NO329664B1 - Forbindelse av typen 1-alkyl-1-azoniabisyklo [2.2.2] oktankarbamatderivater, mellomforbindelser; og anvendelse derav ved tivirkning av medikament - Google Patents
Forbindelse av typen 1-alkyl-1-azoniabisyklo [2.2.2] oktankarbamatderivater, mellomforbindelser; og anvendelse derav ved tivirkning av medikament Download PDFInfo
- Publication number
- NO329664B1 NO329664B1 NO20043064A NO20043064A NO329664B1 NO 329664 B1 NO329664 B1 NO 329664B1 NO 20043064 A NO20043064 A NO 20043064A NO 20043064 A NO20043064 A NO 20043064A NO 329664 B1 NO329664 B1 NO 329664B1
- Authority
- NO
- Norway
- Prior art keywords
- azoniabicyclo
- octane
- fluorophenyl
- alkyl
- bromide
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 46
- 239000003814 drug Substances 0.000 title claims description 9
- 239000000543 intermediate Substances 0.000 title description 41
- 229940079593 drug Drugs 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 4
- 206010046543 Urinary incontinence Diseases 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
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- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
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- 101100134925 Gallus gallus COR6 gene Proteins 0.000 claims description 2
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- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 2
- 229910052736 halogen Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 88
- 239000007787 solid Substances 0.000 description 62
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 43
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
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- -1 β2 agonists Substances 0.000 description 28
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- BDDIUTHMWNWMRJ-UHFFFAOYSA-N octane;hydrobromide Chemical compound Br.CCCCCCCC BDDIUTHMWNWMRJ-UHFFFAOYSA-N 0.000 description 21
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- 238000000034 method Methods 0.000 description 15
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- 239000005557 antagonist Substances 0.000 description 11
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 11
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- 230000002829 reductive effect Effects 0.000 description 7
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- DYEHDACATJUKSZ-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octane;bromide Chemical compound [Br-].C1CC2CC[NH+]1CC2 DYEHDACATJUKSZ-UHFFFAOYSA-N 0.000 description 2
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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- 238000005917 acylation reaction Methods 0.000 description 1
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- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 description 1
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- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
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- ATIPBKCFGLKIGH-UHFFFAOYSA-N ethyl n-benzyl-n-phenylcarbamate Chemical compound C=1C=CC=CC=1N(C(=O)OCC)CC1=CC=CC=C1 ATIPBKCFGLKIGH-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
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- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
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- ZXVJACKMMUOZDX-UHFFFAOYSA-N octane;hydrate Chemical compound O.CCCCCCCC ZXVJACKMMUOZDX-UHFFFAOYSA-N 0.000 description 1
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
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- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 1
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- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229960001491 trospium Drugs 0.000 description 1
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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- Ophthalmology & Optometry (AREA)
- Hematology (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Den foreliggende oppfinnelse angår forbindelser av type 3-alkylfenyl-karbamoyloksy-l-alkyl-l-azoniabisyklo[2.2.2]oktan, som virker som muskarine reseptorantagonister, mellomforbindelser, og anvendelse av forbindelsene til fremstilling av medikament for behandling av sykdommer relatert til luftveiene, fordøyelseskanalen og urinsystemet.
Bakgrunnsteknikk
Det er kjent at forbindelser med virkning som muskarine reseptorantagonister induserer bronkodilasjon, inhibering av gastrointestinal motilitet, reduksjon i sekresjon av gastrisk syre, tørr munn, mydriasis, takykardi samt inhibering av urin-blærekontraksjon.
Mellom 1983 og 1993 ble det gjort kontinuerlige fremskritt innen muskarin-reseptorfarmakologi. Under denne perioden ble totalt fem humane gener som kodifiserte muskarine reseptorsubtyper (ml, m2, m3, m4 og m5) klonet og uttrykt, og kodet fem funksjonelle reseptorer (Mi, M2, M3, M4 og M5).
Mi-reseptoren er en postsynaptisk, neuronal reseptor som hovedsakelig er lokalisert i hjernen og de perifere parasympatiske kjertler. I glatte hjertemuskler er det en overveiende populasjon av M2-reseptorer. M3-reseptoren er overveiende lokalisert i
glandulært, eksokrint vev, slik som spyttkjertler. M4-reseptoren er hovedsakelig til stede i cerebral korteks, striatum og noen perifere steder i spesifikke arter. M5-reseptoren er blitt beskrevet å være til stede i cerebrale blodkar. I den glatte muskelen i fordøyelseskanalen, urinblæren og bronkier eksisterer M2- og M3-reseptorene sammen. Funksjonell informasjon som er vanlig akseptert, angir ikke desto mindre at M3-reseptoren er ansvarlig for den kontraktile virkning av den endogene neurotransmitter i de tre sistnevnte vev.
Det er blitt utviklet få M3-antagonister som mangler M2-affinitet. Den foreliggende oppfinnelse bidrar til å fylle dette behov ved å tilveiebringe denne type antagonister.
Det synes å være av interesse å oppnå M3-reseptorselektive antagonister for å unngå de uheldige virkninger som skyldes blokkering av andre muskarine reseptorer, hovedsakelig de kardiale virkninger som skyldes inhibering av M2-reseptoren. For tiden er blant andre oksybutynin (Alza), trospium (Madaus) og tolterodin (Pharmacia) kommersielt tilgjengelige forbindelser som viser redusert selektivitet for M2- og M3-reseptorer. Imidlertid viser darifenacin (Pfizer) og solifenacin (Yamanouchi), som begge er i klinisk fase, M3-antagonistaktivitet med en redusert affinitet for M2-reseptor.
I motsetning til dette binder tiotropiumbromid (Boehringer Ingelheim) seg med samme affinitet til muskarine M3- og M2-reseptorer. Imidlertid dissosierer det saktere fra M3-reseptoren enn fra M2-reseptoren, og følgelig har det en langtidsvirkning overfor M3-reseptoren. Følgelig kan det derfor anses å være en funksjonelt selektiv M3-antagonistforbindelse.
Det følgende er noen patentsøknader hvor det beskrives forbindelser med karbamidstrukturer som selektive M3-reseptorantagonister: JP 04/95071, WO 9506635, EP 747355, EP 801067 og WO 0200652.1 alle disse publikasjoner beskrives karbamater som er forskjellige fra dem som er beskrevet i den foreliggende oppfinnelse, og i de to sistnevnte beskrives slike som er strukturmessig nærmest dem som er angitt i de foreliggende krav. I publikasjon WO 0104188 er det beskrevet noen alkylkinuklidiniumestere som selektive antagonister for M3-reseptorer, men også de er forskjellige fra forbindelsene som den foreliggende oppfinnelse er rettet på.
Forbindelsene som den foreliggende oppfinnelse er rettet på, kan anvendes enten alene eller sammen med andre terapeutiske midler valgt blant: kalsiumkanal-blokkere, a-adrenoseptorantagonister, p2-agonister, dopaminagonister, kortikoidsteroider, fosfodiesterase IV-inhibitorer, leukotrien-D4-antagonister, endotelinantagonister, substans P-antagonister, antihostemidler, dekongestanter, histamin Hrantagonister, 5-lipooksygenaseinhibitorer, VLA-4-antagonister og teofyllin.
Sammenfatnin<g> av oppfinnelsen
Et aspekt ved den foreliggende oppfinnelse angår å tilveiebringe nye alkylkinuklidiniumkarbamater. Med den foreliggende oppfinnelse tilveiebringes således forbindelser som er kjennetegnet ved at de har generell formel (I)
og farmasøytisk akseptable salter av forbindelsen, hvor
RI, R2 og R3 er radikaler som uavhengig av hverandre er valgt blant H, F, Cl, Br, I, og(CrC4)alkyl;
R4 er et radikal valgt blant:
sykloheksyl,
tienyl substituert med (Ci-C6)alkyl eller halogen, og fenyl substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant F, Cl, Br og I,
R5 er et radikal valgt blant:
syklopropyl, syklobutyl, syklopentyl, sykloheksyl og (Ci-Cio)alkyl som er substituert med ett eller flere radikaler som uavhengig av hverandre er valgt blant R6, COR6, NR6R7, CONR6R7, NR7COR6, OH, OR6, COOR6, OCOR6, S02R6, SH, SR6, SOR6, COSR6 og SCOR6;
R6 er et radikal valgt blant:
(C]-C5)alkyl, syklopropyl, syklobutyl, syklopentyl, sykloheksyl, (Cr C4)alkoksykarbonyl, fenyl som eventuelt er substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant N02, CN, F, Cl, Br, I, NR7CO-(C,-C4)alkyl, (C,-C4)alkyl og (C,-C4)-alkoksyl, en heterosyklisk ring valgt blant tiazolyl, pyrrolyl, tienyl, imidazolyl, dihydroisoindolyl, pyrimidinyl og pyridyl, og denne heterosykliske ring er eventuelt substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant (=0), (Cr C4)alkylsulfanyl, (C,-C4)alkylsulfinyl, (C,-C4)alkylsulfonyl og (C,-C4)alkyl, et bisyklisk ringsystem valgt blant dihydro-benzofuranyl og benzoksazolyl;
R7 er et radikal valgt blant H, benzyloksykarbonyl, (CrC4)alkylkarbonyl,
og
X" er et fysiologisk akseptabelt anion.
I en utførelsesform er R4 lik et fenyl som er substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant F, Cl, Br og I.
I en annen utførelsesform er
R5 lik et (C|-C5)alkyl som er substituert med ett radikal valgt blant R6, COR6, NR6R7, CONR6R7, NR7COR6, OR6, COOR6, OCOR6, SR6, SOR6, S02R6; og R6 er et radikal valgt blant: a) fenyl som eventuelt er substituert med én eller flere substituenter valgt blant CN, F, Cl, Br, I, (CrC4)alk<y>l, og (CrC4)alkoksyl, b) en heterosyklisk ring valgt blant tiazolyl, pyrrolyl, tienyl, imidazolyl, dihydroisoindolyl, pyrimidinyl og pyridyl, og denne heterosykliske ring er eventuelt substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant (Ci-C4)alkylsulfanyl, (C|-C4)-alkylsulfinyl, (C,-C4)alkylsulfonyl og (C,-C4)alkyl. En annen side ved den foreliggende oppfinnelse angår en mellomforbindelse
med formel (X)
og farmasøytisk akseptable salter av forbindelsen, for fremstilling av en forbindelse med formel (I), som definert ovenfor, hvor RI, R2, R3, R8 og R9 er radikaler som uavhengig av hverandre er valgt blant H, F, Cl, Br, I og (C,-C4).
I enda en utførelsesform av den foreliggende oppfinnelse er konfigurasjonen i posisjon 3 i kinuklidinringen hos alle de foregående forbindelser lik ( R).
I tilfeller hvor forbindelser med formel (I) har et asymmetrisk karbonatom, kan racemiske blandinger av disse bli spaltet i sine enantiomerer med konvensjonelle metoder, slik som separering med kolonnekromatografi med kiral, stasjonær fase, eller ved fraksjonert krystallisasjon av forbindelsenes diastereoisomere salter. De sistnevnte kan tilberedes ved omsetning med enantiomert rene syrer eller baser. Kirale forbindelser med formel (I) kan også oppnås med enantioselektiv syntetisering gjennom de kirale forløpere.
Den foreliggende oppfinnelse angår også fysiologisk akseptable salter av karbamater med generell struktur (I). I denne beskrivelsen betyr "fysiologisk akseptable salter" salter som er farmasøytisk akseptable og som har utgangsforbindelsens ønskede farmakologiske aktivitet. Slike salter innbefatter: syreaddisjonssalter dannet med uorganiske syrer som saltsyre,
hydrogenbromsyre, salpetersyre, svovelsyre og fosforsyre, samt med organiske syrer som eddiksyre, benzensulfonsyre, benzosyre, kamfersulfonsyre, mandelsyre, metansulfonsyre, oksalsyre, ravsyre, fumarsyre, vinsyre og maleinsyre,
salter dannet ved at et surt proton som er til stede i utgangs-forbindelsen enten erstattes med et metallion, f.eks. et alkali-metallion, et jordalkalimetallion eller et aluminiumion, eller ko-ordinerer med en organisk eller uorganisk base. Akseptable organiske baser innbefatter dietylamin og trietylamin. Akseptable uorganiske baser innbefatter aluminiumhydroksid, kalsium-hydroksid, kaliumhydroksid, natriumkarbonat og natriumhydroksid.
Det er underforstått at alle henvisninger til farmasøytisk akseptable salter innbefatter løsningsmiddeladdisjonsformer (solvater) eller krystallformer (polymorfer) av det samme syreaddisjonssalt.
I denne beskrivelsen innbefatter betegnelsene "alkyl" og "alkoksyl" rett-kjedede og forgrenede strukturer.
Forbindelser med generell struktur (I) kan oppnås fra mellomproduktene med generell formel (IV), som kan fremstilles med tre generelle fremgangsmåter (nemlig A, B og C) representert i skjemaet nedenfor.
Utgangsarylalkylaminene (II) er kommersielt tilgjengelige eller de kan oppnås med fremgangsmåter som er kjent fra litteraturen, slik som alkylering av aniliner, reduserende aminering eller reduksjon av anilider.
I henhold til metode A utføres først acylering av arylalkylaminet (II) gjennom et klorformiat (f.eks. metylklorformiat, etylklorformiat eller 4-nitrofenylklor-formiat) i et inert løsningsmiddel [f.eks. dimetylformamid (DMF), diklormetan (DCM), 1,2-dikloretan (1,2-DCE), tetrahydrofuran (THF) eller toluen] ved en temperatur i området fra 0 °C til løsningsmidlets reflukstemperatur. I noen tilfeller er det tilrådelig å utføre reaksjonen ved å anvende det korresponderende klorformiat som løsningsmiddel, eller ved å anvende en base som et tertiært amin eller kaliumkarbonat. Deretter blir alkoksylgruppen innført med en transforestringsreaksjon mellom karbamatmellom-produktet (III) og 3-kinuklidol ved å anvende en base, slik som metallisk natrium, natriumhydrid eller natriummetoksid. Reaksjonen kan utføres ved en temperatur i området fra 0 °C til løsningsmidlets reflukstemperatur.
Metode A
I henhold til metode B blir 3-kinuklidol først omsatt med et klorformiat (f.eks. triklormetylklorformiat) i et inert løsningsmiddel (f.eks. DMF, DCM, 1,2-DCE) ved en temperatur i området fra 0 °C til løsningsmidlets reflukstemperatur for å oppnå det korresponderende hydrogenklorid av kinuklidolklorformiat. Deretter acyleres arylalkylamin (II) med kinuklidolklorformiat. Reaksjonen utføres i et inert løsningsmiddel (f.eks. DMF, DCM, CHCI3, 1,2-DCE) ved en temperatur i området fra 20 °C til løsningsmidlets reflukstemperatur.
Metode B
I henhold til metode C blir 3-kinuklidol først omsatt med en karbonyldi-imidazol (DC1) i et inert løsningsmiddel (f.eks. DCM, 1,2-DCE) ved romtemperatur for å oppnå den korresponderende imidazol-l-karboksylsyre-l-azabisyklo[2.2.2]okt-3-ylester. Deretter blir arylalkylamin (II) metallert i et inert løsningsmiddel (f.eks. THF) ved å anvende BuLi, og esteren tilsettes ved en temperatur i området fra 0 °C til romtemperatur.
