CN1047497A - 抗炎药氨基苯酚衍生物 - Google Patents
抗炎药氨基苯酚衍生物 Download PDFInfo
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- CN1047497A CN1047497A CN90103739A CN90103739A CN1047497A CN 1047497 A CN1047497 A CN 1047497A CN 90103739 A CN90103739 A CN 90103739A CN 90103739 A CN90103739 A CN 90103739A CN 1047497 A CN1047497 A CN 1047497A
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- Prior art keywords
- formula
- compound
- phenyl
- alkyl
- amino
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- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 title description 6
- 230000003110 anti-inflammatory effect Effects 0.000 title description 2
- -1 N-oxide compound Chemical class 0.000 claims abstract description 115
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 10
- 150000001408 amides Chemical class 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N anhydrous cyanoacetic acid Natural products OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 28
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000002585 base Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000002253 acid Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- JEFSTMHERNSDBC-UHFFFAOYSA-N 1,2-dimethylcyclohexa-2,4-dien-1-ol Chemical compound CC1=CC=CCC1(C)O JEFSTMHERNSDBC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- LCTONWCANYUPML-UHFFFAOYSA-N PYRUVIC-ACID Natural products CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000003820 Lipoxygenases Human genes 0.000 description 2
- 108090000128 Lipoxygenases Proteins 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-N dithionous acid Chemical compound OS(=O)S(O)=O GRWZHXKQBITJKP-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- MIHIJWOEDDPOLG-DUXPYHPUSA-N (2e)-2-methoxyiminoacetic acid Chemical compound CO\N=C\C(O)=O MIHIJWOEDDPOLG-DUXPYHPUSA-N 0.000 description 1
- BRXPBXVCBBXWTA-UHFFFAOYSA-N (2z)-2-amino-2-methoxyiminoacetic acid Chemical compound CO\N=C(/N)C(O)=O BRXPBXVCBBXWTA-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VMDFHVIGDTVKFZ-UHFFFAOYSA-N 2-amino-4-(1-phenylpyrazol-3-yl)phenol Chemical compound C1(=CC=CC=C1)N1N=C(C=C1)C1=CC(=C(C=C1)O)N VMDFHVIGDTVKFZ-UHFFFAOYSA-N 0.000 description 1
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 1
- ZQZAHPFFZWEUCL-UHFFFAOYSA-N 2-chloropyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1Cl ZQZAHPFFZWEUCL-UHFFFAOYSA-N 0.000 description 1
- OFUFXTHGZWIDDB-UHFFFAOYSA-N 2-chloroquinoline Chemical compound C1=CC=CC2=NC(Cl)=CC=C21 OFUFXTHGZWIDDB-UHFFFAOYSA-N 0.000 description 1
- LNJZJDLDXQQJSG-UHFFFAOYSA-N 2-phenylpyrazine Chemical class C1=CC=CC=C1C1=CN=CC=N1 LNJZJDLDXQQJSG-UHFFFAOYSA-N 0.000 description 1
- ZQHUYIQAARXNGI-UHFFFAOYSA-N 3-amino-2,5-dimethoxy-6-methyl-4-(1-phenylpyrazol-3-yl)phenol Chemical compound COC=1C(=C(C(=C(C=1C1=NN(C=C1)C1=CC=CC=C1)N)OC)O)C ZQHUYIQAARXNGI-UHFFFAOYSA-N 0.000 description 1
- IBKZXBCAHIUVQH-UHFFFAOYSA-N 3-amino-2,6-dimethyl-4-(1-phenylpyrazol-3-yl)phenol Chemical compound CC1=C(C(=CC(=C1N)C1=NN(C=C1)C1=CC=CC=C1)C)O IBKZXBCAHIUVQH-UHFFFAOYSA-N 0.000 description 1
- CORWZYBWDPCUIR-UHFFFAOYSA-N 3-amino-2,6-dimethyl-4-(2-phenyl-3,4-dihydropyrazol-5-yl)phenol Chemical compound C1(=CC=CC=C1)N1N=C(CC1)C1=C(C(=C(C(=C1)C)O)C)N CORWZYBWDPCUIR-UHFFFAOYSA-N 0.000 description 1
