DE60215028T2 - Indol derivate als beta-3-adrenerge agonisten zur behandlung von typ 2 diabetes - Google Patents

Info

Publication number

DE60215028T2

DE60215028T2 DE60215028T DE60215028T DE60215028T2 DE 60215028 T2 DE60215028 T2 DE 60215028T2 DE 60215028 T DE60215028 T DE 60215028T DE 60215028 T DE60215028 T DE 60215028T DE 60215028 T2 DE60215028 T2 DE 60215028T2

Authority

DE

Germany

Prior art keywords

mmol

alkyl

amine

mixture

phenyl

Prior art date

2001-08-14

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.)

Expired - Fee Related

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• 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 16
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 14
• 239000000556 agonist Substances 0.000 title description 10
• 150000003839 salts Chemical class 0.000 claims abstract description 21
• 208000008589 Obesity Diseases 0.000 claims abstract description 16
• 235000020824 obesity Nutrition 0.000 claims abstract description 16
• 150000001875 compounds Chemical class 0.000 claims description 165
• -1 D is NR 8 Inorganic materials 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 41
• 239000002904 solvent Substances 0.000 claims description 38
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
• 229910052799 carbon Inorganic materials 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 19
• 150000003536 tetrazoles Chemical class 0.000 claims description 16
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 16
• 125000000623 heterocyclic group Chemical group 0.000 claims description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 150000002367 halogens Chemical class 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 claims description 10
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 8
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 150000003852 triazoles Chemical class 0.000 claims description 8
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 7
• KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical group C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 6
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 6
• 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000001544 thienyl group Chemical group 0.000 claims description 4
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
• 229910052717 sulfur Inorganic materials 0.000 claims description 3
• 229930192474 thiophene Natural products 0.000 claims description 3
• 125000002837 carbocyclic group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 125000004043 oxo group Chemical group O=* 0.000 claims 1
• 230000004130 lipolysis Effects 0.000 abstract description 2
• 229940126158 β3 adrenergic receptor agonist Drugs 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 396
• 150000001412 amines Chemical class 0.000 description 222
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
• 239000000203 mixture Substances 0.000 description 181
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 173
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 166
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 151
• 239000000243 solution Substances 0.000 description 133
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
• 238000000434 field desorption mass spectrometry Methods 0.000 description 72
• 239000011541 reaction mixture Substances 0.000 description 60
• 150000002924 oxiranes Chemical class 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
• 238000000034 method Methods 0.000 description 52
• 238000006243 chemical reaction Methods 0.000 description 50
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• 239000012267 brine Substances 0.000 description 46
• 239000012074 organic phase Substances 0.000 description 46
• 239000011734 sodium Substances 0.000 description 46
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 46
• 239000000460 chlorine Substances 0.000 description 37
• 239000012458 free base Substances 0.000 description 37
• 239000000047 product Substances 0.000 description 37
• 238000010992 reflux Methods 0.000 description 37
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• 238000002360 preparation method Methods 0.000 description 36
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• 238000003756 stirring Methods 0.000 description 31
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
• 238000003818 flash chromatography Methods 0.000 description 28
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 26
• 239000000706 filtrate Substances 0.000 description 24
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
• 239000000284 extract Substances 0.000 description 22
• 102000005962 receptors Human genes 0.000 description 21
• 108020003175 receptors Proteins 0.000 description 21
• 229910004298 SiO 2 Inorganic materials 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 229910052938 sodium sulfate Inorganic materials 0.000 description 20
• 235000011152 sodium sulphate Nutrition 0.000 description 20
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• 239000004593 Epoxy Substances 0.000 description 18
• 239000012071 phase Substances 0.000 description 18
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 17
• AIHIHVZYAAMDPM-QMMMGPOBSA-N [(2s)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@H]2OC2)=C1 AIHIHVZYAAMDPM-QMMMGPOBSA-N 0.000 description 16
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 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 14
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 13
• 229910021529 ammonia Inorganic materials 0.000 description 13
