HRP20020816A2 - Pyridazinyl phenyl hydrazones useful against congestive heart failure - Google Patents
Pyridazinyl phenyl hydrazones useful against congestive heart failure Download PDFInfo
- Publication number
- HRP20020816A2 HRP20020816A2 HRP20020816A HRP20020816A2 HR P20020816 A2 HRP20020816 A2 HR P20020816A2 HR P20020816 A HRP20020816 A HR P20020816A HR P20020816 A2 HRP20020816 A2 HR P20020816A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- phenyl
- hydrogen
- pyridazin
- hydroxy
- Prior art date
Links
- -1 Pyridazinyl phenyl hydrazones Chemical class 0.000 title claims description 24
- 206010007559 Cardiac failure congestive Diseases 0.000 title 1
- 206010019280 Heart failures Diseases 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 229910052801 chlorine Chemical group 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 132
- 238000005160 1H NMR spectroscopy Methods 0.000 description 66
- 238000002844 melting Methods 0.000 description 63
- 230000008018 melting Effects 0.000 description 63
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 11
- 229910052791 calcium Inorganic materials 0.000 description 11
- 239000011575 calcium Substances 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 9
- 150000002429 hydrazines Chemical class 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 239000000835 fiber Substances 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- 102000002585 Contractile Proteins Human genes 0.000 description 6
- 108010068426 Contractile Proteins Proteins 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004165 myocardium Anatomy 0.000 description 6
- 230000002861 ventricular Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000002349 favourable effect Effects 0.000 description 5
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 210000005240 left ventricle Anatomy 0.000 description 4
- 230000010412 perfusion Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000004816 latex Substances 0.000 description 3
- 229920000126 latex Polymers 0.000 description 3
- 210000003540 papillary muscle Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- HDJKGUBFDGUPFK-SSDOTTSWSA-N (4r)-3-(4-hydrazinylphenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound C[C@@H]1CC(=O)NN=C1C1=CC=C(NN)C=C1 HDJKGUBFDGUPFK-SSDOTTSWSA-N 0.000 description 2
- SULYEHHGGXARJS-UHFFFAOYSA-N 2',4'-dihydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1O SULYEHHGGXARJS-UHFFFAOYSA-N 0.000 description 2
- AQKWZDZQPZSATN-UHFFFAOYSA-N 3-(3-hydrazinylphenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=CC(NN)=C1 AQKWZDZQPZSATN-UHFFFAOYSA-N 0.000 description 2
- HDJKGUBFDGUPFK-UHFFFAOYSA-N 3-(4-hydrazinylphenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=C(NN)C=C1 HDJKGUBFDGUPFK-UHFFFAOYSA-N 0.000 description 2
- HFXZFCMCJBCLKJ-UHFFFAOYSA-N 3-[4-[2-[(3-ethyl-2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CCC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C=2C(CC(=O)NN=2)C)=C1O HFXZFCMCJBCLKJ-UHFFFAOYSA-N 0.000 description 2
- CESZJTKLRJWMOD-UHFFFAOYSA-N 3-[4-[2-[1-(2,4-dihydroxyphenyl)ethylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=C(C)C1=CC=C(O)C=C1O CESZJTKLRJWMOD-UHFFFAOYSA-N 0.000 description 2
- GZSNAXVXGFVPNU-UHFFFAOYSA-N 3-[4-[2-[1-(2,5-dihydroxyphenyl)ethylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=C(C)C1=CC(O)=CC=C1O GZSNAXVXGFVPNU-UHFFFAOYSA-N 0.000 description 2
- OIJFPFSSXABMNR-UHFFFAOYSA-N 3-[4-[2-[bis(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=C(C=1C(=CC(O)=CC=1)O)C1=CC=C(O)C=C1O OIJFPFSSXABMNR-UHFFFAOYSA-N 0.000 description 2
- VBBCUFVTWROALH-UHFFFAOYSA-N 6-(4-hydrazinylphenyl)-2-methylpyridazin-3-one Chemical compound C1=CC(=O)N(C)N=C1C1=CC=C(NN)C=C1 VBBCUFVTWROALH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 239000007993 MOPS buffer Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- MWDICCJVJOMHSI-UHFFFAOYSA-N 2,4-dihydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC(O)=C([N+]([O-])=O)C=C1C=O MWDICCJVJOMHSI-UHFFFAOYSA-N 0.000 description 1
- JWYQQJDNADRNEL-UHFFFAOYSA-N 2-[c-[4-(4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenyl]carbonohydrazonoyl]benzoic acid Chemical compound CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C(=CC=CC=2)C(O)=O)C=C1 JWYQQJDNADRNEL-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-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
- SNHLRYZWIWHWFX-UHFFFAOYSA-N 3-(3-aminophenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=CC(N)=C1 SNHLRYZWIWHWFX-UHFFFAOYSA-N 0.000 description 1
- NWUOGOISBQCNKQ-UHFFFAOYSA-N 3-(4-aminophenyl)-4-methyl-1h-pyridazin-6-one Chemical compound CC1=CC(=O)NN=C1C1=CC=C(N)C=C1 NWUOGOISBQCNKQ-UHFFFAOYSA-N 0.000 description 1
- FVTHDBGLGNPRCR-UHFFFAOYSA-N 3-(4-hydrazinylphenyl)-4-methyl-1h-pyridazin-6-one Chemical compound CC1=CC(=O)NN=C1C1=CC=C(NN)C=C1 FVTHDBGLGNPRCR-UHFFFAOYSA-N 0.000 description 1
- TUGVJPGYSDTJAG-UHFFFAOYSA-N 3-[4-[2-[(2,3-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=CC(O)=C1O TUGVJPGYSDTJAG-UHFFFAOYSA-N 0.000 description 1
- OJWAQBWUBKDRFC-UHFFFAOYSA-N 3-[4-[2-[(2,4-dichlorophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(Cl)C=C1Cl OJWAQBWUBKDRFC-UHFFFAOYSA-N 0.000 description 1
- RGYYZELZQNFCDM-UHFFFAOYSA-N 3-[4-[2-[(2,4-dihydroxy-3-propylphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CCCC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C=2C(CC(=O)NN=2)C)=C1O RGYYZELZQNFCDM-UHFFFAOYSA-N 0.000 description 1
- YQTPKDPKVJNQRL-UHFFFAOYSA-N 3-[4-[2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-ethyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CCC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C=C1O YQTPKDPKVJNQRL-UHFFFAOYSA-N 0.000 description 1
- GULVWDKYICTUFG-UHFFFAOYSA-N 3-[4-[2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-1H-pyridazin-6-one Chemical compound CC1=CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C=C1O GULVWDKYICTUFG-UHFFFAOYSA-N 0.000 description 1
- UUTFRQRDALQVDC-UHFFFAOYSA-N 3-[4-[2-[(2,4-dinitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UUTFRQRDALQVDC-UHFFFAOYSA-N 0.000 description 1
- YZVXQAINTJEDSP-UHFFFAOYSA-N 3-[4-[2-[(2,5-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC(O)=CC=C1O YZVXQAINTJEDSP-UHFFFAOYSA-N 0.000 description 1
- VQHMWDVBRXVIAY-UHFFFAOYSA-N 3-[4-[2-[(2,6-dinitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=C([N+]([O-])=O)C=CC=C1[N+]([O-])=O VQHMWDVBRXVIAY-UHFFFAOYSA-N 0.000 description 1
- OLDBHOFMKXDMAO-UHFFFAOYSA-N 3-[4-[2-[(2-hydroxy-3-methoxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound COC1=CC=CC(C=NNC=2C=CC(=CC=2)C=2C(CC(=O)NN=2)C)=C1O OLDBHOFMKXDMAO-UHFFFAOYSA-N 0.000 description 1
- NDDNYERKAPSDBT-UHFFFAOYSA-N 3-[4-[2-[(2-hydroxy-5-nitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC([N+]([O-])=O)=CC=C1O NDDNYERKAPSDBT-UHFFFAOYSA-N 0.000 description 1
- JSNFRHBBODUWGL-UHFFFAOYSA-N 3-[4-[2-[(2-hydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=CC=C1O JSNFRHBBODUWGL-UHFFFAOYSA-N 0.000 description 1
- AEYIEDOXYQIXCL-UHFFFAOYSA-N 3-[4-[2-[(2-methoxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound COC1=CC=CC=C1C=NNC1=CC=C(C=2C(CC(=O)NN=2)C)C=C1 AEYIEDOXYQIXCL-UHFFFAOYSA-N 0.000 description 1
- GSOJJZLZJNNPDP-UHFFFAOYSA-N 3-[4-[2-[(3,4-dihydroxy-2-nitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C(O)=C1[N+]([O-])=O GSOJJZLZJNNPDP-UHFFFAOYSA-N 0.000 description 1
- ADJJXYKQXXZQKF-UHFFFAOYSA-N 3-[4-[2-[(3-acetyl-2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C(C(C)=O)=C1O ADJJXYKQXXZQKF-UHFFFAOYSA-N 0.000 description 1
- QRJXGQFMBDQICY-UHFFFAOYSA-N 3-[4-[2-[(3-butyl-2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CCCCC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C=2C(CC(=O)NN=2)C)=C1O QRJXGQFMBDQICY-UHFFFAOYSA-N 0.000 description 1
- FSGJSUXXXAVURH-UHFFFAOYSA-N 3-[4-[2-[(3-hydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=CC(O)=C1 FSGJSUXXXAVURH-UHFFFAOYSA-N 0.000 description 1
- CBYGFAUAIISNTA-UHFFFAOYSA-N 3-[4-[2-[(4-hydroxy-3-methoxy-2-nitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-1H-pyridazin-6-one Chemical compound COC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C=2C(=CC(=O)NN=2)C)=C1[N+]([O-])=O CBYGFAUAIISNTA-UHFFFAOYSA-N 0.000 description 1
- ZGGBTNDTFFNWRD-UHFFFAOYSA-N 3-[4-[2-[(4-hydroxy-3-methoxy-2-nitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound COC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C=2C(CC(=O)NN=2)C)=C1[N+]([O-])=O ZGGBTNDTFFNWRD-UHFFFAOYSA-N 0.000 description 1
- HCYVLFNPMQHDOA-UHFFFAOYSA-N 3-[4-[2-[(4-hydroxy-3-nitrophenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C([N+]([O-])=O)=C1 HCYVLFNPMQHDOA-UHFFFAOYSA-N 0.000 description 1
- BZMKSBXNAQOSJU-UHFFFAOYSA-N 3-[4-[2-[(4-hydroxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C=C1 BZMKSBXNAQOSJU-UHFFFAOYSA-N 0.000 description 1
- CBBOCUUCYGFBMI-UHFFFAOYSA-N 3-[4-[2-[(4-methoxyphenyl)methylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound C1=CC(OC)=CC=C1C=NNC1=CC=C(C=2C(CC(=O)NN=2)C)C=C1 CBBOCUUCYGFBMI-UHFFFAOYSA-N 0.000 description 1
