[go: up one dir, main page]

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Withdrawn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)
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Withdrawn legal-status Critical Current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)

Abstract

Le composé ci-décrit qui possède une excellente action cardiotonique est exprimé par la formule générale (I), dans laquelle R' représente halogène ou cyano; n représente 0, 1 ou 2 (à condition que lorsque n est égal à 2, R' puisse être différent de chaque autre); R représente hydrogène, thiényle, le radical exprimé par la formule (II), cycloalkyle pouvant être substitué par cyano, ou un radical hydrocarbure aliphatique qui peut être substitué par un radical cyano, halogène, cycloalkyle, morpholino, le radical exprimé par la formule (III) (dans laquelle r1 et r2 représentent chacun hydrogène ou alkyle C1-6), le radical exprimé par la formule (IV) {dans laquelle A représente CH ou N, X représente hydroxy ou alkoxy C1-6; m vaut 0, 1 ou 2 (à condition que lorsque m vaut 2, X puisse être différent de chaque autre)}, le radical exprimé par la formule -Y-R1 {dans laquelle Y représente O ou S(O)k (où k vaut 0, 1 ou 2), R1 représente hydrogène, alkyle C1-6 qui peut être substitué par cyano ou alkylcarbonyle C2-7} ou bien le radical exprimé par la formule -COR2 {dans laquelle R2 représente alkyle C1-6, hydroxy, alkoxy C1-6 ou bien le radical exprimé par la formule (V) (où r3 et r4 représentent chacun hydrogène ou alkyle C1-6)}.The compound described below which has an excellent cardiotonic action is expressed by the general formula (I), in which R 'represents halogen or cyano; n represents 0, 1 or 2 (provided that when n is equal to 2, R 'can be different from each other); R represents hydrogen, thienyl, the radical expressed by formula (II), cycloalkyl which can be substituted by cyano, or an aliphatic hydrocarbon radical which can be substituted by a cyano, halogen, cycloalkyl, morpholino radical, the radical expressed by formula ( III) (in which r1 and r2 each represent hydrogen or C1-6 alkyl), the radical expressed by the formula (IV) {in which A represents CH or N, X represents hydroxy or C1-6 alkoxy; m is 0, 1 or 2 (provided that when m is 2, X can be different from each other)}, the radical expressed by the formula -Y-R1 {in which Y represents O or S (O) k (where k is 0, 1 or 2), R1 represents hydrogen, C1-6 alkyl which may be substituted by cyano or alkylcarbonyl C2-7} or the radical expressed by the formula -COR2 {in which R2 represents C1-6 alkyl, hydroxy , C1-6 alkoxy or the radical expressed by formula (V) (where r3 and r4 each represent hydrogen or C1-6 alkyl)}.

