DK162228B - Substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3- benzazepines, their preparation and pharmaceutical preparations which comprise the compounds - Google Patents
Substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3- benzazepines, their preparation and pharmaceutical preparations which comprise the compounds Download PDFInfo
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- DK162228B DK162228B DK087689A DK87689A DK162228B DK 162228 B DK162228 B DK 162228B DK 087689 A DK087689 A DK 087689A DK 87689 A DK87689 A DK 87689A DK 162228 B DK162228 B DK 162228B
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Description
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i 5 Nærværende opfindelse angår hidtil ukendte substituerede 7-aminocarbonyloxy-2,3,4,5-tetrahydro-lH-3-benzazepiner med formlen I ifølge krav 1, som er nyttige prodrugs ved behandling af mentale sygdomme. Anvendt i denne beskrivelse definerer udtrykket "prodrug” et derivat af en biolo-10 gisk aktiv forbindelse, som, når den absorberes i blodbanen hos dyr og mennesker, nedbrydes på en sådan måde, at den frigør de aktive forbindelser og lader disse opnå en højere biotilgængelighed end den, der opnås hvis den aktive forbindelse, per se, blev indgivet peroralt. Den akti-15 ve forbindelse kan således indgives intravenøst uden problemer; imidlertid foretrækkes peroral indgivelse almindeligvis af indlysende årsager. Peroral indgivelse af den aktive forbindelse er ofte utilfredsstillende, da denne dekomponerer i spiserøret og ved første passage af leve-20 ren; men peroral indgivelse af prodrug giver både fordelene ved let indgivelse og en høj biotilgængelighed.The present invention relates to novel substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepines of formula I according to claim 1 which are useful prodrugs in the treatment of mental disorders. As used herein, the term "prodrug" defines a derivative of a biologically active compound which, when absorbed into the bloodstream of animals and humans, is degraded in such a way that it releases the active compounds and allows them to obtain a higher bioavailability than that obtained if the active compound, per se, was administered orally, thus the active compound can be administered intravenously without problems, however, oral administration is usually preferred for obvious reasons. Oral administration of the active compound is often unsatisfactory; since it decomposes in the esophagus and at the first passage of the liver, but oral administration of prodrug provides both the advantages of easy administration and a high bioavailability.
I den europæiske patentansøgning nr. 200455 beskrives 2-,3,4,5-tetrahydro-lH-3-benzazepiner, der er nyttige ved 25 behandling af mentale sygdomme. Når disse benzazepiner indgives intravenøst, er de meget nyttige ved behandling af mentale sygdomme, som beskrevet i den europæiske patentansøgning; men hvis de indgives oralt, har de den ulempe, at de skal indgives i meget store doser,f.eks. fra ca.European Patent Application No. 200455 discloses 2-, 3,4,5-tetrahydro-1H-3-benzazepines which are useful in the treatment of mental disorders. When these benzazepines are administered intravenously, they are very useful in the treatment of mental illnesses, as described in the European patent application; but if administered orally, they have the disadvantage of being administered in very large doses, e.g. from approx.
30 0,5 mg til ca. 150 mg, for at den ønskede effekt kan op nås.0.5 mg to approx. 150 mg to achieve the desired effect.
Der er således behov for en måde, hvorpå de i europæiske patentansøgning nr. 200455 beskrevne benzazepiner kan ind-35 gives oralt i meget mindre doser, men alligevel kan give den ønskede effekt.Thus, there is a need for a way in which the benzazepines described in European Patent Application 200455 can be administered orally in much smaller doses, but still produce the desired effect.
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Det har vist sig, at en udvalgt gruppe af de i europæisk patentansøgning nr. 200455 beskrevne benzazepiner, d.v.s. den gruppe der indeholder en hydroxygruppe i position nr.It has been found that a selected group of the benzazepines disclosed in European Patent Application No. 200455, i.e. the group containing a hydroxy group at position no.
3 7 i benzazepinkernen (svarende til tilfældet hvor R er 5 hydroxy i terminologien for den europæiske patentansøgning), kan omdannes til brugbare prodrugs, ved omsætning af disse benzazepiner med særligt udvalgte carbaminsyrer til dannelse af de omhandlede forbindelser.3 7 of the benzazepine nucleus (similar to the case where R is 5 hydroxy in the European patent application terminology) can be converted into useful prodrugs by reacting these benzazepines with specially selected carbamic acids to form the compounds of the invention.
10 Som det vil fremgå af den efterfølgende beskrivelse, er de omhandlede forbindelsers biotilgængélighed markant højere end de fra den europæiske patentansøgning kendte forbindelsers biotilgængelighed ved oral indgivelse, hvilket gør det tydeligt for en fagmand at der ved oral indgivel-15 se kan anvendes meget mindre doser af forbindelserne med formlen I end af de kendte forbindelser, til opnåelse af den samme effekt.10 As will be apparent from the following description, the bioavailability of the compounds of the present invention is significantly higher than the bioavailability of the compounds known from the European patent application by oral administration, which makes it clear to one skilled in the art that much smaller doses can be used in oral administration. of the compounds of formula I than of the known compounds, to obtain the same effect.
Forbindelserne ifølge opfindelsen har den generelle for-20 mel IThe compounds of the invention have the general formula I
/CH\ , / \ /CH2-CH2\ 25 0 R -C CT \ 1 li i /-r? c-o-c c X (I) \ /VcH-CH2 N CH1 2 30 /\ R5 2 5 hvor R er halogen, R er benzufuran-7-yl eller 2,3-dihy- 8 2 35 drobenzofuran-7-yl, R er H eller C1_4~alkyl R er H, alkyl, allyl, aralkyl, cycloalkyl eller aryl R3 er H, eller 3 8 R sammen med R danner en pyrrolidinylgruppe eller en 3/ CH \, / \ / CH2-CH2 \ 25 0 R -C CT \ 1 li i / -r? where c is halogen, R is benzufuran-7-yl or 2,3-dihydro-drobenzofuran-7-yl, R is H or C 1-4 alkyl R is H, alkyl, allyl, aralkyl, cycloalkyl or aryl R 3 is H, or 38 R together with R forms a pyrrolidinyl group or a 3
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pyrrolidinylgruppe med formlenpyrrolidinyl group of the formula
Cr1^ 10 g eller R kan være alkyl eller en alkoxycarbonylgruppe med formlen ,r 0 15 ηCr 1 10 g or R may be alkyl or an alkoxycarbonyl group of formula, r 0 15 η
11 11 IS11 11 IS
-(GHRJ"L) - C - OR J ; n = 0,1 hvor R11 er -H, -CHg, -CH(CH3)2, CH2CH(CH3)2, 20 -CH - CH2 - CH3 CH3 -2-^> 25 13 eller er R er H, alkyl, cycloalkyl eller aralkyl, eller er farmaceutisk acceptable salte deraf.- (GHRJ "L) - C - OR J; n = 0.1 where R11 is -H, -CHg, -CH (CH3) 2, CH2CH (CH3) 2, -CH - CH2 - CH3 CH3 -2- Or R is H, alkyl, cycloalkyl or aralkyl, or are pharmaceutically acceptable salts thereof.
30 I en foretrukken udformning af carbaminsyreestrene ifølge 2 opfindelsen er R chlor eller fluor. Den tilsvarende grundforbindelse udviser en meget høj affinitet til receptoren.In a preferred embodiment of the carbamic acid esters of the invention, R is chlorine or fluorine. The corresponding basic compound exhibits a very high affinity for the receptor.
I denne beskrivelse er grundforbindelsen svarende til et bestemt prodrug en forbindelse beslægtet med prodruget, 35 idet den eneste forskel er, at position nr. 7 i benzaze-pinkernen i grundforbindelsen kun bærer en uesterificeret hydroxygruppe.In this specification, the basic compound corresponding to a particular prodrug is a compound akin to the prodrug, with the only difference being that position # 7 in the benzene pink core of the basic compound carries only one unesterified hydroxy group.
5 45 4
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I carbaminsyreestrene ifølge opfindelsen er R benzofura-nyl eller 2,3-dihydrobenzofuranyl. På grund af den store 5 og lipophile R -del er den farmakologiske effekt meget potent.In the carbamic acid esters of the invention, R is benzofuranyl or 2,3-dihydrobenzofuranyl. Due to the large 5 and lipophilic R moiety, the pharmacological effect is very potent.
5 I en foretrukken udformning af carbaminsyreestrene ifølge 7 opfindelsen er R hydrogen eller methyl. Sådanne carbamin-syreestre udviser en potent farmakologisk effekt.In a preferred embodiment of the carbamic acid esters of the invention, R is hydrogen or methyl. Such carbamic acid esters exhibit a potent pharmacological effect.
10 I en foretrukken udformning af carbaminsyreestrene ifølge 8 opfindelsen er R H, alkyl, allyl, aralkyl eller cyclo- g alkyl og R er H, alkyl, eller alkoxycarbonyl.In a preferred embodiment of the carbamic acid esters of the invention, R is H, alkyl, allyl, aralkyl or cycloalkyl and R is H, alkyl, or alkoxycarbonyl.
I en foretrukken udformning af carbaminsyreestrene ifølge 8 9 15 opfindelsen danner R og R sammen en ring med formlen I 0 /v II .In a preferred embodiment of the carbamic acid esters of the invention, R and R together form a ring of formula I0 / v II.
20 ' \>R13 13 25 hvor R er alkyl, fortrinsvis C^-Cg-alkyl.Wherein R is alkyl, preferably C 1 -C 6 alkyl.
