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

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 Download PDF

Info

Publication number: NO316932B1
Authority: NO; Norway
Prior art keywords: ethyl; diazepan; benzimidazol; mixture; trimethoxybenzoyl
Prior art date: 1995-12-20

Application number

NO19982867A

Other languages

English (en)

Norwegian (no)

Other versions

NO982867L (no

NO982867D0 (no

Inventor

John Michael Kane

George Daniel Maynard

Timothy Paul Burkholder

Larry Don Bratton

Christopher Robin Dalton

Braulio Santiago

Elizabeth Mary Kudlacz

Original Assignee

Aventis Pharma Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-12-20

Filing date

1998-06-19

Publication date

2004-06-28

1998-06-19 Application filed by Aventis Pharma Inc filed Critical Aventis Pharma Inc

1998-06-19 Publication of NO982867D0 publication Critical patent/NO982867D0/no

1998-08-19 Publication of NO982867L publication Critical patent/NO982867L/no

2004-06-28 Publication of NO316932B1 publication Critical patent/NO316932B1/no

Links

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
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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
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
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UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 73
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239000007787 solid Substances 0.000 description 60
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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
239000010410 layer Substances 0.000 description 43
239000012467 final product Substances 0.000 description 40
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125000006239 protecting group Chemical group 0.000 description 37
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238000004587 chromatography analysis Methods 0.000 description 34
238000001704 evaporation Methods 0.000 description 34
230000008020 evaporation Effects 0.000 description 34
239000000047 product Substances 0.000 description 34
238000001953 recrystallisation Methods 0.000 description 34
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238000001665 trituration Methods 0.000 description 27
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235000011114 ammonium hydroxide Nutrition 0.000 description 26
239000002585 base Substances 0.000 description 26
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
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239000000706 filtrate Substances 0.000 description 25
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
238000001914 filtration Methods 0.000 description 23
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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
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 16
125000003118 aryl group Chemical group 0.000 description 16
235000011089 carbon dioxide Nutrition 0.000 description 16
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
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 14
239000002168 alkylating agent Substances 0.000 description 14
229940100198 alkylating agent Drugs 0.000 description 14
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
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
239000007868 Raney catalyst Substances 0.000 description 13
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-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
235000017550 sodium carbonate Nutrition 0.000 description 13
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
239000012359 Methanesulfonyl chloride Substances 0.000 description 11
238000004458 analytical method Methods 0.000 description 11
238000004128 high performance liquid chromatography Methods 0.000 description 11
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
235000011181 potassium carbonates Nutrition 0.000 description 11
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
239000003153 chemical reaction reagent Substances 0.000 description 9
239000003795 chemical substances by application Substances 0.000 description 9
