JPS61289032A - Cardiac - Google Patents

Abstract

PURPOSE:A cardiac having high activity and durability of effects, comprising a specific pyridazinone derivative or its salt as an active ingredient. CONSTITUTION:A cardiac comprising a pyridazinone derivative shown by the formula I (A is 1-3N heterocyclic ring of 5-membered ring or 6-membered ring, containing optionally substituent group such as 1-6C alkyl, cyano, amino, etc., on the ring) or its salt as an active ingredient. To be concrete, a compound shown by the formula IV, etc., may be cited as the derivative. The compound shown by the formula I, for example, is obtained by heating a compound shown by the formula II and a compound shown by the formula III (X is halogen) in a polar solvent such as DMF, etc., at 50-200 deg.C for 0.5-10hr. The compound shown by the formula I has high activity as a cardiac and improved durability of effects.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a cardiotonic agent, and more particularly to a cardiotonic agent containing a pyridazinone derivative or a salt thereof as an active ingredient.

(Prior Art and Problems) Cardiotropic agents have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure. However, these inotropic agents have extremely narrow safety margins, cause arrhythmia, or have short-lived inotropic effects, and are not suitable for oral administration. However, it is not necessarily completely satisfactory.

(Structure of the Invention) The present inventors have searched for a compound that is active as a cardiotonic agent and has a sufficiently long-lasting effect, and has arrived at the present invention.

That is, the gist of the present invention is the following general formula (1) H (wherein A represents a !-membered ring or 6-membered heterocyclic group containing 7 to 3 nitrogen atoms, and C2 to C5 on the ring). Alkyl group, cyano group, hydroxyl group, 01-C3 alkoxy group, amino group, C1-C5 alkylamino group, C7-
C6 dialkylamino group, C7-C5 acylamino group, carboxyl lot~0. may have at least one substituent selected from an alkoxycarbonyl group and a carbamoyl group. ) A cardiotonic agent containing a pyridazinone derivative or its salt as an active ingredient.

The present invention will be explained in detail below.

In the above general formula (I), specific examples of A include pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, θ-triazinyl group, C8-triazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, etc. and may have at least 7 substituents on the ring. The substituents include a, + a, straight chain or branched alkyl groups such as methyl, ethyl, propyl, butyl, pentyl; cyan group; hydroxyl group: methoxy;
01 to 0, such as ethoxy, propoxy, butoxy. Nao @
or branched alkoxy group; amino group; a of methylamino, ethylamino, propylamino, butylamino
, -C, straight chain or branched alkylamino group; C2 to C6 straight or branched dialkylamino group such as dimethylamino, diethylamino; C2 to C1 straight chain such as acylamino group propionylamino, butyrylamine 7, etc. or a branched acylamino group; a carboxyl group; a C8 to C6 straight or branched alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl; and a carbamoyl group. ) Specific examples of the pyridazinone derivatives include the following compounds.

HH HH shi's' kiH2B
IH Cardiotropes containing pharmaceutically acceptable salts of the above compounds as active ingredients are also included within the scope of the present invention. Examples of the above salts include salts of mineral acids such as hydrochloric acid and phosphoric acid, and salts of organic acids such as lactic acid and acetic acid. All of these compounds are useful as cardiotonic agents.

Next, a method for producing the compound according to the present invention will be explained.

The pyridazinone derivative according to the present invention is produced, for example, by the following route.

(1) (nl,) (In the above formula, A is as defined above, and X represents a halogen atom.) That is, the compound (ff) and (i[l,) are combined with dimethylformamide or dimethylacetamide. In a polar bath medium such as! θ
Approximately 0.0 at ~200°C. The desired pyridazinone derivative (1) can be synthesized by heating for 10 hours. Note that a steel compound may be used as a catalyst.

The compound produced by the above method is used as a cardiotonic agent, and in that case, it can be administered by an appropriate oral or parenteral administration method. In this case, the forms provided for oral administration include powders, coarse granules, tablets, capsules, pills, capsules, liquid preparations, etc., and the forms for parenteral administration include layers, suspensions, solutions, etc. , emulsions, angles and injection solutions. Of course, a combination of these can also be provided. For formulation, conventional methods in this field can be used.

In addition, the dosage should be determined in consideration of age, sex, body weight, sensitivity differences, administration method, administration timing/interval, degree of medical condition, physical condition, nature/preparation/oil of the pharmaceutical preparation, type of active ingredient, etc. , as determined by the physician.

For example, in the case of oral administration, per 7 kg of body weight, 7 days.
7 to 70■ = The dosage at the foot is important, but of course there is no limit to this.

(Examples) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Reference Example/Production of t-[y-(tt'-pyridyl)aminophenyl]dihydro(,2H)-pyridazinone Dapromopyridine hydrochloride 3. ? del and 6-(4t-aminophenyl)-<t,s-dihydro-3(2H)-
Pyridazinone j, 7/#! N of θ-.

