NO834352L - NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST. - Google Patents

NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST.

Info

Publication number
NO834352L
NO834352L NO834352A NO834352A NO834352L NO 834352 L NO834352 L NO 834352L NO 834352 A NO834352 A NO 834352A NO 834352 A NO834352 A NO 834352A NO 834352 L NO834352 L NO 834352L
Authority
NO
Norway
Prior art keywords
compound
formula
pyrrole
carboxylic acid
phenyl
Prior art date
Application number
NO834352A
Other languages
Norwegian (no)
Inventor
Rainer Henning
Hansjoerg Urbach
Rolf Geiger
Volker Teetz
Reinhard Becker
Original Assignee
Hoechst Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Publication of NO834352L publication Critical patent/NO834352L/en
Application filed by Hoechst Ag filed Critical Hoechst Ag

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/022Peptides 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
    • C07K5/0222Peptides 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24Oxygen atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Description

Foreliggende oppfinnelse vedrører nye derivater av bicykliske aminosyrer med formelen I The present invention relates to new derivatives of bicyclic amino acids with the formula I

i hvilken hydrogenatomene til brohodet-C-atomene 4 og (7+n) er cis- eller trans-konfigurert til hverandre, hvorved karboksylgruppen til C-atomet 1 kan være orientert til hydrogenatomet til C-atom 7+n i cis- eller trans-stilling og hvori in which the hydrogen atoms of the bridgehead C atoms 4 and (7+n) are cis- or trans-configured to each other, whereby the carboxyl group of C-atom 1 can be oriented to the hydrogen atom of C-atom 7+n in cis- or trans- position and in which

n = 1/2 eller 3,n = 1/2 or 3,

R"^ = hydrogen, (C^-Cg)-alkyl, som eventuelt kan være substituert med amino, (C^-C^)-acylamino, fortrinnsvis (ci~C4)-alkanoylamino eller benzoylamino, (C2--C6)-alkenyl, (C5~C9)-cykloalkyl, (C5-Cg-cyklo-alkenyl, (C5~C7)-cykloalkyl-(C^-C^ )-alkyl, (C<g-C>^Q)-aryl eller delhydrert (Cg-C^0)-aryl, som hver kan være substituert med (C^~C2)-alkyl, (C1-C2)-alkyl, (C^-C^)-alkoksy eller halogen, (Cg-C^Q)-aryl-(C^-C^)-alkyl, som som ovenfor defi-nert kan være substituert i aryl-resten, en mono-resp. bicyklisk heterocyklenrest med 5 til 7 resp. 8 til 10 ringatomer, hvorav 1 til 2 ringatomer er svovel- eller oksygenatomer og/eller hvorav 1 til 4 ringatomer er nitrogenatomer, eller en sidekjede av en naturlig forekommende aminosyre, R"^ = hydrogen, (C^-Cg)-alkyl, which may optionally be substituted with amino, (C^-C^)-acylamino, preferably (Ci-C4)-alkanoylamino or benzoylamino, (C2--C6) -alkenyl, (C5~C9)-cycloalkyl, (C5-Cg-cycloalkenyl, (C5~C7)-cycloalkyl-(C^-C^ )-alkyl, (C<g-C>^Q)-aryl or partially hydrogenated (C 8 -C 10 )-aryl, each of which may be substituted with (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl or halogen, (C 8 -C 2 Q)-aryl-(C^-C^)-alkyl, which as defined above may be substituted in the aryl residue, a mono- or bicyclic heterocyclen residue with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which 1 to 4 ring atoms are nitrogen atoms, or a side chain of a naturally occurring amino acid,

2 2

R = hydrogen, (C-j-Cg)-alkyl, (C2-Cg)-alkenyl eller R = hydrogen, (C-1-C8)-alkyl, (C2-C8)-alkenyl or

(C6--C10) -aryl- (C]_-C4 ) -alkyl,(C 6 -C 10 )-aryl-(C 1 -C 4 )-alkyl,

Y = hydrogen er hydroksy,Y = hydrogen is hydroxy,

Z = hydrogen ellerZ = hydrogen or

Y og Z = tilsammen oksygen,Y and Z = combined oxygen,

X = (C1-Cg)-alkyl, (C2-Cg)-alkenyl, (C5-Cg)-dykloalkyl, X = (C1-C8)-alkyl, (C2-C8)-alkenyl, (C5-C8)-dichloroalkyl,

(Cg-C^Q9-aryl, som kan være mono-, di- eller trisubstituert med (C^-C^)-alkyl, (C1~C4)-alkoksy, hydroksy, halogen, nitro, amino, (C-^-C^-alkylamino, di-(C^-C4)-alkyl-amino eller metylendioksy (Cg-C^Q9-aryl, which may be mono-, di- or tri-substituted with (C^-C^)-alkyl, (C1-C4)-alkoxy, hydroxy, halogen, nitro, amino, (C-^ -C 1 -alkylamino, di-(C 1 -C 4 )-alkylamino or methylenedioxy

eller betyr indol-3-yl,or means indol-3-yl,

samt deres fysiologiske godtagbare salter.as well as their physiologically acceptable salts.

Som salter kommer spesielt på tale alkali- og jordalkali-salter, salter med fysiologiske godtagbare aminer og salter med uorganiske eller organiske syrer som f.eks. HC1, HBr, H2S04'maleinsYre'fumarsyre. As salts, alkali and alkaline earth salts, salts with physiologically acceptable amines and salts with inorganic or organic acids such as e.g. HC1, HBr, H2S04'maleic Acid'fumaric acid.

Med aryl skal her som nedenfor fortrinnsvis forståes fenyl eller naftyl. Alkyl kan være rettkjedet eller forgrenet. Here, as below, aryl preferably means phenyl or naphthyl. Alkyl can be straight chain or branched.

Forbindelser med formel I har chiriale C-atomer i stillingene C-l, C-4, C-(7+n), samt i de med en stjerne markerte C-atomer i sidekjeden. Både R- og S-konfigurasjonene til alle sentra er gjenstand for foreliggende oppfinnelse. Forbindelsene med formel I kan derfor foreligge som optiske isomerer, som diastereomerer, som racemater eller som blandinger av disse. Foretrukket er forbindelsene med formel I, i hvilken C-atomet 1 i det bicykliske ringsysstem samt de med en stjerne markerte C-atomer av sidekjeden har S-konfigurasjon. Compounds of formula I have chiral C atoms in the positions C-1, C-4, C-(7+n), as well as in the C atoms in the side chain marked with an asterisk. Both the R and S configurations of all centers are subject to the present invention. The compounds of formula I can therefore exist as optical isomers, as diastereomers, as racemates or as mixtures of these. Preferred are the compounds of formula I, in which the C atom 1 in the bicyclic ring system as well as the C atoms of the side chain marked with an asterisk have the S configuration.

Foretrukne forbindelser med formel I er slike, i hvilkenPreferred compounds of formula I are those in which

R"*" betyr hydrogen, (C^-C^)-alkyl, (C2~C3)-alkenyl, benzyl R"*" means hydrogen, (C^-C^)-alkyl, (C2~C3)-alkenyl, benzyl

4-amino-butyl, 4-metoksybenzyl eller 4-etoksybenzyl R 2betyr hydrogen, (C1~C4)-alkyl eller benzyl og 4-amino-butyl, 4-methoxybenzyl or 4-ethoxybenzyl R 2 means hydrogen, (C1~C4)-alkyl or benzyl and

X betyr fenyl, som kan være mono- eller disubstituer ellerX means phenyl, which may be mono- or di-substituted or

i tilfelle av metoksy trisubstituert med (C^-C^)-alkyl, (C^-C2)-alkoksy, hydroksy, fluor, klor, in the case of methoxy trisubstituted by (C 1 -C 2 )-alkyl, (C 1 -C 2 )-alkyl, hydroxy, fluorine, chlorine,

brom, amino, (C^-C^)-alkylamino, di-(C^-C^)alkyl-amino, nitro eller metylendioksy. bromine, amino, (C 1 -C 4 )alkylamino, di-(C 1 -C 4 )alkylamino, nitro or methylenedioxy.

Spesielt foretrukket er slike forbindelser med formel I,Particularly preferred are such compounds of formula I,

i hvilken n betyr 1 eller 2, R"<*>" betyr metyl, 4-metoksybenzyl eller 4-etoksybenzyl og X betyr fenyl, hvorved slike, i hvilken R 2 betyr hydrogen eller etyl, foretrekkes. in which n means 1 or 2, R"<*>" means methyl, 4-methoxybenzyl or 4-ethoxybenzyl and X means phenyl, whereby those in which R 2 means hydrogen or ethyl are preferred.

Oppfinnelsen vedrører videre fremgangsmåte til fremstilling av forbindelsene med formel I. En fremgangsmåtevariant erkarakterisert vedat man omsetter en forbindelse med formel II The invention further relates to the method for producing the compounds of formula I. A method variant is characterized by reacting a compound of formula II

1 2 hvori R , R , X, Y og Z har betydningene som i formel I, med en forbindelse med formel III, 1 2 in which R , R , X, Y and Z have the meanings as in formula I, with a compound of formula III,

i hvilken konfigurasjonen av dat bicykliske ringsystem og substituenten til C-l er den samme som i formel I og hvori n betyr 1, 2 eller 3 og in which the configuration of said bicyclic ring system and the substituent of C-1 is the same as in formula I and wherein n means 1, 2 or 3 and

W betyr en hydrogenolyttisk eller sur avspaltbar rest, W means a hydrogenolytic or acidic cleavable residue,

spesielt en benzyl- eller en tert.-butyl-rest, in particular a benzyl or a tert.-butyl residue,

ifølge kjente amiddannelsesmetoder fra peptidkjemien og deretter avspalter ved katalytisk hydrering eller syre-behandling resten W og eventuelt ved ytterligere syre-eller basebehandling også avspalte resten R 2, hvorved alltid fåes de frie karboksylsyrer. according to known amide formation methods from peptide chemistry and then split off by catalytic hydrogenation or acid treatment the residue W and optionally by further acid or base treatment also split off the residue R 2 , whereby the free carboxylic acids are always obtained.

Ytterligere syntesefremgangsmåter til fremstilling av forbindelser med formel I, i hvilken Y og Z tilsammen betyr hydrogen, består deri at man omsetter en forbindelse med formel IV, Further synthesis methods for the preparation of compounds of formula I, in which Y and Z together represent hydrogen, consist in reacting a compound of formula IV,

i hvilken konfigurasjonen av det bicykliske ringsystem og til substituenten til C-l er den samme som i formel I og hvori n og R"*" har betydningene som i formel I og W har betydningen som i formel III, med en forbindelse med formel in which the configuration of the bicyclic ring system and of the substituent of C-1 is the same as in formula I and wherein n and R"*" have the meanings as in formula I and W has the meaning as in formula III, with a compound of formula

V, W,

hvori R 2 og X har betydningene som i formel I, på kjent måte ved en Michael-reaksjon (Organikum, 6. opplag, s. 492, 1967) og avspalter resten W og eventuelt resten R 2som ovenfor beskrevet, eller at man omsetter en forbindelse med den ovenfor angitte formel IV med en forbindelse med den generelle formel VI, hvori R 2 har betydningen som i formel I, og omsetter med en forbindelse med den generelle formel VII in which R 2 and X have the meanings as in formula I, in a known manner by a Michael reaction (Organikum, 6th edition, p. 492, 1967) and split off the residue W and optionally the residue R 2 as described above, or that one reacts a compound of the above formula IV with a compound of the general formula VI, in which R 2 has the meaning as in formula I, and reacts with a compound of the general formula VII

hvori X har betydningen.som i formel I, på kjent måte ved en Mannich-reaksjon (s. Bull.Soc.Chim. France 1973, s. 625) og deretter avspalter resten W og eventuelt resten R 2som ovenfor beskrevet under dannelse av de frie karboksygrupper. wherein X has the meaning as in formula I, in a known manner by a Mannich reaction (s. Bull.Soc.Chim. France 1973, p. 625) and then splits off the residue W and possibly the residue R 2 as described above to form the free carboxy groups.

Videre kan fremstilles forbindelser med formel I medFurthermore, compounds of formula I can be prepared with

Y og Z = hydrogen også på den måte at man omsetter en forbindelse med den ovenfor nevnte formel IV ifølge den i J.Amer. Chem. Soc. 9_3, 2897 (1971) beskrevne fremgangsmåte med en forbindelse med formel VIII Y and Z = hydrogen also in the way that one reacts a compound with the above-mentioned formula IV according to that in J.Amer. Chem. Soc. 9_3, 2897 (1971) described method with a compound of formula VIII

hvori R 2og X har betydningene som i formel I, reduserer de fremstilte Schiffske baser og deretter avspalter resten W og eventuelt resten R 2som ovenfor beskrevet, under dannelse av de frie karboksygrupper, eller at man reduserer en ifølge ovenfor angitte fremgangsmåter dannede forbindelse med formel I, i hvilken Y og Z tilsammen betyr hydrogen. Foretrukket er den katalyttiske hydrering. Reduksjonen av de Schiffske baser kan skje katalyttisk, elektrolyttisk eller med reduksjonsmidler som eksempelvis komplekse boranater, fortrinnsvis natriumborhydrid eller natriumcyanborhydrid. in which R 2 and X have the meanings as in formula I, the prepared Schiff's bases are reduced and then the residue W and possibly the residue R 2 is split off as described above, forming the free carboxy groups, or that a compound of formula I formed according to the methods specified above is reduced , in which Y and Z together mean hydrogen. Preferred is the catalytic hydrogenation. The reduction of the Schiff bases can take place catalytically, electrolytically or with reducing agents such as, for example, complex borates, preferably sodium borohydride or sodium cyanoborohydride.

Forbindelser med formel I med Y = hydroksy og Z = hydrogen kan eksempelvis også fåes ved reduksjon av en ifølge de ovenfor nevnte fremgangsmåter dannede forbindelser I med Y og Z = tilsammen oksygen. Denne reduksjon kan skje katalyttisk med hydrogen eller med et annet reduksjonsmiddel som eksempelvis komplekse boranater, fortrinnsvis natriumbor- Compounds of formula I with Y = hydroxy and Z = hydrogen can, for example, also be obtained by reduction of a compound I formed according to the above-mentioned methods with Y and Z = together oxygen. This reduction can take place catalytically with hydrogen or with another reducing agent such as, for example, complex boranates, preferably sodium boron

hydrid.hydride.

