Abstract:
There are provided novel pyridazinone derivatives having the general formula (I): ##STR1## wherein A represents 5- or 6-membered heterocyclic ring having 1-3 nitrogen atoms, which may be substituted by at least one member selected from the group consisting of C 1-5  alkyl, cyano, hydroxyl, C 1-5  alkoxy, amino, C 1-5  alkylamino, C 2-6  dialkylamino, C 2-5  acylamino, carboxyl, C 2-5  alkoxycarbonyl and carbamoyl, and R 1  and R 2  independently represent hydrogen atom or C 1-5  alkyl or R 1  and R 2  may form together C 1-5  alkylene, and salts thereof.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to a novel pyridazinone derivative or a salt thereof which is useful for a cardiac stimulant. 
     Various cardiac stimulants, which effect a direct enhancement of the cardiac contraction, have been available in the treatment of cardiac insufficiency. However, these cardiac stimulants may have some defects such as follows: (1) their safety margin is extremely small; (2) they may cause arrhythmia; (3) their cardiac stimulating activity is transient; and (4) they may not be suitable for oral administration. 
     A primary object of the present invention is to provide a novel cardiac compound having a high and sustained activity. 
     SUMMARY OF THE INVENTION 
     In the course of the present inventors&#39; study onto compounds which act as cardiac stimulants with a high and sustained activity, the present invention has been achieved. 
     The present invention pertains to pyridazinone derivatives having the general formula (I): ##STR2## wherein A represents 5- or 6-membered heterocyclic ring having 1-3 nitrogen atoms, the ring being optionally substituted by at least a member selected from the group consisting of C 1-5  alkyl, cyano, hydroxyl, C 1-5  alkoxyl, amino, C 1-5  alkylamino, C 2-6   dialkylamino, C 2-5  acylamino, carboxyl, C 2-5  alkoxycarbonyl and carbamoyl, and R 1  and R 2  independently represent hydrogen atom or C 1-5  alkyl or R 1  and R 2  may form together C 1-5  alkylene, and salts thereof. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The group A in the general formula (I) includes, for instance, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, sym-triazinyl, asym-triazinyl, pyrrolyl, imidazolyl, pyrazolyl and the like, which may also be substituted by at least one substituent. By way of illustrating the substituent, mention may be made of normal or branched C 1-5  alkyl such as methyl, ethyl, propyl, butyl and pentyl; cyano; hydroxyl; normal or branched C 1-5  alkoxyl such as methoxy, ethoxy, propoxy and butoxy; amino; normal or branched C 1-5  alkylamino such as methylamino, ethylamino, propylamino and butylamino; normal or branched C 2-6  dialkylamino such as dimethylamino and diethylamino; normal or branched C 2-5  acylamino such as acetylamino, propionylamino and butyrylamino; carboxyl; normal or branched C 2-5  alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl; and carbamoyl. 
     Examples of pyridazinone derivatives having the general formula (I) are the following compounds: ##STR3## 
     Pharmaceutically acceptable salts of pyridazinone derivatives having the general formula (I) are also included in the scope of the present invention. By illustrating those salts, mention may be made of salts of inorganic acid such as hydrochloric acid and phosphoric acid and of organic acid such as lactic acid and acetic acid. All these compounds are useful as cardiac stimulants. 
     Preparation of the compound according to the present invention will be described below. 
     A pyridazinone derivative according to the present invention, for example, may be prepared as follows: ##STR4## wherein A, R 1  and R 2  are as defined hereinabove and X represents a halogen atom. 
     That is, a desired pyridazinone derivative (I) may be synthesized by heating a mixture of a compound (II) and a compound (III) in a polar solvent such as dimethylformamide, dimethylacetamide and phenol at 50°-200° C. for about 0.5-10 hours. A copper compound may be used as a catalyst. 
     A compound (II) is a known compound described in Journal of Medicinal Chemistry, 17, 273-280 (1974). 
     The compounds according to the present invention, when used as a cardiac stimulant, may be administered suitably by an oral and parenteral route. By way of illustrating available dosage unit form, mention may be made of powder, granule, tablet, sugar-coated tablet, pill, capsule, solution and the like in case of oral administration, and suppository, suspension, solution, emulsion, ampoule, injectable solution and the like in case of parenteral administration. A combination of these dosage forms may of course be also available. These dosage forms of the compound according to the present invention may be formulated pharmaceutically by the usual way in the art. Dosage can be determined by a physician according to age, sex, body weight, sensitivity to the drug, degree of symptom and physical condition of a patient, administration route, duration and interval of administration, properties, formulation and type of pharmaceutical preparation, kind of active ingredient and so on. Dosage range, for example, is 0.01-30 mg/kg/day, and preferably 0.05-10 mg/kg/day by oral administration, but is not restricted by the above. 
     The invention will be more clearly understood with reference to the following examples, but these examples are not to be construed to limit the scope of the invention. 
    
