CA2094012C - 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents - Google Patents
1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents Download PDFInfo
- Publication number
- CA2094012C CA2094012C CA002094012A CA2094012A CA2094012C CA 2094012 C CA2094012 C CA 2094012C CA 002094012 A CA002094012 A CA 002094012A CA 2094012 A CA2094012 A CA 2094012A CA 2094012 C CA2094012 C CA 2094012C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- formula
- compound
- oxadiazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000003443 antiviral agent Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- -1 cyano, 2,2,2-trifluoro-ethyl Chemical group 0.000 claims abstract description 112
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 35
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 30
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 22
- 125000006371 dihalo methyl group Chemical group 0.000 claims abstract description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 18
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 13
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000004970 halomethyl group Chemical group 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 239000012442 inert solvent Substances 0.000 claims description 28
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000002585 base Substances 0.000 claims description 27
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 150000004820 halides Chemical class 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 150000008065 acid anhydrides Chemical class 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 claims description 8
- 241000709664 Picornaviridae Species 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 230000001476 alcoholic effect Effects 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- 125000002346 iodo group Chemical group I* 0.000 claims description 7
- 241000709661 Enterovirus Species 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 239000007822 coupling agent Substances 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 4
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 4
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 101150074884 CNX1 gene Proteins 0.000 claims description 3
- 101100005050 Schizosaccharomyces pombe (strain 972 / ATCC 24843) cal1 gene Proteins 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Chemical group 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- NAWWOLFUBWVPAE-UHFFFAOYSA-N 3-[3,5-dichloro-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(Cl)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1Cl NAWWOLFUBWVPAE-UHFFFAOYSA-N 0.000 claims description 2
- OUXVMIIGJBLSQG-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(fluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(CF)ON=2)C=C1C OUXVMIIGJBLSQG-UHFFFAOYSA-N 0.000 claims description 2
- HNYLNDUVGSJOGD-UHFFFAOYSA-N 3-[4-[3-[3-(ethoxymethyl)-1,2-oxazol-5-yl]propoxy]-3,5-dimethylphenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(COCC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C HNYLNDUVGSJOGD-UHFFFAOYSA-N 0.000 claims description 2
- DHTGEEMLNWMWLC-UHFFFAOYSA-N 4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenol Chemical compound C1=CC(O)=CC=C1C1=NOC(C(F)(F)F)=N1 DHTGEEMLNWMWLC-UHFFFAOYSA-N 0.000 claims description 2
- JDIYZDKGYOOFFB-UHFFFAOYSA-N 5-cyclopropyl-3-[4-[3-(3-cyclopropyl-1,2-oxazol-5-yl)propoxy]-3,5-dimethylphenyl]-1,2,4-oxadiazole Chemical compound CC1=CC(C=2N=C(ON=2)C2CC2)=CC(C)=C1OCCCC(ON=1)=CC=1C1CC1 JDIYZDKGYOOFFB-UHFFFAOYSA-N 0.000 claims description 2
