NO174584B - Analogous methods for the preparation of therapeutically active kinuk lidin derivatives - Google Patents
Analogous methods for the preparation of therapeutically active kinuk lidin derivatives Download PDFInfo
- Publication number
- NO174584B NO174584B NO903254A NO903254A NO174584B NO 174584 B NO174584 B NO 174584B NO 903254 A NO903254 A NO 903254A NO 903254 A NO903254 A NO 903254A NO 174584 B NO174584 B NO 174584B
- Authority
- NO
- Norway
- Prior art keywords
- cis
- quinuclidine
- methylamino
- formula
- carbon atoms
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title claims description 19
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 110
- -1 2,3-dihydrobenzofuranyl Chemical group 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000004122 cyclic group Chemical group 0.000 claims description 27
- 239000007795 chemical reaction product Substances 0.000 claims description 26
- 150000008584 quinuclidines Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000005002 aryl methyl group Chemical group 0.000 claims description 22
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- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
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- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 claims description 8
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- 125000001424 substituent group Chemical group 0.000 claims description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
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Description
Denne oppfinnelse angår en fremgangsmåte for fremstilling av nye og anvendelige kinuklidinderivater av interesse innen det medisinsk/kjemiske og kjemoterapeutiske felt. Mer spesielt angår den fremstilling av en ny rekke av cis-3-[(cyklisk)-metylamino]-2-[(a-substituert)arylmetyl]kinuklidiner, 3-[(cyklisk)metylimino]-2-[(a-substituert)arylmetyl]kinuklidiner og cis-3-[(cyklisk)metylenamino]-2-[(a-substituert)arylmetyl]-kinuklidiner, innbefattet deres farmasøytisk akseptable salter, som er av spesiell verdi som følge av deres evne til å antagonisere substans P. På denne måte er forbindelsene anvendelige ved behandling av gastrointestinale forstyrrelser, forstyrrelser i sentralnervesystemet, inflammatoriske sykdommer, samt smerte og migrene. This invention relates to a process for the production of new and applicable quinuclidine derivatives of interest in the medical/chemical and chemotherapeutic field. More particularly, it relates to the preparation of a new series of cis-3-[(cyclic)-methylamino]-2-[(α-substituted)arylmethyl]quinuclidines, 3-[(cyclic)methylimino]-2-[(α-substituted )arylmethyl]quinuclidines and cis-3-[(cyclic)methyleneamino]-2-[(α-substituted)arylmethyl]-quinuclidines, including their pharmaceutically acceptable salts, which are of particular value due to their ability to antagonize substance P In this way, the compounds are useful in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, as well as pain and migraine.
Bakgrunn for oppfinnelsen Background for the invention
E. J. Warawa omtaler i US-patent 3.560.510 visse 3-amino-2-benzhydrylkinuklidiner som nyttige diuretiske midler, hvor de tilsvarende usubstituerte 3-benzylamino-forbindelser virker som mellomprodukter for de samme. Dessuten har E. J. Warawa et al. i Journal of Medicinal Chemistrv. Vol. 18, s. 587 (1975) utvidet dette arbeidet til å innbefatte andre medlemmer av serien, hvor 3-amino-delen er etylamino, /3-fenyletylamino, f3-isopropylamino eller 2-furfurylamino, men det er ikke i noe tilfelle tale om substitusjon på selve fenylgruppen, og 2-benzhydryl-delen er alltid symmetrisk substituert (eller usubstituert). Ingen av de nevnte dokumenter nevner heller at noen av disse forbindelsene skulle være egnet som substans P antagonister. E. J. Warawa mentions in US patent 3,560,510 certain 3-amino-2-benzhydrylquinuclidines as useful diuretics, where the corresponding unsubstituted 3-benzylamino compounds act as intermediates for the same. Moreover, E. J. Warawa et al. in Journal of Medicinal Chemistry. Vol. 18, p. 587 (1975) extended this work to include other members of the series, where the 3-amino moiety is ethylamino, /3-phenylethylamino, 3-isopropylamino or 2-furfurylamino, but it is in no case this is about substitution on the phenyl group itself, and the 2-benzhydryl part is always symmetrically substituted (or unsubstituted). Neither of the aforementioned documents mentions that any of these compounds should be suitable as substance P antagonists.
Substans P er et naturlig forekommende undekapeptid tilhørende peptidfamilien tachykinin, hvor sistnevnte har denne betegnelsen på grunn av deres raskt innsettende stimulerende virkning på glatt muskelvev. Mer spesifikt er substans P et farmakologisk aktivt neuropeptid som dannes i pattedyr (opprinnelig isolert fra tarmen) og har en karakte-ristisk aminosyresekvens som er illustrert av D. F. Veber et al., i US-patent 4.680.283. Det foreligger omfattende demon-strasjoner på feltet som viser den utstrakte medvirkning av substans P og andre tachykininer i patofysiologien for en rekke sykdommer. For eksempel har substans P nylig vist seg å være involvert i overføringen av smerte eller migrene [se B. E. B. Sandberg et al. Journal of Medicinal Chemistry, Vol. 25, s. 1009 (1982)], så vel som ved slike forstyrrelser i sentralnervesystemet som angst og schizofreni, ved respiratoriske og inflammatoriske sykdommer som henholdsvis astma og reumatoid artritt, og ved gastrointestinale forstyrrelser og sykdommer i den gastrointestinale trakt, så som ulcerativ kolitt og Crohn's sykdom, etc. (se D. Regoli i " Trends in Cluster Headache". Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, s. 85-95). Substance P is a naturally occurring undecapeptide belonging to the tachykinin peptide family, the latter having this designation due to their rapid onset stimulating effect on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide produced in mammals (originally isolated from the gut) and having a characteristic amino acid sequence illustrated by D.F. Veber et al., in US Patent 4,680,283. There are extensive demonstrations in the field that show the extensive involvement of substance P and other tachykinins in the pathophysiology of a number of diseases. For example, substance P has recently been shown to be involved in the transmission of pain or migraine [see B. E. B. Sandberg et al. Journal of Medicinal Chemistry, Vol. 25, p. 1009 (1982)], as well as in such disorders of the central nervous system as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis respectively, and in gastrointestinal disorders and diseases of the gastrointestinal tract, such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache". Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
Relativt nylig er det gjort enkelte forsøk på å frembringe peptidlignende substanser som er antagonister av substans P og andre tachykinin-peptider for mer effektivt å behandle de ovenfor angitte ulike lidelser og sykdommer. Den peptidlignende natur av slike substanser gjør at de fra et metabolsk synspunkt er for labile til å tjene som praktisk terapeutiske midler ved behandling av sykdom. De ikke-peptidiske antagonister i henhold til oppfinnelsen har imidlertid ikke disse ulemper, og er sett fra den metabolske side langt mer stabile enn tidligere omtalte kjente midler. Relatively recently, some attempts have been made to produce peptide-like substances which are antagonists of substance P and other tachykinin peptides in order to more effectively treat the above-mentioned various disorders and diseases. The peptide-like nature of such substances means that, from a metabolic point of view, they are too labile to serve as practical therapeutic agents in the treatment of disease. However, the non-peptidic antagonists according to the invention do not have these disadvantages, and are far more stable from the metabolic point of view than previously mentioned known agents.
Beskrivelse av oppfinnelsen Description of the invention
Det er nå gjort det overraskende funn at forskjellige nye cis-3-[cyklisk]metylamino-2-[(asubstituert)arylmetyl]-kinuklidin-forbindelser og de korresponderende cis-3-f-(cyklisk)metylimino]-2-[(a-substituert)arylmetyl]kinuklidiner og cis-3-[(cyklisk)metylenamino]-2-[(a-substituert)arylmetyl]-kinuklidiner er nyttige ved terapeutisk anvendelse som substans P antagonister for behandling av gastrointestinale forstyrrelser, av forstyrrelser i sentralnervesystemet, av inflammatoriske sykdommer og smerte eller migrene hos pattedyr med slike lidelser. Mer spesifikt er de nye forbindelsene fremstilt i henhold til oppfinnelsen, samtlige kinuklidin-derivater med formel som innbefatter de farmasøytisk akseptable salter derav, hvor Ar er tienyl, fenyl, fluorfenyl, klorfenyl eller bromfenyl; R' er cykloalkyl med fra fem til syv karbonatomer, norbornyl, 2,3-dihydrobenzofuranyl, tienyl, alkoksytienyl som har fra ett til tre karbonatomer i alkoksy-delen, pyridyl, hydroksy-pyridyl, kinolinyl, indolyl, naftyl, alkoksynaftyl med fra ett til tre karbonatomer i alkoksy-delen, bifenyl-2,3-metylen-dioksyfenyl eller fenyl som eventuelt er substituert med én eller to substituenter valgt fra nitro, amino, N-monoalkyl-amino med fra ett til tre karbonatomer i alkyldelen, fluor, klor, brom, trifluormetyl, alkyl med fra ett til tre karbonatomer, benzyl, alkoksy med fra ett til tre karbonatomer, allyloksy, hydroksy, hydroksymetyl, hydroksyetoksy, karboksy, alkoksykarbonyl og alkoksykarbonylmetoksy hver med fra ett til tre karbonatomer i alkoksy-delen, eller karboksymetoksy; og R" er en forgrenet alkylkjede med fra tre til fire karbonatomer, forgrenet alkenylkjede med fra fem til seks karbonatomer, cykloalkyl med fra fem til syv karbonatomer, furyl, tienyl, pyridyl, bifenyl eller fenyl som eventuelt er substituert med opptil to substituenter valgt fra fluor, klor, brom, trifluormetyl, alkyl med opptil tre karbonatomer, benzyl, alkoksy med fra ett til tre karbonatomer eller karboksy, med det forbehold at R" alltid er forskjellig fra usubstituert fenyl, fluorfenyl, klorfenyl, bromfenyl eller alkylfenyl når nevnte R' er usubstituert fenyl eller tienyl og Ar er forskjellig fra tienyl, og med det ytterligere forbehold at minst én av nevnte It has now been surprisingly discovered that various new cis-3-[cyclic]methylamino-2-[(asubstituted)arylmethyl]-quinuclidine compounds and the corresponding cis-3-f-(cyclic)methylimino]-2-[( α-substituted)arylmethyl]quinuclidines and cis-3-[(cyclic)methyleneamino]-2-[(α-substituted)arylmethyl]-quinuclidines are useful in therapeutic use as substance P antagonists for the treatment of gastrointestinal disorders, of central nervous system disorders , of inflammatory diseases and pain or migraine in mammals with such disorders. More specifically, the new compounds produced according to the invention are all quinuclidine derivatives with the formula which includes the pharmaceutically acceptable salts thereof, where Ar is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl; R' is cycloalkyl with from five to seven carbon atoms, norbornyl, 2,3-dihydrobenzofuranyl, thienyl, alkoxythienyl having from one to three carbon atoms in the alkoxy part, pyridyl, hydroxy-pyridyl, quinolinyl, indolyl, naphthyl, alkoxynaphthyl with from one to three carbon atoms in the alkoxy part, biphenyl-2,3-methylenedioxyphenyl or phenyl which is optionally substituted with one or two substituents selected from nitro, amino, N-monoalkyl-amino with from one to three carbon atoms in the alkyl part, fluorine, chlorine, bromine, trifluoromethyl, alkyl with from one to three carbon atoms, benzyl, alkoxy with from one to three carbon atoms, allyloxy, hydroxy, hydroxymethyl, hydroxyethoxy, carboxy, alkoxycarbonyl and alkoxycarbonylmethoxy each with from one to three carbon atoms in the alkoxy part, or carboxymethoxy; and R" is a branched alkyl chain of from three to four carbon atoms, branched alkenyl chain of from five to six carbon atoms, cycloalkyl of from five to seven carbon atoms, furyl, thienyl, pyridyl, biphenyl or phenyl optionally substituted with up to two substituents selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl with up to three carbon atoms, benzyl, alkoxy with from one to three carbon atoms or carboxy, with the proviso that R" is always different from unsubstituted phenyl, fluorophenyl, chlorophenyl, bromophenyl or alkylphenyl when said R' is unsubstituted phenyl or thienyl and Ar is different from thienyl, and with the further proviso that at least one of said
Ar, R' og R'' alltid er forskjellig fra usubstituert fenyl. Ar, R' and R'' are always different from unsubstituted phenyl.
Innenfor rammen av foreliggende oppfinnelse faller også fremstilling av stereoisomerer og radiomerkede former av de nye forbindelsene. Forbindelsene fremstilt i henhold til oppfinnelsen er anvendelige som substans P antagonister, dvs. de har evne til å antagonisere virkningene av substans P på dens reseptorseter i pattedyr, og kan derfor tjene som terapeutiske midler ved behandling av de nevnte forstyrrelser og sykdommer i pattedyr med slike lidelser. Forbindelsene med formel II og III er dessuten egnet som mellomprodukter for fremstilling av sluttproduktene med formel I. The production of stereoisomers and radiolabelled forms of the new compounds also falls within the scope of the present invention. The compounds produced according to the invention are applicable as substance P antagonists, i.e. they have the ability to antagonize the effects of substance P on its receptor sites in mammals, and can therefore serve as therapeutic agents in the treatment of the aforementioned disorders and diseases in mammals with such disorders. The compounds of formula II and III are also suitable as intermediates for the production of the final products of formula I.
En foretrukket gruppe av forbindelser fremstilt i henhold til foreliggende oppfinnelse, som er av særlig interesse, er forbindelser med strukturformel II og III hvori Ar er fenyl, R' er 2-klorfenyl, 2-trifluormetylfenyl eller 2-metoksyfenyl og R" også er fenyl. En annen gruppe av foretrukne forbindelser av særlig interesse er forbindelser med strukturformel I hvori Ar er fenyl, R' er fenyl eller 2-tienyl og R" er substituert fenyl; spesielt foretrukne forbindelser innen sistnevnte gruppe innbefatter forbindelser hvori R" er 3-metoksyfenyl eller 4-metoksykarbonylfenyl. Ytterligere en gruppe av foretrukne forbindelser som er av særlig interesse er forbindelser med strukturformel I hvori Ar er fenyl, R' er pyridyl, indolyl eller substituert fenyl og R" også er fenyl; spesielt foretrukne forbindelser innen denne gruppe innbefatter slike forbindelser hvor R' er 4-pyridyl, 3-indolyl, fluorfenyl, difluorfenyl, klorfenyl, trifluormetylfenyl, C1-C3alkylf enyl, så som 4-metylf enyl, C^-Cg. alkoksyfenyl, så som metoksyfenyl og Ci-Caalkoksykarbonyl fenyl, så som 4-metoksykarbonylfenyl. Den foretrukne konfigurasjon for forbindelser med strukturformel I og III er cis med hensyn til de substituenter som befinner seg i 2- og 3-stillingene i kinuklidinkj ernen. A preferred group of compounds produced according to the present invention, which are of particular interest, are compounds of structural formula II and III in which Ar is phenyl, R' is 2-chlorophenyl, 2-trifluoromethylphenyl or 2-methoxyphenyl and R" is also phenyl Another group of preferred compounds of particular interest are compounds of structural formula I wherein Ar is phenyl, R' is phenyl or 2-thienyl and R" is substituted phenyl; particularly preferred compounds within the latter group include compounds in which R" is 3-methoxyphenyl or 4-methoxycarbonylphenyl. A further group of preferred compounds which are of particular interest are compounds of structural formula I in which Ar is phenyl, R' is pyridyl, indolyl or substituted phenyl and R" is also phenyl; particularly preferred compounds within this group include such compounds where R' is 4-pyridyl, 3-indolyl, fluorophenyl, difluorophenyl, chlorophenyl, trifluoromethylphenyl, C1-C3 alkylphenyl, such as 4-methylphenyl, C1-C8. alkoxyphenyl, such as methoxyphenyl and C 1 -C 10 alkoxycarbonyl phenyl, such as 4-methoxycarbonylphenyl. The preferred configuration for compounds of structural formula I and III is cis with respect to the substituents located in the 2- and 3-positions of the quinuclidine nucleus.
Av spesiell interesse i denne sammenheng er slike typiske og foretrukne forbindelser fremstilt i henhold til oppfinnelsen som cjLs-3-[ (2-klorfenyl)metylamino]-2-benzhydryl-kinuklidin, cis-3-f(2-trifluormetylfenyl)metylamino]-2-benzhydrylkinuklidin og cis-3-[(2-metoksyfenyl)metylamino]-2-benzhydrylkinuklidin og deres farmasøytisk akseptable syreaddisjonssalter. Disse nøkkelforbindelsene er alle potente substans P antagonister og derfor av de forskjellige tidligere omtalte grunner av terapeutisk verdi. Of particular interest in this context are such typical and preferred compounds prepared according to the invention as cjLs-3-[(2-chlorophenyl)methylamino]-2-benzhydryl-quinuclidine, cis-3-f(2-trifluoromethylphenyl)methylamino]- 2-benzhydrylquinuclidine and cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine and their pharmaceutically acceptable acid addition salts. These key compounds are all potent substance P antagonists and therefore for the various previously discussed reasons of therapeutic value.
Forbindelsene fremstilt ifølge oppfinnelsen kan anvendes The compounds produced according to the invention can be used
i farmasøytiske preparater egnet for behandling av gastrointestinale forstyrrelser, forstyrrelser av sentralnervesystemet, inflammatoriske sykdommer og smerte eller migrene i behandlingstrengende pattedyr. Disse omfatter farmasøytisk akseptable bære- eller fortynningsmidler og en terapeutisk effektiv mengde av en forbindelse valgt fra kinuklidin-derivater med formel I, II eller III eller et farmasøytisk salt derav, hvor Ar, R' og R" hver er som tidligere definert, innbefattet de angittet forbehold. in pharmaceutical preparations suitable for the treatment of gastrointestinal disorders, disorders of the central nervous system, inflammatory diseases and pain or migraine in mammals requiring treatment. These comprise pharmaceutically acceptable carriers or diluents and a therapeutically effective amount of a compound selected from quinuclidine derivatives of formula I, II or III or a pharmaceutical salt thereof, wherein Ar, R' and R" are each as previously defined, including those stated caveats.
Innenfor rammen av oppfinnelsen faller dessuten en ny fremgangsmåte for behandling av gastrointestinale forstyrrelser, forstyrrelser i sentralnervesystemet, inflammatoriske sykdommer og smerte eller migrene i behandlingstrengende pattedyr, som består i å gi dyret en terapeutisk effektiv mengde av en forbindelse valgt blant kinuklidin-derivater med formel I, II eller III, eller et farmasøytisk akseptabelt salt derav, hvor Ar, R, R' og R" er som tidligere definert, men uten de nevnte forbehold. Innenfor rammen av oppfinnelsen faller dessuten en ny fremgangsmåte for å antagonisere virkningene av substans P på dens reseptorseter i et behandlingstrengende dyr, som består i å gi dyret en forbindelse valgt fra gruppen av kinuklidin-derivater med formel I, II eller III, eller et farmasøytisk akseptabelt salt derav, hvor Ar, R, R' og R" hver er som tidligere definert, Also within the scope of the invention is a new method for the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases and pain or migraine in mammals requiring treatment, which consists in giving the animal a therapeutically effective amount of a compound selected from quinuclidine derivatives of formula I , II or III, or a pharmaceutically acceptable salt thereof, where Ar, R, R' and R" are as previously defined, but without the aforementioned reservations. The scope of the invention also includes a new method for antagonizing the effects of substance P on its receptor sites in an animal in need of treatment, which consists in administering to the animal a compound selected from the group of quinuclidine derivatives of formula I, II or III, or a pharmaceutically acceptable salt thereof, wherein Ar, R, R' and R" are each as previously defined,
men uten de nevnte forbehold, i en mengde som effektivt antagoniserer virkningene av substans P på dens reseptorseter i dyret. Den nye behandlingsmetode i henhold til foreliggende oppfinnelse innbefatter nødvendigvis bruken av både gamle og nye forbindelser for de aktuelle formål ettersom den dessuten inkluderer den nye bruk av kjente forbindelser med strukturformel 1/ II og III, så som de forbindelsene hvor Ar er but without the aforementioned caveats, in an amount which effectively antagonizes the effects of substance P on its receptor sites in the animal. The new treatment method according to the present invention necessarily includes the use of both old and new compounds for the relevant purposes as it also includes the new use of known compounds of structural formula 1/ II and III, such as those compounds where Ar is
usubstituert fenyl, R er hydrogen, R' er usubstituert fenyl, 2-pyrrolyl eller 2-tienyl og R" også er usubstituert fenyl. unsubstituted phenyl, R is hydrogen, R' is unsubstituted phenyl, 2-pyrrolyl or 2-thienyl and R" is also unsubstituted phenyl.
