JP5236499B2 - グルコキナーゼ活性化剤 - Google Patents

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Publication number

JP5236499B2

JP5236499B2 JP2008552395A JP2008552395A JP5236499B2 JP 5236499 B2 JP5236499 B2 JP 5236499B2 JP 2008552395 A JP2008552395 A JP 2008552395A JP 2008552395 A JP2008552395 A JP 2008552395A JP 5236499 B2 JP5236499 B2 JP 5236499B2

Authority

JP

Japan

Prior art keywords

alkyl

mmol

heteroaryl

saturated

partially unsaturated

Prior art date

2006-01-27

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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• 229940124828 glucokinase activator Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 289
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 55
• 208000035475 disorder Diseases 0.000 claims abstract description 30
• 208000002705 Glucose Intolerance Diseases 0.000 claims abstract description 12
• 201000009104 prediabetes syndrome Diseases 0.000 claims abstract description 12
• -1 CF 3 Chemical group 0.000 claims description 293
• 125000000217 alkyl group Chemical group 0.000 claims description 157
• 125000000623 heterocyclic group Chemical group 0.000 claims description 146
• 229920006395 saturated elastomer Polymers 0.000 claims description 136
• 125000001072 heteroaryl group Chemical group 0.000 claims description 107
• 229910052720 vanadium Inorganic materials 0.000 claims description 89
• 125000003342 alkenyl group Chemical group 0.000 claims description 87
• 125000000304 alkynyl group Chemical group 0.000 claims description 87
• 125000003118 aryl group Chemical group 0.000 claims description 85
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 76
• 229910052731 fluorine Inorganic materials 0.000 claims description 58
• 229910052794 bromium Inorganic materials 0.000 claims description 53
• 229910052801 chlorine Inorganic materials 0.000 claims description 51
• 229910052740 iodine Inorganic materials 0.000 claims description 49
• 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 claims description 44
• 239000008103 glucose Substances 0.000 claims description 43
• 239000000203 mixture Substances 0.000 claims description 37
• 125000004043 oxo group Chemical group O=* 0.000 claims description 36
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 229910052757 nitrogen Inorganic materials 0.000 claims description 32
• 125000004429 atom Chemical group 0.000 claims description 28
• 239000003814 drug Substances 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 27
• 229910052799 carbon Inorganic materials 0.000 claims description 24
• 229910052760 oxygen Inorganic materials 0.000 claims description 24
• 150000003839 salts Chemical class 0.000 claims description 21
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 21
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000005842 heteroatom Chemical group 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 14
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 12
• 125000002947 alkylene group Chemical group 0.000 claims description 11
• 229910004013 NO 2 Inorganic materials 0.000 claims description 10
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
• 125000004450 alkenylene group Chemical group 0.000 claims description 9
• 125000002619 bicyclic group Chemical group 0.000 claims description 9
• 201000001421 hyperglycemia Diseases 0.000 claims description 9
• 125000002950 monocyclic group Chemical group 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 125000004419 alkynylene group Chemical group 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 2
• 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 2
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• 125000005493 quinolyl group Chemical group 0.000 claims description 2
• 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 claims description 2
• ZRHUHDUEXWHZMA-UHFFFAOYSA-N 1,4-dihydropyrazol-5-one Chemical compound O=C1CC=NN1 ZRHUHDUEXWHZMA-UHFFFAOYSA-N 0.000 claims 1
• LJKOFHPXVQFIQA-UHFFFAOYSA-N 1-[4-[2-[[4-(2,6-dichlorophenyl)sulfanylpyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(SC=3C(=CC=CC=3Cl)Cl)C=2)=N1 LJKOFHPXVQFIQA-UHFFFAOYSA-N 0.000 claims 1
• ZNEVZQJMMIYNCM-UHFFFAOYSA-N 1-[4-[2-[[4-(2,6-dimethylphenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3C)C)C=2)=N1 ZNEVZQJMMIYNCM-UHFFFAOYSA-N 0.000 claims 1
• UTIDUWCJLKFEMM-UHFFFAOYSA-N 1-[4-[2-[[4-(2-chloro-6-methylphenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3C)Cl)C=2)=N1 UTIDUWCJLKFEMM-UHFFFAOYSA-N 0.000 claims 1
• GBASZHHIBQYYME-UHFFFAOYSA-N 1-[4-[2-[[4-(2-chlorophenoxy)pyridin-2-yl]amino]-1,3-thiazol-4-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=CC=3)Cl)C=2)=N1 GBASZHHIBQYYME-UHFFFAOYSA-N 0.000 claims 1
• GKGPSKQWWOBPCF-UHFFFAOYSA-N 3-[2-[[3-(1-acetylpiperidin-4-yl)-1,2,4-thiadiazol-5-yl]amino]-5-bromopyridin-4-yl]oxy-4-chloro-n-[2-(dimethylamino)ethyl]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=C(Cl)C(OC=2C(=CN=C(NC=3SN=C(N=3)C3CCN(CC3)C(C)=O)C=2)Br)=C1 GKGPSKQWWOBPCF-UHFFFAOYSA-N 0.000 claims 1
• CJTXXGSSOGGONY-UHFFFAOYSA-N 3-[2-[[4-(1-acetylpiperidin-4-yl)-1,3-thiazol-2-yl]amino]pyridin-4-yl]oxypyridine-4-carbonitrile Chemical compound C1CN(C(=O)C)CCC1C1=CSC(NC=2N=CC=C(OC=3C(=CC=NC=3)C#N)C=2)=N1 CJTXXGSSOGGONY-UHFFFAOYSA-N 0.000 claims 1
• 125000001589 carboacyl group Chemical group 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 54
• 102000030595 Glucokinase Human genes 0.000 abstract description 53
• 108010021582 Glucokinase Proteins 0.000 abstract description 53
• 206010012601 diabetes mellitus Diseases 0.000 abstract description 35
• 230000000694 effects Effects 0.000 abstract description 20
• 230000001404 mediated effect Effects 0.000 abstract description 14
• 230000003213 activating effect Effects 0.000 abstract description 9
• 208000037765 diseases and disorders Diseases 0.000 abstract description 7
• 230000006806 disease prevention Effects 0.000 abstract description 2
• 206010056997 Impaired fasting glucose Diseases 0.000 abstract 3
• 230000002950 deficient Effects 0.000 abstract 1
• 230000001771 impaired effect Effects 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 248
• 238000000034 method Methods 0.000 description 219
• 238000005481 NMR spectroscopy Methods 0.000 description 175
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 132
• 238000002360 preparation method Methods 0.000 description 127
• 239000011541 reaction mixture Substances 0.000 description 121
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 116
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 105
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 104
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
• 235000019439 ethyl acetate Nutrition 0.000 description 92
• 239000007787 solid Substances 0.000 description 92
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 82
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 76
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
• 238000006243 chemical reaction Methods 0.000 description 71
• 238000001819 mass spectrum Methods 0.000 description 68
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 53
• 229910000160 potassium phosphate Inorganic materials 0.000 description 52
• 235000011009 potassium phosphates Nutrition 0.000 description 52
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
• 239000000243 solution Substances 0.000 description 48
• 229910000104 sodium hydride Inorganic materials 0.000 description 43
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 43
• OUQMXTJYCAJLGO-UHFFFAOYSA-N 4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(N)=N1 OUQMXTJYCAJLGO-UHFFFAOYSA-N 0.000 description 42
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 41
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 40
• LIEPVGBDUYKPLC-UHFFFAOYSA-N 2-chloro-4-nitropyridine Chemical compound [O-][N+](=O)C1=CC=NC(Cl)=C1 LIEPVGBDUYKPLC-UHFFFAOYSA-N 0.000 description 40
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 40
• 239000012312 sodium hydride Substances 0.000 description 40
• 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 38
• 239000002480 mineral oil Substances 0.000 description 38
• 235000010446 mineral oil Nutrition 0.000 description 38
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 37
• 239000012044 organic layer Substances 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
• 239000000047 product Substances 0.000 description 34
• 239000000543 intermediate Substances 0.000 description 31
• 239000003921 oil Substances 0.000 description 29
• 201000010099 disease Diseases 0.000 description 25
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
• HVHKUWRSDVJVIH-UHFFFAOYSA-N n-[5-bromo-4-(2,6-difluorophenoxy)pyridin-2-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(NC=2N=CC(Br)=C(OC=3C(=CC=CC=3F)F)C=2)=N1 HVHKUWRSDVJVIH-UHFFFAOYSA-N 0.000 description 22
• 102000004877 Insulin Human genes 0.000 description 19
• 108090001061 Insulin Proteins 0.000 description 19
• 229940125396 insulin Drugs 0.000 description 19
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
• 239000002585 base Substances 0.000 description 18
• 239000012267 brine Substances 0.000 description 18
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• 125000001424 substituent group Chemical group 0.000 description 18
• 125000004404 heteroalkyl group Chemical group 0.000 description 17
• 239000002904 solvent Substances 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 16
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 125000001309 chloro group Chemical group Cl* 0.000 description 15
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
• 229910052938 sodium sulfate Inorganic materials 0.000 description 15
• 235000011152 sodium sulphate Nutrition 0.000 description 15
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 14
• 125000001246 bromo group Chemical group Br* 0.000 description 14
• 229940079593 drug Drugs 0.000 description 14
• 150000003254 radicals Chemical class 0.000 description 14
• 239000004215 Carbon black (E152) Substances 0.000 description 13
• 239000012039 electrophile Substances 0.000 description 13
• 229930195733 hydrocarbon Natural products 0.000 description 13
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 12
• 239000012954 diazonium Substances 0.000 description 12
• 150000001989 diazonium salts Chemical class 0.000 description 12
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 12
• 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 11
• 125000004432 carbon atom Chemical group C* 0.000 description 11
• 239000003054 catalyst Substances 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 239000000463 material Substances 0.000 description 11
• 239000000843 powder Substances 0.000 description 11
• 239000000741 silica gel Substances 0.000 description 11
• 229910002027 silica gel Inorganic materials 0.000 description 11
• RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 10
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 10
• AJVLUWIRLKEYEX-UHFFFAOYSA-N 2-chloro-4-(2-methylphenyl)sulfanylpyridine Chemical compound CC1=CC=CC=C1SC1=CC=NC(Cl)=C1 AJVLUWIRLKEYEX-UHFFFAOYSA-N 0.000 description 10
• QMHIMXFNBOYPND-UHFFFAOYSA-N 4-methylthiazole Chemical compound CC1=CSC=N1 QMHIMXFNBOYPND-UHFFFAOYSA-N 0.000 description 10
• BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 10
• 239000008280 blood Substances 0.000 description 10
• 210000004369 blood Anatomy 0.000 description 10
• 239000013058 crude material Substances 0.000 description 10
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• 229940124597 therapeutic agent Drugs 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 9
• 239000003112 inhibitor Substances 0.000 description 9
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