- LHPPSFBLUSFKAS-UHFFFAOYSA-N 3-[4-[2-[1-(2,4-dihydroxyphenyl)-3-(3,4-dimethoxyphenyl)propylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one Chemical compound C1=C(OC)C(OC)=CC=C1CCC(C=1C(=CC(O)=CC=1)O)=NNC1=CC=C(C=2C(CC(=O)NN=2)C)C=C1 LHPPSFBLUSFKAS-UHFFFAOYSA-N 0.000 description 1
- UMQMQZBOIFUKSY-UHFFFAOYSA-N 3-[4-[2-[1-(2,4-dihydroxyphenyl)ethylidene]hydrazinyl]phenyl]-4-methyl-1H-pyridazin-6-one Chemical compound C=1C=C(O)C=C(O)C=1C(C)=NNC(C=C1)=CC=C1C1=NNC(=O)C=C1C UMQMQZBOIFUKSY-UHFFFAOYSA-N 0.000 description 1
- PJHFZBJCGRRVRK-UHFFFAOYSA-N 3-[4-[2-[1-(3,5-dihydroxyphenyl)ethylidene]hydrazinyl]phenyl]-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=C(C)C1=CC(O)=CC(O)=C1 PJHFZBJCGRRVRK-UHFFFAOYSA-N 0.000 description 1
- WNSKAOYXHZFUSY-UHFFFAOYSA-N 3-[c-[4-(4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenyl]carbonohydrazonoyl]benzonitrile Chemical compound CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C=C(C=CC=2)C#N)C=C1 WNSKAOYXHZFUSY-UHFFFAOYSA-N 0.000 description 1
- LZWQAZGAGMVSOW-UHFFFAOYSA-N 4-(2,4-dihydroxyphenyl)-4-[[4-(1-methyl-6-oxopyridazin-3-yl)phenyl]hydrazinylidene]butanoic acid Chemical compound C1=CC(=O)N(C)N=C1C(C=C1)=CC=C1NN=C(CCC(O)=O)C1=CC=C(O)C=C1O LZWQAZGAGMVSOW-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- YYKMCVNHJJRUSP-UHFFFAOYSA-N 4-[4-[2-[(2,4-dihydroxyphenyl)-(4-hydroxyphenyl)methylidene]hydrazinyl]phenyl]-2H-phthalazin-1-one Chemical compound C1=CC(O)=CC=C1C(C=1C(=CC(O)=CC=1)O)=NNC1=CC=C(C=2C3=CC=CC=C3C(=O)NN=2)C=C1 YYKMCVNHJJRUSP-UHFFFAOYSA-N 0.000 description 1
- VIWABHGDMMUHDN-UHFFFAOYSA-N 4-[4-[2-[(2,4-dihydroxyphenyl)-phenylmethylidene]hydrazinyl]phenyl]-2H-phthalazin-1-one Chemical compound OC1=CC(O)=CC=C1C(C=1C=CC=CC=1)=NNC1=CC=C(C=2C3=CC=CC=C3C(=O)NN=2)C=C1 VIWABHGDMMUHDN-UHFFFAOYSA-N 0.000 description 1
- QAVYWQLRYGCWOV-UHFFFAOYSA-N 4-[4-[2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-2H-phthalazin-1-one Chemical compound OC1=CC(O)=CC=C1C=NNC1=CC=C(C=2C3=CC=CC=C3C(=O)NN=2)C=C1 QAVYWQLRYGCWOV-UHFFFAOYSA-N 0.000 description 1
- UNCCJZWULYJIPK-UHFFFAOYSA-N 4-[4-[2-[bis(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-2H-phthalazin-1-one Chemical compound OC1=CC(O)=CC=C1C(C=1C(=CC(O)=CC=1)O)=NNC1=CC=C(C=2C3=CC=CC=C3C(=O)NN=2)C=C1 UNCCJZWULYJIPK-UHFFFAOYSA-N 0.000 description 1
- ZUHSJRIRZDJLLS-UHFFFAOYSA-N 4-[c-[4-(4-methyl-6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenyl]carbonohydrazonoyl]benzonitrile Chemical compound CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C=CC(=CC=2)C#N)C=C1 ZUHSJRIRZDJLLS-UHFFFAOYSA-N 0.000 description 1
- PHCNQUJHXJQLQR-UHFFFAOYSA-N 4-hydroxy-3-methoxy-2-nitrobenzaldehyde Chemical compound COC1=C(O)C=CC(C=O)=C1[N+]([O-])=O PHCNQUJHXJQLQR-UHFFFAOYSA-N 0.000 description 1
- QPOLJQKSZXUNDS-UHFFFAOYSA-N 4-methyl-3-[4-[2-[(2,4,5-trihydroxyphenyl)methylidene]hydrazinyl]phenyl]-4,5-dihydro-1H-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1c1ccc(NN=Cc2cc(O)c(O)cc2O)cc1 QPOLJQKSZXUNDS-UHFFFAOYSA-N 0.000 description 1
- BGIUWSRRSRFGRW-UHFFFAOYSA-N 4-methyl-3-[4-[2-[(2-nitrophenyl)methylidene]hydrazinyl]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=CC=C1[N+]([O-])=O BGIUWSRRSRFGRW-UHFFFAOYSA-N 0.000 description 1
- GLQXRSIRLLUZKW-UHFFFAOYSA-N 4-methyl-3-[4-[2-[(4-methylsulfonylphenyl)methylidene]hydrazinyl]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C(S(C)(=O)=O)C=C1 GLQXRSIRLLUZKW-UHFFFAOYSA-N 0.000 description 1
- ZLVUQJXSUYUWCL-UHFFFAOYSA-N 4-methyl-3-[4-[2-[(4-nitrophenyl)methylidene]hydrazinyl]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=C([N+]([O-])=O)C=C1 ZLVUQJXSUYUWCL-UHFFFAOYSA-N 0.000 description 1
- OOFXCPMROHHXFO-UHFFFAOYSA-N 4-methyl-3-[4-[2-[[2-(trifluoromethyl)phenyl]methylidene]hydrazinyl]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C(C=C1)=CC=C1NN=CC1=CC=CC=C1C(F)(F)F OOFXCPMROHHXFO-UHFFFAOYSA-N 0.000 description 1
- MDVFJPDMXLCQFR-UHFFFAOYSA-N 6-(4-aminophenyl)-2,5-dimethylpyridazin-3-one Chemical compound CC1=CC(=O)N(C)N=C1C1=CC=C(N)C=C1 MDVFJPDMXLCQFR-UHFFFAOYSA-N 0.000 description 1
- PAPOUVTXLICLIG-UHFFFAOYSA-N 6-(4-aminophenyl)-2-methylpyridazin-3-one Chemical compound C1=CC(=O)N(C)N=C1C1=CC=C(N)C=C1 PAPOUVTXLICLIG-UHFFFAOYSA-N 0.000 description 1
- ARHJNGMCJNVJSD-UHFFFAOYSA-N 6-(4-hydrazinylphenyl)-2,5-dimethylpyridazin-3-one Chemical compound CC1=CC(=O)N(C)N=C1C1=CC=C(NN)C=C1 ARHJNGMCJNVJSD-UHFFFAOYSA-N 0.000 description 1
- CZWVAADEUHVYAY-UHFFFAOYSA-N 6-[4-[2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-2,5-dimethylpyridazin-3-one Chemical compound CC1=CC(=O)N(C)N=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C=C1O CZWVAADEUHVYAY-UHFFFAOYSA-N 0.000 description 1
- YQVJIKHGMMMOLO-UHFFFAOYSA-N 6-[4-[2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-2-methylpyridazin-3-one Chemical compound C1=CC(=O)N(C)N=C1C(C=C1)=CC=C1NN=CC1=CC=C(O)C=C1O YQVJIKHGMMMOLO-UHFFFAOYSA-N 0.000 description 1
- QLPHQZOWBNRKAM-UHFFFAOYSA-N 6-[4-[2-[(3-ethyl-2,4-dihydroxyphenyl)methylidene]hydrazinyl]phenyl]-2-methylpyridazin-3-one Chemical compound CCC1=C(O)C=CC(C=NNC=2C=CC(=CC=2)C2=NN(C)C(=O)C=C2)=C1O QLPHQZOWBNRKAM-UHFFFAOYSA-N 0.000 description 1
- KNZCTXROKMKIBC-UHFFFAOYSA-N 6-[4-[2-[1-(2,4-dihydroxyphenyl)ethylidene]hydrazinyl]phenyl]-2-methylpyridazin-3-one Chemical compound C=1C=C(O)C=C(O)C=1C(C)=NNC(C=C1)=CC=C1C=1C=CC(=O)N(C)N=1 KNZCTXROKMKIBC-UHFFFAOYSA-N 0.000 description 1
- DKBFREYPIRTHPK-UHFFFAOYSA-N 6-[4-[2-[1-(2,4-dihydroxyphenyl)propylidene]hydrazinyl]phenyl]-2-methylpyridazin-3-one Chemical compound C=1C=C(O)C=C(O)C=1C(CC)=NNC(C=C1)=CC=C1C=1C=CC(=O)N(C)N=1 DKBFREYPIRTHPK-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GNTHYXUHUUFRCB-UHFFFAOYSA-N CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C(=C(C(O)=O)C(O)=CC=2)O)C=C1 Chemical compound CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C(=C(C(O)=O)C(O)=CC=2)O)C=C1 GNTHYXUHUUFRCB-UHFFFAOYSA-N 0.000 description 1
- FCUDQNGNCWVYHL-UHFFFAOYSA-N CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C(=CC(NC(C)=O)=CC=2)O)C=C1 Chemical compound CC1CC(=O)NN=C1C1=CC=C(C(=NN)C=2C(=CC(NC(C)=O)=CC=2)O)C=C1 FCUDQNGNCWVYHL-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- WXNRYSGJLQFHBR-UHFFFAOYSA-N bis(2,4-dihydroxyphenyl)methanone Chemical compound OC1=CC(O)=CC=C1C(=O)C1=CC=C(O)C=C1O WXNRYSGJLQFHBR-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000001964 calcium overload Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000006277 halobenzyl group Chemical group 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- KLAKIAVEMQMVBT-UHFFFAOYSA-N p-hydroxy-phenacyl alcohol Natural products OCC(=O)C1=CC=C(O)C=C1 KLAKIAVEMQMVBT-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 102000005681 phospholamban Human genes 0.000 description 1
- 108010059929 phospholamban Proteins 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003492 pulmonary vein Anatomy 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Prikazani izum se odnosi na piridazinil fenil hidrazonske spojeve i njihove farmaceutski prihvatljive soli i estere. Izum se također odnosi na farmaceutske pripravke koji obuhvaćaju takve spojeve kao aktivne komponente. Spojevi prema izumu povećavaju osjetljivost na kalcij kontraktilnih proteina srčanog mišića i zbog toga su korisni u tretiranju kongestivnog srčanog udara.
Kongestivni srčani udar karakterizira smanjenje rada srca i povećanje tlaka punjenja u desnoj i lijevoj srčanoj klijetki. Ovi hemodinamički uvjeti mogu uzrokovati simptome dispneje, umora i edema.
Kontrakcija srčanog mišića izaziva se vezivanjem kalcija na kontraktilne proteine. Klinički je ispitan niz inhibitora fosfodiesteraza izoenzima III (PDE III) za tretiranje kongestivnog srčanog udara. Ovi spojevi povećavaju kontraktilnost srčanog mišića i izazivaju vazodilataciju. Međutim, poznato je da dugotrajna primjena ovih spojeva može dovesti do preopterećenja kalcijem u srčanom mišiću i izazvati aritmije. Zbog toga je poželjno da se razviju lijekovi koji djeluju pomoću mehanizma koji će povećati srčanu kontraktilnost, a da ne izazovu preopterećenje kalcijem. Jedan takav mehanizam biti će povećanje osjetljivosti kontraktilnih proteina.
Piridazinil fenil hidrazonski spojevi su opisani ranije u europskoj patentnoj prijavi EP 383449. Spojevi pokazuju kalcij ovisno vezivanje za kontraktilne proteine srčanog mišića kao i PDE III inhibirajuću aktivnost. U specifičnim primjerima opisan je 1-acetil-1-fenil metiliden derivat (Pr. 16). Premda 1-acetil-1-fenil metiliden derivat ima nešto djelovanja u srčanoj kontraktilnosti, on ne povećava kalcijsku osjetljivost kontraktilnih proteina.
Izvjesni piridazinil fenil hidrazonski spojevi javljaju se kao intermedijeri u europskim patentnim prijavama EP 223937 i EP 280224. Međutim, spojevi nisu specifično naznačeni. Mertens, A. i sur., J. Med. Chem. 1990, 33, 2870-2875 opisuju fenil, 4-meoksifenil i 2-hidroksifenil derivate piridazinil fenil hidrazonskih spojeva kao intermedijere.
Sada je pronađeno da spojevi formule (I) imaju snažno djelovanje na povećanje osjetljivosti na kalcij kontraktilnih proteina srčanog mišića:
[image]
gdje
R1 do R4 označava vodik, alkil, alkenil, aril, arilalkil, karboksialkil, hidroksialkil ili halogenalkil, ili R2 i R3 formiraju prsten od 5 do 7 ugljikovog atoma,
R5 do R9 označava vodik, alkil, alkenil, aril, arilalkil, acil, hidroksi, alkoksi, alkoksikarbonil, amino, acilamino, alkilamino, ariloksi, halogen, cijano, nitro, karboksi, alkilsulfonil, sulfonamino ili trifluorometil,
gdje svaki ranije naveden aril ostatak može biti supstituiran sam po sebi ili kao dio druge skupine,
i njihove farmaceutski prihvatljive soli i estere,
pod uvjetom da
a) kada su R1, R2, R3, R5, R6, R8 i R9 vodik, R4 je metil, a R7 nije vodik ili metoksi, te
b) kada su R1, R2, R3, R5, R6, R7 i R8 vodik, R4 je metil, a R9 nije hidroksi.
Izum se također odnosi na spojeve formule (I) gdje su R1, R2, R3, R5, R6, R8 i R9 vodik, R4 je metil, a R7 je vodik ili metoksi, ili gdje su R1, R2, R3, R5, R6, R7 i R8 vodik, R4 je metil, a R9 je hidroksi i njihove farmaceutski prihvatljive soli i esteri, za upotrebu kao lijek.
U skupini povoljnih spojeva i farmaceutski prihvatljivih soli i estera su spojevi formule (I) gdje su R5 do R9 neovisno vodik, Cl-6 alkil, C1-6 alkenil, C6-10 aril, C7-12 arilalkil, C1-6 acil, hidroksi, C1-6 alkoksi, Cl-6 alkoksikarbonil, amino, Cl-6 acilamino, C1-6 alkilamino, C6-10 ariloksi, halogen, cijano, nitro, karboksi, Cl-6 alkilsulfonil, sulfonamido ili trifluorometil. U podskupini ove skupine spojeva i njihovih farmaceutski prihvatljivih soli su spojevi formule (I) gdje su R5 do R9 neovisno vodik, hidroksi, Cl-6 alkil, Cl-6 alkoksi, karboksi, Cl-6 alkoksikarbonil ili nitro. U podskupini ove skupine spojeva i njihovih farmaceutski prihvatljivih soli su spojevi formule (I) gdje je R5 hidroksi, Cl-6 alkil, Cl-6 alkoksi, karboksi, Cl-6 alkoksikarbonil ili nitro, najpovoljnije hidroksi ili nitro.
U drugoj skupini povoljnih spojeva i farmaceutski povoljnih soli su R1 do R4 neovisno vodik, Cl-6 alkil, Cl-6 alkenil, C6-10 aril, C7-12 arilalkil, Cl-6 karboksialkil, Cl-6 hidroksialkil ili Cl-6 halogenalkil ili R2 i R3 formiraju fenil prsten. U podskupini ove skupine spojeva i njihovih farmaceutski prihvatljivih soli su spojevi formule (I) gdje su R1 do R3 neovisno vodik ili Cl-6 alkil.
Svaki aril ostatak u svakoj od ovih povoljnih skupina spojeva može biti supstituiran sam po sebi ili kao dio druge skupine s 1 do 3 povoljno 1 ili 2 fluora, klora, broma, joda, hidroksi, ni tro, karboksi, trifluorometil, amino, Cl-4 alkil, Cl-4 alkoksi, C1-6 acil, Cl-6 karboksialkil, fenil, naftil, halofenil, halonaftil, benzil, fenetil, halobenzil, halofenetil, naftilmetil, naftiletil, C4-7 cikloalkil, Cl-4 alkil C4-7 cikloalkil, mono Cl-4 alkilamino, di Cl-4 alkilamino, Cl-6 alkanoilamino, fenilkarbonilamino, naftilkarbonilamino, cijano, tiol, ili Cl-6 alkiltio.
Spojevi formule (I) mogu sadržavati jedan ili više asimetričnih centara i mogu postojati kao enantiomeri ili dijastereoizomeri. Izum uključuje i smjese i odvojene samostalne izomere.
Naročito povoljni samostalni spojevi prema izumu uključuju:
(R)-6-{4-[N'-(4-hidroksi-3-metoksi-2-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on;
6-{4-[N'-(4-hidroksi-trimetoksi-2-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on;
6-(4-{N'-[1-(2,5-dihidroksi-fenil)-etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on;
6-(4-{N-[1-(2,4-dihidroksi-3-metilfenil)-etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on;
6-(4-{N'-[bis (2,4-dihidroksi-fenil)-metilen]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on;
6-(4-{N'-[1-(2,4-dihidroksi-fenil)-etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on;
2,6-dihidroksi-3-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazinometil}etil ester benzojeve kiseline; te
6-{4-[N'-(3-etil-2,4-dihidroksi-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on.
Spojevi prema izumu se mogu pripremiti pomoću dobro poznate kondenzacijske rekcije karbonil spoja i hidrazina kao što je prikazano u shemi 1:
Shema 1. Hidrazoni
[image]
gdje Ar označava
[image]
a R1 do R9 su isti kao ranije navedeni.
Povoljan postupak dobivanja hidrazina (III) je diazotiranje anilina i redukcija kao sinteza u jednoj posudi. Shema 2 pokazuje ovu reakciju:
Shema 2. Hidrazini gdje je Ar gore.
[image]
gdje je Ar kao gore.
Spojevi formula (II) i (IV) su komercijalno dostupni ili se mogu dobiti koristeći postupke poznate u literaturi.
Opći postupak 1: U slučaju gdje je R4 vodik reakcija iz sheme 1 izvodi se refluksiranjem smjese spojeva (II) i (III) u prikladnom otapalu kao Što je etanol, 2-propanol, acetonitril ili octena kiselina tijekom 1 do 24 sata. Proizvod (I) se filtrira.
Opći postupak 2: U slučaju gdje R4 nije vodik reakcija iz sheme l izvodi se zagrijavanjem čiste smjese spojeva (II) i (III) na 140 do 170°C pod inertnom atmosferom. Smjesa se zatim trituira s etil acetatom i proizvod (I) filtrira.
Soli i esteri spojeva, koji su primjenjivi, mogu se dobiti poznatim postupcima. Fiziološki prihvatljive soli su korisne kao aktivni lijekovi, međutim, povoljne su soli s alkalnim ili zemnoalkalnim metalima. Fiziološki prihvatljivi esteri su također korisni kao aktivni lijekovi. Primjeri su esteri s alifatskim ili aromatskim alkoholima.
Izraz "alkil" kao što je upotrebljen ovdje sam po sebi ili kao dio neke druge skupine uključuje normalne, razgranate i cikličke lančane radikale od do 18 ugljikovih atoma, povoljno 1 do 8 ugljikovih atoma, najpovoljnije 1 do 4 ugljikova atoma. Izraz "niži alkil" kao što je upotrebljen ovdje sam po sebi ili kao dio neke druge skupine uključuje normalne, razgranate i cikličke lančane radikale od 1 do 7, povoljnije 1 do 4, najpovoljnije 1 ili 2 ugljikova atoma. Specifični primjeri za alkil i niže alkil ostatke, respektivno, su metil, etil, propil, izopropil, butil, terc. butil, pentil, ciklopentil, heksil, cikloheksil, oktil, decil i dodecil uključujući i njihove različite razgranate lančane izomere.
Izraz "acil" kao što je upotrebljen ovdje sam po sebi ili kao dio neke druge skupine odnosi se na alkilkarbonil ili alkenilkarbonil skupinu, alkil i alkenil skupine su iste kao ranije navedene.
Izraz "aril" kao što je upotrebljen ovdje sam po sebi ili kao dio neke druge skupine odnosi se na monocikličku ili bicikličku skupinu koja sadrži od 6 do 10 ugljikovih atoma u dijelu prstena. Specifični primjeri za aril skupine su fenil, naftil i slično. "Aroil" označava na odgovarajući način arilkarbonil skupinu.
Izraz "alkoksi" kao što je upotrebljen ovdje sam po sebi ili kao dio neke druge skupine uključuje alkil skupinu kao što je navedeno ranije vezanu za atom kisika. "Ariloksi" označava na odgovarajući način aril skupinu vezanu za atom kisika.
Izraz "supstituirani" kao što je upotrebljen u svezi s različitim ostacima odnosi se na halogene supstituente kao što su fluor, klor, brom, jod ili trifluormetil skupinu, amino, alkil, alkoksi, aril, alkil-aril, halogen-aril, cikloalkil, alkilcikloalkil, hidroksi, alkilamino, alkanoilamino, arilkarbonilamino, nitro, cijano, tiol ili alkiltio supstituente.
"Supstituirane" skupine sadrže l do 3, povoljno l ili 2 ranije navedena supstituenta.
Spojevi prema izumu primjenjuju se na pacijente u terapeutski djelotvornim količinama koje se nalaze u području obično od oko 0.1 do 500 mg na dan ovisno o starosti, težini, stanju pacijenta, načinu davanja i upotrebljenog fosfolamban inhibitora. Spojevi prema izumu pripremaju se u dozirnim oblicima koristeći postupke poznate u tehnici. Davati se mogu kao takvi ili u kombinaciji s prihvatljivim farmaceutskim podlogama u obliku tableta, dražeja, kapsula, supozitorija, emulzija, suspenzija ili otopina. Izbor povoljnih komponenti za pripravak je rutina za osobe uobičajeno verzirane u tehnici. Evidentno ja da mogu biti upotrebljeni povoljni nosači, otapala, komponente koje formiraju gel, komponente koje formiraju disperziju, antioksidansi, boje, sredstva za zaslađivanje, sredstva za vlaženje i druge komponente koje se normalno koriste u ovom području tehnologije. Pripravak koji sadrži aktivni spoj može se davati enteralno ili parenteralno kod čega je oralni način povoljan. Sadržaj aktivnog spoja u pripravku je od oko 0.5 do 100% težinski, povoljno od oko 0.5 do oko 20% težinski u odnosu na ukupnu težinu.
Korisnost spojeva prema izumu je prikazana pomoću slijedećih eksperimenata.
Eksperiment 1. Djelovanje kalcijeve senzitivizacije u ogoljenim srčanim vlaknima
Postupak
Izvadi se srce zamorca i prelije/perfuzionira/ sa 125 mg/1 ledeno-hladne otopine saponina za ljuštenje koja se sastoji od (mM): K+-acetat 74.7, EGTA-Na2 10, MgSO4 5.4, ATP-Na2 4, MOPS 20, pH 7.0 (pomoću 1M KOH). Lijevi ventrikularni papilarni mišić se disecira i tretira ultrazvukom na 10 W u toku 60 s. Udaljenost između ultrazvučne probe/sonde i papilarnog mišića je 10 mm. Vlakna (<200 μm u promjeru) se disecira ju iz površine papilarnih mišića tretiranih ultrazvukom u istoj otopini.
Vlakno se zalijepi između platinskih žica, jedne spojene za izometrički transduktor sile (tip AE-801, SensoNor, Horten, Norveška), a drugi za mikromanipulator. Vlakno se relaksira u otopini koja se sastoji od (mM): EGTA-Na2 10, MgSO4 5.4, ATP-Na2 4, MOPS 20, pH otopine je namještena na 7.0, a ionska snaga na 0.16 M dodavanjem KOH i K+-acetata. Kreatin kinaza i kreatin fosfat nisu dodavani kao ATP generirajući sustav jer se razvijeno zatezanje dobro održavalo tijekom potrebnog vremena za eksperiment. Proračun ionske snage i slobodnog kalcija (pCa 7.0 do 6.2) izvedeni su koristeći povoljan program. Vlakna su istezana u relaksacijskoj otopini sve dok napon mirovanja nije postao jedva primjetan. Kada je kalcij (pCa 6.0 do 6.2)-izazvan napon postigao ravnotežne stanje test spoj (finalne koncentracije 0.1, 0.3, 1.3 i 10 μM) se kumulativno dodaje u otopinu u 6-minutnim intervalima. Svi eksperimenti su izvedeni sa svježim vlaknima na normalnoj sobnoj temperaturi.
Rezultati
Djelovanja kalcijeve senzitivizacije spoja prikazani su u tabeli 1.
Tabela 1. Maksimalno djelovanje kalcijeve senzitivizacije u oljuštenom vlaknu (promjena sile, % promjene u odnosu na kontrolu). Referentni spoj je Pr. 16 iz EP 383449.
[image]
Eksperiment 2. Djelovanje na tlak u lijevoj komori u izoliranom srcu
Nakon žrtvovanja srce zamorca je brzo izvađeno i isprano u oksigeniranom perfuzionom puferu. U aortu je uvučena kanila i osigurana ligaturom. Retrogradna perfuzija nastupila je odmah jer je srce stavljeno u termostatski reguliranu vlažnu komoru Langendorffovog aparata (Hugo Sachs Elektronik, KG) . Modificirana Tyrod otopina na 37°C uravnotežena u termostatski kontroliranom balonskom oksigenatoru s ugljikovim dioksidom (95% O2 i 5% CO2) upotrebijena je kao perfuzioni pufer. Sastav Tyrod otopine je (u mM) : NaCl 135; MgCl2 x 6H2O 1; KCl 5; CaCl2 x 2H2O 2; NaHCO3 15; Na2HPO4 x 2H2O 1; glukoza 10; pH 7.3-7.4. Perfuzioni pufer se dovodi na vrh oksigenatora pomoću pumpe i tjera automatski pomoću svog regulatora/kontrolora. Zatim se pufer napaja u balone oksigenatorske komore pomoću rotirajućeg diska. Dispergira se formiranjem tankog fluidnog sloja na velikoj unutrašnjoj površini oksigenatora u O2/CO2 atmosferi dovodeći do zasićenja perfuzata s kisikom (parcijalni tlak 660 mmHg na 37°C).
Eksperimenti se izvode pod konstantnim uvjetima tlaka (50 mmHg). Nakon kratke predstabilizacije (10 minuta) lateks balon (veličina 4) se pažljivo uvede u lijevu komoru kroz lijevu pulmonarnu venu i lijevi atrijum. Lateks balon se spaja za kanilu od nerdajućeg čelika spojenu s transduktorom tlaka. Lateks balon, kanila i komora transduktora tlaka se pažljivo pune smjesom etilen glikol/voda (1:1) izbjegavajući sve zračne mjehuriće. Izovolumetrijski lijevi ventrikularni /komorni tlak je zabilježen pomoću transduktora tlaka. Na početku eksperimenta, volumen balona je namješten da se dobije dijastolički tlak od oko 5 mmHg. Prije početka eksperimenta dopušta se stabilizacija srca daljnjih 30 do 50 minuta. Sistolički i krajnji dijastolički lijevi komorni/ventrikularni tlakovi se zabilježe radi proračuna maksimalnih pozitivnih i negativnih derivata lijevog ventrikularnog tlaka.
Rezultati
EC50 vrijednost (μM) različitih spojeva prema izumu na maksimalno pozitivno izveden sistolički tlak lijeve ventrikule/komore prikazani su u tabeli 2.
[image]
Da bi dalje prikazali izum bez ograničenja, navode se daljnji primjeri. Točke taljenja su određivane na Reichert ploči aparature za točku taljenja i nisu korigirane. NMR spektri su određivani pomoću Bruker ARX 400 spektrometra s internim TMS kao referencom (0 ppm).
PRIMJERI
Primjer 1 (intermedijarni spoj)
(R)-6-(4-hidrazino-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Mala modifikacija postupka opisanog u J. Med. Chem. (1990), 33(10), 2870-2875 upotrebijena je na slijedeći način. Otopina 1.7 g natrijevog nitrita u 12.5 ml vode polagano se dodaje na 0 do 5°C u otopinu 5 g (R)-6-(4-aminofenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona u 75 ml 1M klorovodične kiseline. Dobivena otopina se miješa u kupki s ledom tijekom 5 minuta te se polagano dodaje u otopinu 17 g kalij(II)klorid dihidrata u 150 ml 1M klorovodične kiseline održavajući temperaturu reakcije ispod 5°C. Otopina se miješa na ledu tijekom 40 minuta, a zatim se brzo dodaje otopina 75 ml 50% NaOH. Dobivena smjesa se miješa u kupki s ledom dok temperatura ne dostigne 0°C. Kristali se filtriraju i peru razrijeđenim amonijakom. Prinos je 5.0 g, 93%.
HPLC: enantiomerno čist.
1H NMR (400 MHz, DMSO-d6) : δ= 1.04 (d, 3H, CH3), 2.17 (d, 1H, J=16 Hz), 2.60 (m, 1H), 3.29 (m, 1H), 4.04 (s, 2H, NH2), 6.77 (d, 2H, J=8 Hz), 7.09 (b, 1H, NH), 7.54 (d, 2H, J=8 Hz), 10.66 (s, 1H, NHCO).
Primjer 2
(R)-6-{4-[N'-(4-hidroksi-3-metoksi-2-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Otopina 1.6 g 4-hidroksi-3-metoksi-2-nitro-benzaldehida u 15 ml etanola dodaje se u suspenziju 1.75 g (R)-6-(4-hidrazino-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona u 20 ml etanola i dobivena smjesa se refluktira 2 sata. Dobiveni kristali se filtriraju na sobnoj temperaturi i peru s etanolom. Prinos 2.37 g. HPLC: čistoća 99.4%, optička čistoća 99.8%.
1H NMR (DMSO-d6): δ= 1.06 (d, 3H, CH3), 2.18-2.22 (m, 1H), 2.64 (m, 1H), 3.34 (m, 1H), 3.84 (s, 3H, CH3O), 6.98 (d, 2H), 7.08 (d, 1H), 7.37 (d, 1H), 7.66 (d, 2H), 7.67 (s, 1H), 10.68 (s, 1H, NH), 10.77 (s, 1H, NHCO).
Daljnji primjeri
Slijedeći spojevi se sintetiziraju prema Općem postupku 1 (kao što je prikazano u ranijem primjeru) ili prema Općem postupku 2.
Opći postupak 1:
Refluksira se smjesa derivata hidrazina (II) i derivata benzaldehida (III) u povoljnom otapalu (etanol, 2-propanol, acetonitril ili octena kiselina) tijekom l do 24 sata. Proizvod se filtrira.
Opći postupak 2:
Zagrijava se čista smjesa derivata hidrazina (II) i ketona (III) na 140 do 170°C pod inertnom atmosferom. Trituira se s etil acetatom i proizvod filtrira.
Slijedeći spojevi se sintetiziraju prema općem postupku l ukoliko nije drugačije specificirano.
Primjer 3
2,6-dihidroksi-3-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il) -fenil]-hidrazonometil}-etil ester benzojeve
kiseline
Prinos 73%, točka taljenja: 203 do 208°C
1H NMR (DMSO-d6): δ= 1.06 (d, 3H), 2.20-2.23 (m, 1H), 2.64-2.68 (m, 1H), 3.30-3.33 (m, 1H), 3.83 (s, 3H, COOCH3), 6.49 (d, 1H), 6.93 (d, 2H), 7.40 (d, 1H), 7.69 (d, 2H), 8.09 (s, 1H), 10.40 (s, 1H), 10.57 (s, 1H), 10.76 (s, 1H), 11.54 (s, 1H).
Primjer 4
6-{4-[N'-(2,4,5-trihidroksi-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 82%, točka taljenja: 286 do 290°C
1H NMR (DMSO-d6): δ= 1.06 (d, 3H), 2.18-2.22 (m, 1H), 2.61-2.67 (m, 1H), 3.30-3.35 (m, 1H), 6.32 (s, 1H), 6.93-6.95 (m, 1H), 7.66 (d, 2H), 8.03 (s, 1H), 8.42 (s, 1H), 9.24 (s, 1H), 9.76 (s, 1H), 10.32 (s, 1H), 10.74 (s, 1H).
Primjer 5
6-{4-[N'-(2-hidroksi-5-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 89%, točka taljenja: 299 do 300°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.19-2.23 (m, 1H), 2.63-2.68 (m, 1H), 3.31-3.37 (m, 1H), 7.05-7.10 (m, 3H), 7.72 (d, 2H), 8.05-8.08 (m, 1H), 8.21 (s, 1H), 8.55-8.56 (m, 1H), 10.78 (s, 1H), 10.89 (s, 1H), 11.61 (s, 1H).
Primjer 6
6-{4-[N'-(4-hidroksi-3-metoksi-2-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 87%, točka taljenja: 235 do 239°C
1H NMR (DMSO-d6) : δ= 1.06 (d, 3H), 2.18-2.22 (m, 1H), 2.62-2.68 (m, 1H), 3.31-3.34 (m, 1H), 3.84 (s, 3H, CH3O), 6.98 (d, 2H), 7.08 (d, 1H), 7.37 (d, 1H), 7.65 (d, 2H), 7.67 (s, 1H), 10.67 (s, 1H), 10.76 (s, 1H).
Primjer 7
6-{4-[N'-(2,3-dihidroksi-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 69%, točka taljenja: 245 do 247°C
1H NMR (DMSO-d6) : δ= 1.06 (d, 3H), 2.19-2.23 (m, 1H), 2.64-2.68 (m, 1H), 3.33-3.38 (m, 1H), 6.68-6.77 (m, 2H), 6.99-7.03 (m, 3H), 7.70 (d, 2H), 8.17 (s, 1H), 9.2 (b, 1H), 9.95 (s, 1H), 10.63 (s, 1H), 10.77 (s, 1H).
Primjer 8
6-{4-[N'-(2,5-dihidroksi-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 89%, točka taljenja: 317 do 320°C
1H NMR (DMSO-d6): δ= 1.06 (d, 3H), 2.18-2.22 (m, 1H), 2.62-2.68 (m, 1H), 3.30-3.36 (m, 1H), 6.59-6.62 (m, 1H), 6.69-7.03 (m, 1H), 7.68 (d, 2H), 8.12 (s, 1H), 8.82 (s, 1H), 9.57 (s, 1H), 10.57 (s, 1H), 10.76 (s, 1H).
Primjer 9
6-{4-[N'-(3,4-dihidroksi-2-nitro-benziliden)-hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 70%, točka taljenja: 239 do 241°C
1H NMR (DMSO-d6): δ= 1.06 (d, 3H), 2.18-2.22 (m, 1H), 2.61-2.67 (m, 1H), 3.33-3.38 (m, 1H), 6.94-6.98 (m, 1H), 7.06 (d, 1H), 7.64-7.66 (m, 3H, ArH, CH=N), 9.94 (b, 1H), 10.48 (b, 1H), 10.59 (s, 1H), 10.75 (s, 1H).
Primjer 10
2-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazonometil}-benzojeva kiselina
Prinos: 61%, točka taljenja: 250 do 251°C
1H NMR (DMSO-d6) : 8= 1.12 (d, 3H), 2.25-2.30 (m, 1H), 2.72-2.78 (m, 1H), 3.42-3.51 (m, 1H), 7.72 (d, 2H), 7.90-7.95 (m, 3H), 7.98-8.05 (m, 2H), 8.34-8.36 (m, 1H), 8.61 (s, 1H), 11.03 (s, 1H).
Primjer 11
6-{4-[N'-(2-trifluorometil-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 62%, točka taljenja: 113 do 115°C
1H NMR (DMSO-d6) : δ= 1.06 (d, 3H), 2.19-2.23 (m, 1H), 2.63-2.69 (m, 1H), 3.33-3.37 (m, 1H), 7.14 (d, 2H), 7.50-7.52 (m, 1H), 7.68-7.75 (m, 4H), 8.19-8.27 (m, 2H), 10.79 (s, 1H), 11.04 (s, 1H).
Primjer 12
Octena kiselina 2-metoksi-4-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazinometil}-3-nitro-fenil ester
Prinos: 65%, točka taljenja: 220 do 223°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.18-2.23 (m, 1H), 2.38 (s, 3H, OCOCH3), 2.62-2.67 (m, 1H), 3.33-3.38 (m, 1H), 3.85 (s, 3H), 7.03 (d, 2H), 7.46 (d, 1H), 7.60 (d, 1H), 7.72 (d, 2H), 7.75 (s, 1H), 10.79 (s, 1H), 10.98 (s, 1H).
Primjer 13
6-(4-{N'-[1-(3,5-dihidroksi-fenil)etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 27%, točka taljenja: 162 do 166°C
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.17 (s, 3H), 2.18-2.22 (m, 1H), 2.62-2.68 (m, 1H), 3.35-3.41 (m, 1H), 6.17 (s, 1H), 6.67 (s, 2H), 7.23 (d, 2H), 7.67 (d, 2H), 9.21 (s, 1H), 9.44 (s, 1H), 10.75 (s, 1H).
Primjer 14
6-(4-{N'-[1-(2,4-dihidroksi-fenil)-3-(3,4-dimetoksi-fenil)-propiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 71%, točka taljenja: 135 do 140°C
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.19-2.23 (m, 1H), 2.64-2.67 (m, 1H), 2.77 (t, 2H), 3.15 (t, 2H), 3.31-3.33 (m, 1H), 3.69 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 6.29-6.35 (m, 2H), 6.83-6.87 (m, 2H), 6.93 (d, 1H), 7.03 (d, 2H), 7.36 (d, 1H), 7.71 (d, 2H), 9.1 (s, 1H), 9.5 (s, 1H), 10.78 (s, 1H), 12.91 (s, 1H).
Primjer 15
4-(4-{N'-[(2,4-dihidroksi-fenil)-fenil-metilen]-hidrazino}-fenil)-2H-ftalazin-1-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 95%, točka taljenja: 160 do 170°C
1H NMR (400 MHz, DMSO-d6) : δ= 6.7 (m, 2H), 7.3-7.9 (m, 13H), 8.3 (m, 1H), 10.1 (s, 1H), 10.7 (s, 1H), 12.1 (s, 1H), 12.7 (s, 1H).
Primjer 16
4-(4-{N'-[(2,4-dihidroksi-fenil)-(4-hidroksi-fenil)-metilen]-hidrazino}-fenil)-2H-ftalazin-1-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 95%, točka taljenja: 150 do 160°C
1H NMR (400 MHz, DMSO-d6) : δ= 6.3 (m, 2H), 6.8 (m, 2H), 7.4-7.9 (m, 10H), 8.3 (m, 1H), 10.1 (s, 1H), 10.2 (s, 1H), 10.4 (s, 1H), 12.1 (s, 1H), 12.7 (s, 1H).
Primjer 17
4-(4-{N'-[bis-(2,4-dihidroksi-fenil)-metilen]-hidrazino}-fenil)-2H-ftalazin-1-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 60%, točka taljenja: 140 do 146°C
1H NMR (400 MHz, DMSO-d6) : δ= 6.3 (m, 4H), 7.1-8.3 (m, 10H), 10.1 (s, 1H), 10.2 (s, 2H), 11.2 (s, 2H), 12.7 (s, 1H).
Primjer 18
4-{4-[N'-(2,4-dihidroksi-benziliden)-hidrazino]-fenil}-2H-ftalazin-1-on
Prinos: 50%, točka taljenja: 278 do 283°C
1H NMR (400 MHz, DMSO-d6) : δ= 6.3 (m, 1H), 6.4 (m, 1H), 7.4-7.9 (m, 8H), 8.3 (m, 1H), 8.9 (s, 1H), 10.3 (s, 1H), 12.8 (s, 1H), 13.4 (s, 1H).
Primjer 19
6-{4-[N'-(4-metansulfonilbenziliden) hidrazino]fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 54.3%, točka taljenja: 130 do 137°C
1H NMR (400 MHz, DMSO-d6) : δ= 1.08 (d, 3H, CH3), 2.21 (d, 1H, CH), 2.66 (d of d, 1H, CH), 3.22 (s, 3H, CH3), 3.33 (m, 1H, CH), 7.17 (d, 2H, CH), 7.71 (d, 2H, CH), 7.97 (s, 1H, CH), 10.79 (s, 1H, NH), 10.95 (s, 1H, NH).
Primjer 20
3-{[4-(4-metil-6-okso-l,4,5,6-tetrahidropiridazin-3-il)fenil]-hidrazonometil}-benzonitril
Prinos: 60%, točka taljenja: 220 do 224°C
1H NMR (400 MHz, DMSO-d6) : δ= 1.08 (d, 3H, CH3), 2.22 (d, 1H, CH), 2.66 (d of d, 1H, CH), 3.35 (m, 1H, CH), 7.16 (d, 2H, CH), 7.59 (t, 1H, CH), 7.69 (d, 2H, CH), 7.74 (d, 1H, CH), 7.92 (s, 1H, CH), 8.01 (d, 1H, CH), 8.10 (s, 1H, CH), 10.78 (s, 1H, NH), 10.86 (s, 1H, NH).
Primjer 21
6-{4-[N'-(2,4-dihidroksi-benziliden) hidrazino]fenil}-5-metil-2H-piridazin-3-on
Proizvod se prekristalizira iz dimetilformamida. Prinos: 55%, točka taljenja: 303 do 310°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.16 (s, 3H, CH3), 6.35 (m, 2H, CH), 6.79 (s, 1H, CH), 6.97 (d, 2H, CH), 7.34 (m, 3H, CH), 8.10 (s, 1H, CH), 9.69 (s, 1H, OH), 10.33 (s, 1H, NH), 10.63 (s, 1H, OH), 12.90 (s, 1H, NH).
Primjer 22
6-{4-[N'-(4-hidroksi-3-metoksi-2-nitrobenziliden)hidrazino]-fenil}-5-metil-2H-piridazin-3-on
Prinos: 71.0%, točka taljenja: 264 do 268°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.15 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.79 (s, 1H, CH), 7.01 (d, 2H, CH), 7.09 (d, 1H, CH), 7.33 (d, 2H, CH), 7.38 (d, 1H, CH), 7.68 (s, 1H, CH), 10.62 (s, 1H, NH), 10.65 (s, 1H, OH), 12.91 (s, 1H, NH).
Primjer 23
6-{4-{N'-[1-(2,4-dihidroksifenil) etiliden]hidrazino}fenil}-5-metil-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2.
Proizvod se refluksira u propionitrilu s octenom kiselinom kao katalizatorom.
Prinos: 32%, točka taljenja: 299 do 303°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.16 (d, 3H, CH3), 2.35 (s, 3H, CH3), 6.28 (d, 1H, CH), 6.33 d of d, 1H, CH), 6.79 (s, 1H, CH), 7.07 (d, 2H, CH), 7.38 (d, 1H, CH), 7.39 (d, 2H, CH), 9.50 (s, 1H, NH), 9.69 (s, 1H, OH), 12.92 (s, 1H, OH), 12.97 (s, 1H, NH) .
Primjer 24
6-{4-[N’-(2,4-dihidroksibenziliden) hidrazino]fenil}-2,5-dimetil-2H-piridazin-3-on
Prinos: 82%, točka taljenja: 266 do 269°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.16 (d, 3H, CH3), 3.66 (s, 3H, CH3), 6.32 (d, 1H, CH), 6.34 (d of d, 1H, CH), 6.84 (d, 1H, CH), 6.97 (d, 2H, CH), 7.32 (d, 1H, CH), 7.36 (d, 2H, CH), 8.10 (s, 1H, CH), 9.69 (s, 1H), 10.36 (s, 1H), 10.61 (s, 1H).
Primjer 25
6-{4-[N’-(2,4-dihidroksibenziliden)hidrazino]fenil}-2-metil-2H-piridazin-3-on
Prinos: 82.4%, točka taljenja: 304 do 306°C
1H NMR (400 MHz, DMSO-d6) : δ= 3.72 (s, 3H, CH3), 6.36 (m, 2H, CH), 6.99 (m, 3H, CH), 7.36 (d, 1H, CH), 7.76 (d, 2H, CH), 7.96 (d, 1H, CH), 8.12 (s, 1H, CH), 9.72 (s, 1H), 10.44 (s, 1H), 10.57 (s, 1H).
Primjer 26
6-{4-{N'-[1-(2,4-dihidroksifenil) etiliden]hidrazino}fenil}-2-metil-2H-piridazin-3-on
Otopina 0.78 g 6-(4-hidrazinofenil)-2-metil-2H-piridazin-3-ona i 0.55 g 2.4-dihidroksi-acetofenona u 20.0 ml acetonitrilu se zagrijava pod refluksom tokom 5 sati. Kristali koji se formiraju na sobnoj temperaturi se filtriraju. Proizvod se iskristalizira hlađenjem filtrata preko noći. Proizvod se filtrira, pere toplim etanolom i suši pod smanjenim tlakom. Prinos: 5.6%, točka taljenja: 263 do 268°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.35 (s, 3H, CH3), 3.72 (s, 3H, CH3), 6.30 (s, 1H, CH), 6.34 (d, 1H, CH), 6.99 (d, 1H, CH), 7.09 (d, 2H, CH), 7.39 (d, 1H, CH), 7.82 (d, 2H, CH), 7.99 (d, 1H, CH), 9.58 (s, 1H, NH), 9.71 (s, 1H, OH), 12.90 (s, 1H, OH).
Primjer 27
6-{4-{N'-[1-(2,4-dihidroksifenil)propiliden]hidrazino}fenil}-2-metil-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 29%, točka taljenja: 225 do 233°C
1H NMR (400 MHz, DMSO-d6) : δ= 1.15 (t, 3H, CH3), 2.87 (q, 2H, CH2), 3.73 (s, 3H, CH3), 6.33 (d, 1H, CH), 6.37 (d of d, 1H, CH), 6.99 (d, 1H, CH), 7.13 (d, 2H, CH), 7.37 (d, 1H, CH), 7.82 (d, 1H, CH), 7.99 (d, 1H, CH), 9.67 (s, 1H), 9.73 (s, 1H), 12.98 (s, 1H).
Primjer 28
6-{4-[N’-(2,4-dihidroksi-3-etilbenziliden) hidrazino]fenil}-2-metil-2H-piridazin-3-on
Prinos: 37%, točka taljenja: 262 do 266°C
1H NMR (400 MHz, DMSO~d6) : δ= 1.08 (t, 3H, CH3), 2.61 (q, 2H, CH2), 3.71 (s, 3H, CH3), 6.43 (d, 1H, CH), 6.96 (d, 2H, CH), 6.99 (d, 1H, CH), 7.01 (d, 1H, CH), 7.79 (d, 2H, CH), 7.96 (d, 1H, CH), 8.05 (s, 1H, CH), 9.67 (s, 1H), 10.49 (s, 1H), 11.30 (s, 1H).
Primjer 29
4-(2,4-dihidroksifenil)-4-{[4-(1-metil-6-okso-1,6-dihidropiridazin-3-il) fenil]hidrazono}maslačna kiselina
Naslovni spoj se dobije prema općem postupku 2. Prinos: 15.9%, točka taljenja: 138 do 141°C
1H NMR (400 MHz, DMSO-d6) : δ= 2.51 (t, 2H, CH2), 3.06 (t, 2H, CH2), 3.72 (s, 3H, CH3), 6.30 (s, 1H, CH), 6.34 (d, 1H, CH), 7.01 (d, 1H, CH), 7.10 (d, 2H, CH), 7.32 (d, 1H, CH), 7.83 (d, 2H, CH), 7.01 (d, 1H, CH), 9.72 (s, 1H), 9.78 (s, 1H), 12.31 (s, 1H), 12.74 (s, 1H).
Primjer 30 (intermedijer)
6-(4-hidrazinofenil)-5-metil-2H-piridazin-3-on
Naslovni spoj se dobije iz 6-(4-aminofenil)-5-metil-2H-piridazin-3-ona slično kao 6-(4-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
1H NMR (400 MHz, DMSO-d6) : 8= 2.13 (s, 3H, CH3), 4.11 (s, 2H, NH2), 6.75 (s, 1H, CH), 6.81 (d, 2H, CH), 6.95 (s, 1H, NH), 7.21 (d, 2H, CH), 12.82 (s, 1H, NH).
Primjer 31 (intermedijer)
6-(4-hidrazinofenil)-2,5-dimetil-2H-piridazin-3-on
Naslovni spoj se dobije iz 6-(4-aminofenil)-2,5-dimetil-2H-piridazin-3-ona slično kao 6-(4-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
:H NMR (400 MHz, DMSO-d6) : 8= 2.14 (d, 3H, CH3), 3.63 (s, 3H, CH3), 4.12 (s, 2H, NH2), 6.81 (d, 2H, CH), 6.82 (d, 1H, CH), 6.98 (s, 1H, NH), 7.22 (d, 2H, CH).
Primjer 32 (intermedijer)
6-(4-hidrazinofenil)-2-metil-2H-piridazin-3-on
Naslovni spoj se dobije iz 6-(4-aminofenil)-2-metil-2H-piridazin-3-ona slično kao 6-(4-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
1H NMR (400 MHz, DMSO-d6) : δ= 3.69 (s, 3H, CH3), 4.18 (s, 2H, NH2), 6.83 (d, 2H, CH), 6.94 (d, 1H, CH), 7.11 (s, 1H, NH), 7.65 (d, 2H, CH), 7.93 (d, 1H, CH).
Primjer 33
6-(4-{N'-[1-(2,4-dihidroksi-fenil) etiliden]hidrazino}fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 74%, točka taljenja: 259 do 261°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.21 (d, 1H), 2.35 (s, 3H), 2.63-2.68 (m, 1H), 3.30-3.36 (m, 1H), 6.28 (d, 1H), 6.34 (q, 1H), 7.03 (d, 2H), 7.37 (d, 1H), 7.71 (d, 2H), 9.57 (s, 1H), 9.70 (s, 1H), 10.78 (s, 1H), 12.91 (s, 1H).
Primjer 34
6-(4-{N'-[bis-(2,4-dihidroksi-fenil) -metilen]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 13%, točka taljenja: 150 do >175°C
1H NMR (DMSO-d6) : δ= 1.06 (d, 3H), 2.19 (d, 1H), 2.61-2.67 (m, 1H), 3.30-3.36 (m, 1H), 6.16-6.19 (q, 1H), 6.03 (d, 1H), 6.37-6.39 (q, 1H), 6.47 (d, 1H), 6.55 (d, 1H), 6.84 (d, 1H), 7.02 (d, 2H), 7.66 (d, 2H), 8.93 (broad, 1H), 9.72 (broad, 3H), 10.76 (s, 1H), 12.71 (s, 1H).
Primjer 35
6-(4-{N'-[1-(2,5-dihidroksi-fenil)etiliden]hidrazino}fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos: 73%, točka taljenja: 279 do 284°C
1H NMR (DMSO-d6) : δ= 1.08 (d, 3H), 2.21 (d, 1H), 2.34 (s, 3H), 2.63-2.69 (m, 1H), 3.32-3.38 (m, 1H), 6.66-6.73 (m, 2H), 6.93 (s, 1H), 7.09 (d, 2H), 7.73 (d, 2H), 8.85 (s, 1H), 9.73 (s, 1H), 10.80 (s, 1H), 11.85 (s, 1H).
Primjer 36
6-{4-[N’-(2,4-dihidroksi-benziliden)-hidrazino]-fenil}-5-etil-4,5-dihidro-2H-piridazin-3-on
Prinos: 29%, točka taljenja: 270 do 275°C
1H NMR (DMSO-d6) : δ= 0.87 (t, 3H), 1.38-1.54 (m, 2H), 2.36 (d, 1H), 2.56-2.62 (q, 1H), 3.12-3.38 (m, 1H), 6.32 (m, 2H), 6.93 (d, 2H), 7.33 (d, 1H), 7.67 (d, 2H), 8.08 (s, 1H), 9.68 (s, 1H), 10.34 (s, 1H), 10.55 (s, 1H), 10.71 (s, 1H).
Primjer 37
N-[4-(1-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazino}etil) -fenilj-acetamid
Naslovni spoj se dobije prema općem postupku 2. Prinos: 41%, točka taljenja: 145 do 155°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.05 (s, 3H), 2.23 (d, 1H), 2.24 (s, 3H), 2.61-2.68 (m, 1H), 3.30-3.36 (m, 1H), 7.24 (d, 2H), 7.60 (d, 2H), 7.67 (d, 2H), 7.74 (d, 2H), 9.45 (s, 1H), 10.01 (s, 1H), 10.75 (s, 1H).
Primjer 38
6-(4-{N'-[1-(2,4-dihidroksi-3-metil-fenil)-etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 47%, točka taljenja: 244 do 248°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.03 (s, 3H), 2.20 (d, 1H), 2.63-2.68 (m, 1H), 3.30-3.36 (m, 1H), 6.43 (d, 1H), 6.91 (d, 2H), 7.01 (d, 1H), 7.70 (d, 2H), 8.05 (s, 1H), 9.69 (s, 1H), 10.46 (s, 1H), 10.76 (s, 1H), 11.31 (s, 1H).
Primjer 39
6-{4-[N’-(3-acetil-2,4-dihidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 72%, točka taljenja: 268 do 270°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.20 (d, 1H), 2.61-2.66 (m, 1H), 2.69 (s, 3H), 3.30-3.36 (m, 1H), 6.53 (d, 1H), 6.98 (d, 2H), 7.70 (m, 3H), 8.15 (s, 1H), 10.56 (s, 1H), 10.76 (s, 1H), 11.89 (s, 1H), 13.91 (s, 1H).
Primjer 40
6-{4-[N’-(3-etil-2,4-dihidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 36%, točka taljenja: 238 do 240°C
1H NMR (DMSO-d6) : δ= 1.05-1.09 (m, 3H, 3H), 2.21 (d, 1H), 2.60-2.64 (m, 3H), 3.30-3.36 (m, 1H), 6.42 (d, 1H), 6.90 (d, 2H), 7.00 (d, 1H), 7.71 (d, 2H), 8.04 (s, 1H), 9.65 (s, 1H), 10.46 (s, 1H), 10.76 (s, 1H), 11.31 (s, 1H).
Primjer 41
N-(3-hidroksi-4{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazonometil}-fenil)-acetamid
Prinos: 39%, točka taljenja: 269 do 275°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.03 (s, 3H), 2.20 (d, 1H), 2.61-2.67 (m, 1H), 3.28-3.34 (m, 1H), 6.97-7.01 (m, 3H), 7.36 (d, 1H), 7.49 (d, 1H), 7.68 (d, 2H), 8.12 (s, 1H), 9.96 (s, 1H), 10.42 (s, 1H), 10.52 (s, 1H), 10.75 (s, 1H).
Primjer 42
6-{4-[N’-(2,4-diklor-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 53%, točka taljenja: 252 do 254°C
1H NMR (DMSO-d6) : δ= 1.07 (d, 3H), 2.21 (d, 1H), 2.63-2.68 (m, 1H), 3.28-3.37 (m, 1H), 7.13 (d, 2H), 7.45 (q, 1H), 7.64 (d, 1H), 7.70 (d, 2H), 8.04 (d, 1H), 8.19 (s, 1H), 10.78 (s, 1H), 11.02 (s, 1H).
Primjer 43
6-{4-[N’-(2,4-dihidroksi-3-propil-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 61%, točka taljenja: 160 do 170°C
1H NMR (DMSO-d6) : δ= 0.92 (t, 3H), 1.07 (d, 3H), 1.48-1.53 (m, 2H), 2.21 (d, 1H), 2.55-2.58 (m, 2H), 2.62-2.68 (m, 1H), 3.30-3.35 (m, 1H), 6.42 (d, 1H), 6.91 (d, 2H), 7.00 (d, 1H), 7.70 (d, 2H), 8.04 (s, 1H), 9.25 (s, 1H), 10.45 (s, 1H), 10.76 (s, 1H), 11.29 (s, 1H).
Primjer 44
6-{4-[N’-(3-butil-2 ,4-dihidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos: 74%, točka taljenja: 218°C
1H NMR (DMSO-d6) : δ= 0.91 (t, 3H), 1.07 (d, 3H), 1.29-1.38 (m, 2H), 1.45-1.51 (m, 2H), 2.21 (d, 1H), 2.57-2.68 (m, 2H, 1H), 3.29-3.36 (m, 1H), 6.42 (d, 1H), 6.91 (d, 2H), 6.99 (d, 1H), 7.71 (d, 2H), 8.04 (s, 1H), 9.62 (s, 1H), 10.46 (s, 1H), 10.76 (s, 1H), 11.28 (s, 1H).
Primjer 45 (intermedijer)
6-(3-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije upotrebljavajući postupak iz primjera l polazeći od 1.5 g 6-(3-aminofenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona (J. Med. Chem. 1974 17 (3) ) . Proizvod se izolira (poslije dodatka otopine natrijevog hidroksida) ekstrakcijom u tetrahidrofuranu. Kristalizacija iz acetonitrila daje 1.0 g naslovnog spoja.
1H NMR (DMSO-d6, 400 MHz) : 1.06 (d, 3H), 2.22 (d, 1H), 2.66 (dd, 1H), 3.30 (m, 1H), 3.97 (s, 2H), 6.78 (s, 1H), 6.81 (m, 1H), 6.98 (m, 1H), 7.14 (t, 1H), 7.23 (t, 1H), 10.86 (s, 1H).
Primjer 46
6-(3-{N-[bis (2,4-dihidroksi-fenil) metilen]hidrazino}fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Smjesa 0.38 g 6-(3-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona, 0.51 g 2,2',4,4'-tetrahidroksibenzofenona, 0.4 ml octene kiseline i 7.0 ml acetonitrila se refluktira 20 sati. Otapala se uklanjanju u vakuumu i proizvod se odvaja koristeći kromatografiju na koloni (silikagel; toluol, etilacetat, octena kiselina 8:3:3). Kristalizacija iz smjese etil acetata i diklormetana daje 290 mg, točka taljenja 195 do 205°C.
1H NMR (DMSO-d6, 400 MHz) : 1.08 (d, 3H), 2.23 (d, 1H), 2.68 (dd, 1H), 3.31 (m, 1H), 6.17 (dd, 1H), 6.30 (d, 1H), 6.36 (dd, 1H), 6.46 (d, 1H), 6.57 (d, 1H), 6.83 (d, 1H), 7.01 (m, 1H), 7.19 (m, 1H), 7.28 (t, 1H), 7.45 (t, 1H), 10.92 (s, 1H), 8-14 (široki singleti, 5H).
Primjer 47
6-{4-[N-(2,4-dihidroksi-5-nitrobenziliden) hidrazino]fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
1.10 g 6-(4-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona, 0.92 g 2,4-dihidroksi-5-nitrobenzaldehida i 20 ml octene kiseline se objedine i dobivena smjesa se refluksira 20 minuta. Smjesa se ohladi do sobne temperature i proizvod se profiltrira, prinos 1.95 g solvatiranih kristala s l molom octene kiseline, točka taljenja oko 290°C uz razgradnju.
1H NMR (DMSO-d6, 400 MHz): 1.08 (d, 3H), 1.91 (s, 3H), 2.22 (d, 1H), 2.66 (dd, 1H), 3.36 (m, 1H), 6.58 (s, 1H), 7.03 (d, 2H), 7.70 (d, 2H), 8.11 (s, 1H), 8.34 (s, 1H), 10.69 (s, 1H), 10.76 (s, 1H), 13.04 (s, 1H), 13.58 (s, 1H), 13.95 (s, 1H).
Primjer 48
6-{4-{N-[4-(dimetilamino)benziliden]hidrazino}fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
1.1 g 6-(4-hidrazinofenil)-5-metil-4,5-dihidro-2H-piridazin-3-ona, 0.83 g 4-(dimetilamino)benzaldehida, 0.60 ml octene kiseline i 15 ml acetonitrila se objedine i dobijena smjesa se zagrijava do ključanja, ohladi se do sobne temperature i proizvod se profiltrira i pere s acetonitrilom, prinos 1.50 g, točka taljenja 225 do 232°C.
1H NMR (DMSO-d6, 400 MHz) : 1.07 (d, 3H), 2.21 (d, 1H), 2.64 (dd, 1H), 2.94 (s, 6H), 3.34 (m, 1H), 6.73 (d, 2H), 7.04 (d, 2H), 7.49 (d, 2H), 7.65 (d, 2H), 7.81 (s, 1H), 10.24 (s, 1H), 10.73 (s, 1H).
Primjer 49
6-(4-{N-[1-(2,4-dihidroksi-3-metilfenil) etilidenjhidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Naslovni spoj se dobije prema općem postupku 2. Prinos 41%, točka taljenja 268 do 271°C.
1H NMR (DMSO-d6, 400 MHz): 1.07 (d, 3H), 2.20 (d, 1H), 2.65 (dd, 1H), 3.35 (m, 1H), 6.40 (d, 1H), 7.05 (d, 2H), 7.24 (d, 1H), 7.73 (d, 2H), 9.55 (s, 1H), 9.57 (s, 1H), 10.77 (s, 1H), 13.25 (s, 1H).
Primjer 50
6-{4-[N-(2,4-dimetoksibenziliden) hidrazino]fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 90%, točka taljenja 215 do 218°C.
1H NMR (DMSO-d6, 400 MHz): 1.07 (d, 3H), 2.17 (d, 1H), 2.63 (dd, 1H), 3.31 (m, 1H), 3.80 (s, 3H), 3.84 (s, 3H), 6.58-6.61 (m, 2H), 7.03 (d, 2H), 7.65 (d, 2H), 7.78 (d, 1H), 8.16 (s, 1H), 10.43 (s, 1H), 10.73 (s, 1H).
Primjer 51
6-{4-[N-(2-hidroksi-4-metoksibenziliden) hidrazino]fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 93%, točka taljenja 214 do 216°C.
1H NMR (DMSO-d6, 400 MHz) : 1.07 (d, 3H), 2.20 (d, 1H), 2.64 (dd, 1H), 3.34 (m, 1H), 3.75 (s, 3H), 6.46-6.51 (m, 2H), 6.96 (d, 2H), 7.47 (d, 1H), 7.68 (d, 2H), 8.12 (s, 1H), 10.48 (s, 1H), 10.66 (s, 1H), 10.75 (s, 1H).
Primjer 52
6-{4-[N’-(4-nitrobenziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 80%, točka taljenja 216 do 217°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.08 (d, 3H), 2.21 (d, 1H), 2.63-2.66 (m, 1H), 3.29-3.31 (m, 1H), 7.19 (d, 2H), 7.72 (d, 2H), 7.72 (d, 2H), 7.92 (s, 1H), 7.99 (s, 1H), 8.24 (d, 2H), 10.80 (s, 1H), 10.10 (s, 1H).
Primjer 53
6-{4-[N’-(2-metoksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 78%, točka taljenja 180 do 183°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.20 (d, 1H), 2.62-2.67 (m, 1H), 3.32-3.34 (m, 1H), 3.85 (s, 3H), 6.97-7.00 (m, 1H), 7.06 (d, 2H), 7.29-7.32 (m, 1H), 7.66 (d, 2H), 7.87 (d, 1H), 8.25 (s, 1H), 10.61 (s, 1H), 10.75 (s, 1H).
Primjer 54
6-{4-[N’-(2-hidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 90%, točka taljenja 265 do 268°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.20 (d, 1H), 2.62-2.68 (m, 1H), 3.32-3.36 (m, 1H), 6.86-6.90 (m, 1H), 7.01 (d, 2H), 7.16-7.20 (m, 1H), 7.60 (d, 2H), 7.69 (d, 1H), 8.20 (s, 1H), 10.37 (s, 1H), 10.64 (s, 1H), 10.76 (s, 1H).
Primjer 55
6-{4-[N’-(4-metoksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 82%, točka taljenja 172 do 174°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.08 (d, 3H), 2.19 (d, 1H), 2.61-2.67 (m, 1H), 3.29-3.31 (m, 1H), 3.79 (s, 3H), 6.98 (d, 2H), 7.07 (d, 2H), 7.61 (d, 2H), 7.66 (s, 2H), 7.87 (s, 1H), 10.43 (s, 1H), 10.75 (s, 1H).
Primjer 56
2,6-dihidroksi-3-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il) -fenil]-hidrazonometil}-benzojeva kiselina
Prinos 51%, točka taljenja 215 do 218°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.06 (d, 3H), 2.20 (d, 1H), 2.61-2.67 (m, 1H), 3.30-3.36 (m, 1H), 6.24 (d, 1H), 6.99 (d, 2H), 7.63 (d, 2H), 7.65 (d, 1H), 8.16 (s, 1H), 10.00 (s, 1H), 10.71 (s, 1H), 10.90 (s, 1H).
Primjer 57
6-{4-[N’-(2-hidroksi-3-metoksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 93%, točka taljenja 210 do 213°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.08 (d, 3H), 2.20 (d, 1H), 2.62-2.67 (m, 1H), 3.35-3.39 (m, 1H), 3.81 (s, 1H), 6.82 (t, 1H), 6.93 (d, 1H), 7.02 (d, 2H), 7.22 (d, 1H), 7.69 (d, 2H), 8.21 (s, 1H), 9.88 (s, 1H), 10.64 (s, 1H), 10.77 (s, 1H).
Primjer 58
6-{4-[N’-(2-nitro-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 77%, točka taljenja 250 do 253°C.
1H NMR (400 MHz, DMSO-d6): δ= 1.07 (d, 3H), 2.20 (d, 1H), 2.63-2.70 (m, 1H), 3.29-3.36 (m, 1H), 7.14 (d, 2H), 7.50-7.54 (m, 1H), 7.70 (d, 2H), 7.71-7.75 (m, 1H), 7.99 (d, 1H), 8.17 (s, 1H), 8.30 (s, 1H), 10.79 (s, 1H), 11.11 (s, 1H).
Primjer 59
6-{4-[N’-(2,6-dinitro-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 20%, točka taljenja 216 do 218°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.06 (d, 3H), 2.20 (d, 1H), 2.63-2.70 (m, 1H), 3.29-3.36 (m, 1H), 6.96 (d, 2H), 7.68-7.74 (m, 3H), 8.11 (s, 1H), 8.22 (d, 2H), 10.81 (s, 1H), 11.29 (s, 1H).
Primjer 60
4-{[4-(4-metil-6-okso-l,4,5,6-tetrahidro-piridazin-3-il)-fenil]-hidrazonometil}-benzonitril
Prinos 85%, točka taljenja 246 do 248°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.21 (d, 1H), 2.63-2.67 (m, 1H), 3.30-3.35 (m, 1H), 7.16 (d, 2H), 7.70 (d, 2H), 7.82 (d, 2H), 7.84 (d, 2H), 7.93 (d, 2H), 10.79 (s, 1H), 10.97 (s, 1H).
Primjer 61
6-{4-[N’-(4-hidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 86%, točka taljenja 258 do 261°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.19 (d, 1H), 2.61-2.67 (m, 1H) ,. 3.30-3.35 (m, 1H), 6.79 (d, 2H), 7.04 (d, 2H), 7.48 (d, 2H), 7.65 (d, 2H), 7.82 (s, 1H), 9.66 (s, 1H), 10.33 (s, 1H), 10.73 (s, 1H).
Primjer 62
6-{4-[N’-(3-hidroksi-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 80%, točka taljenja 267 do 270°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.20 (d, 1H), 2.61-2.67 (m, 1H), 3.33-3.36 (m, 1H), 6.71-6.73 (dd, 1H), 7.04-7.12 (m, 4H), 7.18-7.21 (m, 1H), 7.68 (d, 2H), 7.82 (s, 1H), 9.46 (s, 1H), 10.54 (s, 1H), 10.76 (s, 1H).
Primjer 63
6-{4-[N’-(4-hidroksi-3-nitro-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 21%, točka taljenja 230 do 233°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.19 (d, 1H), 2.62-2.69 (m, 1H), 3.31-3.36 (m, 1H), 7.09 (d, 2H), 7.16 (d, 1H), 7.67 (d, 2H), 7.88 (s, 1H), 7.89-7.91 (dd, 1H), 8.11 (d, 1H), 10.64 (s, 1H), 10.76 (s, 1H), 11.00 (s, 1H).
Primjer 64
4-(2,4-dihidroksi-fenil) -4-{[4- (4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il) -fenil]-hidrazino}-maslačna kiselina
Prinos 26%, točka taljenja 299 do 302°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.19 (d, 1H), 2.49-2.51 (t, 2H), 2.64-2.67 (m, 1H), 3.03-3.05 (t, 2H), 3.28-3.31 (m, 1H), 6.29 (d, 1H), 6.33-6.35 (dd, 1H), 7.04 (d, 2H), 7.32 (d, 1H), 7.72 (d, 2H), 9.71 (s, 1H), 9.79 (s, 1H), 10.78 (s, 1H).
Primjer 65
6-{4-[N’-(2,4-dinitro-benziliden) -hidrazino]-fenil}-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 50%, točka taljenja 278 do 280°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.07 (d, 3H), 2.21 (d, 1H), 2.64-2.70 (m, 1H), 3.37-3.40 (m, 1H), 7.22 (d, 2H), 7.75 (d, 2H), 8.37 (s, 1H), 8.43 (d, 1H), 8.44 (d, 1H), 8.74 (d, 1H), 10.84 (s, 1H), 11.62 (s, 1H).
Primjer 66
5-(2,4-dihidroksi-fenil)-5-{[4-(4-metil-6-okso-1,4,5,6-tetrahidro-piridazin-3-il) -fenil]-hidrazino}-pentanova kiselina
Prinos 39%, točka taljenja 235 do 240°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.04-1.08 (m, 5H), 1.72-1.74 (m, 2H), 2.22 (d, 1H), 2.64-2.67 (m, 1H), 2.80-2.82 (m, 2H), 3.30-3.36 (m, 1H), 6.29 (d, 1H), 6.32-6.35 (dd, 1H), 7.04 (d, 2H), 7.41 (d, 1H), 7.72 (d, 2H), 9.77 (s, 1H), 9.71 (s, 1H), 10.78 (s, 1H), 12.00 (s, 1H), 12.88 (s, 1H).
Primjer 67
6-(4-{N'-[1-(4-hidroksi-3-metoksi-2-nitro-fenil)-etiliden]-hidrazino}-fenil)-5-metil-4,5-dihidro-2H-piridazin-3-on
Prinos 46%, točka taljenja 251 do 254°C.
1H NMR (400 MHz, DMSO-d6) : δ= 1.06 (d, 3H), 2.19 (d, 1H), 2.21 (s, 3H), 2.61-2.65 (m, 1H), 3.30-3.36 (m, 1H), 3.83 (s, 3H), 7.06 (d, 2H), 7.08 (d, 2H), 7.28 (d, 2H), 7.63 (d, 1H), 9.49 (s, 1H), 10.55 (s, 1H), 10.75 (s, 1H).
Claims (10)
1. Spojevi formule (I):
[image]
naznačeni time, da
R1 do R4 označava vodik, alkil, alkenil, aril, arilalkil, karboksialkil, hidroksialkil ili halogenalkil, ili R2 i R3 formiraju prsten od 5 do 7 ugljikovih atoma,
R5 do R9 označava vodik, alkil, alkenil, aril, arilalkil, acil, hidroksi, alkoksi, alkoksikarbonil, amino, acilamino, alkilamino, ariloksi, halogen, cijano, nitro, karboksi, alkilsulfonil, sulfonamino ili trifluorometil, gdje svaki ranije naveden aril ostatak može biti supstituiran sam po sebi ili kao dio druge skupine,
i njihove farmaceutski prihvatljive soli i estere,
pod uvjetom da
a) kada su R1, R2, R3, R5, R6, R8 i R9 vodik, R4 je metil, a R7 nije vodik, metoksi, cijano ili metil, te
b) kada su R1, R2, R3, R5, R6, R7 i R8 vodik, R4 je metil, a R9 nije hidroksi ili klor, te
c) kada su R1, R2, R3, R5, R6, R7 i R9 vodik, R4 je metil, a R8 nije trifluorometil.
2. Spoj prema zahtjevu 1, naznačen time, da su R5 do R9 neovisno vodik, C1-6 alkil, C1-6 alkenil, C6-10 aril, C7-12 arilalkil, C1-6 acil, hidroksi, C1-6 alkoksi, C1-6 alkoksikarbonil, amino, C1-6 acilamino, C1-6 alkilamino, C6-10 ariloksi, halogen, cijano, nitro, karboksi, C1-6 alkilsulfonil, sulfonamido ili trifluorometil.
3. Spoj prema zahtjevu 2, naznačen time, da su R5 do R9 neovisno vodik, hidroksi, C1-6 alkil, C1-6 alkoksi, karboksi, C1-6 alkoksikarbonil ili nitro.
4. Spoj prema zahtjevu 3, naznačen time, da je R5 hidroksi, C1-6 alkil, C1-6 alkoksi, karboksi, C1-6 alkoksikarbonil ili nitro.
5. Spoj prema zahtjevu 4, naznačen time, da je R5 hidroksi ili nitro.
6. Spoj prema bilo kojem od zahtjeva od 1 do 5, naznačen time, da su R1 do R4 neovisno vodik, C1-6 alkil, C1-6 alkenil, C6-10 aril, C7-12 arilalkil, C1-6 karboksialkil, C1-6 hidroksialkil ili C1-6 halogenalkil ili R2 i R3 formiraju fenil prsten.
7. Spoj prema bilo kojem od zahtjeva od 1 do 6, naznačen time, da su R1 do R3 neovisno vodik ili C1-6 alkil.
8. Spojevi formule (I) u kojima su R1, R2, R3, R5, R6, R8 i R9 vodik, R4 je metil, a R7 je vodik, metoksi, cijano ili metil, ili u kojima su R1, R2, R3, R5, R6, R7 i R8 vodik, R4 je metil, a R9 je hidroksi ili klor, ili u kojima su R:, R2, R3, R5, R6, R7 i R9 vodik, R4 je metil, a R8 je trifluorometil, i njihove farmaceutski prihvatljive soli i esteri, naznačeni time, da se upotrebljavaju kao lijek.
9. Farmaceutski pripravak, naznačen time, da obuhvaća spojeve prema zahtjevu 1 kao aktivnu komponentu zajedno s farmaceutski prihvatljivom podlogom.
10. Postupak tretiranja kongestivnog srčanog udara, naznačen time, da obuhvaća primjenu terapeutski učinkovite količine spoja prema zahtjevu 1 na pacijentu kojem je to potrebno.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20000577A FI20000577A0 (fi) | 2000-03-13 | 2000-03-13 | Pyridatsinyylifenyylihydratsoneja |
| PCT/FI2001/000241 WO2001068611A1 (en) | 2000-03-13 | 2001-03-12 | Pyridazinyl phenyl hydrazones useful against congestive heart failure |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20020816A2 true HRP20020816A2 (en) | 2004-12-31 |
Family
ID=8557913
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20020816 HRP20020816A2 (en) | 2000-03-13 | 2002-10-11 | Pyridazinyl phenyl hydrazones useful against congestive heart failure |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US6699868B2 (hr) |
| EP (1) | EP1265871B1 (hr) |
| JP (1) | JP2003527375A (hr) |
| KR (1) | KR20030001379A (hr) |
| CN (1) | CN1191241C (hr) |
| AR (1) | AR027644A1 (hr) |
| AT (1) | ATE317388T1 (hr) |
| AU (2) | AU4657701A (hr) |
| BG (1) | BG65859B1 (hr) |
| BR (1) | BR0109136A (hr) |
| CA (1) | CA2403188A1 (hr) |
| CZ (1) | CZ20022997A3 (hr) |
| DE (1) | DE60117131T2 (hr) |
| DK (1) | DK1265871T3 (hr) |
| EA (1) | EA005574B1 (hr) |
| EE (1) | EE200200520A (hr) |
| ES (1) | ES2256222T3 (hr) |
| FI (1) | FI20000577A0 (hr) |
| HK (1) | HK1052008A1 (hr) |
| HR (1) | HRP20020816A2 (hr) |
| HU (1) | HUP0300177A3 (hr) |
| IL (2) | IL151492A0 (hr) |
| MX (1) | MXPA02008997A (hr) |
| NO (1) | NO324172B1 (hr) |
| NZ (1) | NZ521162A (hr) |
| PL (1) | PL357107A1 (hr) |
| RS (1) | RS50439B (hr) |
| SI (1) | SI1265871T1 (hr) |
| SK (1) | SK287163B6 (hr) |
| UA (1) | UA74571C2 (hr) |
| WO (1) | WO2001068611A1 (hr) |
| ZA (1) | ZA200206917B (hr) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0015228D0 (en) * | 2000-06-21 | 2000-08-16 | Portela & Ca Sa | Substituted nitrated catechols, their use in the treatment of some central and peripheral nervous system disorders |
| JP4561698B2 (ja) * | 2002-02-19 | 2010-10-13 | 小野薬品工業株式会社 | 縮合ピリダジン誘導体化合物およびその化合物を有効成分として含有する薬剤 |
| EP1612204A4 (en) * | 2003-03-31 | 2007-04-11 | Daiichi Seiyaku Co | HYDRAZONE DERIVATIVE |
| GB0503962D0 (en) | 2005-02-25 | 2005-04-06 | Kudos Pharm Ltd | Compounds |
| WO2008013838A2 (en) | 2006-07-25 | 2008-01-31 | Cephalon, Inc. | Pyridizinone derivatives |
| US20100286150A1 (en) | 2007-01-17 | 2010-11-11 | Fia Westerholm | Levosimendan for use in treating chronic valvular disease |
| EP2762465B1 (en) * | 2011-09-27 | 2018-01-10 | Zeon Corporation | Intermediate for manufacture of polymerizable compound and process for manufacture thereof |
| ES2684776T3 (es) * | 2013-01-18 | 2018-10-04 | Bristol-Myers Squibb Company | Ftalazinonas e isoquinolinonas como inhibidores de ROCK |
| JPWO2019235569A1 (ja) * | 2018-06-08 | 2021-07-08 | 日産化学株式会社 | キナーゼ阻害剤 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3531658A1 (de) | 1985-09-05 | 1987-03-12 | Boehringer Mannheim Gmbh | Heterocyclisch substituierte indole, zwischenprodukte, verfahren zu ihrer herstellung und arzneimittel |
| GB8903130D0 (en) * | 1989-02-11 | 1989-03-30 | Orion Yhtymae Oy | Substituted pyridazinones |
| US5185332A (en) * | 1989-02-11 | 1993-02-09 | Orion-Yhtyma Oy | Thiadiazines and pharmaceutical compositions thereof as well as method of use |
| FI973804A (fi) * | 1997-09-26 | 1999-03-27 | Orion Yhtymae Oy | Levosimendaanin oraalisia koostumuksia |
-
2000
- 2000-03-13 FI FI20000577A patent/FI20000577A0/fi unknown
-
2001
- 2001-03-12 BR BR0109136-0A patent/BR0109136A/pt not_active IP Right Cessation
- 2001-03-12 JP JP2001567705A patent/JP2003527375A/ja not_active Withdrawn
- 2001-03-12 US US10/221,348 patent/US6699868B2/en not_active Expired - Fee Related
- 2001-03-12 CZ CZ20022997A patent/CZ20022997A3/cs unknown
- 2001-03-12 AT AT01919489T patent/ATE317388T1/de not_active IP Right Cessation
- 2001-03-12 NZ NZ521162A patent/NZ521162A/en unknown
- 2001-03-12 RS YUP-685/02A patent/RS50439B/sr unknown
- 2001-03-12 IL IL15149201A patent/IL151492A0/xx active IP Right Grant
- 2001-03-12 WO PCT/FI2001/000241 patent/WO2001068611A1/en active IP Right Grant
- 2001-03-12 SK SK1288-2002A patent/SK287163B6/sk not_active IP Right Cessation
- 2001-03-12 SI SI200130518T patent/SI1265871T1/sl unknown
- 2001-03-12 EE EEP200200520A patent/EE200200520A/xx unknown
- 2001-03-12 MX MXPA02008997A patent/MXPA02008997A/es active IP Right Grant
- 2001-03-12 AR ARP010101149A patent/AR027644A1/es unknown
- 2001-03-12 AU AU4657701A patent/AU4657701A/xx active Pending
- 2001-03-12 KR KR1020027012066A patent/KR20030001379A/ko not_active Application Discontinuation
- 2001-03-12 EP EP01919489A patent/EP1265871B1/en not_active Expired - Lifetime
- 2001-03-12 PL PL01357107A patent/PL357107A1/xx not_active Application Discontinuation
- 2001-03-12 CA CA002403188A patent/CA2403188A1/en not_active Abandoned
- 2001-03-12 CN CNB018065309A patent/CN1191241C/zh not_active Expired - Fee Related
- 2001-03-12 HU HU0300177A patent/HUP0300177A3/hu unknown
- 2001-03-12 DE DE60117131T patent/DE60117131T2/de not_active Expired - Fee Related
- 2001-03-12 DK DK01919489T patent/DK1265871T3/da active
- 2001-03-12 EA EA200200973A patent/EA005574B1/ru not_active IP Right Cessation
- 2001-03-12 AU AU2001246577A patent/AU2001246577B2/en not_active Ceased
- 2001-03-12 ES ES01919489T patent/ES2256222T3/es not_active Expired - Lifetime
- 2001-12-03 UA UA2002108100A patent/UA74571C2/uk unknown
-
2002
- 2002-08-26 IL IL151492A patent/IL151492A/en not_active IP Right Cessation
- 2002-08-28 ZA ZA200206917A patent/ZA200206917B/en unknown
- 2002-09-05 NO NO20024247A patent/NO324172B1/no not_active IP Right Cessation
- 2002-10-08 BG BG107175A patent/BG65859B1/bg unknown
- 2002-10-11 HR HRP20020816 patent/HRP20020816A2/hr not_active Application Discontinuation
-
2003
- 2003-06-16 HK HK03104272A patent/HK1052008A1/xx not_active IP Right Cessation
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018287777B2 (en) | SSAO inhibitor | |
| FI105183B (fi) | Menetelmä sydämen vajaatoiminnan hoidossa käyttökelpoisen (-)-[[4-(1,4,5,6-tetrahydro-4-metyyli-6-okso-3-pyridatsinyyli)-fenyyli]hydratsono]propaanidinitriilin valmistamiseksi | |
| US5679688A (en) | Quinaldoyl-amine derivatives of oxo-and hydroxy-substituted hydrocarbons | |
| US6121266A (en) | Pyridazines as interleukin-1β converting enzyme inhibitors | |
| US20090306078A1 (en) | Compounds that inhibit hif-1 activity, the method for preparation thereof and the pharmaceutical composition containing them as an effective component | |
| US8859553B2 (en) | Protein kinase inhibitors | |
| JP7469522B2 (ja) | ベンゾチアゾール類誘導体及びその使用 | |
| HRP20020816A2 (en) | Pyridazinyl phenyl hydrazones useful against congestive heart failure | |
| WO1992005162A1 (fr) | Compose d'isoxazol, son sel pharmaceutiquement acceptable, et utilisation medicale dudit compose | |
| JPH06508375A (ja) | インダン−１，３−ジオンおよびインダン−１，２，３−トリオンの誘導体、それらの調製方法およびそれらの治療上の使用 | |
| JPH0570347A (ja) | 臓器用保護剤 | |
| RU2156252C2 (ru) | Триазолопиридазины, способ их получения, фармацевтические композиции на их основе и способ лечения | |
| Sircar et al. | Cardiotonic agents. 6. Synthesis and inotropic activity of 2, 4-dihydro-5-[4-(1H-imidazol-1-yl) phenyl]-3H-pyrazol-3-ones: ring-contracted analogs of imazodan (CI-914) | |
| US6323238B1 (en) | Benzopyranyl guanidine derivatives, process for preparation thereof, and pharmaceutical compositions containing them | |
| CN112876419A (zh) | 烯丙胺衍生物及其制备方法和用途 | |
| JP3159995B2 (ja) | トルイジン誘導体及びその製造方法 | |
| JP3553158B2 (ja) | ピリダジノインドール誘導体 | |
| JPH07101954A (ja) | ベンズイミダゾール誘導体およびその用途 | |
| EP3115359B1 (en) | Pyridazin-3(2h)-one derivatives which are selective inhibitors of the isoform b of monoamine oxidase | |
| JPS60197660A (ja) | ピリダジノン誘導体またはその塩類 | |
| CN117903126A (zh) | 含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用 | |
| CN113831323A (zh) | 芳杂环酰胺类化合物及其用途 | |
| WO2003067979A1 (fr) | Medicaments destines a etre utilises dans la transplantation d'organes | |
| FR2872158A1 (fr) | Nouveaux composes diazeniumdiolates, leur procede de preparation et leur utilisation therapeutique |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1OB | Publication of a patent application | ||
| ARAI | Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application | ||
| ODBC | Application rejected |