Detaljert beskrivelse Detailed description
I henhold til den fremgangsmåte som benyttes for fremstilling av de nye cis-3-[(cyklisk)metylamino-2-[(a-substituert)-arylmetyl]kinuklidin-forbindelser med formel I i henhold til foreliggende oppfinnelse, underkastes en 3-[(cyklisk)metylimino]-2-[(a-substituert)arylmetyl]kinuklidin-forbindelse med formel II eller en cis-3[(cyklisk)metylen-amino-2-[(a-substituert)arylmetyl]kinuklidin-forbindelse med formel III, hvor Ar, R, R' og R" hver er som tidligere definert, med de nevnte forbehold, en selektiv reduserende virkning av et passende metallholdig reduksjonsmiddel, så som metallhydrid, f.eks. et borhydrid, aluminiumhydrid eller et metallhydrid-kompleks som litiumaluminiumhydrid eller natriumborhydrid, eller et metallorganisk kompleks så som boran-metylsulfid, 9-borabicyklononan (9-BBN), trietylsilan og lignende. Generelt foretas reduksjonstrinnet i et reaksjons-inert organisk oppløsningsmiddel ved en temperatur i området fra ca. 0°C opptil ca. 120°C inntil reduksjonstrinnet for å danne det ønskede cis-3-[(cyklisk)metylamino]-2-[(a-substituert)arylmetyl]kinuklidin-sluttprodukt i det vesentlige er fullført. Den foretrukne reaksjonstemperatur for reduksjonstrinnet ligger ofte i den lavere del av det nevnte område, f.eks. ved ca. 15-40°C, med en temperatur ved eller nær romtemperatur (ca. 20°C) som den vanligvis mest foretrukne. Reaksjonstrykket er ikke av avgjørende betydning, f.eks. benyttes i alminnelighet et reaksjonstrykk på 0,5 til ca. 2,0 atmosfærer, med det foretrukne trykk vanligvis ved eller nær normaltrykk (dvs. ved ca. 1 atmosfære). Foretrukne reaksjons-inerte orgrniske oppløsningsmidler for bruk i denne sammenheng innbefatter polare protiske oppløsningsmidler, så som metansulfonsyre og trifluoreddiksyre når det er tale om trietylsilan, og polare eller upolare aprotiske oppløsningsmidler så som acetonitril, dimetylformamid, dietylformamid, dimetylacet-amid, benzen og etere som dietyleter, diisopropyleter, di-n-butyleter, tetrahydrofuran, dioksan og 1,2-dimetoksyetan (glyme) og dimetylcellusolve når det er tale om de øvrige metallhydrider. I en foretrukket utførelsesform inngår bruk av 9-borabicyklononan som reduksjonsmiddel i et eter-oppløsnings-middel, så som en cyklisk eter som tetrahydrofuran eller dioksan, eller en glykol-avledet eter som 1,2-dimetoksyetan, ved en temperatur varierende fra ca. romtemperatur (ca. 2 0°C) opp til reaksjonsblandingens tilbakeløpstemperatur. På denne måte fremstilles den ønskede cis-isomer av sluttproduktet med høy grad av selektivitet. Etter at reduksjonstrinnet er full-ført, isoleres det ønskede metylamin-sluttprodukt lett fra reaksjonsblandingen gjennom én av en rekke konvensjonelle velkjente fremgangsmåter. According to the method used for the preparation of the new cis-3-[(cyclic)methylamino-2-[(α-substituted)-arylmethyl]quinuclidine compounds of formula I according to the present invention, a 3-[ (cyclic)methylimino]-2-[(α-substituted)arylmethyl]quinuclidine compound of formula II or a cis-3[(cyclic)methylene-amino-2-[(α-substituted)arylmethyl]quinuclidine compound of formula III, where Ar, R, R' and R" are each as previously defined, with the aforementioned caveats, a selective reducing action of a suitable metal-containing reducing agent, such as a metal hydride, e.g. a borohydride, aluminum hydride or a metal hydride complex such as lithium aluminum hydride or sodium borohydride, or an organometallic complex such as borane-methylsulfide, 9-borabicyclononane (9-BBN), triethylsilane, etc. In general, the reduction step is carried out in a reaction-inert organic solvent at a temperature in the range from about 0°C up to about 120°C until the reduction step to form the desired cis-3-[(cyclic)methylamino]-2-[(α-substituted)arylmethyl]quinuclidine final product is substantially complete. The preferred reaction temperature for the reduction step is often in the lower part of the mentioned range, e.g. at approx. 15-40°C, with a temperature at or near room temperature (about 20°C) usually being most preferred. The reaction pressure is not of decisive importance, e.g. a reaction pressure of 0.5 to approx. 2.0 atmospheres, with the preferred pressure usually at or near normal pressure (ie at about 1 atmosphere). Preferred reaction-inert organic solvents for use in this context include polar protic solvents such as methanesulfonic acid and trifluoroacetic acid in the case of triethylsilane, and polar or non-polar aprotic solvents such as acetonitrile, dimethylformamide, diethylformamide, dimethylacetamide, benzene and ethers such as diethyl ether, diisopropyl ether, di-n-butyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane (glyme) and dimethylcellusolve when it comes to the other metal hydrides. In a preferred embodiment, the use of 9-borabicyclononane as a reducing agent is included in an ether solvent, such as a cyclic ether such as tetrahydrofuran or dioxane, or a glycol-derived ether such as 1,2-dimethoxyethane, at a temperature varying from approx. room temperature (approx. 20°C) up to the reflux temperature of the reaction mixture. In this way, the desired cis-isomer of the final product is produced with a high degree of selectivity. After the reduction step is completed, the desired methylamine end product is easily isolated from the reaction mixture by one of a number of conventional well-known methods.
De nye 3-[((cyklisk)metylimino]-2-[(a-substituert)aryl-metyl] kinuklidin-forbindelser med formel II som trengs for fremstilling av de nye sluttproduktene med formel I, er også anvendelige som substans P antagonister. De fremstilles på sin side, ved å kondensere en tilsvarende 2-[(a-substituert)aryl-metyl ]kinuklidin-3-on-forbindelse med formel IV: The new 3-[((cyclic)methylimino]-2-[(α-substituted)aryl-methyl] quinuclidine compounds of formula II, which are needed for the production of the new end products of formula I, are also applicable as substance P antagonists. They are prepared, in turn, by condensing a corresponding 2-[(α-substituted)aryl-methyl]quinuclidin-3-one compound of formula IV:
hvor Ar og R" hver er som definert tidligere, med et (cyklisk)metylamin med formel R'CH2NH2, hvor R' også er som definert tidligere, for å danne det ønskede imin-sluttprodukt med strukturformel II. Denne spesielle reaksjon utføres normalt ved at de to reaktanter oppvarmes sammen til en høyere temperatur i et reaksjons-inert organisk oppløsningsmiddel, så som et aromatisk hydrokarbon-oppløsningsmiddel som benzen, toluen og xylen, og fortrinnsvis i nærvær av en katalytisk where Ar and R" are each as defined previously, with a (cyclic) methylamine of formula R'CH2NH2, where R' is also as defined previously, to form the desired imine end product of structural formula II. This particular reaction is normally carried out by that the two reactants are heated together to a higher temperature in a reaction-inert organic solvent, such as an aromatic hydrocarbon solvent such as benzene, toluene and xylene, and preferably in the presence of a catalytic
mengde av et passende surt kondensasjonsmiddel som p-toluensulfonsyre eller kamfersulfonsyre slik at vannet som oppstår som biprodukt ved reaksjonen deretter umiddelbart oppsamles idet det destillerer over ved oppløsningsmidlets kokepunkt. Alternativt, kan reaksjonen også foretas ved bruk av et dehydreringsmiddel så som titantetraklorid, i et egnet reaksjons-inert organisk oppløsningsmiddel, så som en cyklisk eter som tetrahydrofuran eller dioksan. I begge tilfeller foretas den totale generelle kondensasjonsreaksjon vanligvis ved en temperatur i området fra ca. 35°C opptil ca. 14 0°C, fortrinnsvis ved ca. 65-110°C, inntil kondensasjonen i det vesentlige er fullført, dvs. inntil det ikke lenger dannes reaksjons-vann, noe som vanligvis fordrer minst ca. 1 time, fortrinnsvis opptil ca. 18-24 timer. Selv om det normalt fordres tilnærmet ekvimolare forhold mellom reaktantene, er det i praksis fordelaktig å benytte et overskudd av (cyklisk)metylamin-basen, f.eks. opptil 2,0 mol amin per mol 2-[ (a-substituert) arylmetyl]kinuklidin-3-on-utgangsmateriale for å sikre fullstendig omsetning uten at det i nevneverdig grad forårsakes uønskede bireaksjoner. Etter at reaksjonen er fullført, isoleres metylimin-sluttproduktet deretter lett fra reaksjonsblandingen på konvensjonell måte; f.eks. ved først å konsentrere blandingen i vakuum og deretter utgni residuet med et egnet oppløsningsmiddel, så som isopropanol, hvilket etter-følges av omkrystallisasjon fra det samme oppløsningsmiddel eller om nødvendig fra tetrahydrofuran, eller at produktet benyttes som sådant i det neste og avsluttende reduksjonstrinn, for å gi det ønskede metylamin-sluttprodukt uten bruk av ytterligere rensing. quantity of a suitable acidic condensing agent such as p-toluenesulfonic acid or camphorsulfonic acid so that the water which occurs as a by-product of the reaction is then immediately collected as it distills over at the boiling point of the solvent. Alternatively, the reaction can also be carried out using a dehydrating agent such as titanium tetrachloride, in a suitable reaction-inert organic solvent, such as a cyclic ether such as tetrahydrofuran or dioxane. In both cases, the overall general condensation reaction is usually carried out at a temperature in the range from approx. 35°C up to approx. 14 0°C, preferably at approx. 65-110°C, until the condensation is essentially complete, i.e. until reaction water is no longer formed, which usually requires at least approx. 1 hour, preferably up to approx. 18-24 hours. Although approximately equimolar ratios between the reactants are normally required, in practice it is advantageous to use an excess of the (cyclic) methylamine base, e.g. up to 2.0 moles of amine per mole of 2-[(α-substituted) arylmethyl]quinuclidin-3-one starting material to ensure complete conversion without appreciably causing unwanted side reactions. After the reaction is complete, the methylimine end product is then easily isolated from the reaction mixture in a conventional manner; e.g. by first concentrating the mixture in vacuo and then trituring the residue with a suitable solvent, such as isopropanol, which is followed by recrystallization from the same solvent or, if necessary, from tetrahydrofuran, or that the product is used as such in the next and final reduction step, for to give the desired methylamine end product without the use of further purification.
De nødvendige utgangsmaterialer for fremstilling av de nye 3-[(cyklisk)metylimino]-2-[(a-substituert)aryl-metyl ]kinuklidin-forbindelser med formel II, er enten kjente forbindelser som er lett tilgjengelige kommersielt i likhet med mange av aminene med formel R'CH2NH2 (f.eks. benzylamin eller cykloheksylamin, etc.) eller beskrevet i litteraturen, så som 2-benzhydrylkinuklidin-3-on (se E. J. Warawa i US-patent 3.560.510), eller som lett kan syntetiseres av fagmannen ved å gå ut fra vanlige kjemiske reagenser og benytte konvensjonelle organiske syntesemetoder. For eksempel kan 2-[(a-substituert)arylmetyl]-kinuklidin-3-on-forbindelsene lett fremstilles fra det kjente kinuklidin-3-on [se R. Clemo et al., i Journal of the Chemical Society (London), s. 1241 The necessary starting materials for the preparation of the new 3-[(cyclic)methylimino]-2-[(α-substituted)aryl-methyl]quinuclidine compounds of formula II are either known compounds that are readily available commercially, like many of the amines of formula R'CH2NH2 (eg, benzylamine or cyclohexylamine, etc.) or described in the literature, such as 2-benzhydrylquinuclidin-3-one (see E. J. Warawa in US Patent 3,560,510), or which can be easily synthesized by the person skilled in the art by starting from usual chemical reagents and using conventional organic synthesis methods. For example, the 2-[(α-substituted)arylmethyl]-quinuclidin-3-one compounds can be readily prepared from the known quinuclidin-3-one [see R. Clemo et al., in Journal of the Chemical Society (London), p. 1241
(1939)] via en to-trinns reaksjonsserie som innebærer (1) kondensasjon med en passende aldehydforbindelse med formel R"CHO for å danne det tilsvarende 2-[(a-substituert)metyliden-kinuklidin-3-on, etterfulgt av (2) behandling av sistnevnte mellomprodukt med arylmagnesiumbromid, så som fenylmagnesiumbromid, i en Grignard-reaksjon, for å gi det ønskede 2-[(a-substituert)arylmetyl]kinuklidin-3-on-utgangsmateriale (f.eks. se i denne sammenheng Fremstillingene A-C). (1939)] via a two-step series of reactions involving (1) condensation with an appropriate aldehyde compound of formula R"CHO to form the corresponding 2-[(α-substituted)methylidene-quinuclidin-3-one, followed by (2 ) treatment of the latter intermediate with arylmagnesium bromide, such as phenylmagnesium bromide, in a Grignard reaction, to give the desired 2-[(a-substituted)arylmethyl]quinuclidin-3-one starting material (e.g. see in this context the Preparations A-C).
De nye cis-3-[(cyklisk)metylenamino]-2-[(a-substituert)-arylmetyl]kinuklidin-forbindelser med formel III, som også benyttes for å fremstille de nye sluttprodukter med formel I, og som dessuten er egnet som substans P antagonister, fremstilles ved å kondensere en tilsvarende 3-amino-2-[(a-substituert)fenylmetyl]kinuklidin-forbindelse med formel V: The new cis-3-[(cyclic)methyleneamino]-2-[(α-substituted)-arylmethyl]quinuclidine compounds of formula III, which are also used to prepare the new end products of formula I, and which are also suitable as substance P antagonists, are prepared by condensing a corresponding 3-amino-2-[(a-substituted)phenylmethyl]quinuclidine compound of formula V:
hvor Ar og R" hver er som ovenfor definert, med en passende cyklisk aldehydforbindelse med formel R'CHO, hvori R' også er som tidligere definert, for å danne det ønskede metylenamin-sluttprodukt med strukturformel III. Denne spesielle reaksjon utføres vanligvis på samme måte som beskrevet ovenfor for kondensasjonsreaksjonen mellom kinuklidin-3-oner med formel IV og aminer med formel R'CH2NH2 for å danne iminer med formel II, bortsett fra at det i dette tilfelle er fordelaktig å benytte where Ar and R" are each as defined above, with an appropriate cyclic aldehyde compound of formula R'CHO, wherein R' is also as previously defined, to form the desired methyleneamine end product of structural formula III. This particular reaction is usually carried out on the same manner as described above for the condensation reaction between quinuclidin-3-ones of formula IV and amines of formula R'CH2NH2 to form imines of formula II, except that in this case it is advantageous to use
et overskudd av R'CHO-aldehyd-reagenset fremfor av 3-amino-basen, for å sikre fullstendig omsetning med liten eller ingen biprodukt-dannelse som ville kunne forurense det ønskede sluttprodukt med strukturformel III. I praksis har det vist seg mest hensiktsmessig å benytte opptil ca. 3,0-6,0 mol cyklisk aldehyd per mol 3-amino-2-[(a-substituert)-arylmetyl]kinuklidin-utgangsmateriale for foreliggende tilfeller. Etter fullført omsetning, isoleres enten det ønskede metylenamin-sluttprodukt og renses på samme måte som beskrevet tidligere for den tilsvarende metylimin-forbindelse, eller benyttes det som nøkkel-substrat uten noen videre rensing i det neste og avsluttende reduksjonstrinn, for å danne det ønskede metylamin-sluttprodukt med strukturformel I. an excess of the R'CHO-aldehyde reagent rather than of the 3-amino base, to ensure complete reaction with little or no by-product formation which would contaminate the desired final product of structural formula III. In practice, it has proven most appropriate to use up to approx. 3.0-6.0 moles of cyclic aldehyde per mole of 3-amino-2-[(α-substituted)-arylmethyl]quinuclidine starting material for the present cases. After completion of the reaction, either the desired methylenamine end product is isolated and purified in the same manner as described previously for the corresponding methylimine compound, or it is used as the key substrate without any further purification in the next and final reduction step, to form the desired methylamine -end product with structural formula I.
De nødvendige utgangsmaterialene for å fremstille de nye cis-3-f(cyklisk)metylenamino]-2-[(a-substituert)arylmetyl]-kinuklidin-forbindelser med formel III er enten kjente forbindelser som er lett kommersielt tilgjengelige i likhet med mange av aldehydene med formel R'CH0 (f.eks. 2,6-diklorbenzaldehyd) eller de er beskrevet i litteraturen i likhet med 3-amino-2-benzhydrylkinuklidin [E. J. Warawa et al., i Journal of Medicinal Chemistry, Vol. 18, s. 587 (1975)], eller ellers lett er syntetiserbare for fagmannen ved å gå ut fra vanlige kjemiske reagenser og benytte konvensjonelle organiske syntesemetoder. For eksempel kan 3-amino-2-[a-substituert)-arylmetyl]kinuklidin-forbindelsene lett fremstilles fra de tilsvarende 3-benzylamino-forbindelser med formel I, ved å behandle sistnevnte type forbindelser med ammoniumformiat i nærvær av en edelmetall-katalysator, så som palladium-på-kull (fortrinnsvis ca. 10 vektprosent), i et reaksjons-inert organisk oppløsningsmiddel, så som en lavere alkanol som metanol, etanol eller isopropanol, ved en temperatur som kan variere fra ca. 20°C opptil ca. 100°C, fortrinnsvis ved reaksjonsblandingens kokepunkt. The necessary starting materials to prepare the new cis-3-f(cyclic)methyleneamino]-2-[(α-substituted)arylmethyl]-quinuclidine compounds of formula III are either known compounds that are readily available commercially as are many of the aldehydes with the formula R'CH0 (eg 2,6-dichlorobenzaldehyde) or those described in the literature like 3-amino-2-benzhydrylquinuclidine [E. J. Warawa et al., in Journal of Medicinal Chemistry, Vol. 18, p. 587 (1975)], or are otherwise easily synthesizable by the person skilled in the art by starting from common chemical reagents and using conventional organic synthesis methods. For example, the 3-amino-2-[α-substituted)-arylmethyl]quinuclidine compounds can be readily prepared from the corresponding 3-benzylamino compounds of formula I, by treating the latter type of compounds with ammonium formate in the presence of a noble metal catalyst, such as palladium-on-charcoal (preferably about 10% by weight), in a reaction-inert organic solvent, such as a lower alkanol such as methanol, ethanol or isopropanol, at a temperature which can vary from about 20°C up to approx. 100°C, preferably at the boiling point of the reaction mixture.
Dessuten kan cis-3-[(cyklisk)metylamino]-2-[(a-substituert)arylmetyl]kinuklidin-sluttprodukter med formel I også fremstilles etter en alternativ syntesevei som innebærer at en tilsvarende 3-[(cyklisk)karbonylamino]-2-[(a-substituert)arylmetyl]kinuklidin-forbindelse med formel: Moreover, cis-3-[(cyclic)methylamino]-2-[(α-substituted)arylmethyl]quinuclidine end products of formula I can also be prepared according to an alternative synthesis route which entails that a corresponding 3-[(cyclic)carbonylamino]-2 -[(α-substituted)arylmethyl]quinuclidine compound of formula:
underkastes den selektivt reduserende virkning av et passende metallholdig reduksjonsmiddel, så som et metallhydrid som f.eks. borhydrid, aluminiumhydrid eller hydridkompleks som litiumaluminiumhydrid, eller et metallorganisk kompleks, så som boran-metylsulfid og lignende. Denne spesielle reaksjon utføres vanligvis på samme måte som beskrevet for reduksjonen av de tilsvarende metyliminer med formel II og metylenamin-forbindelsene med formel III, for å danne metylenamin-sluttproduktene med formel I, bortsett fra at reaksjonstemperaturen i dette tilfelle vanligvis ligger i området fra ca. 20°C opptil 120<:>C, men den foretrukne temperatur er den øvre del av dette område, f.eks. ca. 65-100°C, og med temperaturen omkring tilbakeløpstemperaturen for reaksjonsblandingen som den vanligvis mest foretrukne. Etter at reduksjonsreaksjonen er fullført, isoleres det ønskede metylamin-sluttprodukt med formel I, fra reaksjonsblandingen i det vesentlige som tidligere. is subjected to the selective reducing action of a suitable metal-containing reducing agent, such as a metal hydride such as borohydride, aluminum hydride or hydride complex such as lithium aluminum hydride, or an organometallic complex such as borane-methylsulfide and the like. This particular reaction is generally carried out in the same manner as described for the reduction of the corresponding methylimines of formula II and the methyleneamine compounds of formula III to form the methyleneamine end products of formula I, except that the reaction temperature in this case is usually in the range from about . 20°C up to 120<:>C, but the preferred temperature is the upper part of this range, e.g. about. 65-100°C, and with the temperature around the reflux temperature of the reaction mixture being usually the most preferred. After the reduction reaction is complete, the desired methylamine end product of formula I is isolated from the reaction mixture essentially as before.
3-[(cyklisk)karbonylamino]-2-[(a-substituert)arylmetyl]-kinuklidiner med formel VI, som trengs som utgangsmaterialer for frems<+->illing av de nye sluttprodukter med formel I, fremstilles på sin side fra de tidligere omtalte tilsvarende 3-amino-2-[(a-substituert)arylmetyl]kinuklidiner med formel V, ved å omsette denne med et aktivert derivat av en kjent karboksylsyre med formel R'COOH. Dette oppnås lett ved først å aktivere den nevnte syre med formel R'COOH ved å omdanne den 3-[(cyclic)carbonylamino]-2-[(α-substituted)arylmethyl]-quinuclidines of formula VI, which are needed as starting materials for the production of the new end products of formula I, are in turn prepared from the previously mentioned corresponding 3-amino-2-[(α-substituted)arylmethyl]quinuclidines of formula V, by reacting this with an activated derivative of a known carboxylic acid of formula R'COOH. This is easily achieved by first activating the aforementioned acid of formula R'COOH by converting it
til et derivat, så som syrekloridet, acylimidazolet eller acylazidet, ved å benytte konvensjonelle velkjente organiske syntesemetoder. For eksempel kan syren først omsettes i et reaksjons-inert organisk oppløsningsmiddel, så som dioksan, tetrahydrofuran, dietyleter, 1,2-dimetoksyetan (glyme) eller metylenklorid, med et aktiverende middel, så som tionylklorid, karbonyl-diimidazol eller difenylfosforylazid, alt etter forholdende, eventuelt i nærvær av en organisk base, så som trietylamin, ved en temperatur som kan variere fra romtemperatur (ca. 20°C) til reaksjonsblandingens tilbakeløps-temperatur (f.eks. ca. 20-80°C) , med den foretrukne reaksjonstemperatur i den nedre del av det nevnte område (f.eks. ved ca. 20-35°C) . Etter at dette spesielle reaksjonstrinn er fullført, tilsettes forbindelsen med formel V til blandingen, hvorpå omsetningen fortsettes ved en temperatur på fra ca. 65°C opptil ca. 100°C, fortrinnsvis ved blandingens tilbakeløps-temperatur, inntil dannelsen av det ønskede 3(cyklisk)-karbonylamino-derivat i det vesentlige er fullført (dette vil i alminnelighet fordre minst ca. 1/2 time og enkelte ganger helt opp til 24 timer). Ved dette tidspunkt isoleres det ønskede 3-(cyklisk)karbonylamino-derivat lett fra reaksjonsblandingen på konvensjonell måte, hvoretter det reduseres til den korresponderende 3-(cyklisk)metylamin-forbindelse, dvs. metylamin-sluttproduktet med formel I, som tidligere beskrevet. to a derivative, such as the acid chloride, acyl imidazole or acyl azide, using conventional well-known organic synthesis methods. For example, the acid can first be reacted in a reaction-inert organic solvent, such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane (glyme) or methylene chloride, with an activating agent, such as thionyl chloride, carbonyl diimidazole or diphenylphosphoryl azide, depending relatively, optionally in the presence of an organic base, such as triethylamine, at a temperature which can vary from room temperature (about 20°C) to the reflux temperature of the reaction mixture (e.g. about 20-80°C), with the preferred reaction temperature in the lower part of the mentioned range (e.g. at approx. 20-35°C). After this particular reaction step is completed, the compound of formula V is added to the mixture, whereupon the reaction is continued at a temperature of from about 65°C up to approx. 100°C, preferably at the reflux temperature of the mixture, until the formation of the desired 3(cyclic)-carbonylamino derivative is substantially complete (this will generally require at least about 1/2 hour and sometimes up to 24 hours ). At this point, the desired 3-(cyclic)carbonylamino derivative is easily isolated from the reaction mixture in a conventional manner, after which it is reduced to the corresponding 3-(cyclic)methylamine compound, i.e. the methylamine end product of formula I, as previously described.
Når det gjelder forbindelser ifølge oppfinnelsen med strukturformel I, hvori R' er aminofenyl, kan disse lett fremstilles fra de tilsvarende forbindelser med strukturformel I, hvor R' er nitrofenyl, ved ganske enkelt å underkaste sistnevnte katalytisk hydrogenering i nærvær av en edelmetall-katalysator (f.eks. palladium-på-kull-katalysator), fortrinnsvis ved bruk av et lavere alkanol-oppløsningsmiddel, så som metanol, etanol eller isopropanol, i henhold til fremgangsmåter som er velkjente for fagmannen. På denne måte omdannes cis-3-f(2-metoksy-5-nitrofenyl]metylamino]-2-benzhydrylkinuklidin lett til den korresponderende 5-amino-fenylforbindelse. As regards compounds according to the invention with structural formula I, in which R' is aminophenyl, these can be easily prepared from the corresponding compounds with structural formula I, where R' is nitrophenyl, by simply subjecting the latter to catalytic hydrogenation in the presence of a noble metal catalyst ( eg palladium-on-charcoal catalyst), preferably using a lower alkanol solvent such as methanol, ethanol or isopropanol, according to methods well known to those skilled in the art. In this way, cis-3-f(2-methoxy-5-nitrophenyl]methylamino]-2-benzhydrylquinuclidine is readily converted to the corresponding 5-amino-phenyl compound.
