JPH0259574A - Pyrazinone derivative or salt thereof - Google Patents

Abstract

NEW MATERIAL:The pyrazinone derivative of formula I (A is 5- or 6-membered heterocyclic group containing 1-3 N atoms and optionally having one or more substituents selected from 1-5C alkyl, cyano, carboxyl, 1-5C alkoxycarbonyl, hydroxyl, 1-5C alkoxy, amino, 1-5C alkylamino, 2-4C acylamino and carbamoyl group on the ring; R<1> and R<2> are H or 1-5C alkyl) and its salt. EXAMPLE:5-[4-(4-Pyridylamino)phenyl]-2(1H)-pyrazinone. USE:Useful as a cardiotonic. It can be administered orally or parenterally. PREPARATION:The compound of formula I can be produced according to the reaction formula by heating and reacting a compound of formula II with a compound of formula III in an inert solvent at 50-2000 deg.C for 0.5-10hr.

Description

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

[Problems to be solved by conventional technology and invention]

Cardiac inotropes 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, many of these cardiotonic agents have disadvantages such as extremely narrow safety margins, causing arrhythmia, or their inotropic effects are temporary, and are not suitable for oral administration.

The present inventors have searched for a compound that is highly active as a cardiotonic agent and has a sufficiently long-lasting effect, and as a result of intensive studies, they have arrived at the present invention.

[Means for solving problems]

That is, the gist of the present invention is the following general formula (I): ~C5 alkyl group, cyan group, carboxyl Ti, (+ −
At least one selected from Cs alkoxycarbonyl group, hydroxyl group, C1 to C5 alkoxy group, amino group, C1 to C5 alkylamino group, 02 to C6 dialkylamino group, C2 to C5 acylamino group, and carbamoyl group It may have a substituent.

Further, R1 and R2 each independently represent a hydrogen atom or a Cl-C5 alkyl group. ) and its salts.

Hereinafter, the present invention will be explained in detail with reference to specific examples.

Specific examples of A in the above general formula (1) include a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group,
The δ-triazinyl group, ω-triazinyl group, 'pyrrolyl group, imidazolyl group, and p may have at least one substituent.

The substituents include methyl group, ethyl group, propyl group,
C1-C5 straight chain or branched alkyl group such as butyl group; cyano group; carboxyl group: C1-C5 straight chain or branched such as methoxycarbonyl group, ethoxycarbonyl group, puboxycarbonyl group, butoxycarbonyl group alkoxycarbonyl group; hydroxyl group; C, -C such as methoxy group, ethoxy group, propoxy group, butoxy group;

straight chain or branched alkoxy group; amino group; 01-C5 straight chain or branched alkylamino group such as methylamino group, ethylamino group, propylamine group, butylamino group; dimethylamine group, diethylamino group , a C2-C5 straight-chain or branched dialkylamino group such as a dipropylamino group; a C2-C5 straight-chain or branched acylamino group such as a niacetylamino group, a globionylamino group, a butyrylamino group; and a carbamoyl group. Examples include groups.

Specific examples of R1 and R2 include hydrogen atoms and Cl-C such as methyl, ethyl, propyl, and butyl groups.
Examples include straight chain or branched alkyl groups of a.

Specific examples of the birazinone derivative represented by the above general formula (1) include the compounds shown below.

2H5 2H5 Ru.

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

q, 1 (II) (I[I) Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. 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 (in the above formula, A, R' and R2 are as defined above), X represents a halogen atom), that is, the compound (II) and the compound (I[[) is 500-200
By heating at 0° C. for 0.5 to /θ hours, the desired birazinone derivative (I) can be synthesized.

In addition, triethylamine and/or ? are used as bases. -An organic base such as diazabishiro (17)-7-undecene or an inorganic base such as potassium carbonate and sodium carbonate may be added.

Further, a copper compound may be used as a catalyst.

The compound (II) used as a starting material is T, Seradsky (T, 5heradsky),
Journal of the Chemical Society Perkin Transactions I (J, C, S, Perk
iku ■), 129th ~ 12th page (1977)
(according to the method described in ), and is produced by the following route.

R' (F/) (V) (In the above formula, RI R2 and
- Represents an alkoxycarbonyl group such as a butoxycarbonyl group. ) When the compound of 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, for example, powders, granules, tablets, dragees, pills, capsules, liquid preparations, etc. for oral administration, and e.g. waste tablets, suspensions, solutions, emulsions, ampoules, etc. for parenteral administration. and injection solutions. Of course, a combination of these may 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 depends on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, severity of disease, physical condition, nature/preparation/type of pharmaceutical preparation, etc.
This will be determined by your doctor, taking into account the type of active ingredient.

For example, in the case of oral administration, body weight/kl/daily, 0,
A dosage of about /-/Om9/14 is selected, but of course it is not limited to this.

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.

(a) t-(4 = lbopenzyloxyaminophenyl)-2(/H)-virazinone Chlorobirazinone 2,239 and N-carbobenzyloxy-N-phenylhydroxyamine B, θ, l' f
'I was dissolved in 2jrttl of N,N-dimethylformamide, and 6θ sodium thihydride/1 was added at once while cooling with water and stirring at room temperature. After stirring at the same temperature overnight, the reaction mixture was cooled with water, then 2 atts of water and 30 atts of ether were added, and the precipitated solid was separated, washed with water, and then washed with ether. After air drying, the above-mentioned target product 2.079 was obtained. This product was used in the next step without purification.