Metode C
Det kvaternære ammoniumsalt med generell formel (I) kan fremstilles ved en N-alkyleringsreaksjon mellom et alkyleringsreagens (R5-X) og en forbindelse med generell formel (IV) ved å anvende et inert løsningsmiddel [f.eks. DMF, DCM, CHC13, 1,2-DCE, CH3CN (acetonitril)] ved en temperatur i området fra 20 °C til løsningsmidlets reflukstemperatur.
R5-X-forbindelsene er enten kommersielt tilgjengelige eller de kan fremstilles ved kjente fremgangsmåter, slik som illustrert nedenfor.
R
(f JL PBr, (l^l
x-f-W^ \hs-Htx
?)?.0 <L>^<J>n S^<L> Jm~X
fa
R2
''^ CI.SO
Jp^) Br-( CH2) n- CI R1 «V f
R2
^^CICOfCH^Br
R1
R2
R,
Br-(CH2)n-OH^ °a Jir°H |PBr3
^<*>j Br-(CH 2) n-Br^ [f^l ;CICO(CH^^ R. ;;Når R5 er -CH2-CHOH-A, hvor A er ethvert radikal unntatt H, kan i tillegg det kvaternære ammoniumsalt med generell formel (I) bli fremstilt ved alkylering mellom et epoksid og en forbindelse med generell formel (IV) i et inert løsningsmiddel (f.eks. DMF, DCM, CHCI3, 1,2-DCE, CH3CN) ved en temperatur i området fra 20 °C til løsningsmidlets reflukstemperatur. ;Forbindelsene ifølge den foreliggende oppfinnelse er selektive M3-reseptorantagonister versus M2-reseptor. Av denne årsak kan de anvendes ved behandling av urininkontinens (spesielt når den er forårsaket av overaktiv blære), irritabel tarm-syndrom og respirasjonslidelser (spesielt kronisk obstruktiv pulmonal sykdom, kronisk bronkitt, astma, emfysem og rhinitt), samt i oftalmiske intervensjoner. ;Et annet aspekt ved den foreliggende oppfinnelse er således anvendelse av forbindelser med formel (I) ved fremstilling av medikamenter for behandling av følgende sykdommer: urininkontinens, spesielt når den er forårsaket av overaktiv blære, irritabel tarm-syndrom, respirasjonslidelser, spesielt kronisk obstruktiv pulmonal sykdom, kronisk bronkitt, astma, emfysem og rhinitt. Videre vil anvendelse av forbindelsene ved fremstilling av et medikament for oftalmiske intervensjoner også utgjøre en del av dette aspekt av oppfinnelsen. ;Bindingstest til humane M?- og Mi- muskarinreseptorer ;De følgende tester viser M3-antagonistaktiviteten for forbindelser med formel (I), samt deres selektivitet overfor M2-reseptoren. Det er listet opp noen resultater oppnådd med klonede humane, muskarine M2- og M3-reseptorer, og den anvendte metodologi er beskrevet. ;Membraner fra CHO-K1-celler transfektert med humane M2- eller M3-reseptorer ble anvendt. For begge reseptorer kan den eksperimentelle prosedyre oppsummeres som følger: Cellemembraner (15-20 ug) ble inkubert med [<3>H]-NMS (0,3-0,5 nM) i 60 minutter ved 25 °C i nærvær eller fravær av antagonistene. Inkubering ble utført i 96-brønners polystyrenmikroplater i et totalt inkubasjons volum på 0,2 ml PBS, pH 7,4. Uspesifikk binding ble bestemt med parallelle analyser i nærvær av atropin (5 uM). Prøver ble filtrert gjennom glassfiber av type GF/C, preinkubert med 0,3 % PEL Filtre ble vasket 3-4 ganger med 50 mM Tris-HCl, 0,9 % NaCl, pH 7,4, ved 4 °C og så tørket ved 50 °C i 45 minutter. Filterbundet radioaktivitet ble kvantifisert med væske-scintillasjonstelling. ;For beregning av inhiberingskonstanten (Kj) ble fortrengningskurver analysert med ikke-lineær regresjon (GraphPad Prism). Dissosiasjonskonstanten (Kd) for [<3>H]-NMS for hver reseptor ble bestemt ved hjelp av metningskurver oppnådd under de samme betingelser som forsøkene utført med de korresponderende antagonister. De oppnådde resultater, uttrykt som middelverdien av to uavhengige forsøk, hvert utført med to paralleller, er vist i tabellen nedenfor. Forhold M2/M3 på over 1 indikerer en M3-selektiv aktivitet. ;Eksempler ;Oppfinnelsen skal illustreres med følgende eksempler. ;Strukturen hos de forskjellige forbindelser ble bekreftet med 'H-NMR, som ble registrert ved å anvende instrumentene "Varian GEMINI-200" eller "Gemini-300 MHz", og kjemiske forskyvninger er uttrykt som ppm (8) fra den interne referanse TMS. Nomenklaturen anvendt i dette dokumentet er basert på AUTONOM (Automatic Nomenclature), et databasert system fra Beilstein institutt for generering av systematisk nomenklatur ifølge IUPAC. ;Mellomprodukt 1 ;( i?)- 3- kinuklidvlklorfonniat- hydrogenklorid ;Til en oppløsning av 8,7 ml (74,8 mmol) triklonnetylklorformiat i 240 ml diklormetan ble det tilsatt dråpevis en oppløsning av 4,75 g (37,4 mmol) (Z?)-3-kinuklidol i 240 ml diklormetan ved 0 °C under inert atmosfære og med kontinuerlig omrøring. Deretter ble blandingen omrørt ved romtemperatur i 24 timer, og løsningsmidlet ble destillert av under redusert trykk. Dette ga 8,46 g (37,4 mmol) av et hvitt, fast stoff som tilsvarte tittelforbindelsen. IR (KBr, cm"<1>): 3380, 2650-2500, 1776. ;Mellomprodukt 2 ;( jg)- imidazol- 1 - karboksylsyre- 1 - azabisyklo|" 2. 2. 2" lokt- 3- ylester ;Til en suspensjon av 20,0 g (157 mmol) (/?)-3-kinuklidol i 400 ml diklormetan ble det ved romtemperatur tilsatt 31,55 g (189 mmol) DC1. Den gule oppløsningen ble omrørt i 4 timer under inert atmosfære. Deretter ble 340 ml vann tilsatt. Det organiske lag ble tørket over vannfritt natriumsulfat. Løsningsmidlet ble destillert av under redusert trykk. Det oppnådde faste stoff ble krystallisert med isopropylacetat(IPAC)-heptan. Dette ga 23,5 g (68 %) av tittelforbindelsen. IR (KBr, cm"<1>): 1746. ;Mellomprodukt 3 ;(- R)- benzylfenylkarbaminsvre- 1 - azabisyklo[ 2. 2. 2] okt- 3- ylester- hydrogenklorid ;Metode A ;Til en oppløsning av 5,1 g (20 mmol) benzylfenylkarbaminsyreetylester (Dannley, L., J. Org. Chem., 1957, 22, 268) og 7,63 g (60 mmol) 3-kinuklidol i 120 ml toluen ble det tilsatt 800 mg (20 mmol) natriumhydrid (60 % dispersjon i olje), og blandingen ble refluksert i 3 timer. I løpet av denne tiden ble toluen tilsatt for å erstatte avdestillert volum. Reaksjonsblandingen fikk avkjøles og ble så fortynnet med toluen (250 ml), vasket med vann og tørket over vannfritt natriumsulfat. Deretter ble løsnings-midlet destillert av under redusert trykk. Den oppnådde olje ble behandlet ved romtemperatur med etanol mettet med hydrogenklorid, løsningsmidlet ble destillert av, og det oppnådde faste stoff ble brutt opp med en l:l-blanding av etylacetat og dietyleter. Dette ga 230 mg (0,6 mmol) av et hvitt, fast stoff som tilsvarte tittelforbindelsen (smp. 54 °C). ;Metode B ;Til en suspensjon av 750 mg (2,58 mmol) 3-kinuklidylklorformiat-hydrogenklorid i 20 ml 1,2-DCE ble det dråpevis tilsatt en oppløsning av 395 mg (2,15 mmol) N-fenylbenzylamin i 5 ml 1,2-DCE. Så snart tilsetningen var ferdig, ble blandingen refluksert i 3 timer. Reaksjonsblandingen fikk avkjøles, og løsningsmidlet ble destillert av under redusert trykk. Residuet ble renset med kolonnekromatografi (Si02, elueringsmiddel: CHCl3-metanol 10:1), hvilket ga 720 mg (1,95 mmol) av et hygroskopisk skum som tilsvarte tittelforbindelsen. ;IR (KBr, cm'<1>): 3400-3200, 2700-2300, 1700 cm-<1>. ;'H-NMR (CDC13): 12,30 (s, 1 H), 7,20-6,90 (m, 10 H), 5,10 (m, 1 H), 4,83 (m, 2 H), 3,52 (m, 1 H), 3,18 (m, 4 H), 2,80 (m, 1 H), 2,34 (s, 1 H), 1,92 (m, 2 H), 1,60 (m, 2 H). ;Metode C ;Til en oppløsning av 2,73 g (14,9 mmol) N-fenylbenzylamin i 20 ml THF, som på forhånd var avkjølt til -10 °C, ble det tilsatt dråpevis 5,96 ml n-BuLi (2,5 M). Ved -10 °C ble det tilsatt sakte 3,29 g (14,9 mmol) av mellomprodukt 2 i 35 ml THF. Den resulterende blanding ble omrørt i 2 timer, og temperaturen fikk stige til romtemperatur, deretter ble 35 ml vann tilsatt. Oppløsningen ble ekstrahert med etylacetat, den organiske fase ble tørket over vannfritt natriumsulfat, og løsningsmidlet ble fjernet under redusert trykk. Residuet ble oppløst i EtOH/HCl, og løsningsmidlet ble igjen dampet av. Det nye residuet ble renset med kolonnekromatografi (elueringsmiddel: kloroform-metanol 10:1), hvilket ga 1,53 g av et hygroskopisk skum som tilsvarte tittelforbindelsen. IR (KBr, cm-<1>): 3400-3200, 2700-2300, 1700 cm-<1>. ;De følgende mellomprodukter (4-15) ble fremstilt ved å benytte metode B, beskrevet i patentsøknaden WO 0200652: mellomprodukt 4: (/?)-benzyl-/w-tolylkarbaminsyre-l-azabisyklo[2.2.2]okt-3 -y lester-hydrogenklorid, ;mellomprodukt 5: (Æ)-benzyl-(3-fluorfenyl)karbaminsyre-1 -azabisyklo-[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 6: (/?)-(4-fluorbenzyl)fenylkarbaminsyre-1 -azabisyklo-[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 7: (Æ)-(4-fluorbenzyl)-m-tolylkarbaminsyre-1 -azabisyklo-[2.2.2]okt-3 -y lester-hydrogenklorid, ;mellomprodukt 8: (/?)-(4-fluorbenzyl)-(2-fluorfenyl)karbaminsyre-1-azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 9: (Æ)-(4-fluorbenzyl)-(3-lfuorfenyl)karbaminsyre-1 - azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 10: (if)-(3,4-difluorbenzyl)fenylkarbaminsyre-l-azabisyklo-[2.2.2] okt-3 -y lester-hydrogenklorid, ;mellomprodukt 11: (i?)-(3,4-difluorbenzyl)-m-tolylkarbaminsyre-l-azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 12: (Æ)-(3,4-difluorbenzyl)-(2-fluorfenyl)karbamins<y>re-1 - azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 13: (Æ)-(3,4-difluorbenzyl)-(3-fluorfenyl)karbaminsyre-1 - azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 14: (/?)-(2-fluorfenyl)-(3,4,5-trifluorbenzyl)karbaminsyre-l-azabisyklo[2.2.2] okt-3 -y lester-hydrogenklorid, ;mellomprodukt 15: (i?)-(3-fluorfenyl)-(3,4,5-trifluorbenzyl)karbaminsyre-1 - azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;mellomprodukt 16: (Æ)-3-sykloheksylmetylfenylkarbamoyloksy-l-azoniabisyklo[2.2.2]oktan-hydrogenklorid. ;De følgende nye mellomprodukter ble fremstilt ved å benytte metodene beskrevet ovenfor: Mellomprodukt 17 ;('/ ?)- tiofen- 2- vlmetvl- m- tolvlkarbaminsvre- l- azabisvklo[ 2. 2. 21okt- 3- vlester ;'H-NMR (CDC13): 7,25 (d, 1 H), 7,22 (d, 1 H), 7,06 (d, 1 H), 6,94 (m, 1 H), 6,91 (dd, 2 H), 6,84 (dd, 1 H), 4,95 (s, 2 H), 4,88 (m, 1 H), 3,32 (dd, 1 H), 3,10-2,60 (m, 5 H), 2,31 (s, 3 H), 2,14 (m, 1 H), 1,80-1,30 (m, 4 H). ;Mellomprodukt 18 ;(■ RV( 2- fluorfenvl) tiofen- 2- vlmetvlkarbaminsvre- 1 - azabisyklo[ 2. 2. 2] okt- 3 - vlester ;'H-NMR (CDCI3): 7,35-7,20 (m, 2 H), 7,15-7,00 (m, 3 H), 6,86 (m, 2 H), 4,95 (s, 2 H), 4,82 (m, 1 H), 3,22 (m, 1 H), 3,15-2,50 (m, 5 H), 2,01 (m, 1 H), 1,80-1,50 (m,2H), 1,45-1,20 (m, 2 H). ;Mellomprodukt 19 ;( 7?)-(' 3- fluorfenvl) tiofen- 2- vlmetvlkarbaminsvre- l- azabisvklor2. 2. 21okt- 3- ylester-hvdrogenklorid ;'H-NMR (CDCI3): 7,35-7,20 (m, 2 H), 7,15-7,00 (m, 3 H), 6,86 (m, 2 H), 4,95 (s, 2 H), 4,82 (m, 1 H), 3,22 (m, 1 H), 3,15-2,50 (m, 5 H), 2,01 (m, 1 H), 1,80-1,50 (m,2H), 1,45-1,20 (m, 2 H). ;Mellomprodukt 20 ;C/ g)-( 3- metvltiofen- 3- vlmetvnfenvlkarbaminsvre- l- azabisyklo[ 2. 2. 21okt- 3- vlester-hydrogenklorid ;'H-NMR (CDCI3): 11,69 (br, 1 H), 7,29 (m, 3 H), 7,17-6,90 (m, 3 H), 6,71 (dd, 1 H), 5,08 (m, 1 H), 4,89 (s, 2 H), 3,61 (m, 1 H), 3,40-2,60 (m, 5 H), 2,37 (m, 1 H), 2,19-1,80 (m, 3 H), 1,87 (s, 3 H), 1,61 (m, 1 H). ;Mellomprodukt 21 ;( i?)- 3-[( 4- bromtiofen- 2- vlmetvnfenvlkarbamovloksvl- l- azoniabisvklo[ 2. 2. 21oktan-hydrogenklorid ;'H-NMR (CDCI3): 7,42-7,30 (m, 3 H), 7,15 (d, 1 H), 7,08 (br, 2 H), 6,79 (d, 1 H), 5,30 (br, 1 H), 5,04 (m, 1 H), 4,90 (s, 2 H), 3,55-3,40 (m, 1 H), 3,20-2,95 (m, 4 H), 2,80 (br, 1 H), 2,32 (m, 1 H), 2,00-1,65 (m, 2 H), 1,59 (m, 2 H). ;Mellomprodukt 22 ;(/ g)-( 5- metyltiofen- 2- ylmetvnfenylkarbaminsyre- l- azabisyklo[ 2. 2. 2] okt- 3- ylester-hydrogenklorid ;'H-NMR (CDCI3): 12,20 (br, 1 H), 7,40-7,28 (m, 3 H), 7,16-6,90 (br, 2 H), 6.59 (d, 1 H), 6,53 (d, 1 H), 5,09 (m, 1 H), 4,85 (s, 2 H), 3,53 (br, 1 H), 3,35-3,00 (m, 4 H), 2,82 (br, 1 H), 2,45 (s, 3 H), 2,39 (m, 1 H), 2,10-1,55 (m, 4 H). ;Mellomprodukt 23 ;( j?V( 5- klortiofen- 2- vlmetvlV( 2- fluorfenynkarbaminsvre- l- azabisyklo[ 2. 2. 21okt- 3-ylester- hydrogenklorid ;'H-NMR (CDCI3): 7,40-7,27 (m, 1 H), 7,23-7,05 (m, 3 H), 6,71 (d, 1 H), 6.60 (d, 1 H), 5,07 (m, 1 H), 4,81 (s, 2 H), 3,49 (m, 1 H), 3,30-3,00 (m, 4 H), 2,87 (m, 1 H), 2,39 (m, 1 H), 2,00-1,80 (m, 2 H), 1,75-1,53 (m, 2 H). ;Mellomprodukt 24 ;(■ ft)-( 5- bromtiofen- 2- y lmety Dfeny lkarbaminsyre- 1 - azabisyklo [ 2. 2. 21 okt- 3 - ylester-hydrogenklorid ;'H-NMR (CDCI3): 7,42-7,29 (m, 3 H), 7,12-7,00 (m, 2 H), 6,86 (d, 1 H), 6,59 (d, 1 H), 5,30 (br, 1 H), 5,04 (m, 1 H), 4,86 (s, 2 H), 3,50-3,35 (m, 1 H), 3,20-2,90 (m, 4 H), 2,80 (br, 1 H), 2,32 (m, 1 H), 2,00-1,65 (m, 3 H), 1,59 (m, 1 H). ;Mellomprodukt 25 ;(/ g)-( 5- bromtiofen- 2- ylmetyn- m- tolylkarbaminsvre- l- azabisyklor2. 2. 21okt- 3- ylester-hydrogenklorid 1 H-NMR (CDCI3): 7,21 (d, 1 H), 7,11 (d, 1 H), 6,95-6,80 (m, 2 H), 6,86 (d, 1 H), 6,60 (d, 1 H), 5,03 (m, 1 H), 4,84 (s, 2 H), 3,50-3,35 (m, 1 H), 3,20-2,95 (m, 4 H), 2,80 (br, 1 H), 2,34 (m, 1 H), 2,34 (s, 3 H), 2,00-1,60 (m, 4 H). ;Mellomprodukt 26 ;( 7gVf3- fluorfenyntiofen- 3- vlmetvlkarbaimnsvre- l- azabisvklo[ 2. 2. 21okt- 3- vlester-hvdrogenklorid ;'H-NMR (CDCI3): 8,14 (br, 1 H), 7,38-7,24 (m, 2 H), 7,08 (d, 1 H), 6,99-6,92 (m, 4 H), 5,07 (m, 1 H), 4,81 (s, 2 H), 3,65 (ddd, 1 H), 3,27-3,08 (m, 4 H), 2,90 (q, 1 H), 2,31 (m, 1 H), 2,10-1,80 (m, 2 H), 1,70-1,55 (m, 2 H). ;Mellomprodukt 27 ;(/ gV( 2- fluorfenyn-( 3- metvltiofen- 2- vlmetyl) karbaminsvre- l- azabisyklo[ 2. 2. 21okt- 3-vlester- hvdrogenklorid ;'H-NMR (CDCI3): 7,31 (m, 1 H), 7,13 (d, 1 H), 7,10-6,92 (m, 2 H), 7,07 (d, 1 H), 6,72 (d, 1 H), 5,11 (m, 1 H), 4,87 (m, 2 H), 3,51 (m, 1 H), 3,35-2,98 (m, 4 H), 2,85 (m, 1 H), 2,42 (m, 1 H), 1,93 (s, 3 H), 2,10-1,50 (m, 4 H). ;Mellomprodukt 28 ;(/ ?V(' 2- fluorfenvl)-(' 5- metvltiofen- 2- vlmetvnkarbaminsyre- l- azabisvklo[ 2. 2. 21okt- 3-vlester- hvdrogenklorid ;'H-NMR (CDCI3): 7,31 (m, 1 H), 7,20-7,04 (m, 3 H), 6,59 (d, 1 H), 6,53 (dd, 1 H), 5,09 (m, 1 H), 4,80 (m, 2 H), 3,53 (m, 1 H), 3,37-3,00 (m, 4 H), 2,86 (br, 1 H), 2,45 (s, 3 H), 2,44 (m, 1 H), 2,10-1,55 (m, 4 H). ;Mellomprodukt 29 ;(/ g)-( 5- klortiofen- 2- vlmetvl)-( 3- fluorfenvl) karbaminsvre- l- azabisyklo[ 2. 2. 21okt- 3-vlester- hvdrogenklorid ;'H-NMR (CDCI3): 7,34 (td, 1 H), 7,04 (td, 1 H), 6,95-6,78 (m, 2 H), 6,73 (d, 1 H), 6,62 (d, 1 H), 5,09 (m, 1 H), 4,83 (s, 2 H), 3,52 (m, 1 H), 3,35-3,05 (m, 4 H), 2,93 (br, 1 H), 2,41 (m, 1 H), 2,10-1,55 (m, 4 H). ;Mellomprodukt 30 ;( i?V( 5- etvltiofen- 2- vlmetvn- m- tolvlkarbaminsyre- l- azabisvklo[ 2. 2. 21okt- 3- vlester-hvdrogenklorid ;'H-NMR (CDCI3): 7,40-7,28 (m, 3 H), 7,15-7,02 (m, 2 H), 6,61 (d, 1 H), 6,57 (d, 1 H), 5,12 (m, 1 H), 4,87 (s, 2 H), 3,55-3,35 (m, 1 H), 3,20-2,95 (m, 4 H), 2,80 (q, 2 H), 2,80-2,70 (m, 1 H), 2,35 (m, 1 H), 2,00-1,55 (m, 4 H), 1,28 (t, 3 H). ;Mellomprodukt 31 ;( i?)- fenvltiofen- 3- vlmetylkarbaminsvre- l- azabisyklo[ 2. 221okt- 3- ylester- hydrogenklorid ;'H-NMR (CDCI3): 7,35-7,24 (m, 4 H), 7,12-6,92 (m, 2 H), 7,03 (d, 1 H), 6.96 (dd, 1 H), 5,01 (m, 1 H), 4,77 (s, 2 H), 3,48 (ddd, 1 H), 3,25-2,97 (m, 4 H), 2,80 (m, 1 H), 2,27 (m, 1 H), 2,01-1,77 (m, 2 H), 1,65-1,45 (m, 2 H). ;Mellomprodukt 32 ;( 7g)- tiofen- 3- vlmetvl-/ w- tolylkarbaminsyre- l- azabisyklo[ 2. 2. 21okt- 3- vlester-hvdrogenklorid ;'H-NMR (CDCI3): 7,27 (dd, 1 H), 7,18 (t, 1 H), 7,06 (d, 1 H), 7,04 (s, 1 H), 6.97 (dd, 1 H), 6,82 (br, 2 H), 5,03 (m, 1 H), 4,76 (s, 2 H), 3,50 (m, 1 H), 3,28-2,98 (m, 4 H), 2,83 (m, 1 H), 2,30 (s, 3 H), 2,30 (m, 1 H), 2,05-1,75 (m, 2 H), 1,70-1,50 (m, 2 H). ;Mellomprodukt 33 ;( i?)-( 2- fluorfenvl) tiofen- 3- vlmetvlkarbaminsyre- l- azabisvklo[ 2. 2. 21okt- 3- vlester-hvdrogenklorid ;'H-NMR (CDCI3): 7,38-7,20 (m, 2 H), 7,11 (d, 1 H), 7,10-6,95 (m, 2 H), 7,05 (s, 1 H), 6,99 (dd, 1 H), 5,02 (m, 1 H), 4,78 (dd, 2 H), 3,48 (m, 1 H), 3,30-2,95 (m, 4 H), 2,83 (m, 1 H), 2,29 (m, 1 H), 2,05-1,80 (m, 2 H), 1,70-1,50 (m, 2 H. ;De følgende nye mellomprodukter ble også fremstilt ved å benytte metodene beskrevet ovenfor, og de ble identifisert med 'H-NMR: (/?)-(3-fluorfenyl)-(3-metyltiofen-2-ylmetyl)karbaminsyre-l-azabisyklo-[2.2.2] okt-3 -y lester-hydrogenklorid, ;(/?)-3-(4-bromtiofen-2-ylmetyl)-/n-tolylkarbaminsyre-l-azabisyklo[2.2.2]-okt-3 -y lester-hydrogenklorid, ;(i?)-(4-bromtiofen-2-ylmetyl)-(2-fluorfenyl)karbaminsyre-l-azabisyklo-[2.2.2]okt-3 -ylester-hy drogenklorid, ;(i?)-(4-bromtiofen-2-ylmetyl)-(3-fluorfenyl)karbaminsyre-l-azabisyklo-[2.2.2]okt-3-ylester-hydrogenklorid, ;(i?)-(3-fluorfenyl)-(5-metyltiofen-2-ylmetyl)karbaminsyre-l-azabisyklo-[2.2.2]okt-3 -ylester-hy drogenklorid, ;(/?)-(5-klortiofen-2-ylmetyl)fenylkarbaminsyre-l-azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;(^)-(5-bromtiofen-2-ylmetyl)-(2-fluorfenyl)karbaminsyre-l-azabisyklo-[2.2.2] okt-3 -ylester-hy drogenklorid, ;(i?)-(5-bromtiofen-2-ylmetyl)-(3-fluorfenyl)karbaminsyre-l-azabisyklo-[2.2.2]okt-3 -ylester-hy drogenklorid, ;(/?)-(5-etyltiofen-2-ylmetyl)fenylkarbaminsyre-l-azabisyklo[2.2.2]okt-3-ylester-hydrogenklorid, ;(/?)-(5-etyltiofen-2-ylmetyl)-(2-fluorfenyl)karbaminsyre-l-azabisyklo-[2.2.2] okt-3 -ylester-hy drogenklorid, ;(/?)-(5-et<y>ltiofen-2-<y>lmet<y>l)-(3-fiuorofen<y>l)karbaminsyre-l-azabisyklo-[2.2.2]okt-3-ylester-hydrogenklorid. ;Eksempel 1 ;( j?V3-( benzylfenylkarbamovloksvVl- svklopropyl- l- azoniabisvklor2. 2. 21oktan- bromid ;200 mg (0,59 mmol) av mellomprodukt 3 og 0,47 ml bromsyklopropan (0,59 mmol) ble blandet i 5 ml acetonitril/kloroform (2:3). Den resulterende oppløsning ble refluksert i 12 timer. Løsningsmidlet ble dampet av, og residuet ble renset med kolonnekromatografi [Si02, elueringsmiddel: diklormetan-metanol (20:1)], hvilket ga 130 mg (47 %) av et hygroskopisk, hvitt, fast stoff som tilsvarte tittelforbindelsen. ;'H-NMR (CDC13): 7,27 (m, 10 H), 4,87 (m, 2 H), 4,80 (m, 1 H), 3,18 (ddd, 1 H), 3,01 (m, 1 H), 2,80-2,50 (m, 5 H), 2,23 (m, 1 H), 1,98 (m, 2 H), 1,65-1,18 (m, 6 H). ;De følgende forbindelser ble syntetisert i henhold til eksempel 1: Eksempel 2 ;(/ g)- 3-( benzvlfenvlkarbamovloksv)- l-( 2- klorbenzyl)- l- azoniabisvklor2. 2. 21oktan- klorid Utbyttet var 131 mg (45 %) i form av en gul olje. ;IR (film, cm-<1>): 1694. ;'H-NMR (CDCI3): 7,60-7,16 (m, 14 H), 5,03 (m, 1 H), 4,92 (dd, 2 H), 4,80 (s, 2 H), 4,10 (m, 1 H), 3,77 (m, 3 H), 3,35 (m, 1 H), 2,78 (m, 1 H), 2,28 (m, 1 H), 1,98 (m, 2 H), 1,78 (m, 1 H), 1,60 (m, 1 H). ;Eksempel 3 ;(/ g)- 3-( benzvlfenvlkarbamovloksv)- l-( 5- metvlsulfanvin. 3. 41tiadiazol- 2- vlsulfanvl-metvP- 1 - azoniabisyklof 2. 2. 21 oktan- klorid ;Utbyttet var 77 mg (53 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,27-7,18 (m, 10 H), 6,97 (t, 2 H), 6,82 (dd, 2 H), 5,12 (dd, 1 H), 4,82 (m, 2 H), 4,34 (s, 2 H), 4,30-4,05 (m, 3 H), 4,05-3,70 (m, 4 H), 3,05 (dd, 1 H), 2,33 (m, 1 H), 2,10-1,50 (m, 4 H). ;Eksempel 4 ;( i?)- 3-( benzvlfenylkarbamovloksv)- 1 - etoksykarbonvlmetyl- 1 - azoniabisyklo[ 2. 2. 21oktan-bromid ;Utbyttet var 60 mg (35 %) i form av en olje. ;IR (film, cm-<1>): 1743, 1701. ;'H-NMR (CDCI3): 7,28 (m, 10 H), 5,15-4,80 (m, 5 H), 4,40-3,50 (m, 8 H), 2,38 (m, 1 H), 2,01 (m, 2 H), 1,78 (m, 1 H), 1,58 (m, 1 H), 1,29 (t, 3 H). ;Eksempel 5 ;(^ V3-( benzvl- m- tolvlkarbamovloksv)- l- r2-( 23- dihvdrobenzoiuran- 5- vl) etvn- l-azoniabisvklof 2. 2. 2] oktan- bromid ;Utbyttet var 120 mg (25 %) i form av et hvitt, fast stoff. ;IR (film, cm-<1>): 1694. ;'H-NMR (CDCI3): 7,30-6,80 (m, 11 H), 6,62 (d, 1 H), 5,16 (m, 1 H), 4,77 (m, 2 H), 4,48 (t, 2 H), 4,21 (m, 1 H), 3,90-3,40 (m, 6 H), 3,09 (t, 2 H), 2,88 (m, 3 H), 2,29 (s,3H), 2,01-1,40 (m, 5 H). ;Eksempel 6 ;( K )- 3 - rbenzvl-( 3- fluorfenvDkarbamovloksv1 - 1 - r2-( 2. 3 - dihy drobenzofuran- 5 - vDetvll - 1 - azoniabisvklor2. 2. 21oktan- bromid ;Utbyttet var 51 mg (16 %) i form av et hvitt, fast stoff. ;IR (film, cm-<1>): 1705. ;'H-NMR (CDCI3): 7,30-6,90 (m, 10 H), 6,80 (d, 1 H), 6,68 (d, 1 H), 5,17 (m, 1 H), 4,90 (m, 2 H), 4,52 (t, 2 H), 4,16 (m, 1 H), 3,90-3,60 (m, 5 H), 3,41 (m, 1 H), 3,13 (t, 2 H), 2,88 (m, 3 H), 2,21-1,60 (m, 5 H). ;Eksempel 7 ;(/ gV3- r( 4- lfuorbenzvnfenvlkarbamovloksvlVl-(' 2- m- tolvletvlVl- azoniabisvklor2. 2. 21-oktan- bromid ;Utbyttet var 110 mg (42 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,40-7,00 (m, 10 H), 7,09 (s, 1 H), 6,98 (t, 2 H), 5,09 (m, 1 H), 4,78 (m, 2 H), 4,13 (m, 1 H), 4,00-3,60 (m, 5 H), 3,30 (br, 1 H), 2,95 (br, 1 H), 2,93 (t, 2 H), 2,33 (m, 1 H), 2,30 (s, 3 H), 2,10-1,70 (m, 3 H), 1,61 (m, 1 H). ;Eksempel 8 ;( R )- 1 - r2-( 4- etoksvfenvnetvn- 3- r( 4- fluorbenzvnfenvlkarbamovloksv1- 1 - azoniabisvklor2. 2. 21oktan- bromid ;Utbyttet var 106 mg (38 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,40-6,95 (m, 11 H), 6,79 (d, 2 H), 5,06 (m, 1 H), 4,78 (m, 2 H), 4,15-3,60 (m, 6 H), 3,95 (q, 2 H), 3,35 (br, 1 H), 3,05 (br, 1 H), 2,93 (t, 2 H), 2,32 (m, 1 H), 2,10-1,70 (m, 4 H), 1,38 (t, 3 H). ;Eksempel 9 ;( iO- 3- f( 4- lfuorbenzyl) fenylkarbamoyloksyl- M r2. 