HYDRAZONE DERIVATIVES

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 r<1> and r<2> 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 r<3> and r<4> 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. (1 ) o38w (1979)) 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 C 1 _. alkyl), the radical expressed by the formula {wherein A denotes CH or N, X denotes hydroxy or . _r 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-R, {wherein Y denotes 0 or S(0), (wherein k denotes 0, 1 or 2) ; R. denotes hydrogen, C. g alkyl which may be substituted by cyano or C„_„ alkylcarbonyl } or the radical expressed by the formula -COR {wherein R-, denotes C-,_g alkyl, hydroxy, C.. . alkoxy or the radical expressed by the formula (wherein each of r and r . denotes hydrogen or C._. 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. (II) (in) (I) 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. (IV) (V) (I) Wherein R" denotes hydroxy, halogen or C., /- 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 0. 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. c-(l) Wherein R_ denotes 0._r alkyl and B denotes bivalent hydrocarbon radical which may have substituents. C-(2) N ' +R i| -Hai W herein R denotes ->*,_-: alkyl and Hal denotes halogen. c-(3) ( R ' ) n Q NNHCOCCN CH, CH-R r Wherein R c denotes Ci,—o. alkyl, c-( 4 ) c- ( 5) Wherein R ^ denotes bivalent hydrocarbon which may have substituent(s) and R„ denotes hydrogen, or hydrocarbon radical which may have substituents. In whichever methods the manufacture proceeds, the reac¬ tion 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 -CHCH-. or any other asymmetric carbons, there occur I 3 CN 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; CHC1-: Me0H=10:l) 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; CHCl 3 :Me0H=20: 1) gave a desired compound, 0.5g. (yield 50. ) m.p. 153.5-154.5 ° C Example 3 : Methyl 4-pyridyl ketone methoxycarbonylacetylhydrazone (Compound No. 35) A ixtuer 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-l6θ ° C for 2.5 hours. After cooling, isolation from the mixture by column chromatography on silica gel (developing solvent; CHC1 • MeOH=20:l) gave a desired compound, 5.8g. (yield 69.4. ) m.p. 139.5-140. ° 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 NH^ 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, l.Og. (yield 89.1. ) m.p. 226.5- 227. ° C. Example 5 : Methyl 4-pyridyl ketone hydroxycarbonylacetylhydrazone (Compound No. 34) A suspension of l.Og (4.3 mmol.) of methyl 4-ρyridylketone 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 onohydrate 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 mi of ethanol. To the solution 3-lg 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-ρyridyl 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 CH„C1 2 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 l.Og. (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. 1 ' 2 Table 1 C 185—188) C 166.5—167.5) C 190) C174) 7 C 2,H I 5 140—144) S -C 3 H 7 C 125—130 ) 9 - CHCH 3 C 142.5—143.5) I CH 3 0 - C 4 Hg 108—110) 1 - CHC,H S C 130—131.5) I CH 3 - C 5 H 1X C 114.5—116 ) -C 7 H 15 C S 5— 86) { 4 - C 9 H l9 C 99—101 ) -C 1S H 31 C 99—100 ) 6 ( CH 2 ) 7 CH= CH ( CH 2 ) 7 CH 3 C 67.5 — 69 7 C 185-188 ) S - CH, C 17 J-l 73) 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% 0 2 and 5% C0 2 ) Krebs-Henseleit solution at 30 ° C of the following composition in mM : NaCl 118; KC1 4.7; CaCl 2 -2H 2 0 2.5; MgS0 it -7H 2 0 1.2; KHgPO^ 1.2; aHC0 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 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. 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 pre¬ ssure with pressure transducer. Heart rate was recorded with heart rate counter triggered by the R wave of electrocardiogram (SCG) . 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 J electric differentiator. Drugs were dissolved in a physiological saline and injected through the cannula in femoral vein at doses of 0.1- 3.Omg/0. lml/kg. The results are shown in Table 3- Table 3

Claims: 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 ^r (wherein each of r 1 and r2 denotes hydrogen or C._ alkyl) , the radical expressed by the formula {wherein A denotes CH or N, X denotes hydroxy or C-_. 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 "γ - R ι {wherein Y denotes 0 or S(0). (wherein k denotes 0, 1 or 2); R. denotes hydrogen, C. ^ alkyl which may be substituted by cyano or C 2 _ 7 alkylcarbonyl } or the radical expressed by the formula -COR. {wherein R.-, denotes C-_g alkyl, hydroxy, C-_. alkoxy or the radical expressed by the formula ,3 -N 4 (wherein each of r 3 and r4 denotes hydrogen or . _ ( * 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 H 2 NNHC0R 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 r 1 (wherein each of r 1 and r2 denotes hydrogen or C- g alkyl) , the radical expressed by the formula {wherein A denotes CH or N, X denotes hydroxy or C. g 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-R, {wherein Y denotes 0 or S(0), (where k denotes 0, 1 or 2); R 1 denotes hydrogen, C._g alkyl which may be substituted by cyano or C ? _ 7 alkylcarbonyl} or the radical expressed by the formula -C0R ? {wherein R ? denotes S γ _r alkyl, hydroxy, C-_. alkoxy or the radical expressed by the formula (wherein each of r 3- ) and r4 denote hydrogen or C 1 _g 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 r 1 ~N ^r2 (wherein each of r1 and r2 denotes hydrogen or C. alkyl) , the radical expressed by the formula {wherein A denotes CH or N, X denotes hydroxy or C.. . 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 "γ - R ι {wherein Y denotes 0 or S(O), (wherein k denotes 0, 1 or 2), R 1 denotes hydrogen, C^_g alkyl which may be substituted by cyano or C ? _ 7 alkylcarbonyl} or the radical expressed by the formula -C0R. {wherein R 2 denotes C. g alkyl, hydroxy, Ci g alkoxy or the radical expressed by the formula ,3 -N 4 (wherein each of r . and r4 denotes hydrogen or . _ ( - alkyl) } and R" denotes hydroxy, halogen or C. g alkoxy,

Inventors: ICHIMORI TATSUHIKO, KUSASE YOU, MAEDA KUNIYASU, MOCHIZUKI NOBUO, MURAKATA MASATOSHI, YOKOSUKA IKUO, ICHIMORI, TATSUHIKO, KUSASE, YOU, MAEDA, KUNIYASU, MOCHIZUKI, NOBUO, MURAKATA, MASATOSHI, YOKOSUKA, IKUO
Applicants: NIPPON SODA CO, NIPPON SODA CO., LTD.
Application year: 1986
Main classification: C07D213
IPC codes: C07D213, C07D401, C07D409, C07D413