JP5255455B2 - 抗ウイルス剤としての置換アリールスルホンアミド類 - Google Patents
抗ウイルス剤としての置換アリールスルホンアミド類 Download PDFInfo
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- JP5255455B2 JP5255455B2 JP2008557628A JP2008557628A JP5255455B2 JP 5255455 B2 JP5255455 B2 JP 5255455B2 JP 2008557628 A JP2008557628 A JP 2008557628A JP 2008557628 A JP2008557628 A JP 2008557628A JP 5255455 B2 JP5255455 B2 JP 5255455B2
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- halogen
- represents hydrogen
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- 125000004421 aryl sulphonamide group Chemical group 0.000 title description 4
- 239000003443 antiviral agent Substances 0.000 title description 3
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- 238000000034 method Methods 0.000 claims description 49
- -1 methylcarbonylamino Chemical group 0.000 claims description 48
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- 239000001257 hydrogen Substances 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
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- 238000002360 preparation method Methods 0.000 claims description 9
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
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- 241000700159 Rattus Species 0.000 description 8
- 241000700605 Viruses Species 0.000 description 8
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- 239000012043 crude product Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
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- 239000003826 tablet Substances 0.000 description 7
- 238000000825 ultraviolet detection Methods 0.000 description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000701022 Cytomegalovirus Species 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
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- 230000015572 biosynthetic process Effects 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
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- 241000282472 Canis lupus familiaris Species 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
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- 239000005457 ice water Substances 0.000 description 5
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- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 241000894007 species Species 0.000 description 5
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- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 4
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- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- HNJOAIYFUCQZAA-UHFFFAOYSA-N Cc1n[o]c(C)n1 Chemical compound Cc1n[o]c(C)n1 HNJOAIYFUCQZAA-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000515 collagen sponge Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 208000019836 digestive system infectious disease Diseases 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000001023 inorganic pigment Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 159000000003 magnesium salts 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- PEMGGJDINLGTON-UHFFFAOYSA-N n-(3-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(N)=C1 PEMGGJDINLGTON-UHFFFAOYSA-N 0.000 description 1
