NO882321L - CONNECTIONS. - Google Patents
CONNECTIONS.Info
- Publication number
- NO882321L NO882321L NO882321A NO882321A NO882321L NO 882321 L NO882321 L NO 882321L NO 882321 A NO882321 A NO 882321A NO 882321 A NO882321 A NO 882321A NO 882321 L NO882321 L NO 882321L
- Authority
- NO
- Norway
- Prior art keywords
- benzimidazole
- pyridinyl
- methoxy
- ring
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 150
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 40
- 239000001257 hydrogen Substances 0.000 claims abstract description 40
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 230000027119 gastric acid secretion Effects 0.000 claims abstract description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- -1 2-[5-ethoxy-2-(4-methyl-2-pyridinyl)phenylthio]-1H-benzimidazole Chemical compound 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000002837 carbocyclic group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000001120 cytoprotective effect Effects 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 230000004968 inflammatory condition Effects 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000006413 ring segment Chemical group 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 5
- RVKPUMMXNJFBBU-UHFFFAOYSA-N 2-[5-methoxy-2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC(OC)=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 RVKPUMMXNJFBBU-UHFFFAOYSA-N 0.000 claims 2
- SMTQSNBMQYEDTN-UHFFFAOYSA-N 2-[5-methoxy-2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC(OC)=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 SMTQSNBMQYEDTN-UHFFFAOYSA-N 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- MNJRZDGCYZKPET-UHFFFAOYSA-N 1-[2-(1h-benzimidazol-2-ylsulfanyl)phenyl]-6,7-dimethoxyisoquinoline Chemical compound C1=CC=C2NC(SC3=CC=CC=C3C=3N=CC=C4C=C(C(=CC4=3)OC)OC)=NC2=C1 MNJRZDGCYZKPET-UHFFFAOYSA-N 0.000 claims 1
- NOQGIVWKFQARKI-UHFFFAOYSA-N 1-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-6,7-dimethoxyisoquinoline Chemical compound C1=CC=C2NC(S(=O)C3=CC=CC=C3C=3N=CC=C4C=C(C(=CC4=3)OC)OC)=NC2=C1 NOQGIVWKFQARKI-UHFFFAOYSA-N 0.000 claims 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 1
- YQQLQOOEMNTGEV-UHFFFAOYSA-N 2-(5-methoxy-2-pyridin-2-ylphenyl)sulfanyl-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1SC1=CC(OC)=CC=C1C1=CC=CC=N1 YQQLQOOEMNTGEV-UHFFFAOYSA-N 0.000 claims 1
- AVMFOIOSALXGDU-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfanyl)phenyl]-1-methylbenzimidazole Chemical compound C1=CC=C2NC(SC3=CC=CC=C3C=3N(C4=CC=CC=C4N=3)C)=NC2=C1 AVMFOIOSALXGDU-UHFFFAOYSA-N 0.000 claims 1
- ZAXAQFUOVIIQKJ-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfanyl)phenyl]-5,6-dichloro-1-methylbenzimidazole Chemical compound C1=CC=C2NC(SC3=CC=CC=C3C=3N(C4=CC(Cl)=C(Cl)C=C4N=3)C)=NC2=C1 ZAXAQFUOVIIQKJ-UHFFFAOYSA-N 0.000 claims 1
- VMKOGSAIAZXAQI-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfanyl)phenyl]-5-chloro-1-methylbenzimidazole Chemical compound C1=CC=C2NC(SC3=CC=CC=C3C=3N(C4=CC=C(Cl)C=C4N=3)C)=NC2=C1 VMKOGSAIAZXAQI-UHFFFAOYSA-N 0.000 claims 1
- KUKDWHIYEAMGRB-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-1-methylbenzimidazole Chemical compound C1=CC=C2NC(S(=O)C3=CC=CC=C3C=3N(C4=CC=CC=C4N=3)C)=NC2=C1 KUKDWHIYEAMGRB-UHFFFAOYSA-N 0.000 claims 1
- QMKBRINYIGHHCI-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-5,6-dichloro-1-methylbenzimidazole Chemical compound C1=CC=C2NC(S(=O)C3=CC=CC=C3C=3N(C4=CC(Cl)=C(Cl)C=C4N=3)C)=NC2=C1 QMKBRINYIGHHCI-UHFFFAOYSA-N 0.000 claims 1
- YCXDXPWBUFWBOS-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-5-chloro-1-methylbenzimidazole Chemical compound C1=CC=C2NC(S(=O)C3=CC=CC=C3C=3N(C4=CC=C(Cl)C=C4N=3)C)=NC2=C1 YCXDXPWBUFWBOS-UHFFFAOYSA-N 0.000 claims 1
- UOKJYFMGISKQOL-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-6-chloro-1-methylbenzimidazole Chemical compound C1=CC=C2NC(S(=O)C3=CC=CC=C3C=3N(C4=CC(Cl)=CC=C4N=3)C)=NC2=C1 UOKJYFMGISKQOL-UHFFFAOYSA-N 0.000 claims 1
- IMQOTXGNOUYOMN-UHFFFAOYSA-N 2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]-n-methyl-n-phenylpyridin-4-amine Chemical compound C=1C=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=CC=1N(C)C1=CC=CC=C1 IMQOTXGNOUYOMN-UHFFFAOYSA-N 0.000 claims 1
- XRCRRRJQICLVIR-UHFFFAOYSA-N 2-[2-(3-ethylpyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound CCC1=CC=CN=C1C1=CC=CC=C1S(=O)C1=NC2=CC=CC=C2N1 XRCRRRJQICLVIR-UHFFFAOYSA-N 0.000 claims 1
- QAXHZUZZNADLAC-UHFFFAOYSA-N 2-[2-(3-methylpyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound CC1=CC=CN=C1C1=CC=CC=C1SC1=NC2=CC=CC=C2N1 QAXHZUZZNADLAC-UHFFFAOYSA-N 0.000 claims 1
- MRCWAPJVXBIUBA-UHFFFAOYSA-N 2-[2-(4-ethylpyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound CCC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 MRCWAPJVXBIUBA-UHFFFAOYSA-N 0.000 claims 1
- VIHHDFHGYRJRAD-UHFFFAOYSA-N 2-[2-(4-methoxy-6-methylpyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC(C)=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 VIHHDFHGYRJRAD-UHFFFAOYSA-N 0.000 claims 1
- XTANQNORBUSBOT-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1,3-benzoxazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2OC3=CC=CC=C3N=2)=C1 XTANQNORBUSBOT-UHFFFAOYSA-N 0.000 claims 1
- VKYCQTPYPDHUBT-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-6-methyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=C(C)C=C3N=2)=C1 VKYCQTPYPDHUBT-UHFFFAOYSA-N 0.000 claims 1
- HYOPIVGMHIOEKI-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-6-nitro-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=C(C=C3N=2)[N+]([O-])=O)=C1 HYOPIVGMHIOEKI-UHFFFAOYSA-N 0.000 claims 1
- RHHRCHCLGUJILD-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1,3-benzoxazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2OC3=CC=CC=C3N=2)=C1 RHHRCHCLGUJILD-UHFFFAOYSA-N 0.000 claims 1
- AWPVYTYSNQBFCC-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-3h-benzimidazol-5-amine Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=C(N)C=C3N=2)=C1 AWPVYTYSNQBFCC-UHFFFAOYSA-N 0.000 claims 1
- GUGRPGFOKKEFQE-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-4,5-dimethyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=C(C)C(C)=C3N=2)=C1 GUGRPGFOKKEFQE-UHFFFAOYSA-N 0.000 claims 1
- AYSYUYOFCXXROE-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-6-methyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=C(C)C=C3N=2)=C1 AYSYUYOFCXXROE-UHFFFAOYSA-N 0.000 claims 1
- HTGBSHDNVVQXLG-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)thiophen-3-yl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C2=C(C=CS2)SC=2NC3=CC=CC=C3N=2)=C1 HTGBSHDNVVQXLG-UHFFFAOYSA-N 0.000 claims 1
- DBTVWBXOHFIDSI-UHFFFAOYSA-N 2-[2-(4-methoxypyridin-2-yl)thiophen-3-yl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C2=C(C=CS2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 DBTVWBXOHFIDSI-UHFFFAOYSA-N 0.000 claims 1
- FDRZWHMMDLCNAI-UHFFFAOYSA-N 2-[2-(4-methylpyridin-2-yl)phenyl]sulfanyl-1,3-benzoxazole Chemical compound CC1=CC=NC(C=2C(=CC=CC=2)SC=2OC3=CC=CC=C3N=2)=C1 FDRZWHMMDLCNAI-UHFFFAOYSA-N 0.000 claims 1
- VTQRBDYBISIBRK-UHFFFAOYSA-N 2-[2-(4-methylpyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound CC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 VTQRBDYBISIBRK-UHFFFAOYSA-N 0.000 claims 1
- OELVGRMWGBZXQC-UHFFFAOYSA-N 2-[2-(4-methylpyridin-2-yl)phenyl]sulfinyl-1,3-benzoxazole Chemical compound CC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2OC3=CC=CC=C3N=2)=C1 OELVGRMWGBZXQC-UHFFFAOYSA-N 0.000 claims 1
- UKZIFWBIJKBBOH-UHFFFAOYSA-N 2-[2-(4-methylpyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound CC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 UKZIFWBIJKBBOH-UHFFFAOYSA-N 0.000 claims 1
- OIJJFISEFRRFEU-UHFFFAOYSA-N 2-[2-(4-propan-2-yloxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound CC(C)OC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 OIJJFISEFRRFEU-UHFFFAOYSA-N 0.000 claims 1
- KRUAKNXUUOWDGH-UHFFFAOYSA-N 2-[2-(4-propoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound CCCOC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 KRUAKNXUUOWDGH-UHFFFAOYSA-N 0.000 claims 1
- ZZYNDKGDAXGMOD-UHFFFAOYSA-N 2-[2-(4-propoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound CCCOC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 ZZYNDKGDAXGMOD-UHFFFAOYSA-N 0.000 claims 1
- KNHVFLFZARBNQL-UHFFFAOYSA-N 2-[2-(5-methylpyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound N1=CC(C)=CC=C1C1=CC=CC=C1SC1=NC2=CC=CC=C2N1 KNHVFLFZARBNQL-UHFFFAOYSA-N 0.000 claims 1
- OBRZFCLINWCXBG-UHFFFAOYSA-N 2-[2-[(6-methoxy-1h-benzimidazol-2-yl)sulfinyl]phenyl]-1-methylbenzimidazole Chemical compound C1=CC=C2N(C)C(C3=CC=CC=C3S(=O)C=3NC4=CC=C(C=C4N=3)OC)=NC2=C1 OBRZFCLINWCXBG-UHFFFAOYSA-N 0.000 claims 1
- SIBUIURPIQAQPW-UHFFFAOYSA-N 2-[2-[4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]pyridin-2-yl]phenyl]sulfanyl-1h-benzimidazole Chemical compound C=1C=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=CC=1OCC1(C)OCCO1 SIBUIURPIQAQPW-UHFFFAOYSA-N 0.000 claims 1
- JAULFALGRXCJPZ-UHFFFAOYSA-N 2-[5-chloro-2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC(Cl)=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 JAULFALGRXCJPZ-UHFFFAOYSA-N 0.000 claims 1
- NMDNKRRTAXWKQH-UHFFFAOYSA-N 2-[5-chloro-2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC(Cl)=CC=2)S(=O)C=2NC3=CC=CC=C3N=2)=C1 NMDNKRRTAXWKQH-UHFFFAOYSA-N 0.000 claims 1
- BHXJGPCCSASREK-UHFFFAOYSA-N 4,7-dimethoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=C(OC)C=CC(OC)=C3N=2)=C1 BHXJGPCCSASREK-UHFFFAOYSA-N 0.000 claims 1
- OVMWHMJUIGDTEI-UHFFFAOYSA-N 4-[2-[2-(1h-benzimidazol-2-ylsulfanyl)phenyl]pyridin-4-yl]morpholine Chemical compound C1COCCN1C1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC=C3N=2)=C1 OVMWHMJUIGDTEI-UHFFFAOYSA-N 0.000 claims 1
- CRJDBCFYJSKJMK-UHFFFAOYSA-N 4-[2-[2-(1h-benzimidazol-2-ylsulfinyl)phenyl]pyridin-4-yl]morpholine Chemical compound N=1C2=CC=CC=C2NC=1S(=O)C1=CC=CC=C1C(N=CC=1)=CC=1N1CCOCC1 CRJDBCFYJSKJMK-UHFFFAOYSA-N 0.000 claims 1
- BAUXGIQIYJFZTL-UHFFFAOYSA-N 4-methoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=CC(OC)=C3N=2)=C1 BAUXGIQIYJFZTL-UHFFFAOYSA-N 0.000 claims 1
- PIIWVZCRWMCMIT-UHFFFAOYSA-N 4-methoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=CC(OC)=C3N=2)=C1 PIIWVZCRWMCMIT-UHFFFAOYSA-N 0.000 claims 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 1
- KZPYGJXARSTZJO-UHFFFAOYSA-N 5,6-dimethoxy-2-(5-methoxy-2-pyridin-2-ylphenyl)sulfanyl-1h-benzimidazole Chemical compound N=1C2=CC(OC)=C(OC)C=C2NC=1SC1=CC(OC)=CC=C1C1=CC=CC=N1 KZPYGJXARSTZJO-UHFFFAOYSA-N 0.000 claims 1
- JZCKYWQYAZVFLQ-UHFFFAOYSA-N 5,6-dimethoxy-2-(5-methoxy-2-pyridin-2-ylphenyl)sulfinyl-1h-benzimidazole Chemical compound N=1C2=CC(OC)=C(OC)C=C2NC=1S(=O)C1=CC(OC)=CC=C1C1=CC=CC=N1 JZCKYWQYAZVFLQ-UHFFFAOYSA-N 0.000 claims 1
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 1
- XUHJAWSMIUQWNY-UHFFFAOYSA-N 6-chloro-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=C(Cl)C=C3N=2)=C1 XUHJAWSMIUQWNY-UHFFFAOYSA-N 0.000 claims 1
- SNHCMHHQLDKSAC-UHFFFAOYSA-N 6-chloro-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)S(=O)C=2NC3=CC=C(Cl)C=C3N=2)=C1 SNHCMHHQLDKSAC-UHFFFAOYSA-N 0.000 claims 1
- ISGHVVQVHARTNA-UHFFFAOYSA-N 6-methoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC=CC=2)SC=2NC3=CC=C(OC)C=C3N=2)=C1 ISGHVVQVHARTNA-UHFFFAOYSA-N 0.000 claims 1
- CCTJJJWSSSRXET-UHFFFAOYSA-N 6-methoxy-2-[5-methoxy-2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-1h-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1SC1=CC(OC)=CC=C1C1=CC(OC)=CC=N1 CCTJJJWSSSRXET-UHFFFAOYSA-N 0.000 claims 1
- DTVDDPVJTHVMAX-UHFFFAOYSA-N 6-methoxy-2-[5-methoxy-2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-1h-benzimidazole Chemical compound COC1=CC=NC(C=2C(=CC(OC)=CC=2)S(=O)C=2NC3=CC=C(OC)C=C3N=2)=C1 DTVDDPVJTHVMAX-UHFFFAOYSA-N 0.000 claims 1
- MUNDQQNJPCBVLG-UHFFFAOYSA-N ethyl 6-ethoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-3h-benzimidazole-5-carboxylate Chemical compound N=1C=2C=C(OCC)C(C(=O)OCC)=CC=2NC=1SC1=CC=CC=C1C1=CC(OC)=CC=N1 MUNDQQNJPCBVLG-UHFFFAOYSA-N 0.000 claims 1
- DVELHEHQGZDKQI-UHFFFAOYSA-N ethyl 6-ethoxy-2-[2-(4-methoxypyridin-2-yl)phenyl]sulfinyl-3h-benzimidazole-5-carboxylate Chemical compound N=1C=2C=C(OCC)C(C(=O)OCC)=CC=2NC=1S(=O)C1=CC=CC=C1C1=CC(OC)=CC=N1 DVELHEHQGZDKQI-UHFFFAOYSA-N 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- WEGXHIGVMALKNN-UHFFFAOYSA-N methyl 2-[2-(4-methoxypyridin-2-yl)phenyl]sulfanyl-3h-benzimidazole-5-carboxylate Chemical compound N=1C2=CC(C(=O)OC)=CC=C2NC=1SC1=CC=CC=C1C1=CC(OC)=CC=N1 WEGXHIGVMALKNN-UHFFFAOYSA-N 0.000 claims 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Forbindelser med formelen:. hvor A er en S- eller 6-leddet, fullstendig umettet,. karboeyk Ilsk eller heterocykllsk ring. B er en 5-eller 6-leddet, fullstendig umettet, nltrogenholdlg heterocykllsk ring, X er KR. 0 er S, Rer hydrogen eller alkyl eventuelt substituert med -OCOR, n er 0 eller 1, R, R. R, R(,, R, R, R<j og Ro har forskjellige betydninger. Rj og Rg er hydrogen eller alkyl, eller sammen med de rlngkarbonatomer til hvilke de er festet danner en benzen- eller pyrldlnrlng, hvilken ring bærer substltuenter R5, R,, R17 og Ris-hvor5,. Rog Rg har forskjellige betydninger, med visse forbehold.Fremgangsmåter for fremstilling av forbindelsene og farmasøytiske preparater Inneholdende disse forbindelser, f.eks. for behandling av tilstander Inkludert for sterk mavesyresekresjon er også beskrevet.Compounds of the formula :. wherein A is an S- or 6-membered, completely unsaturated,. karboeyk Angry or heterocyclic ring. B is a 5- or 6-membered, completely unsaturated, nitrogen-containing heterocyclic ring, X is KR. 0 is S, R is hydrogen or alkyl optionally substituted with -OCOR, n is 0 or 1, R, R, R, R (,, R, R, R <j and Ro have different meanings. R , or together with the ring carbon atoms to which they are attached form a benzene or pyridine ring, which ring carries substituents R5, R17, R17 and R5- wherein R8 has different meanings, with certain reservations. pharmaceutical preparations Containing these compounds, eg for the treatment of conditions Including excessive gastric acid secretion are also described.
Description
Foreliggende oppfinnelse vedrører nye forbindelser, fremgangsmåte for deres fremstilling og farmasøytiske preparater inneholdende forbindelsene. The present invention relates to new compounds, methods for their production and pharmaceutical preparations containing the compounds.
Ifølge oppfinnelsen tilveiebringes forbindelser med formelen: According to the invention, compounds of the formula are provided:
hvor A er en 5- eller 6-leddet, fullstendig umettet, karbocyklisk eller heterocykllsk ring, where A is a 5- or 6-membered, fully unsaturated, carbocyclic or heterocyclic ring,
B er en 5- eller 6-leddet, fullstendig umettet, nitrogenholdig heterocykllsk ring, B is a 5- or 6-membered, fully unsaturated, nitrogen-containing heterocyclic ring,
X er NRig, 0 eller S,X is NRig, 0 or S,
R-L9 er hydrogen eller alkyl, eventuelt substituert med R-L9 is hydrogen or alkyl, optionally substituted with
-OCOR,-OCOR,
n er 0 eller 1,n is 0 or 1,
<R>3,<R>4,<R>5, Rfc, R7, R8, Rg og Rio»som kan være like eller forskjellige, er valgt fra hydrogen, alkyl, halogen, -SR, benzoyl, —NO2, —N<R>2o<R>21»—COOH eller en ester eller amid derav, eller alkoksy eventuelt substituert med hydroksy eller med en eventuelt beskyttet oksogruppe, eller <R>3,<R>4,<R>5, Rfc, R7, R8, Rg and Rio»which may be the same or different, are selected from hydrogen, alkyl, halogen, -SR, benzoyl, —NO2, — N<R>2o<R>21»—COOH or an ester or amide thereof, or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group, or
i tillegg til de ovenfor angitte betydninger, kan et til-støtende par av R3til R^,, eller R7til R^q sammen med de in addition to the meanings given above, an adjacent pair of R 3 to R 2 , or R 7 to R 2 q together with the
ringatomer til hvilke de er festet danne en 5- eller 6-leddet, fullstendig umettet, karbocyklisk eller heterocyklisk ring som hærer substituenter Rn,<R>12»R13°S<R>14» ring atoms to which they are attached form a 5- or 6-membered, fully unsaturated, carbocyclic or heterocyclic ring bearing substituents Rn,<R>12»R13°S<R>14»
Rll»<R>12»<R>13 °S R14som kan vaere Uke eller forskjellige, er valgt fra hydrogen, alkyl, alkoksy, halogen, -SR, benzoyl, -N02, -NR2oR21eller -CO2H eller en ester eller et amid derav, R11»<R>12»<R>13 °S R14 which may be Uke or different, is selected from hydrogen, alkyl, alkoxy, halogen, -SR, benzoyl, -NO2, -NR2oR21 or -CO2H or an ester or an amide thereof ,
med unntagelse for at når ring A, ring B eller ringen dannet av et tilstøtende par av R3til R5eller R7til R^q er 5_ leddet, så har henholdsvis R5, R^q eller R14ingen betydning, with the exception that when ring A, ring B or the ring formed by an adjacent pair of R3 to R5 or R7 to R^q is 5_ membered, then R5, R^q or R14 respectively have no meaning,
Ri og R2, som kan være like eller forskjellige, er valgt fra hydrogen eller alkyl, eller kan sammen med de ringkarbonatomer til hvilke de er festet, danne en benzen- eller pyridinring, hvilken ring bærer substituenter R15,<R>16»<R>17og R^g, R15'<R>16»<R>17 °S<R>18»som kan være like eller forskjellige, er valgt fra hydrogen, alkyl, halogen, -SR, benzoyl, alkoksy, —N02, —NR20,<R>21 eller —CO2H eller en ester eller et amid derav, eller R 1 and R 2 , which may be the same or different, are selected from hydrogen or alkyl, or may, together with the ring carbon atoms to which they are attached, form a benzene or pyridine ring, which ring carries substituents R 15 ,<R>16»<R >17 and R^g, R15'<R>16»<R>17 °S<R>18» which may be the same or different, are selected from hydrogen, alkyl, halogen, -SR, benzoyl, alkoxy, -NO2, —NR20,<R>21 or —CO2H or an ester or an amide thereof, or
i tillegg til de ovenfor angitte betydninger kan et til-støtende par av R15, Ri6»<R>17og<R>18sammen med de ringkarbonatomer til hvilke de er festet, danne en 5- eller 6-leddet, karbocyklisk eller heterocykllsk ring, in addition to the meanings given above, an adjacent pair of R 15 , R 16 , R 17 and R 18 , together with the ring carbon atoms to which they are attached, can form a 5- or 6-membered, carbocyclic or heterocyclic ring,
R2Qog<R>2i»som kan være like eller forskjellige, er valgt fra hydrogen, alkyl, fenyl eller kan sammen med det nitrogenatom til hvilket de er festet, danne en 5- eller 6-leddet, mettet ring, hvilken ring kan inneholde et ytterligere heteroatom, R er hydrogen, fenyl eller alkyl, eventuelt substituert med fenyl, R2Q and<R>2i»which may be the same or different, are selected from hydrogen, alkyl, phenyl or may, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring, which ring may contain a further heteroatom, R is hydrogen, phenyl or alkyl, optionally substituted with phenyl,
forutsatt at når R^og R2sammen med de ringkarbonatomer til hvilke de er festet, danner en benzenring, A er en benzenring, og B er en pyridinring, så provided that when R^ and R2 together with the ring carbon atoms to which they are attached form a benzene ring, A is a benzene ring, and B is a pyridine ring, then
i) når R3til R^og R7til<R>10hver er forskjellig fra alkoksy substituert med OH eller med en eventuelt beskyttet oksogruppe, og enten et tilstøtende par av R3til R^eller av R15til R18ikke danner en 5-leddet fullstendig umettet karbocyklisk eller nitrogenholdig heterocykllsk ring eller en 5- eller 6-leddet fullstendig umettet oksygen- eller svovelholdig heterocykllsk ring, eller et tilstøtende par av R7til R10ikke danner en 5- eller 6-leddet fullstendig umettet karbocyklisk eller heterocykllsk ring, og hver av R3til R6, R7til<R>10og<R>15til<R>18er forskjellig fra NR2o<R>21»hvor R20og R21»sammen med det nitrogenatom til hvilke de er festet, danner en 5- eller 6-leddet mettet ring, hvilken ring kan inneholde et ytterligere heteroatom, så er i det minste en av R3til R-^g valgt fra alkyl, alkoksy, SR eller N<R>2oR21nvor<R>20°S R21'som kan være Uke eller forskjellige, kan være hydrogen, alkyl eller fenyl, og i) when R 3 to R^ and R 7 to<R> 10 are each different from alkoxy substituted by OH or by an optionally protected oxo group, and either an adjacent pair of R 3 to R^ or of R 15 to R 18 does not form a 5-membered fully unsaturated carbocyclic or nitrogen-containing heterocyclic ring or a 5- or 6-membered fully unsaturated oxygen- or sulfur-containing heterocyclic ring, or an adjacent pair of R7 to R10 does not form a 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring, and each of R3 to R6, R7 to<R> 10 and <R>15 to <R>18 are different from NR20<R>21», where R20 and R21», together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring, which ring may contain an additional heteroatom, then at least one of R3 to R-^g is selected from alkyl, alkoxy, SR or N<R>2oR21nvor<R>20°S R21' which may be Uke or different, may be hydrogen, alkyl or phenyl, and
ii) når X er NR-^g, Rig, R3til R^og R15til R^g hver er hydrogen, og en av R7til R^q er en metoksygruppe plassert para til ring-nitrogenatomet, så er resten av R7til R^q ikke hver hydrogen, ii) when X is NR-^g, R1, R3 to R^ and R15 to R^g are each hydrogen, and one of R7 to R^q is a methoxy group positioned para to the ring nitrogen atom, then the remainder of R7 to R^q is not each hydrogen,
og farmasøytisk akseptable salter derav.and pharmaceutically acceptable salts thereof.
Ifølge oppfinnelsen tilveiebringes også en fremgangsmåte for fremstilling av en forbindelse med formel (I) eller et farmasøytisk akseptabelt salt derav, som innbefatter According to the invention, a method for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof is also provided, which includes
a) selektiv oksydasjon av en forbindelse med formel (I) hvor n er 0, til en tilsvarende forbindelse med formel (I) a) selective oxidation of a compound of formula (I) where n is 0, to a corresponding compound of formula (I)
hvor n er 1,where n is 1,
b) modifikasjon av en forbindelse med formel (I) inneholdende en eller flere grupper som kan omdannes til en b) modification of a compound of formula (I) containing one or more groups which can be converted into a
gruppe —NH2, —CH2OH eller C=0, til en forbindelse med formel (I) Inneholdende en gruppe -NH2-, CH2OH eller C=0, group —NH2, —CH2OH or C=0, to a compound of formula (I) Containing a group —NH2-, CH2OH or C=0,
c) omsetning av en forbindelse med formel (I) hvor X er N<R>^g hvor R^g er hydrogen, med en forbindelse R22Z hvor R22c) reacting a compound of formula (I) where X is N<R>^g where R^g is hydrogen, with a compound R22Z where R22
er som definert for R^g ovenfor, med unntagelse av at den ikke kan være hydrogen, og Z er en god avspaltningsgruppe, is as defined for R^g above, except that it cannot be hydrogen, and Z is a good leaving group,
d) omsetning av en forbindelse med formelen:d) conversion of a compound of the formula:
hvor Ri, R2og X har de ovenfor angitte betydninger, med en where R 1 , R 2 and X have the meanings given above, with a
hvor R3, R4, R5, R6, R7, R8, Rg, Rio»A og B har de ovenfor angitte betydninger, og where R3, R4, R5, R6, R7, R8, Rg, Rio»A and B have the meanings given above, and
en av D og E er -SH eller S", og den andre er en god av-spal tningsgruppe, eller one of D and E is -SH or S", and the other is a good leaving group, or
e) omsetning av en forbindelse med formelen:e) reaction of a compound with the formula:
hvor % til R5, n, X og A har de ovenfor angitte betydninger, med en forbindelse med formelen: where % to R 5 , n, X and A have the meanings given above, with a compound of the formula:
hvor R7til R10og B har de ovenfor angitte betydninger, where R7 to R10 and B have the meanings given above,
og, om ønsket eller nødvendig, omdannelse av den resulterende forbindelse med formel (I) til et farmasøytisk akseptabelt salt derav, eller vice versa. and, if desired or necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof, or vice versa.
Den selektive oksydasjonen i metode a) kan utføres i et opp-løsningsmiddel som er inert under reaksjonsbetingelsene, f.eks. etylacetat, diklormetan, kloroform eller en blanding derav. Reaksjonen utføres fortrinnsvis ved under romtemperatur, f.eks. fra —20 til +20°C. Egnede oksydasjons-midler for bruk i reaksjonen er hydrogenperoksyd; persyrer, f.eks. m-klorperbenzoesyre; eller t-butylhydroperoksyd i nærvær av en egnet katalysator, f.eks. vanadylacetylacetonat, eller periodater, f.eks. natrlumperiodat i vandig alkohol, f.eks. metanol. The selective oxidation in method a) can be carried out in a solvent which is inert under the reaction conditions, e.g. ethyl acetate, dichloromethane, chloroform or a mixture thereof. The reaction is preferably carried out at below room temperature, e.g. from -20 to +20°C. Suitable oxidizing agents for use in the reaction are hydrogen peroxide; peracids, e.g. m-chloroperbenzoic acid; or t-butyl hydroperoxide in the presence of a suitable catalyst, e.g. vanadyl acetylacetonate, or periodates, e.g. Natrlum periodate in aqueous alcohol, e.g. methanol.
Modifikasjonen av en gruppe til en annen i metode b) kan være selektiv reduksjon, f.eks. -N02til -NH2eller HC=0 til CH2-0H, eller selektiv hydrolyse, f.eks. av en beskyttet karbonylgruppe til C=0. Den selektive reduksjonen av —N02til NH2kan f.eks. utføres kjemisk under basiske betingelser, f.eks. ved bruk av hydrazin og Raney-nikkel, men utføres fortrinnsvis ved bruk av hydrogen og en katalysator, f.eks. Pt02i etanol, som reaksjonsmedium. Den selektive reduksjon av CH=0 til CHqH kan f.eks. uføres ved bruk av natriumborhydrid. Den selektive hydrolyse utføres fortrinnsvis i en vandig oppløsning under sure betingelser. The modification of one group to another in method b) can be selective reduction, e.g. -NO2 to -NH2 or HC=0 to CH2-OH, or selective hydrolysis, e.g. of a protected carbonyl group to C=0. The selective reduction of —N02 to NH2 can e.g. is carried out chemically under basic conditions, e.g. using hydrazine and Raney nickel, but is preferably carried out using hydrogen and a catalyst, e.g. PtO 2 in ethanol, as reaction medium. The selective reduction of CH=0 to CHqH can e.g. unreduced by the use of sodium borohydride. The selective hydrolysis is preferably carried out in an aqueous solution under acidic conditions.
I metode c) kan den gode avspaltningsgruppen f.eks. være halogen (klor eller lod), og reaksjonen kan utføres i et oppløsningsmiddel eller oppløsningsmlddelblanding som er inert under reaksjonsbetingelsene, f.eks. dimetylformamid, i nærvær av en base, f.eks. kaliumkarbonat og ved en temperatur i området 15-35°C, f.eks. ved 20-25°C. In method c), the good leaving group can e.g. be halogen (chlorine or lead), and the reaction can be carried out in a solvent or solvent mixture which is inert under the reaction conditions, e.g. dimethylformamide, in the presence of a base, e.g. potassium carbonate and at a temperature in the range 15-35°C, e.g. at 20-25°C.
For metode d) kan en gode avspaltningsgruppen være et sulfon, f.eks. —S02Me, eller et halogen, f.eks. klor eller brom. Reaksjonen kan utføres i et hvilket som helst egnet opp-løsningsmiddel, f.eks. N,N-dimetylformamid, N,N-dimetyl-acetamid eller metanol, ved en eventuelt forhøyet temperatur, og kan finne sted i nærvær av en katalysator, f.eks. Cu eller en syreakseptor, f.eks. kaliumkarbonat. Det er foretrukket at D er en god avspaltningsgruppe, og E er SH eller S-. For method d), a good leaving group can be a sulfone, e.g. —SO 2 Me, or a halogen, e.g. chlorine or bromine. The reaction can be carried out in any suitable solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide or methanol, at a possibly elevated temperature, and can take place in the presence of a catalyst, e.g. Cu or an acid acceptor, e.g. potassium carbonate. It is preferred that D is a good leaving group, and E is SH or S-.
Reaksjonen i metode e) kan utføres i et hvilket som helst egnet oppløsningsmiddel, f.eks. vann, og ved en temperatur i området 50-100°C, f.eks. ved ca. 80°C. The reaction in method e) can be carried out in any suitable solvent, e.g. water, and at a temperature in the range 50-100°C, e.g. at approx. 80°C.
Forbindelsene med formel (II) kan fremstilles fra kjente forbindelser ved bruk av i og for seg kjente konvensjonelle teknikker, f.eks. kan de forbindelser med formel (II) hvor X er NH, og D er SH eller S", fremstilles f.eks. ved omsetningg av en forbindelse med formelen: The compounds of formula (II) can be prepared from known compounds using conventional techniques known per se, e.g. the compounds of formula (II) where X is NH, and D is SH or S", can be prepared, for example, by reacting a compound with the formula:
hvor R^og R2har de ovenfor angitte betydninger, med CS2. Reaksjonen utføres fortrinnsvis under nitrogen og ved en temperatur i området 50-80°C. De forbindelser med formel (II) hvor D er et suldfon, f.eks. -S02Me, kan fremstilles fra den tilsvarende tiolforbindelsen, f.eks. ved omsetning først med metyliodid og kaliumkarbonat i dimetylformamid ved en where R 2 and R 2 have the meanings given above, with CS 2 . The reaction is preferably carried out under nitrogen and at a temperature in the range 50-80°C. The compounds of formula (II) where D is a sulfone, e.g. -SO 2 Me, can be prepared from the corresponding thiol compound, e.g. by reaction first with methyl iodide and potassium carbonate in dimethylformamide at a
temperatur i området 0-50°C fulgt av behandling med Okson (registrert varemerke til DuPont Co, peroksymonosulfat) i vandig metanol ved en temperatur i området 0-50°C. temperature in the range 0-50°C followed by treatment with Okson (registered trademark of DuPont Co, peroxy monosulfate) in aqueous methanol at a temperature in the range 0-50°C.
Forbindelsene med formel (III) kan fremstilles fra kjente forbindelser ved bruk av i og for seg kjente konvensjonelle teknikker, f.eks. de forbindelser med formel (III) hvor E er The compounds of formula (III) can be prepared from known compounds using conventional techniques known per se, e.g. the compounds of formula (III) where E is
—SH eller S", kan fremstilles ved bruk av følgende reaksjons- —SH or S", can be prepared using the following reaction-
vei : road :
hvor R3til Rio»A og B har de ovenfor angitte betydninger. where R 3 to Rio, A and B have the meanings given above.
Oksydasjonen i trinn (I) kan utføres som beskrevet for metode The oxidation in step (I) can be carried out as described for method
a) ovenfor. Trinn 2 kan utføres f.eks. med trifluoreddiksyre og trietylamin i metanol. Under oksydasjonsbetlngelser a) above. Step 2 can be carried out e.g. with trifluoroacetic acid and triethylamine in methanol. Under oxidation conditions
(f.eks. i nærvær av luft) kan et disulfid være et biprodukt i trinn 2. Disulfidet kan omdannes til det tilsvarende sulfid ved reduksjon. Egnede reagenser for denne reduksjonen er natriumborhydrid og natriumcyanoborhydrid. (e.g. in the presence of air) a disulfide may be a by-product in step 2. The disulfide may be converted to the corresponding sulfide by reduction. Suitable reagents for this reduction are sodium borohydride and sodium cyanoborohydride.
Forbindelsene med formel (VIII) kan fremstilles ved en koblings- eller ringslutningsreaksjon som vist nedenfor. The compounds of formula (VIII) can be prepared by a coupling or ring closure reaction as shown below.
a) Kobl inga) Coupling
Omsetning av en forbindelse med formelen: hvor R3til R5og A har de ovenfor angitte betydninger, og G er et metallion (f.eks. litium) eller en Grignard-reagens (f.eks. MgBr), med en forbindelse med formel (Va) eller dens N-oksyd eller orto-halogen (f.eks. o-fluor )-derivat, Reaction of a compound of the formula: where R 3 to R 5 and A have the meanings given above, and G is a metal ion (e.g. lithium) or a Grignard reagent (e.g. MgBr), with a compound of formula (Va) or its N-oxide or ortho-halo (e.g. o-fluoro) derivative,
hvor R7til R^oog B har de ovenfor angitte betydninger, where R 7 to R 7 and B have the meanings given above,
b) Ringslutningb) Looping
Omsetning av en forbindelse med formelen:Reaction of a compound with the formula:
hvor Z er en god avspaltningsgruppe, f.eks. klor, med f.eks. where Z is a good leaving group, e.g. chlorine, with e.g.
i) når ring B er pyridin, CH3-C(0 )-CH=CH-OMe, fulgt av NH3, eller i) when ring B is pyridine, CH3-C(0 )-CH=CH-OMe, followed by NH3, or
ii) når ring B er imidazol, NH2C(R7 ) = C(R8)NH2, hvor R7og Rg har de ovenfor angitte betydninger. ii) when ring B is imidazole, NH2C(R7 ) = C(R8)NH2, where R7 and Rg have the above meanings.
Forbindelsene med formel (IV) kan fremstilles ved diazote-ring av en forbindelse med formelen: The compounds of formula (IV) can be prepared by diazotization of a compound of the formula:
hvor R^til R5, X, n og A har de ovenfor angitte betydninger. Diazoteringen kan utføres i et hvilket som helst egnet opp-løsningsmiddel, f.eks. vann, i nærvær av syre, f.eks. saltsyre, ved en temperatur i området 0-15°C, f.eks. under 5°C, med et alkalimetallnitritt, f.eks. natriumnitritt. where R 1 to R 5 , X, n and A have the meanings given above. The diazotization can be carried out in any suitable solvent, e.g. water, in the presence of acid, e.g. hydrochloric acid, at a temperature in the range 0-15°C, e.g. below 5°C, with an alkali metal nitrite, e.g. sodium nitrite.
Forbindelsene med formel (VI) er enten kjente eller kan fremstilles ved i og for seg kjente konvensjonelle prosesser, f.eks. ved prosesser analoge med metoder a), b), c) eller d) beskrevet ovenfor for fremstilling av forbindelser med formel The compounds of formula (VI) are either known or can be prepared by conventional processes known per se, e.g. by processes analogous to methods a), b), c) or d) described above for the preparation of compounds of formula
(I). (IN).
Forbindelsene med formler (V), (Va), (VII), (IX) og (X) er enten kjente eller kan fremstilles ved i og for seg kjente konvensjonelle prosesser. The compounds with formulas (V), (Va), (VII), (IX) and (X) are either known or can be prepared by conventional processes known per se.
Forbindelsene med formel (I) og mellomproduktene for disse kan isoleres fra deres reaksjonsblandinger ved bruk av konvensjonelle teknikker. The compounds of formula (I) and their intermediates can be isolated from their reaction mixtures using conventional techniques.
Enkelte av forbindelsene med formler (III), (VIII) og (Villa) er nye, og disse nye forbindelsene tilveiebringes for bruk som mellomprodukter 1 syntesen av forbindelser med formel (I) som definert ovenfor. Some of the compounds of formulas (III), (VIII) and (Villa) are new, and these new compounds are provided for use as intermediates in the synthesis of compounds of formula (I) as defined above.
Spesielt er forbindelser med formelen: In particular, compounds with the formula:
hvor Eaer SH, S~, SMe eller SOMe, ring A er en benzen-eller tiofenring, R3til R^har de ovenfor angitte betydninger, og ring B er enten en pyridinring som bærer substituenter R7til Rig som definert ovenfor, unntatt at et til-støtende par av R7til R^q ikke sammen med de karbonatomer til hvilke de er festet kan danne en ring, eller ring B og et tilstøtende par av R7til R^q danner en 1-isokinolinyl-, 2-imidazo(l,2-a)pyridin- eller 2-N-alkylert-benzimidazoylgruppe, nye og er tilveiebragt for bruk som mellomprodukter i syntesen av forbindelser med formel (I) som definert ovenfor . where Ea is SH, S~, SMe or SOMe, ring A is a benzene or thiophene ring, R3 to R^ have the meanings given above, and ring B is either a pyridine ring bearing substituents R7 to Rig as defined above, except that an additional opposing pairs of R7 to R^q cannot together with the carbon atoms to which they are attached form a ring, or ring B and an adjacent pair of R7 to R^q form a 1-isoquinolinyl-, 2-imidazo(l,2-a )pyridine- or 2-N-alkylated-benzimidazolyl group, new and are provided for use as intermediates in the synthesis of compounds of formula (I) as defined above.
Farmasøytisk akseptable salter av forbindelsene med formel (I) innbefatter salter med egnede organiske eller uorganiske syrer, f.eks. med en hydrohalogensyre, svovelsyre, alkan-sulfonsyre, vinsyre eller sitronsyre. Når forbindelsen med formel (I) bærer en —COH eller annen sur gruppe, tilveiebringes også salter med egnede organiske og uorganiske baser, f.eks. ammonium-, alkalimetal1-, jordalkalimetall-, alkyl-amino-, osv. salter. Selve benzimidazolkjernen er sur og kan danne salter med hensiktsmessige baser som angitt ovenfor. Forbindelsene med formel (I) og farmasøytisk akseptable salter derav tilveiebringes også for bruk som farmasøytika, f.eks. for bruk som cytobeskyttende midler, i behandlingen, eller profylaksen av inflammatoriske tilstander, som slim-hinnebeskyttende midler, eller i hindringen eller inhiberin-gen av mavesyresekresjon. Pharmaceutically acceptable salts of the compounds of formula (I) include salts with suitable organic or inorganic acids, e.g. with a hydrohalic acid, sulfuric acid, alkanesulfonic acid, tartaric acid or citric acid. When the compound of formula (I) carries a —COH or other acidic group, salts with suitable organic and inorganic bases are also provided, e.g. ammonium, alkali metal1, alkaline earth metal, alkylamino, etc. salts. The benzimidazole nucleus itself is acidic and can form salts with appropriate bases as indicated above. The compounds of formula (I) and pharmaceutically acceptable salts thereof are also provided for use as pharmaceuticals, e.g. for use as cytoprotective agents, in the treatment or prophylaxis of inflammatory conditions, as mucosal protective agents, or in the prevention or inhibition of gastric acid secretion.
Forbindelsene med formel (I) og farmasøytisk akseptable salter derav er nyttige fordi de er i besittelse av farmako-logisk aktivitet i dyr, spesielt er de nyttige fordi de har cytobeskyttende egenskaper, er nyttige i behandlingen eller profylaksen av inflammatoriske tilstander og/eller for å hindre eller inhibere mavesyresekresjon, f.eks. i testen angitt Am. J. Physiol., 1982, 243(6), G505-510. Forbindelsene med formel (I) er også nyttige som mellomprodukter i syntesen av andre kjemikalier. The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful because they possess pharmacological activity in animals, in particular they are useful because they have cytoprotective properties, are useful in the treatment or prophylaxis of inflammatory conditions and/or to prevent or inhibit gastric acid secretion, e.g. in the test indicated Am. J. Physiol., 1982, 243(6), G505-510. The compounds of formula (I) are also useful as intermediates in the synthesis of other chemicals.
De nye forbindelsene er således indikert for bruk ved hindring eller inhibering av mavesyresekresjon, og/eller tilstander som normalt innebærer sterk mavesyresekresjon, f.eks. peptisk, duodenal, gastrisk, tilbakevendende eller stormal ulcerasjon, dyspepsi, duodenitis, Zollinger-Ellison syndrom, reflux oesophagitis og blødning, f.eks. fra erosjon av magesår i den øvre delen av mave-tarmkanalen, spesielt når et større blodkar ikke er involvert. Forbindelsene kan også benyttes for å behandle gastritis eller dyspepsi forbundet med administrasjon av ikke-steroide antiinflammato-riske legemidler, i profylaksen av blødning i mage-tarmkanalen fra stress-ulcerasjon i alvorlig syke eller brente pasienter, i profylaksen av tilbakevendende blødning hos pasienter med blødende peptisk magesår, før generell anestesi av pasientene ved risiko for syreaspirasjonssyndrom (Mendel-son's syndrom) og for å redusere sjansen for blødning hos pasienter med leukemi, vert-sykdom I forbindelse med trans-plantasjon eller med alvorlig hepatisk svikt. De ovenfor nevnte tilstander kan behandles enten de er forbundet med for sterk mavesyresekresjon eller ikke. The new compounds are thus indicated for use in preventing or inhibiting gastric acid secretion, and/or conditions that normally involve strong gastric acid secretion, e.g. peptic, duodenal, gastric, recurrent or storm ulceration, dyspepsia, duodenitis, Zollinger-Ellison syndrome, reflux oesophagitis and bleeding, e.g. from erosion of ulcers in the upper part of the gastrointestinal tract, especially when a major blood vessel is not involved. The compounds can also be used to treat gastritis or dyspepsia associated with the administration of non-steroidal anti-inflammatory drugs, in the prophylaxis of bleeding in the gastrointestinal tract from stress ulceration in severely ill or burned patients, in the prophylaxis of recurrent bleeding in patients with bleeding peptic ulcer, before general anesthesia of the patients at risk of acid aspiration syndrome (Mendelson's syndrome) and to reduce the chance of bleeding in patients with leukaemia, host disease In connection with transplantation or with severe hepatic failure. The conditions mentioned above can be treated whether they are associated with excessive gastric acid secretion or not.
Forbindelsene kan også benyttes for å behandle kolera, para-tyfus, turist-diaré, toksinindusert diaré og lokal gastritisk katarr. The compounds can also be used to treat cholera, para-typhoid, tourist's diarrhoea, toxin-induced diarrhea and local gastric catarrh.
De nye forbindelsene er også indikert for bruk som cytobeskyttende midler, spesielt for mave-tarmkanalen, og kan benyttes for behandling eller hindring av en ikke-mavesyre-indusert, ikke-traumatisk indusert, ikke-neoplastisk mave-tarm-inflammatorisks sykdom, f.eks. Crohn's sykdom, inflamma-torisk sykdom i tykktarmen, infektiøs enteritt, kolitt, ulce-rativ kolitt, pseudomembran-kolitt, divertikulitt og allerge-niske og radiologiske inflammatoriske sykdommer. The new compounds are also indicated for use as cytoprotective agents, especially for the gastrointestinal tract, and can be used for the treatment or prevention of a non-gastric acid-induced, non-traumatically induced, non-neoplastic gastrointestinal inflammatory disease, e.g. e.g. Crohn's disease, inflammatory bowel disease, infectious enteritis, colitis, ulcerative colitis, pseudomembranous colitis, diverticulitis and allergic and radiological inflammatory diseases.
Forbindelsene er også indikert for bruk ved behandling eller profylakse av inflammatori ske tilstander hos pattedyr, inkludert menneske, spesielt de som innebærer lysozymale enzymer. Tilstander som spesielt kan nevnes, er: rheumatoid artritt, podagra, eksem, polyserositt og allergenisk alveolitt. The compounds are also indicated for use in the treatment or prophylaxis of inflammatory conditions in mammals, including humans, especially those involving lysozymal enzymes. Conditions that can be particularly mentioned are: rheumatoid arthritis, gout, eczema, polyserositis and allergic alveolitis.
Mønstere for terapeutisk bruk som kan nevnes er:Patterns of therapeutic use that can be mentioned are:
a) en høy dose til å begynne med, i f. eks. 2-4 uker, fulgt av fortsatt terapi med lavere dose etter at tilstanden a) a high dose to begin with, in e.g. 2-4 weeks, followed by continued therapy at a lower dose after the condition
har forbedret seg, f.eks. mavesåret har blitt helet,has improved, e.g. the stomach ulcer has healed,
b) som i a) ovenfor, men den fortsatte terapi innbefatter et annet cytobeskyttende middel, f.eks. et PGE_ b) as in a) above, but the continued therapy includes another cytoprotective agent, e.g. a PGE_
derivat,derivative,
c) kombinasjonsterapi ved bruk av en lav dose av forbindelsen i foreliggende oppfinnelse i forbindelse med en c) combination therapy using a low dose of the compound of the present invention in conjunction with a
lav, godt tolerert dose av et annet cytobeskyttende middel og/eller syrenøytraliserende middel, d) intermitterende dosering, f.eks. hver 2. dag, kan være hensiktsmessig som fortsatt terapi. low, well-tolerated dose of another cytoprotective agent and/or antacid, d) intermittent dosing, e.g. every 2 days, may be appropriate as continued therapy.
For de ovennevnte anvendelser vil den dose som administreres, naturligvis variere med den forbindelse som benyttes, ad-ministrasjonsmåten og den ønskede behandling. Generelt oppnås imidlertid tilfredsstillende resultater når forbindelsene administreres ved en dose fra 10~^M til 10"^M i testen angitt i Am. J. Physiol , 1982, 243 (6), G505-G510. For mennesket er den indikerte totale daglige dose i området fra ca. 1 mg til 3000 mg, fortrinnsvis til 500 mg, og -mer foretrukket fra ca. 10 mg til 200 mg, som kan administreres i oppdelte doser fra 1 til 6 ganger daglig eller i en form med langvarig frigjøring. Enhetsdoseringsform regnet for administrasjon omfatter således fra ca.1,0 mg til 600 mg av forbindelsen blandet med et fast eller flytende farmasøytisk akseptabelt fortynningsmiddel, bærer eller hjelpemiddel. For the above applications, the dose administered will naturally vary with the compound used, the method of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds are administered at a dose of from 10~^M to 10"^M in the test set forth in Am. J. Physiol , 1982, 243 (6), G505-G510. For man, the indicated total daily dose is in the range of from about 1 mg to 3000 mg, preferably to 500 mg, and -more preferably from about 10 mg to 200 mg, which can be administered in divided doses from 1 to 6 times daily or in a sustained release form. calculated for administration thus comprises from about 1.0 mg to 600 mg of the compound mixed with a solid or liquid pharmaceutically acceptable diluent, carrier or excipient.
Forrbindelsene med formel (I) og farmasøytisk akseptable salter derav har en eller flere av følgende fordeler. De absorberes lettere, har forøket biotilgjengelighet, er mer stabile omkring nøytral pH-verdi, er mindre irriterende overfor mave-tarmkanalen, er mer spesifikke i virkning, har mindre toksiske bivirkninger, aktiveres lettere av syre, f.eks. mavesyre, er mer stabile overfor syre, f.eks. mavesyre, gir fordelaktige resultater, f.eks. i "Shay-rotte-testen" som beskrevet av H. Shay et al. i Gastroenterology, 5 43-61 (11945) eller har andre fordelaktige egenskaper sammen-lignet med kjente forbindelser med lignende struktur. The compounds of formula (I) and pharmaceutically acceptable salts thereof have one or more of the following advantages. They are absorbed more easily, have increased bioavailability, are more stable around neutral pH, are less irritating to the gastrointestinal tract, are more specific in their effect, have less toxic side effects, are more easily activated by acid, e.g. stomach acid, are more stable against acid, e.g. stomach acid, gives beneficial results, e.g. in the "Shay rat test" as described by H. Shay et al. in Gastroenterology, 5 43-61 (11945) or has other advantageous properties compared to known compounds with a similar structure.
Ring A kan være karbocyklisk eller en heterocykel inneholdende 0, S eller N. Når ring A er en heterocykllsk ring, er det foretrukket at den inneholder et heteroatom. Spesifikke grupper som ring A kan representere, innbefatter furan, pyridin, benzen eller tiofen. Det er foretrukket at ring A er en benzen- eller tipofenring. Når ring A er en pyridinring, kan den være knyttet til -S(0)n-gruppen i 4-stillingen, og til ring B i 3-stillingen, eller den kan være knyttet til -S(0)n-gruppen i 3-stillingen og til ring B i 2- stillingen. Når ring A er en tiofenring, kan den være knyttet til —S(0)n-gruppen ved 2-stillingen og til ring B ved 3-stillingen, eller den kan være knyttet til —S(0 )n-gruppen ved 3-stillingen og til ring B ved 2-stillingen. Ring A may be carbocyclic or a heterocycle containing O, S or N. When ring A is a heterocyclic ring, it is preferred that it contains a heteroatom. Specific groups that ring A may represent include furan, pyridine, benzene or thiophene. It is preferred that ring A is a benzene or tipophene ring. When ring A is a pyridine ring, it may be attached to the -S(0)n group in the 4-position, and to ring B in the 3-position, or it may be attached to the -S(0)n group in the 3 - position and to ring B in the 2 position. When ring A is a thiophene ring, it may be attached to the —S(0)n group at the 2-position and to ring B at the 3-position, or it may be attached to the —S(0 )n group at the 3- the position and to ring B at the 2 position.
Ring B kan inneholde en eller to ytterligere heteroatomer og fortrinnsvis en eller to ytterligere nitrogenatomer. Det er spesielt foretrukket at ring B er en pyridin- eller imidazolring. Når ring B er en imidazolring, kan den være knyttet til ring A ved dens 2- eller 4-stilling. Når ring B er en imidazolring, kan den være N-substituert, f.eks. N-alkylert. Når ring B er en imidazolring knyttet til ring A ved dens 2-stilling, er det foretrukket at den er en N-metylert imidazol. Ring B may contain one or two further heteroatoms and preferably one or two further nitrogen atoms. It is particularly preferred that ring B is a pyridine or imidazole ring. When ring B is an imidazole ring, it may be attached to ring A at its 2- or 4-position. When ring B is an imidazole ring, it may be N-substituted, e.g. N-alkylated. When ring B is an imidazole ring linked to ring A at its 2-position, it is preferred that it be an N-methylated imidazole.
Det er foretrukket at X er 0 eller mer foretrukket NR-^g. R-^g kan være metyl eller fortrinnsvis hydrogen. It is preferred that X is 0 or more preferably NR-2g. R-^g can be methyl or preferably hydrogen.
Det er foretrukket at n er 1.It is preferred that n is 1.
Når en hvilken som helst av R^3til R-^g er halogen, kan den være klor eller fluor. When any of R 3 to R 3 is halogen, it may be chlorine or fluorine.
Når en hvilken som helst av R^til R22eller R representerer eller inneholder en karbonholdig gruppe, er det foretrukket at gruppen inneholder opptil og inklusive 10, og fortrinnsvis opptil og inklusive 6, karbonatomer. When any of R 1 to R 22 or R 2 represents or contains a carbonaceous group, it is preferred that the group contains up to and including 10, and preferably up to and including 6, carbon atoms.
Når en hvilken som helst av R3til R-^g representerer en ester, er det foretrukket at den er avledet fra en C^-C^alkohol, f.eks. at den er en metyl- eller etylester. When any one of R 3 to R 4 represents an ester, it is preferred that it is derived from a C 1 -C 4 alcohol, e.g. that it is a methyl or ethyl ester.
Spesifikke grupper R3, R4, R5 , R6 , R7, Rg, Rg og R10innbefatter hydrogen, metyl, etyl, klor -NR20<R>21, metoksy, etoksy, propyloksy, isopropyloksy, etoksy substituert med 0H, med oksogruppe og med en beskyttet oksogruppe, f.eks. et ketal, spesielt etylendioksy. Specific groups R3, R4, R5, R6, R7, Rg, Rg and R10 include hydrogen, methyl, ethyl, chlorine -NR20<R>21, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted with OH, with oxo group and with a protected oxo group, e.g. a ketal, especially ethylenedioxy.
Når et tilstøtende par av R3til R^eller R7til R-^g sammen med de ringkarbonatomer til hvilke de er festet, danner en ring, er det foretrukket at denne ringen er en karbocyklisk ring og mer spesielt en benzenring. Når et tilstøtende par R7til R^g danner en slik ring, er det foretrukket at ring B er en pyridin- eller imidazolring. Når et tilstøtende par R7til R-Lg danner en ring, så er det spesielt foretrukket at de med ring B danner en 1-isokinolinyl-, 2-imidazo(1,2-a)-pyridin- eller mer spesielt en 2-benzimidazolyl-gruppe. When an adjacent pair of R 3 to R 1 or R 7 to R 1 together with the ring carbon atoms to which they are attached form a ring, it is preferred that this ring be a carbocyclic ring and more particularly a benzene ring. When an adjacent pair R 7 to R 8 forms such a ring, it is preferred that ring B is a pyridine or imidazole ring. When an adjacent pair of R7 to R-Lg forms a ring, it is particularly preferred that those with ring B form a 1-isoquinolinyl-, 2-imidazo(1,2-a)-pyridine- or more particularly a 2-benzimidazolyl- group.
Spesifikke grupper<R>n,<R>12»<R>13eller R14innbefatter hydrogen, halogen (f.eks. klor) eller alkoksy. Specific groups<R>n,<R>12»<R>13or R14 include hydrogen, halogen (eg chlorine) or alkoxy.
Det er foretrukket at R^og R2 , sammen med r ingkarbonatomer til hvilke de er festet, danner en benzenring. It is preferred that R 1 and R 2 , together with ring carbon atoms to which they are attached, form a benzene ring.
Spesifikke grupper R15,<R>16, R17og R18innbefatter hydrogen, metyl, metoksy, etoksy, klor -N02, -NR20<R>21, benzoyl, metoksykarbonyl og etoksykarbonyl. Specific groups R15, <R>16, R17 and R18 include hydrogen, methyl, methoxy, ethoxy, chlorine -NO2, -NR20<R>21, benzoyl, methoxycarbonyl and ethoxycarbonyl.
Når et tilstøtende par av R15til R-^g danner en 5- eller 6-leddet ring, kan den være mettet, delvis umettet eller fullstendig umettet, og kan inneholde 0, 1 eller 2 heteroatomer. Det er foretrukket at ringen er karbocyklisk, eller at den er en oksygenholdig heterocykllsk ring. Det er spesielt foretrukket at ringen er en benzenring eller en 1,3-dioksylan-ring. When an adjacent pair of R 15 to R 15 forms a 5- or 6-membered ring, it may be saturated, partially unsaturated or fully unsaturated, and may contain 0, 1 or 2 heteroatoms. It is preferred that the ring is carbocyclic, or that it is an oxygen-containing heterocyclic ring. It is particularly preferred that the ring is a benzene ring or a 1,3-dioxylan ring.
Det er foretrukket at R15til R18er valgt fra hydrogen, alkyl eller alkoksy. It is preferred that R 15 to R 18 are selected from hydrogen, alkyl or alkoxy.
Spesifikke grupper R20og<R>21innbefatter hydrogen, metyl og fenyl. Specific groups R 20 and<R> 21 include hydrogen, methyl and phenyl.
Når R20og R2i, sammen med det nitrogenatom til hvilket de er festet, danner en ring inneholdende et ytterligere hetero atom, er det foretrukket at heteroatomet er oksygen. Når R20og R21»sammen med det nitrogenatom til hvilket de er festet, danner en ring, er det foretrukket at ringen er en pyrrolidino- eller morfolinoring. When R 20 and R 21 , together with the nitrogen atom to which they are attached, form a ring containing a further hetero atom, it is preferred that the hetero atom is oxygen. When R 20 and R 21 , together with the nitrogen atom to which they are attached, form a ring, it is preferred that the ring is a pyrrolidino or morpholino ring.
Når R-L og R2danner en benzenring, A er en benzenring og B er en pyridinring, er det foretrukket at minst en av R3til Rfc, R7til R10og Rn til R14er valgt fra metyl, etyl, metoksy, etoksy, propyloksy, isopropyloksy, etoksy substituert med OH, med en oksygruppe eller med en beskyttet oksogruppe, eller -N<R>2o<R>21hvor R20og R2^representerer metyl, fenyl eller, sammen med det nitrogenatom til hvilket de er festet, danner en pyrrolidino- eller morfolinoring. When R-L and R2 form a benzene ring, A is a benzene ring and B is a pyridine ring, it is preferred that at least one of R3 to Rfc, R7 to R10 and Rn to R14 is selected from methyl, ethyl, methoxy, ethoxy, propyloxy, isopropyloxy, ethoxy substituted with OH , with an oxy group or with a protected oxo group, or -N<R>2o<R>21where R 20 and R 2 ^ represent methyl, phenyl or, together with the nitrogen atom to which they are attached, form a pyrrolidino or morpholino ring.
Når ring A er en benzenring festet til —S(0 )n-gruppen i 2-stillingen og til ring B i 1-stillingen, er det spesielt foretrukket at substituenten i 4-stillingen (dvs. para til stillingen for festing av ring B) er valgt fra alkyl, —SR, —NR20R2Ieller alkoksy eventuelt substituert med hydroksy eller med en eventuelt beskyttet oksogruppe. When ring A is a benzene ring attached to the —S(0 )n group in the 2-position and to ring B in the 1-position, it is particularly preferred that the substituent in the 4-position (i.e. para to the position for attachment of ring B ) is selected from alkyl, —SR, —NR 20 R 2 I or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group.
Når ring B er en pyridinring festet til ring A i 2-stillingen, er det foretrukket at substituenten i 4-stillingen (dvs. para til ring-N-atomet) er valgt fra alkyl, —SR, —NR2fjR21 eller alkoksy eventuelt substituert med hydroksy eller med en eventuelt beskyttet oksogruppe. When ring B is a pyridine ring attached to ring A in the 2-position, it is preferred that the substituent in the 4-position (i.e. para to the ring N atom) is selected from alkyl, —SR, —NR2fjR21 or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group.
Det er spesielt foretrukket forbindelser med formel (I) hvor Ri og R2, sammen med de r ingkarbonatomer til hvilke de er festet, danner en benzenring hvilken benzenring bærer substituenter Rifc, Ri6»R17°g R18»x er NR19» R19 er hydrogen, n er 1, A er en benzenring, og ringB er en pyridinring festet til ring A I 2-stillingen og har en substituent para til ring-N-atomet valgt fra alkyl, —SR, —NR2qR21eller alkoksy eventuelt substituert med hydroksy eller med en eventuelt beskyttet oksogruppe, eller at ring B er en imidazolring festet til ring A i 2-stillingen, og hvor substituentene i 4- og 5-stiIlingene sammen med de ringkarbonatomer til hvilke de er festet, danner en benzenring, hvilken benzenring bærer substituenter Rj^, Ri2><R>13°S<R>14* Particularly preferred are compounds of formula (I) where Ri and R2, together with the ring carbon atoms to which they are attached, form a benzene ring which benzene ring carries substituents Rifc, Ri6»R17°g R18»x is NR19»R19 is hydrogen, n is 1, A is a benzene ring, and ring B is a pyridine ring attached to ring A in the 2 position and has a substituent para to the ring N atom selected from alkyl, —SR, —NR2qR21 or alkoxy optionally substituted with hydroxy or with an optionally protected oxo group, or that ring B is an imidazole ring attached to ring A in the 2-position, and where the substituents in the 4- and 5-style rings, together with the ring carbon atoms to which they are attached, form a benzene ring, which benzene ring carries substituents Rj^, Ri2><R>13°S<R>14*
Spesifikke grupper av forbindelser med formel (1) innbefatter : Specific groups of compounds of formula (1) include:
hvor minst en av R5a, R6a,<R>7a,<R>8a,<R>ga,<R>10a, Rllaog R12a er valgt fra alkyl, alkoksy, eller -NR20<R>21, °& resten av R5a til' Ri2ahver er hydrogen, halogen, —N02, eller —COOH eller en ester eller amid derav, where at least one of R5a, R6a,<R>7a,<R>8a,<R>ga,<R>10a, Rlla and R12a is selected from alkyl, alkoxy, or -NR20<R>21, °& the rest of R5a to' Ri 2 ah is hydrogen, halogen, —NO 2 , or —COOH or an ester or amide thereof,
<R>la><R>2a»<R>3a °§<R>4a»som kan være like eller forskjellige, hver er hydrogen, halogen, alkyl, alkoksy, -N02, -NRaR14a eller —COOH eller en ester eller amid derav, <R>la><R>2a»<R>3a °§<R>4a»which may be the same or different, each being hydrogen, halogen, alkyl, alkoxy, -NO2, -NRaR14a or -COOH or an ester or amide thereof,
<R>19><R>20 °S<R>21nar de ovenfor angitte betydninger,<R>19><R>20 °S<R>21when the meanings given above,
Ra og<R>i4a, som kan være like eller forskjellige, hver er hydrogen, fenyl, eller alkyl, Ra and<R>i4a, which may be the same or different, are each hydrogen, phenyl, or alkyl;
forutsatt at når Rla,<R>2a,<R>3a, R4a, R5a,<R>6a, R7a,<R>ga><R>ga,<R>lla»<R>12a°S<R>15aaile er hydrogen, så er Rioaikke metoksy, provided that when Rla,<R>2a,<R>3a, R4a, R5a,<R>6a, R7a,<R>ga><R>ga,<R>lla»<R>12a°S<R> 15aaile is hydrogen, then Rioa is not methoxy,
hvor Atø representerer en 5- eller 6-leddet nitrogen-, oksygen- eller svovelholdig fullstendig umettet heterocykllsk ring som er forbundet med —SO-gruppen gjennom et ringkarbon-atom, og som kan være sammensmeltet med en benzenring, where Atø represents a 5- or 6-membered nitrogen, oxygen or sulfur-containing fully unsaturated heterocyclic ring which is connected to the —SO group through a ring carbon atom, and which may be fused to a benzene ring,
Etø representerer en 5- eller 6-leddet nitrogenholdig fullstendig umettet heterocykllsk ring, som kan være sammensmeltet med en benzenring, Etø represents a 5- or 6-membered nitrogen-containing fully unsaturated heterocyclic ring, which may be fused to a benzene ring,
R^bog R2b»som kan være like eller forskjellige, hver er hydrogen eller alkyl, eller kan, sammen med de karbonatomer til hvilke de er festet, danne en benzen- eller pyridinring som igjen kan være substituert med en eller flere substituenter<R>ia,<R>2a><R>3a><R>4asom definert ovenfor, R^bog R2b»which may be the same or different, each is hydrogen or alkyl, or may, together with the carbon atoms to which they are attached, form a benzene or pyridine ring which in turn may be substituted with one or more substituents<R> ia,<R>2a><R>3a><R>4as defined above,
Rio har den ovenfor angitte betydning,Rio has the meaning set out above,
hvor minst ett tilstøtende par av Rgc, Rifjc» Rllc °g R12c» sammen med de ringatomer til hvilke de er festet, danner en where at least one adjacent pair of Rgc, Rifjc» Rllc °g R12c» together with the ring atoms to which they are attached, form a
5- eller 6-leddet fullstendig umettet karbocyklisk eller heterocykllsk ring, 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring,
og resten av Rgctil Ri2cer som definert for R^aovenfor,and the remainder of Rgctil Ri2cer as defined for R^ao above,
A er en 5- eller 6-leddet fullstendig umettet nitrogenholdig heterocykllsk ring, A is a 5- or 6-membered fully unsaturated nitrogen-containing heterocyclic ring,
<R>19a«<R>la»<R>2a»R3a°S R4anar de ovenfor angitte betydninger , <R>19a«<R>la»<R>2a»R3a°S R4anar the meanings given above,
R5c<R>6c«<R>7c °S<R>8cnar de betydninger som er gitt for R^atil R4aovenfor, og, i tillegg, kan et tilstøtende par av R5c»<R>6c»R7c°S R8c• sammen med de ringatomer til hvilke de er festet, danne en 5- eller 6-leddet fullstendig umettet karbocyklisk eller heterocykllsk ring. R5c<R>6c«<R>7c °S<R>8c have the meanings given for R^a to R4ao above, and, in addition, an adjacent pair of R5c»<R>6c»R7c°S R8c• together with the ring atoms to which they are attached, form a 5- or 6-membered fully unsaturated carbocyclic or heterocyclic ring.
Ifølge foreliggende oppfinnelse er det også tilveiebragt et farmasøytisk preparat innbefattende (fortrinnsvis en mindre andel av) en forbindelse med formel (1), eller et farmasøy-tisk akseptabelt salt derav, som aktiv bestanddel, i blanding med et farmasøytisk akseptabelt hjelpemiddel, fortynningsmiddel eller bærer. Eksempler på egnede hjelpemidler, for-tynningsmidler eller bærere er: - for tabletter og dragéer; laktose, stivelse, talk eller stearinsyre; for kapsler, vinsyre eller laktose; for suppositorier, naturlige eller her-dede oljer eller voks; og for injeksjoner (i.m. eller i.v.) eller enema-vann, overflateaktive midler og preservativer. Forbindelsene kan også administreres transdermalt, f.eks. i en salvebasis. Forbindelsen med formel (I) eller det farma-søytisk akseptable saltet derav, har fortrinnsvis en midlere massediameter på 0,01-10 pm. Forbindelsen med slik par-tikkel størrelse kan fremstilles ved knusing eller maling fulgt om nødvendig av partikkelstørrelsesklassifikasjon ved bruk f.eks. av en sikt. Preparatene kan også inneholde egnede preservering-, stabiliserings- og fuktemidler, opp-løseliggjørende midler, søtnings-, farge-, og smaksstoffer. Preparatene kan ora ønsket formuleres i form med langvarig frigjøringseffekt. According to the present invention, there is also provided a pharmaceutical preparation including (preferably a smaller proportion of) a compound of formula (1), or a pharmaceutically acceptable salt thereof, as active ingredient, in admixture with a pharmaceutically acceptable aid, diluent or carrier . Examples of suitable aids, diluents or carriers are: - for tablets and dragées; lactose, starch, talc or stearic acid; for capsules, tartaric or lactose; for suppositories, natural or hardened oils or waxes; and for injections (i.m. or i.v.) or enema water, surfactants and preservatives. The compounds can also be administered transdermally, e.g. in an ointment base. The compound of formula (I) or the pharmaceutically acceptable salt thereof preferably has an average mass diameter of 0.01-10 µm. The compound with such a particle size can be produced by crushing or grinding followed, if necessary, by particle size classification using e.g. of a term. The preparations may also contain suitable preserving, stabilizing and wetting agents, solubilizing agents, sweetening, coloring and flavoring agents. The preparations can, if desired, be formulated in a form with a long-term release effect.
Forbindelsene kan om ønsket koadministreres med (f.eks. som en blanding med) en syrenøytraliserende buffer. The compounds may, if desired, be co-administered with (eg as admixture with) an antacid buffer.
Det er foretrukket preparater som er beregnet for inntak ved svelging eller rektalt, og som friggjør deres innhold i tar-men. Det er særlig foretrukket preparater som vil passere gjennom de sure delene av mage-tarmkanalen upåvirket, f.eks. enterisk belagte preparater. Preparations which are intended for ingestion or rectally and which release their contents in the intestine are preferred. Preparations which will pass through the acidic parts of the gastrointestinal tract unaffected, e.g. enteric-coated preparations.
Noen av forbindelsene med formel (I) er optisk aktive og kan oppløses i deres optiske isomerer ved bruk av i og for seg kjente konvensjonelle teknikker. Oppfinnelsen tilveiebringer derfor forbindelsene som deres optiske isomerer, eller som blandinger, f.eks. racemiske blandinger derav. Some of the compounds of formula (I) are optically active and can be resolved into their optical isomers using conventional techniques known per se. The invention therefore provides the compounds as their optical isomers, or as mixtures, e.g. racemic mixtures thereof.
Forbindelsene med formel (I) kan foreligge i tautomere former, og disse tautomere formene er innbefattet i definisjonen av forbindelsene med formel (I). Spesielt når X er R19, og Rig er hydrogen, kan imidazolkjernen eksistere i tautomere former. The compounds of formula (I) can exist in tautomeric forms, and these tautomeric forms are included in the definition of the compounds of formula (I). In particular, when X is R19, and R1 is hydrogen, the imidazole nucleus can exist in tautomeric forms.
Oppfinnelsen illustreres, men begrenses på ingen måte, av følgende eksempler hvori temperaturer er i grader Celcius. The invention is illustrated, but not limited in any way, by the following examples in which temperatures are in degrees Celcius.
Eksempel 1 Example 1
2- r4- dimetylamino- 2-( 4- metoksy- 2- pyridinyl) fenylsulfinyll- 1H-benziraidazol 2- r4- dimethylamino- 2-( 4- methoxy- 2- pyridinyl) phenylsulfinyl- 1H- benziraidazole
a) 2-( 2- hydroksy- 5- nitrofenyl)- 4- metoksypyridin a) 2-(2-hydroxy-5-nitrophenyl)-4-methoxypyridine
4-nitrobenzendiazoniumtetrafluorborat (65,8 mmol) ble tilsatt 4-Nitrobenzenediazonium tetrafluoroborate (65.8 mmol) was added
porsjonsvis under omrøring ved romtemperatur til en oppløs- portionwise while stirring at room temperature to a dissolve-
ning av 4-metoksypyridin-N-oksyd (50 mmol ) i acetonitril (150 ml). Blandingen ble omrørt natten over ved romtemperatur, behandlet med trietylamin (100 mmol), og den bruke oppløsnin-gen ble oppvarmet under tilbakeløp i 15 min. ing of 4-methoxypyridine-N-oxide (50 mmol) in acetonitrile (150 ml). The mixture was stirred overnight at room temperature, treated with triethylamine (100 mmol), and the spent solution was heated under reflux for 15 min.
Oppløsningsmiddelet ble fjernet i en rotasjonsfordamper og resten flammekromatografert på silisiumdioksyd og eluert med kloroform for oppnåelse av undertittelforbindelse. The solvent was removed in a rotary evaporator and the residue flame chromatographed on silica eluting with chloroform to give the sub-title compound.
b) 2-( 2- hydroksy- 5- nitrofenyl)- 4- metoksypyridln- N. N- dimetyltiokarbamat b) 2-(2-hydroxy-5-nitrophenyl)-4-methoxypyridln-N.N-dimethylthiocarbamate
Forbindelsen fra trinn a) ovenfor (24,2 mmol), N,N-dimetyl-aminotiokarbamoylklorid (37 mmol) i dimetylformamid (250 ml) ble omrørt hurtig i nærvær av kaliumkarbonat (60 mmol) i 24 timer, idet mer kaliumkarbonat (1 g) ble tilsatt etter 18 timer. Blandingen ble surgjort (til pH 4) med fortynnet saltsyre og ekstrahert med etylacetat (3 ganger). De kombinerte ekstraktene ble vasket med vann ( ganger), tørket (vannfritt natriumsulfat) og fordampet til dannelse av et brunt faststoff, som ble triturert med eter, og filtrert for oppnåelse av undertittelforbindelsen. The compound from step a) above (24.2 mmol), N,N-dimethylaminothiocarbamoyl chloride (37 mmol) in dimethylformamide (250 ml) was stirred rapidly in the presence of potassium carbonate (60 mmol) for 24 hours, as more potassium carbonate (1 g) was added after 18 hours. The mixture was acidified (to pH 4) with dilute hydrochloric acid and extracted with ethyl acetate (3 times). The combined extracts were washed with water (x), dried (anhydrous sodium sulfate) and evaporated to give a brown solid, which was triturated with ether and filtered to afford the sub-title compound.
' HNMR (CDC13) S (d), 8,61 (d, 1H), 8,52 (d, 1H) , 8,28 (dd, 1H), 7,33 (d, 1H), 7,22 (d, 1H), 6,65 (m, 1H), 3,86 (S, 3H), 3,38 & 3,26 (NMe26H). ' HNMR (CDCl 3 ) S (d), 8.61 (d, 1H), 8.52 (d, 1H), 8.28 (dd, 1H), 7.33 (d, 1H), 7.22 ( d, 1H), 6.65 (m, 1H), 3.86 (S, 3H), 3.38 & 3.26 (NMe26H).
c) 2-( 2- merkapto- 5- nitrofenyl)- 4- metoksypyridin- N. N- dimetyl-karbamat c) 2-(2-mercapto-5-nitrophenyl)-4-methoxypyridine-N.N-dimethylcarbamate
Forbindelsen fra trinn a) ovenfor (13,5 mmol) i 2,2'-oksybis-etanol (130 ml) ble oppvarmet under nitrogen ved 175° i 2 timer. Blandingen ble avkjølt, helt i vann og ekstrahert med etylacetat (3 ganger). De kombinerte ekstraktene ble vasket med vann (3 ganger), tørket (vannfritt natriumsulfat) og fordampet for oppnåelse av en mørkebrun olje, flammekromatografert på silisiumdioksyd og krystallisert ved hen-stand under eter 1 fryseren. Undertittelforblndelsen ble frafiltrert og oppnådd som et gult faststoff. The compound from step a) above (13.5 mmol) in 2,2'-oxybis-ethanol (130 ml) was heated under nitrogen at 175° for 2 hours. The mixture was cooled, poured into water and extracted with ethyl acetate (3 times). The combined extracts were washed with water (3 times), dried (anhydrous sodium sulfate) and evaporated to give a dark brown oil, flash chromatographed on silica and crystallized on standing under ether 1 freezer. The subtitle mixture was filtered off and obtained as a yellow solid.
m/z (FÅB) 334 (M+l), 289, 247, (basistopp, bp) 72.m/z (FOB) 334 (M+1), 289, 247, (base peak, bp) 72.
d) 2 - ( 5- amino- 2- mekapto)- 4- metoksypyridln- N. N- dlmetylkarbamat d) 2 - ( 5- amino- 2- mecapto)- 4- methoxypyridln- N. N- dlmethylcarbamate
Forbindelsen fra trinn c) ovenfor (3,75 mmol) ble hydrogenert The compound from step c) above (3.75 mmol) was hydrogenated
ved romtemperatur ved 3,33 atmosfærer i 6 dager i nærvær av 10$ palladium på trekull (150 mg) i etanol (150 ml) som opp-løsningsmiddel. Blandingen ble filtrert og fordampet til dannelse av undertittelforblndelsen som et blekt, gult skum. m/z 303 (M+), 283, (bp) 231. at room temperature at 3.33 atmospheres for 6 days in the presence of 10$ palladium on charcoal (150 mg) in ethanol (150 ml) as solvent. The mixture was filtered and evaporated to give the sub-title compound as a pale yellow foam. m/z 303 (M+), 283, (bp) 231.
e ) 2-( 5- N. N- dimetylamino- 2- merkapto ) - 4- metoksypyridln- N . N-dimetylkarbamat e) 2-(5-N.N-dimethylamino-2-mercapto)-4-methoxypyridln-N. N-dimethylcarbamate
Forbindelsen fra trinn d) ovenfor (2,97 mmol) i acetonitril (15 ml) og formaldehydoppløsning (2,4 ml, ca. 30 mmol) ble behandlet porsjonsvis med natriumcyanoborhydrid (7,1 mmol) og omrørt med tilsetning av eddiksyre av og til (for opprett-holdelse av pH-verdien på ca. 5). Etter tilsetningen ble omrøring fortsatt i 1 time da blandingen ble helt i fortynnet vandig natriumhydrogenkarbonatoppløsning og ekstrahert med etylacetat, tørket (natriumsulfat), flammekromatografert på silisiumdioksyd, eluert med etylacetat til dannelse av tittelforbindelsen som et blekgult, faststoff. The compound from step d) above (2.97 mmol) in acetonitrile (15 mL) and formaldehyde solution (2.4 mL, ca. 30 mmol) was treated portionwise with sodium cyanoborohydride (7.1 mmol) and stirred with the addition of acetic acid of and to (to maintain the pH value of approx. 5). After the addition, stirring was continued for 1 hour when the mixture was poured into dilute aqueous sodium bicarbonate solution and extracted with ethyl acetate, dried (sodium sulfate), flame chromatographed on silica, eluted with ethyl acetate to give the title compound as a pale yellow solid.
m/z (liten basistopp) 331, (bp) 259.m/z (minor base peak) 331, (bp) 259.
f) Disulfld av 2-( 5- N. N- dlmetylamino- 2- merkapto)- 4- metoksypyridin f) Disulfide of 2-(5-N.N-dlmethylamino-2-mercapto)-4-methoxypyridine
Forbindelsen fra trinn e) ovenfor (110 mg, 0,33 mmol) i metanol (3 ml) ble opplvarmet under tilbakeløp i nærvær av natriumhydroksyd (0,4 mmol) i 8 timer. En ytterligere aliquot av NaOH (0,4 mmol) ble tilsatt, og oppvarming ble fortsatt i 15 timer. Blandingen ble helt i vann, surgjort med fortynnet vandig HC1, og pH-verdien ble deretter bragt tilbake til 8 med fortynnet vandig natriumhydrogenkarbonat. The compound from step e) above (110 mg, 0.33 mmol) in methanol (3 mL) was heated under reflux in the presence of sodium hydroxide (0.4 mmol) for 8 h. An additional aliquot of NaOH (0.4 mmol) was added and heating was continued for 15 h. The mixture was poured into water, acidified with dilute aqueous HCl, and the pH was then brought back to 8 with dilute aqueous sodium bicarbonate.
Den vandige oppløsningen ble ekstrahert med etylacetat (3 ganger) og ekstraktene vasket med vann (2 ganger), tørket (vannfritt natriumsulfat) og fordampet til dannelse av undertittelforblndelsen som en gul olje. The aqueous solution was extracted with ethyl acetate (3 times) and the extracts washed with water (2 times), dried (anhydrous sodium sulfate) and evaporated to give the sub-title compound as a yellow oil.
m/z 259 (MW/Z), 244, 228 m/z 259 (MW/Z), 244, 228
g) 2- r4- dimetvlamino- 2-( 4- metoksy- 2- pvridinvltlo) l- lH-benzenlmidazol g) 2- r4-Dimethylamino-2-(4-Methoxy-2-pyridinyl)1-1H-benzenemidazole
2-klorbenzimidazol (700 mg) og forbindelsen fra trinn f) ovenfor (1,2 g) ble oppvarmet under tilbakeløp med natriumcyanoborhydrid (290 mg) i isopropanol (33 ml) og eddiksyre (7 ml) i 2 timer. Oppløsningsmiddelet ble fjernet på en rotasjonsfordamper og resten fordampet med fortynnet, vandig natriumhydrogenkarbonat og ekstrahert med CHC13på vanlig måte, tørket (Na2S04) og omkrystallisert fra etylacetat til dannelse av undertittelforblndelsen som et hvitt, faststoff, smp. 218-220°. 2-Chlorobenzimidazole (700 mg) and the compound from step f) above (1.2 g) were heated under reflux with sodium cyanoborohydride (290 mg) in isopropanol (33 ml) and acetic acid (7 ml) for 2 hours. The solvent was removed on a rotary evaporator and the residue evaporated with dilute aqueous sodium bicarbonate and extracted with CHCl 3 in the usual manner, dried (Na 2 SO 4 ) and recrystallized from ethyl acetate to give the subtitle compound as a white solid, m.p. 218-220°.
h ) 2- r2- dlmetylamino- 2-( 4 - me toks v- 2- pyr idinylsulf lnyl )~ 1 - 1H-benzlmldazol h ) 2- r 2 - dlmethylamino- 2-( 4 - methoxy v - 2- pyr idinylsulf lnyl )~ 1 - 1H-benzlmldazole
Forbindelsen fra trinn g) ovenfor (2,39 mmol) i metylenklorld (40 ml) ble behandlet porsjonsvis med m-klorperbenzoesyre (500 mg av 8556, 2,46 mmol) ved -10° under omrøring i løpet av 15 min. Omrøring ble fortsatt i ytterligere 1 time, hvoretter blandingen ble opparbeidet til dannelse etter triturering med eter av tittelforbindelsen som et grått, faststoff. The compound from step g) above (2.39 mmol) in methylene chloride (40 ml) was treated portionwise with m-chloroperbenzoic acid (500 mg of 8556, 2.46 mmol) at -10° with stirring over 15 min. Stirring was continued for an additional 1 hour, after which the mixture was worked up to give, after trituration with ether, the title compound as a gray solid.
m/z FAB 393 (M?l), 275 (bp).m/z FAB 393 (M?l), 275 (bp).
Eksempel 2 Example 2
5- metoksy- 2- f2-( 4- metoksy- 2- pyridinyl) feny1 sulfinyl1- 1H-benzimldazol 5-Methoxy-2-f2-(4-Methoxy-2-pyridinyl)phenyl1sulfinyl1-1H-benzimldazole
a) 4- metoksy- 2-( 2- metyltiofenyl) pyridina) 4-Methoxy-2-(2-methylthiophenyl)pyridine
Under en nitrogenatmosfære ble 2-bromtioanisol (9,6 g) i tørr Under a nitrogen atmosphere, 2-bromothioanisole (9.6 g) was dried
eter (20 ml) tilsatt dråpevis til magnesium (1,15 g) i eter (5 ml) inneholdende lod (et lite krystall). Reaksjonen ble initiert ved tilsetning av metylmagnesiumiodid (0,1 ml av 3,0 M eter). Blandingen ble oppvarmet under tilbakeløp i 1,5 timer for å gi en klar oppløsning av Grignard-reagensen (20 ml). 4-metoksypyridin-N-oksyd (2 g) i tørr tetrahydrofuran (50 ml) ble mekanisk omrørt, og etylklorformiat (1,52 ml) ble tilsatt dråpevis. Den omrørte blanding ble avkjølt til -78° og behandlet med den ovenfor angitte Grignard-oppløsning (7,5 ml). Etter omrøring i 2 timer fikk blandingen oppvarmes til romtemperatur. Blandingen ble helt poå fortynnet saltsyre og vasket med etylacetat. Etylacetat ble ekstrahert med fortynnet saltsyre. Den vandige oppløsningen ble vasket med kloroform, deretter gjort basisk og reekstrahert med etylacetat. Etylacetatet ble vasket med saltoppløsning, der- ether (20 ml) added dropwise to magnesium (1.15 g) in ether (5 ml) containing lead (a small crystal). The reaction was initiated by the addition of methylmagnesium iodide (0.1 mL of 3.0 M ether). The mixture was heated under reflux for 1.5 hours to give a clear solution of the Grignard reagent (20 mL). 4-Methoxypyridine-N-oxide (2 g) in dry tetrahydrofuran (50 mL) was mechanically stirred, and ethyl chloroformate (1.52 mL) was added dropwise. The stirred mixture was cooled to -78° and treated with the above Grignard solution (7.5 mL). After stirring for 2 hours, the mixture was allowed to warm to room temperature. The mixture was poured into dilute hydrochloric acid and washed with ethyl acetate. Ethyl acetate was extracted with dilute hydrochloric acid. The aqueous solution was washed with chloroform, then basified and re-extracted with ethyl acetate. The ethyl acetate was washed with saline, where-
etter tørket og inndampet til dannelse av undertittelforblndelsen som en lysebrun olje MS MW 231 bp 216. after drying and evaporation to form the sub-title compound as a light brown oil MS MW 231 bp 216.
b) 4- metoksy- 2-( 2- metylsulfinylfenyl1- pyridinb) 4-Methoxy-2-(2-methylsulfinylphenyl1-pyridine).
Produktet fra trinn a) ovenfor (750 mg) i etylacetat (7 ml) The product from step a) above (750 mg) in ethyl acetate (7 ml)
ble avkjølt til —10° og behandlet med en oppløsning av m-klorperbenzoesyre (660 mg) i etylacetat (4 ml). Etter 1 time ble oppløsningen vasket med natriumbikarbonatoppløsning, natriumbisulfatoppløsning og saltoppløsning, og deretter tørket og inndampet. Resten ble flammekromatografert (etylacetat) til dannelse av undertittelforblndelsen som en klar olje MS (FAB) M+l ved 248 bp 32. was cooled to -10° and treated with a solution of m-chloroperbenzoic acid (660 mg) in ethyl acetate (4 ml). After 1 hour, the solution was washed with sodium bicarbonate solution, sodium bisulfate solution and saline solution, and then dried and evaporated. The residue was flame chromatographed (ethyl acetate) to give the sub-title compound as a clear oil MS (FAB) M+1 at 248 bp 32.
c) 5- metoksy- 2- r2-( 4- metoksy- 2- pyridinyl) fenyltiol- lH-benzimidazol c) 5-Methoxy-2-r2-(4-Methoxy-2-pyridinyl)phenylthiol-1H-benzimidazole
Produktet fra trinn b) ovenfor (180 mg) ble behandlet med trifluoreddiksyreanhydrid (1,5 ml) og oppvarmet under til-bakeløp i 1 time. Oppløsningsmiddelet ble fjernet i vakuum, og resten behandlet med metanol (10 ml) og trietylamin (10 ml). Blandingen ble konsentrert i vakuum og resten opptatt i diklormetan. Oppløsningen ble vasket med ammoniumklorid-oppløsning, deretter tørket og inndampet. Resten ble opptatt i tørr dimetylformamid og 2-klor-5-metoksy-lH-benzimidazol (133 mg) og kaliumkarbonat (101 mg) tilsatt. Blandingen ble oppvarmet ved 90-95° i 1 time, deretter helt på vann og ekstrahert med etylacetat. Etylacetatet ble vasket med vann og saltoppløsning, deretter tørket og inndampet. Flammekromatografi ga undertittelforblndelsen som et lyserødt skum MS MW 363 bp 216. The product from step b) above (180 mg) was treated with trifluoroacetic anhydride (1.5 ml) and heated under reflux for 1 hour. The solvent was removed in vacuo and the residue treated with methanol (10 mL) and triethylamine (10 mL). The mixture was concentrated in vacuo and the residue taken up in dichloromethane. The solution was washed with ammonium chloride solution, then dried and evaporated. The residue was taken up in dry dimethylformamide and 2-chloro-5-methoxy-1H-benzimidazole (133 mg) and potassium carbonate (101 mg) added. The mixture was heated at 90-95° for 1 hour, then poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated. Flame chromatography gave the subtitle compound as a bright red foam MS MW 363 bp 216.
d) 5- me tok sy- 2- f 2- ( 4- metoksy- 2- pyridlnyl) fenylsulf inyll - 1H-benzimidazol d) 5- me toc sy- 2- f 2- ( 4- methoxy- 2- pyridlnyl) phenylsulfinyl - 1H- benzimidazole
Produktet fra trinn c) ovenfor (103 mg) ble oppløst i etylacetat (7,5 ml) og omrørt ved —10°. En oppløsning av m-klorperbenoinsyre (58 mg av 85$) i etylacetat (0,5 ml) ble tilsatt, og blandingen omrørt i 50 min. Oppløsningen ble vasket med natriumbikarbonatoppløsning, natriumbisulfitt-oppløsning, vann og saltoppløsning, deretter tørket og inndampet. Etter triturering med eter ble det faste stoffet tørket for oppnåelse av tittelforbindelsen MS (FAB) M+l ved 380. The product from step c) above (103 mg) was dissolved in ethyl acetate (7.5 ml) and stirred at -10°. A solution of m-chloroperbenoic acid (58 mg of 85$) in ethyl acetate (0.5 ml) was added and the mixture stirred for 50 min. The solution was washed with sodium bicarbonate solution, sodium bisulfite solution, water and brine, then dried and evaporated. After trituration with ether, the solid was dried to give the title compound MS (FAB) M+1 at 380.
Eksempel 3Example 3
Ved fremgangsmåter analoge med dem i eksempel 2, ved anvendelse av passende utgangsmaterilaer, ble følgende forbindelser fremstilt. By procedures analogous to those of Example 2, using appropriate starting materials, the following compounds were prepared.
Eksempel 4 Example 4
2- f( 5- metoksy- 2-( 4- metoksy- 2- pyrldlnyl ) fenylsulfinyll - 1H-benzlmidazol 2-f(5-Methoxy-2-(4-Methoxy-2-pyrldlnyl)phenylsulfinyl-1H-benzlmidazole
a) 0- ( 2- brom- 5- metoksyfenyl)- N. N- dlmetyltiokarbamat a) 0-(2-bromo-5-methoxyphenyl)-N.N-dlmethylthiocarbamate
2-brom-5-metoksyfenol (29 g) ble oppløst 1 tørr dimetylformamid (100 ml) og avkjølt til 0°. Vannfritt kaliumkarbonat (21,7 g) ble tilsatt og blandingen omrørt i 15 min. En oppløsning av dimetyltiokarbamoylklorid (22,1 g) i tørr dimetylformamid (50 ml) ble tilsatt, og blandingen fikk oppvarmes til romtemperatur. Etter omrøring i 5 timer ble blandingen helt i vann og ekstrahert med etylacetat. Etylacetatet ble vasket med vann, fortynnet natriumhydroksyd-oppløsning, igjen med vann, deretter tørket og inndampet. Flammekromatografi (10$ etylacetat/petroleumeter) ga undertittelforblndelsen som et fargeløst faststoff, NMR (CDC13) d 7,45 (dod, 1H) 6,72 (m, 2H) 3,79 (s, 3H) 3,40 (s, 3H). 2-Bromo-5-methoxyphenol (29 g) was dissolved in dry dimethylformamide (100 ml) and cooled to 0°. Anhydrous potassium carbonate (21.7 g) was added and the mixture stirred for 15 min. A solution of dimethylthiocarbamoyl chloride (22.1 g) in dry dimethylformamide (50 ml) was added and the mixture was allowed to warm to room temperature. After stirring for 5 hours, the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, dilute sodium hydroxide solution, again with water, then dried and evaporated. Flash chromatography (10% ethyl acetate/petroleum ether) gave the subtitle compound as a colorless solid, NMR (CDCl 3 ) d 7.45 (dod, 1H) 6.72 (m, 2H) 3.79 (s, 3H) 3.40 (s, 3H).
b ) S-( 2- brom- 5- metoksyfenyl)- N. N- dimetyltiokarbamat b ) S-(2-bromo-5-methoxyphenyl)-N.N-dimethylthiocarbamate
Produktet fra trinn a) ovenfor (32,5 g) ble oppløst I dietyl-anilin (330 ml) og oppløsningen oppvarmet under tilbakeløp i 4 timer. Den avkjølte blanding ble helt i fortynnet saltsyre og ekstrahert med etylacetat. Etylacetatet ble vasket med fortynnet saltsyre, vann og saltoppløsning, og deretter tør-ket og Inndampet til oppnåelse av en brun gummi. Flammekromatografi ( 10% etylacetat/petroleumeter) ga undertittelforblndelsen som et brunt faststoff. MW M+l ved 288/290 bp 72. The product from step a) above (32.5 g) was dissolved in diethylaniline (330 ml) and the solution heated under reflux for 4 hours. The cooled mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with dilute hydrochloric acid, water and saline, and then dried and evaporated to obtain a brown gum. Flame chromatography (10% ethyl acetate/petroleum ether) gave the subtitle compound as a brown solid. MW M+l at 288/290 bp 72.
c) 2- brom- 5- metoksytiofenolc) 2-bromo-5-methoxythiophenol
Produktet fra trinn b) ovenfor (200 mg) ble oppløst i metanol The product from step b) above (200 mg) was dissolved in methanol
(4 ml). Vandig natriumhydroksydoppløsning (1,4 ml av 10$) ble tilsatt og blandingen oppvarmet under tilbakeløp i nitrogenatmosfære i 2 timer. Blandingen ble avkjølt, helt i fortynnet saltsyre og ekstrahert med etylacetat. Etylacetatet ble vasket med vann og saltoppløsning, deretter tørket og inndampet til dannelse av undertittelforblndelsen som en olje MS MW 218/220 bp 218. (4 ml). Aqueous sodium hydroxide solution (1.4 mL of 10$) was added and the mixture heated under reflux under nitrogen atmosphere for 2 hours. The mixture was cooled, poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to give the sub-title compound as an oil MS MW 218/220 bp 218.
d) 1- brom- 4- metoksy- 2- metyltiobenzend) 1- bromo- 4- methoxy- 2- methylthiobenzene
Produktet fra trinn c) ovenfor (140 mg) ble oppløst i tørr The product from step c) above (140 mg) was dissolved in dry
dimetylformamid (2 ml). Kaliumkarbonat (114 mg) ble tilsatt fulgt av metyliodid (47 ml). Blandingen ble omrørt i 2 timer, helt i vann og ekstrahert med etylacetat. Etylacetatet ble vasket med vann og saltoppløsning, deretter tørket og inndampet til dannelse av undertittelforblndelsen som en lysebrun olje MS MW 232/4 bp 232. dimethylformamide (2 mL). Potassium carbonate (114 mg) was added followed by methyl iodide (47 mL). The mixture was stirred for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to give the sub-title compound as a light brown oil MS MW 232/4 bp 232.
e) 4- metoksy- 2-( 4- metoksy- 2- metyItiofenyl) pyridine) 4- methoxy- 2-( 4- methoxy- 2- methylthiophenyl) pyridine
En Grignard-reagens ble fremstilt fra produktet i trinn d) A Grignard reagent was prepared from the product of step d)
ovenfor (12,3 g), magnesium (1,28 g) og lod (1 krystall) i tørr tetrahydrofuran (150 ml). 4-metoksypyridin (5,76 g) ble oppløst i tørr tetrahydrofuran (300 ml) og omrørt under nitrogen. Oppløsningen ble avkjølt til -70° og behandlet above (12.3 g), magnesium (1.28 g) and lead (1 crystal) in dry tetrahydrofuran (150 ml). 4-Methoxypyridine (5.76 g) was dissolved in dry tetrahydrofuran (300 mL) and stirred under nitrogen. The solution was cooled to -70° and processed
med ovennevnte Grignard-oppløsning i en porsjon. Etter om-røring i 10 min.<i->ble fenylklorformiat (6,6 ml) tilsatt dråpevis. Etter omrøWing ved -70° i 30 min. fikk blandingen oppvarmes til romteniperatur. Etter omrøring i 90 min. ble blandingen helt i vann og ekstrahert med eter. Eteren ble vasket med vann og saltoppløsning, deretter tørket og inndampet. Resten ble opptatt i toluen (250 ml) og omrørt ved romtemperatur. Erti!? oppløsning av 3 ,4,5,6-tetraklor-l,2-benzo-kinon (13,0 g) i eddiksyre (120 ml) ble tilsatt dråpevis. Da tilsetningen var-! fullstendig, ble blandingen omrørt i ytterligere 18 timertr Blandingen ble isavkjølt og behandlet med en kald oppløsning av natriumhydroksyd (700 ml av 10%). Etter omrøringii2i0 min. ble blandingen filtrert og separert. De vandige filtratene ble ekstrahert med eter, og de kombinerte organiske filtratene ble ekstrahert med fortynnet saltsyre. Ekstraktene ble kombinert og gjort basiske med natriumhydrok£yd$>ppløsning. Blandingen ble ekstrahert med eter, og de kombinerte ekstraktene vasket med saltoppløsning, deretter tørket og inndampet. Flammekromatografi (1:1 etylacetat/petroleumeter) ga undertittelforblndelsen som en klar olje (5,4 g). NMR (CDC13) d 8,50 (d, 1H), 7,39 (d, 1H), 760 (d, 1H), 6,85 (d, 1H), 6,77 (m, 2H), 3,88 (s, 3H), 3,86 (s, 3H ) , 2,40 (s, ;3H). with the above Grignard solution in one portion. After stirring for 10 min, phenyl chloroformate (6.6 ml) was added dropwise. After stirring at -70° for 30 min. the mixture was allowed to warm to room temperature. After stirring for 90 min. the mixture was poured into water and extracted with ether. The ether was washed with water and brine, then dried and evaporated. The residue was taken up in toluene (250 ml) and stirred at room temperature. Erti!? solution of 3,4,5,6-tetrachloro-1,2-benzoquinone (13.0 g) in acetic acid (120 ml) was added dropwise. When the addition was-! completely, the mixture was stirred for an additional 18 h. The mixture was ice-cooled and treated with a cold solution of sodium hydroxide (700 mL of 10%). After stirring 2i0 min. the mixture was filtered and separated. The aqueous filtrates were extracted with ether and the combined organic filtrates were extracted with dilute hydrochloric acid. The extracts were combined and basified with sodium hydroxide solution. The mixture was extracted with ether and the combined extracts washed with brine, then dried and evaporated. Flash chromatography (1:1 ethyl acetate/petroleum ether) gave the subtitle compound as a clear oil (5.4 g). NMR (CDCl 3 ) d 8.50 (d, 1H), 7.39 (d, 1H), 760 (d, 1H), 6.85 (d, 1H), 6.77 (m, 2H), 3, 88 (p, 3H), 3.86 (p, 3H ), 2.40 (p, ; 3H).
■ ■
Tittelforbindelsen ble fremstilt ved bruk av fremgangsmåter analoge med eksempel 2b), c) og d) via: f) 4- metoksy- 2-( 4- metoksv- 2- metylsulflnylfenyl) pyridin MS M<+>277 g) 2- r5- metoksy- 2-( 4- metoksv- 2- pyrldinvI) fenyltloi- 1H-benzlmldazol ;MS M<+>363. h) 2- r5- metokrsv- 2- ( 4- me toks v- 2- pyr idinvl ) fenyl sul f invll- 1H-benzimldazol , rsmp. 204-207°. The title compound was prepared using methods analogous to example 2b), c) and d) via: f) 4- methoxy- 2-( 4- methoxy- 2- methylsulflnylphenyl) pyridine MS M<+>277 g) 2- r5- Methoxy-2-(4-methoxy-2-pyrridine)phenylthiol-1H-benzlmidazole; MS M<+>363. h) 2-r5-methocrsv-2-(4-methoxyv-2-pyridinvl)phenylsulfinvll-1H-benzimldazole, rsmp. 204-207°.
r; r;
Eksempel 5Example 5
Ved hjelp av fremgangsmåter analoge med dem 1 eksempel 4 ovenfor og ved bruk av de passende utgangsmaterlalene, hie følgende forbindelser fremstilt: Using procedures analogous to those in Example 1 4 above and using the appropriate starting materials, the following compounds were prepared:
Eksempel 6 Example 6
5, 6- dlmetoksy- 2- r5- metoksy- 2-( 2- pyrldinyl) fenylsulfinyll- 1H-benzimidazol 5, 6- dlmethoxy- 2- r5- methoxy- 2-( 2- pyrldinyl) phenylsulfinyl- 1H- benzimidazole
a) 5 , 6- dimetoksy- 2-( 5 - me toks y- 2 - ni tr of enyl 11 o )- lH- benzimldazol a) 5,6-dimethoxy-2-(5-methoxy-2-nitriofenyl 11o)-1H-benzimldazole
5,6-dimetoksybenzimidazol-2-tion (4,0 g), 2-klor-4-metoksy-nitrobenzen (3,6 g), og kaliumkarbonat (2,65 g) ble omrørt sammen i tørr dimetylformamid (30 ml) ved 95° i 3 dager. Den avkjølte blandingen ble helt i vann (300 ml) og bunnfallet oppsamlet. Det faste stoffet ble vasket med vann og tørket for oppnåelse av undertittelforblndelsen som et blekgult faststoff, MS 361 bp 2207. 5,6-dimethoxybenzimidazol-2-thione (4.0 g), 2-chloro-4-methoxynitrobenzene (3.6 g), and potassium carbonate (2.65 g) were stirred together in dry dimethylformamide (30 mL) at 95° for 3 days. The cooled mixture was poured into water (300 mL) and the precipitate collected. The solid was washed with water and dried to afford the sub-title compound as a pale yellow solid, MS 361 bp 2207.
b) 2- f 5 , 6- dimetoksy- 2- lH- benzimidazolyItio]- 4- metoksybenzen-amin b) 2- f 5 , 6- dimethoxy-2- 1H- benzimidazolyItio]- 4- methoxybenzene-amine
Produktet fra trinn a) ovenfor (6,3 g), jernpulver (6,3 g) og ammoniumklorid (6,3 g) ble omrørt sammen med etanol (63 ml) og vann (120 ml) og oppvarmet under tilbakeløp i 1 time. Den varme blandingen ble filtrert og resten vasket med varmt etylacetat (500 ml). De kombinerte filtratene ble separert og den vandige fasen ekstrahert med etylacetat. De kombinerte etylacetatekstraktene ble vasket med vann og salt-oppløsning, deretter tørket og inndampet til et skum. Ved triturering med eter ble undertittelforblndelsen oppnådd som et grått faststoff, MS MW bp 331. The product from step a) above (6.3 g), iron powder (6.3 g) and ammonium chloride (6.3 g) were stirred together with ethanol (63 ml) and water (120 ml) and heated under reflux for 1 hour . The hot mixture was filtered and the residue washed with hot ethyl acetate (500 mL). The combined filtrates were separated and the aqueous phase extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine, then dried and evaporated to a foam. Trituration with ether gave the subtitle compound as a gray solid, MS MW bp 331.
c) 5. 6- dimetoksy- 2- r5- metoksy- 2-( 2- pyridinyl) f enyl ti ol- 1H-benzimldazol c) 5.6-dimethoxy-2- r5-methoxy-2-(2-pyridinyl)phenylthiol-1H-benzimldazole
Produktet fra trinn b) ovenfor (500 mg) ble behandlet med konsentrert saltsyre (0,8 ml) og vann (0,8 ml) til dannelse av en pasta. Pastaen ble omrørt ved 0-10°, og en oppløsning av natriumnitritt (105 mg) i vann (0,5 ml) ble tilsatt dråpevis. Etter omrøring i 40 min. ble den resulterende oppløs-ning tilsatt langsomt til pyridin (5 ml), omrørt ved 80°. Blandingen ble omrørt i ytterligere 40 min. og deretter konsentrert i vakuum. Resten ble oppslemmet med 0,880 ammoni-akk, og blandingen igjen konsentrert i vakuum. Resten ble oppslemmet med vann og ekstrahert med etylacetat. Etylacetatet ble vasket med vann og saltoppløsning, deretter tørket og inndampet til dannelse av en brun ggummi. Flammekromatografi ga det ønskede produkt som et lysebrunt faststoff, MS MW 393 bp 216. The product from step b) above (500 mg) was treated with concentrated hydrochloric acid (0.8 ml) and water (0.8 ml) to form a paste. The paste was stirred at 0-10° and a solution of sodium nitrite (105 mg) in water (0.5 ml) was added dropwise. After stirring for 40 min. the resulting solution was added slowly to pyridine (5 mL), stirred at 80°. The mixture was stirred for an additional 40 min. and then concentrated in vacuo. The residue was slurried with 0.880 ammonium hydroxide, and the mixture again concentrated in vacuo. The residue was slurried with water and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated to form a brown gum. Flame chromatography gave the desired product as a light brown solid, MS MW 393 bp 216.
d ) 5 , 6- dimetoksy- 2- r5- metoksy- 2-( 2- pyridlnyl) fenylsulfinyll - lH- benzimidazol d ) 5 , 6- dimethoxy-2- r5- methoxy- 2-( 2- pyridlnyl) phenylsulfinyl - 1H- benzimidazole
Produktet fra trinn c) ovenfor (370 mg) ble oppløst i etylacetat (90 ml) og avkjølt til -10°C. Til den omrørte oppløs-ning ble det tilsatt en oppløsning av m-klorperbenzoesyre (191 mg av 85%) i etylacetat (10 ml). Etter omrøring i 1 time ble oppløsningen vasket med natriumbikarbonatoppløs-ning, natriummetabisulfittoppløsning, vann og saltoppløsning og deretter tørket og inndampet. Resten ble flammekromatografert for oppnåelse av tittelforbindelsen som et lysebrunt faststoff, smp. 208-210°. The product from step c) above (370 mg) was dissolved in ethyl acetate (90 ml) and cooled to -10°C. To the stirred solution was added a solution of m-chloroperbenzoic acid (191 mg of 85%) in ethyl acetate (10 ml). After stirring for 1 hour, the solution was washed with sodium bicarbonate solution, sodium metabisulfite solution, water and brine and then dried and evaporated. The residue was flame chromatographed to give the title compound as a light brown solid, m.p. 208-210°.
Eksempel 7Example 7
Ved fremgangsmåter analoge med dem i eksempel 6 og ved bruk av de passende utgangsmaterialene ble følgende forbindelser fremstilt: By procedures analogous to those of Example 6 and using the appropriate starting materials, the following compounds were prepared:
Eksempel 8 Example 8
2- f2-( lH- benzimidazol- 2- yl- sulf inyl ) f envl"!- 1- metyl- lH- benzimidazol 2-f2-(1H-benzimidazol-2-yl-sulfinyl)fenvl"1-1-methyl-1H-benzimidazol
a) 2-( 2- metyltiofenyl)- lH- benzimldazol a) 2-(2-methylthiophenyl)-1H-benzimldazole
2-metyltiobenzoesyreklorld (4 g), o-fenylendiamin (2,32 g) og 2-methylthiobenzoic acid chloride (4 g), o-phenylenediamine (2.32 g) and
polyfosforsyre (64 g) ble oppvarmet ved 135° under omrøring i 24 timer. Reaksjonsblandingen ble helt på is, gjort basisk med natriumhydroksydoppløsning og ekstrahert med etylacetat som ble vasket med saltoppløsning, tørket over magnesiumsulfat og inndampet til tørrhet til dannelse av undertittelforblndelsen som et blekgult faststoff, MS MW 240 bp 225. polyphosphoric acid (64 g) was heated at 135° with stirring for 24 hours. The reaction mixture was poured onto ice, basified with sodium hydroxide solution and extracted with ethyl acetate which was washed with brine, dried over magnesium sulfate and evaporated to dryness to give the sub-title compound as a pale yellow solid, MS MW 240 bp 225.
b) 1- metyl- 2-( 2- metyltiofenyl)- lH- benzimldazolb) 1-methyl-2-(2-methylthiophenyl)-1H-benzimldazole
Produktet fra trinn a) ovenfor (3,25 g), metyliodid (1,92 g) The product from step a) above (3.25 g), methyl iodide (1.92 g)
og kaliumkarbonat (5,2 g) ble omrørt sammen i tørr dimetylformamid (50 ml) ved romtemperatur i 24 timer. Reaksjonsblandingen ble helt i saltoppløsning og ekstrahert i etylacetat, ekstraktet ble vasket med overskudd saltoppløsning, tørket over magnesiumsulfat og inndampet til tørrhet i vakuum, og resten ble renset ved flammekromatografi (SiOg/- CH2CI29:1 etylacetat) for oppnåelse av undertittelforblndelsen som et gult faststoff, MS MW 254 bp 239. and potassium carbonate (5.2 g) were stirred together in dry dimethylformamide (50 mL) at room temperature for 24 hours. The reaction mixture was poured into brine and extracted into ethyl acetate, the extract was washed with excess brine, dried over magnesium sulfate and evaporated to dryness in vacuo, and the residue was purified by flame chromatography (SiOg/-CH2CI29:1 ethyl acetate) to afford the sub-title compound as a yellow solid , MS MW 254 bp 239.
c) l- metyl- 2-( 2- metylsulfinylfenyl)- lH- benzlmldazol c) 1- methyl- 2-( 2- methylsulfinylphenyl)- 1H- benzlmldazole
Produktet fra trinn b) ovenfor (2 g) ble oppløst i diklormetan (50 ml) og avkjølt til 10° under omrøring. 85% m-klorperbenzoesyre (1,6 g) ble tilsatt porsjonsvis. Reaksjonsblandingen ble langsomt oppvarmet til romtemperatur, og etter 3 timer var reaksjonen fullstendig. Reaksjonsblandingen ble vasket med vandig metabisulfittoppløsning, deretter bi- karbonatoppløsning og sluttlig saltoppløsning, tørket over magnesiumsulfat og inndampet til tørrhet i vakuum, hvoretter resten ble renset ved flammekromatografi (SiC^/etylacetat 3:2 CH2CI2) for oppnåelse av undertittelforblndelsen som et gult, krystallinsk faststoff, smp. 157-159°. The product from step b) above (2 g) was dissolved in dichloromethane (50 ml) and cooled to 10° with stirring. 85% m-chloroperbenzoic acid (1.6 g) was added portionwise. The reaction mixture was slowly warmed to room temperature, and after 3 hours the reaction was complete. The reaction mixture was washed with aqueous metabisulphite solution, then bicarbonate solution and finally brine, dried over magnesium sulfate and evaporated to dryness in vacuo, after which the residue was purified by flame chromatography (SiCl 2 /ethyl acetate 3:2 CH 2 Cl 2 ) to obtain the sub-title compound as a yellow, crystalline solid, m.p. 157-159°.
d) 2 - 12 - 1 lH- benzimidazol- 2- vl- tlo) fenvll- 1- metvl- lH- benzimidazol d) 2 - 12 - 1 1H- benzimidazole- 2- vl- tlo) phenvll- 1- metvl- 1H- benzimidazole
Produktet fra trinn c) ovenfor (1,83 g) ble oppvarmet ved tilbakeløpstemperatur med trifluoreddiksyreanhydrid (10 ml) og tørr diklormetan (15 ml) i 30 min. Det hele ble inndampet til tørrhet, og den resulterende oljen ble oppløst i tørr metanol (220 ml) og trietylamin (20 ml). 2-(fenylsul-fonyl)-lH-benzimidazol (1,75 g) ble tilsatt til oppløsningen, og det hele ble oppvarmet ved 70° i 15 min. før inndampning til tørrhet. The product from step c) above (1.83 g) was heated at reflux with trifluoroacetic anhydride (10 ml) and dry dichloromethane (15 ml) for 30 min. The whole was evaporated to dryness and the resulting oil was dissolved in dry methanol (220 mL) and triethylamine (20 mL). 2-(Phenylsulfonyl)-1H-benzimidazole (1.75 g) was added to the solution and the whole was heated at 70° for 15 min. before evaporation to dryness.
Den blekgule resten ble oppløst i iso-propanol (50 ml) og oppvarmet ved tilbakeløpstemperatur i 30 min. før tilsetningen av natriumborhydrid (0,26 g) og ytterligere oppvarming i 1 time ved tilbakeløpstemperatur og 18 timer ved 50°. The pale yellow residue was dissolved in iso-propanol (50 ml) and heated at reflux temperature for 30 min. before the addition of sodium borohydride (0.26 g) and further heating for 1 hour at reflux temperature and 18 hours at 50°.
Volumet av isopropanol ble redusert til ca. 5 ml, og re-aks j onsblandingen ble helt i saltoppløsning, ekstrahert med diklormetan, tørket over magnesiumsulfat og inndampet til tørrhet i vakuum. Resten ble renset ved flammekromatografi (S102/etylacetat 1:9 CH2CI2) for oppnåelse av undertittelforblndelsen som et hvitt pulver, smp. 246-247°. The volume of isopropanol was reduced to approx. 5 ml, and the reaction mixture was poured into brine, extracted with dichloromethane, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by flame chromatography (SO 2 /ethyl acetate 1:9 CH 2 Cl 2 ) to give the sub-title compound as a white powder, m.p. 246-247°.
e) 2 -\ 2 -( lH- benzimldazol- 2- vl- sulfinvl) fenvll- 1- metyl- 1H-benzimidazol e) 2 -\ 2 -( 1H- benzimldazol- 2- vl- sulfinvl) phenvlll- 1- methyl- 1H- benzimidazole
Produktet fra trinn d) ovenfor (0,99 g) ble oppløst i diklormetan (60 ml) og metanol (5 ml) og avkjølt til-10°. 85$ m-klorperbenzoesyre (0,56 g) ble tilsatt,, og det hele ble langsomt oppvarmet til romtemperatur under omrøring. Etter 2 timer ble reaksjonsblaningen vasket med metabisulfatoppløs-ning, deretter bikarbonatoppløsning og til slutt med salt-oppløsning, tørket over magnesiumsulfat og inndampet til tørrhet i vakuum, og resten ble renset ved flammekromatografi (S102/CH2C122:3 etylacetat) for oppnåelse av tittelforbindelsen som et hvitt, faststoff, smp. 164°. The product from step d) above (0.99 g) was dissolved in dichloromethane (60 ml) and methanol (5 ml) and cooled to -10°. 85% m-chloroperbenzoic acid (0.56 g) was added and the whole was slowly warmed to room temperature with stirring. After 2 hours, the reaction mixture was washed with metabisulfate solution, then bicarbonate solution and finally with brine, dried over magnesium sulfate and evaporated to dryness in vacuo, and the residue was purified by flame chromatography (S102/CH2C122:3 ethyl acetate) to give the title compound as a white solid, m.p. 164°.
Eksempel 9Example 9
Ved fremgangsmåter analoge med dem i eksempel 8 ble følgende forbindelser fremstilt: By methods analogous to those in Example 8, the following compounds were prepared:
Eksempel 10 Example 10
2- r2-( 6. 7- dlmetoksv- l- lsoklnollnvl) fenvlsul flnvil - 1H-benimidazol 2- r2-(6.7- dlmethoxy-l- isoclnolnlvl) fenvlsul flnvil - 1H-benimidazole
a) N- f3, 4- dimetoksyfenyl) etyl]- 2- metyltiobenzamid a) N- (3, 4- dimethoxyphenyl) ethyl]- 2- methylthiobenzamide
2-(3,4-dimetoksyfenyl)etylamin (4,8 ml), poly(4-vinylpyrIdln) 2-(3,4-dimethoxyphenyl)ethylamine (4.8 mL), poly(4-vinylpyridine)
(PVP) (5,7 g) og 2-metyltiobenzoylklorid (5,3 g) ble omrørt i diklormetan (50 ml) under avkjøling i et vannbad ved 20° i løpet av en natt. PVP-materialet ble frafUtrert og vasket med CHCI3. Inndampning av ekstraktene fulgt av flamme-kromatograf i (etylacetat/petroleumeter) ga undertittelforblndelsen, smp. 94-95°. (PVP) (5.7 g) and 2-methylthiobenzoyl chloride (5.3 g) were stirred in dichloromethane (50 ml) under cooling in a water bath at 20° overnight. The PVP material was filtered off and washed with CHCl 3 . Evaporation of the extracts followed by flame chromatography in (ethyl acetate/petroleum ether) gave the sub-title compound, m.p. 94-95°.
b) 6. 7- dimetoksv- l- r( 2- metvltlo) fenyll- 33. 4- dihvdroisokinolin b) 6. 7- dimethoxysv-l- r(2- metvltlo) phenyl- 33. 4- dihydroisoquinoline
Produktet fra trinn a) ovenfor ble oppvarmet med fosforpent-oksyd (6 g) i tørr acetonitril (500 ml) under tilbakeløp med omrøring i 2 timer. Blandingen ble avkjølt, forsiktig behandlet med vann og nøytralisert med fast NaHC03og ekstrahert med etylacetat, hvilket ved inndampning ga undertittelforblndelsen som en olje, MS elektron-anslag (EI) 298 { 100%, M-15 ). The product from step a) above was heated with phosphorus pentoxide (6 g) in dry acetonitrile (500 ml) under reflux with stirring for 2 hours. The mixture was cooled, carefully treated with water and neutralized with solid NaHCO 3 and extracted with ethyl acetate, which on evaporation gave the subtitle compound as an oil, MS electron estimate (EI) 298 { 100%, M-15 ).
c) 6. 7- dimetoksyf( 2- metyltio) fenyl] lsokinolinc) 6.7-Dimethoxy(2-methylthio)phenyl]isoquinoline
produktet fra trinn b) ovenfor (3,4 g) ble behandlet med the product from step b) above (3.4 g) was treated with
svovel (2 g) under tilbakeløp i xylen (80 ml), mens ytterligere mengder svovel (0,2 g) ble tilsatt hver 3. dag i 2 uker. Oppløsningsmiddelet ble inndampet, og resten ble kromatografert (etylacetatpetroleumeter), hvilket ga undertittelforblndelsen som en olje, MS 311 (M.556), 296 (M-15, 10056). sulfur (2 g) under reflux in xylene (80 mL), while additional amounts of sulfur (0.2 g) were added every 3 days for 2 weeks. The solvent was evaporated and the residue was chromatographed (ethyl acetate petroleum ether) to give the sub-title compound as an oil, MS 311 (M.556), 296 (M-15, 10056).
d) 6. 7- dimetoksy- l- r( 2- metyIsulfinyl) fenyl1isokinolin d) 6.7-dimethoxy-l-r(2-methylsulfinyl)phenyl1isoquinoline
Produktet fra trinn c) ovenfor ble behandlet med 85$ m-klorperbenzoesyre (1,58 g) i etylacetat for dannelse etter kromatografi av undertittelforblndelsen, smp. 64°. The product from step c) above was treated with 85% m-chloroperbenzoic acid (1.58 g) in ethyl acetate to give, after chromatography, the sub-title compound, m.p. 64°.
e) Bisr2-( 6. 7- dimetoksv- l- isokinolinyl) fenyldisulfid e) Bisr2-(6.7-dimethoxy-1-isoquinolinyl)phenyldisulfide
Produktet fra trinn d) ovenfor (1,14 g) og og trifluoreddiksyreanhydrid (0,98 ml) ble behandlet i CH2C12(20 ml) opp-løsning med tilbakeløp i 1 time. Oppløsningsmiddelet ble inndampet, og den resulterende gummien ble oppvarmet i trietylamin (5 ml) og metanol (25 ml) under tilbakeløp i 1 time. Oppløsningsmiddelet ble fjernet, og resten kromatografert (etylacetat/petroleumeter) hvilket ga undertittelforblndelsen som et hvitt, faststoff, MS 593 (M + 1, 5%), 296 (10056). The product from step d) above (1.14 g) and trifluoroacetic anhydride (0.98 ml) was treated in CH 2 Cl 2 (20 ml) solution at reflux for 1 hour. The solvent was evaporated and the resulting gum was heated in triethylamine (5 mL) and methanol (25 mL) under reflux for 1 hour. The solvent was removed and the residue chromatographed (ethyl acetate/petroleum ether) to give the sub-title compound as a white solid, MS 593 (M + 1.5%), 296 (10056).
f) 2- f 2-( 6. 7- dimetoksv- l- isokinolinyl) fenylti ol- lH- benzimidazol f) 2-f 2-(6.7-dimethoxy-1-isoquinolinyl)phenylthiol-1H-benzimidazole
Produktet fra trinn e) ovenfor (59 mg) ble oppvarmet med natriumcyanborhydrid (6 mg) i nærvær av 2-klorbenzimidazol (31 mg) i eddiksyre (1 ml) og isopropanol (5 ml) i 1 time under nitrogen ved 80°. Produktet ble nøytralisert med vandig NaHC03og ekstrahert med etylacetat, hvilket ga undertittelforblndelsen som et faststoff, MS 413 (M, 70%), 296 (10056). The product from step e) above (59 mg) was heated with sodium cyanoborohydride (6 mg) in the presence of 2-chlorobenzimidazole (31 mg) in acetic acid (1 ml) and isopropanol (5 ml) for 1 hour under nitrogen at 80°. The product was neutralized with aqueous NaHCO 3 and extracted with ethyl acetate to give the subtitle compound as a solid, MS 413 (M, 70%), 296 (10056).
g) 2 - f 2-( 6. 7- dimetoksv- l- isokinolinvl ) fenylsulfinyl1 - 1H-benzimidazol g) 2 - f 2-(6.7-dimethoxy-1-isoquinolinyl)phenylsulfinyl1-1H-benzimidazole
Produktet fra trinn f) ovenfor ble oppløst i 1:1•CH2C12-CHC13(10 ml), behandlet med 8556 m-klorperbenzoesyre (24 mg) ved —5°, og opparbeidet i vandig NaHC03til dannelse av tittelforbindelsen, NMR (CDCl3)d, 8,5 (d, 1H), 8,35 (dd, 1H), 7,26 (1H, s), 7,21 (1H, s), 7,7-7,2 (kompleks, 8H), 4,30 (s, 3H), 3,85 (s, 3H) ppm, smp. 250° (d). The product from step f) above was dissolved in 1:1•CH2Cl2-CHCl3 (10 mL), treated with 8556 m-chloroperbenzoic acid (24 mg) at -5°, and worked up in aqueous NaHCO3 to give the title compound, NMR (CDCl3)d , 8.5 (d, 1H), 8.35 (dd, 1H), 7.26 (1H, s), 7.21 (1H, s), 7.7-7.2 (complex, 8H), 4.30 (s, 3H), 3.85 (s, 3H) ppm, m.p. 250° (d).
Eksempel 11 Example 11
2- f 2-( 4- metoksy- 2- pyridinvl)- 3- 1lenvlsul finyl1- lH- benzimidazol 2- f 2-( 4- methoxy- 2- pyridine )- 3- 1-phenylsulfinyl 1- 1H- benzimidazole
a) 4- metoksy- l- fenoksykarbonyl- 22-( 2- tienyl )- l. 2- dlhydro-pyridin a) 4-methoxy-1-phenoxycarbonyl-22-(2-thienyl)-1.2-dlhydro-pyridine
2-iodtiofen (21 g) ble omsatt med magnesium (2,43 g) i tørr dietyleter (200 ml) og et krystall av lod under tilbakeløp i en nitrogenatmosfære, i 1 time. Oppløsningen ble dekantert i en oppløsning av 4-metoksypyridin (7,94 g) i tørr tetrahydrofuran (200 ml) ved -225° under kraftig omrøring. Etter 5 min. ble fenylklorformiat (9,17 ml) tilsatt dråpevis, og blandingen fikk oppvarmes til romtemperatur natten over. Vandig opparbeidelse og etylacetat-ekstraksjon ga undertittelforblndelsen som en brun olje, MS (EI) 313 (M, 20$), 230 2-Iodothiophene (21 g) was reacted with magnesium (2.43 g) in dry diethyl ether (200 ml) and a crystal of lead under reflux in a nitrogen atmosphere for 1 hour. The solution was decanted into a solution of 4-methoxypyridine (7.94 g) in dry tetrahydrofuran (200 mL) at -225° with vigorous stirring. After 5 min. phenyl chloroformate (9.17 ml) was added dropwise and the mixture was allowed to warm to room temperature overnight. Aqueous work-up and ethyl acetate extraction gave the subtitle compound as a brown oil, MS (EI) 313 (M, 20$), 230
(7096) , 220 ( 10056 ). (7096) , 220 ( 10056 ).
b) 4- metoksy- 2-( 2- tienyl) pyridinb) 4-Methoxy-2-(2-thienyl)pyridine
Produktet fra trinn a) ovenfor (24 g) ble oppløst i toluen The product from step a) above (24 g) was dissolved in toluene
(240 ml) ved romtemperatur og behandlet med tetraklor-1,2-benzokinon (18,9 g) i en oppløsning av eddiksyre (90 ml) dråpevis i løpet av 1/2 time og omrørt natten over. Is ble tilsatt, og blandingen ble gjort basisk med 4056 vandig NaOH, hvilket ga et sort bunnfall. Blandingen ble filtrert, vasket med toluen, deretter CH2CI2. De kombinerte filtratene ble avkjølt, og ekstrahert med konsentrert HCl-syre (6 ganger 100 ml). Nøytralisering av den vandige oppløsningen med NaHC03(faststoff) og etylacetat-ekstraksjon og kromatografi ga undertittelforblndelsen smp. 43-45°. (240 ml) at room temperature and treated with tetrachloro-1,2-benzoquinone (18.9 g) in a solution of acetic acid (90 ml) dropwise over 1/2 hour and stirred overnight. Ice was added and the mixture was basified with 4056 aqueous NaOH, which gave a black precipitate. The mixture was filtered, washed with toluene, then CH 2 Cl 2 . The combined filtrates were cooled, and extracted with concentrated HCl acid (6 x 100 mL). Neutralization of the aqueous solution with NaHCO 3 (solid) and ethyl acetate extraction and chromatography gave the sub-title compound m.p. 43-45°.
c) 4- metoksy- 2-( 3- metyltio- 2- tienylIpyridinc) 4-Methoxy-2-(3-methylthio-2-thienylpyridine).
Produktet fra trinn b) ovenfor (5 g) oppløst i tørr dietyleter (100 ml) ble avkjølt til -50° og behandlet med butyllitium i heksan (2,2 M, 13 ml) dråpevis i løpet av 1/2 time. Blandingen ble oppvarmet til -10° i 10 min., deretter avkjølt til -30°. Dimetylsulfid (3,5 ml) ble deretter tilsatt dråpevis. Blandingen ble holdt ved -30° i 1/2 time, deretter oppvarmet til romtemperatur i løpet av flere timer. Vandig opparbeidelse og etylacetat-ekstraksjon ga undertittelforblndelsen som en olje. The product from step b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyllithium in hexane (2.2 M, 13 ml) dropwise over 1/2 hour. The mixture was heated to -10° for 10 min., then cooled to -30°. Dimethyl sulfide (3.5 mL) was then added dropwise. The mixture was kept at -30° for 1/2 hour, then warmed to room temperature over several hours. Aqueous work-up and ethyl acetate extraction gave the subtitle compound as an oil.
d) 4- metoksy- 2-( 3- metylsulfInyl- 2- tienyl) pyridind) 4- methoxy- 2-( 3- methylsulfInyl- 2- thienyl) pyridine
Produktet fra trinn c) ovenfor ble oppløst i etylacetat (100 The product from step c) above was dissolved in ethyl acetate (100
ml) og avkjølt til -10°. m-klorperbenzoesyre (2,98 g) ble tilsatt, og etter 1,5 timer ble blandingen opparbeidet og deretter kromatografert (etylacetat) for oppnåelse av undertittelforblndelsen som et faststoff, smp. 103-105°). ml) and cooled to -10°. m-chloroperbenzoic acid (2.98 g) was added and after 1.5 hours the mixture was worked up and then chromatographed (ethyl acetate) to give the sub-title compound as a solid, m.p. 103-105°).
e) r2-( 4- metoksv- 2- pyridinyl)- 3- t1envlldi sulfide) r2-(4-Methoxys-2-pyridinyl)-3- trienyl disulfide
Produktet fra trinn d) ovenfor (1,61 g) og trifluoreddiksyreanhydrid (1,79 ml) ble oppvarmet under tilbakeløp i diklormetan (50 ml), hvilket ga et rikelig hvitt bunnfall i løpet av 1,5 timer. Oppløsningsmiddelet ble inndampet og resten oppvarmet under tilbakeløp med metanol (10 ml) og trietylamin (10 ml) i 0,5 timer. Inndampning til tørrhet i vakuum, vandig opparbeidelse, ekstraksjon i etylacetat og kromatografl ga undertittelforblndelsen som en gummi. MS (FAB) 445 (M +1), 5%), 222 (100$). The product from step d) above (1.61 g) and trifluoroacetic anhydride (1.79 ml) were heated under reflux in dichloromethane (50 ml) to give an abundant white precipitate over 1.5 hours. The solvent was evaporated and the residue heated under reflux with methanol (10 mL) and triethylamine (10 mL) for 0.5 h. Evaporation to dryness in vacuo, aqueous workup, extraction into ethyl acetate and chromatography gave the sub-title compound as a gum. MS (FAB) 445 (M +1), 5%), 222 ($100).
f) 2- r2-( 4- metoksv- 2- pyridinvl)- 3- tlenvltiol- lH- benzimldazol f) 2- r2-(4- methoxy-2- pyridine )- 3- ethylene thiol- 1H- benzimildazole
Produktet fra trinn e) ovenfor ble omsatt med natriumcyanborhydrid (0,236 g) og 2-klorbenzimidazol (1,14 g) i isopropanol (20 ml) og eddiksyre (5 ml) ved 80° i 1 time. Avkjøling, NaHCOs-opparbeidelse, etylacetat-ekstraksjon og vasking med dietyleter ga undertittelforblndelsen som et hvitt faststoff, MS (EI) 339 (M, 100$), 306 ( 80%). The product from step e) above was reacted with sodium cyanoborohydride (0.236 g) and 2-chlorobenzimidazole (1.14 g) in isopropanol (20 ml) and acetic acid (5 ml) at 80° for 1 hour. Cooling, NaHCO 3 workup, ethyl acetate extraction and washing with diethyl ether gave the sub-title compound as a white solid, MS (EI) 339 (M, 100$), 306 (80%).
g) 2- \ 2 -( 4- metoksv- 2- pyrldlnvl )- 3- tienvlsulf lnvll - lH- benzlmldazol g) 2- \ 2 -( 4- methoxy- 2-pyrrlidlnyl )- 3- thienylsulf lnyl - 1H- benzlmldazole
Produktet fra trinn f) ovenfor (1,25 g) ble oppløst i kloroform (500 ml). Den omrørte oppløsning ble avkjølt til -5°, og m-klorperbenzoesyre (85%, 0,75 g) ble tilsatt i porsjoner i løpet av 10 min. Etter 1 time ga NaHCOs-opparbeidelse og kromatografl tittelforbindelsen, smp. 192°. The product from step f) above (1.25 g) was dissolved in chloroform (500 ml). The stirred solution was cooled to -5° and m-chloroperbenzoic acid (85%, 0.75 g) was added portionwise over 10 min. After 1 hour, NaHCO 3 workup and chromatography gave the title compound, m.p. 192°.
Eksempel 12Example 12
Ved fremgangsmåter analoge med dem i eksempel 11 ble følgende forbindelser fremstilt: i ) 5-metyl -2- [ 3-(2-pyridinyltien-2-yl-tio]-lH-benzimidazol, MS m/e 323 (70%, M<+>) bp 290. By methods analogous to those in Example 11, the following compounds were prepared: i) 5-methyl-2-[3-(2-pyridinylthien-2-yl-thio]-1H-benzimidazole, MS m/e 323 (70%, M <+>) bp 290.
il) 5-metyl-2-[3-(2-pyridinyltien-2-yl-sulfinyl]-lH-benzlmldazol, smp. 100° (d). 11) 5-methyl-2-[3-(2-pyridinylthien-2-yl-sulfinyl]-1H-benzlmidazole, mp 100° (d).
Eksempel 13 Example 13
2- f 2 - ( 4- metoksy- 2- pyridinyl)- fenylsulfInyl1- lH- benzimldazol-5- amin 2- f 2 - ( 4- methoxy- 2- pyridinyl)- phenylsulfInyl 1- 1H- benzimldazol-5- amine
Forbindelsen 1 eksempel 5 b) il) ble hydrogenert over en 10% palladium-karbon-katalysator ved 3 atmosfærers trykk i etanol. Katalysatoren ble frafUtrert, og etanolen ble inndampet hvilket ga tittelforbindelsen, smp. 192-193°. The compound 1 example 5 b) 11) was hydrogenated over a 10% palladium-carbon catalyst at 3 atmospheres pressure in ethanol. The catalyst was filtered off and the ethanol was evaporated to give the title compound, m.p. 192-193°.
Eksempel 14 1 - \ 2 -\ 2 -( lH- 2- benzlmidazolvlsulfinyl) fenyl- 4- pyridinyloksvl-propan- 2- ol, (FAB ms M2+ +1). Example 14 1-\2-\2-(1H-2-benzylimidazolylsulfinyl)phenyl-4-pyridinyloxyl-propan-2-ol, (FAB ms M2+ +1).
Tittelforbindelsen ble oppnådd fra forbindelsen i eksempel 2 m) ovenfor ved bruk av en standard NaBE^/etanol-reduksjon. The title compound was obtained from the compound of Example 2 m) above using a standard NaBE 2 /ethanol reduction.
Eksempel 15 Example 15
2- ( 2- lH- benzimidazol- 2- yl- suIfinyl) fenylimidazoTl. 2- alpyridin 2-(2-1H-benzimidazol-2-yl-sulfinyl)phenylimidazoTl. 2- alpyridine
a) 2-( 2- bromfenyl Umldazofl . 2- alpyridina) 2-( 2- bromophenyl Umldazofl . 2- alpyridine
En oppløsning av 2-aminopyridin (1,63 g) og 2-brom-l-(2-brom-f enyl )-etanon (4,8 g) i tørr etanol (40 ml) ble oppvarmet under tilbakeløp i 1 time. Blandingen ble konsentrert i vakuum. Resten ble behandlet med fortynnet natrium-bikarbonatoppløsning og ekstrahert med etylacetat. Etylacetatet. Etylacetatet ble vasket med vann og saltoppløs-ning, deretter tørket og inndampet. Flammekromatografi ga undertittelforblndelsen som en lysegrå olje. MS MW 272/274 bp 272. A solution of 2-aminopyridine (1.63 g) and 2-bromo-1-(2-bromo-phenyl)-ethanone (4.8 g) in dry ethanol (40 ml) was heated under reflux for 1 hour. The mixture was concentrated in vacuo. The residue was treated with dilute sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate. The ethyl acetate was washed with water and brine, then dried and evaporated. Flame chromatography gave the subtitle compound as a light gray oil. MS MW 272/274 bp 272.
b) 2-( 2- metvItiofenyl Umldazofl . 2- alpyridinb) 2-(2-methylthiophenyl Umldazofl. 2-alpyridine
Produktet i trinn a) ovenfor (546 mg) ble oppløst i tørr eter The product in step a) above (546 mg) was dissolved in dry ether
(10 ml) og omrørt under en nitrogenatmosfære ve —60°. En oppløsning av n-butyllitium (1,25 ml av 1,6 M) ble tilsatt dråpevis. Etter omrøring i 5 min. ble metyldisulfid (179 ml) tilsatt dråpevis og blandingen omrørt i ytterligere 45 min. Blandingen fikk oppvarmes til romtemperatur og ble deretter bråkjølt med vann. Lagene ble separert, og det vandige laget ekstrahert med etylacetat. Den kombinerte organiske oppløs-ning ble vasket med vann og saltoppløsning, deretter tørket og inndampet til oppnåelse av undertittelforblndelsen som en gummi. MS MW 240 bp 207. (10 ml) and stirred under a nitrogen atmosphere at -60°. A solution of n-butyllithium (1.25 mL of 1.6 M) was added dropwise. After stirring for 5 min. methyl disulfide (179 ml) was added dropwise and the mixture stirred for a further 45 min. The mixture was allowed to warm to room temperature and was then quenched with water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic solution was washed with water and brine, then dried and evaporated to give the sub-title compound as a gum. MS MW 240 bp 207.
c ) 2-( 2- metylsulfinyl ) imidazol" l . 2- alpyridin c) 2-(2-methylsulfinyl)imidazole" 1.2-alpyridine
Undertittelforblndelsen ble fremstilt fra produktet fra trinn b) ovenfor ved bruk av en metode analog med den i eksempel 8 The subtitle compound was prepared from the product of step b) above using a method analogous to that of Example 8
c) ovenfor. MS MW 257 bp 78.c) above. MS MW 257 bp 78.
d) 2-( 2- lH- benzimidazol- 2- vl- tlo) fenvl- imidazo- ri. 2- alpyridin Undertittelforblndelsen ble fremstilt fra produktet fra trinn c) ovenfor ved bruk av en metode analog med den i eksempel 8 d) 2-(2-1H-benzimidazol-2-yl-tlo)phenylimidazolium. 2-alpyridine The subtitle compound was prepared from the product from step c) above using a method analogous to that in Example 8
d) ovenfor. MS MW 342 bp 225.d) above. MS MW 342 bp 225.
e ) 2 - ( 2- lH- benzimidazol- 2- yl- suIf inyl) fenyl- Imidazo- f 1. 2- al-<py>ridin e) 2 - (2-lH-benzimidazol-2-yl-suIfinyl)phenyl-Imidazo-f 1.2-al-<pyr>idine
Tittelforbindelsen ble fremstilt fra produktet fra trinn b) ovenfor ved bruk av en metode analog med den i eksempe 18 e) ovenfor. MS (FAB) M+ 1/bp 359. The title compound was prepared from the product of step b) above using a method analogous to that in Example 18 e) above. MS (FAB) M+ 1/bp 359.
Claims (14)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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GB868623301A GB8623301D0 (en) | 1986-09-27 | 1986-09-27 | Nitrogen heterocyclic compounds |
GB868623299A GB8623299D0 (en) | 1986-09-27 | 1986-09-27 | N heterocyclic compounds |
GB878705017A GB8705017D0 (en) | 1987-03-04 | 1987-03-04 | Biologically active compounds |
GB878719644A GB8719644D0 (en) | 1987-08-20 | 1987-08-20 | Compounds |
PCT/GB1987/000656 WO1988002367A1 (en) | 1986-09-27 | 1987-09-21 | Compounds |
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NO882321D0 NO882321D0 (en) | 1988-05-26 |
NO882321L true NO882321L (en) | 1988-07-11 |
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NO882321A NO882321L (en) | 1986-09-27 | 1988-05-26 | CONNECTIONS. |
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