I og med at kinuklidin-forbindelsene i henhold til oppfinnelsen alle har minst ett asymmetrisk senter, kan de forekomme i forskjellige stereoisomere former eller konfigurasjoner. Forbindelsene kan således forekomme i adskilte (+)- og (-)-optisk aktive former, og som racemiske eller (±)-blandinger av disse. Når det gjelder forbindelser med to asymmetriske sentra, kan de dessuten forekomme som diastereomerer med respektive optiske isomerer derav. Foreliggende oppfinnelse er ment å omfatte fremstilling av samtlige av disse former. Diastereomerene kan kan for eksempel separeres etter fremgangsmåter som er velkjent på feltet, f.eks. ved fraksjonert krystallisasjon og lignende, mens optisk aktive isomerer kan oppnås ved ganske enkelt å spalte racematene ved hjelp av de standardmetoder innen den organiske kjemi som er kjent for disse formål. As the quinuclidine compounds according to the invention all have at least one asymmetric centre, they can occur in different stereoisomeric forms or configurations. The compounds can thus occur in separate (+)- and (-)-optically active forms, and as racemic or (±)-mixtures of these. In the case of compounds with two asymmetric centers, they can also occur as diastereomers with respective optical isomers thereof. The present invention is intended to include the production of all of these forms. The diastereomers can, for example, be separated according to methods that are well known in the field, e.g. by fractional crystallization and the like, while optically active isomers can be obtained by simply resolving the racemates using the standard methods of organic chemistry known for these purposes.
De radioaktivt merkede kinuklidin-forbindelsene med formel I, II og III er egnet som forsknings- og diagnostiske hjelpemidler ved farmakokinetiske metabolismeundersøkelser og i bindingsforsøk med medikamentet i både mennesker og dyr. Spesifikke forskningsanvendelser innbefatter radioligand-bindingsforsøk, autoradiografiske undersøkelser og in vivo bindingsstudier, mens spesifikke anvendelser på det diagnostiske område innbefatter studier av substans P reseptorer i menneskehjernen, så som opp/ned regulering under sykdomstilstand, og in vivo binding i relevant vev for inflammasjon, f.eks. immuntype celler eller celler som er direkte involvert i inflammatoriske tarmforstyrrelser og lignende. Blant de radioaktivt merkede former av kinuklidin-forbindelsene med formel I, II og III er tritium og C<1A>" isotoper av (-)-cis-3-[(2-metoksyfenyl)metylamino]-2-benzhydrylkinuklidin. The radioactively labeled quinuclidine compounds of formula I, II and III are suitable as research and diagnostic aids in pharmacokinetic metabolism studies and in binding experiments with the drug in both humans and animals. Specific research applications include radioligand binding experiments, autoradiographic investigations and in vivo binding studies, while specific applications in the diagnostic area include studies of substance P receptors in the human brain, such as up/down regulation during disease states, and in vivo binding in relevant tissue for inflammation, e.g. .ex. immune-type cells or cells directly involved in inflammatory bowel disorders and the like. Among the radiolabelled forms of the quinuclidine compounds of formula I, II and III are the tritium and C<1A>" isotopes of (-)-cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine.
Siden majoriteten av 3-metylamino-2-[(a-substituert)aryl-metyl ] kinuklidin-f orbindelsene med formel I fremstilt i henhold til oppfinnelsen er basiske forbindelser, slik som de tilsvarende metyliminer og metylenaminer med formel II og III, er de alle i stand til å danne et bredt utvalg av forskjellige salter med ulike uorganiske og organiske syrer. Selv om slike salter må være farmasøytisk akseptable for administrasjon til dyr, er det i praksis ofte ønskelig først å isolere kinuklidin-basen fra reaksjonsblandingen som et farmasøytisk uakseptabelt salt og deretter ganske enkelt omdanne sistnevnte til den frie baseforbindelse ved behandling med et alkalisk reagens, hvorpå sistnevnte frie base omdannes til et farma-søytisk akseptabelt syreaddisjonssalt. Syreaddisjonssaltene av kinuklidin-baseforbindelsene fremstilt i henhold til oppfinnelsen fremstilles lett ved å behandle baseforbindelsen med en tilnærmet ekvivalent mengde av den valgte mineralsyre eller organiske syre i et vandig oppløsningsmiddel eller i et egnet organisk oppløssningsmiddel, så som metanol eller etanol. Etter forsiktig fordampning av oppløsningsmidlet, kan det ønskede faste salt lett oppnås. Since the majority of the 3-methylamino-2-[(α-substituted)aryl-methyl] quinuclidine compounds of formula I prepared according to the invention are basic compounds, such as the corresponding methylimines and methylenamines of formulas II and III, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first isolate the quinuclidine base from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter to the free base compound by treatment with an alkaline reagent, whereupon the latter free base is converted to a pharmaceutically acceptable acid addition salt. The acid addition salts of the quinuclidine base compounds prepared according to the invention are easily prepared by treating the base compound with an approximately equivalent amount of the selected mineral acid or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt can be easily obtained.
Syrene som benyttes for å fremstille farmasøytisk akseptable syreaddisjonssalter av de omtalte kinuklidin-baseforbindelsene fremstilt i henhold til oppfinnelsen, er de som danner ugiftige syreaddisjonssalter, dvs. salter inneholdende farmakologisk akseptable anioner, så som hydroklorid-, hydrobromid-, hydrojodid-, nitrat-, sulfat- eller bisulfat-, fosfat- eller sure fosfat-, acetat-, laktat-, citrat- eller sure citrat-, tartrat- eller bitartrat-, succinat-, maleat-, fumarat-, glukonat-, sakkarat-, benzoat-, metansulfonat-, etansulfonat-, benzensulfonat-, p-toluensulfonat- og pamoat-[dvs. 1,1'-metylen-bis-(2-hydroksy-3-naftoat)]saltene. The acids used to prepare pharmaceutically acceptable acid addition salts of the mentioned quinuclidine base compounds prepared according to the invention are those which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate-[i.e. The 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
A/ A/
De kinuklidin-forbindelsene fremstilt i henhold til oppfinnelsen som også har sur natur, f.eks. hvor R" er karboksyfenyl, kan danne basesalter med forskjellige farmakologisk akseptable kationer. Eksempler på slike salter innbefatter alkalimetall- eller jordalkalimetallsaltene og spesielt natrium- og kaliumsaltene. Disse saltene fremstilles alle etter konvensjonell teknikk. De kjemiske basene som benyttes som reagenser for fremstilling av farmasøytisk akseptable basesalter i henhold til oppfinnelsen, er de som danner ugiftige basesalter med de her beskrevne sure kinuklidin-derivatene. Disse spesielle ugiftige basesaltene innbefatter farmakologisk akseptable kationer som natrium, kalium, kalsium og magnesium, etc. Disse saltene kan lett fremstilles ved å behandle de omtalte sure kinuklidin-forbindelsene med en vandig oppløsning som inneholder det ønskede farmakologisk akseptable kation, og deretter inndampe den resulterende oppløsning til tørrhet, fortrinnsvis under redusert trykk. Som et alternativ, kan de også fremstilles ved å blande lavere alkanoliske oppløsninger av de sure forbindelsene og det ønskede alkalimetallalkoksyd og deretter inndampe den resulterende oppløsning til tørrhet på samme måte som tidligere. I begge tilfeller anvendes støkiometriske mengder av reagenser for å sikre full omsetning og maksimalt utbytte av det ønskede sluttprodukt. The quinuclidine compounds prepared according to the invention which are also acidic in nature, e.g. where R" is carboxyphenyl, can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and especially the sodium and potassium salts. These salts are all prepared according to conventional techniques. The chemical bases used as reagents for the preparation of pharmaceutical acceptable base salts according to the invention are those which form non-toxic base salts with the acidic quinuclidine derivatives described herein. These particular non-toxic base salts include pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the said acidic quinuclidine compounds with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure.Alternatively, they can also be prepared by mixing lower alkanol solutions of the acidic fo the compounds and the desired alkali metal alkoxide and then evaporate the resulting solution to dryness in the same manner as before. In both cases, stoichiometric quantities of reagents are used to ensure full conversion and maximum yield of the desired end product.
De aktive kinuklidin-forbindelsene fremstilt i henhold til foreliggende oppfinnelse, dvs. forbindelser med strukturformel I, II og III, hvor Ar, R' og R" hver er som tidligere definert, oppviser signifikant substans P reseptorbindende aktivitet og er derfor verdifulle ved behandling av en rekke kliniske tilstander som er karakterisert ved et overskudd av nevnte substans P aktivitet. Slike tilstander innbefatter gastrointestinale forstyrrelser, så som ulcus og kolitt og andre lignende sykdommer i den gastrointestinale trakt, forstyrrelser i sentralnervesystemet så som angst og psykose, inflammatoriske sykdommer så som reumatoid artritt og inflammatoriske tarmsykdommer, respirasjonslidelser som astma, samt smerte under de ovenfor nevnte tilstander, innbefattet migrene. Disse forbindelsene kan lett tilpasses terapeutisk bruk som substans P antagonister for kontroll og/eller behandling av de ovennevnte kliniske tilstander i pattedyr, innbefattet mennesket. For eksempel oppviser cis-3-[(2-klorfenyl) metylamino]-2-benzhydrylkinuklidin, en foretrukket forbindelse i henhold til oppfinnelsen, når den undersøkes som et antiinflammatorisk middel, en signifikant aktivitetsgrad i den standardiserte carrageenin-induserte rottefot ødemtest [beskrevet av C. A. Winter et al., Proceedings of the Society of Experimental Biology and Medicine, Vol. 111. s. 544 The active quinuclidine compounds produced according to the present invention, i.e. compounds of structural formula I, II and III, where Ar, R' and R" are each as previously defined, exhibit significant substance P receptor-binding activity and are therefore valuable in the treatment of a number of clinical conditions which are characterized by an excess of said substance P activity. Such conditions include gastrointestinal disorders, such as ulcers and colitis and other similar diseases in the gastrointestinal tract, central nervous system disorders such as anxiety and psychosis, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, respiratory disorders such as asthma, as well as pain in the above-mentioned conditions, including migraine. These compounds can be readily adapted for therapeutic use as substance P antagonists for the control and/or treatment of the above-mentioned clinical conditions in mammals, including humans. For example exhibits cis-3-[(2-k lorphenyl) methylamino]-2-benzhydrylquinuclidine, a preferred compound of the invention, when examined as an anti-inflammatory agent, a significant degree of activity in the standardized carrageenin-induced rat foot edema test [described by C. A. Winter et al., Proceedings of the Society of Experimental Biology and Medicine, Vol. 111. p. 544
(1962)], hvor den viste seg å forårsake en 50% hemming av hevelsen ved oral tilførsel av 100 mg/kg. Ved undersøkelse som antipsykotisk middel viste dessuten samme forbindelse seg å forårsake en 50% hemming av substans P-indusert lokomosjon i rotter ved intraperitoneal dosering av 32 mg/kg. De foran omtalte aktive kinuklidin-forbindelser kan administreres oralt, parenteralt eller lokalt. I alminnelighet foretrekkes administrasjon i doser varierende fra ca. 5,0 mg opptil ca. 1500 mg per dag, selv om variasjoner nødvendigvis vil måtte foretas avhengig av pasientens vekt og tilstand og av den valgte administrasjonsmåte. Helst benyttes et doseringsnivå som ligger i området fra ca. 0,07 mg til ca. 21 mg per kg legemsvekt per dag. Variasjoner kan likevel måtte foretas avhengig av hvilken dyreart som behandles og dens individuelle respons på medikamentet, samt av den valgte type av farmasøytisk formulering og tidsrommet og intervallet som administrasjonen foretas med. Enkelte ganger kan doserings-nivåer lavere enn den nedre grense av det nevnte område være mer enn tilstrekkelig, mens det i andre tilfeller kan benyttes enda høyere doser uten at det forårsaker noen skadelige bivirkninger, forutsatt at slike høyere dosenivåer først deles opp i flere mindre doser for administrasjon i løpet av dagen. Forbindelsene fremstilt i henhold til foreliggende oppfinnelse kan administreres alene, eller i kombinasjon med farmasøytisk akseptable bære- eller fortynningsmidler, ved en av de ovenfor nevnte administrasjonsmåter, og kan gis som enkle eller avdelte doser. Mer spesielt, kan de nye forbindelsene fremstilt i henhold til oppfinnelsen gis i forskjellige doseringsformer, dvs. at de kan kombineres med forskjellige farmasøytisk akseptable inerte bæremidler i form av tabletter, kapsler, pastiller, hårde drops, pulvere, spray, kremer, salver, suppositorier, geleer, gelpasta, lotions, vandige suspensjoner, injiserbare oppløsninger, miksturer, siruper og lignende, like bæremidler innbefatter faste fortynnings- eller fyllstoffer, sterile vandige medier og forskjellige ugiftige organiske oppløsningsmidler, etc. Orale farmasøytiske preparater kan dessuten være tilsatt passende søtnings- og/eller smaksforbedrende midler. I alminnelighet forekommer den terapeutisk virksomme forbindelsen fremstilt i henhold til foreliggende oppfinnelse i disse doseringsformer i konsentrasjonsnivåer som varierer fra ca. 5,0 til ca. 70 vektprosent. For oral administrasjon kan det benyttes tabletter som inneholder forskjellige hjelpestoffer, så som mikro-krystallinsk cellulose, natriumcitrat, kalsiumkarbont, dikalsiumfosfat og glycin sammen med diverse sprengmidler, så som stivelse og fortrinnsvis mais-, potet- eller tapioka-stivelse, alginsyre og visse komplekse silikater, sammen med granulerings-bindemidler som polyvinylpyrrolidon, sukrose, gelatin og akasie. Dessuten kan glattemidler så som magnesium-stearat, natriumlaurylsulfat og talk ofte være meget nyttig for tabletteringsformål. Faste preparater av en lignende type kan også benyttes som innhold i gelatinkapsler; foretrukne materialer i denne forbindelse innbefatter laktose eller melkesukker, samt høymolekylære polyetylenglykoler. Når vandige suspensjoner og/eller miksturer ønskes for oral administrasjon, kan virkestoffet kombineres med forskjellige søtnings- eller smaksforbedrende midler eller med farvestoffer, og eventuelt med emulgerings- og/eller suspenderingsmidler, sammen med slike fortynningsmidler som vann, etanol, propylenglykol, glycerol og forskjellige kombinasjoner av disse. For parenteral administrasjon kan det benyttes oppløsninger av en forbindelse fremstilt i henhold til foreliggende oppfinnelse i sesam- eller jordnøttolje eller i vandig propylenglykol. De vandige oppløsningene bør om nødvendig være tilsatt buffer (fortrinnsvis pH > 8) og det vandige fortynningsmiddel først gjort isotonisk. Disse vandige oppløsningene er egnet for intravenøs injeksjon. Oljebaserte oppløsninger er egnet for intra-artikulær, intramuskulær og subkutan injeksjon. Fremstilling av samtlige oppløsninger under sterile betingelser oppnås lett gjennom farmasøytisk standardteknikk som er velkjent for fagmannen. Forbindelsene fremstilt i henhold til foreliggende oppfinnelse kan ved behandling av inflammatoriske tilstander i huden, påføres lokalt og dette kan fortrinnsvis gjøres ved hjelp av kremer, geleer, gel, pastaer, salver og lignende, i henhold til vanlig farmasøytisk praksis. Aktiviteten av forbindelsene fremstilt i henhold til oppfinnelsen som substans P antagonister, bestemmes gjennom deres evne til å hemme binding av substans P på dens reseptorseter i bovint kaudatvev, ved å benytte radioaktive ligander for å synliggjøre tachykininreseptorene ved hjelp av auto-radiografi. Substans P antagonistaktiviteten av de her beskrevne kinuklidinforbindelser vurderes ved bruk av den standardmetode som er beskrevet av M. A. Cascieri et al., i Journal of Bioloqical Chemistry. Vol. 258, s. 5158 (1983). Denne metode innebærer i det vesentlige bestemmelse av den konsentrasjon av de enkelte forbindelser som er nødvendig for å oppnå 50% reduksjon av mengden av radioaktivt merkede substans P-ligander på deres reseptorseter i det nevnte isolerte storfe-vev, hvorved det oppnås karakteristiske IC50-verdier for hver undersøkt forbindelse. Den antiinflammatoriske virkning av forbindelsene fremstilt i henhold til foreliggende oppfinnelse demonstreres gjennom den foran nevnte standardiserte test for bestemmelse av carrageenin-indusert ødem på rottefot. Ved denne under-søkelse bestemmes antiinflammatorisk aktivitet som den prosentuelle hemming av ødemdannelse i bakfoten til albino hannrotter (vekt 150-190 g) som respons på en subplantar injeksjon av carrageenin. Carrageenin injiseres som en 1% vandig oppløsning. Ødemdannelsen bestemmes deretter ved å måle volumet av foten initialt, så vel som 3 timer etter carrageenin-injeksjonen. Økningen i volum 3 timer etter carrageenin-injeksjonen utgjør den individuelle respons. Forbindelser ansees aktive dersom differansen i respons mellom medikamentbehandlede dyr (6 rotter/gruppe) og en kontroll-gruppe som kun får bæremidlet, er signifikant ved sammen-ligning med resultater oppnådd med en standardforbindelse som fenylbutazon, ved oral administrasjon av 33 mg/kg. Den antipsykotiske aktivitet av forbindelsene som neuroleptiske midler for kontroll av forskjellige psykotiske forstyrrelser, bestemmes primært ved studium av deres evne til å undertrykke substans P-indusert hypermotilitet i rotter. Denne undersøkelse utføres ved først å gi rottene en dose av en kontrollforbindelse eller en passende testforbindelse i henhold til oppfinnelsen, hvorpå rottene injiseres substans P ved intracerebral administrasjon med en kanyle, hvorpå deres individuelle lokomotoriske respons på denne stimulus måles. (1962)], where it was found to cause a 50% inhibition of swelling when administered orally at 100 mg/kg. When tested as an antipsychotic, the same compound was also shown to cause a 50% inhibition of substance P-induced locomotion in rats at an intraperitoneal dose of 32 mg/kg. The previously mentioned active quinuclidine compounds can be administered orally, parenterally or locally. In general, administration is preferred in doses varying from approx. 5.0 mg up to approx. 1500 mg per day, although variations will necessarily have to be made depending on the patient's weight and condition and on the chosen method of administration. Ideally, a dosage level is used that is in the range from approx. 0.07 mg to approx. 21 mg per kg of body weight per day. Variations may nevertheless have to be made depending on the species of animal being treated and its individual response to the drug, as well as on the chosen type of pharmaceutical formulation and the time and interval at which the administration is made. Sometimes dosage levels lower than the lower limit of the mentioned range can be more than sufficient, while in other cases even higher doses can be used without causing any harmful side effects, provided that such higher dosage levels are first divided into several smaller doses for administration during the day. The compounds produced according to the present invention can be administered alone, or in combination with pharmaceutically acceptable carriers or diluents, by one of the above-mentioned administration methods, and can be given as single or divided doses. More particularly, the new compounds produced according to the invention can be given in different dosage forms, i.e. they can be combined with different pharmaceutically acceptable inert carriers in the form of tablets, capsules, pastilles, hard drops, powders, sprays, creams, ointments, suppositories , gels, gel pastes, lotions, aqueous suspensions, injectable solutions, potions, syrups and the like, similar carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Oral pharmaceutical preparations may also be supplemented with suitable sweetening and /or flavor enhancers. In general, the therapeutically active compound produced according to the present invention occurs in these dosage forms in concentration levels varying from approx. 5.0 to approx. 70 percent by weight. For oral administration, tablets can be used that contain various excipients, such as micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine together with various disintegrants, such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Also, smoothing agents such as magnesium stearate, sodium lauryl sulfate and talc can often be very useful for tableting purposes. Solid preparations of a similar type can also be used as contents in gelatin capsules; preferred materials in this regard include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or mixtures are desired for oral administration, the active ingredient can be combined with various sweetening or taste-improving agents or with coloring agents, and possibly with emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerol and various combinations of these. For parenteral administration, solutions of a compound prepared according to the present invention in sesame or peanut oil or in aqueous propylene glycol can be used. If necessary, the aqueous solutions should have buffer added (preferably pH > 8) and the aqueous diluent first made isotonic. These aqueous solutions are suitable for intravenous injection. Oil-based solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Preparation of all solutions under sterile conditions is readily accomplished through standard pharmaceutical techniques well known to those skilled in the art. The compounds produced according to the present invention can be applied locally when treating inflammatory conditions in the skin and this can preferably be done using creams, gels, gels, pastes, ointments and the like, in accordance with normal pharmaceutical practice. The activity of the compounds produced according to the invention as substance P antagonists is determined through their ability to inhibit binding of substance P to its receptor sites in bovine caudate tissue, by using radioactive ligands to visualize the tachykinin receptors by means of auto-radiography. The substance P antagonist activity of the quinuclidine compounds described here is assessed using the standard method described by M. A. Cascieri et al., in the Journal of Biological Chemistry. Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compounds that is necessary to achieve a 50% reduction in the amount of radioactively labeled substance P ligands on their receptor sites in the aforementioned isolated bovine tissue, whereby characteristic IC50 values are obtained for each investigated compound. The anti-inflammatory effect of the compounds produced according to the present invention is demonstrated through the above-mentioned standardized test for determining carrageenin-induced edema on rat feet. In this investigation, anti-inflammatory activity is determined as the percentage inhibition of edema formation in the hind foot of albino male rats (weight 150-190 g) in response to a subplantar injection of carrageenin. Carrageenin is injected as a 1% aqueous solution. Edema formation is then determined by measuring the volume of the foot initially, as well as 3 hours after the carrageenin injection. The increase in volume 3 hours after the carrageenin injection constitutes the individual response. Compounds are considered active if the difference in response between drug-treated animals (6 rats/group) and a control group receiving only the vehicle is significant when compared with results obtained with a standard compound such as phenylbutazone, by oral administration of 33 mg/kg. The antipsychotic activity of the compounds as neuroleptic agents for the control of various psychotic disorders is determined primarily by studying their ability to suppress substance P-induced hypermotility in rats. This investigation is carried out by first giving the rats a dose of a control compound or a suitable test compound according to the invention, after which the rats are injected with substance P by intracerebral administration with a needle, after which their individual locomotor response to this stimulus is measured.
Fremstilling A Preparation A
I en 50 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør ble det anbragt 5,28 g (0,04258 mol) kinuklidin-3-on [C. R. Clemo et al., i Journal of the Chemical Society (London), s. 1241 [1939], 11,18 g (0,06387 mol) 2,4-diklorbenzaldehyd, 340 mg (0,0852 mol) natriumhydroksyd og 21 ml etanol. Den resulterende reaksjonsblandingen ble deretter tilbakeløpsbehandlet i 40 minutter og avkjølt til romtemperatur, hvorpå det utfelte produkt ble isolert ved sugfiltrering. Etter vasking av sistnevnte materiale med etanol og tørking i vakuum til konstant vekt, ble det tilslutt oppnådd 8,71 g (70%) rent 2,4-diklorbenzyliden-kinuklidin-3-on i form av et gult faststoff som smeltet ved 117-119°C; 5.28 g (0.04258 mol) quinuclidin-3-one [C. R. Clemo et al., in Journal of the Chemical Society (London), p. 1241 [1939], 11.18 g (0.06387 mol) of 2,4-dichlorobenzaldehyde, 340 mg (0.0852 mol) of sodium hydroxide and 21 ml of ethanol. The resulting reaction mixture was then refluxed for 40 minutes and cooled to room temperature, whereupon the precipitated product was isolated by suction filtration. After washing the latter material with ethanol and drying in vacuum to constant weight, 8.71 g (70%) of pure 2,4-dichlorobenzylidene-quinuclidin-3-one were finally obtained in the form of a yellow solid which melted at 117- 119°C;
IR (cm"<1>, KBr) 1710, 1700 (C=0) . IR (cm"<1>, KBr) 1710, 1700 (C=0).