#m in N-dimethylformamide under a nitrogen stream for 10
! The reaction was carried out at ℃ for 2 hours. 2. Add the reaction solution to soda carbonate. /
The precipitated crystals were filtered, washed with water, and dried under reduced pressure to form 6-(g-(
1-pyridyl)aminophenyl]-da! -dihydro-
J'(2H)-pyridazinone was proposed (Collection 547o,
7%). The obtained crystals were dissolved in methyl alcohol in a heating bath, hydrochloric acid-ethyl alcohol was added, and ether was added to obtain a hydrochloride.

Engineering R (KBr): / 64t2 cm-'MASS
2w(g, 4≦,≦; Reference example λ H t -[a-(J'-pyrimidinyl)aminophenyl]-ta,!-dihydro-3(2H)-pyridazinone j-(￥-7minophenyl )-a, Z--)hydro-3
-(-n)-Pyridazinone-1 and co-chloropyrimidine/2.21 were reacted in dimethylformamide 1Od under heating and reflux for 1 hour, and after cooling, the precipitated crystals were separated from each other and treated with dimethylformamide and tetrahydrofuran. After washing and dry recording, the target object t-(a-(al
-pyrimidinyl)aminophenyl)-a,t-dihydro-3(-H)-pyridazinone was obtained at 8-θI (yield: 0!%).

ICBr: / 670 cm-' Pharmacological tests and acute toxicity tests to demonstrate the usefulness of the pyridazinone derivatives obtained in Examples and Reference Examples as cardiotonic agents were conducted according to the following methods.

l Method using canine isolated papillary muscle chiasm perfusion specimen Canine isolated papillary muscle chiasm perfusion specimen was prepared using the method of Rensho and Hashimoto [American Journal Opphysiology (American J,
P)! yaiol), 2/♂vol./gjtar/4
ttJ page, /Ref. 7o]. Compounds dissolved in a therapeutic medium were injected into the specimen, and the effect on the contractile force of the papillary muscles was recorded. Table 7 shows the increase rate of papillary muscle contraction force.
Shown below.

2 Method using guinea pig vent and atrium 1120θ~
A male guinea pig No. 3009 was hit in the hindquarters, and the left atrium immediately ruptured.

The left ventricle portion was fixed at the bottom of an organ bath containing Krebs-Henslide solution 301 kept at 3J°C. What about the Krebs-Henslide solution in the organ bath? ! Chi's 0. A mixed gas consisting of A thread was tied to the atrial appendage of the left atrium, and the other end of the thread was connected to a transducer to measure isostatic tension. A resting tension of 0j77 was applied to the specimen. Specimen through a platinum electrode lasts / milliseconds, dark value /,! It was electrically driven twice in 7 seconds with a square wave of twice the voltage. After stabilizing for 30 minutes after preparation, compounds dissolved in solvent were added into the organ bath and the reaction was recorded. , the rate of increase in left atrial contractile force is shown in Table 1, 3 Method using anesthetized dogs Body weight! ~/jkg male and female dogs were used. The dog is JO47
The animal was anesthetized with sodium bentoparbital (intravenous injection) and artificial respiration was performed. A thoracotomy was made between the fourth and fifth left ribs, and the fifth rib was removed. The heart membrane was incised and Kameyama's heart was removed.

An M6 blood meter probe was attached to the ascending aorta to measure the aortic blood flow, which was used as an approximate index of cardiac output (00). A polyethylene cannula was inserted into the left ventricle, the left ventricular pressure was measured, and the rate of change in the left ventricular pressure (ap7at) was determined visually. A strain measurement gauge was attached to the right ventricular wall to measure the contractile force (0ont) of the right heart muscle. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured by electrocardiogram (1st IiW conductor). The compound dissolved in the solvent was administered intravenously through the left femoral vein.

Anesthetized dP/dt wax, 0oht and C
o (7) The increase rate is shown in Table/.

Acutely toxic male mice were given intravenous (i, v,) or faucet (p,
Acute toxicity (LD, .1yL) when administered was determined by the Litchfield and Wilcoxon method (Journal of Pharmacology and Experimental Therapeutics (J.

Pharmaao'l, ]Czp, Ther, )
? Volume 6, Tata // J Negative, / Free 2 Years] Table 7 shows the results obtained from VC.

(Effects of the Invention) The cardiotonic agent according to the present invention has high activity and good persistence of effect.

Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase - Others/names

Claims (1)

[Claims] (1) The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A represents a 5-membered or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms. , C_1 to C_5 on the ring
Alkyl group, cyano group, hydroxyl group, C_1-C_5 alkoxy group, amino group, C_1-C_5 alkylamino group, C_2-C_6 dialkylamino group, C_2-
C_5 acylamino group, carboxyl group, C_2-C
It may have at least one substituent selected from the alkoxycarbonyl group and carbamoyl group of _5. ) A cardiotonic agent containing a pyridacinone derivative or a salt thereof as an active ingredient.