WO2001004118A2 - Quinuclidine derivatives and their use as muscarinic m3 receptor ligands - Google Patents
Quinuclidine derivatives and their use as muscarinic m3 receptor ligands Download PDFInfo
- Publication number
- WO2001004118A2 WO2001004118A2 PCT/EP2000/006469 EP0006469W WO0104118A2 WO 2001004118 A2 WO2001004118 A2 WO 2001004118A2 EP 0006469 W EP0006469 W EP 0006469W WO 0104118 A2 WO0104118 A2 WO 0104118A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- octane
- hydroxy
- bromide
- azoniabicyclo
- compound according
- Prior art date
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- 102000007202 Muscarinic M3 Receptor Human genes 0.000 title abstract 2
- 108010008405 Muscarinic M3 Receptor Proteins 0.000 title abstract 2
- 150000008584 quinuclidines Chemical class 0.000 title description 2
- 239000003446 ligand Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- -1 5,6,7,8-tetrahydronaphthalenyl Chemical group 0.000 claims abstract description 204
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 5
- 125000006267 biphenyl group Chemical group 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
- 150000002390 heteroarenes Chemical class 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 194
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical group [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 108
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 35
- 238000002360 preparation method Methods 0.000 claims description 34
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 29
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 208000023504 respiratory system disease Diseases 0.000 claims description 8
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000002723 alicyclic group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 208000014001 urinary system disease Diseases 0.000 claims description 7
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 208000010643 digestive system disease Diseases 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 208000018685 gastrointestinal system disease Diseases 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000000241 respiratory effect Effects 0.000 claims description 5
- 230000002485 urinary effect Effects 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- NENRZCSTZIWMEU-NSHDSACASA-N [(3r)-1-azabicyclo[2.2.2]octan-3-yl] 2-(furan-2-yl)-2-oxoacetate Chemical compound O([C@@H]1C2CCN(CC2)C1)C(=O)C(=O)C1=CC=CO1 NENRZCSTZIWMEU-NSHDSACASA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 230000003551 muscarinic effect Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- YYXNXGQEMYTJDE-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-4-yl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C1CN(CC2)CCC12OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 YYXNXGQEMYTJDE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 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
- VZCLCKQUGUCPTO-NFVORSKWSA-N [(2r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2,2-diphenylacetate Chemical compound C([C@H]1OC(=O)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C(CC2)CC[N+]12CCCOC1=CC=CC=C1 VZCLCKQUGUCPTO-NFVORSKWSA-N 0.000 claims description 3
- HOSIJIINLUWTDR-ZDUSSCGKSA-N [(3r)-1-azabicyclo[2.2.2]octan-3-yl] 2,2-bis(furan-2-yl)-2-hydroxyacetate Chemical compound O([C@@H]1C2CCN(CC2)C1)C(=O)C(O)(C=1OC=CC=1)C1=CC=CO1 HOSIJIINLUWTDR-ZDUSSCGKSA-N 0.000 claims description 3
- RZYBPZPILUXNNH-JTQLQIEISA-N [(3r)-1-azabicyclo[2.2.2]octan-3-yl] 2-oxo-2-thiophen-2-ylacetate Chemical compound O([C@@H]1C2CCN(CC2)C1)C(=O)C(=O)C1=CC=CS1 RZYBPZPILUXNNH-JTQLQIEISA-N 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 208000007451 chronic bronchitis Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002414 normal-phase solid-phase extraction Methods 0.000 claims description 3
- 206010039083 rhinitis Diseases 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- WVSLILWGBHCSMD-PNXYCFKJSA-M OC(C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCOC2=CC=CC=C2)(C=2SC=CC2)C2=CC=CC=C2.[Br-] Chemical compound OC(C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCOC2=CC=CC=C2)(C=2SC=CC2)C2=CC=CC=C2.[Br-] WVSLILWGBHCSMD-PNXYCFKJSA-M 0.000 claims description 2
- DSLVZRHZOGHRPL-BCMCEQKHSA-M OC1(C2=CC=CC=C2C=2C=CC=CC12)C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCC=2SC=CC2.[Br-] Chemical compound OC1(C2=CC=CC=C2C=2C=CC=CC12)C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCC=2SC=CC2.[Br-] DSLVZRHZOGHRPL-BCMCEQKHSA-M 0.000 claims description 2
- SMCLERNDEYAHHL-WJOQIKPCSA-M [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-diphenylacetate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCCOC1=CC=CC=C1 SMCLERNDEYAHHL-WJOQIKPCSA-M 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 208000023819 chronic asthma Diseases 0.000 claims description 2
