JP2002533301A - 置換フェニレンジアミン群を含む、複素環式カルボキサミド含有の、ヘルペスウイルスのチオ尿素インヒビター - Google Patents
置換フェニレンジアミン群を含む、複素環式カルボキサミド含有の、ヘルペスウイルスのチオ尿素インヒビターInfo
- Publication number
- JP2002533301A JP2002533301A JP2000586708A JP2000586708A JP2002533301A JP 2002533301 A JP2002533301 A JP 2002533301A JP 2000586708 A JP2000586708 A JP 2000586708A JP 2000586708 A JP2000586708 A JP 2000586708A JP 2002533301 A JP2002533301 A JP 2002533301A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- thioureido
- chloro
- carbon atoms
- amide
- 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.)
- Pending
Links
- 241001529453 unidentified herpesvirus Species 0.000 title claims abstract description 24
- -1 Heterocyclic carboxamide Chemical class 0.000 title description 237
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title description 15
- 239000003112 inhibitor Substances 0.000 title description 11
- 150000004986 phenylenediamines Chemical class 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 117
- 150000001875 compounds Chemical class 0.000 claims abstract description 111
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 48
- 239000001257 hydrogen Substances 0.000 claims abstract description 47
- 241000701024 Human betaherpesvirus 5 Species 0.000 claims abstract description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 14
- 208000007514 Herpes zoster Diseases 0.000 claims abstract description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 7
- 241000700584 Simplexvirus Species 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000004001 thioalkyl group Chemical group 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 256
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims description 69
- 239000002253 acid Substances 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- RTHGALAUXSQETR-UHFFFAOYSA-N 5-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-(furan-2-carbonylamino)benzoic acid Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1C(O)=O)=CC=C1NC(=O)C1=CC=CO1 RTHGALAUXSQETR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- IVZPBGXWYFFTRA-UHFFFAOYSA-N n-[2-chloro-4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]phenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1Cl)=CC=C1NC(=O)C1=CC=CO1 IVZPBGXWYFFTRA-UHFFFAOYSA-N 0.000 claims description 3
- IVWGGGIKOICPHX-UHFFFAOYSA-N n-[3-chloro-4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]phenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)Cl)=CC=C1NC(=O)C1=CC=CO1 IVWGGGIKOICPHX-UHFFFAOYSA-N 0.000 claims description 3
- JPZGNXJCBOMBMR-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2,5-dimethoxyphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)OC)=CC(OC)=C1NC(=O)C1=CC=CO1 JPZGNXJCBOMBMR-UHFFFAOYSA-N 0.000 claims description 3
- VVCYTMKINNBCAU-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-(phenylcarbamoyl)phenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1C(=O)NC=2C=CC=CC=2)=CC=C1NC(=O)C1=CC=CO1 VVCYTMKINNBCAU-UHFFFAOYSA-N 0.000 claims description 3
- BALIPFKCBQPMKC-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-(trifluoromethyl)phenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1C(F)(F)F)=CC=C1NC(=O)C1=CC=CO1 BALIPFKCBQPMKC-UHFFFAOYSA-N 0.000 claims description 3
- IMKYKPMGBIAZML-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-cyanophenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1C#N)=CC=C1NC(=O)C1=CC=CO1 IMKYKPMGBIAZML-UHFFFAOYSA-N 0.000 claims description 3
- MVDDTRTYCQAJNC-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-methoxy-5-methylphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)C)=CC(OC)=C1NC(=O)C1=CC=CO1 MVDDTRTYCQAJNC-UHFFFAOYSA-N 0.000 claims description 3
- YMWKSEPIFCEVMT-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-methylphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C=C1C)=CC=C1NC(=O)C1=CC=CO1 YMWKSEPIFCEVMT-UHFFFAOYSA-N 0.000 claims description 3
- BXFNYZZUCCFYSD-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-3-cyanophenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)C#N)=CC=C1NC(=O)C1=CC=CO1 BXFNYZZUCCFYSD-UHFFFAOYSA-N 0.000 claims description 3
- MVPZQPMABBRKST-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-3-methoxyphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)OC)=CC=C1NC(=O)C1=CC=CO1 MVPZQPMABBRKST-UHFFFAOYSA-N 0.000 claims description 3
- GDUBTFSXSUOPTA-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-3-methylphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)C)=CC=C1NC(=O)C1=CC=CO1 GDUBTFSXSUOPTA-UHFFFAOYSA-N 0.000 claims description 3
- HQSLZZTYRDVJIX-UHFFFAOYSA-N n-[4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]naphthalen-1-yl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C1=CC=CC=C11)=CC=C1NC(=O)C1=CC=CO1 HQSLZZTYRDVJIX-UHFFFAOYSA-N 0.000 claims description 3
- NSOSRWUCBJXURG-UHFFFAOYSA-N n-[5-chloro-4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-hydroxyphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)Cl)=CC(O)=C1NC(=O)C1=CC=CO1 NSOSRWUCBJXURG-UHFFFAOYSA-N 0.000 claims description 3
- UDAPAWGOOPLTNL-UHFFFAOYSA-N n-[5-chloro-4-[(5-chloro-2,4-dimethoxyphenyl)carbamothioylamino]-2-methylphenyl]furan-2-carboxamide Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC(C(=C1)Cl)=CC(C)=C1NC(=O)C1=CC=CO1 UDAPAWGOOPLTNL-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000010076 replication Effects 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 4
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims 1
- UWOVYROADFVHLJ-UHFFFAOYSA-N 1-[4-amino-2-(trifluoromethyl)phenyl]-3-(5-chloro-2,4-dimethoxyphenyl)thiourea Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=S)NC1=CC=C(N)C=C1C(F)(F)F UWOVYROADFVHLJ-UHFFFAOYSA-N 0.000 claims 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 24
- 201000010099 disease Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 11
- 241000701044 Human gammaherpesvirus 4 Species 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 243
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
- 239000002904 solvent Substances 0.000 description 159
- 239000000243 solution Substances 0.000 description 143
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 136
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 135
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 109
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- 239000000203 mixture Substances 0.000 description 105
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 90
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 79
- 239000000047 product Substances 0.000 description 76
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
- 239000007787 solid Substances 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 239000007858 starting material Substances 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 60
- 238000010992 reflux Methods 0.000 description 55
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 239000003921 oil Substances 0.000 description 43
- 235000019198 oils Nutrition 0.000 description 43
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 43
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 37
- 239000003480 eluent Substances 0.000 description 37
- 150000001412 amines Chemical class 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 35
- 229910002027 silica gel Inorganic materials 0.000 description 35
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000284 extract Substances 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- HJZYBDPHAHGHAZ-UHFFFAOYSA-N thiadiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSN=N1 HJZYBDPHAHGHAZ-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- 239000002585 base Substances 0.000 description 22
- 229910000027 potassium carbonate Inorganic materials 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 21
- 230000008020 evaporation Effects 0.000 description 21
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 241000700605 Viruses Species 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 150000003512 tertiary amines Chemical class 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000011877 solvent mixture Substances 0.000 description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 6
- 150000001448 anilines Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- XXWIYOBCHKCWNT-UHFFFAOYSA-N 2,4-dimethoxy-1-nitrobenzene Chemical compound COC1=CC=C([N+]([O-])=O)C(OC)=C1 XXWIYOBCHKCWNT-UHFFFAOYSA-N 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 5
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/20—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/22—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Furan Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20816498A | 1998-12-09 | 1998-12-09 | |
US09/208,164 | 1998-12-09 | ||