- KGIGQSKHGNOYGG-UHFFFAOYSA-N 5-cyclopropyl-3-[4-[3-(3-ethyl-1,2-oxazol-5-yl)propoxy]-3,5-dimethylphenyl]-1,2,4-oxadiazole Chemical compound O1N=C(CC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C2CC2)C=C1C KGIGQSKHGNOYGG-UHFFFAOYSA-N 0.000 claims description 2
- BXEXYKIVTLCFJN-UHFFFAOYSA-N 5-cyclopropyl-3-[4-[3-[3-(methoxymethyl)-1,2-oxazol-5-yl]propoxy]-3,5-dimethylphenyl]-1,2,4-oxadiazole Chemical compound O1N=C(COC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C2CC2)C=C1C BXEXYKIVTLCFJN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 40
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 19
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 15
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 5
- 239000003937 drug carrier Substances 0.000 claims 4
- 239000008024 pharmaceutical diluent Substances 0.000 claims 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims 2
- FNORQWNVAYJADI-UHFFFAOYSA-N 2-(2,2,2-trifluoroethylidene)-1,3-dithiane Chemical compound FC(F)(F)C=C1SCCCS1 FNORQWNVAYJADI-UHFFFAOYSA-N 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- WRGQAWAVRAVFMC-UHFFFAOYSA-N 2,6-dichloro-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenol Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1C1=NOC(C(F)(F)F)=N1 WRGQAWAVRAVFMC-UHFFFAOYSA-N 0.000 claims 1
- ITUYVBZOLSFUNQ-UHFFFAOYSA-N 2,6-dimethyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenol Chemical compound CC1=C(O)C(C)=CC(C=2N=C(ON=2)C(F)(F)F)=C1 ITUYVBZOLSFUNQ-UHFFFAOYSA-N 0.000 claims 1
- UANNUVPHHFMLKL-UHFFFAOYSA-N 2-[5-[3-[2,6-dimethyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]propyl]-1,2-oxazol-3-yl]ethanol Chemical compound CC1=CC(C=2N=C(ON=2)C(F)(F)F)=CC(C)=C1OCCCC1=CC(CCO)=NO1 UANNUVPHHFMLKL-UHFFFAOYSA-N 0.000 claims 1
- UYJZBMFNRYYTBQ-UHFFFAOYSA-N 2-[[5-[3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2-oxazol-3-yl]oxy]ethanol Chemical compound CC1=CC(C=2N=C(ON=2)C2CC2)=CC(C)=C1OCCCC1=CC(OCCO)=NO1 UYJZBMFNRYYTBQ-UHFFFAOYSA-N 0.000 claims 1
- GHLXMNZJDVYTMV-UHFFFAOYSA-N 3-[3,5-dichloro-4-[5-(3-methyl-1,2-oxazol-5-yl)pentoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCCCOC1=C(Cl)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1Cl GHLXMNZJDVYTMV-UHFFFAOYSA-N 0.000 claims 1
- IHZWZVMRQVNMAR-UHFFFAOYSA-N 3-[3,5-difluoro-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(F)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1F IHZWZVMRQVNMAR-UHFFFAOYSA-N 0.000 claims 1
- YHXNWTZJAZKBCO-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trichloromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(Cl)(Cl)Cl)C=C1C YHXNWTZJAZKBCO-UHFFFAOYSA-N 0.000 claims 1
- ADCAIZVOWQNKID-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-ethoxy-1,2,4-oxadiazole Chemical compound O1C(OCC)=NC(C=2C=C(C)C(OCCCC=3ON=C(C)C=3)=C(C)C=2)=N1 ADCAIZVOWQNKID-UHFFFAOYSA-N 0.000 claims 1
- DDPAQYNSDSJGLU-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-methoxy-1,2,4-oxadiazole Chemical compound O1C(OC)=NC(C=2C=C(C)C(OCCCC=3ON=C(C)C=3)=C(C)C=2)=N1 DDPAQYNSDSJGLU-UHFFFAOYSA-N 0.000 claims 1
- HFEOVHWGZJHVGN-UHFFFAOYSA-N 3-[3,5-dimethyl-4-[5-(3-methyl-1,2-oxazol-5-yl)pentoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C HFEOVHWGZJHVGN-UHFFFAOYSA-N 0.000 claims 1
