JP4530612B2 - 広域スペクトルの２−（置換−アミノ）−ベンゾチアゾールスルホンアミドｈｉｖプロテアーゼインヒビター - Google Patents
広域スペクトルの２−（置換−アミノ）−ベンゾチアゾールスルホンアミドｈｉｖプロテアーゼインヒビター Download PDFInfo
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- JP4530612B2 JP4530612B2 JP2002581413A JP2002581413A JP4530612B2 JP 4530612 B2 JP4530612 B2 JP 4530612B2 JP 2002581413 A JP2002581413 A JP 2002581413A JP 2002581413 A JP2002581413 A JP 2002581413A JP 4530612 B2 JP4530612 B2 JP 4530612B2
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- alkyl
- het
- aryl
- amino
- cycloalkyl
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- -1 2- (substituted-amino) -benzothiazolesulfonamide Chemical class 0.000 title claims description 116
- 239000004030 hiv protease inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 228
- 125000003118 aryl group Chemical group 0.000 claims abstract description 162
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 100
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 62
- 239000000203 mixture Substances 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 40
- 125000003277 amino group Chemical group 0.000 claims abstract description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 32
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 150000001204 N-oxides Chemical class 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 407
- 239000000543 intermediate Substances 0.000 claims description 145
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 60
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 57
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 55
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 52
- 150000002431 hydrogen Chemical class 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 37
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
- 239000003814 drug Substances 0.000 claims description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000004104 aryloxy group Chemical group 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000004043 oxo group Chemical group O=* 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 15
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 239000011593 sulfur Substances 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000000169 tricyclic heterocycle group Chemical group 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 241001430294 unidentified retrovirus Species 0.000 claims description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 7
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 108091005804 Peptidases Proteins 0.000 claims description 5
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 239000004365 Protease Substances 0.000 claims description 4
- 206010038997 Retroviral infections Diseases 0.000 claims description 4
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 4
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 4
- 125000005201 cycloalkylcarbonyloxy group Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- FODOUIXGKGNSMR-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O FODOUIXGKGNSMR-UHFFFAOYSA-L 0.000 claims description 4
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 3
- 101100219283 Amycolatopsis orientalis cyp165C4 gene Proteins 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 230000010076 replication Effects 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 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 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000002829 nitrogen Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 15
- HBJMMMAJSBLTMB-UHFFFAOYSA-N 2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl n-[4-[[2-[3-(dimethylamino)propyl-methylamino]-1,3-benzothiazol-6-yl]sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound C=1C=C2N=C(N(C)CCCN(C)C)SC2=CC=1S(=O)(=O)N(CC(C)C)CC(O)C(NC(=O)OC1C2CCOC2OC1)CC1=CC=CC=C1 HBJMMMAJSBLTMB-UHFFFAOYSA-N 0.000 claims 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
- BIPRNLSSLKASRT-UHFFFAOYSA-N 2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl n-[4-[[2-[2-(dimethylamino)ethylamino]-1,3-benzothiazol-6-yl]sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound C=1C=C2N=C(NCCN(C)C)SC2=CC=1S(=O)(=O)N(CC(C)C)CC(O)C(NC(=O)OC1C2CCOC2OC1)CC1=CC=CC=C1 BIPRNLSSLKASRT-UHFFFAOYSA-N 0.000 claims 1
- JVLZNIMEAPHPMC-UHFFFAOYSA-N [4-[[2-[(1-ethylpyrrolidin-2-yl)methylamino]-1,3-benzothiazol-6-yl]sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamic acid Chemical compound C(C1=CC=CC=C1)C(C(CN(CC(C)C)S(=O)(=O)C1=CC2=C(N=C(S2)NCC2N(CCC2)CC)C=C1)O)NC(O)=O JVLZNIMEAPHPMC-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 1
- 238000003556 assay Methods 0.000 abstract description 11
- 239000000651 prodrug Substances 0.000 abstract description 11
- 229940002612 prodrug Drugs 0.000 abstract description 11
- 229940124522 antiretrovirals Drugs 0.000 abstract description 8
- 239000003903 antiretrovirus agent Substances 0.000 abstract description 8
- 150000002148 esters Chemical class 0.000 abstract description 6
- 239000002207 metabolite Substances 0.000 abstract description 4
- 238000009007 Diagnostic Kit Methods 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 216
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 45
- 239000002904 solvent Substances 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 230000003595 spectral effect Effects 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 229940079593 drug Drugs 0.000 description 18
- 238000011282 treatment Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 241000700605 Viruses Species 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000012503 blood component Substances 0.000 description 12
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 12
- 229920000858 Cyclodextrin Polymers 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 9
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 208000030507 AIDS Diseases 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- JQUNFHFWXCXPRK-AMMMHQJVSA-N [(3as,4r,6ar)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] n-[(2s,3r)-4-[[2-[(1-cyclopentylpiperidin-4-yl)amino]-1,3-benzothiazol-6-yl]sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical group C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=C2SC(NC3CCN(CC3)C3CCCC3)=NC2=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 JQUNFHFWXCXPRK-AMMMHQJVSA-N 0.000 description 8
- 230000036436 anti-hiv Effects 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000000306 component Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 230000001177 retroviral effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007962 solid dispersion Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 208000031886 HIV Infections Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 206010001513 AIDS related complex Diseases 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 0 CC(C)C(C*(*)S(Cc(cc1)cc(C2)c1N=C2N(*)**)(=O)=O)O Chemical compound CC(C)C(C*(*)S(Cc(cc1)cc(C2)c1N=C2N(*)**)(=O)=O)O 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 108010010369 HIV Protease Proteins 0.000 description 4
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
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- 229910021529 ammonia Inorganic materials 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229940125810 compound 20 Drugs 0.000 description 4
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000006104 solid solution Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01200529 | 2001-02-14 | ||
| US28775801P | 2001-05-02 | 2001-05-02 | |
| PCT/EP2002/001788 WO2002083657A2 (en) | 2001-02-14 | 2002-02-14 | Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2004518767A JP2004518767A (ja) | 2004-06-24 |
| JP2004518767A5 JP2004518767A5 (enExample) | 2005-12-22 |
| JP4530612B2 true JP4530612B2 (ja) | 2010-08-25 |
Family
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Family Applications (1)
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Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA01012270A (es) | 1999-05-28 | 2003-06-24 | Virco Nv | Nuevos perfiles mutacionales en la transcriptasa reversa de vih-1 correlacionadas con resistencia fenotipica a farmacos. |
| AU2002226316B2 (en) | 2000-10-20 | 2008-06-26 | Virco Bvba | Mutational profiles in HIV-1 reverse transcriptase correlated with phenotypic drug resistance |
| EP1370543B1 (en) | 2001-02-14 | 2006-10-25 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors |
| US7109230B2 (en) | 2002-01-07 | 2006-09-19 | Sequoia Pharmaceuticals, Inc. | Resistance-repellent retroviral protease inhibitors |
| US7157489B2 (en) | 2002-03-12 | 2007-01-02 | The Board Of Trustees Of The University Of Illinois | HIV protease inhibitors |
| CA2490764C (en) | 2002-07-01 | 2011-11-22 | Tibotec Pharmaceuticals Ltd. | New mutational profiles in hiv-1 reverse transcriptase correlated with phenotypic drug resistance |
| EP1520247B1 (en) | 2002-07-01 | 2009-05-27 | Tibotec Pharmaceuticals Ltd. | Mutational profiles in hiv-1 protease correlated with phenotypic drug resistance |
| OA12893A (en) * | 2002-08-02 | 2006-10-13 | Tibotec Pharm Ltd | Broadspectrum 2-Amino-Benzothiazole Sulfonamide HIV Protease Inhibitors. |
| BR0305717A (pt) * | 2002-08-02 | 2004-09-28 | Tibotec Pharm Ltd | Inibidores da protease do hiv 2-amino-benzotiazol sulfonamida de amplo espectro |
| WO2005030739A1 (en) * | 2003-09-30 | 2005-04-07 | Tibotec Pharmaceuticals Ltd. | Methods for the preparation of benzoxazole sulfonamide compounds and intermediates thereof |
| DE10360835A1 (de) * | 2003-12-23 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Imidazolverbindungen, deren Herstellung und deren Verwendung als Arzneimittel |
| AU2005244121B2 (en) * | 2004-05-07 | 2012-01-19 | Sequoia Pharmaceuticals, Inc. | Resistance-repellent retroviral protease inhibitors |
| ES2331257T3 (es) | 2005-02-25 | 2009-12-28 | Tibotec Pharmaceuticals | Sintesis de precursores de inhibidores de proteasas. |
| AR053845A1 (es) | 2005-04-15 | 2007-05-23 | Tibotec Pharm Ltd | 5-tiazolilmetil[(1s,2r)-3-[[(2-amino-6-benzoxazolil)sulfonil)](2-metilpropil)amino]-2-hidroxi-1-(fenilmetil)propil]carbamato como mejorador de farmacos metabolizados por el citocromo p450 |
| JO2841B1 (en) * | 2006-06-23 | 2014-09-15 | تيبوتيك فارماسيوتيكالز ليمتد | 2-(substituted-amino) -benzothiazole sulfonamide as protease inhibitors HIV (HIV) |
| WO2011061590A1 (en) | 2009-11-17 | 2011-05-26 | Hetero Research Foundation | Novel carboxamide derivatives as hiv inhibitors |
| JO3090B1 (ar) * | 2009-12-11 | 2017-03-15 | Janssen Sciences Ireland Uc | 5- امينو-4- هيدروكسي-بنتويل اميدات |
| US9024038B2 (en) * | 2010-12-27 | 2015-05-05 | Purdue Research Foundation | Compunds and methods for treating HIV |
| ES2571479T3 (es) | 2012-04-20 | 2016-05-25 | Gilead Sciences Inc | Derivados del ácido benzotiazol-6-il acético y su uso para tratar una infección por VIH |
| CN104000824B (zh) * | 2014-05-28 | 2016-07-06 | 中山大学 | 苯并五元杂环类化合物在制备抗hiv-1病毒药物中的应用 |
| US11439608B2 (en) | 2017-09-25 | 2022-09-13 | Qun Lu | Roles of modulators of intersectin-CDC42 signaling in Alzheimer's disease |
| CN116354903B (zh) * | 2021-12-28 | 2025-09-09 | 南京药石科技股份有限公司 | 一种6-苯并噻唑磺酰氯的制备方法 |
| WO2024206093A1 (en) * | 2023-03-24 | 2024-10-03 | Purdue Research Foundation | Hiv-1p rotease inhibitors and uses thereof |
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| DE69121436T2 (de) | 1990-03-09 | 1997-01-09 | Milliken Res Corp | Organische Materialien, die sulfonamidogebundene Poly(oxyalkylen)gruppen tragen und ihre Herstellung |
| US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
| DE122007000045I2 (de) | 1992-08-25 | 2011-07-21 | Gd Searle Llc Gd Searle Llc | Darunavir oder pharmazeutisch vertragliche Salze, Hydroxyethylaminosulfonamide verwendbar als InhibiEster oder Prodrugs davon. toren retroviraler Proteasen. |
| PH30929A (en) | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
| IS2334B (is) * | 1992-09-08 | 2008-02-15 | Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) | Aspartyl próteasi hemjari af nýjum flokki súlfonamíða |
| ES2127938T3 (es) * | 1993-08-24 | 1999-05-01 | Searle & Co | Hidroxietilamino sulfonamidas utiles como inhibidores de proteasas retroviricas. |
| ES2166786T3 (es) | 1993-10-01 | 2002-05-01 | Astrazeneca Ab | Procedimiento i. |
| DE69637380T2 (de) | 1995-01-20 | 2009-09-17 | G.D. Searle Llc, Chicago | Bis-sulfonamid-hydroxyethylamino-derivate als inhibitoren retroviraler proteasen |
| US6140505A (en) * | 1995-03-10 | 2000-10-31 | G. D. Searle & Co. | Synthesis of benzo fused heterocyclic sulfonyl chlorides |
| US5756533A (en) | 1995-03-10 | 1998-05-26 | G.D. Searle & Co. | Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6861539B1 (en) * | 1995-03-10 | 2005-03-01 | G. D. Searle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6150556A (en) * | 1995-03-10 | 2000-11-21 | G. D. Dearle & Co. | Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors |
| CN1149223C (zh) * | 1995-03-10 | 2004-05-12 | G·D·瑟尔公司 | 杂环羰基氨基酸羟乙氨基磺酰胺逆转录病毒蛋白酶抑制剂 |
| US6143788A (en) * | 1995-03-10 | 2000-11-07 | G.D. Searle & Co. | Bis-amino acid hydroxyethlamino sulfonamide retroviral protease inhibitors |
| US5705500A (en) * | 1995-03-10 | 1998-01-06 | G.D. Searle & Co. | Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US5753660A (en) * | 1995-11-15 | 1998-05-19 | G. D. Searle & Co. | Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors |
| US6509038B2 (en) | 1996-05-20 | 2003-01-21 | Janssen Pharmaceutica N.V. | Antifungal compositions with improved bioavailability |
| CZ295502B6 (cs) | 1997-03-26 | 2005-08-17 | Janssen Pharmaceutica N. V. | Antifungální peleta, způsob její přípravy a farmaceutická dávková forma s obsahem těchto pelet |
| US6436989B1 (en) | 1997-12-24 | 2002-08-20 | Vertex Pharmaceuticals, Incorporated | Prodrugs of aspartyl protease inhibitors |
| AU2012199A (en) | 1997-12-24 | 1999-07-19 | Vertex Pharmaceuticals Incorporated | Prodrugs of aspartyl protease inhibitors |
| EP1042280A2 (en) | 1997-12-24 | 2000-10-11 | Vertex Pharmaceuticals Incorporated | Prodrugs of aspartyl protease inhibitors |
| AU2010299A (en) | 1997-12-24 | 1999-07-19 | Vertex Pharmaceuticals Incorporated | Prodrugs os aspartyl protease inhibitors |
| BR9912169A (pt) * | 1998-06-19 | 2001-04-10 | Vertex Pharma | Inibidores de sulfonamida de protease de aspartil |
| PT2336134T (pt) * | 1998-06-23 | 2016-10-19 | The Board Of Trustees Of The Univ Of Illionis | Ensaio de aptidão e métodos para reduzir a resistência do hiv à terapia |
| AU4828199A (en) | 1998-06-23 | 2000-01-10 | Board Of Trustees Of The University Of Illinois, The | Multi-drug resistant retroviral protease inhibitors and associated methods |
| AR031520A1 (es) * | 1999-06-11 | 2003-09-24 | Vertex Pharma | Un compuesto inhibidor de aspartilo proteasa, una composicion que lo comprende y un metodo para tratar un paciente con dicha composicion |
| EP1370543B1 (en) | 2001-02-14 | 2006-10-25 | Tibotec Pharmaceuticals Ltd. | Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors |
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