- 201000009151 chronic rhinitis Diseases 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- ONCOOCBPBLYVNY-BCMCEQKHSA-M [(3R)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 9-hydroxyxanthene-9-carboxylate bromide Chemical compound OC1(C2=CC=CC=C2OC=2C=CC=CC12)C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCC=2SC=CC2.[Br-] ONCOOCBPBLYVNY-BCMCEQKHSA-M 0.000 claims 1
- BGOFOSMLNNTRNP-ZWBOZGNMSA-M [(3r)-1-(4-phenylbutyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCCC1=CC=CC=C1 BGOFOSMLNNTRNP-ZWBOZGNMSA-M 0.000 claims 1
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- XLAKJQPTOJHYDR-QTQXQZBYSA-M aclidinium bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 XLAKJQPTOJHYDR-QTQXQZBYSA-M 0.000 claims 1
- 150000001649 bromium compounds Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 304
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- MSJOMBPJYBWHIE-CXSPSCEVSA-N [(2R)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-di(thiophen-3-yl)acetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCOc1ccccc1)CC2)(c1ccsc1)c1ccsc1 MSJOMBPJYBWHIE-CXSPSCEVSA-N 0.000 description 1
- YCKHNJZDIYMCGS-CXSPSCEVSA-N [(2R)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@H]1OC(=O)C(O)(C=2SC=CC=2)C=2SC=CC=2)C(CC2)CC[N+]12CCOC1=CC=CC=C1 YCKHNJZDIYMCGS-CXSPSCEVSA-N 0.000 description 1
- QVJACSKVTBNRMZ-YGVWRKSZSA-N [(2R)-1-(3-naphthalen-2-yloxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCOc1ccc3ccccc3c1)CC2)(c1cccs1)c1cccs1 QVJACSKVTBNRMZ-YGVWRKSZSA-N 0.000 description 1
- XRVIROXSETXCQM-KJUSFPLJSA-N [(2R)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2,2-diphenylpropanoate Chemical compound C1(=CC=CC=C1)C(C(=O)O[C@H]1[N+]2(CCC(C1)CC2)CCCOC1=CC=CC=C1)(C)C1=CC=CC=C1 XRVIROXSETXCQM-KJUSFPLJSA-N 0.000 description 1
- UAAZZFCQPNAHOC-CLBCXVIASA-N [(2R)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2,2-dithiophen-2-ylacetate Chemical compound O=C(O[C@@H]1CC2CC[N+]1(CCCOc1ccccc1)CC2)C(c1cccs1)c1cccs1 UAAZZFCQPNAHOC-CLBCXVIASA-N 0.000 description 1
- RTVRYZFXXPZMJP-SRCXMTRWSA-N [(2R)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-bis(4-methylphenyl)acetate Chemical compound Cc1ccc(cc1)C(O)(C(=O)O[C@@H]1CC2CC[N+]1(CCCOc1ccccc1)CC2)c1ccc(C)cc1 RTVRYZFXXPZMJP-SRCXMTRWSA-N 0.000 description 1
- HKHNSBQVQRJJAC-DSYMUFTKSA-N [(2R)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-di(thiophen-3-yl)acetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCc1ccccc1)CC2)(c1ccsc1)c1ccsc1 HKHNSBQVQRJJAC-DSYMUFTKSA-N 0.000 description 1
- VODWPMTYFBHONZ-DSYMUFTKSA-N [(2R)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCc1ccccc1)CC2)(c1cccs1)c1cccs1 VODWPMTYFBHONZ-DSYMUFTKSA-N 0.000 description 1
- PFXGEDUCWGKPAM-CLBCXVIASA-N [(2R)-1-(3-phenylsulfanylpropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCSc1ccccc1)CC2)(c1cccs1)c1cccs1 PFXGEDUCWGKPAM-CLBCXVIASA-N 0.000 description 1
- SUFTZXMUFGEPDT-ABFROGAOSA-N [(2R)-1-(4-oxo-4-phenylbutyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-(furan-2-yl)-2-hydroxy-2-thiophen-2-ylacetate Chemical compound C([C@H]1OC(=O)C(O)(C=2OC=CC=2)C=2SC=CC=2)C(CC2)CC[N+]12CCCC(=O)C1=CC=CC=C1 SUFTZXMUFGEPDT-ABFROGAOSA-N 0.000 description 1
- WCWXQFXCSWXHHZ-ZUYJMMGOSA-N [(2R)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-di(thiophen-3-yl)acetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCCOc1ccccc1)CC2)(c1ccsc1)c1ccsc1 WCWXQFXCSWXHHZ-ZUYJMMGOSA-N 0.000 description 1
- ZTCVQTWPJAKIIR-ZUYJMMGOSA-N [(2R)-1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCCOc1ccccc1)CC2)(c1cccs1)c1cccs1 ZTCVQTWPJAKIIR-ZUYJMMGOSA-N 0.000 description 1
- BIRASVXDZLYBGL-VSGCJZCHSA-N [(2R)-1-[3-(1-methylimidazol-2-yl)sulfanylpropyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@H]1[N+]2(CCC(C1)CC2)CCCSC=2N(C=CN2)C)(C=2SC=CC2)C=2SC=CC2 BIRASVXDZLYBGL-VSGCJZCHSA-N 0.000 description 1
- SHGDJRLVBFSZNK-CKRRMXRSSA-N [(2R)-1-[3-(2,4,6-trimethylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@H]1[N+]2(CCC(C1)CC2)CCCOC2=C(C=C(C=C2C)C)C)(C=2SC=CC2)C=2SC=CC2 SHGDJRLVBFSZNK-CKRRMXRSSA-N 0.000 description 1
- UBGKLWFFIUWEDK-NZQYTBKXSA-O [(2R)-1-[3-(2-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound Oc1ccccc1OCCC[N+]12CCC(CC1)C[C@H]2OC(=O)C(O)(c1cccs1)c1cccs1 UBGKLWFFIUWEDK-NZQYTBKXSA-O 0.000 description 1
- BYVONKIWMVLFCL-ZUYJMMGOSA-N [(2R)-1-[3-(2-methylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound Cc1ccccc1OCCC[N+]12CCC(CC1)C[C@H]2OC(=O)C(O)(c1cccs1)c1cccs1 BYVONKIWMVLFCL-ZUYJMMGOSA-N 0.000 description 1
- NEMFSGSYLFNWDU-NZQYTBKXSA-O [(2R)-1-[3-(3-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC1=CC=CC(OCCC[N+]23CCC(CC2)C[C@H]3OC(=O)C(O)(C=2SC=CC=2)C=2SC=CC=2)=C1 NEMFSGSYLFNWDU-NZQYTBKXSA-O 0.000 description 1
- IIQXFDXGVIWBNC-MCSXIPJESA-N [(2R)-1-[3-(3-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound COc1cccc(OCCC[N+]23CCC(CC2)C[C@H]3OC(=O)C(O)(c2cccs2)c2cccs2)c1 IIQXFDXGVIWBNC-MCSXIPJESA-N 0.000 description 1
- QGXAZODHTKSUTL-YTPQQOOLSA-N [(2R)-1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCOc1cccc(c1)[N+]([O-])=O)CC2)(c1cccs1)c1cccs1 QGXAZODHTKSUTL-YTPQQOOLSA-N 0.000 description 1
