NO831614L - 3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridaziner, deres fremstilling og deres anvendelse - Google Patents
3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridaziner, deres fremstilling og deres anvendelseInfo
- Publication number
- NO831614L NO831614L NO831614A NO831614A NO831614L NO 831614 L NO831614 L NO 831614L NO 831614 A NO831614 A NO 831614A NO 831614 A NO831614 A NO 831614A NO 831614 L NO831614 L NO 831614L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- carbon atoms
- compound
- groups
- amino
- Prior art date
Links
- 150000004892 pyridazines Chemical class 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- -1 phenoxyphenyl Chemical group 0.000 claims abstract description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 16
- 239000000460 chlorine Substances 0.000 claims abstract description 15
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 9
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 7
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004305 biphenyl Substances 0.000 claims abstract description 6
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 4
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000000949 anxiolytic effect Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 239000002249 anxiolytic agent Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 206010022437 insomnia Diseases 0.000 claims description 2
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 claims 1
- 230000002920 convulsive effect Effects 0.000 claims 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 19
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 abstract description 4
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 abstract description 3
- BUTTVUBNXIIXRH-UHFFFAOYSA-N 1-(cyclopropylmethyl)pyrazole-4-carbaldehyde Chemical compound C1=C(C=O)C=NN1CC1CC1 BUTTVUBNXIIXRH-UHFFFAOYSA-N 0.000 abstract description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 abstract description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 abstract description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 abstract description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 abstract description 2
- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical compound COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 abstract description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JVANLUCASVHWEW-UHFFFAOYSA-N pyridazine Chemical compound N1=C=C=C=C=N1 JVANLUCASVHWEW-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- IXENSJHJYLAODF-UHFFFAOYSA-N 3-bromo-6-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazine Chemical compound C1=CC(C)=CC=C1C1=NN2C(Br)=NN=C2C=C1 IXENSJHJYLAODF-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- SBBMDEIIUUWPEF-UHFFFAOYSA-N 6-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazine Chemical compound C1=CC(C)=CC=C1C1=NN2C=NN=C2C=C1 SBBMDEIIUUWPEF-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- UZBFYYNRFGFLGI-UHFFFAOYSA-N [(6-phenylpyridazin-3-yl)amino]thiourea Chemical compound N1=NC(NNC(=S)N)=CC=C1C1=CC=CC=C1 UZBFYYNRFGFLGI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ZNGXOKMCRDQBON-UHFFFAOYSA-N (6-phenylpyridazin-3-yl)hydrazine Chemical compound N1=NC(NN)=CC=C1C1=CC=CC=C1 ZNGXOKMCRDQBON-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BUBRFWDEAVIFMV-UHFFFAOYSA-N 3-chloro-6-phenylpyridazine Chemical compound N1=NC(Cl)=CC=C1C1=CC=CC=C1 BUBRFWDEAVIFMV-UHFFFAOYSA-N 0.000 description 1
- YIWADZFLXOZDQQ-UHFFFAOYSA-N 4-(3-amino-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzonitrile Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=C(C#N)C=C1 YIWADZFLXOZDQQ-UHFFFAOYSA-N 0.000 description 1
- NESUCTBTEUQLOZ-UHFFFAOYSA-N 6-(1-methylpyrrol-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound CN1C=CC=C1C1=NN2C(N)=NN=C2C=C1 NESUCTBTEUQLOZ-UHFFFAOYSA-N 0.000 description 1
- GRRRNIQVPWPHQS-UHFFFAOYSA-N 6-(1H-pyrrol-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound NC1=NN=C2N1N=C(C=C2)C=1NC=CC=1 GRRRNIQVPWPHQS-UHFFFAOYSA-N 0.000 description 1
- PSCUSLLLANPIAJ-UHFFFAOYSA-N 6-(2-bromophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=CC=C1Br PSCUSLLLANPIAJ-UHFFFAOYSA-N 0.000 description 1
- VTRWYNGBVUXCEG-UHFFFAOYSA-N 6-(2-ethylphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound CCC1=CC=CC=C1C1=NN2C(N)=NN=C2C=C1 VTRWYNGBVUXCEG-UHFFFAOYSA-N 0.000 description 1
- JTBQVGVMBBFRNF-UHFFFAOYSA-N 6-(2-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound CC1=CC=CC=C1C1=NN2C(N)=NN=C2C=C1 JTBQVGVMBBFRNF-UHFFFAOYSA-N 0.000 description 1
- PBSVCHYZZQKCCD-UHFFFAOYSA-N 6-(2-nitrophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=CC=C1[N+]([O-])=O PBSVCHYZZQKCCD-UHFFFAOYSA-N 0.000 description 1
- MVALQLWINGFNCC-UHFFFAOYSA-N 6-(3,4-dichlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=C(Cl)C(Cl)=C1 MVALQLWINGFNCC-UHFFFAOYSA-N 0.000 description 1
- RYFALDHNEPTXIF-UHFFFAOYSA-N 6-(4-aminophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=C(N)C=C1 RYFALDHNEPTXIF-UHFFFAOYSA-N 0.000 description 1
- RHGGVVAPFBYAQX-UHFFFAOYSA-N 6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine;hydrochloride Chemical compound Cl.N=1N2C(N)=NN=C2C=CC=1C1=CC=C(F)C=C1 RHGGVVAPFBYAQX-UHFFFAOYSA-N 0.000 description 1
- OWMAODZSQHQTFC-UHFFFAOYSA-N 6-(4-methylphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound C1=CC(C)=CC=C1C1=NN2C(N)=NN=C2C=C1 OWMAODZSQHQTFC-UHFFFAOYSA-N 0.000 description 1
- OOAVJMKRMCZRIB-UHFFFAOYSA-N 6-(4-nitrophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=C([N+]([O-])=O)C=C1 OOAVJMKRMCZRIB-UHFFFAOYSA-N 0.000 description 1
- ZTHXWLWNXCCCEA-UHFFFAOYSA-N 6-(4-propylsulfanylphenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound C1=CC(SCCC)=CC=C1C1=NN2C(N)=NN=C2C=C1 ZTHXWLWNXCCCEA-UHFFFAOYSA-N 0.000 description 1
- IZRVHCGGFMGJTB-UHFFFAOYSA-N 6-(5-methylfuran-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound O1C(C)=CC=C1C1=NN2C(N)=NN=C2C=C1 IZRVHCGGFMGJTB-UHFFFAOYSA-N 0.000 description 1
- IWTZBWDZUCQHFQ-UHFFFAOYSA-N 6-[2-(trifluoromethyl)phenyl]-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=CC=C1C(F)(F)F IWTZBWDZUCQHFQ-UHFFFAOYSA-N 0.000 description 1
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- BWDKRNKKDDGBRF-UHFFFAOYSA-N 6-pyridin-3-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=CN=C1 BWDKRNKKDDGBRF-UHFFFAOYSA-N 0.000 description 1
- JDWCNSLLTCFOFR-UHFFFAOYSA-N 6-pyridin-4-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine Chemical compound N=1N2C(N)=NN=C2C=CC=1C1=CC=NC=C1 JDWCNSLLTCFOFR-UHFFFAOYSA-N 0.000 description 1
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- MHGGAHUZDJJPHB-UHFFFAOYSA-N [6-(4-fluorophenyl)pyridazin-3-yl]hydrazine Chemical compound N1=NC(NN)=CC=C1C1=CC=C(F)C=C1 MHGGAHUZDJJPHB-UHFFFAOYSA-N 0.000 description 1
- MORPXDYMWBGQNW-UHFFFAOYSA-N [6-(4-methylphenyl)pyridazin-3-yl]hydrazine Chemical compound C1=CC(C)=CC=C1C1=CC=C(NN)N=N1 MORPXDYMWBGQNW-UHFFFAOYSA-N 0.000 description 1
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- MTHMVLLKCNMJQL-UHFFFAOYSA-N oxalonitrile hydrobromide Chemical compound Br.N#CC#N MTHMVLLKCNMJQL-UHFFFAOYSA-N 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Liquid Crystal Substances (AREA)
Description
Oppfinnelsens gjenstand er nye 3-amino-6-aryl-l,2,4-triazolo [4,3-b]pyridaziner med den generelle-formel. I - -
og deres salter med en fysiologisk tålbar syre, og hvori R 1 og R 2 er like eller forskjellige og betyr hydrogen, alkylgrupper med 1-6 C-atomer, fenyl eller klor og Ar betyr aromatiske rester som fenyl, bifenyl, fenoksyfenyl, fenyltiofenyl, fenylsulfinylfenyl, fenylsulfonylfenyl, 1- eller 2-naftyl, 2- eller 3-tienyl, 2-furyl, 2-pyrrolyl, 1-metyl-2-pyrrolyl, 2-, 3- eller 4-pyridyl, som eventuelt kan være substituert med en, to , tre. fire eller fem rester som fluor, klor, brom, jod, alkylgrupper med 1-6 C-atomer, cykloalkylgrupper med 3-8 C-atomer, fenylalkylgrupper med 1-4 alkyl-C-atomer, alkoksy- eller alkyltiogrupper med hver gang 1-6 C-atomer, hydroksy. nitro, cyano, trifluormetyl, karboksygrupper, deres estere med C^-C^-alkoholer, aminokarbonyl, amino, acetamino, alkoksykarbonylamino med 1-6 C-atomer i alkylresten.
Blant forbindelsene med den generelle formel I er slike fore-1 2
trukket hvori R og R er like eller forskjellige og betyr hydrogen, metyl, etyl, fenyl.eller klor og hvori Ar betyr fenyl, bifenyl, 2- eller 3-tienyl, 2-furyl, 2-, 3- eller 4-pyridyl, som eventuelt kan være substituert med en, to eller tre fluor, klor, brom, alkylgrupper med 1-6 C-atomer, cykloalkylgrupper med 3-6 C-atomer eller trifluormetyl.
Spesielt foretrukket er slike forbindelser med formel I
1 2
hvori R og R er like eller forskjellige og betyr hydrogen,
metyl eller etyl og Ar betyr fenyl, 2- eller 3-tienyl, 2-,
3- eller 4-pyridyl, eventuelt substituert™en eller to fluor-, klor, metyl, etyl eller trifluormetyl.
Oppfinnelsens gjenstand er også fremgangsmåte til fremstilling av disse forbindelser samt farmasøytiske tilberedninger av disse forbindelser og deres anvendelse som legemiddel.
Fremgangsmåten til fremstilling av forbindelsene, med formel I erkarakterisert vedat et aryl-hydrazino-pyridazin med formel
II
hvori R 1 og R 2 og Ar har den under formel I angitte betydning, a) omsettes med et cykliseringsreagens som klorcyan, bromcyan, O-metylisourinstoff eller S-metylisotiourinstoff,
guanidin eller deres salter, kloroformamidinhydroklorid eller cyanamid, eller
b) omsettes med N-(R 3-oksy)-karbonyl-O-metylisourinstoff
til en forbindelse med formel III
1 2
hvori Ar, R og R har den under formelen I angitte betyd-nmg og R 3 betyr alkyl med 1-10 C-atomer, benzyl eller fenyl og deretter forsåpes den således dannede forbindelse eller,
c) at en forbindelse med formel IV,
4 12
R betyr klor brom eller metyltio, og Ar, R og R har den under formel I angitte betydning omsettes med ammoniakk, eller
d) at en forbindelse med formel V
12 hvori Ar, R og R har den under formel I angitte betydning og at Z betyr 0, S eller NH, cykliseres eventuelt under tilsetning av et kondensasjonsmiddel til en forbindelse med formel I. Forbindelser med formel II er f.eks. kjent fra J.Heterocyclic Chem. 15_, 881 (1978) og kan fremstilles av klorforbindelser med formel VI med hydrazinhydrat
etter litteraturkjente fremgangsmåter (The Chemistry of Heterocyclic Compounds, Vol 28 Pyridazines, Editors A. Weissberger og E.C. Taylor, John Wiley, New York 1973). Begge litteratursitater omtaler også fremstillingen av klorforbindelsene VI og deres forløpere.
Fremgangsmåte a) gjennomføres i et egnet oppløsningsmiddel i et temperaturområde fra 0°C yil det anvendte oppløsnings-middels kokepunkt, fortrinnsvis ved 50 til 100°C.
Som oppløsningsmiddel for fremgangsmåte a) kommer det f.eks.
på tale vann, eddiksyre, alifatiske alkoholer som metanol, etanol, isopropanol, dioksan, DMF, toluen, klorerte hydro-karboner som metylenklorid, kloroform, dikloretan, karbon-tetraklorid.
Fremgangsmåte b) gjennomføres i et egnet oppløsningsmiddel
i nærvær av en syre. Eksempelvis arbeider man i en blanding metanol/iseddik i et volumforhold på f.eks. 10:1 ved til-bakeløpstemperatur. Forsåpningen av karbaminatet III fore-
går under alkaliske betingelser ved oppvarming med et alkali-eller jordalkalimetallhydroksyd som f-eks- NaOH, KOH, Ca(OH)2, Ba(OH)2i et oppløsningsmiddel eller oppløsningsmiddelblanding til 60-180°C, fortrinnsvis til 100-140°C. Som oppløsnings-middel kommer det spesielt<*>på tale vann og alifatiske alkoholer og dioler som etanol, propanol, isopropanol, butanol, 2-metoksyetanol, glykol.
For fremgangsmåte c) omsettes utgangsstoffer med formel IV ved oppvarming av arylhydrazinopyridaziner II med maursyre eller dens estere (ved r<4>= H), klormaursyreestere eller et dialkyl-karbonat (ved R 4= OH) eller med svovelkarbon og alkali
(ved R 4= SH), eventuelt under tilsetning av et oppløsnings-eller fortynningsmiddel som kloroform, toluen, dioksan, vann, etanol til en forbindelse med formel IV<1>, hvori R 4= H, OH eller SH. Ved oppvarming med brom i iseddik/natriumacetat (ved R 4= H), fosforoksyklorid (ved R 4= OH) respektiv metyljodid eller dimetylsulfat (ved R = SH) fåes herav de tilsvarende forbind-eiser IV med R 4= Br, Cl, SCH3.
Ifølge fremgangsmåte c) foregår omsetningen av forbindelsene
med formel IV med flytende vandig eller alkoholisk ammoniakk eller i .et inert oppløsningsmiddel som metanol, dioksan,
eller toluen med gassformet ammoniakk ved innføring eller under trykk. Temperaturområdet strekker seg fra temperaturen for flytende ammoniakk inntil 20 0°C.
Ved fremgangsmåte d) overføres de for eksempel ved omsetning
av klorforbindelsene VI med semikarbazid, -tiosemikarbazid eller aminoguanidin i et oppløsningsmiddel som f.eks. metanol, etanol, isopropanol, DMF, tetrahydrofuran. toluen, kloroform eller dikloretan dannede forbindelser V ved oppvarming f.eks.
i et av de nevnte oppløsningsmidler til 40 - 150°C eventuelt under tilsetning av et kondensasjonsmiddel som iseddik, cyklo-heksylkarbodiimid, 1-hydroksybenztriazol til forbindelser med formel I. Når forbindelsene med formel I fåes etter de omtalte fremgangsmåter som salter så kan det herav med ammoniakk, aminer og hydroksyder frigjøres de tilsvarende baser.
De fire baser med formel I overføres med fysiologisk tålbare syrer til de tilsvarende salter. Som syrer kommer det i betraktning uorganiske eller organiske syrer som klor- eller bromhydrogensyre. fosforsyre, eddiksyre, benzosyre, sitron-syre, maleinsyre, fumarsyre, melkesyre, vinsyre, ravsyre, acetylglycin. Det foretrekkes hydrokloridene med formel I.
Forbindelsene ifølge oppfinnelsen med formel I er egnet til fremstilling av legemidler. Legemidlene kan inneholde en eller flere av forbindelsene ifølge oppfinnelsen eller også blandinger av disse med andre farmasøytisk virksomme stoffer. Til fremstilling av legemidler kan det anvendes de vanlige farmasøytiske bærer- og hjelpestoffer og kjente geleniske fremgangsmåter. Legemidlene kan anvendes enteralt, parenteralt, oralt eller perlingualt. Eksempelvis kan administreringen foregå i form av tabletter, kapsler, piller, dragéer, tapper, geleer, kremer, pudder, liquida, stavpulver eller aerosoler. Som liquida kommer det eksempelvis på tale: oljeaktige eller vandige oppløsninger eller suspensjoner, emulsjoner, injiser-bare vandige oppløsninger eller suspensjoner.
Forbindelsene ifølge oppfinnelsen kan dessuten finne anvendelse som mellomprodukter til fremstilling av andre legemidler. Som forbindelser ifølge oppfinnelsen skal det nevnes: 3-amino-6—(2-bromfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-trifluormetylfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-klor-3-trifluormetylfenyl)-1,2,4-triazolo[4,3-b]~pyridazin, ,3-amino-6-(3-etylfenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(2-metylfenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(2-etylfenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(3-metoksyfenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(4-propyltiofenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(4-acetamidofenyl)-1,2,4-triazolo[4-3-b]-pyridazin, 3-amino-6-(4-aminofenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(4-metoksykarbonylaminofenyl-1,2,4-triazolo-[4,3-b]pyridazin, 3-amino-6-(4-nitrofenyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(3-nitrofenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-nitrofenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-cyanofenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(3-cyanofenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-cyanofenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-fenylsulfinylfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-fenylsulfonylfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-hydroksyfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(3-hydroksyfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(3,4-dihydroksyfenyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(1-naftyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-naftyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(3-tienyl)-l,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-klor-2-tienyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(3-metyl-2-tienyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-metyl-2-tienyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-furyl)-1,2,4-triazolof 4,3-b]pyridazin, 3-amino-6-(5-metyl-2-furyl)-1,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(4-pyridyl)-1,2,4-triazolo-[4,3-b]pyridazin, 3-amino-6-(3-pyridyl)-1,2,4-triazolo[4,3-b]-pyridazin, 3-amino-6-(2-pyridyl-l,2,4-triazolo[4,3-b]pyridazin, 3-amino-6-(2-pyrrolyl)-1,2,4-triazolo[4,3-b]pyridazin og 3-amino-6-(1-metyi-2-pyrrolyl)-1,2,4-triazolo[4,3-b]pyridazin. Forbindelsene ifølge oppfinnelsen med formel I har farmako-logiske egenskaper, spesielt virker de anxiolittiske og anti-konvulsive. Som indikasjoner kommer det derfor i betraktning søvnløshet,, opphisselse og vegetative depresjoner.
De farmasøytiske tilberedningene inneholder vanligvis mellom 1 til 10% av den eller de aktive komponenter ifølge oppfinnelsen.
Den anxiolyttiske- virkning av forbindelsen med formel I er fulgt av en meget liten sedering og gode tålbarheter (Ld^Qi.a. over 3 00'mg/kg i.p på mus). Dette fremgår av under-søkelser hvor innvirkningen av forbindelsene ifølge oppfinnelsen ble målt på den motoriske aktivitet, heksobarbital-narkosen og kardiazolkrampér hos mus. Dessuten ble dessuten Beller-anxiolysetesten anvendt samt Lick-Shock-prøven på rotter.
ti
Den laveste allerede virksomme dose i de angitte forsøk er eksempelvis 5 mg/kg oralt, 2,5 mg/kg sublingualt, 1 mg/kg intravenøst. Som generell dosisområde for virkningen (dyre-forsøk som ovenfor) kommer det eksempelvis på tale: 5 til 50 mg/kg oralt, 2,5 - 25 mg/kg sublingualt, 1 til 10 mg/kg intravenøst.
Eksempelvis kan det appliseres 3 ganger daglig 1 til 3
tabletter med et innhold fra 10 til 100 mg virksomt stoff eller eksempelvis ved intravenøs injeksjon 1 til 3 ganger daglig en ampulle på 2 til 4 mg innhold med 0,5 til 5 mg stoff.
Eksempel 1: Framgangsmåte a)
3-amini-6-fenyl-1,2,4-triazolo[4,3-b]pyridazin-hydroklorid 25 g 3-hydrazino-6-fenylpyridazin og 17,1 g bromcyan omrøres
i 15 0 ml etanol i 3 timer under tilbakeløp og inndampes deretter i vakuum. Residuet oppløses varmt-i- -vann, filtreres og gjøres alkalisk med overskytende ammoniakk. Den frie base frasuges, vaskes nøytralt og tørkes, suspenderes i etanol, blandes med etanolisk saltsyre og inndampes i vakuum.
Det utfelte hydroklorid frasuges, vaskes med etanol og tørkes, smeltepunkt 280°C under spaltning.
Eksempel 2: Fremgangsmåte a)
3-amino-6-(4~--f luorf enyl)-1,2,4-triazolo[4,3-bJpyridazin-hydroklorid
I en oppløsning av 5 g 3-(4-fluorfenyl)-6-hydrazino-pyridazin i 50 ml etanol innføres ved 0 - 10°C et lite overskudd av klorcyan og videreomrøres ved værelsetemperatur til full-stendig omsetning (DC-kontroll).
Det utfelte hydroklorid frasuges, vaskes med isopropanol og tørkes, smeltepunkt 284°C under spaltning.
Eksempel 3: Fremgangsmåte b)
3-amino-6-(3,4-diklorfenyl)-1,2,4-triazolo[4,3-b]pyridazin
3 g 6-(3,4-diklorfenyl)-3-metoksykarbonylamino-l,2,4-tri-azolo [*4 ^3-b]pyridazin og 3 g kaliumhydroksyd oppvarmes i 10 ml vann og 20 ml 2-metoksyetanol i 16 timer til tilbake-løp.
Det utfelte produkt frasuges, vaskes nøytralt og omkrystalliseres fra isopropanol, smeltepunkt 281°C.
Eksempel 3: Fremgangsmåte c)
6-(4-metylfenyl)-1,2,4-triazolo[4,3-b]pyridazin
5 g 3-hydrazino-6-(4-metylfenyl)-pyridazin omrøres i 10 ml maursyre i 2 timer under tilbakeløp.. Etter avkjøling fortynnes med vann og det utfelte produkt frasuges og vaskes nøytralt og tørkes, smeltepunkt 186°C.
Eksempel 4: -~Fremgangsmåte c)
3-brom-6-(4-metylfenyl)-1,2,4-triazolo[4,3-b]pyridazin
4 g 6-(4-metylfenyl)-1,2,4-triazolo[4,3-b]pyridazin og 3 g natriumacetat suspenderes i 20 ml iseddik. 1 ml brom i 5 ml iseddik tildryppes oppløsningen og oppvarmes 5 timer til tilbakeløp. Man inndamper til tørrhet, blander med vann og frasuger<*>produktet. Etter omkrystallisering fra isopropanol og tørkning, smeltepunkt 211°C.
Eksempel 5: Fremgangsmåte c)
3-amino-6-(4-metylfenyl)-1,2,4-triazolo[4,3-b]pyridazin
3 g 3-brom-6-(4-metylfenyl)-1,2,4-triazolo[4,3-b]pyridazin behandles med 25 ml metanol og 25 ml konsentrert ammoniakk-oppløsning ved 100°C i autoklav. Etter avkjøling fortynnes med vann, frasuges, vaskes nøytralt og tørkes, smeltepunkt 261°C.
Eksempel 6: Fremgangsmåte d)
3-fenyl-6-tiosemikarbazidopyridazin
6 g 3-klor-6-fenylpyridazin og 6 g tiosemikarbazid oppvarmes i 60 ml etanol i 3 timer til tilbakeløp. Man frasuger den dannede utfelling, vasker med etanol og vann og tørker i vakuum, smeltepunkt 213°C under spaltning.
Eksempel 7: Fremgangsmåte d)
3-amino-6-fenyl-1,2,4-triazolo[4,3-b]pyridazin
2 g 3-fenyl-6-tiosemikarbazidopyridazin oppvarmes i 20 ml iseddik i 6 timer under tilbakeløp. Etter inndampning av reaksjonsoppløsningen utrøres med vandig ammoniakk, frasuges, vaskes nøytralt med vann, tørkes og omkrystalliseres fra isopropanol, smeltepunkt 212°C.
Analogt eksempelene 1-7 kan det fremstilles følgende forbindelser:
Claims (1)
1. 3-amino-6-aryl-l,2/ 4-triazolo[4,3-b]pyridaziner med den generelle formel I
og deres salter med en fysiologisk tålbar syrey hvori R og R 2 er like eller forskjellige og betyr hydrogen, alkylgrupper med 1-6 C-atomer, "fenyl eller klor og Ar betyr aromatiske rester som fenyl, bifenyl, fenoksyfenyl, fenyltiofenyl, fenylsulfinyl, fenylsulfonyl, 1- eller 2-naftyl,
2- eller 3-tienyl, 2-furyl, 2-pyrrolyl, l-metyl-2-pyrrolyl, 2- , 3- eller 4-pyridyl som eventuelt kan være substituerte en r ■ to, tre, fire eller fem rester som fluor, klor, brom, jod, alkylgrupper med 1-6 C-atomer, cykloalkylgrupper med
3- 8 C-atomer, fenylalkylgrupper med 1-4 alkyl-C-atomer, alkoksy- eller alkyltiogrupper med hver gang 1-6 C-atomer, hydroksy, nitro, cyano, trifluormetyl, karboksygrupper, deres estere med C^ -Cg-alkoholer, aminokarbonyl, amino, acetamino, alkoksykarbonaylamino med 1-6 C-atomer i alkylresten.
1 2 2. Forbindelser ifølge krav 1, hvori R og R er like eller forskjellige og betyr hydrogen, metyl, etyl, fenyl eller klor, og hvori Ar betyr fenyl, bifenyl, 2- eller 3-tienyl, 2-furyl, 2-, 3- eller 4-pyridyl som eventuelt kan være substituert med en, to eller tre fluor, klor, brom alkylgrupper med 1-6 C-atomer, cykloalkylgrupper med 3-6 C-atomer eller trifluormetyl.
3. Fremgangsmåte til fremstilling av forbindelser med formel I i krav 1, karakterisert ved at et aryl-hydrazinopyridazin med formel II
1 2
hvori R , R og Ar har den i formel I angitte betydning,
a) omsettes med et cykliseringsreagens, eller
b) omsettes med et N-(R 3-oksy)-karbonyl-O-metylisourinstoff
til en forbindelse med'formel III
1 2
hvori Ar, R og R har den til formel I angitte betydning og R 3 betyr alkyl med 1-10 C-atomer, benzyl eller fenyl og deretter forsåpes den således dannede forbindelse, ellerc) at en forbindelse med formel IV
4 12 hvori R betyr klor, brom eller metyltio og Ar, R og R har den til formel I angitte betydning, omsettes med ammoniakk eller
d) at en forbindelse med formel V
12-
hvori Ar, R og R har den til formelen I angitte betydning at Z betyr 0, S eller NH, cykliseres ved oppvarming eventuelt under tilsetning-av et kondensasjonsmiddel til en forbindelse med formel I,
og eventuelt 'overføres den således dannede forbindelse med en fysiologisk tålbar syre til saltet.
4. Farmasøytisk preparater med anxiolyttisk og anti-konvulsiv virkning, karakterisert ved et innehold av en forbindelse med den generelle formel I i krav 1 /
5. Anvendelse av en forbindelse med den generelle formel I i krav 1 til behandling av opphissingstilstander, søvnløs-het, krampetilstander og vegetative dystoni.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823217325 DE3217325A1 (de) | 1982-05-08 | 1982-05-08 | 3-amino-6-aryl-1,2,4-triazolo(4,3-b)-pyridazine, ihre herstellung und ihre verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO831614L true NO831614L (no) | 1983-11-09 |
Family
ID=6163075
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO831614A NO831614L (no) | 1982-05-08 | 1983-05-06 | 3-amino-6-aryl-1,2,4-triazolo(4,3-b)pyridaziner, deres fremstilling og deres anvendelse |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0094038B1 (no) |
| JP (1) | JPS58203992A (no) |
| KR (1) | KR840004753A (no) |
| AT (1) | ATE24728T1 (no) |
| AU (1) | AU1434383A (no) |
| CA (1) | CA1201122A (no) |
| DE (2) | DE3217325A1 (no) |
| DK (1) | DK204783A (no) |
| ES (4) | ES522144A0 (no) |
| FI (1) | FI831548L (no) |
| GR (1) | GR79281B (no) |
| HU (1) | HU189277B (no) |
| IE (1) | IE55096B1 (no) |
| IL (1) | IL68611A0 (no) |
| MA (1) | MA19791A1 (no) |
| NO (1) | NO831614L (no) |
| NZ (1) | NZ204153A (no) |
| PT (1) | PT76654B (no) |
| ZA (1) | ZA833239B (no) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3311753A1 (de) * | 1983-03-31 | 1984-10-04 | Hoechst Ag, 6230 Frankfurt | Substituierte 6-aryl-1,2,4-triazolo(4,3-b)pyridazine - ihre herstellung und verwendung - |
| FR2562071B1 (fr) * | 1984-03-30 | 1986-12-19 | Sanofi Sa | Triazolo(4,3-b)pyridazines, procede pour leur preparation et compositions pharmaceutiques les contenant |
| US4654343A (en) * | 1985-10-31 | 1987-03-31 | American Cyanamid Company | N-substituted-N[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]alkanamides, carbamates and ureas |
| ES2543813T3 (es) | 2004-11-02 | 2015-08-24 | Northwestern University | Compuestos de piridazina para el tratamiento de enfermedades inflamatorias |
| ATE523199T1 (de) | 2004-11-02 | 2011-09-15 | Univ Northwestern | Pyridazinverbindungen und verfahren |
| WO2007127375A2 (en) | 2006-04-28 | 2007-11-08 | Northwestern University | Formulations containing pyridazine compounds for treating neuroinflammatory diseases |
| WO2007127474A2 (en) | 2006-04-28 | 2007-11-08 | Northwestern University | Compositions and treatments using pyridazine compounds and cholinesterase inhibitors |
| EP2131839A2 (en) * | 2007-03-02 | 2009-12-16 | Northwestern University | Compositions comprising derivatives of 3-phenylpyridazine for treating seizure-related disorders |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL128809C (no) * | 1966-06-18 | |||
| US3708484A (en) * | 1970-10-16 | 1973-01-02 | Sandoz Ag | Amino and substituted amino-s-triazolo-(4,3-b)-pyridazines |
| DE2113438A1 (de) * | 1971-03-19 | 1972-09-21 | Boehringer Mannheim Gmbh | Nitrofuryl-triazolo[4,3-b]pyridazinderivate |
| CA1080712A (en) * | 1976-09-22 | 1980-07-01 | Jay D. Albright | Hypotensive agents |
| US4260756A (en) * | 1979-11-15 | 1981-04-07 | American Cyanamid Company | 6- And 8-heteroaryl-1,2,4-triazolo[4,3-b]pyridazines |
-
1982
- 1982-05-08 DE DE19823217325 patent/DE3217325A1/de not_active Withdrawn
-
1983
- 1983-05-04 GR GR71294A patent/GR79281B/el unknown
- 1983-05-05 EP EP83104427A patent/EP0094038B1/de not_active Expired
- 1983-05-05 DE DE8383104427T patent/DE3368931D1/de not_active Expired
- 1983-05-05 FI FI831548A patent/FI831548L/fi not_active Application Discontinuation
- 1983-05-05 AT AT83104427T patent/ATE24728T1/de not_active IP Right Cessation
- 1983-05-06 DK DK204783A patent/DK204783A/da not_active Application Discontinuation
- 1983-05-06 AU AU14343/83A patent/AU1434383A/en not_active Abandoned
- 1983-05-06 ES ES522144A patent/ES522144A0/es active Granted
- 1983-05-06 CA CA000427630A patent/CA1201122A/en not_active Expired
- 1983-05-06 ZA ZA833239A patent/ZA833239B/xx unknown
- 1983-05-06 HU HU831579A patent/HU189277B/hu unknown
- 1983-05-06 KR KR1019830001924A patent/KR840004753A/ko not_active Application Discontinuation
- 1983-05-06 MA MA20012A patent/MA19791A1/fr unknown
- 1983-05-06 IE IE1043/83A patent/IE55096B1/en unknown
- 1983-05-06 NZ NZ204153A patent/NZ204153A/en unknown
- 1983-05-06 NO NO831614A patent/NO831614L/no unknown
- 1983-05-06 PT PT76654A patent/PT76654B/pt unknown
- 1983-05-06 IL IL68611A patent/IL68611A0/xx unknown
- 1983-05-06 JP JP58078423A patent/JPS58203992A/ja active Pending
-
1984
- 1984-03-15 ES ES530640A patent/ES530640A0/es active Granted
- 1984-03-15 ES ES530639A patent/ES530639A0/es active Granted
- 1984-03-15 ES ES530638A patent/ES8501398A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES530638A0 (es) | 1984-11-16 |
| FI831548L (fi) | 1983-11-09 |
| JPS58203992A (ja) | 1983-11-28 |
| EP0094038A1 (de) | 1983-11-16 |
| KR840004753A (ko) | 1984-10-24 |
| ES8501399A1 (es) | 1984-11-16 |
| ES530639A0 (es) | 1984-11-16 |
| PT76654B (de) | 1986-01-28 |
| CA1201122A (en) | 1986-02-25 |
| ES8501400A1 (es) | 1984-11-16 |
| DK204783A (da) | 1983-11-09 |
| PT76654A (de) | 1983-06-01 |
| DE3217325A1 (de) | 1983-11-10 |
| HU189277B (en) | 1986-06-30 |
| NZ204153A (en) | 1985-04-30 |
| MA19791A1 (fr) | 1983-12-31 |
| DK204783D0 (da) | 1983-05-06 |
| IL68611A0 (en) | 1983-09-30 |
| GR79281B (no) | 1984-10-22 |
| ES8405800A1 (es) | 1984-06-16 |
| ATE24728T1 (de) | 1987-01-15 |
| ES8501398A1 (es) | 1984-11-16 |
| FI831548A0 (fi) | 1983-05-05 |
| AU1434383A (en) | 1983-11-10 |
| DE3368931D1 (en) | 1987-02-12 |
| ES522144A0 (es) | 1984-06-16 |
| IE55096B1 (en) | 1990-05-23 |
| EP0094038B1 (de) | 1987-01-07 |
| ZA833239B (en) | 1984-01-25 |
| ES530640A0 (es) | 1984-11-16 |
| IE831043L (en) | 1983-11-08 |
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