• 238000010828 elution Methods 0.000 description 13
• 229920006395 saturated elastomer Polymers 0.000 description 13
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
• 238000001914 filtration Methods 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• 239000002002 slurry Substances 0.000 description 12
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
• 239000008346 aqueous phase Substances 0.000 description 11
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical class C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
• 238000000746 purification Methods 0.000 description 11
• 238000010898 silica gel chromatography Methods 0.000 description 11
• BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 10
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 10
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
• ZEMSPQCZQNWQGR-UHFFFAOYSA-N [3-[2-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-1h-indol-7-yl] trifluoromethanesulfonate Chemical compound C1=CC=C2C(CC(C)(C)NC(=O)OC(C)(C)C)=CNC2=C1OS(=O)(=O)C(F)(F)F ZEMSPQCZQNWQGR-UHFFFAOYSA-N 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 10
• 150000001502 aryl halides Chemical class 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
• 241001465754 Metazoa Species 0.000 description 9
• 229910052786 argon Inorganic materials 0.000 description 9
• 238000001704 evaporation Methods 0.000 description 9
• 230000008020 evaporation Effects 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• 229910000104 sodium hydride Inorganic materials 0.000 description 8
• KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 8
• 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 8
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 7
• 241000282414 Homo sapiens Species 0.000 description 7
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 239000003480 eluent Substances 0.000 description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
• 239000011737 fluorine Substances 0.000 description 7
• 229910052731 fluorine Inorganic materials 0.000 description 7
• 238000009472 formulation Methods 0.000 description 7
• 229910052763 palladium Inorganic materials 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 6
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
• 239000004480 active ingredient Substances 0.000 description 6
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
• 239000012043 crude product Substances 0.000 description 6
• 239000005457 ice water Substances 0.000 description 6
• 238000004007 reversed phase HPLC Methods 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 229910000029 sodium carbonate Inorganic materials 0.000 description 6
• 238000005406 washing Methods 0.000 description 6
• REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 5
• KLAIOABSDQUNSA-WUKNDPDISA-N 3-[(e)-octadec-2-enyl]oxolane-2,5-dione Chemical compound CCCCCCCCCCCCCCC\C=C\CC1CC(=O)OC1=O KLAIOABSDQUNSA-WUKNDPDISA-N 0.000 description 5
• CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 5
• 239000007868 Raney catalyst Substances 0.000 description 5
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
• 229910000564 Raney nickel Inorganic materials 0.000 description 5
• 238000006069 Suzuki reaction reaction Methods 0.000 description 5
• 239000002253 acid Substances 0.000 description 5
• 239000012298 atmosphere Substances 0.000 description 5
• 229910002092 carbon dioxide Inorganic materials 0.000 description 5
• 229910052801 chlorine Inorganic materials 0.000 description 5
• 208000035475 disorder Diseases 0.000 description 5
• 230000000694 effects Effects 0.000 description 5
• 230000014509 gene expression Effects 0.000 description 5
• 239000004615 ingredient Substances 0.000 description 5
• 239000012280 lithium aluminium hydride Substances 0.000 description 5
• 239000002609 medium Substances 0.000 description 5
• 239000012299 nitrogen atmosphere Substances 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 230000008569 process Effects 0.000 description 5
• 150000003254 radicals Chemical class 0.000 description 5
• LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 5
• GLDWVEMBLRENOV-UHFFFAOYSA-N tert-butyl n-[1-[7-(cyanomethoxy)-1h-indol-3-yl]-2-methylpropan-2-yl]carbamate Chemical compound C1=CC=C2C(CC(C)(C)NC(=O)OC(C)(C)C)=CNC2=C1OCC#N GLDWVEMBLRENOV-UHFFFAOYSA-N 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
• ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 4
• 108060003345 Adrenergic Receptor Proteins 0.000 description 4
• 102000017910 Adrenergic receptor Human genes 0.000 description 4
• 206010020772 Hypertension Diseases 0.000 description 4
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
• BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
• 238000005576 amination reaction Methods 0.000 description 4
• 235000010338 boric acid Nutrition 0.000 description 4
• 238000005341 cation exchange Methods 0.000 description 4
• 239000010779 crude oil Substances 0.000 description 4
• 239000006185 dispersion Substances 0.000 description 4
• 239000011521 glass Substances 0.000 description 4
• 238000010438 heat treatment Methods 0.000 description 4
• 238000005984 hydrogenation reaction Methods 0.000 description 4
• 230000007062 hydrolysis Effects 0.000 description 4
• 238000006460 hydrolysis reaction Methods 0.000 description 4
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
• 239000000463 material Substances 0.000 description 4
• 239000002480 mineral oil Substances 0.000 description 4
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