DK3009426T3 - 4-ALKYNYL-IMIDAZOLE DERIVATIVE AND MEDICINE COMPREHENSIVE AS AN ACTIVE INGREDIENT - Google Patents

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Publication number

DK3009426T3

DK3009426T3 DK14811154.5T DK14811154T DK3009426T3 DK 3009426 T3 DK3009426 T3 DK 3009426T3 DK 14811154 T DK14811154 T DK 14811154T DK 3009426 T3 DK3009426 T3 DK 3009426T3

Authority

DK

Denmark

Prior art keywords

group

mmol

compound

methyl

added

Prior art date

2013-06-12

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• 239000004480 active ingredient Substances 0.000 title claims description 6
• 101150109738 Ptger4 gene Proteins 0.000 claims abstract description 57
• 150000003839 salts Chemical class 0.000 claims abstract description 45
• 201000010099 disease Diseases 0.000 claims abstract description 35
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 35
• 208000002193 Pain Diseases 0.000 claims abstract description 32
• 230000036407 pain Effects 0.000 claims abstract description 32
• 206010061218 Inflammation Diseases 0.000 claims abstract description 18
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 11
• 150000001875 compounds Chemical class 0.000 claims description 240
• -1 acyl cyanamide Chemical compound 0.000 claims description 36
• 125000000217 alkyl group Chemical group 0.000 claims description 23
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
• 125000005843 halogen group Chemical group 0.000 claims description 20
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 239000002464 receptor antagonist Substances 0.000 claims description 12
• 229940044551 receptor antagonist Drugs 0.000 claims description 12
• 201000006417 multiple sclerosis Diseases 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
• 206010065390 Inflammatory pain Diseases 0.000 claims description 7
• 239000002253 acid Substances 0.000 claims description 7
• 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 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
• 150000001721 carbon Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
• 208000011231 Crohn disease Diseases 0.000 claims description 5
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
• 206010012442 Dermatitis contact Diseases 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
• 201000008937 atopic dermatitis Diseases 0.000 claims description 5
• 208000010247 contact dermatitis Diseases 0.000 claims description 5
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• 208000008035 Back Pain Diseases 0.000 claims description 4
• 208000008930 Low Back Pain Diseases 0.000 claims description 4
• 206010034464 Periarthritis Diseases 0.000 claims description 4
• 208000000491 Tendinopathy Diseases 0.000 claims description 4
• 206010043255 Tendonitis Diseases 0.000 claims description 4
• 230000002917 arthritic effect Effects 0.000 claims description 4
• 125000001072 heteroaryl group Chemical group 0.000 claims description 4
• 201000008482 osteoarthritis Diseases 0.000 claims description 4
• 201000004415 tendinitis Diseases 0.000 claims description 4
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 3
• 125000003118 aryl group Chemical group 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 229950000033 proxetil Drugs 0.000 claims description 3
• 229940124530 sulfonamide Drugs 0.000 claims description 3
• 150000003456 sulfonamides Chemical class 0.000 claims description 3
• 229910052717 sulfur Inorganic materials 0.000 claims description 3
• 125000004434 sulfur atom Chemical group 0.000 claims description 3
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
• 239000008177 pharmaceutical agent Substances 0.000 claims 6
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 4
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 1
• 125000000623 heterocyclic group Chemical group 0.000 claims 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
• 230000003042 antagnostic effect Effects 0.000 abstract description 25
• 239000003814 drug Substances 0.000 abstract description 25
• 230000003110 anti-inflammatory effect Effects 0.000 abstract description 17
• 208000026278 immune system disease Diseases 0.000 abstract description 14
• 230000004054 inflammatory process Effects 0.000 abstract description 13
• 210000000447 Th1 cell Anatomy 0.000 abstract description 9
• 230000004913 activation Effects 0.000 abstract description 8
• 210000000068 Th17 cell Anatomy 0.000 abstract description 7
• 230000006378 damage Effects 0.000 abstract description 6
• 239000000730 antalgic agent Substances 0.000 abstract description 5
• 230000000763 evoking effect Effects 0.000 abstract description 5
• 229940035676 analgesics Drugs 0.000 abstract description 4
• 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 4
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 306
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
• 239000000243 solution Substances 0.000 description 112
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 106
• 239000012044 organic layer Substances 0.000 description 97
• 239000002904 solvent Substances 0.000 description 93
• 239000000203 mixture Substances 0.000 description 88
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 85
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
• 239000011541 reaction mixture Substances 0.000 description 81
• 230000002829 reductive effect Effects 0.000 description 81
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 66
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
• 238000010898 silica gel chromatography Methods 0.000 description 65
• 238000006243 chemical reaction Methods 0.000 description 59
• 238000000605 extraction Methods 0.000 description 59
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
• 239000007864 aqueous solution Substances 0.000 description 57
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 45
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
• 238000000034 method Methods 0.000 description 41
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• 229920006395 saturated elastomer Polymers 0.000 description 36
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• 238000012360 testing method Methods 0.000 description 32
• XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 29
• 239000011877 solvent mixture Substances 0.000 description 28
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
• 229960002986 dinoprostone Drugs 0.000 description 26
• XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 26
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
• 241000700159 Rattus Species 0.000 description 21
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
• 230000009471 action Effects 0.000 description 20
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• 235000017557 sodium bicarbonate Nutrition 0.000 description 20
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
• 230000001404 mediated effect Effects 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
• 239000002585 base Substances 0.000 description 16
• CEBKHWWANWSNTI-UHFFFAOYSA-N 2-methylbut-3-yn-2-ol Chemical compound CC(C)(O)C#C CEBKHWWANWSNTI-UHFFFAOYSA-N 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
• 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 14
• 235000010418 carrageenan Nutrition 0.000 description 13
• 229920001525 carrageenan Polymers 0.000 description 13
• 230000035484 reaction time Effects 0.000 description 13
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 150000002148 esters Chemical class 0.000 description 12
• 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 12
• 241001465754 Metazoa Species 0.000 description 11
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 11
• 125000001424 substituent group Chemical group 0.000 description 11
• 239000007821 HATU Substances 0.000 description 10
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-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
• 230000000202 analgesic effect Effects 0.000 description 10
• YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 10
• GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 10
• PZPSRTWFJCGJLP-UHFFFAOYSA-N hydron;methyl 4-(aminomethyl)cyclohexane-1-carboxylate;chloride Chemical compound Cl.COC(=O)C1CCC(CN)CC1 PZPSRTWFJCGJLP-UHFFFAOYSA-N 0.000 description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
• 235000019270 ammonium chloride Nutrition 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• GIZCKBSSWNIUMZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=C(CN)C=C1 GIZCKBSSWNIUMZ-UHFFFAOYSA-N 0.000 description 9
• 239000007787 solid Substances 0.000 description 9
• 125000003545 alkoxy group Chemical group 0.000 description 8
• 150000004945 aromatic hydrocarbons Chemical group 0.000 description 8
• 238000001035 drying Methods 0.000 description 8
• 150000002170 ethers Chemical class 0.000 description 8
• 125000001188 haloalkyl group Chemical group 0.000 description 8
• 239000012442 inert solvent Substances 0.000 description 8
• PUDBFKBIJFECFZ-UHFFFAOYSA-N methyl 4-[[[2-chloro-3-[2-(4-chlorophenoxy)ethyl]-5-(4-hydroxy-3,3-dimethylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]cyclohexane-1-carboxylate Chemical compound COC(=O)C1CCC(CNC(=O)c2c(nc(Cl)n2CCOc2ccc(Cl)cc2)C#CC(C)(C)CO)CC1 PUDBFKBIJFECFZ-UHFFFAOYSA-N 0.000 description 8
• 238000006386 neutralization reaction Methods 0.000 description 8
• 230000003040 nociceptive effect Effects 0.000 description 8
• 230000001376 precipitating effect Effects 0.000 description 8
• 230000001629 suppression Effects 0.000 description 8
• 206010030113 Oedema Diseases 0.000 description 7
• 230000008859 change Effects 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 230000028709 inflammatory response Effects 0.000 description 7
• 150000002825 nitriles Chemical class 0.000 description 7
• VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 7
• FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 7
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 7
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
• BTGXDHVCIKPJTG-MEZFUOHNSA-N Cl.N=1NN=NC1[C@@H]1CC[C@H](CC1)CN Chemical compound Cl.N=1NN=NC1[C@@H]1CC[C@H](CC1)CN BTGXDHVCIKPJTG-MEZFUOHNSA-N 0.000 description 6
• LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 6
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
• 238000004440 column chromatography Methods 0.000 description 6
• 150000004820 halides Chemical class 0.000 description 6
• 150000008282 halocarbons Chemical class 0.000 description 6
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
• 238000004519 manufacturing process Methods 0.000 description 6
• DVLGIQNHKLWSRU-UHFFFAOYSA-N methyl 1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CN=CN1 DVLGIQNHKLWSRU-UHFFFAOYSA-N 0.000 description 6
• BADCIGONGJEOFJ-UHFFFAOYSA-N methyl 2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound ClC=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F BADCIGONGJEOFJ-UHFFFAOYSA-N 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• 239000002798 polar solvent Substances 0.000 description 6
• 229940002612 prodrug Drugs 0.000 description 6
• 239000000651 prodrug Substances 0.000 description 6
• 235000019345 sodium thiosulphate Nutrition 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
• 210000001519 tissue Anatomy 0.000 description 6
• 239000008096 xylene Substances 0.000 description 6
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
• 208000006820 Arthralgia Diseases 0.000 description 5
• QLKCWFVXDVXMEO-SAABIXHNSA-N ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NC[C@@H]1CC[C@H](CC1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NC[C@@H]1CC[C@H](CC1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F QLKCWFVXDVXMEO-SAABIXHNSA-N 0.000 description 5
• LHHVRMJIVWIFBJ-MXVIHJGJSA-N ClC=1N(C(=C(N=1)C#CC(COC)(C)C)C(=O)NC[C@@H]1CC[C@H](CC1)C(=O)OC)CCOC1=CC=C(C=C1)Cl Chemical compound ClC=1N(C(=C(N=1)C#CC(COC)(C)C)C(=O)NC[C@@H]1CC[C@H](CC1)C(=O)OC)CCOC1=CC=C(C=C1)Cl LHHVRMJIVWIFBJ-MXVIHJGJSA-N 0.000 description 5
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 5
• YDYFWZBWPUDNAQ-UHFFFAOYSA-N [4-(Difluoromethyl)phenyl]methanol Chemical compound OCC1=CC=C(C(F)F)C=C1 YDYFWZBWPUDNAQ-UHFFFAOYSA-N 0.000 description 5
• 150000008044 alkali metal hydroxides Chemical class 0.000 description 5
• 150000001412 amines Chemical class 0.000 description 5
• 229940114079 arachidonic acid Drugs 0.000 description 5
• 235000021342 arachidonic acid Nutrition 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
• VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 5
• 125000004438 haloalkoxy group Chemical group 0.000 description 5
• 229910052740 iodine Inorganic materials 0.000 description 5
• JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 5
• 210000003141 lower extremity Anatomy 0.000 description 5
• 239000002609 medium Substances 0.000 description 5
• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
• 150000007530 organic bases Chemical class 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 235000011181 potassium carbonates Nutrition 0.000 description 5
• 125000006239 protecting group Chemical group 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 239000000741 silica gel Substances 0.000 description 5
• 229910002027 silica gel Inorganic materials 0.000 description 5
• 229910000029 sodium carbonate Inorganic materials 0.000 description 5
• 235000017550 sodium carbonate Nutrition 0.000 description 5
• 239000012312 sodium hydride Substances 0.000 description 5
• 229910000104 sodium hydride Inorganic materials 0.000 description 5
• 229940079827 sodium hydrogen sulfite Drugs 0.000 description 5
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• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
• 150000007529 inorganic bases Chemical class 0.000 description 3
• 239000000543 intermediate Substances 0.000 description 3
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
• ZIBCCORJSVRQFH-UHFFFAOYSA-N methyl 2-bromo-3-[2-(4-chlorophenoxy)ethyl]imidazole-4-carboxylate Chemical compound BrC=1N(C(=CN=1)C(=O)OC)CCOC1=CC=C(C=C1)Cl ZIBCCORJSVRQFH-UHFFFAOYSA-N 0.000 description 3
• ZZRYXPXGIUJMKV-UHFFFAOYSA-N methyl 2-bromo-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound BrC=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F ZZRYXPXGIUJMKV-UHFFFAOYSA-N 0.000 description 3
• OBPLYINRLSTJSD-UHFFFAOYSA-N methyl 2-chloro-3-[(4-fluorophenyl)methyl]-5-(3-hydroxy-3-methylbut-1-ynyl)imidazole-4-carboxylate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)OC)CC1=CC=C(C=C1)F OBPLYINRLSTJSD-UHFFFAOYSA-N 0.000 description 3
• NYPWIXLLQSIEGZ-UHFFFAOYSA-N methyl 2-chloro-3-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound ClC=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)F NYPWIXLLQSIEGZ-UHFFFAOYSA-N 0.000 description 3
• YAAGRDVGYYPUCK-UHFFFAOYSA-N methyl 2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F YAAGRDVGYYPUCK-UHFFFAOYSA-N 0.000 description 3
• QGAQMUGBLBOWFN-UHFFFAOYSA-N methyl 2-cyclopropyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound C1(CC1)C=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F QGAQMUGBLBOWFN-UHFFFAOYSA-N 0.000 description 3
• PGDHEGJZUJVLRZ-UHFFFAOYSA-N methyl 2-ethyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound C(C)C=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F PGDHEGJZUJVLRZ-UHFFFAOYSA-N 0.000 description 3
• QURCROLANGZYQS-UHFFFAOYSA-N methyl 3-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound FC1=CC=C(CN2C=NC=C2C(=O)OC)C=C1 QURCROLANGZYQS-UHFFFAOYSA-N 0.000 description 3
• WZUKJRCWCOKJDE-UHFFFAOYSA-N methyl 3-[(4-methylphenyl)methyl]imidazole-4-carboxylate Chemical compound COC(=O)C1=CN=CN1CC1=CC=C(C)C=C1 WZUKJRCWCOKJDE-UHFFFAOYSA-N 0.000 description 3
• CTUNEFJJWFAGEP-UHFFFAOYSA-N methyl 4-(difluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C(F)F)C=C1 CTUNEFJJWFAGEP-UHFFFAOYSA-N 0.000 description 3
• KRRMKJHNLNKGME-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F KRRMKJHNLNKGME-UHFFFAOYSA-N 0.000 description 3
• DMKZRTFMGGQASS-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-methoxy-3-methylbut-1-ynyl)-3-[(4-methylphenyl)methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C DMKZRTFMGGQASS-UHFFFAOYSA-N 0.000 description 3
• LJAVAVQUNWCXNR-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-methoxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F LJAVAVQUNWCXNR-UHFFFAOYSA-N 0.000 description 3
• RODIREPAJNQJFQ-UHFFFAOYSA-N methyl 4-[[[2-bromo-3-[2-(4-chlorophenoxy)ethyl]-5-(3-hydroxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CCOC1=CC=C(C=C1)Cl RODIREPAJNQJFQ-UHFFFAOYSA-N 0.000 description 3
• SIQXLICRVGRTCT-UHFFFAOYSA-N methyl 4-[[[2-bromo-3-[2-(4-chlorophenoxy)ethyl]-5-iodoimidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N(C(=C(N=1)I)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CCOC1=CC=C(C=C1)Cl SIQXLICRVGRTCT-UHFFFAOYSA-N 0.000 description 3
• DIPDFCPNNMRGSS-UHFFFAOYSA-N methyl 4-[[[2-chloro-3-[(4-fluorophenyl)methyl]-5-(3-methoxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)F DIPDFCPNNMRGSS-UHFFFAOYSA-N 0.000 description 3
• PFCHONQRDONUMB-UHFFFAOYSA-N methyl 4-[[[2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=CN=1)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F PFCHONQRDONUMB-UHFFFAOYSA-N 0.000 description 3
• BZROHFHFYXUSCT-UHFFFAOYSA-N methyl 4-[[[2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F BZROHFHFYXUSCT-UHFFFAOYSA-N 0.000 description 3
• CUMQUELVXPLZLO-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=CN=1)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F CUMQUELVXPLZLO-UHFFFAOYSA-N 0.000 description 3
• NFDSEZZAODNNHW-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F NFDSEZZAODNNHW-UHFFFAOYSA-N 0.000 description 3
• KTMVEQADPNRPSC-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-5-iodo-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=C(N=1)I)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F KTMVEQADPNRPSC-UHFFFAOYSA-N 0.000 description 3
• YWNCLDGVONLMKQ-UHFFFAOYSA-N methyl 4-[[[3-[2-(4-chlorophenoxy)ethyl]-2-cyclopropyl-5-(3-methoxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC1=CC=C(OCCN2C(=NC(=C2C(=O)NCC2=CC=C(C(=O)OC)C=C2)C#CC(C)(C)OC)C2CC2)C=C1 YWNCLDGVONLMKQ-UHFFFAOYSA-N 0.000 description 3
• KTFJOWJYEBVKHN-UHFFFAOYSA-N methyl 4-[[[5-bromo-2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N=C(N(C=1C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F)Cl KTFJOWJYEBVKHN-UHFFFAOYSA-N 0.000 description 3
• QYCYJEYXDDHYSX-UHFFFAOYSA-N methyl 5-bromo-2-chloro-3-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound BrC=1N=C(N(C=1C(=O)OC)CC1=CC=C(C=C1)F)Cl QYCYJEYXDDHYSX-UHFFFAOYSA-N 0.000 description 3
• MAHITNHPDTUDBW-UHFFFAOYSA-N methyl 5-bromo-2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound BrC=1N=C(N(C=1C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F)Cl MAHITNHPDTUDBW-UHFFFAOYSA-N 0.000 description 3
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