EA014720B1 - Соединения и способы модуляции fxr - Google Patents

Info

Publication number

EA014720B1

EA014720B1 EA200870569A EA200870569A EA014720B1 EA 014720 B1 EA014720 B1 EA 014720B1 EA 200870569 A EA200870569 A EA 200870569A EA 200870569 A EA200870569 A EA 200870569A EA 014720 B1 EA014720 B1 EA 014720B1

Authority

EA

Eurasian Patent Office

Prior art keywords

isopropyl

hydrogen

group

alkyl

dichlorophenyl

Prior art date

2006-05-24

Links

• Espacenet
• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 198
• 238000000034 method Methods 0.000 title abstract description 44
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
• 201000010099 disease Diseases 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
• -1 benzoisothiazolyl Chemical group 0.000 claims description 119
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• 229910052739 hydrogen Inorganic materials 0.000 claims description 55
• 239000001257 hydrogen Substances 0.000 claims description 49
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
• 229910052801 chlorine Inorganic materials 0.000 claims description 42
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 42
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 41
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 39
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 37
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
• 125000001424 substituent group Chemical group 0.000 claims description 27
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
• 125000001153 fluoro group Chemical group F* 0.000 claims description 22
• 229910052731 fluorine Inorganic materials 0.000 claims description 20
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 20
• 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 19
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 18
• 125000001041 indolyl group Chemical group 0.000 claims description 18
• 239000000460 chlorine Substances 0.000 claims description 17
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 125000000217 alkyl group Chemical group 0.000 claims description 13
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 11
• 239000000126 substance Substances 0.000 claims description 11
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 10
• 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 9
• 125000002541 furyl group Chemical group 0.000 claims description 9
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 9
• 125000000335 thiazolyl group Chemical group 0.000 claims description 9
• 125000001544 thienyl group Chemical group 0.000 claims description 9
• 238000011282 treatment Methods 0.000 claims description 7
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 150000003839 salts Chemical class 0.000 claims description 6
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• 229910052736 halogen Inorganic materials 0.000 claims description 5
• 150000002367 halogens Chemical class 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• WNJCAUVBQDAAFY-UHFFFAOYSA-N 6-[4-[[3-(2,6-dichlorophenyl)-5-(trifluoromethyl)triazol-4-yl]methoxy]-2-methylphenyl]-1-propan-2-ylindazole-3-carboxylic acid Chemical compound C1=C2N(C(C)C)N=C(C(O)=O)C2=CC=C1C(C(=C1)C)=CC=C1OCC1=C(C(F)(F)F)N=NN1C1=C(Cl)C=CC=C1Cl WNJCAUVBQDAAFY-UHFFFAOYSA-N 0.000 claims description 3
• BEGCLZGRPXQHPZ-UHFFFAOYSA-N 6-[4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)triazol-4-yl]methoxy]-2-methylphenyl]-1-propan-2-ylindazole-3-carboxylic acid Chemical compound C1=C2N(C(C)C)N=C(C(O)=O)C2=CC=C1C(C(=C1)C)=CC=C1OCC1=C(C2CC2)N=NN1C1=C(Cl)C=CC=C1Cl BEGCLZGRPXQHPZ-UHFFFAOYSA-N 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 21