Opfindelsen angår også farmaceutiske præparater, især til behandling af mental sygsom, som er ejendommelige ved, at de indeholder en effektiv mængde af en forbindelse med 30 formlen I eller et farmaceutisk acceptabelt salt deraf, sammen, med et farmaceutisk acceptabelt bærestof eller fortyndingsmiddel. Det farmaceutiske præparat fremstilles sædvanligvis som en tablet eller en kapsel, fortrinsvis som en enterisk overtrukket tablet.The invention also relates to pharmaceutical compositions, in particular for the treatment of mental illness, which are characterized in that they contain an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. The pharmaceutical composition is usually prepared as a tablet or capsule, preferably as an enteric coated tablet.
Opfindelsen omfatter også et farmaceutisk præparat som et neuroleptikum.The invention also encompasses a pharmaceutical composition as a neuroleptic.
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Opfindelsen omfatter yderligere et farmaceutisk præparat til behandling af schizofreni, andre psykoser og manio-depressive sygdomme.The invention further includes a pharmaceutical composition for the treatment of schizophrenia, other psychoses and manic-depressive disorders.
5 Opfindelsen angår også anvendelsen af en forbindelse med formlen I eller et farmaceutisk acceptablet salt deraf til fremstilling af et farmaceutisk præparat ifølge opfindelsen til behandling af en mental sygdon.The invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition according to the invention for the treatment of a mental illness.
10 Forbindelserne med formlen I eller salte deraf, kan fremstilles ved en fremgangsmåde, der er ejendommelig ved, at man omsætter en benzazepinforbindelse med den generelle formel IIThe compounds of formula I or salts thereof can be prepared by a process which is characterized by reacting a benzazepine compound of the general formula II
15 CH\ / \/CH2-CH2\ R -C C \ N-R7 (II) 20 HO-C C / \ /XcH'°H2 CH' R5 25 2 5 hvor R er halogen, R er benzofuran-7-yl eller 2,3-dihy- 7Where CH is halogen, R is benzofuran-7-yl, CH is a halogen, R is benzofuran-7-yl. or 2,3-dihy- 7
drobenzofuran-7-yl, og R er H eller C1_4~alkyl, med et reaktivt derivat af carbaminsyren med formlen IIIdrobenzofuran-7-yl, and R is H or C 1-4 alkyl, with a reactive derivative of the carbamic acid of formula III
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\ O\ O
\ II\ II
,N-C-0H (III) Å 35 Ry 6, N-C-OH (III) Å 35 Ry 6
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fortrinsvis syrehalogenidet med formlen IVpreferably the acid halide of formula IV
R\ 5 \ β .N-C-X (IV) / 10 o ...R \ 5 \ β .N-C-X (IV) / 10 o ...
hvor R er H, alkyl, allyl, aralkyl, cycloalkyl eller 9 9 8 aryl, R er H, eller R sammen med R danner en pyrroli- dinylgruppe eller en pyrrolidinylgruppe med formlen 15 I 0wherein R is H, alkyl, allyl, aralkyl, cycloalkyl or 9,98 aryl, R is H, or R together with R forms a pyrrolidinyl group or a pyrrolidinyl group of formula 15
Λ IIΛ II
r \—c 'Njr13 20 - g eller R kan være alkyl eller en alkoxycarbonylgruppe med formlen 25 0 11 M iq -(CHRj"1 ) - C - OR ° ; n = 0,1 30 hvor R11 er -H, -CHg, -CH(CH3)2, CH2CH(CH3)2, -|H - CH2 - CH3 CH3 35 13 7r - C 'Njr13 20 - g or R may be alkyl or an alkoxycarbonyl group of the formula 25 0 11 M iq - (CHR2 "1) - C - OR °; n = 0.1 where R11 is -H, -CH , -CH (CH3) 2, CH2CH (CH3) 2, - | H - CH2 - CH3 CH3 35 13 7
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og R er H, alkyl, cycloalkyl eller aralkyl, og X er halogen, fortrinsvis chlor, eller med et isocyanat V eller V 5 R8-N=O0, (V) R9-N=C=0 (V) 8 9 hvor R og R har de ovenfor anførte betydninger, hvor-10 efter forbindelsen med formlen I isoleres og, om ønsket, konvertéres til et farmaceutisk acceptabelt salt deraf.and R is H, alkyl, cycloalkyl or aralkyl, and X is halogen, preferably chlorine, or with an isocyanate V or V 5 R 8 -N = O0, (V) R 9-N = C = O (V) 8 9 where R and R has the meanings set forth above, after which the compound of formula I is isolated and, if desired, converted to a pharmaceutically acceptable salt thereof.
Forbindelserne med formlen I kan indeholde flere optisk aktive centre og det må forstås, at opfindelsen omfatter 15 både racemiske blandinger og alle optiske isomere.The compounds of formula I may contain several optically active centers and it is to be understood that the invention encompasses both racemic mixtures and all optical isomers.
Ved syntesen af de omhandlede forbindelser med formlen I er også forskellige andre nye forbindelser blevet syntetiseret ifølge metoder publiceret i litteraturen. Således 20 er carbamoylchlorider af N-substituerede amino pro-dele fremstillet ved at omsætte den aktuelle N-substituerede aminoforbindelse i dens grundform med fosgen i et passende organisk opløsningsmiddel (se f.eks. J.Org.Chem., 51, 1986, 3494-3498), og isocyanater af usubstituerede amino 25 pro-dele er generelt fremstillet ved at omsætte aminofor-bindelsen i dens grundform med difosgenreagenset trichlor-methylchlorformiat (TCF, f.eks. J.Org.Chem. 41, 1976, 2070-71; Org.Synth., 59, 1979, 195-201). Identiteten af disse pro-dele mellemprodukter er blevet bekræftet ved mi-30 kroanalyse, IR, og NMR spektroskopi. 1 europæisk patentansøgning nr. 170 090 fremgår det af siderne 4 og 5, at det ikke er muligt nøjagtigt at forudsige hvilken prodrugstruktur der vil være velegnet for ét 35 specielt lægemiddel, og at et derivat, som fungerer godt for et lægemiddel måske ikke vil gøre det for et andet, da forskelle hvad angår absorption, metabolisme, distri-In the synthesis of the compounds of formula I, various other novel compounds have also been synthesized according to methods published in the literature. Thus, carbamoyl chlorides of N-substituted amino moieties are prepared by reacting the current N-substituted amino compound in its basic form with phosgene in an appropriate organic solvent (see, e.g., J. Org.Chem., 51, 1986, 3494 -3498), and isocyanates of unsubstituted amino parts are generally prepared by reacting the amino compound in its basic form with the diphosgene reagent trichloromethyl chloroformate (TCF, e.g., J.Org.Chem. 41, 1976, 2070-71 ; Org.Synth., 59, 1979, 195-201). The identity of these partial intermediates has been confirmed by microanalysis, IR, and NMR spectroscopy. In European Patent Application No. 170 090, pages 4 and 5 show that it is not possible to accurately predict which prodrug structure will be suitable for one particular drug and that a derivative that works well for a drug may not do secondly, since differences in absorption, metabolism, distribution,
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s bution og udskillelse i forbindelse med lægemidler umuliggør generalisering omkring prodrug-konstruktion. Endvidere fremgår det af side 34 i denne europæiske patentansøgning nr. 170 090 at forskellige (men beslægtede) grundfor-5 bindeiser med den samme prodrugmolekyldel, udviser vidt forskellige relative biotilgængeligheder, som bekræfter ovennævnte udsagn, om at det ikke er muligt at forudsige nøjagtigt hvilken prodrugstruktur, der vil være passende for et bestemt lægemiddel, selvom det er kendt, at et lig-10 nende lægemiddel udviser en tilfredsstillende relativ bio-tilgængelighed med en specifik prodrugstruktur.s bution and excretion associated with drugs makes it impossible to generalize around prodrug design. Furthermore, on page 34 of this European Patent Application No. 170 090, it appears that different (but related) basic compounds with the same prodrug molecule exhibit very different relative bioavailability, confirming the above statement, that it is not possible to predict exactly which prodrug structure that will be appropriate for a particular drug, although it is known that a similar drug exhibits a satisfactory relative bioavailability with a specific prodrug structure.
Selvom det fremgår af US patent nr. 4,284,555, at en bestemt klasse af benzazepiner kan esterificeres med carba-15 minsyreestre og derved danne prodrugs med forbedret relativ biotilgængelighed, adskiller grundforbindelserne af forbindelserne med formlen I ifølge opfindelsen (den tidligere beskrevne undergruppe af benzazepiner beskrevet i europæisk patent ansøgning nr. 200455) sig således markant 20 fra grundforbindelserne af de benzazepiner, der er beskrevet i US patent nr. 4,284,555, og der vil således ikke være nogen eksakt måde at forudsige hvilken type prodrugstruktur, der vil være passende for grundforbindelsen af forbindelserne med formlen 1.Although US Patent No. 4,284,555 states that a particular class of benzazepines can be esterified with carbamic acid esters, thereby producing prodrugs with improved relative bioavailability, the basic compounds of the compounds of formula I according to the invention differ (the previously described subgroup of benzazepines described in Thus, European Patent Application No. 200455) is markedly 20 from the base compounds of the benzazepines disclosed in U.S. Patent No. 4,284,555, and thus there will be no exact way to predict what type of prodrug structure will be appropriate for the basic compound of the compounds. of formula 1.
