EP0252986A1 - Hydrazone derivatives - Google Patents

Hydrazone derivatives

Info

Publication number
EP0252986A1
EP0252986A1 EP87900274A EP87900274A EP0252986A1 EP 0252986 A1 EP0252986 A1 EP 0252986A1 EP 87900274 A EP87900274 A EP 87900274A EP 87900274 A EP87900274 A EP 87900274A EP 0252986 A1 EP0252986 A1 EP 0252986A1
Authority
EP
European Patent Office
Prior art keywords
denotes
formula
radical
expressed
cyano
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP87900274A
Other languages
German (de)
English (en)
French (fr)
Inventor
Tatsuhiko Ichimori
Ikuo Yokosuka
Nobuo Mochizuki
Masatoshi Murakata
You Kusase
Kuniyasu Maeda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Soda Co Ltd
Original Assignee
Nippon Soda Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Soda Co Ltd filed Critical Nippon Soda Co Ltd
Publication of EP0252986A1 publication Critical patent/EP0252986A1/en
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP87900274A 1985-12-26 1986-12-22 Hydrazone derivatives Withdrawn EP0252986A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP293991/85 1985-12-26
JP29399185 1985-12-26
JP91539/86 1986-04-21
JP9153986 1986-04-21

Publications (1)

Publication Number Publication Date
EP0252986A1 true EP0252986A1 (en) 1988-01-20

Family

ID=26432975

Family Applications (1)

Application Number Title Priority Date Filing Date
EP87900274A Withdrawn EP0252986A1 (en) 1985-12-26 1986-12-22 Hydrazone derivatives

Country Status (6)

Country Link
EP (1) EP0252986A1 (da)
KR (1) KR880700791A (da)
DK (1) DK443787A (da)
FI (1) FI873683A7 (da)
NO (1) NO873583L (da)
WO (1) WO1987003872A1 (da)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
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
CN100355748C (zh) * 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 芳酰肼类化合物及其用于制备免疫抑制剂的用途
RU2426719C2 (ru) * 2009-12-29 2011-08-20 Государственное научное учреждение Всероссийский научно-исследовательский институт биологической защиты растений Россельхозакадемии 2,3-дихлор-4-[(6-хлор-5-циано-4-метилпиридил-2)-метилгидразоно]-бутен-2-овая кислота в качестве антидота 2,4-д на подсолнечнике

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
See references of WO8703872A1 *

Also Published As

Publication number Publication date
KR880700791A (ko) 1988-04-12
WO1987003872A1 (en) 1987-07-02
NO873583D0 (no) 1987-08-25
FI873683A0 (fi) 1987-08-25
DK443787D0 (da) 1987-08-25
DK443787A (da) 1987-08-25
NO873583L (no) 1987-08-25
FI873683A7 (fi) 1987-08-25

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RIN1 Information on inventor provided before grant (corrected)

Inventor name: KUSASE, YOU

Inventor name: YOKOSUKA, IKUO

Inventor name: MOCHIZUKI, NOBUO

Inventor name: ICHIMORI, TATSUHIKO

Inventor name: MAEDA, KUNIYASU

Inventor name: MURAKATA, MASATOSHI