- FJLZBMUKZKSJBA-NZQYTBKXSA-O [(2R)-1-[3-(4-hydroxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C1=CC(O)=CC=C1OCCC[N+]1([C@@H](C2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)CCC2CC1 FJLZBMUKZKSJBA-NZQYTBKXSA-O 0.000 description 1
- HAZODLQCNYVYRF-YTPQQOOLSA-N [(2R)-1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCOc1ccc(cc1)[N+]([O-])=O)CC2)(c1cccs1)c1cccs1 HAZODLQCNYVYRF-YTPQQOOLSA-N 0.000 description 1
- HKAWDLAEKTYSQE-YGVWRKSZSA-N [(2R)-1-[3-(5,6,7,8-tetrahydronaphthalen-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@@H]1CC2CC[N+]1(CCCOc1ccc3CCCCc3c1)CC2)(c1cccs1)c1cccs1 HKAWDLAEKTYSQE-YGVWRKSZSA-N 0.000 description 1
- LBVFLKFOMAGTJD-MCSXIPJESA-N [(2R)-1-[3-[2-(hydroxymethyl)phenoxy]propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OCc1ccccc1OCCC[N+]12CCC(CC1)C[C@H]2OC(=O)C(O)(c1cccs1)c1cccs1 LBVFLKFOMAGTJD-MCSXIPJESA-N 0.000 description 1
- AJZAUFUOZOJRFK-MCSXIPJESA-N [(2R)-1-[3-[3-(hydroxymethyl)phenoxy]propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OCc1cccc(OCCC[N+]23CCC(CC2)C[C@H]3OC(=O)C(O)(c2cccs2)c2cccs2)c1 AJZAUFUOZOJRFK-MCSXIPJESA-N 0.000 description 1
- DMPGLQAJZVUSTM-KFQUYWJNSA-N [(2R)-1-[3-[3-(trifluoromethyl)phenoxy]propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OC(C(=O)O[C@H]1[N+]2(CCC(C1)CC2)CCCOC1=CC(=CC=C1)C(F)(F)F)(C=1SC=CC=1)C=1SC=CC=1 DMPGLQAJZVUSTM-KFQUYWJNSA-N 0.000 description 1
- COFZWORWHOBFRV-DLPZQXBVSA-N [(2R)-1-[3-[4-(3-hydroxypropyl)phenoxy]propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OCCCc1ccc(OCCC[N+]23CCC(CC2)C[C@H]3OC(=O)C(O)(c2cccs2)c2cccs2)cc1 COFZWORWHOBFRV-DLPZQXBVSA-N 0.000 description 1
- KTYMNUVVFMPZAV-MCSXIPJESA-N [(2R)-1-[3-[4-(hydroxymethyl)phenoxy]propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound OCc1ccc(OCCC[N+]23CCC(CC2)C[C@H]3OC(=O)C(O)(c2cccs2)c2cccs2)cc1 KTYMNUVVFMPZAV-MCSXIPJESA-N 0.000 description 1
- WTKMWYQOVGXZBL-CLBCXVIASA-N [(2r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-di(thiophen-3-yl)acetate Chemical compound C([C@H]1OC(=O)C(O)(C2=CSC=C2)C2=CSC=C2)C(CC2)CC[N+]12CCCOC1=CC=CC=C1 WTKMWYQOVGXZBL-CLBCXVIASA-N 0.000 description 1
- QQSGBYBVVFFNCF-WTJPCUSZSA-N [(2r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2-phenyl-2-thiophen-2-ylacetate Chemical compound C([C@H]1OC(=O)C(O)(C=2SC=CC=2)C=2C=CC=CC=2)C(CC2)CC[N+]12CCCOC1=CC=CC=C1 QQSGBYBVVFFNCF-WTJPCUSZSA-N 0.000 description 1
- RYLRKJPKDIDJQE-MCSXIPJESA-N [(2r)-1-[3-(4-methoxyphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C1=CC(OC)=CC=C1OCCC[N+]1([C@@H](C2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)CCC2CC1 RYLRKJPKDIDJQE-MCSXIPJESA-N 0.000 description 1
- GUARHEPRQTXFTK-IEPGKUISSA-N [(2r)-1-[6-(4-phenylbutoxy)hexyl]-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@H]1OC(=O)C(O)(C=2SC=CC=2)C=2SC=CC=2)C(CC2)CC[N+]12CCCCCCOCCCCC1=CC=CC=C1 GUARHEPRQTXFTK-IEPGKUISSA-N 0.000 description 1
- NZEQHVXFILCVRD-OTBAGVBSSA-N [(2s)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-2-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H]1OC(=O)C(O)(C=2SC=CC=2)C=2SC=CC=2)C(CC2)CC[N+]12CCCOC1=CC=CC=C1 NZEQHVXFILCVRD-OTBAGVBSSA-N 0.000 description 1
- LIVFOVVBZGGJFD-AWEZNQCLSA-N [(3R)-1-azabicyclo[2.2.2]octan-3-yl] cyclohept-4-ene-1-carboxylate Chemical compound O=C(O[C@H]1CN2CCC1CC2)C1CCC=CCC1 LIVFOVVBZGGJFD-AWEZNQCLSA-N 0.000 description 1
- NETKUYSZWVBUQE-ZVOVCPRUSA-N [(3r)-1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCOCC1=CC=CC=C1 NETKUYSZWVBUQE-ZVOVCPRUSA-N 0.000 description 1
- UAUSTCLJJODBIH-VITNCHFBSA-N [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2,2-bis(furan-2-yl)-2-hydroxyacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3OC=CC=3)C=3OC=CC=3)[N+]21CCCOC1=CC=CC=C1 UAUSTCLJJODBIH-VITNCHFBSA-N 0.000 description 1
- ZPUIFOBXUIMYGP-YMVPHMABSA-N [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2,2-dithiophen-2-ylpropanoate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(C)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 ZPUIFOBXUIMYGP-YMVPHMABSA-N 0.000 description 1
- IYWRNILAOARDKA-WDVLHWPLSA-N [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2-(furan-2-yl)-2-hydroxy-2-thiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3OC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 IYWRNILAOARDKA-WDVLHWPLSA-N 0.000 description 1
- WZXRPTLWADRYET-GYNTZMJKSA-N [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 6,11-dihydro-5h-dibenzo[1,2-a:1',2'-e][7]annulene-11-carboxylate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C3C4=CC=CC=C4CCC4=CC=CC=C43)[N+]21CCCOC1=CC=CC=C1 WZXRPTLWADRYET-GYNTZMJKSA-N 0.000 description 1
- QFOWZIANZZMDKR-CBQRAPNFSA-N [(3r)-1-(3-phenylmethoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOCC1=CC=CC=C1 QFOWZIANZZMDKR-CBQRAPNFSA-N 0.000 description 1
- USKNUYDOJZZWSC-VONVOUFKSA-N [(3r)-1-[3-(1,3-benzothiazol-2-yloxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound O([C@@H]1C2CC[N+](CC2)(CCCOC=2SC3=CC=CC=C3N=2)C1)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 USKNUYDOJZZWSC-VONVOUFKSA-N 0.000 description 1