- OTCMKDPJWMNLRD-UHFFFAOYSA-N 3-amino-2,6-dimethyl-4-pyrazin-2-ylphenol Chemical compound CC1=C(C(=CC(=C1N)C1=NC=CN=C1)C)O OTCMKDPJWMNLRD-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OXOWTLDONRGYOT-UHFFFAOYSA-N 4-(dimethylamino)butanoic acid Chemical compound CN(C)CCCC(O)=O OXOWTLDONRGYOT-UHFFFAOYSA-N 0.000 description 1
- OMVFXCQLSCPJNR-UHFFFAOYSA-N 4-amino-2,6-dimethylphenol Chemical compound CC1=CC(N)=CC(C)=C1O OMVFXCQLSCPJNR-UHFFFAOYSA-N 0.000 description 1
- ADMDZPQWKDHLFB-UHFFFAOYSA-N 4-amino-3,6-dimethoxy-2-methylphenol Chemical compound COC1=CC(N)=C(OC)C(C)=C1O ADMDZPQWKDHLFB-UHFFFAOYSA-N 0.000 description 1
- PMZBHPUNQNKBOA-UHFFFAOYSA-N 5-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C(O)=O)=C1 PMZBHPUNQNKBOA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000011730 Arachidonate 12-Lipoxygenase Human genes 0.000 description 1
- 108010076676 Arachidonate 12-lipoxygenase Proteins 0.000 description 1
- 102000009515 Arachidonate 15-Lipoxygenase Human genes 0.000 description 1
- 108010048907 Arachidonate 15-lipoxygenase Proteins 0.000 description 1
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 1
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 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 1
- BQICTTOMFGWLGP-UHFFFAOYSA-N O-[2,3,5,6-tetramethyl-4-(1-phenylpyrazol-3-yl)phenyl]hydroxylamine Chemical compound CC1=C(C(=C(C(=C1C)C1=NN(C=C1)C1=CC=CC=C1)C)C)ON BQICTTOMFGWLGP-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- ZHWLPDIRXJCEJY-UHFFFAOYSA-N alpha-hydroxyglycine Chemical compound NC(O)C(O)=O ZHWLPDIRXJCEJY-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N alpha-isobutyric acid Natural products CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 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
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RQIFXTOWUNAUJC-UHFFFAOYSA-N ethanesulfinic acid Chemical compound CCS(O)=O RQIFXTOWUNAUJC-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- TWIIRMSFZNYMQE-UHFFFAOYSA-N methyl pyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=CC=N1 TWIIRMSFZNYMQE-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- CAWHJQAVHZEVTJ-UHFFFAOYSA-N methylpyrazine Chemical compound CC1=CN=CC=N1 CAWHJQAVHZEVTJ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N para-methoxy benzoic acid Natural products COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/38—Nitrogen atoms
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- 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
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- C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- 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
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- 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
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
- C07D237/20—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
- C07D237/22—Nitrogen and oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
- C07D241/20—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
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- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/14—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
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- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having 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
-
- C—CHEMISTRY; METALLURGY
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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- C07D263/48—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
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- 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
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Abstract
本发明公开了用作一种药物,例如一种抗炎药剂的式I化合物或其药物上可接受的N-氧化物、N-烷基盐、盐、酯或酰胺衍生物、其组合物及其制备方法。
式I为:
其中,R1、R2、R3、R4、R5、R6和X如说明书所定义。
Description
本发明涉及新的化合物、其组合物及其制备方法。
按照本发明,提供一种用作药物的式Ⅰ化合物或其药物上可接受的N-氧化物、N-烷基盐、盐、酯或酰胺衍生物。
式Ⅰ为:
其中,R1表示C(O)YZ或SO2R10;Y表示一个单键、O、NR11或CO;Z表示氢、烷基或被一个或多个选自羟基、烷氧基、酰氧基、羧基、烷氧羰基、CONR12R13、芳基烷氧基、Ar1、杂环、卤素、氰基或NR14R15的取代基所取代的烷基;R2、R3、R5和R6可相同或不同,表示氢、烷基、烷氧基或卤素;R4和R11可相同或不同,表示氢或烷基;R10表示烷基;X表示一个任意被一个或多个选自烷基、环烷基、烷氧基、烷氧羰基、羧基、羟烷基、卤素、CONR16R17、NR18R19或Ar2的取代基所取代的杂环;Ar1和Ar2可相同或不同,表示芳基或被一个或多个选自卤素、硝基、烷氧基、羧基、烷基或三囟烷基的取代基所取代的芳基;R12、R13、R14、R15、R16、R17、R18和R19可相同或不同,表示氢、烷基或苄氧羰基。
按照本发明,还提供如上定义的、但R2和R6中至少一个不为氢的那种新的式Ⅰ化合物和其衍生物。
按照本发明还提供一种制备式Ⅰ化合物的方法,该方法包括:
a)使式Ⅱ的化合物同式Ⅲ的化合物反应,式Ⅱ为X-L1,其中L1为一离去基团,X如上所定义,式Ⅲ为:
其中,R1、R2、R3、R4、R5和R6如上所定义。
b)使式Ⅳ的化合物同式Ⅴ的化合物反应,式Ⅳ为:
其中,X、R2、R3、R4、R5和R6如上所定义,式Ⅴ为R1L2,其中,L2为一离去基团,R1如上所定义。
c)通过氧化一相应的式Ⅵ化合物,制备其中X为不饱和杂环的一种式Ⅰ化合物,式Ⅵ为:
其中,Xc表示一个比X更为饱和的相应的杂环,R1、R2、R3、R4、R5和R6如上所定义。
d)通过还原一相应的其中的合适取代基含有一个或多个碳碳双键或碳碳叁键的式Ⅰ化合物,制备具有一个或多个至少含有2个碳原子的烷基取代基的一种式Ⅰ化合物。
e)通过还原一相应的其中X被苯基取代的式Ⅰ化合物,制备其中X被环己基所取代的一种式Ⅰ化合物。
f)制备一种被一个或多个OH、NHR14或COOH所取代的式Ⅰ化合物的方法,包括从一相应的具有保护的OH、NHR14或COOH基的式Ⅰ化合物中除去保护基。
g)通过使一相应的其中Z为被卤素所取代的烷基的式Ⅰ化合物与氰化物盐反应,制备其中Z为被氰基所取代的烷基的一种式Ⅰ化合物。
h)通过使一相应的其中X为一含氮杂环的式Ⅰ化合物同一种烷基化剂反应,制备一种为N-烷基盐的式Ⅰ化合物。
实施例中进一步详细叙述了制备式Ⅰ化合物和其中间体的方法。
式Ⅱ的化合物可通过步骤b)的方法,从相应的4-氨基苯酚制得,这种4-氨基苯酚为已知物或可用常规方法从已知化合物制得。
某些式Ⅳ的化合物由EP-A-254,259或EP-A-178,035已知,某些式Ⅳ的中间体是新的,因此按照本发明的又一个方面,可提供式Ⅳa的化合物,式Ⅳa为:
其中,Xa表示由1-苯基或1-三氟甲基苯基所取代的1H-吡唑-3-基,R2a和R6a可相同或不同,选自低级烷基、囟素和低级烷氧基,R3a和R5a均表示氢。
新的式Ⅳ酚可由上述所引用的欧洲专利申请中指出的方法或由本文所述的方法制得。
式Ⅵ的化合物可用类似于步骤(a)、(b)、(d)、(e)、(f)、(g)或(h)中所述的方法制备。
式Ⅱ和式Ⅴ的那些化合物为已知物或可用原来已知的常规方法从已知化合物制得。
式Ⅰ化合物的酸加成盐可通过使游离碱同一种合适的酸反应来制备,该酸加成盐可通过一种强碱的作用转化为相应的游离碱。
用如上所述的方法可以制备式Ⅰ的化合物或其衍生物。处理如此得到的任一种衍生物以释放出游离的式Ⅰ化合物,或将一种衍生物转化为另一种衍生物也包括在本发明的范围内。
式Ⅰ化合物药物上可接受的衍生物包括药物上可接受的酸加成盐,合适的盐包括无机酸盐或有机酸盐。无机酸盐中的无机酸例如氢卤酸,如氢氯酸或氢溴酸,有机酸盐中的有机酸例如甲酸、乙酸或乳酸。
当式Ⅰ化合物含有羧酸基团时,它可形成药物上可接受的盐、酯和酰胺衍生物。适合的盐包括铵盐、碱金属(如钠、钾和锂)盐和碱土金属(如钙或镁)盐;适合的酯包括简单的低级烷基酯如乙酯;酰胺例如可以是未取代的或一-或二-C1-C6烷基酰胺或苯基酰胺,可通过常规技术,例如使一种相应酸的酯同氨或一种合适的胺反应而制得。
我们优选其中R1表示C(O)YZ的式Ⅰ化合物。
我们优选其中y为一个单键的化合物。当Y为单键时,我们优选Z不是氢。当Z表示烷基时,我们优选的烷基为低级烷基,尤其是C1-C4烷基,烷基可以是饱和的或不饱和的,直链的或支链的。可提及的特定烷基包括甲基、乙基、正丙基、异丙基、正丁基和叔丁基。当烷基被取代时,我们优选它为三取代、二取代和特别是一取代的,该取代基的位置可在烷基的任何部位,但是我们优选位于烷基末端含有一个取代基的那些化合物,可提及的特定取代基包括羟基;低级烷氧基例如甲氧基或乙氧基;低级酰氧基,特别是C1-C4酰氧基例如乙酰氧基、丙酰氧基;CONH2;苯基烷氧基,特别是苯基甲氧基;囟素,特别是溴,尤其是氯;氰基或NH2。
我们优选其中R2、R3、R5和R6中至少有一个不为氢的式Ⅰ化合物,我们特别优选其中R2、R3、R5和R6中至少有2个不为氢的那些化合物,尤其优选的是其中R2和R6均不为氢的那些化合物。尤其优选X为含有1-3个选自氮、氧和硫杂原子的5员或6员杂环。
X表示的特定杂环基包括吡唑基,尤其是1H-3-吡唑基。
当X被取代时,特别优选它由三个、两个或最好为一个取代基所取代,取代基选自:烷基,最好是低级烷基,尤其是甲基、乙基、丙基或丁基;环烷基,例如环丁基、环戊基、环庚基,最好是环己基;烷氧基,最好是低级烷氧基,尤其是C1-C4烷氧基;烷氧羰基最好是低级烷氧羰基,尤其是甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基和叔丁氧羰基;羧基;羟烷基,最好是羟基低级烷基,它包括一羟基C1-C6烷基如羟甲基、2-羟乙基、3-羟丙基;卤素包括氯、氟、溴和碘;氨基或Ar2。可为Ar2的特定芳基包括萘基和最好是苯基,它们可任意地由三个、两个或最好是一个取代基所取代,取代基选自卤素例如氯、氟或溴;烷氧基,最好是低级烷氧基例如甲氧基或乙氧基;羧基;烷基,最好是低级烷基例如甲基、乙基、丙基或三卤代烷基,最好是三囟代低级烷基,尤其是CF3或CH2CF3。
