FI65617C - Mellanprodukt foer framstaellning av magsyrasekretionsinhiberande 2-(2-pyridylmetylsulfinyl)-benzimidazolderivat - Google Patents
Mellanprodukt foer framstaellning av magsyrasekretionsinhiberande 2-(2-pyridylmetylsulfinyl)-benzimidazolderivat Download PDFInfo
- Publication number
- FI65617C FI65617C FI811747A FI811747A FI65617C FI 65617 C FI65617 C FI 65617C FI 811747 A FI811747 A FI 811747A FI 811747 A FI811747 A FI 811747A FI 65617 C FI65617 C FI 65617C
- Authority
- FI
- Finland
- Prior art keywords
- acid
- alkyl
- het
- halogen
- benzimidazole
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- -1 C 2-5 carboalkoxy Chemical group 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- HBDKFZNDMVLSHM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfinyl)-1h-benzimidazole Chemical class N=1C2=CC=CC=C2NC=1S(=O)CC1=CC=CC=N1 HBDKFZNDMVLSHM-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 230000027119 gastric acid secretion Effects 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 5
- PLITYYGQMDTHMM-UHFFFAOYSA-N 2-(pyridin-2-ylmethylsulfanyl)-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1SCC1=CC=CC=N1 PLITYYGQMDTHMM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000277284 Salvelinus fontinalis Species 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- RYXPMWYHEBGTRV-UHFFFAOYSA-N Omeprazole sodium Chemical compound [Na+].N=1C2=CC(OC)=CC=C2[N-]C=1S(=O)CC1=NC=C(C)C(OC)=C1C RYXPMWYHEBGTRV-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- SPDVQSDBSYUSIC-UHFFFAOYSA-N n-methyl-2-(pyridin-2-ylmethylsulfanyl)-1h-benzimidazole-4-carboxamide Chemical compound N1C=2C(C(=O)NC)=CC=CC=2N=C1SCC1=CC=CC=N1 SPDVQSDBSYUSIC-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 description 1
- LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 244000263375 Vanilla tahitensis Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/28—Sulfur atoms
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Description
1 6561 7 Välituote vatsahapon eritystä estävien 2-(2-pyridyyli-metyylisulfinyyli)-bentsimidatsolijohdannaisten valmistamiseksi
Jakamalla erotettu hakemuksesta 752327 (patentti 63756) Tämä keksintö koskee välituotetta vatsahapon eritystä estävien uusien 2-(2-pyridyylimetyylisulfinyyli)-bentsimidatsoli johdannaisten valmistamiseksi.
Suomalaisessa patenttijulkaisussa FI-63 756 on kuvattu 2-(2-pyridyylimetyylisulfinyyli)-bentsimidatsolijohdannaisia, niiden valmistusta ja niiden arvokkaita terapeuttisia ominaisuuksia vatsahapon eritystä estävinä yhdisteinä.
Keksinnön mukaisella välituotteella on kaava R -- S-R6-Het (XXI) R8 3 jossa R ja R ovat samanlaisia tai erilaisia ja ovat vety, C^_^-alkyyli, halogeeni, syano, C2_5-karboalkoksi, karbamo-yyli, C^^-alkoksi, trifluorimetyyli tai _^-alkanoyyli missä hyvänsä asemassa, R8 on _4-alkyyli, karbamoyyli, Cj^-alkyylikarbamoyyli tai _^-alkyylisulfonyyli, R8 on suora tai haarautunut C^^-alkyyli, jolloin kuitenkin korkeintaan yksi metyleeniryhmä on ryhmän S ja Het välillä, ja Het on 2-pyridyyli, joka voi olla substituoitu alkyylillä tai halogeenilla. Keksinnön mukainen välituote voi esiintyä myös terapeuttisesti hyväksyttävänä suolana.
3
Kaavan XXI mukainen alkyyli R ]a R voi olla metyyli, etyyli, n-propyyli, isopropyyli, n-butyyli tai isobutyyli.
2 65617
Halogeeni R ja on fluori, jodi, bromi tai kloori, edullisesti bromi tai kloori.
3
Karboalkoksi R ja R on esimerkiksi karbometoksi (CH^OOC-) tai karbetoksi (C2H5~OOC-).
3
Alkoksi R ja R on metoksi, etoksi, n-propoksi tai iso-propoksi.
3
Alkanoyyli R 3a R on esimerkiksi formyyli, asetyyli tai propionyyli.
Q
Alkyyli R on esimerkiksi metyyli, etyyli tai n-propyyli.
Q
Alkyylisulfonyyli R on esimerkiksi metyylisulfonyyli, etyylisulfonyyli tai isopropyylisulfonyyli.
2-pyridyyliryhmä Het voi olla edelleen substituoitu alkyylillä tai halogeenilla 3-5-asemassa. Tällaisia alkyyli-ryhmiä ovat esimerkiksi metyyli, etyyli tai propyyli. Halo-geenisubstituentti on edullisesti kloori tai bromi.
Kaavan XXI mukaisia välituotteita voidaan valmistaa sinänsä tunnetulla tavalla, kuten esimerkiksi a) saattamalla yhdiste, jolla on kaava VIII r3 R —- S"R6_Het (VIII)
H
3 6 jossa R, R , R ja Het tarkoittavat samaa kuin yllä, reagoimaan yhdisteen kanssa, jolla on kaava Z-R7 3 6561 7 7 jossa Z on reaktiokykyinen esteröity hydroksiryhmä ja R on karbamoyyli tai C^^-alkyylisulfonyyli, kaavan XXI mukaisen välituotteen muodostamiseksi/ jossa R® tarkoittaa 7 samaa kuin R , tai 3 b) saattamalla yhdiste, jolla on kaava VIII, jossa R, R , 6 R ja Het tarkoittavat samaa kuin yllä, reagoimaan alkyyli-isosyanaatin kanssa kaavan XXI mukaisen välituotteen muo-
O
dostamiseksi, jossa R on C^^-alkyylikarbamoyyli, joka välituote voidaan muuttaa happoadditiosuolakseen, jos se esiintyy emäksenä tai emäsmuotoon, jos se esiintyy suolana.
Reaktiokykyinen esteröity hydroksiryhmä on ennen kaikkea hydroksiryhmä, joka esteröidään voimakkaan epäorgaanisen tai orgaanisen hapon, edullisesti halogeenivetyhapon, kuten kloorivetyhapon, bromivetyhapon tai jodivetyhapon kanssa, edelleen rikkihapon tai voimakkaan orgaanisen sulfonihapon, kuten voimakkaan aromaattisen hapon, esimerkiksi bentseeni-sulfonihapon, 4-bromibentseenisulfonihapon tai 4-tolueeni-sulfonihapon kanssa. Täten Z on edullisesti kloori, bromi tai jodi.
/ » k ‘ 6561 7
Riippuen valmistusolosuhteista ja lähtöaineesta saadaan keksinnön mukainen välituote vapaassa muodossa tai hap-poadditiosuolana. Niinpä voidaan saada esimerkiksi emäksisiä, neutraaleja tai seossuoloja, mahdollisesti myös hemiammonium-, seskvi- tai polyhydraattia. Happoaddi-tiosuolat voidaan muuttaa tunnetulla tavalla vapaiksi yhdisteiksi esimerkiksi käyttäen emäksisiä aineita, kuten alkaleita tai ioninvaihtajia. Toiselta puolen voivat saadut vapaat emäkset muodostaa suoloja orgaanisten tai epäorgaanisten happojen kanssa. Happoadditio-suolojen valmistamiseksi käytetään erikoisesti sellaisia happoja, joista voidaan muodostaa terapeuttisesti käyttökelpoisia suoloja. Tällaisina happoina voidaan mainita esimerkiksi halogeenivetyhapot, rikkihapot, fosfo-rihapot, typpihappo, perkloorihappo, alifaattiset, ali-sykliset, aromaattiset tai heterosykliset hiili- tai sulfonihapot, kuten muurahais-, etikka-, propioni-, meripihka-, glykoli-, maito-, omena-, viini-, sitruuna-, askorbiini-, maleiini-, hydroksimaleiini- tai palorypä-lehappo, fenyylietikka-, bentsoe-, p-aminobentsoe-, antraniili-, p-hydroksibentsoe-, salisyyli- tai p-amino-salisyylihappo, embonihappo, metaanisulfoni-, etaani-sulfoni-, hydroksietaanisulfoni-, etyleenisulfonihappo, halogeenibentsolisulfoni-, toluolisulfoni-, naftaliini-sulfoni- tai sulfaniilihappo, metioniini , tryptofaani , lysiini tai.arginiini.
Nämä ja näiden uusien välituotteiden muut suolat, kuten esimerkiksi pikraatit, voivat myös toimia saatujen vapaiden emästen puhdistustarkoituksessa, jolloin vapaat emäkset muutetaan suoloiksi, nämä erotetaan ja vapautetaan jälleen emäksenä suoloista.
Keksinnön mukaiset välituotteet voivat, mitä tulee lähtöaineiden ja työtavan valintaan, esiintyä myös optisina antipodeina tai rasemaatteina, tai mikäli saa- s 65617 daan vähintään kaksi epäsymmetristä hiiliatomia, myös isomeeriseoksena (rasemaattiseos).
Saadut isomeeriseokset (rasemaattiseokset) voidaan jakaa niiden ainesosien fysikaaliskemiallisten erilaisuuksien perusteella tunnetulla tavalla molemmiksi stereoisomeeri-siksi (diastereomeerisiksi) puhtaiksi rasemaateiksi, esimerkiksi kromatografiän ja/tai fraktiokiteyttämisen avulla.
Saadut rasemaatit voidaan jakaa tunnetuilla menetelmillä, esimerkiksi kiteyttämällä, uudelleen optisesti aktiivisesta liuottimesta mikro-organismien avulla tai reaktion avulla optisesti aktiivisen hapon kanssa, joka muodostaa suoloja rasemaattisen yhdisteen kanssa, ja erottamalla tällä tavoin saadut suolat esimerkiksi niiden erilaisen liukoisuuden perusteella diastereoisomeereiksi, joista antipodit voidaan vapauttaa sopivien aineiden avulla. Erittäin tavallisia optisesti aktiivisia happoja ovat esimerkiksi viini-hapon D- ja L-muodot,Di-o-tolyyliviinihappo, omenahappo, mantelihappo, kamferisulfonihappo tai kiinanhappo.
Keksinnön mukaiset välituotteet hapetetaan terapeuttisesti aktiivisiksi 2-(2-pyridyylimetyylisulfinyyli)-bentsimidat-solijohdannaisiksi kuten suomalaisessa patentissa n:o 63756 (pat.hak. n:o 752327) on esitetty.
Seuraavissa esimerkeissä kuvataan keksinnön mukaisten välituotteiden valmistusta.
Lähtöaineet ovat tunnettuja tai niitä voidaan saada, mikäli ne ovat uusia, tunnettujen menetelmien avulla.
Esimerkki I
4,82 g (0,02 moolia) 2-(2-pyridyylimetyylitio)-bentsimidat-solia ja 1,5 g metyyli-isosyanaattia kuumennettiin palautus jäähdyttäen 150 ml:ssa tolueenia 2 tuntia. Seos jäähdy- 6 6561 7 tettiin, muodostunut sakka erotettiin suodattamalla ja kiteytettiin uudelleen tolueenista. 2-(2-pyridyylimetyylitio)-(N-metyylikarbamoyyli)bentsimidatsolin saanto oli 4,5 g.
Sp. 135°C.
Esimerkki II
4,82 g (0,02 moolia) 2-(2-pyridyylimetyylitio)-bentsimidat-solia ja 4,05 g (0,04 moolia) trietyyliamiinia liuotettiin 200 mlraan asetonitriiliä. Sitten lisättiin tipottain 2,52 g (0,022 moolia) metyylisulfonikloridia 20 mlissa asetonitriiliä, minkä jälkeen liuos sai seistä yli yön. Seos kaadettiin jäähän, jolloin tuote kiteytyi. 2-(2-pyridyylimetyylitio) -(N-metyylisulfonyyli)bentsimidatsolin uudelleenkitey-tys tapahtui asetonitriilistä.
Saanto 3,7 g, sp. 142°C.
7 6561 7
Denna uppfinning avser en mellanprodukt för framställning av nya magsyrasekretionsinhiberande 2-(2-pyridylmetylsulfinyl)-benzimidazolderivat.
2-(2-pyridylmetylsulfinyl)-benzimidazolderivat, deras fraraställ-ning och deras värdefulla terapeutiska egenskaper som magsyrasekretionsinhiberande föreningar är beskrivna i den finska patentskriften FI-63 756.
Mellanprodukten enligt uppfinningen har formeln R3 R—^- S-R6-Het (XXI) “o R8 3 väri R och R är samma eller olika, och är väte, C1_4-alkyl, halogen, cyano, C2_5“karboalkoxi, karbamoyl, C^_4~alkoxi, tri-fluormetyl eller C^^-alkanoyl i valfri position, R8 är c-j_4~ alkyl, karbamoyl, C2_,--alkylkarbamoyl eller _4-alkylsulfonyl, R8 är rak eller grenad C^_4~alkyl, varvid dock högst en metylen-grupp förefinns mellan S och Het, och Het är 2-pyridyl, vilken kan vara substituerad med C^_4~alkyl eller halogen. Mellanprodukten enligt uppfinningen kan även föreligga som ett terä-peutiskt acceptabelt sait.
Alkyl R och R enligt formel XXI kan vara metyl, etyl, n-propyl, isopropyl, n-butyl eller isobutyl.
Halogen R och R är fluor, jod, brom eller klor, företrädesvis brom eller klor.
3
Karbalkoxi R och R är exempelvis karbometoxi (CH^OOC-) eller karbetoxi (C2H5-OOC-).
Alkoxi R och R3 är metoxi, etoxi, n-propoxi eller isopropoxi.
3 8 65617
Alkanoyl R och R är exempelvis formyl, acetyl eller propionyl.
Q
Alkyl R är exempelvis metyl, etyl eller n-propyl.
Q
Alkylsulfonyl R är exempelvis metylsulfonyl, etylsulfonyl eller isopropylsulfonyl.
2-pyridylgruppen Het kan vara ytterligare substituerad med C^_4~alkyl eller halogen i 3-5-ställning. Sädana alkylgrupper är exempelvis metyl, etyl eller propyl. Halogensubstituenten är företrädesvis klor eller brom.
Mellanprodukterna enligt formel XXI kan framställas pä i och för sig känt sätt säsom genom att t.ex.
a) omsätta en förening enligt formel VIII
R3 R —^- S-R6-Het (VIII)
H
3 6 väri R, R , R och Het har ovan angivna betydelse, med en förening med formeln Z-R7 7 väri Z är en reaktiv förestrad hydroxigrupp och R är karbamoyl eller C. ,-alkylsulfonyl, till bildning av en mellanprodukt enligt 8 7 formel XXI, väri R har den för R angivna betydelsen, eller 3 b) omsätta en förening enligt formel Vili, väri R, R , R och Het har ovan angivna betydelse, med alkylisocyanat till bildning
Q
av en mellanprodukt enligt formel XXI, väri R är C1_4~alkylkar-bamoyl, vilken mellanprodukt om förefintlig som bas kan omvandlas till ett syraadditionssalt eller om förefintlig som ett salt kan omvandlas till basform.
9 65617
En reaktiv förestrad hydroxigrupp är framförallt en hydroxi-grupp som förestrats med en stark oorganisk eller organisk syra företrädesvis en halogenvätesyra, sAsom klorvätesyra, bromväte-syra eller jodvätesyra, vidare svavelsyra eller en stark organisk sulfonsyra sAsom en stark aromatisk syra exempelvis bensensulfon-syra, 4-brombensensulfonsyra eller 4-toluensulfonsyra. SAlunda är Z företrädesvis klor, brom eller jod.
Beroende pA tillverkningsbetingelserna och utgAngsmaterialet erhäller man mellanprodukten enligt uppfinningen i fri form eller i form av dess syraadditionssalt. SA kan exempelvis erhAllas basiska, neutrala eller blandsalt eventuellt ocksA hemiammonium-, sesqui- eller polyhydrat. Syraadditionssalterna kan överföras pA känt sätt i fria föreningar t.ex. med basiska medel som alkalier eller jonbytare. A andra sidan kan de erhAllna fria baserna bilda salter med organiska eller oorganiska syror. För framställning av syraadditionssalter används särskilt sAdana syror som kan bilda terapeutiskt användbara salter. Som sAdana syror kan exempelvis nämnas: halogenvätesyror, svavelsyror, fosforsyror, salpetersyra, perklorsyra, alifatiska, alicykliska, aromatiska eller hetero-cykliska koi- eller sulfonsyror, som myr-, ättik-, propion-, bärnstens-, glykol-, mjölk-, äpple-, vin-, citron-, askorbin-, malein-, hydroximalein- eller pyrodruvsyra, fenylättik-, bensoe-, p-aminobensoe-, antranil-, p-hydroxibensoe-, salicyl- eller p-aminosalicylsyra, embonsyra, metansulfon-, etansulfon-, hydroxi-etansulfon-, etylensulfonsyra, halogenbensolsulfon-, toluol-sulfon-, naftalinsulfon- eller sulfanilsyra, metionin, tryptofan, lysin eller arginin.
Dessa och andra salter av de nya mellanprodukterna som t.ex. pik-rater kan ocksä tjäna som rening av de erh&llna fria baserna i det man överför de fria baserna tili salter, avskiljer dessa och frigör Ater baserna ur salterna.
De nya mellanprodukterna kan med hänsyn tili vai av utgAngsämnen och arbetssätt föreligga även som optiska antipoder eller racemat 10 6561 7 eller, s ci v ida man erhiller minst tvi asymmetriska kolatomer, ocksä som isomerblandning (racematblandning).
Erhillna isomerblandningar (racematblandningar) kan pi grund av fysikalisk-kemiska olikheter hos bestindsdelarna pä känt sätt uppdelas i de bada stereoisomera (diastereomera) rena racematen exempelvis genom kromatografi och/eller fraktionerad kristalli-sation.
Erhillna racemat liter sig uppdelas enligt kända metoder exempelvis genom omkristallisation ur ett optiskt aktivt lösnings-medel med hjälp av mikroorganismer eller genom omsättning med en optiskt aktiv syra, som bildar salter med den racemiska föreningen och separation av pi detta sätt erhällna salter, t.ex. pi grund av deras oiikä löslighet, i diastereoisomerer ur vilka antipoderna kan friläggas genom inverkan av lämpliga medel. Särskilt vanliga optiskt aktiva syror är t.ex. D- och L-formerna av vinsyra, Di-o-tolylvinsyra, äppelsyra, mandel-syra, kamfersulfonsyra eller kinasyra.
Mellanprodukterna enligt uppfinningen oxideras tili terapeutiskt aktiva 2-(2-pyridylmetylsulfinyl)-benzimidazolderivat sisom är beskrivet i det finska patentet nr 63756 (pat.ans. nr 752327).
Följande exempel illustrerar framställningen av mellanprodukterna enligt uppfinningen.
Utgingsmaterialen är kända eller kan om de är nya erhallas genom kända metoder.
Exempel I
4,82 g (0,02 moler) 2-(2-pyridylmetyltio)-benzimidazol och 1,5 g metylisocyanat aterloppskokades i 150 ml toluen under 2 timmar. Blandningen kyldes, den bildade fällningen filtrerades av och omkristalliserades ur toluen. Utbytet av 2-(2-pyridylmetyltio)--(N-metylkarbamoyl)-benzimidazol var 4,5 g. Smiltpunkt 135°C.
11 - 6561 7
Exempel II
4,82 g (0,02 moler) 2-(2-pyridylmetyltio)-benzimidazol och 4,05 g (0,04 moler) trietylamin löstes i 200 ml acetonitril.
2,52 g (0,022 moler) metylsulfonklorid i 20 ml acetonitril till-sattes därefter droppvis, varefter lösningen fick sta över natt. Blandningen hälldes ut över is, varvid produkten kristallise-rade. Omkristallisation av 2-(2-pyridylmetyltio)-(N-metylsulfo-nyl)benzimidazol skedde ur acetonitril. Utbyte 3,7 g. Smält-punkt 142°C.
Claims (1)
- 6561 7 Patenttivaatimus Välituote terapeuttisesti aktiivisten vatsahapon eritystä estävien 2-(2-pyridyylimetyylisulfinyyli)-bentsimidatsoli-johdannaisten valmistamiseksi, tunnettu siitä, että välituotteella on kaava !8 3 jossa R ja R ovat samanlaisia tai erilaisia ja ovat vety, C1_4~alkyyli, halogeeni, syano, C2_5-karboalkoksi, karbamo- yyli, _4~alkoksi, trifluorimetyyli tai _4~alkanoyyli missä hyvänsä asemassa, R® on C1 ,-alkyyli, karbamoyyli, ^ 6 C2_t--alkyylikarbamoyyli tai _4-alkyylisulfonyyli, R on suora tai haarautunut C1_4~alkyyli, jolloin kuitenkin korkeintaan yksi metyleeniryhmä on ryhmien S ja Het välillä, ja Het on 2-pyridyyli, joka voi olla substituoitu C^_4~ alkyylillä tai halogeenilla, tai tämän terapeuttisesti hyväksyttävät suolat.
Applications Claiming Priority (50)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE7406513 | 1974-05-16 | ||
| SE7406513A SE416649B (sv) | 1974-05-16 | 1974-05-16 | Forfarande for framstellning av foreningar som paverkar magsyrasekretionen |
| NO752851 | 1975-08-15 | ||
| NO75752851A NO143222C (no) | 1974-05-16 | 1975-08-15 | Analogifremgangsmaate for fremstilling av nye substituerte pyridylsulfinyl-benzimidazoler med terapeutisk aktivitet |
| FI752327A FI63756C (fi) | 1974-05-16 | 1975-08-15 | Foerfarande foer framstaellning av 2-(2-pyridylmetylsulfinyl)-bensimidazolderivat med magsyrasekretionsinhiberande verkan |
| FI752327 | 1975-08-15 | ||
| DK372175 | 1975-08-18 | ||
| DK372175AA DK140840B (da) | 1974-05-16 | 1975-08-18 | Analogifremgangsmåde til fremstilling af benzimidazolderivater eller syreadditionssalte deraf. |
| ZA7506600 | 1975-10-20 | ||
| GB4303975 | 1975-10-20 | ||
| GB43039/75A GB1525958A (en) | 1974-05-16 | 1975-10-20 | 2-(heterocyclic substituted alkylsulphinyl)-benzimidazoles and their pharmaceutical compositions |
| ZA00756600A ZA756600B (en) | 1974-05-16 | 1975-10-20 | Gastric acid secretion agents |
| IE231375 | 1975-10-23 | ||
| IE2313/75A IE42451B1 (en) | 1974-05-16 | 1975-10-23 | 2-(heterocyclic substituted alkylsulphinyl)-benzimidazoles and their pharmaceutical compositions |
| DE2548340 | 1975-10-29 | ||
| DE19752548340 DE2548340A1 (de) | 1974-05-16 | 1975-10-29 | Benzimidazole, verfahren zu deren herstellung und sie enthaltende mittel |
| AT838075 | 1975-11-04 | ||
| AT838075A AT337697B (de) | 1974-05-16 | 1975-11-04 | Verfahren zur herstellung von neuen benzimidazolderivaten und ihren salzen |
| CS757458A CS196289B2 (en) | 1974-05-16 | 1975-11-05 | Process for preparing new compounds |
| CS745875 | 1975-11-05 | ||
| NL7513141A NL7513141A (nl) | 1974-05-16 | 1975-11-10 | Benzimidazoolderivaten en werkwijze voor het be- reiden daarvan alsmede preparaten voor het bein- vloeden van de maagzuursecretie. |
| NL7513141 | 1975-11-10 | ||
| US05/630,916 US4045563A (en) | 1974-05-16 | 1975-11-11 | Substituted 2-[pyridylalkylenesulfinyl]-benzimidazoles with gastric acid secretion inhibiting effects |
| US63091675 | 1975-11-11 | ||
| HUHE000696 | 1975-11-12 | ||
| HU75HE00000696A HU172653B (hu) | 1974-05-16 | 1975-11-12 | Sposob poluchenija zamehhennykh 2-skobka-2-piridil-metil-sul'finil-skobka zakryta-benzimidazolov |
| SU2189960 | 1975-11-13 | ||
| SU752189960A SU602118A3 (ru) | 1974-05-16 | 1975-11-13 | Способ получени производных бензимидазола или их солей |
| FR7534910A FR2331340A1 (fr) | 1974-05-16 | 1975-11-14 | Nouveaux derives du benzimidazole, procede pour leur obtention et compositions pharmaceutiques les contenant |
| DD18946375 | 1975-11-14 | ||
| CA239643 | 1975-11-14 | ||
| DD189463A DD122534A5 (fi) | 1974-05-16 | 1975-11-14 | |
| CH1481475 | 1975-11-14 | ||
| CA239,643A CA1055033A (en) | 1974-05-16 | 1975-11-14 | 2-(2-heterocyclic-methylsulphinyl)-benzimidazole compounds |
| FR7534910 | 1975-11-14 | ||
| CH1481475A CH623814A5 (en) | 1974-05-16 | 1975-11-14 | Process for the preparation of novel benzimidazoles |
| JP50137712A JPS5262275A (en) | 1974-05-16 | 1975-11-15 | Production of organic compound |
| JP13771275 | 1975-11-15 | ||
| FR7616732 | 1976-06-03 | ||
| FR7616732A FR2392021A1 (fr) | 1974-05-16 | 1976-06-03 | Nouveaux derives du benzimidazole et procede pour leur obtention |
| AT752276A AT351524B (de) | 1974-05-16 | 1976-10-11 | Verfahren zur herstellung von neuen benzimida- zolderivaten, ihren salzen und optischen isomeren |
| AT752276 | 1976-10-11 | ||
| DK365978 | 1978-08-18 | ||
| DK783659A DK365978A (da) | 1974-05-16 | 1978-08-18 | Mellemprodukt til anvendelse ved fremstilling af benzimidazolderivater |
| CS688678 | 1978-10-23 | ||
| CS786886A CS196290B2 (en) | 1974-05-16 | 1978-10-23 | Process for preparing new compounds |
| HU8782 | 1982-02-25 | ||
| HU8782 | 1982-02-25 | ||
| MY8200159 | 1982-12-30 | ||
| MY159/82A MY8200159A (en) | 1974-05-16 | 1982-12-30 | 2-[heterocylic substituted alkylsulphinyl]-benzimidazoles and their pharmaceutical compositions |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI811747L FI811747L (fi) | 1981-06-04 |
| FI65617B FI65617B (fi) | 1984-02-29 |
| FI65617C true FI65617C (fi) | 1984-06-11 |
Family
ID=40486266
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI752327A FI63756C (fi) | 1974-05-16 | 1975-08-15 | Foerfarande foer framstaellning av 2-(2-pyridylmetylsulfinyl)-bensimidazolderivat med magsyrasekretionsinhiberande verkan |
| FI811747A FI65617C (fi) | 1974-05-16 | 1981-06-04 | Mellanprodukt foer framstaellning av magsyrasekretionsinhiberande 2-(2-pyridylmetylsulfinyl)-benzimidazolderivat |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI752327A FI63756C (fi) | 1974-05-16 | 1975-08-15 | Foerfarande foer framstaellning av 2-(2-pyridylmetylsulfinyl)-bensimidazolderivat med magsyrasekretionsinhiberande verkan |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4045563A (fi) |
| JP (1) | JPS5262275A (fi) |
| AT (2) | AT337697B (fi) |
| CA (1) | CA1055033A (fi) |
| CH (2) | CH623814A5 (fi) |
| CS (2) | CS196289B2 (fi) |
| CY (1) | CY1125A (fi) |
| DD (1) | DD122534A5 (fi) |
| DE (1) | DE2548340A1 (fi) |
| DK (2) | DK140840B (fi) |
| FI (2) | FI63756C (fi) |
| FR (2) | FR2331340A1 (fi) |
| GB (1) | GB1525958A (fi) |
| HK (1) | HK8782A (fi) |
| HU (1) | HU172653B (fi) |
| IE (1) | IE42451B1 (fi) |
| MY (1) | MY8200159A (fi) |
| NL (1) | NL7513141A (fi) |
| NO (1) | NO143222C (fi) |
| SE (1) | SE416649B (fi) |
| SU (1) | SU602118A3 (fi) |
| ZA (1) | ZA756600B (fi) |
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- 1975-10-29 DE DE19752548340 patent/DE2548340A1/de active Granted
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- 1975-11-05 CS CS757458A patent/CS196289B2/cs unknown
- 1975-11-10 NL NL7513141A patent/NL7513141A/xx not_active Application Discontinuation
- 1975-11-11 US US05/630,916 patent/US4045563A/en not_active Expired - Lifetime
- 1975-11-12 HU HU75HE00000696A patent/HU172653B/hu unknown
- 1975-11-13 SU SU752189960A patent/SU602118A3/ru active
- 1975-11-14 CA CA239,643A patent/CA1055033A/en not_active Expired
- 1975-11-14 DD DD189463A patent/DD122534A5/xx unknown
- 1975-11-14 CH CH1481475A patent/CH623814A5/de not_active IP Right Cessation
- 1975-11-14 FR FR7534910A patent/FR2331340A1/fr active Granted
- 1975-11-15 JP JP50137712A patent/JPS5262275A/ja active Granted
-
1976
- 1976-06-03 FR FR7616732A patent/FR2392021A1/fr active Granted
- 1976-10-11 AT AT752276A patent/AT351524B/de not_active IP Right Cessation
-
1978
- 1978-08-18 DK DK783659A patent/DK365978A/da unknown
- 1978-10-23 CS CS786886A patent/CS196290B2/cs unknown
-
1979
- 1979-10-31 CH CH976079A patent/CH623582A5/de not_active IP Right Cessation
-
1981
- 1981-06-04 FI FI811747A patent/FI65617C/fi not_active IP Right Cessation
-
1982
- 1982-02-25 HK HK87/82A patent/HK8782A/xx unknown
- 1982-12-30 MY MY159/82A patent/MY8200159A/xx unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: AB HAESSLE |