- OJHJKJUMTUGYJU-UHFFFAOYSA-N 3-[4-[3-(3-cyclopropyl-1,2-oxazol-5-yl)propoxy]-3,5-dimethylphenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound CC1=CC(C=2N=C(ON=2)C(F)(F)F)=CC(C)=C1OCCCC(ON=1)=CC=1C1CC1 OJHJKJUMTUGYJU-UHFFFAOYSA-N 0.000 claims 1
- PBMPIGNEBFRWDQ-UHFFFAOYSA-N 3-[4-[3-(3-ethyl-1,2-oxazol-5-yl)propoxy]-3,5-dimethylphenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(CC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C PBMPIGNEBFRWDQ-UHFFFAOYSA-N 0.000 claims 1
- KSZQNFLZEHBIDV-UHFFFAOYSA-N 3-[4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=CC=C(C=2N=C(ON=2)C(F)(F)F)C=C1 KSZQNFLZEHBIDV-UHFFFAOYSA-N 0.000 claims 1
- HTTDXJQJBZLXRA-UHFFFAOYSA-N 3-[4-[3-[3-(2-methoxyethyl)-1,2-oxazol-5-yl]propoxy]-3,5-dimethylphenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(CCOC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C HTTDXJQJBZLXRA-UHFFFAOYSA-N 0.000 claims 1
- GCDPFPMXIZHXTB-UHFFFAOYSA-N 3-[4-[3-[3-(methoxymethyl)-1,2-oxazol-5-yl]propoxy]-3,5-dimethylphenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole Chemical compound O1N=C(COC)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C GCDPFPMXIZHXTB-UHFFFAOYSA-N 0.000 claims 1
- YHEYWJUAGHSEJW-UHFFFAOYSA-N 5-(difluoromethyl)-3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)F)C=C1C YHEYWJUAGHSEJW-UHFFFAOYSA-N 0.000 claims 1
- RPRWGNOMCAHDPB-UHFFFAOYSA-N [5-[3-[2,6-dimethyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]propyl]-1,2-oxazol-3-yl]methanol Chemical compound CC1=CC(C=2N=C(ON=2)C(F)(F)F)=CC(C)=C1OCCCC1=CC(CO)=NO1 RPRWGNOMCAHDPB-UHFFFAOYSA-N 0.000 claims 1
- JMGVJPDUOKIIAQ-UHFFFAOYSA-N [5-[3-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2-oxazol-3-yl]methanol Chemical compound CC1=CC(C=2N=C(ON=2)C2CC2)=CC(C)=C1OCCCC1=CC(CO)=NO1 JMGVJPDUOKIIAQ-UHFFFAOYSA-N 0.000 claims 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims 1
- YEPDFBPHFOZPTA-UHFFFAOYSA-N ethyl 6-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]hex-2-ynoate Chemical compound C1=C(C)C(OCCCC#CC(=O)OCC)=C(C)C=C1C1=NOC(C2CC2)=N1 YEPDFBPHFOZPTA-UHFFFAOYSA-N 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 claims 1
- SYUAVQBWKXFZFT-UHFFFAOYSA-N tert-butyl-[[5-[3-[2,6-dimethyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy]propyl]-1,2-oxazol-3-yl]methoxy]-dimethylsilane Chemical compound CC1=CC(C=2N=C(ON=2)C(F)(F)F)=CC(C)=C1OCCCC1=CC(CO[Si](C)(C)C(C)(C)C)=NO1 SYUAVQBWKXFZFT-UHFFFAOYSA-N 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 34
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 33
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract description 17
- 125000003282 alkyl amino group Chemical group 0.000 abstract description 7
- 125000005113 hydroxyalkoxy group Chemical group 0.000 abstract description 7
- 125000004663 dialkyl amino group Chemical group 0.000 abstract description 6
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 174
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 101
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 101
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 239000000047 product Substances 0.000 description 77
- 238000000034 method Methods 0.000 description 64
- 239000007787 solid Substances 0.000 description 54
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 44
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 25
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 230000000875 corresponding effect Effects 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Inorganic materials [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- 229940093956 potassium carbonate Drugs 0.000 description 16
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- YRIZCZQOWPBLHL-UHFFFAOYSA-N 5-(chloromethyl)-3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(CCl)ON=2)C=C1C YRIZCZQOWPBLHL-UHFFFAOYSA-N 0.000 description 1
- UXFIKVWAAMKFQE-UHFFFAOYSA-N 5-chloropent-1-yne Chemical compound ClCCCC#C UXFIKVWAAMKFQE-UHFFFAOYSA-N 0.000 description 1
- SDNUNQZMNBLHPI-UHFFFAOYSA-N 5-cyclopropyl-3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-1,2,4-oxadiazole Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C2CC2)C=C1C SDNUNQZMNBLHPI-UHFFFAOYSA-N 0.000 description 1
- MGNWBSFRQUPKJM-UHFFFAOYSA-N 5-cyclopropyl-3-[4-[3-(3-pentoxy-1,2-oxazol-5-yl)propoxy]phenyl]-1,2,4-oxadiazole Chemical compound O1N=C(OCCCCC)C=C1CCCOC1=CC=C(C=2N=C(ON=2)C2CC2)C=C1 MGNWBSFRQUPKJM-UHFFFAOYSA-N 0.000 description 1
- CWHYLHUGGLZUOI-UHFFFAOYSA-N CCOCC=NO Chemical compound CCOCC=NO CWHYLHUGGLZUOI-UHFFFAOYSA-N 0.000 description 1
- UJPOEFZIGXLDMP-UHFFFAOYSA-N COCCC=NO Chemical compound COCCC=NO UJPOEFZIGXLDMP-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 241000710124 Human rhinovirus A2 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- YJFXWNSNMVKGNA-UHFFFAOYSA-N N',4-dihydroxybenzenecarboximidamide Chemical compound ON=C(N)C1=CC=C(O)C=C1 YJFXWNSNMVKGNA-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241001144416 Picornavirales Species 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- DOIGFGCNKPOVBK-UHFFFAOYSA-N [3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-2-methyl-3h-1,2,4-oxadiazol-5-yl] acetate Chemical compound CN1OC(OC(C)=O)=NC1C(C=C1C)=CC(C)=C1OCCCC1=CC(C)=NO1 DOIGFGCNKPOVBK-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- 230000003197 catalytic effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-M cyclohexanesulfonate Chemical compound [O-]S(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-M 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical class ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- ZBHDTYQJAQDBIH-UHFFFAOYSA-N fluoroacetyl chloride Chemical compound FCC(Cl)=O ZBHDTYQJAQDBIH-UHFFFAOYSA-N 0.000 description 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical group O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 102220092886 rs143733205 Human genes 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US869,287 | 1992-04-15 | ||
| US07/869,287 US5349068A (en) | 1992-04-15 | 1992-04-15 | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2094012A1 CA2094012A1 (en) | 1993-10-16 |
| CA2094012C true CA2094012C (en) | 2001-08-21 |
Family
ID=25353269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002094012A Expired - Lifetime CA2094012C (en) | 1992-04-15 | 1993-04-14 | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
Country Status (26)
| Country | Link |
|---|---|
| US (3) | US5349068A (en:Method) |
| EP (1) | EP0566199B1 (en:Method) |
| JP (1) | JP3103845B2 (en:Method) |
| KR (1) | KR100314158B1 (en:Method) |
| AT (1) | ATE189958T1 (en:Method) |
| AU (1) | AU666528B2 (en:Method) |
| CA (1) | CA2094012C (en:Method) |
| CZ (1) | CZ285845B6 (en:Method) |
| DE (1) | DE69327913T2 (en:Method) |
| DK (1) | DK0566199T3 (en:Method) |
| ES (1) | ES2143487T3 (en:Method) |
| FI (1) | FI112229B (en:Method) |
| GR (1) | GR3033486T3 (en:Method) |
| HU (2) | HU220606B1 (en:Method) |
| IL (1) | IL105372A (en:Method) |
| MX (1) | MX9302169A (en:Method) |
| MY (1) | MY110191A (en:Method) |
| NO (1) | NO302700B1 (en:Method) |