Gjenstand for foreliggende oppfinnelse er også forbindelser med formel III', Subject matter of the present invention are also compounds of formula III',

hvori C-atomene 1, 4 og (7+n) har de samme konfigurasjoner som i formel III, n betyr 1, 2 eller 3 og W har betydningen av W i formel III og betyr dessuten hydrogen. Disse forbindelser tjener ifølge oppfinnelsen som utgangsstoffer ved syntesen av forbindelsen med formel I og kan fremstilles ifølge oppfinnelsen etter følgende fremgangsmåter. Ved en syntesevariant utgår man fra en forbindelse med formel IX in which the C atoms 1, 4 and (7+n) have the same configurations as in formula III, n means 1, 2 or 3 and W has the meaning of W in formula III and also means hydrogen. According to the invention, these compounds serve as starting materials in the synthesis of the compound of formula I and can be prepared according to the invention according to the following methods. In a synthesis variant, one starts from a compound of formula IX

i hvilke H-atomene til C-atomene 4 og (7+n) er cis- eller trans-orientert til hverandre og n betyr tallet 1, 2 eller 3. in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-oriented to each other and n means the number 1, 2 or 3.

Forbindelser med formel IX med n=l er kjent- fra R.Griot, Heiv.Chim.Acta _42' 67 (1959), slike med n= 2 er kjent fra Compounds of formula IX with n=1 are known from R.Griot, Heiv.Chim.Acta _42' 67 (1959), those with n=2 are known from

C.M.Rice et al., J.Org. Chem. 21, 1687 (1955)C. M. Rice et al., J. Org. Chem. 21, 1687 (1955)

Disse forbindelser med formel IX acyleres på kjent måte, These compounds of formula IX are acylated in a known manner,

hvorved en alifatisk eller aromatisk acylrest, fortrinnsvis en acetyl- eller benzoylrest,blir bundet til nitrogenatomet, og de dannede N-acylerte forbindelser blir anodisk oksydert i en alifatisk alkohol, fortrinnsvis en alkanol med 1 til 4 C-atomer, spesielt metanol, i nærvær av et lettsalt, fortrinnsvis ved temperaturer i området fra 0° til +40°C under dannelse av en forbindelse med formel X, hvori n betyr 1, 2, 3 og whereby an aliphatic or aromatic acyl residue, preferably an acetyl or benzoyl residue, is attached to the nitrogen atom, and the formed N-acylated compounds are anodically oxidized in an aliphatic alcohol, preferably an alkanol with 1 to 4 C atoms, especially methanol, in the presence of a light salt, preferably at temperatures in the range from 0° to +40°C to form a compound of formula X, in which n means 1, 2, 3 and

R 3 betyr (C^-C^)-alkyl, (analogt: Liebigs Ann. Chem. 1978, R 3 means (C^-C^)-alkyl, (analogously: Liebigs Ann. Chem. 1978,

s. 1719). p. 1719).

Den dannede forbindelse med den generelle formelX blir omsatt med trimetylsilylcyanid ifølge Tetrahedron Letters 1981, s. 141 i et aprotisk organisk oppløsningsmiddel som eksempelvis i et hydrogenkarbon, halogenhydrokarbon, i eter eller i THF ved temperaturer i omradet fra -60°C til +20°C, fortrinnsvis -40°C til - 0°C i-nærvær av en Lewis-syre som eksempelvis ZnCl2, SnCl2, SnCl4, TiCl4, BF3~eterat, fortrinnsvis BF^-eterat, og den dannede forbindelse med formel XI, The formed compound with the general formula X is reacted with trimethylsilyl cyanide according to Tetrahedron Letters 1981, p. 141 in an aprotic organic solvent such as in a hydrocarbon, halohydrocarbon, in ether or in THF at temperatures in the range from -60°C to +20° C, preferably -40°C to -0°C in the presence of a Lewis acid such as for example ZnCl2, SnCl2, SnCl4, TiCl4, BF3-etherate, preferably BF^-etherate, and the formed compound of formula XI,

hvori H-atomene til C-atomene 4 og 7+n er orientert i cis- eller trans-stilling til hverandre, hvorved CN-gruppen befinner seg i cis-stilling til H-atomet til C-atom (7+n) og hvori n har den ovenfor nevnte betydning, etter rensning og fraskilling fra biprodukter ved hjelp av omkrystallisasjon eller kolonnekromatografi ved innvirkning av syrer eller baser på kjent måte forestrer den dannede forbindelse til en forbindelse med formel III med W = hydrogen og sistnevnte forestres eventuelt. Ved den sure hydrolyse av nitrilgruppen blir spesielt anvendt HC1 ellerHBr som syre. Forestringen blir gjennomført her som etterfølgende ifølge de i amino-syrekjemien vanlige fremgangsmåter. Forbindelser med den generelle formel III' kan også fremstilles idet man overfører en forbindelse med formel XII, in which the H atoms of the C atoms 4 and 7+n are oriented in the cis or trans position to each other, whereby the CN group is in the cis position to the H atom of the C atom (7+n) and in which n has the meaning mentioned above, after purification and separation from by-products by means of recrystallization or column chromatography under the action of acids or bases in a known manner, the formed compound esterifies to a compound of formula III with W = hydrogen and the latter is optionally esterified. In the acidic hydrolysis of the nitrile group, HC1 or HBr is particularly used as acid. The esterification is carried out here subsequently according to the methods common in amino acid chemistry. Compounds of the general formula III' can also be prepared by transferring a compound of the formula XII,

i hvilken H-atomet til C-atomene 4 og (7+n) er cis- eller trans-konfigurert og n har den ovenfor nevnte betydning, in which the H atom of the C atoms 4 and (7+n) is cis- or trans-configured and n has the above-mentioned meaning,

i en Beckmann-omleiring ved omsetning med en mineralsyre som eksempelvis svovelsyre eller polyfosforsyre eller med benzensulfonylklorid eller p-toluensulfonylklorid og en base som trietylamin i en forbindelse med formel XIII, i hvilken in a Beckmann rearrangement by reaction with a mineral acid such as sulfuric acid or polyphosphoric acid or with benzenesulfonyl chloride or p-toluenesulfonyl chloride and a base such as triethylamine in a compound of formula XIII, in which

n har den ovenfor nevnte betydning, og halogenerer denne til en forbindelse med formel XIV n has the meaning mentioned above, and halogenates this to a compound of formula XIV

i hvilken n har den ovenfor nevnte betydning og Hal betyr et halogenatom, fortrinnsvis klor eller brom. Som halo-generingsmiddel kommer eksempelvis i betraktning uorganiske syrehalogenider som PCI,-, S02C12, P0C13, S0C12, PBr^ eller halogener som brom. Med fordel anvendes PC1b C eller P0C1j-, in which n has the above-mentioned meaning and Hal means a halogen atom, preferably chlorine or bromine. Examples of halogenating agents include inorganic acid halides such as PCI, -, SO2C12, POC13, SOC12, PBr^ or halogens such as bromine. It is advantageous to use PC1b C or P0C1j-,

i kombinasjon med S02C12. Som mellomprodukt danner seg først et imidhalogenid som reagerer videre med de nevnte halogeneringsmidler og etterfølgende hydrolyse under basiske betingelser, fortrinnsvis med vandig alkalikarbonat, til en forbindelse med formel XIV. in combination with S02C12. As an intermediate, an imide halide is first formed which reacts further with the aforementioned halogenating agents and subsequent hydrolysis under basic conditions, preferably with aqueous alkali carbonate, to a compound of formula XIV.

Forbindelsene med formel XIV blir etterfølgende katalyttisk redusert i et polart protisk oppløsningsmiddel som eksempelvis en alkohol, fortrinnsvis etanol, eller i en karboksylsyre som eksempelvis eddiksyre under tilsetning av en syre-akseptor som eksempelvis natriumacetat eller trietylamin til en forbindelse med formel XV The compounds of formula XIV are subsequently catalytically reduced in a polar protic solvent such as an alcohol, preferably ethanol, or in a carboxylic acid such as acetic acid with the addition of an acid acceptor such as sodium acetate or triethylamine to a compound of formula XV

i hvilken n og Hal har de ovenfor nevnte betydninger. in which n and Hal have the above meanings.

Som katalysator kommer eksempelvis i betraktning Raney-nikkel eller palladium hhv. platina på animalsk kull. As a catalyst, for example, Raney nickel or palladium or platinum on animal charcoal.

Forbindelser med formel XV kan også bli fremstilt direkte ved halogenering av forbindelser med formel XIII ved anvendelse av mindre mengder av de ovenfor nevnte halogeneringsmidler. Compounds of formula XV can also be prepared directly by halogenation of compounds of formula XIII using smaller amounts of the above-mentioned halogenating agents.

Forbindelser med formel XV blir omsatt ifølge den kjente Favorskii-reaksjon i nærvær av en base til en forbindelse med formel III' med W'= hydrogen og denne blir eventuelt forestret. Den ovenfor nevnte Favorskii-reaksjon blir utført i et alkoholisk oppløsningsmiddel som metanol, etanol eller tert.-butanol eller i vann eller i blandinger av disse ved temperaturer i området fra 20°C til 140°C, fortrinnsvis mellom 60°C og 100°C. Som base blir hensikts-messig anvendt alkali- eller jordalkalihydroksyder som natrium-, kalium- eller bariumhydroksyd eller alkali-alkoholater som eksempelvis natriummetylat eller kalium-tert.-butanolat. Compounds of formula XV are reacted according to the known Favorskii reaction in the presence of a base to a compound of formula III' with W'= hydrogen and this is optionally esterified. The above-mentioned Favorskii reaction is carried out in an alcoholic solvent such as methanol, ethanol or tert-butanol or in water or in mixtures thereof at temperatures in the range from 20°C to 140°C, preferably between 60°C and 100° C. Alkali or alkaline earth hydroxides such as sodium, potassium or barium hydroxide or alkali alcoholates such as sodium methylate or potassium tert-butanolate are suitably used as the base.

Mellomproduktene med formel XIII kan også bli fremstilt ifølge Can.J.Chem. 38.' 557 (1960) av umettede nitriler med formelen XVI The intermediates of formula XIII can also be prepared according to Can.J.Chem. 38.' 557 (1960) of unsaturated nitriles of the formula XVI

i hvilken n har den ovenfor nevnte betydning, ved omsetning med maleonestere i en Michael-addisjon fulgt av reduserende cyklisering, forsåpning og dekarboks<y>lering. De som utgangsstoffer for fremstilling av forbindelser med formel I anvendte forbindelser med formel II med Y og Z = hydrogen, R 1 ' metyl og R<2>= metyl eller etyl og X = fenyl er kjente (europeisk patentansøkning nr. 37.231). Forbindelsene med formel II lar seg fremstille ved forskjellige fremgangsmåter. Ved en syntesevariant utgår man fra et keton av den ovenfor nevnte formel VII som omsettes ifølge kjente fremgangsmåter i en Mannich-reaksjon med en forbindelse med den ovenfor nevnte formel VI sammen med aminosyreesterer med formel XVII in which n has the above meaning, by reaction with maleone esters in a Michael addition followed by reductive cyclization, saponification and decarboxylation. The compounds of formula II with Y and Z = hydrogen, R 1 ' methyl and R<2> = methyl or ethyl and X = phenyl used as starting materials for the preparation of compounds of formula I are known (European patent application no. 37,231). The compounds of formula II can be prepared by various methods. In a synthesis variant, one starts from a ketone of the above-mentioned formula VII which is reacted according to known methods in a Mannich reaction with a compound of the above-mentioned formula VI together with amino acid esters of the formula XVII

hvori R og W har de ovenfor nevnte betydninger, til en forbindelse med formel XVIII, hvori R 2 , R 2, X og W har de ovenfor nevnte betydninger, med den begrensning at dersom W betyr en hydrogenolyttisk avspaltbar rest, spesielt benzyl, skal R 2 ikke ha betydningen av W. Dersom man avspalter resten W hydrogenolyttisk med hjelp av eksempelvis palladium, fåes forbindelser med formel II med Y og Z =■ hydrogen. Dersom resten W avspaltes med syrer som eksempelvis trifluoreddiksyre eller saltsyre i 'et inert organisk oppløsningsmiddel som eksempelvis dioksan, får man forbindelser med formel II med Y og Z tilsammen = oksygen. in which R and W have the above-mentioned meanings, to a compound of formula XVIII, in which R 2 , R 2 , X and W have the above-mentioned meanings, with the restriction that if W means a hydrogenolytically cleavable residue, especially benzyl, R 2 does not have the meaning of W. If the residue W is cleaved off hydrogenolytically with the help of, for example, palladium, compounds of formula II with Y and Z =■ hydrogen are obtained. If the residue W is split off with acids such as trifluoroacetic acid or hydrochloric acid in an inert organic solvent such as dioxane, compounds of formula II are obtained with Y and Z together = oxygen.

Forbindelser med formel XVIII er også tilgjengelig ved Michael-addisjon av en forbindelse med den ovenfor nevnte formel V med en forbindelse med den ovennevnte formel XVII ifølge kjente fremgangsmåter. Fortrinnsvis egner seg denne fremgangsmåte til fremstilling av slike forbindelser med Compounds of formula XVIII are also available by Michael addition of a compound of the above-mentioned formula V with a compound of the above-mentioned formula XVII according to known methods. Preferably, this method is suitable for the production of such compounds with

1 2 1 2

formel XVIII, i hvilken R betyr metyl, R betyr etyl ogformula XVIII, in which R is methyl, R is ethyl and

X betyr aryl.X means aryl.

Forbindelsene med formel XVIII fåes som diastereomerbland-inger. Foretrukne diastereomerer med formel XVIII er slike, i hvilke de med en stjerne markerte chiriale C-atomer har S-konfigurasjon. Disse kan ved omkrystallisering eller ved kromatografi, eksempelvis på kiselgel, bli- adskilt. Ved en etterfølgende avspaltning av resten W opprettholdes konfigurasjonene av de chiriale C-atomer. The compounds of formula XVIII are obtained as diastereomer mixtures. Preferred diastereomers of formula XVIII are those in which the chiral C atoms marked with an asterisk have the S configuration. These can be separated by recrystallization or by chromatography, for example on silica gel. In a subsequent cleavage of the residue W, the configurations of the chiral C atoms are maintained.

