EA021359B1 - N-((6-аминопиридин-3-ил)метил)гетероарилкарбоксамиды в качестве ингибиторов калликреина в плазме - Google Patents

Info

Publication number

EA021359B1

EA021359B1 EA201300200A EA201300200A EA021359B1 EA 021359 B1 EA021359 B1 EA 021359B1 EA 201300200 A EA201300200 A EA 201300200A EA 201300200 A EA201300200 A EA 201300200A EA 021359 B1 EA021359 B1 EA 021359B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

amino

carboxamide

dimethylpyridin

pyrazole

Prior art date

2010-08-04

Links

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• Global Dossier
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• 239000003112 inhibitor Substances 0.000 title description 10
• 102000003827 Plasma Kallikrein Human genes 0.000 title 1
• 108090000113 Plasma Kallikrein Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 456
• 150000003839 salts Chemical group 0.000 claims abstract description 53
• -1 (6-amino-2,4-dimethylpyridin-3-yl) methyl Chemical group 0.000 claims description 761
• 238000000034 method Methods 0.000 claims description 375
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 167
• 229910052736 halogen Inorganic materials 0.000 claims description 132
• 150000002367 halogens Chemical class 0.000 claims description 131
• 125000004122 cyclic group Chemical group 0.000 claims description 127
• 229910052760 oxygen Inorganic materials 0.000 claims description 107
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 104
• 239000001301 oxygen Chemical group 0.000 claims description 104
• 229910052757 nitrogen Inorganic materials 0.000 claims description 98
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 78
• 229910052717 sulfur Chemical group 0.000 claims description 78
• 239000011593 sulfur Chemical group 0.000 claims description 78
• 125000003118 aryl group Chemical group 0.000 claims description 71
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 67
• 125000003277 amino group Chemical group 0.000 claims description 65
• 125000006413 ring segment Chemical group 0.000 claims description 63
• 125000005842 heteroatom Chemical group 0.000 claims description 62
• 125000001424 substituent group Chemical group 0.000 claims description 60
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 55
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 55
• 125000000623 heterocyclic group Chemical group 0.000 claims description 53
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 53
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 239000001257 hydrogen Substances 0.000 claims description 50
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 49
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
• 125000004434 sulfur atom Chemical group 0.000 claims description 43
• ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 claims description 40
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 40
• 229910052799 carbon Inorganic materials 0.000 claims description 36
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 35
• 201000010099 disease Diseases 0.000 claims description 35
• 229920006395 saturated elastomer Polymers 0.000 claims description 35
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 32
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 31
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
• 125000002950 monocyclic group Chemical group 0.000 claims description 28
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 21
• 208000035475 disorder Diseases 0.000 claims description 19
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 125000000217 alkyl group Chemical group 0.000 claims description 14
• 125000002947 alkylene group Chemical group 0.000 claims description 13
• 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims description 13
• OSKSVLBJJXQUPI-UHFFFAOYSA-N 2h-triazole-4-carboxamide Chemical compound NC(=O)C1=CNN=N1 OSKSVLBJJXQUPI-UHFFFAOYSA-N 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 11
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000005605 benzo group Chemical group 0.000 claims description 9
• 125000002619 bicyclic group Chemical group 0.000 claims description 7
• 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 6
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
• AKWIAIDKXNKXDI-UHFFFAOYSA-N 1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 claims description 5
• VAELWSLNTRVXQS-UHFFFAOYSA-N 1,3-oxazole-4-carboxamide Chemical compound NC(=O)C1=COC=N1 VAELWSLNTRVXQS-UHFFFAOYSA-N 0.000 claims description 4
• GOLHZPOXCLTFRB-UHFFFAOYSA-N furan-3-carboxamide Chemical compound NC(=O)C=1C=COC=1 GOLHZPOXCLTFRB-UHFFFAOYSA-N 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 claims description 3
• 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
• 230000002159 abnormal effect Effects 0.000 claims description 3
• 125000004432 carbon atom Chemical group C* 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• FOEOJKNUMDSKMO-UHFFFAOYSA-N 2-[4-[[4-[(6-amino-2,4-dimethylpyridin-3-yl)methylcarbamoyl]pyrazol-1-yl]methyl]phenoxy]acetic acid Chemical compound CC1=CC(N)=NC(C)=C1CNC(=O)C1=CN(CC=2C=CC(OCC(O)=O)=CC=2)N=C1 FOEOJKNUMDSKMO-UHFFFAOYSA-N 0.000 claims description 2
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 2
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 3
• LNYMJXVFIFMSOW-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxamide Chemical compound C1=C(C(=O)N)C=NN1CC1=CC=CC=C1 LNYMJXVFIFMSOW-UHFFFAOYSA-N 0.000 claims 1
• 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims 1
• ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 claims 1
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 1
• JJSWHKFLXYOTHY-UHFFFAOYSA-N n-[(6-amino-2,4-dimethylpyridin-3-yl)methyl]-1-[[6-(hydroxymethyl)pyridin-2-yl]methyl]pyrazole-4-carboxamide Chemical compound CC1=CC(N)=NC(C)=C1CNC(=O)C1=CN(CC=2N=C(CO)C=CC=2)N=C1 JJSWHKFLXYOTHY-UHFFFAOYSA-N 0.000 claims 1
• RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 claims 1
• 238000002360 preparation method Methods 0.000 abstract description 160
• 239000003814 drug Substances 0.000 abstract description 22
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 223
• 238000004128 high performance liquid chromatography Methods 0.000 description 215
• 239000000203 mixture Substances 0.000 description 173
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
• 239000011541 reaction mixture Substances 0.000 description 124
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 108
• 239000000243 solution Substances 0.000 description 104
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 100
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 93
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 84
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 56
• 239000012044 organic layer Substances 0.000 description 50
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 43
• 239000012043 crude product Substances 0.000 description 42
• 230000002829 reductive effect Effects 0.000 description 39
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 39
• 238000002953 preparative HPLC Methods 0.000 description 38
• 238000000746 purification Methods 0.000 description 38
• 239000002904 solvent Substances 0.000 description 34
• 150000001721 carbon Chemical group 0.000 description 32
• 239000000725 suspension Substances 0.000 description 32
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 27
• 125000000753 cycloalkyl group Chemical group 0.000 description 27
• 239000000047 product Substances 0.000 description 27
• CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
• 239000007864 aqueous solution Substances 0.000 description 24
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
• 238000005160 1H NMR spectroscopy Methods 0.000 description 22
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 21
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
• 239000012267 brine Substances 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 20
• 238000005481 NMR spectroscopy Methods 0.000 description 20
• 235000019253 formic acid Nutrition 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
• 125000006643 (C2-C6) haloalkenyl group Chemical group 0.000 description 18
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 18
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
• 239000000126 substance Substances 0.000 description 18
• 229910052805 deuterium Inorganic materials 0.000 description 17
• 239000000651 prodrug Substances 0.000 description 17
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• 229940079593 drug Drugs 0.000 description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 16
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• 238000003756 stirring Methods 0.000 description 15
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 14
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• 235000011152 sodium sulphate Nutrition 0.000 description 14
• 239000007787 solid Substances 0.000 description 14
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
• 239000013256 coordination polymer Substances 0.000 description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
• GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
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• 230000015572 biosynthetic process Effects 0.000 description 11
• KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 11
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• 238000004440 column chromatography Methods 0.000 description 10
• 230000001965 increasing effect Effects 0.000 description 10
• 125000003367 polycyclic group Chemical group 0.000 description 10
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• 238000001704 evaporation Methods 0.000 description 9
• 230000008020 evaporation Effects 0.000 description 9
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• 239000011734 sodium Substances 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 8
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• PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 8
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
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• 206010012601 diabetes mellitus Diseases 0.000 description 8
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• 125000000232 haloalkynyl group Chemical group 0.000 description 8
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• 239000003826 tablet Substances 0.000 description 8
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
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• 230000004913 activation Effects 0.000 description 6
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• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
• 239000012634 fragment Substances 0.000 description 6
• 208000020658 intracerebral hemorrhage Diseases 0.000 description 6
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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• PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 6
• 235000010378 sodium ascorbate Nutrition 0.000 description 6
• 229960005055 sodium ascorbate Drugs 0.000 description 6
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• LXDSHZCTNZCBOS-UHFFFAOYSA-N tert-butyl n-[5-(aminomethyl)-4,6-dimethylpyridin-2-yl]carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=NC(C)=C1CN LXDSHZCTNZCBOS-UHFFFAOYSA-N 0.000 description 6
• KGDOHXYALMXHLF-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1 KGDOHXYALMXHLF-UHFFFAOYSA-N 0.000 description 5
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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