PCT/US1999/028916 WO2000034261A2 (en) | 1998-12-09 | 1999-12-06 | Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing a substituted phenylenediamine group |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2002533301A true JP2002533301A (ja) | 2002-10-08 |
Family
ID=22773466
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2000586708A Pending JP2002533301A (ja) | 1998-12-09 | 1999-12-06 | 置換フェニレンジアミン群を含む、複素環式カルボキサミド含有の、ヘルペスウイルスのチオ尿素インヒビター |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1144399A3 (no) |
JP (1) | JP2002533301A (no) |
KR (1) | KR20010086091A (no) |
CN (1) | CN1367785A (no) |
AU (1) | AU2353900A (no) |
BR (1) | BR9916043A (no) |
CA (1) | CA2351690A1 (no) |
CZ (1) | CZ20012063A3 (no) |
EA (1) | EA200100639A1 (no) |
HU (1) | HUP0203405A2 (no) |
IL (1) | IL143263A0 (no) |
NO (1) | NO20012835L (no) |
WO (1) | WO2000034261A2 (no) |
ZA (1) | ZA200104322B (no) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007523868A (ja) * | 2003-07-10 | 2007-08-23 | アキリオン ファーマシューティカルズ,インコーポレーテッド | ウイルス複製の阻害薬として有用な置換アリールチオウレア誘導体類 |
US7365068B2 (en) | 2004-05-18 | 2008-04-29 | Achillion Pharmaceuticals, Inc. | Substituted aryl acylthioureas and related compounds; inhibitors of viral replication |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6844367B1 (en) | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
DK1259485T3 (da) | 2000-02-29 | 2006-04-10 | Millennium Pharm Inc | Benzamider og beslægtede inhibitorer for faktor Xa |
DE102004015007A1 (de) | 2004-03-26 | 2005-10-13 | Bayer Healthcare Ag | Substituierte Imidazole |
DE102005008183A1 (de) | 2005-02-23 | 2006-08-31 | Bayer Healthcare Ag | Heterocyclylamid-substituierte Imidazole |
PT2077995E (pt) | 2006-11-02 | 2012-05-10 | Millennium Pharm Inc | Métodos de sintetizar sais farmacêuticos de um inibidor de fator xa |
WO2014070978A1 (en) * | 2012-11-03 | 2014-05-08 | Boehringer Ingelheim International Gmbh | Inhibitors of cytomegalovirus |
WO2014070979A1 (en) * | 2012-11-03 | 2014-05-08 | Boehringer Ingelheim International Gmbh | Inhibitors of cytomegalovirus |
CN112807294B (zh) * | 2019-11-18 | 2023-09-05 | 武汉大学 | 一种酰基硫脲类化合物在制备治疗或预防单纯疱疹病毒i型感染药物中的应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU6783698A (en) * | 1997-04-10 | 1998-10-30 | Pharmacia & Upjohn Company | Polyaromatic antiviral compositions |
-
1999
- 1999-12-06 HU HU0203405A patent/HUP0203405A2/hu unknown
- 1999-12-06 AU AU23539/00A patent/AU2353900A/en not_active Abandoned
- 1999-12-06 EA EA200100639A patent/EA200100639A1/ru unknown
- 1999-12-06 KR KR1020017007117A patent/KR20010086091A/ko not_active Application Discontinuation
- 1999-12-06 CA CA002351690A patent/CA2351690A1/en not_active Abandoned
- 1999-12-06 WO PCT/US1999/028916 patent/WO2000034261A2/en not_active Application Discontinuation
- 1999-12-06 CN CN99815998A patent/CN1367785A/zh active Pending
- 1999-12-06 IL IL14326399A patent/IL143263A0/xx unknown
- 1999-12-06 JP JP2000586708A patent/JP2002533301A/ja active Pending
- 1999-12-06 CZ CZ20012063A patent/CZ20012063A3/cs unknown
- 1999-12-06 BR BR9916043-9A patent/BR9916043A/pt not_active Application Discontinuation
- 1999-12-06 EP EP99967213A patent/EP1144399A3/en not_active Withdrawn
-
2001
- 2001-05-25 ZA ZA200104322A patent/ZA200104322B/en unknown
- 2001-06-08 NO NO20012835A patent/NO20012835L/no not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007523868A (ja) * | 2003-07-10 | 2007-08-23 | アキリオン ファーマシューティカルズ,インコーポレーテッド | ウイルス複製の阻害薬として有用な置換アリールチオウレア誘導体類 |
US7365068B2 (en) | 2004-05-18 | 2008-04-29 | Achillion Pharmaceuticals, Inc. | Substituted aryl acylthioureas and related compounds; inhibitors of viral replication |
US7767706B2 (en) | 2004-05-18 | 2010-08-03 | Achillion Pharmaceuticals, Inc. | Substituted aryl acylthioureas and related compounds; inhibitors of viral replication |
Also Published As
Publication number | Publication date |
---|---|
NO20012835D0 (no) | 2001-06-08 |
CN1367785A (zh) | 2002-09-04 |
EP1144399A2 (en) | 2001-10-17 |
ZA200104322B (en) | 2002-10-25 |
CA2351690A1 (en) | 2000-06-15 |
WO2000034261A2 (en) | 2000-06-15 |
AU2353900A (en) | 2000-06-26 |
BR9916043A (pt) | 2001-12-04 |
EP1144399A3 (en) | 2002-09-11 |
CZ20012063A3 (cs) | 2001-10-17 |
NO20012835L (no) | 2001-07-19 |
EA200100639A1 (ru) | 2002-06-27 |
HUP0203405A2 (hu) | 2003-02-28 |
IL143263A0 (en) | 2002-04-21 |
KR20010086091A (ko) | 2001-09-07 |
WO2000034261A3 (en) | 2002-01-31 |
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