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WO1987003872A1 - Hydrazone derivatives - Google Patents

Hydrazone derivatives Download PDF

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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
denotes
formula
radical
expressed
cyano
Prior art date
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PCT/JP1986/000644
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French (fr)
Inventor
Tatsuhiko Ichimori
Ikuo Yokosuka
Nobuo Mochizuki
Masatoshi Murakata
You Kusase
Kuniyasu Maeda
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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.)
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Publication date
Application filed by Nippon Soda Co Ltd filed Critical Nippon Soda Co Ltd
Priority to JP62500210A priority Critical patent/JPS63502109A/en
Publication of WO1987003872A1 publication Critical patent/WO1987003872A1/en
Priority to NO873583A priority patent/NO873583D0/en
Priority to FI873683A priority patent/FI873683A7/en
Priority to DK443787A priority patent/DK443787D0/en
Priority to KR870700776A priority patent/KR880700791A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compound which is expressed by general formula given below, and which have an excellent cardiotonic action (I), 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 formula (II), 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 formula (III), (wherein each of r1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by formula (IV) {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 O or S(O)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 formula (V), (wherein each of r3 and r4 denotes 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.
Figure imgf000003_0001
Figure imgf000003_0002
Figure imgf000003_0003
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:
Figure imgf000004_0001
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
Figure imgf000004_0002
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
Figure imgf000004_0003
(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
Figure imgf000005_0001
(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.
Figure imgf000005_0002
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.
Figure imgf000006_0001
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.
Figure imgf000007_0001
Wherein R3 denotes C1-6 alkyl and B denotes bivalent hydrocarbon radical which may have substituents.
Figure imgf000007_0002
Wherein R4 denotes C1-6 alkyl and Hal denotes haloge.n.
Figure imgf000007_0003
Figure imgf000008_0001
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
Figure imgf000008_0002
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)
Figure imgf000009_0001
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)
Figure imgf000010_0001
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)
Figure imgf000010_0002
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)
Figure imgf000011_0001
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)
Figure imgf000011_0002
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)
Figure imgf000012_0001
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)
Figure imgf000013_0001
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.
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
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.
Figure imgf000020_0001
Figure imgf000021_0001
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.
Figure imgf000023_0001

Claims

(1) A compound expressed by the general formula below and its salt and its complex which are pharmaceutically allowable:
Figure imgf000024_0001
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
Figure imgf000024_0002
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
Figure imgf000024_0003
(wherein each of r 1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
Figure imgf000024_0004
{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
Figure imgf000025_0001
(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
Figure imgf000025_0002
which comprises reacting a compound expressed by the formula
Figure imgf000025_0003
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
Figure imgf000026_0001
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
Figure imgf000026_0002
(wherein each of r 1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
Figure imgf000026_0003
{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
Figure imgf000027_0002
(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
Figure imgf000027_0001
which comprises reacting a compound expressed by the formula
Figure imgf000027_0003
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
Figure imgf000027_0004
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
Figure imgf000027_0005
(wherein each of r1 and r2 denotes hydrogen or C1-6 alkyl), the radical expressed by the formula
Figure imgf000028_0001
{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
Figure imgf000028_0002
(wherein each of r3 and r4 denotes hydrogen or C1-6 alkyl)} and R" denotes hydroxy, halogen or C1-6 alkoxy.
PCT/JP1986/000644 1985-12-26 1986-12-22 Hydrazone derivatives Ceased WO1987003872A1 (en)

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JP62500210A JPS63502109A (en) 1985-12-26 1986-12-22 hydrazone derivative
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FI873683A FI873683A7 (en) 1985-12-26 1987-08-25 HYDRAZONDER RIBS.
DK443787A DK443787D0 (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

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JP60/293991 1985-12-26
JP9153986 1986-04-21
JP61/91539 1986-04-21

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Cited By (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
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
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

Citations (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

Patent Citations (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
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 (4)

* 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
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
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

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