De som utgangsstoffer til fremstilling av forbindelsene med formel I anvendte forbindelser med den ovenfor nevnte formel IV får ved kjente fremgangsmåter av forbindelsene med den ovenfor nevnte formel III ved omsetning med en N-beskyttet 2-aminokarboksylsyre med formelen XIX, The compounds of the above-mentioned formula IV used as starting materials for the preparation of the compounds of formula I are obtained by known methods from the compounds of the above-mentioned formula III by reaction with an N-protected 2-aminocarboxylic acid of the formula XIX,

hvori V betyr en beskyttelsesgruppe og R har den ovenfor nevnte betydning. Som beskyttelsesgruppe V, som etter slutt-ført reaksjon igjen avspaltes, kommer eksempelvis på tale gruppene benzyloksykarbonyl eller tert.-butoksykarbonyl. wherein V means a protecting group and R has the above meaning. As protective group V, which is cleaved off again after the reaction has been completed, examples include the groups benzyloxycarbonyl or tert.-butoxycarbonyl.

Utgangsstoffene med formel XII får man på vanlig måte avThe starting materials of formula XII are obtained in the usual way

de kjente ketoner med formel XXthe known ketones of formula XX

hvorved H-atomene til brohodet-karbonatomene kan være i cis-eller trans-stilling og n har den ovenfor angitte betydning. Forbindelser med formel XX med n = 1 er kjent fra S.Dev, J.Indian Chem. Soc. 30, 815 (1953), slike med n =2 fra whereby the H atoms of the bridgehead carbon atoms can be in the cis or trans position and n has the above meaning. Compounds of formula XX with n = 1 are known from S.Dev, J.Indian Chem. Soc. 30, 815 (1953), those with n =2 from

A.Kandiah, J.Chem. Soc. 922 (1931) og slike med n - 3 er kjent fra A.M. Islam. R.A. Raphael, J.Chem. Soc. 315 (1955). A. Kandiah, J. Chem. Soc. 922 (1931) and such with n - 3 are known from A.M. Islam. RAW. Raphael, J. Chem. Soc. 315 (1955).

Omsetningen av en forbindelse med formel II med en forbindelse med formel III til fremstilling av en forbindelse med formel I skjer ifølge en av de i peptidkjemien kjente kondensasjonsreaksjoner, hvorved som kondensasjonsmiddel blir tilsatt eksempelvis dicykloheksylkarbodiimid og 1-hydroksy-benzotriazol. Ved den etterfølgende hydrogeno-lyttiske åvspaltning av resten W anvendes fortrinnsvis som katalysator palladium, mens ved den sure åvspaltning av resten W blir anvendt som syrer fortrinnsvis trifluoreddiksyre eller klorhydrogen. The reaction of a compound of formula II with a compound of formula III to produce a compound of formula I takes place according to one of the condensation reactions known in peptide chemistry, whereby for example dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole are added as condensation agents. In the subsequent hydrogenolytic cleavage of residue W, palladium is preferably used as catalyst, while in the acidic cleavage of residue W, trifluoroacetic acid or hydrogen chloride is preferably used as acids.

I de ovenfor beskrevne reaksjoner til fremstilling av forbindelsene med formelene III', IV og I opprettholdes alltid konfigurasjonene av mellomproduktene til brohode-atomene 4 og (7+n). Utgangsmaterialene med formlene IX, In the above-described reactions for preparing the compounds of the formulas III', IV and I, the configurations of the intermediates of the bridgehead atoms 4 and (7+n) are always maintained. The starting materials of the formulas IX,

XII og XIII dannes ved syntesen enten som rene diastereomerer eller som blandinger av de mulige diastereomerer, XII and XIII are formed during the synthesis either as pure diastereomers or as mixtures of the possible diastereomers,

som eventuelt kan separeres ved kromatografi eller krystallisasjon. which can optionally be separated by chromatography or crystallization.

De ifølge de ovenfor beskrevne fremgangsmåter dannede forbindelser med formel III' fåes som racemiske blandinger og kan anvendes som slike i de ovenfor beskrevne synteser. Men de kan også etter separering av racematene med vanlige metoder, eksempelvis over saltdannelse med optisk aktive baser eller syrer i de optiske antipoder anvendes som rene enantiomere. The compounds of formula III' formed according to the methods described above are obtained as racemic mixtures and can be used as such in the syntheses described above. But they can also be used as pure enantiomers after separation of the racemates by usual methods, for example via salt formation with optically active bases or acids in the optical antipodes.

Dersom forbindelsene med formel I fåes som racemater, kan også disse spaltes ifølge de vanlige metoder som eksempelvis over saltdannelse med optisk aktive baser eller syrer i deres enantiomerer. If the compounds of formula I are obtained as racemates, these can also be cleaved according to the usual methods such as, for example, via salt formation with optically active bases or acids in their enantiomers.

Forbindelsene med formel I ifølge oppfinnelsen foreliggerThe compounds of formula I according to the invention are present

som indre salter. Som amfotere forbindelser kan de danne salter med syrer eller baser. Disse salter blir fremstilt på vanlig måte med omsetning med en ekvivalent syre hhv. as internal salts. As amphoteric compounds, they can form salts with acids or bases. These salts are prepared in the usual way by reaction with an equivalent acid or

base.base.

Forbindelsene med formel I og deres salter har langtids-virkende, intensiv blodtrykksenkende virkning. De er sterke hemmere av angiotensin-converting-enzymer (ACE-hemmere). De kan anvendes til minskning av høyt blodtrykk av ulik The compounds of formula I and their salts have a long-acting, intensive blood pressure-lowering effect. They are strong inhibitors of angiotensin-converting enzymes (ACE inhibitors). They can be used to reduce high blood pressure in different ways

art. Også deres kombinasjon med andre blodtrykksenkende, karutvidende eller diuretiske virksomme forbindelser er mulig. Typiske representanter av denne virkningsklasse er beskrevet f.eks. i Erhardt-Ruschig, Arzneimittel, 2. opplag, Weinheim. 1972. Anvendelsen kan skje intravenøst, subkutant eller peroralt. species. Their combination with other blood pressure lowering, vasodilating or diuretic active compounds is also possible. Typical representatives of this effect class are described e.g. in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim. 1972. It can be administered intravenously, subcutaneously or orally.

Doseringen ved oral administrering ligger ved 1-100 mg, fortrinnsvis ved 1-40 mg for hver enkeltdose ved en voksen pasient av normal vekt, denne er ca. 0,013-1,3 mg/kg/dag, fortrinnsvis 0,013-0,5 3 mg/kg/dag. Dosene kan ved alvor-ligere tilfelle ogsåøkes, da toksiske egenskaper hittil ikke har blitt påvist. Også en minskning av dosen er mulig og fremforalt da på sin plass når samtidig diuretika administreres. The dosage for oral administration is 1-100 mg, preferably 1-40 mg for each individual dose in an adult patient of normal weight, this is approx. 0.013-1.3 mg/kg/day, preferably 0.013-0.5 3 mg/kg/day. In more serious cases, the doses can also be increased, as toxic properties have not been demonstrated so far. A reduction in the dose is also possible and especially appropriate when diuretics are administered at the same time.

Forbindelsene i henhold til oppfinnelsen kan administreres oralt eller parenteralt i tilsvarende farmasøytiske til-beredninger. For en oralt anvendelsesform blir de aktive forbindelser blandet med de derfor vanlige tilsetnings-stoffer som bærestoffer, stabilisatorer eller inerte fortynningsmidler, og bragt ved vanlige metoder i egnede administreringsformer, som tabletter, drageer, stikkapsler vandige, alkoholiske eller oljeinneholdende suspensjoner eller vandige, alkoholiske eller oljeinneholdende opp-løsninger. Som inerte bærestoffer kan anvendes f.eks. gummiarabikum, magnesiumkarbonat, kaliumfosfat, melkesukker, glukose eller stivelse, spesielt maisstivelse. Derved kan fremstillingen skje både som tørr- eller fuktgranulat. Som oljeinneholdende bærestoffer eller oppløsningsmiddel kommer i betraktning eksempelvis planteoljer og animalske oljer, som solsikkeolje eller levertran. The compounds according to the invention can be administered orally or parenterally in corresponding pharmaceutical preparations. For an oral application form, the active compounds are mixed with the usual additives such as carriers, stabilizers or inert diluents, and brought by usual methods into suitable administration forms, such as tablets, dragees, suppositories, aqueous, alcoholic or oil-containing suspensions or aqueous, alcoholic or solutions containing oil. As inert carriers can be used e.g. gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Thereby, the production can take place both as dry or wet granules. For example, plant oils and animal oils, such as sunflower oil or cod liver oil, are considered as oil-containing carriers or solvents.

For subkutan eller intravenøs applikasjon blir de aktive forbindelser eller deres fysiologiske godtagbare salter, For subcutaneous or intravenous application, the active compounds or their physiologically acceptable salts,

om ønsket med de derfor vanlige substanser som oppløsnings-formidlere, emulgatorer eller ytterligere hjelpestoffer bragt i oppløsning, suspensjoner eller emulsjoner. Som oppløsningsmiddel for de nye aktive forbindelser og de tilsvarende fysiologisk godtagbare salter kommer på tale f.eks.: vann, fysiologiske kokesaltoppløsninger eller alkoholer, f.eks. etanol, propandiol eller glycerin, foruten også sukkeroppløsninger som glukose- eller mannittoppløsninger, eller også en blanding av de ulike nevnte oppløsningsmidler. if desired with the therefore usual substances such as dissolution agents, emulsifiers or further auxiliaries brought into solution, suspensions or emulsions. Examples of solvents for the new active compounds and the corresponding physiologically acceptable salts are: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerin, besides also sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

Den ualminnelig sterke virkning av forbindelsene i henhold til formel I fremgår av de farmakologiske data i den etterfølgende tabell: The unusually strong effect of the compounds according to formula I is evident from the pharmacological data in the following table:

Intraduodenale (i.d.) hhv. intravenøse (i.v.) administrer-inger på narkotiserte rotter, 50% hemming av 310 ng angiotensin I utløst pressreaksjon 30 min. etter applikasjon ved dosen ...... = ED^Q Intraduodenal (i.d.) or intravenous (i.v.) administrations to anesthetized rats, 50% inhibition of 310 ng angiotensin I triggered pressor reaction 30 min. after application at the dose ...... = ED^Q

Symbolene n, X, Y, Z, R 1 og R 2 henfører seg til forbindelsene med formel I. The symbols n, X, Y, Z, R 1 and R 2 refer to the compounds of formula I.

De etterfølgende eksempler tjener.-som illustrering av oppfinnelsen uten at denne blir begrenset til de represen-terte nevnte forbindelser. The following examples serve as an illustration of the invention without this being limited to the compounds mentioned.

Eksempel 1 Example 1

(-)-( IS, 4S, 8S)- oktahydrocyklopenta[ c] pyrrol- 1- karboksylsyre(-)-( IS, 4S, 8S )- octahydrocyclopenta[ c ] pyrrole- 1- carboxylic acid

a) N- acetyl- cis- oktahydrocyklopenta[ c] pyrrola) N-acetyl-cis-octahydrocyclopenta[c]pyrrole

Til en oppløsning av 3 g oktahydrocyklopenta[c]pyrrol ogTo a solution of 3 g of octahydrocyclopenta[c]pyrrole and

4,2 ml trietylamin i 30 ml tørr tetrahydrofuran blir til-dryppet ved 0°C 2,1 ml acetylklorid. Etter 15 min. omrøring ved 0°C fortynnes med 150 ml vann, innstilles sur med IN saltsyre og ekstraheres med metylenklorid. Den organiske fase 4.2 ml of triethylamine in 30 ml of dry tetrahydrofuran are added dropwise at 0°C to 2.1 ml of acetyl chloride. After 15 min. stirring at 0°C, dilute with 150 ml of water, make acidic with 1N hydrochloric acid and extract with methylene chloride. The organic phase

blir tørket og inndampet. Råproduktet destilleres i høyvakuum. is dried and evaporated. The raw product is distilled in high vacuum.

Utbytte: 2,4 g; kokepunkt 71°C/o,2 mm.Yield: 2.4 g; boiling point 71°C/o.2 mm.

b) N- acetyl- 2- metoksy- cis- oktahydrocyklopenta[ c] pyrrol 2,4 g N-acetyl-cis-oktahydrocyklopenta[c]pyrrol oksyderes b) N-acetyl-2-methoxy-cis-octahydrocyclopenta[c]pyrrole 2.4 g N-acetyl-cis-octahydrocyclopenta[c]pyrrole is oxidized

anodisk i metanol under tilsetning av tetrametylammonium-tetrafluorborat ifølge angivelsene i Liebigs Ann.Chem. 1978, side 1719. Oppløsningsmidlet fjernes, residuumet opptas 1 eter, filtreres og filtratet inndampes. anodic in methanol with the addition of tetramethylammonium tetrafluoroborate according to the indications in Liebig's Ann.Chem. 1978, page 1719. The solvent is removed, the residue is taken up in ether, filtered and the filtrate is evaporated.

<1>H-NMR-data: 3,33 + 3,27 (2s,OCH3)<1>H-NMR data: 3.33 + 3.27 (2s,OCH3)

2,12 + 2,06 (2s,COCH3) 2.12 + 2.06 (2s,COCH3)

c) (-)-( lS, 4S, 8S)- N- acetyl- oktahydrocyklopenta[ e]- pyrrøl- 1-karboksylsyre c) (-)-( 1S, 4S, 8S)- N- acetyl- octahydrocyclopenta[ e]- pyrrole- 1-carboxylic acid

Til en oppløsning av 2,4 g N-acetyl-2-metoksy-cis-oktahydrocyklopenta[c]pyrrol i 15 ml metylenklorid tilsettes ved -40°C 1,31 g trimetylsilylcyanid i 3 ml metylenklorid. Deretter tildrypper man 1,88 g bortrifluorid-eterat, hvorved temperaturen stiger til -30°C. Etter 2 timer ved -20°C og 2 timer ved 0°C tilsetter man vann og ekstraherer tre ganger med metylenklorid. Den organiske fase vaskes med natrium-karbonatoppløsning og vann samt mettet kokesaltoppløsning, tørkes og inndampes. Man får 2,2 g av tittelforbindelsen som farveløs olje. To a solution of 2.4 g of N-acetyl-2-methoxy-cis-octahydrocyclopenta[c]pyrrole in 15 ml of methylene chloride, 1.31 g of trimethylsilyl cyanide in 3 ml of methylene chloride is added at -40°C. 1.88 g of boron trifluoride etherate is then added dropwise, whereby the temperature rises to -30°C. After 2 hours at -20°C and 2 hours at 0°C, water is added and extracted three times with methylene chloride. The organic phase is washed with sodium carbonate solution and water and saturated sodium chloride solution, dried and evaporated. 2.2 g of the title compound is obtained as a colorless oil.

d) (-)-( IS, 4S, 8S)- oktahydrocyklopenta[ c] pyrrol- 1- karboksylsyre 2,2 g (-)-(l,S,4S,8S)-N-acetyl-oktahydrocyklopenta[c]-l-karboksylsyre-nitril kokes i 2 timer i 8 ml konsentrert brom-hydrogen. Etter avdestillering av bromhydrogenet utrøres residuumet med litt aceton og avsuges. En vandig oppløsning av produktet innstilles med en svak basisk ioneveksler til en pH-verdi av 6,0. Etter filtrering inndampes oppløsningen og residuumet filtreres over kieselgel med en blanding av metylenklorid, metanol, iseddik og vann i forholdet 20:10:0,5: 0,5. Eluatet inndampes og residuumet utrøres med diiso- d) (-)-( IS, 4S, 8S)- octahydrocyclopenta[c] pyrrole-1- carboxylic acid 2.2 g (-)-(1,S,4S,8S)-N-acetyl-octahydrocyclopenta[c]- 1-carboxylic acid-nitrile is boiled for 2 hours in 8 ml of concentrated hydrogen bromine. After the hydrogen bromide has been distilled off, the residue is stirred with a little acetone and suctioned off. An aqueous solution of the product is adjusted with a weak basic ion exchanger to a pH value of 6.0. After filtration, the solution is evaporated and the residue is filtered over silica gel with a mixture of methylene chloride, methanol, glacial acetic acid and water in the ratio 20:10:0.5:0.5. The eluate is evaporated and the residue is stirred with diiso-

propyleter.propyl ether.

