JP7254792B2 - グルコース感受性アルブミン結合誘導体 - Google Patents
グルコース感受性アルブミン結合誘導体 Download PDFInfo
- Publication number
- JP7254792B2 JP7254792B2 JP2020525911A JP2020525911A JP7254792B2 JP 7254792 B2 JP7254792 B2 JP 7254792B2 JP 2020525911 A JP2020525911 A JP 2020525911A JP 2020525911 A JP2020525911 A JP 2020525911A JP 7254792 B2 JP7254792 B2 JP 7254792B2
- Authority
- JP
- Japan
- Prior art keywords
- nhch
- cooh
- formula
- linker
- covalent bond
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title description 35
- 239000008103 glucose Substances 0.000 title description 35
- 102000009027 Albumins Human genes 0.000 title description 12
- 108010088751 Albumins Proteins 0.000 title description 12
- -1 diboron compound Chemical class 0.000 claims description 234
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 68
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 62
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 50
- 229910052731 fluorine Inorganic materials 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 36
- HCMJWOGOISXSDL-UHFFFAOYSA-N (2-isothiocyanato-1-phenylethyl)benzene Chemical compound C=1C=CC=CC=1C(CN=C=S)C1=CC=CC=C1 HCMJWOGOISXSDL-UHFFFAOYSA-N 0.000 claims description 35
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 35
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 239000004471 Glycine Substances 0.000 claims description 31
- KYXOSSZIPTXYDE-UHFFFAOYSA-N 2-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetic acid Chemical compound C12=C(C=C(C(=C2)C(=O)NCCN(C(=O)C2=C(C=C3COB(C3=C2)O)F)CC(=O)O)F)COB1O KYXOSSZIPTXYDE-UHFFFAOYSA-N 0.000 claims description 29
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 25
- 229940088679 drug related substance Drugs 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- KMTNEBVTDNRXGF-UHFFFAOYSA-N 2-[(1-hydroxy-4-methylsulfonyl-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(1-hydroxy-4-methylsulfonyl-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetic acid Chemical compound CS(=O)(=O)C1=CC(=CC2=C1COB2O)C(=O)NCCN(CC(O)=O)C(=O)C1=CC2=C(COB2O)C(=C1)S(C)(=O)=O KMTNEBVTDNRXGF-UHFFFAOYSA-N 0.000 claims description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
- 150000008575 L-amino acids Chemical group 0.000 claims description 11
- 239000004472 Lysine Substances 0.000 claims description 11
- WCOQAGPRGRKKLM-UHFFFAOYSA-N pyrrolidine-3,4-diamine Chemical compound NC1CNCC1N WCOQAGPRGRKKLM-UHFFFAOYSA-N 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- BSTWEDGDAUAJGS-INIZCTEOSA-N (2S)-2,3-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]propanoic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(=O)NC[C@H](NC(=O)C1=CC2=C(COB2O)C(=C1)C(F)(F)F)C(O)=O BSTWEDGDAUAJGS-INIZCTEOSA-N 0.000 claims description 7
- IFPSNUVIKOCJJS-UHFFFAOYSA-N 2-[[4-(difluoromethyl)-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl]-[2-[[4-(difluoromethyl)-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl]amino]ethyl]amino]acetic acid Chemical compound B1(C2=CC(C(=O)N(CCNC(=O)C3=CC4=C(C(C(F)F)=C3)COB4O)CC(=O)O)=CC(C(F)F)=C2CO1)O IFPSNUVIKOCJJS-UHFFFAOYSA-N 0.000 claims description 7
- MRGFTTLPAZFITK-UHFFFAOYSA-N 3-borono-5-(3-borono-5-fluorobenzoyl)benzoic acid Chemical compound B(O)(O)C=1C=C(C(=O)O)C=C(C=1)C(C1=CC(=CC(=C1)F)B(O)O)=O MRGFTTLPAZFITK-UHFFFAOYSA-N 0.000 claims description 7
- AGGOZXDCVADXOG-PMACEKPBSA-N 4-[(3S,4S)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]pyrrolidin-1-yl]-4-oxobutanoic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(=O)N[C@H]1CN(C[C@@H]1NC(=O)C=1C=C(C2=C(B(OC2)O)C=1)C(F)(F)F)C(CCC(=O)O)=O AGGOZXDCVADXOG-PMACEKPBSA-N 0.000 claims description 7
- AVXAWRYJOASUAO-UHFFFAOYSA-N 2-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carbonyl)-[2-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carbonyl)amino]ethyl]amino]acetic acid Chemical compound B1(O)C2=CC(F)=C(C(=O)NCCN(C(=O)C3=CC4=C(B(OC4)O)C=C3F)CC(=O)O)C=C2CO1 AVXAWRYJOASUAO-UHFFFAOYSA-N 0.000 claims description 6
- YYEDEFNVBGUOAE-UHFFFAOYSA-N 2-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetic acid Chemical compound B1(OCC2=CC=C(C(=O)N(CCNC(=O)C3=C(C4=C(COB4O)C=C3)F)CC(=O)O)C(F)=C12)O YYEDEFNVBGUOAE-UHFFFAOYSA-N 0.000 claims description 6
- PNJCUNQJHAZVNW-UHFFFAOYSA-N 2-[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]-[2-[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]ethyl]amino]acetic acid Chemical compound FC(C1=C2COB(C2=CC(C(=O)N(CCNC(=O)C2=CC(C(F)(F)F)=C3COB(C3=C2)O)CC(=O)O)=C1)O)(F)F PNJCUNQJHAZVNW-UHFFFAOYSA-N 0.000 claims description 6
- FYDSFWPETZKCEZ-INIZCTEOSA-N (2S)-2,3-bis[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoic acid Chemical compound OB1OCC2=C1C=C(C=C2F)C(=O)NC[C@H](NC(=O)C1=CC2=C(COB2O)C(F)=C1)C(O)=O FYDSFWPETZKCEZ-INIZCTEOSA-N 0.000 claims description 5
- WKRRJDCYDXEALH-LBPRGKRZSA-N (2S)-2,3-bis[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoic acid Chemical compound OB1OCC2=C1C(F)=C(C=C2)C(=O)NC[C@H](NC(=O)C1=C(F)C2=C(COB2O)C=C1)C(O)=O WKRRJDCYDXEALH-LBPRGKRZSA-N 0.000 claims description 5
- WBNFCQHAVHZZNR-UHFFFAOYSA-N 2-[(4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetic acid Chemical compound OB1OCC2=C1C=C(C=C2Cl)C(=O)NCCN(CC(O)=O)C(=O)C1=CC2=C(COB2O)C(Cl)=C1 WBNFCQHAVHZZNR-UHFFFAOYSA-N 0.000 claims description 5
- GYHHUFZIOCQQPE-UHFFFAOYSA-N 2-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetic acid Chemical compound C12=C(C(=CC(=C2)C(=O)NCCN(C(=O)C2=CC3=C(COB3O)C(F)=C2)CC(=O)O)F)COB1O GYHHUFZIOCQQPE-UHFFFAOYSA-N 0.000 claims description 5
- YHAQWGCPUZAMBH-UHFFFAOYSA-N 3-borono-5-(5-borono-2,4-difluorobenzoyl)benzoic acid Chemical compound B(O)(O)C=1C=C(C(=O)O)C=C(C=1)C(C1=C(C=C(C(=C1)B(O)O)F)F)=O YHAQWGCPUZAMBH-UHFFFAOYSA-N 0.000 claims description 5
- RGILTGWUMCGOFP-INIZCTEOSA-N (2S)-2,3-bis[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoic acid Chemical compound OB1OCC2=C1C=C(C(=O)NC[C@H](NC(=O)C1=CC3=C(COB3O)C=C1F)C(O)=O)C(F)=C2 RGILTGWUMCGOFP-INIZCTEOSA-N 0.000 claims description 4
- PHMHAPKORFPYJN-UHFFFAOYSA-N 2-[[3-borono-5-(3-borono-5-fluorobenzoyl)benzoyl]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C(=O)NCC(=O)O)C=C(C=1)C(C1=CC(=CC(=C1)F)B(O)O)=O PHMHAPKORFPYJN-UHFFFAOYSA-N 0.000 claims description 4
- NDBOJEVGWQXYHB-UHFFFAOYSA-N 2-[[3-borono-5-[[3-borono-5-(trifluoromethyl)phenyl]-difluoromethyl]benzoyl]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C(=O)NCC(=O)O)C=C(C=1)C(F)(F)C1=CC(=CC(=C1)C(F)(F)F)B(O)O NDBOJEVGWQXYHB-UHFFFAOYSA-N 0.000 claims description 4
- XDBBUIGDFHGGBH-UHFFFAOYSA-N 2-[[bis[3-borono-5-(trifluoromethyl)phenyl]-oxo-lambda6-sulfanylidene]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C=C(C=1)C(F)(F)F)S(=O)(C1=CC(=CC(=C1)C(F)(F)F)B(O)O)=NCC(=O)O XDBBUIGDFHGGBH-UHFFFAOYSA-N 0.000 claims description 4
- ZKLFZDRMVOOGEA-UHFFFAOYSA-N 3,5-bis[[(4-borono-2-fluorobenzoyl)amino]methyl]benzoic acid Chemical compound B(O)(O)C1=CC(=C(C(=O)NCC=2C=C(C(=O)O)C=C(C=2)CNC(C2=C(C=C(C=C2)B(O)O)F)=O)C=C1)F ZKLFZDRMVOOGEA-UHFFFAOYSA-N 0.000 claims description 4
- SNUJJPVZCDPFAI-UHFFFAOYSA-N 3,5-bis[[(4-borono-3-fluorobenzoyl)amino]methyl]benzoic acid Chemical compound B(O)(O)C1=C(C=C(C(=O)NCC=2C=C(C(=O)O)C=C(C=2)CNC(C2=CC(=C(C=C2)B(O)O)F)=O)C=C1)F SNUJJPVZCDPFAI-UHFFFAOYSA-N 0.000 claims description 4
- GBJWMUIRJPSXDI-UHFFFAOYSA-N 3,5-bis[[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]methyl]benzoic acid Chemical compound OB1OCC2=C1C(F)=C(C=C2)C(=O)NCC1=CC(=CC(CNC(=O)C2=C(F)C3=C(COB3O)C=C2)=C1)C(O)=O GBJWMUIRJPSXDI-UHFFFAOYSA-N 0.000 claims description 4
- DMHQMKRFJWBZLV-UHFFFAOYSA-N 3-borono-5-(3-borono-4-fluorophenyl)sulfonyl-4-fluorobenzoic acid Chemical compound B(O)(O)C=1C=C(C(=O)O)C=C(C=1F)S(=O)(=O)C1=CC(=C(C=C1)F)B(O)O DMHQMKRFJWBZLV-UHFFFAOYSA-N 0.000 claims description 4