Det rene produkt ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data. The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data.
Massespektrum (%): 281/283/285 (parent, 2,5 for 281), 248(34), 246(78), 220(26), 218(100), 192(25), 190(60), 186(27), 184(40), 172(25), 164(24), 162(24), 149(24), 136(26), 135(24), 172(32), 126(24), 123(26), 114(26), 99(26), 55(40), 53 (22) . Mass spectrum (%): 281/283/285 (parent, 2.5 for 281), 248(34), 246(78), 220(26), 218(100), 192(25), 190(60), 186(27), 184(40), 172(25), 164(24), 162(24), 149(24), 136(26), 135(24), 172(32), 126(24), 123(26), 114(26), 99(26), 55(40), 53 (22) .
NMR data: ^-NMR (5, CDC13) 1,9-2,0 (m, 4H) , 2,49 (m, 1H) , 2,8-3,2 (m, 4H), 7,1-7,3 og 8,4-8,5 (m, 8H). NMR data: 3-NMR (δ, CDCl 3 ) 1.9-2.0 (m, 4H) , 2.49 (m, 1H) , 2.8-3.2 (m, 4H), 7.1- 7.3 and 8.4-8.5 (m, 8H).
Fremstilling B Production B
I en 250 ml rundkolbe forsynt med magnetrørestav og nitrogeninnløpsrør ble det anbragt 15 ml (0,04575 mol) av en 1,5M oppløsning fenylmagnesiumbromid i dietyleter og 76 ml tørr toluen. Omrøringen ble startet og oppløsningen avkjølt til 0°C, hvorunder 8,57 g (0,03049 mol) 2,4-diklorbenzyliden-kinuklidin-3-on (produktet fra Fremstilling A) i 10 ml toluen ble tilsatt dråpevis. Reaksjonsblandingen ble deretter oppvarmet til romtemperatur (ca. 20°C) og fikk omrøres i 14 timer før reaksjonen ble avbrutt med vandig ammoniumklorid. Dette førte til dannelse av to lag som deretter ble separert, hvorpå det fraskilte vandige lag ble ekstrahert med frisk metylenklorid. De resulterende organiske lagene ble deretter kombinert og deretter tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast produkt som deretter krystalliserte fra etanol og ga 6,70 g (61%) rent 2-[(2,4-diklorfenyl)fenylmetyl]kinuklidin-3-on i form av et hvitt faststoff som smeltet ved 144-152°C; 15 ml (0.04575 mol) of a 1.5 M solution of phenylmagnesium bromide in diethyl ether and 76 ml of dry toluene were placed in a 250 ml round flask fitted with a magnetic stir bar and a nitrogen inlet tube. Stirring was started and the solution cooled to 0°C, during which 8.57 g (0.03049 mol) of 2,4-dichlorobenzylidene-quinuclidin-3-one (the product from Preparation A) in 10 ml of toluene was added dropwise. The reaction mixture was then warmed to room temperature (approx. 20°C) and allowed to stir for 14 hours before the reaction was quenched with aqueous ammonium chloride. This led to the formation of two layers which were then separated, after which the separated aqueous layer was extracted with fresh methylene chloride. The resulting organic layers were then combined and then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid product was finally obtained which then crystallized from ethanol to give 6.70 g (61%) of pure 2-[(2,4-dichlorophenyl)phenylmethyl] quinuclidin-3-one as a white solid melting at 144-152°C;
IR (cm"<1>, KBr) , 1725 (C=0) . Det rene produkt ble videre karakterisert ved massespektrometrisk analyse og kjernemagnetiske resonans-data. IR (cm"<1>, KBr), 1725 (C=0). The pure product was further characterized by mass spectrometric analysis and nuclear magnetic resonance data.
Massespektrum (%): 360/362/364 (parent, 1,5 for 360), 333(24), 331(27), 292(22), 290(33), 227(26), 214(26), 199(23), 178(64), 177(22), 176(26), 172(43), 165(72), 164(23), 161(56), 159(84), 131(30), 130(34), 91(100), 77(29), 68(22), 55(54). Mass spectrum (%): 360/362/364 (parent, 1.5 for 360), 333(24), 331(27), 292(22), 290(33), 227(26), 214(26), 199(23), 178(64), 177(22), 176(26), 172(43), 165(72), 164(23), 161(56), 159(84), 131(30), 130(34), 91(100), 77(29), 68(22), 55(54).
NMR-data: <X>H-NMR (<5, CDC13) 1,9-2,1 (m, 4H) , 2,44 (m, 1H) , 2,6-2,8 (m, 2H) , 2,9-3,1 (m, 2H) , 3,85 (d, 1H), 5,12 (d, 1H) , 7,1-7,4 (m, 8H). NMR data: <X>H-NMR (<5, CDCl 3 ) 1.9-2.1 (m, 4H) , 2.44 (m, 1H) , 2.6-2.8 (m, 2H) , 2.9-3.1 (m, 2H), 3.85 (d, 1H), 5.12 (d, 1H), 7.1-7.4 (m, 8H).
Fremstilling C Manufacturing C
I en 50 ml rundkolbe forsynt med tilbakeløpskjøler, magnetrørestav og nitrogen-innløpsrør ble det anbragt 805,9 mg (0,005757 mol) 2-norbornankarboksylsyre, 932,6 mg (0,005757 mol) karbonyldiimidazol og 19 ml tørr tetrahydrofuran. Reaksjonsblandingen ble deretter omrørt ved romtemperatur (ca. 20°C) i 30 minutter og deretter tilsatt 1,1207 g (0,003838 mol) 3-amino-2-benzhydrylkinuklidin [E. J. Warawa et al., i Journal of Medicinal Chemistrv. Vol. 18. s. 71 (1975)]. Den resulterende blanding ble deretter tilbakeløpsbehandlet i 18 timer, avkjølt til romtemperatur og så fordelt mellom vann og metylenklorid. Det fraskilte organiske lag ble deretter vasket med saltoppløsning og tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast restprodukt som deretter ble krystallisert fra isopropanol for å gi 963 mg (61%) rent cis-3-(2-norbornylkarbonylamino)-2-benzhvdryl-kinuklidin i form av et hvitt faststoff som smeltet ved 203-2 07°C; 805.9 mg (0.005757 mol) of 2-norbornene carboxylic acid, 932.6 mg (0.005757 mol) of carbonyldiimidazole and 19 ml of dry tetrahydrofuran were placed in a 50 ml round-bottomed flask equipped with a reflux condenser, magnetic stir bar and nitrogen inlet tube. The reaction mixture was then stirred at room temperature (about 20°C) for 30 minutes and then 1.1207 g (0.003838 mol) of 3-amino-2-benzhydrylquinuclidine [E. J. Warawa et al., in Journal of Medicinal Chemistry. Vol. 18. p. 71 (1975)]. The resulting mixture was then refluxed for 18 hours, cooled to room temperature and then partitioned between water and methylene chloride. The separated organic layer was then washed with brine and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid residue was finally obtained which was then crystallized from isopropanol to give 963 mg (61%) of pure cis-3-(2-norbornylcarbonylamino)-2- benzhvdrylquinuclidine as a white solid melting at 203-207°C;
IR (cm"<1>, KBr), 1645 (C=0). Det rene produktet ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data i tillegg til elementanalyse. IR (cm"<1>, KBr), 1645 (C=0). The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data in addition to elemental analysis.
Massespektrum (%): 414(29, parent), 291(23), 248(31), 247(100), 181(28), 180(96), 167(22), 165(20), 125(28), 97(30), 96(25), 95(77), 91(34), 69(21), 67(26). Mass spectrum (%): 414(29, parent), 291(23), 248(31), 247(100), 181(28), 180(96), 167(22), 165(20), 125(28 ), 97(30), 96(25), 95(77), 91(34), 69(21), 67(26).
NMR-data: 4I-NMR (5, CDC13) 0,8-3,1 (flere multipletter, 19H), 3,94 (m, 2H), 4,14 (m, 1H), 4,35 (m, 1H), 5,6-5,8 (m, 1H), 7,0-7,4 (m, 10H). NMR data: 4I-NMR (5, CDCl 3 ) 0.8-3.1 (several multiplets, 19H), 3.94 (m, 2H), 4.14 (m, 1H), 4.35 (m, 1H), 5.6-5.8 (m, 1H), 7.0-7.4 (m, 10H).
Analyse beregnet for C28H34N20. 0, 5H20: Analysis calculated for C28H34N20. 0.5H2O:
C, 79,39; H, 8,33; N, 6,61. C, 79.39; H, 8.33; N, 6.61.
Funnet: C, 79,33; H, 8,13; N, 6,72. Found: C, 79.33; H, 8.13; N, 6.72.
Fremstilling D Manufacturing D
Fremgangsmåten beskrevet i Fremstilling C ble gjentatt for å fremstille de følgende cis-3-(homocyklisk-karbonyl-amino)-2-benzhydrylkinuklidiner, ved i hvert tilfelle å gå ut fra den korresponderende homocyklisk-karboksylsyre og 3-amino-2-benzhydrylkinuklidin i hvert tilfelle, og benytte de samme molare forhold som tidligere: cis-3-(1-norbornylkarbonylamino)-2-benzhydrylkinuklidin, smp. 220-230°C. The procedure described in Preparation C was repeated to prepare the following cis-3-(homocyclic-carbonyl-amino)-2-benzhydrylquinuclidines, starting in each case from the corresponding homocyclic-carboxylic acid and 3-amino-2-benzhydrylquinuclidine in in each case, and use the same molar ratios as before: cis-3-(1-norbornylcarbonylamino)-2-benzhydrylquinuclidine, m.p. 220-230°C.
cis-3-(2-benzylfenylkarbonylamino)-2-benzhydryl-kinuklidin, smp. 215-222°C. cis-3-(2-benzylphenylcarbonylamino)-2-benzhydryl-quinuclidine, m.p. 215-222°C.
cis-3-(3,5-difluorfenylkarbonylamino)-2-benzhydryl-kinuklidin, smp. 225-230°C. cis-3-(3,5-difluorophenylcarbonylamino)-2-benzhydryl-quinuclidine, m.p. 225-230°C.
cis-3-(2,3-difluorfenylkarbonylamino)-2-benzhydryl-kinuklidin, smp. 250-256°C. cis-3-(2,3-difluorophenylcarbonylamino)-2-benzhydryl-quinuclidine, m.p. 250-256°C.
Fremstilling E Manufacturing E
cis-3-benzylamino-2-benzhydrylkinuklidin (smp. 145-148°C) ble fremstillet i henhold til fremgangsmåten beskrevet av E. J. Warawa et al., som først omtalt i Journal of Medicinal Chemistr<y>, Vol. 18, s. 587 (1975), hvor 3-keto-2-benzhydryl-kinuklidin ble kondensert med benzylamin og det resulterende mellomprodukt, dvs. 3-benzylimino-2-benzhydrylkinuklidin, deretter ble redusert med natriumborhydrid for å gi det ønskede sluttprodukt. Smeltepunkt av sluttproduktet var 151,5-152°C i henhold til E. J. Warawa et al. cis-3-benzylamino-2-benzhydrylquinuclidine (m.p. 145-148°C) was prepared according to the method described by E. J. Warawa et al., as first reported in Journal of Medicinal Chemistr<y>, Vol. 18, p. 587 (1975), where 3-keto-2-benzhydrylquinuclidine was condensed with benzylamine and the resulting intermediate, i.e. 3-benzylimino-2-benzhydrylquinuclidine, was then reduced with sodium borohydride to give the desired final product. Melting point of the final product was 151.5-152°C according to E. J. Warawa et al.
Fremstilling F Production F
cis-3-[(2-tienyl)metylamino]-2-benzhydrylkinuklidin (smp. 140-145°C) ble fremstillet etter fremgangsmåten beskrevet i Fremstilling E ved kondensasjon av 3-keto-2-benzhydryl-kinuklidin med (2-tienyl)metylamin (dvs. 2-tenylamin), etterfulgt av reduksjon av det resulterende mellomprodukt (dvs. 3-[(2-tienyl)metylimino]-2-benzhydrylkinuklidin) med natriumborhydrid for tilslutt å gi det ønskede sluttprodukt. cis-3-[(2-thienyl)methylamino]-2-benzhydrylquinuclidine (m.p. 140-145°C) was prepared according to the procedure described in Preparation E by condensation of 3-keto-2-benzhydrylquinuclidine with (2-thienyl )methylamine (ie 2-thenylamine), followed by reduction of the resulting intermediate (ie 3-[(2-thienyl)methylimino]-2-benzhydrylquinuclidine) with sodium borohydride to finally give the desired final product.
Fremstilling G Production G
cis-3-[(2-pyrroly1)metylamino]-2-benzhydrylkinuklidin (smp. 137,5-138,5°C) ble fremstillet etter fremgangsmåten angitt i Fremstilling E, ved kondensasjon av 3-keto-2-benzhydrylkinuklidin med (2-pyrrolyl)metylamin, etterfulgt av reduksjon av det resulterende mellomprodukt (dvs. 3-[(2-pyrrolyl)metylimino]-2-benzhydrylkinuklidin] med natriumborhydrid for tilslutt å gi det ønskede sluttprodukt. cis-3-[(2-pyrrolyl)methylamino]-2-benzhydrylquinuclidine (m.p. 137.5-138.5°C) was prepared according to the procedure indicated in Preparation E, by condensation of 3-keto-2-benzhydrylquinuclidine with ( 2-pyrrolyl)methylamine, followed by reduction of the resulting intermediate (ie 3-[(2-pyrrolyl)methylimino]-2-benzhydrylquinuclidine] with sodium borohydride to finally give the desired final product.
Eksempel 1 Example 1
A. I en 50 ml rundkolbe forsynt med en Dean-Stark-felle, tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 1,12 g (0,00385 mol) 3-keto-2-benzhydrylkinuklidin [E. J. Warawa et al., Journal of Medicinal Chemistry, Vol. 17, s. 497 (1974)], 652 mg (0,00577 mol) cykloheksylmetylamin, A. Into a 50 ml round bottom flask fitted with a Dean-Stark trap, reflux condenser and nitrogen inlet tube was placed 1.12 g (0.00385 mol) of 3-keto-2-benzhydrylquinuclidine [E. J. Warawa et al., Journal of Medicinal Chemistry, Vol. 17, p. 497 (1974)], 652 mg (0.00577 mol) cyclohexylmethylamine,
17,8 mg (0,00077 mol) kamfersulfonsyre og 19 ml toluen. Reaksjonsblandingen ble deretter kokt azeotropisk (med 17.8 mg (0.00077 mol) of camphorsulfonic acid and 19 ml of toluene. The reaction mixture was then boiled azeotropically (with
separasjon av vann) i 18 timer, avkjølt til romtemperatur og konsentrert i vakuum for å gi et fast residuum. separation of water) for 18 hours, cooled to room temperature and concentrated in vacuo to give a solid residue.
B. Det ovenfor oppnådde residuum [rå 3-(cykloheksyl-metylimino) -2-benzhydrylkinuklidin] ble deretter oppløst i 13 ml tørr tetrahydrofuran og den resulterende oppløsning avkjølt til 0°C under omrøring mens den befant seg under tørr nitrogenatmosfære. På dette tidspunkt ble 10,8 ml (0,00539 mol) av en 1,5M oppløsning 9-borabicyklononan (9-BBN) i tetrahydrofuran tilsatt til den avkjølte oppløsning (under omrøring), hvorpå den resulterende reaksjonsblanding fikk oppvarmes til romtemperatur (ca. 20°C) og deretter ble omrørt i 3 dager ved romtemperatur. Etter fullføring av dette trinn, ble reaksjonen avbrutt med vann, hvorpå blandingen ble fordelt mellom vandig IN saltsyre og metylenklorid, hvoretter de to lagene ble separert. Det fraskilte vandige lag ble deretter justert til pH 14 med fast natriumhydroksyd og deretter ekstrahert med frisk metylenklorid. De kombinerte organiske ekstraktene ble deretter tørket over vannfri natriumsulfat og filtrert, og det resulterende filtrat deretter inndampet til tørrhet under redusert trykk for å gi et fast restprodukt. Krystallisasjon av sistnevnte materiale fra isopropanol ga B. The residue obtained above [crude 3-(cyclohexyl-methylimino)-2-benzhydrylquinuclidine] was then dissolved in 13 ml of dry tetrahydrofuran and the resulting solution cooled to 0°C with stirring while under a dry nitrogen atmosphere. At this point, 10.8 mL (0.00539 mol) of a 1.5 M solution of 9-borabicyclononane (9-BBN) in tetrahydrofuran was added to the cooled solution (with stirring), whereupon the resulting reaction mixture was allowed to warm to room temperature (ca. . 20°C) and then was stirred for 3 days at room temperature. After completion of this step, the reaction was quenched with water, whereupon the mixture was partitioned between aqueous 1N hydrochloric acid and methylene chloride, after which the two layers were separated. The separated aqueous layer was then adjusted to pH 14 with solid sodium hydroxide and then extracted with fresh methylene chloride. The combined organic extracts were then dried over anhydrous sodium sulfate and filtered, and the resulting filtrate then evaporated to dryness under reduced pressure to give a solid residue. Crystallization of the latter material from isopropanol gave
334 mg (22%) rent cis-3-(cvkloheksylmetylamino)-2-benzhydrylkinuklidin som hvite krystaller som smeltet ved 152-153°C. Den rene produkt ble videre karakterisert ved massespektrometrisk analyse og kjernemagnetiske resonans-data, i tillegg til elementanalyse. 334 mg (22%) of pure cis-3-(cyclohexylmethylamino)-2-benzhydrylquinuclidine as white crystals melting at 152-153°C. The pure product was further characterized by mass spectrometric analysis and nuclear magnetic resonance data, in addition to elemental analysis.
Massespektrum (%): 389 (parent +1, <1,0), 274(3), 222(40), 221(100), 178(25), 165(21), 164(24), 154(44), 110(40), 108(21), 97(25), 96(31), 82(35), 70(21), 56(30), 55(33). Mass spectrum (%): 389 (parent +1, <1.0), 274(3), 222(40), 221(100), 178(25), 165(21), 164(24), 154(44 ), 110(40), 108(21), 97(25), 96(31), 82(35), 70(21), 56(30), 55(33).
NMR data: tø-NMR (5, CDC13) 0,4-0,6 (m, 2H) , 1,0-1,2 (m, 6H) , 1,5-1,7 (m, 4H) , 1,8-2,0 (m, 2H), 2,23 (m, 1H), 2,63 (t, 1H), 2,7-2,9 (m, 4H), 3,18 (m, 1H), 3,69 (dd, 1H), 4,42 (d, 1H), 7,0-7,4 (m, 10H). NMR data: thaw-NMR (5, CDCl 3 ) 0.4-0.6 (m, 2H) , 1.0-1.2 (m, 6H) , 1.5-1.7 (m, 4H) , 1.8-2.0 (m, 2H), 2.23 (m, 1H), 2.63 (t, 1H), 2.7-2.9 (m, 4H), 3.18 (m, 1H), 3.69 (dd, 1H), 4.42 (d, 1H), 7.0-7.4 (m, 10H).
<13>C-NMR (CDC13) 20,0, 24,9, 25,5, 25,9, 26,1, 26,6, 30,9, 31,1, 36,9, 42,1, 49,4, 49,6, 55,1, 56,0, 62,0, 126,0, 126,5, 127,5, 128,4, 129,1, 143,2, 145,4. <13>C-NMR (CDC13) 20.0, 24.9, 25.5, 25.9, 26.1, 26.6, 30.9, 31.1, 36.9, 42.1, 49 .4, 49.6, 55.1, 56.0, 62.0, 126.0, 126.5, 127.5, 128.4, 129.1, 143.2, 145.4.
Analyse beregnet for C27H36N2: Analysis calculated for C27H36N2:
C, 83,45; H, 9,34; N, 7,21. C, 83.45; H, 9.34; N, 7.21.
Funnet: C, 83,20; H, 9,34; N, 7,21. Found: C, 83.20; H, 9.34; N, 7.21.
Eksempel 2 Example 2
To-trinns reaksjonen beskrevet i Eksempel 1 ble gjentatt bortsett fra at 2-klorbenzylamin ble benyttet som reagens i stedet for cykloheksylamin, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det tilsvarende oppnådde sluttprodukt cis-3-[(2klorfenyl)metyl-amino] -2-benzhydrylkinuklidin (utbytte, 58%), smp. 172-174°C. The two-step reaction described in Example 1 was repeated except that 2-chlorobenzylamine was used as reagent instead of cyclohexylamine, using the same molar ratios as before. In this particular case, the correspondingly obtained final product was cis-3-[(2chlorophenyl)methyl-amino]-2-benzhydrylquinuclidine (yield, 58%), m.p. 172-174°C.
Analyse beregnet for C27H29C1N2: Analysis calculated for C27H29C1N2:
C, 77,77; H, 7,01; N, 6,72. C, 77.77; H, 7.01; N, 6.72.
Funnet: C, 77,34; H, 6,95; N, 6,65. Found: C, 77.34; H, 6.95; N, 6.65.
Eksempel 3 Example 3
To-trinns reaksjonen beskrevet i Eksempel 1 ble gjentatt bortsett fra at 2-trifluormetylbenzylamin ble benyttet som reagens i stedet for cykloheksylamin, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det tilsvarende oppnådde sluttprodukt cis-3-[(2-trifluormetylfenyl)metylamino]-2-benzhydrylkinuklidin (utbytte, 41%), smp. 164-167°C. The two-step reaction described in Example 1 was repeated except that 2-trifluoromethylbenzylamine was used as reagent instead of cyclohexylamine, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-[(2-trifluoromethylphenyl)methylamino]-2-benzhydrylquinuclidine (yield, 41%), m.p. 164-167°C.
Analyse beregnet for C28H29F3N2: Analysis calculated for C28H29F3N2:
C, 74,64; H, 6,49; N, 6,22. C, 74.64; H, 6.49; N, 6.22.
Funnet: C, 74,08; H, 6,48; N, 6,06. Found: C, 74.08; H, 6.48; N, 6.06.
Eksempel 4 Example 4
To-trinns reaksjonen beskrevet i Eksempel 1 ble gjentatt bortsett fra at 2-metoksybenzylamin ble brukt som reagens i stedet for cykloheksylamin, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det tilsvarende oppnådde sluttprodukt cis-3-[(2-metoksyfenyl)-metylamino]-2-benzhydrylkinuklidin (utbytte, 71%), smp. 132-135°C. The two-step reaction described in Example 1 was repeated except that 2-methoxybenzylamine was used as the reagent instead of cyclohexylamine, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-[(2-methoxyphenyl)-methylamino]-2-benzhydrylquinuclidine (yield, 71%), m.p. 132-135°C.
Analyse beregnet for C28H32N20: Analysis calculated for C28H32N20:
C, 81,51; H, 7,82; N, 6,79. C, 81.51; H, 7.82; N, 6.79.
Funnet: C, 81,56; H, 7,86; N, 6,68. Found: C, 81.56; H, 7.86; N, 6.68.
Eksempel 5 Example 5
To-trinns reaksjonen beskrevet i Eksempel 1 ble gjentatt for å fremstille de etterfølgende: cis-3-[(cyklisk)metylamino]-2-benzhydrylkinuklidiner, ved i hvert tilfelle å gå ut fra 3-keto-2-benzhydrylkinuklidin og det respektivt passende N-(cyklisk)-metylamin, under bruk av de samme molare forhold som tidligere: cis-3-[(3-trifluormetylfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 197-199°C. The two-step reaction described in Example 1 was repeated to prepare the following: cis-3-[(cyclic)methylamino]-2-benzhydrylquinuclidines, starting in each case from 3-keto-2-benzhydrylquinuclidine and the respective appropriate N-(cyclic)-methylamine, using the same molar ratios as before: cis-3-[(3-trifluoromethylphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 197-199°C.
cis-3-[(4-metoksyfenyl)metylamino]-2-benzhydry1-kinuklidin, smp. 154-157°C. cis-3-[(4-methoxyphenyl)methylamino]-2-benzhydry1-quinuclidine, m.p. 154-157°C.
cis-3-[(3-pyridyl)metylamino]-2-benzhydrylkinuklidin, smp. 130-140°C. cis-3-[(3-pyridyl)methylamino]-2-benzhydrylquinuclidine, m.p. 130-140°C.
cis-3-f(3,4-diklorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 182-184°C. cis-3-f(3,4-dichlorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 182-184°C.
cis-3-[(4-fluorfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 170-172°C. cis-3-[(4-fluorophenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 170-172°C.
cis-3-[(2-pyridyl)metylamino]-2-benzhydrylkinuklidin, smp. 95-115°C. cis-3-[(2-pyridyl)methylamino]-2-benzhydrylquinuclidine, m.p. 95-115°C.
cis-3-[(4-pyridyl)metylamino]-2-benzhydrylkinuklidin, smp. 110-130°C. cis-3-[(4-pyridyl)methylamino]-2-benzhydrylquinuclidine, m.p. 110-130°C.
cis-3-[(4-klorfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 157-160°C. cis-3-[(4-chlorophenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 157-160°C.
cis-3-[(3-metoksyfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 156-158°C. cis-3-[(3-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 156-158°C.
cis-3-[(2,3-diklorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 151-154°C. cis-3-[(2,3-dichlorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 151-154°C.
cis-3-[(3-klorfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 186-188°C. cis-3-[(3-chlorophenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 186-188°C.
cis-3-\(4-trifluormetylfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 171-173°C. cis-3-[(4-trifluoromethylphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 171-173°C.
cis-3-[(2-metylfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 173-176°C. cis-3-[(2-methylphenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 173-176°C.
cis-3-[(3-metylfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 170-174°C. cis-3-[(3-methylphenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 170-174°C.
cis-3-[(4-metylfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 175-178°C. cis-3-[(4-methylphenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 175-178°C.
cis-3-[(3-fluorfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 156-159°C. cis-3-[(3-fluorophenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 156-159°C.
cis-3-[(4-metoksykarbony1feny1)metylamino]-2-benzhydry1-kinuklidin, smp. 175-182°C. cis-3-[(4-methoxycarbonylphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 175-182°C.
cis-3-[(2-fluorfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 164-166°C. cis-3-[(2-fluorophenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 164-166°C.
cis-3-[(2,5-difluorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 163-165°C. cis-3-[(2,5-difluorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 163-165°C.
cis-3-[(2,6-difluorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 154-157°C. cis-3-[(2,6-difluorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 154-157°C.
cis-3-[(3-metoksykarbony1fenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 182-185°C. cis-3-[(3-methoxycarbonylphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 182-185°C.
cis-3-[(3-indoly1)mety1amino]-2-benzhydrylkinuklidin, smp. 207-212°C. cis-3-[(3-indolyl)methylamino]-2-benzhydrylquinuclidine, m.p. 207-212°C.
Eksempel 6 Example 6
A. I en 25 ml rundkolbe forsynt med en Dean-Stark-felle, tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 505 mg (0,001405 mol) 2-[(2,4-diklorfenyl)fenylmetyl]kinuklidin-3-on (produktet fra Fremstilling B), 225 mg (0,002107 mol) benzylamin, 6,5 mg (0,000028 mol) kamfersulfonsyre og 7 ml toluen. Reaksjonsblandingen ble deretter kokt azeotropisk i 18 timer, avkjølt til romtemperatur og konsentrert i vakuum for å gi et fast residuum. A. Into a 25 ml round bottom flask fitted with a Dean-Stark trap, reflux condenser and nitrogen inlet tube was placed 505 mg (0.001405 mol) of 2-[(2,4-dichlorophenyl)phenylmethyl]quinuclidin-3-one (the product of Preparation B), 225 mg (0.002107 mol) of benzylamine, 6.5 mg (0.000028 mol) of camphorsulfonic acid and 7 ml of toluene. The reaction mixture was then boiled azeotropically for 18 hours, cooled to room temperature and concentrated in vacuo to give a solid residue.
B. Det ovenfor oppnådde faste residuum (rå 3-benzylimino-2-[(2,4-diklorfenyl)fenylmetyl]kinuklidin) ble deretter oppløst i 13 ml tørr tetrahydrofuran og den resulterende oppløsning avkjølt til 0°C under omrøring mens den befant seg under tørr nitrogenatmosfære. På dette tidspunkt ble 5,6 ml (0,002809 mol) av en 0,5M oppløsning 9-borabicyklononan (9-BBN) i tetrahydrofuran tilsatt til den avkjølte oppløsning (under omrøring), hvorpå den resulterende reaksjonsblandingen fikk oppvarmes til romtemperatur (ca. 20°C) og deretter ble omrørt i 24 timer ved romtemperatur. Etter fullføring av dette trinn, ble reaksjonen avbrutt med vann, hvorpå blandingen ble fordelt mellom vandig IN saltsyre og metylenklorid, hvorpå det organiske lag ble fraskilt. Den vandige fase ble deretter justert til pH 14 med fast natriumhydroksyd og deretter ekstrahert med frisk metylenklorid. De kombinerte organiske ekstraktene ble deretter tørket over vannfri natriumsulfat og filtrert, og det resulterende filtrat deretter inndampet til tørrhet under redusert trykk for å gi et fast restprodukt. Krystallisasjon av sistnevnte materiale fra isopropanol ga deretter 154 mg (24%) rent cis-3-benzylamino-2-[(2,4-diklorfenyl)fenylmetyl]-kinuklidin, som hvite krystaller som smeltet ved 142-147°C. Det rene produkt ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data, i tillegg til elementanalyse. B. The solid residue obtained above (crude 3-benzylimino-2-[(2,4-dichlorophenyl)phenylmethyl]quinuclidine) was then dissolved in 13 mL of dry tetrahydrofuran and the resulting solution cooled to 0°C with stirring while under a dry nitrogen atmosphere. At this point, 5.6 mL (0.002809 mol) of a 0.5 M solution of 9-borabicyclononane (9-BBN) in tetrahydrofuran was added to the cooled solution (with stirring), after which the resulting reaction mixture was allowed to warm to room temperature (ca. . 20°C) and then was stirred for 24 hours at room temperature. After completion of this step, the reaction was quenched with water, whereupon the mixture was partitioned between aqueous 1N hydrochloric acid and methylene chloride, whereupon the organic layer was separated. The aqueous phase was then adjusted to pH 14 with solid sodium hydroxide and then extracted with fresh methylene chloride. The combined organic extracts were then dried over anhydrous sodium sulfate and filtered, and the resulting filtrate then evaporated to dryness under reduced pressure to give a solid residue. Crystallization of the latter material from isopropanol then gave 154 mg (24%) of pure cis-3-benzylamino-2-[(2,4-dichlorophenyl)phenylmethyl]-quinuclidine as white crystals melting at 142-147°C. The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data, in addition to elemental analysis.
Masséspektrum (%): 451 (parent, 0,5), 216(22), 215(72); 96(21), 91(100). Mass spectrum (%): 451 (parent, 0.5), 216(22), 215(72); 96(21), 91(100).
NMR data: <X>H-NMR (<5, CDC13) , 1,2-2,1 (serier på fem multipletter, 5H), 2,7-2,8 (m, 4H), 3,1-3,3 (m, 2H), 3,6-3,7 (m, 2H), 4,84 (d, 1H), 6,7-6,8 og 7,1-7,4 (m, 8H). NMR data: <X>H-NMR (<5, CDCl 3 ), 1.2-2.1 (series of five multiplets, 5H), 2.7-2.8 (m, 4H), 3.1-3 .3 (m, 2H), 3.6-3.7 (m, 2H), 4.84 (d, 1H), 6.7-6.8 and 7.1-7.4 (m, 8H) .
<13>C-NMR (CDC13) 20,1, 24,6, 25,5, 42,1, 44,1, 49,6, 51,9, 53,8, 62,9, 126,4, 126,8, 127,5, 127,9, 128,2, 128,3, 132,3, 139,8, 139,9, 142,6. <13>C-NMR (CDC13) 20.1, 24.6, 25.5, 42.1, 44.1, 49.6, 51.9, 53.8, 62.9, 126.4, 126 .8, 127.5, 127.9, 128.2, 128.3, 132.3, 139.8, 139.9, 142.6.
Analyse beregnet for C27H28C12N2: Analysis calculated for C27H28C12N2:
C, 71,84; H, 6,25; N, 6,21. C, 71.84; H, 6.25; N, 6.21.
Funnet: C, 71,04; H, 6,28; N, 5,63. Found: C, 71.04; H, 6.28; N, 5.63.
Eksempel 7 Example 7
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt bortsett fra at 2-[(3-metoksyfenyl)fenylmetyl]kinuklidin-3-on (et produkt fra Fremstilling C) ble benyttet som reaktant i stedet for 2-[(2,4-diklorfenyl)fenylmetyl]kinuklidin-3-on, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-benzylamino-2-[(3-metoksyfenyl)fenylmetyl]kinuklidin (utbytte, 33%), smp. 80-90°C. The two-step reaction described in Example 6 was repeated except that 2-[(3-methoxyphenyl)phenylmethyl]quinuclidin-3-one (a product of Preparation C) was used as reactant instead of 2-[(2,4- dichlorophenyl)phenylmethyl]quinuclidin-3-one, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-benzylamino-2-[(3-methoxyphenyl)phenylmethyl]quinuclidine (yield, 33%), m.p. 80-90°C.
Analyse beregnet for C28H32N20 . 0,5H2O: Analysis calculated for C28H32N20. 0.5H2O:
C, 79,77; H, 7,89; N, 6,64. C, 79.77; H, 7.89; N, 6.64.
Funnet: C, 79,36; H, 7,78; N, 6,48. Found: C, 79.36; H, 7.78; N, 6.48.
Eksempel 8 Example 8
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt bortsett fra at 2-[(4-metoksykarbony1fenyl)fenyl-metyl ]kinuklidin-3-on (et produkt fra Fremstilling C) ble benyttet som reaktant i stedet for 2-[(2,4-diklorfenyl)-fenylmetyl]kinuklidin-3-on, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-benzylamino-2- f(4-metoksykarbonylfenyl)fenylmetyl]kinuklidin (utbytte, 47%), smp. 156-166°C. The two-step reaction described in Example 6 was repeated except that 2-[(4-methoxycarbonylphenyl)phenyl-methyl]quinuclidin-3-one (a product of Preparation C) was used as reactant in place of 2-[(2, 4-dichlorophenyl)-phenylmethyl]quinuclidin-3-one, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-benzylamino-2-f(4-methoxycarbonylphenyl)phenylmethyl]quinuclidine (yield, 47%), m.p. 156-166°C.
Analyse beregnet for C29H32N2O2: Analysis calculated for C29H32N2O2:
C, 79,06; H, 7,32; N, 6,36. C, 79.06; H, 7.32; N, 6.36.
Funnet: C, 78,80; H, 7,28; N, 6,28. Found: C, 78.80; H, 7.28; N, 6.28.
Eksempel 9 Example 9
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt for å fremstille de etterfølgende cis-3-benzylamino-2-[( a-substituert)fenylmetyl]kinuklidiner, ved i hvert tilfelle å gå ut fra de tilsvarende 2-[(a-substituert)fenylmetyl]kinuklidin-3-on-forbindelser og benzylamin, under bruk av de samme molare forhold som tidligere: cis-3-benzylamino-2-[(2,3-diklorfenyl)fenylmetyl]-kinuklidin, smp. 150-165°C. The two-step reaction described in Example 6 was repeated to prepare the subsequent cis-3-benzylamino-2-[(α-substituted)phenylmethyl]quinuclidines, starting in each case from the corresponding 2-[(α-substituted )phenylmethyl]quinuclidin-3-one compounds and benzylamine, using the same molar ratios as before: cis-3-benzylamino-2-[(2,3-dichlorophenyl)phenylmethyl]-quinuclidine, m.p. 150-165°C.
cis-3-benzylamino-2-[(2,4-difluorfenyl)fenylmetyl]-kinuklidin, smp. 115-140°C. cis-3-benzylamino-2-[(2,4-difluorophenyl)phenylmethyl]-quinuclidine, m.p. 115-140°C.
cis-3-benzylamino-2-[(3-tri fluormetylfenyl)fenylmetyl]-kinuklidin, smp. 158-160°C. cis-3-benzylamino-2-[(3-trifluoromethylphenyl)phenylmethyl]-quinuclidine, m.p. 158-160°C.
cis-3-benzylamino-2-f(2-furyl)fenylmetyl]kinuklidin, smp. 135-143°C. cis-3-benzylamino-2-f(2-furyl)phenylmethyl]quinuclidine, m.p. 135-143°C.
cis-3-benzylamino-2-[(3,4-diklorfenyl)fenylmetyl]-kinuklidin, smp. 136-139°C. cis-3-benzylamino-2-[(3,4-dichlorophenyl)phenylmethyl]-quinuclidine, m.p. 136-139°C.
cis-3-benzylamino-2-[(4-pyridyl)fenylmetyl]kinuklidin, smp. 120-135°C. cis-3-benzylamino-2-[(4-pyridyl)phenylmethyl]quinuclidine, m.p. 120-135°C.
cis-3-benzylamino-2-[(E- og Z-2-tert-butylvinyl)fenyl-metyl] kinuklidin, smp. 85-92°C. cis-3-benzylamino-2-[(E- and Z-2-tert-butylvinyl)phenyl-methyl] quinuclidine, m.p. 85-92°C.
cis-3-benzylamino-2-[(2-metoksyfenyl)fenylmetyl]-kinuklidin, smp. 155-175°C. cis-3-benzylamino-2-[(2-methoxyphenyl)phenylmethyl]-quinuclidine, m.p. 155-175°C.
cis-3-benzylamino-2-[2-(isopropyl)fenylmetyl]kinuklidin, smp. 140-145°C. cis-3-benzylamino-2-[2-(isopropyl)phenylmethyl]quinuclidine, m.p. 140-145°C.
cis-3-benzylamino-2-[(4-karboksyfenyl)fenylmetyl]-kinuklidin, smp. 180°C (dekomp.). cis-3-benzylamino-2-[(4-carboxyphenyl)phenylmethyl]-quinuclidine, m.p. 180°C (decomp.).
cis-3-benzylamino-2-[(2-tienyl)fenylmetyl]kinuklidin, smp. 150-163°C. cis-3-benzylamino-2-[(2-thienyl)phenylmethyl]quinuclidine, m.p. 150-163°C.
cis-3-benzylamino-2-[(2-bifenyl)fenylmetyl]kinuklidin, smp. 185-195°C. cis-3-benzylamino-2-[(2-biphenyl)phenylmethyl]quinuclidine, m.p. 185-195°C.
Eksempel 10 Example 10
Fremgangsmåten beskrevet i Eksempel 6 ble gjentatt for å fremstille de etterfølgende cis-3-(2-tienyl)amino-2-[(a-substituert)fenylmetyl]kinuklidiner, ved i hvert tilfelle å gå ut fra de tilsvarende 2-[(a-substituert)fenylmetyl]kinuklidin-3-on og 2-tenylamin [som er (2-tienyl)metylamin], under bruk av de samme molare forhold som tidligere: cis-3-r(2-tienyl)metylamino]-2-[(2,3-diklorfenyl)fenyl-metyl] kinuklidin, smp. 129-142°C. The procedure described in Example 6 was repeated to prepare the subsequent cis-3-(2-thienyl)amino-2-[(a-substituted)phenylmethyl]quinuclidines, starting in each case from the corresponding 2-[(a -substituted)phenylmethyl]quinuclidin-3-one and 2-thenylamine [which is (2-thienyl)methylamine], using the same molar ratios as before: cis-3-r(2-thienyl)methylamino]-2- [(2,3-dichlorophenyl)phenyl-methyl] quinuclidine, m.p. 129-142°C.
cis-3-f(2-tienyl)metylamino]-2-[(2,4-diklorfenyl)fenyl-metyl] kinukl idin, smp. 133-138°C. cis-3-f(2-thienyl)methylamino]-2-[(2,4-dichlorophenyl)phenyl-methyl]quinuclidine, m.p. 133-138°C.
cis-3-[(2-tienyl)metylamino]-2-[(3-metoksyfenyl)fenyl-metyl] kinukl idin, smp. 105-115°C. cis-3-[(2-thienyl)methylamino]-2-[(3-methoxyphenyl)phenyl-methyl] quinuclidine, m.p. 105-115°C.
cis-3-[(2-tienyl)metylamino]-2-[(cykloheksyl)fenylmetyl]-kinuklidin, smp. 140-147°C. cis-3-[(2-thienyl)methylamino]-2-[(cyclohexyl)phenylmethyl]-quinuclidine, m.p. 140-147°C.
cis-3-[(2-tienyl)metylamino]-2-[(3-pyridyl)fenylmetyl]-kinuklidin, smp. 147-153°C. cis-3-[(2-thienyl)methylamino]-2-[(3-pyridyl)phenylmethyl]-quinuclidine, m.p. 147-153°C.
Eksempel 11 Example 11
I en 50 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 1,022 g (0,0035 mol) 3-amino-2-benzhydrylkinuklidin [fremstillet ifølge fremgangsmåten beskrevet av E. J. Warawa et al., i Journal of Medicinal Chemistry. Vol. 18, s. 71 (1975)], 918,7 mg (0,00525 mol) 2,6-diklorbenzaldehyd, 16 mg kamfersulfonsyre og 18 ml toluen. Den resulterende reaksjonsblanding ble deretter kokt azeotropisk i 18 timer og deretter avkjølt til romtemperatur (ca. 20°C) og Into a 50 ml round bottom flask fitted with a reflux condenser and nitrogen inlet tube was placed 1.022 g (0.0035 mol) of 3-amino-2-benzhydrylquinuclidine [prepared according to the method described by E. J. Warawa et al., in the Journal of Medicinal Chemistry. Vol. 18, p. 71 (1975)], 918.7 mg (0.00525 mol) of 2,6-dichlorobenzaldehyde, 16 mg of camphorsulfonic acid and 18 ml of toluene. The resulting reaction mixture was then boiled azeotropically for 18 hours and then cooled to room temperature (about 20°C) and
inndampet nesten til tørrhet under redusert trykk for å gi et evaporated almost to dryness under reduced pressure to give a
fast residuum. Krystallisasjon av det sistnevnte materiale fra isopropanol ga deretter 1,32 g (84%) rent cis-3-[(2,6-diklor-fenyl)metylenamino]-2-benzhydrylkinuklidin som et hvitt faststoff, smp. 178-182°C; solid residue. Crystallization of the latter material from isopropanol then gave 1.32 g (84%) of pure cis-3-[(2,6-dichloro-phenyl)methyleneamino]-2-benzhydrylquinuclidine as a white solid, m.p. 178-182°C;
IR (cm-<1>, KBr) , 1642 (C=N) . Det rene produkt ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data, i tillegg til elementanalyse. IR (cm-<1>, KBr), 1642 (C=N). The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data, in addition to elemental analysis.
Massespektrum (%): 427(<1, parent + 1), 291(38), 274(21), 260(310, 259(100), 135(21), 96(21), 91(27). Mass spectrum (%): 427(<1, parent + 1), 291(38), 274(21), 260(310, 259(100), 135(21), 96(21), 91(27).
NMR-data: ^-NMR (6, CDC13) 1,45 (m, 1H) , 1,81 (m, 3H) , 2,26 (m, 1H), 2,89 (m, 1H), 3,08 (m, 2H), 3,60 (m, 1H), 3,71 (m, 1H), 4,01 (dd, 2H), 4,68 (d, 1H), 7,1-7,5 (m, 13H), 7,96 (2, 1H). NMR data: δ-NMR (6, CDCl 3 ) 1.45 (m, 1H), 1.81 (m, 3H), 2.26 (m, 1H), 2.89 (m, 1H), 3, 08 (m, 2H), 3.60 (m, 1H), 3.71 (m, 1H), 4.01 (dd, 2H), 4.68 (d, 1H), 7.1-7.5 (m, 13H), 7.96 (2, 1H).
<13>C-NMR (CDC13) 22,0, 25>4, 31,8, 42,4, 49,5, 50,2, 63,1, 71,3, 125,9, 127,8, 128,2, 128,3, 128,4, 129,3, 130,0, 130,8, 135,5, 143,4, 145,4, 155,8. <13>C-NMR (CDC13) 22.0, 25>4, 31.8, 42.4, 49.5, 50.2, 63.1, 71.3, 125.9, 127.8, 128 ,2, 128.3, 128.4, 129.3, 130.0, 130.8, 135.5, 143.4, 145.4, 155.8.
Analyse beregnet for C27H28C12N2: Analysis calculated for C27H28C12N2:
C, 72,16; H, 5,83; N, 6,23. C, 72.16; H, 5.83; N, 6.23.
Funnet: C, 71,50; H, 5,79; N, 6,14. Found: C, 71.50; H, 5.79; N, 6.14.
Eksempel 12 Example 12
Fremgangsmåten beskrevet i Eksempel 11 ble gjentatt bortsett fra at 2-metoksybenzaldehyd ble benyttet som reagens i stedet for 2,6-diklorbenzaldehyd, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-[(2-metoksyfenyl)-metylenamino]-2-benzhydrylkinuklidin (utbytte, 78%), smp. 157-161°C. The procedure described in Example 11 was repeated except that 2-methoxybenzaldehyde was used as reagent instead of 2,6-dichlorobenzaldehyde, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-[(2-methoxyphenyl)-methyleneamino]-2-benzhydrylquinuclidine (yield, 78%), m.p. 157-161°C.
Analyse beregnet for C28H30N2O: Analysis calculated for C28H30N2O:
C, 81,91; H, 7,36; N, 6,82. C, 81.91; H, 7.36; N, 6.82.
Funnet: C, 81,49; H, 4,76; N, 6,70. Found: C, 81.49; H, 4.76; N, 6.70.