2. 21oktan- bromid ;Utbyttet var 72 mg (26 %) i form av et gult, fast stoff. ;'H-NMR (CDC13): 8,04 (d, 2 H), 7,59 (d, 2 H), 7,40-7,03 (m, 7 H), 6,98 (t, 2 H), 5,11 (m, 1 H), 4,79 (m, 2 H), 4,25 (m, 1 H), 4,05 (m, 1 H), 3,95-3,70 (m, 4 H), 3,55 (br, 1 H), 3,16 (t, 2 H), 3,05 (br, 1 H), 2,93 (t, 2 H), 2,32 (m, 1 H), 2,10-1,50 (m, 4 H). ;Eksempel 10 ;( R )- 1 -|" 2-( 2, 4- difluorfenvlsulfanvnetyn- 3- r( 4- fluorbenzyl) fenylkarbamovloksvl- 1 - azoniabisyklo|" 2. 2. 2] oktan- bromid ;Utbyttet var 182 mg (64 %) i form av et gult, fast stoff. ;'H-NMR (CDC13): 7,61 (ddd, 1 H), 7,40-7,17 (m, 6 H), 7,09 (m, 1 H), 7,00-6,88 (m, 2 H), 6,97 (t, 1 H), 6,82 (dd, 1 H), 5,11 (m, 1 H), 4,78 (s, 2 H), 4,23 (ddd, 1 H), 4,00-3,50 (m, 5 H), 3,45-3,20 (m, 3 H), 2,93 (br, 1 H), 2,32 (m, 1 H), 2,10-1,80 (m, 3 H) 1,60 (m, 1 H). ;Eksempel 11 ;(■/ gV3-[( 4- fluorbenzyDfenylkarbamoyloksv1- 1 -( 3- fenoksypropylV 1 - azoniabisyklor2. 2. 2]-oktan- bromid ;Utbyttet var 32 mg (10 %) i form av et hvitt, fast stoff. ;IR (film, cm<-1>): 1703. ;'H-NMR (CDCI3): 7,40-6,80 (m, 12 H), 6,85 (d, 2 H), 5,13 (m, 1 H), 4,88 (m, 2 H), 4,18 (m, 1 H), 4,05 (t, 2 H), 3,90-3,60 (m, 4 H), 3,47 (m, 1 H), 3,23 (m, 1 H), 2,80 (m, 1 H), 2,40-1,80 (m, 7 H). ;Eksempel 12 ;( R )- 1 - syklobutvlmetvl- S- f^- fluorbenzvD- m- tolvlkarbamovloksyl- 1 - azoniabisvklor2. 2. 21oktan- bromid ;Utbyttet var 132 mg (63 %) i form av en olje. ;'H-NMR (CDCI3): 7,25-7,17 (m, 3 H), 7,06 (d, 2 H), 7,00 (d, 2 H), 6,88 (br, 1 H), 5,09 (m, 1 H), 4,78 (m, 2 H), 4,10-3,80 (m, 3 H), 3,56 (d, 2 H), 3,55 (m, 1 H), 3,05 (br, 1 H), 2,75 (br, 1 H), 2,35 (m, 1 H), 2,32 (s, 3 H), 2,10-0,90 (m, 11 H). ;Eksempel 13 ;( R )- 1 -\ 2 -( 3 . 4- dimetoksvfenv Oetvll- 3 - r( 4- lfuorbenzvn-( 2- fluorfenvnkarbamovloks vi- 1 - azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 190 mg (60 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,35-6,92 (m, 10 H), 6,76 (s, 2 H), 5,08 (m, 1 H), 4,78 (s, 2 H), 4,25-3,60 (m, 6 H), 3,95 (s, 3 H), 3,82 (s, 3 H), 3,26 (m, 1 H), 2,97 (m, 3 H), 2,30 (m, 1 H), 2,10-1,50 (m,4H). ;Eksempel 14 ;(/ gV3- r( 4- lfuorbenzyn-( 2- fluorfenvnkarbamovloksv1- l-[ 2-(' 4- metoksyfenvlV2- oksoetvl1-1 - azoniabisvklo[ 2. 2. 2 ] oktan- bromid ;Utbyttet var 47 mg (19 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 8,11 (d, 2 H), 7,30-6,87 (m, 10 H), 5,80-5,50 (m, 2 H), 5,15 (m, 1 H), 4,78 (m, 2 H), 4,53 (m, 1 H), 4,35-3,90 (m, 3 H), 3,82 (s, 3 H), 3,55 (m, 1 H), 2,86 (m, 1 H), 2,45-1,80 (m, 4 H), 1,60 (m, 1 H). ;Eksempel 15 ;( jg>3- r( 4- fluorbenzvlH2- fluorfenv^^ l- azoniabisyklo[ 2. 2. 2"| oktan- bromid ;Utbyttet var 90 mg (55 %) i form av et brunt, fast stoff. ;'H-NMR (CDCI3): 7,35-7,00 (m, 9 H), 6,97 (t, 2 H), 5,30 (m, 2 H), 5,11 (m, 1 H), 4,76 (m, 2 H), 4,43 (m, 1 H), 4,10-3,80 (m, 4 H), 3,49 (m, 1 H), 3,20 (br, 1 H), 2,33 (m, 1 H), 2,10-1,55 (m, 4 H). ;Eksempel 16 ;Ci?V3- r( 4- fluorbenzvn-( 2- fluorfenvnkarbamovloksvl- l- f2- okso- 2- tiofen- 2- vletvn- l-azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 101 mg (60 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 8,39 (d, 2 H), 7,73 (d, 1 H), 7,30-7,18 (m, 3 H), 7,13 (s, 1 H), 7,10-7,05 (m, 3 H), 6,97 (t, 2 H), 5,71 (dd, 2 H), 5,15 (m, 1 H), 4,78 (dd, 2 H), 4,51 (m, 1 H), 4,35-3,90 (m, 4 H), 3,56 (m, 1 H), 2,35 (m, 1 H), 2,45-1,55 (m, 4 H). ;Eksempel 17 ;( i?V3- r( 4- fluorbenzyn-(' 2- fluorfenvnkarbamoyloksv1- l-( 3- metoksvfenoksykarbonvl-metylM- azoniabisyklo[ 2. 2. 21oktan- bromid ;Utbyttet var 43 mg (24 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,35-7,16 (m, 7 H), 7,13-7,00 (m, 3 H), 6,97 (t, 2 H), 5,21-4,90 (m, 3 H), 4,85 (d, 1 H), 4,76 (d, 1 H), 4,41 (m, 1 H), 4,25-3,60 (m, 4 H), 3,76 (s, 3 H), 3,53 (m, 1 H), 2,35 (m, 1 H), 2,20-1,70 (m, 3 H), 1,60 (m, 1 H). ;Eksempel 18 ;figVl- svklopentvlkarbamovlmetvl- 3- r( 4- fluorbenzyn-( 2- fluorfenvnkarbamoyloksyl- l-azoniabisyklo|~ 2. 2. 21oktan- bromid ;Utbyttet var 100 mg (39 %) i form av et brunt, fast stoff. ;'H-NMR (CDCI3): 8,78 (m, 1 H), 7,35-7,00 (m, 6 H), 6,97 (t, 2 H), 5,11 (m, 1 H), 4,78 (s, 2 H), 4,61 (d, 1 H), 4,30-3,85 (m, 4 H), 4,23 (d, 1 H), 3,80-3,60 (m, 3 H), 3,21 (m, 1 H), 2,37 (m, 1 H), 2,10-1,40 (m, 12 H). ;Eksempel 19 ;( ig)- 3-[( 4- fluorbenzvn-( 2- fluorfenvnkarbamoyloksvl- l-[( 2- fluorfenylkarbamovl) metyll-l- azoniabisvklo[ 2. 2. 21oktan- bromid ;Utbyttet var 93 mg (60 %) i form av et brunt, fast stoff. ;'H-NMR (CDCI3): 10,23 (br, 1 H), 7,73 (td, 1 H), 7,40-6,98 (m, 9 H), 6,94 (t, 2 H), 5,15 (m, 1 H), 5,01 (d, 1 H), 4,79 (s, 2 H), 4,72 (d, 1 H), 4,45 (m, 1 H), 4,30-3,70 (m, 4 H), 3,39 (m, 1 H), 2,38 (m, 1 H), 2,10-1,60 (m, 4 H). ;Eksempel 20 ;( 7?Vl-[ 2-( 4- acetylaminofenylsulfanvl') etvl1- 3- r( 4- fluorbenzvn-( 2- fluorfenvnkarbamovl-oksv]- 1 - azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 30 mg (9 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 9,52 (s, 1 H), 7,63 (d, 2 H), 7,40-6,94 (m, 9 H), 5,10 (m, 1 H), 4,73 (s, 2 H), 4,30-4,00 (m, 2 H), 3,95-3,60 (m, 4 H), 3,40-3,20 (m, 3 H), 2,90 (m, 1 H), 2,35 (m, 1 H), 2,19 (s, 3 H), 2,10-1,50 (m, 4 H). ;Eksempel 21 ;( j?)- l-[ 2-( 2, 3- dimetylfenylsulfanyl) etyll- 3- r( 4- fluorbenzvn-( 2- fluorfenvnkarbamoyloksvl- l- azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 94 mg (59 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,35-7,00 (m, 9 H), 6,96 (t, 2 H), 5,11 (m, 1 H), 4,76 (s, 2 H), 4,25-3,90 (m, 3 H), 3,85-3,40 (m, 3 H), 3,40-3,10 (m, 3 H), 2,86 (m, 1 H), 2,35 (s, 3 H), 2,33 (m, 1 H), 2,30 (s, 3 H), 2,20-1,50 (m, 4 H). ;Eksempel 22 ;(^ V3-[( 4- fluorbenzvn-( 2- fluorfenvnkarbamovloksv1- l- r2-(' l- metvl- l//- imidazol- 2-vlsulfanvnetvll- l- azoniabisvklo[ 2. 2. 21oktan- klorid ;Utbyttet var 79 mg (49 %) i form av en brun olje. ;'H-NMR (CDCI3): 7,67 (d, 1 H), 7,32-7,05 (m, 6 H), 6,97 (t, 2 H), 6,73 (d, 1,H), 5,13 (m, 1 H), 4,77 (s, 2 H), 4,65 (m, 2 H), 4,40-4,10 (m, 2 H), 4,10-3,60 (m, 4 H), 3,56 (s, 3 H), 3,12 (m, 1 H), 2,85 (m, 1 H), 2,31 (m, 1 H), 2,20-1,70 (m, 3 H), 1,60 (m, 1 ;H). ;Eksempel 23 ;( 3R . SS )- og ( 3R. SjgV3- r( 4- fluorbenzvn-( 2- fluorfenvnkarbamovloksvl- l-\ 2 -( 2 - metoksvbenzensulfinvl) etvll- 1 - azoniabisvklo[ 2. 2. 2"| oktan- klorid ;Utbyttet var 72 mg (47 %) i fonn av et hvitt, fast stoff. ;'H-NMR (CDC13): 7,62 (d, 1 H), 7,52 (t, 1 H), 7,35-7,00 (m, 8 H), 6,96 (t, 2 H), 5,12 (m, 1 H), 4,76 (s, 2 H), 4,20 (m, 1 H), 4,10-3,80 (m, 2 H), 3,94 (s, 3 H), 3,75-3,50 (m, 4 H), 3,41 (m, 1 H), 3,17 (m, 1 H), 2,85 (m, 1 H), 2,33 (m, 1 H), 2,20-1,80 (m, 3 H), 1,59 (m,lH). ;Eksempel 24 ;(/ gV3- r( 4- fluorbenzvlV( 2- fluorfenvnkarbamoyloksyl- l-( 2- metoksyfenvlsulfanv karbonvlmetvl)- l- azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 66 mg (31 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,35-7,00 (m, 10 H), 6,97 (t, 2 H), 5,25-5,05 (m, 3 H), 4,77 (dd, 2 H), 4,50-3,80 (m, 5 H), 3,76 (s, 3 H), 3,50 (m, 1 H), 2,32 (m, 1 H), 2,10-1,50 (m, 4 H). ;Eksempel 25 ;(/ gVl-^- benzovloksvetvlVS- r^- fluorbenzvn-^- lfuorfenvnkarbamovloksvl- l-azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 52 mg (30 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 8,02 (d, 2 H), 7,62 (t, 1 H), 7,48 (t, 2 H), 7,30-6,85 (m, 8 H), 5,12 (m, 1 H), 4,80-4,65 (m, 4 H), 4,45-3,80 (m, 6 H), 3,59 (m, 1 H), 3,20 (m, 1 H), 2,37 (m, 1 H), 2,10-1,60 (m, 4 H). ;Eksempel 26 ;( R )- 1 -( 2- benzovlaminoetyl)- 3- r( 4- fluorbenzvn- 2- fluorfenvnkarbamovloksyl- 1 - azoniabisyklo[ 2. 2. 2] oktan- klorid ;Utbyttet var 56 mg (39 %) i form av et brunaktig, fast stoff. ;'H-NMR (CDCI3): 9,38 (s, 1 H), 8,06 (d, 2 H), 7,55-7,30 (m, 4 H), 7,30-7,00 (m, 5 H), 6,94 (t, 2 H), 5,09 (m, 1 H), 4,74 (s, 2 H), 4,10 (m, 1 H), 4,05-3,60 (m, 5 H), 3,32 (m, 1 H), 2,95 (m, 1 H), 2,40 (m, 2 H), 2,27 (m, 1 H), 2,10-1,70 (m, 3 H), 1,59 (m, 1 H). ;Eksempel 27 ;ri?Vl- r2-(' 1. 3- diokso- 1. 3- dihvdroisoindol- 2- vnetvl1- 3- r( 4- fluorbenzvl)-( 2- fluorfenvn-karbamoyloksv]- 1 - azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 56 mg (39 %) i form av et brunaktig, fast stoff. ;'H-NMR (CDCI3): 7,82-7,70 (m, 4 H), 7,35-7,00 (m, 6 H), 6,96 (t, 2 H), 5,13 (m, 1 H), 4,77 (s, 2 H), 4,35-3,80 (m, 8 H), 3,40-2,95 (m, 2 H), 2,35 (m, 1 H), 2,10-1,70 (m,3H), 1,59 (m, 1 H). ;Eksempel 28 ;( i?)- l-( 2- benzensulfonvlaminoet^ azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 64 mg (39 %) i form av et brunaktig, fast stoff. ;'H-NMR (CDCI3): 7,90-7,76 (m, 3 H), 7,47 (dd, 2 H), 7,45-7,30 (m, 1 H), 7,35 (dd, 1 H), 7,25-7,00 (m, 4 H), 6,93 (t, 2 H), 5,03 (m, 1 H), 4,75 (dd, 2 H), 4,00 (m, 1 H), 3,80-3,50 (m, 6 H), 3,40-3,00 (m, 3 H), 2,37 (m, 1 H), 2,10-1,60 (m, 4 H). ;Eksempel 29 ;( i?Vl-[ 3-( 2- cvanofenoksv>) propyll- 3-[( 4- fluorbenzvlV( 2- fluorfenvnkarbamovloksvl- l-azoniabisyklof 2. 2. 21 oktan- klorid ;Utbyttet var 92 mg (55 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,54 (m, 2 H), 7,35-6,90 (m, 10 H), 5,17 (m, 1 H), 4,78 (s, 2 H), 4,35-3,80 (m, 8 H), 3,31 (m, 1 H), 3,01 (m, 1 H), 2,45-1,80 (m, 6 H), 1,65 (m, 1 ;H). ;Eksempel 30 ;fig)- 3-[( 4- fluorbenzvl)-( 2- fluorfenvnkarbamoyloksvl- l-[ 3-( 3- nitrofenoksy) propyl]- l-azoniabisyklo[ 2. 2. 21oktan- klorid ;Utbyttet var 250 mg (47 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,83 (ddd, 1 H), 7,67 (t, 1 H), 7,44 (t, 1 H), 7,33-7,00 (m, 7 H), 6,96 (t, 2 H), 5,16 (m, 1 H), 4,78 (s, 2 H), 4,18 (t, 2 H), 4,15-3,60 (m, 6 H), 3,25 (m, 1 H), 2,97 (m, 1 H), 2,35-1,80 (m, 6 H), 1,63 (m, 1 H). ;Eksempel 31 ;( i?)- 3-[( 4- fluorbenzyn-( 2- fluorfenynkarbamovloksyl- l-[ 3-( 4- metylpyrimidin- 2-yloksy) propvll- l- azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 25 mg (11 %) i form av et oransje, fast stoff. ;'H-NMR (CDCI3): 7,50-6,90 (m, 10 H), 5,16 (m, 1 H), 4,78 (s, 2 H), 4,15 (m, 1 H), 4,15-3,40 (m, 7 H), 3,22 (m, 1 H), 2,92 (m, 1 H), 2,40-1,80 (m, 9 H), 1,63 (m, 1 ;H). ;Eksempel 32 ;( iZ)- 3-[( 4- fluorbenzvl)-( 2- fluorfenyl) karbamoyloksyl- l-[ 3-( pyridin- 2- vlsulfanvl') propyll-1 - azoniabisyklo|" 2. 2. 21 oktan- bromid ;Utbyttet var 24 mg (11 %) i fonn av en rød olje. ;'H-NMR (CDC13): 8,41 (ddd, 1 H), 7,51 (td, 1 H), 7,35-6,90 (m, 10 H), 5,13 (m, 1 H), 4,76 (s, 2 H), 4,20-3,55 (m, 6 H), 3,23 (t, 2 H), 3,15 (m, 1 H), 2,85 (m, 1 H), 2,34 (m, 1 H), 2,20-1,60 (m, 6 H). ;Eksempel 33 ;( i?Vl- f3-( benzooksazol- 2- ylsulfanvl') propvn- 3-[(' 4- fluorbenzvn-( 2- fluorfenvl)-karbamoyloksv]- l- azoniabisvklo[ 2. 