- WHBKQAURLKIMOC-HOTGVXAUSA-N 4-[(3S,4S)-3,4-bis[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]pyrrolidin-1-yl]-4-oxobutanoic acid Chemical compound OB1OCC2=C1C(F)=C(C=C2)C(=O)N[C@H]1CN(C[C@@H]1NC(=O)C1=C(F)C2=C(COB2O)C=C1)C(=O)CCC(O)=O WHBKQAURLKIMOC-HOTGVXAUSA-N 0.000 claims description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- SNAPCMGWKWKWID-HNNXBMFYSA-N (2S)-2,4-bis[(4-borono-3-fluorobenzoyl)amino]butanoic acid Chemical compound B(O)(O)C1=C(C=C(C(=O)N[C@H](C(=O)O)CCNC(C2=CC(=C(C=C2)B(O)O)F)=O)C=C1)F SNAPCMGWKWKWID-HNNXBMFYSA-N 0.000 claims description 3
- MDVFAWOHRRNTKZ-UHFFFAOYSA-N 2-[[1-hydroxy-4-(trifluoromethylsulfonyl)-3H-2,1-benzoxaborole-6-carbonyl]-[2-[[1-hydroxy-4-(trifluoromethylsulfonyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]ethyl]amino]acetic acid Chemical compound C(F)(S(=O)(=O)C1=C2COB(C2=CC(C(=O)N(CCNC(=O)C2=CC(S(=O)(=O)C(F)(F)F)=C3COB(C3=C2)O)CC(=O)O)=C1)O)(F)F MDVFAWOHRRNTKZ-UHFFFAOYSA-N 0.000 claims description 3
- AYUFKECOJZWSET-UHFFFAOYSA-N 2-[[3-borono-5-(3-borono-5-fluorophenyl)sulfonylbenzoyl]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C(=O)NCC(=O)O)C=C(C=1)S(=O)(=O)C1=CC(=CC(=C1)F)B(O)O AYUFKECOJZWSET-UHFFFAOYSA-N 0.000 claims description 3
- VSRBGIOHJQEUQH-UHFFFAOYSA-N 2-[[bis(3-borono-5-chlorophenyl)-oxo-lambda6-sulfanylidene]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C=C(C=1)Cl)S(=O)(C1=CC(=CC(=C1)Cl)B(O)O)=NCC(=O)O VSRBGIOHJQEUQH-UHFFFAOYSA-N 0.000 claims description 3
- TZHIKJDMMOQQOE-UHFFFAOYSA-N 2-[[bis(3-boronophenyl)-oxo-lambda6-sulfanylidene]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C=CC=1)S(=O)(C1=CC(=CC=C1)B(O)O)=NCC(=O)O TZHIKJDMMOQQOE-UHFFFAOYSA-N 0.000 claims description 3
- IWSSNZPGZWGHCX-UHFFFAOYSA-N 2-[[bis[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborol-6-yl]-oxo-lambda6-sulfanylidene]amino]acetic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)S(=O)(=NCC(O)=O)C1=CC2=C(COB2O)C(=C1)C(F)(F)F IWSSNZPGZWGHCX-UHFFFAOYSA-N 0.000 claims description 3
- OMCMNRVUXKYUSM-UHFFFAOYSA-N 2-[[bis[3-borono-5-(difluoromethyl)phenyl]-oxo-lambda6-sulfanylidene]amino]acetic acid Chemical compound OB(O)C1=CC(=CC(=C1)S(=O)(=NCC(O)=O)C1=CC(=CC(=C1)C(F)F)B(O)O)C(F)F OMCMNRVUXKYUSM-UHFFFAOYSA-N 0.000 claims description 3
- KVEOIDBXMCFVPO-UHFFFAOYSA-N 3-[2,3-bis[(4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoylamino]propanoic acid Chemical compound OB1OCC2=C1C=C(C=C2Cl)C(=O)NCC(NC(=O)C1=CC2=C(COB2O)C(Cl)=C1)C(=O)NCCC(O)=O KVEOIDBXMCFVPO-UHFFFAOYSA-N 0.000 claims description 3
- YSNDNJMKHKLTNK-INIZCTEOSA-N (2S)-2,3-bis[(1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoic acid Chemical compound OB1OCC2=C1C=C(C=C2)C(=O)NC[C@H](NC(=O)C1=CC2=C(COB2O)C=C1)C(O)=O YSNDNJMKHKLTNK-INIZCTEOSA-N 0.000 claims description 2
- DDVKTHUXRVZKTQ-UHFFFAOYSA-N 2-[[3-borono-5-(3-boronophenyl)sulfonylbenzoyl]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C(=O)NCC(=O)O)C=C(C=1)S(=O)(=O)C1=CC(=CC=C1)B(O)O DDVKTHUXRVZKTQ-UHFFFAOYSA-N 0.000 claims description 2
- NFDMEVUWFFHGTD-UHFFFAOYSA-N 2-[[3-borono-5-[3-borono-5-(trifluoromethyl)benzoyl]benzoyl]amino]acetic acid Chemical compound B(O)(O)C=1C=C(C(=O)NCC(=O)O)C=C(C=1)C(C1=CC(=CC(=C1)C(F)(F)F)B(O)O)=O NFDMEVUWFFHGTD-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 65
- FSBSTRDJNASFCP-UHFFFAOYSA-N 4-borono-2-[3-borono-5-(trifluoromethyl)phenyl]sulfonyl-6-(trifluoromethyl)benzoic acid Chemical compound OB(O)C1=CC(=CC(=C1)S(=O)(=O)C1=C(C(O)=O)C(=CC(=C1)B(O)O)C(F)(F)F)C(F)(F)F FSBSTRDJNASFCP-UHFFFAOYSA-N 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims 1
- 238000001212 derivatisation Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 588
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 534
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 307
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 299
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 289
- 239000000203 mixture Substances 0.000 description 180
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 175
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 166
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 164
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 139
- 239000011541 reaction mixture Substances 0.000 description 137
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 129
- 239000007787 solid Substances 0.000 description 127
- 239000000243 solution Substances 0.000 description 126
- 238000006243 chemical reaction Methods 0.000 description 125
- 125000005647 linker group Chemical group 0.000 description 123
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 118
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 108
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 104
- 238000000105 evaporative light scattering detection Methods 0.000 description 91
- 239000012267 brine Substances 0.000 description 80
- 239000000741 silica gel Substances 0.000 description 80
- 229910002027 silica gel Inorganic materials 0.000 description 80
- 229960001866 silicon dioxide Drugs 0.000 description 80
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 80
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 239000012044 organic layer Substances 0.000 description 75
- 239000003480 eluent Substances 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 63
- 238000003756 stirring Methods 0.000 description 63
- 238000000034 method Methods 0.000 description 56
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 54
- 230000002829 reductive effect Effects 0.000 description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 54
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 51
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- 238000003818 flash chromatography Methods 0.000 description 48
- 239000012043 crude product Substances 0.000 description 47
- LDOKWNQBODDHOT-UHFFFAOYSA-N tert-butyl 2-[[oxo-bis[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-lambda6-sulfanylidene]amino]acetate Chemical compound O=S(C1=CC(=CC=C1)B1OC(C(O1)(C)C)(C)C)(C1=CC(=CC=C1)B1OC(C(O1)(C)C)(C)C)=NCC(=O)OC(C)(C)C LDOKWNQBODDHOT-UHFFFAOYSA-N 0.000 description 47
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 229910052938 sodium sulfate Inorganic materials 0.000 description 36
- 235000011152 sodium sulphate Nutrition 0.000 description 36
- 239000000377 silicon dioxide Substances 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 239000002244 precipitate Substances 0.000 description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 29
- 229960002449 glycine Drugs 0.000 description 28
- 238000001914 filtration Methods 0.000 description 27
- 235000011056 potassium acetate Nutrition 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- 239000003039 volatile agent Substances 0.000 description 25
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 21
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 21
- 229910052681 coesite Inorganic materials 0.000 description 21
- 229910052906 cristobalite Inorganic materials 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 235000012239 silicon dioxide Nutrition 0.000 description 21
- 229910052682 stishovite Inorganic materials 0.000 description 21
- 229910052905 tridymite Inorganic materials 0.000 description 21
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- PDSMXCBNXMITIY-UHFFFAOYSA-N tert-butyl 2-(trifluoromethyl)-6-[3-(trifluoromethyl)phenyl]sulfanylbenzoate Chemical compound FC(C1=C(C(=O)OC(C)(C)C)C(=CC=C1)SC1=CC(=CC=C1)C(F)(F)F)(F)F PDSMXCBNXMITIY-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- GCOVMLYKRBOYFK-UHFFFAOYSA-N tert-butyl 2-[[3-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(=O)C1=CC(=CC(=C1)B1OC(C)(C)C(C)(C)O1)S(=O)(=O)C1=CC(F)=CC(=C1)B1OC(C)(C)C(C)(C)O1 GCOVMLYKRBOYFK-UHFFFAOYSA-N 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- 239000006260 foam Substances 0.000 description 16
- JMCOYJWUCDGIPI-UHFFFAOYSA-N methyl 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC(F)=C(C)C(B2OC(C)(C)C(C)(C)O2)=C1 JMCOYJWUCDGIPI-UHFFFAOYSA-N 0.000 description 16
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 16
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 15
- NHZJZGSLUCGXFL-UHFFFAOYSA-N 2-[[3-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino]acetic acid Chemical compound CC1(C)OB(OC1(C)C)C1=CC(=CC(F)=C1)S(=O)(=O)C1=CC(=CC(=C1)C(=O)NCC(O)=O)B1OC(C)(C)C(C)(C)O1 NHZJZGSLUCGXFL-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 229940022663 acetate Drugs 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 235000011181 potassium carbonates Nutrition 0.000 description 13
- 238000002953 preparative HPLC Methods 0.000 description 13
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Substances [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 13
- 229940095102 methyl benzoate Drugs 0.000 description 12
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- XVSAONVFHVFAJI-UHFFFAOYSA-N 4-(difluoromethyl)-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)F)C(O)=O XVSAONVFHVFAJI-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229960003646 lysine Drugs 0.000 description 10
- WUSQONUPNHFBOU-UHFFFAOYSA-N methyl 3-bromo-5-iodobenzoate Chemical compound COC(=O)C1=CC(Br)=CC(I)=C1 WUSQONUPNHFBOU-UHFFFAOYSA-N 0.000 description 10
- 235000015497 potassium bicarbonate Nutrition 0.000 description 10
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 10
- 239000011736 potassium bicarbonate Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 10
- 235000019345 sodium thiosulphate Nutrition 0.000 description 10
- 239000007821 HATU Substances 0.000 description 9
- 229910004298 SiO 2 Inorganic materials 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 239000011347 resin Substances 0.000 description 9
- 229920005989 resin Polymers 0.000 description 9
- NEACBPHJNVVONN-UHFFFAOYSA-N 6,6-dichlorohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1PCCCCCC(Cl)Cl NEACBPHJNVVONN-UHFFFAOYSA-N 0.000 description 8
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 7
- 102000008100 Human Serum Albumin Human genes 0.000 description 7
- 108091006905 Human Serum Albumin Proteins 0.000 description 7
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 7
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical class OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 208000030159 metabolic disease Diseases 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 125000005062 perfluorophenyl group Chemical group FC1=C(C(=C(C(=C1F)F)F)F)* 0.000 description 7
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 6
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- SKWCZPYWFRTSDD-DKWTVANSSA-N (2s)-2,3-diaminopropanoic acid;hydrochloride Chemical compound Cl.NC[C@H](N)C(O)=O SKWCZPYWFRTSDD-DKWTVANSSA-N 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- PIINGYXNCHTJTF-UHFFFAOYSA-N 2-(2-azaniumylethylamino)acetate Chemical compound NCCNCC(O)=O PIINGYXNCHTJTF-UHFFFAOYSA-N 0.000 description 5
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 5
- 239000012425 OXONE® Substances 0.000 description 5
- 241000209094 Oryza Species 0.000 description 5
- 235000007164 Oryza sativa Nutrition 0.000 description 5
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 5
- 235000009566 rice Nutrition 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 5
- PCRLZGCXLNNMFL-UHFFFAOYSA-N 3-bromo-5-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC(Br)=CC(C=O)=C1 PCRLZGCXLNNMFL-UHFFFAOYSA-N 0.000 description 4
- MKJBJYCBKXPQSY-UHFFFAOYSA-N 3-bromo-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC(I)=C1 MKJBJYCBKXPQSY-UHFFFAOYSA-N 0.000 description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 4
- AGGOZXDCVADXOG-WOJBJXKFSA-N 4-[(3R,4R)-3,4-bis[[1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carbonyl]amino]pyrrolidin-1-yl]-4-oxobutanoic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(=O)N[C@@H]1CN(C[C@H]1NC(=O)C1=CC2=C(COB2O)C(=C1)C(F)(F)F)C(=O)CCC(O)=O AGGOZXDCVADXOG-WOJBJXKFSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 208000013016 Hypoglycemia Diseases 0.000 description 4
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 4
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- DJGNICGQUHOEAO-UHFFFAOYSA-N methyl 3-bromo-5-[3-bromo-5-(trifluoromethyl)benzoyl]benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1)C(C1=CC(=CC(=C1)C(F)(F)F)Br)=O DJGNICGQUHOEAO-UHFFFAOYSA-N 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- MNKCGUKVRJZKEQ-MIXQCLKLSA-N (1z,5z)-cycloocta-1,5-diene;iridium;methanol Chemical compound [Ir].[Ir].OC.OC.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 MNKCGUKVRJZKEQ-MIXQCLKLSA-N 0.000 description 3
- LCHKCXJFJWILII-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound CC1(C)OB(OC1(C)C)C1=CC(F)=C(C=C1)C(=O)ON1C(=O)CCC1=O LCHKCXJFJWILII-UHFFFAOYSA-N 0.000 description 3
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 description 3
- OFNXSUANJLHGQN-UHFFFAOYSA-N 1,3-dibromo-5-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(Br)=CC(Br)=C1 OFNXSUANJLHGQN-UHFFFAOYSA-N 0.000 description 3
- PAAKRIQUPXJQIW-UHFFFAOYSA-N 2-fluoro-3-iodo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(F)=C1I PAAKRIQUPXJQIW-UHFFFAOYSA-N 0.000 description 3
- BKJBHQXEYLPXTQ-UHFFFAOYSA-N 3,5-bis(aminomethyl)benzoic acid;dihydrochloride Chemical compound Cl.Cl.NCC1=CC(CN)=CC(C(O)=O)=C1 BKJBHQXEYLPXTQ-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 208000016097 disease of metabolism Diseases 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- KTFQDZCNPGFKAH-UHFFFAOYSA-N methyl 3-chloro-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(Cl)=C1 KTFQDZCNPGFKAH-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- KAYNEFHCQUKTAV-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C=C2)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F KAYNEFHCQUKTAV-UHFFFAOYSA-N 0.000 description 2
- LTMPMNIGELAWSL-KBPBESRZSA-N (2,5-dioxopyrrolidin-1-yl) 4-[(3S,4S)-3,4-bis[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidin-1-yl]-4-oxobutanoate Chemical compound C(C)(C)(C)OC(=O)N[C@H]1CN(C[C@@H]1NC(=O)OC(C)(C)C)C(CCC(=O)ON1C(CCC1=O)=O)=O LTMPMNIGELAWSL-KBPBESRZSA-N 0.000 description 2
- FNBSHKZKRBBDLS-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carboxylate Chemical compound OB1OCC2=C1C=C(F)C(=C2)C(=O)ON1C(=O)CCC1=O FNBSHKZKRBBDLS-UHFFFAOYSA-N 0.000 description 2
- QYCQNXJLWFPDLH-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C(F)=C(C=C2)C(=O)ON1C(=O)CCC1=O QYCQNXJLWFPDLH-UHFFFAOYSA-N 0.000 description 2
- SLDOOASMMAMZQK-UHFFFAOYSA-N (3-bromo-4-fluoro-5-iodophenyl)methanol Chemical compound OCc1cc(Br)c(F)c(I)c1 SLDOOASMMAMZQK-UHFFFAOYSA-N 0.000 description 2
- NRDBEGMTZGNVTH-UHFFFAOYSA-N (3-bromo-5-nitrophenyl)-pentafluoro-$l^{6}-sulfane Chemical compound [O-][N+](=O)C1=CC(Br)=CC(S(F)(F)(F)(F)F)=C1 NRDBEGMTZGNVTH-UHFFFAOYSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- RLMQWRRODRPLSJ-UHFFFAOYSA-N 1-(trifluoromethyl)-3-[3-(trifluoromethyl)phenyl]sulfanylbenzene Chemical compound FC(F)(F)C1=CC=CC(SC=2C=C(C=CC=2)C(F)(F)F)=C1 RLMQWRRODRPLSJ-UHFFFAOYSA-N 0.000 description 2
- UDNHRKCCVZPOAK-UHFFFAOYSA-N 1-bromo-5-iodo-2-methyl-3-(trifluoromethyl)benzene Chemical compound CC1=C(Br)C=C(I)C=C1C(F)(F)F UDNHRKCCVZPOAK-UHFFFAOYSA-N 0.000 description 2
- VECFIRWWXYYZIG-UHFFFAOYSA-N 1-chloro-3-(3-chlorophenyl)sulfanylbenzene Chemical compound ClC1=CC=CC(SC=2C=C(Cl)C=CC=2)=C1 VECFIRWWXYYZIG-UHFFFAOYSA-N 0.000 description 2
- VXDGEAYKTHEYPI-UHFFFAOYSA-N 1-hydroxy-3h-2,1-benzoxaborole-6-carboxylic acid Chemical compound C1=C(C(O)=O)C=C2B(O)OCC2=C1 VXDGEAYKTHEYPI-UHFFFAOYSA-N 0.000 description 2
- IJBFCJIIWBYEHT-UHFFFAOYSA-N 1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(O)=O IJBFCJIIWBYEHT-UHFFFAOYSA-N 0.000 description 2
- JYRJERNGMHBYSQ-UHFFFAOYSA-N 1-hydroxy-5-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound OB1OCC2=C1C=C(C(O)=O)C(=C2)C(F)(F)F JYRJERNGMHBYSQ-UHFFFAOYSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- QITBKIGOBMSJBN-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-5,5,5-trifluoro-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)NC(CC(C)C(F)(F)F)C(O)=O)C3=CC=CC=C3C2=C1 QITBKIGOBMSJBN-UHFFFAOYSA-N 0.000 description 2
- WCJSBZQQLKPJSB-UHFFFAOYSA-N 2-bromo-5-iodo-3-methylbenzoic acid Chemical compound CC1=CC(I)=CC(C(O)=O)=C1Br WCJSBZQQLKPJSB-UHFFFAOYSA-N 0.000 description 2
- HYKCLWQMKWGJDD-UHFFFAOYSA-N 2-fluoro-3-iodo-4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C(F)=C1I HYKCLWQMKWGJDD-UHFFFAOYSA-N 0.000 description 2
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 2
- LINBWYYLPWJQHE-UHFFFAOYSA-N 3-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)NCCC(=O)O)C3=CC=CC=C3C2=C1 LINBWYYLPWJQHE-UHFFFAOYSA-N 0.000 description 2
- KVEOIDBXMCFVPO-SFHVURJKSA-N 3-[[(2S)-2,3-bis[(4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]propanoyl]amino]propanoic acid Chemical compound ClC1=CC(=CC=2B(OCC=21)O)C(=O)N[C@H](C(=O)NCCC(=O)O)CNC(=O)C=1C=C(C2=C(B(OC2)O)C=1)Cl KVEOIDBXMCFVPO-SFHVURJKSA-N 0.000 description 2
- UFNYFGZMALWWQR-UHFFFAOYSA-N 3-bromo-4-fluoro-5-iodobenzoic acid Chemical compound OC(=O)C1=CC(Br)=C(F)C(I)=C1 UFNYFGZMALWWQR-UHFFFAOYSA-N 0.000 description 2
- DKEKDYDTVBYPGJ-UHFFFAOYSA-N 3-bromo-4-methyl-5-(trifluoromethyl)aniline Chemical compound CC1=C(Br)C=C(N)C=C1C(F)(F)F DKEKDYDTVBYPGJ-UHFFFAOYSA-N 0.000 description 2
- FUKITJMBFMUDGQ-UHFFFAOYSA-N 3-bromo-4-methyl-5-(trifluoromethyl)benzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1C)C(F)(F)F FUKITJMBFMUDGQ-UHFFFAOYSA-N 0.000 description 2
- ZFJOMUKPDWNRFI-UHFFFAOYSA-N 3-bromo-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1Br ZFJOMUKPDWNRFI-UHFFFAOYSA-N 0.000 description 2
- NUGDEICXEZSLCZ-UHFFFAOYSA-N 3-bromo-5-(3-bromo-4-fluorophenyl)sulfonyl-4-fluorobenzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1F)S(=O)(=O)C1=CC(=C(C=C1)F)Br NUGDEICXEZSLCZ-UHFFFAOYSA-N 0.000 description 2
- QCQHJTZTZKIKQJ-UHFFFAOYSA-N 3-bromo-5-(3-bromophenyl)sulfonylbenzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1)S(=O)(=O)C1=CC(=CC=C1)Br QCQHJTZTZKIKQJ-UHFFFAOYSA-N 0.000 description 2
- HCROKBUNMALNHZ-UHFFFAOYSA-N 3-bromo-5-(pentafluoro-$l^{6}-sulfanyl)aniline Chemical compound NC1=CC(Br)=CC(S(F)(F)(F)(F)F)=C1 HCROKBUNMALNHZ-UHFFFAOYSA-N 0.000 description 2
- BIOUKJLBCCXLHW-UHFFFAOYSA-N 3-bromo-5-(trifluoromethyl)benzenethiol Chemical compound FC(F)(F)C1=CC(S)=CC(Br)=C1 BIOUKJLBCCXLHW-UHFFFAOYSA-N 0.000 description 2
- MEFQRXHVMJPOKZ-UHFFFAOYSA-N 3-bromo-5-fluorobenzaldehyde Chemical compound FC1=CC(Br)=CC(C=O)=C1 MEFQRXHVMJPOKZ-UHFFFAOYSA-N 0.000 description 2
- LYVFIZDTOOBDPB-UHFFFAOYSA-N 3-bromo-5-iodo-4-methylbenzoic acid Chemical compound CC1=C(Br)C=C(C(O)=O)C=C1I LYVFIZDTOOBDPB-UHFFFAOYSA-N 0.000 description 2
- LDAXWVOHZOKFEL-USPAICOZSA-N 4-[(3S,4S)-3,4-diaminopyrrolidin-1-yl]-4-oxobutanoic acid dihydrochloride Chemical compound Cl.Cl.N[C@H]1CN(C[C@@H]1N)C(CCC(=O)O)=O LDAXWVOHZOKFEL-USPAICOZSA-N 0.000 description 2
- TVNVDRMGOOLVOX-UHFFFAOYSA-N 4-borono-3-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C=C1F TVNVDRMGOOLVOX-UHFFFAOYSA-N 0.000 description 2
- PHJOGJTZXVBKJO-UHFFFAOYSA-N 4-methyl-2-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=C(C(O)=O)C(C(F)(F)F)=C1 PHJOGJTZXVBKJO-UHFFFAOYSA-N 0.000 description 2
- UFNBTKFAPDUBCY-UHFFFAOYSA-N 5-bromo-2,4-difluorobenzaldehyde Chemical compound FC1=CC(F)=C(C=O)C=C1Br UFNBTKFAPDUBCY-UHFFFAOYSA-N 0.000 description 2
- BGBAXZILVNOSAT-UHFFFAOYSA-N 5-bromo-2-fluoro-4-methylbenzoic acid Chemical compound CC1=CC(F)=C(C(O)=O)C=C1Br BGBAXZILVNOSAT-UHFFFAOYSA-N 0.000 description 2
- XNTKXXOTDXHIKP-UHFFFAOYSA-N 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound FC=1C(=CC2=C(COB2O)C=1)C(=O)O XNTKXXOTDXHIKP-UHFFFAOYSA-N 0.000 description 2
- CHKAVLMEPLZHHC-UHFFFAOYSA-N 5-iodo-4-methyl-2-(trifluoromethyl)benzoic acid Chemical compound IC=1C(=CC(=C(C(=O)O)C=1)C(F)(F)F)C CHKAVLMEPLZHHC-UHFFFAOYSA-N 0.000 description 2
- ATFMSPPPQNUERA-UHFFFAOYSA-N 7-fluoro-1-hydroxy-3h-2,1-benzoxaborole-6-carboxylic acid Chemical compound C1=C(C(O)=O)C(F)=C2B(O)OCC2=C1 ATFMSPPPQNUERA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000270322 Lepidosauria Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XEMGYXULHWMCCC-UHFFFAOYSA-N [3-bromo-5-(3-bromo-4-fluorophenyl)sulfonyl-4-fluorophenyl]methanol Chemical compound BrC=1C=C(C=C(C=1F)S(=O)(=O)C1=CC(=C(C=C1)F)Br)CO XEMGYXULHWMCCC-UHFFFAOYSA-N 0.000 description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- YQUSJUJNDKUWAM-UHFFFAOYSA-N benzenesulfonylsulfanylsulfonylbenzene Chemical compound C=1C=CC=CC=1S(=O)(=O)SS(=O)(=O)C1=CC=CC=C1 YQUSJUJNDKUWAM-UHFFFAOYSA-N 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000005620 boronic acid group Chemical class 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- JBJGSVBGUBATNH-UHFFFAOYSA-N methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC=CC(B2OC(C)(C)C(C)(C)O2)=C1 JBJGSVBGUBATNH-UHFFFAOYSA-N 0.000 description 2
- VVACSDNKQJXQHR-UHFFFAOYSA-N methyl 3-bromo-4-(bromomethyl)-5-methylsulfonylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1CBr)S(=O)(=O)C VVACSDNKQJXQHR-UHFFFAOYSA-N 0.000 description 2
- CFJQBNFFHMBNKQ-UHFFFAOYSA-N methyl 3-bromo-4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C(Br)=C1 CFJQBNFFHMBNKQ-UHFFFAOYSA-N 0.000 description 2
- XJLBJHXGEARPTH-UHFFFAOYSA-N methyl 3-bromo-4-methyl-5-(trifluoromethyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1C)C(F)(F)F XJLBJHXGEARPTH-UHFFFAOYSA-N 0.000 description 2
- KIEZGTKEYSTCMS-UHFFFAOYSA-N methyl 3-bromo-5-(difluoromethyl)-4-methylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1C)C(F)F KIEZGTKEYSTCMS-UHFFFAOYSA-N 0.000 description 2
- MBOAEPYPUBWIRI-UHFFFAOYSA-N methyl 3-bromo-5-fluoro-4-methylbenzoate Chemical compound COC(=O)C1=CC(F)=C(C)C(Br)=C1 MBOAEPYPUBWIRI-UHFFFAOYSA-N 0.000 description 2
- CWYZDZOQRNCQNW-UHFFFAOYSA-N methyl 3-bromo-5-iodo-4-methylbenzoate Chemical compound COC(=O)C1=CC(Br)=C(C)C(I)=C1 CWYZDZOQRNCQNW-UHFFFAOYSA-N 0.000 description 2
- AEZMUBHCIUTXLG-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-chloro-5-iodobenzoate Chemical compound COC(C1=CC(=C(C(=C1)I)CBr)Cl)=O AEZMUBHCIUTXLG-UHFFFAOYSA-N 0.000 description 2
- XETVWRMKXDTMNL-UHFFFAOYSA-N methyl 5-bromo-2-fluoro-4-(2-oxopropyl)benzoate Chemical compound BrC=1C(=CC(=C(C(=O)OC)C=1)F)CC(C)=O XETVWRMKXDTMNL-UHFFFAOYSA-N 0.000 description 2
- OEZJLPRXYNPFHE-UHFFFAOYSA-N methyl 5-bromo-4-(bromomethyl)-2-fluorobenzoate Chemical compound COC(C1=C(C=C(C(=C1)Br)CBr)F)=O OEZJLPRXYNPFHE-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SZZZXFKLFTXERQ-UHFFFAOYSA-N tert-butyl 2-(2-aminoethylamino)acetate hydrochloride Chemical compound Cl.NCCNCC(=O)OC(C)(C)C SZZZXFKLFTXERQ-UHFFFAOYSA-N 0.000 description 2
- STTPWCAWYGNDQF-UHFFFAOYSA-N tert-butyl 2-[[3-bromo-5-(3-bromo-5-fluorophenyl)sulfonylbenzoyl]amino]acetate Chemical compound BrC=1C=C(C(=O)NCC(=O)OC(C)(C)C)C=C(C=1)S(=O)(=O)C1=CC(=CC(=C1)F)Br STTPWCAWYGNDQF-UHFFFAOYSA-N 0.000 description 2
- ALSQQVSJPVVTFY-UHFFFAOYSA-N tert-butyl 2-[[3-bromo-5-[3-bromo-5-(trifluoromethyl)benzoyl]benzoyl]amino]acetate Chemical compound BrC=1C=C(C(=O)NCC(=O)OC(C)(C)C)C=C(C=1)C(C1=CC(=CC(=C1)C(F)(F)F)Br)=O ALSQQVSJPVVTFY-UHFFFAOYSA-N 0.000 description 2
