AU2006274036B2 - Isotopically substituted proton pump inhibitors - Google Patents
Isotopically substituted proton pump inhibitors Download PDFInfo
- Publication number
- AU2006274036B2 AU2006274036B2 AU2006274036A AU2006274036A AU2006274036B2 AU 2006274036 B2 AU2006274036 B2 AU 2006274036B2 AU 2006274036 A AU2006274036 A AU 2006274036A AU 2006274036 A AU2006274036 A AU 2006274036A AU 2006274036 B2 AU2006274036 B2 AU 2006274036B2
- Authority
- AU
- Australia
- Prior art keywords
- methoxy
- compounds
- benzimidazole
- trideuteriomethoxy
- hydrogen
- 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.)
- Ceased
Links
- 229940126409 proton pump inhibitor Drugs 0.000 title description 6
- 239000000612 proton pump inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 209
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 78
- -1 methoxy, 2,2,2-trifluoroethoxy Chemical group 0.000 claims description 73
- 239000012453 solvate Substances 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- 229910052805 deuterium Inorganic materials 0.000 claims description 27
- 150000001975 deuterium Chemical group 0.000 claims description 25
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 22
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 22
- 125000004431 deuterium atom Chemical group 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
- 238000011321 prophylaxis Methods 0.000 claims description 8
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000005227 alkyl sulfonate group Chemical group 0.000 claims description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001556 benzimidazoles Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 78
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
- 235000013350 formula milk Nutrition 0.000 description 65
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- 239000007787 solid Substances 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- 235000011121 sodium hydroxide Nutrition 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 13
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 229960005019 pantoprazole Drugs 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 12
- 229960000381 omeprazole Drugs 0.000 description 12
- CMZHQFXXAAIBKE-UHFFFAOYSA-N 5'-hydroxyomeprazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(CO)C(OC)=C1C CMZHQFXXAAIBKE-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 241000282414 Homo sapiens Species 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 150000004677 hydrates Chemical class 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 230000009471 action Effects 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 8
- UKILEIRWOYBGEJ-FIBGUPNXSA-N 6-(difluoromethoxy)-2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-FIBGUPNXSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 230000009858 acid secretion Effects 0.000 description 6
- 239000013590 bulk material Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 229940083608 sodium hydroxide Drugs 0.000 description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 5
- UZYOEPBKRIJNLU-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3,5-dimethylpyridin-1-ium;chloride Chemical compound Cl.CC1=CN=C(CCl)C(C)=C1Cl UZYOEPBKRIJNLU-UHFFFAOYSA-N 0.000 description 5
- IQPSEEYGBUAQFF-NZIJTQCXSA-N 6-(difluoromethoxy)-2-[(s)-[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-NZIJTQCXSA-N 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 206010013710 Drug interaction Diseases 0.000 description 5
- 229940022682 acetone Drugs 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 159000000003 magnesium salts Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000005191 phase separation Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 241000894007 species Species 0.000 description 5
- BELFYULMHTWOBA-UHFFFAOYSA-N 2-[(4-chloro-3-methoxypyridin-2-yl)methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole;hydrate Chemical compound O.COC1=C(Cl)C=CN=C1CSC1=NC2=CC(OC(F)F)=CC=C2N1 BELFYULMHTWOBA-UHFFFAOYSA-N 0.000 description 4
- XURCIPRUUASYLR-LIJFRPJRSA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound N1C2=CC(OC([2H])([2H])[2H])=CC=C2N=C1SCC1=NC=C(C)C(OC([2H])([2H])[2H])=C1C XURCIPRUUASYLR-LIJFRPJRSA-N 0.000 description 4
- KOFBRZWVWJCLGM-FIBGUPNXSA-N 5-(trideuteriomethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound [2H]C([2H])([2H])OC1=CC=C2NC(=S)NC2=C1 KOFBRZWVWJCLGM-FIBGUPNXSA-N 0.000 description 4
- IQPSEEYGBUAQFF-BFLAAXAOSA-N 6-(difluoromethoxy)-2-[(r)-[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-BFLAAXAOSA-N 0.000 description 4
- IQPSEEYGBUAQFF-FIBGUPNXSA-N 6-(difluoromethoxy)-2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC IQPSEEYGBUAQFF-FIBGUPNXSA-N 0.000 description 4
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 4
