DK2570128T3 - Antagonists to muskarinerg acetylcholine. - Google Patents
Antagonists to muskarinerg acetylcholine. Download PDFInfo
- Publication number
- DK2570128T3 DK2570128T3 DK12170402.7T DK12170402T DK2570128T3 DK 2570128 T3 DK2570128 T3 DK 2570128T3 DK 12170402 T DK12170402 T DK 12170402T DK 2570128 T3 DK2570128 T3 DK 2570128T3
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- hydroxy
- azoniabicyclo
- octane bromide
- oxy
- Prior art date
Links
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 title claims description 10
- 229960004373 acetylcholine Drugs 0.000 title claims description 9
- 239000005557 antagonist Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 93
- -1 2 - {[(3-fluorophenyl) methyl] oxy} ethyl Chemical group 0.000 claims description 48
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 46
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims description 44
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 22
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000004305 biphenyl Substances 0.000 claims description 14
- 235000010290 biphenyl Nutrition 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 102000005962 receptors Human genes 0.000 claims description 7
- 108020003175 receptors Proteins 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- JGZCAKYICCHTOV-UHFFFAOYSA-M bis(3-methylphenyl)-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].CC1=CC=CC(C(O)(C=2C=C(C)C=CC=2)C23CC[N+](CCOCC=4C=CC=CC=4)(CC2)CC3)=C1 JGZCAKYICCHTOV-UHFFFAOYSA-M 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- FQGXKIQQELWWLZ-UHFFFAOYSA-M bis(3-methoxyphenyl)-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].COC1=CC=CC(C(O)(C=2C=C(OC)C=CC=2)C23CC[N+](CCOCC=4C=CC=CC=4)(CC2)CC3)=C1 FQGXKIQQELWWLZ-UHFFFAOYSA-M 0.000 claims description 3
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- BIJYAIPLEKXBGU-UHFFFAOYSA-N 2-[3-[4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octan-1-yl]propoxy]phenol;bromide Chemical compound [Br-].OC1=CC=CC=C1OCCC[N+]1(CC2)CCC2(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 BIJYAIPLEKXBGU-UHFFFAOYSA-N 0.000 claims description 2
- 206010061876 Obstruction Diseases 0.000 claims description 2
- GXSUPSQXDPKCBP-UHFFFAOYSA-M [1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 GXSUPSQXDPKCBP-UHFFFAOYSA-M 0.000 claims description 2
- DHRPQUDMYBRWKJ-UHFFFAOYSA-M [1-(2-phenoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-dithiophen-2-ylmethanol;bromide Chemical compound [Br-].C=1C=CSC=1C(C12CC[N+](CCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CS1 DHRPQUDMYBRWKJ-UHFFFAOYSA-M 0.000 claims description 2
- RCJDDQUDTGKEGA-UHFFFAOYSA-M [1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-di(thiophen-3-yl)methanol;bromide Chemical compound [Br-].C1=CSC=C1C(C12CC[N+](CCCOC=3C=CC=CC=3)(CC1)CC2)(O)C=1C=CSC=1 RCJDDQUDTGKEGA-UHFFFAOYSA-M 0.000 claims description 2
- MVYUVZORWYSLPK-UHFFFAOYSA-M [1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 MVYUVZORWYSLPK-UHFFFAOYSA-M 0.000 claims description 2
- AZFBLKOSLDSFLF-UHFFFAOYSA-M [1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-dithiophen-2-ylmethanol;bromide Chemical compound [Br-].C=1C=CSC=1C(C12CC[N+](CCCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CS1 AZFBLKOSLDSFLF-UHFFFAOYSA-M 0.000 claims description 2
- COPKCSVWCOELAC-UHFFFAOYSA-M [1-(4-phenoxybutyl)-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 COPKCSVWCOELAC-UHFFFAOYSA-M 0.000 claims description 2
- NBNRDFMHLAKVME-UHFFFAOYSA-M [1-[3-(2-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOC=3C(=CC=CC=3)F)(CC1)CC2)(O)C1=CC=CC=C1 NBNRDFMHLAKVME-UHFFFAOYSA-M 0.000 claims description 2
- OKBSOVWMXJPOJU-UHFFFAOYSA-M [1-[3-(2-methylphenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].CC1=CC=CC=C1OCCC[N+]1(CC2)CCC2(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 OKBSOVWMXJPOJU-UHFFFAOYSA-M 0.000 claims description 2
- XIDWOLDYKKJTMX-UHFFFAOYSA-M [1-[3-(3-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOC=3C=C(C=CC=3)[N+]([O-])=O)(CC1)CC2)(O)C1=CC=CC=C1 XIDWOLDYKKJTMX-UHFFFAOYSA-M 0.000 claims description 2
- ZMIFYLXDBQOKGF-UHFFFAOYSA-M [1-[3-(4-fluorophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOC=3C=CC(F)=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 ZMIFYLXDBQOKGF-UHFFFAOYSA-M 0.000 claims description 2
- XQVCZCXPHZGYBQ-UHFFFAOYSA-M [1-[3-(4-nitrophenoxy)propyl]-1-azoniabicyclo[2.2.2]octan-4-yl]-diphenylmethanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOC=3C=CC(=CC=3)[N+]([O-])=O)(CC1)CC2)(O)C1=CC=CC=C1 XQVCZCXPHZGYBQ-UHFFFAOYSA-M 0.000 claims description 2
- FTFQOHPIVJFSFN-UHFFFAOYSA-M bis(3-fluorophenyl)-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].C=1C=CC(F)=CC=1C(C12CC[N+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC(F)=C1 FTFQOHPIVJFSFN-UHFFFAOYSA-M 0.000 claims description 2
- LHOPKDSVDNZVFB-UHFFFAOYSA-M bis(4-fluorophenyl)-[1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].C=1C=C(F)C=CC=1C(C12CC[N+](CCCOC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=C(F)C=C1 LHOPKDSVDNZVFB-UHFFFAOYSA-M 0.000 claims description 2
- CFXRBEDIYVRMIQ-UHFFFAOYSA-M bis(4-methylphenyl)-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].C1=CC(C)=CC=C1C(O)(C12CC[N+](CCOCC=3C=CC=CC=3)(CC1)CC2)C1=CC=C(C)C=C1 CFXRBEDIYVRMIQ-UHFFFAOYSA-M 0.000 claims description 2
- KEMWNQKRGGOVDG-UHFFFAOYSA-M diphenyl-[1-(3-phenylmethoxypropyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C12CC[N+](CCCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 KEMWNQKRGGOVDG-UHFFFAOYSA-M 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 2
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- 125000006267 biphenyl group Chemical group 0.000 claims 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 3
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- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims 1
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- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 150000008584 quinuclidines Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229960002052 salbutamol Drugs 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
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940046810 spiriva Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 230000007384 vagal nerve stimulation Effects 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