Utbytte: 1,6 g, Smeltepunkt 190 - 195°C.Yield: 1.6 g, Melting point 190 - 195°C.

Dersom man arbeider analogt fremgangsmåtene som beskrevet i eksempel 1 så får man de følgende i eksempel 2 og eksempel 3 nevnte forbindelser: Eksempel 2 If one works analogously to the methods described in example 1, the following compounds mentioned in example 2 and example 3 are obtained: Example 2

(-+)-( IS, 4S, 8S)- oktahydro- 2H- cykloheksa[ c]- pyrrol- l- karboksy1-syre (-+)-( IS, 4S, 8S)- octahydro- 2H- cyclohexa[ c]- pyrrole- l- carboxylic acid

a) N- acetyl- cis- oktahydro- 2H- isoindola) N-acetyl-cis-octahydro-2H-isoindole

b) N- acetyl- l- metoksy- cis- oktahydro- 2H- isolndol b) N-acetyl-1-methoxy-cis-octahydro-2H-isolndole

i in

c) N- acetyl- l- cyano- cis- oktahydro- 2H- isoindol d) (-)-( IS, 4S, 9S)- oktahydro- 2H- cykloheksa[ c]- pyrrol- 1-karboksylsyre c) N- acetyl- l- cyano- cis- octahydro- 2H- isoindole d) (-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa[c]- pyrrole- 1-carboxylic acid

Eksempel 3 Example 3

(-)- ( IS, 4S, lOS)- dekahydro- cyklohepta[ c] pyrrol- 1- karboksylsyre (-)-( IS, 4S, lOS)- decahydro- cyclohepta[ c] pyrrole- 1- carboxylic acid

a) N- acety1- cis- dekahydrocyklohepta[ c] pyrrola) N-acety1-cis-decahydrocyclohepta[c]pyrrole

b) - N- acetyl- l- metoksy- cis- dekahydrocyklohepta[ c] pyrrol c) N- acetyl- l- cyano- cis- dekahydrocyklohepta[ c] pyrrol d) (-)-( lS, 4S, lOS)- dekahydrocyklohepta[ c] pyrrol- l-karboksy lsy re b) - N- acetyl- l- methoxy- cis- decahydrocyclohepta[ c] pyrrole c) N- acetyl- l- cyano- cis- decahydrocyclohepta[ c] pyrrole d) (-)-( lS, 4S, lOS)- decahydrocyclohepta [c] pyrrole-l-carboxylic acid

Eksempel 4 Example 4

(-)- ( IS, 4S, 9S)- oktahydro- 2H- cykloheksa-'[ c] pyrrol- l- karboksylsyre (-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa-'[c] pyrrole-l- carboxylic acid

a) cis- oktahydro- 2H- isochinolin- 3- ona) cis-octahydro-2H-isoquinolin-3-one

Til en blanding av 33,6 g (0,22 mol)cis-heksahydro-indan-2-on-oksim og 300 ml 5 N natronlut tilsettes 41 g (0,24 mol) benzensulfonylklorid, hvorved temperaturen holdes under 50°C. En time etter fullført tilsetning ekstraheres med metylenklorid, tørkes og inndampes, residuumet sublimeres ved 100-110°C/ 20 mm, Utbytte: 20 g, Smeltepunkt 149 - 151°C. To a mixture of 33.6 g (0.22 mol) of cis-hexahydro-indan-2-one-oxime and 300 ml of 5 N sodium hydroxide solution, 41 g (0.24 mol) of benzenesulfonyl chloride are added, whereby the temperature is kept below 50°C. One hour after the addition is complete, extract with methylene chloride, dry and evaporate, the residue is sublimed at 100-110°C/ 20 mm, Yield: 20 g, Melting point 149 - 151°C.

b) 4, 4- diklor- cis- oktahydro- 2H- isochinolin- 3- on En oppløsning av 23 g cis-oktahydro-2H-isochinolin-3-on i b) 4, 4-dichloro-cis-octahydro-2H-isoquinolin-3-one A solution of 23 g of cis-octahydro-2H-isoquinolin-3-one in

350 ml vannfritt kloroform tilsettes med 28,8 g fosforpentaklorid ved værelsetemperatur. Hertil tilsettes 43,1 g sulforylklorid i 45 ml vannfritt kloroform dråpevis i løpet av 30 minutter ved 20 til 30°C og reaksjonsblandingen om-røres ved kokepunkttemperatur. Etter enstand over natten stilles blandingen nøytralt med ved 0°C kjølt vandig kalium-karbonatoppløsning. Den vandige fase ekstraheres 2 ganger med metylenklorid. De forenede organiske faser tørkes over natriumsulfat og inndampes. Residuumet omkrystalliseres av etanol under tilsetning av aktivkull. Man får 32 g blekgule krystaller. 350 ml of anhydrous chloroform are added with 28.8 g of phosphorus pentachloride at room temperature. To this, 43.1 g of sulphuryl chloride in 45 ml of anhydrous chloroform are added dropwise over the course of 30 minutes at 20 to 30°C and the reaction mixture is stirred at the boiling point temperature. After standing overnight, the mixture is neutralized with an aqueous potassium carbonate solution cooled at 0°C. The aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residue is recrystallized from ethanol with the addition of activated carbon. You get 32 g of pale yellow crystals.

c) 4- klor- cis- oktahydro- 2H- isochinolin- 3- onc) 4-chloro-cis-octahydro-2H-isoquinolin-3-one

15,9 g 4,4-klor-cis-oktahydro-2H-isokinolin-3-on hydreres15.9 g of 4,4-chloro-cis-octahydro-2H-isoquinolin-3-one is hydrogenated

i en liter etanol under tilsetning av 10 ml trietylamin og Raney-nikkel ved 20 til 25°C under normaltrykk inntil opp-tak av en mol-ekvivalent hydrogen. Etter filtrering inndampes oppløsningen, residuumet opptas i eddikester, opp-løsningen ekstraheres to ganger med vann og tørkes over natriumsulfat. Etter fjerning av oppløsningsmidlet utrøres produktet med diisopropyleter og avsuges. Det fåes farve-løse krystaller av tittelforbindelsen. in one liter of ethanol with the addition of 10 ml of triethylamine and Raney nickel at 20 to 25°C under normal pressure until uptake of one molar equivalent of hydrogen. After filtration, the solution is evaporated, the residue is taken up in vinegar, the solution is extracted twice with water and dried over sodium sulphate. After removal of the solvent, the product is stirred with diisopropyl ether and suctioned off. Colorless crystals of the title compound are obtained.

d) (-)-( IS, 4S, 9S)- oktahydro- 2H- cykloheksa[ c] pyrrol- l- karboksy lsyre d) (-)-( IS, 4S, 9S)- octahydro- 2H- cyclohexa[ c] pyrrole- l- carboxylic acid

3,75 g 4-klor-cis-oktahydro-2H-isochinolin-3-on tilsettes i en kokende oppløsning av 6,63 g bariumhydroksydoktahydrat i 120 ml vann. Etter 3,5 timers oppvarming under tilbake-løp tilsettes reaksjonsblandingen med 0,9 ml kons. svovelsyre, kokes en ytterligere time og las deretter stå over natten for koagulasjon. 3.75 g of 4-chloro-cis-octahydro-2H-isoquinolin-3-one is added to a boiling solution of 6.63 g of barium hydroxide octahydrate in 120 ml of water. After 3.5 hours of heating under reflux, the reaction mixture is added with 0.9 ml conc. sulfuric acid, boil for a further hour and then leave overnight for coagulation.

Det utfelte bunnfall avsuges og det ved en pH-verdi av 6,5 stilt filtrat inndampes til tørrhet. Residuumet ekstraheres med kokende etanol, inndampes og bringes til krystallisasjon. The precipitate that has formed is suctioned off and the filtrate adjusted to a pH value of 6.5 is evaporated to dryness. The residue is extracted with boiling ethanol, evaporated and brought to crystallization.

Utbytte: 3,1 g (identisk med den i eksempel 2d beskrevne forbindelse) . Yield: 3.1 g (identical to the compound described in example 2d).

Eksempel 5 Example 5

(-)-( IS, 4R, 9S)- oktahydro- 2H- cykloheksa[ c] pyrrol- l- karboksylsyre (-)-( IS, 4R, 9S )- octahydro- 2H- cyclohexa[ c ] pyrrole- l- carboxylic acid

a) trans- oktahydro- 2H- isochinolin- 3- ona) trans-octahydro-2H-isoquinolin-3-one

Analogt eksempel 4a) omsettes 14,1 g trans-heksahydroindan-2-on-oksim med 17,2 g benzensulfonylklorid til 8 g av tittelforbindelsen, Analogously to example 4a), 14.1 g of trans-hexahydroindan-2-one-oxime are reacted with 17.2 g of benzenesulfonyl chloride to give 8 g of the title compound,

Smeltepunkt: 165 - 167°C.Melting point: 165 - 167°C.

b) 4, 4- diklor- trans- oktahydro- 2H- isochinoliri- 3- on Analogt eksempel 4b) omdannes 7,1 g trans-oktahydro-2H-isochinolin-3-on ved omsetning med 8,9 g fosforpentaklorid og 14 ml sulfurylklorid til 11 g av tittelforbindelsen: b) 4, 4-dichloro-trans-octahydro-2H-isoquinoliri-3-one Analogously to example 4b), 7.1 g of trans-octahydro-2H-isoquinolin-3-one is converted by reaction with 8.9 g of phosphorus pentachloride and 14 ml sulfuryl chloride to 11 g of the title compound:

blekgule krystaller, smeltepunkt 133 - 137°C.pale yellow crystals, melting point 133 - 137°C.

c) 4- klor- trans- oktahydro- 2H- isokinolin- 3-^ onc) 4-chloro-trans-octahydro-2H-isoquinolin-3-^one

Analogt eksempel 4c) overføres 8 g 4,4-diklor-trans-oktahydro-2H-isochinolin-3-on ved hydrering i 5 g av tittelforbindelsen. Analogously to example 4c), 8 g of 4,4-dichloro-trans-octahydro-2H-isoquinolin-3-one are transferred by hydration in 5 g of the title compound.

d) (-)-( IS, 4R, 9S)- oktahydro- 2H- cykloheksa[ c] pyrrol- l- karboksy lsyre d) (-)-( IS, 4R, 9S )- octahydro- 2H- cyclohexa[ c] pyrrole- l- carboxylic acid

Analogt eksempel 4d) får man av 4,2 g 4-klor-transoktahydro-2H-isochinolin-3-on 3,4 g av tittelforbindelsen som farveløst, amorft pulver. Analogously to example 4d), 4.2 g of 4-chloro-transoctahydro-2H-isoquinolin-3-one gives 3.4 g of the title compound as colorless, amorphous powder.

De nedenfor angitte aminosyrer lar seg fremstille analogt fremgangsmåtene som beskrevet i eksempel 4a) til d). The amino acids listed below can be prepared analogously to the methods described in examples 4a) to d).

Eksempel 6 Example 6

(-)-( 1S, 4S, 8S)- oktahydro- cyklopenta[ c] pyrrol- 1- karboksylsyre Farveløse krystaller, smeltepunkt 190 - 195°C (identisk med den i eksempel ld) beskrevne forbindelse). Eksempel 7 (-)-( lS, 4R, 8S)- oktahydro- cyklopenta[ c] pyrrol- 1- karboksylsyre Farveløst, amorft pulver. Eksempel 8 (-) - ( IS , 4S , 10S) - dekahydro- cyklohepta [ c] pyrrol- l- karboksy- 1 syre Farveløst amorft pulver. Eksempel 9 (-)-( IS, 4R, 10S)- dekahydro- cyklohepta[ c] pyrrol- l- karboksylsyre Farveløst amorft pulver. (-)-( 1S, 4S, 8S)- octahydro- cyclopenta[ c] pyrrole- 1- carboxylic acid Colorless crystals, melting point 190 - 195°C (identical to the compound described in example 1d). Example 7 (-)-(1S, 4R, 8S)-octahydrocyclopenta[c]pyrrole-1-carboxylic acid Colorless, amorphous powder. Example 8 (-) - ( IS , 4S , 10S ) - decahydro- cyclohepta [ c ] pyrrole- l - carboxy- 1 acid Colorless amorphous powder. Example 9 (-)-(IS, 4R, 10S)-decahydro-cyclohepta[c]pyrrole-l-carboxylic acid Colorless amorphous powder.

Eksempel 10 Example 10

(-)-( IS, 4S, 8S)- oktahydrocyklopenta[ c3pyrrol- l- karboksylsyre-benzylester- hydroklorid (-)-( IS, 4S, 8S )- octahydrocyclopenta[ c3pyrrole- l- carboxylic acid benzyl ester hydrochloride

Til en ved -40°C fremstilt oppløsning av 0,7 ml tionylkloridTo a solution prepared at -40°C of 0.7 ml of thionyl chloride

i 7 ml benzylalkohol tilsettes ved -5°C 0,7 g (-)-(IS,4S,8S)-oktahydro-cyklopenta[c]pyrrol-l-karboksylsyre. Etter 20 timers reaksjonstid ved værelsetemperatur fjernes benzyl-alkoholen og residuumet utrøres med diisopropyleter. Man får 0,84 g av tittelforbindelsen som farveløse krystaller med smeltepunkt 120-122°C. 0.7 g of (-)-(IS,4S,8S)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid is added to 7 ml of benzyl alcohol at -5°C. After a reaction time of 20 hours at room temperature, the benzyl alcohol is removed and the residue is stirred with diisopropyl ether. 0.84 g of the title compound is obtained as colorless crystals with a melting point of 120-122°C.

Analogt fremgangsmåten som beskrevet i eksempel 10, lar Analogous to the method described in example 10, lar

seg fremstille de nedenfor angitte benzylester- derivater fra eksemplene 11 til 15: the following benzyl ester derivatives from examples 11 to 15 are prepared:

Eksempel 11Example 11

(-) -( 1S, 4S, 9S)- oktahydrocykloheksa[ c] pyrrol- 1- karboksylsyre-benzylester-hydroklorid (-) -( 1S, 4S, 9S )- octahydrocyclohexa[ c ] pyrrole- 1- carboxylic acid benzyl ester hydrochloride

Eksempel 12 (-)- ( IS, 4S, lOS)- dekahydrocyklohepta[ c]- 1- karboksylsyre-benzylester- hydroklorid Eksempel 13 (-)- CIS , 4R , 8S )- oktahydrocyklopenta [ c ] pyrrol - l - karboksylsyre -benzylester-hydroklorid Eksempel 14 (-)-( IS, 4R, 9S)- oktahydrocykloheksa[ c] pyrrol- 1- karboksylsyre-benzylester- hydroklorid Eksempel 15 (-) -( IS, 4R, lOS)- dekahydrocyklohepta[ c] pyrrol- l- karboksylsyre-benzylester- hydroklorid Example 12 (-)- (IS, 4S, 10S)-decahydrocyclohepta[c]-1-carboxylic acid benzyl ester hydrochloride Example 13 (-)-CIS, 4R, 8S)-octahydrocyclopenta[c] pyrrole-l-carboxylic acid benzyl ester -hydrochloride Example 14 (-)-( IS, 4R, 9S)- octahydrocyclohexa[ c] pyrrole- 1- carboxylic acid benzyl ester hydrochloride Example 15 (-) -( IS, 4R, 1OS)- decahydrocyclohepta[ c] pyrrole- l - carboxylic acid benzyl ester hydrochloride

Eksempel 16 Example 16

(-+)- ( IS, 4S, 8S)- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre-tert.- butylester- hydroklorid (-+)- (IS, 4S, 8S)- octahydrocyclopenta[c] pyrrole-l- carboxylic acid-tert-butyl ester- hydrochloride

Til en ved -10°C kjølt oppløsning av 10 g [-)-(IS,4S,8S)-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre i 100 ml dioksan settes til 10 ml kons. svovelsyre og 50 g isobutylen. Reaksjonsblandingen oppvarmes i autoklav*langsomt til 20 til 25°C og omrøres 20 timer ved denne temperatur. 10 ml of conc. sulfuric acid and 50 g of isobutylene. The reaction mixture is heated in an autoclave *slowly to 20 to 25°C and stirred for 20 hours at this temperature.

Man tilsetter blandingen i iskold 50%-ig vandig natrium-hydroksydoppløsning og ekstraherer med metylenklorid. De forenede organiske faser vaskes med vann, tørkes med natrium-sulf at og inndampes. Residuumet opptas i eter og stilles ved hjelp av eterisk klorhydrogen til en pH-verdi av 2,0 til 3,0. Man inndamper til tørrhet og utrører produktet med diisopropyl eter. Etter avsugning fåes 7,3 g av tittelforbindelsen. The mixture is added to ice-cold 50% aqueous sodium hydroxide solution and extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate and evaporated. The residue is taken up in ether and adjusted using ethereal hydrogen chloride to a pH value of 2.0 to 3.0. It is evaporated to dryness and the product is stirred with diisopropyl ether. After suction, 7.3 g of the title compound are obtained.

tert.- butylesterene i de etterfølgende eksempler 17 til 19 kan fremstilles analogt: Eksempel 17 (-)-( IS, 4S, 9S)- oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre-tert.- butylester- hydroklorid Eksempel 18 (-)-( IS, 4R, 8S)- oktahydrocyklopenta[ c3 pyrrol- l- karboksylsyre-tert.- butylester- hydroklorid Eksempel 19 (*)—( IS, 4R, 9S)- oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre-tert.-butylester-hydroklorid The tert-butyl esters in the subsequent examples 17 to 19 can be prepared analogously: Example 17 (-)-( IS, 4S, 9S)- octahydrocyclohexa[c] pyrrole-l-carboxylic acid tert-butyl ester hydrochloride Example 18 (-) -( IS, 4R, 8S)- octahydrocyclopenta[ c3 pyrrole- l- carboxylic acid-tert.- butyl ester- hydrochloride Example 19 (*)—( IS, 4R, 9S)- octahydrocyclohexa[ c] pyrrole- l- carboxylic acid-tert. -butyl ester hydrochloride

Eksempel 20 Example 20

N-( lS- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyrebenzylester ( =diastereomer. A 20) og N-( lS- karbetoksy- 3- fenyl- propyl)- S-alanyl- lR, 4R, 8R- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre-benzylester ( =diastereomer B 20) N-(1S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester (=diastereomer. A 20) and N-(1S-carbethoxy-3- phenyl- propyl)- S-alanyl- 1R, 4R, 8R- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester ( = diastereomer B 20)

0,82 g N-(lS-karbetoksy-3-fenyl-propyl)-S-alanin, 0,39 g 1-hydroksy-benztriazol, 0, 82 g {-)-(IS,4S,8S)-oktahydrocyklopenta [c]pyrrol-l-karboksylsyrebenzylester-hydroklorid, 0,5 ml N-etylmorfolin og 0,59 g dicykloheksylkarbodiimid tilsettes ved 20°C i 4 ml dimetylformamid. Man omrører 3 timer, fortynner med 50 ml eddikester, ekstraherer to ganger med vann, tørker over natriumsulfat og inndamper. 0.82 g N-(1S-carbethoxy-3-phenyl-propyl)-S-alanine, 0.39 g 1-hydroxy-benztriazole, 0.82 g {-)-(1S,4S,8S)-octahydrocyclopenta [ c]pyrrole-1-carboxylic acid benzyl ester hydrochloride, 0.5 ml of N-ethylmorpholine and 0.59 g of dicyclohexylcarbodiimide are added at 20°C in 4 ml of dimethylformamide. It is stirred for 3 hours, diluted with 50 ml of acetic acid, extracted twice with water, dried over sodium sulphate and evaporated.

Det fåes en blanding av de ovennevnte diastereomere A 20A mixture of the above-mentioned diastereomers A 20 is obtained

og B 20, hvilke separeres over kiselgel med en blanding av cykloheksan/eddikester (2:1). and B 20, which are separated over silica gel with a mixture of cyclohexane/acetic ester (2:1).

Forbindelsene i de etterfølgende eksempler 21 til 29 fremstilles på analog måte, som beskrevet i eksempel 20: Eksempel 21 N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzylester ( = diastereomer A 21) The compounds in the following examples 21 to 29 are prepared in an analogous way, as described in example 20: Example 21 N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c ] pyrrole-l-carboxylic acid benzyl ester ( = diastereomer A 21)

Eksempel 22 N-( l- S- karbetoksy- 3- fenyl- propyl)- S- aianyl- lS, 4S , 9S- oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- benzylester ( =diastereomer A 22) Example 22 N-(1-S-carbethoxy-3-phenyl-propyl)-S-aianyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester (=diastereomer A 22)

Eksempel 23 Example 23

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 9S- okta hydrocykloheksa[ c] pyrrol- l- karboksylsyre- benzylester N- (l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 9S- octahydrocyclohexa[c] pyrrole- l- carboxylic acid- benzyl ester

( =diastereomer A 23)( = diastereomer A 23)

Eksempel 24 Example 24

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 10S-dekahydrocyklohepta[ c] pyrrol- l- karboksylsyrebenzylester N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester

(=diastereomer A 24)(=diastereomer A 24)

Eksempel 25 Example 25

N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 10S-ocyklohepta[ c] pyrrol- l- karboksylsyrebenzylester N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,10S-ocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester

( =diastereomer A 25)( = diastereomer A 25)

Eksempel 2 6 Example 2 6

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c 3 pyrroi- 1- karboksylsyre- tert.- butylester N- (1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[ c 3 pyrroi- 1- carboxylic acid- tert.- butyl ester

( =diastereomer A- 26)( = diastereomer A- 26)

Eksempel 27 Example 27

N- ( 1- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 9S- oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- tert.- butylester N- ( 1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 9S- octahydrocyclohexa[c] pyrrole- 1- carboxylic acid- tert.- butyl ester

(- diastereomer A 27)(- diastereomer A 27)

Eksempel 28 Example 28

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- tert. butylester N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S, 4R, 8S- octahydrocyclopenta[c] pyrrole-1- carboxylic acid tert. butyl ester

( =diastereomer A 28)( = diastereomer A 28)

Eksempel 29 Example 29

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl)- 1S, 4R, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- tert.- butylester N- (1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl)- 1S, 4R, 9S-octahydrocyclohexa[c] pyrrole- l- carboxylic acid- tert-butyl ester

( =diastereomer A 29)( = diastereomer A 29)

Eksempel 30 Example 30

N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S- okta-hydropenta[ c] pyrrol- l- karboksylsyre- hydroklorid N-(l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octa-hydropenta[c] pyrrole- l- carboxylic acid hydrochloride

Metode A:Method A:

0,7 g diastereomer A 20 fra eksempel 20 hydreres i 25 ml etanol med 100 mg palladium-animalsk kull (10%) ved 20 til 25°C under atmosfærisk trykk. Etter fraskilling av katalysatoren tilsettes oppløsningen 0,5 n etanolisk klorhydrogen inntil sur reaksjon. Oppløsningen inndampes i vakuum og residuumet utrøres med diisopropyleter. Det fåes 400 mg av tittelforbindelsen som amorft pulver. 0.7 g of diastereomer A 20 from Example 20 is hydrated in 25 ml of ethanol with 100 mg of palladium-animal charcoal (10%) at 20 to 25°C under atmospheric pressure. After separation of the catalyst, 0.5 n ethanolic hydrogen chloride is added to the solution until an acidic reaction. The solution is evaporated in vacuo and the residue is stirred with diisopropyl ether. 400 mg of the title compound are obtained as amorphous powder.

Metode B: Method B:

En oppløsning av 0,8 diastereomer A 26 fra eksempel 26 iA solution of 0.8 diastereomer A 26 from Example 26 i

5 ml metylenklorid mettes med tørr klorhydrogengass og las stå 16 timer ved 20 til 2 5°C. Oppløsningen inndampes i vakuum, residuumet utrøres med diisopropyleter og avsuges. 5 ml of methylene chloride is saturated with dry chlorine hydrogen gas and left to stand for 16 hours at 20 to 25°C. The solution is evaporated in vacuo, the residue is stirred with diisopropyl ether and filtered off with suction.

Utbytte: 550 mg.Yield: 550 mg.

Eksempel 31 Example 31

N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lR, 4R, 8R- oktahydrocyklopenta[ c] pyrrol- 1- karboksylsyre- hydroklorid N-(1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1R, 4R, 8R- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid hydrochloride

Denne forbindelse fåes av diastereomeren B 20 fra eksempel 20 på en analog måte til metoden A fra eksempel 30. This compound is obtained from diastereomer B 20 from example 20 in an analogous way to method A from example 30.

Farveløse krystaller med smeltepunkt 185 - 188°C. Colorless crystals with melting point 185 - 188°C.

Eksempel 32 Example 32

N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- hydroklorid N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid hydrochloride

Denne forbindelse fåes av diastereomerene A 21 fra eksempel 21 ved en metode som er analog til metoden A i eksempel 30. This compound is obtained from the diastereomers A 21 from example 21 by a method analogous to method A in example 30.

Eksempel 33 Example 33

N- ( l- S- karbetoksy- 3- fenyl- propyl- S- alanyl- lS, 4S, 9S)- oktahydrocykloheksa [ c] pyrrol- 1- karboksylsyré- hydroklorid N-(1-S-carbethoxy-3-phenyl-propyl-S-alanyl-1S,4S,9S)-octahydrocyclohexa[c]pyrrole-1-carboxylic acid hydrochloride

Denne forbindelse fåes av diastereomerene A 22 fra eksempel 22 ved en metode som er analog til metode A i eksempel 30. This compound is obtained from the diastereomers A 22 from example 22 by a method analogous to method A in example 30.

Eksempel 34 Example 34

N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 9S- okta-hydrdheksa[ c] pyrrol- l- karboksylsyre- hydroklorid N-(l- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 9S- octa-hydrhexa[c] pyrrole- l- carboxylic acid hydrochloride

Denne forbindelse fremstilles av diastereomerene A 23 fra eksempel 23 analogt til metodn A, som er beskrevet i eksempel 30. This compound is prepared from the diastereomers A 23 from example 23 analogously to method A, which is described in example 30.

Forbindelsene fra eksemplene 32 til 34 kan også fremstilles av diastereomerene A 26 til A 28 i henhold til den i eksempel 30 beskrevne metode B. The compounds from examples 32 to 34 can also be prepared from the diastereomers A 26 to A 28 according to the method B described in example 30.

Eksempel 35 Example 35

N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 10S-dekahydrocyklohepta[ c] pyrrol- l- karboksyIsyre- hydroklorid N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid hydrochloride

Denne forbindelse blir fremstilt av diastereomeren A 24 fra eksempel 24 analogt den i eksempel 30 beskrevne metode A. This compound is prepared from the diastereomer A 24 from example 24 analogously to the method A described in example 30.

Eksempel 36 Example 36

N-( 1- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 10S- dekahydrocyklohepta[ c] pyrrol- l- karboksylsyre- hydroklorid N-( 1- S- carbethoxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 10S- decahydrocyclohepta[c] pyrrole- 1- carboxylic acid hydrochloride

Denne forbindelse blir fremstilt av diastereomeren A 25 fra eksempel 25 analogt den i eksempel 30 beskrevne metode A. This compound is prepared from the diastereomer A 25 from example 25 analogously to the method A described in example 30.

Eksempel 37 Example 37

N-( l- S- karboksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

En oppløsning av 1 g N-(l-S-karbetoksy-3-fenyl-propyl)-S-alanyl-lS,4S,8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre-hydroklorid i 10 ml vann blir tilsatt to ekvivalente kaliumhydroksyd og et 10%-ig overskudd av 4n-kaliumhydroksyd-oppløsning. Etter 8 timers omrøring ved 20 til 25°C innstilles reaksjonsoppløsningen med 2n-saltsyre til en pH-verdi av 4,0 og inndampes i vakuum. Residuumet opptas i eddikester, avfiltreres fra utskilt salt. Eddikesteropp-løsningen blir inndampet, residuumet blir utrørt med diisopropyleter og avsuget. A solution of 1 g of N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid hydrochloride in 10 ml of water is added to two equivalents of potassium hydroxide and a 10% excess of 4n-potassium hydroxide solution. After stirring for 8 hours at 20 to 25°C, the reaction solution is adjusted with 2n-hydrochloric acid to a pH value of 4.0 and evaporated in vacuo. The residue is taken up in vinegar, filtered off from the secreted salt. The acetic ester solution is evaporated, the residue is stirred with diisopropyl ether and suctioned off.

Utbytte: 0,6 gYield: 0.6 g

Eksempel 38 Example 38

N-( l- S- karboksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

Denne forbindelse blir fremstilt av forbindelsen fra eksempel 32 analogt den i eksempel 37 beskrevne fremgangsmåte. This compound is prepared from the compound from example 32 analogously to the method described in example 37.

Eksempel 39 Example 39

N-( l- S- karboksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 9S- okta-. hydrocykloheksa[ c] pyrrol- l- karboksylsyre N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S, 4S, 9S- octa-. hydrocyclohexa[c]pyrrole-l-carboxylic acid

Denne forbindelse blir fremstilt av forbindelsen fra eksempel 33 analogt den i eksempel 37 beskrevne fremgangsmåte. This compound is prepared from the compound from example 33 analogously to the method described in example 37.

Eksempel 40 ( cKÅaJ^ din,) N- ( 1- S- karboksy- 3- f enyl- propyl) - S- alanyl) - IS , 4R, 9S- alcyklo-heksa[ c] pyrrol- l- karboksylsyre Example 40 ( cKÅaJ^ din,) N-( 1- S- carboxy- 3- phenyl- propyl)- S- alanyl)- IS , 4R, 9S- alcyclo-hexa[c] pyrrole-l- carboxylic acid

Denne forbindelse blir fremstilt av forbindelsen fra eksempel 34 analogt den i eksempel 37 beskrevne fremgangsmåte . This compound is prepared from the compound from example 34 analogously to the method described in example 37.

Eksempel 41 Example 41

N-( l- S- karboksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, lOS- deka hydrocyklohepta[ c] pyrrol- l- karboksylsyre N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4S, lOS- deca hydrocyclohepta[c] pyrrole- l- carboxylic acid

Denne forbindelse blir fremstilt av forbindelsen fra eksempel 35 analogt den i eksempel 37 beskrevne fremgangsmåte. This compound is prepared from the compound from example 35 analogously to the method described in example 37.

Eksempel 42 Example 42

N-( l- S- karboksy- 3- fenyl- propyl)- S- alanyl- lS, 4R, 10S- dekahydrocyklohepta[ c] pyrrol- l- karboksylsyre N-(l- S- carboxy- 3- phenyl- propyl)- S- alanyl- 1S, 4R, 10S- decahydrocyclohepta[c] pyrrole- l- carboxylic acid

Denne forbindelse blir fremstilt av forbindelsen fra eksempel 36 analogt den i eksempel 37 beskrevne fremgangsmåte.. This compound is prepared from the compound from example 36 analogously to the method described in example 37.

Eksempel 4 3 N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyrebenzylester 2,5 g N-(l-S-karbetoksy-3-fenyl-3-okso-propyl)-S-alanin tilsettes sammen med 1,2 g 1-hydroksybenztriazol, 2,5 g (-)-IS,4S,8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre-benzylester-hydroklorid, 1,25 ml N-etylmorfolin og 2 g dicykloheksylkarbodiimid i 20 ml dimetylformamid. Man omrører 1 time ved 0°C og deretter 12 timer ved 20 til 25°C. Example 4 3 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester 2.5 g N-(1-S -carbethoxy-3-phenyl-3-oxo-propyl)-S-alanine is added together with 1.2 g of 1-hydroxybenztriazole, 2.5 g of (-)-IS,4S,8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid benzyl ester hydrochloride, 1.25 ml of N-ethylmorpholine and 2 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide. The mixture is stirred for 1 hour at 0°C and then for 12 hours at 20 to 25°C.

Reaksjonsoppløsningen fortynnes med 25 ml eddikester, utskilt urinstoff avsuges. Etter inndampning i vakuum opptas det dannede residuum i eter og den eteriske oppløsning vaskes med mettet vandig natriumbikarbonatoppløsning og med vann, tørkes og inndampes. Man får 3 g av tittelforbindelsen som diastereomerblanding. Diastereomerblandingen kan separeres over kiselgel med cykloheksan-eddikester som elueringsmiddel i de optisk rene forbindelser. The reaction solution is diluted with 25 ml of acetic acid, secreted urea is suctioned off. After evaporation in vacuo, the residue formed is taken up in ether and the ethereal solution is washed with saturated aqueous sodium bicarbonate solution and with water, dried and evaporated. 3 g of the title compound are obtained as a mixture of diastereomers. The diastereomer mixture can be separated over silica gel with cyclohexane-acetic acid ester as eluent in the optically pure compounds.

Eksempler 44 til 50Examples 44 to 50

De nedenfor angitte forbindelser i eksemplene 44 til 50 lar seg fremstille ved en fremgangsmåte som er analog til den som er angitt i eksempel 4 3 under anvendelse av de tilsvarende bicykliske karboksylsyreester-forbindelser. The compounds indicated below in examples 44 to 50 can be prepared by a method which is analogous to that indicated in example 4 3 using the corresponding bicyclic carboxylic acid ester compounds.

Eksempel 44 Example 44

N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4R, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzylester N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester

Eksempel 45 Example 45

N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S , 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- benzylester N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester

Eksempel 46 N- ( l- S- karbetoksy- 3- fenyl- 3- okso- propyl) - S- alanyl- lS , 4R, 9S- g^U^^ cykloheksa[ c] pyrrol- 1- karboksylsyre- benzylester Eksempel 4 7 N- ( l- S- karbetoksy- 3- f enyl- 3- okso- propyl) - S- alanyl- lS , 4S , 8S- ^txJ^oL-o cyklopenta[ c] pyrrol- l- karboksylsyre- tert.- butylester Example 46 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S, 4R, 9S-g^U^^ cyclohexa[c] pyrrole-1-carboxylic acid benzyl ester Example 4 7 N- ( l- S- carbethoxy- 3- phenyl- 3- oxo- propyl) - S- alanyl- lS , 4S , 8S- ^txJ^oL-o cyclopenta[ c] pyrrole- l- carboxylic acid- tert. - butyl ester

Eksempel 48 Example 48

N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4R, 8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre-tert.-butylester N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4R,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester

Eksempel 49 N- ( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- tert.- butylester Eksempel 50 N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4R, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- tert.- butylester Example 49 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid-tert-butyl ester Example 50 N- (l- S- carbethoxy- 3- phenyl- 3- oxo- propyl)- S- alanyl- 1S, 4R, 9S-octahydrocyclohexa[c] pyrrole- l- carboxylic acid- tert-butyl ester

Eksempel 51 Example 51

N- ( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S,8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid

0,9 g av forbindelsen fra eksempel 4 7 omrøres i 6 ml trifluoreddiksyre i 2 timer ved 20°C. Man inndamper i vakuum, utrører med diisopropyleter og avsuger. 0.9 g of the compound from example 4 7 is stirred in 6 ml of trifluoroacetic acid for 2 hours at 20°C. Evaporate in a vacuum, stir with diisopropyl ether and filter with suction.

Utbytte: 0,4 gYield: 0.4 g

Analogt til den i eksempel 51 beskrevne fremgangsmåte kan fremstilles forbindelsene i de nedenfor angitte eksempler 52 til 54: Eksempel 52 N- ( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4R, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre Eksempel 53 N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre Analogous to the method described in example 51, the compounds in examples 52 to 54 can be prepared below: Example 52 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S, 4R, 8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid Example 53 N-(l-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-lS,4S,9S-octahydrocyclohexa[c]pyrrole-l - carboxylic acid

Eksempel 54 Example 54

N-( 1- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alany1- 1S, 4R, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alany1-1S,4R,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid

Eksempel 55 Example 55

N- ( l- S- karboksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-( l- S- carboxy- 3- phenyl- 3- oxo- propyl)- S- alanyl- 1S, 4S, 8S-octahydrocyclopenta[c] pyrrole- l- carboxylic acid

For fremstilling av denne forbindelse omsettes 0,5 g N-(l-S-karbetoksy-3-fenyl-3-okso-propyl)-S-alanyl-lS,4S,8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre analogt den i eksempel 37 beskrevne fremgangsmåte med kaliumhydroksyd: To prepare this compound, 0.5 g of N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is reacted analogously to that in example 37 described method with potassium hydroxide:

Eksempel 56 Example 56

N-( l- S- karbetoksy- 3- fenyl- 3- hydroksy- propyl)- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l- S- carbethoxy- 3- phenyl- 3- hydroxy- propyl)- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- l- carboxylic acid

lg N-(l-S-karbetoksy-3-fenyl-3-okso-propyl)-S-alanyl-lS,4S, 8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre oppløses i 50 ml vannfritt etanol og hydreres med 50 mg palladium/ kull ved 20 til 25°C under atmosfærisk trykk med 1 mol ekvivalent hydrogen. Etter avfiltrering av katalysatoren inndampes oppløsningen, Residuumet utrøres med diisoprppyl-eter og avsuges. 1 g of N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid is dissolved in 50 ml of anhydrous ethanol and hydrated with 50 mg of palladium / coal at 20 to 25°C under atmospheric pressure with 1 mole equivalent of hydrogen. After filtering off the catalyst, the solution is evaporated. The residue is stirred with diisopropyl ether and suctioned off.

Utbytte: 0,7 gYield: 0.7 g

Eksempel 57 Example 57

S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzy le ster S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester

a) N- tert.- butoksykarbonyl- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzylester a) N- tert.- butoxycarbonyl- S- alanyl- 1S, 4S, 8S- octahydrocyclopenta[c] pyrrole- 1- carboxylic acid benzyl ester

Til en oppløsning av 19 g BOC-ala-OH i 100 ml DMF tilsettesTo a solution of 19 g of BOC-ala-OH in 100 ml of DMF is added

13 ml N-etylmorfolin, 13,5 g 1-hydroksy-benzotriazol og 29,6 g IS,4S,8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre-benzylester-hydroklorid. Blandingen kjøles i isbad og tilsettes 21 g dicykloheksylkarbodiimid. Man omrører 15 timer ved 20 til 25°C. Det utfelte urinstoff avsuges, filtratet inndampes i vakuum og opptas i eddikester. Den organiske fase ekstraheres 3 ganger med vandig kaliumhydrogensulfat-oppløsning, 3 ganger med vandig kaliumhydrogenkarbonat-oppløsning og vandig natriumkloridoppløsning, tørkes og inndampes. Residuumet kromatograferes på kiselgel med eddikester/cykloheksan (1:3). Den første fraksjon inneholder det ønskede produkt. 13 ml of N-ethylmorpholine, 13.5 g of 1-hydroxy-benzotriazole and 29.6 g of 1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester hydrochloride. The mixture is cooled in an ice bath and 21 g of dicyclohexylcarbodiimide are added. The mixture is stirred for 15 hours at 20 to 25°C. The precipitated urea is suctioned off, the filtrate is evaporated in a vacuum and taken up in vinegar. The organic phase is extracted 3 times with aqueous potassium hydrogen sulfate solution, 3 times with aqueous potassium hydrogen carbonate solution and aqueous sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate/cyclohexane (1:3). The first fraction contains the desired product.

Utbytte: 21 gYield: 21 g

b) S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l-karboksy lsy r e- benzy les ter b) S-alanyl-1S, 4S, 8S- octahydrocyclopenta[c] pyrrole-1-carboxylic acid r e- benzyl ester

20,5 g N-tert.-butoksykarbonyl-5-alanyl-lS,4S,8S-oktahydrocyklopenta[c]pyrrol-l-karboksylsyre-benzylester ble oppløst i 50 ml trifluoreddiksyre. Etter en reaksjonstid på 10 min. 20.5 g of N-tert.-butoxycarbonyl-5-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester were dissolved in 50 ml of trifluoroacetic acid. After a reaction time of 10 min.

inndamper man oppløsningen i vakuum, utrører residuumet flere ganger med diisopropyleter og tørker dette i vakuum. Utbytte: 12,5 g. the solution is evaporated in a vacuum, the residue is stirred several times with diisopropyl ether and this is dried in a vacuum. Yield: 12.5 g.

Eksemplene 58 til 62Examples 58 to 62

Disse forbindelser fremstilles analogt den i eksempel 57 under a) og b) beskrevne fremgangsmåter: Eksempel 58 S- alanyl- lS, 4R, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzylester Eksempel 59 S- alanyl- lS, 4S, 9S- oktahydrocykloheksa[ c] pyrrol- l- karboksy1-syre- benzylester These compounds are prepared analogously to the methods described in example 57 under a) and b): Example 58 S-alanyl-1S, 4R, 8S- octahydrocyclopenta[c] pyrrole-1-carboxylic acid benzyl ester Example 59 S-alanyl-1S, 4S, 9S- octahydrocyclohexa[c] pyrrole-1-carboxylic acid benzyl ester

Eksempel 60 Example 60

S- alanyl- lS, 4R, 9S- oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- benzylester S- alanyl- 1S, 4R, 9S- octahydrocyclohexa[c] pyrrole- 1- carboxylic acid benzyl ester

Eksempel 61 S- alanyl- lS, 4S, lOS- dekahydrocyklohepta[ c] pyrrol- l- karboksy 1 sy re- benzy lester Eksempel 62 S- alanyl- lS, 4R, lOS- dekahydrocyklohepta[ c] pyrrol- l- karboksylsyre- benzylester Eksempel 6 3 N- ( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre a) N-( l- S- karbetoksy- 3- fenyl- propyl)- S- alanyl- lS, 4S, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre- benzylester 10 ml mol S-alanyl-lS,4S,8S-oktahydrocyklopenta[c]pyrrol-1-karboksylsyre-benzylester oppløses i 30 ml vannfritt etanol. Man stiller oppløsningen ved hjelp av etanolisk kaliumhydroksyd til en pH-verdi av 7,0 og tilsetter 1 g pulverisert molekylsikt (4Å) og deretter 10 mmol 2-keto-4-fenyl-smørsyreetylester. Det tildryppes langsomt en oppløsning av 1 g natriumcyanborhydrid i 10 ml vannfritt etanol. Example 61 S- alanyl- lS, 4S, lOS- decahydrocyclohepta[ c] pyrrole- l- carboxylic acid benzyl ester Example 62 S- alanyl- lS, 4R, lOS- decahydrocyclohepta[ c] pyrrole- l- carboxylic acid benzyl ester Example 6 3 N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid a) N-(1-S-carbethoxy-3 - phenyl- propyl)- S- alanyl- 1S, 4S, 8S-octahydrocyclopenta[c]pyrrole-l- carboxylic acid- benzyl ester 10 ml mol S-alanyl-1S,4S,8S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid- benzyl ester is dissolved in 30 ml of anhydrous ethanol. The solution is adjusted to a pH value of 7.0 using ethanolic potassium hydroxide and 1 g of powdered molecular sieve (4Å) and then 10 mmol of 2-keto-4-phenyl-butyric acid ethyl ester are added. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise.

Etter en reaksjonstid på 20 timer ved 20 til 25°C filtreres reaksjonsoppløsningen og oppløsningsmidlet avdestilleres. Residuumet opptas i eddikester/vann. Etter inndampning av eddikesterfasen kromatograferes residuumet på kiselgel med eddikester/cykloheksan (1:4). H-NMR-data stemmer overens med dataene av forbindelsene fra eksempel 20. b) Den ovenfor fremstilte forbindelse omsettes videre som som beskrevet i eksempel 30, metode A, til ønsket forbindelse. Eksempel 64 N-( l- S- karbetoksy- 3- fenyl- 3- okso- propyl)- S- alanyl- lS, 4S, 9S-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre- benzylester 10 mmol S-alanyl-lS,4S,9S-oktahydrocyklopenta[c]pyrrol-1-karboksylsyre-benzylester oppløses sammen med 10 mmol 3-benzoyl-akrylsyreetylester og 10 mmol trietylamin i 100 ml vannfri etanol og blandingen omrøres 2 4 timer ved 20 til 25°C. Man nøytraliserer med 1 n saltsyre, inndamper til tørrhet og opptar residuumet med eddikester/vann. Eddik-esterf asen tørkes, inndampes og kromatograferes på kiselgel. Eksempel 65 N-( l- S- karbetoksy- 3- okso- 3- fenyl- propyl)- IS, 4S, 10S- dekahydrocyklohepta[ c] pyrrol- l- karboksylsyre- benzylester 10 mmol acetofenon, 10 mmol glyoksylsyreetylester og 10 mmol S-alanyl-lS,4S,10S-dekahydrocyklohepta[c]pyrrol-l-karboksylsyre-benzylester oppvarmes i 3o ml iseddik i 36 timer ved 45°C. Etter inndampning i vakuum innstilles alkalisk med vandig nat-riumbikarbonatoppløsning og ekstraheres med eddikester. Eddik-esterf asen inndampes og kromatograferes på kiselgel. After a reaction time of 20 hours at 20 to 25°C, the reaction solution is filtered and the solvent is distilled off. The residue is taken up in vinegar/water. After evaporation of the acetate phase, the residue is chromatographed on silica gel with acetate/cyclohexane (1:4). H-NMR data agree with the data of the compounds from example 20. b) The compound prepared above is further reacted as described in example 30, method A, to the desired compound. Example 64 N-(1-S-carbethoxy-3-phenyl-3-oxo-propyl)-S-alanyl-1S,4S,9S-octahydrocyclohexa[c]pyrrole-1-carboxylic acid benzyl ester 10 mmol S-alanyl-1S ,4S,9S-octahydrocyclopenta[c]pyrrole-1-carboxylic acid benzyl ester is dissolved together with 10 mmol of 3-benzoyl acrylic acid ethyl ester and 10 mmol of triethylamine in 100 ml of anhydrous ethanol and the mixture is stirred for 24 hours at 20 to 25°C. Neutralize with 1 N hydrochloric acid, evaporate to dryness and take up the residue with vinegar/water. The acetic ester phase is dried, evaporated and chromatographed on silica gel. Example 65 N-(1-S-carbethoxy-3-oxo-3-phenyl-propyl)-IS,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester 10 mmol acetophenone, 10 mmol glyoxylic acid ethyl ester and 10 mmol S -alanyl-1S,4S,10S-decahydrocyclohepta[c]pyrrole-1-carboxylic acid benzyl ester is heated in 30 ml of glacial acetic acid for 36 hours at 45°C. After evaporation in vacuo, make alkaline with aqueous sodium bicarbonate solution and extract with acetic acid. The acetic ester phase is evaporated and chromatographed on silica gel.

Eksempel 66 Example 66

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- etyl- S- tyrosyl- lS, 4S, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

a) N-( 1- R, S- karbetoksy- 3- fenyl- propyl)- O- etyl- S- tyrosyl-, benzylbenzylester a) N-(1- R, S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosyl-, benzyl benzyl ester

Man omsetter 24 g benzoylakrylsyre-etylester i 100 ml etanol med 30 g O-etyl-S-tyrosin-benzylester i nærvær av 0,5 ml trietylamin og får etter inndampning av oppløsningen og utrøring av residuumet med dietylester/petroleter (1:1) og tørking i vakuum 42 g av tittelforbindelsen. One reacts 24 g of benzoyl acrylic acid ethyl ester in 100 ml of ethanol with 30 g of O-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml of triethylamine and after evaporating the solution and stirring the residue with diethyl ester/petroleum ether (1:1) and drying in vacuo 42 g of the title compound.

b) N-( 1- R, S- karbetoksy- 3- fenyl- propyl)- o- etyl- S- tyrosinb) N-(1-R,S-carbethoxy-3-phenyl-propyl)-o-ethyl-S-tyrosine

40 g av den ifølge eksempel 66a fremstilte forbindelse hydreres i 800 ml iseddik med 4 g Pd/C (10%) ved 100 bar og værelsetemperatur. Etter kromatografi på kiselgel med eddikester/cykloheksan (1:3) som løpemiddel og tørking av inndampningsresiduumet får man 25 g tynnskiktkromatografisk nesten enhetlig tittelforbindelse, smeltepunkt 205-213°C. 40 g of the compound prepared according to example 66a is hydrated in 800 ml of glacial acetic acid with 4 g of Pd/C (10%) at 100 bar and room temperature. After chromatography on silica gel with ethyl acetate/cyclohexane (1:3) as eluent and drying of the evaporation residue, 25 g of the thin-layer chromatographically almost uniform title compound are obtained, melting point 205-213°C.

c) N-( l- S- karbetoksy- 3- fenylpropyl)- 0- etyl- S- tyrosyl- lS, 4S, 8S- oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre c) N-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-1S,4S,8S- octahydrocyclopenta[c]pyrrole-1-carboxylic acid

Man omsetter analogt den i eksempel 20 beskrevne fremgangsmåte 1,5 g av den i eksempel 10 beskrevne benzylester med 2,5 N-(1-R,S-karbetoksy-3-fenyl-propyl)-0-etyl-S-tyrosin, Analogous to the method described in example 20, 1.5 g of the benzyl ester described in example 10 is reacted with 2.5 N-(1-R,S-carbethoxy-3-phenyl-propyl)-0-ethyl-S-tyrosine,

1,3 dicykloheksylkarbodiimid og 0,8 g 1-hydroksybenztriazol. Kromatografi av råproduktet på kiselgel med cykloheksan/ eddikester (1:1) som løpemiddel gir 1 g av tittelforbindelsen som farveløs olje. 1.3 dicyclohexylcarbodiimide and 0.8 g 1-hydroxybenztriazole. Chromatography of the crude product on silica gel with cyclohexane/acetic ester (1:1) as eluent gives 1 g of the title compound as a colorless oil.

'''H-NMR-dataene og massespektrumet er i overensstemmelse med den angitte struktur. '''The H-NMR data and mass spectrum are consistent with the given structure.

Benzylesteren hydrogenolyseres analogt den i eksempel 30 beskrevne fremgangsmåte. Man får 0,6 g av tittelforbindelsen som farveløst amorft pulver. The benzyl ester is hydrogenolyzed analogously to the method described in example 30. 0.6 g of the title compound is obtained as a colorless amorphous powder.

Eksempel 67 Example 67

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- metyl- S- tyrosyl- lS, 4S, 8S-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-lS,4S,8S-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

Man får tittelforbindelsen analogt den i eksempel 66 beskrevne fremgangsmåte under anvendelse av 0-metyl-tyrosin-benzylester i steden for O-etyl-tyrosin-benzylester i det 66a) analoge trinn. The title compound is obtained analogously to the method described in example 66 using O-methyl-tyrosine benzyl ester instead of O-ethyl tyrosine benzyl ester in the 66a) analogous step.

Eksempel 68 Example 68

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- etyl- S- tyrosyl- lS, 4S, 9S-oktahydroisoindol- 1- karboksylsyre N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-1S,4S,9S-octahydroisoindole-1-carboxylic acid

Fremstilt analogt den i eksempel 6 6 beskrevne fremgangsmåte av den i eksempel 2 beskrevne aminosyre. ^"H-NMR-dataene stemmer overens med den angitte struktur. Prepared analogously to the method described in example 6 6 of the amino acid described in example 2. ^"The H-NMR data is consistent with the given structure.

Eksempel 69 Example 69

N-( 1- S-( karbetoksy- 3- fenyl- propyl)- 0- metyl- S- tyrosyl- lS, 4S, 9S-oktahydroisoindol- 2- karboksylsyre N-( 1- S-( carbethoxy- 3- phenyl- propyl)- 0- methyl- S- tyrosyl- 1S, 4S, 9S- octahydroisoindole- 2- carboxylic acid

Fremstilt analogt den i eksempel 68 beskrevne fremgangsmåte under anvendelse av den i eksempel 2 beskrevne aminosyre. "'"H-NMR-dataene stemmer overens med den angitte struktur. Prepared analogously to the method described in example 68 using the amino acid described in example 2. "'"The H-NMR data is consistent with the given structure.

Eksempel 70 Example 70

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- etyl- S- tyrosy1- 1S, 4S, 8R-oktahydrocyklopenta[ c] pyrrol- 2- karboksylsyre N-(1- S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosy1- 1S, 4S, 8R-octahydrocyclopenta[c] pyrrole- 2- carboxylic acid

Fremstilt analogt den i eksempel 6 6 beskrevne fremgangsmåte under anvendelse åv den i eksempel 7 beskrevne aminosyre. Prepared analogously to the method described in example 6 6 using the amino acid described in example 7.

Eksempel 71 Example 71

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- metyl- S- tyrosyl- lS, 4S, 8R-oktahydrocyklopenta[ c] pyrrol- l- karboksylsyre N-(l-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-lS,4S,8R-octahydrocyclopenta[c]pyrrole-l-carboxylic acid

Fremstilt analogt den i eksempel 67 beskrevne fremgangmåte under anvendelse av den i eksempel 7 beskrevne aminosyre. ^H-NMR-dataene stemmer overens med den angitte struktur. Prepared analogously to the procedure described in example 67 using the amino acid described in example 7. The ^H-NMR data is consistent with the given structure.

Eksempel 72 Example 72

N- ( l- S- karbetoksy- 3- fenyl- propyl)- O- etyl- S- tyrosyl- lS, 4S, 9R-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre N-(l- S- carbethoxy- 3- phenyl- propyl)- O- ethyl- S- tyrosyl- lS, 4S, 9R-octahydrocyclohexa[c] pyrrole-l- carboxylic acid

Fremstilt analogt den i eksempel 66 beskrevne fremgangsmåte. De analyttiske dataer stmmmer overens med den angitte struktur. Produced analogously to the method described in example 66. The analytical data are consistent with the stated structure.

Eksempel 73 Example 73

N-( l- S- karbetoksy- 3- fenyl- propyl)- O- metyl- S- tyrosyl- lS, 4S, 9R-oktahydrocykloheksa[ c] pyrrol- l- karboksylsyre N-(1-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-1S,4S,9R-octahydrocyclohexa[c]pyrrole-1-carboxylic acid

Fremstilt analogt den i eksempel 67 beskrevne fremgangsmåte. De analyttiske dataer stemmer overens med den angitte struktur. Produced analogously to the method described in example 67. The analytical data are consistent with the stated structure.

Claims (2)

1. Forbindelse med formel III' 1. Compound of formula III' i hvilken C-atomene 1, 4 og (7+n) har den samme konfigurasjon som i formel III, og hvori n betyr 1, 2 eller 3, W betyr hydrogen eller en hydrogenolyttisk eller sur avspaltbar rest.in which the C atoms 1, 4 and (7+n) have the same configuration as in formula III, and in which n means 1, 2 or 3, W means hydrogen or a hydrogenolytic or acidic cleavable residue. 2. Fremgangsmåte til fremstilling av forbindelser med formel III' ifølge krav 1, karakterisert veda) at man acylerer en forbindelse med formel IX, 2. Process for the preparation of compounds of formula III' according to claim 1, characterized by) that a compound of formula IX is acylated, hvori H-atomene til C-atomene 4 og (7+n) er cis- eller trans-konfigurert til hvera-dre og hvori n betyr tallet 1, 2 eller 3, deretter anodisk oksyderer den dannede forbindelse med en alkohol i nærvær av et ledningssalt til en forbindelse med formel X in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured to each end and in which n means the number 1, 2 or 3, then anodically oxidizes the formed compound with an alcohol in the presence of a lead salt of a compound of formula X hvori n har den ovenfor angitte betydning og R 3 betyr (C^ -C^ )-alkyl, omsetter denne med trimetylsilylcyanid i nærvær av en Lewis-syre til en forbindelse med formel XI, wherein n has the above meaning and R 3 means (C 1 -C 2 )-alkyl, reacts this with trimethylsilyl cyanide in the presence of a Lewis acid to a compound of formula XI, hvori H-atomene til C-atomene 4 og (7+n) er cis- eller trans-konfigurert til hverandre og hvorved CN-gruppen befinner seg i cis-stilling til H-atomet til C-atomet (7+n) og hvori n har den overfor nevnte betydning, og hydrolyserer denne ved innvirkning av syrer eller baser til en forbindelse med formel III' med W=hydrogen og forestret eventuelt sistnevnte forbindelse, ellerb) at man omsetter en forbindelse med formel XII in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured to each other and whereby the CN group is in the cis position to the H atom of the C atom (7+n) and in which n has the aforementioned meaning, and this is hydrolysed by the action of acids or bases to a compound of formula III' with W=hydrogen and optionally esterified the latter compound, orb) that one reacts a compound of formula XII hvori H-atomene til C-atomene 4 og (7+n) er cis- eller trans-konfigurert og n har den ovenfor nevnte betydning, i en Beck- mann-omleiring til en forbindelse med formel XIII in which the H atoms of the C atoms 4 and (7+n) are cis- or trans-configured and n has the above meaning, in a Beck- mann rearrangement to a compound of formula XIII hvori n har den ovenfor nevnte betydning, halogenerer denne til en forbindelse med formel XIV, wherein n has the above-mentioned meaning, this halogenates to a compound of formula XIV, hvori n har den ovenfor nevnte betydning og Hal betyr et halogenatom, reduserer denne til en forbindelse med formel XV, wherein n has the above meaning and Hal means a halogen atom, reduces this to a compound of formula XV, hvori n og Hal har de ovenfor nevnte betydninger, og omsetter denne deretter under innvirkning av en base til en forbindelse med formelen III <1> med W'=hydrogen, og forestrer denne eventuelt.in which n and Hal have the meanings mentioned above, and then converts this under the influence of a base into a compound of the formula III <1> with W'=hydrogen, and optionally esterifies this.
NO834352A 1982-03-30 1983-11-25 NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST. NO834352L (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19823211676 DE3211676A1 (en) 1982-03-30 1982-03-30 NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF AND NEW CYCLOALKA (C) PYRROL CARBONIC ACIDS AS THE INTERMEDIATE LEVELS AND METHODS

Publications (1)

Publication Number Publication Date
NO834352L true NO834352L (en) 1983-10-03

Family

ID=6159702

Family Applications (2)

Application Number Title Priority Date Filing Date
NO831168A NO831168L (en) 1982-03-30 1983-03-29 NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACIDS, PROCEDURES FOR THEIR PREPARATION, MENTALS CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL SARMSYLS CARBONYLS
NO834352A NO834352L (en) 1982-03-30 1983-11-25 NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST.

Family Applications Before (1)

Application Number Title Priority Date Filing Date
NO831168A NO831168L (en) 1982-03-30 1983-03-29 NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACIDS, PROCEDURES FOR THEIR PREPARATION, MENTALS CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL SARMSYLS CARBONYLS

Country Status (17)

Country Link
EP (1) EP0090362A3 (en)
JP (1) JPS58177967A (en)
KR (1) KR840004069A (en)
AU (1) AU560124B2 (en)
CA (1) CA1198118A (en)
DE (1) DE3211676A1 (en)
DK (1) DK144783A (en)
ES (2) ES521041A0 (en)
FI (1) FI831049L (en)
GR (1) GR78157B (en)
HU (1) HU193876B (en)
IL (1) IL68267A (en)
NO (2) NO831168L (en)
NZ (1) NZ203719A (en)
PH (1) PH19003A (en)
PT (1) PT76472B (en)
ZA (1) ZA832229B (en)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3226768A1 (en) * 1981-11-05 1983-05-26 Hoechst Ag, 6230 Frankfurt DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF
GR78413B (en) * 1981-12-29 1984-09-27 Hoechst Ag
DE3246503A1 (en) * 1982-12-16 1984-06-20 Hoechst Ag, 6230 Frankfurt DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (5.3.0) -DECAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THESE AGENTS AND THE USE THEREOF
US5175306A (en) * 1983-01-31 1992-12-29 Hoechst Aktiengesellschaft Process for the resolution of racemates of optically active bicyclic imino-α-carboxylic esters
DE3303344A1 (en) 1983-02-02 1984-08-02 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED AMINO ACIDS AND THEIR ESTERS
DK156484A (en) * 1983-03-16 1984-09-17 Usv Pharma Corp AMINO ACID DERIVATIVES
FR2546886B2 (en) * 1983-06-06 1986-05-16 Adir DERIVATIVES OF ISOINDOLEDICARBOXYLIC ACIDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
DE3333454A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS
DE3333455A1 (en) * 1983-09-16 1985-04-11 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS
DE3410732A1 (en) * 1984-03-23 1985-09-26 Hoechst Ag, 6230 Frankfurt METHOD FOR TREATING GLAUCOMA
US5684016A (en) * 1984-04-12 1997-11-04 Hoechst Aktiengesellschaft Method of treating cardiac insufficiency
DE3413710A1 (en) * 1984-04-12 1985-10-24 Hoechst Ag, 6230 Frankfurt METHOD FOR TREATING HEART INSUFFICIENCY
JPS61502818A (en) * 1984-07-30 1986-12-04 シェリング・コ−ポレ−ション New method for producing cis,endo-octahydrocyclopenta[b]pyrrol-2-carboxylate
DE3431541A1 (en) * 1984-08-28 1986-03-06 Hoechst Ag, 6230 Frankfurt CIS, ENDO-2-AZABICYCLOALKAN-3-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND INTERMEDIATE PRODUCTS IN THEIR PRODUCTION
US5231080A (en) * 1985-10-15 1993-07-27 Hoechst Aktiengesellschaft Method for the treatment of atherosclerosis, thrombosis, and peripheral vessel disease
US5231084A (en) * 1986-03-27 1993-07-27 Hoechst Aktiengesellschaft Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfuncitons
DE3633496A1 (en) * 1986-10-02 1988-04-14 Hoechst Ag COMBINATION OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS WITH CALCIUMANTAGONISTS AND THEIR USE IN MEDICINAL PRODUCTS
DE3639879A1 (en) * 1986-11-21 1988-06-01 Hoechst Ag METHOD FOR PRODUCING MONO, BI AND TRICYCLIC AMINO ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD, AND A METHOD FOR PRODUCING THE SAME
DE3722007A1 (en) * 1987-07-03 1989-01-12 Hoechst Ag METHOD FOR PRODUCING BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD AND THE USE THEREOF
JPH0278659A (en) * 1988-09-12 1990-03-19 Shionogi & Co Ltd Compound of azabicycloalkanes
DE3839127A1 (en) * 1988-11-19 1990-05-23 Hoechst Ag PYRROLIDONE-2-CARBONIC ACID DERIVATIVES WITH PSYCHOTROPER EFFECT
DD284030A5 (en) 1988-11-24 1990-10-31 Hoechst Ag,De PROCESS FOR THE PREPARATION OF PEPTIDES WITH BRADYKININ-ANTAGONISTIC EFFECT
LT3872B (en) 1993-12-06 1996-04-25 Hoechst Ag Novel peptides and pharmaceutical compositions containing them
EP0796855B1 (en) 1996-03-20 2002-02-06 Hoechst Aktiengesellschaft Inhibitors of bone resorption and vitronectin receptor antagonists
FR2746394B1 (en) 1996-03-20 1998-05-29 Roussel Uclaf NOVEL TRICYCLIC COMPOUNDS, THEIR PREPARATION PROCESS, AND INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
PL192280B1 (en) 1996-10-18 2006-09-29 Vertex Pharma Inhibitors of serinic proteases in particular that of hepatitis c virus ns3
DE19653647A1 (en) 1996-12-20 1998-06-25 Hoechst Ag Vitronectin receptor antagonists, their preparation and their use
DE19741235A1 (en) 1997-09-18 1999-03-25 Hoechst Marion Roussel De Gmbh Novel imidazolidine derivatives, their preparation, their use and pharmaceutical compositions containing them
DE19741873A1 (en) * 1997-09-23 1999-03-25 Hoechst Marion Roussel De Gmbh New 5-ring heterocycles, their preparation, their use and pharmaceutical preparations containing them
DE19751251A1 (en) 1997-11-19 1999-05-20 Hoechst Marion Roussel De Gmbh Substituted imidazolidine derivatives, their manufacture, their use and pharmaceutical preparations containing them
DE19821483A1 (en) 1998-05-14 1999-11-18 Hoechst Marion Roussel De Gmbh New imidazolidine derivatives useful as leukocyte adhesion and migration inhibitors and/or VLA-4 receptor antagonists for treating E.G. inflammatory and allergic disorders
SV2003000617A (en) 2000-08-31 2003-01-13 Lilly Co Eli INHIBITORS OF PROTEASA PEPTIDOMIMETICA REF. X-14912M
MY148123A (en) 2003-09-05 2013-02-28 Vertex Pharma Inhibitors of serine proteases, particularly hcv ns3-ns4a protease
CN102382170A (en) * 2005-08-19 2012-03-21 弗特克斯药品有限公司 Method for preparation of protease inhibitors and intermediates
US8399615B2 (en) 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
AR055395A1 (en) 2005-08-26 2007-08-22 Vertex Pharma INHIBITING COMPOUNDS OF THE ACTIVITY OF SERINA PROTEASA NS3-NS4A OF HEPATITIS C VIRUS
US7964624B1 (en) 2005-08-26 2011-06-21 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
WO2007098270A2 (en) 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-crystals comprising vx-950 and pharmaceutical compositions comprising the same
US20070225297A1 (en) 2006-03-16 2007-09-27 Perni Robert B Deuterated hepatitis C protease inhibitors
CA2679426A1 (en) 2007-02-27 2008-09-04 Luc Farmer Inhibitors of serine proteases
NZ579442A (en) 2007-02-27 2012-02-24 Vertex Pharma Co-crystals of VX-950 (telaprevir) and other components, and pharmaceutical compositions comprising the same
MX2010002407A (en) 2007-08-30 2010-03-26 Vertex Pharma Co-crystals and pharmaceutical compositions comprising the same.
KR20110048509A (en) 2008-06-24 2011-05-11 코덱시스, 인코포레이티드 Biocatalyst Process for Preparation of Fused Bicyclic Proline Compounds with Substantially Stereoisomerically Pure
JP5829529B2 (en) * 2011-08-29 2015-12-09 日本曹達株式会社 Optically active quaternary ammonium salt and method for producing optically active compound

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL58849A (en) * 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
FR2487829A2 (en) * 1979-12-07 1982-02-05 Science Union & Cie NOVEL SUBSTITUTED IMINO ACIDS, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR
DE19575012I2 (en) * 1980-10-23 2002-01-24 Schering Corp Carboxyalkyl dipeptides Process for their preparation and medicaments containing them
DE3260423D1 (en) * 1981-02-17 1984-08-30 Warner Lambert Co Substituted acyl derivatives of octahydro-1h-isoindole-1-carboxylic acids and esters
ZA826022B (en) * 1981-08-21 1983-08-31 Univ Miami Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides
EP0081094A1 (en) * 1981-11-12 1983-06-15 Merck & Co. Inc. Substituted omega-amino-carboxymethyldipeptide antihypertensive agents
EP0088350B1 (en) * 1982-03-08 1985-02-20 Schering Corporation Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
PH19003A (en) 1985-12-03
AU560124B2 (en) 1987-04-02
GR78157B (en) 1984-09-26
ES8402570A1 (en) 1984-02-01
ZA832229B (en) 1983-12-28
FI831049A0 (en) 1983-03-28
FI831049L (en) 1983-10-01
HU193876B (en) 1987-12-28
CA1198118A (en) 1985-12-17
DK144783A (en) 1983-10-01
PT76472A (en) 1983-04-01
EP0090362A2 (en) 1983-10-05
PT76472B (en) 1986-01-24
ES521741A0 (en) 1984-02-01
NO831168L (en) 1983-10-03
DE3211676A1 (en) 1983-10-06
AU1297083A (en) 1983-10-06
KR840004069A (en) 1984-10-06
IL68267A (en) 1987-03-31
DK144783D0 (en) 1983-03-29
ES8401937A1 (en) 1984-01-01
JPS58177967A (en) 1983-10-18
EP0090362A3 (en) 1985-09-18
ES521041A0 (en) 1984-01-01
IL68267A0 (en) 1983-06-15
NZ203719A (en) 1986-02-21

Similar Documents

Publication Publication Date Title
NO834352L (en) NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBOXYLIC ACID, PROCEDURE FOR THEIR PREPARATION, SUBSTANCES CONTAINING THESE AND THEIR USE, AND NEW CYCLOALKA (C) PYRROLE CARBOXYL CARROCYRO FOR THEIR FIRST.
DK170444B1 (en) Analogous Process for Preparation of Bicyclic Amino Acid Derivatives and Their Physiologically Harmless Salts
US4727160A (en) Method for making 2-azabicyclo-[3.3.0]-octane-3-carboxylic acids
EP0252713B1 (en) Indolinone derivatives
KR900001191B1 (en) Preparation process for 3-amino-(1)benzazepin-2-one-1-alkanoic acid
DK171256B1 (en) Analogous Process for Preparation of Bicyclic Amino Acid Derivatives or Physiologically Acceptable Salts thereof
NO165148B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF TRICYCLIC AMINO ACIDS.
NO164536B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (5,3,0) -DECAN-3-CARBOXYLIC ACID, AND INTERMEDIATES FOR USE IN PREPARATION.
KR910003185B1 (en) Processes for preparation of spirocyclic aminoacid derivatives
NO165921B (en) PROCEDURE FOR THE PREPARATION OF DISUBSTITUTED PROLINE DERIVATIVES.
NO832648L (en) NEW DERIVATIVES OF 2-AZA-BICYCLO (2.2.2) OCTAN-3-CARBONIC ACID, PROCEDURE FOR THEIR PREPARATION, MEDIUM CONTAINING THIS AND THEIR USE, AND 2-AZA-BICYCLO (2.2.2) OCTAN-3BAR-3-CARBON-3 . FOR THEIR FIRST
US4134991A (en) Derivatives of 2-(3-phenyl-2-aminopropionyloxy)-acetic acid
JPH0559105B2 (en)
US5064852A (en) Indolinone derivatives
US4226860A (en) Spiroindolones
US4960785A (en) Indolinone derivatives
US4405787A (en) 3-Carboxy-2-azabicyclo[2.2.1]heptane derivatives
FI73197C (en) FOERFARANDE FOER FRAMSTAELLNING AV ETT NYTT, VAENSTERVRIDANDE, TERAPEUTISKT VERKANDE BASISKT DERIVAT AV 9,10-ETANOANTRACEN.
CA1206478A (en) Bicyclic amino acid derivatives useful as medical intermediates
NZ214877A (en) Cepyrrol-2-ylcarboxylic acid derivatives
IE56170B1 (en) Derivatives of bicyclic aminoacids,processes for their preparation,agents containing these compounds and their use,and new bicyclic aminoacids as intermediates and processes for their preparation
IE43448B1 (en) Substitued pheylacetic acids