    
     EXAMPLE I 
     Preparation of 6-[4-(4&#39;-pyridyl)aminophenyl]-3(2H)-pyridazinone ##STR5## 
     A mixture of 2.33 g of 4-bromopyridine hydrochloride and 1.87 g of 6-(4-aminophenyl)-3(2H)-pyridazinone was reacted in 30 ml of N,N-dimethylformamide under the nitrogen gas flow at 110° C. for 4 hours. 
     After cooling the reaction mixture, 75 ml of water was added. The reaction mixture was neutralized with 2N sodium hydroxide followed by the filtration of deposited crystal. 
     The crude crystal thus obtained was recrystallized from a mixed solvent of ethanol-water and thoroughly purified with a silica gel chromatography to remove a trace amount of impurity contained in the crystal. 
     Fractions containing a desired substance were gathered, and the solvent was evaporated. Addition of HCl-ethanol and of ether to the condensate dissolved in a small amount of methanol yielded 0.23 g of 6-[4-(4&#39;-pyridyl)aminophenyl]-3(2H)-pyridazinone hydrochloride. 
     
         IR(KBr): 1650 cm.sup.-1 
    
     EXAMPLE II 
     Pharmacological and toxicological studies of a pyridazinone derivative according to the present invention were carried out by the following methods to show their utility as a cardiac stimulant. 
     1. Effect on contraction of an isolated and cross-circulated papillary muscle preparation of the dog 
     An isolated and cross-circulated papillary muscle preparation of the dog was prepared by Endo and Hashimoto&#39;s method (referred to American Journal of Physiology, 218, 1459-1463, 1970). The effect of the compound was measured by closely intraarterially injecting the compound dissolved in a solvent to the papillary muscle for the purpose of recording its effect on contraction of papillary muscle. Rate of increase in contraction of papillary muscle is shown in Table 1. 
     2. Effect on contraction of an isolated left atrium of the guinea pig 
     A left atrium was isolated from a male guinea pig with 200-300 g of body weight soon after striking on the back of its head. The mitral orifice was fixed to the bottom of an organ bath filled with 30 ml of Krebs-Henseleit solution maintained at 35° C. A gas mixture comprising 95% of O 2  and 5% of CO 2  was passed through the Krebs-Henseleit solution in the organ bath. Isometric tension was measured by connecting a left auricle of heart and a transducer by a yarn. A resting tension of 0.5 g was given to the atrium, which was then electrically driven with square pulses with duration of 1 msec and voltage of 1.5 times as much as threshold in the rate of 2 Hz via dipolar platinum electrodes. 
     After stabilizing the atrium for 30 minutes from its preparation, the compound dissolved in a solvent was added to the organ bath to measure its effect. The rate of increase in contraction of left atrium is shown in Table 1. 
     3. Effects on myocardial contraction in anesthetized dogs 
     Male and female mongrel dogs with body weight of 8-15  kg were used. A dog was anesthetized by intraveneous injection of 30 mg/kg of sodium pentobarbital and practiced artificial respiration. The dog was thoractomized between fourth and fifth costa which was cut off. The pericardium was incised to expose heart. Blood flow through the aorta, which was measured with an electromagnetic blood flowmeter whose probe was attached to the ascending aorta, was used as an approximate index of cardiac output (CO). Left ventricular pressure (LVP) was measured with a Miller Catheter-tip pressure transducer and the first derivative of the LVP (dP/dt) was measured with a differentiater. Contraction of right ventricular muscle (Cont) was determined with a strain-gauge attached to the wall. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured with electrocardiogram (lead II) and a cardiotachometer. The compound dissolved in a solvent was administered intravenously from a left femoral vein. 
     Maximum value of dP/dt (dP/dt max) and rate of increase in Cont and CO are shown in Table 1. 
     4. Acute Toxicity 
     Acute toxicity (LD 50 ) for intravenous administration in male mice was determined by the method of Richfield and Wilcoxon (referred to Journal of Pharmacology and Experimental Therapeutics, 96, 99-113, 1949). The result is shown in Table 1. 
     
                                           TABLE 1__________________________________________________________________________                  Contraction of                          Contraction of                  papillary                          left atrium of                  muscle of dog                          quinea pig                                  Anesthetized dog    LD.sub.50                  dosage                      in-     in- dosage                                      dP/dt max                                            Cont CO   (mg/                  (μg                      crease                          dosage                              crease                                  (μg/kg                                      increase                                            increase                                                 increase                                                      kg)Compound               i.a.)                      (%) (g/ml)                              (%) i.v.)                                      (%)   (%)  (%)  i.v.__________________________________________________________________________ ##STR6##              30  12.4                          10.sup.-5                              163  30  64   31   13   103Example I                              100 108   39   11__________________________________________________________________________