Eksempel 13 Example 13
Fremgangsmåten beskrevet i Eksempel 11 følges for å fremstille de etterfølgende cis-[3-(homocyklisk)metylenamino]-2-benzhydrylkinuklidiner, ved i hvert tilfelle å gå ut fra 3-amino-2-benzhydrylkinuklidin og den passende alicykliske eller aromatiske aldehyd-forbindelse, under bruk av de samme molare forhold som tidligere: cis-3-[(2-karboksyfenyl)metylenamino]-2-benzhydry1-kinuklidin, cis-3-[(cyklopentyl)metylenamino]-2-benzhydrylkinuklidin, cis-3-[(2-bi fenyl)metylenamino]-2-benzhydrylkinuklidin. The procedure described in Example 11 is followed to prepare the subsequent cis-[3-(homocyclic)methyleneamino]-2-benzhydrylquinuclidines, starting in each case from 3-amino-2-benzhydrylquinuclidine and the appropriate alicyclic or aromatic aldehyde compound , using the same molar ratios as before: cis-3-[(2-carboxyphenyl)methyleneamino]-2-benzhydry1-quinuclidine, cis-3-[(cyclopentyl)methyleneamino]-2-benzhydrylquinuclidine, cis-3-[ (2-biphenyl)methyleneamino]-2-benzhydrylquinuclidine.
Eksempel 14 Example 14
I en 25 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 401 mg (0,000894 mol) cis-3-[(2,6-diklorfeny1)metylenamino]-2-benzhydrylkinuklidin (produktet fra Eksempel 11) i 4 ml tørr tetrahydrofuran og 2,2 ml (0,004471 mol) av en 2,OM oppløsning boran-metylsulfid i tetrahydrofuran. Reaksjonsblandingen ble deretter tilbake-løpsbehandlet i fem dager, og deretter avkjølt til romtemperatur (ca. 20°C) og inndampet nesten til tørrhet under redusert trykk. Det således oppnådde faste residuum ble deretter tatt opp i 5 ml etanol, behandlet med 500 mg fast natriumkarbonat og deretter tilbakeløpsbehandlet i to dager. Reaksjonsblandingen ble avkjølt til romtemperatur og deretter fordelt mellom etylacetat og vann, etterfulgt av separasjon av de to lagene. Det fraskilte etylacetatlag ble deretter ekstrahert med IN vandig saltsyre og det resulterende vandige sure lag justert til pH 10 med fast natriumhydroksyd-pellets, etterfulgt av ekstraksjon med metylenklorid. Det således oppnådde organiske lag ble deretter vasket med saltoppløsning og så tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og av oppløsningsmidlet ved inndampning under redusert trykk, ble det tilslutt oppnådd et fast residuum som krystalliserte fra isopropanol for å gi 124 mg (31%) rent cis-3-[(2,6-diklorfenyl)metylamino]-2-benz-hydrylkinuklidin som et hvitt fast materiale som smeltet ved 155-160°C. Det rene produkt ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data, i tillegg til elementanalyse. In a 25 ml round bottom flask fitted with a reflux condenser and nitrogen inlet tube, 401 mg (0.000894 mol) of cis-3-[(2,6-dichlorophenyl)methyleneamino]-2-benzhydrylquinuclidine (the product of Example 11) was placed in 4 ml of dry tetrahydrofuran and 2.2 ml (0.004471 mol) of a 2.0M solution of borane methyl sulphide in tetrahydrofuran. The reaction mixture was then refluxed for five days, and then cooled to room temperature (about 20°C) and evaporated almost to dryness under reduced pressure. The solid residue thus obtained was then taken up in 5 ml of ethanol, treated with 500 mg of solid sodium carbonate and then refluxed for two days. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water, followed by separation of the two layers. The separated ethyl acetate layer was then extracted with 1N aqueous hydrochloric acid and the resulting aqueous acidic layer adjusted to pH 10 with solid sodium hydroxide pellets, followed by extraction with methylene chloride. The organic layer thus obtained was then washed with saline and then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid residue was finally obtained which crystallized from isopropanol to give 124 mg (31%) of pure cis-3-[(2,6-dichlorophenyl)methylamino] -2-benz-hydrylquinuclidine as a white solid which melted at 155-160°C. The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data, in addition to elemental analysis.
Massespektrum (%): 394 (1,4, parent), 289(19), 228(20), 227(100), 158(28), 110(19). Mass spectrum (%): 394 (1.4, parent), 289(19), 228(20), 227(100), 158(28), 110(19).
NMR data tø-NMR («5, CDC13) 1,38 (m, 1H) , 1,6-1,8 (m, 3H) , 2,1-2,2 (m, 1H), 2,72 (m, 1H), 2,88 (m, 2H), 3,15 (m, 1H), 3,30 (m, 1H), 3,57 (m, 1H), 3,82 (m, 1H), 3,93 (m, 1H), 4,51 (3, 1H), 7,0-7,5 (m, 13H) NMR data thaw-NMR («5, CDCl 3 ) 1.38 (m, 1H) , 1.6-1.8 (m, 3H) , 2.1-2.2 (m, 1H), 2.72 ( m, 1H), 2.88 (m, 2H), 3.15 (m, 1H), 3.30 (m, 1H), 3.57 (m, 1H), 3.82 (m, 1H), 3.93 (m, 1H), 4.51 (3, 1H), 7.0-7.5 (m, 13H)
<13>C-NMR (CDC13) 20,1, 25,6, 25,7, 42,1, 47,3, 49,0, 49,6, 56,1, 61,9, 125,9, 126,6, 127,5, 127,6, 128,1, 128,4, 128,6, 129,2, 136,0, 136,1, 142,8, 145,8. <13>C-NMR (CDC13) 20.1, 25.6, 25.7, 42.1, 47.3, 49.0, 49.6, 56.1, 61.9, 125.9, 126 .6, 127.5, 127.6, 128.1, 128.4, 128.6, 129.2, 136.0, 136.1, 142.8, 145.8.
Analyse beregnet for C27H28CI2N2 . 0,5H2O: Analysis calculated for C27H28CI2N2. 0.5H2O:
C, 70,43; H, 6,35; N, 6,08. C, 70.43; H, 6.35; N, 6.08.
Funnet: C, 70,64; H, 6,17; N, 6,08. Found: C, 70.64; H, 6.17; N, 6.08.
Eksempel 15 Example 15
Fremgangsmåten beskrevet i Eksempel 14 ble gjentatt for å fremstille de etterfølgende cis-3-[(homocyklisk)metylamino]-2-benzhydrylkinuklidiner, ved i hvert tilfelle å gå ut fra de tilsvarende cis-3-f(homocyklisk)metylenamino]-2-benzhydryl-kinuklidin-sluttprodukter fra Eksempel 13, under bruk av de samme molare forhold som tidligere: cis-3-[(2-karboksyfenyl)metylamino]-2-benzhydry1-kinuklidin, smp. 238-241°C. The procedure described in Example 14 was repeated to prepare the subsequent cis-3-[(homocyclic)methylamino]-2-benzhydrylquinuclidines, starting in each case from the corresponding cis-3-f(homocyclic)methyleneamino]-2- benzhydryl-quinuclidine end products from Example 13, using the same molar ratios as before: cis-3-[(2-carboxyphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 238-241°C.
cis-3-[(cyklopentyl)metylamino]-2-benzhydrylkinuklidin, smp. 158-160°C. cis-3-[(cyclopentyl)methylamino]-2-benzhydrylquinuclidine, m.p. 158-160°C.
cis-3-r(2-bifenyl)metylamino]-2-benzhydrylkinuklidin, smp. 137-143°C. cis-3-r(2-biphenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 137-143°C.
Eksempel 16 Example 16
I en 50 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 838 mg (0,002024 mol) 3-(2-norbornylkarbonylamino)-2-benzhydrylkinuklidin (produktet fra Fremstilling D) , 10 ml tørr tetrahydrofuran og 5,06 ml (0,010119 mol) av en 2,OM oppløsning boranmetylsulfid i tetrahydrofuran. Reaksjonsblandingen ble deretter tilbakeløps-behandlet i fire dager og så avkjølt til romtemperatur (ca. 20°C) og inndampet nesten til tørrhet under redusert trykk. Det således oppnådde faste residuum ble tatt opp i 20 ml etanol, behandlet med 100 mg fast natriumkarbonat og deretter tilbake-løpsbehandlet i 2 4 timer. Reaksjonsoppløsningen ble deretter avkjølt til romtemperatur og fordelt mellom vann og metylenklorid, etterfulgt av separasjon av de to lagene. Det fraskilte metylenkloridlag ble deretter ekstrahert med IN saltsyre og det resulterende vandige sure lag justert til pH 10 med fast natriumhydroksyd-pellets, etterfulgt av ny ekstraksjon med metylenklorid. Det således oppnådde organiske lag ble deretter vasket med saltoppløsning og tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast residuum som krystalliserte fra isopropanol for å gi 474 mg (58%) rent cis-3-[(2-norbornyl)metylamino]-2-benzhydrylkinuklidin som et hvitt faststoff som smeltet ved 183-189°C. Det rene produkt ble videre karakterisert ved hjelp av massespektrometrisk analyse og kjernemagnetiske resonans-data, i tillegg til elementanalyse. Into a 50 ml round bottom flask fitted with a reflux condenser and nitrogen inlet tube, was placed 838 mg (0.002024 mol) of 3-(2-norbornylcarbonylamino)-2-benzhydrylquinuclidine (the product of Preparation D), 10 ml of dry tetrahydrofuran and 5.06 ml (0.010119 mol) of a 2.0M solution of borane methyl sulfide in tetrahydrofuran. The reaction mixture was then refluxed for four days and then cooled to room temperature (about 20°C) and evaporated almost to dryness under reduced pressure. The solid residue thus obtained was taken up in 20 ml of ethanol, treated with 100 mg of solid sodium carbonate and then refluxed for 24 hours. The reaction solution was then cooled to room temperature and partitioned between water and methylene chloride, followed by separation of the two layers. The separated methylene chloride layer was then extracted with 1N hydrochloric acid and the resulting aqueous acidic layer adjusted to pH 10 with solid sodium hydroxide pellets, followed by re-extraction with methylene chloride. The organic layer thus obtained was then washed with saline and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid residue was finally obtained which crystallized from isopropanol to give 474 mg (58%) of pure cis-3-[(2-norbornyl)methylamino]-2 -benzhydrylquinuclidine as a white solid which melted at 183-189°C. The pure product was further characterized using mass spectrometric analysis and nuclear magnetic resonance data, in addition to elemental analysis.
Massespektrum(%): 401 (< 1, parent+1), 234(43), 233(100), 176(21), 164(25), 110(29), 67(29). Mass spectrum (%): 401 (< 1, parent+1), 234(43), 233(100), 176(21), 164(25), 110(29), 67(29).
NMR data: ^-NMR (<5, CDC13) 0,6-3,0 (flere multipletter, 22H), 3,27 (m, 1H), 3,75 (dd, 1H), 4,51 (dd, 1H), 7,1-7,5 (10H) , NMR data: 3-NMR (<5, CDCl 3 ) 0.6-3.0 (several multiplets, 22H), 3.27 (m, 1H), 3.75 (dd, 1H), 4.51 (dd, 1H), 7.1-7.5 (10H),
<13>C-NMR (CDC13) 19,9, 20,1, 20,2, 21,9, 22,9, 25,0, 25,1, 25,2, 25.5, 25,6, 28,9, 30,0, 30,1, 35,4, 36,1, 36,6, 36,8, 37,6, 38.6, 38,7, 38,8, 39,3, 39,7, 39,8, 42,1, 42,2, 49,3, 49,5, 49,6, 49,7, 51,4, 51,5, 55,7, 56,9, 57,1, 61,9, 62,0, 126,0, 126,9, 126,6, 127,4, 127,5, 128,4, 129,2, 143,2, 143,4, 145,4. Analyse beregnet for C28H36N2 . 0,25H2O: C, 83,02; H, 9,08; N, 6,92. <13>C-NMR (CDC13) 19.9, 20.1, 20.2, 21.9, 22.9, 25.0, 25.1, 25.2, 25.5, 25.6, 28.9 , 30.0, 30.1, 35.4, 36.1, 36.6, 36.8, 37.6, 38.6, 38.7, 38.8, 39.3, 39.7, 39.8 , 42.1, 42.2, 49.3, 49.5, 49.6, 49.7, 51.4, 51.5, 55.7, 56.9, 57.1, 61.9, 62 ,0, 126.0, 126.9, 126.6, 127.4, 127.5, 128.4, 129.2, 143.2, 143.4, 145.4. Analysis calculated for C28H36N2. 0.25H 2 O: C, 83.02; H, 9.08; N, 6.92.
Funnet: C, 82,98; H, 8,91; N, 6,84. Found: C, 82.98; H, 8.91; N, 6.84.
Eksempel 17 Example 17
Fremgangsmåten beskrevet i Eksempel 16 ble gjentatt for å fremstille de etterfølgende cis-3-[(homocyklisk)metylamino]-2-benzhydrylkinuklidiner, ved i hvert tilfelle å gå ut fra de tilsvarende cis-[(homocyklisk)karbonylamino]-2-benzhydryl-kinuklidin-sluttprodukter fra Fremstilling E, under bruk av de samme molare forhold som tidligere: cis-3-[(1-norbornyl)metylamino]-2-benzhydrylkinuklidin, smp. 173-179°C. The procedure described in Example 16 was repeated to prepare the subsequent cis-3-[(homocyclic)methylamino]-2-benzhydrylquinuclidines, starting in each case from the corresponding cis-[(homocyclic)carbonylamino]-2-benzhydryl- quinuclidine end products from Preparation E, using the same molar ratios as before: cis-3-[(1-norbornyl)methylamino]-2-benzhydrylquinuclidine, m.p. 173-179°C.
cis-3-[(2-benzylfenyl)metylamino]-2-benzhydrylkinuklidin, smp. 119-121°C. cis-3-[(2-benzylphenyl)methylamino]-2-benzhydrylquinuclidine, m.p. 119-121°C.
cis-3-[(3,5-difluorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 119-127°C. cis-3-[(3,5-difluorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 119-127°C.
cis-3-[(2,3-difluorfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 148-157°C. cis-3-[(2,3-difluorophenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 148-157°C.
Kinuklidinforbindelsene i henhold til foreliggende oppfinnelse er undersøkt på substans P antagonist-virkning i kaudatvev fra storfe ved bruk av en modifikasjon av standard-fremgangsmåten beskrevet av M. A. Cascieri et al., omtalt i Journal of Biological Chemistry. Vol. 258, s. 5158 (1983). The quinuclidine compounds according to the present invention have been investigated for substance P antagonist action in caudate tissue from cattle using a modification of the standard method described by M. A. Cascieri et al., discussed in the Journal of Biological Chemistry. Vol. 258, p. 5158 (1983).
Etter denne fremgangsmåte tas bovint kaudatvev ut fra en Following this procedure, bovine caudate tissue is taken from a
-70°C fryser og homogeniseres i 50 volumer (vekt/volum) iskald 50 mM Tris (dvs., trometamin som er 2-amino-2-hydroksymetyl-1,3-propandiol) hydroklorid-buffer med en pH på 7,7. Homogenatet sentrifugeres ved 30.000 x G i 20 minutter. Den oppnådde pellet resuspenderes i 50 volumer Tris-buffer, rehomogeniseres og sentrifugeres deretter på nytt ved 30.000 x G i en ny 20 minutters periode. Denne pellet resuspenderes så 1 40 volumer iskald 50 mM Tris-buffer (pH 7,7) inneholdende 2 mM kalsiumklorid, 2 mM magnesiumklorid, 40 jig/ml bacitracin, 4 /ig/ml leupeptin, 2 ug chymostatin og 200 /xg/ml bovint serumalbumin. -70°C freeze and homogenize in 50 volumes (w/v) of ice-cold 50 mM Tris (ie, tromethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer with a pH of 7.7 . The homogenate is centrifuged at 30,000 x G for 20 minutes. The pellet obtained is resuspended in 50 volumes of Tris buffer, rehomogenized and then centrifuged again at 30,000 x G for another 20 minute period. This pellet is then resuspended in 140 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM calcium chloride, 2 mM magnesium chloride, 40 µg/ml bacitracin, 4 µg/ml leupeptin, 2 µg chymostatin and 200 µg/ml bovine serum albumin.
Dette trinnet avslutter fremstillingen av vevspreparatet. This step completes the preparation of the tissue preparation.
Måling av radioligand-bindingen foretas deretter på følgende måte. Reaksjonen initieres ved tilsetning av 100 /il testforbindelse fremstillet i en konsentrasjon på 1 /LtM, etterfulgt av tilsetning av 100 /xl radioaktiv ligand fremstillet i en sluttkonsentrasjon på 0,5 mM og deretter tilslutt ved tilsetning av 800 /il av vevspreparatet fremstillet som beskrevet ovenfor. Sluttvolumet blir derved 1,0 ml, og reaksjonsblandingen omvirvles og inkuberes ved romtemperatur (ca. 20°C) i 20 minutter. Rørene filtreres deretter ved bruk av en cellehøster (cell harvester) og glassfiberfilterne vaskes 4 ganger med 50 mM Tris-buffer (pH 7,7), idet filterne på forhånd er gjennomtrukket i 2 timer før filtreringen. Radioaktiviteten bestemmes deretter i en beta-teller med 53% telle-effektivitet, og IC50-verdiene beregnes ved bruk av statistiske standardmetoder. Measurement of the radioligand binding is then carried out in the following way. The reaction is initiated by the addition of 100 µl of test compound prepared at a concentration of 1 µM, followed by the addition of 100 µl of radioactive ligand prepared at a final concentration of 0.5 mM and then finally by the addition of 800 µl of the tissue preparation prepared as described above. The final volume thereby becomes 1.0 ml, and the reaction mixture is swirled and incubated at room temperature (approx. 20°C) for 20 minutes. The tubes are then filtered using a cell harvester (cell harvester) and the glass fiber filters are washed 4 times with 50 mM Tris buffer (pH 7.7), the filters having previously been soaked for 2 hours before filtration. The radioactivity is then determined in a beta counter with 53% counting efficiency, and the IC50 values are calculated using standard statistical methods.
De etterfølgende cis-[(cyklisk)metylamino]-2-benzhydryl-kinuklidin- sluttprodukter fra henholdsvis Eksempel 2, 3 og 4, ble undersøkt på antiinflammatorisk aktivitet i rotter, ved bruk av den standardiserte ødemtest på rottefot i henhold til den generelle fremgangsmåte beskrevet av C. A. Winther et al., først angitt i Proceedin<g>s of the Society for Experimental Biology and Medicine, Vol. 111. s. 544 (1962). Forbindelsene ble gitt oralt (med sonde) i mengder på 32 mg/kg og de oppnådde resultater er angitt nedenfor som prosent (%) hemming av ødemdannelse forårsaket av hver testforbindelse sammenlignet med kontrollen (dvs. bæremiddel alene uten forbindelse): The subsequent cis-[(cyclic)methylamino]-2-benzhydryl-quinuclidine end products from Examples 2, 3 and 4, respectively, were examined for anti-inflammatory activity in rats, using the standardized rat foot edema test according to the general procedure described by C. A. Winther et al., first reported in Proceedin<g>s of the Society for Experimental Biology and Medicine, Vol. 111. p. 544 (1962). The compounds were administered orally (by gavage) in amounts of 32 mg/kg and the results obtained are given below as percent (%) inhibition of edema formation caused by each test compound compared to the control (ie, vehicle alone without compound):
Eksempel 18 Example 18
To-trinns reaksjonen beskrevet i Eksempel 1 ble gjentatt bortsett fra at 3,4-dimetoksybenzylamin ble benyttet som reagens i stedet for cykloheksylamin, under bruk av de samme molare forhold som tidligere. I dette spesielle var det oppnådde tilsvarende sluttprodukt cis-3-[(3,4-dimetoksyfenyl)-metylamino]-2-benzhydrylkinuklidin som et kvart hydrat, smp. 120-123°C. The two-step reaction described in Example 1 was repeated except that 3,4-dimethoxybenzylamine was used as reagent instead of cyclohexylamine, using the same molar ratios as before. In this particular, the corresponding end product obtained was cis-3-[(3,4-dimethoxyphenyl)-methylamino]-2-benzhydrylquinuclidine as a quarter hydrate, m.p. 120-123°C.
Analyse beregnet for C29H3i(N202. 0,25H20: Analysis calculated for C29H3i(N2O2. 0.25H20:
C, 77,91; H, 7,78; N, 6,27 C, 77.91; H, 7.78; N, 6.27
Funnet: C, 78,07; H, 7,64; N, 6,30. Found: C, 78.07; H, 7.64; N, 6.30.