230000014759 maintenance of location Effects 0.000 description 9
239000012312 sodium hydride Substances 0.000 description 9
229910000104 sodium hydride Inorganic materials 0.000 description 9
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
229960000583 acetic acid Drugs 0.000 description 8
238000005804 alkylation reaction Methods 0.000 description 8
235000019270 ammonium chloride Nutrition 0.000 description 8
238000001035 drying Methods 0.000 description 8
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
239000001530 fumaric acid Substances 0.000 description 7
235000011087 fumaric acid Nutrition 0.000 description 7
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
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
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
229910021529 ammonia Inorganic materials 0.000 description 5
230000008485 antagonism Effects 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 5
MOLWDHUTJGGDTJ-UHFFFAOYSA-N diethyl 3-cyano-3-(3,4-dichlorophenyl)pentanedioate Chemical compound CCOC(=O)CC(CC(=O)OCC)(C#N)C1=CC=C(Cl)C(Cl)=C1 MOLWDHUTJGGDTJ-UHFFFAOYSA-N 0.000 description 5
VFIQYNCJSDGNGB-UHFFFAOYSA-N diethyl 3-cyano-3-phenylpentanedioate Chemical compound CCOC(=O)CC(CC(=O)OCC)(C#N)C1=CC=CC=C1 VFIQYNCJSDGNGB-UHFFFAOYSA-N 0.000 description 5
150000002825 nitriles Chemical class 0.000 description 5
229910052938 sodium sulfate Inorganic materials 0.000 description 5
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PNPWFQMQFAWMEH-DIPNUNPCSA-N [(3s)-3-(3,4-dichlorophenyl)-3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]pyrrolidin-1-yl]-[2-methoxy-5-(tetrazol-1-yl)phenyl]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)C(C(=CC=1)OC)=CC=1N1C=NN=N1 PNPWFQMQFAWMEH-DIPNUNPCSA-N 0.000 description 1
MVICKKNUVLVVRA-UHFFFAOYSA-N [3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCO)(CCC2)C=2C=C(Cl)C(Cl)=CC=2)=C1 MVICKKNUVLVVRA-UHFFFAOYSA-N 0.000 description 1
XQHDASACUQCJFW-UHFFFAOYSA-N [3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCO)(CC2)C=2C=C(F)C(F)=CC=2)=C1 XQHDASACUQCJFW-UHFFFAOYSA-N 0.000 description 1
KSWWJJRYXIWDIE-UHFFFAOYSA-N [3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCO)(CC2)C=2C=C(C)C(C)=CC=2)=C1 KSWWJJRYXIWDIE-UHFFFAOYSA-N 0.000 description 1
TXOBRLRNUKKOEA-UHFFFAOYSA-N [3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCO)(CC2)C=2C=C(Cl)C=CC=2)=C1 TXOBRLRNUKKOEA-UHFFFAOYSA-N 0.000 description 1
ZLTRYJQRMNFZFN-UHFFFAOYSA-N [3-(4-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2CC(CCO)(CC2)C=2C=CC(Cl)=CC=2)=C1 ZLTRYJQRMNFZFN-UHFFFAOYSA-N 0.000 description 1
RLYUHVGBHXBKEV-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(2,3,4-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2C=CC=CC=2)CCN1C(=O)C1=CC=C(OC)C(OC)=C1OC RLYUHVGBHXBKEV-UHFFFAOYSA-N 0.000 description 1
HNQXIRWVVYFZIH-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-phenylpyrrolidin-1-yl]-(4-hydroxy-3,5-dimethoxyphenyl)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(O)C(OC)=C1 HNQXIRWVVYFZIH-UHFFFAOYSA-N 0.000 description 1
UHNGIHDFFCOBJX-UHFFFAOYSA-N [3-[2-[4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepan-1-yl]ethyl]-3-pyridin-2-ylpyrrolidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N(CC1)CCCN1CCC(C1)(C=2N=CC=CC=2)CCN1C(=O)C1=CC(OC)=C(OC)C(OC)=C1 UHNGIHDFFCOBJX-UHFFFAOYSA-N 0.000 description 1
VVBFKFMUDZYPBX-UHFFFAOYSA-N [3-phenyl-3-[2-[4-[1-[4-(2h-tetrazol-5-yl)butyl]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)CCCCC=3NN=NN=3)(CC2)C=2C=CC=CC=2)=C1 VVBFKFMUDZYPBX-UHFFFAOYSA-N 0.000 description 1
241000179532 [Candida] cylindracea Species 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
230000009471 action Effects 0.000 description 1
125000002723 alicyclic group Chemical group 0.000 description 1
125000001931 aliphatic group Chemical group 0.000 description 1
229910000272 alkali metal oxide Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
230000007815 allergy Effects 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
239000007900 aqueous suspension Substances 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
239000011668 ascorbic acid Substances 0.000 description 1
229960005070 ascorbic acid Drugs 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
IUKQLMGVFMDQDP-UHFFFAOYSA-N azane;piperidine Chemical compound N.C1CCNCC1 IUKQLMGVFMDQDP-UHFFFAOYSA-N 0.000 description 1
RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
235000010233 benzoic acid Nutrition 0.000 description 1
230000031018 biological processes and functions Effects 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
206010006451 bronchitis Diseases 0.000 description 1
239000000872 buffer Substances 0.000 description 1
244000309464 bull Species 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
239000004202 carbamide Substances 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
229960004424 carbon dioxide Drugs 0.000 description 1
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
210000004027 cell Anatomy 0.000 description 1
235000013985 cinnamic acid Nutrition 0.000 description 1
229930016911 cinnamic acid Natural products 0.000 description 1
235000015165 citric acid Nutrition 0.000 description 1
GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 1
YTKRILODNOEEPX-NSCUHMNNSA-N crotyl chloride Chemical compound C\C=C\CCl YTKRILODNOEEPX-NSCUHMNNSA-N 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
239000008367 deionised water Substances 0.000 description 1
229910021641 deionized water Inorganic materials 0.000 description 1
XLMBIZDYYVRQHQ-UHFFFAOYSA-N diethyl 3-(3-chlorophenyl)-3-cyanopentanedioate Chemical compound CCOC(=O)CC(CC(=O)OCC)(C#N)C1=CC=CC(Cl)=C1 XLMBIZDYYVRQHQ-UHFFFAOYSA-N 0.000 description 1
FJOJDRNZFVUZKE-UHFFFAOYSA-N diethyl 3-cyano-3-(3,4-difluorophenyl)pentanedioate Chemical compound CCOC(=O)CC(CC(=O)OCC)(C#N)C1=CC=C(F)C(F)=C1 FJOJDRNZFVUZKE-UHFFFAOYSA-N 0.000 description 1
OUWSNHWQZPEFEX-UHFFFAOYSA-N diethyl glutarate Chemical compound CCOC(=O)CCCC(=O)OCC OUWSNHWQZPEFEX-UHFFFAOYSA-N 0.000 description 1
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
230000000694 effects Effects 0.000 description 1
239000012039 electrophile Substances 0.000 description 1
230000002255 enzymatic effect Effects 0.000 description 1
UJTPZISIAWDGFF-UHFFFAOYSA-N ethenylsulfonylbenzene Chemical compound C=CS(=O)(=O)C1=CC=CC=C1 UJTPZISIAWDGFF-UHFFFAOYSA-N 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
QQOVRPBUAUNBAV-UHFFFAOYSA-N ethyl 2-(chloromethyl)benzoate Chemical compound CCOC(=O)C1=CC=CC=C1CCl QQOVRPBUAUNBAV-UHFFFAOYSA-N 0.000 description 1
SFMRJRPIPXYQJI-UHFFFAOYSA-N ethyl 2-[3-(3,4-difluorophenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(F)C(F)=CC=1C1(CC(=O)OCC)CNC(=O)C1 SFMRJRPIPXYQJI-UHFFFAOYSA-N 0.000 description 1
XUZADJKKEYDQMJ-UHFFFAOYSA-N ethyl 2-[3-(3,4-dimethoxyphenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(OC)C(OC)=CC=1C1(CC(=O)OCC)CNC(=O)C1 XUZADJKKEYDQMJ-UHFFFAOYSA-N 0.000 description 1
RCYUASDVKVHRML-UHFFFAOYSA-N ethyl 2-[3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(C)C(C)=CC=1C1(CC(=O)OCC)CNC(=O)C1 RCYUASDVKVHRML-UHFFFAOYSA-N 0.000 description 1
YGEHOUBZTLYHKD-UHFFFAOYSA-N ethyl 2-[3-(3-chlorophenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=CC(Cl)=CC=1C1(CC(=O)OCC)CNC(=O)C1 YGEHOUBZTLYHKD-UHFFFAOYSA-N 0.000 description 1
ROTMQABJNRKCPD-UHFFFAOYSA-N ethyl 2-[3-(4-fluorophenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(F)C=CC=1C1(CC(=O)OCC)CNC(=O)C1 ROTMQABJNRKCPD-UHFFFAOYSA-N 0.000 description 1
HZHVOEQDZKLVSG-UHFFFAOYSA-N ethyl 2-[3-(4-methoxyphenyl)-5-oxopyrrolidin-3-yl]acetate Chemical compound C=1C=C(OC)C=CC=1C1(CC(=O)OCC)CNC(=O)C1 HZHVOEQDZKLVSG-UHFFFAOYSA-N 0.000 description 1
ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
CFENAYZLXHQLKY-UHFFFAOYSA-N ethyl 4-[1-(2-ethoxyethyl)benzimidazol-2-yl]-1,4-diazepane-1-carboxylate Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCN(C(=O)OCC)CC1 CFENAYZLXHQLKY-UHFFFAOYSA-N 0.000 description 1
JBACYJRMCXLIQU-UHFFFAOYSA-N ethyl 5-(chloromethyl)furan-2-carboxylate Chemical compound CCOC(=O)C1=CC=C(CCl)O1 JBACYJRMCXLIQU-UHFFFAOYSA-N 0.000 description 1
VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
238000010575 fractional recrystallization Methods 0.000 description 1
239000012458 free base Substances 0.000 description 1