- OWNFKAVNRIRBLE-UHFFFAOYSA-N n-[3-[[4-(n'-hydroxycarbamimidoyl)phenyl]sulfonylamino]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(NS(=O)(=O)C=2C=CC(=CC=2)C(\N)=N\O)=C1 OWNFKAVNRIRBLE-UHFFFAOYSA-N 0.000 description 1
- FTZMYPCGDDAQSX-UHFFFAOYSA-N n-[3-[[4-[2-(6-aminopyridin-2-yl)ethynyl]phenyl]sulfonylamino]phenyl]-1-cyanocyclopropane-1-carboxamide;hydrochloride Chemical compound Cl.NC1=CC=CC(C#CC=2C=CC(=CC=2)S(=O)(=O)NC=2C=C(NC(=O)C3(CC3)C#N)C=CC=2)=N1 FTZMYPCGDDAQSX-UHFFFAOYSA-N 0.000 description 1
- QSKOUCRUDRNRQU-UHFFFAOYSA-N n-[3-[[4-[5-(6-acetamidopyridin-2-yl)-1,2,4-oxadiazol-3-yl]phenyl]sulfonylamino]-5-fluorophenyl]-1-cyanocyclopropane-1-carboxamide Chemical compound CC(=O)NC1=CC=CC(C=2ON=C(N=2)C=2C=CC(=CC=2)S(=O)(=O)NC=2C=C(NC(=O)C3(CC3)C#N)C=C(F)C=2)=N1 QSKOUCRUDRNRQU-UHFFFAOYSA-N 0.000 description 1
- SFOGBTSWOZAVAK-UHFFFAOYSA-N n-[3-[[4-[5-(6-acetamidopyridin-2-yl)-1,2,4-oxadiazol-3-yl]phenyl]sulfonylamino]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(NS(=O)(=O)C=2C=CC(=CC=2)C=2N=C(ON=2)C=2N=C(NC(C)=O)C=CC=2)=C1 SFOGBTSWOZAVAK-UHFFFAOYSA-N 0.000 description 1
- BOFOIVDUYWEGIU-UHFFFAOYSA-N n-[3-[[4-[5-(6-aminopyridin-2-yl)-1,2,4-oxadiazol-3-yl]phenyl]sulfonylamino]-2-methylphenyl]-1-cyanocyclopropane-1-carboxamide Chemical compound C1=CC=C(NS(=O)(=O)C=2C=CC(=CC=2)C=2N=C(ON=2)C=2N=C(N)C=CC=2)C(C)=C1NC(=O)C1(C#N)CC1 BOFOIVDUYWEGIU-UHFFFAOYSA-N 0.000 description 1
- JSONRKJLNYJHHF-UHFFFAOYSA-N n-[6-[3-(4-benzylsulfanylphenyl)-1,2,4-oxadiazol-5-yl]pyridin-2-yl]acetamide Chemical compound CC(=O)NC1=CC=CC(C=2ON=C(N=2)C=2C=CC(SCC=3C=CC=CC=3)=CC=2)=N1 JSONRKJLNYJHHF-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010972 statistical evaluation Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 229960002149 valganciclovir Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 230000031143 xenobiotic glucuronidation Effects 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Aは、式
そして、#は、フェニル環の炭素原子への結合部位である)
の基を表し、
R1は、水素、アミノまたはメチルカルボニルアミノを表し、
R2は、水素またはハロゲンを表し、
R3は、水素、ハロゲンまたはシアノを表し、
R4は、水素、ハロゲンまたはシアノを表し、
R5は、水素またはハロゲンを表し、
R6は、水素またはハロゲンを表し、
R7は、水素、ハロゲンまたはC1−C3−アルキルを表し、
R8は、水素、ハロゲンまたはC1−C3−アルキルを表す]
の化合物、並びにそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物に関する。
本発明の化合物が互変異性体で生じ得る場合、本発明は、全ての互変異性体を含む。
アルキルは、通常1個ないし6個、特に好ましくは1個ないし2個の炭素原子を有する直鎖または分枝鎖のアルキルラジカル、例えば、そして好ましくは、メチル、エチル、n−プロピルおよびイソプロピルを表す。
ハロゲンは、フッ素、塩素、臭素およびヨウ素、好ましくはフッ素および塩素を表す。
Aが、式
そして、#は、フェニル環の炭素原子への結合部位である)
の基を表し、
R1が、水素、アミノまたはメチルカルボニルアミノを表し、
R2、R3およびR4が水素を表し、
R5が水素またはハロゲンを表し、
R6が水素またはハロゲンを表し、
R7およびR8が水素を表す、
式(I)の化合物、並びにそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物である。
Aが、式
そして、#は、フェニル環の炭素原子への結合部位である)
の基を表し、
R1が、アミノまたはメチルカルボニルアミノを表し、
R2、R3およびR4が水素を表し、
R5が水素を表し、
R6が水素またはハロゲンを表し、
R7およびR8が水素を表す、
式(I)の化合物、並びにそれらの塩、それらの溶媒和物およびそれらの塩の溶媒和物である。
好ましいのは、また、式中、R2が水素を表す、式(I)の化合物である。
好ましいのは、また、式中、R3が水素を表す、式(I)の化合物である。