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/452—Piperidinium derivatives
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56562304P | 2004-04-27 | 2004-04-27 | |
| EP05746609A EP1740177B1 (en) | 2004-04-27 | 2005-04-27 | Muscarinic acetylcholine receptor antagonists |
| PCT/US2005/014386 WO2005104745A2 (en) | 2004-04-27 | 2005-04-27 | Muscarinic acetylcholine receptor antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2570128T3 true DK2570128T3 (en) | 2016-11-07 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12170402.7T DK2570128T3 (en) | 2004-04-27 | 2005-04-27 | Antagonists to muskarinerg acetylcholine. |
| DK05746609.6T DK1740177T3 (da) | 2004-04-27 | 2005-04-27 | Antagonister til muskarinfølsomme acetylcholinreceptorer |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK05746609.6T DK1740177T3 (da) | 2004-04-27 | 2005-04-27 | Antagonister til muskarinfølsomme acetylcholinreceptorer |
Country Status (38)
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| TW200519108A (en) * | 2003-07-17 | 2005-06-16 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
| TW200528448A (en) * | 2003-10-17 | 2005-09-01 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
| AR046225A1 (es) * | 2003-11-04 | 2005-11-30 | Glaxo Group Ltd | Compuesto de 8-azoniabiciclo(3.2.1)octano, composicion farmaceutica para el tratamiento de enfermedades mediadas por receptores de acetilcolina muscarinicos que lo comprende y uso del compuesto para preparar dicha composicion |
| US20090253908A1 (en) * | 2004-03-11 | 2009-10-08 | Glaxo Group Limited | Novel m3 muscarinic acetylchoine receptor antagonists |
| US7384946B2 (en) * | 2004-03-17 | 2008-06-10 | Glaxo Group Limited | M3 muscarinic acetylcholine receptor antagonists |
| WO2005094251A2 (en) * | 2004-03-17 | 2005-10-13 | Glaxo Group Limited | M3muscarinic acetylcholine receptor antagonists |
| DE602005009158D1 (de) * | 2004-04-05 | 2008-10-02 | Samaritan Pharmaceuticals Inc | Anti-hiv-chinuklidinverbindungen |
| UY28871A1 (es) | 2004-04-27 | 2005-11-30 | Glaxo Group Ltd | Antagonistas del receptor de acetilcolina muscarinico |
| WO2005112644A2 (en) * | 2004-05-13 | 2005-12-01 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
| JP2008520579A (ja) * | 2004-11-15 | 2008-06-19 | グラクソ グループ リミテッド | 新規ｍ３ムスカリン性アセチルコリン受容体アンタゴニスト |
| US20080275079A1 (en) * | 2005-08-02 | 2008-11-06 | Glaxo Group Limited | M3 Muscarinic Acetylcholine Receptor Antagonists |
| EP1937068A4 (en) * | 2005-08-18 | 2010-08-04 | Glaxo Group Ltd | ANTAGONISTS OF ACETYLCHOLINE MUSCARINIC RECEPTORS |
| US7943651B2 (en) | 2006-04-20 | 2011-05-17 | Glaxo Group Limited | Compounds |
| GB0611587D0 (en) | 2006-06-12 | 2006-07-19 | Glaxo Group Ltd | Novel compounds |
| HRP20110434T1 (hr) | 2006-08-01 | 2011-08-31 | Glaxo Group Limited | Spojevi pirazolo[3,4-b]piridina i njihova upotreba kao inhibitora pde4 |
| PE20081889A1 (es) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | Indol carboxamidas como inhibidores de ikk2 |
| TW200946525A (en) | 2008-02-06 | 2009-11-16 | Glaxo Group Ltd | Dual pharmacophores-PDE4-muscarinic antagonistics |
| CL2009000250A1 (es) | 2008-02-06 | 2009-09-11 | Glaxo Group Ltd | Compuestos derivados de pirazolo[3,4-b]piridina carboxamida; composicion farmaceutica que los comprende; y su uso en el tratamiento del asma, epoc y rinitis. |
| UY31635A1 (es) | 2008-02-06 | 2009-08-31 | Farmacóforos duales-antagonistas muscarínicos de pde4 | |
| EP2280959B1 (en) | 2008-06-05 | 2012-04-04 | Glaxo Group Limited | 4-amino-indazoles |
| JP5502858B2 (ja) | 2008-06-05 | 2014-05-28 | グラクソ グループ リミテッド | Ｐｉ３キナーゼの阻害剤として有用な４−カルボキサミドインダゾール誘導体 |
| WO2010094643A1 (en) | 2009-02-17 | 2010-08-26 | Glaxo Group Limited | Quinoline derivatives and their uses for rhinitis and urticaria |
| US11116721B2 (en) | 2009-02-26 | 2021-09-14 | Glaxo Group Limited | Pharmaceutical formulations comprising 4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol |
| US8524751B2 (en) | 2009-03-09 | 2013-09-03 | GlaxoSmithKline Intellecutual Property Development | 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases |
| WO2010102968A1 (en) | 2009-03-10 | 2010-09-16 | Glaxo Group Limited | Indole derivatives as ikk2 inhibitors |
| US20120058984A1 (en) | 2009-03-17 | 2012-03-08 | Catherine Mary Alder | Pyrimidine derivatives used as itk inhibitors |
| PE20120321A1 (es) | 2009-04-30 | 2012-04-19 | Glaxo Group Ltd | Indazoles sustituidos con oxazol como inhibidores de pi3-quinasa |
| WO2011029896A1 (en) | 2009-09-11 | 2011-03-17 | Glaxo Group Limited | Methods of preparation of muscarinic acetylcholine receptor antagonists |
| GB0921075D0 (en) | 2009-12-01 | 2010-01-13 | Glaxo Group Ltd | Novel combination of the therapeutic agents |
| EP2507231A1 (en) | 2009-12-03 | 2012-10-10 | Glaxo Group Limited | Indazole derivatives as pi 3 - kinase inhibitors |
| JP2013512878A (ja) | 2009-12-03 | 2013-04-18 | グラクソ グループ リミテッド | 新規化合物 |
| US20120245171A1 (en) | 2009-12-03 | 2012-09-27 | Glaxo Group Limited | Benzpyrazole derivatives as inhibitors of pi3 kinases |
| US8426611B2 (en) * | 2010-01-28 | 2013-04-23 | Theron Pharmaceuticals Inc. | 7-azoniabicyclo[2.2.1]heptane derivatives, methods of production, and pharmaceutical uses thereof |
| WO2011110575A1 (en) | 2010-03-11 | 2011-09-15 | Glaxo Group Limited | Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases |
| PH12012502404A1 (en) * | 2010-06-22 | 2013-02-18 | Chiesi Farm Spa | Dry powder formulation comprising an antimuscarinic drug |
| EP2614058B1 (en) | 2010-09-08 | 2015-07-08 | GlaxoSmithKline Intellectual Property Development Limited | POLYMORPHS AND SALTS OF N-[5-[4-(5-{[(2R,6S)-2,6-DIMETHYL-4-MORPHOLINYL]METHYL}-& xA;1,3-OXAZOL-2-YL)-1H-INDAZOL-6-YL]-2-(METHYLOXY)-3-PYRIDINYL]METHANESULFONAMIDE |
| WO2012035055A1 (en) | 2010-09-17 | 2012-03-22 | Glaxo Group Limited | Novel compounds |
| GB201018124D0 (en) | 2010-10-27 | 2010-12-08 | Glaxo Group Ltd | Polymorphs and salts |
| AU2012266541A1 (en) * | 2011-06-08 | 2014-01-09 | Glaxo Group Limited | Combination comprising umeclidinium and a corticosteroid |
| US20140116434A1 (en) | 2011-06-08 | 2014-05-01 | Glaxo Group Limited | Dry Powder Inhaler Compositions |
| CA2869849A1 (en) | 2012-04-13 | 2013-10-17 | Glaxosmithkline Intellectual Property Development Limited | Aggregate particles comprising nanoparticulate drug particles of umeclidinium bromide, vilanterol trifenatate and fluticasone furoate |
| RU2502743C1 (ru) * | 2012-08-03 | 2013-12-27 | Федеральное государственное бюджетное учреждение "Российский кардиологический научно-производственный комплекс" Министерства здравоохранения и социального развития РФ (ФГБУ "РКНПК" Минздравсоцразвития России) | Синтетический антиген, обладающий способностью связывать аутоантитела к мускариновому м2-рецептору |
| JP6389174B2 (ja) * | 2012-08-15 | 2018-09-12 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | 化学的方法 |
| GB201222679D0 (en) * | 2012-12-17 | 2013-01-30 | Glaxo Group Ltd | Pharmaceutical combination products |
| TR201906532T4 (tr) * | 2013-07-13 | 2019-05-21 | Beijing Shuobai Pharmaceutical Co Ltd | Kinin bileşikleri ve optik izomerleri, hazırlanış yöntemleri ve tıbbi kullanımları. |
| CA2919979A1 (en) | 2013-07-30 | 2015-02-05 | Glaxosmithkline Intellectual Property Development Limited | Topical compositions for treatment of excessive sweating and methods of use thereof |
| JP6475707B2 (ja) | 2013-10-17 | 2019-02-27 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | 呼吸器疾患の治療のためのｐｉ３ｋ阻害剤 |
| US20160256466A1 (en) | 2013-10-17 | 2016-09-08 | Glaxosmithkline Intellectual Property Development Limited | Pi3k inhibitor for treatment of respiratory disease |
| EA201692111A1 (ru) | 2014-05-12 | 2017-08-31 | Глаксосмитклайн Интеллекчуал Проперти (№ 2) Лимитед | Фармацевтические композиции, содержащие данириксин, для лечения инфекционных заболеваний |
| EP3148521B1 (en) | 2014-05-28 | 2019-12-18 | GlaxoSmithKline Intellectual Property Development Limited | Fluticasone furoate in the treatment of copd |
| JP6615212B2 (ja) * | 2014-11-03 | 2019-12-04 | オロン ソシエタ ペル アチオニ | １−（２−ハロゲン−エチル）−４−ピぺリジンカルボン酸エチルエステルの製法 |
| KR101613245B1 (ko) | 2015-04-27 | 2016-04-18 | 주식회사 대웅제약 | 신규의 4-메톡시 피롤 유도체 또는 이의 염 및 이를 포함하는 약학 조성물 |
| CN105461710A (zh) * | 2015-10-23 | 2016-04-06 | 安徽德信佳生物医药有限公司 | 一种芜地溴铵的制备方法 |
| KR102794286B1 (ko) * | 2016-01-08 | 2025-04-09 | 테론 파마슈티칼즈, 인크. | 7-아조니아바이사이클로[2.2.1]헵탄 유도체의 건조 분말 흡입기 조성물 |
| GB201602527D0 (en) | 2016-02-12 | 2016-03-30 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| CN107200734B (zh) * | 2016-03-18 | 2019-12-24 | 益方生物科技（上海）有限公司 | 奎宁环衍生物及其制备方法和用途 |
| EP3248970A1 (en) | 2016-05-27 | 2017-11-29 | Zentiva K.S. | Forms of umeclidinium bromide |
| US20190161480A1 (en) | 2016-08-08 | 2019-05-30 | Glaxosmithkline Intellectual Property Development Limited | Chemical Compounds |
| PT109740B (pt) * | 2016-11-14 | 2020-07-30 | Hovione Farmaciencia Sa | Processo para a preparação de brometo de umeclidínio |
| WO2018163212A1 (en) * | 2017-03-08 | 2018-09-13 | Gbr Laboratories Pvt. Ltd | A process for the preparation of umeclidinium bromide and intermediates thereof |
| GB201706102D0 (en) | 2017-04-18 | 2017-05-31 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| IT201700058796A1 (it) * | 2017-05-30 | 2018-11-30 | Olon Spa | Procedimento per la preparazione di un nuovo intermedio di sintesi dell’umeclidinio. |
| GB201712081D0 (en) | 2017-07-27 | 2017-09-13 | Glaxosmithkline Ip Dev Ltd | Chemical compounds |
| ES2991988T3 (es) | 2017-10-30 | 2024-12-05 | Takeda Pharmaceuticals Co | Detergentes compatibles con el medio ambiente para la inactivación de virus con envoltura lipídica |
| CN108558860B (zh) * | 2018-06-04 | 2020-12-25 | 成都伊诺达博医药科技有限公司 | 一种合成芜地溴铵的方法 |
| WO2020047225A1 (en) | 2018-08-30 | 2020-03-05 | Theravance Biopharma R&D Ip, Llc | Methods for treating chronic obstructive pulmonary disease |
| PT115583B (pt) | 2019-06-17 | 2022-05-02 | Hovione Farm S A | Processo contínuo para a preparação de medicamentos anticolinérgicos |
| CN113387923A (zh) * | 2020-03-13 | 2021-09-14 | 诺华股份有限公司 | 硫辛酸胆碱酯盐的药物组合物及使用其的治疗方法 |
| EP4125919A1 (en) | 2020-03-26 | 2023-02-08 | GlaxoSmithKline Intellectual Property Development Limited | Cathepsin inhibitors for preventing or treating viral infections |
| CN111484445B (zh) * | 2020-04-21 | 2021-05-18 | 广东莱佛士制药技术有限公司 | 分离纯化高纯度乌美溴铵的中间体的方法 |
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| WO2022053651A2 (en) | 2020-09-10 | 2022-03-17 | Precirix N.V. | Antibody fragment against fap |
| CN112479983B (zh) * | 2020-11-25 | 2022-07-12 | 江苏豪森药业集团有限公司 | 乌美溴铵中间体及其制备方法 |
| PT117440B (pt) | 2021-09-03 | 2024-04-26 | Hovione Farm S A | Processo para a preparação de aminas cíclicas cloroaquilo substituídas |
| WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
| JP2025517625A (ja) | 2022-05-02 | 2025-06-10 | プレシリックス・ナームローゼ・ベンノートシヤープ | プレターゲティング |
| WO2024251812A1 (en) | 2023-06-07 | 2024-12-12 | Pharmazell Gmbh | A process for the preparation of umeclidinium bromide intermediate |
Family Cites Families (63)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2800481A (en) * | 1955-07-01 | 1957-07-23 | Smith Kline French Lab | Tertiary alcohol derivatives of 8-alkylnortropanes and the acid and quaternary ammonium salts thereof |
| US2800478A (en) * | 1955-07-01 | 1957-07-23 | Smith Kline French Lab | 3-substituted-8-alkylnortropanes and the acid and quaternary ammonium salts thereof |
| AT298118B (de) * | 1967-06-08 | 1972-04-25 | Siemens Ag | Verfahren zur Umsetzung von Spannungen in digitale Werte und Vorrichtung zur Durchführung des Verfahrens |
| GB1242211A (en) | 1967-08-08 | 1971-08-11 | Fisons Pharmaceuticals Ltd | Pharmaceutical composition |
| GB1230087A (enExample) | 1967-08-17 | 1971-04-28 | ||
| GB1381872A (en) | 1971-06-22 | 1975-01-29 | Fisons Ltd | Pharmaceutical compositions for inhalation |
| CY1308A (en) | 1979-12-06 | 1985-12-06 | Glaxo Group Ltd | Device for dispensing medicaments |
| DE3274065D1 (de) | 1981-07-08 | 1986-12-11 | Draco Ab | Powder inhalator |
| GB2169265B (en) | 1982-10-08 | 1987-08-12 | Glaxo Group Ltd | Pack for medicament |
| CA1224992A (en) | 1982-10-08 | 1987-08-04 | Robert E. Newell | Device for administering medicament to patients |
| FI88112C (fi) | 1985-07-30 | 1993-04-13 | Glaxo Group Ltd | Anordning foer administrering av laekemedel till patienter |
| IT1204826B (it) | 1986-03-04 | 1989-03-10 | Chiesi Farma Spa | Composizioni farmaceutiche per inalazione |
| GB9004781D0 (en) * | 1990-03-02 | 1990-04-25 | Glaxo Group Ltd | Device |
| US5780466A (en) * | 1995-01-30 | 1998-07-14 | Sanofi | Substituted heterocyclic compounds method of preparing them and pharmaceutical compositions in which they are present |
| EP0944626A4 (en) * | 1996-12-02 | 2002-09-04 | Univ Georgetown | TROPANDERIVATIVES AND METHOD FOR YOUR SYNTHESIS |
| US6248752B1 (en) * | 1998-02-27 | 2001-06-19 | Charles Duane Smith | Azabicyclooctane compositions and methods for enhancing chemotherapy |
| US6262066B1 (en) * | 1998-07-27 | 2001-07-17 | Schering Corporation | High affinity ligands for nociceptin receptor ORL-1 |
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| HUP0303524A3 (en) * | 2000-12-28 | 2008-03-28 | Almirall Ag | Novel quinuclidine derivatives, process for their preparation and medicinal compositions containing the same and their use |
| WO2003033495A1 (en) * | 2001-10-17 | 2003-04-24 | Ucb, S.A. | Quinuclidine derivatives, processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors |
| US6951868B2 (en) * | 2001-11-09 | 2005-10-04 | Pfizer Inc. | Azabicyclic-phenyl-fused-heterocyclic compounds for treatment of disease |
| 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 |
| US6696462B2 (en) | 2002-01-31 | 2004-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions |
| ES2206021B1 (es) | 2002-04-16 | 2005-08-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de pirrolidinio. |
| ES2204295B1 (es) * | 2002-07-02 | 2005-08-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de quinuclidina-amida. |
| AR040779A1 (es) | 2002-08-06 | 2005-04-20 | Glaxo Group Ltd | Compuesto de tiazol anilina su uso para preparar una formulacion farmaceutica dicha formulacion recipiente que la contiene y dispositivo adaptado para la administracion intranasal de la formulacion |
| EP1613307A4 (en) | 2003-04-07 | 2008-03-12 | Glaxo Group Ltd | M SB 3 / SB MUSCARIN ACETYLCHOLINE RECEPTOR ANTAGONISTS |
| AR048573A1 (es) | 2003-07-17 | 2006-05-10 | Glaxo Group Ltd | Compuesto de 8-azoniabiciclo[3.2.1]octano sustituido en la posicion 3, composicion farmceutica que lo comprende y su uso para preparar esta ultima |
| AR045913A1 (es) | 2003-07-17 | 2005-11-16 | Glaxo Group Ltd | Derivados olefinicos de 8-azabiciclo[3,2,1]octanos como antagonistas de receptores muscarinicos de acetilcolina |
| TW200519108A (en) | 2003-07-17 | 2005-06-16 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
| DE602004030930D1 (de) | 2003-10-14 | 2011-02-17 | Glaxo Group Ltd | Muscarinische acetylcholin-rezeptor-antagonisten |
| TW200528448A (en) | 2003-10-17 | 2005-09-01 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
| AR046225A1 (es) | 2003-11-04 | 2005-11-30 | Glaxo Group Ltd | Compuesto de 8-azoniabiciclo(3.2.1)octano, composicion farmaceutica para el tratamiento de enfermedades mediadas por receptores de acetilcolina muscarinicos que lo comprende y uso del compuesto para preparar dicha composicion |
| US7345060B2 (en) * | 2003-11-21 | 2008-03-18 | Theravance, Inc. | Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity |
| AR046783A1 (es) | 2003-12-03 | 2005-12-21 | Glaxo Group Ltd | Compuesto de sal ciclica de amonio cuaternario composicion farmaceutica que lo comprende y su uso para preparar esta ultima |
| UY28645A1 (es) | 2003-12-03 | 2005-06-30 | Glaxo Group Ltd | Nuevos antagonistas del receptor muscarinico m3 de acetilcolina |
| TW200534855A (en) | 2004-01-13 | 2005-11-01 | Glaxo Group Ltd | Muscarinic acetylcholine receptor antagonists |
| US20090253908A1 (en) | 2004-03-11 | 2009-10-08 | Glaxo Group Limited | Novel m3 muscarinic acetylchoine receptor antagonists |
| JP2007530451A (ja) | 2004-03-11 | 2007-11-01 | グラクソ グループ リミテッド | 新規ｍ３ムスカリン性アセチルコリン受容体アンタゴニスト |
| US20070185090A1 (en) | 2004-03-17 | 2007-08-09 | Jakob Busch-Petersen | Muscarinic acetylchoine receptor antagonists |
| JP2007529514A (ja) | 2004-03-17 | 2007-10-25 | グラクソ グループ リミテッド | Ｍ３ムスカリン性アセチルコリン受容体アンタゴニスト |
| WO2005094251A2 (en) | 2004-03-17 | 2005-10-13 | Glaxo Group Limited | M3muscarinic acetylcholine receptor antagonists |
| US7384946B2 (en) | 2004-03-17 | 2008-06-10 | Glaxo Group Limited | M3 muscarinic acetylcholine receptor antagonists |
| EP1732923A2 (en) | 2004-04-07 | 2006-12-20 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| UY28871A1 (es) * | 2004-04-27 | 2005-11-30 | Glaxo Group Ltd | Antagonistas del receptor de acetilcolina muscarinico |
| WO2005112644A2 (en) | 2004-05-13 | 2005-12-01 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| EP1749012A4 (en) | 2004-05-28 | 2009-07-29 | Glaxo Group Ltd | ANTAGONISTS OF MUSCARIN ACETYLCHOLIN RECEPTOR |
| JP2008505118A (ja) | 2004-06-30 | 2008-02-21 | グラクソ グループ リミテッド | ムスカリン性アセチルコリン受容体アンタゴニスト |
| WO2006017768A2 (en) | 2004-08-05 | 2006-02-16 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| WO2006017767A2 (en) | 2004-08-06 | 2006-02-16 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| WO2006050239A2 (en) | 2004-10-29 | 2006-05-11 | Glaxo Group Limited | Muscarinic acetylcholine receptor antagonists |
| JP2008520579A (ja) | 2004-11-15 | 2008-06-19 | グラクソ グループ リミテッド | 新規ｍ３ムスカリン性アセチルコリン受容体アンタゴニスト |
| EP1827439A4 (en) | 2004-11-15 | 2009-11-18 | Glaxo Group Ltd | NEW M3 MUSCARIN ACETYLCHOLINE RECEPTOR ANTAGONISTS |
| PE20060826A1 (es) | 2004-12-06 | 2006-10-08 | Smithkline Beecham Corp | Derivado oleofinico de 8-azoniabiciclo[3.2.1]octano y combinacion farmaceutica que lo comprende |
| PE20061162A1 (es) | 2004-12-06 | 2006-10-14 | Smithkline Beecham Corp | Compuestos derivados olefinicos de 8-azoniabiciclo[3.2.1]octanos |
| WO2006065755A2 (en) | 2004-12-13 | 2006-06-22 | Glaxo Group Limited | Quaternary ammonium salts of fused hetearomatic amines as novel muscarinic acetylcholine receptor antagonists |
| WO2006065788A2 (en) | 2004-12-13 | 2006-06-22 | Glaxo Group Limited | Novel muscarinic acetylcholine receptor antagonists |
| WO2007018514A1 (en) | 2005-07-28 | 2007-02-15 | Glaxo Group Limited | Novel m3 muscarinic acetylcholine receptor antagonists |
| WO2007018508A1 (en) | 2005-07-28 | 2007-02-15 | Glaxo Group Limited | Novel m3 muscarinic acetycholine receptor antagonists |
| US20080275079A1 (en) | 2005-08-02 | 2008-11-06 | Glaxo Group Limited | M3 Muscarinic Acetylcholine Receptor Antagonists |
| EP1937230A4 (en) | 2005-08-02 | 2009-08-26 | Glaxo Group Ltd | M3-MUSCARIN ACETYLCHOLIN RECEPTOR ANTAGONISTS |
| EP1937068A4 (en) | 2005-08-18 | 2010-08-04 | Glaxo Group Ltd | ANTAGONISTS OF ACETYLCHOLINE MUSCARINIC RECEPTORS |
| GB0921075D0 (en) * | 2009-12-01 | 2010-01-13 | Glaxo Group Ltd | Novel combination of the therapeutic agents |
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