| NZ (1) | NZ247411A (en:Method) |
| PH (1) | PH30454A (en:Method) |
| PT (1) | PT566199E (en:Method) |
| RU (1) | RU2114112C1 (en:Method) |
| SG (1) | SG50663A1 (en:Method) |
| SK (1) | SK279786B6 (en:Method) |
| TW (1) | TW239140B (en:Method) |
| UA (1) | UA35557C2 (en:Method) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5349068A (en) * | 1992-04-15 | 1994-09-20 | Sterling Winthrop Inc. | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
| US5552420A (en) * | 1994-05-13 | 1996-09-03 | Sterling Winthrop Inc. | Therapeutic phenoxyalkylazoles and phenoxyalkylazines |
| IL118657A0 (en) * | 1996-06-14 | 1996-10-16 | Arad Dorit | Inhibitors for picornavirus proteases |
| IL122591A0 (en) | 1997-12-14 | 1998-06-15 | Arad Dorit | Pharmaceutical compositions comprising cystein protease inhibitors |
| US6348324B1 (en) | 1999-01-21 | 2002-02-19 | Hypoguard America Limited | Composition and device for detecting leukocytes in urine |
| US6528652B1 (en) * | 1999-01-21 | 2003-03-04 | Chronimed | Composition and device for detecting leukocytes in urine |
| AUPQ105499A0 (en) | 1999-06-18 | 1999-07-08 | Biota Scientific Management Pty Ltd | Antiviral agents |
| AUPR213700A0 (en) * | 2000-12-18 | 2001-01-25 | Biota Scientific Management Pty Ltd | Antiviral agents |
| MXPA03011196A (es) * | 2001-06-08 | 2004-10-28 | Cytovia Inc | 3-aril-5-aril-[1,2,4]-oxadiazoles sustituidos y analogos. |
| US7129359B2 (en) * | 2002-07-09 | 2006-10-31 | National Health Research Institutes | Imidazolidinone compounds |
| CA2459376A1 (en) * | 2001-08-29 | 2003-03-13 | Viropharma Incorporated | Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents |
| WO2003020270A1 (en) * | 2001-08-29 | 2003-03-13 | Viropharma Incorporated | Oxadiazolyl-phenoxyalkylisoxazoles, compositions thereof and methods for their use as anti-picornaviral agents |
| US7652050B2 (en) | 2001-12-07 | 2010-01-26 | Laboratorio de Siagnóstico GAM S.A | Methods for increasing the survival of aquatic animals infected with an aquatic virus |
| US20060167109A1 (en) * | 2002-02-14 | 2006-07-27 | Pevear Daniel C | Methods of reducing rhinovirus contagion and related compositions |
| EP1581213A4 (en) * | 2002-12-18 | 2008-11-19 | Cytovia Inc | 3,5-DISUBSTITUTED 1,2,4-OXADIAZOLE AND ANALOGUE TO ACTIVATE CASPASE AND INTRODUCTION OF APOPTOSIS AND THEIR USE |
| US7259174B2 (en) * | 2004-05-25 | 2007-08-21 | National Health Research Institutes | Imidazolidinone compounds |
| CA2575932A1 (en) * | 2004-08-04 | 2006-02-16 | Schering Corporation | Pharmaceutical formulations comprising pleconaril for the treatment of airway diseases |
| WO2007095043A2 (en) * | 2006-02-09 | 2007-08-23 | Schering Corporation | Pharmaceutical formulations |
| AR059357A1 (es) * | 2006-02-09 | 2008-03-26 | Schering Corp | Formulaciones farmaceuticas |
| WO2007095041A2 (en) * | 2006-02-09 | 2007-08-23 | Schering Corporation | Pharmaceutical formulations |
| CN101553483B (zh) | 2006-12-13 | 2013-04-17 | 弗·哈夫曼-拉罗切有限公司 | 作为非核苷逆转录酶抑制剂的2-(哌啶-4-基)-4-苯氧基-或苯基氨基-嘧啶衍生物 |
| KR101031584B1 (ko) * | 2009-04-21 | 2011-04-27 | 파인오토시스템(주) | 전면부가 개폐되는 차량용 적외선 조사장치 |
| CN103102322B (zh) * | 2011-11-14 | 2016-02-24 | 上海交通大学 | 噁唑类化合物及其制备方法、药物组合物及其用途 |
| CN112752761B (zh) | 2018-08-21 | 2024-03-29 | 杏林制药株式会社 | 双环杂芳族环衍生物 |
| CA3152534A1 (en) * | 2019-09-27 | 2021-04-01 | Collaborations Pharmaceuticals, Inc. | Isoxazole-3-carboxamide derivatives and their use for treatment of diseases caused by virus infection |