好ましいのは、また、式中、R4が水素を表す、式(I)の化合物である。
好ましいのは、また、式中、R5が水素を表す、式(I)の化合物である。
好ましいのは、また、式中、R6がフッ素を表す、式(I)の化合物である。
好ましいのは、また、式中、R5が水素を表し、R6がフッ素を表す、式(I)の化合物である。
好ましいのは、また、式中、R7が水素を表す、式(I)の化合物である。
好ましいのは、また、式中、R8が水素を表す、式(I)の化合物である。
ことさら特に好ましいのは、上述の好ましい範囲の2つまたはそれ以上の組合せである。
の化合物を、式
X1は、ハロゲン、好ましくは塩素もしくは臭素、またはヒドロキシを表す)
の化合物と反応させる。
[A]式
の化合物を、式
の化合物と反応させ、式
の化合物を得る、
または、
の化合物を、式
の化合物と反応させ、式
の化合物を得る、
または、
の化合物と反応させ、第2段階で、オキシ塩化リンと反応させ、式
の化合物を得る、
または、
X2は、ハロゲン、好ましくはヨウ素または臭素を表す)
の化合物を、式
の化合物と反応させ、式
の化合物を得る、
に従い製造できる。
塩基の例には、トリエチルアミンなどのアミン塩基が含まれる。
不活性溶媒の例には、ジオキサン、テトラヒドロフランまたは1,2−ジメトキシエタンなどのエーテル類、ベンゼン、キシレンまたはトルエンなどの炭化水素類、または、ニトロベンゼン、ジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシドまたはN−メチルピロリドンなどの他の溶媒が含まれ、好ましいのは、例えばジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシドまたは1,2−ジメトキシエタンなどの溶媒である。
X3は、ハロゲン、好ましくはヨウ素または臭素、ヒドロキシカルボニルまたはシアノを表す)
の化合物を、式
の化合物と反応させることにより製造できる。
1)AIDS患者におけるHCMV感染の処置および予防(網膜炎、肺臓炎、胃腸の感染)。
2)生命を脅かすHCMV肺臓炎または脳炎、並びに、胃腸および全身のHCMV感染をしばしば発症する、骨髄および臓器移植患者におけるサイトメガロウイルス感染の処置および予防。
3)新生児および幼児におけるHCMV感染の処置および予防。
4)妊婦における急性HCMV感染の処置。
5)癌および癌治療中の免疫抑制患者におけるHCMV感染の処置。
6)HCMVに媒介される腫瘍の進行を低減することを目的とする、HCMV陽性癌患者の処置(J. Cinatl, et al., FEMS Microbiology Reviews 2004, 28, 59-77 参照)。
経口投与に適するのは、先行技術に準じて機能し、本発明の化合物を、迅速に、かつ/または、修飾された方法で送達し、そして、本発明の化合物を結晶形および/または無定形および/または溶解形で含む投与形、例えば、錠剤(非被覆または被覆錠剤、例えば、胃液耐性であるか、遅れて溶解するか、または、不溶であり、本発明の化合物の放出を制御する被覆を有するもの)、口腔中で迅速に崩壊する錠剤またはフィルム/オブラート、フィルム/凍結乾燥剤、カプセル剤(例えば、ハードまたはソフトゼラチンカプセル剤)、糖衣錠、顆粒剤、ペレット剤、散剤、乳剤、懸濁剤、エアゾール剤または液剤である。
方法1(LC−MS):MS装置タイプ:Micromass ZQ、HPLC装置タイプ:HP 1100 series; UV DAD;カラム:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm;溶離剤A:水1l+50%ギ酸0.5ml、溶離剤B:アセトニトリル1l+50%ギ酸0.5ml;グラジエント:0.0分90%A→2.5分30%A→3.0分5%A→4.5分5%A;流速:0.0分1ml/分、2.5分/3.0分/4.5分2ml/分;オーブン:50℃;UV検出:210nm。
実施例1A
4−(ベンジルチオ)ベンゾニトリル
LC−MS(方法1):Rt=2.85分
MS(ESI):m/z=226[M+H]+
4−(ベンジルチオ)−N'−ヒドロキシベンゾカルボキシイミドアミド
LC−MS(方法1):Rt=1.79分
MS(ESI):m/z=229[M+H]+
N−(6−{3−[4−(ベンジルチオ)フェニル]−1,2,4−オキサジアゾール−5−イル}ピリジン−2−イル)アセトアミド
LC−MS(方法1):Rt=2.98分
MS(ESI):m/z=403[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.96 (s, 1H), 8.38 (d, 1H), 8.08 (t, 1H), 8.02-7.95 (m, 3H), 7.53 (d, 2H), 7.43 (d, 2H), 7.35-7.21 (m, 3H), 4.36 (s, 2H), 2.15 (s, 3H).
6−{3−[4−(ベンジルチオ)フェニル]−1,2,4−オキサジアゾール−5−イル}ピリジン−2−アミン塩酸塩
LC−MS(方法2):Rt=2.76分
MS(ESI):m/z=361[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 7.95 (d, 2H), 7.73 (t, 1H), 7.53 (d, 2H), 7.51 (m, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.25 (m, 1H), 6.85 (d, 1H), 4.38 (s, 2H).
4−[5−(6−アミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]ベンゾスルホニルクロリド
LC−MS(方法3):Rt=2.22分
MS(ESI):m/z=337[M+H]+
2−クロロ−5−フルオロ−1,3−ジニトロベンゼン
1H−NMR(400MHz,DMSO−d6):δ=8.56(d,2H)
5−フルオロ−1,3−アミノベンゼン
LC−MS(方法4):Rt=0.58分
MS(ESI):m/z=127[M+H]+
N−(3−アミノ−5−フルオロフェニル)−1−シアノシクロプロパンカルボキサミド
LC−MS(方法1):Rt=1.31分
MS(ESI):m/z=220[M+H]+
N−(3−{[(4−シアノフェニル)スルホニル]アミノ}フェニル)アセトアミド
LC−MS(方法1):Rt=1.79分
MS(ESI):m/z=316[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.52 (s, 1H), 9.94 (s, 1H), 8.05 (d, 2H), 7.90 (d, 2H), 7.46 (s, 1H), 7.27 (d, 1H), 7.13 (t, 1H), 6.72 (d, 1H), 2.00 (s, 3H).
N−{3−[({4−[(Z)−アミノ(ヒドロキシイミノ)メチル]フェニル}スルホニル)アミノ]フェニル}アセトアミド
LC−MS(方法1):Rt=1.14分
MS(ESI):m/z=349[M+H]+
N−(6−{3−[4−({[3−(アセチルアミノ)フェニル]アミノ}スルホニル)フェニル]−1,2,4−オキサジアゾール−5−イル}ピリジン−2−イル)アセトアミド
HPLC(方法5):Rt=4.03分
MS(ESI):m/z=493[M+H]+
N−(3−アミノフェニル)−4−[5−(6−アミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]ベンゾスルホンアミド
HPLC(方法5):Rt=3.53分
MS(ESI):m/z=409[M+H]+
1H-NMR (300 MHz, DMSO-d6): δ = 10.16 (br s, 1H), 8.23 (d, 2H), 7.97 (d, 2H), 7.63 (t, 1H), 7.45 (d, 1H), 6.85 (t, 1H), 6.74 (d, 1H), 6.58 (br s, 2H), 6.42 (s, 1H), 6.28 (t, 1H), 5.44 (br s, 2H).
N−(6−ブロモピリジン−2−イル)アセトアミド
HPLC(方法6):Rt=3.66分
MS(DCI/NH3):m/z=215および217[M+H]+、232および234[M+NH4]+、249および251[M+NH4+NH3]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.79 (s, 1H, NH), 8.08 (d, 1H), 7.71 (t, 1H), 7.31 (d, 1H), 2.09 (s, 3H).
N−[6−(3−ヒドロキシ−3−メチルブト−1−イン−1−イル)ピリジン−2−イル]アセトアミド
HPLC(方法6):Rt=3.30分
MS(方法M−40,DCI/NH3):m/z=219[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1H, NH), 8.05 (d, 1H), 7.75 (t, 1H), 7.14 (d, 1H), 5.55 (s, 1H, OH), 2.07 (s, 3H), 1.46 (s, 6H).
N−(6−エチニルピリジン−2−イル)アセトアミド
HPLC(方法6):Rt=3.18分
MS(方法M−40,DCI/NH3):m/z=161[M+H]+、178[M+NH4]+,
1H-NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1H, NH), 8.10 (d, 1H), 7.78 (t, 1H), 7.26 (d, 1H), 4.31 (s, 1H), 2.08 (s, 3H).
N−(3−{[(4−ヨードフェニル)スルホニル]アミノ}フェニル)アセトアミド
HPLC(方法6):Rt=4.14分
MS(ES+,ES−):m/z=417[M+H]+、415[M−H]−
1H-NMR (400 MHz, DMSO-d6): δ = 10.31 (s, 1H, NH), 9.91 (s, 1H, NH), 7.93 (d, 2H), 7.51 (d, 2H), 7.45 (s, 1H), 7.26 (d, 1H), 7.12 (t, 1H), 6.73 (d, 1H), 2.00 (s, 3H).
N−(6−{[4−({[3−(アセチルアミノ)フェニル]アミノ}スルホニル)フェニル]エチニル}ピリジン−2−イル)アセトアミド
HPLC(方法6):Rt=3.86分
MS(ES+,ES−):m/z=449[M+H]+、447[M−H]−
1H-NMR (400 MHz, DMSO-d6): δ = 10.76 (s, 1H, NH), 10.38 (s, 1H, NH), 9.93 (s, 1H, NH), 8.13 (d, 1H), 7.88-7.78 (m, 3H), 7.73 (d, 2H), 7.48 (s, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.12 (t, 1H), 6.76 (d, 1H), 2.09 (s, 3H), 2.00 (s, 3H).
N−(3−アミノフェニル)−4−[(6−アミノピリジン−2−イル)エチニル]ベンゾスルホンアミド二塩酸塩
HPLC(方法6):Rt=3.65分
MS(ES+,ES−):m/z=365[M+H]+、363[M−H]−、
1H-NMR (400 MHz, DMSO-d6): δ = 10.70 (s, 1H, NH), 7.91-7.78 (m, 5H), 7.24 (t, 1H), 7.09 (d, 1H), 7.02 (s, 1H), 6.96-6.83 (m, 3H).
4−[5−(6−アセチルアミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]ベンゾスルホニルクロリド
LC−MS(方法3):Rt=2.31分
MS(ESI):m/z=379[M+H]+
実施例1
N−{3−[({4−[5−(6−アミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]フェニル}スルホニル)アミノ]−5−フルオロフェニル}−1−シアノシクロプロパンカルボキサミド
LC−MS(方法3):Rt=2.07分
MS(ESI):m/z=520[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 8.37 (d, 2H), 8.01 (d, 2H), 7.64 (t, 1H), 7.45 (d, 1H), 7.35 (s, 1H), 7.21 (br d, 1H), 6.73 (d, 1H), 6.68 (br d, 1H), 6.56 (br s, 2H), 1.65 (s, 4H).
N−{3−[({4−[5−(6−アミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]フェニル}スルホニル)アミノ]フェニル}−1−シアノシクロプロパンカルボキサミド
LC−MS(方法2):Rt=2.13分
MS(ESI):m/z=502[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.47 (s, 1H), 10.06 (s, 1H), 8.23 (d, 2H), 7.97 (d, 2H), 7.64 (t, 1H), 7.53 (s, 1H), 7.45 (d, 1H), 7.28 (d, 1H), 7.17 (t, 1H), 6.84 (d, 1H), 6.73 (d, 1H), 1.65 (s, 4H).
N−{3−[({4−[5−(6−アミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]フェニル}スルホニル)アミノ]−2−メチルフェニル}−1−シアノシクロプロパンカルボキサミド
LC−MS(方法3):Rt=1.91分
MS(ESI):m/z=516[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 9.91 (s, 1H), 9.67 (s, 1H), 8.26 (d, 2H), 7.87 (d, 2H), 7.65 (t, 1H), 7.47 (d, 1H), 7.10 (m, 2H), 6.84 (dd, 1H), 6.76 (d, 1H), 1.91 (s, 3H), 1.63 (m, 4H).
N−{3−[({4−[(6−アミノピリジン−2−イル)エチニル]フェニル}スルホニル)アミノ]フェニル}−1−シアノシクロプロパンカルボキサミド塩酸塩
HPLC(方法6):Rt=3.87分
MS(ES+,ES−):m/z=458[M−HCl+H]+、456[M−HCl−H]−、
1H-NMR (400 MHz, DMSO-d6): δ = 10.45 (s, 1H, NH), 10.07 (s, 1H, NH), 7.83 (d, 2H), 7.79-7.66 (m, 3H), 7.51 (s, 1H), 7.27 (d, 1H), 7.17 (t, 1H), 7.01 (d, 1H), 6.82 (d, 2H), 1.65 (s, 4H).
N−{3−[({4−[5−(6−アセチルアミノピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]フェニル}スルホニル)アミノ]−5−フルオロフェニル}−1−シアノシクロプロパンカルボキサミド
LC−MS(方法7):Rt=2.46分
MS(ESI):m/z=562[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ = 10.99 (s, 1H), 10.78 (s, 1H), 10.26 (s, 1H), 8.40 (d, 1H), 8.17 (d, 2H), 8.06 (m, 4H), 7.37 (s, 1H), 7.21 (d, 1H), 6.68 (d, 1H), 2.15 (s, 3H), 1.66 (s, 4H).
本発明の化合物のインビトロでの活性は、以下のアッセイで示すことができる:
抗−HCMV(抗−ヒトサイトメガロウイルス)細胞変性試験
試験化合物は、ジメチルスルホキシド(DMSO)中の50ミリモル濃度(mM)溶液として用いる。ガンシクロビル(登録商標)を参照化合物として供する。50、5、0.5および0.05mMのDMSO原液各2μlを、2A−H行の細胞培養培地98μlにデュプリケート測定で添加した後、培地50μlで96ウェルプレートの11行まで1:2希釈を実施する。1および12行のウェルは、各々50μlの培地を含む。次いで、細胞1x104個(ヒト包皮線維芽細胞[NHDF])の懸濁液150μlを各ウェルにピペットで加え(1行=細胞対照)、2−12行には、HCMV感染および非感染NHDF細胞の混合物(M.O.I.=0.001−0.003)、即ち、1000個の非感染細胞につき1−3個の感染細胞を加える。行12(物質なし)は、ウイルス対照として役立つ。最終試験濃度は、250−0.0005μMである。プレートを37℃/5%CO2で6日間、即ち、ウイルス対照の全細胞が感染する(100%細胞変性効果[CPE])までインキュベートする。次いで、ウェルを固定し、ホルマリンとギムザ染料の混合物の添加により染色し(30分間)、二重蒸留水で洗浄し、乾燥オーブン中50℃で乾燥させる。次いで、オーバーヘッド顕微鏡を使用してプレートを目視評価する(Technomara のプラーク拡大装置(plaque multiplier))。
CC50(NHDF)=非処理細胞対照と比較して、細胞に対する目視できる細胞変性効果が明白ではない、μM表記の物質濃度;
EC50(HCMV)=非処理ウイルス対照と比較して、CPE(細胞変性効果)を50%まで阻害する、μM表記の物質濃度;
SI(選択性指数)=CC50(NHDF)/EC50(HCMV)
HCMV異種移植 Gelfoam (登録商標) モデル
動物:
5−6週齢の免疫不全マウス(16−20g)の Fox Chase SCID.NOD または NOD.CB17-Prkdc/J を、育種業者(Taconic M&B, Denmark; Jackson, USA)から入手する。動物を隔離飼育器中、滅菌条件(寝床および飼料を含む)下で飼育する。
Davis または AD169 系統のヒトサイトメガロウイルス(HCMV)を、ヒト胚性包皮線維芽細胞(NHDF細胞)において、インビトロで増殖させる。NHDF細胞を感染効率(M.O.I.)0.01−0.03で感染させた後、ウイルス感染細胞を5−10日後に回収し、最小必須培地(MEM)、20%ウシ胎児血清(FCS)(v/v)、1%グルタミン(v/v)、1%Pen/Strep(v/v)(10%DMSOを含む)の存在下、−80℃で保存する。ウイルス感染細胞の連続10倍希釈の後、コンフルエントNHDF細胞の24ウェルプレートで、ギムザホルムアルデヒド溶液による固定および染色の後、力価を決定する。
サイズ1x1x1cmのコラーゲンスポンジ(Gelfoam(登録商標); Peasel & Lorey, order no. 407534; K.T. Chong et al., Abstracts of 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439)を、最初にリン酸緩衝塩水(PBS)で湿らせ、閉じ込められた気泡を脱気により除去し、次いで、MEM、10%FCS(v/v)、1%グルタミン(v/v)、1%Pen/Strep(v/v)中で保存する。1x106個のウイルス感染NHDF細胞(HCMV Davis または HCMV AD169 に感染、M.O.I.=0.03)を、感染の3時間後に剥がし、20μlのMEM、10%FCS(v/v)、1%グルタミン(v/v)、1%Pen/Strep(v/v)中で滴下して、湿ったスポンジに添加する。スポンジを3−4時間インキュベートして、細胞を接着させる。続いて、培地(MEM、10%FCS(v/v)、1%グルタミン(v/v)、1%Pen/Strep(v/v))を添加した後、スポンジを終夜インキュベートする。移植のために、免疫不全マウスをアベルチン(Avertin)またはケタミン/キシラジン/アゼプロマジン(azepromazine)混合物で麻酔し、電気カミソリを使用して背中の毛を除去し、表皮を1−2cm切開し、緊張を解き(unstressed)、背側の皮膚の下に湿ったスポンジを移植する。手術創を組織接着剤(tissue glue)またはクリップで閉じる。移植の4−6時間後、マウスを初めて処置できる(手術当日に1回の処置を行う)。翌日、物質による処置を、経口で1日3回(7.00時および14.00時および19.00時)、1日2回(8時および18時)または1日1回(9時)、8日間実施する。1日の用量は、例えば1または3または10または30または100mg/体重kgであり、投与体積は、10ml/体重kgである。各物質は、2%DMSOを含む0.5%タイローズ(tylose)懸濁液/PBS、または、物質の溶解を補助する他の適する混合物、例えば2%エタノール、2.5% ソルトール(solutol)、95.5%PBSの形態で製剤化する。移植の10日後および最後の物質投与の約16時間後、動物を無痛に殺し、スポンジを取り出す。コラゲナーゼ切断(330U/1.5ml)によりウイルス感染細胞をスポンジから解放し、MEM、10%FCS(v/v)、1%グルタミン(v/v)、1%Pen/Strep(v/v)、10%DMSOの存在下、−140℃で保存する。評価は、ウイルス感染細胞の連続10倍希釈の後、コンフルエントNHDF細胞の24ウェルプレートで、ギムザホルムアルデヒド溶液による固定および染色の後、力価を決定することにより行う。プラセボ処置対照群と比較して、物質処置後の感染細胞または感染性ウイルス粒子(感染中心アッセイ)の数を決定する。GraphPad Prism などの適するコンピュータープログラムにより、統計的評価を行う。
活性物質の薬物動態を、投与経路につき3匹のオスの Wistar ラットへの1mg/kg静脈内および3mg/kg経口の範囲の用量の静脈内または経口投与後に調査する。血液の反復採取を可能にするために、実験前日に動物の頸静脈にカテーテルを移植する。物質を静脈内および経口で溶液として投与する。そこで、殆どの場合、血漿製剤(1−2%エタノールまたはDMSOを含むラット血漿、2ml/kg)を静脈内投与に使用し、PEG製剤(10%エタノール、40%PEG400、50%水、5ml/kg)を経口投与に使用する。
Vss=分布容積;
CL=排出速度;
t1/2=半減期;
AUC=薬物濃度の経時曲線下の総面積;
Cmax=最高濃度;
F=バイオアベイラビリティー;
表B
2:10%エタノール、40%PEG400、50%水中の溶液、5ml/kg
活性化合物の代謝において異なる種は、その展開性(developability)に大きな影響を有し得る。ヒトと、例えばラットおよびイヌなどの通常の毒性試験種との間で代謝分解経路が有意に異ならない物質を見出すのが目的である。このために、第I相代謝を比較する目的で、新しい活性物質を最初にインビトロでラット、イヌおよびヒトの肝臓ミクロソームと共にインキュベートする。続いて、完全な肝臓の第I相および第II相代謝を得、それを比較するために、依然として関心のある化合物を、さらにラットおよびヒトの肝細胞中でインキュベートする。
本発明の化合物は、以下の方法で医薬製剤に変換できる:
錠剤:
組成:
実施例1の化合物100mg、ラクトース(一水和物)50mg、トウモロコシデンプン(天然)50mg、ポリビニルピロリドン (PVP 25) (BASF, Ludwigshafen, Germany) 10mgおよびステアリン酸マグネシウム2mg。
錠剤重量212mg。直径8mm、曲率半径12mm。
製造:
有効成分、ラクトースおよびデンプンの混合物を、5%PVP水溶液(m/m)で造粒する。次いで、顆粒を乾燥させ、ステアリン酸マグネシウムと5分間混合する。この混合物を常套の打錠機を使用して打錠する(錠剤の形状について、上記参照)。打錠に使用する打錠力のガイドラインは、15kNである。
組成:
実施例1の化合物1000mg、エタノール(96%)1000mg、Rhodigel (FMCのキサンタンゴム、Pennsylvania, USA) 400mgおよび水99g。
経口懸濁液10mlは、本発明の化合物100mgの単回用量に相当する。
製造:
Rhodigel をエタノールに懸濁し、有効成分を懸濁液に添加する。撹拌しながら水を添加する。Rhodigel の膨潤が完了するまで、混合物を約6時間撹拌する。
組成:
実施例1の化合物10−500mg、ポリエチレングリコール400 15g、および注射用水250g。
製造:
実施例1の化合物を、ポリエチレングリコール400と共に、撹拌しながら水に溶解する。溶液を濾過(孔直径0.22μm)により滅菌し、加熱滅菌した点滴瓶に無菌条件下で分注する。これらを点滴ストッパーおよびクリンプキャップで閉じる。
Claims (11)
- X1が、塩素、臭素、またはヒドロキシを表すことを特徴とする、請求項4に記載の方法。
- 疾患の処置および/または予防のための、請求項1ないし請求項3のいずれかに記載の化合物。
- 請求項1ないし請求項3のいずれかに記載の化合物を、不活性、非毒性の医薬的に許容し得る補助剤と組み合わせて含む、医薬。
- ウイルス感染の処置および/または予防用の医薬を製造するための、請求項1ないし請求項3のいずれかに記載の化合物の使用。
- ウイルス感染が、ヒトサイトメガロウイルス(HCMV)またはヘルペスウイルス科の群の他の代表例による感染であることを特徴とする、請求項8に記載の使用。
- ウイルス感染の処置および/または予防用の請求項7に記載の医薬。
- 抗ウイルス的に有効な量の、少なくとも1種の請求項1ないし請求項3のいずれかに記載の化合物、請求項7に記載の医薬、または、請求項8もしくは請求項9により得られる医薬を投与することによる、ヒト以外の動物におけるウイルス感染の制御方法。
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DE102006009928A DE102006009928A1 (de) | 2006-03-03 | 2006-03-03 | Substituierte Arylsulfonamide |
DE102006009928.1 | 2006-03-03 | ||
PCT/EP2007/001620 WO2007101573A1 (de) | 2006-03-03 | 2007-02-26 | Substituierte arylsulfonamide als antivirale mittel |
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US (1) | US8318761B2 (ja) |
EP (1) | EP1991529B1 (ja) |
JP (1) | JP5255455B2 (ja) |
KR (1) | KR101447758B1 (ja) |
CN (1) | CN101389607B (ja) |
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AU (1) | AU2007222689B2 (ja) |
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DE10319612A1 (de) | 2003-05-02 | 2004-11-18 | Bayer Healthcare Ag | Substituierte Dihydrochinazoline |
EP2103318A1 (de) * | 2008-03-20 | 2009-09-23 | Bayer MaterialScience AG | Medizinische Geräte mit hydrophilen Beschichtungen |
EP2103317A1 (de) * | 2008-03-20 | 2009-09-23 | Bayer MaterialScience AG | Medizinische Geräte mit hydrophilen Beschichtungen |
EP2103316A1 (de) * | 2008-03-20 | 2009-09-23 | Bayer MaterialScience AG | Hydrophile Polyurethandispersionen |
EP2103638A1 (de) * | 2008-03-20 | 2009-09-23 | Bayer MaterialScience AG | Hydrophile Polyurethanlösungen |
DE102008025614A1 (de) * | 2008-05-28 | 2009-12-03 | Bayer Materialscience Ag | Hydrophile Polyurethanbeschichtungen |
DE102008025613A1 (de) * | 2008-05-28 | 2009-12-03 | Bayer Materialscience Ag | Hydrophile Polyurethanbeschichtungen |
JP2012502119A (ja) | 2008-09-04 | 2012-01-26 | バイエル・マテリアルサイエンス・アクチェンゲゼルシャフト | Tcd系親水性ポリウレタン分散体 |
DE102011101446A1 (de) | 2011-05-10 | 2012-11-15 | Aicuris Gmbh & Co. Kg | Herstellung von "Dense Bodies" (DB) |
EP2853532B1 (en) * | 2013-09-28 | 2020-12-09 | Instytut Farmakologii Polskiej Akademii Nauk | 1,2,4-oxadiazole derivatives as allosteric modulators of metabotropic glutamate receptors belonging to group III |
CN109879817B (zh) * | 2019-03-19 | 2020-10-02 | 扬州大学 | 甲基二磺隆的制备方法 |
RU2738848C1 (ru) * | 2019-10-24 | 2020-12-17 | Общество с ограниченной ответственностью "Научно-исследовательский институт ХимРар" (ООО "НИИ ХимРар") | Ингибитор вируса гепатита В (ВГВ), представляющий собой производные N-{ 3-[6-(диалкиламино)пиридазин-3-ил]фенил} арилсульфонамида и производные N-{ 4-[6-(диалкиламино)пиридазин-3-ил]фенил} арилсульфонамида |
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DE19802437A1 (de) | 1998-01-23 | 1999-07-29 | Bayer Ag | Verwendung von substituierten Sulfonamiden als anitvirale Mittel und neue Stoffe |
AU765203B2 (en) | 1999-04-19 | 2003-09-11 | Shionogi & Co., Ltd. | Sulfonamide derivatives having oxadiazole rings |
DE19920790A1 (de) * | 1999-05-06 | 2000-11-09 | Bayer Ag | Bis-Sulfonamide mit anti-HCMV-Wirkung |
DE19930075A1 (de) | 1999-06-30 | 2001-01-04 | Bayer Ag | Neue Amino- und Amidosulfonamide als antivirale Mittel |
JP4480941B2 (ja) | 2001-04-19 | 2010-06-16 | アイキュリス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング・ウント・コムパニー・コマンディットゲゼルシャフト | 抗ウイルス剤としての新規アリールスルホンアミド |
DE10138578A1 (de) | 2001-08-06 | 2003-02-27 | Bayer Ag | Heterocyclylarylsulfonamide |
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