NO841270L - SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, AND THEIR PREPARATION AND USE - Google Patents
SUBSTITUTED 6-ARYL-1,2,4-TRIAZOLO (4,3-B) PYRIDAZINES, AND THEIR PREPARATION AND USEInfo
- Publication number
- NO841270L NO841270L NO841270A NO841270A NO841270L NO 841270 L NO841270 L NO 841270L NO 841270 A NO841270 A NO 841270A NO 841270 A NO841270 A NO 841270A NO 841270 L NO841270 L NO 841270L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- alkyl
- atoms
- phenyl
- chlorine
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract 3
- 150000004892 pyridazines Chemical class 0.000 title description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 47
- -1 phenoxyphenyl Chemical group 0.000 claims abstract description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 239000000460 chlorine Substances 0.000 claims abstract description 32
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 32
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 23
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000011737 fluorine Substances 0.000 claims abstract description 22
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 22
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 6
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims abstract description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 230000000949 anxiolytic effect Effects 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 230000001773 anti-convulsant effect Effects 0.000 claims description 3
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 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
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 206010022437 insomnia Diseases 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000005490 tosylate group Chemical group 0.000 claims description 2
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 claims 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000002920 convulsive effect Effects 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 125000002346 iodo group Chemical group I* 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 abstract 2
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 229910052717 sulfur Inorganic materials 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 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
- 229940079593 drug Drugs 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ZNGXOKMCRDQBON-UHFFFAOYSA-N (6-phenylpyridazin-3-yl)hydrazine Chemical compound N1=NC(NN)=CC=C1C1=CC=CC=C1 ZNGXOKMCRDQBON-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance 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
- MDKCFLQDBWCQCV-UHFFFAOYSA-N benzyl isothiocyanate Chemical compound S=C=NCC1=CC=CC=C1 MDKCFLQDBWCQCV-UHFFFAOYSA-N 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-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
- 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
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 1
- HDBACITVPQEAGG-UHFFFAOYSA-N 1-fluoro-3-isothiocyanatobenzene Chemical compound FC1=CC=CC(N=C=S)=C1 HDBACITVPQEAGG-UHFFFAOYSA-N 0.000 description 1
- NFIUJHJMCQQYDL-UHFFFAOYSA-N 1-fluoro-4-isothiocyanatobenzene Chemical compound FC1=CC=C(N=C=S)C=C1 NFIUJHJMCQQYDL-UHFFFAOYSA-N 0.000 description 1
- IBWYHNOFSKJKKY-UHFFFAOYSA-N 3-chloropyridazine Chemical class ClC1=CC=CN=N1 IBWYHNOFSKJKKY-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- NSKOUMSIYPDVPZ-UHFFFAOYSA-N 6-(4-fluorophenyl)-n-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-amine;hydrochloride Chemical compound Cl.N=1N2C(NC)=NN=C2C=CC=1C1=CC=C(F)C=C1 NSKOUMSIYPDVPZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 241000766026 Coregonus nasus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 1
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- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-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
- 241000700159 Rattus Species 0.000 description 1
- 241001180873 Saposhnikovia divaricata Species 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 101100054666 Streptomyces halstedii sch3 gene Proteins 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
- RBACLVJXYZIJGQ-UHFFFAOYSA-N [6-(4-phenylsulfanylphenyl)pyridazin-3-yl]hydrazine Chemical compound N1=NC(NN)=CC=C1C(C=C1)=CC=C1SC1=CC=CC=C1 RBACLVJXYZIJGQ-UHFFFAOYSA-N 0.000 description 1
- PXEUYRFAPQWCHN-UHFFFAOYSA-N [6-[3-(trifluoromethyl)phenyl]pyridazin-3-yl]hydrazine Chemical compound N1=NC(NN)=CC=C1C1=CC=CC(C(F)(F)F)=C1 PXEUYRFAPQWCHN-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 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
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- QPJDMGCKMHUXFD-UHFFFAOYSA-N cyanogen chloride Chemical compound ClC#N QPJDMGCKMHUXFD-UHFFFAOYSA-N 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 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
- 238000010410 dusting 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
- 235000019253 formic acid Nutrition 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
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- MZSJGCPBOVTKHR-UHFFFAOYSA-N isothiocyanatocyclohexane Chemical compound S=C=NC1CCCCC1 MZSJGCPBOVTKHR-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910000464 lead oxide Inorganic materials 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
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 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
- 150000007530 organic bases Chemical class 0.000 description 1
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940117953 phenylisothiocyanate Drugs 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- WFJZBOIOPMOUCB-UHFFFAOYSA-N pyridazine;hydrochloride Chemical compound Cl.C1=CC=NN=C1 WFJZBOIOPMOUCB-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension 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
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material 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)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
Description
Oppfinnelsens gjenstand er nye substituerte 6-aryl-l,2 , 4-triazolo/~4,3-b/pyridaziner, med den generelle formel I The object of the invention is new substituted 6-aryl-1,2,4-triazolo/~4,3-b/pyridazines, with the general formula I
og deres salter, med en fysiologisk tålbar syre, hvori R1 og R<2>er like eller forskjellige og betyr hydrogen, alkylgrupper med 1-6 C-atomer, fenyl eller klor, hvori R 3 betyr hydrogen, rettlinjet eller forgrenet alkyl med 1-6 C-atomer eller fenyl, som eventuelt er substituert med 1,2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, og R 4 betyr rettlinjet eller forgrenet alkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, fenylalkyl med 1-4 C-atomer i alkyldelen, og eventuelt i fenyldelen substituert med 1,2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer, betyr videre alkylkarbonyl med 1-6 C-atomer i alkyldelen, cykloalkylkarbonyl med 5-7 C-atomer i cykloalkyldelen, eventuelt med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl eller alkyl med 1-4 C-atomer substituert benzoyl eller Ar, og hvori Ar betyr aromatiske rester som fenyl, bifenyl, fenoksyfenyl, fenyltiofenyl, fenylsulfinylfenyl, fenylsulfonylfenyl, 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 substituert med 1,2, 3 eller 4 eller 5 rester som fluor, klor, brom, jod, alkylgrupper med 1-6 C-atomer, cykloalkylgruppen med 3-8 C-atomer, fenylalkylgruppe med 1-4 alkyl-C-atomer, alkoksy- eller alkyltiogrupper med hver gang 1-6 C-atomer, hydroksy, nitro, cyano, trifluormetyl, karboksygruppen, deres estere, med C-^-Cg-alkoholer, aminokarbonyl, amino, acetamido, alkoksykarbonylamino med 1-6 C-atomer i alkylresten, hvori videre kan bety en rest med den generelle formel II hvori and their salts, with a physiologically tolerable acid, in which R1 and R<2> are the same or different and mean hydrogen, alkyl groups with 1-6 C atoms, phenyl or chlorine, in which R 3 means hydrogen, straight or branched alkyl with 1 -6 C atoms or phenyl, which is optionally substituted with 1,2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms, and R 4 means straight or branched alkyl with 1-6 C -atoms, cycloalkyl with 3-8 C atoms, phenylalkyl with 1-4 C atoms in the alkyl part, and optionally in the phenyl part substituted with 1,2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C -atoms, further means alkylcarbonyl with 1-6 C atoms in the alkyl part, cycloalkylcarbonyl with 5-7 C atoms in the cycloalkyl part, optionally with 1, 2 or 3 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C -atoms substituted by benzoyl or Ar, and in which Ar means aromatic residues such as phenyl, biphenyl, phenoxyphenyl, phenylthiophenyl, phenylsulfinylphenyl, phenylsulfonylphenyl, 1- or 2-naphthyl, 2- or 3-thienyl, 2-furyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-, 3- or 4-pyridyl, which may optionally be substituted with 1,2, 3 or 4 or 5 residues which fluorine, chlorine, bromine, iodine, alkyl groups with 1-6 C atoms, the cycloalkyl group with 3-8 C atoms, phenylalkyl group with 1-4 alkyl C atoms, alkoxy or alkylthio groups with each 1-6 C atoms . II in which
X betyr CH2, CHR<5>, C=0, 0, S eller NR , hvori R betyr hydrogen, alkyl med 1-6 G-atomer, cykloalkyl med 3-8 C-atomer, alkylkarbonyl med 1-6 C-atomer i alkylresten, alkoksykarbonyl med X means CH2, CHR<5>, C=0, 0, S or NR, where R means hydrogen, alkyl with 1-6 G atoms, cycloalkyl with 3-8 C atoms, alkylcarbonyl with 1-6 C atoms in the alkyl residue, alkoxycarbonyl with
1-4 C-atomer i alkoksyresten, eventuelt substituert fenylalkyl med 1-4 C-atomer i alkylresten, eventuelt substituert fenyl eller eventuelt substituert benzoyl, hvori fenylringen hver gang kan være substituert med 1, 2 eller 3 fluor, klor, brom, jod, trifluormetyl, eller alkyl med 1-6 C-atomer, 1-4 C atoms in the alkoxy residue, optionally substituted phenylalkyl with 1-4 C atoms in the alkyl residue, optionally substituted phenyl or optionally substituted benzoyl, in which the phenyl ring can each be substituted with 1, 2 or 3 fluorine, chlorine, bromine, iodine , trifluoromethyl, or alkyl with 1-6 C atoms,
og m betyr 1,2 eller 3.and m means 1,2 or 3.