The total amount of the crude product obtained in the above synthesis reaction (ω) was added with io acetic acid and l.
! 10 rttl of hydrogen thiobromide/acetic acid was added and heated on an oil bath at θ°C for one evening. After cooling the reaction mixture with water, add acetone 3θ
ml and 70 ml of ether were added, and the precipitated crystals were counted. Dissolve the crystals in 100 m of hot water and cool with ice/
N-sodium hydroxide was added to neutralize. The precipitated crystals were collected, washed with water, and dried to obtain the above-mentioned target product 0.9rf.

Example t-(g-(\-pyridylamino)phenyl)
--2(/H)-bilazinone t-(4t-aminophenyl)-,2(/H)-bilazinone o,rty is dissolved in N-methyl-copyrrolidongo, ? Triethylamine 0,2/rnl and dark chlorpyridine hydrochloride θ,4 were heated and stirred on an oil bath at θ°C.
trt was added one after another, and stirring was continued at the same temperature for 2 hours. The reaction mixture was ice-cooled, 20 td of acetone was added, and the precipitated solid was collected.

The solid was air-dried, then dissolved in warm water lθOytl, and neutralized with /N-sodium hydroxide while cooling on ice.

The precipitated solid was collected and subjected to silica gel column chromatography (solvent: chloroform/methanol/acetic acid = 20///
θ, l → //110. l) I did. The fractions containing the target product were collected and concentrated, and the residue was mixed with 20 ml of methanol and 10 ml of acetone.
1, and after cooling with water (<N-hydrochloric acid/dioxane O0♂d
added. Next, acetonko θgo and ether 30rxl
Yield: Oo (toughness: 60 cm), melting point:〉
3θ0°C IR: /4 to 5 sub-l Test Examples The usefulness of the compounds of the present invention as cardiotonic agents was demonstrated by causing a significant increase in cardiac contractility in both in vitro and in vivo tests. .

(1) In vitro test In vitro tests were conducted on both the isolated right atrium and isolated papillary muscle systems of guinea pigs using the method described below.

(a) Method using isolated right atrium of guinea pig Weight 20
A male guinea pig of 0 to 3θθ2 was hit on the back of the head, and the right atrium was immediately removed. The right atrium ventricle ostium was kept warm at 3t°C and 7'C Krebs-Henslide solution 30rptl.
The body was fixed at the bottom of an organ bath filled with water. 9 for the Kreps-Henslide solution in the organ bath! A mixed gas consisting of 02% and j% CO2 was bubbled through. A thread was attached to the atrial appendage of the right atrium, the other end of the thread was connected to a transducer, and the isometric tension was measured. A resting tension of O1!1 was applied to the specimen. After stabilizing for 30 minutes after specimen preparation, the compound obtained in the above example dissolved in a solvent was added into the organ bath and the reaction was recorded.

(b) Method using isolated guinea pig papillary muscle Similar to the method using isolated guinea pig right atrium in (a), guinea pig right ventricular papillary muscle was used to record the reaction when the drug was added. However, in this case the specimen is passed through two platinum electrodes for a duration of lms, a threshold of /,! It was electrically driven twice every 97 seconds with a square wave of twice the voltage.

(2) In-vivo test In the in-vivo test, mixed male and female dogs weighing between ♂ and 1-l were used. The dog was anesthetized with 307n9/<9 intravenous sodium bentoparbital and artificially ventilated. A thoracotomy was made between the fourth and fifth left ribs, and the fifth rib was removed. The heart sac 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). A polyethylene cannula was inserted into the left ventricle, the left ventricular pressure was measured, and the rate of change in left ventricular pressure (dp/dt) was determined electrically. A strain measurement gauge was attached to the right ventricular wall to measure the contractile force (Cont) of the right ventricular muscle. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured by electrocardiogram (Lead ■).

The compound obtained in the above example dissolved in a solvent was intravenously administered into the left femoral vein.

When the above pharmacological test was conducted, the compound of the present invention increased the contractile force of the right atrium and papillary muscles of guinea pigs, and also increased the maximum rate of change in left ventricular pressure (dp/dt max) in anesthetized dogs.
), right ventricular contractile force (Cont) and cardiac output (C
o), causing an increase in cardiac contractility.

The rate of increase in guinea pig right atrium and papillary muscle contractile force, and the rate of increase in dp/dt max and ConLCO during anesthesia are shown in the table below.

Claims (1)

[Claims] (1) The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ (I) (In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms. and C_1 to C_ on the ring
5 alkyl group, cyano group, carboxyl group, C_1~
C_5 alkoxycarbonyl group, hydroxyl group, C_1 to C
_5 alkoxy group, amino group, C_1 to C_5 alkylamino group, C_2 to C_6 dialkylamino group,
It may have at least one substituent selected from C_2 to C_5 acylamino groups and carbamoyl groups. Further, R^1 and R^2 each independently represent a hydrogen atom or an alkyl group of C_1 to C_5. ) Pyrazinone derivatives or salts thereof.