Eksempel 19 Example 19
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt for å fremstille de etterfølgende cis-3-[(cyklisk)metylamino]-2-[(a-substituert)arylmetyl]kinuklidiner <(karakterisert, i noen tilfeller, som hydrokloridsaltet), ved i hvert tilfelle å gå ut fra de tilsvarende 2-[(a-substituert)arylmetyl]-kinuklidin-3-on-forbindelser og det passende N-(cyklisk)-metylamin, under bruk av de samme molare forhold som tidligere: cis-3-benzylamino-2-[(2-benzylfenyl)fenylmetyl]-kinuklidin-dihydroklorid 1,5 hydrat, smp. 175-180°C. The two-step reaction described in Example 6 was repeated to prepare the following cis-3-[(cyclic)methylamino]-2-[(α-substituted)arylmethyl]quinuclidines <(characterized, in some cases, as the hydrochloride salt), by in each case starting from the corresponding 2-[(α-substituted)arylmethyl]-quinuclidin-3-one compounds and the appropriate N-(cyclic)-methylamine, using the same molar ratios as before: cis- 3-Benzylamino-2-[(2-benzylphenyl)phenylmethyl]-quinuclidine dihydrochloride 1.5 hydrate, m.p. 175-180°C.
cis-3-r(2-metoksyfenyl)metylamino]-2-[(2-tienyl)fenyl-metyl] kinukl idin, smp. 130-140°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(2-thienyl)phenylmethyl]quinuclidine, m.p. 130-140°C,
cis-3-r(2-metoksyfenyl)metylamino]-2-[(3-metoksyfenyl)-fenylmetyl]kinuklidin-dihydroklorid 1,5 hydrat, smp. 170-177°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(3-methoxyphenyl)-phenylmethyl]quinuclidine dihydrochloride 1.5 hydrate, m.p. 170-177°C,
cis-3-r(2-metoksyfenyl)metylamino]-2-[(2,4-difluorfenyl)-fenylmetyl]kinuklidin semihydrat, smp. 115-131°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(2,4-difluorophenyl)-phenylmethyl]quinuclidine hemihydrate, m.p. 115-131°C,
cis-3-r(2-metoksyfenyl)metylamino]-2-[(2-furyl)fenyl-metyl] kinuklidin, smp. 105-110°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(2-furyl)phenyl-methyl] quinuclidine, m.p. 105-110°C,
cis-3-r(2-metoksyfenyl)metylamino]-2-[(2,3-diklorfenyl)-fenylmetyl]kinuklidin 0,25 hydrat, smp. 132-136°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(2,3-dichlorophenyl)-phenylmethyl]quinuclidine 0.25 hydrate, m.p. 132-136°C,
cis-3-[(2-metoksyfenyl)metylamino]-2-[(2,4-diklorfenyl)-fenylmetyl]kinuklidin 0,25 hydrat, smp. 135-138°C, cis-3-[(2-methoxyphenyl)methylamino]-2-[(2,4-dichlorophenyl)-phenylmethyl]quinuclidine 0.25 hydrate, m.p. 135-138°C,
cis-3-[(2-metoksyfenyl)metylamino]-3-[(3,4-diklorfenyl)-fenylmetyl]kinuklidin semihydrat, smp. 115-118°C, cis-3-[(2-methoxyphenyl)methylamino]-3-[(3,4-dichlorophenyl)-phenylmethyl]quinuclidine hemihydrate, m.p. 115-118°C,
cis-3-[(2-metoksyfenyl)metylamino]-3-[(3-pyridyl)fenyl-metyl] kinuklidin dihydroklorid 3,5 hydrat, smp. 170-190°C, cis-3-[(2-methoxyphenyl)methylamino]-3-[(3-pyridyl)phenyl-methyl] quinuclidine dihydrochloride 3.5 hydrate, m.p. 170-190°C,
cis-3-f(2-metoksyfenyl)metylamino]-3-[(2-metoksyfenyl)-fenylmetyl]kinuklidin semihydrat, smp. 150-155°C, cis-3-f(2-methoxyphenyl)methylamino]-3-[(2-methoxyphenyl)-phenylmethyl]quinuclidine hemihydrate, m.p. 150-155°C,
cis-3-f(2-metoksyfenyl)metylamino]-3-[(3-trifluormetylfenyl)fenylmetyl]kinuklidin trihydrat, smp. 190-200°C, cis-3-f(2-methoxyphenyl)methylamino]-3-[(3-trifluoromethylphenyl)phenylmethyl]quinuclidine trihydrate, m.p. 190-200°C,
cis-3-benzylamino-2-[(2-benzylfenyl)fenylmetyl]kinuklidin hydroklorid, smp. 175-180°C, cis-3-benzylamino-2-[(2-benzylphenyl)phenylmethyl]quinuclidine hydrochloride, m.p. 175-180°C,
cis-3-benzylamino-2-[(3-tienyl)fenylmetyl]kinuklidin, smp. 165-175°C, cis-3-benzylamino-2-[(3-thienyl)phenylmethyl]quinuclidine, m.p. 165-175°C,
cis-3-r(2-metoksyfenyl)metylamino]-2-[(3-tienyl)fenyl-metyl] kinuklidin semihydrat, smp. 145-153°C, cis-3-r(2-methoxyphenyl)methylamino]-2-[(3-thienyl)phenyl-methyl] quinuclidine hemihydrate, m.p. 145-153°C,
cis-3-[(2-metoksyfenyl)metylamino]-2-[bis-(2-tienyl)-metylkinuklidin 0,25 hydrat, smp. 135-140°C, cis-3-[(2-methoxyphenyl)methylamino]-2-[bis-(2-thienyl)-methylquinuclidine 0.25 hydrate, m.p. 135-140°C,
cis-3-benzylamino-2-[bis-(2-tienyl)metyl]-kinuklidin, smp. 147-150°C, cis-3-benzylamino-2-[bis-(2-thienyl)methyl]-quinuclidine, m.p. 147-150°C,
cis-3-benzylamino-2-[(2-tienyl, 3-tienyl)metyl]-kinuklidin, smp. 152-160°C, cis-3-benzylamino-2-[(2-thienyl, 3-thienyl)methyl]-quinuclidine, m.p. 152-160°C,
cis-3-[(2-metylfenyl)metylamino]-2-[(2-tienyl, 3-tienyl)-metyl]kinuklidin, smp. 115-125°C, cis-3-[(2-methylphenyl)methylamino]-2-[(2-thienyl, 3-thienyl)-methyl]quinuclidine, m.p. 115-125°C,
cis-3-benzylamino-2-[(2-fluorfenyl)fenylmetyl]kinuklidin 0,25 hydrat, smp. 144-150°C. cis-3-benzylamino-2-[(2-fluorophenyl)phenylmethyl]quinuclidine 0.25 hydrate, m.p. 144-150°C.
cis-3-f(2-metoksyfenyl)metylamino]-2-[(2-fluorfenyl)-fenylmetyl]kinuklidin, smp. 156-164°C, cis-3-f(2-methoxyphenyl)methylamino]-2-[(2-fluorophenyl)-phenylmethyl]quinuclidine, m.p. 156-164°C,
cis-3-benzylamino-2-[bis-(4-fluorfenyl)metyl]kinuklidin, smp. 148-152°C, cis-3-benzylamino-2-[bis-(4-fluorophenyl)methyl]quinuclidine, m.p. 148-152°C,
cis-3-benzylamino-2-[bis-(4-bromfeny1)metyl]kinuklidin-semihydrat, smp. 198-200°C, cis-3-benzylamino-2-[bis-(4-bromophenyl)methyl]quinuclidine semihydrate, m.p. 198-200°C,
cis-3-[(2-metoksyfenyl)metylamino]-2-[bis-(4-bromfenyl)-metyl]kinuklidin, smp. 166-169°C; cis-3-[(2-methoxyphenyl)methylamino]-2-[bis-(4-bromophenyl)methyl]quinuclidine, m.p. 166-169°C;
cis-3-[(3,4-dimetoksyfenyl)metylamino]-2-[bis(4-bromfenyl)metyl]kinuklidin, smp. 173-177°C, cis-3-[(3,4-dimethoxyphenyl)methylamino]-2-[bis(4-bromophenyl)methyl]quinuclidine, m.p. 173-177°C,
cis-3-benzylamino-2-[bis(3-tienyl)metyl]kinuklidin, smp. 168-173°C, cis-3-benzylamino-2-[bis(3-thienyl)methyl]quinuclidine, m.p. 168-173°C,
cis-3-[(2-metoksyfenyl)metylamino]-2-[bis(4-tienyl)-metyl]kinuklidin semihydrat, smp. 135-138°C, cis-3-[(2-methoxyphenyl)methylamino]-2-[bis(4-thienyl)methyl]quinuclidine hemihydrate, m.p. 135-138°C,
cis-3-benzylamino-2-[bis-(3-fluorfenyl)metyl]kinuklidin, smp. 132-136°C, cis-3-benzylamino-2-[bis-(3-fluorophenyl)methyl]quinuclidine, m.p. 132-136°C,
cis-3-f(2-metoksyfenyl)metylamino]-2-[bis-(3-fluorfenyl)-metyl]kinuklidin, smp. 125-129°C, cis-3-f(2-methoxyphenyl)methylamino]-2-[bis-(3-fluorophenyl)methyl]quinuclidine, m.p. 125-129°C,
cis-3-benzylamino-2-[(2-fluorfenyl)(3-fluorfenyl)metyl]-kinuklidin, smp. 139-144°C, cis-3-benzylamino-2-[(2-fluorophenyl)(3-fluorophenyl)methyl]-quinuclidine, m.p. 139-144°C,
cis-3-f(2-metoksyfenyl)metylamino]-2-[(2-fluorfenyl-3-fluorfenyl)metyl]kinuklidin, smp. 127-131°C. cis-3-f(2-methoxyphenyl)methylamino]-2-[(2-fluorophenyl-3-fluorophenyl)methyl]quinuclidine, m.p. 127-131°C.
Eksempel 2 0 Example 2 0
Fremgangsmåten beskrevet i Eksempel 11 ble gjentatt bortsett fra at 2-allyloksybenzaldehyd ble benyttet som reagens i stedet for 2,6-diklorbenzaldehyd, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det tilsvarende oppnådde sluttprodukt cis-3-[(2-allyloksy-fenyl)metylenamino]-2-benzhydrylkinuklidin, smp. 155-162°C. The procedure described in Example 11 was repeated except that 2-allyloxybenzaldehyde was used as reagent instead of 2,6-dichlorobenzaldehyde, using the same molar ratios as before. In this particular case, the correspondingly obtained final product was cis-3-[(2-allyloxy-phenyl)methyleneamino]-2-benzhydrylquinuclidine, m.p. 155-162°C.
Analyse beregnet for C30H32N2O: Analysis calculated for C30H32N2O:
C, 82,53; H, 7,39; N, 6,42. C, 82.53; H, 7.39; N, 6.42.
Funnet: C, 82,03; H, 7,48; N, 6,21. Found: C, 82.03; H, 7.48; N, 6.21.
Eksempel 21 Example 21
I en 50 ml rundkolbe forsynt med nitrogen-innløpsrør ble det anbragt 615 mg (0,0011412 mol) cis-3-[(2-allyloksyfenyl)-metylenamino]-2-benzhydrylkinuklidin (produktet fra Eksempel 26), 7,0 ml trifluoreddiksyre <p>g 0,70 ml (0,004235 mol) trietylsilan. Reaksjonsblandingen ble deretter omrørt ved romtemperatur (ca. 2 0°C) i 3 dager og deretter helt over i IN vandig saltsyre og vasket med metylenklorid. Etter justering av pH i det fraskilte vandige lag til pH 9,0 med fast natriumkarbonat og påfølgende ekstraksjon med frisk metylenklorid, ble de organiske lagene kombinert og deretter tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast residuum som krystalliserte fra isopropanol for å gi 275 mg (45%) rent cis-3-[(2-allyloksyfenyl)metylamino]-2-benzhydrylkinuklidin som kvart-hydratet i form av et hvitt faststoff som smeltet ved 117-120°C. 615 mg (0.0011412 mol) of cis-3-[(2-allyloxyphenyl)-methyleneamino]-2-benzhydrylquinuclidine (the product from Example 26), 7.0 ml of trifluoroacetic acid were placed in a 50 ml round bottom flask fitted with a nitrogen inlet tube <p>g 0.70 ml (0.004235 mol) triethylsilane. The reaction mixture was then stirred at room temperature (about 20°C) for 3 days and then poured into 1N aqueous hydrochloric acid and washed with methylene chloride. After adjusting the pH of the separated aqueous layer to pH 9.0 with solid sodium carbonate and subsequent extraction with fresh methylene chloride, the organic layers were combined and then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and the solvent by evaporation under reduced pressure, a solid residue was finally obtained which crystallized from isopropanol to give 275 mg (45%) of pure cis-3-[(2-allyloxyphenyl)methylamino]-2- benzhydrylquinuclidine as the quaternary hydrate in the form of a white solid melting at 117-120°C.
Analyse beregnet for C30H3AN2O . 0,2 5H2O: Analysis calculated for C30H3AN2O. 0.2 5H2O:
C, 81,32; H, 7,85; N, 6,32. C, 81.32; H, 7.85; N, 6.32.
Funnet: C, 81,38; H, 7,72; N, 6,35. Found: C, 81.38; H, 7.72; N, 6.35.
Eksempel 2 2 Example 2 2
A. Reaksjonen beskrevet i Eksempel 11 ble gjentatt bortsett fra at 2-(metoksykarbonylmetoksy)benzaldehyd ble benyttet som reagens i stedet for 2,6-diklorbenzaldehyd, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-{[2-(metoksykarbonylmetoksy)fenyl]metylenamino}-2-benzhydrylkinuklidin. A. The reaction described in Example 11 was repeated except that 2-(methoxycarbonylmethoxy)benzaldehyde was used as the reagent instead of 2,6-dichlorobenzaldehyde, using the same molar ratios as before. In this particular case, the corresponding end product obtained was cis-3-{[2-(methoxycarbonylmethoxy)phenyl]methyleneamino}-2-benzhydrylquinuclidine.
B. I en 100 ml rundkolbe forsynt med nitrogen-inn-løpsrør ble det anbragt 5,47 g (0,01168 mol) av det ovenfor oppnådde metylenamin, 4,06 g (0,03504 mol) trietylsilan, 29 ml trifluoreddiksyre og 0,4 ml metansulfonsyre. Reaksjonsblandingen ble deretter omrørt ved romtemperatur (ca. 2 0°C) i 7 dager og deretter hellet over i en blanding av metylenklorid og vandig natriumbikarbonat. De to lagene ble deretter separert og det organiske lag vasket med 6N vandig saltsyre. Det resulterende vandige lag ble fraskilt og nøytralisert med 6N vandig natriumhydroksyd, etterfulgt av ekstraksjon med frisk metylenklorid. De organiske lagene ble deretter kombinert og tørket over vannfri natriumsulfat. Etter fjerning av tørkemidlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast residuum som deretter ble behandlet med 30 ml etanol og 3,0 ml 6N vandig saltsyre. Sistnevnte blanding ble deretter omrørt og oppvarmet i 4 timer, deretter opparbeidet ved å gjøres basisk og så ekstraheres med metylenklorid. Inndampning av sistnevnte oppløsning under redusert trykk ga tilslutt et fast residuum som deretter krystalliserte fra isopropanol (i to fraksjoner) for tilslutt å gi 140 mg (2,5%) rent cis-3-[2-(metoksykarbonylmetoksy)fenyl]metylamin-2-benzhydrylkinuklidin 0,75 hydrat i form av et hvitt faststoff som smeltet ved 114-117°C. B. 5.47 g (0.01168 mol) of the methyleneamine obtained above, 4.06 g (0.03504 mol) of triethylsilane, 29 ml of trifluoroacetic acid and 0 .4 ml of methanesulfonic acid. The reaction mixture was then stirred at room temperature (about 20°C) for 7 days and then poured into a mixture of methylene chloride and aqueous sodium bicarbonate. The two layers were then separated and the organic layer washed with 6N aqueous hydrochloric acid. The resulting aqueous layer was separated and neutralized with 6N aqueous sodium hydroxide, followed by extraction with fresh methylene chloride. The organic layers were then combined and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid residue was finally obtained which was then treated with 30 ml of ethanol and 3.0 ml of 6N aqueous hydrochloric acid. The latter mixture was then stirred and heated for 4 hours, then worked up by basification and then extracted with methylene chloride. Evaporation of the latter solution under reduced pressure finally gave a solid residue which was then crystallized from isopropanol (in two fractions) to finally give 140 mg (2.5%) of pure cis-3-[2-(methoxycarbonylmethoxy)phenyl]methylamine-2 -benzhydrylquinuclidine 0.75 hydrate in the form of a white solid which melted at 114-117°C.
Analyse beregnet for C30H34N2O3 . 0,75 H20: Analysis calculated for C30H34N2O3. 0.75 H2O:
C, 74,43; H, 7,39; N, 5,79. C, 74.43; H, 7.39; N, 5.79.
Funnet: C, 74,46; H, 7,09; N, 5,82. Found: C, 74.46; H, 7.09; N, 5.82.
Eksempel 23 Example 23
Kondensasjons- og reduksjonsreaksjonene (to-trinns) beskrevet i henholdsvis Eksempel 11 og 14, ble gjentatt for å fremstille de etterfølgende cis-3-[(cyklisk)metylamino]-2-benzhydrylkinuklidiner (karakterisert, i enkelte tilfeller, som hydrokloridsaltet), ved i hvert tilfelle å gå ut fra 3-amino-2-benzhydrylkinuklidin og det passende valgte cykliske aldehyd og fortsette via det tilsvarende cis-[(cyklisk)metyl-enamino] -2 -benzhydrylkinukl idin-mellomprodukt, under bruk av de samme molare forhold som tidligere i hvert trinn: cis-3-[(2,3-dimetoksyfenyl)metylamino]-2-benzhydryl-kinuklidin 0,25 hydrat, smp. 158-162°C, The condensation and reduction reactions (two-step) described in Examples 11 and 14, respectively, were repeated to prepare the subsequent cis-3-[(cyclic)methylamino]-2-benzhydrylquinuclidines (characterized, in some cases, as the hydrochloride salt), by in each case starting from 3-amino-2-benzhydrylquinuclidine and the appropriately chosen cyclic aldehyde and proceeding via the corresponding cis-[(cyclic)methyl-enamino]-2-benzhydrylquinuclidine intermediate, using the same molar ratios as before in each step: cis-3-[(2,3-dimethoxyphenyl)methylamino]-2-benzhydryl-quinuclidine 0.25 hydrate, m.p. 158-162°C,
cis-3-[(2,4-dimetoksyfenyl)metylamino]-2-benzhydryl-kinuklidin semihydrat, smp. 120-125°C, cis-3-[(2,4-dimethoxyphenyl)methylamino]-2-benzhydryl-quinuclidine hemihydrate, m.p. 120-125°C,
cis-3-[(2,5-dimetoksyfenyl)metylamino]-2-benzhydryl-kinuklidin semihydrat, smp. 120-122°C, cis-3-[(2,5-dimethoxyphenyl)methylamino]-2-benzhydryl-quinuclidine hemihydrate, m.p. 120-122°C,
cis-3-[(2-hydroksyfenyl)metylamino]-2-benzhydrylkinuklidin 1,25 hydrat, smp. 169-175°C, cis-3-[(2-hydroxyphenyl)methylamino]-2-benzhydrylquinuclidine 1.25 hydrate, m.p. 169-175°C,
cis-3-[(2-etoksyfeny1)metylamino]-2-benzhydrylkinuklidin hydrat, smp. 159-166°C, cis-3-[(2-ethoxyphenyl)methylamino]-2-benzhydrylquinuclidine hydrate, m.p. 159-166°C,
cis-3-[(2-etoksy-3-metoksyfenyl)metylamino]-2-benzhydry1-kinuklidin 1,25 hydrat, smp. 128-138°C, cis-3-[(2-ethoxy-3-methoxyphenyl)methylamino]-2-benzhydry1-quinuclidine 1.25 hydrate, m.p. 128-138°C,
cis-3-[(2-hydroksy-3-etoksyfenyl)metylamino]-2-benzhydrylkinuklidin dihydroklorid-dihydrat, smp. 170-190°C, cis-3-[(2-hydroxy-3-ethoxyphenyl)methylamino]-2-benzhydrylquinuclidine dihydrochloride dihydrate, m.p. 170-190°C,
cis-3-[(2-hydroksy-3-metoksyfenyl)metylamino]-2-benz-hydrylkinuklidin-dihydroklorid-dihydrat, smp. 180-200°C, cis-3-[(2-hydroxy-3-methoxyphenyl)methylamino]-2-benz-hydrylquinuclidine dihydrochloride dihydrate, m.p. 180-200°C,
cis-3-[(2-metoksynaft-1-ylmetylamino]-2-benzhydry1-kinuklidin-dihydroklorid 2,2 hydrat, smp. 210-230°C, cis-3-[(2-methoxynaphth-1-ylmethylamino]-2-benzhydryl-quinuclidine dihydrochloride 2,2 hydrate, m.p. 210-230°C,
cis-3-[(5-klor-2-metoksyfenyl)metylamino]-2-benzhydryl-kinuklidin semihydrat, smp. 183-188°C, cis-3-[(5-chloro-2-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine hemihydrate, m.p. 183-188°C,
cis-3-f(2-hydroksyetoksy)fenyl]metylamino-2-benzhydryl-kinuklidin, smp. 136-139°C, cis-3-f(2-hydroxyethoxy)phenyl]methylamino-2-benzhydryl-quinuclidine, m.p. 136-139°C,
cis-3-[(5-hydroksymety1-2-metoksyfenyl)metylamino]-2-benzhydrylkinuklidin semihydrat, smp. 155-160°C, cis-3-[(5-hydroxymethyl-2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine hemihydrate, m.p. 155-160°C,
cis-3-r(2-metoksynaft-l-yl)metylamino]-2-benzhydryl-kinuklidin 0,25 hydrat, smp. 156-163°C, cis-3-r(2-methoxynaphth-1-yl)methylamino]-2-benzhydryl-quinuclidine 0.25 hydrate, m.p. 156-163°C,
cis-3-[(3-metoksytien-2-yl)metylamino]-2-benzhydry1-kinuklidin, smp. 13 0-13 5°C, cis-3-[(3-methoxythien-2-yl)methylamino]-2-benzhydryl-quinuclidine, m.p. 13 0-13 5°C,
cis-3-r(3,5-dimetoksyfenyl)metylamino]-2-benzhydryl-kinuklidin 0,25 hydrat, smp. 154-157°C, cis-3-r(3,5-dimethoxyphenyl)methylamino]-2-benzhydryl-quinuclidine 0.25 hydrate, m.p. 154-157°C,
cis-3-[(kinol-8-yl)metylamino]-2-benzhydrylkinuklidin hydroklorid 3,75 hydrat, smp. 245-255°C, cis-3-[(quinol-8-yl)methylamino]-2-benzhydrylquinuclidine hydrochloride 3.75 hydrate, m.p. 245-255°C,
cis-3-[ (2,3-dihydrobenzofur-7-yl)metyl]-2-benzhydryl-kinuklidin, smp. 148-151°C, cis-3-[(2,3-dihydrobenzofur-7-yl)methyl]-2-benzhydryl-quinuclidine, m.p. 148-151°C,
cis-3-[(2,6-dimetylfenyl)metylamino]-2-benz-hydrylkinuklidin, smp. 156-159°C, cis-3-[(2,6-dimethylphenyl)methylamino]-2-benz-hydrylquinuclidine, m.p. 156-159°C,
cis-3-[(2,3-metylendioksyfenyl)metylamino]-benzhydryl-kinuklidin, smp. 161-164°C, (-) - cis-3-[(2-metoksyfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 154-155°C; cis-3-[(2,3-methylenedioxyphenyl)methylamino]-benzhydryl-quinuclidine, m.p. 161-164°C, (-)-cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 154-155°C;
[a]D<20> = -23 , 8° (c=l, metylenklorid) ved 589 nM. [α]D<20> = -23 , 8° (c=1, methylene chloride) at 589 nM.
Eksempel 24 Example 24
Reaksjonen (to-trinns) beskrevet i henholdsvis Eksempel 11 og 14 ble gjentatt bortsett fra at 6-hydroksy-2-metoksybenzaldehyd ble benyttet som utgangsmateriale i stedet for 2,6-diklorbenzaldehyd i første trinn (se Eksempel 14), under bruk av de samme molare forhold som tidligere i hvert trinn. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt (etter først å gå via det korresponderende metylen-amino-mellomprodukt) cis-3-f(6-hydroksy-2-metoksyfenyl)metyl-amino] -2-benzhydrylkinuklidin som et kvart-hydrat, smp. 176-180°C. The reaction (two-step) described in Examples 11 and 14 respectively was repeated except that 6-hydroxy-2-methoxybenzaldehyde was used as starting material instead of 2,6-dichlorobenzaldehyde in the first step (see Example 14), using the same molar ratio as before in each step. In this particular case, the corresponding final product obtained (after first proceeding via the corresponding methylene-amino intermediate) was cis-3-f(6-hydroxy-2-methoxyphenyl)methyl-amino]-2-benzhydrylquinuclidine as a quaternary hydrate , m.p. 176-180°C.
Analyse beregnet for C28H32N2O2 . 0,25H2O: Analysis calculated for C28H32N2O2. 0.25H2O:
C, 77,66; H, 7,56; N, 6,47. C, 77.66; H, 7.56; N, 6.47.
Funnet: C, 77,24; H, 7,47; N, 6,29. Found: C, 77.24; H, 7.47; N, 6.29.
Eksempel 2 5 Example 2 5
Reaksjonen (to-trinns) beskrevet i henholdsvis Eksempel 11 og 21 ble gjentatt bortsett fra at 2-metoksy-5-nitrobenz-aldehyd ble benyttet som reagens i stedet for 2,6-diklorbenzaldehyd i første trinn (se Eksempel 11) og under bruk av de samme molare forhold som tidligere, for enkelt å gi cis-3-f(2-metoksy-5-nitrofenyl)metylamino]-2-benzhydrylkinuklidin som det ønskede mellomprodukt; hvorpå det sistnevnte ble benyttet som utgangsmateriale i det annet trinn (se Eksempel 21), igjen ved bruk av de samme molare forhold som tidligere, for tilslutt å gi cis-3-[(2-metoksy-5-nitrofenyl)metylamino]-2-benz-hydrylkinuklidin semihydrat (smp. 212-215°C) som det tilsvarende sluttprodukt. The reaction (two-step) described in Examples 11 and 21 respectively was repeated except that 2-methoxy-5-nitrobenzaldehyde was used as reagent instead of 2,6-dichlorobenzaldehyde in the first step (see Example 11) and during use of the same molar ratios as before, to easily give cis-3-f(2-methoxy-5-nitrophenyl)methylamino]-2-benzhydrylquinuclidine as the desired intermediate; whereupon the latter was used as starting material in the second step (see Example 21), again using the same molar ratios as before, to finally give cis-3-[(2-methoxy-5-nitrophenyl)methylamino]-2 -benz-hydrylquinuclidine hemihydrate (m.p. 212-215°C) as the corresponding end product.
Analyse beregnet for C28H31N303 . 0,5H2O: Analysis calculated for C28H31N303. 0.5H2O:
C, 72,08; H, 6,91; N, 9,01. C, 72.08; H, 6.91; N, 9.01.
Funnet: C, 72,15; H, 6,71; N, 9,21. Found: C, 72.15; H, 6.71; N, 9.21.
Eksempel 2 6 Example 2 6
Fremgangsmåten beskrevet i Eksempel 16 ble gjentatt for å fremstille de etterfølgende cis-3-[(cyklisk)metylamino]-2-benzhydrylkinulidiner, ved i hvert tilfelle å gå ut fra den tilsvarende cis-3-f(cyklisk)karbonylamino]-2-benzhydryl-kinukl idin-f orbindelse, under bruk av de samme molare forhold som tidligere: cis-3-[(3-hydroksy-2-pyridyl)metylamino]-2-benzhydryl-kinuklidin 1,75 hydrat, smp. 175-190°C, The procedure described in Example 16 was repeated to prepare the subsequent cis-3-[(cyclic)methylamino]-2-benzhydrylquinulidines, starting in each case from the corresponding cis-3-f(cyclic)carbonylamino]-2- benzhydryl-quinuclidine compound, using the same molar ratios as before: cis-3-[(3-hydroxy-2-pyridyl)methylamino]-2-benzhydryl-quinuclidine 1.75 hydrate, m.p. 175-190°C,
cis-3-[(2-etylfenyl)metylamino]-2-benzhydrylkinuklidin 0,25 hydrat, smp. 145-150°C, cis-3-[(2-ethylphenyl)methylamino]-2-benzhydrylquinuclidine 0.25 hydrate, m.p. 145-150°C,
cis-3-[(2-metoksy-5-tri fluormetylfenyl)metylamino]-2-benzhydrylkinuklidin 0,25 hydrat, smp. 137-140°C, cis-3-[(2-methoxy-5-trifluoromethylphenyl)methylamino]-2-benzhydrylquinuclidine 0.25 hydrate, m.p. 137-140°C,
cis-3-[(5-fluor-2-metoksyfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 164-167°C, cis-3-[(5-fluoro-2-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 164-167°C,
cis-3-[(3-fluor-2-metoksyfenyl)metylamino]-2-benzhydryl-kinuklidin, smp. 159-162°C, cis-3-[(3-fluoro-2-methoxyphenyl)methylamino]-2-benzhydryl-quinuclidine, m.p. 159-162°C,
cis-3-([(2-(N-monometylamino)fenyl]metylamino}-2-benz-hydrylkinuklidin 0,75 hydrat, smp. 173-176°C. cis-3-([(2-(N-monomethylamino)phenyl]methylamino}-2-benz-hydrylquinuclidine 0.75 hydrate, mp 173-176°C).
Eksempel 27 Example 27
A. I en 125 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt en oppløsning av 2,28 g (0,00507 mol) cis-3-amino-2-[bis(4-bromfenyl)metyl]-kinuklidin (fremstillet ifølge fremgangsmåten beskrevet av E. J. Warawa et al., i US-patent 3.560.510) og 1,0 g A. Into a 125 mL round bottom flask fitted with a reflux condenser and nitrogen inlet tube was placed a solution of 2.28 g (0.00507 mol) cis-3-amino-2-[bis(4-bromophenyl)methyl]-quinuclidine (prepared according to the method described by E. J. Warawa et al., in US patent 3,560,510) and 1.0 g
(0,00507 mol) S-(+)-(1-naftyl)etylisocyanat alt oppløst i (0.00507 mol) S-(+)-(1-naphthyl)ethyl isocyanate all dissolved in
4 0 ml toluen. Oppløsningen ble tilbakeløpsbehandlet i 4 timer og filtrert i varm tilstand for å gjenvinne uoppløselig hvitt bunnfall som var dannet under tilbakeløpstrinnet. Det således oppnådde faste produkt ble deretter vasket med toluen og så luft-tørket til konstant vekt for å gi 1,17 g (36%) rent (+)-cis-[(1-n-naftyletylureido]-2-[bis(4-bromfenyl)metyl]-kinuklidin som 1,5 hydratet, smp. 284-285°C; 40 ml of toluene. The solution was refluxed for 4 hours and filtered while hot to recover insoluble white precipitate formed during the reflux step. The solid product thus obtained was then washed with toluene and then air-dried to constant weight to give 1.17 g (36%) of pure (+)-cis-[(1-n-naphthylethylureido]-2-[bis( 4-bromophenyl)methyl]-quinuclidine as the 1,5 hydrate, mp 284-285°C;
[a]D<20> = + 62 , 0° (c=l,0, dimetylsulfoksyd) ved 589 nm. [a]D<20> = + 62 , 0° (c=1.0, dimethylsulfoxide) at 589 nm.
Analyse beregnet for C33H33Br2N30: Analysis calculated for C33H33Br2N30:
C, 61,22; H, 5,14; N, 6,49. C, 61.22; H, 5.14; N, 6.49.
Funnet: C, 60,96; H, 5,14; N, 6,43. Found: C, 60.96; H, 5.14; N, 6.43.
B. I en 125 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 1,10 g (0,0017 mol) av mellomproduktet oppnådd ovenfor og 4,0 ml vann. Til den resulterende omrørte vandige blanding ble det deretter forsiktig tilsatt 8,0 ml konsentrert svovelsyre, etterfulgt av forsiktig tilbakeløpsbehandling (bad-temperatur ca. 160°C) i 22 timer. Den resulterende mørke reaksjonsblandingen ble deretter avkjølt til romtemperatur (ca. 20°C) , helt over i is og pH i den avkjølte vandige blanding deretter justert til pH 12 med 6N vandig natriumhydroksydoppløsning. Den alkaliserte vandige blandingen ble deretter ekstrahert to ganger med metylenklorid, hvorpå de organiske lagene ble tørket over vannfri natriumsulfat og filtrert. Etter fjerning av tørke-midlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det gjenværende materiale deretter kromatografert på en silikagelkolonne ved bruk av 2:1 (volumdeler) metylenklorid/metanol-blanding som eluent for å gi produktet som en rå olje. Avfarvning av dette siste materialet med kull- i varm etylacetat ga deretter 643 mg (84%) rent (-)-cis-3-amino-2-[bis(4-bromfen<y>l)met<y>l1kinuklidin i form av et hvitt fast produkt, smp. 185-187°C; B. Into a 125 mL round bottom flask fitted with a reflux condenser and nitrogen inlet tube was placed 1.10 g (0.0017 mol) of the intermediate obtained above and 4.0 mL of water. To the resulting stirred aqueous mixture was then carefully added 8.0 ml of concentrated sulfuric acid, followed by careful reflux (bath temperature approx. 160°C) for 22 hours. The resulting dark reaction mixture was then cooled to room temperature (about 20°C), poured into ice and the pH of the cooled aqueous mixture then adjusted to pH 12 with 6N aqueous sodium hydroxide solution. The alkalized aqueous mixture was then extracted twice with methylene chloride, after which the organic layers were dried over anhydrous sodium sulfate and filtered. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, the remaining material was then chromatographed on a silica gel column using a 2:1 (v/v) methylene chloride/methanol mixture as eluent to give the product as a crude oil. . Decolorization of this last material with charcoal in hot ethyl acetate then gave 643 mg (84%) of pure (-)-cis-3-amino-2-[bis(4-bromophen<y>l)meth<y>l1quinuclidine in the form of a white solid product, m.p. 185-187°C;
[a]D<20> = -38 , 8° (c=l,0, metylenklorid) ved 589 nm. [a]D<20> = -38 , 8° (c=1.0, methylene chloride) at 589 nm.
Analyse beregnet for C20H22Br2N2: Analysis calculated for C20H22Br2N2:
C, 53,36; H, 4,93; N, 6,22. C, 53.36; H, 4.93; N, 6.22.
Funnet: C, 53,16; H, 4,99; N, 6,16. Found: C, 53.16; H, 4.99; N, 6.16.
C. I en 100 ml rundkolbe forsynt med en Dean-Stark-felle, tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 270 mg (0,0006 mol) (-)- cis-3-amino-2-[bis(4-bron C. Into a 100 ml round bottom flask fitted with a Dean-Stark trap, reflux condenser and nitrogen inlet tube was placed 270 mg (0.0006 mol) (-)-cis-3-amino-2-[bis(4- the bridge
fenyl)metyl]kinuklidin (oppnådd som ovenfor), 122 mg (0,0009 mol) 2-metoksybenzaldehyd, 2,0 mg kamfersulfonsyre og 17 ml toluen. Den resulterende reaksjonsblanding ble deretter tilbakeløpsbehandlet i 24 timer og avkjølt til romtemperatur (ca. 2 0°C) og inndampet nesten til tørrhet under redusert trykk for å gi et fast residuum som i det vesentlige besto av rå (-) - cis-3-[(2-metoksyfenyl)metylenamino]-2-[bis(4-bromfenyl)-metyl]kinuklidin. D. Det ovennevnte metylenamin-mellomprodukt (oppnådd som ovenfor) ble deretter tatt opp i 3,0 ml tetrahydrofuran og den resulterende eterblanding behandlet med 1,5 ml (0,003 mol) 2,OM oppløsning boran-metylsulfid. Reaksjonsblandingen ble deretter tilbakeløpsbehandlet i 24 timer og så avkjølt til romtemperatur (ca. 20°C) og inndampet nesten til tørrhet under redusert trykk. Det således oppnådde faste residuum ble tatt opp i 20 ml etanol, behandlet med 500 mg fast natriumkarbonat og 500 mg cesiumfluorid og blandingen tilbakeløpsbehandlet i 3,5 dager. Den resulterende reaksjonsblanding ble deretter avkjølt til romtemperatur, inndampet nesten til tørrhet under redusert trykk og deretter fordelt mellom etylacetat og vann, etterfulgt av separasjon av de to lagene. Det fraskilte organiske lag ble deretter vasket med vandig natrium-bikarbonatoppløsning og så med saltoppløsning og deretter tørket over vannfri natriumsulfat. Etter fjerning av tørke-midlet ved filtrering og av oppløsningsmidlet ved fordampning under redusert trykk, ble det tilslutt oppnådd et fast produkt som et residuum. Dette materialet ble deretter kromatografert på silikagel ved bruk av 7:3 (volumdeler) metylenklorid/- metanol-oppløsningsmiddelblanding som eluent for etter utgnidning med isopropanol tilslutt å gi 226 mg (66%) rent (-)- cis-3-f(2-metoksyfenyl)metylamino]-2-[bis(4-bromfenyl)-metyl] kinukl idin i form av et hvitt fast produkt, smp.' 176-177,5°C; phenyl)methyl]quinuclidine (obtained as above), 122 mg (0.0009 mol) of 2-methoxybenzaldehyde, 2.0 mg of camphorsulfonic acid and 17 ml of toluene. The resulting reaction mixture was then refluxed for 24 hours and cooled to room temperature (about 20°C) and evaporated almost to dryness under reduced pressure to give a solid residue consisting essentially of crude (-)-cis-3- [(2-Methoxyphenyl)methyleneamino]-2-[bis(4-bromophenyl)methyl]quinuclidine. D. The above methyleneamine intermediate (obtained as above) was then taken up in 3.0 mL of tetrahydrofuran and the resulting ether mixture treated with 1.5 mL (0.003 mol) of a 2.0M solution of borane methyl sulfide. The reaction mixture was then refluxed for 24 hours and then cooled to room temperature (about 20°C) and evaporated almost to dryness under reduced pressure. The solid residue thus obtained was taken up in 20 ml of ethanol, treated with 500 mg of solid sodium carbonate and 500 mg of cesium fluoride and the mixture refluxed for 3.5 days. The resulting reaction mixture was then cooled to room temperature, evaporated almost to dryness under reduced pressure and then partitioned between ethyl acetate and water, followed by separation of the two layers. The separated organic layer was then washed with aqueous sodium bicarbonate solution and then with brine and then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and of the solvent by evaporation under reduced pressure, a solid product was finally obtained as a residue. This material was then chromatographed on silica gel using a 7:3 (v/v) methylene chloride/methanol solvent mixture as eluent to give, after trituration with isopropanol, 226 mg (66%) of pure (-)-cis-3-f(2 -methoxyphenyl)methylamino]-2-[bis(4-bromophenyl)methyl]quinuclidine in the form of a white solid product, m.p.' 176-177.5°C;
[a]D<20> = -23 , 7° (c=l,5, metylenklorid) ved 589 nm. [a]D<20> = -23 , 7° (c=1.5, methylene chloride) at 589 nm.
Analyse beregnet for C28H30Br2N2O: Analysis calculated for C28H30Br2N2O:
C, 58,96; H, 5,30; N, 4,91. C, 58.96; H, 5.30; N, 4.91.
Funnet: C, 58,62; H, 5,06; N, 4,97. Found: C, 58.62; H, 5.06; N, 4.97.
Eksempel 28 Example 28
I en 2 0 ml rundkolbe forsynt med tilbakeløpskjøler og nitrogen-innløpsrør, ble det anbragt 200 mg (0,000438 mol) cis-[2-metoksy-5-nitrofenyl)metylamino]-2-benzhydrylkinuklidin (produktet fra Eksempel 31) i 1,0 ml etanol som inneholdt 138 mg (0,002188 mol) ammoniumformiat og 80 mg 10% palladium-på-kull-katalysator. Reaksjonsblandingen ble deretter omrørt ved romtemperatur (ca. 2 0°C) i 45 minutter, filtrert gjennom Celite (kiselgur) og det resulterende filtrat inndampet nesten til tørrhet under redusert trykk. Det således oppnådde faste residuum ble krystallisert fra isopropanol for å gi 86 mg (46%) rent cis-3-f(5-amino-2-metoksyfenyl)metylamino]-2-benz-hydrylkinuklidin, smp. 164-169°C. In a 20 ml round bottom flask fitted with a reflux condenser and nitrogen inlet tube, 200 mg (0.000438 mol) of cis-[2-methoxy-5-nitrophenyl)methylamino]-2-benzhydrylquinuclidine (the product of Example 31) was placed in 1 .0 ml of ethanol containing 138 mg (0.002188 mol) of ammonium formate and 80 mg of 10% palladium-on-charcoal catalyst. The reaction mixture was then stirred at room temperature (about 20°C) for 45 minutes, filtered through Celite and the resulting filtrate evaporated almost to dryness under reduced pressure. The solid residue thus obtained was crystallized from isopropanol to give 86 mg (46%) of pure cis-3-f(5-amino-2-methoxyphenyl)methylamino]-2-benz-hydrylquinuclidine, m.p. 164-169°C.
Analyse beregnet for C28H33N3O: Analysis calculated for C28H33N3O:
C, 78,65; H, 7,78; N, 9,83. C, 78.65; H, 7.78; N, 9.83.
Funnet: C, 78,73; H, 7,87; N, 9,71. Found: C, 78.73; H, 7.87; N, 9.71.
Eksempel 29 Example 29
I en 65 ml rundkolbe forsynt med nitrogen-innløpsrør ble det anbragt 730 mg (0,0025 mol) cis-3-amino-2-benzhydryl-kinuklidin [E. J. Warawa et al., i Journal of Medicinal Chemistry, Vol. 18, s. 71 (1975)] i 12 ml metanol som inneholdt 1,0 ml 2,5M metanolisk saltsyre. Omrøringen ble startet og så snart en fullstendig oppløsning forelå, ble det tilsatt 810 mg (0,00375 mol) 5-brom-2-metoksybenzaldehyd til blandingen, etterfulgt av videre omrøring inntil oppløsning igjen ble oppnådd. Til den resulterende omrørte oppløsning ble det deretter tilsatt 320 mg (0,0050 mol) natriumcyanoborhydrid, hvorpå den resulterende reaksjonsblanding ble omrørt ved romtemperatur (ca. 2 0°C) i 16 timer. Det således oppnådde bunnfall ble deretter isolert fra reaksjonsblandingen ved sugfiltrering, vasket med metanol og deretter tørket i vakuum til konstant vekt for å gi 715 mg (58%) rent cis-3-[(5-brom-2-metoksyfenyl)metylamino]-2-benzylhydrylkinuklidin semihydrat, smp. 190-191°C. 730 mg (0.0025 mol) of cis-3-amino-2-benzhydryl-quinuclidine [E. J. Warawa et al., in Journal of Medicinal Chemistry, Vol. 18, p. 71 (1975)] in 12 ml of methanol containing 1.0 ml of 2.5M methanolic hydrochloric acid. Stirring was started and as soon as a complete solution was present, 810 mg (0.00375 mol) of 5-bromo-2-methoxybenzaldehyde was added to the mixture, followed by further stirring until solution was again obtained. To the resulting stirred solution was then added 320 mg (0.0050 mol) of sodium cyanoborohydride, whereupon the resulting reaction mixture was stirred at room temperature (about 20°C) for 16 hours. The precipitate thus obtained was then isolated from the reaction mixture by suction filtration, washed with methanol and then dried in vacuo to constant weight to give 715 mg (58%) of pure cis-3-[(5-bromo-2-methoxyphenyl)methylamino]- 2-benzylhydrylquinuclidine hemihydrate, m.p. 190-191°C.
Analyse beregnet for C28H31BrN20 . 0,5H20: Analysis calculated for C28H31BrN20. 0.5H2O:
C, 67,20; H, 6,44; N, 5,60. C, 67.20; H, 6.44; N, 5.60.
Funnet: C, 67,16; H, 6,13; N, 5,66. Found: C, 67.16; H, 6.13; N, 5.66.
Eksempel 3 0 Example 3 0
Fremgangsmåten beskrevet i Eksempel 29 ble gjentatt bortsett fra at 2-(karboksymetoksy)benzaldehyd ble benyttet som reagens i stedet for 5-brom-2-metoksybenzaldehyd, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-{[2-(karboksymetoksy)fenyl]metylamino}-2-benzhydryl-kinuklidin, smp. 132-137°C. Utbyttet av rent produkt utgjorde 70% av den teoretiske verdi. The procedure described in Example 29 was repeated except that 2-(carboxymethoxy)benzaldehyde was used as reagent instead of 5-bromo-2-methoxybenzaldehyde, using the same molar ratios as before. In this particular case, the corresponding end product obtained was cis-3-{[2-(carboxymethoxy)phenyl]methylamino}-2-benzhydryl-quinuclidine, m.p. 132-137°C. The yield of pure product was 70% of the theoretical value.
Eksempel 31 Example 31
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt bortsett fra at 2-benzhydryl-5-etylkinuklidin-3-on (et produkt fra Fremstilling C) og 2-metoksybenzylamin utgjorde de opp-rinnelige utgangsmaterialer i stedet for 2-[(2,4-diklorfenyl)-fenylmetyl]kinuklidin-3-on og benzylamin, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-[(2-metoksyfenyl)metylamino]-2-benzhydryl-5-etylkinuklidin (utbytte, 11%) . Den frie base ble omdannet til hydrokloridsaltet ved oppløsning av basen i dietyleter og behandling av oppløsningen med en eterisk oppløsning av hydrogenklorid. The two-step reaction described in Example 6 was repeated except that 2-benzhydryl-5-ethylquinuclidin-3-one (a product of Preparation C) and 2-methoxybenzylamine constituted the initial starting materials instead of 2-[(2, 4-dichlorophenyl)-phenylmethyl]quinuclidin-3-one and benzylamine, using the same molar ratios as before. In this particular case, the corresponding final product obtained was cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydryl-5-ethylquinuclidine (yield, 11%). The free base was converted to the hydrochloride salt by dissolving the base in diethyl ether and treating the solution with an ethereal solution of hydrogen chloride.
Analyse beregnet for C30H36N2O . 2HC1: Analysis calculated for C30H36N2O. 2HC1:
C, 70,16; H, 7,45; N, 5,45. C, 70.16; H, 7.45; N, 5.45.
Funnet: C, 70,52; H, 7,47; N, 5,03. Found: C, 70.52; H, 7.47; N, 5.03.
Eksempel 3 2 Example 3 2
To-trinns reaksjonen beskrevet i Eksempel 6 ble gjentatt bortsett fra at 2-benzhydryl-5-etylkinuklidin-3-on ble benyttet som reaktant i stedet for 2-[(2,4-diklorfenyl)fenyl]-kinuklidin-3-on, under bruk av de samme molare forhold som tidligere. I dette spesielle tilfelle var det oppnådde tilsvarende sluttprodukt cis-3-benzylamino-2-benzhydryl-5-etyl-kinuklidin. Den frie base ble omdannet til hydrokloridsaltet ved oppløsning av basen i dietyleter og behandling av oppløsningen med en eterisk oppløsning av hydrogenklorid for å gi det ønskede saltprodukt i form av et semihydrat. The two-step reaction described in Example 6 was repeated except that 2-benzhydryl-5-ethylquinuclidin-3-one was used as reactant instead of 2-[(2,4-dichlorophenyl)phenyl]-quinuclidin-3-one, using the same molar ratios as before. In this particular case, the corresponding end product obtained was cis-3-benzylamino-2-benzhydryl-5-ethyl-quinuclidine. The free base was converted to the hydrochloride salt by dissolving the base in diethyl ether and treating the solution with an ethereal solution of hydrogen chloride to give the desired salt product in the form of a semihydrate.
Analyse beregnet for C29H3AN2 . 2HC1 . 0,5H2O: Analysis calculated for C29H3AN2. 2HC1 . 0.5H2O:
C, 70,72; H, 7,16; N, 5,68. C, 70.72; H, 7.16; N, 5.68.
Funnet: C, 70,85; H, 7,64; N, 5,37. Found: C, 70.85; H, 7.64; N, 5.37.
Claims (4)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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PCT/US1988/004205 WO1990005525A1 (en) | 1988-11-23 | 1988-11-23 | Quinuclidine derivatives as substance p antagonists |
PCT/US1989/005338 WO1990005729A1 (en) | 1988-11-23 | 1989-11-20 | Quinuclidine therapeutic agents |
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NO903254D0 NO903254D0 (en) | 1990-07-20 |
NO903254L NO903254L (en) | 1990-09-20 |
NO174584B true NO174584B (en) | 1994-02-21 |
NO174584C NO174584C (en) | 1994-06-01 |
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NO903254A NO174584C (en) | 1988-11-23 | 1990-07-20 | Analogous Process for Preparing Therapeutically Active Quinuclidine Derivatives |
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NO903254L (en) | 1990-09-20 |
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