Blant forbindelsene med den generelle formel I er slike fore-Among the compounds of the general formula I, such pre-
1 2 trukket hvori R dg R er like eller forskjellige og betyr hydrogen, metyl, etyl, fenyl eller klor, R 3 betyr hydrogen, eller alkyl med 1-6 C-atomer, og R 4 betyr rettlinjet eller forgrenet ilkyl med 1-6 C-atomer, cykloalkyl med 3-8 C-atomer, fenylalkyl ned 1-4 C-atomer i alkyldelen og eventuelt i fenyldelen substituert med 1 eller 2 fluor, klor, brom, jod, trifluormetyl eller ilkyl med 1-4 C-atomer, eller betyr Ar, og hvori Ar betyr fenyl,Difenyl, fenoksyfenyl, fenyltiofenyl, 2- eller 3-tienyl, 2-iuryl, 2-, 3- eller 4-pyridyl som eventuelt kan være substituert ned 1, 2 eller 3 fluor, klor, brom, trifluormetyl, alkylgruppe ned 1-6 C-atomer eller cykloalkylgrupper med 3-6 C-atomer, eller slike hvori 1 2 drawn in which R dg R are the same or different and mean hydrogen, methyl, ethyl, phenyl or chlorine, R 3 means hydrogen, or alkyl of 1-6 C atoms, and R 4 means linear or branched alkyl of 1-6 C- atoms, cycloalkyl with 3-8 C atoms, phenylalkyl down 1-4 C atoms in the alkyl part and optionally in the phenyl part substituted with 1 or 2 fluorine, chlorine, bromine, iodine, trifluoromethyl or alkyl with 1-4 C atoms, or means Ar, and in which Ar means phenyl, diphenyl, phenoxyphenyl, phenylthiophenyl, 2- or 3-thienyl, 2-iuryl, 2-, 3- or 4-pyridyl which may optionally be substituted down 1, 2 or 3 fluorine, chlorine, bromine, trifluoromethyl, alkyl group down to 1-6 C atoms or cycloalkyl groups with 3-6 C atoms, or those in which
iar den til formel II angitte betydning. iar the meaning given to formula II.
Spesielt foretrukket er slike forbindelser med formel I hvori Particularly preferred are such compounds of formula I in which
* 1 og R 2 er like eller forskjellige, og betyr hydrogen, metyl siler etyl, R<3>betyr hydrogen eller alkyl med 1-6 C-atomer, R<4>3e tyr rettlinjet eller forgrenet alkyl med 1-6 C-atomer, cyklo-ilkyl med 5 eller 6 C-atomer, benzyl eller fenyletyl, eventuelt ;i fenylringen substituert med 1 eller 2 fluor, klor, trifluormetyl, metyl eller etyl, eller betyr Ar, og Ar betyr fenyl, fenoksyfenyl, fenyltiofenyl, 2- eller 3- tienyl, 2-furyl eller 3-pyridyl, eventuelt substituert med 1 eller 2 fluor, klor, trifluormetyl, metyl eller etyl. ;Imidlertid omfattes ikke de forbindelser med formel I hvori ;12 3 4 ;R , R og R betyr hydrogen, R fenyl og Ar betyr fenyl, 4-metyl-r fenyl eller 4-bromfenyl. Disse forbindelser er omtalt i Rev. Roum. Chim. 10, 641, (1965) og Rev, Med. Chir. 81, 469 ;(1977) og skal virke delvis antihypertensive. Derimot virker forbindelsen ifølge oppfinnelsen med formel I anxiolytiske og antikonvulsive. ;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 forbindelsen med formel I ;erkarakterisert vedat;a) en forbindelse med formel III; ; 12 3 4 ;hvori Ar, R , R , R og R har de til formel I angitte betydning, og Z betyr 0 eller S, cykliseres ved oppvarming eventuelt under tilsetning av et kondensasjonsmiddel til en forbindelse med formel I eller ;b) en forbindelse med formel IV; ; hvori R betyr klor, brom, eller metyltio, Ar, R og R har den ;med formel I angitte betydning, omsettes med et amin med formel ;V ; ; hvori R<3>og R<4>eventuelt sammen med N-atomet har de til formel I angitte betydninger, eller ;c) en forbindelse med formel VI, eller av dens salter; ; hvori Ar, R 1 og R 2har de til formel-1 angitte betydninger, ;omsettes med en forbindelse med formel VII; ; hvori R 4 har den tinder formel I angitte betydning, og Y;betyr en avspaltbar gruppe som f. eks. fluor, klor, brom,;Dod, _0_c_R3;eller tosylatresten, eventuelt under tilsetning av et kondensasjonsmiddel eller katalysator. ;Ved fremgangsmåte a) fåes utgangsstoffer med formel III, f. eks. ved omsetning av aryl-hydrazinopyridaziner med formel VIII ; ; hvori R 1 , R 2 og Ar har den under formel I angitte betydning,;med isocyanater eller isotiocyanater med formel IX;R<4->N=C-Z (IX);hvori R 4 og Z har den under formel I resp. III angitte betydning, ved oppvarming ved 40-150°C, hensiktsmessig i et oppløsnings-middel som f. eks. metanol, etanol, isopropanol, diisopropyleter, dioksan, tetrahydrofuran, toluen, metylenklorid, kloro- ;form, eller dikloretan.;Forbindelsene med formel III overføres til forbindelser med formel I ved oppvarming, f. eks. i et av de nevnte oppløsnings-midler ved 4 0-150°C eventuelt under tilsetning av et kondensasjonsmiddel, som f. eks. iseddik, cykloheksylkarbodiimid, 1-hydroksybenztriazol, fosforoksyklorid, fosforoksyklorid/N,N-dimetylanilin, fosforoksybromid, fosforpentaklorid, tionylklorid, kvikksølvoksyd, blyoksyd. Forbindelsen med den generelle formel III kan også ved omsetning av klorpyridaziner med ; 1 2 hvori Ar, R og R har den til formel I angitte betydning, med substituerte semikarbaziner eller tiosemikarbaziner med formel XI ; 3 4 ;hvori R , R og Z har den til formel I angitte betydning, ved oppvarming, f. eks. i et av de nevnte oppløsningsmidler eller i DMF, DMSO eller acetonitril ved 40-150°C. ;For fremgangsmåte b) fåes utgangsstoffer med formel IV ved oppvarming av arylhydrazinopyridaziner VIII med maursyre eller deres estere (til R = H), fosgen, klormaursyreestere med dialkylpyrokarbonat eller en dialkylkarbonat (til R<6>= OH) eller med svovelkarbon og alkali (til R^ = SH), eventuelt under tilsetning av et oppløsnings-og fortynningsmiddel som kloroform, toluen, dioksan, eddikester, vann, etanol til en forbindelse med formel IV, hvori R<6>betyr H, OH eller SH. ;Ved oppvarming med brom i iseddik/natriumacetat (ved R<6>= H) fosforoksyklorid (ved R<6>OH) med metyljodid eller dimetyl-sulfat (ved R = SH) fåes herav de tilsvarende forbindelser IV med R6 = Br, Cl, SCH3. ;Ifølge fremgangsmåte b) foregår omsetningen av forbindelsene med formel IV med aminer med formel V uten oppløsningsmiddel eller i et inert<*>oppløsningsmiddel som metanol, isopropanol, 2-metoksyetanol, tetrahydrofuran, dioksan, toluen, kloroform, * 1 and R 2 are the same or different, and mean hydrogen, methyl siler ethyl, R<3> means hydrogen or alkyl with 1-6 C atoms, R<4>3e means straight or branched alkyl with 1-6 C- atoms, cycloalkyl with 5 or 6 C atoms, benzyl or phenylethyl, optionally substituted in the phenyl ring with 1 or 2 fluorine, chlorine, trifluoromethyl, methyl or ethyl, or means Ar, and Ar means phenyl, phenoxyphenyl, phenylthiophenyl, 2 - or 3-thienyl, 2-furyl or 3-pyridyl, optionally substituted with 1 or 2 fluorine, chlorine, trifluoromethyl, methyl or ethyl. However, the compounds of formula I in which ;12 3 4 ;R , R and R mean hydrogen, R phenyl and Ar means phenyl, 4-methyl-r phenyl or 4-bromophenyl are not included. These compounds are discussed in Rev. Rome. Chim. 10, 641, (1965) and Rev, Med. Chir. 81, 469 ; (1977) and is supposed to be partially antihypertensive. In contrast, the compound according to the invention with formula I has anxiolytic and anticonvulsant effects. The object of the invention is also a method for the production of these compounds as well as pharmaceutical preparations of these compounds, and their use as medicine. The method for preparing the compound of formula I is characterized by: a) a compound of formula III; ; 12 3 4 ; in which Ar, R , R , R and R have the meanings specified for formula I, and Z means 0 or S, is cyclized by heating, optionally with the addition of a condensing agent to a compound of formula I or ;b) a compound with formula IV; ; in which R means chlorine, bromine or methylthio, Ar, R and R have the meaning given in formula I, are reacted with an amine of formula V; ; in which R<3> and R<4>, optionally together with the N atom, have the meanings specified for formula I, or ;c) a compound of formula VI, or of its salts; ; in which Ar, R 1 and R 2 have the meanings given to formula-1, ; is reacted with a compound of formula VII; ; in which R 4 has the meaning given in formula I, and Y; means a leasable group such as e.g. fluorine, chlorine, bromine,; Dod, _O_c_R3; or the tosylate residue, optionally with the addition of a condensing agent or catalyst. ;In method a) starting substances with formula III are obtained, e.g. by reacting aryl-hydrazinopyridazines with formula VIII; ; in which R 1 , R 2 and Ar have the meaning