由于式Ⅰ化合物及其药物上可接受的衍生物对动物具有药理学活性,因此它们是有用的,特别是这些化合物可用作广谱的抗炎药剂,特别是它们是脂氧合酶例如5、12和15脂氧合酶的抑制剂。
本发明指出上述化合物可用于治疗或预防包括人在内的动物的炎症,尤其是风湿病、牛皮癣、胃肠炎和其它与炎症有关的病,特别是其中脂氧合酶和环氧合酶为致症因素的那些病。
对于上述应用,所给的药剂量当然可随所使用的化合物、给药方式和治疗要求而异,但是,一般来说,每公斤动物体重以日剂量为约0.1mg-60mg,最好将其药剂量分为1-4次/天或以缓释形式给予化合物时可得到满意的结果。对于人,总日剂量为7.0mg-4.2g,适用于口服的单位剂量型含有2.0mg-4.2g化合物与一种固体或液体药物载体或稀释剂混合。
式Ⅰ化合物和其药物上可接受的衍生物可以其本身或以合适的药物制剂形式用于肠内、肠胃外或局部给药,因此,该新化合物可与药物上可接受的佐剂、稀释剂或载体混合使用。
组合物中含式Ⅰ化合物或其药物上可接受的衍生物的量,以不超过50%(以重量计)较好,以不超过25%为更好。
式Ⅰ化合物和其药物上可接受的衍生物与相似结构的化合物比较具有如下优点:毒性小、效力大、作用长、具有更广范围的活性、潜效大、副作用小、选择性高、较易吸收、较稳定或其它有用的药理学性能。
本发明通过以下实施例说明,其中温度均以摄氏表示。
A.中间体的制备
实施例A
乙酸4-氨基-2,6-二甲基苯酯
于0℃,向含有2,6-二甲基-4-硝基苯酚(10g)和三乙胺(21ml)的无水二氯甲烷(100ml)中慢慢加入乙酰氯(5.6ml),16小时后,用水洗涤混合物,干燥和蒸发得到乙酸酯(9.4g),熔点109-110℃。于大气压下,在氧化铂上,在乙醇中使该乙酸酯氢化4小时,过滤、蒸发并使残余物结晶(乙酸乙酯/己烷)得到标题乙酸酯(5.6g),熔点82-83℃。
实施例B
4-氨基-3,6-二甲氧基-2-甲基苯酚。
按“有机合成”Coll.第二卷,第35页中所述,使磺胺酸(10.8g)重氮化,20分钟后,将所生成的悬浮液加入在水(100ml)中的3,6-二甲氧基-2-甲基苯酚(8.1g)和氢氧化钠(10.8g)的冰冷却溶液中。一小时后,将该混合物加热至45-50℃并分批加入亚硫酸氢钠(22.2g),当红色染料脱色后,冷却混合物得到一黄色沉淀,标题苯酚的亚硫酸氢盐(10g)。
实施例C
用上述实施例B的方法,经苯酚的亚硫酸氢盐制备如下苯酚:
a)4-氨基-2,6-二甲基苯酚;
b)4-氨基-2,3,4,5-四甲基苯酚;
c)4-氨基-2,6-双(1,1-二甲乙基)苯酚;
实施例D
2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酚。
在160℃,于氮气下,将2,6-二甲基-4-氨基苯酚(15g)和4,5-二氢-1-苯基-1H-吡唑-3-胺(17.6g)同对甲苯磺酸(0.2g)一起加热一小时。冷却该混合物,将其溶解在二氯甲烷中并用稀盐酸和水洗涤,蒸发,残余物进行色谱层析(硅胶,二氯甲烷/乙酸乙酯〔9∶1〕),得到4-(4,5-二氢-1-苯基-1H-吡唑-3-基)氨基-2,6-二甲基苯酚(14.2g),熔点154-158℃。将该苯酚置于甲苯(40ml)和10%披钯木炭(10g)中回流3小时,过滤混合物并蒸发,从环己烷/乙酸乙酯中结晶后,得到标题化合物(8g),熔点154-155℃。
实施例E
用实施例D的方法制得如下中间体:
a)2,3,5,6-四甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酚,熔点160-162℃;
b)3,6-二甲氧基-2-甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酚,熔点107-108℃;
c)2,6-双(1,1-二甲乙基)-3-(1-苯基-1H-吡唑-3-基)氨基苯酚,熔点114-115℃;
d)2,6-二氯-4-(1-苯基-1H-吡唑-3-基)氨基苯酚,熔点144-146℃。
实施例F
2,6-二甲基-4-〔N-甲基-N-(1-苯基-1H-吡唑-3-基)氨基苯酚。
向在乙腈(40ml)中的2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酚(8g)、乙酸(2.8ml)和40%甲醛水溶液(3.1ml)中加入氰基硼氢钠(5.4g)。2小时后,用水急冷混合物并用二氯甲烷萃取,用碳酸氢钠水溶液洗涤有机相,然后用水洗涤,干燥、蒸发和色谱层析(硅胶,二氯甲烷),得到标题产物(3g),熔点139-140℃(自乙醇结晶)。
实施例G
用实施例F的方法制得如下中间体:
a)2,6-双(1,1-二甲乙基)-4-〔N-甲基-N-(1-苯基-1H-吡唑-3-基)氨基〕苯酚,熔点117-118℃。
实施例H
2-乙亚磺酸基-6,7,8,9-四氢-4H-1-萘并〔2,3-b〕吡喃-4-酮。
由1-(3-羟基-6,7,8,9-四氢萘-2-基)乙酮经与二硫化碳一起缩合,再用乙基碘使其烷基化并按J.Heterocyclic Chem.,1981,18,679中所述方法氧化,制得标题化合物(熔点158-159℃)。
实施例Ⅰ
5,6-二乙氧基-2-甲磺酰-1H-苯并咪唑。
由5,6-二乙氧基-1,3-二氢-2H-苯并咪唑-2-硫酮经烷基化(用甲基碘)并氧化,制得标题化合物(熔点182-184℃)。
实施例J
用EP-A-254259所述方法,由合适的氨基杂环制得如下中间体:
a)2,6-二甲基-4-(吡嗪-2-基)氨基苯酚,熔点188-190℃)。
b)4-(4-氯-6-甲基嘧啶-2-基)氨基-2,6-二甲基苯酚,熔点160-163℃。
B.式Ⅰ化合物的制备
由上述中间体或由现有技术中已知的化合物,包括EP-A-254259和EP-A-178035中所述的那些已知化合物制备如下式Ⅰ化合物。
实施例1
乙酸4-〔4,5-二氢-1-苯基-1H-吡唑-3-基〕氨基-2,6-二甲基苯酯。
于氮气氛下,将4,5-二氢-1-苯基-1H-吡唑-3-胺(0.16g)、乙酸4-氨基-2,6-二甲基苯酯(0.2g)和甲苯-4-磺酸(0.02g)于甲苯中回流8小时。蒸发、将残余物色谱层析(硅胶,二氧甲烷/乙酸乙酯〔95∶5〕),得到固体标题产物(0.15g)。
实施例2
用实施例1的方法,制备如下化合物:
a)乙酸4-〔4,5-二氢-1-(3-三氟甲基苯基)-1H-吡唑-3-基〕氨基-2,6-二甲基苯酯,熔点190-191℃。
b)乙酸2,6-二甲基-4-〔6,7,8,9-四氢-4-氧代-4H-1-萘并〔2,3-b〕吡喃-2-基〕氨基苯酯,熔点224-226℃(由实施例H的亚砜中间体制得)。
c)乙酸4-(5,6-二乙氧-1H-苯并咪唑-2-基)氨基-2,6-二甲基苯酯(由实施例I的中间体制得),熔点91-94℃。
d)乙酸2,6-二甲基-4-(喹啉-2-基)氨基苯酯(由2-氯喹啉制得),熔点154-155。
e)乙酸4-(3-氨基羰基吡啶-2-基)氨基-2,6-二甲基苯酯(由2-氯烟酰胺制得),熔点209-211℃。
f)乙酸2,6-二甲基-4-(2-嘧啶基)氨基苯酯(由2-氯嘧啶制得)。
实施例3
乙酸4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二(丙-2-烯基)苯酯。
a)4-(1-苯基-1H-吡唑-3-基)氨基-2-(丙-2-烯基)苯酚。
将4-(1-苯基-1H-吡唑-3-基)氨基苯酚(19g)加入含氢化钠(4.0g,50%油悬浮液)的无水二甲基甲酰胺(150ml)中,半小时后加烯丙基溴(7.2ml),搅拌混合物16小时,倒入水中并用乙酸乙酯萃取。蒸发溶剂,色谱层析(硅胶/二氯甲烷),得到1-苯基-N-(4-〔〔丙-2-烯基〕氧〕苯基)-1H-吡唑-3-胺(21.9g),熔点80-81℃。于200℃,氮气氛下加热该固体(2.9g)5小时,色谱层析(硅胶/二氯甲烷),得到一种粘性油状的小标题产物(1.4g)。
显示1HNMR(DMSO):
δ8.7(1H,s,NH);8.4(1H,s,OH);6.0(1H,m,-CH=);5.1(2H,dd,=CH2);3.25(2H,d,OCH2).
b)4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二(丙-2-烯基)苯酚。
用类似(a)的方法,将取自(a)的小标题产物(10.5g)转化为1-苯基-N-(3-〔丙-2-烯基〕-4-〔丙-2-烯基〕氧苯基)-1H-吡唑-3-胺(7.6g,油),然后再将其转化为该小标题苯酚(5.5g),熔点87-88℃。
c)乙酸4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二(丙-2-烯基)苯酯。
将乙酰氯(1.1ml))慢慢加入搅拌的含有4-二甲基氨基吡啶(10mg)和三乙胺(2.1ml)在二氯甲烷(100ml)中的取自步骤b的产物(5.0g)中。6小时后,加入水,蒸发有机相后,残余物进行色谱层析(硅胶/二氯甲烷),接着从环己烷中结晶,得到标题产物(4.5g),熔点110-111℃。
实施例4
用实施例3c)的方法,由相应的苯酚和合适的碳酰氯或磺酰氯制备如下化合物:
a)丁酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点138-140℃。
b)2,2-二甲基丙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点139-140℃。
c)碳酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·苯基酯,熔点138-139℃。
d)碳酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·甲基酯,熔点110-112℃。
e)苯甲酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点117-118℃。
f)甲磺酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点144-145℃。
g)2-甲基丙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点127-128℃。
h)碳酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·苯甲基酯,熔点105-106℃。
i)4-甲氧苯甲酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点185-187℃。
j)甲氧乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点149-150℃。
k)氯乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点141-142℃。
l)碳酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基(1,1-二甲乙基)酯,熔点122-123℃。
m)4-硝基苯甲酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点210-211℃。
n)碳酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·丁基酯,熔点72-73℃。
o)3-吡啶羧酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点158-160℃。
p)乙酸4-(4-氯-6-甲基嘧啶-2-基)氨基-2,6-二甲基苯酯,熔点143-144℃。
q)甲氧乙酸4-(4-氯-6-甲基嘧啶-2-基)氨基-2,6-二甲基苯酯,熔点126-127℃。
r)乙酸2,6-二甲基-4-(吡嗪-2-基)氨基苯酯,熔点176-177℃。
s)4-氯苯甲酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点166-167℃。
t)3-甲氧丙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点125-126℃。
u)二甲基氨基甲酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点171-173℃。
v)4-二甲基氨基-4-氧代丁酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点210-211℃。
w)乙酸基乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点127-128℃。
x)丙二酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·甲基酯,熔点112-113℃。
y)1,5-戊二酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·甲基酯,熔点108-109℃。
z)1,4-丁二酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基·甲基酯,熔点90-91℃。
aa)乙酸3,6-二甲氧基-2-甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点132-134℃。
ab)乙酸2,6-二甲基-4-〔N-甲基-N-(1-苯基-1H-吡唑-3-基)〕氨基苯酯,熔点111-112℃。
ac)乙酸2,3,5,6-四甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点179-180℃。
ad)乙酸2,6-二氯-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点169-170℃。
ae)苯基甲氧乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点101-101.5℃。
af)乙酸2,5-二甲氧基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点149-150℃。
ag)苯-1,4-二羧酸单-〔2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯单苯甲基酯。
实施例5
乙酸2,6-双(1,1-二甲乙基)-4-(N-甲基-N-〔1-苯基-1H-吡唑-3-基〕氨基)苯酯
于-78℃,在氮气氛下,将丁基锂(1.29ml,1.4M己烷溶液)加入在无水四氢呋喃(15ml)中的2,6-双(1,1-二甲乙基)-4-(N-甲基-N-〔1-苯基-1H-吡唑-3-基〕氨基)苯酚(0.6g)中,10分钟后加入乙酰氯(0.2ml),使反应进行16小时后倾入水中,用乙酸乙酯萃取。蒸发,残留物进行色谱层析(硅胶,二氯甲烷/己烷〔1∶1〕),随后于-20℃由己烷重结晶,得到标题化合物(0.35g),熔点102-103℃。
实施例6
用合适的酰氯和苯酚,按实施例5的方法制备如下化合物:
a)甲氧乙酸2,6-双(1,1-二甲乙基)-4-(N-甲基-N-〔1-苯基-1H-吡唑-3-基〕氨基)苯酯,熔点102-103℃。
b)乙酸2,6-双(1,1-二甲乙基)-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点186-187℃;酰基的位置由核极化效应(NOE)差光谱证实。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-甲基-1H-吡唑-3-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(2-噁唑基氨基)苯酯。
乙酸4-〔(6-氯吡嗪基)氨基〕-2,6-双(1,1-二甲乙基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1H-1,2,3-三唑-4-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(4-嘧啶基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(4-甲基-2-嘧啶基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(2-嘧啶基氨基)苯酯。
乙酸4-〔(3,6-二氯-4-哒嗪基)氨基〕-2,6-双(1,1-二甲乙基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(4-哒嗪氨基)苯酯。
乙酸6-〔〔3,5-双(1,1-二甲乙基)-4-乙酰氧基苯基〕氨基〕-3-哒嗪甲醇苯酯。
乙酸4-〔(6-氯-3-哒嗪基)氨基〕-2,6-双(1,1-二甲基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(6-乙氧基-3-哒嗪基氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(6-甲基-3-哒嗪基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(3-哒嗪基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-6-(1-甲乙基)-4-(吡嗪基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(4H-1,2,4-三唑-4-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(吡嗪氨基)苯酯。
乙酸2,6-二甲基-4-(吡嗪基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1H-咪唑-2-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(3-苯基-1,2,4-噻二唑-5-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1,2,4-三嗪-3-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(2-甲基-3-噻吩基)氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(5-甲基-1,3,4-噻二唑-2-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-甲基-1H-吡唑-5-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1H-吡唑-3-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(吡嗪基氨基)苯酯。
乙酸4-〔(4-氨基-5-嘧啶基)氨基〕-2,6-双(1,1-二甲乙基)苯酯。
乙酸2,6-双(1-甲乙基)-4-(吡嗪基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(6-甲氧吡嗪基)氨基〕苯酯。
6-〔〔3,5-双(1,1-二甲乙基)-4-乙酰氧基苯基〕氨基〕-3-哒嗪羧酸甲酯。
乙酸2,6-双(1,1-二甲基乙基)-4-〔(6-甲氧基-3-哒嗪基)氨基〕苯酯。
5-〔〔3,5-双(1,1-二甲乙基)-4-羟苯基〕氨基〕吡嗪羧酸甲酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(5-苯基吡嗪基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(5-甲基吡嗪基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(5-嘧啶基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(4-哒嗪基氨基)苯酯。
乙酸2-(1,1-二甲乙基)-6-(1-甲乙基)-4-(3-哒嗪基氨基)苯酯。
乙酸2,3,6-三甲基-4-(吡嗪基氨基)苯酯。
乙酸4-〔(6-氯-4-嘧啶基)氨基〕-2,6-双(1,1-二甲乙基)苯酯。
5-〔〔3,5-双(1,1-二甲乙基)-4-乙酰氧基苯基〕氨基〕吡嗪甲醇。
乙酸2,3,6-三甲基-4-(2-嘧啶基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(4,6-二甲基-2-嘧啶基)氨基〕苯酯。
乙酸2-(1,1-二甲乙基)-6-(1-甲乙基)-4-(1H-吡唑-3-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1H-1,2,4-三唑-3-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(2-甲基-2H-1,2,3-三唑-4-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-甲基-1H-1,2,3-三唑-4-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(5-甲基-3-异噁唑基)氨基〕苯酯。
乙酸3-〔〔3,5-双(1,1-二甲乙基)-4-乙酰氧基苯基〕氨基〕苯酯2-噻吩羧酸甲酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-甲基-1H-吡唑-4-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1H-〔吡唑-4-基〕氨基)苯酯。
5-〔〔3,5-双(1,1-二甲乙基)-4-乙酰氧基苯基〕氨基〕-1-甲基-1H-吡唑-4-羧酸乙酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1,3-二苯基-1H-吡唑-5-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔((1-甲基-3-苯基-1H-吡唑-5-基〕氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-丙基-1H-吡唑-5-基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(1-丙基-1H-吡唑-3-基)氨基〕苯酯。
乙酸2,3,6-三甲基-4-(1H-吡唑-3-基氨基)苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(6-甲基-3-哒嗪基)氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(吡嗪基氨基)苯酯N-氧化物。
乙酸2,6-双(1,1-二甲乙基)-4-〔(2-甲基-3-噻吩基氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-〔(5,6-二甲基-1,2,4-三嗪-3-基氨基〕苯酯。
乙酸2,6-双(1,1-二甲乙基)-4-(1,3,4-噻二唑-2-基氨基〕苯酯。
乙酸2,6-双(甲乙基)-4-(1H-吡唑-3-基氨基)苯酯。
实施例7
1,4-丁二酸单(2,6-二甲基-4-〔1-苯基-1H-吡唑-3-基〕氨基苯基)酯。
于0℃,在氮气氛下,将琥珀酐(0.84g)加入在无水二氯甲烷(30ml)和三乙胺(2.25ml)中的4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二甲基苯酚(1.8g)中,于室温搅拌混合物16小时,然后倾入水中,干燥并蒸除有机相,所生成的油进行色谱层析(硅胶,2%甲醇/二氯甲烷),由己烷/乙酸乙酯结晶后得到标题产物(1.5g)。
实施例8
用实施例7的方法制备如下化合物:
a)1,5-戊二酸单(2,6-二甲基-4-〔1-苯基-1H-吡唑-3-基〕氨基苯酯,熔点138-140℃。
实施例9
2-氧代丙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯。
将1,1′-羰基二咪唑(4.9g)分批加入在二氯甲烷(100ml)中的丙酮酸(2.6g)中,0.5小时后加入2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酚(2.8g),该混合物放置16小时后蒸发,残余物进行色谱层析(硅胶,二氯甲烷),用己烷/乙酸乙酯结晶后,得到标题产物(1.0g),熔点123-125℃。
实施例10
用实施例9的方法制备如下化合物:
a)N-〔(苯甲氧基)羰基〕甘氨酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点142-143℃。
b)4-二甲基氨基丁酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点83-85℃。
实施例11
乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯。
取自实施例1的产物同5%披钯木炭(0.15g)在甲苯中回流4小时,过滤、蒸发并将残余物进行色谱层析(硅胶,二氯甲烷/乙酸乙酸〔95∶5〕),得到标题化合物(0.07g),熔点114-116℃(由环己烷结晶);另一种多晶形物,熔点134℃。
实施例12
用实施例11的方法,由实施例2a的化合物制备如下化合物:
乙酸2,6-二甲基-4-(1-〔3-三氟甲基苯基〕-1H-吡唑-3-基)氨基苯酯,熔点142-143℃。
实施例13
乙酸4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二丙基苯酯。
取自实施例3b)的乙酸4-(1-苯基-1H-吡唑-3-基)氨基-2,6-二(丙-2-烯基)苯酯(3.5g)置于乙醇(150ml)中,于大气压下,在10%披钯木炭上氢化,自环己烷结晶后,得到标题产物(1.8g),熔点71-74℃。
实施例14
用实施例13的方法,由所指定的前体,制得如下化合物:
a)羟乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯,熔点155-157℃。
b)羟乙酸4-(1-环己基-1H-吡唑-3-基)氨基-2,6-二甲基苯酯,熔点160-164℃。
将苯基甲氧基乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯于5个大气压下氢化6天,所得混合物经色谱层析(硅胶,二氯甲烷/乙酸乙酯(9∶1)),分离出a)和b)化合物。
c)取自实施例10a的产物,随后用醚盐酸处理,制得甘氨酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯盐酸盐,熔点230-231℃。
d)取自实施例4ag)的化合物,由单苄酯制得苯-1,4-二羧酸单-〔2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯基〕酯,熔点221-222℃。
实施例15
氰基乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯。
取自实施例4K的氯乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯(1g)和氰化钠(0.5g)在二甲亚砜中搅拌16小时,经用盐水稀释后,用乙酸乙酸萃取,随后蒸发,制得标题化合物(0.3g),熔点116-117℃(由乙酸乙酯/己烷结晶)。
实施例16
3-〔2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯氧羰基〕-1-甲基吡啶鎓碘化物。
将实施例4o)的3-吡啶羧酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯(0.5g)于甲基碘(100ml)中回流4天,蒸除未反应的甲基碘,经用乙醚研制所得到的油,制得标题化合物(0.15g),熔点150℃(分解)。
Claims (7)
1、一种制备式I化合物或其药物上可接受的N-氧化物、N-烷基盐、盐、酯或酰胺衍生物的方法,
式I为:
其中R1表示C(O)YZ或SO2R10;Y表示一个单键、O、NR11或CO;Z表示氢、烷基或被一个或多个选自羟基、烷氧基、酰氧基、羧基、烷氧羰基、CONR12R13、芳基烷氧基、Ar1、杂环、囟素、氰基或NR14R15的取代基所取代的烷基;R2、R3、R5和R6可相同或不同,表示氢、烷基、烷氧基或囟素,条件是R2和R6中至少有一个不是氢;R4和R11可相同或不同,表示氢或烷基;R10表示烷基;X表示一个任意被一个或多个选自烷基、环烷基、烷氧基、烷氧羰基、羧基、羟烷基、卤素、CONR16R17、NR18R19或Ar2的取代基所取代的杂环;Ar1和Ar2可相同或不同,表示芳基或被一个或多个选自囟素、硝基、烷氧基、羧基、烷基或三囟烷基的取代基所取代的芳基;R12、R13、R14、R15、R16、R17、R18和R19可相同或不同,表示氢、烷基或苄氧羰基,
该方法包括;
a)使式Ⅱ的化合物同式Ⅲ的化合物反应,式Ⅱ为X-L1,其中L1为一离去基团,X如上所定义,式Ⅲ为:
其中,R1、R2、R3、R4、R5和R6如上所定义;
b)使式Ⅳ的化合物同式V的化合物反应,式Ⅵ为:
其中,X、R2、R3、R4、R5和R6如上所定义,式V为R1L2,其中,L2为一离去基团,R1如上所定义;
c)通过氧化一相应的式Ⅵ化合物,制备其中X为不饱和杂环的一种式Ⅰ化合物,式Ⅵ为:
其中,Xc表示一个比X更为饱和的相应的杂环,R1、R2、R3、R4、R5和R6如上所定义;
d)通过还原一相应的其中的合适取代基含有一个或多个碳碳双键或碳碳叁键的式Ⅰ化合物,制备具有一个或多个至少含有2个碳原子的烷基取代基的一种式Ⅰ化合物;
e)通过还原一相应的其中X被苯基取代的式Ⅰ化合物,制备其中X被环己基所取代的一种式Ⅰ化合物;
f)制备一种被一个或多个OH、NHR14或COOH所取代的式Ⅰ化合物的方法,包括从一相应的具有保护的OH、NHR14或COOH基的式Ⅰ化合物中除去保护基;
g)通过使一相应的其中Z为被卤素所取代的烷基的式Ⅰ化合物与氰化物盐反应,制备其中Z为被氰基所取代的烷基的一种式Ⅰ化合物;
h)通过使一相应的其中X为一含氮杂环的式Ⅰ化合物同一种烷基化剂反应,制备一种为N-烷基盐的式Ⅰ化合物。
2、一种按照权利要求1所述的方法,其中R1表示C(O)YZ。
3、一种按照权利要求1或2所述的方法,其中R2和R6均表示烷基。
4、一种按照权利要求1至3的任一项方法,其中R3和R5均表示氢。
5、一种按照权利要求1至4的任一项方法,其中X表示一个含有1至3个选自氮、氧和硫杂原子的5或6员杂环,该杂环可任意被1个或多个选自烷基、烷氧基、烷氧羰基、羧基、羟烷基、卤素、CONH2、NH2或Ar2的取代基所取代。
6、一种按照权利要求2至6的任一项方法,其中X表示任意被Ar2所取代的吡唑。
7、一种制备如权利要求1中所定义的式Ⅰ化合物或其药物上可接受的盐的方法,该方法所制备的化合物是:
乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯;
甲氧基乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯;
氰基乙酸2,6-二甲基-4-(1-苯基-1H-吡唑-3-基)氨基苯酯。
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GB8911655 | 1989-05-20 | ||
GB898911654A GB8911654D0 (en) | 1989-05-20 | 1989-05-20 | Compound |
GB8911654 | 1989-05-20 | ||
GB898911655A GB8911655D0 (en) | 1989-05-20 | 1989-05-20 | Compound |
GB90/03044 | 1990-02-10 | ||
GB909003044A GB9003044D0 (en) | 1990-02-10 | 1990-02-10 | Compounds |
RO145922A RO105958B1 (ro) | 1989-05-20 | 1990-09-12 | Procedeu pentru prepararea unor derivati de aminofenol |
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EP (1) | EP0425650B1 (zh) |
JP (1) | JPH07116155B2 (zh) |
CN (1) | CN1047497A (zh) |
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CA (1) | CA2017169A1 (zh) |
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ES (1) | ES2077066T3 (zh) |
FI (1) | FI910222A0 (zh) |
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PL (2) | PL164432B1 (zh) |
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RO (1) | RO105958B1 (zh) |
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GB9312891D0 (en) * | 1993-06-22 | 1993-08-04 | Boots Co Plc | Therapeutic agents |
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1990
- 1990-05-16 GR GR900100380A patent/GR900100380A/el unknown
- 1990-05-17 JP JP2507734A patent/JPH07116155B2/ja not_active Expired - Lifetime
- 1990-05-17 DE DE69021501T patent/DE69021501T2/de not_active Expired - Fee Related
- 1990-05-17 DK DK90908298.4T patent/DK0425650T3/da active
- 1990-05-17 AU AU56682/90A patent/AU630196B2/en not_active Ceased
- 1990-05-17 ES ES90908298T patent/ES2077066T3/es not_active Expired - Lifetime
- 1990-05-17 RU SU904894663A patent/RU2049779C1/ru active
- 1990-05-17 AT AT90908298T patent/ATE126215T1/de not_active IP Right Cessation
- 1990-05-17 WO PCT/GB1990/000762 patent/WO1990014338A1/en active IP Right Grant
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- 1990-05-18 PL PL90285248A patent/PL164432B1/pl unknown
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- 1990-05-18 CA CA002017169A patent/CA2017169A1/en not_active Abandoned
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- 1990-05-18 CZ CS902444A patent/CZ280637B6/cs unknown
- 1990-05-18 PL PL90289487A patent/PL164480B1/pl unknown
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- 1990-05-18 HU HU903094A patent/HU206323B/hu not_active IP Right Cessation
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1991
- 1991-01-16 FI FI910222A patent/FI910222A0/fi not_active Application Discontinuation
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1993
- 1993-02-26 HR HR930239A patent/HRP930239A2/xx not_active Application Discontinuation
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