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 4
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 4
- 210000004211 gastric acid Anatomy 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229960001407 sodium bicarbonate Drugs 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- CQKHUAFREIMBJI-UHFFFAOYSA-N (4-chloro-3,5-dimethylpyridin-2-yl)methanol Chemical compound CC1=CN=C(CO)C(C)=C1Cl CQKHUAFREIMBJI-UHFFFAOYSA-N 0.000 description 3
- BNUHAJGCKIQFGE-FIBGUPNXSA-N 1-nitro-4-(trideuteriomethoxy)benzene Chemical compound [2H]C([2H])([2H])OC1=CC=C([N+]([O-])=O)C=C1 BNUHAJGCKIQFGE-FIBGUPNXSA-N 0.000 description 3
- YYRIKJFWBIEEDH-TXHXQZCNSA-N 2-(chloromethyl)-3,4-bis(trideuteriomethoxy)pyridin-1-ium;chloride Chemical compound [Cl-].[2H]C([2H])([2H])OC1=CC=[NH+]C(CCl)=C1OC([2H])([2H])[2H] YYRIKJFWBIEEDH-TXHXQZCNSA-N 0.000 description 3
- VWXRGCXTVTZBQL-FJCVKDQNSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-(trideuteriomethoxy)-1H-benzimidazole hydrate Chemical compound O.[2H]C([2H])([2H])Oc1ccc2[nH]c(SCc3ncc(C)c(Cl)c3C)nc2c1 VWXRGCXTVTZBQL-FJCVKDQNSA-N 0.000 description 3
- HVAJOLFRLWQQQL-ZGKVGPQDSA-N 2-[(s)-[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole;sodium Chemical compound [Na].C([S@](=O)C1=NC2=CC=C(C=C2N1)OC([2H])([2H])[2H])C1=NC=C(C)C(OC([2H])([2H])[2H])=C1C HVAJOLFRLWQQQL-ZGKVGPQDSA-N 0.000 description 3
- UKILEIRWOYBGEJ-WFGJKAKNSA-N 2-[[3,4-bis(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC([2H])([2H])[2H] UKILEIRWOYBGEJ-WFGJKAKNSA-N 0.000 description 3
- IQPSEEYGBUAQFF-WFGJKAKNSA-N 2-[[3,4-bis(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC([2H])([2H])[2H] IQPSEEYGBUAQFF-WFGJKAKNSA-N 0.000 description 3
- XURCIPRUUASYLR-GKOSEXJESA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-6-methoxy-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(C)C=NC(CSC=2NC3=CC(OC)=CC=C3N=2)=C1C XURCIPRUUASYLR-GKOSEXJESA-N 0.000 description 3
- SUBDBMMJDZJVOS-GKOSEXJESA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(C)C=NC(CS(=O)C=2NC3=CC(OC)=CC=C3N=2)=C1C SUBDBMMJDZJVOS-GKOSEXJESA-N 0.000 description 3
- UKILEIRWOYBGEJ-MICDWDOJSA-N 2-[[4-(deuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]COC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-MICDWDOJSA-N 0.000 description 3
- UKILEIRWOYBGEJ-DICFDUPASA-N 2-[[4-(dideuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=CC=NC(CSC=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC UKILEIRWOYBGEJ-DICFDUPASA-N 0.000 description 3
- IQPSEEYGBUAQFF-DICFDUPASA-N 2-[[4-(dideuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC IQPSEEYGBUAQFF-DICFDUPASA-N 0.000 description 3
- YWYOLOVNOGZWLY-NIIDSAIPSA-N 4-chloro-2-(chloromethyl)-3-(trideuteriomethoxy)pyridin-1-ium;chloride Chemical compound [Cl-].[2H]C([2H])([2H])OC1=C(Cl)C=C[NH+]=C1CCl YWYOLOVNOGZWLY-NIIDSAIPSA-N 0.000 description 3
- YWYOLOVNOGZWLY-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methoxypyridine;hydrochloride Chemical compound [Cl-].COC1=C(Cl)C=C[NH+]=C1CCl YWYOLOVNOGZWLY-UHFFFAOYSA-N 0.000 description 3
- TWXMQDRFBLSXFN-BMSJAHLVSA-N 4-chloro-2-methyl-1-oxido-3-(trideuteriomethoxy)pyridin-1-ium Chemical compound [2H]C([2H])([2H])OC1=C(Cl)C=C[N+]([O-])=C1C TWXMQDRFBLSXFN-BMSJAHLVSA-N 0.000 description 3
- IQPSEEYGBUAQFF-AREMUKBSSA-N 6-(difluoromethoxy)-2-[(r)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-AREMUKBSSA-N 0.000 description 3
- UKILEIRWOYBGEJ-BMSJAHLVSA-N 6-(difluoromethoxy)-2-[[4-methoxy-3-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(OC)C=CN=C1CSC1=NC2=CC=C(OC(F)F)C=C2N1 UKILEIRWOYBGEJ-BMSJAHLVSA-N 0.000 description 3
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 3
- 102100029363 Cytochrome P450 2C19 Human genes 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 101150053185 P450 gene Proteins 0.000 description 3
- 239000004133 Sodium thiosulphate Substances 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 229960002626 clarithromycin Drugs 0.000 description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960004770 esomeprazole Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 210000001853 liver microsome Anatomy 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- XPGAWFIWCWKDDL-UHFFFAOYSA-N propan-1-olate;zirconium(4+) Chemical compound [Zr+4].CCC[O-].CCC[O-].CCC[O-].CCC[O-] XPGAWFIWCWKDDL-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YYRIKJFWBIEEDH-NIIDSAIPSA-N 2-(chloromethyl)-3-methoxy-4-(trideuteriomethoxy)pyridin-1-ium;chloride Chemical compound [Cl-].[2H]C([2H])([2H])OC1=CC=[NH+]C(CCl)=C1OC YYRIKJFWBIEEDH-NIIDSAIPSA-N 0.000 description 2
- VWXRGCXTVTZBQL-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-methoxy-1H-benzimidazole hydrate Chemical compound O.N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(Cl)=C1C VWXRGCXTVTZBQL-UHFFFAOYSA-N 0.000 description 2
- XURCIPRUUASYLR-HPRDVNIFSA-N 2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound N1C2=CC(OC([2H])([2H])[2H])=CC=C2N=C1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-HPRDVNIFSA-N 0.000 description 2
- SUBDBMMJDZJVOS-DPISGPMWSA-N 2-[(s)-[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound C([S@](=O)C=1NC2=CC=C(C=C2N=1)OC([2H])([2H])[2H])C1=NC=C(C)C(OC([2H])([2H])[2H])=C1C SUBDBMMJDZJVOS-DPISGPMWSA-N 0.000 description 2
- SUBDBMMJDZJVOS-LIJFRPJRSA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound N1C2=CC(OC([2H])([2H])[2H])=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC([2H])([2H])[2H])=C1C SUBDBMMJDZJVOS-LIJFRPJRSA-N 0.000 description 2
- JKMKBLFKKYXWJZ-FIBGUPNXSA-N 2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole Chemical compound [2H]C([2H])([2H])Oc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1OC JKMKBLFKKYXWJZ-FIBGUPNXSA-N 0.000 description 2
- IQPSEEYGBUAQFF-MICDWDOJSA-N 2-[[4-(deuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]COC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC IQPSEEYGBUAQFF-MICDWDOJSA-N 0.000 description 2
- QFMJFXFXQAFGBO-FIBGUPNXSA-N 2-nitro-4-(trideuteriomethoxy)aniline Chemical compound [2H]C([2H])([2H])OC1=CC=C(N)C([N+]([O-])=O)=C1 QFMJFXFXQAFGBO-FIBGUPNXSA-N 0.000 description 2
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 description 2
- ZBFDAUIVDSSISP-UHFFFAOYSA-N 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C ZBFDAUIVDSSISP-UHFFFAOYSA-N 0.000 description 2
- WHCXDEORRDVLKS-FOWCFNCZSA-N 6-(difluoromethoxy)-2-[(r)-[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole;sodium Chemical compound [Na].[2H]C([2H])([2H])OC1=CC=NC(C[S@@](=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC WHCXDEORRDVLKS-FOWCFNCZSA-N 0.000 description 2
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 description 2
- WHCXDEORRDVLKS-SUTZSDIMSA-N 6-(difluoromethoxy)-2-[(s)-[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole;sodium Chemical compound [Na].[2H]C([2H])([2H])OC1=CC=NC(C[S@](=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC WHCXDEORRDVLKS-SUTZSDIMSA-N 0.000 description 2
- ILMHAGCURJPNRZ-UHFFFAOYSA-N 6-methoxy-1h-benzimidazole Chemical group COC1=CC=C2N=CNC2=C1 ILMHAGCURJPNRZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108010074922 Cytochrome P-450 CYP1A2 Proteins 0.000 description 2
- 108010000561 Cytochrome P-450 CYP2C8 Proteins 0.000 description 2
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 2
- 102100026533 Cytochrome P450 1A2 Human genes 0.000 description 2
- 102100029359 Cytochrome P450 2C8 Human genes 0.000 description 2
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 2
- 102100039205 Cytochrome P450 3A4 Human genes 0.000 description 2
- 102100039208 Cytochrome P450 3A5 Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- RJRBTVMZZGMTQI-ADBWCSELSA-N O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC([2H])([2H])[2H])OC([2H])([2H])[2H])C=C1)F Chemical compound O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC([2H])([2H])[2H])OC([2H])([2H])[2H])C=C1)F RJRBTVMZZGMTQI-ADBWCSELSA-N 0.000 description 2
- RJRBTVMZZGMTQI-GXXYEPOPSA-N O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F Chemical compound O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F RJRBTVMZZGMTQI-GXXYEPOPSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229960004821 amikacin Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 235000017168 chlorine Nutrition 0.000 description 2
- 229940060038 chlorine Drugs 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 230000000332 continued effect Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- OKKJLVBELUTLKV-DICFDUPASA-N dideuteriomethanol Chemical compound [2H]C([2H])O OKKJLVBELUTLKV-DICFDUPASA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- DCUGZOBNIZLALZ-UHFFFAOYSA-N magnesium;dihydrate Chemical compound O.O.[Mg] DCUGZOBNIZLALZ-UHFFFAOYSA-N 0.000 description 2
- YYINWHOQKIUBNL-UHFFFAOYSA-N magnesium;trihydrate Chemical compound O.O.O.[Mg] YYINWHOQKIUBNL-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 244000309715 mini pig Species 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-NIIDSAIPSA-N sodium;trideuteriomethanolate Chemical compound [Na+].[2H]C([2H])([2H])[O-] WQDUMFSSJAZKTM-NIIDSAIPSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- ISRRJUHDGVMYLE-UHFFFAOYSA-N (4-chloro-3-methoxypyridin-2-yl)methanol Chemical compound COC1=C(Cl)C=CN=C1CO ISRRJUHDGVMYLE-UHFFFAOYSA-N 0.000 description 1
- JDFDHBSESGTDAL-SMZGMGDZSA-N 1,1-dideuterio-3-methoxypropan-1-ol Chemical compound [2H]C([2H])(O)CCOC JDFDHBSESGTDAL-SMZGMGDZSA-N 0.000 description 1
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- VWZADIKKZPXXMZ-FIBGUPNXSA-N 1-(difluoromethoxy)-2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]benzimidazole Chemical compound FC(ON1C(=NC2=C1C=CC=C2)SCC2=NC=CC(=C2OC)OC([2H])([2H])[2H])F VWZADIKKZPXXMZ-FIBGUPNXSA-N 0.000 description 1
- PXVMLAJFILUEQV-FIBGUPNXSA-N 1-(difluoromethoxy)-2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]benzimidazole Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CS(=O)C=2N(C3=CC=CC=C3N=2)OC(F)F)=C1OC PXVMLAJFILUEQV-FIBGUPNXSA-N 0.000 description 1
- PWWDEIMGEBPTJL-UHFFFAOYSA-N 1-(pyridin-2-ylmethylsulfinyl)benzimidazole Chemical class C1=NC2=CC=CC=C2N1S(=O)CC1=CC=CC=N1 PWWDEIMGEBPTJL-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- OXXDGKNPRNPMLS-UHFFFAOYSA-N 2-Hydroxy-3-methyl-4H-pyran-4-one Natural products CC1=C(O)OC=CC1=O OXXDGKNPRNPMLS-UHFFFAOYSA-N 0.000 description 1
- UAFFAJFXCSHXTI-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-5-methoxy-1h-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC)=CC=C2NC=1SCC1=NC=C(C)C(Cl)=C1C UAFFAJFXCSHXTI-UHFFFAOYSA-N 0.000 description 1
- UPVARCHBWKDWRW-HPRDVNIFSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound N1C2=CC(OC([2H])([2H])[2H])=CC=C2N=C1SCC1=NC=C(C)C(Cl)=C1C UPVARCHBWKDWRW-HPRDVNIFSA-N 0.000 description 1
- UPVARCHBWKDWRW-UHFFFAOYSA-N 2-[(4-chloro-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-methoxy-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(Cl)=C1C UPVARCHBWKDWRW-UHFFFAOYSA-N 0.000 description 1
- SEHIARBDRGKABK-UHFFFAOYSA-N 2-[(4-chloro-3-methoxypyridin-2-yl)methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound COC1=C(Cl)C=CN=C1CSC1=NC2=CC(OC(F)F)=CC=C2N1 SEHIARBDRGKABK-UHFFFAOYSA-N 0.000 description 1
- NKBICFMRRCFCFT-UHFFFAOYSA-N 2-[(4-chloro-3-methylpyridin-2-yl)methylsulfanyl]-1h-benzimidazole Chemical compound CC1=C(Cl)C=CN=C1CSC1=NC2=CC=CC=C2N1 NKBICFMRRCFCFT-UHFFFAOYSA-N 0.000 description 1
- ZEXIUCIJSLNDSX-UDISENJQSA-N 2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfanyl]-6-(trideuteriomethoxy)-1H-benzimidazole 2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-6-(trideuteriomethoxy)-1H-benzimidazole Chemical compound [2H]C(OC1=CC2=C(NC(=N2)SCC2=NC=C(C(=C2C)OC)C)C=C1)([2H])[2H].[2H]C(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=C(C(=C2C)OC)C)C=C1)([2H])[2H] ZEXIUCIJSLNDSX-UDISENJQSA-N 0.000 description 1
- SUBDBMMJDZJVOS-HPRDVNIFSA-N 2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound N1C2=CC(OC([2H])([2H])[2H])=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-HPRDVNIFSA-N 0.000 description 1
- IQPSEEYGBUAQFF-JFGMNRAASA-N 2-[(r)-[4-(dideuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-JFGMNRAASA-N 0.000 description 1
- SUBDBMMJDZJVOS-QRVJKMBESA-N 2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound C([S@](=O)C=1NC2=CC=C(C=C2N=1)OC([2H])([2H])[2H])C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-QRVJKMBESA-N 0.000 description 1
- FIIHNCOJFCXJSW-KJEZIRHGSA-N 2-[(s)-[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole;magnesium Chemical compound [Mg].C([S@](=O)C1=NC2=CC=C(C=C2N1)OC([2H])([2H])[2H])C1=NC=C(C)C(OC([2H])([2H])[2H])=C1C.C([S@](=O)C1=NC2=CC=C(C=C2N1)OC([2H])([2H])[2H])C1=NC=C(C)C(OC([2H])([2H])[2H])=C1C FIIHNCOJFCXJSW-KJEZIRHGSA-N 0.000 description 1
- SUBDBMMJDZJVOS-LOWKRFAESA-N 2-[(s)-[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(C)C=NC(C[S@](=O)C=2NC3=CC=C(OC)C=C3N=2)=C1C SUBDBMMJDZJVOS-LOWKRFAESA-N 0.000 description 1
- SUBDBMMJDZJVOS-FAIGGOSCSA-N 2-[(s)-[3-methyl-4-(trideuteriomethoxy)-5-(trideuteriomethyl)pyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound C([S@](=O)C=1NC2=CC=C(C=C2N=1)OC([2H])([2H])[2H])C1=NC=C(C([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C1C SUBDBMMJDZJVOS-FAIGGOSCSA-N 0.000 description 1
- SUBDBMMJDZJVOS-MSQLWDHUSA-N 2-[(s)-[4-(dideuteriomethoxy)-3,5-dimethylpyridin-2-yl]methylsulfinyl]-6-(trideuteriomethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=C(C)C=NC(C[S@](=O)C=2NC3=CC=C(OC([2H])([2H])[2H])C=C3N=2)=C1C SUBDBMMJDZJVOS-MSQLWDHUSA-N 0.000 description 1
- SUBDBMMJDZJVOS-CFGDKDRQSA-N 2-[(s)-[4-(dideuteriomethoxy)-3,5-dimethylpyridin-2-yl]methylsulfinyl]-6-methoxy-1h-benzimidazole Chemical compound [2H]C([2H])OC1=C(C)C=NC(C[S@](=O)C=2NC3=CC=C(OC)C=C3N=2)=C1C SUBDBMMJDZJVOS-CFGDKDRQSA-N 0.000 description 1
- IQPSEEYGBUAQFF-SFRSKVPJSA-N 2-[(s)-[4-(dideuteriomethoxy)-3-methoxypyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SFRSKVPJSA-N 0.000 description 1
- RYOOHIUJEJZCFT-UHFFFAOYSA-N 2-[2-(diethylamino)ethylamino]-2-phenylacetic acid 3-methylbutyl ester Chemical compound CCN(CC)CCNC(C(=O)OCCC(C)C)C1=CC=CC=C1 RYOOHIUJEJZCFT-UHFFFAOYSA-N 0.000 description 1
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- IQPSEEYGBUAQFF-LNLMKGTHSA-N 2-[[3,4-bis(dideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])OC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC([2H])[2H] IQPSEEYGBUAQFF-LNLMKGTHSA-N 0.000 description 1
- ZZRLRRBNMPMTIL-GKOSEXJESA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-5-methoxy-1h-imidazo[4,5-b]pyridine Chemical compound [2H]C([2H])([2H])OC1=C(C)C=NC(CSC=2NC3=CC=C(OC)N=C3N=2)=C1C ZZRLRRBNMPMTIL-GKOSEXJESA-N 0.000 description 1
- ZBFDAUIVDSSISP-GKOSEXJESA-N 2-[[3,5-dimethyl-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-5-methoxy-1h-imidazo[4,5-b]pyridine Chemical compound [2H]C([2H])([2H])OC1=C(C)C=NC(CS(=O)C=2NC3=CC=C(OC)N=C3N=2)=C1C ZBFDAUIVDSSISP-GKOSEXJESA-N 0.000 description 1
- ZBFDAUIVDSSISP-MXOMHCEVSA-N 2-[[3-methyl-4-(trideuteriomethoxy)-5-(trideuteriomethyl)pyridin-2-yl]methylsulfinyl]-5-(trideuteriomethoxy)-1h-imidazo[4,5-b]pyridine Chemical compound N=1C2=NC(OC([2H])([2H])[2H])=CC=C2NC=1S(=O)CC1=NC=C(C([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C1C ZBFDAUIVDSSISP-MXOMHCEVSA-N 0.000 description 1
- CCHLMSUZHFPSFC-KNXIQCGSSA-N 2-[[4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methylpyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound FC(F)(F)C([2H])([2H])OC1=CC=NC(CSC=2NC3=CC=CC=C3N=2)=C1C CCHLMSUZHFPSFC-KNXIQCGSSA-N 0.000 description 1
- MJIHNNLFOKEZEW-KNXIQCGSSA-N 2-[[4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound FC(F)(F)C([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C MJIHNNLFOKEZEW-KNXIQCGSSA-N 0.000 description 1
- BSXAHDOWMOSVAP-ZWGOZCLVSA-N 2-[[4-(1,1-dideuterio-3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfanyl]-1h-benzimidazole Chemical compound COCCC([2H])([2H])OC1=CC=NC(CSC=2NC3=CC=CC=C3N=2)=C1C BSXAHDOWMOSVAP-ZWGOZCLVSA-N 0.000 description 1
- YREYEVIYCVEVJK-ZWGOZCLVSA-N 2-[[4-(1,1-dideuterio-3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound COCCC([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-ZWGOZCLVSA-N 0.000 description 1
- SUBDBMMJDZJVOS-APZFVMQVSA-N 2-[[4-(dideuteriomethoxy)-3,5-dimethylpyridin-2-yl]methylsulfinyl]-6-methoxy-1H-benzimidazole Chemical compound [2H]C([2H])OC1=C(C)C=NC(CS(=O)C=2NC3=CC(OC)=CC=C3N=2)=C1C SUBDBMMJDZJVOS-APZFVMQVSA-N 0.000 description 1
- YREYEVIYCVEVJK-NGBLLNSUSA-N 2-[[4-[1,1,2,2,3,3-hexadeuterio-3-(trideuteriomethoxy)propoxy]-3-(trideuteriomethyl)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC([2H])([2H])C([2H])([2H])C([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C([2H])([2H])[2H] YREYEVIYCVEVJK-NGBLLNSUSA-N 0.000 description 1
- SEHIARBDRGKABK-FIBGUPNXSA-N 2-[[4-chloro-3-(trideuteriomethoxy)pyridin-2-yl]methylsulfanyl]-6-(difluoromethoxy)-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(Cl)C=CN=C1CSC1=NC2=CC=C(OC(F)F)C=C2N1 SEHIARBDRGKABK-FIBGUPNXSA-N 0.000 description 1
- UMVFRRJTPKYVAY-XERRXZQWSA-N 2-methyl-1-oxido-3,4-bis(trideuteriomethoxy)pyridin-1-ium Chemical compound [2H]C([2H])([2H])OC1=CC=[N+]([O-])C(C)=C1OC([2H])([2H])[2H] UMVFRRJTPKYVAY-XERRXZQWSA-N 0.000 description 1
- GNWSQENQZGWCSW-BMSJAHLVSA-N 2-methyl-3-(trideuteriomethoxy)-1h-pyridin-4-one Chemical compound [2H]C([2H])([2H])OC1=C(C)NC=CC1=O GNWSQENQZGWCSW-BMSJAHLVSA-N 0.000 description 1
- NGGPLHHTRNJSDT-BMSJAHLVSA-N 2-methyl-3-(trideuteriomethoxy)pyran-4-one Chemical compound [2H]C([2H])([2H])OC1=C(C)OC=CC1=O NGGPLHHTRNJSDT-BMSJAHLVSA-N 0.000 description 1
- GRANLUCAESLKBX-FIBGUPNXSA-N 3-(trideuteriomethoxy)-1H-benzimidazole-2-thione Chemical compound [2H]C(ON1C(=NC2=C1C=CC=C2)S)([2H])[2H] GRANLUCAESLKBX-FIBGUPNXSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- UMVFRRJTPKYVAY-BMSJAHLVSA-N 3-methoxy-2-methyl-1-oxido-4-(trideuteriomethoxy)pyridin-1-ium Chemical compound [2H]C([2H])([2H])OC1=CC=[N+]([O-])C(C)=C1OC UMVFRRJTPKYVAY-BMSJAHLVSA-N 0.000 description 1
- GMZALNFVKYJBJJ-FIBGUPNXSA-N 3-methoxy-4-(trideuteriomethoxy)-1h-pyridin-2-one Chemical compound [2H]C([2H])([2H])OC=1C=CNC(=O)C=1OC GMZALNFVKYJBJJ-FIBGUPNXSA-N 0.000 description 1
- OEIVKNYMXKWILN-UHFFFAOYSA-N 4-chloro-2,3,5-trimethyl-1-oxidopyridin-1-ium Chemical compound CC1=C[N+]([O-])=C(C)C(C)=C1Cl OEIVKNYMXKWILN-UHFFFAOYSA-N 0.000 description 1
- YIDBERCXNYKRKU-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methylpyridin-1-ium;chloride Chemical compound Cl.CC1=C(Cl)C=CN=C1CCl YIDBERCXNYKRKU-UHFFFAOYSA-N 0.000 description 1
- RYGXNMUVOHCPBF-BMSJAHLVSA-N 4-chloro-2-methyl-3-(trideuteriomethoxy)pyridine Chemical compound [2H]C([2H])([2H])OC1=C(C)N=CC=C1Cl RYGXNMUVOHCPBF-BMSJAHLVSA-N 0.000 description 1
- TWXMQDRFBLSXFN-UHFFFAOYSA-N 4-chloro-3-methoxy-2-methyl-1-oxidopyridin-1-ium Chemical compound COC1=C(C)[N+]([O-])=CC=C1Cl TWXMQDRFBLSXFN-UHFFFAOYSA-N 0.000 description 1
- KOFBRZWVWJCLGM-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazole-2-thione Chemical compound COC1=CC=C2NC(S)=NC2=C1 KOFBRZWVWJCLGM-UHFFFAOYSA-N 0.000 description 1
- WHCXDEORRDVLKS-NIIDSAIPSA-N 6-(difluoromethoxy)-2-[[3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole;sodium Chemical compound [Na].[2H]C([2H])([2H])OC1=CC=NC(CS(=O)C=2NC3=CC(OC(F)F)=CC=C3N=2)=C1OC WHCXDEORRDVLKS-NIIDSAIPSA-N 0.000 description 1
- IQPSEEYGBUAQFF-BMSJAHLVSA-N 6-(difluoromethoxy)-2-[[4-methoxy-3-(trideuteriomethoxy)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound [2H]C([2H])([2H])OC1=C(OC)C=CN=C1CS(=O)C1=NC2=CC=C(OC(F)F)C=C2N1 IQPSEEYGBUAQFF-BMSJAHLVSA-N 0.000 description 1
- SUBDBMMJDZJVOS-QHWOWTQCSA-N 6-methoxy-2-[(s)-[3-methyl-4-(trideuteriomethoxy)-5-(trideuteriomethyl)pyridin-2-yl]methylsulfinyl]-1h-benzimidazole Chemical compound C1=C(C([2H])([2H])[2H])C(OC([2H])([2H])[2H])=C(C)C(C[S@](=O)C=2NC3=CC=C(OC)C=C3N=2)=N1 SUBDBMMJDZJVOS-QHWOWTQCSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- PXVYHHMYZWPHBJ-MUTAZJQDSA-N ClC1=C(C(=[N+](C=C1)[O-])C)OC.COC=1C(=[N+](C=CC1OC([2H])([2H])[2H])[O-])C Chemical compound ClC1=C(C(=[N+](C=C1)[O-])C)OC.COC=1C(=[N+](C=CC1OC([2H])([2H])[2H])[O-])C PXVYHHMYZWPHBJ-MUTAZJQDSA-N 0.000 description 1
- 241000581444 Clinidae Species 0.000 description 1
- 244000258136 Costus speciosus Species 0.000 description 1
- 235000000385 Costus speciosus Nutrition 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 108010000543 Cytochrome P-450 CYP2C9 Proteins 0.000 description 1
- 102100029358 Cytochrome P450 2C9 Human genes 0.000 description 1
- 241000252164 Elopidae Species 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000017189 Gastrointestinal inflammatory disease Diseases 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LEQAQBFYCMENLP-FIBGUPNXSA-N N-phenyl-2-(trideuteriomethoxy)acetamide Chemical compound [2H]C(OCC(=O)NC1=CC=CC=C1)([2H])[2H] LEQAQBFYCMENLP-FIBGUPNXSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- NQQUSKPRIDXCEX-NIIDSAIPSA-N O.FCOC1=CC(=CC2=C1NC(=N2)SCC2=NC=CC(=C2OC([2H])([2H])[2H])Cl)OCF Chemical compound O.FCOC1=CC(=CC2=C1NC(=N2)SCC2=NC=CC(=C2OC([2H])([2H])[2H])Cl)OCF NQQUSKPRIDXCEX-NIIDSAIPSA-N 0.000 description 1
- MADWPVWUCONOAD-QJGBNARZSA-N O.O.O.[Mg].FC(OC1=CC2=C(NC(=N2)[S@@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.FC(OC1=CC2=C(NC(=N2)[S@@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F Chemical compound O.O.O.[Mg].FC(OC1=CC2=C(NC(=N2)[S@@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.FC(OC1=CC2=C(NC(=N2)[S@@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F MADWPVWUCONOAD-QJGBNARZSA-N 0.000 description 1
- MADWPVWUCONOAD-CKTWJNPWSA-N O.O.O.[Mg].FC(OC1=CC2=C(NC(=N2)[S@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.FC(OC1=CC2=C(NC(=N2)[S@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F Chemical compound O.O.O.[Mg].FC(OC1=CC2=C(NC(=N2)[S@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.FC(OC1=CC2=C(NC(=N2)[S@](=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F MADWPVWUCONOAD-CKTWJNPWSA-N 0.000 description 1
- BELFYULMHTWOBA-NIIDSAIPSA-N O.[2H]C([2H])([2H])Oc1c(Cl)ccnc1CSc1nc2cc(OC(F)F)ccc2[nH]1 Chemical compound O.[2H]C([2H])([2H])Oc1c(Cl)ccnc1CSc1nc2cc(OC(F)F)ccc2[nH]1 BELFYULMHTWOBA-NIIDSAIPSA-N 0.000 description 1
- ZEPXBFIPCFSUOZ-BMYPLOHWSA-N O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.O.O.FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.[Na] Chemical compound O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.O.O.FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])([2H])[2H])C=C1)F.[Na] ZEPXBFIPCFSUOZ-BMYPLOHWSA-N 0.000 description 1
- RJRBTVMZZGMTQI-SRTIKVJZSA-N O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])[2H])C=C1)F Chemical compound O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC([2H])[2H])C=C1)F RJRBTVMZZGMTQI-SRTIKVJZSA-N 0.000 description 1
- RJRBTVMZZGMTQI-QCNSCHFVSA-N O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC[2H])C=C1)F Chemical compound O.[Na].FC(OC1=CC2=C(NC(=N2)S(=O)CC2=NC=CC(=C2OC)OC[2H])C=C1)F RJRBTVMZZGMTQI-QCNSCHFVSA-N 0.000 description 1
- 101100168374 Oryctolagus cuniculus CYP2C1 gene Proteins 0.000 description 1
- DUDKAZCAISNGQN-UHFFFAOYSA-N Oxyphencyclimine Chemical compound CN1CCCN=C1COC(=O)C(O)(C=1C=CC=CC=1)C1CCCCC1 DUDKAZCAISNGQN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- BKTHTLOKUUJKDF-WFGJKAKNSA-N [3,4-bis(trideuteriomethoxy)pyridin-2-yl]methanol Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CO)=C1OC([2H])([2H])[2H] BKTHTLOKUUJKDF-WFGJKAKNSA-N 0.000 description 1
- BKTHTLOKUUJKDF-FIBGUPNXSA-N [3-methoxy-4-(trideuteriomethoxy)pyridin-2-yl]methanol Chemical compound [2H]C([2H])([2H])OC1=CC=NC(CO)=C1OC BKTHTLOKUUJKDF-FIBGUPNXSA-N 0.000 description 1
- ISRRJUHDGVMYLE-FIBGUPNXSA-N [4-chloro-3-(trideuteriomethoxy)pyridin-2-yl]methanol Chemical compound [2H]C([2H])([2H])OC1=C(Cl)C=CN=C1CO ISRRJUHDGVMYLE-FIBGUPNXSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- JIFPTBLGXRKRAO-UHFFFAOYSA-K aluminum;magnesium;hydroxide;sulfate Chemical compound [OH-].[Mg+2].[Al+3].[O-]S([O-])(=O)=O JIFPTBLGXRKRAO-UHFFFAOYSA-K 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 230000001262 anti-secretory effect Effects 0.000 description 1
- 230000000026 anti-ulcerogenic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- JGTJANXYSNVLMQ-UHFFFAOYSA-N bietamiverine Chemical compound C=1C=CC=CC=1C(C(=O)OCCN(CC)CC)N1CCCCC1 JGTJANXYSNVLMQ-UHFFFAOYSA-N 0.000 description 1
- 229950005940 bietamiverine Drugs 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229960005242 camylofin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000011083 clear filtration Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- OKKJLVBELUTLKV-MICDWDOJSA-N deuteriomethanol Chemical compound [2H]CO OKKJLVBELUTLKV-MICDWDOJSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001493 etofenamate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 210000000111 lower esophageal sphincter Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229960004018 magaldrate Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000004783 oxidative metabolism Effects 0.000 description 1
- 229960002369 oxyphencyclimine Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002831 pharmacologic agent 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
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- BZGIPVGCJGXQTA-UHFFFAOYSA-N s-[2-(diethylamino)ethyl] n,n-diphenylcarbamothioate Chemical compound C=1C=CC=CC=1N(C(=O)SCCN(CC)CC)C1=CC=CC=C1 BZGIPVGCJGXQTA-UHFFFAOYSA-N 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
- 238000000926 separation method Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- RYXPMWYHEBGTRV-JIDHJSLPSA-N sodium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [Na+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-JIDHJSLPSA-N 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 229950008375 tenatoprazole Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 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
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (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)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05106868 | 2005-07-26 | ||
| EP05106868.2 | 2005-07-26 | ||
| PCT/EP2006/064666 WO2007012650A1 (en) | 2005-07-26 | 2006-07-26 | Isotopically substituted proton pump inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2006274036A1 AU2006274036A1 (en) | 2007-02-01 |
| AU2006274036A2 AU2006274036A2 (en) | 2008-03-20 |
| AU2006274036B2 true AU2006274036B2 (en) | 2012-05-24 |
Family
ID=35734406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2006274036A Ceased AU2006274036B2 (en) | 2005-07-26 | 2006-07-26 | Isotopically substituted proton pump inhibitors |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP1910293A1 (de) |
| JP (1) | JP5448448B2 (de) |
| KR (1) | KR101358509B1 (de) |
| CN (2) | CN102134232B (de) |
| AR (1) | AR054584A1 (de) |
| AU (1) | AU2006274036B2 (de) |
| BR (1) | BRPI0614039A2 (de) |
| CA (1) | CA2615670C (de) |
| EA (1) | EA016814B1 (de) |
| IL (1) | IL188773A (de) |
| MX (1) | MX2008000901A (de) |
| NO (1) | NO20080839L (de) |
| NZ (1) | NZ565078A (de) |
| TW (1) | TWI394750B (de) |
| WO (1) | WO2007012650A1 (de) |
| ZA (1) | ZA200800303B (de) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006274037B2 (en) * | 2005-07-26 | 2012-04-26 | Takeda Gmbh | Isotopically substituted pantoprazole |
| EP1934201A1 (de) * | 2005-10-06 | 2008-06-25 | Auspex Pharmaceuticals Inc. | Deuterierte hemmer von gastrischer h+, k+-atpase mit verstärkten therapeutischen eigenschaften |
| US20080255200A1 (en) * | 2007-04-11 | 2008-10-16 | Auspex Pharmaceuticals, Inc. | Substituted benzimidazoles |
| WO2008127640A2 (en) * | 2007-04-11 | 2008-10-23 | Auspex Pharmaceuticals, Inc. | Substituted benzimidazoles |
| CA2789298A1 (en) | 2010-02-12 | 2011-08-18 | Esteve Quimica, S.A. | Preparation process of the sodium salt of esomeprazole |
| CN104530003A (zh) * | 2014-06-10 | 2015-04-22 | 广东东阳光药业有限公司 | 吡啶甲基亚磺酰基-1h-苯并咪唑类化合物的盐的制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005129A1 (de) * | 1978-04-14 | 1979-10-31 | Aktiebolaget Hässle | Substituierte Pyridylsulfinylbenzimidazole, diese enthaltende pharmazeutische Präparate und Zwischenprodukte zu ihrer Herstellung |
| EP0254588A1 (de) * | 1986-07-25 | 1988-01-27 | Tokyo Tanabe Company Limited | Imidazo[4,5-b]pyridin,Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen |
| US6818200B2 (en) * | 1994-03-25 | 2004-11-16 | Isotechnika Inc. | Method of using deuterated calcium channel blockers |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2293638T3 (es) * | 1994-03-25 | 2008-03-16 | Isotechnika, Inc. | Mejora de la eficacia de farmacos por deuteracion. |
| US6884429B2 (en) * | 1997-09-05 | 2005-04-26 | Isotechnika International Inc. | Medical devices incorporating deuterated rapamycin for controlled delivery thereof |
| NO309305B1 (no) * | 1999-02-19 | 2001-01-15 | Norsk Hydro As | Anvendelse av benzaldehydderivater ved fremstilling av farmasöytiske preparater for forebygging og/eller behandling av kreft, samt visse nye benzaldehydderivater |
| DE10123129A1 (de) * | 2001-05-02 | 2002-11-14 | Berolina Drug Dev Ab Svedala | Deuterierte 3-Piperidinopropiophenone sowie diese Verbindungen enthaltende Arzneimittel |
| DE10162121A1 (de) * | 2001-12-12 | 2003-06-18 | Berolina Drug Dev Ab Svedala | Deuterierte substituierte Pyrazolyl-Benzolsulfonamide sowie diese Verbindungen enthaltende Arzneimittel |
| AU2006274037B2 (en) * | 2005-07-26 | 2012-04-26 | Takeda Gmbh | Isotopically substituted pantoprazole |
-
2006
- 2006-07-26 MX MX2008000901A patent/MX2008000901A/es active IP Right Grant
- 2006-07-26 CA CA2615670A patent/CA2615670C/en not_active Expired - Fee Related
- 2006-07-26 JP JP2008523354A patent/JP5448448B2/ja not_active Expired - Fee Related
- 2006-07-26 EA EA200800203A patent/EA016814B1/ru not_active IP Right Cessation
- 2006-07-26 WO PCT/EP2006/064666 patent/WO2007012650A1/en not_active Ceased
- 2006-07-26 NZ NZ565078A patent/NZ565078A/en not_active IP Right Cessation
- 2006-07-26 EP EP06764258A patent/EP1910293A1/de not_active Withdrawn
- 2006-07-26 KR KR1020087003989A patent/KR101358509B1/ko not_active Expired - Fee Related
- 2006-07-26 CN CN2011100224850A patent/CN102134232B/zh not_active Expired - Fee Related
- 2006-07-26 AR ARP060103224A patent/AR054584A1/es unknown
- 2006-07-26 BR BRPI0614039-4A patent/BRPI0614039A2/pt not_active IP Right Cessation
- 2006-07-26 CN CN2006800345034A patent/CN101268051B/zh not_active Expired - Fee Related
- 2006-07-26 AU AU2006274036A patent/AU2006274036B2/en not_active Ceased
- 2006-07-26 TW TW095127340A patent/TWI394750B/zh not_active IP Right Cessation
-
2008
- 2008-01-10 ZA ZA2008/00303A patent/ZA200800303B/en unknown
- 2008-01-15 IL IL188773A patent/IL188773A/en not_active IP Right Cessation
- 2008-02-18 NO NO20080839A patent/NO20080839L/no not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0005129A1 (de) * | 1978-04-14 | 1979-10-31 | Aktiebolaget Hässle | Substituierte Pyridylsulfinylbenzimidazole, diese enthaltende pharmazeutische Präparate und Zwischenprodukte zu ihrer Herstellung |
| EP0254588A1 (de) * | 1986-07-25 | 1988-01-27 | Tokyo Tanabe Company Limited | Imidazo[4,5-b]pyridin,Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen |
| US6818200B2 (en) * | 1994-03-25 | 2004-11-16 | Isotechnika Inc. | Method of using deuterated calcium channel blockers |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2006274036A1 (en) | 2007-02-01 |
| IL188773A (en) | 2014-02-27 |
| AU2006274036A2 (en) | 2008-03-20 |
| ZA200800303B (en) | 2009-01-28 |
| KR101358509B1 (ko) | 2014-02-05 |
| NZ565078A (en) | 2010-03-26 |
| CA2615670C (en) | 2015-01-20 |
| CN101268051A (zh) | 2008-09-17 |
| CN102134232B (zh) | 2012-11-21 |
| CN102134232A (zh) | 2011-07-27 |
| EP1910293A1 (de) | 2008-04-16 |
| CN101268051B (zh) | 2011-08-31 |
| HK1160126A1 (en) | 2012-08-10 |
| KR20080037676A (ko) | 2008-04-30 |
| JP5448448B2 (ja) | 2014-03-19 |
| WO2007012650A1 (en) | 2007-02-01 |
| HK1125098A1 (en) | 2009-07-31 |
| NO20080839L (no) | 2008-02-18 |
| AR054584A1 (es) | 2007-06-27 |
| TW200714596A (en) | 2007-04-16 |
| EA016814B1 (ru) | 2012-07-30 |
| TWI394750B (zh) | 2013-05-01 |
| MX2008000901A (es) | 2008-03-26 |
| CA2615670A1 (en) | 2007-02-01 |
| BRPI0614039A2 (pt) | 2011-03-09 |
| EA200800203A1 (ru) | 2008-08-29 |
| IL188773A0 (en) | 2008-08-07 |
| JP2009502871A (ja) | 2009-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006274037B2 (en) | Isotopically substituted pantoprazole | |
| AU2006274036B2 (en) | Isotopically substituted proton pump inhibitors | |
| US7601737B2 (en) | Isotopically substituted proton pump inhibitors | |
| HK1160126B (en) | Isotopically substituted proton pump inhibitors | |
| HK1125098B (zh) | 同位素取代的质子泵抑制剂 | |
| ZA200608395B (en) | Dialkoxy-imidazopyridines derivatives | |
| CA2447675A1 (en) | Novel pyridylmethylaminopyrimidines | |
| WO2005123730A1 (en) | Amino-halogen-imidazopyridines as proton pump inhibitors | |
| HK1106504A (en) | Amino-halogen-imidazopyridines as proton pump inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| DA3 | Amendments made section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE NAME OF THE CO-INVENTOR FROM MULLER, BERND TO MUELLER, BERND Free format text: THE NATURE OF THE AMENDMENT IS AS SHOWN IN THE STATEMENT(S) FILED 19 FEB 2008 |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| DA2 | Applications for amendment section 104 |
Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE PATENTEE TO READ TAKEDA GMBH . |
|
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |