JP4413781B2 - 非ヌクレオシド逆転写酵素インヒビター - Google Patents
非ヌクレオシド逆転写酵素インヒビター Download PDFInfo
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- JP4413781B2 JP4413781B2 JP2004541500A JP2004541500A JP4413781B2 JP 4413781 B2 JP4413781 B2 JP 4413781B2 JP 2004541500 A JP2004541500 A JP 2004541500A JP 2004541500 A JP2004541500 A JP 2004541500A JP 4413781 B2 JP4413781 B2 JP 4413781B2
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- Prior art keywords
- alkyl
- substituted
- mmol
- methyl
- phenyl
- Prior art date
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- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 title description 4
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims description 64
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- -1 monosubstituted phenyl Chemical group 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 43
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 33
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 150000003248 quinolines Chemical class 0.000 claims description 10
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 abstract description 46
- 239000002777 nucleoside Substances 0.000 abstract description 21
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 20
- 239000003112 inhibitor Substances 0.000 abstract description 17
- 238000011282 treatment Methods 0.000 abstract description 12
- 238000000338 in vitro Methods 0.000 abstract description 10
- 238000001727 in vivo Methods 0.000 abstract description 9
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 abstract description 4
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 abstract description 4
- 102100034343 Integrase Human genes 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 102100034349 Integrase Human genes 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 125000004429 atom Chemical group 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- 239000002904 solvent Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 35
- 125000005647 linker group Chemical group 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 229910052717 sulfur Inorganic materials 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 125000003342 alkenyl group Chemical group 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 125000000304 alkynyl group Chemical group 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
- 229910052760 oxygen Inorganic materials 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 239000008346 aqueous phase Substances 0.000 description 22
- 241000725303 Human immunodeficiency virus Species 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 230000003612 virological effect Effects 0.000 description 14
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 150000003852 triazoles Chemical class 0.000 description 11
- 208000031886 HIV Infections Diseases 0.000 description 10
- 108060001084 Luciferase Proteins 0.000 description 10
- 150000002460 imidazoles Chemical class 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000005089 Luciferase Substances 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- JMIAPORGEDIDLT-UHFFFAOYSA-N ethyl ethanimidate Chemical compound CCOC(C)=N JMIAPORGEDIDLT-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- LJAROVLJNWCCPM-UHFFFAOYSA-N 2-chloro-n-(2-chloropyridin-3-yl)acetamide Chemical compound ClCC(=O)NC1=CC=CN=C1Cl LJAROVLJNWCCPM-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000011593 sulfur Chemical group 0.000 description 5
- MEQBJJUWDCYIAB-UHFFFAOYSA-N 2-chloropyridin-3-amine Chemical compound NC1=CC=CN=C1Cl MEQBJJUWDCYIAB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960002555 zidovudine Drugs 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- KYZYAPVNLSANPX-UHFFFAOYSA-N 4,5-dimethyl-3-(4-methylphenyl)-1h-imidazole-2-thione Chemical compound CC1=C(C)NC(=S)N1C1=CC=C(C)C=C1 KYZYAPVNLSANPX-UHFFFAOYSA-N 0.000 description 3
- MQFYUZCANYLWEI-UHFFFAOYSA-N 4-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(C)=CC=C(N)C2=C1 MQFYUZCANYLWEI-UHFFFAOYSA-N 0.000 description 3
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 3
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical group NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- NUAKKRMYBBXGFP-UHFFFAOYSA-N tert-butyl n-(3-oxobutan-2-yl)carbamate Chemical compound CC(=O)C(C)NC(=O)OC(C)(C)C NUAKKRMYBBXGFP-UHFFFAOYSA-N 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- 125000005425 toluyl group Chemical group 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- CBMXCNPQDUJNHT-UHFFFAOYSA-N 1,6-dimethylnaphthalene Chemical compound CC1=CC=CC2=CC(C)=CC=C21 CBMXCNPQDUJNHT-UHFFFAOYSA-N 0.000 description 2
- OFKWHEHUTRXYMT-UHFFFAOYSA-N 1-[4-(dimethylamino)naphthalen-1-yl]-3-prop-2-ynylthiourea Chemical compound C1=CC=C2C(N(C)C)=CC=C(NC(=S)NCC#C)C2=C1 OFKWHEHUTRXYMT-UHFFFAOYSA-N 0.000 description 2
- ABQKHKWXTUVKGF-UHFFFAOYSA-N 1-isothiocyanato-4-methylbenzene Chemical compound CC1=CC=C(N=C=S)C=C1 ABQKHKWXTUVKGF-UHFFFAOYSA-N 0.000 description 2
- FRLVKAJKOYFHKQ-UHFFFAOYSA-N 1-methyl-4-nitronaphthalene Chemical compound C1=CC=C2C(C)=CC=C([N+]([O-])=O)C2=C1 FRLVKAJKOYFHKQ-UHFFFAOYSA-N 0.000 description 2
- QPUYECUOLPXSFR-UHFFFAOYSA-N 1-methylnaphthalene Chemical compound C1=CC=C2C(C)=CC=CC2=C1 QPUYECUOLPXSFR-UHFFFAOYSA-N 0.000 description 2
- ZTRJVDUHNRWPAI-UHFFFAOYSA-N 2,4-dimethylnaphthalen-1-amine Chemical compound C1=CC=CC2=C(N)C(C)=CC(C)=C21 ZTRJVDUHNRWPAI-UHFFFAOYSA-N 0.000 description 2
- ZAHKVIRLTVQZQD-UHFFFAOYSA-N 2,5,7-trimethyl-8-nitroquinoline Chemical compound CC1=CC(C)=C([N+]([O-])=O)C2=NC(C)=CC=C21 ZAHKVIRLTVQZQD-UHFFFAOYSA-N 0.000 description 2
- MZKAXLQFMDDWBE-UHFFFAOYSA-N 2,5,7-trimethylquinolin-8-amine Chemical compound CC1=CC(C)=C(N)C2=NC(C)=CC=C21 MZKAXLQFMDDWBE-UHFFFAOYSA-N 0.000 description 2
- LKRBLYAAKQMBSD-UHFFFAOYSA-N 2,5-dimethylquinolin-8-amine Chemical compound CC1=CC=C(N)C2=NC(C)=CC=C21 LKRBLYAAKQMBSD-UHFFFAOYSA-N 0.000 description 2
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 0.000 description 2
- UTVZWVRTUIUNLO-UHFFFAOYSA-N 2-chloro-n-(2-methyl-4-sulfamoylphenyl)acetamide Chemical compound CC1=CC(S(N)(=O)=O)=CC=C1NC(=O)CCl UTVZWVRTUIUNLO-UHFFFAOYSA-N 0.000 description 2
- MKARNSWMMBGSHX-UHFFFAOYSA-N 3,5-dimethylaniline Chemical compound CC1=CC(C)=CC(N)=C1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 2
- PRXNKTGXESJDAU-UHFFFAOYSA-N 3-(methoxymethyl)-4-phenyl-1h-1,2,4-triazole-5-thione Chemical compound COCC1=NNC(=S)N1C1=CC=CC=C1 PRXNKTGXESJDAU-UHFFFAOYSA-N 0.000 description 2
- VPLXBSKVKOEGBN-UHFFFAOYSA-N 3-[4-(dimethylamino)naphthalen-1-yl]-4-methyl-1h-imidazole-2-thione Chemical compound C12=CC=CC=C2C(N(C)C)=CC=C1N1C(C)=CN=C1S VPLXBSKVKOEGBN-UHFFFAOYSA-N 0.000 description 2
- TWQNFAMLCGTCCK-UHFFFAOYSA-N 3-methyl-4-(2,5,7-trimethylquinolin-8-yl)-1h-1,2,4-triazole-5-thione Chemical compound CC1=NN=C(S)N1C1=C(C)C=C(C)C2=CC=C(C)N=C12 TWQNFAMLCGTCCK-UHFFFAOYSA-N 0.000 description 2
- JKRJVVWJUAWVCI-UHFFFAOYSA-N 3-methyl-4-(4-methylnaphthalen-1-yl)-1h-1,2,4-triazole-5-thione Chemical compound CC1=NN=C(S)N1C1=CC=C(C)C2=CC=CC=C12 JKRJVVWJUAWVCI-UHFFFAOYSA-N 0.000 description 2
- VITIJXJNRKRDKF-UHFFFAOYSA-N 3-methyl-4-phenyl-1h-1,2,4-triazole-5-thione Chemical compound CC1=NNC(=S)N1C1=CC=CC=C1 VITIJXJNRKRDKF-UHFFFAOYSA-N 0.000 description 2
- CYEVFXOJJIMJGD-UHFFFAOYSA-N 4,7-dimethylnaphthalen-1-amine Chemical compound CC1=CC=C(N)C2=CC(C)=CC=C21 CYEVFXOJJIMJGD-UHFFFAOYSA-N 0.000 description 2
- FRKSWISVPLRSNU-UHFFFAOYSA-N 4-(2,4-dimethylnaphthalen-1-yl)-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound CC1=NN=C(S)N1C1=C(C)C=C(C)C2=CC=CC=C12 FRKSWISVPLRSNU-UHFFFAOYSA-N 0.000 description 2
- ZTJIRSOFGIVFID-UHFFFAOYSA-N 4-(2,5-dimethylquinolin-8-yl)-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound CC1=NN=C(S)N1C1=CC=C(C)C2=CC=C(C)N=C12 ZTJIRSOFGIVFID-UHFFFAOYSA-N 0.000 description 2
- OXLYBXGLTHLGAD-UHFFFAOYSA-N 4-(4,7-dimethylnaphthalen-1-yl)-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound CC1=NN=C(S)N1C1=CC=C(C)C2=CC=C(C)C=C12 OXLYBXGLTHLGAD-UHFFFAOYSA-N 0.000 description 2
- NLKAAMWSLCZWPN-UHFFFAOYSA-N 4-(4-chloro-2-methoxy-5-methylquinolin-8-yl)-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound C12=NC(OC)=CC(Cl)=C2C(C)=CC=C1N1C(C)=NN=C1S NLKAAMWSLCZWPN-UHFFFAOYSA-N 0.000 description 2
- CGWQTJSCBLYQSF-UHFFFAOYSA-N 4-(4-ethylnaphthalen-1-yl)-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound C12=CC=CC=C2C(CC)=CC=C1N1C(C)=NN=C1S CGWQTJSCBLYQSF-UHFFFAOYSA-N 0.000 description 2
- JXBUVDXWYHVVJW-UHFFFAOYSA-N 4-[5-(dimethylamino)-2-methylquinolin-8-yl]-3-methyl-1h-1,2,4-triazole-5-thione Chemical compound C12=NC(C)=CC=C2C(N(C)C)=CC=C1N1C(C)=NN=C1S JXBUVDXWYHVVJW-UHFFFAOYSA-N 0.000 description 2
- LTZDTUJCHVBAGS-UHFFFAOYSA-N 4-chloro-2-methoxy-5-methylquinolin-8-amine Chemical compound CC1=CC=C(N)C2=NC(OC)=CC(Cl)=C21 LTZDTUJCHVBAGS-UHFFFAOYSA-N 0.000 description 2
- UVZZTECIUXUZEA-UHFFFAOYSA-N 4-methyl-n-(1-methylsulfanyl-2-nitroethenyl)aniline Chemical compound [O-][N+](=O)C=C(SC)NC1=CC=C(C)C=C1 UVZZTECIUXUZEA-UHFFFAOYSA-N 0.000 description 2
- KKIGUVBJOHCXSP-UHFFFAOYSA-N 4-phenylthiosemicarbazide Chemical compound NNC(=S)NC1=CC=CC=C1 KKIGUVBJOHCXSP-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
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- 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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 to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
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| US0226816 | 2002-08-23 | ||
| PCT/US2003/027433 WO2004030611A2 (en) | 2002-08-23 | 2003-08-22 | Non-nucleoside reverse transcriptase inhibitors |
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| JP2006505543A JP2006505543A (ja) | 2006-02-16 |
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| EP (2) | EP1545483B1 (enExample) |
| JP (1) | JP4413781B2 (enExample) |
| CN (1) | CN1697650B (enExample) |
| AT (1) | ATE504294T1 (enExample) |
| AU (2) | AU2003295324B2 (enExample) |
| BR (1) | BR0313747A (enExample) |
| CA (1) | CA2496565C (enExample) |
| DE (1) | DE60336664D1 (enExample) |
| EA (1) | EA009478B1 (enExample) |
| MX (1) | MXPA05002070A (enExample) |
| WO (1) | WO2004030611A2 (enExample) |
| ZA (1) | ZA200502384B (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE60336664D1 (de) | 2011-05-19 |
| US20060135556A1 (en) | 2006-06-22 |
| EP2353593B1 (en) | 2012-08-22 |
| BR0313747A (pt) | 2005-06-21 |
| ZA200502384B (en) | 2007-03-28 |
| AU2008246249A1 (en) | 2008-12-11 |
| WO2004030611A3 (en) | 2004-06-17 |
| JP2006505543A (ja) | 2006-02-16 |
| WO2004030611A2 (en) | 2004-04-15 |
| AU2008246249B2 (en) | 2010-09-30 |
| HK1085667A1 (en) | 2006-09-01 |
| EP1545483A4 (en) | 2009-03-25 |
| CA2496565C (en) | 2013-04-02 |
| CN1697650A (zh) | 2005-11-16 |
| AU2003295324B2 (en) | 2008-08-28 |
| EA009478B1 (ru) | 2008-02-28 |
| MXPA05002070A (es) | 2005-07-05 |
| EP1545483B1 (en) | 2011-04-06 |
| AU2003295324A1 (en) | 2004-04-23 |
| CN1697650B (zh) | 2010-11-10 |
| EP2353593A1 (en) | 2011-08-10 |
| ATE504294T1 (de) | 2011-04-15 |
| US20080249131A1 (en) | 2008-10-09 |
| CA2496565A1 (en) | 2004-04-15 |
| EA200500399A1 (ru) | 2005-12-29 |
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