SK171499A3 - Benzimidazole derivatives, process for their production pharmaceutical composition containing said derivatives and use of said derivatives - Google Patents

Info

Publication number

SK171499A3

SK171499A3 SK1714-99A SK171499A SK171499A3 SK 171499 A3 SK171499 A3 SK 171499A3 SK 171499 A SK171499 A SK 171499A SK 171499 A3 SK171499 A3 SK 171499A3

Authority

SK

Slovakia

Prior art keywords

group

carbon atoms

alkyl

benzimidazole

hydrogen

Prior art date

1997-06-10

Links

• Espacenet
• Global Dossier
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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 9
• 238000000034 method Methods 0.000 title claims description 157
• 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title abstract description 6
• 238000004519 manufacturing process Methods 0.000 title description 6
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
• 238000002360 preparation method Methods 0.000 claims abstract description 116
• 230000009385 viral infection Effects 0.000 claims abstract description 21
• 238000011282 treatment Methods 0.000 claims abstract description 17
• 238000011321 prophylaxis Methods 0.000 claims abstract description 10
• 150000001875 compounds Chemical class 0.000 claims description 248
• 229910052739 hydrogen Inorganic materials 0.000 claims description 130
• 125000004432 carbon atom Chemical group C* 0.000 claims description 120
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 117
• 125000000217 alkyl group Chemical group 0.000 claims description 91
• 229910052757 nitrogen Inorganic materials 0.000 claims description 90
• 229910052799 carbon Inorganic materials 0.000 claims description 68
• 239000001257 hydrogen Substances 0.000 claims description 67
• -1 hydroxy hydroxy Chemical group 0.000 claims description 66
• 150000002367 halogens Chemical class 0.000 claims description 65
• 229910052736 halogen Inorganic materials 0.000 claims description 62
• 125000003118 aryl group Chemical group 0.000 claims description 53
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
• 150000002431 hydrogen Chemical class 0.000 claims description 35
• 125000003545 alkoxy group Chemical group 0.000 claims description 34
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 33
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 31
• 125000001188 haloalkyl group Chemical group 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 125000001424 substituent group Chemical group 0.000 claims description 26
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• 208000036142 Viral infection Diseases 0.000 claims description 20
• 125000005843 halogen group Chemical group 0.000 claims description 19
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 17
• 150000001336 alkenes Chemical class 0.000 claims description 15
• 150000002576 ketones Chemical class 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
• 241001465754 Metazoa Species 0.000 claims description 8
• OOAVDXDURLPULP-GWOFURMSSA-N (2r,3r,4r,5r)-2-(2-bromo-5,6-dichlorobenzimidazol-1-yl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Br OOAVDXDURLPULP-GWOFURMSSA-N 0.000 claims description 7
• 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 claims description 7
• 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 claims description 7
• 208000024891 symptom Diseases 0.000 claims description 7
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 6
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 6
• UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical compound ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 claims description 5
• 230000000694 effects Effects 0.000 claims description 5
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
• ASICPWKBTMIXNS-GMTAPVOTSA-N (2r,3r,4r)-2-(2-bromo-5,6-dichlorobenzimidazol-1-yl)oxane-3,4-diol Chemical compound O[C@@H]1[C@H](O)CCO[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Br ASICPWKBTMIXNS-GMTAPVOTSA-N 0.000 claims description 4
• 206010011831 Cytomegalovirus infection Diseases 0.000 claims description 4
• 206010019972 Herpes viral infections Diseases 0.000 claims description 4
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
• 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 4
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
• ZHKNTGOJXGQPEL-DDHJBXDOSA-N (2r,3r,4r,5r)-2-(2-bromo-6-chloro-5-methylbenzimidazol-1-yl)oxane-3,4,5-triol Chemical compound C1=2C=C(Cl)C(C)=CC=2N=C(Br)N1[C@@H]1OC[C@@H](O)[C@@H](O)[C@H]1O ZHKNTGOJXGQPEL-DDHJBXDOSA-N 0.000 claims description 3
• IJESABNALPBLAO-QBPKDAKJSA-N [(3r,4r,5r,6r)-4,5-diacetyloxy-6-(2-bromo-5,6-dichlorobenzimidazol-1-yl)oxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(=O)C)CO[C@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Br IJESABNALPBLAO-QBPKDAKJSA-N 0.000 claims description 3
• FHXXWAWFWPVOAX-UHFFFAOYSA-N benzimidazole-2-thione Chemical compound C1=CC=CC2=NC(=S)N=C21 FHXXWAWFWPVOAX-UHFFFAOYSA-N 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• LOMBFOAWBUJDCF-VVFBATEQSA-N (2r,3r,4r,5r)-2-(2-bromo-5,6-dichloro-4-fluorobenzimidazol-1-yl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1N1C2=CC(Cl)=C(Cl)C(F)=C2N=C1Br LOMBFOAWBUJDCF-VVFBATEQSA-N 0.000 claims description 2
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
• 125000004650 C1-C8 alkynyl group Chemical group 0.000 claims 1
• 125000005015 aryl alkynyl group Chemical group 0.000 claims 1
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims 1
• 208000002672 hepatitis B Diseases 0.000 claims 1
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 19
• 150000001556 benzimidazoles Chemical class 0.000 abstract description 8
• 241001529453 unidentified herpesvirus Species 0.000 abstract description 5
• 238000013160 medical therapy Methods 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 337
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 213
• 239000000243 solution Substances 0.000 description 155
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 152
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 125
• 239000000203 mixture Substances 0.000 description 117
• 239000011541 reaction mixture Substances 0.000 description 116
• 235000019439 ethyl acetate Nutrition 0.000 description 113
• 238000005481 NMR spectroscopy Methods 0.000 description 102
• 239000000047 product Substances 0.000 description 101
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 96
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 72
• 239000002904 solvent Substances 0.000 description 68
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• 239000000460 chlorine Substances 0.000 description 60
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 57
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 53
• 239000007787 solid Substances 0.000 description 50
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 49
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• 238000006243 chemical reaction Methods 0.000 description 48
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
• 238000002844 melting Methods 0.000 description 45
• 230000008018 melting Effects 0.000 description 45
• 229910052801 chlorine Inorganic materials 0.000 description 44
• 238000010992 reflux Methods 0.000 description 44
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 41
• 239000000741 silica gel Substances 0.000 description 41
• 229910002027 silica gel Inorganic materials 0.000 description 41
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 38
• 235000019441 ethanol Nutrition 0.000 description 38
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 35
• 235000019341 magnesium sulphate Nutrition 0.000 description 35
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• 238000009472 formulation Methods 0.000 description 33
• 238000004458 analytical method Methods 0.000 description 32
• 238000003756 stirring Methods 0.000 description 32
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
• 239000013543 active substance Substances 0.000 description 25
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
• 239000004480 active ingredient Substances 0.000 description 24
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
• 235000017557 sodium bicarbonate Nutrition 0.000 description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 23
• 230000002829 reductive effect Effects 0.000 description 23
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
• 238000001704 evaporation Methods 0.000 description 22
• 230000008020 evaporation Effects 0.000 description 22
• 239000012044 organic layer Substances 0.000 description 22
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• 238000004440 column chromatography Methods 0.000 description 20
• 229960000583 acetic acid Drugs 0.000 description 19
• 239000003480 eluent Substances 0.000 description 19
• 239000003921 oil Substances 0.000 description 19
• 239000003795 chemical substances by application Substances 0.000 description 18
• 235000019198 oils Nutrition 0.000 description 18
• 150000003839 salts Chemical class 0.000 description 18
• 229910000029 sodium carbonate Inorganic materials 0.000 description 18
• 235000011054 acetic acid Nutrition 0.000 description 17
• 239000000306 component Substances 0.000 description 17
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 16
• 239000010410 layer Substances 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• 239000011734 sodium Substances 0.000 description 16
• 238000004809 thin layer chromatography Methods 0.000 description 16
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
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• FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 15
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• 239000006260 foam Substances 0.000 description 14
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• 239000002775 capsule Substances 0.000 description 13
• OOAVDXDURLPULP-RCWTZXSCSA-N (2s,3s,4s,5r)-2-(2-bromo-5,6-dichlorobenzimidazol-1-yl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)[C@H](O)CO[C@@H]1N1C2=CC(Cl)=C(Cl)C=C2N=C1Br OOAVDXDURLPULP-RCWTZXSCSA-N 0.000 description 12
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• 235000011152 sodium sulphate Nutrition 0.000 description 12
• 239000003826 tablet Substances 0.000 description 12
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• 238000004587 chromatography analysis Methods 0.000 description 11
• 238000010828 elution Methods 0.000 description 11
• 239000012299 nitrogen atmosphere Substances 0.000 description 11
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• SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 10
• 239000003039 volatile agent Substances 0.000 description 10
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• 238000009835 boiling Methods 0.000 description 9
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• IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 9
• 230000004054 inflammatory process Effects 0.000 description 9
• 125000000168 pyrrolyl group Chemical group 0.000 description 9
• 239000007858 starting material Substances 0.000 description 9
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• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
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• CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 8
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
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• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
• 229910000564 Raney nickel Inorganic materials 0.000 description 6
• 238000002399 angioplasty Methods 0.000 description 6
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• 125000004429 atom Chemical group 0.000 description 6
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