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Prodrugeffekten måles som forholdet mellem arealet under kurven repræsenterende koncentrationen af grundforbindelsen i blodstrømmen versus tid i forbindelse med oral indgift af prodruget og det tilsvarende areal i forbindelse 30 med intravenøs indgift af en ekvimolær mængde af den tilsvarende grundforbindelse. Man har erfaret, at hovedsageligt grundforbindelsen er til stede i blodet, hvis prodruget er indgivet oralt.The prodrug effect is measured as the ratio of the area under the curve representing the concentration of the basic compound in the blood stream versus time in connection with oral administration of the prodrug and the corresponding area in connection with intravenous administration of an equimolar amount of the corresponding basic compound. It has been found that mainly the basic compound is present in the blood if the prodrug is administered orally.
35 For mere detaljeret information i forbindelse med prodrug definition henvises der til A.A. Sinkula og S.H. Yalkowsky; J.Pharm.Sci., 64, 1975, 183-210, H. Bundgaard (ed.) (1985), 935 For more detailed information related to prodrug definition, see A.A. Sinkula and S.H. Yalkowsky; J.Pharm.Sci., 64, 1975, 183-210, H. Bundgaard (ed.) (1985), 9
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Design of Prodrugs, Elsevier, Amsterdam, E.B. Roche (ed.) 1977, Design of Biopharmaceutical Properties through Pro-drugs and Analogs, American Pharmaceutical Association, Washington D.C.Design of Prodrugs, Elsevier, Amsterdam, E.B. Roche (ed.) 1977, Design of Biopharmaceutical Properties through Pro-drugs and Analogs, American Pharmaceutical Association, Washington D.C.
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Mere præcist er prodrugeffekten eller biotilgængeligheden målt på følgende måde.More precisely, the prodrug effect or bioavailability is measured as follows.
Prodruget indgives peroralt til et forsøgsdyr og i en sam- 10 let dosis betegnet "dosis ", udtrykt på molbasis. Kon- p.o.The prodrug is orally administered to an experimental animal and in a single dose designated "dose", expressed on a molar basis. Kon.p.o.
centrationen af grundforbindelsen i blodet i mg af grund-forbindelsen/ml plasma er målt med regelmæssige tidsintervaller efter indgift, og en kurve repræsenterende denne koncentration versus tid, f.eks. i timer, er optegnet.the concentration of the basic compound in the blood in mg of the basic compound / ml of plasma is measured at regular time intervals after administration, and a curve representing this concentration versus time, e.g. in hours, is recorded.
15 Arealet under kurven (AUC ) i (mg/ml) x minutter bereg- p*o« nes.The area under the curve (AUC) for (mg / ml) x minutes is calculated.
Ligeledes indgives grundforbindelsen intravenøst i en samlet dosis betegnet "dosis. ", udtrykt på molbasis. En X · V · 20 lignende kurve optegnes, og arealet under denne kurve er tilsvarende "AUC. ".Likewise, the basic compound is administered intravenously in a single dose designated "dose.", Expressed on a molar basis. An X · V · 20 similar curve is plotted and the area under this curve is corresponding to "AUC."
X · V ·X · V ·
Nu beregnes biotilgængeligheden F i overensstemmelse med formlen 25 AUC /dosis_ p·O· β·0· F - - . 100% AUC. /dosis. .. i.v. i.v.Now the bioavailability F is calculated according to the formula 25 AUC / dose_ p · O · β · 0 · F - -. 100% AUC. /dosage. .. i.v. i.v.
30 Mere specifikt, i relation til denne opfindelse, måles biotilgængeligheden af prodruget i hunde.More specifically, in relation to this invention, the bioavailability of the prodrug is measured in dogs.
I et overkrydsningsforsøg indgives grundforbindelsen af en forbindelse med formlen I og det tilsvarende prodrug 35 med en uges interval, grundforbindelsen som en intravenøs bolus og det tilsvarende prodrug som en oral opløsning.In a cross-over experiment, the basic compound is administered by a compound of formula I and the corresponding prodrug 35 at a one-week interval, the basic compound as an intravenous bolus and the corresponding prodrug as an oral solution.
1010
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Ved brug af fast fase-ekstraktion af plasmaprøverne og HPLC er plasmakoncentrationen af både grundforbindelsen af en forbindelse med formlen 1 og prodruget bestemt op til 24 timer efter indgivelse.Using solid phase extraction of the plasma samples and HPLC, the plasma concentration of both the basic compound of a compound of formula 1 and the prodrug is determined up to 24 hours after administration.
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Efter den i eksemplerne illustrerede syntese af prodrug vil resultater for biotilgængeligheden af nogle af de eks-emplifiserede prodrug med formlen I, blive vist.Following the synthesis of prodrugs illustrated in the examples, results for the bioavailability of some of the exemplified prodrugs of formula I will be shown.
10 Nærværende opfindelse belyses nærmere ved hjælp af de efterfølgende eksempler.The present invention is further illustrated by the following examples.
EKSEMPEL 1 15 (+)-8-chlor-7[(N,N-dimethylamino)carbonyloxy]-5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin, HCl.EXAMPLE 1 (+) - 8-chloro-7 [(N, N-dimethylamino) carbonylloxy] -5- (7-benzo-furanyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 -benzazepine, HCl.
1,0 g (3,04 mmol) af grundforbindelsen (+)-8-chlor-7-hy-20 droxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl- 3-benzazepin) opløstes i 20 ml tør pyridin. Til denne opløsning sattes i en enkelt arbejdsgang 0,56 ml (6,08 mmol) Ν,Ν-dimethylcarbamoylchlorid. Den dermed fremkomne blanding placeredes i et oliebad og refluxedes i 24 timer.1.0 g (3.04 mmol) of the basic compound (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl - 3-benzazepine) was dissolved in 20 ml of dry pyridine. To this solution was added 0.56 ml (6.08 mmol) of Ν, Ν-dimethylcarbamoyl chloride in a single operation. The resulting mixture was placed in an oil bath and refluxed for 24 hours.
25 Pyridin inddampedes i vakuum sammen med overskud af reagenset . Residualmaterialet blev opløst i 30,0 ml tør æter og bundfældedes med en 1,0 N HCl-opløsning i æter. Det hvide bundfald blev vasket med 2 x 10 ml tør æter. Tørring i nærvær af ^2^5 udført i 24 timer ved 0,2 mm Hg.Pyridine was evaporated in vacuo along with excess reagent. The residual material was dissolved in 30.0 ml of dry ether and precipitated with a 1.0 N HCl solution in ether. The white precipitate was washed with 2 x 10 ml dry ether. Drying in the presence of ^ 2 ^ 5 performed for 24 hours at 0.2 mm Hg.
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Produktets renhed i dette eksempel og i eksemplerne 2-6 bestemtes ved brug af den i det efterfølgende angivne- HP-LC-metode.The purity of the product in this example and in Examples 2-6 was determined using the HP-LC method set forth below.
35 Den syntetiserede forbindelse blev kromatograferet på en kolonne med en Nucleosil RP C-18 kieselbærer (gennemsnitlig partikelstørrelse 5 pm) ved hjælp af en trin-gradient- 11The synthesized compound was chromatographed on a column with a Nucleosil RP C-18 silica support (average particle size 5 µm) by a step gradient.
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metode. Elueringsprogrammet blev initieret med en blanding af 25% acetonitril og 75% af en 0,1M ammoniumsulfatbuffer med pH 3,0. Ved hjælp af to trin blev acetonitrilvolumen-fraktionen af eluenten hævet til 55%. Detektering af ko-5 lonneoutflow blev udført ved UV absorptionsmåling.method. The elution program was initiated with a mixture of 25% acetonitrile and 75% of a 0.1M ammonium sulfate buffer of pH 3.0. By two steps, the acetonitrile volume fraction of the eluent was raised to 55%. Column effluent detection was performed by UV absorption measurement.
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en retentionstid på 16,0 minutter.Purity by HPLC> 98%. Product maximum corresponds to a retention time of 16.0 minutes.
10 1H-NMR, ppm. (CDClg, TMS): 2,36 3H(s); 3,00 6H(s); 2,70-3,30 6H(m); 4,60 lH(t); 6,10 lH(s); 6,70-7,55 6H(m); EKSEMPEL 2 15 (+)-8-chlor-7-[(N,N-diethylamino)carbonyloxy]-5-(7-benzo- furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin, HC1.1 H-NMR, ppm. (CDCl 3, TMS): 2.36 3H (s); 3.00 6H (s); 2.70-3.30 6H (m); 4.60 lH (t); 6.10 1H (s); 6.70-7.55 6H (m); EXAMPLE 2 (+) - 8-chloro-7 - [(N, N-diethylamino) carbonylloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl 3-benzazepine, HCl.
0,5 g (1,52 mmol) af (+)-8-chlor-7-hydroxy-5-(7-benzofura-nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin) opløstes 20 i 20 ml tør pyridin. Til denne opløsning sattes i et trin 0,39 ml (3,04 mmol) Ν,Ν-diethylcarbamoylchlorid. Den derved fremkomne blanding placeredes i et oliebad og refluxe-des i 24 timer. Pyridin blev inddampet i vacuum sammen med overskud af reagens. Resten opløstes i 20 ml tør æter 25 og udskiltes med et 10 %'s overskud af IN HCl-opløsning i æter. Det hvide bundfald blev vasket med 2x10 ml tør æter. Tørring med P2°5 blev udført i 24 timer ved 0,2 mmHg.0.5 g (1.52 mmol) of (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 (benzazepine) was dissolved in 20 ml of dry pyridine. To this solution was added 0.39 ml (3.04 mmol) of Ν, Ν-diethylcarbamoyl chloride in one step. The resulting mixture was placed in an oil bath and refluxed for 24 hours. Pyridine was evaporated in vacuo along with excess reagent. The residue was dissolved in 20 ml dry ether 25 and separated with a 10% excess of 1N HCl solution in ether. The white precipitate was washed with 2x10 ml dry ether. Drying with P2 ° 5 was performed for 24 hours at 0.2 mmHg.
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en 30 retentionstid på 24,0 minutter.Purity by HPLC> 98%. Product maximum corresponds to a retention time of 24.0 minutes.
35 H-NMR, ppm. (CDClg, TMS): 1,15 6H(m); 2,84 3H(s): 2,9-4,2 6H(m); 3,30 4H(m); 5,48 lH(s); 6,30 lH(s); 6,84-7,70 6H(m); 2,9-4,2 6H(m).1 H-NMR, ppm. (CDCl 3, TMS): 1.15 6H (m); 2.84 3H (s): 2.9-4.2 6H (m); 3.30 4H (m); 5.48 lH (s); 6.30 lH (s); 6.84-7.70 6H (m); 2.9-4.2 6H (m).
(+)-8-chlor-7-[(N-methyl-N-ethoxycarbonyl)aminocarbonyl- oxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl- 5 3-benzazepin, HC1.(+) - 8-chloro-7 - [(N-methyl-N-ethoxycarbonyl) aminocarbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-5 3-benzazepine, HCl.
EKSEMPEL 3 12EXAMPLE 3 12
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0,98 g (3,0 mmol) af (+)-8-chlor-7-hydroxy-5-(7-benzofura-nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin opløstes i 10 ml tør pyridin. Denne opløsning blev tilsat dråbevis 10 ved stuetemperatur til en opløsning med 1,5 g (9 mmol) af N-methyl-N-chlorformylethylcarbamat i 5 ml tør pyridin.0.98 g (3.0 mmol) of (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3 -benzazepine was dissolved in 10 ml of dry pyridine. This solution was added dropwise at room temperature to a solution of 1.5 g (9 mmol) of N-methyl-N-chloroformylethylcarbamate in 5 ml of dry pyridine.
Den herved fremkomne blanding blev placeret i et oliebad og refluxet i 16 timer. Pyridin inddampedes in vacuo sammen med overskud af reagenset. Resten opløstes i 20 ml 15 tør æter og bundfældedes med 10% overskud af IN HC1 opløst i æter. Det hvide bundfald blev vasket to gange med 10 ml tør æter.The resulting mixture was placed in an oil bath and refluxed for 16 hours. Pyridine was evaporated in vacuo together with excess reagent. The residue was dissolved in 20 ml of 15 dry ether and precipitated with 10% excess of 1N HCl dissolved in ether. The white precipitate was washed twice with 10 ml of dry ether.
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en 20 retentionstid på 15,8 minutter.Purity by HPLC> 98%. Product maximum corresponds to a 20 retention time of 15.8 minutes.
1H-NMR, ppm. (CDClg, TMS): 1,30 3H(t); 2,96 3H(s); 3,28 3H(s); 4,25 2H(q); 2,9-4,2 6H(m); 5,50 lH(s); 6,30 lH(s); 6,85-7,70 6H(m).1 H-NMR, ppm. (CDCl 3, TMS): 1.30 3H (t); 2.96 3H (s); 3.28 3H (s); 4.25 2H (q); 2.9-4.2 6H (m); 5.50 1H (s); 6.30 lH (s); 6.85-7.70 6H (m).
25 EKSEMPEL 4 (+)-8-chlor-7-[ (R, S)-N-(1-methoxycarbonyl-l-ethyl)amino-carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-30 methyl-3-benzazepin.EXAMPLE 4 (+) - 8-Chloro-7- [(R, S) -N- (1-methoxycarbonyl-1-ethyl) amino-carbonylloxy] -5- (7-benzofuranyl) -2,3,4, 5-tetrahydro-1H-3-30 methyl-3-benzazepine.
0,40 g (3,05 mmol) af N-carbonyl D,L-alaninmethylester opløstes i 5 ml acetonitril. Denne opløsning sattes dråbevis til en refluxende opløsning af 0,50 g (1,52 mmol) (+)-8-35 chlor-7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH- 3-methyl-3-benzazepin i 20 ml acetonitril, og refluxedes fortsat i yderligere 8. timer. Acetonitril og overskud af 130.40 g (3.05 mmol) of N-carbonyl D, L-alanine methyl ester was dissolved in 5 ml of acetonitrile. This solution was added dropwise to a refluxing solution of 0.50 g (1.52 mmol) (+) - 8-35 chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-hydrochloride. 1H-3-methyl-3-benzazepine in 20 ml of acetonitrile and continued to reflux for an additional 8 hours. Acetonitrile and excess of 13
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reagenset blev inddampet in vacuo, efterladende en gul olie, som let blev renset ved brug af flashchromatografi på en kieselgelkolonne og inddampedes in vacuo til en hvid krystalliseret forbindelse.the reagent was evaporated in vacuo, leaving a yellow oil which was readily purified using flash chromatography on a silica gel column and evaporated in vacuo to a white crystallized compound.
55
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en retentionstid på 14,3 minutter.Purity by HPLC> 98%. Product maximum corresponds to a retention time of 14.3 minutes.
1H-NMR, ppm. (CD^SO-CDg, TMS): 1,25 3H(8d); 2,28 3H(s); 10 2,80-4,20 8H(m); 3,56 3H(s); 4,80 lH(d); 6,30 lH(s); 7,0- 8,0 6H(m).1 H-NMR, ppm. (CD ^SO-CDg, TMS): 1.25 3H (8d); 2.28 3H (s); 2.80-4.20 8H (m); 3.56 3H (s); 4.80 lH (d); 6.30 lH (s); 7.0 - 8.0 6H (m).
EKSEMPEL 5 15 (+)-8-chlor-7-[(S)(2-methoxycarbonyl)-1-pyrrolidinyl-carbo- nyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl- 3-benzazepin.EXAMPLE 5 (+) - 8-Chloro-7 - [(S) (2-methoxycarbonyl) -1-pyrrolidinyl-carbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydroalkyl 1H-3-methyl-3-benzazepine.
En opløsning af 0,58 g (3,05 mmol) N-chlorcarbonyl-L-pro-20 linmethylester i 10 ml tør pyridin blev sat dråbevis til 0,5 g (1,52 mmol) (+)-8-chlor-7-hydroxy-5-(7-benzofu-ranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin i 10 ml tør pyridin. Efter endt tilsætning blev blandingen placeret i et oliebad i 16 timer med reflux. Pyridin og over-25 skud af reagenset inddampedes in vacuo, og resten optoges i 50 ml æter, og vaskedes med 5% NaHCOg, mættet NaCl og ^O. Æterfasen blev tørret over MgSO^ og inddampedes til en olie. Residualolien blev renset på en kieselgelkolonne ved brug af flashchromotografi, og efter vacuminddamp-30 ning af opløsningen fremkom en hvid krystalliseret forbindelse.A solution of 0.58 g (3.05 mmol) of N-chlorocarbonyl-L-proline methyl ester in 10 ml of dry pyridine was added dropwise to 0.5 g (1.52 mmol) of (+) - 8-chloro 7-Hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine in 10 ml of dry pyridine. After completion of the addition, the mixture was placed in an oil bath for 16 hours with reflux. Pyridine and excess reagent were evaporated in vacuo and the residue was taken up in 50 ml of ether and washed with 5% NaHCO 3, saturated NaCl and 2 O. The ether phase was dried over MgSO4 and evaporated to an oil. The residual oil was purified on a silica gel column using flash chromatography and, after vacuum evaporation of the solution, a white crystallized compound was obtained.
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en retentionstid på 18,*6 minutter.Purity by HPLC> 98%. Product maximum corresponds to a retention time of 18, * 6 minutes.
1H-NMR, ppm. (CDC13, TMS): 1,50-4,50 19H(m,complex); 4,80 lH(d); 6,40 lH(d); 6,80-7,70 6H(m).1 H-NMR, ppm. (CDCl3, TMS): 1.50-4.50 19H (m, complex); 4.80 lH (d); 6.40 lH (d); 6.80-7.70 6H (m).
35 EKSEMPEL 6 14EXAMPLE 6 14
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(+)-8-chlor-7-(isopropylaminocarbonyloxy)-5-(7-benzofuranyl)- 2.3.4.5- tetrahydro-lH-3-methyl-3-benzazepin 5(+) - 8-chloro-7- (isopropylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 5
Til en refluxende blanding af 0,5 g(l,52 mmol) (+)-8-chlor- 7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-me-thyl- 3-benzazepin i 20 ml acetonitril sattes dråbevis 0,30 ml (3,04 mmol) isopropylisocyanat. Blandingen refluxe-10 des i yderligere 6 timer, og derefter fjernedes acetonitril ved inddampning in vacuo. Residualmaterialet fremkom som analytisk rene krystaller fra varm isopropanol.To a refluxing mixture of 0.5 g (1.52 mmol) (+) - 8-chloro-7-hydroxy-5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-me -thyl-3-benzazepine in 20 ml of acetonitrile was added dropwise 0.30 ml (3.04 mmol) of isopropyl isocyanate. The mixture was refluxed for an additional 6 hours and then acetonitrile was removed by evaporation in vacuo. The residual material appeared as analytically pure crystals from hot isopropanol.