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims 9
• YCHYFHOSGQABSW-RTBURBONSA-N (6ar,10ar)-1-hydroxy-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene-9-carboxylic acid Chemical compound C1C(C(O)=O)=CC[C@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@@H]21 YCHYFHOSGQABSW-RTBURBONSA-N 0.000 claims 2
• POPANIGZHUWMKL-UHFFFAOYSA-N 4-[[4-[[3-(2,6-dichlorophenyl)-5-(trifluoromethyl)triazol-4-yl]methoxy]-n,2-dimethylanilino]methyl]-2-methylbenzoic acid Chemical compound C=1C=C(OCC=2N(N=NC=2C(F)(F)F)C=2C(=CC=CC=2Cl)Cl)C=C(C)C=1N(C)CC1=CC=C(C(O)=O)C(C)=C1 POPANIGZHUWMKL-UHFFFAOYSA-N 0.000 claims 2
• 125000005037 alkyl phenyl group Chemical group 0.000 claims 2
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
• 208000032928 Dyslipidaemia Diseases 0.000 abstract description 14
• 208000017170 Lipid metabolism disease Diseases 0.000 abstract description 14
• 239000011541 reaction mixture Substances 0.000 description 161
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
• 239000000243 solution Substances 0.000 description 111
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 97
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
• 238000002360 preparation method Methods 0.000 description 93
• 239000000203 mixture Substances 0.000 description 78
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
• 230000002829 reductive effect Effects 0.000 description 74
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 68
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• 238000010411 cooking Methods 0.000 description 49
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
• 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 36
• 239000012044 organic layer Substances 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 32
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 31
• 239000007787 solid Substances 0.000 description 31
• 239000012267 brine Substances 0.000 description 30
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• 239000007858 starting material Substances 0.000 description 30
• 239000010410 layer Substances 0.000 description 29
• 238000006243 chemical reaction Methods 0.000 description 28
• 238000003818 flash chromatography Methods 0.000 description 28
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• 239000005711 Benzoic acid Substances 0.000 description 19
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
• 235000010233 benzoic acid Nutrition 0.000 description 17
• 239000000741 silica gel Substances 0.000 description 17
• 229910002027 silica gel Inorganic materials 0.000 description 17
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
• 235000012000 cholesterol Nutrition 0.000 description 15
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 13
• 230000015572 biosynthetic process Effects 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 239000012074 organic phase Substances 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• IJVUIOCXNVEGKH-UHFFFAOYSA-N [3-(2,6-dichlorophenyl)-5-propan-2-yltriazol-4-yl]methanol Chemical compound OCC1=C(C(C)C)N=NN1C1=C(Cl)C=CC=C1Cl IJVUIOCXNVEGKH-UHFFFAOYSA-N 0.000 description 12
• 125000005843 halogen group Chemical group 0.000 description 12
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 11
• 229910052938 sodium sulfate Inorganic materials 0.000 description 11
• 235000011152 sodium sulphate Nutrition 0.000 description 11
• 102000052567 Anaphase-Promoting Complex-Cyclosome Apc1 Subunit Human genes 0.000 description 10
• 108091006463 SLC25A24 Proteins 0.000 description 10
• 238000010828 elution Methods 0.000 description 10
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 238000004587 chromatography analysis Methods 0.000 description 9
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
• 239000011777 magnesium Substances 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• 239000012298 atmosphere Substances 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
• 235000019341 magnesium sulphate Nutrition 0.000 description 8
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• 239000006188 syrup Substances 0.000 description 8
• 235000020357 syrup Nutrition 0.000 description 8
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 7
• 108010010234 HDL Lipoproteins Proteins 0.000 description 7
• 102000015779 HDL Lipoproteins Human genes 0.000 description 7
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 7
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 108090000623 proteins and genes Proteins 0.000 description 7
• 150000003626 triacylglycerols Chemical class 0.000 description 7
• TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 7
• 229920002554 vinyl polymer Polymers 0.000 description 7
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
• 239000000556 agonist Substances 0.000 description 6
• 238000004458 analytical method Methods 0.000 description 6
• MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 150000002632 lipids Chemical class 0.000 description 6
• LHJKZERUIPGPCK-UHFFFAOYSA-N methyl 4-formyl-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1C LHJKZERUIPGPCK-UHFFFAOYSA-N 0.000 description 6
• 239000011734 sodium Substances 0.000 description 6
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
• HJMZTUQYJYZXAE-UHFFFAOYSA-N 1-[4-[[3-(2,6-dichlorophenyl)-5-propan-2-yltriazol-4-yl]methoxy]-2-methylphenyl]ethanone Chemical compound CC(C)C=1N=NN(C=2C(=CC=CC=2Cl)Cl)C=1COC1=CC=C(C(C)=O)C(C)=C1 HJMZTUQYJYZXAE-UHFFFAOYSA-N 0.000 description 5
• BYRWOSJFHWKXET-UHFFFAOYSA-N 2-azido-1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1N=[N+]=[N-] BYRWOSJFHWKXET-UHFFFAOYSA-N 0.000 description 5
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 5
• 101000587820 Homo sapiens Selenide, water dikinase 1 Proteins 0.000 description 5
• 101000701815 Homo sapiens Spermidine synthase Proteins 0.000 description 5
• 108010007622 LDL Lipoproteins Proteins 0.000 description 5
• 102000007330 LDL Lipoproteins Human genes 0.000 description 5
• 102100030413 Spermidine synthase Human genes 0.000 description 5
• 108010062497 VLDL Lipoproteins Proteins 0.000 description 5
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
• 229910000024 caesium carbonate Inorganic materials 0.000 description 5
• 229910002091 carbon monoxide Inorganic materials 0.000 description 5
• MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 5
• 235000019256 formaldehyde Nutrition 0.000 description 5
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• BMPVWNJQCJQBFW-UHFFFAOYSA-N 1,2-thiazole-3-carboxylic acid Chemical compound OC(=O)C=1C=CSN=1 BMPVWNJQCJQBFW-UHFFFAOYSA-N 0.000 description 4
• SXXNXMHOSBDART-UHFFFAOYSA-N 3-[1-[4-[[3-(2,6-dichlorophenyl)-5-propan-2-yltriazol-4-yl]methoxy]-2-methylphenyl]ethylsulfanyl]benzoic acid Chemical compound CC(C)C=1N=NN(C=2C(=CC=CC=2Cl)Cl)C=1COC(C=C1C)=CC=C1C(C)SC1=CC=CC(C(O)=O)=C1 SXXNXMHOSBDART-UHFFFAOYSA-N 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• 102100037580 Sesquipedalian-1 Human genes 0.000 description 4
• 101710169844 Sesquipedalian-1 Proteins 0.000 description 4
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
• 125000003545 alkoxy group Chemical group 0.000 description 4
• 239000007864 aqueous solution Substances 0.000 description 4
• DQDPZIRMUJBHTI-UHFFFAOYSA-N ethyl 3-(2,6-dichlorophenyl)-5-propan-2-yltriazole-4-carboxylate Chemical compound CCOC(=O)C1=C(C(C)C)N=NN1C1=C(Cl)C=CC=C1Cl DQDPZIRMUJBHTI-UHFFFAOYSA-N 0.000 description 4