- QEXWJULWOZTIGD-WJUMYPGWSA-N [(3r)-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=C(F)C=C1F QEXWJULWOZTIGD-WJUMYPGWSA-N 0.000 description 1
- VUBTVAJZRQUMAG-JZETWELJSA-N [(3r)-1-[3-(2,4-difluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 9-methylfluorene-9-carboxylate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C3(C)C4=CC=CC=C4C4=CC=CC=C43)[N+]21CCCOC1=CC=C(F)C=C1F VUBTVAJZRQUMAG-JZETWELJSA-N 0.000 description 1
- RHVNLHKKXWNLHB-LGCWNYSLSA-O [(3r)-1-[3-(2-carbamoylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound NC(=O)C1=CC=CC=C1OCCC[N+]1(C[C@@H]2OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)CCC2CC1 RHVNLHKKXWNLHB-LGCWNYSLSA-O 0.000 description 1
- MBYLOEWSZFYCBU-JKLGZZSBSA-N [(3r)-1-[3-(2-chlorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1Cl MBYLOEWSZFYCBU-JKLGZZSBSA-N 0.000 description 1
- ZMYATJJAGNSEED-JWALKRTLSA-N [(3r)-1-[3-(2-tert-butyl-6-methylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound CC1=CC=CC(C(C)(C)C)=C1OCCC[N+]1(C[C@@H]2OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)CCC2CC1 ZMYATJJAGNSEED-JWALKRTLSA-N 0.000 description 1
- HVUYZXPDGVAYIH-ICFHYRHXSA-N [(3r)-1-[3-(3-cyanophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC(C#N)=C1 HVUYZXPDGVAYIH-ICFHYRHXSA-N 0.000 description 1
- VCAGNOUEEGLZFM-SLRLHWDHSA-O [(3r)-1-[3-(4-acetamidophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C1=CC(NC(=O)C)=CC=C1OCCC[N+]1(C[C@@H]2OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)CCC2CC1 VCAGNOUEEGLZFM-SLRLHWDHSA-O 0.000 description 1
- JSCPTYQCJKZVJX-ICFHYRHXSA-N [(3r)-1-[3-(4-cyanophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=C(C#N)C=C1 JSCPTYQCJKZVJX-ICFHYRHXSA-N 0.000 description 1
- WGVMNUVUUCHNMA-JZWOKSBVSA-N [(3r)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] 2-hydroxy-2,2-di(thiophen-3-yl)acetate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C3=CSC=C3)C3=CSC=C3)[N+]21CCCOC1=CC=C(F)C=C1 WGVMNUVUUCHNMA-JZWOKSBVSA-N 0.000 description 1
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
Definitions
- This invention relates to new therapeutically useful quinuclidme derivatives, to some processes for their preparation and to pharmaceutical compositions containing them.
- novel structures according to the invention are antimuscarmic agents with a potent and long lasting effect.
- these compounds show high affinity for musca ⁇ nic M 3 receptors (Hm3) .
- the new compounds are suitable for treating the following diseases: respiratory disorders such as chronic obstructive pulmonary disease (COPD) , chronic bronchitis, bronchial hyperreactivity, asthma and rhinitis; urological disorders such as urinary incontinence, pollakmuria m neu ⁇ penia pollakmuria, neurogenic or unstable bladder, cystospasm and chronic cystitis; and gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulceration.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- chronic bronchitis chronic bronchitis
- bronchial hyperreactivity asthma and rhinitis
- urological disorders such as urinary incontinence, pollakmuria m neu ⁇ penia pollakmuria, neurogenic or unstable bladder, cystospasm and chronic cystitis
- gastrointestinal disorders such as irritable bowel syndrome, spastic colitis,
- the compounds claimed are also useful for the treatment of the respiratory diseases detailed above in association with ⁇ , agonists, steroids, antiallergic drugs or phosphodiesterase IV inhibitors.
- Compounds of the present invention may also be expected to have anti-tussive properties.
- the new compounds may be suitable for treating vagally induced sinus bradycardia.
- R is H, OH or an alkyl group having 1 to 4 carbon atoms
- R 2 is a phenyl or thienyl group
- R 2 is a cyclohexyl, cyclopentyl or thienyl group, or, when R is H, R x and R 2 together with the carbon atom to which they are attached, form a tricyclic group of the formula:
- X is -0-, -S- or -CH 2 -, or an acid addition or quaternary ammonium salt thereof.
- EP- 418716 describes thienyl carboxylate esters of formula
- R x is a thienyl, phenyl, furyl, cyclopentyl or cyclohexyl group, optionally substituted
- R 2 is H, OH, C 1 -C 4 alkoxy or Cj-C, alkyl and R a is H, F, Cl, CH 3 - or -NR.
- US 5,654,314 describes compounds of formula:
- R is an optionally halo- or hydroxy-substituted C : _ 4 alkyl group; R is a C 1-4 alkyl group; or R and R' together form a C 4-6 alkylene group;
- X " is an anion; and
- R x is H, OH, -CH 2 OH, C ⁇ _ 4 alkyl or C 1-4 alkoxy.
- ⁇ is a phenyl ring, a C 4 to C 9 heteroaromatic group containing one or more heteroatoms (preferably selected from nitrogen, oxygen and sulphur atoms), or a naphthalenyl, 5, 6, 7 , 8-tetrahydronaphthalenyl or biphenyl group;
- R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom, or a hydroxy group, or a phenyl, -OR 4 , -SR 4 , -NRR 5 , -NHCOR 4 , -CONR 4 R 5 ,
- n is an integer from 0 to 4;
- R 10 represents a hydrogen atom, a hydroxy or methyl group
- R 8 and R 9 each independently represents
- X represents a pharmaceutically acceptable anion of a mono or polyvalent acid.