2. 21oktan- klorid ;Utbyttet var 80 mg (35 %) i form av et oransje, fast stoff. ;'H-NMR (CDCI3): 7,35-7,00 (m, 10 H), 6,96 (t, 2 H), 5,17 (m, 1 H), 4,77 (s, 2 H), 4,20 (m, 1 H), 4,00-3,55 (m, 5 H), 3,69 (t, 2 H), 3,15 (m, 1 H), 2,85 (m, 1 H), 2,57 (m, 2 H), 2,40-1,80 (m, 4 H), 1,57 (m, 1 H). ;Eksempel 34 ;(/ gVl- f3-( 2- fluorbenzensulfonvnpropyll- 3-[( 4- fluorbenzyl)-( 2- lfuorfenvl) karbamoyl-oksy~|- 1 - azoniabisyklo[ 2. 2. 2] oktan- klorid ;Utbyttet var 81 mg (45 %) i form av et brunt, fast stoff. ;'H-NMR (CDCI3): 7,89 (td, 1 H), 7,68 (tdd, 1 H), 7,34 (td, 1 H), 7,30-7,00 (m, 7 H), 6,96 (t, 2 H), 5,12 (m, 1 H), 4,76 (s, 2 H), 4,10 (m, 1 H), 4,00-3,60 (m, 5 H), 3,48 (t, 2 H), 3,21 (m, 1 H), 2,93 (m, 1 H), 2,50-1,70 (m, 6 H), 1,60 (m, 1 H). ;Eksempel 35 ;(/ gVl-( 3- racetvl- r3- klorfenvl) aminolpropvU- 3-[( 4- fluorbenzyl)-( 2- fluorfenvnkarbamovloks v] - 1 - azoniabisyklor2. 2. 21 oktan- klorid ;Utbyttet var 23 mg (9 %) i form av et brunt, fast stoff. ;'H-NMR (CDCI3): 7,30-7,02 (m, 10 H), 6,97 (t, 2 H), 5,14 (m, 1 H), 4,77 (s, 2 II), 4,19 (m, 1 H), 4,09-3,50 (m, 5 H), 3,69 (t, 2 H), 3,20 (m, 1 H), 2,90 (m, 1 H), 2,50-1,80 (m, 6 H), 2,17 (s, 3 H), 1,58 (m, 1 H). ;Eksempel 36 ;( R )- 1 - ( 3- rbenzvloksvkarbonvl-(' 2- fluorfenvl) aminolpropvU- 3 IY4- fluorfenvO-( 2-fluorfenvDkarbamoyloksy]- 1 - azoniabisyklo[ 2. 2. 2] oktan- klorid ;Utbyttet var 410 mg (65 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,38-7,02 (m, 15 H), 6,96 (t, 2 H), 5,09 (s, 2 H), 5,08 (m, 1 H), 4,76 (dd, 2 H), 4,20-3,30 (m, 6 H), 3,72 (t, 2 H), 3,05 (iri, 1 H), 2,77 (m, 1 H), 2,27 (m, 1 H), 2,10-1,80 (m, 5 H), 1,56 (m, 1 H). ;Eksempel 37 ;( i?)- 3- r( 4- fluorbenzyn-( 2- fluorfenvnkarbamoyloksv1- 1 -( 2- fenylkarbamoyletyD- 1 - azoniabisyklor2. 2. 21oktan- klorid ;Utbyttet var 95 mg (66 %) i form av et gult, fast stoff. ;'H-NMR (CDC13): 10,95 (s, 1 H), 7,79 (d, 2 H), 7,31-7,00 (m, 9 H), 6,95 (t, 2 H), 5,11 (m, 1 H), 4,75 (s, 2 H), 4,09 (m, 1 H), 3,95-3,10 (m, 6 H), 2,87 (m, 1 H), 2,29 (m, 1 H), 2,10-1,70 (m, 5 H) 1,58 (m, 1 H). ;Eksempel 38 ;( R )- 1 -( 3 - benzoy loksypropy 0- 3 - f( 4- fluorfeny IV ( 2- fluorfeny Qkarbamoyloksy]- 1 - azoniabisvklor2. 2. 21oktan- bromid ;Utbyttet var 22 mg (13 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 8,02 (m, 2 H), 7,56 (m, 1 H), 7,45 (m, 2 H), 7,30-6,92 (m, 8 H), 5,15 (m, 1 H), 4,75 (s, 2 H), 4,43 (m, 2 H), 4,15 (m, 1 H), 4,05-3,77 (m, 5 H), 3,18 (m, 1 H), 2,87 (m, 1 H), 2,42-1,80 (m, 6 H), 1,56 (m, 1 H). ;Eksempel 39 ;( i?)- l- f2-( 4- acetvlaminofenvlsulfanynetvll- 3- r( 4- fluorbenzvn-( 3- fluorfenynkarbamoyl-oksy)- 1 - azoniabisvklo[ 2. 2. 21oktan- bromid ;Utbyttet var 99 mg (33 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 9,66 (s, 1 H), 7,62 (d, 2 H), 7,26-7,14 (m, 6 H), 7,00-6,90 (m, 6 H), 5,05 (m, 1 H), 4,80 (m, 2 H), 4,10 (m, 1 H), 3,90-3,40 (m, 6 H), 3,10 (m, 3 H), 2,30 (m, 1 H), 2,17 (s, 3 H), 2,10-1,50 (m, 4 H). ;Eksempel 40 ;f3^. 2' j?ty)- 3- r( 3, 4- difluorbenzvnfenvlkarbamovloksy1- l- r3-( 4- fluorfenoksvV2-hydroksypropyl]- 1 - azoniabisyklo[ 2. 2. 21oktan- hydroksid ;Utbyttet var 18 mg (8 %) i form av en gul olje. ;'H-NMR (CDCI3): 7,45-7,80 (m, 12 H), 6,38 (br, 1 H), 5,12 (m, 1 H), 4,90-4,58 (m, 3 H), 4,35-4,15 (m, 1 H), 4,10-3,44 (m, 8 H), 3,10 (br, 1 H), 2,35 (m, 1 H), 2,10-1,60 (m,4H). ;Eksempel 41 ;(/ gVl- r2-( 3- klor- 5- fluorfenvnetvl1- 3- r( 3. 4- difluorbenzylVr2- fluorfenvnkarbamovloksvl-l- azoniabisyklor2. 2. 2] oktan- klorid ;Utbyttet var 101 mg i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,67 (m, 1 H), 7,38-6,85 (m, 9 H), 5,17 (m, 1 H), 4,76 (s, 2 H), 4,33-3,70 (m, 7 H), 3,57 (m, 1 H), 3,33 (m, 1 H), 3,17 (m, 2 H), 2,99 (m, 1 H), 2,35 (m, 1 H), 2,10-1,80 (m, 3 H), 1,60 (m, 1 H). ;Eksempel 42 ;( R )- 1 -( 2- sykloheksvlsulfanyletyl)- 3 [( 3, 4- difluorbenzvD-( 2- fluorfeny Qkarbamoyloksvl- 1 - azoniabisyklo[ 2. 2. 2"| oktan- klorid ;Utbyttet var 58 mg (28 %) i form av en gul olje. ;'H-NMR (CDC13): 7,30 (m, 1 H), 7,20-7,00 (m, 5 H), 6,95 (m, 1 H), 5,13 (m, 1 H), 4,75 (s, 2 H), 4,25-4,00 (m, 2 H), 4,00-3,80 (m, 1 H), 3,73 (m, 2 H), 3,50 (m, 1 H), 3,27 (m, 1 H), 2,88 (m, 4 H), 2,35 (m, 1 H), 2,10-1,80 (m, 4 H), 1,80-1,50 (m, 4 H), 1,45-1,10 (m, 6 H). ;Eksempel 43 ;( R )- 1 -( 2- benzensulfonvletyO- 3- r( 3. 4- difluorbenzvl)-( 2- fluorfenvl) karbamovloksy1- 1 - azoniabisyklo[ 2. 2. 21oktan- klorid ;Utbyttet var 43 mg (20 %) i form av en gul olje. ;'H-NMR (CDCI3): 7,35-6,90 (m, 12 H), 5,08 (m, 1 H), 4,74 (s, 2 H), 4,15-3,85 (m, 3 H), 3,75-3,45 (m, 4 H), 3,20-3,05 (m, 1 H), 2,95-2,80 (m, 1 H), 2,71 (t, 2 H), 2,35 (m, 1 H), 2,10-1,70 (m, 4 H). ;Eksempel 44 ;(■/ ?)- 3-[( 3, 4- difluorbenzvn- m- tolvlkarbamoyloksyl- l-( 2- fenylsulfanvletvlVl-azoniabisyklo[ 2. 2. 21oktan- klorid ;Utbyttet var 170 mg (63 %) i form av et hvitt, fast stoff. 'H-NMR (CDC13): 7,58 (s, 2 H), 7,36-6,94 (m, 10 H), 5,57 (m, 2 H), 5,06 (m, 1 H), 4,74 (s, 2 H), 4,13 (m, 1 H), 4,00-3,40 (m, 6 H), 3,10 (br, 1 H), 2,32 (m, 1 H), 2,32 (s, 3 H), 2,20-1,50 (m, 4 H). ;Eksempel 45 ;( i?)- 3-[( 3, 4- difluorbenzvn- m- tolvlkarbamoyloksy1- l-[ 3-( 4- fluorfenylsulfanvl) propvll- l-azoniabisyklo[ 2. 2. 21 oktan- klorid ;Utbyttet var 96 mg (43 %) i form av et grønt, fast stoff. ;'H-NMR (CDCI3): 7,40 (dd, 2 H), 7,25-6,80 (m, 9 H), 5,09 (m, 1 H), 4,72 (m, 2 H), 4,11 (m, 1 H), 3,90-3,60 (m, 5 H), 3,27 (m, 1 H), 2,96 (t, 2 H), 2,64 (m, 1 H), 2,31 (m, 1 H), 2,31 (s, 3 H), 2,10-1,70 (m, 5 H), 1,55 (m, 1 H). ;Eksempel 46 ;( R )- 3-[( 3, 4- difluorbenzvn-( 3- fluorfenvnkarbamoyloksy- 1 -( 2- fenoksvetvO- 1 - azoniabisyklo[ 2. 2. 21oktan- bromid ;Utbyttet var 145 mg (56 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCb): 7,37-7,16 (m, 3 H), 7,15-6,96 (m, 6 H), 6,94-6,80 (m, 3 H), 5,11 (m, 1 H), 4,81 (m, 2 H), 4,50-4,12 (m, 6 H), 4,10-3,70 (m, 3 H), 3,45 (br, 1 H), 2,32 (m, 1 H), 2,02 (m, 2 H), 1,90-1,60 (m, 2 H). ;Eksempel 47 ;(■ R)- 3-[( 3, 4- difluorbenzvn-( 3- fluorfenyl) karbamovloksvl- 1 -( 3- fenylpropvO- 1 - azoniabis vklo [ 2. 2. 21 oktan- bromi d ;Utbyttet var 151 mg (67 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,37-6,82 (m, 12 H), 5,09 (m, 1 H), 4,78 (m, 2 H), 4,07 (m, 1 H), 3,68 (m, 5 H), 3,25 (br, 1 H), 3,00 (br, 1 H), 2,70 (m, 2 H), 2,32 (m, 1 H), 2,20-1,60 (m, 6 H). ;Eksempel 48 ;( ig)- l- syklopropylmetvl- 3-[( 2- lfuorfenyn-( 3, 4, 5- trifluorbenzvl) karbamovloksvl- l-azoniabisyklo[ 2. 2. 21oktan- bromid ;Utbyttet var 107 mg (54 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,40-7,05 (m, 4 H), 6,90 (m, 1 H), 6,89 (dd, 1 H), 5,13 (m, 1 H), 4,74 (s, 2 H), 4,20-3,90 (m, 3 H), 3,85-3,60 (m, 2 H), 3,55 (m, 2 H), 3,38 (m, 1 H), 3,09 (m, 1 H), 2,35 (m, 1 H), 2,20-1,85 (m, 3 H), 1,54 (m, 1 H), 0,93 (m, 1 H), 0,80 (m, 2 H), 0,57 (m, 2 H). ;Eksempel 49 ;( R )- 1 - benzvl- 3-[( 2- fluorfenyl)-( 3, 4, 5- trifluorbenzynkarbamoyloksyl- 1 - azoniabisvklor2. 2. 21oktan- bromid ;Utbyttet var 119 mg (56 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,55 (m, 2 H), 7,44 (s, 3 H), 7,32-7,05 (m, 4 H), 7,00-6,89 (m, 2 H), 5,08 (m, 2 H), 4,91 (m, 1 H), 4,69 (s, 2 H), 4,07 (m, 4 H), 3,77 (m, 2 H), 3,32 (br, 1 H), 2,95 (br, 1 H), 2,31 (m, 1 H), 2,20-1,45 (m, 4 H). ;Eksempel 50 ;( i?)- 3-[( 2- fluorfenyl)-( 3. 4. 5- trifluorbenzvnkarbamoyloksyl- l-( 2- fenvlsulfanvletvl)- l-azoniabisvklo[ 2. 2. 21oktan- klorid ;Utbyttet var 36 mg (17 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,46-7,22 (m, 6 H), 7,20-7,02 (m, 3 H), 6,96-6,83 (m, 2 H), 5,12 (m, 1 H), 4,73 (s, 2 H), 4,25-3,95 (m, 3 H), 3,80-3,50 (m, 3 H), 3,45-3,20 (m, 3 H), 2,90 (br, 1 H), 2,33 (m, 1 H), 2,10-1,80 (m, 3 H), 1,59 (m, 1 H). ;Eksempel 51 ;(/ g)- 3-[( 3- fluorfenyn-( 3. 4, 5- trifluorbenzyl) karbamoyloksyl- l-( 3- fenoksvpropyl)- l-azoniabisyklo[ 2. 2. 21oktan- bromid ;Utbyttet var 126 mg (55 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,40-7,21 (m, 3 H), 7,10-6,80 (m, 9 H), 5,13 (m, 1 H), 4,82 (m, 2 H), 4,16 (m, 1 H), 4,06 (t, 2 H), 4,00-3,60 (m, 6 H), 3,30 (br, 1 H), 2,38 (m, 1 H), 2,25 (m, 2 H), 2,15-1,60 (m, 4 H). ;Eksempel 52 ;r/ ?Vl- r3- r3. 4- difluorfenoksv) proDvn- 3- r( 3- fluorfenvn- r3. 4. 5-trifluorbenzvnkarbamoyloksvl- l- azoniabisyklo[ 2. 2. 21oktan- klorid ;'H-NMR (CDCI3): 7,33 (m, 1 H), 7,12-6,85 (m, 6 H), 6,69 (ddd, 1 H), 6,57 (m, 1 H), 5,16 (m, 1 H), 4,83 (m, 2 H), 4,18 (m, 1 H), 4,04 (t, 2 H), 4,00-3,60 (m, 6 H), 3,30 (br, 1 H), 2,38 (m, 1 H), 2,34 (m, 2 H), 2,15-1,60 (m, 4 H). ;Eksempel 53 ;( jg)- l-( 2- okso- 2- fenyletyl)- 3-( tiofen- 2- ylmetvl-/ w- tolvlkarbamovloksvVl- azoniabisyklo-[ 2. 2. 2] oktan- bromid ;Utbyttet var 23 mg (15 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 8,09 (d, 2 H), 7,56 (t, 1 H), 7,42 (t, 2 H), 7,23 (dd, 1 H), 7,21 (s, 1 H), 7,13-6,96 (m, 3 H), 6,93-6,83 (m, 2 H), 5,79 (s, 2 H), 5,15 (m, 1 H), 4,95 (m, 2 H), 4,60-3,80 (m, 4 H), 3,61 (m, 1 H), 3,29 (m, 1 H), 2,33 (m, 1 H), 2,32 (s, 3 H), 2,20-1,50 (m, 4 H). ;Eksempel 54 ;(/ g)- l-( 3- fenvlpropvn- 3-( tiofen- 2- vlmetvl- m- tolvlkarbamovloksv)- l- azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 36 mg (23 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,34-7,18 (m, 5 H), 7,08 (d, 1 H), 7,01 (d, 1 H), 6,94-6,82 (m, 5 H), 5,11 (m, 1 H), 4,92 (s, 2 H), 4,45-3,90 (m, 6 H), 3,85-3,60 (m, 2 H), 3,15 (m, 1 H), 3,01 (m, 1 H), 2,41 (m, 1 H), 2,31 (s, 3 H), 2,20-1,61 (m, 4 H). ;Eksempel 55 ;(/ ?)- l- benzvl- 3- f( 2- lfuorfenyl) tiofen- 2- vlmetylkarbamoyloksyl- l- azoniabisyklo[ 2. 2. 21-oktan- bromid ;Utbyttet var 163 mg (75 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,75-7,35 (m, 5 H), 7,25-6,82 (m, 7 H), 5,12 (m, 1 H), 5,20-4,80 (m, 5 H), 4,40-3,40 (m, 4 H), 3,19 (m, 1 H), 3,01 (t, 2 H), 2,79 (m, 1 H), 2,27 (m, 1 H), 2,20-1,50 (m, 4 H). ;Eksempel 56 ;( i?Vl- syklobutvlmetvl- 3- f( 3- fluorfen^ azoniabisyklo[ 2. 2. 21oktan- bromid ;Utbyttet var 153 mg (72 %) i form av en olje. ;'H-NMR(CDC13): 7,33 (td, 1 H), 7,25 (dd, 1 H), 7,05-6,88 (m, 5 H), 5,15 (m, 1 H), 5,00 (m, 2 H), 4,15-4,00 (m, 1 H), 3,80-3,95 (m, 2 H), 3,70-3,50 (m, 1 H), 3,60 (dd, 2 H), 3,30 (m, 1 H), 2,73 (m, 1 H), 2,42 (m, 1 H), 2,20-0,90 (m, 11 H). Eksempel 57 ;(/ ?')- 3- r( 3- metvltiofen- 2- ylmetyl') fenylkarbamoyloksv1- 1 -( 2- fenoksyetvD- 1 - azoniabisyklor2. 2. 21oktan- bromid ;Utbyttet var 170 mg (56 %) i form av en olje. ;'H-NMR (CDC13): 7,35-7,25 (m, 1 H), 7,32 (t, 2 H), 7,10-6,80 (m, 6 H), 6,58 (m, 1 H), 6,51 (m, 1,H), 5,13 (m, 1 H), 4,87 (m, 2 H), 4,55-4,30 (m, 3 H), 4,30-4,00 (m, 4 H), 3,80 (m, 2 H), 3,15 (br, 1 H), 2,42 (m, 1 H), 2,41 (s, 3 H), 2,20-1,50 (m, 4 H). ;Eksempel 58 ;(/ ?V3- r( 4- bromtiofen- 2- ylmetvnfenvlkarbamovloksy]- l- syklopropylmetyl- l-azoniabisyklor2. 2. 2] oktan- bromid ;Utbyttet var 90 mg (60 %) i form av et hvitt, fast stoff. ;'H-NMR(CDC13): 7,43-7,28 (m, 3 H), 7,28-7,10 (m, 2 H), 7,15 (d, 1 H), 6,83 (s, 1 H), 5,12 (m, 1 H), 4,91 (m, 2 H), 4,17 (ddd, 1 H), 4,05-3,30 (m, 4 H), 3,57 (d, 2 H), 2,93 (br, 1 H), 2,35 (m, 1 H), 2,20-1,50 (m, 4 H), 0,97 (br, 1 H), 0,78 (m, 2 H), 0,56 (m, 2 H). ;Eksempel 59 ;(/ ?)- 3- r( 4- bromtifen- 2- ylmetyl) fenvlkarbamovloksyl- 1 - fenylsulfanylmetyl- 1 - azoniabisyklor2. 2. 2ioktan- klorid ;Utbyttet var 89 mg (57 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,68 (m, 1 H), 7,58 (br, 3 H), 7,45-7,30 (m, 6 H), 7,13 (m, 2 H), 6,81 (s, 1 H), 5,54 (m, 2 H), 5,07 (m, 1 H), 4,90 (m, 2 H), 4,12 (m, 1 H), 3,90-3,60 (m, 3 H), 3,45 (m, 1 H), 3,11 (m, 1 H), 2,33,(m, 1 H), 2,20-1,50 (m, 4 H). ;Eksempel 60 ;rigVl- r2-( 2. 3- dihvdrobenzomran- 5- vnetvll- 3- r(' 5- metvltiofen- 2- ylmetynfenvlkarbamoyl-oksv1- l- azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 310 mg (63 %) i form av et hvitt, fast stoff. ;'H-NMR(CDC13): 7,36-7,05 (m, 5 H), 7,29 (d, 1 H), 7,15 (s, 1 H), 6,93 (d, 1 H), 6,61 (d, 1 H), 6,54 (d, 1 H), 5,08 (m, 1 H), 4,83 (m, 2 H), 4,47 (t, 2 H), 4,13 (ddd, 1 H), 4,09-3,80 (m, 2 H), 3,80-3,50 (m, 3 H), 3,20 (br, 1 H), 3,09 (t, 2 H), 2,89 (t, 2 H), 2,85 (br, 1 H), 2,39 (s, 3 H), 2,29 (m, 1 H), 2,21-1,80 (m, 4 H), 1,52 (br, 1 H). ;Eksempel 61 ;( 7?')- 3- r( 5- klortiofen- 2- ylmetvn-( 2- fluorfenvl) karbamoyloksyl- 1 -( 2- fenoksyetyP- 1 - azoniabisy klo [ 2. 2. 2] oktan- bromid ;Utbyttet var 200 mg (98 %) i form av et gult, fast stoff. ;'H-NMR (CDC13): 7,40-7,20 (m, 4 H), 7,15-6,95 (m, 3 H), 6,95-6,80 (m, 2 H), 6,69 (br, 1 H), 6,61 (br, 1 H), 5,13 (m, 1 H), 4,80 (s, 2 H), 4,60-4,00 (m, 8 H), 3,53 (m, 1 H), 3,06 (m, 1 H), 2,40 (m, 1 H), 2,20-1,50 (m, 4 H). ;Eksempel 62 ;C/ gV3-[( 5- bromtiofen- 2- ylmetyl') fenvlkarbamoyloksy]- 1 - syklopropylmetyl- 1 - azoniabisvklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 100 mg (60 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,45-7,25 (m, 3 H), 7,25-7,09 (m, 2 H), 6,87 (d, 1 H), 6,64 (br, 1 H), 5,12 (m, 1 H), 4,89 (m, 2 H), 4,40 (m, 1 H), 4,17 (m, 1 H), 4,05-3,80 (m, 2 H), 3,80-3,05 (m, 6 H), 2,36 (m, 1 H), 2,20-1,50 (m, 4 H), 0,95 (m, 1 H), 0,81 (m, 2 H), 0,58 (m, 2 H). ;Eksempel 63 ;( i?V3-[( 5- bromtiofen- 2- ylmetynfenylkarbamoyloksy1- l-( 2- fenylsulfanyletyn- l-azoniabisyklo[ 2. 2. 2] oktan- klorid ;Utbyttet var 50 mg (28 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,47-7,20 (m, 8 H), 7,13 (br, 2 H), 6,85 (d, 1 H), 6,62 (d, 1 H), 5,11 (m, 1 H), 4,84 (s, 2 H), 4,15 (m, 1 H), 4,00 (m, 2 H), 3,85-3,50 (m, 4 H), 3,45-3,20 (m, 2 H), 2,95 (br, 1 H), 2,33 (m, 1 H), 2,20-1,80 (m, 3 H), 1,62 (m, 1 H). ;Eksempel 64 ;(■/ ?V3- r( 5- bromtiofen- 2- ylmetyn- w- tolylkarbamovloksy]- l- fenvlsulfanylmetyl- l-azoniabisykio[ 2. 2. 21oktan- klorid ;Utbyttet var 83 mg (79 %) i form av et gult, fast stoff. ;'H-NMR(CDC13): 7,58 (m, 2 H), 7,46-7,31 (m, 3 H), 7,21 (d, 1 H), 7,12 (m, 1 H), 7,02-6,86 (m, 2 H), 6,86 (d, 1 H), 6,64 (m, 1 H), 5,55 (m, 2 H), 5,07 (m, 1 H), 4,83 (s, 2 H), 4,15-3,60 (m, 4 H), 3,40 (br, 1 H), 3,05 (br, 1 H), 2,34 (s, 3 H), 2,33 (m, 1 H), 2,20-1,50 (m,4H). ;Eksempel 65 ;(- RV3-[( 5- bromtiofen- 2- ylmetyn-( 4- fluorfenvnkarbamovloksy1- 1 - syklopropylmetyl- 1 - azoniabisvklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 81 mg (62 %) i form av et brunaktig, fast stoff. ;'H-NMR (CDC13): 7,32-7,12 (m, 2 H), 7,04 (t, 2 H), 6,87 (d, 1 H), 6,63 (m, 1 H), 5,11 (m, 1 H), 5,05-4,60 (m, 2 H), 4,15 (m, 1 H), 4,00-3,70 (m, 3 H), 3,65-3,45 (m, 3 H), 3,15 (br, 1 H), 2,37 (m, 1 H), 2,15-1,55 (m, 4 H), 0,98 (m, 1 H), 0,80 (m, 2 H), 0,59 (m, 2 H). ;Eksempel 66 ;( igV3- r( 5- bromtiofen- 2- ylmetyn-( 4- fluorfenvnkarbamovloksvl- l-( 2- okso- 2- fenvletvn- l-azoniabisyklof2. 2. 2] oktan- bromid ;Utbyttet var 110 mg (76 %) i form av et gult, fast stoff. ;'H-NMR (CDC13): 8,12 (d, 2 H), 7,58 (t, 1 H), 7,42 (t, 2 H), 7,36-7,24 (m, 2 H), 7,03 (t, 2 H), 6,86 (d, 1 H), 6,63 (m, 1 H), 5,85 (s, 2 H), 5,18 (m, 1 H), 5,00 (m, 1 H), 4,75-3,90 (m, 6 H), 3,66 (m, 1 H), 2,35 (m, 1 H), 2,15-1,55 (m, 4 H). ;Eksempel 67 ;( 7g)- 3-[( 5- bromtiofen- 2- vlmetvl)( 4- fluorfenyl) karbamoyloksyl- 1 -( 3- fenylpropvD- 1 - azoniabisyklo[ 2. 2. 2 ] oktan- bromid ;Utbyttet var 107 mg (73 %) i form av et gult, fast stoff. ;'H-NMR (CDCI3): 7,33-7,15 (m, 7 H), 7,02 (t, 2 H), 6,84 (d, 1 H), 6,61 (m, 1 H), 5,09 (m, 1 H), 5,02-4,60 (m, 2 H), 4,12 (m, 1 H), 3,80-3,55 (m, 5 H), 3,45 (br, 1 H), 3.10 (br, 1 H), 2,70 (t, 2 H), 2,50-1,75 (m, 7 H), 1,60 (m, 1 H). ;Eksempel 68 ;( R )- 1 - svklobutvlmetyl- 3- r( 3- fluorfenvntiofen- 3- vlmetvlkarbamoyloksyl- 1 - azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 89 mg (42 %) i form av et hvitt, fast stoff. ;'H-NMR (CDCI3): 7,40-7,30 (m, 3 H), 7,16 (s, 1 H), 7,03-6,87 (m, 3 H), 5.11 (m, 1 H), 4,86 (m, 2 H), 4,08 (m, 1 H), 3,90-3,70 (m, 2 H), 3,70-3,50 (m, 1 H), 3,59 (d, 2 H), 3,35 (m, 1 H), 3,02 (m, 1 H), 2,72 (m, 1 H), 2,36 (m, 1 H), 2,20-0,90 (m, 11 H). ;Eksempel 69 ;( R )- 3 - IY3 - fluorfenyl) tiofen- 3 - v lmety lkarbamoyloksv]- 1 -( 2- okso- 2- fenvletvD- 1 - azoniabisyklo[ 2. 2. 2] oktan- bromid ;Utbyttet var 161 mg (68 %) i fonn av et hvitt, fast stoff. ;'H-NMR (CDCI3): 8,10 (d, 2 H), 7,56 (t, 1 H), 7,43 (t, 2 H), 7,32-7,18 (m, 3 H), 7,14 (m, 1 H), 7,05-6,85 (m, 3 H), 5,86 (s, 2 H), 5,16 (m, 1 H), 4,77 (m, 2 H), 4,60-3,90 (m, 5 H), 3,70 (m, 1 H), 2,34 (m, 1 H), 2,20-1,50 (m, 4 H). ;Eksempel 70 ;f/ g>3- sykloheksylmetylfenylkart [ 2. 2. 21oktan- bromid ;Utbyttet var 120 mg (75 %) i form av en olje. ;'H-NMR (CDC13): 8,10 (d, 2 H), 7,58 (t, 1 H), 7,43 (t, 2 H), 7,40-7,20 (m, 5 H), 5,75 (s, 2 H), 5,09 (m, 1 H), 4,51-3,90 (m, 5 H), 3,55 (d, 2 H), 2,95 (br, 1 H), 2,35 (m, 1 H), 2,15-0,90 (m, 15H). ;Eksempel 71 ;( i?)- 3- sykloheksylmetylfenylkarbamoyloksy)- 1 -( 3- fenoksypropyl)- 1 - azoniabisyklo-[ 2. 2. 21oktan- bromid ;Utbyttet var 40 mg (35 %) i form av en olje. ;'H-NMR (CDCI3): 7,34 (t, 2 H), 7,30-7,15 (m, 4 H), 7,05 (t, 2 H), 6,88 (d, 2 H), 5,07 (m, 1 H), 4,55-3,90 (m, 6 H), 3,87-3,60 (m, 3 H), 3,48 (d, 2 H), 2,95 (br, 1 H), 2,35 (m, 1 H), 2,15-0,90 (m, 15 H). ;De følgende forbindelser ble også fremstilt, og de ble identifisert med <*>H-NMR: (Æ)-3-(benzylfeny lkarbamoy loksy)-1 -syklopropylmetyl-1 -azoniabisyklo-[2.2.2]oktan-bromid,
(Æ)-3-(benzylfenylkarbamoyloksy)-1 -cyanometyl-1 -azoniabisyklo[2.2.2]-oktan-bromid,
( R)- 1 -benzy 1-3 -(benzyl fenylkarbamoy loksy)-1 -azoniabisyklo [2.2.2] oktan-bromid,
(i?)-3-(benzylfenylkarbamoyloksy)-l-[2-(2,3-dihydrobenzofuran-5-yl)etyl]-1 -azoniabisyklo[2.2.2] oktan-bromid,
(Z?)-3-(benzylfenylkarbamoyloksy)-1 -(4-metoksybenzyl)-1 -azoniabisyklo-[2.2.2]oktan-klorid,
( R)- 3 -(benzylfeny lkarbamoy loksy)-1 -(2-okso-2-feny lety 1) 1 -azoniabisyklo-[2.2.2]oktan-bromid,
(i?)-3-(benzylfeny lkarbamoy loksy)-l-(2-fenoksy etyl)-1-azoniabisyklo-[2.2.2] oktan-bromid,
( R)- 3 -(benzylfeny lkarbamoy loksy)-1 - [2-(4-fluorfenoksy)ety 1]-1 - azoniabisyklo[2.2.2]oktan-klorid,
(Æ)-3-(benzylfenylkarbamoyloksy)-1 -(3-fenylpropyl)-1 -azoniabisyklo-[2.2.2] oktan-bromid,
( R)- 3-(benzylfeny lkarbamoy loksy)-1 -(3-fenoksypropyl)-1 -azoniabisyklo-[2.2.2]oktan-klorid,
(Æ)-3-(benzylfenylkarbamo propyl]-l-azoniabisyklo[2.2.2]oktan-hydroksid,
( R)-1 -syklobutylmetyl-3 -[(4-fluorbenzyl)fenylkarbamoyloksy] -1 - azoniabisyklo[2.2.2]oktan-bromid,
( R)- l-benzyl-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-1 -azoniabisyklo-[2.2.2]oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-1 -fenylsulfanylmetyl-1 - azoniabisyklo[2.2.2] oktan-klorid,
(Æ)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-1 -fenetyl-1 -azoniabisyklo-[2.2.2]oktan-bromid,
(/?)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-l-(2-o-tolyletyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-l-[2-(2-metoksyfenyl)etyl]-l-azoniabisyklo[2.2.2] oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-1 -[2-(3-metoksyfenyl)etyl]-1 - azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)feny lkarbamoy loksy]-1 -[2-(3-fluorfenyl)etyl]-1 - azoniabisyklo[2.2.2] oktan-bromid,
(Æ)-3-[(4-lfuorbenzyl)feny lkarbamoy loksy] -1 - (2-p-tolyletyl)-1 - azoniabisyklo[2.2.2] oktan-bromid,
(/?)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-l-[2-(4-fluorfenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-l-[2-(2,5-dimetoksyfenyl)etyl]-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid, ( R)-1 -[2-(3,4-dimetoksyfenyl)etyl]-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(/2)-3-[(4-fluorbenzyl)fenylkarbamoyloksy]-1 -(2-okso-2-fenyletyl)-1 - azoniabisyklo[2.2.2] oktan-bromid,
( R)- 3 -[(4-fluorbenzyl)fenylkarbamoyloksy] -1 -[2-(4-fluorfenoksy)etyl]-1 - azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)feny lkarbamoy loksy] -1 - [2-(2-fluorfenylsulfany l)ety 1] - l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-m-tolylkarbamoyloksy]-1 -fenetyl-1 -azoniabisyklo-[2.2.2]oktan-bromid,
( R)-1 -[2-(2,3 -dihy drobenzofuran-5 -y l)etyl] -3 - [(4-fluorbenzy l)-/«-tolylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3- [(4-fluorbenzy l)-m-toly lkarbamoy loksy] -1 -(2-okso-2-fenyletyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-m-toly lkarbamoy loksy] -1 -(2-fenoksyetyl)-1 - azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-w-toly lkarbamoy loksy] -1 -(3-fenylpropyl)-1 - azoniabisyklo [2.2.2] oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-/w-tolylkarbamoy loksy] -1 -(3-fenoksypropyl)-1 - azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-fenylsulfanylmetyl-1 -azoniabisyklo[2.2.2] oktan-klorid,
(/?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-1 -(2-ø-tolylety 1)-1 - azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-(2-fluorfeny l)karbamoy loksy] -1 - [2-(2-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(^)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-1 -(2-w-tolyletyl)-1 - azoniabisyklo[2.2.2] oktan-bromid,
(/?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(3-metoksy-fenyl)etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(^)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(3-fluorfenyl)-etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-1 -(2-/?-tolyletyl)-1 - azoniabi sy klo [2.2.2] oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(4-etoksyfenyl)etyl]-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyl-oksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(4-fluorfenyl)-ety 1] -1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(2,5-dimetoksyfenyl)etyl]-3-[(4-lfuorbenzyl)-(2-fluorfenyl)-karbamoy loksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3- [(4-fluorbenzy l)-(2-fluorfenyl)karbamoy loksy] -1-feny lkarbamoy 1-metyl-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-(2-fluorfenyl)karbamoy loksy] -l-(o-toly lkarbamoy 1-metyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(7?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(2-fluorfenoksy)-etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(3-metoksy-fenoksy)etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(4-fluorfenoksy)-ety 1] -1 -azoniabisyklo[2.2.2] oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-(2-fenylsulfan etyl)-1 -azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(2-metoksy-fenylsulfanyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-fluorbenzyl)-(2-lfuorfenyl)karbamoyloksy]-l-[2-(2-fluorfenyl^ sulfanyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[2-(2-klorfenylsulfanyl)etyl]-3-[(4-fluorbenzyl)-(2-lfuorfeny0 karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
(^)-l-[2-(3-klorfenylsulfanyl)etyl]-3-[(4-lfuorbenzyl)-(2-fluorfenyl)-karbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-fluorbenzyl)-(2-lfuorfenyl)karbamoyloksy]-l-[2-(4-fluorfenyl-sulfanyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[2-(4-bromfenylsulfanyl)etyl]-3-[(4-fluorbenzyl)-(2-fluorfenyl^ karbamoy loksy]-1 -azoniabisyklo[2.2.2] oktan-klorid,
(Æ)-l-[2-(2,4-difluorfenylsul^ karbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(2,5-diklorfenylsulfanyl)etyl]-3-[(4-fluorbenzyl)-(2-lfuorfenyl^ karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
( 3R, SS)- og (3R,S^)-l-(2-benzensulfinyletyl)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-klorid,
(/?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-(3-fenoksypropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3-[(4-fluorbenzyl)-(2-lfuorfenyl)karbamoyloksy]-^^ propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
( R)- 3 - [(4-fluorbenzy l)-(2-fluorfenyl)karbamoy loksy] -1 -(3 -/w-tolyloksy-propyl)-l-azoniabisyklo[2.2.2]oktan-klorid,
(7?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[3-(3-metoksy-fenoksy)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[3-(2,4-dilfuorfenoksy)propyl]-3-[(4-lfuorbenzyl)-(2-fluorfenyl)-karbamoy loksy] -1 -azoniabisyklo[2.2.2] oktan-klorid,
( R)- 3 - [(4-fluorbenzy l)-(2-fluorfenyl)karbamoy loksy]-1 - [3 -(py ridin-3 - yloksy)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(/?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[3-(pyrimidin-2-yloksy)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-fluorbenzyl)-(2-lfuorfenyl)karbamoyloksy]-l-(3-fenylsulfanyl-propyl)-l-azoniabisyklo[2.2.2]oktan,
(^)-3-[(4-fluorbenzyl)-(2-lfuorfenyl)karbamoyloksy]-l-[3-(2-fluorfenyl-sulfanyl)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[3-(2-klorfenylsulfanyl)propyl]-34(4-fluorbenzyl)-(2-lfuorfeny0 karbamoy loksy]-1 -azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[3-(3-klorfenylsulfanyl)propyl]-3-[(4-fluorbenzyl)-(2-fluorfenyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
( R)- 3-[(4-fluorbenzy l)-(2-fluorfenyl)karbamoy loksy] -1 - [3-(pyridin-4-y lsulfany l)propyl] -1 -azoniabisyklo[2.2.2] oktan,
(i?)-3-[(4-fluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[3-(pyrimidin-2-ylsulfanyl)propyl]-1 -azoniabisyklo[2.2.2]oktan,
(i?)-l-(3-benzensulfonylpropyl)-3-[(4-fluorbenzyl)-(2-fluorfenyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[3-(3-klorbenzensulfonyl)propyl]-3-[(4-fluorbenzyl)-(2-fluorfenyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
( R)-1 - { 3- [acety l-(2-fluorfeny l)amino]propy 1} -3 - [(4-fluorbenzy l)-(2-fluorfenyl)karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
(Æ)-1 - { 3 - [acety l-(3 -metoksy feny l)amino]propy 1} -3 - [(4-fluorbenzy l)-(2-fluorfenyl)karbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-klorid,
( R)- l -benzy 1-3- [(4-fluorbenzyl)-(3-fluorfenyl)karbamoy loksy]-1 -azoniabisyklo[2.2.2] oktan-bromid,
( R)- 3 - [(4-fluorbenzy l)-(3-fluorfenyl)karbamoy loksy] -1 -feny lsulfany lmetyl-l-azoniabisyklo[2.2.2]oktan-klorid,
(^)-l-[2-(2-klorfenyl)etyl]-3-[(4-lfuorbenzyl)-(3-fluorfenyl)karbamoyl-oksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(3-fluorfenyl)-etyl]-1-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(^)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-fluorfenyl)-etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(2-klor-6-fluorfenyl)etyl]-3-[(4-fluorbenzyl)-(3-fluorfenyl)-karbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-1 -(2-fenoksyetyl)-1 - azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(4-fluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-l-[3-(3,4-difluorfenoksy)propyl]-3-[(4-fluorbenzyl)-(3-fluorfenyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
( R)-1- [3-(3 -klorfeny lsulfany l)propyl]-3 -[(4-fluorbenzy l)-(3-fluorfeny 1)-karbamoy loksy]-1 -azoniabisyklo[2.2.2] oktan-klorid,
( R)- 3 - [(4-fluorbenzy l)-(3 -fluorfenyl)karbamoy loksy ]-1 - [3 -(4-fluorfeny 1-sulfanyl)propyl]-l-zoniabisyklo[2.2.2]oktan-klorid,
(/?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-fenetyl-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoy loksy]- l-[2-(4-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-(2-okso-2-fenyletyl)-1 -azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbainoyloksy]-l-(2-fenoksyetyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(^)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[2-(4-fluor-fenoksy)etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(JR)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-(2-fenylsulfanyl-etyl)-1-azoniabisyklo[2.2.2]oktan-klorid,
(37?,2'/?5)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[3-(4-fluorfenoksy)-2-hydroksypropyl]-l-azoniabisyklo[2.2.2]oktan-hydroksid,
(i?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-(2-fluorfenyl)karbamoyloksy]-l-[3-(2,4-difluor-fenoksy )propy 1] -1 -azoniabisyklo [2.2.2]oktan-klorid,
(Æ)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-1 -fenetyl-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-l-[2-(2-fluorfenyl)etyl]-1 -azoniabisyklo[2.2.2] oktan-bromid,
( R)- 3 - [(3,4-difluorbenzy l)-/n-toly lkarbamoy loksy] -1 - [2-(4-metoksyfeny 1)-etyl]-1-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-l-(2-okso-2-fenyletyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-l-(2-fenoksyetyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(7?)-3-[(3,4-difluorbenzyl)-/w-tolylkarbamoyloksy]-l-[2-(4-fluorfenoksy)-ety 1]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-1 -(2-fenylsulfanyletyl)-1 - azoniabisyklo[2.2.2]oktan-klorid,
(/f)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-1 -(3-fenoksypropyl)-1 - azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(3,4-difluorbenzyl)-w-tolylkarbamoyloksy]-l-(3-fenylsulfanyl-propyl)-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(3,4-difluorbenzyl)-m-tolylkarbamoyloksy]-l-[3-(2-fluorfenyl-sulfanyl)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-l-[3-(3-klorfenylsulfanyl)propyl]-3-[(3,4-difluorbenzyl)-m-tolyl-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-klorid,
( R)-1 -syklopropyl metyl-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyl-oksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-1 -fenetyl-1 - azoniabi sy klo [2.2.2] oktan-bromid,
(i?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(/?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[2-(4-fluor-fenoksy)etyl]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-(2-fenylsulfanyl-etyl)-1 -azoniabisyklo[2.2.2]oktan-klorid,
( R)- 3 - [(3,4-difluorbenzy l)-(3 -fluorfeny l)karbamoy loksy] -1 -(3 -fenoksy-propyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3,4-difluorbenzyl)-(3-fluorfenyl)karbamoyloksy]-l-[3-(4-fluor-fenoksy)propyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(2-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-fenetyl-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-[2-(4-metoksyfenyl)etyl]-1 -azoniabisyklo[2.2.2]oktan-klorid,
( R)- 3 - [(2-fluorfeny l)-(3,4,5 -trifluorbenzy l)karbamoy loksy] -1 -(2-fenoksy-etyl)-1-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(4-fluorfenoksy)etyl]-3-[(2-fluorfenyl)-(3,4,5-trifluorbenzyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-(3-fenyl-propyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-1 -fenetyl-1 - azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(2-fluorfenyl)etyl]-3-[(3-fluorfenyl)-(3,4,5-trifluorbenzyl)-karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3-[(3-fluorfenyl)-(3,4,5-trilfuorbenzyl)karbamoyloksy]-1 -[2-(4-metoksyfenyl)etyl]-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-142-(2,3-dihydrobenzomran-5-yl)etyl]-3-[(3-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-(2-fenoksy-etyl)-1-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-[2-(4-fluorfenoksy)etyl]-3-[(3-fluorfenylH3,4,5-trifluo karbamoy loksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 -[(3 -fluorfenyl)-(3,4,5 -trifluorbenzy l)karbamoy loksy] -1 -(2-feny 1-sulfanyletyl)-l-azoniabisyklo[2.2.2]oktan-klorid,
(7?)-3-[(3-fluorfenyl)-(3,4,5-trifluorbenzyl)karbamoyloksy]-l-(3-fenyl-propy 1)-1 -azoniabisyklo[2.2.2] oktan-bromid,
(i?)-l-s<y>klobut<y>lmet<y>l-3-(tiofen-2-<y>lmet<y>l-w-tol<y>lkarbamoyloksy)-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)-1 -fenety 1-3 -(tiofen-2-y lmety 1-m-toly lkarbamoy loksy)-1 -azoniabisyklo[2.2.2]oktan-bromid,
(7?)-l-[2-(2,3-dihydrobenzofuran-5-yl)etyl]-3-(tiofen-2-ylmetyl-/M-tolylkarbamoyloksy)-1 -azoniabisyklo[2.2.2] oktan-bromid,
(i?)-l-(2-tiofen-2-yletyl)-3-(tiofen-2-ylmetyl-m-tolylkarbamoyloksy)-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)-1 -(3-fenoksypropyl)-3-(tiofen-2-y lmety 1-m-toly lkarbamoy loksy)-1-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-l-syklopropylmetyl-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-fenetyl-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-[2-(4-metoksy-fenyl)etyl]-1-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-(2-fenoksyetyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-(2-fenylsulfanyl-etyl)-l-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(2-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-(3-fenoksypropyl)-1 -azoniabisyklo[2.2.2] oktan-bromid,
(i?)-1 -benzyl-3-[(3-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-1 -azoniabisyklo[2.2.2]oktan-bromid,
(Æ)-3 - [(3-fluorfeny l)tiofe^ l-azoniabisyklo[2.2.2]oktan-klorid,
( R)- 3 -[(3 -fluorfenyl)tiofen-2-y lmety lkarbamoyloksy ] -1 - [2-(4-metoksy-fenyl)etyl]-1-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-[l-[2-(2,3-dihydrobenzomran-5-yl)etyl]-3-[(3-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(3-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-1 -(3-fenylpropyl)-1 - azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3-fluorfenyl)tiofen-2-ylmetylkarbamoyloksy]-l-(3-fenoksypropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-bromtiofen-2-ylmetyl)feny lkarbamoy loksy]-1-fenetyl-1-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(2-okso-2-fenyl-etyl)-1-azoniabisyklo[2.2.2]oktan-bromid,
(/?)-3-[(4-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(2-fenoksyetyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(/2)-3-[(4-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(2-fenylsulfanyl-etyl)-1-azoniabisyklo[2.2.2]oktan-klorid,
(i?)-3-[(4-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(4-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(3-fenoksypropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(7?)-3-[(5-metyltiofen-2-ylmetyl)fenylkarbamoyloksy]-1 -(2-fenoksyetyl)-1 - azoniabisyklo[2.2.2]oktan-bromid,
(7?)-3-[(5-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-fenylsulfanylmetyl-1 -azoniabisyklo[2.2.2] oktan-klorid,
(i?)-3-[(5-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-fenetyl-l-azoniabisyklo[2.2.2]oktan-bromid,
(7?)-3-[(5-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(2-okso-2-feny-lety 1)-1 -azoniabisyklo[2.2.2] oktan-bromid,
(/?)-3-[(5-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(2-fenoksyetyl)-l-azoniabi syklo [2.2.2] oktan-bromid,
(i?)-3-[(5-bromtiofen-2-ylmetyl)fenylkarbamoyloksy]-l-(3-fenylpropyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
( R)- 3 - [(5 -bromtiofen-2-y lmety l)feny lkarbamoy loksy]-1 -(3 -fenoksypropy 1)-1 -azoniabisyklo[2.2.2] oktan-bromid, ( R)- 3- [(5-bromtiofen-2-y lmety l)-m-toly lkarbamoy loksy]-1-(2-fenoksyety 1)-1 -azoniabisyklo[2.2.2] oktan-bromid,
(Æ)-3-[(5-bromtiofen-2-ylme^ etyl)-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(5-bromtiofen-2-ylmetyl)-m-tolylkarbamoyloksy]-l -(3-fenoksy-propyl)- 1 -azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3-fluorfenyl)tiofen-3-ylmetylkarbamoyloksy]-1 -fenetyl-1 -azoniabisyklo[2.2.2] oktan-bromid,
(^)-l-[2-(2,3-dihydrobenzofuran-5-yl)etyl]-3-[(3-fluorfenyl)tiofen-3-ylmetylkarbamoyloksy]-l-azoniabisyklo[2.2.2]oktan-bromid,
(i?)-3-[(3-fluorfenyl)tiofen-3 -ylmety lkarbamoyloksy] -1 -(2-fenoksy etyl)-1 - azoniabisyklo[2.2.2]oktan,
(i?)-3-[(3-fluorfenyl)tiofen-3-ylmetylkarbamoyloksy]-l-(3-fenoksypropyl)-1 -azoniabisyklo[2.2.2] oktan-bromid.
Claims (11)
1. Forbindelse,
karakterisert ved at den har generell formel (I)
og farmasøytisk akseptable salter av forbindelsen, hvor
RI, R2 og R3 er radikaler som uavhengig av hverandre er valgt blant H, F, Cl, Br, I, og (CrC4)alkyl;
R4 er et radikal valgt blant: sykloheksyl, tienyl substituert med (C|-C6)alkyl eller halogen, og fenyl substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant F, Cl, Br og I,
R5 er et radikal valgt blant: syklopropyl, syklobutyl, syklopentyl, sykloheksyl og (Ci-Cio)alkyl som er substituert med ett eller flere radikaler som uavhengig av hverandre er valgt blant R6, COR6, NR6R7, CONR6R7, NR7COR6, OH, OR6, COOR6, OCOR6, S02R6, SH, SR6, SOR6, COSR6 og SCOR6;
R6 er et radikal valgt blant: (Ci-C5)alkyl, syklopropyl, syklobutyl, syklopentyl, sykloheksyl, (Cr C4)alkoksykarbonyl, fenyl som eventuelt er substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant N02, CN, F, Cl, Br, I, NR7CO-(C,-C4)alkyl, (C,-C4)alkyl og (C,-C4)-alkoksyl, en heterosyklisk ring valgt blant tiazolyl, pyrrolyl, tienyl, imidazolyl, dihydroisoindolyl, pyrimidinyl og pyridyl, og denne heterosykliske ring er eventuelt substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant (=0), (Cr C4)alkylsulfanyl, (C,-C4)alkylsulfinyl, (C,-C4)alkylsulfonyl og (C,-C4)alkyl, et bisyklisk ringsystem valgt blant dihydro-benzofuranyl og benzoksazolyl;
R7 er et radikal valgt blant H, benzyloksykarbonyl, (CrC4)alkylkarbonyl,
og
X- er et fysiologisk akseptabelt anion.
2. Forbindelse ifølge krav 1, hvor R4 er et fenyl som er substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant F, Cl, Br og I.
3. Forbindelse ifølge kravene 1 eller 2, hvor
R5 er et (Ci-C5)alkyl som er substituert med ett radikal valgt blant R6, COR6, NR6R7, CONR6R7, NR7COR6, OR6, COOR6, OCOR6, SR6, SOR6, S02R6; og
R6 er et radikal valgt blant: a) fenyl som eventuelt er substituert med én eller flere substituenter valgt blant CN, F, Cl, Br, I, (CrC4)alkyl, og (C,-C4)alkoksyl, b) en heterosyklisk ring valgt blant tiazolyl, pyrrolyl, tienyl, imidazolyl, dihydroisoindolyl, pyrimidinyl og pyridyl, og denne heterosykliske ring er eventuelt substituert med én eller flere substituenter som uavhengig av hverandre er valgt blant (CrC4)alkylsulfanyl, (Ci-C4)-alkylsulfinyl, (C,-C4)alkylsulfonyl og (C,-C4)alkyl.
4. Mellomforbindelse,
karakterisert ved at den har formel (X)
og farmasøytisk akseptable salter av forbindelsen, for fremstilling av en forbindelse med formel (I), som definert i krav 1,
hvor RI, R2, R3, R8 og R9 er radikaler som uavhengig av hverandre er valgt blant H, F, Cl, Br, I og (C,-C4).
5. Forbindelse ifølge kravene 1-4, hvor konfigurasjonen i posisjon 3 i kinuklidinringen er ( R).
6. Anvendelse av en forbindelse som definert i hvilket som helst av kravene 1-5, ved tilvirkning av et medikament for behandling av urininkontinens.
7. Anvendelse ifølge krav 6, hvor urininkontinensen er forårsaket av overaktiv blære.
8. Anvendelse av en forbindelse som definert i hvilket som helst av kravene 1-5, ved tilvirkning av et medikament for behandling av irritabel tarm-syndrom.
9. Anvendelse av en forbindelse som definert i hvilket som helst av kravene 1-5, ved tilvirkning av et medikament for behandling av respirasjonssykdommer.
10. Anvendelse ifølge krav 9, hvor sykdommen er valgt blant kronisk obstruktiv pulmonal sykdom, kronisk bronkitt, astma, emfysem og rhinitt.
11. Anvendelse av en forbindelse som definert i hvilket som helst av kravene 1-5, ved fremstilling av et medikament for oftalmiske intervensjoner.
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| PL362989A1 (en) * | 2000-12-22 | 2004-11-15 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as m3 antagonists |
| ES2203327B1 (es) * | 2002-06-21 | 2005-06-16 | Almirall Prodesfarma, S.A. | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
| ES2204295B1 (es) * | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de quinuclidina-amida. |
| TW200519106A (en) | 2003-05-02 | 2005-06-16 | Novartis Ag | Organic compounds |
| AR044134A1 (es) * | 2003-05-02 | 2005-08-24 | Novartis Ag | Derivados de quinuclidina, metodo de preparacion y composiciones farmaceuticas. |
| JP4616264B2 (ja) | 2003-05-28 | 2011-01-19 | セラヴァンス， インコーポレーテッド | ムスカリン性レセプターアンタゴニストとしてのアザビシクロアルカン化合物 |
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| AR050902A1 (es) * | 2004-04-27 | 2006-12-06 | Glaxo Group Ltd | Compuesto de quinuclidina, composicion farmaceutica que lo comprende y su usopara preparar dicha composicion |
| US7598267B2 (en) * | 2004-05-13 | 2009-10-06 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
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| ES2246170B1 (es) * | 2004-07-29 | 2007-04-01 | Almirall Prodesfarma, S.A. | Nuevo procedimiento para preparar derivados de carbamato de quinuclidinio. |
| EA013227B1 (ru) | 2004-07-30 | 2010-04-30 | Лабораториос Салват, С.А. | ТИРОЗИНОВЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ МОДУЛЯТОРОВ PPARγ |
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| GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
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| WO2016176400A2 (en) * | 2015-04-29 | 2016-11-03 | 7 Hills Interests Llc | Novel compositions and methods for immunotherapies comprising small molecule integrin receptor-ligand agonist adjuvants |
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| JP2022547427A (ja) | 2019-08-28 | 2022-11-14 | ノバルティス アーゲー | 置換１，３－フェニルヘテロアリール誘導体及び疾患の治療におけるその使用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0495071A (ja) * | 1990-08-10 | 1992-03-27 | Kyorin Pharmaceut Co Ltd | カルバミン酸誘導体 |
| WO1995006635A1 (en) * | 1993-09-02 | 1995-03-09 | Yamanouchi Pharmaceutical Co., Ltd. | Carbamate derivative and medicine containing the same |
| HUT76289A (en) * | 1994-02-10 | 1997-07-28 | Yamanouchi Pharma Co Ltd | Carbamate derivative and medicinal composition containing the same |
| NO2005012I1 (no) * | 1994-12-28 | 2005-06-06 | Debio Rech Pharma Sa | Triptorelin og farmasoytisk akseptable salter derav |
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| JP2003516390A (ja) * | 1999-12-07 | 2003-05-13 | セラヴァンス インコーポレーテッド | ムスカリンレセプターアンタゴニスト活性を有するカルバメート誘導体 |
| AU2001266100B9 (en) * | 2000-06-27 | 2005-10-06 | Laboratorios S.A.L.V.A.T., S.A. | Carbamates derived from arylalkylamines |
| PL362989A1 (en) * | 2000-12-22 | 2004-11-15 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as m3 antagonists |
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2002
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