given under formula I,; with isocyanates or isothiocyanates of formula IX; R<4->N=C-Z (IX); in which R 4 and Z have the meaning under formula I resp. III meaning, when heated at 40-150°C, suitably in a solvent such as, for example methanol, ethanol, isopropanol, diisopropyl ether, dioxane, tetrahydrofuran, toluene, methylene chloride, chloroform, or dichloroethane.;The compounds of formula III are transferred to compounds of formula I by heating, e.g. in one of the mentioned solvents at 40-150°C, possibly with the addition of a condensation agent, such as glacial acetic acid, cyclohexylcarbodiimide, 1-hydroxybenztriazole, phosphorus oxychloride, phosphorus oxychloride/N,N-dimethylaniline, phosphorus oxybromide, phosphorus pentachloride, thionyl chloride, mercury oxide, lead oxide. The compound with the general formula III can also by reacting chloropyridazines with ; 1 2 in which Ar, R and R have the meaning indicated for formula I, with substituted semicarbazines or thiosemicarbazines of formula XI; 3 4 ; in which R , R and Z have the meaning specified for formula I, upon heating, e.g. in one of the aforementioned solvents or in DMF, DMSO or acetonitrile at 40-150°C. For method b) starting materials of formula IV are obtained by heating arylhydrazinopyridazines VIII with formic acid or their esters (to R = H), phosgene, chloroformic acid esters with dialkyl pyrocarbonate or a dialkyl carbonate (to R<6>= OH) or with carbon disulfide and alkali ( to R^ = SH), optionally with the addition of a solvent and diluent such as chloroform, toluene, dioxane, acetate, water, ethanol to a compound of formula IV, in which R<6> means H, OH or SH. By heating with bromine in glacial acetic acid/sodium acetate (when R<6>= H) phosphorus oxychloride (when R<6>OH) with methyl iodide or dimethyl sulfate (when R = SH) the corresponding compounds IV with R6 = Br, Cl, SCH3. According to method b) the reaction of the compounds of formula IV with amines of formula V takes place without a solvent or in an inert solvent such as methanol, isopropanol, 2-methoxyethanol, tetrahydrofuran, dioxane, toluene, chloroform,
DMF, DMSO, acetonitril, aceton eller eddiksyreetylester, ved temperaturer på 20-200°C, fortrinnsvis 50-150°C ved normal- DMF, DMSO, acetonitrile, acetone or acetic acid ethyl ester, at temperatures of 20-200°C, preferably 50-150°C at normal
trykk eller i autoklav under trykk. Reaksjonen med gass-pressure or in an autoclave under pressure. The reaction with gas-
formede aminer kan gjennomføres ved normaltrykk ved innføringen eller likeledes under trykk. Eventuelt kan det tilsettes en katalysator som kobber (I)-klorid eller andre Cu (I)-salter til aksellerering av reaksjonen. formed amines can be carried out at normal pressure at the introduction or likewise under pressure. Optionally, a catalyst such as copper (I) chloride or other Cu (I) salts can be added to accelerate the reaction.
Ved fremgangsmåte c) foregår omsetningen av forbindelsene med formel VI som f, eks. fåes ved cyklisering av arylhydrazinopyridaziner med formel VIII med klorcyan eller bromcyan med forbindelser med formel VII uten eller i nærvær av et oppløsnings-eller fortynningsmiddel, som f. eks. aceton, metyletylketon, eddiksyreetylester, toluen, xylen, dioksan, tetrahydrofuran, In method c), the conversion of the compounds of formula VI takes place as f, e.g. are obtained by cyclization of arylhydrazinopyridazines of formula VIII with cyanogen chloride or cyanogen bromide with compounds of formula VII without or in the presence of a solvent or diluent, such as e.g. acetone, methyl ethyl ketone, acetic acid ethyl ester, toluene, xylene, dioxane, tetrahydrofuran,
DMF, DMSO, acetonitril, metylenklorid, kloroform eller dikloretan. DMF, DMSO, acetonitrile, methylene chloride, chloroform or dichloroethane.
Eventuelt kan uorganisk eller organisk base som f. eks. natrium-hydroksyd, trietylamin eller pyridin tilsettes til binding av eventuelt ved reaksjonen dannede syrer, eller også ved reaksjonen med syreanhydrider tilsettes katalytiske mengder av en sterk syre, som f. eks. saltsyre, svovelsyre eller trifluoreddiksyre. Optionally, inorganic or organic base such as e.g. sodium hydroxide, triethylamine or pyridine is added to bind any acids formed during the reaction, or catalytic amounts of a strong acid are added during the reaction with acid anhydrides, such as e.g. hydrochloric acid, sulfuric acid or trifluoroacetic acid.
Arylhydrazinopyridaziner med formel VIII er eksempelvis kjentArylhydrazinopyridazines of formula VIII are known, for example
fra J. Heterocyclic Chem. 15, 881 (1978) eller kan fremstilles av klorforbindelse med formel X med hydrazinhydrat eller littera-turkjente 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 klorforbindelser X og dens fortrinn. from J. Heterocyclic Chem. 15, 881 (1978) or can be prepared from chlorine compound of formula X with hydrazine hydrate or methods known in the literature (The Chemistry of Heterocyclic Compounds, vol, 28 Pyridazines, Editors, A. Weissberger and E. C. Taylor, John Wiley, New York. 1973) . Both literature citations also refer to the production of chlorine compounds X and its advantages.
Når forbindelsene med formel I etter de omtalte fremgangsmåter fåes som salter, så kan herav med ammoniakk, aminer eller hydroksyder den tilhørende base frigjøres. De for baser med formel I kan med fysiologisk tålbare syrer overføres i de til- When the compounds of formula I are obtained as salts according to the described methods, the corresponding base can be released from this with ammonia, amines or hydroxides. Those for bases of formula I can be transferred with physiologically tolerable acids in the
svarende salter. Som syrer kommer det i betraktning uorga-corresponding salts. As acids, inorganic
niske eller organiske syrer som klor- eller bromhydrogensyre, fosforsyre, eddiksyre, benzosyre, sitronsyre, maleinsyre, fumarsyre, melkesyre, vinsyre, ravsyre, acetylglycin. basic or organic acids such as hydrochloric or bromic acid, phosphoric acid, acetic acid, benzoic acid, citric acid, maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, acetylglycine.
Forbindelsen ifølge oppfinnelsen med formel I er egnet til fremstilling av legemidler. Legemidlene kan inneholde en eller flere av forbindelsene ifølge oppfinnelsen eller blandinger herav, med andre farmasøytiske virksomme stoffer. Til fremstilling av legemidlene, kan det anvendes vanlige farmasøytiske bære- The compound according to the invention with formula I is suitable for the production of pharmaceuticals. The medicines may contain one or more of the compounds according to the invention or mixtures thereof, with other pharmaceutical active substances. For the production of the medicines, common pharmaceutical carriers can be used
og hjelpestoffer og kjente galeniske fremgangsmåter. Legemidlene kan anvendes enteralt, parenteralt, oralt eller per-lingualt. Eksempelvis kan administrering foregå i form av and excipients and known galenic procedures. The drugs can be used enterally, parenterally, orally or per-lingually. For example, administration can take place in the form of
tabletter, kapsler, piller, drageer, tapper, geleer, kremer, pudder, liquida, støvningspulvere eller a.erosoler. Som liquida kommer det eksempelvis på tale.: Oljeaktige eller vandige oppløsninger eller suspensjoner og emulsjoner, injiserbare oppløsninger eller suspensjoner. tablets, capsules, pills, dragees, drops, gels, creams, powders, liquids, dusting powders or a. aerosols. Liquids include, for example: Oily or aqueous solutions or suspensions and emulsions, injectable solutions or suspensions.
Forbindelsen ifølge oppfinnelsen kan dessuten finne anvendelse som mellomprodukter til fremstilling av andre legemidler. The compound according to the invention can also find use as intermediate products for the production of other medicinal products.
Som forbindelser ifølge oppfinnelsen skal det nevnes:As compounds according to the invention, the following should be mentioned:
(for stamnavnet "1, 2,4-triazolo /~4,3-b7pyridazin" anvendes(for the generic name "1, 2,4-triazolo/~4,3-b7pyridazine" is used
i det følgende forkortelsen "TP"). hereinafter the abbreviation "TP").
6-(3-fluor fenyl)-3-fenylamino-TP6-(3-fluorophenyl)-3-phenylamino-TP
6-(4-fluorfenyl)-3-fenylamino-TP 6-(4-fluorophenyl)-3-phenylamino-TP
6-(3-trifluormetylfenyl)-3-fenylamino-TP 6-(3-trifluoromethylphenyl)-3-phenylamino-TP
6-(3,4-difluorfenyl)-3-fenylamino-TP 6-(3,4-difluorophenyl)-3-phenylamino-TP
6-(4-fenoksyfenyl)-3-fenylamino-TP 6-(4-phenoxyphenyl)-3-phenylamino-TP
6-(4-fenyltiofenyl)-3-fenylamino-TP 6-(4-phenylthiophenyl)-3-phenylamino-TP
6-(4-(4-fluorfenoksy)fenyl)-3-fenylamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-phenylamino-TP
6-(3-klorfenyl)-3-fenylamino-TP6-(3-chlorophenyl)-3-phenylamino-TP
6-(3-bromfenyl)-3-fenylamino-TP 6-(3-bromophenyl)-3-phenylamino-TP
6-(5-klor-2-tienyl)-3-fenylamino-TP6-(5-chloro-2-thienyl)-3-phenylamino-TP
6-(3-fluorfenyl)-3(subst. fenylamino)-TP 6-(3-fluorophenyl)-3(subst. phenylamino)-TP
6-(4-fluorfenyl)-3-(subst, fenylamino)-TP 6-(4-fluorophenyl)-3-(subst, phenylamino)-TP
6-(3-trifluormetylfenyl)-3-(subst. fenylamino)-TP 6-(3,4-difluorfenyl)-3-(subst. fenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(subst. phenylamino)-TP 6-(3,4-difluorophenyl)-3-(subst. phenylamino)-TP
6-(4-fenoksyfenyl)-3-(subst, fenylamino)-TP 6-(4-phenoxyphenyl)-3-(subst, phenylamino)-TP
6-(4-fenyltiofenyl)-3-(subst. fenylamino)-TP 6-(4-phenylthiophenyl)-3-(subst. phenylamino)-TP
6-(4-(4-fluorfenoksy)fenyl)-3-(subst. fenylamino)-TP 6-(3-klorfenyl)-3-(subst. fenylamino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(subst. phenylamino)-TP 6-(3-chlorophenyl)-3-(subst. phenylamino)-TP
6-(3-bromfenyl)-3-(subst. fenylamino)7TP 6-(3-bromophenyl)-3-(subst. phenylamino)7TP
6-(5-klor-2-tienyl)-3-(subst, fenylamino)-TP.6-(5-chloro-2-thienyl)-3-(subst, phenylamino)-TP.
hvori "subst, fenyl" spesielt betyr 2,3- eller 4-fluorfenyl, 2-, 3- eller 4-klorfenyl, 2-, 3- eller 4-bromfenyl, 2-, 3-eller 4-trifluormetylfenyl, 3,4-diklor- eller 3,4-difluorfenyl, 2,4-diklor-,eller 2,4-difluorfenyl, 2,5-diklor- eller 2,5-difluorfenyl, 3,5-diklor- eller 3,5-difluorfenyl, 2,6-diklor- eller 2,6-difluorfenyl. wherein "subst, phenyl" specifically means 2,3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4 -dichloro- or 3,4-difluorophenyl, 2,4-dichloro- or 2,4-difluorophenyl, 2,5-dichloro- or 2,5-difluorophenyl, 3,5-dichloro- or 3,5-difluorophenyl, 2,6-dichloro- or 2,6-difluorophenyl.
6-(3-fluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-fluorophenyl)-3-(N-methyl-N-phenylamino)-TP
6-(4-fluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fluorophenyl)-3-(N-methyl-N-phenylamino)-TP
6-(3-trifluormetylfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3,4-difluorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fenoksyfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fenyltiofenyl)-3-(N-metyl-N-fenylamino)-TP 6-(4-fluorfenoksyfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-klorfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(N-methyl-N-phenylamino)-TP 6-(3,4-difluorophenyl)-3-(N-methyl-N-phenylamino)-TP 6-(4-phenoxyphenyl) )-3-(N-methyl-N-phenylamino)-TP 6-(4-phenylthiophenyl)-3-(N-methyl-N-phenylamino)-TP 6-(4-fluorophenoxyphenyl)-3-(N-methyl -N-phenylamino)-TP 6-(3-chlorophenyl)-3-(N-methyl-N-phenylamino)-TP
6-(3- bromfenyl)-3-(N-metyl-N-fenylamino)-TP 6-(3-bromophenyl)-3-(N-methyl-N-phenylamino)-TP
6-(5-klor-2-tienyl)-3-(N-metyl-N-metyl-N-fenylamino)-TP 6-(3-fluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3-trifluormetylfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3,4-difluorfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fenoksyfenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-fenyltiofenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(4-(4-fluorfenoksy)fenyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(3-klorfenyl)-3-(N-metyl-N-subst. fenylamino) 6-(3-bromfenyl)-3-(N-metyl-N- subst, fenylamino)-TP 6-(5-klor-2-tienyl)-3-(N-metyl-N-subst. fenylamino)-TP 6-(5-chloro-2-thienyl)-3-(N-methyl-N-methyl-N-phenylamino)-TP 6-(3-fluorophenyl)-3-(N-methyl-N-subst. phenylamino) -TP 6-(4-fluorophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(3-trifluoromethylphenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6- (3,4-difluorophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4-phenoxyphenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4 -phenylthiophenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(N-methyl-N-subst. phenylamino)-TP 6-( 3-chlorophenyl)-3-(N-methyl-N-subst. phenylamino) 6-(3-bromophenyl)-3-(N-methyl-N- subst. phenylamino)-TP 6-(5-chloro-2- thienyl)-3-(N-methyl-N-subst. phenylamino)-TP
hvori "subst.fenyl" spesielt betyr 2-, 3- eller 4-fluorfenyl, wherein "subst.phenyl" specifically means 2-, 3- or 4-fluorophenyl,
2-, 3- eller 4-klorfenyl, 2-, 3- eller 4-bromfenyl, 2-, 3- eller 4-trifluormetylfenyl, 3,4-diklor- eller 3,4-difluorfenyl, 2,4-diklor- eller 2,4-difluorfenyl, 2,5-diklor- eller 2,5-difluorfenyl, 3,5-diklor- eller 3,5-difluorfenyl, 2,6-diklor eller 2,6-difluorfenyl. 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-trifluoromethylphenyl, 3,4-dichloro- or 3,4-difluorophenyl, 2,4-dichloro- or 2,4-difluorophenyl, 2,5-dichloro- or 2,5-difluorophenyl, 3,5-dichloro- or 3,5-difluorophenyl, 2,6-dichloro or 2,6-difluorophenyl.
6-(3-flurofenyl)-3-acetamino-TP 6-(3-Fluorophenyl)-3-acetamino-TP
6-(4-fluorfenyl)-3-acétamino-TP 6-(4-fluorophenyl)-3-acetamino-TP
6-(3-trifluormetylfenyl)-3-acetamino-TP 6-(3-trifluoromethylphenyl)-3-acetamino-TP
6-(3,4-difluorfenyl)-3-acetamino-TP 6-(3,4-difluorophenyl)-3-acetamino-TP
6-(4-fenoksyfenyl)-3-acetamino-TP 6-(4-phenoxyphenyl)-3-acetamino-TP
6-(4-fenyltiofenyl)3-acetamino-TP 6-(4-phenylthiophenyl)3-acetamino-TP
6-(4-(4-fluorfenoksy)fenyl)-3-acetamino-TP 6-(3-klorfenyl)-3-acetamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-acetamino-TP 6-(3-chlorophenyl)-3-acetamino-TP
6-(3-bromfenyl)-3-acetamino-TP 6-(3-Bromophenyl)-3-acetamino-TP
6-(5-klor-2-tienyl)-3-acetamino-TP 6-(5-Chloro-2-thienyl)-3-acetamino-TP
6-(3-fluorfenyl)-3-benzoylamino-TP 6-(3-fluorophenyl)-3-benzoylamino-TP
6-(4-fluorfenyl)-3-benzoylamino-TP 6-(4-fluorophenyl)-3-benzoylamino-TP
6-(3-trifluormetylfenyl)-3-benzoylamino-TP 6-(3,4-difluorfenyl)-3-benzoylamino-TP 6-(3-trifluoromethylphenyl)-3-benzoylamino-TP 6-(3,4-difluorophenyl)-3-benzoylamino-TP
6-(4-fenoksyfenyl)-3-benzoylamino-TP 6-(4-phenoxyphenyl)-3-benzoylamino-TP
6-(4-fenyltiofenyl)-3-benzoylamino-TP 6-(4-phenylthiophenyl)-3-benzoylamino-TP
6-(4-(4-fluorfenoksy)fenyl)-3-benzoylamino-TP 6-(3-klorfenyl)-3-benzoylamino-TP 6-(4-(4-fluorophenoxy)phenyl)-3-benzoylamino-TP 6-(3-chlorophenyl)-3-benzoylamino-TP
6-(3-bromfenyl)-3-benzoylamino-TP 6-(3-Bromophenyl)-3-benzoylamino-TP
6-(5-klor-2-tienyl)-3-benzoylamino-TP 6-(5-Chloro-2-thienyl)-3-benzoylamino-TP
6-(3-fluorfenyl)-3-subst. benzoylamino)-TP 6-(4-fluorfenyl)-3-(subst. benzoylamino)-TP 6- (3-trif luormetylf enyl )-3-( subst. benzoylamino) -TP 6-(3,4-difluorfenyl)-3-(subst. benzoylamino)-TP 6-(4-fenoksyfenyl)-3-(subst, benzoylamino)-TP 6-(4-fenyltiofenyl)-3-(subst, benzoylamino)-TP 6-(4-(4-fluorfenoksy)fenyl)-3-(subst. benzoylamino)-TP 6-(3-klorfenyl)-3-(subst. benzoylamino)-TP 6-(3-bromfenyl)-3-(subst, benzoylamino)-TP 6-(5-klor-2-tienyl)-3-(subst, benzoylamino)-TP 6-(3-fluorophenyl)-3-subst. benzoylamino)-TP 6-(4-fluorophenyl)-3-(subst. benzoylamino)-TP 6-(3-trifluoromethylphenyl)-3-(subst. benzoylamino)-TP 6-(3,4-difluorophenyl)- 3-(subst. benzoylamino)-TP 6-(4-phenoxyphenyl)-3-(subst, benzoylamino)-TP 6-(4-phenylthiophenyl)-3-(subst, benzoylamino)-TP 6-(4-(4 -fluorophenoxy)phenyl)-3-(subst. benzoylamino)-TP 6-(3-chlorophenyl)-3-(subst. benzoylamino)-TP 6-(3-bromophenyl)-3-(subst, benzoylamino)-TP 6 -(5-chloro-2-thienyl)-3-(subst, benzoylamino)-TP
hvori "subst, benzoyl" spesielt betyr 2-, 3- eller 4-fluorbenzoyl, wherein "subst, benzoyl" specifically means 2-, 3- or 4-fluorobenzoyl,
2- , 3- eller 4-klorbenzoyl, 2-, 3- eller 4-brombenzoyl, 2-,2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-bromobenzoyl, 2-,
3- eller 4-trifluormetylbenzoyl, 3,4-diklor- eller 3,4-difluorbenzoyl, 2,5-diklor- eller 2,5-difluorbenzoyl, 3,5-diklor- eller 3,5-difluorbenzoyl, 3,5-diklor- eller 3,5-difluorbenzoyl, 2,6-diklor- eller 2,6-difluorbenzoyl. 3- or 4-trifluoromethylbenzoyl, 3,4-dichloro- or 3,4-difluorobenzoyl, 2,5-dichloro- or 2,5-difluorobenzoyl, 3,5-dichloro- or 3,5-difluorobenzoyl, 3,5- dichloro- or 3,5-difluorobenzoyl, 2,6-dichloro- or 2,6-difluorobenzoyl.
6-(3-fluorfenyl)-3-(subst. amino)-TP6-(3-fluorophenyl)-3-(subst. amino)-TP
6-(4-fluorfenyl)-3-(subst, amino)-TP 6-(4-Fluorophenyl)-3-(subst,amino)-TP
6-(3-trifluormetylfenyl)-3-(subst, amino)-TP 6-(3-trifluoromethylphenyl)-3-(subst,amino)-TP
6-(3,4-difluorfenyl)-3-(subst. amino)-TP 6-(3,4-difluorophenyl)-3-(subst. amino)-TP
6-(4-fenoksyfenyl)-3-(subst. amino)-TP6-(4-phenoxyphenyl)-3-(subst. amino)-TP
6 -(4-fenyltiofenyl)-3-subst. amino)-TP 6 -(4-phenylthiophenyl)-3-subst. amino)-TP
6-(4-(4-fluorfenoksy)fenyl)-3-(subst, amino)-TP 6-(4-(4-fluorophenoxy)phenyl)-3-(subst,amino)-TP
6-(3-klorfenyl)-3-(subst, amino)-TP6-(3-chlorophenyl)-3-(subst,amino)-TP
6-(3-bromfenyl)-3-(subst, amino)-TP6-(3-bromophenyl)-3-(subst,amino)-TP
6-(5-klor-2-tienyl)-3-(subst, amino)-TP6-(5-chloro-2-thienyl)-3-(subst,amino)-TP
hvori "subst, amino" spesielt betyr dimetylamino, dietylamino, 1-pyrrolidinyl, piperidino, morfolino, tiomorfolino, 1-piperazinyl, 4-metyl-l-piperazinyl, 4-fenylpiperidino, 4-fenyl-l-piperazinyl, 4-piperidon-l-yl, 4-etoksykarbonyl-l-piperazinyl. wherein "subst, amino" specifically means dimethylamino, diethylamino, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl, 4-methyl-l-piperazinyl, 4-phenylpiperidino, 4-phenyl-l-piperazinyl, 4-piperidone- 1-yl, 4-ethoxycarbonyl-1-piperazinyl.
Forbindelsene med formel I ifølge oppfinnelsen virker på sentral-nervesystemet, spesielt virker de anxiolytisk og antikonvulsiv. Som indikasjoner kommer det derfor i betraktning søvnløshet, opphisselse og vegetativ depresjon. The compounds of formula I according to the invention act on the central nervous system, in particular they act anxiolytic and anticonvulsant. Insomnia, agitation and vegetative depression are therefore taken into consideration as indications.
De farmasøytiske tilberedninger inneholder vanligvis mellomThe pharmaceutical preparations usually contain between
1 til 10 % den eller de ifølge oppfinnelsen aktive komponenter. 1 to 10% of the active component(s) according to the invention.
Den anxiolytiske virkning av forbindelsene med formel V erThe anxiolytic effect of the compounds of formula V is
fulgt av en meget liten sedering og tålbarhet (LD_r> un i.a. >300 mg/ kg i.p. på mus). Dette fremgår av undersøkelser, hvor det ble målt innvirkningen av forbindelsen ifølge oppfinnelsen på followed by very little sedation and tolerability (LD_r> un i.a. >300 mg/ kg i.p. in mice). This is evident from investigations, where the impact of the compound according to the invention was measured on
den motoriske aktivitet, heksobarbital-narkose og cardiazol-krampe hos mus. Dessuten ble det anvendt Celler-anxiolyse- the motor activity, hexobarbital anesthesia and cardiazole convulsion in mice. In addition, Celler anxiolysis was used
prøve samt Lick-Shock-prøve på rotter.test as well as the Lick-Shock test on rats.
Den laveste allerede virksomme dosis i de overnevnte forsøkThe lowest already effective dose in the above trials
j; j;
er eksempelvis 5 mg/kg oral, 2,5 mg/kg sublingual, 1 mg/kg intravenøs. Som generelt dosisområde for virkning (dyre-forsøk som måleform) kommer det eksempelvis på tale: 5 til 50 mg/kg oralt, 2,5 til 25 mg/kg sublingualt, 1 til 10 mg/kg intravenøs. is, for example, 5 mg/kg oral, 2.5 mg/kg sublingual, 1 mg/kg intravenous. As a general dose range for effect (animal experiments as a form of measurement), the following are for example: 5 to 50 mg/kg orally, 2.5 to 25 mg/kg sublingually, 1 to 10 mg/kg intravenously.
Eksempelvis kan det appliseres tre ganger daglig 1 til 3 For example, it can be applied three times a day 1 to 3
tabletter med et innhold fra 10 til 100 mg virksomt stoff, eller eksempelvis ved intravenøs injeksjon 1 til 3 ganger daglig en ampulle fra 2 til 4 ml innhold med 0,5 til 5 mg stoff. tablets with a content of 10 to 100 mg of active substance, or for example by intravenous injection 1 to 3 times a day an ampoule of 2 to 4 ml content with 0.5 to 5 mg of substance.
Eksempel 1 Example 1
3-cykloheksylamino-6-fenyl-1,2,4-triazolo^ 4,3-b7pyradizin-hydroklorid 5 g 3-hydrazino-6-fenylpyridazin (formel VIII, sm.p. 146°C) oppløses varmt i 50 ml etanol og blandes med 3,8 g cykloheksyl-isotiocyanat. Man omrører 2 timer under tilbakeløp og avkjøler til 0°C, frasuger, vasker med etanol og tørker. Det dannede mellomprodukt (formel III Z = S) oppvarmes med 6,1 g dicykloheksylkarbodiimid i 50 ml 2-metoksyetanol i 5 timer under til-bakeløp. Reaksjonsoppløsningen inndampes under nedsatt trykk til tørrhet, og krystalliseres to ganger fra isopropanol. Ved blanding med etanolisk saltsyre får man hydrokloridet som frasuges, vaskes med vann og tørkes. Sm.p. 268°C. 3-cyclohexylamino-6-phenyl-1,2,4-triazolo^4,3-b7pyridazine hydrochloride 5 g of 3-hydrazino-6-phenylpyridazine (formula VIII, m.p. 146°C) are dissolved hot in 50 ml of ethanol and mixed with 3.8 g of cyclohexyl isothiocyanate. The mixture is stirred for 2 hours under reflux and cooled to 0°C, filtered off with suction, washed with ethanol and dried. The intermediate product formed (formula III Z = S) is heated with 6.1 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 5 hours under reflux. The reaction solution is evaporated under reduced pressure to dryness, and crystallized twice from isopropanol. By mixing with ethanolic hydrochloric acid, the hydrochloride is obtained which is sucked off, washed with water and dried. Sm.p. 268°C.
Eksempel 2 Example 2
3- benzylamino- 6- fenyl- 1, 2, 4- triazolo/~ 4, 3- b7pydidazin- hydroklorid 8 g 3-hydrazino-6-fenylpyridazin oppløses varmt i 70 ml etanol blandes med 7 g benzylisotiocyanat og omrøres i 1 time under tilbakeløp. Mellomtrinnet (formel III, Z = S) frasuges etter avkjøling, vaskes med etanol, tørkes og oppvarmes deretter med 8,9 g dicykloheksylkarbodiimid i 50 ml 2-metoksyetanol i 5 3- benzylamino- 6- phenyl- 1, 2, 4- triazolo/~ 4, 3- b7pydidazine hydrochloride 8 g of 3-hydrazino-6-phenylpyridazine are dissolved hot in 70 ml of ethanol, mixed with 7 g of benzyl isothiocyanate and stirred for 1 hour under backflow. The intermediate step (formula III, Z = S) is filtered off with suction after cooling, washed with ethanol, dried and then heated with 8.9 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 5
timer under tilbakeløp.hours during reflux.
Etter inndampning blånes med etanolisk saltsyre, inndampes og omkrystalliseres en gang fra iseddik og en gang fra toluen, og vaskes med diisopropyleter. Sm.p. 236°C under spaltning. After evaporation, blue with ethanolic hydrochloric acid, evaporate and recrystallize once from glacial acetic acid and once from toluene, and wash with diisopropyl ether. Sm.p. 236°C during decomposition.
Eksempel 3 Example 3
6-(4-fluorfenyl)-3-metylamino-l,2,4-triazolo/~4,3-b/pyridazin-hydroklorid 6-(4-Fluorophenyl)-3-methylamino-1,2,4-triazolo[4,3-b]pyridazine hydrochloride
Til 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin (formel VIII, sm.p. 1940C) i 40 ml kokende dioksan dryppes 1,65 ml metyliso-cyanat i 10 ml dioksan. Man oppvarmer ennå 2 timer til til-bakeløp, inndamper oppløsningen under nedsatt trykk, utrører med etanol, frasuger og tørker. Mellomproduktet (formel III, To 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine (formula VIII, m.p. 1940C) in 40 ml of boiling dioxane, 1.65 ml of methyl isocyanate in 10 ml of dioxane are added dropwise. It is heated for a further 2 hours to reflux, the solution is evaporated under reduced pressure, stirred with ethanol, filtered off with suction and dried. The intermediate (formula III,
Z = 0) oppvarmes med fosforoksyklorid 4 timer til tilbakeløp. Reaksjonsoppløsningen hydrolyseres forsiktig med is. Det ut-felte hydroklorid av produktet frasuges, vaskes med vann, utkokes med ispropanol, frasuges og tørkes. Sm.p. 2 97°C. Z = 0) is heated with phosphorus oxychloride for 4 hours to reflux. The reaction solution is carefully hydrolysed with ice. The precipitated hydrochloride of the product is suctioned off, washed with water, boiled off with isopropanol, suctioned off and dried. Sm.p. 2 97°C.
Eksempel 4 Example 4
6-( 4- fluorfenyl)- 4- fenylamino- 1, 2, 4- triazolo/~ 4, 3- b7pyridazin 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin og 3,7 g fenyliso-tiocyanat omrøre.s i 50 ml etanol i 3 timer .under tilbakeløp. Etter avkjøling frasuges mellomproduktet, (formel III, Z = S) vaskes med etanol, tørkes, smeltepunkt 223°C under sintring. 6-(4-Fluorophenyl)-4-phenylamino-1,2,4-triazolo/~4,3-b7pyridazine 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine and 3.7 g of phenylisothiocyanate stir.s 50 ml of ethanol for 3 hours under reflux. After cooling, the intermediate product is sucked off, (formula III, Z = S) washed with ethanol, dried, melting point 223°C during sintering.
7,5 g av dette mellomprodukt oppvarmes med 5 g dicykloheksylkarbodiimid i 5 0 ml 2-metoksyetanol i 2 timer under tilbakeløp. Den ved avkjøling dannede utfelling frasuges, vaskes med etanol og om krystalliseres fra isopropanol, sm.p. 265°C. 7.5 g of this intermediate product are heated with 5 g of dicyclohexylcarbodiimide in 50 ml of 2-methoxyethanol for 2 hours under reflux. The precipitate formed by cooling is suctioned off, washed with ethanol and recrystallized from isopropanol, m.p. 265°C.
Eksempel 5 Example 5
3-(4-klorfenylamino)-6-(4-fluorfenyl)-1,2,4-triazolo^~4,3-b/ pyridazin 3-(4-chlorophenylamino)-6-(4-fluorophenyl)-1,2,4-triazolo^~4,3-b/ pyridazine
Til 5 g 3-(4-fluorfenyl)-6-hydrazinopyridazin i 40 ml dioksan drypper man 4,1 g 4-klorfenylisocyanat oppløst i 15 ml dioksan og oppvarmer 2,5 timer under tilbakeløp. Etter avkjøling frasuger man, vasker med isopropanol, tørker, sm.p. 223°C. To 5 g of 3-(4-fluorophenyl)-6-hydrazinopyridazine in 40 ml of dioxane, 4.1 g of 4-chlorophenyl isocyanate dissolved in 15 ml of dioxane is added dropwise and heated under reflux for 2.5 hours. After cooling, vacuum off, wash with isopropanol, dry, m.p. 223°C.
5 g av dette mellomprodukt (formel III, Z = 0) oppvarmes 4 05 g of this intermediate product (formula III, Z = 0) is heated to 4 0
ml tørr toluen med 3,5 ml N,N-dimetylanilin og 1,4 ml fosforoksyklorid i 3 timer under tilbakeløp. Etter avkjøling avdekanteres toluenet og gjenblivende oljeaktig residu utrøresmed 2- n HCl. Man frasuger det faste stoff (hydroklorid, sm.p. ml of dry toluene with 3.5 ml of N,N-dimethylaniline and 1.4 ml of phosphorus oxychloride for 3 hours under reflux. After cooling, the toluene is decanted and the remaining oily residue is stirred with 2-n HCl. The solid substance (hydrochloride, m.p.
286°C) koker opp med halvkonsentrert ammoniakk og frasuger basen etter avkjøling og omkrystal liser er. fra isopropanol, sm.p. 257°C. 286°C) boils with semi-concentrated ammonia and sucks off the base after cooling and recrystallisation. from isopropanol, m.p. 257°C.
Eksempel 6 Example 6
3- (3-fluorfenylamino)-6-(3-trifluormetylfenyl)-1,2,4-triazolo / 4, 3- b7 pyridazin 5 g 3-hydrazino-6-(3-trifluormetylfenyl)-pyridazin (formel VIII, sm.p. 167°C) oppvarmes i 40 ml etanol til ca. 50°C. Man tildrypper 3,3 g 3-fluorfenylisotiocyanat oppløst i 10 ml etanol oppvarmer 3 timer til tilbakeløp, og frasuger etter avkjøling den dannede utfelling. Etter vasking med etanol og tørkning, oppvarmes 6 g av mellomproduktet (formel III, Z = S) sm.p. 3-(3-fluorophenylamino)-6-(3-trifluoromethylphenyl)-1,2,4-triazolo / 4,3- b7 pyridazine 5 g 3-hydrazino-6-(3-trifluoromethylphenyl)-pyridazine (formula VIII, sm .p. 167°C) is heated in 40 ml of ethanol to approx. 50°C. 3.3 g of 3-fluorophenyl isothiocyanate dissolved in 10 ml of ethanol is added dropwise, heated to reflux for 3 hours, and after cooling the formed precipitate is filtered off with suction. After washing with ethanol and drying, 6 g of the intermediate product (formula III, Z = S) is heated m.p.
164°C i 40 ml toluen med 3,8 ml N,N-dimetylanilin og 1,5 ml fosforoksyklorid i 3 timer under tilbakeløp. Etter avkjøling avdekanteres toluenfasen og det gjenblivende oljeaktige residu utrøres med 2-n HCl. Det derved dannede faste stoff (hydroklorid)'' suges fra, kokes opp med halvkonsentrert ammoniakk, frasuges koldt (base). Etter omkrystallisering fra iseddik/vann, sm.p. 209°C. 164°C in 40 ml of toluene with 3.8 ml of N,N-dimethylaniline and 1.5 ml of phosphorus oxychloride for 3 hours under reflux. After cooling, the toluene phase is decanted and the remaining oily residue is stirred with 2-n HCl. The resulting solid (hydrochloride)'' is sucked off, boiled with semi-concentrated ammonia, sucked off cold (base). After recrystallization from glacial acetic acid/water, m.p. 209°C.
Eksempel 7 Example 7
3- (4-fluorfenylamino)-6-(4-fenyltio-fenyl)-1,2,4-triazolo / 4, 3- b/ pyridazin- hydroklorid 3-(4-fluorophenylamino)-6-(4-phenylthio-phenyl)-1,2,4-triazolo / 4, 3-b/ pyridazine hydrochloride
5 g 3-hydrazino-6-(4-fenyltio-fenyl) pyridazin (formel VIII,5 g of 3-hydrazino-6-(4-phenylthio-phenyl)pyridazine (formula VIII,
sm.p. 142°C ) oppvarmes i 40 ml etanol til tilbakeløp. Man tildrypper 2,9 g 4-fluorfenylisotiocyanat i 10 ml etanol langsomt, og oppvarmer til sammen 3 timer under tilbakeløp. sm.p. 142°C ) is heated in 40 ml of ethanol to reflux. 2.9 g of 4-fluorophenyl isothiocyanate in 10 ml of ethanol are slowly added dropwise and heated under reflux for a total of 3 hours.
Etter avkjøling frasuges utfellingen, vaskes med etanol og tørk-es, sm.p. 188°C. 6 g av dette mellomprodukt (formel III, Z = After cooling, the precipitate is suctioned off, washed with ethanol and dried, m.p. 188°C. 6 g of this intermediate (formula III, Z =
S) omrøres med 3 g dicykloheksylkarbodiimid i 40 ml 2-metoksy- S) is stirred with 3 g of dicyclohexylcarbodiimide in 40 ml of 2-methoxy-
etanol i 5 timer under tilbakeløp. Etter avkjøling fra-ethanol for 5 hours under reflux. After cooling from
suger man og vasker med isopropanol. Utfellingen kokes opp med etanolisk saltsyre, inndampes, frasuges, vaskes med eta- vacuum and wash with isopropanol. The precipitate is boiled with ethanolic hydrochloric acid, evaporated, filtered off with suction, washed with ethanol
nol og tørkes, sm.p. 263°C.nol and dried, m.p. 263°C.
Analogt eksempel 1-7 kan det fremstilles følgende forbindelser Stamnavnet "1,2,4-triazolo/ 4,3-b7pyridazin" forkortes i det følgende som "TP". Analogous to examples 1-7, the following compounds can be prepared. The generic name "1,2,4-triazolo/4,3-b7pyridazine" is abbreviated in the following as "TP".
8. 3-metylamino-6-fenyl-TP-HCl, sm.p. 254°C.8. 3-methylamino-6-phenyl-TP-HCl, m.p. 254°C.
9. 3-propylamino-6-fenyl-TP-HCl, sm.p. 206°C9. 3-propylamino-6-phenyl-TP-HCl, m.p. 206°C
10. 3-heksylamino-6-fenyl-TP-HCl, sm.p. 164°C.10. 3-hexylamino-6-phenyl-TP-HCl, m.p. 164°C.
11. 3-(3-fluorfenylamino)-6-fenyl-TP-HCl, sm.p. 266°C under spaltning . 11. 3-(3-fluorophenylamino)-6-phenyl-TP-HCl, m.p. 266°C during decomposition.
12. 3-(4-fluorfenylamino)-6-fenyl-TP-HCl, sm.p. 265°C.12. 3-(4-fluorophenylamino)-6-phenyl-TP-HCl, m.p. 265°C.
13. 3-(3-klor fenylamino)-6-fenyl-TP-HCl, sm.p. 260°C under spaltning. 14. 3-(4-klorfenylamino)-6-fenyl-TP-HCl sm.p. 258°C under spaltning . 13. 3-(3-Chlorophenylamino)-6-phenyl-TP-HCl, m.p. 260°C during decomposition. 14. 3-(4-chlorophenylamino)-6-phenyl-TP-HCl m.p. 258°C during decomposition.
15. 3-(3-trifluormetylfenylamino)-6-fenyl-TP-HCL, sm.p.245°C.15. 3-(3-trifluoromethylphenylamino)-6-phenyl-TP-HCL, mp 245°C.
16. 3-propylamino-6-(4-fluorfenyl)-TP-HC1, sm.p. 241°C.16. 3-propylamino-6-(4-fluorophenyl)-TP-HC1, m.p. 241°C.
17. 3-cykloheksylamino-6-(4-fluorfenyl)-TP-HCl, 262°C under spaltning . 17. 3-cyclohexylamino-6-(4-fluorophenyl)-TP-HCl, 262°C during decomposition.
18. 3-(3-klorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 250°C.18. 3-(3-chlorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 250°C.
19. 3-(3,4-diklorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 289-290°C. 19. 3-(3,4-dichlorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 289-290°C.
20. 3-(2-fluorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 242°C.20. 3-(2-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 242°C.
21. 3-(3-fl,uorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 260-262°C. 22. 3-(4-fluorfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 282-284°C. 21. 3-(3-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 260-262°C. 22. 3-(4-fluorophenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 282-284°C.
23. 3-(4-metylfenylamino)-6-(4-fluorfenyl)-TP-HCl, sm.p. 312°C.23. 3-(4-methylphenylamino)-6-(4-fluorophenyl)-TP-HCl, m.p. 312°C.
24. 3-(3-cyanofenylamino)-6-(4-fluorfenyl)-TP-HCl sm.p. 312°C.24. 3-(3-cyanophenylamino)-6-(4-fluorophenyl)-TP-HCl m.p. 312°C.
25. 3-(3-trifluormetylfenylamino)-6-(4-fluorfenyl)-TP-HCl,25. 3-(3-trifluoromethylphenylamino)-6-(4-fluorophenyl)-TP-HCl,
sm.p. 286°C.sm.p. 286°C.
26. 3-fenylamino-6-(3-fluorfenyl)-TP-HCl, sm.p. 266°C under spaltning. 26. 3-phenylamino-6-(3-fluorophenyl)-TP-HCl, m.p. 266°C during decomposition.
27. 3-(4-klorfenylamino)-6-(3-fluorfenyl)-TP, sm.p. 258°C.27. 3-(4-chlorophenylamino)-6-(3-fluorophenyl)-TP, m.p. 258°C.
28. 3-(3-fluorfenylamino)-6-(3-fluorfenyl)-TP sm.p. 236°C.28. 3-(3-fluorophenylamino)-6-(3-fluorophenyl)-TP m.p. 236°C.
29. 3-(4-fluorfenylamino)-6-(3-fluorfenyl)-TP, sm.p. 241°C.29. 3-(4-fluorophenylamino)-6-(3-fluorophenyl)-TP, m.p. 241°C.
30. 3-fenylamino-6-(3-trifluormetylfenyl)-TP, sm.p. 206°C.30. 3-phenylamino-6-(3-trifluoromethylphenyl)-TP, m.p. 206°C.
31. 3-(3-klorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 212°C. 32. 3-(4-klorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 208°C. 33. 3-(3,4-diklorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 198°C. 34. 3-82-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 198°C. 35. 3-(3-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 209°C. 36. 3-(4-fluorfenylamino)-6-(3-trifluormetylfenyl)-TP, sm.p. 234°C. 31. 3-(3-chlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 212°C. 32. 3-(4-chlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 208°C. 33. 3-(3,4-dichlorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 198°C. 34. 3-82-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 198°C. 35. 3-(3-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 209°C. 36. 3-(4-fluorophenylamino)-6-(3-trifluoromethylphenyl)-TP, m.p. 234°C.
37. 3-fenylamino-6-(4-trifluormetylfenyl)-TP-HCl, sm.p. 271°C.37. 3-phenylamino-6-(4-trifluoromethylphenyl)-TP-HCl, m.p. 271°C.
38. 3-(3-fluorfenylamino)-6-(4-fenoksyfenyl)-TP, sm.p. 211°C.38. 3-(3-fluorophenylamino)-6-(4-phenoxyphenyl)-TP, m.p. 211°C.
39. 3-fenylamino-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 247°C.39. 3-phenylamino-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 247°C.
40. 3-(4-klorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 274°C. 41. 3-(3-fluorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 253°C. 42. 3-(4-fluorfenylamino)-6-(4-fenyltio-fenyl)-TP-HCl, sm.p. 263°C, 40. 3-(4-chlorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 274°C. 41. 3-(3-fluorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 253°C. 42. 3-(4-fluorophenylamino)-6-(4-phenylthio-phenyl)-TP-HCl, m.p. 263°C,
43. 3-fenylamino-6-(5-klor-2-tienyl)-TP-HCl, sm.p. 271°C.43. 3-phenylamino-6-(5-chloro-2-thienyl)-TP-HCl, m.p. 271°C.
44. 3-(4-klorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p. 246°C.44. 3-(4-chlorophenylamino)-6-(5-chloro-2-thienyl)-TP, m.p. 246°C.
45. 3-(3-fluorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p. 287°C.45. 3-(3-fluorophenylamino)-6-(5-chloro-2-thienyl)-TP, m.p. 287°C.
46. 3-(2-fluorfenylamino)-6-(5-klor-2-tienyl)-TP, sm.p.232°C.46. 3-(2-fluorophenylamino)-6-(5-chloro-2-thienyl)-TP, mp 232°C.
47. 6-/~4-(4-fluorfenoksy)fenyl/-3-fenylamino-TP, sm.p. 235°C. 47. 6-/~4-(4-fluorophenoxy)phenyl/-3-phenylamino-TP, m.p. 235°C.
48. 6-/~4-(4-fluorfenoksy)fenyl7~3-(3-fluorfenylamino)-TP,48. 6-/~4-(4-fluorophenoxy)phenyl7~3-(3-fluorophenylamino)-TP,
sm.p. 233°C.sm.p. 233°C.
49. 3-(4-klorfenylamino)-6-/~4-(4-fluorfenoksy)fenyl7~TP,49. 3-(4-chlorophenylamino)-6-/~4-(4-fluorophenoxy)phenyl7~TP,
sm.p. 267°C.sm.p. 267°C.
50. 3-(3-fluorfenylamino)-6-(2-furyl)-TP, sm.p. 217-218°C.50. 3-(3-fluorophenylamino)-6-(2-furyl)-TP, m.p. 217-218°C.
51. 3-(4-klorfenylamino)-6-(2-furyl)-TP, sm.p. 201-202°C.51. 3-(4-chlorophenylamino)-6-(2-furyl)-TP, m.p. 201-202°C.
52. 3-fenylamino-6-(2-tienyl)-TP, sm.p. 204°C.52. 3-Phenylamino-6-(2-thienyl)-TP, m.p. 204°C.
53. 3-(3-fluorfenylamino)-6-(2-tienyl)-TP, sm.p. 212°C. 53. 3-(3-fluorophenylamino)-6-(2-thienyl)-TP, m.p. 212°C.
Eksempel 54 fremgangsmåte . b) Example 54 procedure. b)
3-cykloheksylamino-6-fenyl-1,2,4-triazolo/~4,3-b7pyridazin-hydroklorid 3-Cyclohexylamino-6-phenyl-1,2,4-triazolo/~4,3-b7pyridazine hydrochloride
3 g 3-brom-6-fenyl-1,2,4-triazolo/ 4,3-b7pyridazin oppvarmes3 g of 3-bromo-6-phenyl-1,2,4-triazolo/4,3-b7pyridazine is heated
1 10 ml cykloheksylamin 5 timer under tilbakeløp. Etter av-kjøling utrører man med diisopropyleter, frasuger og omkrystalliseres fra isopropanol. Med etanolisk saltsyre får man hydrokloridet, sm.p. 258°C. 1 10 ml cyclohexylamine 5 hours under reflux. After cooling, the mixture is stirred with diisopropyl ether, filtered off with suction and recrystallized from isopropanol. With ethanolic hydrochloric acid, the hydrochloride is obtained, m.p. 258°C.
Analogt får man forbindelsen ifølge oppfinnelsen med eksempelAnalogously, the compound according to the invention is obtained by example
2 til 53.2 to 53.
Derved omsetter en analogt til litteraturfremgangsmåten frem-stillet 6-aryl-3-brom-l,2,4-triazolo/ 4,3-b7pyridazin (generell formel IV), som har de samme 6-substituenter som forbindelsen angjeldende eksempel med diamin (generell formel V), som ligger til grunn for 3-substituenten av eksempelet. Thereby, one reacts analogously to the literature method prepared 6-aryl-3-bromo-1,2,4-triazolo/4,3-b7pyridazine (general formula IV), which has the same 6-substituents as the compound in question with diamine ( general formula V), which underlies the 3-substituent of the example.
Eksempel 55 fremgangsmåte c) Example 55 procedure c)
3-benzylamino-6-fenyl-1,2,4-triazolo/ 4,3-b7pyridazinhydro-klorid 3-benzylamino-6-phenyl-1,2,4-triazolo/4,3-b7pyridazine hydrochloride
5 g 3-amino-6-fenyl-1,2,4-triazolo/~4,3-b7pyridazin og 3 g benzyl-klorid oppvarmes i 25 ml dimetylformamid med 5 g kaliumkarbonat i 10 timer under tilbakeløp. Etter avkjøling blandes med vann, frasuges, og blandes med etanolisk saltsyre og inndampes. Etter omkrystallisering fra iseddik, vaskes med diisopropyleter og tørkes, sm.p. 236°C under spaltning. 5 g of 3-amino-6-phenyl-1,2,4-triazolo/~4,3-b7pyridazine and 3 g of benzyl chloride are heated in 25 ml of dimethylformamide with 5 g of potassium carbonate for 10 hours under reflux. After cooling, mix with water, suck off, and mix with ethanolic hydrochloric acid and evaporate. After recrystallization from glacial acetic acid, wash with diisopropyl ether and dry, m.p. 236°C during decomposition.
Analogt denne fremgangsmåte får man forbindelsene ifølge oppfinnelsen fra eksemplene 1 og 3 til.53. Analogous to this method, the compounds according to the invention are obtained from examples 1 and 3 to 53.
Derved omsettes den til de respektive eksempel tilgrunnliggende 3-amino-6-aryl-l,2,4-triazolo/~4,3-b/pyridazin (generell formel VI beskrevet i DE-OS 32 17 325) med R<4->Y (generell formel VII) hvis alkyl- eller arylrest ligger til grunn for 3-substituenten av det angjeldende eksempel. Thereby, it is converted to the respective example basic 3-amino-6-aryl-1,2,4-triazolo/~4,3-b/pyridazine (general formula VI described in DE-OS 32 17 325) with R<4- >Y (general formula VII) whose alkyl or aryl residue forms the basis of the 3-substituent of the relevant example.
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DE (2) | DE3311753A1 (en) |
DK (1) | DK144884A (en) |
ES (1) | ES8501765A1 (en) |
FI (1) | FI841238A (en) |
GR (1) | GR81812B (en) |
HU (1) | HU189076B (en) |
IL (1) | IL71412A (en) |
MA (1) | MA20080A1 (en) |
NO (1) | NO841270L (en) |
NZ (1) | NZ207691A (en) |
PH (1) | PH20465A (en) |
PT (1) | PT78343B (en) |
ZA (1) | ZA842389B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
US7683060B2 (en) | 2006-08-07 | 2010-03-23 | Incyte Corporation | Triazolotriazines as kinase inhibitors |
PL2099447T3 (en) | 2006-11-22 | 2013-06-28 | Incyte Holdings Corp | Imidazotriazines and imidazopyrimidines as kinase inhibitors |
HUE034716T2 (en) | 2008-05-21 | 2018-02-28 | Incyte Holdings Corp | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
CN102812027B (en) | 2010-02-03 | 2015-01-07 | 因西特公司 | Imidazo[1,2-b][1,2,4]triazines as c-met inhibitors |
WO2012148775A1 (en) * | 2011-04-29 | 2012-11-01 | Amgen Inc. | Bicyclic pyridazine compounds as pim inhibitors |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL128809C (en) * | 1966-06-18 | |||
DE2113438A1 (en) * | 1971-03-19 | 1972-09-21 | Boehringer Mannheim Gmbh | Anti-microbial nitrofuryl-triazolo -(4,3-b) - pyridazine derivs - used for treating urinary system infections |
US3915968A (en) * | 1973-09-21 | 1975-10-28 | Lepetit Spa | Triazolopyridazines |
DE3217325A1 (en) * | 1982-05-08 | 1983-11-10 | Hoechst Ag, 6230 Frankfurt | 3-AMINO-6-ARYL-1,2,4-TRIAZOLO (4,3-B) -PYRIDAZINE, THEIR PRODUCTION AND USE |
DE3222342A1 (en) * | 1982-06-14 | 1983-12-15 | Hoechst Ag, 6230 Frankfurt | 6-Aryl-1,2,4-triazolo[4,3-b]pyridazine-3-carbamates, their preparation and medicaments containing them |
-
1983
- 1983-03-31 DE DE19833311753 patent/DE3311753A1/en not_active Withdrawn
-
1984
- 1984-02-29 DK DK144884A patent/DK144884A/en not_active Application Discontinuation
- 1984-03-26 HU HU841204A patent/HU189076B/en unknown
- 1984-03-28 EP EP84710009A patent/EP0121490B1/en not_active Expired
- 1984-03-28 FI FI841238A patent/FI841238A/en not_active Application Discontinuation
- 1984-03-28 DE DE8484710009T patent/DE3469530D1/en not_active Expired
- 1984-03-28 AT AT84710009T patent/ATE32723T1/en not_active IP Right Cessation
- 1984-03-29 GR GR74257A patent/GR81812B/el unknown
- 1984-03-29 PH PH30469A patent/PH20465A/en unknown
- 1984-03-29 KR KR1019840001627A patent/KR840008361A/en not_active Application Discontinuation
- 1984-03-29 ES ES531084A patent/ES8501765A1/en not_active Expired
- 1984-03-29 NZ NZ207691A patent/NZ207691A/en unknown
- 1984-03-30 IL IL71412A patent/IL71412A/en unknown
- 1984-03-30 PT PT78343A patent/PT78343B/en not_active IP Right Cessation
- 1984-03-30 AU AU26346/84A patent/AU563556B2/en not_active Ceased
- 1984-03-30 ZA ZA842389A patent/ZA842389B/en unknown
- 1984-03-30 CA CA000451005A patent/CA1246568A/en not_active Expired
- 1984-03-30 NO NO841270A patent/NO841270L/en unknown
- 1984-03-30 JP JP59061286A patent/JPS59184179A/en active Pending
- 1984-03-31 MA MA20302A patent/MA20080A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
ZA842389B (en) | 1984-11-28 |
NZ207691A (en) | 1986-07-11 |
EP0121490A1 (en) | 1984-10-10 |
HU189076B (en) | 1986-06-30 |
GR81812B (en) | 1984-12-12 |
AU563556B2 (en) | 1987-07-16 |
ES531084A0 (en) | 1984-12-01 |
PT78343A (en) | 1984-04-01 |
FI841238A (en) | 1984-10-01 |
IL71412A (en) | 1988-05-31 |
DK144884A (en) | 1984-10-01 |
EP0121490B1 (en) | 1988-03-02 |
HUT34193A (en) | 1985-02-28 |
AU2634684A (en) | 1984-10-04 |
MA20080A1 (en) | 1984-10-01 |
KR840008361A (en) | 1984-12-14 |
ATE32723T1 (en) | 1988-03-15 |
DE3311753A1 (en) | 1984-10-04 |
ES8501765A1 (en) | 1984-12-01 |
DK144884D0 (en) | 1984-02-29 |
FI841238A0 (en) | 1984-03-28 |
IL71412A0 (en) | 1984-06-29 |
PT78343B (en) | 1986-07-14 |
CA1246568A (en) | 1988-12-13 |
PH20465A (en) | 1987-01-14 |
DE3469530D1 (en) | 1988-04-07 |
JPS59184179A (en) | 1984-10-19 |
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