ES2203327B1 - Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. - Google Patents
Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen.Info
- Publication number
- ES2203327B1 ES2203327B1 ES200201439A ES200201439A ES2203327B1 ES 2203327 B1 ES2203327 B1 ES 2203327B1 ES 200201439 A ES200201439 A ES 200201439A ES 200201439 A ES200201439 A ES 200201439A ES 2203327 B1 ES2203327 B1 ES 2203327B1
- Authority
- ES
- Spain
- Prior art keywords
- ylmethyl
- azoniabicyclo
- octane
- group
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 title claims description 4
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 4
- -1 furan-2-ylmethyl Chemical group 0.000 claims description 390
- 150000001875 compounds Chemical class 0.000 claims description 279
- 150000002148 esters Chemical class 0.000 claims description 92
- 239000002253 acid Substances 0.000 claims description 82
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 63
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000004122 cyclic group Chemical group 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- ZETQILUTJDIRCU-GLSBDXMNSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-[(4-bromo-5-methylthiophen-2-yl)methyl]-n-[(3-methylthiophen-2-yl)methyl]carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CSC(CN(CC=2SC(C)=C(Br)C=2)C(=O)O[C@@H]2C3CC[N+](CC3)(CCCC=3C=CC=CC=3)C2)=C1C ZETQILUTJDIRCU-GLSBDXMNSA-M 0.000 claims description 19
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 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 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 230000000241 respiratory effect Effects 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- QNJLKXCSRKQDKU-JQXPCOHGSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(3-methylphenyl)-n-[(2,4,5-trifluorophenyl)methyl]carbamate;bromide Chemical compound [Br-].CC1=CC=CC(N(CC=2C(=CC(F)=C(F)C=2)F)C(=O)O[C@@H]2C3CC[N+](CC3)(CCOC=3C=CC=CC=3)C2)=C1 QNJLKXCSRKQDKU-JQXPCOHGSA-M 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- CAKRLTNLKHYGIV-DFXIHDQSSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(3-fluorophenyl)-n-[(3,4,5-trifluorophenyl)methyl]carbamate;bromide Chemical compound [Br-].FC1=CC=CC(N(CC=2C=C(F)C(F)=C(F)C=2)C(=O)O[C@@H]2C3CC[N+](CC3)(CCOC=3C=CC=CC=3)C2)=C1 CAKRLTNLKHYGIV-DFXIHDQSSA-M 0.000 claims description 4
- FZXAKJUEACVCHO-OCCBKRFISA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(3-fluorophenyl)-n-[(3-fluorophenyl)methyl]carbamate;bromide Chemical compound [Br-].FC1=CC=CC(CN(C(=O)O[C@@H]2C3CC[N+](CC3)(CCCC=3C=CC=CC=3)C2)C=2C=C(F)C=CC=2)=C1 FZXAKJUEACVCHO-OCCBKRFISA-M 0.000 claims description 4
- QKWOYWROMVNAEX-QKIIOBKNSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(3-methylphenyl)-n-[(2,4,5-trifluorophenyl)methyl]carbamate;bromide Chemical compound [Br-].CC1=CC=CC(N(CC=2C(=CC(F)=C(F)C=2)F)C(=O)O[C@@H]2C3CC[N+](CC3)(CCCC=3C=CC=CC=3)C2)=C1 QKWOYWROMVNAEX-QKIIOBKNSA-M 0.000 claims description 4
- 230000008485 antagonism Effects 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
- 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 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- CUNGHFMJRNSNPJ-COYDLIIGSA-N [(3R)-1-(3-cyanopropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] N-[5-(2,6-difluorophenyl)pent-4-enyl]carbamate 2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.FC1=CC=CC(F)=C1C=CCCCNC(=O)O[C@@H]1C(CC2)CC[N+]2(CCCC#N)C1 CUNGHFMJRNSNPJ-COYDLIIGSA-N 0.000 claims description 3
- KAEPUDLIBVYOEJ-XAEROCQYSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(4-fluoro-2-methylphenyl)-n-[(3-methylthiophen-2-yl)methyl]carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CSC(CN(C(=O)O[C@@H]2C3CC[N+](CC3)(CCOC=3C=CC=CC=3)C2)C=2C(=CC(F)=CC=2)C)=C1C KAEPUDLIBVYOEJ-XAEROCQYSA-M 0.000 claims description 3
- VUCGKSCREHGGOH-JVOSTZHKSA-M [(3r)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-[(5-bromothiophen-2-yl)methyl]-n-(2,4,5-trifluorophenyl)carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=C(F)C(F)=CC(F)=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(CCCOC=2C=CC=CC=2)C1)CC1=CC=C(Br)S1 VUCGKSCREHGGOH-JVOSTZHKSA-M 0.000 claims description 3
- 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 3
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 3
- GABQKHQNXWNJJJ-UHFFFAOYSA-N diphenylcarbamic acid Chemical compound C=1C=CC=CC=1N(C(=O)O)C1=CC=CC=C1 GABQKHQNXWNJJJ-UHFFFAOYSA-N 0.000 claims description 3
- RWOANIBIINMNEZ-SUVRUAAESA-M ethyl 5-[(3r)-3-[2-(3,4-dimethoxyphenyl)ethyl-[(5-methylfuran-2-yl)methyl]carbamoyl]oxy-1-azoniabicyclo[2.2.2]octan-1-yl]pentanoate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.O([C@@H]1C2CC[N+](CC2)(C1)CCCCC(=O)OCC)C(=O)N(CC=1OC(C)=CC=1)CCC1=CC=C(OC)C(OC)=C1 RWOANIBIINMNEZ-SUVRUAAESA-M 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 230000003551 muscarinic effect Effects 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 3
- 108020003175 receptors Proteins 0.000 claims description 3
- TVSLNRQODQRVJZ-UHFFFAOYSA-N 2-(3,4,5-trifluorophenyl)acetonitrile Chemical group FC1=CC(CC#N)=CC(F)=C1F TVSLNRQODQRVJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- CEGCCCRGQJUBCW-BAMNPNLJSA-N [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-(cyclohexylmethyl)-n-(2-fluorophenyl)carbamate Chemical compound O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C(=CC=CC=1)F)CC1CCCCC1 CEGCCCRGQJUBCW-BAMNPNLJSA-N 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- AAPAVYWERMFERN-UHFFFAOYSA-N ethyl(phenyl)carbamic acid Chemical compound CCN(C(O)=O)C1=CC=CC=C1 AAPAVYWERMFERN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims 3
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- XFJKRKKZNJTPBN-DSIRHRFGSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-(2-methylphenyl)-n-[(2,4,5-trifluorophenyl)methyl]carbamate;iodide Chemical compound [I-].CC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(C)C1)CC1=CC(F)=C(F)C=C1F XFJKRKKZNJTPBN-DSIRHRFGSA-M 0.000 claims 1
- XAKKKEVZQFSYKZ-QBJDRERVSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-[(4-fluorophenyl)methyl]-n-(3-methylphenyl)carbamate;iodide Chemical compound [I-].CC1=CC=CC(N(CC=2C=CC(F)=CC=2)C(=O)O[C@@H]2C3CC[N+](CC3)(C)C2)=C1 XAKKKEVZQFSYKZ-QBJDRERVSA-M 0.000 claims 1
- PDLBBRCYBPPQIC-QNHHWSGXSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-[(4-fluorophenyl)methyl]-n-phenylcarbamate;iodide Chemical compound [I-].O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C=CC=CC=1)CC1=CC=C(F)C=C1 PDLBBRCYBPPQIC-QNHHWSGXSA-M 0.000 claims 1
- ZPDVAXBLZFPQPQ-QNHHWSGXSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-(2-fluorophenyl)carbamate;iodide Chemical compound [I-].O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C(=CC=CC=1)F)CC1=CC=CC=C1 ZPDVAXBLZFPQPQ-QNHHWSGXSA-M 0.000 claims 1
- ICYPDFVERJXLOW-RBPPWHDLSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-(2-methylphenyl)carbamate;iodide Chemical compound [I-].CC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(C)C1)CC1=CC=CC=C1 ICYPDFVERJXLOW-RBPPWHDLSA-M 0.000 claims 1
- RDXICHROOMAYQC-SFYJNAPPSA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-phenylcarbamate;iodide Chemical compound [I-].O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C=CC=CC=1)CC1=CC=CC=C1 RDXICHROOMAYQC-SFYJNAPPSA-M 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 200
- 238000002360 preparation method Methods 0.000 abstract description 27
- DSTLXMSUVMLNBP-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octane;carbamate Chemical class NC(O)=O.C1CC2CCN1CC2 DSTLXMSUVMLNBP-UHFFFAOYSA-N 0.000 abstract description 5
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 abstract description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 abstract description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 131
- 239000000243 solution Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 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 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- WKFZHVFBHYHYAK-UHFFFAOYSA-N benzyl(phenyl)carbamic acid Chemical compound C=1C=CC=CC=1N(C(=O)O)CC1=CC=CC=C1 WKFZHVFBHYHYAK-UHFFFAOYSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 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 6
- 208000023504 respiratory system disease Diseases 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000002485 urinary effect Effects 0.000 description 5
- IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 description 4
- 208000009079 Bronchial Spasm Diseases 0.000 description 4
- 208000014181 Bronchial disease Diseases 0.000 description 4
- 206010006482 Bronchospasm Diseases 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000003266 anti-allergic effect Effects 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 208000014001 urinary system disease Diseases 0.000 description 4
- OUJMNRNXTLOPJI-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-benzyl-N-phenylcarbamate Chemical compound C(C1=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=CC=C1 OUJMNRNXTLOPJI-UHFFFAOYSA-N 0.000 description 3
- GWQUOGDIWKSVOG-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-butyl-N-phenylcarbamate Chemical compound C(CCC)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=CC=C1 GWQUOGDIWKSVOG-UHFFFAOYSA-N 0.000 description 3
- USPDKXJEZWRPBT-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-phenyl-N-(thiophen-2-ylmethyl)carbamate Chemical compound C1(=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)CC=1SC=CC=1 USPDKXJEZWRPBT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- QBNZACLTBQTGJP-VRCWUQCGSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(3-fluorophenyl)-n-[(3-fluorophenyl)methyl]carbamate;bromide Chemical compound [Br-].FC1=CC=CC(CN(C(=O)O[C@@H]2C3CC[N+](CC3)(CCOC=3C=CC=CC=3)C2)C=2C=C(F)C=CC=2)=C1 QBNZACLTBQTGJP-VRCWUQCGSA-M 0.000 description 3
- ROECTEAZZKLWOE-MSZWFKHVSA-M [(3r)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n,n-bis(thiophen-2-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3SC=CC=3)CC=3SC=CC=3)[N+]21CCCC1=CC=CS1 ROECTEAZZKLWOE-MSZWFKHVSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000002723 alicyclic group Chemical group 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- CEWKHVQYIATTIC-UHFFFAOYSA-N butyl(phenyl)carbamic acid Chemical compound CCCCN(C(O)=O)C1=CC=CC=C1 CEWKHVQYIATTIC-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- DSNGLKATJGBVIX-UHFFFAOYSA-N 1-azabicyclo[2.2.1]heptan-4-ol Chemical compound C1CN2CCC1(O)C2 DSNGLKATJGBVIX-UHFFFAOYSA-N 0.000 description 2
- LURFOXLMBGTDCQ-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N,N-bis(furan-2-ylmethyl)carbamate Chemical compound O1C(=CC=C1)CN(C(=O)O[N+]12CCC(CC1)CC2)CC=1OC=CC=1 LURFOXLMBGTDCQ-UHFFFAOYSA-N 0.000 description 2
- LQPFYXOOYCSMEN-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-pent-4-enyl-N-phenylcarbamate Chemical compound C=CCCCN(C(=O)O[N+]12CCC(CC1)CC2)c1ccccc1 LQPFYXOOYCSMEN-UHFFFAOYSA-N 0.000 description 2
- DOYFIBKVLYOACR-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-pentyl-N-phenylcarbamate Chemical compound C(CCCC)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=CC=C1 DOYFIBKVLYOACR-UHFFFAOYSA-N 0.000 description 2
- MQXGZORGNMOFQD-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-phenyl-N-(thiophen-3-ylmethyl)carbamate Chemical compound C1(=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)CC1=CSC=C1 MQXGZORGNMOFQD-UHFFFAOYSA-N 0.000 description 2
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 2
- OUDFNZMQXZILJD-UHFFFAOYSA-N 5-methyl-2-furaldehyde Chemical compound CC1=CC=C(C=O)O1 OUDFNZMQXZILJD-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010066091 Bronchial Hyperreactivity Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 206010063057 Cystitis noninfective Diseases 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 2
- 206010029279 Neurogenic bladder Diseases 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 2
- 206010040741 Sinus bradycardia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- OYRARMGTIHJUKV-OWQBZFBLSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(cyclohexylmethyl)-n-(2-fluorophenyl)carbamate;bromide Chemical compound [Br-].FC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(CCOC=2C=CC=CC=2)C1)CC1CCCCC1 OYRARMGTIHJUKV-OWQBZFBLSA-M 0.000 description 2
- GDLWJBJOVTYAJR-GSEXTUOBSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 GDLWJBJOVTYAJR-GSEXTUOBSA-M 0.000 description 2
- JZCRAMPGFZJPOE-ZZNGFPBBSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-butyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CCCC)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 JZCRAMPGFZJPOE-ZZNGFPBBSA-M 0.000 description 2
- HSGQPXOPCPJENX-CCOWBORGSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(thiophen-2-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3SC=CC=3)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 HSGQPXOPCPJENX-CCOWBORGSA-M 0.000 description 2
- RUMIBZGNGQBYPD-DSSKCDFUSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(thiophen-3-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC3=CSC=C3)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 RUMIBZGNGQBYPD-DSSKCDFUSA-M 0.000 description 2
- PIJFPTVLIXOHMJ-DSSKCDFUSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n,n-bis(thiophen-2-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3SC=CC=3)CC=3SC=CC=3)[N+]21CCCC1=CC=CC=C1 PIJFPTVLIXOHMJ-DSSKCDFUSA-M 0.000 description 2
- VDSSSYAPDUAPAR-ACIYGYOISA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(cyclohexylmethyl)-n-(2-fluorophenyl)carbamate;bromide Chemical compound [Br-].FC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(CCCC=2C=CC=CC=2)C1)CC1CCCCC1 VDSSSYAPDUAPAR-ACIYGYOISA-M 0.000 description 2
- RFHYCEHWBDUMOY-AEDYTTQKSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-(furan-2-ylmethyl)-n-phenylcarbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C([C@@H](C(CC1)CC2)OC(=O)N(CC=3OC=CC=3)C=3C=CC=CC=3)[N+]21CCCC1=CC=CC=C1 RFHYCEHWBDUMOY-AEDYTTQKSA-M 0.000 description 2
- PNWQOMABRMWDMF-LVKSKBLHSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCCC1=CC=CC=C1 PNWQOMABRMWDMF-LVKSKBLHSA-M 0.000 description 2
- ZEKWXBFSCSXDLQ-NRMJQQDLSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-butyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CCCC)C=3C=CC=CC=3)[N+]21CCCC1=CC=CC=C1 ZEKWXBFSCSXDLQ-NRMJQQDLSA-M 0.000 description 2
- MCGSMQKZGMDZFT-AEDYTTQKSA-M [(3r)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCCC1=CC=CS1 MCGSMQKZGMDZFT-AEDYTTQKSA-M 0.000 description 2
- FHESLQGDLROIOJ-SSVLGJNASA-M [(3r)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-butyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CCCC)C=3C=CC=CC=3)[N+]21CCCC1=CC=CS1 FHESLQGDLROIOJ-SSVLGJNASA-M 0.000 description 2
- NBAFBTBCPVIPLO-OCJYMVTRSA-M [(3r)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(thiophen-2-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC=3SC=CC=3)C=3C=CC=CC=3)[N+]21CCCC1=CC=CS1 NBAFBTBCPVIPLO-OCJYMVTRSA-M 0.000 description 2
- AJWNYCANTFUYEF-ZZNGFPBBSA-M [(3r)-1-(3-thiophen-2-ylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(thiophen-3-ylmethyl)carbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CC3=CSC=C3)C=3C=CC=CC=3)[N+]21CCCC1=CC=CS1 AJWNYCANTFUYEF-ZZNGFPBBSA-M 0.000 description 2
- KAJQEDYZTVPRPW-WGLRCJLISA-M [(3r)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] n-(furan-3-ylmethyl)-n-[[5-methyl-2-(trifluoromethyl)furan-3-yl]methyl]carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.O1C(C)=CC(CN(CC2=COC=C2)C(=O)O[C@@H]2C3CC[N+](CC3)(CCCOC=3C=CC(F)=CC=3)C2)=C1C(F)(F)F KAJQEDYZTVPRPW-WGLRCJLISA-M 0.000 description 2
- ZAPBKMWEEFIAGB-WTRWISCVSA-M [(3r)-1-heptyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-butyl-n-(2,5-difluorophenyl)carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.O([C@@H]1C2CC[N+](CC2)(C1)CCCCCCC)C(=O)N(CCCC)C1=CC(F)=CC=C1F ZAPBKMWEEFIAGB-WTRWISCVSA-M 0.000 description 2
- OJBOKNOKZXHCRK-SUPQUVAKSA-M [(3r)-1-heptyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-pent-4-enyl-n-phenylcarbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.O([C@@H]1C2CC[N+](CC2)(C1)CCCCCCC)C(=O)N(CCCC=C)C1=CC=CC=C1 OJBOKNOKZXHCRK-SUPQUVAKSA-M 0.000 description 2
- PJJFWYFVSOKAIA-TULJGGFASA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-cyclopentyl-n-[(4,5-dimethylthiophen-2-yl)methyl]carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.S1C(C)=C(C)C=C1CN(C(=O)O[C@@H]1C2CC[N+](CC2)(C)C1)C1CCCC1 PJJFWYFVSOKAIA-TULJGGFASA-M 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 229940124748 beta 2 agonist Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000036427 bronchial hyperreactivity Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 208000007784 diverticulitis Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000000762 glandular Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000001734 parasympathetic effect Effects 0.000 description 2
- UIMCAHUVQVVYPJ-UHFFFAOYSA-N pentyl(phenyl)carbamic acid Chemical compound CCCCCN(C(O)=O)C1=CC=CC=C1 UIMCAHUVQVVYPJ-UHFFFAOYSA-N 0.000 description 2
- OLTPKMBOLARPFC-UHFFFAOYSA-N phenyl(2-phenylethyl)carbamic acid Chemical compound C=1C=CC=CC=1N(C(=O)O)CCC1=CC=CC=C1 OLTPKMBOLARPFC-UHFFFAOYSA-N 0.000 description 2
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000001148 spastic effect Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- IVLICPVPXWEGCA-SSDOTTSWSA-N (3s)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@H](O)CN1CC2 IVLICPVPXWEGCA-SSDOTTSWSA-N 0.000 description 1
- RQRSQXFVRUWISR-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-4-ol Chemical compound C1CN2CCC1(O)CC2 RQRSQXFVRUWISR-UHFFFAOYSA-N 0.000 description 1
- WFQKPCLZQMECEZ-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N,N-bis(thiophen-2-ylmethyl)carbamate Chemical compound S1C(=CC=C1)CN(C(=O)O[N+]12CCC(CC1)CC2)CC=1SC=CC=1 WFQKPCLZQMECEZ-UHFFFAOYSA-N 0.000 description 1
- RAKWUKMOMDBGAO-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-(furan-2-ylmethyl)-N-(thiophen-2-ylmethyl)carbamate Chemical compound O1C(=CC=C1)CN(C(=O)O[N+]12CCC(CC1)CC2)CC=1SC=CC=1 RAKWUKMOMDBGAO-UHFFFAOYSA-N 0.000 description 1
- HOCYEGVIHOEMKD-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-(furan-2-ylmethyl)-N-phenylcarbamate Chemical compound O1C(=CC=C1)CN(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=CC=C1 HOCYEGVIHOEMKD-UHFFFAOYSA-N 0.000 description 1
- FKELHARXJLGVKU-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-benzyl-N-(4-fluorophenyl)carbamate Chemical compound C(C1=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=C(C=C1)F FKELHARXJLGVKU-UHFFFAOYSA-N 0.000 description 1
- OWZBDOUVXLXXDT-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-benzyl-N-(4-methylphenyl)carbamate Chemical compound C(C1=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=C(C=C1)C OWZBDOUVXLXXDT-UHFFFAOYSA-N 0.000 description 1
- QANNJABNODULAJ-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-butyl-N-(thiophen-2-ylmethyl)carbamate Chemical compound C(CCC)N(C(=O)O[N+]12CCC(CC1)CC2)CC=1SC=CC=1 QANNJABNODULAJ-UHFFFAOYSA-N 0.000 description 1
- OMSMCCHDUVXQDC-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-cyclopentyl-N-(thiophen-2-ylmethyl)carbamate Chemical compound C1(CCCC1)N(C(=O)O[N+]12CCC(CC1)CC2)CC=1SC=CC=1 OMSMCCHDUVXQDC-UHFFFAOYSA-N 0.000 description 1
- YCYGAQICBXNSCT-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octan-1-yl N-phenyl-N-(2-phenylethyl)carbamate Chemical compound C(CC1=CC=CC=C1)N(C(=O)O[N+]12CCC(CC1)CC2)C1=CC=CC=C1 YCYGAQICBXNSCT-UHFFFAOYSA-N 0.000 description 1
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- QMYVWJVVVMIBMM-UHFFFAOYSA-N 2,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C=C1F QMYVWJVVVMIBMM-UHFFFAOYSA-N 0.000 description 1
- CYIFJRXFYSUBFW-UHFFFAOYSA-N 2,4,5-trifluorobenzaldehyde Chemical compound FC1=CC(F)=C(C=O)C=C1F CYIFJRXFYSUBFW-UHFFFAOYSA-N 0.000 description 1
- WUBZVWLDMUDMRL-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-n-[(5-methylfuran-2-yl)methyl]ethanamine Chemical compound C1=C(OC)C(OC)=CC=C1CCNCC1=CC=C(C)O1 WUBZVWLDMUDMRL-UHFFFAOYSA-N 0.000 description 1
- MMZJZOAVHSPESP-UHFFFAOYSA-N 2-(3-bromopropyl)thiophene Chemical compound BrCCCC1=CC=CS1 MMZJZOAVHSPESP-UHFFFAOYSA-N 0.000 description 1
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- HCPTUKROWNAPOK-UHFFFAOYSA-N 3-methyl-n-[(2,4,5-trifluorophenyl)methyl]aniline Chemical compound CC1=CC=CC(NCC=2C(=CC(F)=C(F)C=2)F)=C1 HCPTUKROWNAPOK-UHFFFAOYSA-N 0.000 description 1
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- GFBVUFQNHLUCPX-UHFFFAOYSA-N 5-bromothiophene-2-carbaldehyde Chemical compound BrC1=CC=C(C=O)S1 GFBVUFQNHLUCPX-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- PNWQOMABRMWDMF-IHNSNXCOSA-M C(C1=CC=CC=C1)N(C(=O)O[C@@H]1C[N+]2(CCC1CC2)CCCC1=CC=CC=C1)C1=CC=CC=C1.[Br-] Chemical compound C(C1=CC=CC=C1)N(C(=O)O[C@@H]1C[N+]2(CCC1CC2)CCCC1=CC=CC=C1)C1=CC=CC=C1.[Br-] PNWQOMABRMWDMF-IHNSNXCOSA-M 0.000 description 1
- NDVLVEOMGWRAFL-BKBBZHFCSA-M CCCCCN(C(O[C@@H]1C(CC2)CC[N+]2(C)C1)=O)C1=CC=CC=C1.[Br-] Chemical compound CCCCCN(C(O[C@@H]1C(CC2)CC[N+]2(C)C1)=O)C1=CC=CC=C1.[Br-] NDVLVEOMGWRAFL-BKBBZHFCSA-M 0.000 description 1
- 102000017926 CHRM2 Human genes 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 101150012960 Chrm2 gene Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 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
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 102000007202 Muscarinic M3 Receptor Human genes 0.000 description 1
- 108010008405 Muscarinic M3 Receptor Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- UPGDXQILBOPJFT-NVYXVAJGSA-M [(3R)-1-(1-phenylethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] N-butyl-N-phenylcarbamate bromide Chemical compound C(CCC)N(C(=O)O[C@H]1C[N+]2(CCC1CC2)C(C)C1=CC=CC=C1)C1=CC=CC=C1.[Br-] UPGDXQILBOPJFT-NVYXVAJGSA-M 0.000 description 1
- KIVRXTXQVSUHHY-SUPQUVAKSA-M [(3R)-1-[2-(2-methoxyethoxy)ethyl]-1-azoniabicyclo[2.2.2]octan-3-yl] N-benzyl-N-phenylcarbamate bromide Chemical compound C(C1=CC=CC=C1)N(C(=O)O[C@H]1C[N+]2(CCC1CC2)CCOCCOC)C1=CC=CC=C1.[Br-] KIVRXTXQVSUHHY-SUPQUVAKSA-M 0.000 description 1
- KQCXUICEBXZMTA-RBPPWHDLSA-M [(3R)-1-[2-(2-methoxyethoxy)ethyl]-1-azoniabicyclo[2.2.2]octan-3-yl] N-butyl-N-phenylcarbamate bromide Chemical compound C(CCC)N(C(=O)O[C@H]1C[N+]2(CCC1CC2)CCOCCOC)C1=CC=CC=C1.[Br-] KQCXUICEBXZMTA-RBPPWHDLSA-M 0.000 description 1
- OPEODEHKLCUUJI-MNFPOUGWSA-M [(3R)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] N-butyl-N-phenylcarbamate chloride Chemical compound C(CCC)N(C(=O)O[C@H]1C[N+]2(CCC1CC2)CCCOC1=CC=C(C=C1)F)C1=CC=CC=C1.[Cl-] OPEODEHKLCUUJI-MNFPOUGWSA-M 0.000 description 1
- UOEJRJHVDCIEEM-QBDSJHRTSA-N [(3R)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] N-(2-methylphenyl)-N-[(2,4,5-trifluorophenyl)methyl]carbamate Chemical compound CC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(C)C1)CC1=CC(F)=C(F)C=C1F UOEJRJHVDCIEEM-QBDSJHRTSA-N 0.000 description 1
- VDYFYTAZNMECEL-YVLJNVBMSA-N [(3R)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] N-[(4-fluorophenyl)methyl]-N-(3-methylphenyl)carbamate Chemical compound CC1=CC=CC(N(CC=2C=CC(F)=CC=2)C(=O)O[C@@H]2C3CC[N+](CC3)(C)C2)=C1 VDYFYTAZNMECEL-YVLJNVBMSA-N 0.000 description 1
- DZGOXROATNFULW-BAMNPNLJSA-N [(3R)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] N-[(4-fluorophenyl)methyl]-N-phenylcarbamate Chemical compound O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C=CC=CC=1)CC1=CC=C(F)C=C1 DZGOXROATNFULW-BAMNPNLJSA-N 0.000 description 1
- KCEAFTFWDUSZFZ-RBPPWHDLSA-M [(3R)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] N-phenyl-N-(2-phenylethyl)carbamate bromide Chemical compound C[N+]12C[C@@H](C(CC1)CC2)OC(N(C1=CC=CC=C1)CCC1=CC=CC=C1)=O.[Br-] KCEAFTFWDUSZFZ-RBPPWHDLSA-M 0.000 description 1
- NJCVUBFVVNHWHH-IIIFQBMYSA-N [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(2-phenylethyl)carbamate Chemical compound C([C@@H](C(CC1)CC2)OC(=O)N(CCC=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 NJCVUBFVVNHWHH-IIIFQBMYSA-N 0.000 description 1
- PAZJAFKVOUZUPG-RARKWRLQSA-M [(3r)-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(2-phenylethyl)carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C([C@@H](C(CC1)CC2)OC(=O)N(CCC=3C=CC=CC=3)C=3C=CC=CC=3)[N+]21CCOC1=CC=CC=C1 PAZJAFKVOUZUPG-RARKWRLQSA-M 0.000 description 1
- GNNJTNLPQMHFBR-DSSKCDFUSA-M [(3r)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octan-3-yl] n-cyclopentyl-n-(thiophen-2-ylmethyl)carbamate;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C([C@@H](C(CC1)CC2)OC(=O)N(CC=3SC=CC=3)C3CCCC3)[N+]21CCCC1=CC=CC=C1 GNNJTNLPQMHFBR-DSSKCDFUSA-M 0.000 description 1
- OEHUXJMRJMPURF-MNFPOUGWSA-M [(3r)-1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-3-yl] n-butyl-n-phenylcarbamate;bromide Chemical compound [Br-].C([C@@H](C(CC1)CC2)OC(=O)N(CCCC)C=3C=CC=CC=3)[N+]21CCCOC1=CC=C(F)C=C1 OEHUXJMRJMPURF-MNFPOUGWSA-M 0.000 description 1
- SQCIRCDVJONUBK-BAMNPNLJSA-N [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-(2-fluorophenyl)carbamate Chemical compound O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C(=CC=CC=1)F)CC1=CC=CC=C1 SQCIRCDVJONUBK-BAMNPNLJSA-N 0.000 description 1
- CCFLJRUTANCPRD-CVCZCXRASA-N [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-(2-methylphenyl)carbamate Chemical compound CC1=CC=CC=C1N(C(=O)O[C@@H]1C2CC[N+](CC2)(C)C1)CC1=CC=CC=C1 CCFLJRUTANCPRD-CVCZCXRASA-N 0.000 description 1
- ZBDPTPGWTQLPMM-MMPATGFWSA-N [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-benzyl-n-phenylcarbamate Chemical compound O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C=CC=CC=1)CC1=CC=CC=C1 ZBDPTPGWTQLPMM-MMPATGFWSA-N 0.000 description 1
- IFLRXULRZIQGMB-YEXUYRPESA-M [(3r)-1-methyl-1-azoniabicyclo[2.2.2]octan-3-yl] n-phenyl-n-(thiophen-2-ylmethyl)carbamate;bromide Chemical compound [Br-].O([C@@H]1C2CC[N+](CC2)(C1)C)C(=O)N(C=1C=CC=CC=1)CC1=CC=CS1 IFLRXULRZIQGMB-YEXUYRPESA-M 0.000 description 1
- QPRWDHVZZSSIHZ-QMAMVGRZSA-M [Br-].C1CC([C@H](C2)OC(=O)N(CC=3C=CC=CC=3)C=3C=CC=CC=3)CC[N+]12C(C)C1=CC=CC=C1 Chemical compound [Br-].C1CC([C@H](C2)OC(=O)N(CC=3C=CC=CC=3)C=3C=CC=CC=3)CC[N+]12C(C)C1=CC=CC=C1 QPRWDHVZZSSIHZ-QMAMVGRZSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- VCJUJZHGRYCPGJ-UHFFFAOYSA-N butyl-(4-fluorophenyl)carbamic acid Chemical compound CCCCN(C(O)=O)C1=CC=C(F)C=C1 VCJUJZHGRYCPGJ-UHFFFAOYSA-N 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 201000003139 chronic cystitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 108700025647 major vault Proteins 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- RYTAWEJFPWUHAM-UHFFFAOYSA-N n-(4-phenylbutyl)carbamoyl chloride Chemical compound ClC(=O)NCCCCC1=CC=CC=C1 RYTAWEJFPWUHAM-UHFFFAOYSA-N 0.000 description 1
- CRLHPNUFQXBBAO-UHFFFAOYSA-N n-(thiophen-2-ylmethyl)cyclopentanamine Chemical compound C=1C=CSC=1CNC1CCCC1 CRLHPNUFQXBBAO-UHFFFAOYSA-N 0.000 description 1
- UANSQQFYKHHDJM-KRWDZBQOSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]naphthalene-1-carboxamide Chemical compound C1=CC=C2C(C(N[C@@H]3C4CCN(CC4)C3)=O)=CC=CC2=C1 UANSQQFYKHHDJM-KRWDZBQOSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JVKPGXHNRQRNEO-UHFFFAOYSA-N n-butyl-n-phenylcarbamoyl chloride Chemical compound CCCCN(C(Cl)=O)C1=CC=CC=C1 JVKPGXHNRQRNEO-UHFFFAOYSA-N 0.000 description 1
- VSHTWPWTCXQLQN-UHFFFAOYSA-N n-butylaniline Chemical compound CCCCNC1=CC=CC=C1 VSHTWPWTCXQLQN-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000075 poly(4-vinylpyridine) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Otolaryngology (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (23)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200201439A ES2203327B1 (es) | 2002-06-21 | 2002-06-21 | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
| UY27850A UY27850A1 (es) | 2002-06-21 | 2003-06-16 | Nuevos carbamatos de quinuclidina y composiciones farmacéuticas que los contienen |
| BR0312169-0A BR0312169A (pt) | 2002-06-21 | 2003-06-18 | Composto, composição farmacêutica, uso do composto, método para o tratamento de um sujeito afligido por uma condição patológica ou doença suscpetivel de redução por antagonismo de receptores muscarìnicos m3 e produto de combinação |
| CA002490082A CA2490082A1 (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| PE2003000615A PE20040579A1 (es) | 2002-06-21 | 2003-06-18 | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen |
| JP2004514785A JP2005533799A (ja) | 2002-06-21 | 2003-06-18 | 新規なるキヌクリジンカルバミン酸誘導体およびそれを含む医薬組成物 |
| AU2003279384A AU2003279384A1 (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| CNB038193272A CN100363363C (zh) | 2002-06-21 | 2003-06-18 | 奎宁环衍生物及含有相同化合物的药用组合物 |
| RU2005101409/04A RU2321588C2 (ru) | 2002-06-21 | 2003-06-18 | Карбаматные производные хинуклидина, фармацевтическая композиция на их основе и применение |
| US10/518,496 US7435742B2 (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| PCT/EP2003/006472 WO2004000840A2 (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| EP03740284A EP1515968A2 (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| MXPA04012272A MXPA04012272A (es) | 2002-06-21 | 2003-06-18 | Nuevos derivados de quinuclidina y composiciones medicinales que contienen los mismos. |
| NZ537252A NZ537252A (en) | 2002-06-21 | 2003-06-18 | Quinuclidine derivatives and pharmaceutical compositions containing the same |
| UAA200500504A UA85541C2 (ru) | 2002-06-21 | 2003-06-18 | Карбаматные производные хинуклидина и фармацевтическая композиции, которая содержит эти соединения |
| ARP030102175A AR040275A1 (es) | 2002-06-21 | 2003-06-19 | Carbamatos de quinuclidina y composiciones farmaceuticas que los contienen |
| TW092116832A TW200401776A (en) | 2002-06-21 | 2003-06-20 | Novel quinuclidine carbamate derivatives and medicinal compositions containing the same |
| EC2004005484A ECSP045484A (es) | 2002-06-21 | 2004-12-10 | Derivados de carbamato de quinuclidina |
| IL16577504A IL165775A0 (en) | 2002-06-21 | 2004-12-15 | Novel quinuclidine derivatives and medicinal compositions containing the same |
| ZA200410211A ZA200410211B (en) | 2002-06-21 | 2004-12-17 | Quinuclidine derivatives and pharmaceutical compositions containing the same. |
| NO20050217A NO20050217L (no) | 2002-06-21 | 2005-01-13 | Nye quinuklidin-karbamat-derivater samt medisinske sammensetninger inneholdende slike |
| US12/205,315 US20090005412A1 (en) | 2002-06-21 | 2008-09-05 | Novel quinuclidine derivatives and medicinal compositions containing the same |
| US12/205,334 US20090054480A1 (en) | 2002-06-21 | 2008-09-05 | Novel quinuclidine carbamate derivatives and medicinal compositions containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200201439A ES2203327B1 (es) | 2002-06-21 | 2002-06-21 | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2203327A1 ES2203327A1 (es) | 2004-04-01 |
| ES2203327B1 true ES2203327B1 (es) | 2005-06-16 |
Family
ID=29797397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200201439A Expired - Fee Related ES2203327B1 (es) | 2002-06-21 | 2002-06-21 | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US7435742B2 (https=) |
| EP (1) | EP1515968A2 (https=) |
| JP (1) | JP2005533799A (https=) |
| CN (1) | CN100363363C (https=) |
| AR (1) | AR040275A1 (https=) |
| AU (1) | AU2003279384A1 (https=) |
| BR (1) | BR0312169A (https=) |
| CA (1) | CA2490082A1 (https=) |
| EC (1) | ECSP045484A (https=) |
| ES (1) | ES2203327B1 (https=) |
| IL (1) | IL165775A0 (https=) |
| MX (1) | MXPA04012272A (https=) |
| NO (1) | NO20050217L (https=) |
| NZ (1) | NZ537252A (https=) |
| PE (1) | PE20040579A1 (https=) |
| RU (1) | RU2321588C2 (https=) |
| TW (1) | TW200401776A (https=) |
| UA (1) | UA85541C2 (https=) |
| UY (1) | UY27850A1 (https=) |
| WO (1) | WO2004000840A2 (https=) |
| ZA (1) | ZA200410211B (https=) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ526580A (en) | 2000-12-22 | 2005-04-29 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| ES2203327B1 (es) | 2002-06-21 | 2005-06-16 | Almirall Prodesfarma, S.A. | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. |
| ES2204295B1 (es) | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de quinuclidina-amida. |
| US7056916B2 (en) | 2002-11-15 | 2006-06-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments for the treatment of chronic obstructive pulmonary disease |
| DK2422786T3 (da) * | 2004-04-22 | 2014-11-17 | Boehringer Ingelheim Int | Nye lægemiddelkombinationer til behandling af luftvejssygdomme |
| US20080287487A1 (en) * | 2004-06-30 | 2008-11-20 | Anthony William James Cooper | Muscarinic Acetylcholine Receptor Antagonists |
| ES2246170B1 (es) * | 2004-07-29 | 2007-04-01 | Almirall Prodesfarma, S.A. | Nuevo procedimiento para preparar derivados de carbamato de quinuclidinio. |
| GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
| BRPI0614410A2 (pt) | 2005-08-15 | 2011-03-29 | Boehringer Ingelheim Int | processo para preparação de betamiméticos |
| DE102006028286A1 (de) * | 2006-06-20 | 2007-12-27 | Wirsich, Konrad, Dipl.-Ing. (FH) | Drehmoment- und rutschfest verbundene aus zwei Teilen bestehende Schaltzahnräder |
| EP1882691A1 (en) * | 2006-07-26 | 2008-01-30 | CHIESI FARMACEUTICI S.p.A. | Quinuclidine derivatives as M3 antagonists |
| EP2119716A4 (en) * | 2007-02-09 | 2011-06-01 | Astellas Pharma Inc | AZA BRIDGE CYCLE COMPOUND |
| CA2675942C (en) * | 2007-02-23 | 2016-04-12 | Theravance, Inc. | Quaternary ammonium diphenylmethyl compounds useful as muscarinic receptor antagonists |
| 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 |
| EP2080507A1 (en) * | 2008-01-15 | 2009-07-22 | CHIESI FARMACEUTICI S.p.A. | Pharmaceutical formulations comprising an anticholinergic drug |
| WO2011094434A2 (en) * | 2010-01-28 | 2011-08-04 | Theron Pharmaceuticals, Inc. | 7-azoniabicyclo [2.2.1] heptane derivatives, methods of production, and pharmaceutical uses thereof |
| KR101987736B1 (ko) * | 2011-03-18 | 2019-06-11 | 젠자임 코포레이션 | 글루코실세라마이드 합성효소 억제제 |
| EP2631674A1 (de) * | 2012-02-23 | 2013-08-28 | ELMOS Semiconductor AG | Verfahren und Sensorsystem zur Vermessung der Eigenschaften einer Übertragungsstrecke eines Messsystems zwischen Sender und Empfänger |
| MA37975B2 (fr) | 2012-09-11 | 2021-03-31 | Genzyme Corp | Inhibiteurs de synthase de glucosylcéramide |
| JP6218940B2 (ja) * | 2013-07-13 | 2017-10-25 | ベイジン エフエスウェルカム テクノロジー ディベロップメント カンパニー リミテッド | キニン系化合物、その光学異性体及びその製造方法と医薬用途 |
| US10570127B1 (en) | 2018-11-05 | 2020-02-25 | Renexxion, Llc | Material and methods for the treatment of gastro-intestinal disorders |
| CN114040762A (zh) | 2019-02-04 | 2022-02-11 | 建新公司 | 使用葡糖神经酰胺合酶(gcs)的抑制剂治疗纤毛疾病 |
| JP2023512366A (ja) | 2020-02-03 | 2023-03-27 | ジェンザイム・コーポレーション | リソソーム蓄積性疾患と関連する神経学的症状を処置するための方法 |
| CN115605202B (zh) | 2020-03-26 | 2025-10-28 | 盐野义制药株式会社 | 具有血清素受体结合活性的芳香族杂环衍生物 |
| AU2021311131B2 (en) | 2020-07-24 | 2026-02-19 | Genzyme Corporation | Pharmaceutical compositions comprising venglustat |
| US20240083872A1 (en) * | 2020-12-28 | 2024-03-14 | Shionogi & Co., Ltd. | Cyclic amine derivatives having serotonin receptor binding activity |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2762796A (en) * | 1956-09-11 | Iminodibenzyl derivative | ||
| GB1219606A (en) | 1968-07-15 | 1971-01-20 | Rech S Et D Applic Scient Soge | Quinuclidinol derivatives and preparation thereof |
| GB1246606A (en) | 1969-04-28 | 1971-09-15 | Starogardzkie Zakl Farma | Dibenzo-azepine derivatives |
| GB8825505D0 (en) * | 1988-11-01 | 1988-12-07 | Pfizer Ltd | Therapeutic agents |
| GB8923590D0 (en) | 1989-10-19 | 1989-12-06 | Pfizer Ltd | Antimuscarinic bronchodilators |
| GB9201751D0 (en) | 1992-01-28 | 1992-03-11 | Smithkline Beecham Plc | Compounds |
| GB9202443D0 (en) | 1992-02-05 | 1992-03-18 | Fujisawa Pharmaceutical Co | A novel substituted-acetamide compound and a process for the preparation thereof |
| WO1995006635A1 (en) * | 1993-09-02 | 1995-03-09 | Yamanouchi Pharmaceutical Co., Ltd. | Carbamate derivative and medicine containing the same |
| AU685225B2 (en) | 1994-02-10 | 1998-01-15 | Yamanouchi Pharmaceutical Co., Ltd. | 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 |
| ATE205490T1 (de) | 1995-10-13 | 2001-09-15 | Banyu Pharma Co Ltd | Substituierte heteroaromatische derivate |
| AUPN862996A0 (en) | 1996-03-13 | 1996-04-04 | Fujisawa Pharmaceutical Co., Ltd. | A novel substituted-acetamide compound |
| PE92198A1 (es) * | 1996-08-01 | 1999-01-09 | Banyu Pharma Co Ltd | Derivados de 1,4-piperidina disustituida que contienen fluor |
| ES2165768B1 (es) * | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| KR100751981B1 (ko) * | 2000-06-27 | 2007-08-28 | 라보라토리오스 살바트, 에스.에이. | 아릴알킬아민으로부터 유도된 카바메이트 |
| NZ526580A (en) * | 2000-12-22 | 2005-04-29 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as M3 antagonists |
| DE60121813T2 (de) | 2000-12-28 | 2007-09-20 | Almirall Ag | Neue chinuclidinderivate und medizinische zusammensetzungen, die diese verbindungen enthalten |
| JP4505227B2 (ja) | 2001-12-20 | 2010-07-21 | キエシ・フアルマチエウテイチ・ソチエタ・ペル・アチオニ | １−アルキル−１−アゾニアビシクロ［２．２．２］オクタンカルバメート誘導体およびムスカリンレセプターアンタゴニストとしてのそれらの使用 |
| 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. |
-
2002
- 2002-06-21 ES ES200201439A patent/ES2203327B1/es not_active Expired - Fee Related
-
2003
- 2003-06-16 UY UY27850A patent/UY27850A1/es not_active Application Discontinuation
- 2003-06-18 WO PCT/EP2003/006472 patent/WO2004000840A2/en not_active Ceased
- 2003-06-18 EP EP03740284A patent/EP1515968A2/en not_active Withdrawn
- 2003-06-18 CN CNB038193272A patent/CN100363363C/zh not_active Expired - Fee Related
- 2003-06-18 CA CA002490082A patent/CA2490082A1/en not_active Abandoned
- 2003-06-18 UA UAA200500504A patent/UA85541C2/ru unknown
- 2003-06-18 BR BR0312169-0A patent/BR0312169A/pt not_active IP Right Cessation
- 2003-06-18 US US10/518,496 patent/US7435742B2/en not_active Expired - Fee Related
- 2003-06-18 MX MXPA04012272A patent/MXPA04012272A/es not_active Application Discontinuation
- 2003-06-18 NZ NZ537252A patent/NZ537252A/en unknown
- 2003-06-18 RU RU2005101409/04A patent/RU2321588C2/ru not_active IP Right Cessation
- 2003-06-18 JP JP2004514785A patent/JP2005533799A/ja active Pending
- 2003-06-18 PE PE2003000615A patent/PE20040579A1/es not_active Application Discontinuation
- 2003-06-18 AU AU2003279384A patent/AU2003279384A1/en not_active Abandoned
- 2003-06-19 AR ARP030102175A patent/AR040275A1/es unknown
- 2003-06-20 TW TW092116832A patent/TW200401776A/zh unknown
-
2004
- 2004-12-10 EC EC2004005484A patent/ECSP045484A/es unknown
- 2004-12-15 IL IL16577504A patent/IL165775A0/xx unknown
- 2004-12-17 ZA ZA200410211A patent/ZA200410211B/xx unknown
-
2005
- 2005-01-13 NO NO20050217A patent/NO20050217L/no not_active Application Discontinuation
-
2008
- 2008-09-05 US US12/205,334 patent/US20090054480A1/en not_active Abandoned
- 2008-09-05 US US12/205,315 patent/US20090005412A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| RU2321588C2 (ru) | 2008-04-10 |
| CN1675206A (zh) | 2005-09-28 |
| CN100363363C (zh) | 2008-01-23 |
| NO20050217L (no) | 2005-03-18 |
| EP1515968A2 (en) | 2005-03-23 |
| US7435742B2 (en) | 2008-10-14 |
| RU2005101409A (ru) | 2005-11-20 |
| JP2005533799A (ja) | 2005-11-10 |
| UA85541C2 (ru) | 2009-02-10 |
| AU2003279384A1 (en) | 2004-01-06 |
| US20090005412A1 (en) | 2009-01-01 |
| PE20040579A1 (es) | 2004-09-08 |
| BR0312169A (pt) | 2005-03-29 |
| WO2004000840A3 (en) | 2004-02-19 |
| IL165775A0 (en) | 2006-01-15 |
| ZA200410211B (en) | 2005-09-06 |
| ECSP045484A (es) | 2005-01-28 |
| CA2490082A1 (en) | 2003-12-31 |
| TW200401776A (en) | 2004-02-01 |
| AR040275A1 (es) | 2005-03-23 |
| ES2203327A1 (es) | 2004-04-01 |
| WO2004000840A2 (en) | 2003-12-31 |
| MXPA04012272A (es) | 2005-04-08 |
| US20090054480A1 (en) | 2009-02-26 |
| UY27850A1 (es) | 2003-11-28 |
| NZ537252A (en) | 2006-07-28 |
| US20060094751A1 (en) | 2006-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2203327B1 (es) | Nuevos carbamatos de quinuclidina y composiciones farmaceuticas que los contienen. | |
| ES2248409T3 (es) | Derivados de carbamato de quinuclidina y su uso como antagonistas de m3. | |
| US7718670B2 (en) | Quinuclidine amide derivatives | |
| RU2282629C2 (ru) | Производные хинуклидина, способ их получения и фармацевтическая композиция на их основе | |
| AU2002228015A1 (en) | Quinuclidine carbamate derivatives and their use as M3 antagonists | |
| HK1055120B (en) | Quinuclidine carbamate derivatives and their use as m3 antagonists | |
| KR20050024450A (ko) | 신규한 퀴누클리딘 아미드 유도체 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EC2A | Search report published |
Date of ref document: 20040401 Kind code of ref document: A1 |
|
| FD2A | Announcement of lapse in spain |
Effective date: 20180808 |