Renhed ifølge HPLC > 98%. Produktmaksimum svarer til en 15 retentionstid på 17,5 minutter.Purity by HPLC> 98%. Product maximum corresponds to a retention time of 17.5 minutes.
1H-NMR, ppm. (CD3S0CD3, TMS): 1,00 6H(d); 2,20 3H(s); 2,10- 3,50 8H(m); 4,80 lH(s); 6,25 lH(s); 6,8-7,9 6H(m).1 H-NMR, ppm. (CD 3 SO 3, TMS): 1.00 6H (d); 2.20 3H (s); 2.10 - 3.50 8H (m); 4.80 lH (s); 6.25 lH (s); 6.8-7.9 6H (m).
20 Analogt med fremstillingen beskrevet i eksempel 6 blev følgende forbindelser syntetiseret: EKSEMPEL 7 25 (+)-8-chlor-7-(allylaminocarbonyloxy)-5-(7-benzofuranyl)- 2.3.4.5- tetrahydro-lH-3-methyl-3-benzazepin 1H-NMR, ppm. (CDC13, TMS): 2,35, 3H(s); 2,4-3,3 6H(m); 3,8 2H(t); 4,8 lH(t)? 5,0-5,2 3H(m); 5,8 lH(m); 6,4 lH(s); 6,78 30 lH(s); 7,05 lH(d); 7,25 2H(m); 7,55 2H(m).Analogously to the preparation described in Example 6, the following compounds were synthesized: EXAMPLE 7 (+) - 8-chloro-7- (allylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl 3-benzazepine 1 H-NMR, ppm. (CDCl3, TMS): 2.35, 3H (s); 2.4-3.3 6H (m); 3.8 2H (t); 4.8 lH (t)? 5.0-5.2 3H (m); 5.8 lH (m); 6.4 lH (s); 6.78 1H (s); 7.05 1H (d); 7.25 2H (m); 7.55 2H (m).
EKSEMPEL 8 (+)-8-chlor-7-(benzylaminocarbonyloxy)-5-(7-benzofuranyl)-35 2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin ved opvarmning til 70°C i toluen med 0,5 ækvivalent N-methyl- 15Example 8 (+) - 8-chloro-7- (benzylaminocarbonyloxy) -5- (7-benzofuranyl) -35 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine on heating to 70 ° C in toluene with 0.5 equivalent of N-methyl-15
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piperidin som katalysator.piperidine as a catalyst.
1H-NMR, ppm. (CDClg, TMS): 2,3 3H(s); 2,4-3,4 6H(m); 4,85 lH(d); 5,1-5,3 3H(m); 6,5 lH(s); 6,8 IH(s); 7,0-7,6 10H(m).1 H-NMR, ppm. (CDCl 3, TMS): 2.3 3H (s); 2.4-3.4 6H (m); 4.85 lH (d); 5.1-5.3 3H (m); 6.5 lH (s); 6.8 IH (s); 7.0-7.6 10H (m).
5 EKSEMPEL 9 (+)-8-chlor-7-(n-butylaminocarbonyloxy)-5-(7-benzofuranyl)- 2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin 10 ved opvarmning til 70°C i toluen med 0,2 ækvivalent N-me-thylpiperidin som katalysator.EXAMPLE 9 (+) - 8-Chloro-7- (n-butylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 10 on heating to 70 ° C in toluene with 0.2 equivalent of N-methylpiperidine as catalyst.
^H-NMR, ppm. (CDClg, TMS): 1,2 7H(m); 2,3 3H(s); 2,4-3,3 15 6H(m); 4,7 lH(d); 5,0-5,2 3H(m); 6,4 lH(s); 6,8 lH(d); 7,05 lH(d); 7,25 2H(m); 7,6 2H(m).1 H-NMR, ppm. (CDCl 3, TMS): 1.27H (m); 2.3 3H (s); 2.4-3.3 δ 6H (m); 4.7 lH (d); 5.0-5.2 3H (m); 6.4 lH (s); 6.8 lH (d); 7.05 1H (d); 7.25 2H (m); 7.6 2H (m).
EKSEMPEL 10 20 (+)-8-chlor-7-(cyclohexylaminocarbonyloxy)-5-(7-benzofu- ranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 24 timer i methylenchlorid med 1 ækvivalent triethylamin som katalysator.EXAMPLE 10 (+) - 8-Chloro-7- (cyclohexylaminocarbonyloxy) -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 24 hours hours in methylene chloride with 1 equivalent of triethylamine as catalyst.
25 1H-NMR, ppm. (CD3S0CD3, TMS): 1,0-1,8 10H(m); 2,15 lH(m); 2,25 3H(s); 2,6-3,2 5H(m); 3,7 lH(m); 4,6 lH(d); 6,2 lH(s); 6,8 2H(m); 7,15 2H(m); 7,6 2H(m).1 H NMR, ppm. (CD3 SOCD3, TMS): 1.0-1.8 10H (m); 2.15 lH (m); 2.25 3H (s); 2.6-3.2 5H (m); 3.7 lH (m); 4.6 1H (d); 6.2 lH (s); 6.8 2H (m); 7.15 2H (m); 7.6 2H (m).
30 Analogt med fremstillingen beskrevet i eksempel 4 blev følgende forbindelser syntetiseret: 35 (+)-8-chlor-7-[(S)-N-(1-methoxycarbonyl-phenethyl)amino- carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3- 5 methyl-3-benzazepin EKSEMPEL 11 16Analogously to the preparation described in Example 4, the following compounds were synthesized: 35 (+) - 8-chloro-7 - [(S) -N- (1-methoxycarbonyl-phenethyl) amino-carbonyloxy] -5- (7-benzofuranyl) -2,3,4,5-tetrahydro-1H-3- methyl-3-benzazepine Example 11 16
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^H-NMR, ppm. (CDC13, TMS): 2,25 3H(s); 2,4-3,2 6H(m); 3,8- 4.1 4H(s,m); 4,55 lH(d); 5,1 2H(m); 6,3 lH(s); 6,75 2H(m); 7,15 2H(m); 7,55 2H(m).1 H-NMR, ppm. (CDCl3, TMS): 2.25 3H (s); 2.4-3.2 6H (m); 3.8 - 4.1 4H (s, m); 4.55 lH (d); 5.1 2H (m); 6.3 lH (s); 6.75 2H (m); 7.15 2H (m); 7.55 2H (m).
10 EKSEMPEL 12 (+)-8-chlor-7-[(S)-N-(1-methoxycarbonyl-2-methylbutyl)amino-carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-15 methyl-3-benzazepin 1H-NMR, ppm. (CDClg, TMS): 1,2-1,5 9H(m); 2,3 3H(s); 2,4-3,2 6H(m); 3,8-4,3 4H(s,m); 4,55 lH(d); 5,2 2H(m); 6,3 IH(s); 6,7 2H(m); 7,3 2H(m); 7,6 2H(m).Example 12 (+) - 8-Chloro-7 - [(S) -N- (1-methoxycarbonyl-2-methylbutyl) amino-carbonylloxy] -5- (7-benzofuranyl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ppm. (CDCl 3, TMS): 1.2-1.5 9H (m); 2.3 3H (s); 2.4-3.2 6H (m); 3.8-4.3 4H (s, m); 4.55 lH (d); 5.2 2H (m); 6.3 IH (s); 6.7 2H (m); 7.3 2H (m); 7.6 2H (m).
20 EKSEMPEL 13 (+ )„-8-chlor-7-[ (R, S) -N- (1-methoxycarbonyl-3-methylbutyl) -aminocarbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-25 lH-3-methyl-3-benzazepin 1H-NMR, ρρπκ (CDC13, TMS): 1,2-1,5 9H(m); 2,3J3H(s); 2,4- 3.2 6H(m); 3,8-4,3 4H(s,m); 4,6 lH(d); 5,3 2H(m); 6,5 lH(s); 6,7 2H(m); 7,3 2H(m); 7,7 2H(m).EXAMPLE 13 (+) + - 8-Chloro-7- [(R, S) -N- (1-methoxycarbonyl-3-methylbutyl) aminocarbonyloxy] -5- (7-benzofuranyl) -2,3,4, 5-tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ρρπκ (CDCl 3, TMS): 1.2-1.5 9H (m); 2,3J3H (s); 2.4 - 3.2 6H (m); 3.8-4.3 4H (s, m); 4.6 1H (d); 5.3 2H (m); 6.5 lH (s); 6.7 2H (m); 7.3 2H (m); 7.7 2H (m).
3030
Analogt med fremstillingen beskrevet i eksempel 2 blev følgende forbindelser syntetiseret: 35 (+)-8-chlor-7-[(N,N-dimethylamino)carbonyloxy]-5-(2,3-di- hydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3- 5 benzazepin, HC1 EKSEMPEL 14 17Analogously to the preparation described in Example 2, the following compounds were synthesized: 35 (+) - 8-chloro-7 - [(N, N-dimethylamino) carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-tetrahydro-1H-3-methyl-3- benzazepine, HCl EXAMPLE 14 17
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1H-NMR, ppm. fri base (CDgSOCDg, TMS): 2,2 lH(t); 2,3 3H(s); 2,85 3H(s); 3,0 3H(s); 2,6-3,3 7H(m); 4,35 lH(d); 4,4 2H(t); 6,38 lH(s); 6,95 2H(m); 7,2 2H(m).1 H-NMR, ppm. free base (CDgSOCDg, TMS): 2.2 lH (t); 2.3 3H (s); 2.85 3H (s); 3.0 3H (s); 2.6-3.3 7H (m); 4.35 lH (d); 4.4 2H (t); 6.38 lH (s); 6.95 2H (m); 7.2 2H (m).
10 EKSEMPEL 15 (+)-8-chlor-7-[(N,N-diethylamino)carbonyloxy]-5-(2,3-dihy-dro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-ben-15 zazepin, HC1 1H-NMR, ppm. (CD3SOCD3, TMS): 1,15 6H(dobbelt t); 2,85 3H(s); 3,0-3,8 12H(m); 4,5 2H(m); 4,85 lH(d); 6,3 lH(s); 7,0 2H(m); 7,3 2H(d); 20 EKSEMPEL 16 (+)-8-chlor-7-[(N-methyl-N-cyclohexyl)aminocarbonyloxy]- 5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-25 methyl-3-benzazepin, HC1 ved reflux i 4 timer i pyridin- ^-NMR, ppm. fri base (CD3SOCD3, TMS): 1,0-1,8 10H(m); 30 2,15 1H(t); 2,2 3H(s); 2,7-3,7 HH(m); 4,35 lH(d); 4,45 2H(t); 6,35 lH(s); 6,9 2H(m); 7,2 lH(d); 7,35 lH(s).EXAMPLE 15 (+) - 8-Chloro-7 - [(N, N-diethylamino) carbonylloxy] -5- (2,3-dihydro-benzofuran-7-yl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine, HCl 1 H-NMR, ppm. (CD3SOCD3, TMS): 1.15 6H (double t); 2.85 3H (s); 3.0-3.8 12H (m); 4.5 2H (m); 4.85 lH (d); 6.3 lH (s); 7.0 2H (m); 7.3 2H (d); Example 16 (+) - 8-Chloro-7 - [(N-methyl-N-cyclohexyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-25 methyl-3-benzazepine, HCl at reflux for 4 hours in pyridine-1-NMR, ppm. free base (CD3SOCD3, TMS): 1.0-1.8 10H (m); 2.15 1H (t); 2.2 3H (s); 2.7-3.7 HH (m); 4.35 lH (d); 4.45 2H (t); 6.35 lH (s); 6.9 2H (m); 7.2 lH (d); 7.35 lH (s).
EKSEMPEL 17 35 (+)-8-chlor-7-[(N-methyl-N-ethyl)aminocarbonyloxy]-5-(2,3- dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin, HC1 18EXAMPLE 17 (+) - 8-Chloro-7 - [(N-methyl-N-ethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-methyl-3-benzazepine, HCl 18
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ved reflux i 8 timer i pyridin.by reflux for 8 hours in pyridine.
^H-NMR, ppm. fri base (CD^OCDg, TMS): 1,0-1,15 3H(dobbelt t, efter opvarmning til 90°C fremstår det som en t); 2,15 5 lH(t); 2,25 3H(s); 2,7-3,4 12H(m); 4,4 lH(d); 4,45 2H(t); 6,35 IH(bred s); 6,9 2H(m); 7,2 2H(d).1 H-NMR, ppm. free base (CD2 OCDg, TMS): 1.0-1.15 3H (double t, after heating to 90 ° C it appears as a t); 2.15 δ 1H (t); 2.25 3H (s); 2.7-3.4 12H (m); 4.4 lH (d); 4.45 2H (t); 6.35 IH (broad s); 6.9 2H (m); 7.2 2H (d).
EKSEMPEL 18 10 (+)-8-chlor-7-[(N-methyl-N-isopropyl)aminocarbonyloxy]-5- (2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl- 3-benzazepin, HC1 ved reflux i 8 timer i pyridin.Example 18 (+) - 8-Chloro-7 - [(N-methyl-N-isopropyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1H-3-methyl-3-benzazepine, HCl at reflux for 8 hours in pyridine.
15 1H-NMR, ppm. fri base (CD3S0CD3, TMS): 1,0-1,2 6H(dobbelt d); 2,15 1H(t); 2,25 3H(s); 2,7-3,25 llH(m); 4,4 IH(d); 4,45 2H(t); 6,3 lH(s)? 6,9 2H(m); 7,2 IH(d); 7,4 lH(s).1 H-NMR, ppm. free base (CD3 SOCD3, TMS): 1.0-1.2 6H (double d); 2.15 1H (t); 2.25 3H (s); 2.7-3.25 lH (m); 4.4 IH (d); 4.45 2H (t); 6.3 lH (s)? 6.9 2H (m); 7.2 IH (d); 7.4 lH (s).
20 EKSEMPEL 19 (+)-8-chlor-7-[(N-methyl-N-benzyl)aminocarbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin, HC1 25 ^H-NMR, ppm. fri base (CD3S0CD3, TMS): 2,25 lH(t); 2,3 3H(s); 2,7-3,3 10H(m)? 4,3-4,6 5H(m); 6,3 lH(d); 6,9 2H(m); 7,2-7,5 7H(m).EXAMPLE 19 (+) - 8-Chloro-7 - [(N-methyl-N-benzyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydroxy 1 H-3-methyl-3-benzazepine, HCl 25 H-NMR, ppm. free base (CD3 SOCD3, TMS): 2.25 lH (t); 2.3 3H (s); 2.7-3.3 10H (m)? 4.3-4.6 5H (m); 6.3 lH (d); 6.9 2H (m); 7.2-7.5 7H (m).
30 Analogt med fremstillingen beskrevet i eksempel 5 blev følgende forbindelser syntetiseret: EKSEMPEL 20 35 (+)-8-chlor-7-[(S)-(2-benzyloxycarbonyl)-1-pyrrolidinyl- carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetra-hydro-1H-3-methyl-3-benzazepinAnalogously to the preparation described in Example 5, the following compounds were synthesized: EXAMPLE 20 (+) - 8-chloro-7 - [(S) - (2-benzyloxycarbonyl) -1-pyrrolidinylcarbonyloxy] -5- (2.3) -dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine
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19 ved reflux i 4 timer i pyridin.19 by reflux for 4 hours in pyridine.
ppm. (CD3SOCD3, TMS): 1,8-2,0 3H(m); 2,2 2H(s); 2,3 3H(s); 2,8-3,7 10H(m); 4,4-4,55 3H(m); 4,95-5,2 2H(m); 5 6,45 lH(d); 6,7 lH(s); 6,9 2H(m); 7,2 lH(m); 7,25-7,4 5H(m).ppm. (CD3SOCD3, TMS): 1.8-2.0 3H (m); 2.2 2H (s); 2.3 3H (s); 2.8-3.7 10H (m); 4.4-4.55 3H (m); 4.95-5.2 2H (m); Δ 6.45 lH (d); 6.7 1H (s); 6.9 2H (m); 7.2 lH (m); 7.25-7.4 5H (m).
EKSEMPEL 21 10 (+)-8-chlor-7-[(R)-(2-benzyloxycarbonyl)-1-pyrrolidinyl- carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepin ved reflux i 4 timer i pyridin.Example 21 (+) - 8-chloro-7 - [(R) - (2-benzyloxycarbonyl) -1-pyrrolidinylcarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 , 5-Tetra-hydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.
15 1H-NMR, ppm. (CD3S0CD3, D20, TMS)i 1,8-2,0 3H(m); 2,2 2H(s); 2,3 3H(s); 2,8-3,7 10H(m); 4,4-4,55 3H(m); 4,95-' 5,2 2H(m); 6,45 lH(d); 6,7 lH(s); 6,9 2H(m); 7,2 lH(m); 7,25-7,4 5H(m).1 H-NMR, ppm. (CD3 SOCD3, D20, TMS) in 1.8-2.0 3H (m); 2.2 2H (s); 2.3 3H (s); 2.8-3.7 10H (m); 4.4-4.55 3H (m); 4.95 - 5.2 2H (m); 6.45 lH (d); 6.7 1H (s); 6.9 2H (m); 7.2 lH (m); 7.25-7.4 5H (m).
20 EKSEMPEL 22 (+)-8-chlor-7-[(S)-(2-N,N-diethylaminocarbonyl-methyloxy-carbonyl)-1-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydrobenzo-25 furan-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 4 timer i pyridin.EXAMPLE 22 (+) - 8-Chloro-7 - [(S) - (2-N, N-diethylaminocarbonyl-methyloxy-carbonyl) -1-pyrrolidinyl-carbonylloxy] -5- (2,3-dihydrobenzo-furan) (7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.
^•H-NMR, ppm. (CD3SOCD3, D20, TMS): 1,0-1,1 6H(dobbelt t, 30 efter opvarmning til 90°C fremstår det som en t); 1,9 2H(m); 2,1- 2,3 6H(s,m); 2,6-3,6 13H(m); 4,3-4,55 4H(m); 4,6-4,85 2H(m); 6,35 lH(d); 6,9 2H(m); 7,2 2H(m); 7,4 lH(d).1 H-NMR, ppm. (CD3SOCD3, D20, TMS): 1.0-1.1 6H (double t, 30 after heating to 90 ° C appears as a t); 1.9 2H (m); 2.1-2.36H (s, m); 2.6-3.6 13H (m); 4.3-4.55 4H (m); 4.6-4.85 2H (m); 6.35 lH (d); 6.9 2H (m); 7.2 2H (m); 7.4 lH (d).