- OHHCGMHFFHGOOV-UHFFFAOYSA-N tert-butyl 2-[[3-bromo-5-[3-bromo-5-(trifluoromethyl)phenyl]sulfonylbenzoyl]amino]acetate Chemical compound BrC=1C=C(C(=O)NCC(=O)OC(C)(C)C)C=C(C=1)S(=O)(=O)C1=CC(=CC(=C1)C(F)(F)F)Br OHHCGMHFFHGOOV-UHFFFAOYSA-N 0.000 description 2
- FEKPJTKLMHEVJH-UHFFFAOYSA-N tert-butyl N-[3-bromo-4-methyl-5-(trifluoromethyl)phenyl]carbamate Chemical compound BrC=1C=C(C=C(C=1C)C(F)(F)F)NC(OC(C)(C)C)=O FEKPJTKLMHEVJH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- SPWGLKRZUCQLGL-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F SPWGLKRZUCQLGL-UHFFFAOYSA-N 0.000 description 1
- MOCLUDZKYQWTMY-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 1-hydroxy-4-methylsulfonyl-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C=C2S(=O)(=O)C)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F MOCLUDZKYQWTMY-UHFFFAOYSA-N 0.000 description 1
- IVECMDOMTWLCLU-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 1-hydroxy-5-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C(=C2)C(F)(F)F)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F IVECMDOMTWLCLU-UHFFFAOYSA-N 0.000 description 1
- OPLMXOVJWUFAAH-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 4-(difluoromethyl)-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate Chemical compound FC(C1=CC(=CC=2B(OCC=21)O)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F)F OPLMXOVJWUFAAH-UHFFFAOYSA-N 0.000 description 1
- MJXZNLFJGVWKNR-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate Chemical compound ClC1=CC(=CC=2B(OCC=21)O)C(=O)OC1=C(C(=C(C(=C1F)F)F)F)F MJXZNLFJGVWKNR-UHFFFAOYSA-N 0.000 description 1
- KGXZNKQWFNCEPO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 1-hydroxy-4-(trifluoromethyl)-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C=C2C(F)(F)F)C(=O)ON1C(CCC1=O)=O KGXZNKQWFNCEPO-UHFFFAOYSA-N 0.000 description 1
- MGACDMGJHWUYBH-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound CC1(C)OB(OC1(C)C)C1=C(F)C=C(C=C1)C(=O)ON1C(=O)CCC1=O MGACDMGJHWUYBH-UHFFFAOYSA-N 0.000 description 1
- JORVCDBLGWIVAI-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylate Chemical compound OB1OCC2=C1C=C(C=C2F)C(=O)ON1C(=O)CCC1=O JORVCDBLGWIVAI-UHFFFAOYSA-N 0.000 description 1
- CEEGOSWFFHSPHM-PMERELPUSA-N (2s)-2,3-bis(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(=O)O)CNC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 CEEGOSWFFHSPHM-PMERELPUSA-N 0.000 description 1
- CKAAWCHIBBNLOJ-QTNFYWBSSA-N (2s)-2,4-diaminobutanoic acid;dihydrochloride Chemical compound Cl.Cl.NCC[C@H](N)C(O)=O CKAAWCHIBBNLOJ-QTNFYWBSSA-N 0.000 description 1
- DQUHYEDEGRNAFO-QMMMGPOBSA-N (2s)-6-amino-2-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCCN DQUHYEDEGRNAFO-QMMMGPOBSA-N 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- ASWYHZXKFSLNLN-UHFFFAOYSA-N 1,3-dibromo-5-fluorobenzene Chemical compound FC1=CC(Br)=CC(Br)=C1 ASWYHZXKFSLNLN-UHFFFAOYSA-N 0.000 description 1
- PPUZKAPOPPRMFE-UHFFFAOYSA-N 1,5-dibromo-2,4-difluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1Br PPUZKAPOPPRMFE-UHFFFAOYSA-N 0.000 description 1
- DBHKCZVHGMSFKH-UHFFFAOYSA-N 1-(difluoromethyl)-3-[3-(difluoromethyl)phenyl]sulfanylbenzene Chemical compound FC(C=1C=C(C=CC=1)SC1=CC(=CC=C1)C(F)F)F DBHKCZVHGMSFKH-UHFFFAOYSA-N 0.000 description 1
- HROHDLSABVNCEZ-UHFFFAOYSA-N 1-(difluoromethyl)-3-iodobenzene Chemical compound FC(F)C1=CC=CC(I)=C1 HROHDLSABVNCEZ-UHFFFAOYSA-N 0.000 description 1
- GKZISXVNJDHSSG-UHFFFAOYSA-N 1-bromo-2-(ethoxymethoxymethyl)-5-iodo-3-(trifluoromethyl)benzene Chemical compound CCOCOCC1=C(Br)C=C(I)C=C1C(F)(F)F GKZISXVNJDHSSG-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- JMLWXCJXOYDXRN-UHFFFAOYSA-N 1-chloro-3-iodobenzene Chemical compound ClC1=CC=CC(I)=C1 JMLWXCJXOYDXRN-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- TWINDMKDQZVATN-UHFFFAOYSA-N 1-hydroxy-4-methylsulfonyl-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound CS(=O)(=O)C1=CC(=CC2=C1COB2O)C(O)=O TWINDMKDQZVATN-UHFFFAOYSA-N 0.000 description 1
- IGISPMBUGPHLBY-UHFFFAOYSA-N 1-iodo-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(I)=C1 IGISPMBUGPHLBY-UHFFFAOYSA-N 0.000 description 1
- SKWCZPYWFRTSDD-UHFFFAOYSA-N 2,3-bis(azaniumyl)propanoate;chloride Chemical compound Cl.NCC(N)C(O)=O SKWCZPYWFRTSDD-UHFFFAOYSA-N 0.000 description 1
- AOQYIRCFPBPZMA-UHFFFAOYSA-N 2-(2-aminoethylamino)acetic acid;hydrochloride Chemical compound Cl.NCCNCC(O)=O AOQYIRCFPBPZMA-UHFFFAOYSA-N 0.000 description 1
- BXWGNHMLCCNMPQ-UHFFFAOYSA-N 2-[[3-borono-5-[3-borono-5-(trifluoromethyl)phenyl]sulfonylbenzoyl]amino]acetic acid Chemical compound B(O)(C1=CC(=CC(S(=O)(=O)C2=CC(C(F)(F)F)=CC(B(O)O)=C2)=C1)C(=O)NCC(=O)O)O BXWGNHMLCCNMPQ-UHFFFAOYSA-N 0.000 description 1
- ALFWHEYHCZRVLO-UHFFFAOYSA-N 2-fluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(F)=C1 ALFWHEYHCZRVLO-UHFFFAOYSA-N 0.000 description 1
- WCGNLBCJPBKXCN-UHFFFAOYSA-N 2-fluoro-4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C(F)=C1 WCGNLBCJPBKXCN-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- STJUSBSLJXOSDU-UHFFFAOYSA-N 2-methyl-5-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=C(C(F)(F)F)C=C1C(O)=O STJUSBSLJXOSDU-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- UMVOQQDNEYOJOK-UHFFFAOYSA-N 3,5-dimethylbenzoic acid Chemical compound CC1=CC(C)=CC(C(O)=O)=C1 UMVOQQDNEYOJOK-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- SCURCOWZQJIUGR-UHFFFAOYSA-N 3-(trifluoromethyl)benzenethiol Chemical compound FC(F)(F)C1=CC=CC(S)=C1 SCURCOWZQJIUGR-UHFFFAOYSA-N 0.000 description 1
- YHEYITLLMWYECH-UHFFFAOYSA-N 3-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid Chemical compound CC1(C)OB(OC1(C)C)C1=CC(=CC(F)=C1)C(=O)C1=CC(=CC(=C1)C(O)=O)B1OC(C)(C)C(C)(C)O1 YHEYITLLMWYECH-UHFFFAOYSA-N 0.000 description 1
- GZWACXGVBBELRA-UHFFFAOYSA-N 3-bromo-2-fluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(F)=C1Br GZWACXGVBBELRA-UHFFFAOYSA-N 0.000 description 1
- LXWFFEUPSMBYBS-UHFFFAOYSA-N 3-bromo-4-(bromomethyl)-5-(trifluoromethyl)benzoic acid Chemical compound C1=C(C=C(C(=C1C(F)(F)F)CBr)Br)C(=O)O LXWFFEUPSMBYBS-UHFFFAOYSA-N 0.000 description 1
- FAHZIKXYYRGSHF-UHFFFAOYSA-N 3-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1Br FAHZIKXYYRGSHF-UHFFFAOYSA-N 0.000 description 1
- HXQRAQKAGXRFEM-UHFFFAOYSA-N 3-bromo-4-fluorobenzenethiol Chemical compound FC1=CC=C(S)C=C1Br HXQRAQKAGXRFEM-UHFFFAOYSA-N 0.000 description 1
- ONELILMJNOWXSA-UHFFFAOYSA-M 3-bromo-4-fluorobenzoate Chemical compound [O-]C(=O)C1=CC=C(F)C(Br)=C1 ONELILMJNOWXSA-UHFFFAOYSA-M 0.000 description 1
- ONELILMJNOWXSA-UHFFFAOYSA-N 3-bromo-4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(Br)=C1 ONELILMJNOWXSA-UHFFFAOYSA-N 0.000 description 1
- BGQIBTIPNDMTNO-UHFFFAOYSA-N 3-bromo-4-methyl-5-methylsulfonylbenzoic acid Chemical compound CC1=C(Br)C=C(C(O)=O)C=C1S(C)(=O)=O BGQIBTIPNDMTNO-UHFFFAOYSA-N 0.000 description 1
- ZFJOMUKPDWNRFI-UHFFFAOYSA-M 3-bromo-4-methylbenzoate Chemical compound CC1=CC=C(C([O-])=O)C=C1Br ZFJOMUKPDWNRFI-UHFFFAOYSA-M 0.000 description 1
- VJHFBALSYNJCED-UHFFFAOYSA-N 3-bromo-5-[3-bromo-5-(trifluoromethyl)phenyl]sulfonylbenzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1)S(=O)(=O)C1=CC(=CC(=C1)C(F)(F)F)Br VJHFBALSYNJCED-UHFFFAOYSA-N 0.000 description 1
- XRECGLNXYCDFBH-UHFFFAOYSA-N 3-bromo-5-[[3-bromo-5-(trifluoromethyl)phenyl]-difluoromethyl]benzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1)C(F)(F)C1=CC(=CC(=C1)C(F)(F)F)Br XRECGLNXYCDFBH-UHFFFAOYSA-N 0.000 description 1
- GGVUNSZTZDPBEY-UHFFFAOYSA-N 3-bromo-5-fluorobenzenethiol Chemical compound FC1=CC(S)=CC(Br)=C1 GGVUNSZTZDPBEY-UHFFFAOYSA-N 0.000 description 1
- TXJRHFOYXQUVKW-UHFFFAOYSA-N 3-bromo-5-formyl-4-methylbenzoic acid Chemical compound BrC=1C=C(C(=O)O)C=C(C=1C)C=O TXJRHFOYXQUVKW-UHFFFAOYSA-N 0.000 description 1
- HNGQQUDFJDROPY-UHFFFAOYSA-N 3-bromobenzenethiol Chemical compound SC1=CC=CC(Br)=C1 HNGQQUDFJDROPY-UHFFFAOYSA-N 0.000 description 1
- SDKUOEOJAXGCLU-UHFFFAOYSA-N 3-chloro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1Cl SDKUOEOJAXGCLU-UHFFFAOYSA-N 0.000 description 1
- XUQCONCMPCVUDM-UHFFFAOYSA-N 3-fluoro-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1F XUQCONCMPCVUDM-UHFFFAOYSA-N 0.000 description 1
- RZODAQZAFOBFLS-UHFFFAOYSA-N 3-iodobenzaldehyde Chemical compound IC1=CC=CC(C=O)=C1 RZODAQZAFOBFLS-UHFFFAOYSA-N 0.000 description 1
- BNFRSBIMCFBJHK-UHFFFAOYSA-N 3-methyl-2-methylsulfonylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1S(C)(=O)=O BNFRSBIMCFBJHK-UHFFFAOYSA-N 0.000 description 1
- CZDWJVSOQOMYGC-UHFFFAOYSA-N 4-borono-2-fluorobenzoic acid Chemical compound OB(O)C1=CC=C(C(O)=O)C(F)=C1 CZDWJVSOQOMYGC-UHFFFAOYSA-N 0.000 description 1
- RROAIZSLTZINPA-UHFFFAOYSA-N 4-chloro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound OB1OCC2=C1C=C(C=C2Cl)C(O)=O RROAIZSLTZINPA-UHFFFAOYSA-N 0.000 description 1
- UWFGVERUNYQOIE-UHFFFAOYSA-N 4-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid Chemical compound OB1OCC2=C1C=C(C=C2F)C(O)=O UWFGVERUNYQOIE-UHFFFAOYSA-N 0.000 description 1
- WBKLSDSNRDYOJN-UHFFFAOYSA-N 4-fluoro-1-hydroxy-3h-2,1-benzoxaborole Chemical compound C1=CC=C(F)C2=C1B(O)OC2 WBKLSDSNRDYOJN-UHFFFAOYSA-N 0.000 description 1
- CAPKAYDTKWGFQB-UHFFFAOYSA-N 4-methyl-3-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(F)(F)F CAPKAYDTKWGFQB-UHFFFAOYSA-N 0.000 description 1
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical group CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- GIPODNSBTNDSML-UHFFFAOYSA-N 6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carboxylic acid Chemical compound OB1OCC2=C1C=C(F)C(=C2)C(O)=O GIPODNSBTNDSML-UHFFFAOYSA-N 0.000 description 1
- LIGKOZHDSGAHME-UHFFFAOYSA-N 7-fluoro-1-hydroxy-3h-2,1-benzoxaborole Chemical compound C1=CC(F)=C2B(O)OCC2=C1 LIGKOZHDSGAHME-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LUGFXTJIJHEVSS-UHFFFAOYSA-N C(C)(=O)OIOC(C)=O Chemical compound C(C)(=O)OIOC(C)=O LUGFXTJIJHEVSS-UHFFFAOYSA-N 0.000 description 1
- PSXLCTPHDAEPLK-UHFFFAOYSA-N CC(C)[Mg] Chemical compound CC(C)[Mg] PSXLCTPHDAEPLK-UHFFFAOYSA-N 0.000 description 1
- XWTGJEVGKWHPER-UHFFFAOYSA-N ClC=1C=C(C=CC=1)S(=O)(C1=CC(=CC=C1)Cl)=NCC(=O)OC(C)(C)C Chemical compound ClC=1C=C(C=CC=1)S(=O)(C1=CC(=CC=C1)Cl)=NCC(=O)OC(C)(C)C XWTGJEVGKWHPER-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YBTTUPKAVLJCGU-UHFFFAOYSA-N IN1C(C(CC1=O)Br)=O.IN1C(CCC1=O)=O Chemical compound IN1C(C(CC1=O)Br)=O.IN1C(CCC1=O)=O YBTTUPKAVLJCGU-UHFFFAOYSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- TWUWSMPTAVGVMJ-UHFFFAOYSA-N [2-bromo-4-iodo-6-(trifluoromethyl)phenyl]methyl acetate Chemical compound C(C)(=O)OCC1=C(C=C(C=C1C(F)(F)F)I)Br TWUWSMPTAVGVMJ-UHFFFAOYSA-N 0.000 description 1
- WZXLJRQIBCKECK-UHFFFAOYSA-N [3-(5-borono-2,4-difluorobenzoyl)-5-methoxycarbonylphenyl]boronic acid Chemical compound B(O)(O)C=1C=C(C(=O)C=2C(=CC(=C(C=2)B(O)O)F)F)C=C(C=1)C(=O)OC WZXLJRQIBCKECK-UHFFFAOYSA-N 0.000 description 1
- SJZAPSHKTOTRBQ-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-1-yl)methylidene]-dimethylazanium Chemical compound C1=CC=C2[N+](=C(N(C)C)N(C)C)N=NC2=N1 SJZAPSHKTOTRBQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- AVCOQPBBUQWIEX-UHFFFAOYSA-N acetic acid 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N(=NC(C#N)(C)C)C(C#N)(C)C.C(C)(=O)O AVCOQPBBUQWIEX-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 125000005621 boronate group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 description 1
- 238000010549 co-Evaporation Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- LFQRKUIOSYPVFY-UHFFFAOYSA-L dipotassium diacetate Chemical compound [K+].[K+].CC([O-])=O.CC([O-])=O LFQRKUIOSYPVFY-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- MPOOBUXJJDKJOG-UHFFFAOYSA-M lithium;chloride;hydrochloride Chemical compound [Li+].Cl.[Cl-] MPOOBUXJJDKJOG-UHFFFAOYSA-M 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- VONMYVUXQPKGOT-UHFFFAOYSA-N methyl 2,3-dibromo-5-fluoro-4-methylbenzoate Chemical compound BrC1=C(C(=O)OC)C=C(C(=C1Br)C)F VONMYVUXQPKGOT-UHFFFAOYSA-N 0.000 description 1
- AUQMLSDKYGMQFZ-UHFFFAOYSA-N methyl 2-fluoro-3-iodo-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(I)=C1F AUQMLSDKYGMQFZ-UHFFFAOYSA-N 0.000 description 1
- ZRXGXOINRRURRP-UHFFFAOYSA-N methyl 2-fluoro-4-(2-oxopropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=C(F)C=C(CC(C)=O)C(=C1)B1OC(C)(C)C(C)(C)O1 ZRXGXOINRRURRP-UHFFFAOYSA-N 0.000 description 1
- OSWYZVITFZFCMM-UHFFFAOYSA-N methyl 2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC=C(C)C(B2OC(C)(C)C(C)(C)O2)=C1F OSWYZVITFZFCMM-UHFFFAOYSA-N 0.000 description 1
- VKDYWLKLAIJZPL-UHFFFAOYSA-N methyl 3,5-bis(bromomethyl)benzoate Chemical compound COC(=O)C1=CC(CBr)=CC(CBr)=C1 VKDYWLKLAIJZPL-UHFFFAOYSA-N 0.000 description 1
- JITYFJMCTZXHAX-UHFFFAOYSA-N methyl 3,5-bis[(diformylamino)methyl]benzoate Chemical compound COC(=O)C1=CC(CN(C=O)C=O)=CC(CN(C=O)C=O)=C1 JITYFJMCTZXHAX-UHFFFAOYSA-N 0.000 description 1
- OWGAFGUXZHWZHK-UHFFFAOYSA-N methyl 3-benzoylsulfanyl-5-bromo-4-methylbenzoate Chemical compound C(C1=CC=CC=C1)(=O)SC=1C=C(C(=O)OC)C=C(C=1C)Br OWGAFGUXZHWZHK-UHFFFAOYSA-N 0.000 description 1
- BYRUHRFBYDFJCT-UHFFFAOYSA-N methyl 3-bromo-4-(2-oxopropyl)-5-(trifluoromethyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1CC(C)=O)C(F)(F)F BYRUHRFBYDFJCT-UHFFFAOYSA-N 0.000 description 1
- IRPLVPJDEJYBGM-UHFFFAOYSA-N methyl 3-bromo-4-(bromomethyl)-5-(trifluoromethyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1CBr)C(F)(F)F IRPLVPJDEJYBGM-UHFFFAOYSA-N 0.000 description 1
- LPQWURVUVUJPKX-UHFFFAOYSA-N methyl 3-bromo-4-methyl-5-methylsulfanylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1C)SC LPQWURVUVUJPKX-UHFFFAOYSA-N 0.000 description 1
- ZRGBIDIAIHONSF-UHFFFAOYSA-N methyl 3-bromo-4-methyl-5-methylsulfonylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1C)S(=O)(=O)C ZRGBIDIAIHONSF-UHFFFAOYSA-N 0.000 description 1
- MASRAGFWFYHMFI-UHFFFAOYSA-N methyl 3-bromo-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(Br)=C1 MASRAGFWFYHMFI-UHFFFAOYSA-N 0.000 description 1
- OIJDSGFFXDCCGY-UHFFFAOYSA-N methyl 3-bromo-5-(3-bromo-5-fluorobenzoyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1)C(C1=CC(=CC(=C1)F)Br)=O OIJDSGFFXDCCGY-UHFFFAOYSA-N 0.000 description 1
- SFIXIWISXWJMQO-UHFFFAOYSA-N methyl 3-bromo-5-(3-bromo-5-fluorophenyl)sulfanylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1)SC1=CC(=CC(=C1)F)Br SFIXIWISXWJMQO-UHFFFAOYSA-N 0.000 description 1
- SSSHVIYLUKEBCZ-UHFFFAOYSA-N methyl 3-bromo-5-(5-bromo-2,4-difluorobenzoyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1)C(C1=C(C=C(C(=C1)Br)F)F)=O SSSHVIYLUKEBCZ-UHFFFAOYSA-N 0.000 description 1
- BSWXJWAJBGXCFD-UHFFFAOYSA-N methyl 3-bromo-5-[3-bromo-5-(trifluoromethyl)phenyl]sulfanylbenzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1)SC1=CC(=CC(=C1)C(F)(F)F)Br BSWXJWAJBGXCFD-UHFFFAOYSA-N 0.000 description 1
- YIEMWQJHQKHJOW-UHFFFAOYSA-N methyl 3-bromo-5-formyl-4-methylbenzoate Chemical compound COC(=O)C1=CC(Br)=C(C)C(C=O)=C1 YIEMWQJHQKHJOW-UHFFFAOYSA-N 0.000 description 1
- YLJUMFCAQGZAIZ-UHFFFAOYSA-N methyl 3-chloro-5-iodo-4-methylbenzoate Chemical compound COC(=O)C1=CC(Cl)=C(C)C(I)=C1 YLJUMFCAQGZAIZ-UHFFFAOYSA-N 0.000 description 1
- NPXOIGSBRLCOSD-UHFFFAOYSA-N methyl 3-iodobenzoate Chemical compound COC(=O)C1=CC=CC(I)=C1 NPXOIGSBRLCOSD-UHFFFAOYSA-N 0.000 description 1
- WSWBRLCFFPJOTG-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC(B2OC(C)(C)C(C)(C)O2)=C(COC(C)=O)C(=C1)C(F)(F)F WSWBRLCFFPJOTG-UHFFFAOYSA-N 0.000 description 1
- CPDBPEBBNOXSKY-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC=C(COC(C)=O)C(B2OC(C)(C)C(C)(C)O2)=C1 CPDBPEBBNOXSKY-UHFFFAOYSA-N 0.000 description 1
- UYVZNCGLCUCRSO-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC(C(F)F)=C(COC(C)=O)C(=C1)B1OC(C)(C)C(C)(C)O1 UYVZNCGLCUCRSO-UHFFFAOYSA-N 0.000 description 1
- KLLALTMJKAMULG-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-bromo-5-(difluoromethyl)benzoate Chemical compound C(C)(=O)OCC1=C(C=C(C(=O)OC)C=C1C(F)F)Br KLLALTMJKAMULG-UHFFFAOYSA-N 0.000 description 1
- WCJCZQASQPXLBZ-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-bromo-5-(trifluoromethyl)benzoate Chemical compound BrC=1C=C(C(=O)OC)C=C(C=1COC(C)=O)C(F)(F)F WCJCZQASQPXLBZ-UHFFFAOYSA-N 0.000 description 1
- XBKBBLSWYAIMFL-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-bromobenzoate Chemical compound COC(=O)C1=CC=C(COC(C)=O)C(Br)=C1 XBKBBLSWYAIMFL-UHFFFAOYSA-N 0.000 description 1
- GNMNZWYXAHHPKF-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC(Cl)=C(COC(C)=O)C(=C1)B1OC(C)(C)C(C)(C)O1 GNMNZWYXAHHPKF-UHFFFAOYSA-N 0.000 description 1
- JFHWRMFVPLFVSW-UHFFFAOYSA-N methyl 4-(acetyloxymethyl)-5-iodo-2-(trifluoromethyl)benzoate Chemical compound C(C)(=O)OCC1=CC(=C(C(=O)OC)C=C1I)C(F)(F)F JFHWRMFVPLFVSW-UHFFFAOYSA-N 0.000 description 1
- GXBIEXNBANHJRX-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Chemical compound COC(=O)C1=CC(F)=C(CBr)C(=C1)B1OC(C)(C)C(C)(C)O1 GXBIEXNBANHJRX-UHFFFAOYSA-N 0.000 description 1
- HXRZJJNEXLYOBD-UHFFFAOYSA-N methyl 5-bromo-2-fluoro-4-methylbenzoate Chemical compound COC(=O)C1=CC(Br)=C(C)C=C1F HXRZJJNEXLYOBD-UHFFFAOYSA-N 0.000 description 1
- CQSMCYHUVCAXEJ-UHFFFAOYSA-N methyl 5-iodo-4-methyl-2-(trifluoromethyl)benzoate Chemical compound FC(C1=C(C(=O)OC)C=C(C(=C1)C)I)(F)F CQSMCYHUVCAXEJ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- FSTNQYCPXJMFMT-UHFFFAOYSA-N pentafluoro-(3-nitrophenyl)-$l^{6}-sulfane Chemical compound [O-][N+](=O)C1=CC=CC(S(F)(F)(F)(F)F)=C1 FSTNQYCPXJMFMT-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 1
- 150000003214 pyranose derivatives Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000002002 slurry Substances 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 description 1
- QJXDSDLNUKLDBP-UHFFFAOYSA-M sodium;n-formylmethanimidate Chemical compound [Na+].O=C[N-]C=O QJXDSDLNUKLDBP-UHFFFAOYSA-M 0.000 description 1
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- LFQDNHWZDQTITF-UHFFFAOYSA-N tavaborole Chemical compound FC1=CC=C2B(O)OCC2=C1 LFQDNHWZDQTITF-UHFFFAOYSA-N 0.000 description 1
- UMCLNRCYCLQFTJ-UHFFFAOYSA-N tert-butyl 2-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carbonyl)-[2-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborole-5-carbonyl)amino]ethyl]amino]acetate Chemical compound FC=1C(=CC2=C(B(OC2)O)C=1)C(=O)N(CC(=O)OC(C)(C)C)CCNC(=O)C1=CC2=C(B(OC2)O)C=C1F UMCLNRCYCLQFTJ-UHFFFAOYSA-N 0.000 description 1
- YRNJKGXSVFJWJC-UHFFFAOYSA-N tert-butyl 2-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)-[2-[(7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carbonyl)amino]ethyl]amino]acetate Chemical compound FC1=C(C=CC2=C1B(OC2)O)C(=O)N(CC(=O)OC(C)(C)C)CCNC(=O)C=1C=CC2=C(B(OC2)O)C=1F YRNJKGXSVFJWJC-UHFFFAOYSA-N 0.000 description 1
- JPHOVMGSUKPVEB-UHFFFAOYSA-N tert-butyl 2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzoyl]benzoyl]amino]acetate Chemical compound CC(C)(C)OC(=O)CNC(=O)C1=CC(=CC(=C1)C(=O)C1=CC(=CC(=C1)C(F)(F)F)B1OC(C)(C)C(C)(C)O1)B1OC(C)(C)C(C)(C)O1 JPHOVMGSUKPVEB-UHFFFAOYSA-N 0.000 description 1
- LSGHLVYZLMYVAI-UHFFFAOYSA-N tert-butyl 2-[[3-bromo-5-(3-bromophenyl)sulfonylbenzoyl]amino]acetate Chemical compound BrC=1C=C(C(=O)NCC(=O)OC(C)(C)C)C=C(C=1)S(=O)(=O)C1=CC(=CC=C1)Br LSGHLVYZLMYVAI-UHFFFAOYSA-N 0.000 description 1
- FCGLAXMHBIGMBF-UHFFFAOYSA-N tert-butyl 2-[[3-bromo-5-[[3-bromo-5-(trifluoromethyl)phenyl]-difluoromethyl]benzoyl]amino]acetate Chemical compound BrC=1C=C(C(=O)NCC(=O)OC(C)(C)C)C=C(C=1)C(F)(F)C1=CC(=CC(=C1)C(F)(F)F)Br FCGLAXMHBIGMBF-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 239000007966 viscous suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q3/00—Condition responsive control processes
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B30/00—Methods of screening libraries
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B30/00—Methods of screening libraries
- C40B30/04—Methods of screening libraries by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B30/00—Methods of screening libraries
- C40B30/10—Methods of screening libraries by measuring physical properties, e.g. mass
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
- G01N24/088—Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
- G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6827—Total protein determination, e.g. albumin in urine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/76—Assays involving albumins other than in routine use for blocking surfaces or for anchoring haptens during immunisation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
- G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Pathology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Food Science & Technology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Cell Biology (AREA)
- High Energy & Nuclear Physics (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
- Bioinformatics & Computational Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2023051919A JP7622123B2 (ja) | 2017-11-09 | 2023-03-28 | ジボロン化合物および糖尿病関連ペプチドまたはタンパク質を含むジボロンコンジュゲートならびに1-ヒドロキシ-4-(トリフルオロメチル)-1,3-ジヒドロベンゾ[c][1,2]オキサボロール-6-カルボン酸 |
| JP2025005534A JP2025061325A (ja) | 2017-11-09 | 2025-01-15 | グルコース感受性アルブミン結合誘導体 |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17200734.6 | 2017-11-09 | ||
| EP17200734 | 2017-11-09 | ||
| EP18178294 | 2018-06-18 | ||
| EP18178294.7 | 2018-06-18 | ||
| PCT/EP2018/080650 WO2019092125A1 (en) | 2017-11-09 | 2018-11-08 | Glucose-sensitive albumin-binding derivatives |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2023051919A Division JP7622123B2 (ja) | 2017-11-09 | 2023-03-28 | ジボロン化合物および糖尿病関連ペプチドまたはタンパク質を含むジボロンコンジュゲートならびに1-ヒドロキシ-4-(トリフルオロメチル)-1,3-ジヒドロベンゾ[c][1,2]オキサボロール-6-カルボン酸 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2021502372A JP2021502372A (ja) | 2021-01-28 |
| JP2021502372A5 JP2021502372A5 (enExample) | 2021-11-18 |
| JP7254792B2 true JP7254792B2 (ja) | 2023-04-10 |
Family
ID=64049277
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020525911A Active JP7254792B2 (ja) | 2017-11-09 | 2018-11-08 | グルコース感受性アルブミン結合誘導体 |
| JP2023051919A Active JP7622123B2 (ja) | 2017-11-09 | 2023-03-28 | ジボロン化合物および糖尿病関連ペプチドまたはタンパク質を含むジボロンコンジュゲートならびに1-ヒドロキシ-4-(トリフルオロメチル)-1,3-ジヒドロベンゾ[c][1,2]オキサボロール-6-カルボン酸 |
| JP2025005534A Pending JP2025061325A (ja) | 2017-11-09 | 2025-01-15 | グルコース感受性アルブミン結合誘導体 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2023051919A Active JP7622123B2 (ja) | 2017-11-09 | 2023-03-28 | ジボロン化合物および糖尿病関連ペプチドまたはタンパク質を含むジボロンコンジュゲートならびに1-ヒドロキシ-4-(トリフルオロメチル)-1,3-ジヒドロベンゾ[c][1,2]オキサボロール-6-カルボン酸 |
| JP2025005534A Pending JP2025061325A (ja) | 2017-11-09 | 2025-01-15 | グルコース感受性アルブミン結合誘導体 |
Country Status (7)
| Country | Link |
|---|---|
| US (4) | US11186595B2 (enExample) |
| EP (2) | EP3707145B1 (enExample) |
| JP (3) | JP7254792B2 (enExample) |
| CN (2) | CN111315751B (enExample) |
| ES (1) | ES2956032T3 (enExample) |
| MA (2) | MA50552A (enExample) |
| WO (1) | WO2019092125A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2025061325A (ja) * | 2017-11-09 | 2025-04-10 | ノヴォ ノルディスク アー/エス | グルコース感受性アルブミン結合誘導体 |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3291828A4 (en) | 2015-05-06 | 2018-10-03 | Alborz Mahdavi | Glucose responsive insulins |
| TW202112397A (zh) * | 2019-03-29 | 2021-04-01 | 丹麥商諾佛.儂迪克股份有限公司 | 葡萄糖敏感型胰島素衍生物 |
