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
Links
- 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
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 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
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 3
- 208000020629 overactive bladder Diseases 0.000 claims description 3
- 208000023504 respiratory system disease Diseases 0.000 claims description 3
- 206010039083 rhinitis Diseases 0.000 claims description 3
- 101100134925 Gallus gallus COR6 gene Proteins 0.000 claims description 2
- 101100477978 Hypocrea jecorina (strain QM6a) sor6 gene Proteins 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- -1 β2 agonists Substances 0.000 description 28
- DXNQLZJOTVNBOZ-UHFFFAOYSA-N [O]C(=O)Nc1ccccc1 Chemical group [O]C(=O)Nc1ccccc1 DXNQLZJOTVNBOZ-UHFFFAOYSA-N 0.000 description 27
- BDDIUTHMWNWMRJ-UHFFFAOYSA-N octane;hydrobromide Chemical compound Br.CCCCCCCC BDDIUTHMWNWMRJ-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 18
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 102000017925 CHRM3 Human genes 0.000 description 12
- 101150060249 CHRM3 gene Proteins 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 11
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 11
- 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 description 10
- 102000017926 CHRM2 Human genes 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 101150012960 Chrm2 gene Proteins 0.000 description 9
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 8
- 150000003975 aryl alkyl amines Chemical class 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IVLICPVPXWEGCA-UHFFFAOYSA-N 3-quinuclidinol Chemical compound C1C[C@@H]2C(O)C[N@]1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 4
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 4
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229940126083 M3 antagonist Drugs 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DYEHDACATJUKSZ-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octane;bromide Chemical compound [Br-].C1CC2CC[NH+]1CC2 DYEHDACATJUKSZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- DOAKXPDAEYUFEQ-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-yl carbonochloridate;hydrochloride Chemical compound Cl.C1CC2C(OC(=O)Cl)CN1CC2 DOAKXPDAEYUFEQ-UHFFFAOYSA-N 0.000 description 1
- GEGPDQLJCXSAIK-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-yl imidazole-1-carboxylate Chemical compound C1N(CC2)CCC2C1OC(=O)N1C=CN=C1 GEGPDQLJCXSAIK-UHFFFAOYSA-N 0.000 description 1
- JEPJAGMRBZWMCT-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-yl n-phenylcarbamate Chemical compound C1N(CC2)CCC2C1OC(=O)NC1=CC=CC=C1 JEPJAGMRBZWMCT-UHFFFAOYSA-N 0.000 description 1
- JIGPZKKJKCYLKD-UHFFFAOYSA-M 1-methyl-1-azoniabicyclo[2.2.2]octane;bromide Chemical compound [Br-].C1CC2CC[N+]1(C)CC2 JIGPZKKJKCYLKD-UHFFFAOYSA-M 0.000 description 1
- 125000003070 2-(2-chlorophenyl)ethyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000017924 CHRM4 Human genes 0.000 description 1
- 102000017923 CHRM5 Human genes 0.000 description 1
- 101150064612 CHRM5 gene Proteins 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 102000007205 Muscarinic M2 Receptor Human genes 0.000 description 1
- 108010008407 Muscarinic M2 Receptor Proteins 0.000 description 1
- 102000007202 Muscarinic M3 Receptor Human genes 0.000 description 1
- 108010008405 Muscarinic M3 Receptor Proteins 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 101100107916 Xenopus laevis chrm4 gene Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 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
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229940124748 beta 2 agonist Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 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
- 238000012417 linear regression Methods 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- ZXVJACKMMUOZDX-UHFFFAOYSA-N octane;hydrate Chemical compound O.CCCCCCCC ZXVJACKMMUOZDX-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 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
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 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
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 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
- 229960003855 solifenacin Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000003890 substance P antagonist Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200200043 | 2001-12-20 | ||
| PCT/EP2002/014470 WO2003053966A2 (en) | 2001-12-20 | 2002-12-18 | 1-alkyl-1-azoniabicyclo [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20043064L NO20043064L (no) | 2004-09-17 |
| NO329664B1 true NO329664B1 (no) | 2010-11-29 |
Family
ID=32480019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20043064A NO329664B1 (no) | 2001-12-20 | 2004-07-19 | Forbindelse av typen 1-alkyl-1-azoniabisyklo [2.2.2] oktankarbamatderivater, mellomforbindelser; og anvendelse derav ved tivirkning av medikament |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US7452904B2 (no) |
| EP (1) | EP1461336B1 (no) |
| JP (1) | JP4505227B2 (no) |
| KR (1) | KR100944580B1 (no) |
| CN (1) | CN1832948B (no) |
| BR (1) | BR0215348A (no) |
| CA (1) | CA2470956C (no) |
| EA (1) | EA006505B1 (no) |
| ES (1) | ES2425347T3 (no) |
| GE (1) | GEP20063958B (no) |
| HK (1) | HK1070057A1 (no) |
| HR (1) | HRP20040661A2 (no) |
| HU (1) | HUP0500107A3 (no) |
| IL (1) | IL162596A0 (no) |
| MA (1) | MA26385A1 (no) |
| MX (1) | MXPA04006206A (no) |
| NO (1) | NO329664B1 (no) |
| PL (1) | PL211250B1 (no) |
| RS (1) | RS52522B (no) |
| UA (1) | UA76571C2 (no) |
| WO (1) | WO2003053966A2 (no) |
Families Citing this family (82)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU229306B1 (en) * | 2000-06-27 | 2013-10-28 | L V A T Lab Sa | Carbamates derived from arylalkylamines |
| KR100869722B1 (ko) * | 2000-12-22 | 2008-11-21 | 알미랄 에이쥐 | 퀴누클리딘 카르바메이트 유도체 및 ｍ3 길항제로서 그의사용 |
| 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 |
| GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
| PE20060259A1 (es) * | 2004-04-27 | 2006-03-25 | Glaxo Group Ltd | Compuestos de quinuclidina como antagonistas del receptor de acetilcolina muscarinico |
| EP1747219A4 (en) * | 2004-05-13 | 2010-05-26 | Glaxo Group Ltd | Antagonists of muscarinic acetylcholine receptor |
| GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
| ES2246170B1 (es) * | 2004-07-29 | 2007-04-01 | Almirall Prodesfarma, S.A. | Nuevo procedimiento para preparar derivados de carbamato de quinuclidinio. |
| MX2007001259A (es) | 2004-07-30 | 2007-10-08 | Salvat Lab Sa | Derivados de tirosina como moduladores de receptores activadores proliferadores de peroxisomas-gamma. |
| GT200500281A (es) | 2004-10-22 | 2006-04-24 | Novartis Ag | Compuestos organicos. |
| GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
| GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
| GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| NZ566023A (en) | 2005-09-21 | 2010-02-26 | Pfizer Ltd | Carboxamide derivatives as muscarinic receptor antagonists |
| CA2625664C (en) | 2005-10-21 | 2016-01-05 | Novartis Ag | Human antibodies against il13 and therapeutic uses |
| GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
| ATE549337T1 (de) | 2006-04-21 | 2012-03-15 | Novartis Ag | Purinderivate zur verwendung als adenosin-a2a- rezeptoragonisten |
| EP1882691A1 (en) * | 2006-07-26 | 2008-01-30 | CHIESI FARMACEUTICI S.p.A. | Quinuclidine derivatives as M3 antagonists |
| WO2008037477A1 (en) | 2006-09-29 | 2008-04-03 | Novartis Ag | Pyrazolopyrimidines as p13k lipid kinase inhibitors |
| WO2008041184A2 (en) * | 2006-10-03 | 2008-04-10 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
| PL2104535T3 (pl) | 2007-01-10 | 2011-05-31 | Irm Llc | Związki i kompozycje jako inhibitory proteazy aktywujące kanały |
| ES2361595T3 (es) | 2007-05-07 | 2011-06-20 | Novartis Ag | Compuestos orgánicos. |
| EP2065385A1 (en) * | 2007-11-28 | 2009-06-03 | Laboratorios SALVAT, S.A. | Stable crystalline salt of (R)-3-fluorophenyl-3,4,5-trifluorobenzylcarbamic acid 1-azabiciyclo [2.2.2]oct-3-yl ester |
| MX2010006421A (es) | 2007-12-10 | 2010-06-25 | Novartis Ag | Compuestos organicos. |
| MX2010007604A (es) | 2008-01-11 | 2010-08-02 | Novartis Ag | Pirimidinas como inhibidores de cinasa. |
| EP2080507A1 (en) | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Pharmaceutical formulations comprising an anticholinergic drug |
| EP2080508A1 (en) * | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Dry powder formulation comprising an anticholinergic drug |
| EP2080523A1 (en) | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Compositions comprising an antimuscarinic and a long-acting beta-agonist |
| US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
| BRPI0915018A2 (pt) | 2008-06-10 | 2015-10-27 | Novartis Ag | compostos orgânicos |
| EP2154136A1 (en) * | 2008-08-08 | 2010-02-17 | CHIESI FARMACEUTICI S.p.A. | Quinuclidine carbonate derivatives and medicinal compositions thereof |
| EP2206712A1 (en) | 2008-12-23 | 2010-07-14 | CHIESI FARMACEUTICI S.p.A. | "Alkaloid aminoester derivatives and medicinal composition thereof" |
| WO2010088335A1 (en) | 2009-01-29 | 2010-08-05 | Novartis Ag | Substituted benzimidazoles for the treatment of astrocytomas |
| US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
| BR112012003262A8 (pt) | 2009-08-12 | 2016-05-17 | Novartis Ag | compostos de hidrazona heterocíclica e seus usos para tratar câncer e inflamação |
| IN2012DN01961A (no) | 2009-08-17 | 2015-08-21 | Intellikine Llc | |
| CA2771432A1 (en) | 2009-08-20 | 2011-02-24 | Novartis Ag | Heterocyclic oxime compounds |
| EP2490687A1 (en) | 2009-10-22 | 2012-08-29 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
| US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
| RU2567548C2 (ru) | 2010-06-22 | 2015-11-10 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Производные сложного аминоэфира алкалоида и их лекарственные композиции |
| BR112012032332A2 (pt) | 2010-06-22 | 2016-11-08 | Chiesi Farma Spa | composto, uso de um composto, composição farmacêutica, combinação de um composto e dispositivo |
| CN102947298B (zh) * | 2010-06-22 | 2016-03-02 | 奇斯药制品公司 | 生物碱氨基酯衍生物及其药物组合物 |
| MA34326B1 (fr) | 2010-06-22 | 2013-06-01 | Chiesi Farma Spa | Formulation de poudre sèche comprenant un médicament antimuscarinique |
| UY33597A (es) | 2010-09-09 | 2012-04-30 | Irm Llc | Compuestos y composiciones como inhibidores de la trk |
| WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
| EP3388429A1 (en) * | 2010-11-16 | 2018-10-17 | Texas Heart Institute | Agonists that enhance binding of integrin-expressing cells to integrin receptors |
| WO2012069275A1 (en) | 2010-11-26 | 2012-05-31 | Chiesi Farmaceutici S.P.A. | Glycine derivatives and their use as muscarinic receptor antagonists |
| WO2012107500A1 (en) | 2011-02-10 | 2012-08-16 | Novartis Ag | [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase |
| US20120220557A1 (en) | 2011-02-17 | 2012-08-30 | Chiesi Farmaceutici S.P.A. | Liquid propellant-free formulation comprising an antimuscarinic drug |
| EP2678016B1 (en) | 2011-02-23 | 2016-08-10 | Intellikine, LLC | Heterocyclic compounds and uses thereof |
| BR112013021638A2 (pt) | 2011-02-25 | 2016-08-02 | Irm Llc | "compostos inibidores de trk, seu uso e composições que os compreendem" |
| KR20140019409A (ko) | 2011-04-29 | 2014-02-14 | 키에시 파르마슈티시 엣스. 피. 에이. | 알칼로이드 에스텔 및 카바메이트 유도체와 그들의 의약조성물 |
| US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
| MX339302B (es) | 2011-09-15 | 2016-05-19 | Novartis Ag | 3-(quinolin-6-il-tio)-[1,2,4]-triazolo-[4,3-a]-piridinas 6-sustituidas como cinasas de tirosina. |
| JP6165733B2 (ja) | 2011-09-16 | 2017-07-19 | ノバルティス アーゲー | Ｎ−置換ヘテロシクリルカルボキサミド類 |
| WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| WO2013038386A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Heterocyclic compounds for the treatment of cystic fibrosis |
| WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
| WO2013078440A2 (en) | 2011-11-23 | 2013-05-30 | Intellikine, Llc | Enhanced treatment regimens using mtor inhibitors |
| CA2862008A1 (en) | 2011-12-30 | 2013-07-04 | Chiesi Farmaceutici S.P.A. | Quinuclidine esters of 1-azaheterocyclylacetic acid as antimuscarinic agents, process for their preparation and medicinal compositions thereof |
| US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
| ES2894830T3 (es) | 2012-04-03 | 2022-02-16 | Novartis Ag | Productos combinados con inhibidores de tirosina·cinasa y su uso |
| US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
| WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
| TW201605450A (zh) | 2013-12-03 | 2016-02-16 | 諾華公司 | Ｍｄｍ２抑制劑與ＢＲＡＦ抑制劑之組合及其用途 |
| MX2016013981A (es) | 2014-04-24 | 2016-11-15 | Novartis Ag | Derivados de amino-piridina como inhibidores de fosfatidil-inositol-3-cinasa. |
| CA2945212A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
| JP6404944B2 (ja) | 2014-04-24 | 2018-10-17 | ノバルティス アーゲー | ホスファチジルイノシトール３−キナーゼ阻害薬としてのピラジン誘導体 |
| WO2016011658A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
| US10195208B2 (en) | 2014-07-31 | 2019-02-05 | Novartis Ag | Combination therapy |
| AU2016254034B2 (en) | 2015-04-29 | 2021-11-04 | 7 Hills Pharma LLC | Novel compositions and methods for immunotherapies comprising small molecule integrin receptor-ligand agonist adjuvants |
| US11311619B2 (en) | 2016-04-28 | 2022-04-26 | 7 Hills Pharma Inc. and Texas Heart Institute | Integrin activator vaccine compositions |
| KR20220019015A (ko) | 2019-06-10 | 2022-02-15 | 노파르티스 아게 | Cf, copd, 및 기관지확장증 치료를 위한 피리딘 및 피라진 유도체 |
| WO2021038426A1 (en) | 2019-08-28 | 2021-03-04 | Novartis Ag | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
| TW202140550A (zh) | 2020-01-29 | 2021-11-01 | 瑞士商諾華公司 | 使用抗ｔｓｌｐ抗體治療炎性或阻塞性氣道疾病之方法 |
Family Cites Families (8)
| 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 (fr) * | 1993-09-02 | 1995-03-09 | Yamanouchi Pharmaceutical Co., Ltd. | Derive de carbamate et medicament le contenant |
| CA2182568A1 (en) * | 1994-02-10 | 1995-08-17 | Makoto Takeuchi | Novel 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. |
| ATE299494T1 (de) * | 1999-12-07 | 2005-07-15 | Theravance Inc | Carbamat-derivate als muscarin-rezeptor antonisten |
| HU229306B1 (en) * | 2000-06-27 | 2013-10-28 | L V A T Lab Sa | Carbamates derived from arylalkylamines |
| KR100869722B1 (ko) * | 2000-12-22 | 2008-11-21 | 알미랄 에이쥐 | 퀴누클리딘 카르바메이트 유도체 및 ｍ3 길항제로서 그의사용 |
-
2002
- 2002-12-18 EP EP02796673.8A patent/EP1461336B1/en not_active Expired - Lifetime
- 2002-12-18 BR BR0215348-3A patent/BR0215348A/pt not_active IP Right Cessation
- 2002-12-18 ES ES02796673T patent/ES2425347T3/es not_active Expired - Lifetime
- 2002-12-18 WO PCT/EP2002/014470 patent/WO2003053966A2/en active Search and Examination
- 2002-12-18 US US10/499,130 patent/US7452904B2/en not_active Expired - Fee Related
- 2002-12-18 CN CN028278364A patent/CN1832948B/zh not_active Expired - Fee Related
- 2002-12-18 GE GE5649A patent/GEP20063958B/en unknown
- 2002-12-18 PL PL370972A patent/PL211250B1/pl not_active IP Right Cessation
- 2002-12-18 RS YU53904A patent/RS52522B/en unknown
- 2002-12-18 JP JP2003554682A patent/JP4505227B2/ja not_active Expired - Fee Related
- 2002-12-18 MX MXPA04006206A patent/MXPA04006206A/es active IP Right Grant
- 2002-12-18 CA CA2470956A patent/CA2470956C/en not_active Expired - Fee Related
- 2002-12-18 IL IL16259602A patent/IL162596A0/xx not_active IP Right Cessation
- 2002-12-18 KR KR1020047009786A patent/KR100944580B1/ko not_active IP Right Cessation
- 2002-12-18 HU HU0500107A patent/HUP0500107A3/hu unknown
- 2002-12-18 EA EA200400832A patent/EA006505B1/ru not_active IP Right Cessation
- 2002-12-18 UA UA20040706015A patent/UA76571C2/uk unknown
-
2004
- 2004-07-16 MA MA27789A patent/MA26385A1/fr unknown
- 2004-07-19 HR HR20040661A patent/HRP20040661A2/hr not_active Application Discontinuation
- 2004-07-19 NO NO20043064A patent/NO329664B1/no not_active IP Right Cessation
-
2005
- 2005-03-23 HK HK05102521.9A patent/HK1070057A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO329664B1 (no) | Forbindelse av typen 1-alkyl-1-azoniabisyklo [2.2.2] oktankarbamatderivater, mellomforbindelser; og anvendelse derav ved tivirkning av medikament | |
| AU2002238471B2 (en) | Quinuclidine derivatives and their use as M3 antagonists | |
| RU2143425C1 (ru) | Производные пиперидина, их соли, способы их получения, фармацевтическая композиция на их основе и промежуточные вещества | |
| AU2020256305A1 (en) | Compounds, compositions, and methods for increasing CFTR activity | |
| US7435742B2 (en) | Quinuclidine derivatives and pharmaceutical compositions containing the same | |
| US7115629B2 (en) | Carbamates derived from arylalkylamines | |
| CA2993450C (en) | Compounds, compositions and methods of increasing cftr activity | |
| ES2257422T3 (es) | 1,4-dihidropiridinas como antagonistas de bradiquinina. | |
| WO2016105477A1 (en) | Derivatives of 5-phenyl- or 5-heteroarylthiazol-2-carboxylic amide useful for the treatment of inter alia cystic fibrosis | |
| US20060194837A1 (en) | Tetrahydroisoquinoline compounds | |
| JP2009511552A (ja) | 置換１−アミノ−フタラジン誘導体、これらの調製およびこれらの治療的使用 | |
| US8604015B2 (en) | Alkaloid ester and carbamate derivatives and medicinal compositions thereof | |
| AU2002361158B2 (en) | 1-alkyl-1-azoniabicylco [2.2.2] octane carbamate derivatives and their use as muscarinic receptor antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |