WO1987003872A1 - Hydrazone derivatives - Google Patents
Hydrazone derivatives Download PDFInfo
- Publication number
- WO1987003872A1 WO1987003872A1 PCT/JP1986/000644 JP8600644W WO8703872A1 WO 1987003872 A1 WO1987003872 A1 WO 1987003872A1 JP 8600644 W JP8600644 W JP 8600644W WO 8703872 A1 WO8703872 A1 WO 8703872A1
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- WIPO (PCT)
- Prior art keywords
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- formula
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- cyano
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- 150000007857 hydrazones Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- CPEONABTMRSIKA-UHFFFAOYSA-N 1,4$l^{2}-oxazinane Chemical group C1COCC[N]1 CPEONABTMRSIKA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 5
- 101000687448 Homo sapiens REST corepressor 1 Proteins 0.000 claims 1
- 102100024864 REST corepressor 1 Human genes 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000003177 cardiotonic effect Effects 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- LAMOWOKFWZMLJD-UHFFFAOYSA-N methyl 3-oxo-3-[2-(1-pyridin-4-ylethylidene)hydrazinyl]propanoate Chemical compound COC(=O)CC(=O)NN=C(C)C1=CC=NC=C1 LAMOWOKFWZMLJD-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- WMQUKDQWMMOHSA-UHFFFAOYSA-N 1-pyridin-4-ylethanone Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 2
- VYLWNJDBIZGYGP-UHFFFAOYSA-N 1-pyridin-4-ylethylidenehydrazine Chemical compound NN=C(C)C1=CC=NC=C1 VYLWNJDBIZGYGP-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003191 femoral vein Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- JDRMYOQETPMYQX-UHFFFAOYSA-N monomethyl succinate Chemical compound COC(=O)CCC(O)=O JDRMYOQETPMYQX-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DQRIGEJPDIVLCN-UHFFFAOYSA-N 2-cyano-3-pyridin-4-ylpropanehydrazide Chemical compound NNC(=O)C(C#N)CC1=CC=NC=C1 DQRIGEJPDIVLCN-UHFFFAOYSA-N 0.000 description 1
- QYUASYOLXGWJGM-UHFFFAOYSA-N 2-cyano-N-(dipyridin-4-ylmethylideneamino)-3-pyridin-4-ylpropanamide Chemical compound C(#N)C(C(=O)NN=C(C1=CC=NC=C1)C1=CC=NC=C1)CC1=CC=NC=C1 QYUASYOLXGWJGM-UHFFFAOYSA-N 0.000 description 1
- XLGPMPANVIZEFC-UHFFFAOYSA-N 3-hydroxy-n-(1-pyridin-4-ylethylideneamino)butanamide Chemical compound CC(O)CC(=O)NN=C(C)C1=CC=NC=C1 XLGPMPANVIZEFC-UHFFFAOYSA-N 0.000 description 1
- WEOCDLVKWHLNIQ-UHFFFAOYSA-N 3-oxo-3-[2-(1-pyridin-4-ylethylidene)hydrazinyl]propanoic acid Chemical compound OC(=O)CC(=O)NN=C(C)C1=CC=NC=C1 WEOCDLVKWHLNIQ-UHFFFAOYSA-N 0.000 description 1
- RGDLNKRXZSNTOL-UHFFFAOYSA-N 3-oxo-n-(1-pyridin-4-ylethylideneamino)butanamide Chemical compound CC(=O)CC(=O)NN=C(C)C1=CC=NC=C1 RGDLNKRXZSNTOL-UHFFFAOYSA-N 0.000 description 1
- ZUZAIANRYKVTQF-UHFFFAOYSA-N 5-oxo-5-[2-(1-pyridin-4-ylethylidene)hydrazinyl]pentanoic acid Chemical compound OC(=O)CCCC(=O)NN=C(C)C1=CC=NC=C1 ZUZAIANRYKVTQF-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 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
- 239000007836 KH2PO4 Substances 0.000 description 1
- 229910017621 MgSO4-7H2O Inorganic materials 0.000 description 1
- VJSKVBIBZWBULA-UHFFFAOYSA-N N'-(1-pyridin-4-ylethylideneamino)propanediamide Chemical compound C(N)(=O)CC(=O)NN=C(C)C1=CC=NC=C1 VJSKVBIBZWBULA-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- NWIIZZXSDKYCLR-UHFFFAOYSA-N methyl 4-oxo-4-[2-(1-pyridin-4-ylethylidene)hydrazinyl]butanoate Chemical compound COC(=O)CCC(=O)NN=C(C)C1=CC=NC=C1 NWIIZZXSDKYCLR-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to new hydrazone derivatives and the processes for the production of such compounds.
- the purpose of the present invention is to seek a new substance that has an excellent cardiotonic action and that is safe and free from side effects. It is also to offer the method in which this new substance can be manufactured in a commercially advantageous manner. Disclosure of Invention :
- the present invention concerns both the compounds which are expressed by the general formula below, and the processes for the production of such compounds:
- R' denotes halogen or cyano
- n denotes 0, 1 or 2 (provided when n is 2, R' may differ from each other);
- R denotes hydrogen, thienyl, the radical expressed by the formula
- cycloalkyl which may be substituted by cyano, or aliphatic hydrocarbon radical which may be substituted by cyano, halogen, cycloalkyl, morpholino radical, the radical expressed by the formula
- Y denotes 0 or S(0) k (wherein k denotes 0, 1 or 2);
- R 1 denotes hydrogen, C 1-6 alkyl which may be substituted by cyano or C 2-7 alkylcarbonyl ⁇ or the radical expressed by the formula
- R 2 denotes C 1-6 alkyl, hydroxy, C 1-6 alkoxy or the radical expressed by the formula
- the compounds which the present invention concerns have an excellent cardiotonic action, are low in toxicity and side effects, and useful as drugs. Further, some of the compounds covered by the present invention have a good hypotensive action.
- the compounds under the present invention can be manufactured in the methods specified below.
- the reaction is carried out in an organic solvent at 10-100°C, for 0.1-5 hours, in the presence of an acid catalyst.
- an organic solvent can be used methanol, ethanol, benzene, toluene, chloroform, or any of the other ordinary organic solvents.
- an acid catalyst ordinary acid can be used, but depending on the type of substituents represented by R, e.g., in the case where some of the substituents concerned are those which like cyano radical are susceptible to hydrolysis, it is desirable to use p-toluene sulfonic acid or other sulfonic acids.
- R" denotes hydroxy, halogen or C 1-6 alkoxy.
- the reaction conditions vary with the type of R".
- R" is hydroxy, the reaction is carried out in an organic solvent at 0-50°C, for 5-30 hours, in the presence of a condensing agent.
- the organic solvent DMF or any of the other similar solvents can be used.
- the condensing agent it is desirable to use N,N'-dicyclohexylcarbodiimide (hereunder called D.C.C.), etc.
- R" is C 1-6 alkoxy
- the reaction is carried out in an organic solvent or without solvent at 50-200°C, for 1-5 hours.
- R" is halogen, then the reaction is carried out in an organic solvent at 0-50°C, for 30 minutes to 5 hours, in the presence of triethylamine or any of the other suitable acid binder. 3. Manufacturing method C.
- R 3 denotes C 1-6 alkyl and B denotes bivalent hydrocarbon radical which may have substituents.
- R 4 denotes C 1-6 alkyl and Hal denotes haloge.n.
- R 6 denotes bivalent hydrocarbon which may have substituent(s) and R 7 denotes hydrogen, or hydrocarbon radical which may have substituents.
- the structure of the compound of the present invention has been determined by means of IR, NMR, MASS or other spectrums.
- Example 1 Metyl 4-pyridyl ketone (2-cyano-3-(4-pyridyl) propionyl)hydrazone (Compound No. 7)
- Test 1 Electrically stimulating isolated guinea pig left atria
- the animals were killed by a blow on the head and the hearts were removed.
- the left atria were excised and mounted in an organ bath.
- the bath was filled with 50 ml oxygenated (95% O 2 and 5% CO 2 ) Krebs-Henseleit solution at 30°C of the following composition in mM : NaCl 118; KCl 4.7; CaCl 2 -2H 2 O 2.5; MgSO 4 -7H 2 O 1.2; KH 2 PO 4 1.2; NaHCO 3 25.0; glucose 10.0.
- Square wave pulses of 3 msec in duration with the voltage ranging from 1.2-fold to 1.5-fold of the threshold were applied for stimulation by an electric stimulator at a frequency of 6 ⁇ /min.
- Test 2 Anesthetized dog
- the animals were anesthetized with pentobarbital sodium (30 mg/kg, i.v.), and maintained by i.v. infusion of the anesthetic at a rate of 4 mg/kg per hour.
- a cuffed endotracheal tube was inserted and an artificial respirator installed. Animals were ventilated with room air at 20 breaths per min at an expiratory volume of 20 ml/kg.
- Cannulae were inserted into the femoral vein for a falling drop of physiological saline or for infusion of the anesthetic, and into the femoral artery for measuring arterial blood pressure with pressure transducer. Heart rate was recorded with heart rate counter triggered by the R wave of electrocardiogram (ECG).
- ECG electrocardiogram
- ECG in standard lead II was monitered with bioelectric amplifier.
- Left ventricular pressure was measured with catheter tip pressure transducer inserted via right carotid artery into the left ventricle.
- Left ventricular dp/dtmax was obtained by electric differentiator.
- Drugs were dissolved in a physiological saline and injected through the cannula in femoral vein at doses of 0.1-3.0mg/0.1ml/kg.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50021086A JPS63502109A (en) | 1985-12-26 | 1986-12-22 | hydrazone derivative |
NO873583A NO873583D0 (en) | 1985-12-26 | 1987-08-25 | Hydrazone derivatives. |
FI873683A FI873683A0 (en) | 1985-12-26 | 1987-08-25 | HYDRAZONDERIVAT. |
DK443787A DK443787A (en) | 1985-12-26 | 1987-08-25 | HYDRAZONE DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF |
KR870700776A KR880700791A (en) | 1985-12-26 | 1987-08-26 | Hydrazone derivatives |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29399185 | 1985-12-26 | ||
JP60/293991 | 1985-12-26 | ||
JP9153986 | 1986-04-21 | ||
JP61/91539 | 1986-04-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1987003872A1 true WO1987003872A1 (en) | 1987-07-02 |
Family
ID=26432975
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1986/000644 WO1987003872A1 (en) | 1985-12-26 | 1986-12-22 | Hydrazone derivatives |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0252986A1 (en) |
KR (1) | KR880700791A (en) |
DK (1) | DK443787A (en) |
FI (1) | FI873683A0 (en) |
NO (1) | NO873583D0 (en) |
WO (1) | WO1987003872A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1186946A1 (en) * | 2000-09-11 | 2002-03-13 | Agfa-Gevaert | Photographic material containing a novel hydrazine type |
WO2006032173A1 (en) * | 2004-09-20 | 2006-03-30 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Aryl hydrazide compounds and usage in preparation of immunosuppressive agent theirof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986004582A1 (en) * | 1985-02-11 | 1986-08-14 | The Upjohn Company | Anthelmintic pyridinyl acylhydrazones, method of use and compositions |
-
1986
- 1986-12-22 EP EP87900274A patent/EP0252986A1/en not_active Withdrawn
- 1986-12-22 WO PCT/JP1986/000644 patent/WO1987003872A1/en not_active Application Discontinuation
-
1987
- 1987-08-25 NO NO873583A patent/NO873583D0/en unknown
- 1987-08-25 DK DK443787A patent/DK443787A/en not_active Application Discontinuation
- 1987-08-25 FI FI873683A patent/FI873683A0/en not_active IP Right Cessation
- 1987-08-26 KR KR870700776A patent/KR880700791A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1986004582A1 (en) * | 1985-02-11 | 1986-08-14 | The Upjohn Company | Anthelmintic pyridinyl acylhydrazones, method of use and compositions |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, Vol. 61, No. 9, 26 October 1964 (Columbus, Ohio, USA), see page 1964, column 10661g,h & PL. A, 47469 (Halina Bojarska-Dahlig) 19 September 1963 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1186946A1 (en) * | 2000-09-11 | 2002-03-13 | Agfa-Gevaert | Photographic material containing a novel hydrazine type |
WO2006032173A1 (en) * | 2004-09-20 | 2006-03-30 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Aryl hydrazide compounds and usage in preparation of immunosuppressive agent theirof |
CN100355748C (en) * | 2004-09-20 | 2007-12-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Aromatic hydrazide kind compound and its use in preparation of immune inhibitor |
Also Published As
Publication number | Publication date |
---|---|
KR880700791A (en) | 1988-04-12 |
NO873583L (en) | 1987-08-25 |
EP0252986A1 (en) | 1988-01-20 |
FI873683A (en) | 1987-08-25 |
FI873683A0 (en) | 1987-08-25 |
DK443787D0 (en) | 1987-08-25 |
DK443787A (en) | 1987-08-25 |
NO873583D0 (en) | 1987-08-25 |
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