125000002541 furyl group Chemical group 0.000 description 1
239000011521 glass Substances 0.000 description 1
229960004275 glycolic acid Drugs 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
230000003301 hydrolyzing effect Effects 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
239000013067 intermediate product Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
238000002955 isolation Methods 0.000 description 1
FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
239000004310 lactic acid Substances 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
229960000448 lactic acid Drugs 0.000 description 1
235000019421 lipase Nutrition 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
229910052753 mercury Inorganic materials 0.000 description 1
YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
NEXHXAMAIMAABX-UHFFFAOYSA-N methyl 3-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CCl)=C1 NEXHXAMAIMAABX-UHFFFAOYSA-N 0.000 description 1
POZIFRPMDFGLIW-UHFFFAOYSA-N methyl 3-cyano-2-phenylpropanoate Chemical compound COC(=O)C(CC#N)C1=CC=CC=C1 POZIFRPMDFGLIW-UHFFFAOYSA-N 0.000 description 1
SATDLKYRVXFXRE-UHFFFAOYSA-N methyl 4-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCl)C=C1 SATDLKYRVXFXRE-UHFFFAOYSA-N 0.000 description 1
STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
229940012189 methyl orange Drugs 0.000 description 1
WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
238000006011 modification reaction Methods 0.000 description 1
239000002808 molecular sieve Substances 0.000 description 1
WEVSWKCMKXOKBQ-UHFFFAOYSA-N n,n,2,4,6-pentamethylbenzamide Chemical compound CN(C)C(=O)C1=C(C)C=C(C)C=C1C WEVSWKCMKXOKBQ-UHFFFAOYSA-N 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
150000002790 naphthalenes Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
150000002894 organic compounds Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
150000003891 oxalate salts Chemical class 0.000 description 1
235000006408 oxalic acid Nutrition 0.000 description 1
239000008188 pellet Substances 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
239000008363 phosphate buffer Substances 0.000 description 1
235000011007 phosphoric acid Nutrition 0.000 description 1
150000003016 phosphoric acids Chemical class 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
239000012286 potassium permanganate Substances 0.000 description 1
LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
RMSRWCMCEBGEFB-UHFFFAOYSA-N propyl 2-(chloromethyl)benzoate Chemical compound CCCOC(=O)C1=CC=CC=C1CCl RMSRWCMCEBGEFB-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000004080 punching Methods 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
150000003235 pyrrolidines Chemical class 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
229940107700 pyruvic acid Drugs 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
238000011084 recovery Methods 0.000 description 1
229960004889 salicylic acid Drugs 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
239000001476 sodium potassium tartrate Substances 0.000 description 1
235000011006 sodium potassium tartrate Nutrition 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
230000000707 stereoselective effect Effects 0.000 description 1
239000000126 substance Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
150000003460 sulfonic acids Chemical class 0.000 description 1
239000000725 suspension Substances 0.000 description 1
239000002462 tachykinin receptor antagonist Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
KTJOZDBANQOLHP-UHFFFAOYSA-N tert-butyl-(3-iodopropoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCI KTJOZDBANQOLHP-UHFFFAOYSA-N 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
150000003628 tricarboxylic acids Chemical class 0.000 description 1
JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
239000000052 vinegar Substances 0.000 description 1
235000021419 vinegar Nutrition 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000002023 wood Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pulmonology (AREA)
Immunology (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

NO19982867A 1995-12-20 1998-06-19 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 NO316932B1 (no)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US58000495A	1995-12-20	1995-12-20
US73641196A	1996-10-24	1996-10-24
PCT/US1996/019524 WO1997022604A1 (en)	1995-12-20	1996-12-04	Novel substituted 4-(1h-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases

Publications (3)

Publication Number	Publication Date
NO982867D0 NO982867D0 (no)	1998-06-19
NO982867L NO982867L (no)	1998-08-19
NO316932B1 true NO316932B1 (no)	2004-06-28

Family

ID=27077922

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO19982867A NO316932B1 (no)	1995-12-20	1998-06-19	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

Country Status (19)

Country	Link
EP (1)	EP0874843B1 (ja)
JP (1)	JP2000500772A (ja)
KR (1)	KR20000064487A (ja)
CN (1)	CN1080262C (ja)
AR (1)	AR005120A1 (ja)
AT (1)	ATE221883T1 (ja)
AU (1)	AU707914B2 (ja)
BR (1)	BR9612074A (ja)
CA (1)	CA2241827C (ja)
DE (1)	DE69622889T2 (ja)
DK (1)	DK0874843T3 (ja)
ES (1)	ES2177827T3 (ja)
IL (1)	IL125002A0 (ja)
MX (1)	MX9804991A (ja)
NO (1)	NO316932B1 (ja)
NZ (1)	NZ325581A (ja)
PT (1)	PT874843E (ja)
TW (1)	TW335395B (ja)
WO (1)	WO1997022604A1 (ja)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6194406B1 (en) *	1995-12-20	2001-02-27	Aventis Pharmaceuticals Inc.	Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease
US6423704B2 (en)	1995-12-20	2002-07-23	Aventis Pharmaceuticals Inc.	Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases
GB9600235D0 (en)	1996-01-05	1996-03-06	Pfizer Ltd	Therapeutic agents
US6552188B2 (en) *	2001-06-29	2003-04-22	Kowa Co., Ltd.	Unsymmetrical cyclic diamine compound
CN101001836B (zh)	2004-05-07	2010-12-22	詹森药业有限公司	作为11-β羟基类固醇脱氢酶抑制剂的吡咯烷-2-酮和哌啶-2-酮衍生物
NZ551076A (en)	2004-05-07	2009-05-31	Janssen Pharmaceutica Nv	Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
KR101197672B1 (ko)	2004-08-30	2012-11-07	얀센 파마슈티카 엔.브이.	11-베타 하이드록시스테로이드 데하이드로게나제저해제로서 트리사이클릭 락탐 유도체
DE602005017159D1 (de)	2004-08-30	2009-11-26	Janssen Pharmaceutica Nv	Oxysteroid-dehydrogenase-inhibitoren
BRPI0515121A (pt)	2004-08-30	2008-07-08	Janssen Pharmaceutica Nv	derivados da n-2 adamantil-2-fenóxi acetamida como inibidores da 11-beta hidroxiesteróide desidrogenase
JP2010516731A (ja)	2007-01-24	2010-05-20	グラクソグループリミテッド	２−メトキシ−５−（５−トリフルオロメチル−テトラゾール−１−イル）−ベンジル］−（２ｓ−フェニル−ピペリジン−３ｓ−イル）−アミンを含む医薬組成物
CN105646306B (zh) *	2015-12-11	2020-06-30	广东莱佛士制药技术有限公司	一种4-甲硫基苯乙酸的制备方法
EP3886854A4 (en)	2018-11-30	2022-07-06	Nuvation Bio Inc.	Pyrrole and pyrazole compounds and methods of use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
FR2676054B1 (fr) *	1991-05-03	1993-09-03	Sanofi Elf	Nouveaux composes n-alkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
FR2676055B1 (fr) *	1991-05-03	1993-09-03	Sanofi Elf	Composes polycycliques amines et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
HU224496B1 (hu) *	1993-05-06	2005-10-28	Merrel Dow Pharmaceuticals Inc.	Pirrolidin-3-il-alkil-piperidin-származékok és e vegyületeket tartalmazó gyógyászati készítmények
US5624948A (en) *	1993-05-20	1997-04-29	Kissei Pharmaceutical Co., Ltd.	1-(2-benzimidazolyl)-1,5-diazacyclooctane compounds
DK0777666T3 (da) *	1994-08-25	1999-09-27	Merrell Pharma Inc	Substituerede piperidiner anvendelige ved behandling af allergiske sygdomme

1996
- 1996-12-04 IL IL12500296A patent/IL125002A0/xx unknown
- 1996-12-04 CA CA002241827A patent/CA2241827C/en not_active Expired - Fee Related
- 1996-12-04 WO PCT/US1996/019524 patent/WO1997022604A1/en not_active Ceased
- 1996-12-04 BR BR9612074A patent/BR9612074A/pt unknown
- 1996-12-04 PT PT96944267T patent/PT874843E/pt unknown
- 1996-12-04 NZ NZ325581A patent/NZ325581A/xx unknown
- 1996-12-04 ES ES96944267T patent/ES2177827T3/es not_active Expired - Lifetime
- 1996-12-04 CN CN96199141A patent/CN1080262C/zh not_active Expired - Fee Related
- 1996-12-04 KR KR1019980704684A patent/KR20000064487A/ko not_active Abandoned
- 1996-12-04 AT AT96944267T patent/ATE221883T1/de not_active IP Right Cessation
- 1996-12-04 EP EP96944267A patent/EP0874843B1/en not_active Expired - Lifetime
- 1996-12-04 DK DK96944267T patent/DK0874843T3/da active
- 1996-12-04 DE DE69622889T patent/DE69622889T2/de not_active Expired - Fee Related
- 1996-12-04 AU AU14119/97A patent/AU707914B2/en not_active Ceased
- 1996-12-04 JP JP9522863A patent/JP2000500772A/ja active Pending
- 1996-12-18 AR ARP960105741A patent/AR005120A1/es active IP Right Grant
- 1996-12-21 TW TW085115838A patent/TW335395B/zh active
1998
- 1998-06-19 NO NO19982867A patent/NO316932B1/no not_active IP Right Cessation
- 1998-06-19 MX MX9804991A patent/MX9804991A/es not_active IP Right Cessation

Also Published As

Publication number	Publication date
BR9612074A (pt)	1999-03-30
WO1997022604A1 (en)	1997-06-26
ES2177827T3 (es)	2002-12-16
ATE221883T1 (de)	2002-08-15
EP0874843B1 (en)	2002-08-07
EP0874843A1 (en)	1998-11-04
NZ325581A (en)	2000-03-27
CA2241827A1 (en)	1997-06-26
DE69622889T2 (de)	2003-04-10
AU707914B2 (en)	1999-07-22
KR20000064487A (ko)	2000-11-06
NO982867L (no)	1998-08-19
AR005120A1 (es)	1999-04-14
TW335395B (en)	1998-07-01
DK0874843T3 (da)	2002-11-25
NO982867D0 (no)	1998-06-19
AU1411997A (en)	1997-07-14
CN1080262C (zh)	2002-03-06
MX9804991A (es)	1998-09-30
CA2241827C (en)	2002-04-30
DE69622889D1 (de)	2002-09-12
CN1207097A (zh)	1999-02-03
HK1017684A1 (en)	1999-11-26
PT874843E (pt)	2002-12-31
IL125002A0 (en)	1999-01-26
JP2000500772A (ja)	2000-01-25

Legal Events

Date	Code	Title	Description
2005-09-12	MM1K	Lapsed by not paying the annual fees

Publication	Publication Date	Title
EP0777666B1 (en)	1999-03-03	Substituted piperidines useful for the treatment of allergic diseases
US6423704B2 (en)	2002-07-23	Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases
EP0920425B1 (en)	2003-02-19	Substituted 4-(1h-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
US6194406B1 (en)	2001-02-27	Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic disease
US6211199B1 (en)	2001-04-03	Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
EP0874843B1 (en)	2002-08-07	Substituted 4-(1h-benzimidazol-2-yl) 1,4]diazepanes useful for the treatment of allergic diseases
US5998439A (en)	1999-12-07	Substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases
AU709215B2 (en)	1999-08-26	Novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases
EP0888338B1 (en)	2004-11-17	Novel substituted n-methyl-n-(4-(4-(1h-benzimidazol-2-yl) 1,4]diazepan-1-yl)-2-(aryl)butyl)benzamides useful for the treatment of allergic diseases
NZ330908A (en)	2001-04-27	Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)-2 -(aryl)butyl)benzamides useful for the treatment of allergic diseases
US5922737A (en)	1999-07-13	Substituted N-methyl-N-(4-(4-(1H-Benzimidazol-2-YL-amino) piperidin-1-YL)-2-(arlyl) butyl) benzamides useful for the treatment of allergic diseases
US5932571A (en)	1999-08-03	Substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl) {1,4}diazepan-1-yl)-2-(aryl) butyl) benzamides useful for the treatment of allergic diseases
HK1018065B (en)	2003-06-06	Substituted 4-(1h-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases