JPS63154671A - Pyridazinone derivative or salts thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or 1-5C alkyl; R<2>-R<4> are H, 1-5C alkoxy or OH; two of R<2>-R<4> may together form the group of formula IV or formula V; m is 0-4; n is 1-4; dotted line is single bond or double bond] or its salt. EXAMPLE:The compound of formula VI. USE:A medicine. A cardiotonic agent. It is administered orally or parenterally at a dose of 0.1-10mg/kg body weight daily in the case of oral administration. PREPARATION:The compound of formula I can be produced e.g. by reacting a carboxylic acid of formula II with an alkyl halocarboxylate such as ethyl chloroformate in a mixed solvent consisting of N,N-dimethylformamide and tetrahydrofuran, etc., at -20-+100 deg.C for 5-10hr in the presence of a basic compound such as triethylamine and reacting the resultant mixed acid anhydride with an amine of formula III at -20-+100 deg.C for 5min-10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to novel pyridazinone derivatives or salts thereof useful as cardiotonic agents.

(Problems to be solved by the prior art and the invention) Cardiotropes have the effect of directly acting on the heart to strengthen its contractile force.
Various drugs have been used to treat heart failure.

However, many of these inotropic agents have disadvantages, such as having an extremely narrow safety margin, causing arrhythmia, or having a transient inotropic effect, making them unsuitable for oral administration.

(Means for Solving the Problems) The present inventors have searched for a compound that is highly active as a cardiotonic agent and has a sufficiently long-lasting effect, and has thus arrived at the present invention.

That is, the gist of the present invention is the following general formula (I): (In the above formula, R1 represents a hydrogen atom or an alkyl group of O1%O, R2, R3 and R4 are a hydrogen atom, C16-a
, represents an alkoxy group or a hydroxyl group. Note that R2, R
11 and R4 together -o-ca,
-o-1 or -○-OH, ca2-0- may be formed. Further, mFiO represents an integer of Hiro, and n represents an integer of / to Hiro. Additionally, dotted lines represent single or double bonds. ) Pyridazinone derivatives or salts thereof.

The present invention will be explained in detail below.

In the above general formula (1), specific examples of R1 include a hydrogen atom; a C1 to C5 alkyl group such as methyl, ethyl, and propyl. Examples of R2, Ha and R4 include a hydrogen atom; a hydroxyl group or an 01-C5 alkoxy group such as methoxy, ethoxy, propoxy, etc., and when two of these are taken together, 10-OH, -0- or -0 -0)
120E, -〇- may be formed.

Specific examples of the pyridazinone derivative represented by the general formula (i) include the following compounds.

o Pharmaceutically acceptable salts of the above compounds 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 of the present invention will be explained.

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

(It) (m) (I) The raw material amine (general formula m above) is synthesized according to the following route.

R1 (If(III) [In the above formula, R1, Rg, R'%R', m%n
and the dotted line have already been defined in the above general formula (1). In addition, X in the above reaction formula /), 2) and 3)
represents a halogen atom, and A represents a nitrogen atom protecting group, such as a thick base or a benzyloxycarbonyl group.
Represents a butoxycarbonyl group, a phthaloyl group, etc.

] Through the above process, the compound of the above general formula (I) can be produced by the amide bond forming reaction between carboxylic acid (II) and amine (I).

-1- As a method for producing this amide bond, for example, (a) mixed acid anhydride method, that is, reacting carboxylic acid (II) with K-alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with amine (III). (b) Carbodiimide determination, that is, a method in which carboxylic acid (II) and amine (II) are condensed in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, e→Other carboxylic acid halide methods, active ester methods, etc. Of these, the mixed acid anhydride method is most preferred.

Mixed acid anhydrides are carboxylic acids (■) in the presence of basic compounds (organic bases such as triethylamine, pyridine, diazabicycloundecene; inorganic bases such as potassium carbonate).
and an alkylhalocarboxylic acid in a solvent customary for mixed acid anhydride processes, such as tetrahydrofuran, dioxane, toluene, chloroform, ethyl acetate, dimethylformamide or dimethylacetamide, or a mixture thereof.

The reaction temperature is about -1200 to 100℃, The waiting time is about 5 to 10 hours.

The resulting mixed acid anhydride is usually separated from the amine (
It can be reacted with The reaction with amine (III) is carried out at 0°C to 10θ'CK for about j minutes to IO hours.

Carbon l! l! Cm) is a journal on medicine story (JoMad, Ohem, )
/ Vol. 7, p. 2//-2ft (24L).

When the compound according to the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method.

In this case, the forms provided include powders, granules, tablets, sugar-coated tablets, tablets, capsules, liquid preparations, etc. for oral administration, and preparations, suspensions, solutions, etc. for parenteral administration. Examples include emulsions, ampoules 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 amount of the compound of the present invention to be administered as a cardiotonic drug should be determined based on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, and active ingredients. The decision will be made by your doctor, taking into account the type of

For example, in the case of oral administration, 9/day per body weight 7, θ, 7
The dosage is selected to be approximately .about./θ■/d, but is of course not limited to this.

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

Reference example/After dissolving 3.3t in N,N-dimethylformamide 5θ1, triethylamine/,? - on a 20℃ oil bath, 5
The mixture was heated and stirred for hours. After the reaction is completed, the solvent is concentrated using an evaporator, and 100% of water is added to the residue. 1 was added and the product was then extracted with dichloromethane-100. The dichloromethane layer was dried over anhydrous Na2SO4, concentrated, and the residue was treated with silica gel column chromatography (solvent: chloroform).
did. The fractions containing the target product are collected and concentrated, and the target product/,≠s
f (co/%) was obtained.

/, 4'J' P, ethanol 100M! ! and/N
-Hydrazine hydrate/ethanol/Omwokajt 7
.

The mixture was heated and stirred on a ℃ oil bath during the daytime. After the reaction was completed, the solvent was concentrated using an evaporator, and to the residue was added 10 ptl of water and 10 ptl of /N-hydrochloric acid.
in pH/θ). The target product was extracted three times with dichloromethane sO-, the dichloromethane layer was collected, dried over anhydrous NaSO4, and concentrated to obtain the target product as a light brown solid.
10o%) was obtained.

Objective 7 from reference example. r, 2t (4!j, i%) was obtained.

Reference Example/By the same operation as in b), hydrazine was treated with 21 to obtain the target product 3.679 (7
j, 3%) was obtained.

A mixture of Reference Example 3 and toluene/2θtttl was subjected to a dehydration reaction under reflux for 2 hours while water was removed by azeotropic dehydration to obtain a Schiff base.

This reaction mixture was cooled to room temperature and then heated and stirred for 10 hours. After 70 hours, θ,jlJ-hydrochloric acid 2j0- was added to the thermal reaction mixture, and the mixture was further heated and stirred at 20°C for 7 hours.

The reaction mixture was cooled to room temperature, and 100 ml of ethyl acetate was added to separate the layers. The aqueous layer was further washed with ethyl acetate/jo-, and after cooling with water, 95% NaOHJ'r was added to make it basic. The liberated target product is dichloromethane/JOd! In≠
The organic layer was extracted twice, dried over anhydrous Na2SO4, and concentrated.

The residue was treated with silica gel column chromatography (solvent: chloroform-chloroform/methanol = s//).
Fractions containing the target product were collected and concentrated to obtain the target product J, J j t (27%) as a light brown oil.

Reference example Hiro I (N N-(aFi,), Na, 10m1.Q
-cao 7. A thick base was prepared by dehydrating a mixture of /m/ and toluene jOd under reflux for 7 hours while removing water azeotropically.

/, the solution of toluene λθtri of reference v was added dropwise.

Next, dichloromethane-〇〇- was added, and after stirring at room temperature for 2 hours, water/θ0rttl was added and acidified with concentrated hydrochloric acid (pHHI 3゜. After stirring at room temperature for 2 hours, the layers were separated, and the aqueous layer was washed with dichloromethane. After cooling on ice, the mixture was made basic with N-NaOH (pH 70).
After drying with anhydrous Na2804, it was concentrated to obtain the crude target product/21 (
J/%) was obtained. This target product was used in the next step without purification.

Lithium aluminum hydride/? 100 tnl of tetrahydrofuran solution was added to the suspension of SO- and tetrahydrofuran at room temperature and stirred at υ 3.0V.

This mixture was transferred onto a 0°C oil bath and stirred under reflux for 7 hours. After water cooling, water/,! , jN-NaOH/m/! and 3 d of water were added slowly in this order and stirred for 1 hour. After removing the insoluble materials in the furnace, the P solution is concentrated using an evaporator, and the residue is subjected to silica gel column chromatography (solvent: chloroform-chloroform/methanol=!//'). Fractions containing the target product are collected and concentrated to give a light brown color. Target as oil /, ≠ 4f (
j/%) was obtained.

20 Example/Formamide, 20. / and tetrahydrofuran 2011
After dissolving in L/ and cooling to -200 to -3θ°C, triethylamine 0.4LFd! and ethyl chloroformate 0.33r
A mixed acid anhydride was prepared by sequentially adding d.

This cold reaction mixture K aH,of)NN-((:+H
2) 2N island 0, r/? (7) Add a solution of 10yd of N,N-dimethylformamide and tetrahydrofuran/θd.

After stirring at -2θ°C for 20 minutes, the temperature was gradually raised to room temperature and the reaction was carried out for 2 hours. After concentrating the reaction mixture, the residue was subjected to silica gel column chromatography (solvent: chloroform-chloroform/methanol = sO//), and fractions containing the target product were collected and concentrated.

The residue was dissolved in 20 ml of ethanol, and after cooling on ice, /N-
Add salt e/ethanol hiro-, then process chill 200m
1 was added, and the precipitated solid was collected, washed with ether, and dried to obtain the hydrochloride of the target product as a white solid.

Yield", Of!?, Melting point:, 270'~27℃I R
: /lro, In-1 Example co-synthesis 0.2 J f and OH,0((OH,-N N-(C!
H,) Mountain 0,2! The hydrochloride salt of the target product was obtained as a white solid from t.

Yield: 0,399. Melting point: /6°~/9/°CIR
E/≦, f OCITE-” Synthesis of Example 3 The hydrochloride salt of the target product was obtained as a white solid from 7v.

Yield 20.351, melting point: 2?0~. z37°C decomposition) IR: # to θα-1 The hydrochloride salt of the target product was obtained as a white solid from Synthesis V of Example Hiro.

Yield: θ,';#t, Melting point: 2/reso~, 223
°C (min j I J! It is demonstrated by its effectiveness in producing a significant increase in the contractile force of the papillary muscle and isolated left atrial muscle in guinea pigs, and in producing a significant increase in the contractile force of the heart in anesthetized dogs. The pharmacological test method is described below.

1 Method using a canine isolated papillary muscle cross-reflux specimen A canine isolated papillary muscle cross-reflux specimen was prepared using the method of Endo and Hashimoto [American Journal of Physiology (American J
, Physiol, ) 2 / J' Volume 1/≠59-/
3 pages, / 1970, United States reference]. Compounds dissolved in solvent were applied in close proximity to the specimen, and the effect on the contractile force of the papillary muscles was recorded.

2 Method using isolated left atrium of guinea pig Weight: 0θ~3
A θθV male guinea pig was hit on the back of the head, and the left atrium was immediately removed.

The left atrium ostium! It was fixed at the bottom of an organ bath filled with Krebs-Henslide solution 3θd kept at s°C. Add 5% O to the Krebs-Henslide solution in the organ bath! A mixed gas consisting of 5% CO2 and 5% CO2 was bubbled through. Attach a string to the atrial appendage of the left atrium and connect the other end of the string to the transducer.
to measure isometric tension. The sample has θ, j t
A static tension of . The specimen was exposed to square waves of voltage and pressure for 7.5 times the threshold for a duration of milliseconds through two platinum electrodes.
It was electrically driven twice per second. 30 days after specimen preparation
After stabilizing for a minute, compounds dissolved in solvent were added into the organ bath and the reaction was recorded.

3. Method using anesthetized dogs Mongrel dogs of both sexes weighing ♂~/j4 were used. Dogs weigh 30■/kg
The patient was anesthetized with bentoparbital sodium (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 cardiac membrane was incised and the heart exposed.

An electromagnetic flowmeter probe was attached to the ascending aorta to measure the aortic blood flow, which was used as an approximate index of cardiac output (CO). Insert a polyethylene cannula into the left ventricle,
The left ventricular pressure was measured, and the rate of change (ap/at) in the left ventricular pressure was determined. A strain measurement gauge was attached to the right ventricular wall to measure the contractile force (0 ont) of the right ventricular muscle. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured by electrocardiogram (Lead ■). The compound dissolved in the solvent was administered intravenously into the left femoral vein.

When the above-mentioned pharmacological tests were conducted, all of the cardiotonic agents according to the present invention increased the contractile force of the papillary muscle of dogs and the left atrial muscle of guinea pigs, and the maximum rate of change in left ventricular pressure (dp/
dt max) 0ont, C! caused an increase in O, ie, an increase in cardiac contractility.

Increase rate of canine papillary muscle contraction force, rate of increase of guinea pig left atrial contraction force, and (1p/dt ma:r, 0on
Table 7 shows the increase rates of t and Co.

(Effects of the Invention) It is clear from the above results that the compounds of the present invention are useful as cardiotonic agents.

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

Claims (1)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the above formula, R^1 represents a hydrogen atom or an alkyl group of C_1 to C_5, R^2, R^ 3 and R^4 are
Represents a hydrogen atom, an alkoxy group of C_1 to C_5, or a hydroxyl group. In addition, two of R^2, R^3 and R^4 together form -O-CH_2-O-, or -O-CH
_2CH_2-O- may be formed. Also, m is 0~
represents an integer of 4, and n represents an integer of 1 to 4. Additionally, dotted lines represent single or double bonds. ) Pyridazinone derivatives or salts thereof.