EKSEMPEL 23 35 (+)-8-chlor-7-[(R)-(2-N,N-diethylaminocarbonyl-methyloxy-carbonyl)-1-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydrobenzo-EXAMPLE 23 (+) - 8-Chloro-7 - [(R) - (2-N, N-diethylaminocarbonyl-methyloxy-carbonyl) -1-pyrrolidinyl-carbonylloxy] -5- (2,3-dihydrobenzoic acid)
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20 furan-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 4 timer i pyridin.(Furan-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine by reflux for 4 hours in pyridine.
5 1H-NMR/ ppm. (CDgSOCDg, TMS). 1,0-1,1 6H(dobbelt t, efter opvarmning til 90°C fremstår det som en t); 1,9 2H(m); 2,1- 2,3 6H(s,m); 2,6-3,6 13H(m); 4,3-4,55 4H(m); 4,6-4,85 2H(m); 6,35 lH(d); 6,9 2H(m); 7,2 2H(m); 7,4 lH(d).1 H NMR / ppm. (CDgSOCDg, TMS). 1.0-1.1 6H (double t, after heating to 90 ° C it appears as a t); 1.9 2H (m); 2.1-2.36H (s, m); 2.6-3.6 13H (m); 4.3-4.55 4H (m); 4.6-4.85 2H (m); 6.35 lH (d); 6.9 2H (m); 7.2 2H (m); 7.4 lH (d).
10 EKSEMPEL 24 (+)-8-chlor-7-[(S)-(2-carboxy)-l-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin 15 -- 113 mg (0,2 mmol) (+)-8-chlor-7-[(S)-(2-benzyloxycarbonyl)- 1-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin (eksempel 20 22) blev opløst i 20 ml tetrahydrofuran. 10 mg palladium/- cellit (10%) tilsattes og opslæmningen blev hydrogeneret ved stuetemperatur og 1 atm. i 45 minutter. Yderligere til-sattes 20 mg palladium/carbon (10%), og blandingen blev hydrogeneret i 3 timer. Katalysatoren blev fjernet ved 25 filtrering, og opløsningsmidlet inddampedes in vacuo.EXAMPLE 24 (+) - 8-Chloro-7 - [(S) - (2-carboxy) -1-pyrrolidinyl-carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 5-Tetrahydro-1H-3-methyl-3-benzazepine 15 - 113 mg (0.2 mmol) (+) - 8-chloro-7 - [(S) - (2-benzyloxycarbonyl) -1-pyrrolidinyl] carbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine (Example 20 22) was dissolved in 20 ml of tetrahydrofuran. 10 mg of palladium / cellite (10%) was added and the slurry was hydrogenated at room temperature and 1 atm. for 45 minutes. Further, 20 mg of palladium / carbon (10%) was added and the mixture was hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated in vacuo.
Resten opløstes i få ml methanol/tetrahydrofuran, vand tilsattes, og produktet fremkom ved lyofilisering.The residue was dissolved in few ml of methanol / tetrahydrofuran, water was added and the product obtained by lyophilization.
H-NMR, ppm. (CDgSOCDg, D20, TMS): 1,8-2,0 3H(m); 2,1-2,3 30 lH(m); 2,25 3H(s); 2,9-4,6 22H(m); 6,45 lH(s); 6,9 2H(d); 7,2 !H(broad s); 7,4 lH(d).1 H-NMR, ppm. (CDgSOCDg, D₂O, TMS): 1.8-2.0 3H (m); 2.1-2.3 1H (m); 2.25 3H (s); 2.9-4.6 22H (m); 6.45 lH (s); 6.9 2H (d); 7.2 H (broad s); 7.4 lH (d).
EKSEMPEL 25 35 (+)-8-chlor-7-[(R)-(2-carboxy)-1-pyrrolidinyl-carbonyloxy]- 5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepinExample 25 (+) - 8-chloro-7 - [(R) - (2-carboxy) -1-pyrrolidinyl-carbonyloxy] 5- (2,3-dihydrobenzofuran-7-yl) -2,3,4 , 5-tetrahydro-lH-3-methyl-3-benzazepine
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2121
Forbindelsen blev fremstillet analogt med fremstillingen beskrevet i eksempel 24.The compound was prepared analogously to the preparation described in Example 24.
^NMR, ppm. (CD3SOCD3, H20, TMS): 1,8-2,0 3H(m); 2,1-2,3 5 lH(m); 2,25 3H(s); 2,9-4,6 22H(m); 6,45 lH(s); 6,9 2H(d); 7,2 IH(bred s); 7,4 lH(d).1 NMR, ppm. (CD3SOCD3, H2O, TMS): 1.8-2.0 3H (m); 2.1-2.3 δ 1H (m); 2.25 3H (s); 2.9-4.6 22H (m); 6.45 lH (s); 6.9 2H (d); 7.2 IH (broad s); 7.4 lH (d).
Analogt med fremstillingen beskrevet i eksempel 5 blev følgende forbindelser syntetiseret: 10 EKSEMPEL 26 (+)-8-chlor-7-[(S)-(N-methyl-N-(1-methoxycarbonyl-l-phen-ethyl))aminocarbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-15 2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 4 timer i pyridin.By analogy with the preparation described in Example 5, the following compounds were synthesized: EXAMPLE 26 (+) - 8-chloro-7 - [(S) - (N-methyl-N- (1-methoxycarbonyl-1-phenethyl)) aminocarbonyloxy ] -5- (2,3-dihydrobenzofuran-7-yl) -15 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine at reflux for 4 hours in pyridine.
1H-NMR, ppm. (CD^OCDg, D20, TMS): 2,1-2,2 4H(s,t); 2,6-20 3,2 12H(m); 3,6 3H(d, efter opvarmning til 90°C fremstår det som s); 4,3-4,5 3H(m); 4,8 lH(m); 6,4 lH(d, efter opvarmning til 90°C fremstår det som en enkelt spektrallinie); 6,85 2H(m); 7,15-7,35 7H(m).1 H-NMR, ppm. (CD ^OCDg, D₂O, TMS): 2.1-2.2 4H (s, t); 2.6-20 3.2 12H (m); 3.6 3H (d, after heating to 90 ° C it appears as s); 4.3-4.5 3H (m); 4.8 lH (m); 6.4 lH (d, after heating to 90 ° C it appears as a single spectral line); 6.85 2H (m); 7.15-7.35 7H (m).
25 EKSEMPEL 27 (+)-8-chlor-7-[(S)-N-methyl-N-(1-N',N1-diethylaminocarbonyl-methyloxycarbonyl-l-phenethyl)aminocarbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-30 benzazepin ved reflux i 5 timer i pyridin.EXAMPLE 27 (+) - 8-chloro-7 - [(S) -N-methyl-N- (1-N ', N1-diethylaminocarbonyl-methyloxycarbonyl-1-phenethyl) aminocarbonyloxy] -5- (2,3- dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-30-benzazepine by reflux for 5 hours in pyridine.
1H-NMR, ppm. (CD3S0CD3, TMS): 0,9-1,1 6H(dobbelt t); 2,7-5,1 35 26H(m); 6,1 lH(s); 6,9-7,5 9H(m).1 H-NMR, ppm. (CD 3 SO 3, TMS): 0.9-1.1 6H (double t); 2.7-5.1 26H (m); 6.1 1H (s); 6.9-7.5 9H (m).
EKSEMPEL 28 22EXAMPLE 28 22
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(+)-8-chlor-7-[(S)-N-methyl-N-(1-methoxycarbonyl-l-ethyl)-aminocarbonyloxy] -5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-5 tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 6 timer i pyridin.(+) - 8-chloro-7 - [(S) -N-methyl-N- (1-methoxycarbonyl-1-ethyl) -aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2, 3,4,5-5 tetrahydro-1H-3-methyl-3-benzazepine at reflux for 6 hours in pyridine.
^H-NMR, ppm. (CDgSOCDg, TMS): 1,4 3H(dobbelt d); 2,2 lH(t); 10 2,25 3H(s); 2,7-3,3 10H(m); 3,6 3H(dobbelt s); 4,4 IH(d); 4,5 2H(t); 4,6 lH(m); 6,4 lH(d); 6,9 2H(m); 7,2 lH(d); 7,4 lH(d).1 H-NMR, ppm. (CDgSOCDg, TMS): 1.4 3H (double d); 2.2 lH (t); 2.25 3H (s); 2.7-3.3 10H (m); 3.6 3H (double s); 4.4 IH (d); 4.5 2H (t); 4.6 lH (m); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).
EKSEMPEL 29 15 (+)-8-chlor-7-[N-methyl-N-(benzyloxycarbonyl-methyl)aminocarbonyloxy] -5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepin 20 ^H-NMR, ppm. (CD^OCDg, TMS): 2,1 IH(t); 2,15 3H(s); 2,7- 3,4 9H(m); 4,1-4,3 2H(d, efter opvarmning til 90°C fremstår det som en enkelt spektrallinie); 4,4 lH(t); 4,5 2H(t); 5,15 2H(m); 6,4 lH(d); 6,85 2H(m); 7,15 lH(t); 7,35 6H(m).EXAMPLE 29 (+) - 8-Chloro-7- [N-methyl-N- (benzyloxycarbonylmethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5- tetrahydro-1H-3-methyl-3-benzazepine 20 H-NMR, ppm. (CD ^OCDg, TMS): 2.1 IH (t); 2.15 3H (s); 2.7-3.49H (m); 4.1-4.3 2H (d, after heating to 90 ° C it appears as a single spectral line); 4.4 lH (t); 4.5 2H (t); 5.15 2H (m); 6.4 lH (d); 6.85 2H (m); 7.15 lH (t); 7.35 6H (m).
25 ' EKSEMPEL 30 (+)-8-chlor-7-[N-methyl-N-(methoxycarbonyl-methyl)aminocarbonyloxy] -5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetra-30 hydro-lH-3-methyl-3-benzazepin 1 35 H-NMR, ppm. (CD3S0CD3, TMS): 2,2 lH(t); 2,3 3H(s); 2,8- 3.3 10H(m); 3,65 3H(d); 4,15 2H(d); 4,4 lH(t); 4,5 2H(t); 6.4 lH(d); 6,9 2H(m); 7,2 lH(d); 7,4 lH(d).EXAMPLE 30 (+) - 8-Chloro-7- [N-methyl-N- (methoxycarbonylmethyl) aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5 -tetra-hydro-1H-3-methyl-3-benzazepine 1 H NMR, ppm. (CD 3 SO 3, TMS): 2.2 lH (t); 2.3 3H (s); 2.8 - 3.3 10H (m); 3.65 3H (d); 4.15 2H (d); 4.4 lH (t); 4.5 2H (t); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).
EKSEMPEL 31 23EXAMPLE 31 23
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(+)-8-chlor-7-[ (R, S)-N-methyl-N-(1-methoxycarbonyl-l-ethyl)-aminocarbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-5 tetrahydro-lH-3-methyl-3-benzazepin ved reflux i 6 timer i pyridin.(+) - 8-Chloro-7- [(R, S) -N-methyl-N- (1-methoxycarbonyl-1-ethyl) -aminocarbonyloxy] -5- (2,3-dihydrobenzofuran-7-yl) - 2,3,4,5-5 tetrahydro-1H-3-methyl-3-benzazepine at reflux for 6 hours in pyridine.
1H-NMR, ppm. (CD3SOCD3, TMS): 1,4 3H(dobbelt d); 2,2 lH(t); 10 2,3 3H(s); 2,8-3,4 10H(m); 3,6 3H(t); 4,4 lH(d); 4,5 2H(t); 4,6 lH(m); 6,4 lH(d); 6,9 2H(m); 7,2 lH(d); 7,4 lH(d).1 H-NMR, ppm. (CD3SOCD3, TMS): 1.4 3H (double d); 2.2 lH (t); 2.3 3H (s); 2.8-3.4 10H (m); 3.6 3H (t); 4.4 lH (d); 4.5 2H (t); 4.6 lH (m); 6.4 lH (d); 6.9 2H (m); 7.2 lH (d); 7.4 lH (d).
EKSEMPEL 32 15 (+)-8-chlor-7-[(N-methyl-N-carboxymethyl)aminocarbonyloxy]- 5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepin, HC1EXAMPLE 32 (+) - 8-Chloro-7 - [(N-methyl-N-carboxymethyl) aminocarbonyloxy] 5- (2,3-dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-hydroxy 1H-3-methyl-3-benzazepine, HCl
Forbindelsen blev fremstillet analogt med fremstillingen 20 beskrevet i eksempel 26 ved hydrogenering i 10 timer ved brug af hydrochloridsaltet af (+)-8-chlor-7-[N- methyl-N-(benzyloxycarbonyl-methyl)aminocarbonyloxy]-5-(2,3-dihy-drobenzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-ben-zazepin 25 1H-NMR, ppm. (CD3S0CD3, TMS): -2,75 3H(s); 2,8-3,0 3H(2s); 3,1-3,6 8H(m); 3,9-4,1 2H(2s); 4,5 2H(m); 4,8 lH(s); 6,35 lH(s); 6,9 2H(d); 7,3 lH(d); 7,5 lH(d).The compound was prepared analogously to the preparation 20 described in Example 26 by hydrogenation for 10 hours using the hydrochloride salt of (+) - 8-chloro-7- [N- methyl-N- (benzyloxycarbonylmethyl) aminocarbonyloxy] -5- (2) (3-Dihydrobenzofuran-7-yl) -2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine 1 H-NMR, ppm. (CD 3 SO 3, TMS): -2.75 3H (s); 2.8-3.0 3H (2s); 3.1-3.6 8H (m); 3.9-4.1 2H (2s); 4.5 2H (m); 4.8 lH (s); 6.35 lH (s); 6.9 2H (d); 7.3 lH (d); 7.5 lH (d).
30 EKSEMPEL 33EXAMPLE 33
Tabletter fremstilles ved teknikker kendt af fagmanden, og sammensætningen af hver tablet er som følger: 35 24Tablets are prepared by techniques known to those skilled in the art, and the composition of each tablet is as follows: 24
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Formulering, tabletter mg/tabletFormulation, mg / tablet tablets
Benzazepin 50 5 Lactose 120Benzazepine 50 5 Lactose 120
Avicel (PH 101) 40Avicel (PH 101) 40
Kollidon K25 5Kollidon K25 5
Talkum 4Talc 4
Magnesiumstearat 1 - 10 ----:-Magnesium stearate 1 - 10 ----: -
Tabletvægt 220Tablet weight 220
Biotilgængelighed af prodrugs beskrevet i eksemplerne 1-15 32, målt i bastardhunde i overensstemmelse med den tidli gere angivne metode, er vist i nedenstående tabel.Bioavailability of prodrugs described in Examples 1-15 32, measured in bastard dogs according to the method previously described, is shown in the table below.
Til sammenligning er den absolutte biotilgængelighed af grundforbindelserne, ligeledes målt i bastardhunde, i gen-20 nemsnit omkring 5%.In comparison, the absolute bioavailability of the basic compounds, also measured in bastard dogs, is on average about 5%.
25 ' 30 35 2525 '30 35 25
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TABELTABLE
CH.CH.
5 / \ /CH2-CH2\ O Cl-C c \ \\ II I /-ch3 \ / Xch-ch2/ 10 Λ CH7 Λ.5 / \ / CH2-CH2 \ O Cl-C c \ \\ II I / -ch3 \ / Xch-ch2 / 10 Λ CH7 Λ.
R8 R9 15R8 R9 15
Absolut biotilgængelighed, F (%) 5 8 9 20 Eksempel nr. R R R F (%)Absolute bioavailability, F (%) 5 8 9 20 Example No. R R R F (%)
Eksempel 1 -CH^ "^3 ^0 25Example 1 -CH 2
Eksempel 4 1 -H -CH-C-OCH^ 40 ixy ' ch3 o 30 /CH3 i -CH 15Example 4 1 -H -CH-C-OCH
Eksempel 6 -H CH^ 35Example 6 -H CH 3
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2626
Eksempel 7 (^]^) ”CH2_CH=CH2 _H 24EXAMPLE 7 (3) = CH2_CH = CH2_H24
Eksempel 8 iCH2 -o. -« 5Example 8 iCH2 -o. - «5
Eksempel 10 ^ ”H 6 10 Γ -CH-c-och3Example 10 6 H 6 10 CH -CH-c-och3
Eksempel 11 “H I II 7 ?H2 0 15Example 11 “H I II 7? H2 0 15
20 O20 O
« I -CH-C-0CHo T 3«I -CH-C-0CHo T 3
Eksempel 12 Γ JT \ -H | 11 HC-CHo 25 I - ?H2 ch3Example 12 Γ JT \ -H | 11 HC-CHo 25 I -? H2 ch3
30 I30 I
Eksempel 13 \ -H -CH-C-0CHQExample 13 \ -H -CH-C-OCHQ
I I 3 7 9H2 oI I 3 7 9H2 o
35 ^CH35 CH
Xch3 27Xch3 27
DK 162228 BDK 162228 B
Eksempel 14 ”CH3 ”CH3 30 5 Eksempel 15 "C2H5 ”C2H5 14Example 14 "CH3" CH3 30 Example 15 "C2H5" C2H5 14
Eksempel 28 "CH3 "9H £_C>CH3 IJJ I II 18 10 ch3 o 15 20 25 30 35Example 28 "CH3" 9H £ C> CH3 IJJ I II 18 10 ch3 o 15 20 25 30 35
Claims (14)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK87689A DK162228C (en) | 1988-03-01 | 1989-02-24 | SUBSTITUTED 7-AMINOCARBONYLOXY-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK107688 | 1988-03-01 | ||
DK107688A DK107688D0 (en) | 1988-03-01 | 1988-03-01 | CARBAMIC ACID ESTERS OF SUBSTITUTED 7-HYDROXY-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES |
DK87689 | 1989-02-24 | ||
DK87689A DK162228C (en) | 1988-03-01 | 1989-02-24 | SUBSTITUTED 7-AMINOCARBONYLOXY-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
Publications (4)
Publication Number | Publication Date |
---|---|
DK87689D0 DK87689D0 (en) | 1989-02-24 |
DK87689A DK87689A (en) | 1989-09-29 |
DK162228B true DK162228B (en) | 1991-09-30 |
DK162228C DK162228C (en) | 1992-03-02 |
Family
ID=26064824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK87689A DK162228C (en) | 1988-03-01 | 1989-02-24 | SUBSTITUTED 7-AMINOCARBONYLOXY-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES, THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE COMPOUNDS |
Country Status (1)
Country | Link |
---|---|
DK (1) | DK162228C (en) |
-
1989
- 1989-02-24 DK DK87689A patent/DK162228C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
DK87689A (en) | 1989-09-29 |
DK87689D0 (en) | 1989-02-24 |
DK162228C (en) | 1992-03-02 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PBP | Patent lapsed |