| WO2021209563A1 (en) | 2020-04-16 | 2021-10-21 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus |
Family Cites Families (11)
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| US4861791A (en) * | 1983-08-29 | 1989-08-29 | Sterling Drug Inc. | Dihydro-oxazolyl substituted-phenyl-aliphatic lower alkyl and their use as antiviral agents |
| ZA846525B (en) * | 1983-08-29 | 1985-04-24 | Sterling Drug Inc | (substituted)phenyl-aliphatic-isoxazoles useful as antiviral agents and preparation thereof |
| US4843087A (en) * | 1983-08-29 | 1989-06-27 | Sterling Drug Inc. | Di-heterocyclic compounds and their use as antiviral agents |
| CA1280753C (en) * | 1985-07-02 | 1991-02-26 | Philip Michael Carabateas | Process for preparing heterocyclic substituted- phenoxyalkyl isoxazoles and-furans |
| GB8619433D0 (en) * | 1986-08-08 | 1986-09-17 | Lilly Industries Ltd | Pharmaceutical compounds |
| US5175178A (en) * | 1989-08-21 | 1992-12-29 | Sterling Drug Inc. | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
| NZ234760A (en) * | 1989-08-18 | 1991-09-25 | Sterling Drug Inc | Antiviral oxazole compounds and compositions |
| US4942241A (en) * | 1989-08-21 | 1990-07-17 | Sterling Drug Inc. | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
| US4945164A (en) * | 1989-08-18 | 1990-07-31 | Sterling Drug Inc. | 1,3,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents and intermediates thereof |
| US5175177A (en) * | 1991-07-17 | 1992-12-29 | Sterling Drug Inc. | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
| US5349068A (en) * | 1992-04-15 | 1994-09-20 | Sterling Winthrop Inc. | 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents |
-
1992
- 1992-04-15 US US07/869,287 patent/US5349068A/en not_active Expired - Lifetime
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1993
- 1993-03-31 TW TW082102383A patent/TW239140B/zh not_active IP Right Cessation
- 1993-04-07 CZ CZ93597A patent/CZ285845B6/cs not_active IP Right Cessation
- 1993-04-10 MY MYPI93000665A patent/MY110191A/en unknown
- 1993-04-13 EP EP93201058A patent/EP0566199B1/en not_active Expired - Lifetime
- 1993-04-13 PT PT93201058T patent/PT566199E/pt unknown
- 1993-04-13 ES ES93201058T patent/ES2143487T3/es not_active Expired - Lifetime
- 1993-04-13 DK DK93201058T patent/DK0566199T3/da active
- 1993-04-13 AT AT93201058T patent/ATE189958T1/de active
- 1993-04-13 SG SG1996008085A patent/SG50663A1/en unknown
- 1993-04-13 DE DE69327913T patent/DE69327913T2/de not_active Expired - Lifetime
- 1993-04-14 AU AU36881/93A patent/AU666528B2/en not_active Expired
- 1993-04-14 KR KR1019930006244A patent/KR100314158B1/ko not_active Expired - Lifetime
- 1993-04-14 IL IL10537293A patent/IL105372A/en not_active IP Right Cessation
- 1993-04-14 CA CA002094012A patent/CA2094012C/en not_active Expired - Lifetime
- 1993-04-14 NO NO19931366A patent/NO302700B1/no not_active IP Right Cessation
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- 1993-04-15 JP JP05088647A patent/JP3103845B2/ja not_active Expired - Lifetime
- 1993-04-15 FI FI931707A patent/FI112229B/fi not_active IP Right Cessation
- 1993-04-15 NZ NZ247411A patent/NZ247411A/en not_active IP Right Cessation
- 1993-06-15 UA UA93003099A patent/UA35557C2/uk unknown
- 1993-10-01 US US08/131,050 patent/US5464848A/en not_active Expired - Lifetime
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1995
- 1995-05-19 US US08/444,795 patent/US5643929A/en not_active Expired - Lifetime
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