| CN112174989B (zh) * | 2019-07-02 | 2023-06-20 | 江西同和药业股份有限公司 | 一种克立硼罗的制备方法 |
| JP2022543586A (ja) * | 2019-07-31 | 2022-10-13 | サーマリン インコーポレイテッド | グルコース調節型立体配座スイッチを有するインスリン類似体 |
| MX2022012208A (es) * | 2020-03-31 | 2022-12-15 | Protomer Tech Inc | Conjugados para reactividad selectiva a dioles vecinales. |
| US20240374735A1 (en) * | 2020-11-19 | 2024-11-14 | Protomer Technologies Inc. | Aromatic boron-containing compounds and insulin analogs |
| EP4255468A4 (en) * | 2020-12-02 | 2024-06-05 | The Regents of University of California | Injectable biodegradable polymeric complex for glucose-responsive insulin delivery |
| WO2022235691A1 (en) * | 2021-05-03 | 2022-11-10 | The Trustees Of Indiana University | Molecular design of glucose sensors in glucose-responsive insulin analogues |
| CN114478597B (zh) * | 2021-12-29 | 2023-08-29 | 宁波大学 | 一种快速识别葡萄糖手性的试剂及其制备方法和应用 |
| US12139502B2 (en) | 2022-05-18 | 2024-11-12 | Protomer Technologies Inc. | Aromatic boron-containing compounds and related insulin analogs |
| KR20250165660A (ko) * | 2023-04-11 | 2025-11-26 | 프로토머 테크놀로지스 인크. | 1개 이상의 디보로네이트를 함유하는 화합물 및 관련 인슐린 유사체 |
| KR20250015926A (ko) | 2023-07-18 | 2025-02-03 | 노보 노르디스크 에이/에스 | 인슐린 유도체의 약학적 조성물 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003535106A (ja) | 2000-06-02 | 2003-11-25 | ノボ ノルディスク アクティーゼルスカブ | グルコース検知性インスリン誘導体からの、インスリンのグルコース依存性放出 |
| US20150320837A1 (en) | 2012-12-12 | 2015-11-12 | Massachusetts Institute Of Technology | Insulin derivatives for diabetes treatment |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR930001305B1 (ko) | 1989-10-19 | 1993-02-25 | 니뽕 유우시 가부시끼가이샤 | 당 응답형 고분자 복합체(Polymer Complexes of Sugar Response Type) |
| US7316999B2 (en) * | 2000-06-02 | 2008-01-08 | Novo Nordisk A/S | Glucose dependent release of insulin from glucose sensing insulin derivatives |
| AU2002349295A1 (en) | 2001-12-02 | 2003-06-17 | Novo Nordisk A/S | Glucose dependant release of insulin from glucose sensing insulin derivatives |
| US7317000B2 (en) | 2001-12-02 | 2008-01-08 | Novo Nordisk A/S | Glucose-dependent insulins |
| WO2003105860A1 (en) | 2002-06-14 | 2003-12-24 | Novo Nordisk A/S | Pharmaceutical use of boronic acids and esters thereof |
| CN101970477B (zh) | 2008-03-14 | 2014-12-31 | 诺沃-诺迪斯克有限公司 | 蛋白酶稳定的胰岛素类似物 |
| DE102008052314A1 (de) * | 2008-10-15 | 2010-04-22 | Syntatec Chemicals Gmbh | Aromatische und heteroaromatische Poly-trifluoroborate und Verfahren zur Herstellung |
| ES2611040T3 (es) | 2009-06-30 | 2017-05-04 | Novo Nordisk A/S | Derivados de insulina |
| TWI458732B (zh) * | 2012-06-27 | 2014-11-01 | Univ Nat Chiao Tung | 具硼酸基團連接子及含有其之生物感測元件 |
| WO2015097276A1 (en) * | 2013-12-23 | 2015-07-02 | Syngenta Participations Ag | Benzoxaborole fungicides |
| WO2015106292A1 (en) * | 2014-01-13 | 2015-07-16 | Coferon, Inc. | Bcr-abl tyrosine-kinase ligands capable of dimerizing in an aqueous solution, and methods of using same |
| AR103397A1 (es) * | 2015-01-13 | 2017-05-10 | Syngenta Participations Ag | Oxoborazoles microbicidas |
| EP3270949B1 (en) | 2015-03-13 | 2025-01-29 | Case Western Reserve University | Insulin analogues containing a glucose-regulated conformational switch |
| EP3291828A4 (en) | 2015-05-06 | 2018-10-03 | Alborz Mahdavi | Glucose responsive insulins |
| UA121354C2 (uk) * | 2016-05-12 | 2020-05-12 | Анакор Фармасутікалз, Інк. | Нові сполуки для лікування паразитарних захворювань |
| US10690675B2 (en) * | 2017-04-14 | 2020-06-23 | Georgia Tech Research Corporation | Methods for enriching glycopeptides for global analysis of glycoproteins |
| CN111315751B (zh) | 2017-11-09 | 2023-12-12 | 诺和诺德股份有限公司 | 葡萄糖敏感性白蛋白结合衍生物 |
| EP3781147A4 (en) | 2018-04-16 | 2022-04-20 | University of Utah Research Foundation | Glucose-responsive insulin |
-
2018
- 2018-11-08 CN CN201880072571.2A patent/CN111315751B/zh active Active
- 2018-11-08 CN CN202311566982.6A patent/CN117624207A/zh active Pending
- 2018-11-08 MA MA050552A patent/MA50552A/fr unknown
- 2018-11-08 MA MA71363A patent/MA71363A/fr unknown
- 2018-11-08 ES ES18795692T patent/ES2956032T3/es active Active
- 2018-11-08 WO PCT/EP2018/080650 patent/WO2019092125A1/en not_active Ceased
- 2018-11-08 JP JP2020525911A patent/JP7254792B2/ja active Active
- 2018-11-08 EP EP18795692.5A patent/EP3707145B1/en active Active
- 2018-11-08 US US16/759,378 patent/US11186595B2/en active Active
- 2018-11-08 EP EP23172873.4A patent/EP4227313B1/en active Active
-
2021
- 2021-10-13 US US17/500,242 patent/US11767332B2/en active Active
-
2023
- 2023-03-28 JP JP2023051919A patent/JP7622123B2/ja active Active
- 2023-06-16 US US18/210,763 patent/US12227528B2/en active Active
-
2024
- 2024-12-18 US US18/985,160 patent/US20250122226A1/en active Pending
-
2025
- 2025-01-15 JP JP2025005534A patent/JP2025061325A/ja active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003535106A (ja) | 2000-06-02 | 2003-11-25 | ノボ ノルディスク アクティーゼルスカブ | グルコース検知性インスリン誘導体からの、インスリンのグルコース依存性放出 |
| US20150320837A1 (en) | 2012-12-12 | 2015-11-12 | Massachusetts Institute Of Technology | Insulin derivatives for diabetes treatment |
Non-Patent Citations (1)
| Title |
|---|
| Hoeg-Jensen, Thomas,Preparationand screening of diboronate arrays for identification of carbohydrate binders,QSAR &Combinatorial Science,2004年,Vol.23, No.5,pp.344-351 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2025061325A (ja) * | 2017-11-09 | 2025-04-10 | ノヴォ ノルディスク アー/エス | グルコース感受性アルブミン結合誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| US11767332B2 (en) | 2023-09-26 |
| EP3707145A1 (en) | 2020-09-16 |
| US11186595B2 (en) | 2021-11-30 |
| CN111315751B (zh) | 2023-12-12 |
| MA71363A (fr) | 2025-04-30 |
| EP4227313A1 (en) | 2023-08-16 |
| EP4227313B1 (en) | 2025-10-22 |
| JP2025061325A (ja) | 2025-04-10 |
| CN111315751A (zh) | 2020-06-19 |
| JP7622123B2 (ja) | 2025-01-27 |
| US12227528B2 (en) | 2025-02-18 |
| EP3707145C0 (en) | 2023-06-21 |
| EP4227313C0 (en) | 2025-10-22 |
| US20230331745A1 (en) | 2023-10-19 |
| US20200325160A1 (en) | 2020-10-15 |
| EP3707145B1 (en) | 2023-06-21 |
| MA50552A (fr) | 2020-09-16 |
| US20220081451A1 (en) | 2022-03-17 |
| ES2956032T3 (es) | 2023-12-12 |
| JP2021502372A (ja) | 2021-01-28 |
| US20250122226A1 (en) | 2025-04-17 |
| JP2023080126A (ja) | 2023-06-08 |
| WO2019092125A1 (en) | 2019-05-16 |
| CN117624207A (zh) | 2024-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7254792B2 (ja) | グルコース感受性アルブミン結合誘導体 | |
| JP7640462B2 (ja) | グルコース感受性インスリン誘導体 | |
| CN113164763A (zh) | Nlrp3抑制剂 | |
| CN113474338A (zh) | 吡嗪类衍生物及其在抑制shp2中的应用 | |
| EA027120B1 (ru) | Противофиброзные пиридиноны | |
| CN113423691A (zh) | 肽结合剂 | |
| CN106163509A (zh) | 作为化疗剂的β‑取代的β‑氨基酸及类似物 | |
| JP2005504040A (ja) | カテプシンK阻害剤としてのα−ケトアミド誘導体 | |
| AU2020360342A1 (en) | Sulfo-substituted biaryl compound or salt thereof, preparation method therefor, and use thereof | |
| CN120289354A (zh) | 五元并六元化合物、其中间体、制备方法、组合物和应用 | |
| CN102131802A (zh) | 用作凝血酶抑制剂的新型杂环甲酰胺 | |
| EP2470514B1 (fr) | Pseudo-dipeptides comme inhibiteurs de mmp | |
| EP4545517A1 (en) | Nav1.8 inhibitor | |
| HK40057173A (en) | Nlrp3 inhibitors | |
| HK40061204A (en) | Pyrazine derivative and application thereof in inhibiting shp2 | |
| HK1246280A1 (en) | Pyridine derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211004 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211004 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220915 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220920 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221215 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230227 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230329 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7254792 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |