NO316932B1 - Nye, substituerte 4-(1H-benzimidazol-2-yl)[1,4]diazepaner som er anvendbare for behandling av allergiske sykdommer, fremgangsmate for fremstilling av disse, samt farmasoytisk preparat inneholdende disse - Google Patents

Info

Publication number

NO316932B1

NO316932B1 NO19982867A NO982867A NO316932B1 NO 316932 B1 NO316932 B1 NO 316932B1 NO 19982867 A NO19982867 A NO 19982867A NO 982867 A NO982867 A NO 982867A NO 316932 B1 NO316932 B1 NO 316932B1

Authority

NO

Norway

Prior art keywords

ethyl

diazepan

benzimidazol

mixture

trimethoxybenzoyl

Prior art date

1995-12-20

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• 238000000034 method Methods 0.000 title claims description 127
• 238000011282 treatment Methods 0.000 title claims description 6
• SSPVIXHPLKDPNO-UHFFFAOYSA-N 2-(1,4-diazepan-1-yl)-1h-benzimidazole Chemical class C1CCNCCN1C1=NC2=CC=CC=C2N1 SSPVIXHPLKDPNO-UHFFFAOYSA-N 0.000 title description 12
• 208000026935 allergic disease Diseases 0.000 title 1
• 239000008194 pharmaceutical composition Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 331
• 238000006243 chemical reaction Methods 0.000 claims description 246
• 239000000203 mixture Substances 0.000 claims description 151
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 150
• -1 [1,4 ] diazepan-1-yl Chemical group 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 61
• 239000001257 hydrogen Substances 0.000 claims description 61
• 150000003839 salts Chemical class 0.000 claims description 51
• 238000010511 deprotection reaction Methods 0.000 claims description 45
• 125000001424 substituent group Chemical group 0.000 claims description 34
• 239000002253 acid Substances 0.000 claims description 27
• 150000002431 hydrogen Chemical class 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 22
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
• 229910052794 bromium Inorganic materials 0.000 claims description 22
• 150000003254 radicals Chemical class 0.000 claims description 22
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
• 239000000460 chlorine Substances 0.000 claims description 20
• 229910052801 chlorine Inorganic materials 0.000 claims description 20
• 230000004048 modification Effects 0.000 claims description 20
• 238000012986 modification Methods 0.000 claims description 20
• 150000008064 anhydrides Chemical class 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 19
• 238000004519 manufacturing process Methods 0.000 claims description 19
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 238000002360 preparation method Methods 0.000 claims description 13
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
• 239000012279 sodium borohydride Substances 0.000 claims description 12
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 8
• 239000003638 chemical reducing agent Substances 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
• RFKYZHFDFJPEPT-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 RFKYZHFDFJPEPT-UHFFFAOYSA-N 0.000 claims description 5
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• 101100135641 Caenorhabditis elegans par-3 gene Proteins 0.000 claims description 4
• 229940077388 benzenesulfonate Drugs 0.000 claims description 4
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 4
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 4
• WXZSZKPIXPCMTD-UHFFFAOYSA-N 3-[(3,4-difluorophenyl)methyl]-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-1-[(3,4,5-trimethoxyphenyl)methyl]pyrrolidin-2-one Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC1(C(N(CC=2C=C(OC)C(OC)=C(OC)C=2)CC1)=O)CC1=CC=C(F)C(F)=C1 WXZSZKPIXPCMTD-UHFFFAOYSA-N 0.000 claims description 3
• 240000007594 Oryza sativa Species 0.000 claims description 3
• 235000007164 Oryza sativa Nutrition 0.000 claims description 3
• SAUXWHNQZGRIIC-UHFFFAOYSA-N [3-(3,4-difluorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=C(F)C(F)=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 SAUXWHNQZGRIIC-UHFFFAOYSA-N 0.000 claims description 3
• CKJWDRCOINXTPB-UHFFFAOYSA-N [3-(4-chlorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC(Cl)=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 CKJWDRCOINXTPB-UHFFFAOYSA-N 0.000 claims description 3
• RDLDOILLOPYFGK-UHFFFAOYSA-N [3-[2-[4-(1h-benzimidazol-2-yl)-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3NC4=CC=CC=C4N=3)(CC2)C=2C=CC=CC=2)=C1 RDLDOILLOPYFGK-UHFFFAOYSA-N 0.000 claims description 3
• CHWPRGXFKHYEAZ-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-(4-fluorophenyl)pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC(F)=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 CHWPRGXFKHYEAZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 3
• OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims description 3
• 235000009566 rice Nutrition 0.000 claims description 3
• XCUKQQFNXCTPKV-UHFFFAOYSA-N (2-chloro-3,4,5-trimethoxyphenyl)-[3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1Cl XCUKQQFNXCTPKV-UHFFFAOYSA-N 0.000 claims description 2
• MCYNDCPMZCHETH-UHFFFAOYSA-N 1-[2-[4-[2-[3-phenyl-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl]-1,4-diazepan-1-yl]benzimidazol-1-yl]butan-2-one Chemical compound N=1C2=CC=CC=C2N(CC(=O)CC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 MCYNDCPMZCHETH-UHFFFAOYSA-N 0.000 claims description 2
• YFOZHOALDVPSCM-UHFFFAOYSA-N 2-[2-[2-[4-[2-[3-phenyl-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl]-1,4-diazepan-1-yl]benzimidazol-1-yl]ethoxy]acetonitrile Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCOCC#N)(CC2)C=2C=CC=CC=2)=C1 YFOZHOALDVPSCM-UHFFFAOYSA-N 0.000 claims description 2
• QRIQVAGSZXBMPC-ZBJGQNTJSA-N 3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-[(4-fluorophenyl)methyl]-1-[(1r)-1-phenylethyl]pyrrolidin-2-one Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC1(C(N([C@H](C)C=2C=CC=CC=2)CC1)=O)CC1=CC=C(F)C=C1 QRIQVAGSZXBMPC-ZBJGQNTJSA-N 0.000 claims description 2
• QRIQVAGSZXBMPC-VFIQEOMOSA-N 3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-[(4-fluorophenyl)methyl]-1-[(1s)-1-phenylethyl]pyrrolidin-2-one Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC1(C(N([C@@H](C)C=2C=CC=CC=2)CC1)=O)CC1=CC=C(F)C=C1 QRIQVAGSZXBMPC-VFIQEOMOSA-N 0.000 claims description 2
• NXVLXBRCKGYQRR-UHFFFAOYSA-N 3-[2-[4-[2-[3-phenyl-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl]-1,4-diazepan-1-yl]benzimidazol-1-yl]propanenitrile Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCC#N)(CC2)C=2C=CC=CC=2)=C1 NXVLXBRCKGYQRR-UHFFFAOYSA-N 0.000 claims description 2
• CYEJYQYMNAWMDF-UHFFFAOYSA-N 4-[2-[3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidine-1-carbonyl]-4-(tetrazol-1-yl)phenoxy]butanoic acid Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C(C(=CC=1)OCCCC(O)=O)=CC=1N1C=NN=N1 CYEJYQYMNAWMDF-UHFFFAOYSA-N 0.000 claims description 2
• AHFBTVBTLLBINR-UHFFFAOYSA-N 5-[2-[4-[2-[3-phenyl-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl]-1,4-diazepan-1-yl]benzimidazol-1-yl]pentan-2-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCCC(C)=O)(CC2)C=2C=CC=CC=2)=C1 AHFBTVBTLLBINR-UHFFFAOYSA-N 0.000 claims description 2
• ZSMNNWKALKDIKN-UHFFFAOYSA-N 5-[2-[4-[2-[3-phenyl-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl]ethyl]-1,4-diazepan-1-yl]benzimidazol-1-yl]pentanenitrile Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCCCC#N)(CC2)C=2C=CC=CC=2)=C1 ZSMNNWKALKDIKN-UHFFFAOYSA-N 0.000 claims description 2
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 2
• 206010047700 Vomiting Diseases 0.000 claims description 2
• ZMARBXADMQOCSV-KXQOOQHDSA-N [(3s)-3-(3,4-dichlorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound C([C@@](C1)(CCN2CCCN(CC2)C=2N(C3=CC=CC=C3N=2)CCOCC)C=2C=C(Cl)C(Cl)=CC=2)CN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZMARBXADMQOCSV-KXQOOQHDSA-N 0.000 claims description 2
• SBGLREZUTSQVPN-UHFFFAOYSA-N [3-(3,4-dichlorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]piperidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=C(Cl)C(Cl)=CC=2)CCCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 SBGLREZUTSQVPN-UHFFFAOYSA-N 0.000 claims description 2
• OPGPQAWKHQEUSA-UHFFFAOYSA-N [3-(3-chlorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=C(Cl)C=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 OPGPQAWKHQEUSA-UHFFFAOYSA-N 0.000 claims description 2
• YHDAHMNTKULNGJ-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-[2-methoxy-5-(tetrazol-1-yl)phenyl]methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C(C(=CC=1)OC)=CC=1N1C=NN=N1 YHDAHMNTKULNGJ-UHFFFAOYSA-N 0.000 claims description 2
• UUXMGPXBUMDKJQ-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-[2-methoxy-5-(triazol-1-ylmethyl)phenyl]methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C(C(=CC=1)OC)=CC=1CN1C=CN=N1 UUXMGPXBUMDKJQ-UHFFFAOYSA-N 0.000 claims description 2
• GQSLLCRQRGADDF-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-[2-methoxy-5-(trifluoromethyl)phenyl]methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC(C(F)(F)F)=CC=C1OC GQSLLCRQRGADDF-UHFFFAOYSA-N 0.000 claims description 2
• ZNPLPTSEFKCQNB-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-[2-methylsulfanyl-5-(tetrazol-1-yl)phenyl]methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C(C(=CC=1)SC)=CC=1N1C=NN=N1 ZNPLPTSEFKCQNB-UHFFFAOYSA-N 0.000 claims description 2
• PLCYLSKFQRJCRP-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-phenylmethanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC=CC=C1 PLCYLSKFQRJCRP-UHFFFAOYSA-N 0.000 claims description 2
• GJJNPNNGTFLNJD-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-pyridin-4-ylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CN=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 GJJNPNNGTFLNJD-UHFFFAOYSA-N 0.000 claims description 2
• ZOOYUVSSGKSGKJ-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethylsulfonylethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCS(=O)(=O)CC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZOOYUVSSGKSGKJ-UHFFFAOYSA-N 0.000 claims description 2
• DOJRHSVIXXANQC-UHFFFAOYSA-N [3-[2-[4-[1-(2-hydroxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCO)(CC2)C=2C=CC=CC=2)=C1 DOJRHSVIXXANQC-UHFFFAOYSA-N 0.000 claims description 2
• GAZMPNPSQMOVPQ-UHFFFAOYSA-N [3-[2-[4-[1-(2-imidazol-1-ylethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCN3C=NC=C3)(CC2)C=2C=CC=CC=2)=C1 GAZMPNPSQMOVPQ-UHFFFAOYSA-N 0.000 claims description 2
• GLSKITZPWCZDLE-UHFFFAOYSA-N [3-[2-[4-[1-(2-methylsulfonylethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCS(C)(=O)=O)(CC2)C=2C=CC=CC=2)=C1 GLSKITZPWCZDLE-UHFFFAOYSA-N 0.000 claims description 2
• MWVHPUBICNZZOR-UHFFFAOYSA-N [3-[2-[4-[1-[2-(benzenesulfonyl)ethyl]benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCS(=O)(=O)C=3C=CC=CC=3)(CC2)C=2C=CC=CC=2)=C1 MWVHPUBICNZZOR-UHFFFAOYSA-N 0.000 claims description 2
• MMNHCGLEGXMYBE-UHFFFAOYSA-N [3-[2-[4-[1-[[5-(hydroxymethyl)furan-2-yl]methyl]benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CC=3OC(CO)=CC=3)(CC2)C=2C=CC=CC=2)=C1 MMNHCGLEGXMYBE-UHFFFAOYSA-N 0.000 claims description 2
• KXDXHHKCFVHMNH-UHFFFAOYSA-N [3-phenyl-3-[2-[4-[1-[2-(tetrazol-1-yl)ethyl]benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCN3N=NN=C3)(CC2)C=2C=CC=CC=2)=C1 KXDXHHKCFVHMNH-UHFFFAOYSA-N 0.000 claims description 2
• AWRGBRHYXFQLEB-UHFFFAOYSA-N [3-phenyl-3-[2-[4-[1-[2-(triazol-1-yl)ethyl]benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCN3CCN(CCC3)C=3N(C4=CC=CC=C4N=3)CCN3N=NC=C3)(CC2)C=2C=CC=CC=2)=C1 AWRGBRHYXFQLEB-UHFFFAOYSA-N 0.000 claims description 2
• 201000010105 allergic rhinitis Diseases 0.000 claims description 2
• 208000006673 asthma Diseases 0.000 claims description 2
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
• LRLBCDJTDVPXHY-UHFFFAOYSA-N ethyl 4-[2-[3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidine-1-carbonyl]-4-(tetrazol-1-yl)phenoxy]butanoate Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C(C(=CC=1)OCCCC(=O)OCC)=CC=1N1C=NN=N1 LRLBCDJTDVPXHY-UHFFFAOYSA-N 0.000 claims description 2
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• ZUWHCJWMBMIFAY-UHFFFAOYSA-N 3-[[3,5-bis(trifluoromethyl)phenyl]methyl]-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-1-[(2-methoxyphenyl)methyl]pyrrolidin-2-one Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC1(C(N(CC=2C(=CC=CC=2)OC)CC1)=O)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 ZUWHCJWMBMIFAY-UHFFFAOYSA-N 0.000 claims 1
• KVMGXCDXSRDYNR-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-pyridin-3-ylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=NC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 KVMGXCDXSRDYNR-UHFFFAOYSA-N 0.000 claims 1
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 46
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• 238000001704 evaporation Methods 0.000 description 34
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• 238000000605 extraction Methods 0.000 description 32
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• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
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• KCCFLPBATGOEJM-UHFFFAOYSA-N 2-(1,4-diazepan-1-yl)-1-(2-ethoxyethyl)benzimidazole Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCNCC1 KCCFLPBATGOEJM-UHFFFAOYSA-N 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 239000012267 brine Substances 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• BUHYMJLFRZAFBF-UHFFFAOYSA-N 3,4,5-trimethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=CC(OC)=C1OC BUHYMJLFRZAFBF-UHFFFAOYSA-N 0.000 description 19
• 238000000921 elemental analysis Methods 0.000 description 19
• 150000001298 alcohols Chemical class 0.000 description 18
• 239000007858 starting material Substances 0.000 description 18
• GGNMTJKRHHLJHH-UHFFFAOYSA-N 3,4,5-trimethoxybenzamide Chemical compound COC1=CC(C(N)=O)=CC(OC)=C1OC GGNMTJKRHHLJHH-UHFFFAOYSA-N 0.000 description 17
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 17
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
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• 125000003118 aryl group Chemical group 0.000 description 16
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• 239000000543 intermediate Substances 0.000 description 16
• CCIUQRKCMXXTOI-WOJBJXKFSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid Chemical class C1=CC(OC)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(OC)C=C1 CCIUQRKCMXXTOI-WOJBJXKFSA-N 0.000 description 15
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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• FDAVBROYKQZBTA-GZJHNZOKSA-N (2r,3r)-2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid;2-(3-phenylpyrrolidin-3-yl)ethanol Chemical compound C=1C=CC=CC=1C1(CCO)CCNC1.C1=CC(OC)=CC=C1C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)C1=CC=C(OC)C=C1 FDAVBROYKQZBTA-GZJHNZOKSA-N 0.000 description 13
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• PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 13
• HNJBEVLQSNELDL-UHFFFAOYSA-N gamma-butyrolactam Natural products O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
• 229910000029 sodium carbonate Inorganic materials 0.000 description 13
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• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 12
• WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 12
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• 238000004458 analytical method Methods 0.000 description 11
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• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
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• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
• 230000002829 reductive effect Effects 0.000 description 10
• 239000012047 saturated solution Substances 0.000 description 10
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 10
• 238000012546 transfer Methods 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 9
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• 239000003795 chemical substances by application Substances 0.000 description 9
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• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• JBGZJQULYGMJGT-UHFFFAOYSA-N 2-(3-phenylpyrrolidin-3-yl)ethanol Chemical compound C=1C=CC=CC=1C1(CCO)CCNC1 JBGZJQULYGMJGT-UHFFFAOYSA-N 0.000 description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
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• 150000002148 esters Chemical class 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 239000012280 lithium aluminium hydride Substances 0.000 description 8
• 238000005192 partition Methods 0.000 description 8
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 8
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
• 150000001350 alkyl halides Chemical group 0.000 description 7
• 230000029936 alkylation Effects 0.000 description 7
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• 229910052740 iodine Inorganic materials 0.000 description 7
• 229940087646 methanolamine Drugs 0.000 description 7
• 229910052757 nitrogen Inorganic materials 0.000 description 7
• YANKKIREMROGSD-GZJHNZOKSA-N 2-[3-(3,4-difluorophenyl)pyrrolidin-3-yl]ethanol (2R,3R)-2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid Chemical compound OCCC1(CCNC1)c1ccc(F)c(F)c1.COc1ccc(cc1)C(=O)[C@@](O)(C(O)=O)[C@](O)(C(O)=O)C(=O)c1ccc(OC)cc1 YANKKIREMROGSD-GZJHNZOKSA-N 0.000 description 6
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• 239000003054 catalyst Substances 0.000 description 6
• MMMBNFVTJSJJNN-UHFFFAOYSA-N ethyl 2-[3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(Cl)C(Cl)=CC=1C1(CC(=O)OCC)CNC(=O)C1 MMMBNFVTJSJJNN-UHFFFAOYSA-N 0.000 description 6
• 239000011630 iodine Substances 0.000 description 6
• WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 6
• JHJNPOSPVGRIAN-SFHVURJKSA-N n-[3-[(1s)-1-[[6-(3,4-dimethoxyphenyl)pyrazin-2-yl]amino]ethyl]phenyl]-5-methylpyridine-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN=CC(N[C@@H](C)C=2C=C(NC(=O)C=3C=C(C)C=NC=3)C=CC=2)=N1 JHJNPOSPVGRIAN-SFHVURJKSA-N 0.000 description 6
• SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 6
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
• 238000006268 reductive amination reaction Methods 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 5
• CJMMVDBUGOAMFU-WKTGHYETSA-N 2-[(3S)-3-(3,4-dichlorophenyl)pyrrolidin-3-yl]ethanol (2R,3R)-2,3-dihydroxy-2,3-bis(4-methoxybenzoyl)butanedioic acid Chemical compound C(C1=CC=C(C=C1)OC)(=O)[C@@]([C@@](C(=O)O)(O)C(C1=CC=C(C=C1)OC)=O)(O)C(=O)O.ClC=1C=C(C=CC1Cl)[C@@]1(CNCC1)CCO CJMMVDBUGOAMFU-WKTGHYETSA-N 0.000 description 5
• AIQPWDHVCUXRBI-UHFFFAOYSA-N 2-chloro-1-(2-ethoxyethyl)benzimidazole Chemical compound C1=CC=C2N(CCOCC)C(Cl)=NC2=C1 AIQPWDHVCUXRBI-UHFFFAOYSA-N 0.000 description 5
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 5
• OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
• 239000007832 Na2SO4 Substances 0.000 description 5
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
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• 230000008485 antagonism Effects 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
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