- an equivalent of an anion (X ⁇ ) is associated with the positive charge of the N atom.
- X " may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate, and organic acids such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate .
- X " is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate or succinate. More preferably X " is chloride, bromide or trifluoroacetate .
- R 1 to R 7 or R 11 represents an alkyl group
- said alkyl group contains 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
- any alkyl group is represented by a methyl, ethyl, propyl, including i-propyl, butyl including a n-butyl, sec-butyl and tert- butyl.
- the alicyclic and heterocyclic rings mentioned in relation to formula (I) preferably comprise from 3 to 10, preferably from 5 to 7 members.
- the aromatic rings mentioned in relation to formula (I) above preferably contain from 6 to 14, preferably 6 or 10 members.
- Preferred compounds of formula (I) are those wherein ⁇ represents a phenyl, pyrrolyl, thienyl, furyl, biphenyl, naphthalenyl, 5, 6, 7, 8-tetrahydronaphthalenyl, benzo [1, 3] dioxolyl, imidazolyl or benzothiazolyl group, in particular a phenyl, pyrrolyl, or thienyl group; R 1 , R 2 and R 3 each independently represent a hydrogen or halogen atom, or a hydroxyl, methyl, tert-butyl, -CH 2 OH, 3-hydroxypropyl, -OMe, -NMe 2 , -NHCOMe, -CONH 2 , -CN, -N0 2 , -COOMe or -CF 3 group, in particular a hydrogen atom, a hydroxy group or a halogen atom, wherein the halogen atom is preferably fluorine;
- B is a group of formula i) or ii) as defined above wherein, if B is a group of formula (i) , R 8 and R s each independently represent a phenyl, 2- thienyl, 3-thienyl, 2-furyl or 3-furyl group, wherein R 11 is hydrogen atom; and, if B is a group of formula (ii) , Q represents a single bond, -CH 2 -, -CH 2 -CH 2 -, -0- or -S- group, in particular a single bond, -CH 2 -, -CH 2 -CH 2 - or -0- group, most preferably a single bond or -0- group ; and in any case R 10 is a hydrogen atom or a hydroxy or methyl group; and when i) or ii) contain a chiral centre they may represent either the (R) or the (S) configuration.
- the -0C(0)B group in formula (I) is diphenylacetoxy, 2-hydroxy-2 , 2-diphenyl-acetoxy, 2, 2-diphenylpropionyloxy, 2-hydroxy-2-phenyl-2-thien-2-yl-acetoxy,
- the most preferred compounds of formula (I) are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3- phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylbutyl, 3-phenylpropyl, 3- [2-hydroxyphenoxy] propyl, 3- [4-fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-l-ylpropyl, 2-thien-2-ylethyl, 3-thien-2- ylpropyl, 3-phenylaminopropyl , 3- (methylphenylamino) propyl ,
- Especially preferred compounds are those wherein the azoniabicyclo group is substituted on the nitrogen atom with a 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4- phenylbutyl, 3-phenylpropyl, 3- [2-hydroxyphenoxy] propyl, 3- [4- f luorophenoxy] propyl, 2-benzyloxyethyl, 3-pyrrol-l-ylpropyl, 2-thien-2- ylethyl or 3-thien-2-ylpropyl group.
- the present invention also provides processes for preparing compounds of formula (I) .
- the quaternary ammonium derivatives of general Formula I may be prepared by reaction of an alkylating agent of general Formula II with compounds of general Formula III.
- R 1 , R 2 , R 3 , ⁇ , A, X, B, n, m and p are as defined above.
- This alkylation reaction may be carried out by two different experimental procedures, a) and b) which are described below.
- method b) provides a new experimental process, using solid phase extraction methodologies, that allows the parallel preparation of several compounds. Methods a) and b) are described in the experimental section.
- Compounds of general Formula II which are not commercially available have been prepared by synthesis according to standard methods.
- Some compounds of general formula III where B is a group of formula i) , R 8 and R 9 are as described above and R 10 is a hydroxy group, may also be prepared from the glyoxalate esters of general formula VII by reaction with the corresponding organometallic derivative.
- Compounds of general formula VII may be prepared from the corresponding glyoxylic acids following the standard methods c, d and e described above and detailed in the experimental section.
- the glyoxalate derivatives of formula VII where R 8 is a 2-thienyl or 2- furyl group have not been described before.
- the following compounds are examples of compounds of general formula III and VII which have not been described before: 9-Methyl-9 [H] -fluorene-9-carboxylic acid 1-azabicyclo [2.2.2] oct-3 (R) -yl ester (intermediate I-lc) ; 9-Methyl-9 [H] -xanthene-9-carboxylic acid 1-azabicyclo [2.2.2]oct-3 (R)
- Compounds of Formula V could be: 4-hydroxy-l-azabicyclo [2.2.1] heptane, described in WO150080
- the reaction mixture was applied to the cartridge and washed first with 2 ml of DMSO and then three times with 5 ml of CH3CN, rinsing away all starting materials.
- the ammonium derivative was eluted with 5 ml of 0.03 M TFA solution in CH3CN:CHC13 (2:1). This solution was neutralized with 300 mg of poly (4-vinylpyridine) , filtered and evaporated to dryness.
- Methyl ester derivatives of general Formula VI were prepared by standard methods of esterification from the corresponding carboxylic acid or following the procedures described in examples I-le, I-lf and I-lg or according to procedures described in literature: FR 2012964; Larsson. L et al . Acta Pharm. Suec. (1974), 11(3), 304-308; Nyberg, K. et.al. Acta Chem. Scand. (1970), 24, 1590-1596; and Cohen, V.I. et.al. J. Pharm. Sciences (1992), 81, 326-329.
- Diastereomer 1 2 (*) - (Furan-2-yl)hydroxyphenylacetic acid 1-azabi cyclo[2.2.2]oct-3(R)-yl ester.
- 1 H- NMR (CDC13) ⁇ 1.20-1.70 (m, 4H) , 1.90 (m, IH) , 2.45-2.50 (m, IH) , 2.50-2.80 (m, 4H) , 3.10-3.20 (m, IH) , 4.8 (bs, OH), 4.90-5.0 ( , IH) , 6.20 (m, IH) , 6.35 (m, IH) , 7.30-7.50 (m, 4H) , 7.60-7.70 (m, 2H) .
- Diastereomer 2 2 (*) - (Furan-2-yl)hydroxyphenylacetic acid 1-azabi cyclo[2.2.2]oct-3(R)-yl ester.
- 1 H- NMR (CDC13) ⁇ 1.20-1.70 (m, 4H) , 2.10 (m, IH) , 2.50-2.80 (m, 5H) , 3.20-3.30 (m, IH) , 4.8 (bs, OH), 4.90- 5.0 (m, IH) , 6.20 (m, IH) , 6.35 (m, IH) , 7.30-7.50 (m, 4H) , 7.60-7.70 (m, 2H) .
- Lithium diisopropylamide (26.7 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.053 mol) was added to a stirred solution of 9 [H] -fluorene-9-carboxylic acid (5 g , 0.0237 mol) in THF (70 ml) at between 0 and 5°C in N 2 atmosphere. The mixture was warmed to room temperature and refluxed 1.5 hours. The reaction mixture was cooled to room temperature and a solution of CH3I (1.85 ml, 0.03 mol) in THF (1.85 ml) was added. The mixture was stirred overnight at room temperature and evaporated.
- Example I-lf -Preparation of 9-Methyl-9 [H] -xanthene-9-carboxylic acid methyl ester Prepared as in example I-le. The yield was 2.65 g (47.2%).
- 1 H- NMR (CDC13) ⁇ 1.90 (s, 3H) , 3.6 (s, 3H) , 7.05-7.35 (m, 8H) .
- Example I-lg- Preparation of 9-Hydroxy-9 [H] -xanthene-9-carboxylic acid methyl ester Lithium diisopropylamide (20.3 ml of a 2M solution in heptane/tetrahydrofurane/ethylbenzene, 0.041 mol) was added to a stirred solution of 7 g ( 0.029 mol) of 9 [H] -xantene-9-carboxylic acid methyl ester (prepared by a standard method) in THF (70 ml) at between 0 and 5°C in N 2 atmosphere.
- Example I-2a Preparation of 10 , ll-Dihydro-5 [H] -dibenzo [a,d] cycloheptane-5-carboxylic acid 1-azabicyclo [2.2.2] oct-3- (R) -yl ester.
- 2.15g of 10 ll-Dihydro-5 [H] -dibenzo [a, d] cycloheptane-5-carboxylic acid (9.0 mmol) were dissolved in 40 ml of CHC13 (ethanol free). The solution was cooled at 0 °C and 0.86 ml of oxalyl chloride (9.9 mmols) and a drop of DMF were added.
- Example 1-3 Preparation of 2 ,2-Diphenylpropionic acid 1-azabicyclo [2 . 2 . 2] oct-3 (R) -yl ester .
- a solution of 2-thienylmagnesium bromide was prepared from 220 mg (9 mmols)of Magnesium and 0.86 ml (9 mmols) of 2-bromothiophene in 15 ml of THF. This solution was added to 1.95 g (7mmols) of oxothien-2-yl -acetic acid 1-azabicyclo [2.2.2] oct-4-yl ester (intermediate I-4b) dissolved in 20 ml of THF. The mixture was stirred at room temperature for 1 hour, refluxed for 1 hour, cooled, treated with a saturated solution of ammonium chloride and extracted with ether.
- Oxalyl chloride (1.5ml, 0.017 mol) was added to a solution of oxothien- 2-yl-acetic acid (2.24 g, 0,014 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0°C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHC13 (30 ml) and added to a suspension of 1. lg (0,009mols) of 4-hydroxy-l-azabicyclo [2.2.2] octane, 1.8ml of triethylamine
- Phenylmagnesium bromide 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g ( 0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo [2.2.2] oct-3 (R) -yl ester (intermediate I-4e-) dissolved in 15 ml of THF, at -70°C in N2 atmosphere. The mixture was stirred at this temperature for 10 minuts, and then warmed to room temperature . After 1 hour , the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate . The organic phases were combined, washed with water and dried over Na2S04.
- Oxalyl chloride (9.75 ml, 0.112 mol) was added to a solution of oxofuran-2-ylacetic acid (10 g, 0.071 mol) and dimethylformamide (one drop) in 150 ml of chloroform (etanol free) at 0°C. The mixture was stirred and allowed to warm at room temperature. After five hours the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHC13 (150 ml) and a solution of 3 (R) - quinuclidinol (10.90 g, 0.086 mol) in CHC13 (150 ml) was added to this at 0°C.
- Example I-4f Preparation of 2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-azabicyclo [2.2.2] oct-3 (R) -yl ester.
- the title compound was prepared as described in example I-4c from intermediate I-4g. The yield was 3 g (33%) as a mixture of diastereomers. After five crystallizations of 1.5 g of this mixture from boiling isopropanol, 0.200 g of a pure diastereomer (1) were obtained. The mother liquors from first crystallization were enriched with the other diastereomer (2) .
- Diastereomer 1 2 (R) -2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-aza bicyclo[2.2.2]oct-3(R)-yl ester.
- H-NMR (DMSO-d6) : ⁇ 1.1-1.25 (m, IH) , 1.3-1.6 (m, 3H) , 1.83 (m, IH) , 2.4-2.7 (m, 5H) , 3.1 (m, IH) , 4.8 (m, IH) , 7.0 (m, 2H) , 7.05 (m, IH) , 7.3-7.4 (m, 3H) , 7.4-7.45 (m, 2H) , 7.5 (m, IH) .
- Diastereomer 2 2 (S) -2-Hydroxy-2-phenyl-2-thien-2-ylacetic acid 1-aza bicyclo [2.2.2] oct-3 (R)-yl ester.
- X H-NMR (DMSO-d6) : ⁇ 1.1-1.25 (m, IH) , 1.4-1.6 (m, 3H) , 1.9 (m, IH) , 2.3-2.7 (m, 5H) , 3.05 (m, IH) , 4.8 (m, IH) , 7.0 (m, 2H) , 7.05 (m, IH) , 7.3-7.4 (m, 3H) , 7.4-7.45 (m, 2H) , 7.5 (m, IH) .
- Example I-4g Preparation of oxothien-2-yl-acetic acid 1-azabicyclo [2.2.2]oct-3(R)-yl ester.
- Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0,0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0°C.
- the mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times.
- compositions which comprise, as the active ingredient, at least one quinuclidine derivative of general formula (I) in association with a pharmaceutically acceptable carrier or diluent.
- a pharmaceutically acceptable carrier or diluent Preferably the composition is made up in a form suitable for oral administration .
- composition of this invention The pharmaceutically acceptable carrier or diluents which are mixed with the active compound or compounds, to form the composition of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administration of the composition.
- compositions of this invention are preferably adapted for oral administration.
- the composition for oral administration may take the form of tablets, film-coated tablets, liquid inhalant, powder inhalant and inhalation aerosol; all containing one or more compounds of the invention; such preparations may be made by methods well-known in the art.
- the diluents which may be used in the preparations of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired.
- Tablets or film-coated tablets may conveniently contain between 500 and 1 mg, preferably from 5 to 300 mg of active ingredient.
- the inhalant compositions may contain between 1 ⁇ g and 1,000 ⁇ g, preferably from 10 to 800 ⁇ g of active ingredient .
- the dose of the compound of general formula (I) depend on the desired effect and duration of treatment; adult doses are generally between 3 mg and 300 mg per day as tablets and 10 ⁇ g and 800 ⁇ g per day as inhalant composition.
- membrane preparations were suspended in DPBS to a final concentration of 89 ⁇ g/ml for the Hm3 subtype.
- the membrane suspension was incubated with the tritiated compound for 60 min. After incubation the membrane fraction was separated by filtration and the bound radioactivity determined. Non specific binding was determined by addition of 10 "4 M atropine . At least six concentrations were assayed in duplicate to generate individual displacement curves.
- the compounds of the invention preferably have high affinities for muscarinic M 3 receptors (HM3) , preferably human muscarinic receptors. Affinity levels can typically be measured by in vitro assays, for example, as described above.
- HM3 muscarinic M 3 receptors
- Preferred compounds of the invention have an IC 5: (nM) value for M 3 receptors of less than 35, preferably less than 25,20 or 15, more preferably less than 10,8 or 5.
- the compounds of the present invention inhibited the bronchospasm response to acetylcholine with high potency and a long duration of action .
- M 3 antimuscarinic activity
- the compounds of the present invention have excellent antimuscarinic activity (M 3 ) and thus are useful for the treatment of diseases in which the muscarinic M 3 receptor is implicated, including respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis, urinary diseases such as urinary incontinence and pollakmuria in neuripenia pollakmuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystitis and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis .
- respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis
- urinary diseases such as urinary incontinence and pollakmuria in neuripenia
- the present invention further provides a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of respiratory, urinary or gastrointestinal disease.
- the present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disease.
- the compounds of formula (I) and pharmaceutical compositions comprising a compound of formula (I) can be used in a method of treating respiratory, urinary or gastrointestinal disease, which method comprises administering to a human or animal patient in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) .
- the present invention will be further illustrated by the following examples. The examples are given by way of illustration only and are not to be construed as limiting.
- the title compound was synthesised as a mixture of diastereomers according to methods c and a.
- the yield of final step was 520 mg , 62%.
- Example 62 1- [3- (3-Dimethylaminophenoxy) propyl] -3 (R) - (2-hydroxy-2 ,2-dithien-2-y lacetoxy) -1-azoniabicyclo [2.2.2] octane ; trifluoroacetate
- Example 120 1- [3- (2,4-Difluorophenoxy) propyl] -3 (R) - (9-methyl-9H-fluorene-9- carbonyloxy) -1-azoniabicyclo [2.2.2] octane; trifluoroacetate
- Example 152 3 (R) - (9-Methyl-9 [H] -xanthene-9-carbonyloxy) -1- (3-phenylaminopropyl) - 1-azoniabicyclo [2.2.2] octane; trifluoroacetate
- the Examples 160 to 164 illustrate pharmaceutical compositions according to the present invention and procedure for their preparation.
- a coating solution was prepared by suspending 6.9 g of hydroxypropylmethylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of purified talc in 72.6 g of water. Using a High Coated, the 3,000 tablets prepared above were coated with the coating solution to give film-coated tablets, each having 154.5 mg in weight.
- a 40 mg portion of the compound of the present invention was dissolved in 90 ml of physiological saline, and the solution was adjusted to a total volume of 100 ml with the same saline solution, dispensed in 1 ml portions into 1 ml capacity ampoule and then sterilized at 115° for 30 minutes to give liquid inhalant.
- a 20 g portion of the compound of the present invention was uniformly mixed with 400 g of lactose, and a 200 mg portion of the mixture was packed in a powder inhaler for exclusive use to produce a powder inhalant .
- the active ingredient concentrate is prepared by dissolving 0.0480 g of the compound of the present invention in 2.0160 g of ethyl alcohol. The concentrate is added to an appropriate filling apparatus. The active ingredient concentrate is dispensed into aerosol container, the headspace of the container is purged with Nitrogen or HFC-134A vapor (purging ingredients should not contain more than 1 ppm oxygen) and is sealed with valve. 11.2344 g of HFC-134A propellant is then pressure filled into the sealed container.
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Priority Applications (40)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2381165A CA2381165C (en) | 1999-07-14 | 2000-07-07 | Novel quinuclidine derivatives and medicinal compositions containing the same |
HU0202100A HU228594B1 (en) | 1999-07-14 | 2000-07-07 | Novel quinuclidine derivatives, process for their preparation and medicinal compositions containing the same |
EEP200200017A EE04915B3 (et) | 1999-07-14 | 2000-07-07 | Kinuklidiinderivaadid, nende valmistamismeetod, vaheühendid, farmatseutiline kompositsioon ja nende kasutamine |
EP00951361.5A EP1200431B3 (en) | 1999-07-14 | 2000-07-07 | Quinuclidine derivatives and their use as muscarinic m3 receptors ligands |
ES951361T ES2193098T7 (es) | 1999-07-14 | 2000-07-07 | Derivados de quinuclidina y su uso como ligandos de los receptores muscarínicos M3 |
UA2002010323A UA73509C2 (uk) | 1999-07-14 | 2000-07-07 | Хінуклідинові похідні та їх використання як лігандів мускаринового м3-рецептора |
IL14753300A IL147533A0 (en) | 1999-07-14 | 2000-07-07 | Novel quinuclidine derivatives and medicinal compositions containing the same |
AU64330/00A AU779881C (en) | 1999-07-14 | 2000-07-07 | Quinuclidine derivates and their use as muscarinic M3 receptor ligands |
PL357160A PL204024B1 (pl) | 1999-07-14 | 2000-07-07 | Nowe pochodne chinuklidyny, sposób ich wytwarzania, zastosowanie i zawierające je kompozycje farmaceutyczne |
DE60001840.7T DE60001840T4 (de) | 1999-07-14 | 2000-07-07 | Chinuclidin-derivate und deren verwendung als muscarin-m3-rezeptoren-liganden |
AT00951361T ATE235492T1 (de) | 1999-07-14 | 2000-07-07 | Chinuclidin-derivate und deren verwendung als muscarin-m3-rezeptoren-liganden |
SK43-2002A SK287480B6 (sk) | 1999-07-14 | 2000-07-07 | Chinuklidínové deriváty, spôsob ich prípravy, liečivé kompozície, ktoré ich obsahujú, a ich použitie |
DE60001840A DE60001840D1 (de) | 1999-07-14 | 2000-07-07 | Chinuclidin-derivate und deren verwendung als muscarin-m3-rezeptoren-liganden |
BRPI0012434A BRPI0012434B8 (pt) | 1999-07-14 | 2000-07-07 | compostos ésteres de quinuclidina úteis como antagonistas de receptores m3 muscarínicos |
SI200030108T SI1200431T1 (en) | 1999-07-14 | 2000-07-07 | Quinuclidine derivatives and their use as muscarinic m3 receptors ligands |
JP2001509727A JP4030040B2 (ja) | 1999-07-14 | 2000-07-07 | キヌクリジン誘導体およびそれらのムスカリンm3レセプターリガンドとしての使用 |
DK00951361.5T DK1200431T6 (en) | 1999-07-14 | 2000-07-07 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US10/047,464 US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
NO20020180A NO329484B3 (no) | 1999-07-14 | 2002-01-14 | Nye kinuklidinderivater og medisinske sammensetninger inneholdende det samme, samt anvendelse derav for fremstilling av medikamenter |
HK02103992A HK1042487B (en) | 1999-07-14 | 2002-05-29 | Quinuclidine derivatives and their use as muscarinic m3 receptors ligands |
US10/740,264 US7109210B2 (en) | 1999-07-14 | 2003-12-17 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/116,777 US7078412B2 (en) | 1999-07-14 | 2005-04-28 | Quinuclidine derivatives and medicinal compositions containing the same |
AU2005202144A AU2005202144B2 (en) | 1999-07-14 | 2005-05-18 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US11/324,919 US7214687B2 (en) | 1999-07-14 | 2006-01-03 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/325,059 US7196098B2 (en) | 1999-07-14 | 2006-01-03 | Quinuclidine derivatives and medicinal compositions containing the same |
US11/636,181 US7358260B2 (en) | 1999-07-14 | 2006-12-08 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/074,929 US7750023B2 (en) | 1999-07-14 | 2008-03-07 | Quinuclidine derivatives and medicinal compositions containing the same |
US12/787,772 US7897617B2 (en) | 1999-07-14 | 2010-05-26 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/011,131 US8129405B2 (en) | 1999-07-14 | 2011-01-21 | Quinuclidine derivatives and medicinal compositions containing the same |
US13/354,873 US8513279B2 (en) | 1999-07-14 | 2012-01-20 | Quinuclidine derivatives and medicinal compositions containing the same |
CY2013001C CY2013001I2 (el) | 1999-07-14 | 2013-01-07 | Nεα παραγωγα κινουκλιδινης και ιατρικα σκευασματα που τα πepιεχουν |
FR13C0001C FR13C0001I2 (fr) | 1999-07-14 | 2013-01-08 | Derives de quinuclidine et leur utilisation comme ligands des recepteurs m3 muscariniques |
NO2013002C NO2013002I2 (no) | 1999-07-14 | 2013-01-18 | Aklidiniumsalt med et farmaøytisk akseptabelt anion av en mono-eller polyvalent syre, spesielt aklidiniumbromid |
US13/939,742 US8802699B2 (en) | 1999-07-14 | 2013-07-11 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/311,102 US9056100B2 (en) | 1999-07-14 | 2014-06-20 | Quinuclidine derivatives and medicinal compositions containing the same |
US14/712,866 US9333195B2 (en) | 1999-07-14 | 2015-05-14 | Quinuclidine derivatives and medicinal compositions containing the same |
US15/019,009 USRE46417E1 (en) | 1999-07-14 | 2016-02-09 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
US15/095,036 US9687478B2 (en) | 1999-07-14 | 2016-04-09 | Quinuclidine derivatives and medicinal compositions containing the same |
US15/599,646 US10034867B2 (en) | 1999-07-14 | 2017-05-19 | Quinuclidine derivatives and medicinal compositions containing the same |
US16/045,333 US10588895B2 (en) | 1999-07-14 | 2018-07-25 | Quinuclidine derivatives and medicinal compositions containing the same |
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ES009901580A ES2165768B1 (es) | 1999-07-14 | 1999-07-14 | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
ESP9901580 | 1999-07-14 |
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US10/047,464 Continuation US6750226B2 (en) | 1999-07-14 | 2002-01-14 | Quinuclidine derivatives and their use as muscarinic M3 receptor ligands |
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