• 125000004494 ethyl ester group Chemical group 0.000 description 4
• 238000004128 high performance liquid chromatography Methods 0.000 description 4
• 150000002430 hydrocarbons Chemical group 0.000 description 4
• 108020004999 messenger RNA Proteins 0.000 description 4
• KJKMOADDOGZYQC-UHFFFAOYSA-N methyl 2-(2-trimethylsilylethynyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1C#C[Si](C)(C)C KJKMOADDOGZYQC-UHFFFAOYSA-N 0.000 description 4
• PZNMWPYPPPVNFI-UHFFFAOYSA-N methyl 4-[[(4-hydroxy-2-methylphenyl)methylamino]methyl]-2-methylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC=C1CNCC1=CC=C(O)C=C1C PZNMWPYPPPVNFI-UHFFFAOYSA-N 0.000 description 4
• SFDVDNLBYGHFNF-UHFFFAOYSA-N methyl 6-bromo-1-benzothiophene-2-carboxylate Chemical compound C1=C(Br)C=C2SC(C(=O)OC)=CC2=C1 SFDVDNLBYGHFNF-UHFFFAOYSA-N 0.000 description 4
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
• 238000000746 purification Methods 0.000 description 4
• 210000002966 serum Anatomy 0.000 description 4
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• FSQOQFQTZISUJL-UHFFFAOYSA-N methyl 2-butoxy-4-methylbenzoate Chemical compound CCCCOC1=CC(C)=CC=C1C(=O)OC FSQOQFQTZISUJL-UHFFFAOYSA-N 0.000 description 2
• PSUKHRXMLRWKQF-UHFFFAOYSA-N methyl 2-methyl-4-[[methyl-[2-methyl-6-[[5-propan-2-yl-3-[2-(trifluoromethoxy)phenyl]triazol-4-yl]methoxy]pyridin-3-yl]amino]methyl]benzoate Chemical compound C1=C(C)C(C(=O)OC)=CC=C1CN(C)C(C(=N1)C)=CC=C1OCC1=C(C(C)C)N=NN1C1=CC=CC=C1OC(F)(F)F PSUKHRXMLRWKQF-UHFFFAOYSA-N 0.000 description 2
• OYDOFGBVULDGDS-UHFFFAOYSA-N methyl 3-(diethoxyphosphorylmethyl)benzoate Chemical compound CCOP(=O)(OCC)CC1=CC=CC(C(=O)OC)=C1 OYDOFGBVULDGDS-UHFFFAOYSA-N 0.000 description 2
• YGEWQXHAEMCLQA-UHFFFAOYSA-N methyl 3-[1-[4-[[3-(2,6-dichlorophenyl)-5-propan-2-yltriazol-4-yl]methoxy]-2-methylphenyl]ethylsulfanyl]benzoate Chemical compound COC(=O)C1=CC=CC(SC(C)C=2C(=CC(OCC=3N(N=NC=3C(C)C)C=3C(=CC=CC=3Cl)Cl)=CC=2)C)=C1 YGEWQXHAEMCLQA-UHFFFAOYSA-N 0.000 description 2
• SJVMXEXEYBEEHK-UHFFFAOYSA-N methyl 4-(2-bromo-4-methoxyphenyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C1=CC=C(OC)C=C1Br SJVMXEXEYBEEHK-UHFFFAOYSA-N 0.000 description 2
• JTOJTFMOZMCZKU-UHFFFAOYSA-N methyl 4-(bromomethyl)-2-butoxybenzoate Chemical compound CCCCOC1=CC(CBr)=CC=C1C(=O)OC JTOJTFMOZMCZKU-UHFFFAOYSA-N 0.000 description 2
• DSCDSFHUSZSPLM-UHFFFAOYSA-N methyl 4-(hydroxymethyl)-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(CO)C=C1C DSCDSFHUSZSPLM-UHFFFAOYSA-N 0.000 description 2
• GNEADNFRBXZVDG-UHFFFAOYSA-N methyl 4-[(2-fluoro-4-hydroxyanilino)methyl]-2-methylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC=C1CNC1=CC=C(O)C=C1F GNEADNFRBXZVDG-UHFFFAOYSA-N 0.000 description 2
• WEKDWRRJMSBWOK-UHFFFAOYSA-N methyl 4-[(4-hydroxy-2-methylphenyl)methylamino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NCC1=CC=C(O)C=C1C WEKDWRRJMSBWOK-UHFFFAOYSA-N 0.000 description 2
• PEJFTMUXOSWNSS-UHFFFAOYSA-N methyl 4-[(4-hydroxy-n,2-dimethylanilino)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN(C)C1=CC=C(O)C=C1C PEJFTMUXOSWNSS-UHFFFAOYSA-N 0.000 description 2
• CYEXEOXALMJXDI-UHFFFAOYSA-N methyl 4-bromo-2-methylbenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1C CYEXEOXALMJXDI-UHFFFAOYSA-N 0.000 description 2
• ZCPCZELMTZDPAK-UHFFFAOYSA-N methyl 5-(4-hydroxy-2-methylphenyl)-4-methylthiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC(C)=C1C1=CC=C(O)C=C1C ZCPCZELMTZDPAK-UHFFFAOYSA-N 0.000 description 2
• AALWVKQRLXHHRT-UHFFFAOYSA-N methyl 5-(4-methoxy-2-methylphenyl)-4-methylthiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC(C)=C1C1=CC=C(OC)C=C1C AALWVKQRLXHHRT-UHFFFAOYSA-N 0.000 description 2
• MFOKOKHNSVUKON-UHFFFAOYSA-N methyl 5-bromo-1H-indole-3-carboxylate Natural products C1=C(Br)C=C2C(C(=O)OC)=CNC2=C1 MFOKOKHNSVUKON-UHFFFAOYSA-N 0.000 description 2
• UYFFMVDJHCONSM-UHFFFAOYSA-N methyl 5-cyclopropyl-3-(2,6-dichlorophenyl)triazole-4-carboxylate Chemical compound COC(=O)C1=C(C2CC2)N=NN1C1=C(Cl)C=CC=C1Cl UYFFMVDJHCONSM-UHFFFAOYSA-N 0.000 description 2
• NRTWWGSSWOLVHM-UHFFFAOYSA-N methyl 6-(4-hydroxy-2-methylphenyl)-1-methylindole-3-carboxylate Chemical compound C=1C=C2C(C(=O)OC)=CN(C)C2=CC=1C1=CC=C(O)C=C1C NRTWWGSSWOLVHM-UHFFFAOYSA-N 0.000 description 2
• LFFOXNXUGCBVHQ-UHFFFAOYSA-N methyl 6-[4-[[3-(2,6-dichlorophenyl)-5-(trifluoromethyl)triazol-4-yl]methoxy]-2-methylphenyl]-1-propan-2-ylindazole-3-carboxylate Chemical compound C=1C=C2C(C(=O)OC)=NN(C(C)C)C2=CC=1C(C(=C1)C)=CC=C1OCC1=C(C(F)(F)F)N=NN1C1=C(Cl)C=CC=C1Cl LFFOXNXUGCBVHQ-UHFFFAOYSA-N 0.000 description 2
• SJICLOHNXORMBV-UHFFFAOYSA-N methyl 6-bromo-1-methylindazole-3-carboxylate Chemical compound BrC1=CC=C2C(C(=O)OC)=NN(C)C2=C1 SJICLOHNXORMBV-UHFFFAOYSA-N 0.000 description 2
• RLMWPNDSVWJWHA-UHFFFAOYSA-N methyl 6-bromo-1-methylindole-3-carboxylate Chemical compound BrC1=CC=C2C(C(=O)OC)=CN(C)C2=C1 RLMWPNDSVWJWHA-UHFFFAOYSA-N 0.000 description 2
• SKZJYJMYLUQJPG-UHFFFAOYSA-N methyl 6-bromo-1h-indole-3-carboxylate Chemical compound BrC1=CC=C2C(C(=O)OC)=CNC2=C1 SKZJYJMYLUQJPG-UHFFFAOYSA-N 0.000 description 2
• BMFSVEXJEHZDHD-UHFFFAOYSA-N methyl 6-bromo-3-indoleacetate Natural products BrC1=CC=C2C(CC(=O)OC)=CNC2=C1 BMFSVEXJEHZDHD-UHFFFAOYSA-N 0.000 description 2
• 125000006431 methyl cyclopropyl group Chemical group 0.000 description 2
• 150000004702 methyl esters Chemical class 0.000 description 2
• 239000007800 oxidant agent Substances 0.000 description 2
• 125000004430 oxygen atom Chemical group O* 0.000 description 2
• 230000001575 pathological effect Effects 0.000 description 2
• 239000012071 phase Substances 0.000 description 2
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
• 229910052700 potassium Inorganic materials 0.000 description 2
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
• 229910000160 potassium phosphate Inorganic materials 0.000 description 2
• 235000011009 potassium phosphates Nutrition 0.000 description 2
• 125000006239 protecting group Chemical group 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• 230000004044 response Effects 0.000 description 2
• 239000000523 sample Substances 0.000 description 2
• 229920006395 saturated elastomer Polymers 0.000 description 2
• 239000012047 saturated solution Substances 0.000 description 2
• 229910000029 sodium carbonate Inorganic materials 0.000 description 2
• VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical group COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 2
• 238000007920 subcutaneous administration Methods 0.000 description 2
• 238000012360 testing method Methods 0.000 description 2
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
• 238000004809 thin layer chromatography Methods 0.000 description 2
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 2
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
• UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
• VJVZPTPOYCJFNI-UHFFFAOYSA-M (2-ethoxy-2-oxoethyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC(=O)OCC)C1=CC=CC=C1 VJVZPTPOYCJFNI-UHFFFAOYSA-M 0.000 description 1
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
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• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
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