> a leaving group, or <yl> means a leaving group and Y<2> means amino. Suitable leaving groups are, for example, Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.

Alkyleringen av denne type gjennomfører man hensiktsmessig i vann, eller et organisk oppløsningsmiddel som en lavere alifatisk alkohol (som etanol), benzylalkohol, acetonitril, nitrometan eller glycoleter ved en temperatur mellom -20°C og reaksjonsblandingens kokepunkt i nærvær av en base som et alkalimetallhydroksid eller et organisk amin. The alkylation of this type is suitably carried out in water, or an organic solvent such as a lower aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ether at a temperature between -20°C and the boiling point of the reaction mixture in the presence of a base such as an alkali metal hydroxide or an organic amine.

Videre lar det seg kondensere forbindelser med formel IX med forbindelse med formel X, Furthermore, it is possible to condense compounds of formula IX with compounds of formula X,

hvori enten Ql betyr amino + hydrogen og Q<2> betyr okso, eller O<1> betyr okso og Q<2> betyr amino + hydrogen. Kondensasjonen gjennomføres hensiktsmessig i vann eller et organisk oppløs-ningsmiddel, som en lavere alifatisk alkohol ved en temperatur mellom -20"C og reaksjonsblandingens kokepunkt, i nærvær av et reduksjonsmiddel som NaBB^CN, idet direkte fåes forbindelse med formel I. Man kan imidlertid også redusere de som mellomprodukter dannede skjifske baser eller enaminer, eventuelt etter foregående isolering under dannelse av forbindelse med formel II, eksempelvis ved hydroginering i nærvær av en overgangsmetallkatalysator. Endelig fører også omsetningen av forbindelser med formel IX (Q<1> = H + NH2) med forbindelser med formel XI, eller deres omsetning med forbindelse med formel XII og XIII, hensikt-messig i nærvær av en base som natriumalkoholat i et organisk oppløsningsmiddel som en lavere alkohol, ved en temperatur mellom -10°C og reaksjonsblandingens kokepunkt, til forbindelse med formel II (n=2), wherein either Q1 means amino + hydrogen and Q<2> means oxo, or O<1> means oxo and Q<2> means amino + hydrogen. The condensation is suitably carried out in water or an organic solvent, such as a lower aliphatic alcohol at a temperature between -20°C and the boiling point of the reaction mixture, in the presence of a reducing agent such as NaBB^CN, the compound of formula I being directly obtained. However, one can also reduce the Schiffian bases or enamines formed as intermediates, possibly after previous isolation to form a compound of formula II, for example by hydrogenation in the presence of a transition metal catalyst. Finally, the reaction of compounds of formula IX (Q<1> = H + NH2 ) with compounds of formula XI, or their reaction with compounds of formulas XII and XIII, suitably in the presence of a base such as sodium alcoholate in an organic solvent such as a lower alcohol, at a temperature between -10°C and the boiling point of the reaction mixture, to compound of formula II (n=2),

idet intermediært dannede skjifske baser reduseres som nevnt ovenfor, og en karbonylgruppe overføres reduktivt (eksempelvis med et komplekst hydrid) til metylen. intermediately formed schiff bases are reduced as mentioned above, and a carbonyl group is transferred reductively (for example with a complex hydride) to the methylene.

I overnevnte formler V - XIII har R-R<5> den betydningen angitt under formel II. Temporært til beskyttelse av ikke i reaksjonen deltagende reaktive grupper innførte beskyttelses-grupper avspaltes etter avsluttet reaksjon på i og for seg kjent måte (sml. Schroder, Ltibke, loe. eit., s.1-75 og 246-270; Green "Protective Groups in Organic Synthesis", New York 1981). In the above-mentioned formulas V - XIII, R-R<5> has the meaning indicated under formula II. Protective groups temporarily introduced to protect reactive groups not participating in the reaction are cleaved off after the reaction has ended in a manner known per se (cf. Schroder, Ltibke, loe. eit., pp. 1-75 and 246-270; Green "Protective Groups in Organic Synthesis", New York 1981).

Fremstillingen av de nye forbindelser med den generelle formel II kan eksempelvis også foregå under anvendelse av de for fagfolk kjente forestringsmetoder (se for eksempel Buchler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, s.802-825; Houben-Weyl, Methoden der Organi senen Chemie, Bind E5, 1985, s.656-773). The preparation of the new compounds with the general formula II can, for example, also take place using the esterification methods known to those skilled in the art (see for example Buchler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, pp. 802-825; Houben -Weyl, Methoden der Organi senen Chemie, Volume E5, 1985, pp.656-773).

a) Omsetningen av en mono- eller dikarboksylsyre med den generelle formel II, hvori minst en av restene R<2> og R<3>a) The reaction of a mono- or dicarboxylic acid with the general formula II, in which at least one of the residues R<2> and R<3>

betyr hydrogen, den tilsvarende alkohol under sur katalyse (mineralsyre eller syreionutveksling). means hydrogen, the corresponding alcohol under acid catalysis (mineral acid or acid ion exchange).

b) Alkylering av en mono- eller dikarboksylsyre med den generelle formel II, hvori minst en av restene R<2> og R<3>b) Alkylation of a mono- or dicarboxylic acid of the general formula II, in which at least one of the residues R<2> and R<3>

betyr hydrogen, med en forbindelse R<2>Z eller R<3>Z, hvori Z betyr en nukleofil avspaltbar gruppe (som halogen, tosylat), i et polart protisk eller dipolart aprotisk oppløsningsmiddel i nærvær av en base som alkalimetallhydroksid eller -alkoholat. means hydrogen, with a compound R<2>Z or R<3>Z, where Z means a nucleophilic leaving group (such as halogen, tosylate), in a polar protic or dipolar aprotic solvent in the presence of a base such as alkali metal hydroxide or alcoholate .

c) Omsetningen av en mono- eller dikarboksylsyre med den generelle formel II, hvori minst en av restene R<2> og R<3>c) The reaction of a mono- or dicarboxylic acid of the general formula II, in which at least one of the residues R<2> and R<3>

betyr hydrogen, med et diazoalken i et inert organisk oppløsningsmiddel som CH2CI2. means hydrogen, with a diazoalkene in an inert organic solvent such as CH2Cl2.

Den nootrope virkning av forbindelsen ifølge oppfinnelsen ble prøvet på mus som hadde en kroppsvekt på 20-25 gram i inhibitory (passiv) avoidance prøve (step-through Modell). The nootropic effect of the compound according to the invention was tested on mice that had a body weight of 20-25 grams in an inhibitory (passive) avoidance test (step-through model).

En modifisert form av den av J.KOPP, Z.BODANECKY og M.E. JARVIK omtalte prøvemetode ble omtalt av J. BURES, 0.BURES0VA og J.HUSTON i "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983). A modified form of that of J.KOPP, Z.BODANECKY and M.E. The test method mentioned by JARVIK was discussed by J. BURES, 0.BURES0VA and J.HUSTON in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983).

Tilsvarende disse 1itteraturangivelser betegnes et stoff som nootropt virksomt når det ved forsøksdyrene formår å oppheve den ved hjelp av et elektrokonvulsivt sjokk frembragt amnesi eller den ved hjelp av skopolamin induserte amnesi. Corresponding to these literature statements, a substance is termed as nootropically active when, in experimental animals, it manages to cancel the amnesia produced by means of an electroconvulsive shock or the amnesia induced by means of scopolamine.

Forsøkene ble gjennomført etter modifiserte prøvemetoder. Som sammenligningsforbindelse tjente det kjente nootripikum 2-okso-l-pyrrolidinyleddiksyreamid (pirasetam). Den tidlige overlegenhet av forbindelsene fremstilt ifølge oppfinnelsen i forhold til sammenligningsstoffet viser seg ved at den skopolamininduserte amnesi i inhibitory avoidance test lot seg oppheve med en MED (minimal effektiv dose) på 1,0-30 mg/kg p.o. Sammenligningsstoffet har en MED på ca. 500-1000 mg/kg p.o. The experiments were carried out according to modified test methods. The known nootripic 2-oxo-1-pyrrolidinylacetic acid amide (piracetam) served as a comparison compound. The early superiority of the compounds produced according to the invention in relation to the comparison substance is shown by the fact that the scopolamine-induced amnesia in the inhibitory avoidance test was reversed with a MED (minimum effective dose) of 1.0-30 mg/kg p.o. The comparison substance has a MED of approx. 500-1000 mg/kg p.o.

Forbindelsene fremstilt i fremgangsmåten ifølge oppfinnelsen har for det meste bare en liten toksisitet. The compounds produced in the method according to the invention mostly have only a slight toxicity.

Forbindelsene fremstilt ifølge oppfinnelsen kan videre benyttes i legemidler som inneholder de nevnte forbindelser. Legemidlene fremstilles etter i og for seg kjente fremgangsmåter. Som legemiddel anvendes de ifølge oppfinnelsen fremstilte farmakologisk virksomme forbindelser (=virksomme stoffer) enten som sådan, eller fortrinnsvis i kombinasjon med egnede farmasøytiske hjelpestoffer, i form av tabletter, drageer, kapsler, suppositorier, emulsjoner, suspensjoner eller oppløsninger, idet det virksomme stoffinnhold utgjør inntil ca. 95 % , fortrinnsvis mellom 10 og 75 <t>. The compounds produced according to the invention can further be used in pharmaceuticals containing the aforementioned compounds. The medicines are produced according to procedures known per se. As medicine, the pharmacologically active compounds (=active substances) produced according to the invention are used either as such, or preferably in combination with suitable pharmaceutical excipients, in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions, the active substance content being until approx. 95%, preferably between 10 and 75 <t>.

Hvilke hjelpestoffer som er egnet for de ønskede legemiddel-formuleringer er vanlig for fagfolk på grunn av hans fagkunn-skaper. Ved siden av oppløsningsmidler, geldannere, supposi-toriegrunnlag, tabletthjelpestoffer og andre virksomme stoffbærere, kan det eksempelvis anvendes antioksidanter, dispergeringsmidler, emulgatorer, avskummere, smakskorri-genter, konserveringsmidler, oppløsningsformidlere og farvestoff. Which excipients are suitable for the desired drug formulations is common to the expert due to his professional knowledge. Alongside solvents, gel formers, suppository bases, tablet excipients and other active substance carriers, antioxidants, dispersants, emulsifiers, defoamers, flavor correctors, preservatives, solubilizers and dyes can be used, for example.

De virksomme stoffer kan eksempelvis appliseres oralt, rectalt eller parenteralt (f.eks. intravenøst eller sub-kutant) idet den orale applikasjon er foretrukket. The active substances can, for example, be applied orally, rectally or parenterally (eg intravenously or subcutaneously), the oral application being preferred.

For en oral anvendelsesform blandes de aktive forbindelser med dertil egnede tilsetningsstoffer som bærestoffer, stabilisatorer eller inerte fortynningsmidler og bringes ved vanlige metoder til egnede administreringsformer som tabletter, dragéer, stikkapsler, vandig, alkoholisk eller olje-suspensjon eller vandig, alkoholisk eller oljeoppløsning. Som inerte bærere kan det f.eks. anvendes gummi arabicum, magnesia, magnesiumkarbonat, melkesukker, glukose eller stivelse, spesielt maisstivelse. Derved kan tilberedningen foregå som såvel tørr- som fuktig granulat. Som olje-bærer-stoffer eller oppløsningsmidler kommer det eksempelvis i betraktning plante eller animalske oljer som solsikkeolje eller levertran. For an oral application form, the active compounds are mixed with suitable additives such as carriers, stabilizers or inert diluents and brought by usual methods to suitable administration forms such as tablets, dragees, suppositories, aqueous, alcoholic or oil suspension or aqueous, alcoholic or oil solution. As inert carriers, it can e.g. gum arabic, magnesia, magnesium carbonate, milk sugar, glucose or starch, especially corn starch, are used. Thereby, the preparation can take place as both dry and moist granules. For example, plant or animal oils such as sunflower oil or cod liver oil come into consideration as oil carriers or solvents.

Til subkutan eller intravenøs applikasjon bringes de aktive forbindelser eller deres fysiologisk tålbare salter, hvis ønsket med de dertil vanlige stoffer som oppløsningsfor-midlere, emulgatorer eller ytterligere hjelpestoffer i oppløsning suspensjon eller emulsjon. Som oppløsningsmiddel kommer det for eksempel på tale vann, fysiologisk koksaltopp-løsning eller alkoholer, for eksempel etanol, propanol, glycerin, dertil også sukkeroppløsninger som glucose- eller mannitoppløsninger, eller også en blanding av de forskjellig nevnte oppløsningsmidler. For subcutaneous or intravenous application, the active compounds or their physiologically tolerable salts are brought, if desired, with the usual substances such as solubilizers, emulsifiers or further excipients in solution suspension or emulsion. Solvents include, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerin, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.

I de følgende eksemplene vil oppfinnelsen forklares nærmere. In the following examples, the invention will be explained in more detail.

Eksempel 1 Example 1

2- fN-( IS )- etoks. vkarbonyl- 3- fenylpropyl )- S- alanyl1 - els . endo- 2- azabicvklor3. 3. Oloktan- 3- S- karboksvlsyreoctadesylester 23 g av den analogt EP-A-79 022 fremstilte cis,endo-2-aza-bicyklo[3.3.0]oktan-3-karboksylsyreoctadesylester bringes til reaksjon med 6,7 g HOBt, 13,8 g N-(l-S-karbetoksy-3-fenylpropyl)-S-alanin og 10,2 g dicykloheksylkarbodiimid i 200 ml dimetylformamid. Etter tre timers omrøring ved værelsestemperatur frasuger man fra utfelt dicykloheksylerinstoff, inndamper, opptar ill eddikester og utkryster med 3 x 500 ml 5£ig NaBX03. Den organiske fase inndampes, kromatograferes med eddikester/petroleter i forhold 2:1 over en søyle av 1 kg kiselgel og på denne oppnås tittelforbindelsen og den diastereomere (S,S,R)-forbindelse. 2- fN-( IS )- ethoxy. vcarbonyl-3-phenylpropyl)-S-alanyl1-els. endo- 2- azabicvchlor3. 3. Octane-3-S-carboxylic acid octadecyl ester 23 g of the cis,endo-2-aza-bicyclo[3.3.0]octane-3-carboxylic acid octadecyl ester prepared analogously to EP-A-79 022 are reacted with 6.7 g of HOBt, 13.8 g of N-(1-S-carbethoxy-3-phenylpropyl)-S-alanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After stirring for three hours at room temperature, the precipitated dicyclohexylene substance is filtered off with suction, evaporated, taken up in ethyl acetate and crystallized with 3 x 500 ml of 5£ig NaBX03. The organic phase is evaporated, chromatographed with ethyl acetate/petroleum ether in a 2:1 ratio over a column of 1 kg silica gel and on this the title compound and the diastereomeric (S,S,R) compound are obtained.

Eksempel 2: l- fN-( IS )- dodecykloksykarbonyl- 3- fenylpropyl)- S- alanyl~ l- 2S. 3aR. 7aR- oktahvdroindo1- 2- karboksylsyre a) 1- TN-( IS)- dodecykloksykarbonyl- 3- fenylpropyl)- S- alanyll2S,. 3aR. 7aR- oktahydroindol- 2- karboksylsyre- benzylester 10 mmol S-alanyl]-2S, 3aR,7aR-oktahydroindol-2-karboksylsyre-benzylester (fremstilt iflg. EP-A-84 164) oppløses i 30 ml vannfri etanol. Man innstiller oppløsningen ved Example 2: 1-fN-(1S)-dodecyloxycarbonyl-3-phenylpropyl)-S-alanyl~1-2S. 3 years. 7aR- octahvdroindo1- 2- carboxylic acid a) 1- TN-( IS)- dodecyclooxycarbonyl- 3- phenylpropyl)- S- alanyl2S,. 3 years. 7aR-octahydroindole-2-carboxylic acid benzyl ester 10 mmol S-alanyl]-2S,3aR,7aR-octahydroindole-2-carboxylic acid benzyl ester (prepared according to EP-A-84 164) is dissolved in 30 ml of anhydrous ethanol. The resolution is set by

hjelp av etanolisk kaliumhydroksyd på en pH verdi på 7,0 og tilsetter 1 g pulverisert molekylarsjikt (4A) og deretter etter 10 mmol 2-keto-4-fenyl-smørsyredodecyl-ester. Det tildrypper langsomt en oppløsning av 1 g natriumcyanborhydrid i 10 ml vannfri etanol. Etter en reaksjonstid på 20 t ved 20-25"C filtreres reaksjons-oppløsningen og oppløsningsmiddelet avdestilleres. using ethanolic potassium hydroxide at a pH value of 7.0 and adds 1 g of powdered molecular layer (4A) and then after 10 mmol of 2-keto-4-phenyl-butyric acid dodecyl ester. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise. After a reaction time of 20 h at 20-25°C, the reaction solution is filtered and the solvent is distilled off.

Resten opptas i eddikester/vann. Etter eddikesterfasens inndampning kromatograferes resten på kiselgel med eddikester/cykloheksan (1:4). The rest is taken up in vinegar/water. After evaporation of the acetate phase, the residue is chromatographed on silica gel with acetate/cyclohexane (1:4).

b) Den ifølge a) dannede forbindelse hydrogeneres i etanol i nærvær av palladium-dyrekull ( 1056 ) ved 20-25° C under b) The compound formed according to a) is hydrogenated in ethanol in the presence of palladium-charcoal ( 1056 ) at 20-25° C under

normaltrykk. Etter katalysatorens avslutning bringes oppløsningen med 0,5 normal etanolisk klorhydrogen til sur reaksjon. Oppløsningen inndampes i vakuum og resten utdrives for krystallisering med diisopropylester. normal pressure. After the end of the catalyst, the solution is brought to an acidic reaction with 0.5 normal ethanolic hydrogen chloride. The solution is evaporated in vacuo and the residue is expelled for crystallization with diisopropyl ester.

Eksempel 3: 2- TN- f( 2S)- etoksvkarbonvl- 3- fenvlpropvll- L- alanvlI-[ IS. 3S. 5S1- 2- azabicvklor3. 3. 0loktan- 3- karboksylsvreisobutylester 2,00 g (4,80 mmol) 2-[N-[(lS)-etoksykarbonyl-3-fenylpropyl-] -L-alanyl]-(IS,2S, 5S )-2-azabicyklo[3.3.0]oktan-3-karboksylsyre ble oppløst I 100 ml isobutanol tilsatt 0,1 ml konsen-trert svovelsyre og blandingen kokt under tilbakeløp i 15 timer. Etter avkjøling ble oppløsningsmiddelet fjernet på rotasjonsfordamper og resten opptatt i metylenklorid. En oppløsning ble vasket hver gang en gang med vann, mettet vandig NaCE03- oppløsning og igjen vann, tørket over MgS04, inndampet og ved kroomatografi på 200 g kiselgel (elueringsmiddel etylenklorid/eddikester 8:2) adskilt fra forurens-ninger. Example 3: 2-TN-f(2S)-ethoxycarbonyl-3-phenylpropyl-L-alanyl-[IS. 3S. 5S1- 2- azabicvchlor3. 3. Ooctane-3- carboxyl isobutyl ester 2.00 g (4.80 mmol) 2-[N-[(1S)ethoxycarbonyl-3-phenylpropyl-]-L-alanyl]-(1S,2S,5S)-2- Azabicyclo[3.3.0]octane-3-carboxylic acid was dissolved in 100 ml of isobutanol to which 0.1 ml of concentrated sulfuric acid was added and the mixture boiled under reflux for 15 hours. After cooling, the solvent was removed on a rotary evaporator and the residue taken up in methylene chloride. A solution was washed each time once with water, saturated aqueous NaCE03 solution and again water, dried over MgSO4, evaporated and separated from impurities by chromatography on 200 g of silica gel (eluent ethylene chloride/acetate 8:2).

Ved utbytte: 5156 av det teoretiske, oljeaktig produkt. By yield: 5156 of the theoretical, oily product.

[oc]<g>° = -28,2° (c = l, metanol). [oc]<g>° = -28.2° (c = 1, methanol).

Dette produktet ble oppløst i eter, innstilt med mettet eterisk saltsyre på pH 2, oppløsningsmiddelet avdampet og resten krystallisert fra diisopropyleter. This product was dissolved in ether, adjusted with saturated ethereal hydrochloric acid to pH 2, the solvent evaporated and the residue crystallized from diisopropyl ether.

Hydrokloridets data: Hydrochloride data:

Smeltepunkt: 123 - 124°C Melting point: 123 - 124°C

[a]§° = +17,7° (c = 1, metanol). [α]§° = +17.7° (c = 1, methanol).

Eksempel 4: 2- TN- f( IS)- etoksvkarbonvl- 3- fenvlpropvl)- L- alanvl1-( IS. 3S. 5S )- 2- azat>lcyklof3. 3. Ol oktan- 3- karboksyl syrebenzhydryl-ester Example 4: 2-TN-f(IS)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-(IS.3S.5S)-2-azati>lcyclof3. 3. Ol octane-3-carboxylic acid benzhydryl ester

2.07 g (4,97 mmol) 2-[N-[(IS)-etoksykarbonyl-3-fenylpropyl-L-alanyl]-(IS,3S,5S)-2-azabicyklo[3.3.0]-oktan-3-karboksylsyre ble oppløst i 50 ml aceton og under isavkjøling tildryppet en opløsning av 1,16 g (5,98 mmol) difenyl-dlazometan i 50 ml aceton. Deretter ble oppløsningen omrørt 26 timer ved vaerelsestemperatur, oppløsningsmiddelet avdampet på rotasjonsfordamper og resten renset ved flash-kromatografi på 150 g kiselgel (elueringsmiddel toluen/etanol 98:2). 2.07 g (4.97 mmol) 2-[N-[(IS)-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(IS,3S,5S)-2-azabicyclo[3.3.0]-octane-3- carboxylic acid was dissolved in 50 ml of acetone and, under ice-cooling, a solution of 1.16 g (5.98 mmol) of diphenyl-dlazomethane in 50 ml of acetone was added dropwise. The solution was then stirred for 26 hours at room temperature, the solvent evaporated on a rotary evaporator and the residue purified by flash chromatography on 150 g of silica gel (eluent toluene/ethanol 98:2).

Utbytte: 2,55 g ( 88%) oljeaktig produkt. Yield: 2.55 g (88%) oily product.

[a]<g>° = -33,8° (c = 1, metanol). [α]<g>° = -33.8° (c = 1, methanol).

Eksempel 5: 2- fN- f ( IS )- etoksykarbon. vl- 3- f envlpropvl )- L- alanvll -( IS . 3S. 5S )- 2- azabicvklor3. 3. Oloktan- 3- karboksylsyreoctadesylester 2.08 g (5,00 mmol) 2-[N-[(IS)-etoksykarbonyl-3-fenylpropyl]--L-alanyl]-(IS,3S,5S)-2-azabicyklo[3.3.0]oktan-3-karboksylsyre ble oppløst i 25 ml absolutt dimetylformamid, tilsatt 1,00 g (10,0 mmol) kaliumhydrogenkarbonat og omrørt 90 min. ved 40° C. Etter avkjøling til vaerelsestemperatur ble det tildryppet en oppløsning av 4,0 g (12,0 mmol) 1-bromoktadekan i 20 ml absolutt dimetylformamid, omrørt 4 timer ved 40°C. Oppløsningsmiddelet ble fjernet og rotasjonsfordampet ved ca. 1 torr og resten fordelt mellom vann og metylenklorid. Den organiske fase ble adskilt, tørket over MgS04 og inndampet. Example 5: 2-fN-f (IS)-ethoxycarbon. vl- 3- f envlpropvl )- L- alanvll -( IS . 3S. 5S )- 2- azabicvchlor3. 3. Oloctane-3-carboxylic acid octadecyl ester 2.08 g (5.00 mmol) 2-[N-[(IS)-ethoxycarbonyl-3-phenylpropyl]--L-alanyl]-(IS,3S,5S)-2-azabicyclo[ 3.3.0]octane-3-carboxylic acid was dissolved in 25 ml of absolute dimethylformamide, 1.00 g (10.0 mmol) of potassium bicarbonate was added and stirred for 90 min. at 40° C. After cooling to room temperature, a solution of 4.0 g (12.0 mmol) of 1-bromooctadecane in 20 ml of absolute dimethylformamide was added dropwise, stirred for 4 hours at 40° C. The solvent was removed and rotary evaporated at approx. 1 torr and the rest divided between water and methylene chloride. The organic phase was separated, dried over MgSO 4 and evaporated.

Fra råproduktet (5,40 g ) ble det etter søylekromatografi på 200 g kiselgel (elueringsmiddel toluen/etanol 99:1) isolert 3,05 g ( 9256) av produktet. From the crude product (5.40 g), 3.05 g (9256) of the product was isolated after column chromatography on 200 g of silica gel (eluent toluene/ethanol 99:1).

[a]<g>° = -19,6° (c = 1, metanol). [α]<g>° = -19.6° (c = 1, methanol).

Eksempel 6: 2- fN- f( IS)- benzyhydrvloksykarbonvl- 3- fenvlpropvl)- L- alanvl1-( IS. 3S. 5S)- 2- azabicyklo f 3. 3. 0Toktan- 3- karboksvlsvrebenzvl-ester Example 6: 2- fN- f( IS)- benzylhydroxycarbonvl- 3- phenylpropyl)- L- alanvl1-( IS. 3S. 5S)- 2- azabicyclof 3. 3. 0 Toctane- 3- carboxyvlvrebenzvl-ester

a) ( 2R)- hydroksy- 4- fenvlsmørsvrebenzhvdrylester a) ( 2R)- hydroxy- 4- phenylbutyric acid benzyl ester

Til en oppløsning av 7,40 g (41,1 mmol) (2R)-hyrdoksy-4-fenylsmørsyre i 200 ml absolutt aceton ble det under isavkjøling i løpet av 20 min. tildryppet en oppløsning av 10,1 g (52,1 mmol) i difenyldiazometan i 400 ml absolutt aceton og reaksjonsblandingen omrørt 20 timer ved vaerelsestemperatur. Oppløsningsmiddelet ble avdampet og resten utdrevet med 100 ml petroleter. Det ble dannet 6,4 g krystallinsk produkt. Moderluten ble inndampet og ved søylekromatografi på 700 g kiselgel (elueringsmiddel toluen/etanol 99:1) isolert ytterligere 6,0 g av produktet. To a solution of 7.40 g (41.1 mmol) of (2R)-hyrdoxy-4-phenylbutyric acid in 200 ml of absolute acetone was added under ice cooling during 20 min. added dropwise a solution of 10.1 g (52.1 mmol) in diphenyldiazomethane in 400 ml of absolute acetone and the reaction mixture stirred for 20 hours at room temperature. The solvent was evaporated and the residue extracted with 100 ml of petroleum ether. 6.4 g of crystalline product was formed. The mother liquor was evaporated and a further 6.0 g of the product was isolated by column chromatography on 700 g of silica gel (eluent toluene/ethanol 99:1).

Samlet utbytte: 12,4 g (8756). Total yield: 12.4 g (8756).

Smeltepunkt 88 - 89°C. Melting point 88 - 89°C.

[a]j)° = -1,8° (c = 5, metanol). [α]j)° = -1.8° (c = 5, methanol).

b) 2- fN- f( IS)- benzyhydryloksvkarbonyl- 3- fenvlpropvl)- L-alanvll-( lS. 3S. 5S)- 2- azabicvklof3. 3. 01oktan- 3- karboksvl-svrebenzvlester b) 2-fN-f(1S)-benzylhydryloxycarbonyl-3-phenylpropyl)-L-alanyl-(1S. 3S. 5S)- 2- azabiccyclof3. 3. 01octane- 3- carboxyl-srebenzvlester

bi) 1,80 g (4,33 mmol) 2-(N-tert.butoksykarbonyl-L-alanyl )-(IS,3S,5S)-2-azabicyklo[3.3.0]oktan-3-karboksylsyre-benzylester ble oppløst i 4,5 ml trifluoreddiksyre og bi) 1.80 g (4.33 mmol) of 2-(N-tert.butoxycarbonyl-L-alanyl)-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid benzyl ester was dissolved in 4.5 ml of trifluoroacetic acid and

omrørt 90 min. ved vaerelsestemperatur. Reaksjonsoppløs-ningen ble inndampet og for fjerning av trifluor-eddiksyreester behandlet tre ganger på rotasjonsfordamper med toluen. Resten, bestående av 1,90 g 2-(L-alanyl)-(IS,3S,5S)-2-azabicyklo[3.3.0]oktan-3-karbeoksylsyrebenzylester-trifluor-acetat ble oppløst i 10 ml absolutt metylenklorid (oppløsning A). stirred 90 min. at room temperature. The reaction solution was evaporated and, to remove trifluoroacetic acid ester, treated three times on a rotary evaporator with toluene. The residue, consisting of 1.90 g of 2-(L-alanyl)-(IS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid benzyl ester trifluoroacetate was dissolved in 10 ml of absolute methylene chloride (solution A).

b2) 1,63 g (4,71 mmol) (2R)-hydroksy-4-fenyl-smørsyrebenz-hydrylester fra eksempel 12 a) ble oppløst sammen med 0,4 ml absolutt pyridin i 25 ml absolutt metylenklorid og ved -10°C i løpet av 20 min. tildryppet 1,41 g (5,00 mmol) trifluormetandulfonsyreanhydrid. Deretter ble kjølebadet fjernet og etter oppnåelse av vaerelsestemperatur ble oppløsningsmiddelet avdampet. Resten ble filtrert over 50 g kiselgel med metylenklorid og inndampet. Det ble dannet 1,70 g 4-fenyl-(2R)-trifluormetylsulfonyloksy-smørsyrebenzhydrylester og oppløst i 10 ml absolutt metylenklorid (oppløsning B). b2) 1.63 g (4.71 mmol) of (2R)-hydroxy-4-phenyl-butyric acid benzhydryl ester from example 12 a) was dissolved together with 0.4 ml of absolute pyridine in 25 ml of absolute methylene chloride and at -10° C within 20 min. added dropwise 1.41 g (5.00 mmol) of trifluoromethanesulfonic anhydride. The cooling bath was then removed and, after reaching room temperature, the solvent was evaporated. The residue was filtered over 50 g of silica gel with methylene chloride and evaporated. 1.70 g of 4-phenyl-(2R)-trifluoromethylsulfonyloxy-butyric acid benzhydryl ester was formed and dissolved in 10 ml of absolute methylene chloride (solution B).

b3) Til oppløsningen A ble det satt 1,0 ml (7,40 mmol) b3) 1.0 ml (7.40 mmol) was added to solution A

trietylamin og deretter tildryppet ved 0°C langsomt oppløsning B. Kjølebadet ble fjernet og reaksjonsopp-løsningen omrørt 19 timer ved vaerelsestemperatur, deretter vasket 3 ganger med vann, tørket over MgS04 og inndampet. Resten ble renset kromatografisk på 80 g kiselgel (elueringsmiddel cykloheksan/eddikester 8:2 og 7:3) og det ble dannet 0,95 g ( 30%) av det ønskede produkt. triethylamine and then added dropwise at 0°C slow solution B. The cooling bath was removed and the reaction solution stirred for 19 hours at room temperature, then washed 3 times with water, dried over MgSO 4 and evaporated. The residue was purified chromatographically on 80 g of silica gel (eluent cyclohexane/acetic ester 8:2 and 7:3) and 0.95 g (30%) of the desired product was formed.

Smeltepunkt: 81 - 85°C. Melting point: 81 - 85°C.

[a]jj° = -55,2° (c = 1, metanol). [α]jj° = -55.2° (c = 1, methanol).

Ved egnede kombinasjoner av de i foregående eksempler omtalte fremgangsmåter ble det fremstilt følgende ytterligere forbindelser (betegningene av ringsystemene tilsvarer de for forbindelsene med generell formel II): By suitable combinations of the methods mentioned in the preceding examples, the following additional compounds were prepared (the designations of the ring systems correspond to those of the compounds of general formula II):

Eksempel 25: 1- fN- fIS )- karboetoksybutyl)- S- alanvll- oktahydrocyklopenta-fblpvrrol )- 2- karboksylsyre Example 25: 1-fN-fIS)-carboethoxybutyl)-S-alanyl-octahydrocyclopenta-fblpvrrol)-2-carboxylic acid

a) DL- 2- trifluormetylsulfonyloksy- pentasyreetylester a) DL- 2-trifluoromethylsulfonyloxypentaic acid ethyl ester

5 g (34 mmol) 2-hydroksyvaleriansyreetylester og 2,85 g 5 g (34 mmol) of 2-hydroxyvaleric acid ethyl ester and 2.85 g

(35,9 mmol) absolutt pyridin ble oppløst i 100 ml absolutt CH2CI2 under beskyttelsesgass, avkjølt til 0°C og blandet med 9,66 g (34 mmol) trifluormetansulfonsyreanhydrid• (35.9 mmol) of absolute pyridine was dissolved in 100 ml of absolute CH2CI2 under protective gas, cooled to 0°C and mixed with 9.66 g (34 mmol) of trifluoromethanesulfonic anhydride•

Etter oppvarming til vaerelsestemperatur ble det omrørt i 6 timer. Etter oppløsningens inndampning ble det dannede råprodukt renset søylekromatografisk (kiselgel, petroleter/CH2Cl2 6:1). Utbytte utgjorde 9,3 g av en fargeløs, svakt viskøs vsske. After heating to room temperature, it was stirred for 6 hours. After evaporation of the solution, the crude product formed was purified by column chromatography (silica gel, petroleum ether/CH2Cl2 6:1). Yield was 9.3 g of a colorless, slightly viscous liquid.

IR: 2880 - 3000 1770, 1420 IR: 2880 - 3000 1770, 1420

1200 - 1220 1150, 620 cm-<1>1200 - 1220 1150, 620 cm-<1>

b) N-( 1- S- karboetoksybutyl)- S- alaninbenzylester b) N-(1-S-carboethoxybutyl)-S-alanine benzyl ester

4,9 g (17,6 mmol) av den således dannede trifluormetan-sulf onsyreester ble under nitrogen oppløst i 70 ml CH2CI2 absolutt med 4,08 g L-alaninbenzylester-hydroklorid (19 mmol) under tilsetting av 5,4 ml trietylamin og omrørt i tre timer ved vaerelsestemperatur. Oppløsningen ble 4.9 g (17.6 mmol) of the thus formed trifluoromethanesulfonic acid ester was dissolved under nitrogen in 70 ml of CH2CI2 absolute with 4.08 g of L-alanine benzyl ester hydrochloride (19 mmol) while adding 5.4 ml of triethylamine and stirred for three hours at room temperature. The resolution was

inndampet, råproduktet opptatt i eddikester og vasket tre ganger med vann, tørket og inndampet. De diastereomere ble spaltet ved en søylekromatografi (kiselgel, cyklo-heksan/eddikester 5:1). Utbyttet utgjorde pr. isomer 500 mg. Den i første filtrering isolerte diastereomere har S,S-konfigurasjon. evaporated, the crude product taken up in vinegar and washed three times with water, dried and evaporated. The diastereomers were resolved by column chromatography (silica gel, cyclohexane/acetic ester 5:1). The dividend amounted to isomer 500 mg. The diastereomer isolated in the first filtration has S,S configuration.

<3->H-NMR <3->H-NMR

S = 0,9 (t,CE3), 1,3 (t,CH3), 1,35 (d,CH3), 1,4 (m,CH2), S = 0.9 (t,CE3), 1.3 (t,CH3), 1.35 (d,CH3), 1.4 (m,CH2),

1,6 (m,CH2), 1,9 (s,NH), 3,3 (t.CH), 3,4 • , CE) , 1.6 (m,CH2), 1.9 (s,NH), 3.3 (t.CH), 3.4 • , CE) ,

4,2 (m,CH2), 5,15 (q,CH2 Ph), 7,4 (s, CH aromat.) ppm. 4.2 (m,CH2), 5.15 (q,CH2 Ph), 7.4 (s, CH arom.) ppm.

c) N-( 1- S- karboetoksybutyl)- S- alanln c) N-(1-S-carboethoxybutyl)-S-alanln

600 mg (1,95 mmol) benzylester (diastereomer A) ble 600 mg (1.95 mmol) of benzyl ester (diastereomer A) was

hydrogenert i 34 ml etanol med Pd på kull. Katalysatoren ble deretter frafUtrert og oppløsningen inndampet i vakuum. Produktet fremkom deretter som hvitt fast stoff med et smeltepunkt på 137°C og et utbytte på 430 mg. d) 430 mg (1,98 mmol) N-(1-S-karboetoksybutyl)-S-alanin og 486 mg (1,98 mmol) L(-)-oktahydrocyklopenta-[b]-pyrrol-2-karboksylsyrebenzylester ble oppløst under nitrogen i 20 ml dimetylformamid og avkjølt i -10°C, blandet med 1,5 ml trietylamin og 2 ml n-propylfosfonsyreanhydrid. Det ble omrørt 1 time ved -10°C og deretter natten over ved vaerelsestemperatur. Oppløsningen ble opptatt i 200 ml eddikester og vasket med mettet NaHC03-oppløsning, 1056 vandig sitronsyre og mettet vandig NaCl-oppløsning. Etter tørkning og inndamping av oppløsningen ble de diastereomere forbindelser spaltet ved søylekromatografi (kiselgel, cykloheksan/eddikester 9:1). Utbyttet utgjorde 360 mg. Begge diastereomere hydrogeneres som omtalt i eksempel 94 c) med Pd/C i etanol og fremkom etter inndampning av oppløsningen som hvitt fast stoff. hydrogenated in 34 mL of ethanol with Pd on charcoal. The catalyst was then filtered off and the solution evaporated in vacuo. The product then appeared as a white solid with a melting point of 137°C and a yield of 430 mg. d) 430 mg (1.98 mmol) N-(1-S-carboethoxybutyl)-S-alanine and 486 mg (1.98 mmol) L(-)-octahydrocyclopenta-[b]-pyrrole-2-carboxylic acid benzyl ester were dissolved under nitrogen in 20 ml of dimethylformamide and cooled to -10°C, mixed with 1.5 ml of triethylamine and 2 ml of n-propylphosphonic anhydride. It was stirred for 1 hour at -10°C and then overnight at room temperature. The solution was taken up in 200 ml of ethyl acetate and washed with saturated NaHCO 3 solution, 1056 aqueous citric acid and saturated aqueous NaCl solution. After drying and evaporating the solution, the diastereomeric compounds were separated by column chromatography (silica gel, cyclohexane/acetic ester 9:1). The yield was 360 mg. Both diastereomers are hydrogenated as described in example 94 c) with Pd/C in ethanol and appeared after evaporation of the solution as a white solid.

Eksempel 26: 1- fN-( IS)- karboksybutyl- S- alanyll-( oktahvdrocyklopenta-fblpyrrol)- 2- karboksylsyre 60 mg (0,17 mmol) karboksylsyre ble innrørt i 2 ml 4N vandig KOH-oppløsning inntil fullstendig oppløsning av stoffet. Deretter ble oppløsningen satt til en sterkt sur ioneut-veksler og eluert med vandig 256-ig pyridinoppløsning. Etter oppløsningens inndampning utgjorde utbyttet 39 mg. Analogt med de i eksemplene 25 og 26 fremstilte forbindelser lar det seg ytterligere fremstille følgende forbindelser i henhold til formel II Example 26: 1-fN-(1S)-carboxybutyl-S-alanyl-(octahdrocyclopenta-fblpyrrole)-2-carboxylic acid 60 mg (0.17 mmol) of carboxylic acid was stirred into 2 ml of 4N aqueous KOH solution until complete dissolution of the substance . The solution was then added to a strongly acidic ion exchanger and eluted with aqueous 256 ig pyridine solution. After evaporation of the solution, the yield was 39 mg. Analogous to the compounds prepared in examples 25 and 26, it is possible to further prepare the following compounds according to formula II

hvori in which

n = 2 n = 2

R<1> = CH3R<1> = CH3

R<2> = CH2H5R<2> = CH 2 H 5

R<3> = H R<3> = H

samt R og molekyldelen as well as R and the molecular part

som er substituert i henhold til følgende oppførte tabell: which are substituted according to the following listed table:

Claims (4)

1. Analogifremgangsmåte for fremstilling av ACE-hemmere med nootrop virkning eller deres fysiologisk godtagbare salter med formel (II): der: n =1 eller 2, R = fenyl, r<1> = forgrenet eller uforgrenet lavere alkyl som eventuelt kan være substituert med fenyl, R<2> og R<3> er like eller forskjellige og betyr hydrogen, en alifatisk rest med 1 til 21 C-atomer, difenyllavere-alkyl, benzhydril, metyl eller benzyl, R<4> og r<5> danner sammen med de bærende atomene et ringsystem fra rekken oktahydroindol, oktahydrocyklopenta[b]pyrrol, eller spiro[(bicyklo[2.2.2]oktan)-2,3'pyrrolidin], karakterisert ved at man omsetter deres fragmenter i et egnet oppløsningsmiddel eventuelt i nærvær av en base og/eller et koblingshjelpemiddel, reduserer eventuelt intermediært dannede umettede forbindelser, som Schiffske baser, forestrer eventuelle forbindelser med formel II med frie karboksylgrupper og overfører eventuelt de oppnådde forbindelsene eventuelt til deres fysiologisk godtagbare salter, bortsett fra forbindelser der R, R<*>, R<4>, R^ og n er som definert over og R<2> og R<3> er like eller forskjellige og begge har en av de følgende betydninger: hydrogen, alkyl med 1-6 C-atomer eller benzyl.1. Analogous process for the production of ACE inhibitors with nootropic action or their physiologically acceptable salts of formula (II): there: n = 1 or 2, R = phenyl, r<1> = branched or unbranched lower alkyl as appropriate may be substituted with phenyl, R<2> and R<3> are the same or different and mean hydrogen, an aliphatic radical of 1 to 21 C atoms, diphenyl lower alkyl, benzhydryl, methyl or benzyl, R<4> and r<5> together with the supporting atoms form a ring system from the series octahydroindole, octahydrocyclopenta[b]pyrrole, or spiro[(bicyclo[2.2.2]octane)-2,3'pyrrolidine], characterized by reacting their fragments in a suitable solvent, possibly in the presence of a base and/or a coupling aid, reduces any intermediately formed unsaturated compounds, such as Schiff bases, esterifies any compounds of formula II with free carboxyl groups and optionally transfers the obtained compounds to their physiologically acceptable salts, except for compounds where R, R<*>, R<4>, R^ and n are as defined above and R<2> and R<3> are the same or different and both have one of the following meanings: hydrogen, alkyl with 1-6 C atoms or benzyl. 2. Fremgangsmåte ifølge krav 1 for fremstilling av 2-[N-(IS )-etoksykarbonyl-3-fenylpropyl)-S-alanyl]-cis, endo-2-azabicyklo[3.3.0]oktan-3-S-karboksylsyreoctadesylester i fri form eller i saltform, karakterisert ved at man utgår fra tilsvarende utgangsmaterialer.2. Method according to claim 1 for the production of 2-[N-(1S)-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-cis, endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic acid octadecyl ester in free form or in salt form, characterized by starting from corresponding starting materials. 3. Fremgangsmåte ifølge krav 1 for fremstilling av 1-[N-(1S)-dodecykloksykarbonyl-3-fenylpropyl)-S-alanyl]-2S,3aR,7aR-oktahydroindol-2-karboksylsyre i fri form eller i saltform, karakterisert ved at man utgår fra tilsvarende utgangsmaterialer.3. Method according to claim 1 for the production of 1-[N-(1S)-dodecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-2S,3aR,7aR-octahydroindole-2-carboxylic acid in free form or in salt form, characterized in that based on corresponding starting materials. 4. Fremgangsmåte ifølge krav 1 for fremstilling av 2-[N-[(lS)-etoksykarbonyl-3-fenylpropyl)-L-alanyl]-(IS,3S,5S)-2-aza-bicyklo[3.3.0]oktan-3-karboksylsyreoctadesylester i fri form eller i saltform, karakterisert ved at man utgår fra tilsvarende utgangsmaterialer.4. Method according to claim 1 for the preparation of 2-[N-[(1S)ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-(IS,3S,5S)-2-aza-bicyclo[3.3.0]octane-3 -carboxylic acid octadecyl ester in free form or in salt form, characterized by starting from corresponding starting materials.
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AU612137B2 (en) * 1987-04-27 1991-07-04 E.R. Squibb & Sons, Inc. Method for inhibiting loss of cognitive functions employing an ace inhibitor
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US5037821A (en) * 1988-06-01 1991-08-06 E. R. Squibb & Sons, Inc. Method for inhibiting loss of cognitive functions employing a calcium channel blocker alone or in combination with an ACE inhibitor
US5093129A (en) * 1989-01-30 1992-03-03 E. R. Squibb & Sons, Inc. Method for treating addiction to a drug of abuse employing an ace inhibitor
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