Description

DESCRIPTION
Hydrazone derivatives
Technical Field :
The present invention relates to new hydrazone derivatives and the processes for the production of such compounds.
Background Art :
The compounds given below are known as hydrazone derivatives similar to those covered by the present invention, but the literature on these compounds of prior art describes nothing about a cardiotonic action at all.
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:
wherein 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
(wherein each of r 1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
{wherein A denotes CH or N, X denotes hydroxy or C1-6 alkoxy; m denotes 0, 1 or 2 (provided that when in is 2, X may differ from each other)}, the radical expressed by the formula
-Y-R1 {wherein Y denotes 0 or S(0)k (wherein k denotes 0, 1 or 2); R1 denotes hydrogen, C1-6 alkyl which may be substituted by cyano or C2-7 alkylcarbonyl} or the radical expressed by the formula
-COR2
{wherein R2 denotes C1-6 alkyl, hydroxy, C1-6 alkoxy or the radical expressed by the formula
(wherein each of r 3 and r4 denotes hydrogen or C1-6 alkyl)}.
Compared to known compounds, 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.
Besc Mode for Carrying Out the Invention :
The compounds under the present invention can be manufactured in the methods specified below.
1. Manufacturing method A.
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. As the organic solvent can be used methanol, ethanol, benzene, toluene, chloroform, or any of the other ordinary organic solvents. As the 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.
2. Manufacturing method B.
Wherein R" denotes hydroxy, halogen or C1-6 alkoxy. The reaction conditions vary with the type of R". When 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. As the organic solvent, DMF or any of the other similar solvents can be used. As the condensing agent, it is desirable to use N,N'-dicyclohexylcarbodiimide (hereunder called D.C.C.), etc. When R" is C1-6 alkoxy, the reaction is carried out in an organic solvent or without solvent at 50-200°C, for 1-5 hours. When 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.
Under the general formula (I), it is also possible to manufacture in the method specified below, depending on the type of substituents expressed by R.
Wherein R3 denotes C1-6 alkyl and B denotes bivalent hydrocarbon radical which may have substituents.
Wherein R4 denotes C1-6 alkyl and Hal denotes haloge.n.
Wherein R6 denotes bivalent hydrocarbon which may have substituent(s) and R7 denotes hydrogen, or hydrocarbon radical which may have substituents.
In whichever methods the manufacture proceeds, the reaction is followed by usual after-treatment to obtain the intended product.
The structure of the compound of the present invention has been determined by means of IR, NMR, MASS or other spectrums.
In the compound of the present invention, there occur E- and Z-isomers. Further, when the radicals expressed by R contain or any other asymmetric carbons, there occur optical isomers in the compounds which the present invention concerns. The compound the present invention concerns contains all these isomers.
The following Examples illustrate the present invention.
Example 1 : Metyl 4-pyridyl ketone (2-cyano-3-(4-pyridyl) propionyl)hydrazone (Compound No. 7)
To a mixture of 2-cyano-3-(4-pyridyl)propionhydrazide, 4.7g (24.7 mmole.) and 4-acetylpyridine, 3.0g (25 mmole.), 20 ml of ethanol and a catalytic amount of p-toluenesulfonic acid monohydrate were added. After the mixture was refluxed for 1 hour, solvent was removed under reduced pressure to give a residue.
Isolation from the residue by column chromatography on silica gel (developing solvent; CHCl3: MeOH=10:1) gave a desired compound, 6.0g (yield 82.9%). m.p. 163.5-165°C
Example 2: Methyl 4-pyridyl ketone 3- methoxycarbonylpropionylhydrazone (Compound No. 38)
To a suspension of triphenylphosphine, 1.8 (7 mmole.) in 20 ml of acetonitrile, 2 ml of carbontetrachloride was added and the mixture was stirred till it became a homogeneous solution. To the solution succinic acid monomethylester, 0.5g (4 mmole.) was added and it was stirred for 20 minutes.
So methyl 4-pyridyl ketone hydrazone, 0.5g (3.7 mmole.) and triethylamine, 0.7g (7 mmole.) in 5 ml of acetonitrile were added.
After stirring for 5 hours, solvent was removed under reduced pressure and isolation from the residue by column chromatography on silica gel (developing solvent; CHCl3:MeOH=20: 1) gave a desired compound, 0.5g. (yield 50%) m.p. 153.5-154.5ºC
Example 3 : Methyl 4-pyridyl ketone methoxycarbonylacetylhydrazone (Compound No. 35)
A mixtuer of methyl 4-pyridyl ketone hydrazone, 4.8g (35.6 mmole.) and dimethyl malonate, 52.8g (400 mmole.) was heated at a range of 150-160°C for 2.5 hours. After cooling, isolation from the mixture by column chromatography on silica gel (developing solvent; CHCl3: MeOH=20:1) gave a desired compound, 5.8g. (yield 69.4%) m.p. 139.5-140.5°C
Example 4 : Methyl 4-pyridyl ketone carbamoylacetylhydrazone
(Compound No. 36)
A solution of 1.2g (5.1 mmol.) of methyl 4-pyridyl ketone methoxycarbonylacetylhydrazone in 20 ml of methanol was satulated with NH3 gas on the ice-cooling bath.
After warming to room temperature, the solution was stirred for 12 hours and then the solvent was removed under reduced pressure and the residue was recrystalized from ethanol to yield a desired compound, 1.0g. (yield 89.1. ) m.p. 226.5-227.5°C.
Example 5 : Methyl 4-pyridyl ketone hydroxycarbonylacetylhydrazone (Compound No. 34)
A suspension of 1.0g (4.3 mmol.) of methyl 4-pyridylketone methoxycarbonylacetylhydrazone in 10 ml of water was added to 2,2 ml of 2N-sodium hydroxide solution under stirring at room temperature. After stirring for 2 hours, pH of the reaction mixture was controlled at 4 to 5 by treatment with 3N-hydrochloric acid and then a white precipitate was isolated to yield a desired compound 0.7g (73.7%). m.p. 156-158°C (dec.)
Example 6 : Methyl 4-pyridyl ketone 4- carboxybutanoylhydrazone (Compound No. 39)
1.6g of 90% hydrazine monohydrate was added dropwise to a solution of 3g of gulutaric anhydride in 10 ml of DMF under ice-cooling. After stirring for 30 minutes, the reaction mixture was warmed up to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure. The residue was washed with diethyl ether and dissolved in 50 ml of ethanol.
To the solution 3.1g of 4-acetylpyridine and a catalystic amount of p-toluenesulfonic acid were added and the mixture was refluxed for 2 hours. The precipitated crystal was collected by filtration and gave a desired compound. By concentrating the filtrate and recrystallizing the residue, furthermore, a desired compound was obtained, total yield was 4.59g (72%) m.p. 230°C
Example 7 : Methyl 4-pyridyl ketone acetoacetylhydrazone
(Compound No. 33)
To 23 ml of pyridine, 2.2g of chromic anhydride was added at 0°C for 15 minutes. To the solution 1.5g of methyl 4-pyridyl ketone 3-hydroxybutyrylhydrazone in small amount of pyridine was added all at once at 0°C. After stirring for 30 minutes, the reaction mixture was warmed up to room-temperature and stirred for 12 hours.
The resulting mixture was filtered and to the filtrate CH2Cl2 was added. The mixture was washed with water. Then solvent was removed under reduced pressure and isolation from the residue by column chromatography on silica gel gave a desired compound 1.0g. (yield 67.3%) m.p. 150°C
Inclusive the above, each compound within the scope of this invention which can be prepared in analogous method(s) is tabulated in Table 1.
Industrial Applicability :
The cardiotonic action in the compounds of the present invention is described, by the following Tests.
Test 1 : Electrically stimulating isolated guinea pig left atria
Male Hartley guinea pig, weighing 350-500g were used.
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% O2 and 5% CO2) Krebs-Henseleit solution at 30°C of the following composition in mM : NaCl 118; KCl 4.7; CaCl2-2H2O 2.5; MgSO4-7H2O 1.2; KH2PO4 1.2; NaHCO3 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 6θ/min.
Resting tension was adjusted to 0.5g and contraction was recorded on the Polygraph Systems with a force-displacement transducer.
All preparations were allowed to equilibrate with the bath medium for 90 to 120 min.
The results are shown in Table 2. Test 2 : Anesthetized dog
Mongel dogs either sex, weighing 8 to 15 kg were used.
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 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.
The results are shown in Table 3.

Claims

(1) A compound expressed by the general formula below and its salt and its complex which are pharmaceutically allowable:
wherein 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
(wherein each of r 1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
{wherein A denotes CH or N, X denotes hydroxy or C1-6 alkoxy; m denotes 0, 1 or 2 (provided that when m is 2 , X may differ from each other}, the radical expressed by the formula {wherein Y denotes 0 or S(0)k (wherein k denotes 0, 1 or 2); R1 denotes hydrogen, C1-6 alkyl which may be substituted by cyano or C2-7 alkylcarbonyl} or the radical expressed by the formula
-COR.
{wherein R2 denotes C1-6 alkyl, hydroxy, C1-6 alkoxy or the radical expressed by the formula
(wherein each of r 3 and r4 denotes hydrogen or C1-6 alkyl)}.
(2) A process for the production of a compound expressed by the general formula
which comprises reacting a compound expressed by the formula
with a compound expressed by the formula
H2NNHCOR wherein 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 (wherein each of r 1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
{wherein A denotes CH or N, X denotes hydroxy or C1-6 alkoxy; m denotes 0, 1 or 2 (provided that when m is 2 , X may differ from each ether)}, the radical expressed by the formula
-Y-R1 {wherein Y denotes 0 or S(0)k (where k denotes 0, 1 or 2); R1 denotes hydrogen, C1-6 alkyl which may be substituted by cyano or C2-7 alkylcarbonyl} or the radical expressed by the formula
-COR2 {wherein R2 denotes C1-6 alkyl, hydroxy, C1-6 alkoxy or the radical expressed by the formula (wherein each of r 3 and r4 denote hydrogen or C1-6 alkyl)}.
(3) A process for the production of a compound expressed by the general formula
which comprises reacting a compound expressed by the formula
with a compound expressed by the formula
RCOR" wherein 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 (wherein each of r1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
{wherein A denotes CH or N, X denotes hydroxy or C1-6 alkoxy; m denotes 0, 1 or 2 (provided that when m is 2 , X may differ from each other)}, the radical expressed by the formula
"Y-R1
{wherein Y denotes 0 or S(0)k (wherein k denotes 0, 1 or 2), R1 denotes hydrogen, C1-6 alkyl which may be substituted by cyano or C2_7 alkylcarbonyl} or the radical expressed by the formula
-COR2
{wherein R2 denotes C1-6 alkyl, hydroxy, C1-6 alkoxy or the radical expressed by the formula
(wherein each of r3 and r4 denotes hydrogen or C1-6 alkyl)} and R" denotes hydroxy, halogen or C1-6 alkoxy.
EP87900274A 1985-12-26 1986-12-22 Hydrazone derivatives Withdrawn EP0252986A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP29399185 1985-12-26
JP293991/85 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 (en)
KR (1) KR880700791A (en)
DK (1) DK443787A (en)
FI (1) FI873683A7 (en)
NO (1) NO873583D0 (en)
WO (1) WO1987003872A1 (en)

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 (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
RU2426719C2 (en) * 2009-12-29 2011-08-20 Государственное научное учреждение Всероссийский научно-исследовательский институт биологической защиты растений Россельхозакадемии 2,3-dichloro-4-[(6-chloro-5-cyano-4-methylpyridyl-2)-methylhydrazono]-buten-2-oic acid as antidote 2,4-d on sunflower

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0214158A1 (en) * 1985-02-11 1987-03-18 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
NO873583L (en) 1987-08-25
NO873583D0 (en) 1987-08-25
WO1987003872A1 (en) 1987-07-02
FI873683A0 (en) 1987-08-25
FI873683A7 (en) 1987-08-25
DK443787D0 (en) 1987-08-25
DK443787A (en) 1987-08-25
KR880700791A (en) 1988-04-12

Similar Documents

Publication Publication Date Title
EP0357788B1 (en) Pyridazinone derivatives
US4353905A (en) Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
KR0164842B1 (en) Novel benzoxazine, benzothiazine derivatives and preparation thereof
JPS58170755A (en) Novel 1,4-dihydropyridines
NZ207914A (en) Indeno-pyridazinones and pharmaceutical compositions
US4921856A (en) Dihydropyridazinone derivatives, a process for their preparation and pharmaceutical preparations containing these compounds
JP3083544B2 (en) Drugs to prevent or treat heart disease
SU1342416A3 (en) Method of producing pyridazinone derivatives or water-soluble salts thereof with pharmaceutically acceptable acid
RU2081872C1 (en) Dihydropyridine derivatives, mixture of their isomers, individual isomers or their physiologically tolerantable salts, methods of their synthesis, intermediate compounds and method of their synthesis
EP0252986A1 (en) Hydrazone derivatives
JPS60174781A (en) Cardiac stimulant and antihypertensive oxadiazinone compound
CA1285566C (en) 2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-isoquinoline compounds
US4822797A (en) Piperazinyl carbonyl phenyl pyridazinone derivatives useful as cardiotonics
US4430342A (en) N-Acyl-3-[4-(benzoylalkyl)piperazin-1-yl]-sydnonimine compound, process for prodction thereof, and use thereof
EP0252422A2 (en) Pyridazinone derivatives and salts thereof
GB2101990A (en) Isocarbostyril derivatives
US4845228A (en) Pyridyl-cyclohexanone compounds
EP0138058B1 (en) Novel 1,4-thiazine derivative
US4895947A (en) Process for producing 1-acyl-2-pyrazoline derivative
JPH069575A (en) Aminocarboxylic acid derivative, its production, and medicine containing said derivative and used for treatment of allergy, inflamation and asthama
US4001214A (en) Aminoalkyl ethers of 2,2'- and 3,3'-dihydroxybenzil
JPS63502109A (en) hydrazone derivative
WO1985002843A1 (en) IMIDAZO AD1.5-a BD PYRIDIN-3-ONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION
KR840001105B1 (en) Method for the preparation of pyridine derivatives
US5206231A (en) 2,5-benzodiazocine antiarrhythmic agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19870819

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI NL SE

17Q First examination report despatched

Effective date: 19890621

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19890701

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