JPS60197681A - Pyridine derivative or its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [X is group of formula IV (Y is oxy, thio or imino; R is H, amino, 1-4C alkylamino, etc.), or group of formula V]and its salt. EXAMPLE:4-(4-Aminophenyl)-2-aminothiazole. USE:A cardiotonic agent. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II (Z is halogen) with the compound of formula III according to the reaction formula, in a proper solvent such as DMF, phenol, dioxane, etc. at 50-200 deg.C for 1-15hr. Copper or a copper compound may be used as the catalyst. The compound of formula I is e.g. the compound of formula VI, etc. The compound of formula I can be used as a cardiotonic for oral for parenteral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridine derivatives or salts thereof useful as cardiotonic agents.

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 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.

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.In other words, the spirit of the present invention is based on the following general formula (■): (Y is
Represents an oxy group, thio group or imino group, Rfl, hydrogen atom, amino group, C1-C2 alkyl group, C1-C
4 alkoxy group s C1 to C6 alkylamino group,
Represents a C1-C2 dialkylamino group. ) represents a pyridine derivative or a salt thereof.

The present invention will be explained in detail below.

In the general formula (1), the alkyl group of R is
Methyl, ethyl, propyl, isobutetrabyl, butyl, isobutyl, t-butyl, etc.; alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc.; alkylamino groups include methylamino, ethylamino, butylamino, etc.; dialkyl Examples of the amino group include dimethylamino and diethylamino.

The pyridine derivative in the present invention can be synthesized, for example, by the following route.

eZ 10 HINK and 8-+ 9NH1” (fl) (1
) (1) (In the above reaction formula, 2 represents a halogen atom, and
is as already defined. ), that is, compound (1
1) and compound (1) are reacted in a suitable solvent, for example, dimethylformamide, phenol, ethanol, dioxane, etc. alone or in a mixed solvent thereof, at goC to -〇〇C for 1 hour to 75 hours. By doing so, the desired pyridine derivative can be synthesized.

Additionally, copper or a copper compound may be used as a catalyst.

Examples of the pyridine derivatives of the present invention thus obtained include the following compounds.

Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. The above salts include hydrochloric acid, sulfuric acid,
Examples include salts of mineral acids such as hydrobromic acid, phosphoric acid, and nitric acid, and salts of organic acids such as lactic acid, acetic acid, and oxalate. All of these compounds are useful as cardiotonic agents.

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, for example, powders, granules, tablets, dragees, pills, capsules, solutions, etc. for oral administration, and e.g. suppositories, suspensions, solutions, emulsions, ampoules, etc. for parenteral administration. 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 inventive ornament to be administered as a cardiotonic drug depends on age, sex, body weight, sensitivity differences, administration method, administration timing/interval, degree of medical condition, physical condition, nature/preparation/type of pharmaceutical preparation, and effectiveness. It is determined by a doctor after considering the types of ingredients.

For example, for oral administration, body weight/kl/day, θ
The dosage is selected to be approximately 0 to 10 mf/kf, but is not limited to this.

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The invention is not limited to the embodiments below unless they go beyond the gist thereof.

Reference IyiI Dar(+-Achinophenyl)-coaminothiazole p-nitrophenacyl bromide 2J? and thioureayu 3
Add 95% ethanol Jθθ- to 1, and under reflux, ii
The mixture was heated and stirred for hours. After cooling the reaction solution, 25% hydroxide)
After making it basic by adding a Uram aqueous solution, the precipitated solid was collected, washed with water, and dried in vacuum.
) was obtained.

Next, stannous chloride cohydrate io was added to 31 td of concentrated hydrochloric acid.
y was added and dissolved, and the previously obtained cou(coonitrophenyl)-coaminoteazole Yuko 1 was added little by little while stirring at room temperature. then 6
The reactor was immersed in a 0°C bath, and the reaction was carried out at that temperature for 7 hours.

After the reaction was completed, the reaction solution was cooled and made basic by adding a 35% aqueous sodium hydroxide solution. CpH phantom//) The precipitated solid is collected, washed with water, and dried under vacuum to obtain the desired tri-(couaminophenyl)-coaminothiazole ls9? (Yield &,?9!+) was obtained.

Example Ku [Ku(coubiridyl)aminophenyl]
- Co-aminotheazole phenol was heated and dissolved at yyyioo°C, and 0.33f of Hiro-promopyridine and potassium iodide θO were added thereto. ,
Tei-(Hiro-aminophenyl)-coaminoteazole OQ7 obtained in Reference Example? Add in this order. The resulting mixture Y/? The mixture was heated to 0° C. and the reaction was carried out for 1/hour.

After the reaction is completed, the reaction mixture is poured into a mixture of ice water tsomt and 1N caustic soda 3a- to precipitate a tar-like substance containing the target product. If desired, this is extracted with ethyl, dried over ethyl acetate and sodium sulfate, the solvent is distilled off, and the resulting tar-like residue is treated with silica gel chromatography to obtain the desired product. This was dissolved in ethanol and converted into a hydrochloride with ethanol-hydrochloric acid to obtain the target product, the hydrochloride OS of cou[coupyridyl)aminophenyl]-coaminoteazole (yield: 70%).

1, R, (KBr): /! 33Crll-”
, /6co5crn1/t,II3(M'' Test Examples The usefulness of the compounds obtained in the examples as cardiotonic agents. In accordance with standard pharmacological test methods, e.g. isolated papillary muscle of dogs and isolated left atrium of guinea pigs. causes a significant increase in muscle contraction force,
It is also demonstrated by its effectiveness in causing a significant increase in cardiac contractility in anesthetized dogs. The pharmacological test method is described below.

1. A method using a large-extracted papillary muscle cross-reflux specimen.
, Physiol, ) J/vol., lda, t9
-/4! 43 pages, 1970, USA reference]. The compound dissolved in the solvent is moved close to the specimen,
The effect on the contraction force of papillary muscles was recorded.

? How to use guinea pig isolated left atrium Weight: 200~
JOOOf's male guinea pig was hit on the back of the head, and he immediately gave birth to Left Heart S.

The left atrium ostium was fixed at the bottom of an organ bath filled with 1% Krebs-Hensleit solution JOm kept at 35C. 0 in the Krebs-Henslide solution in the organ bath
A mixed gas consisting of 2 and j% COI was bubbled through. A string was attached to the atrial appendage of the left atrium and connected to the $Yl' transducer, and the isonatural tension was measured. The specimen contains Ol
A resting tension of f was applied. The specimen was electrically driven twice via a single platinum electrode with a square wave of voltage is times the threshold for 1 millisecond duration. After stabilizing for 30 minutes after preparation, compounds dissolved in solvent were added into the organ bath and the reaction was recorded.

3 Method using anesthetized dog Weight t-1! ;kg mixed male and female dogs were used. dog is 30n9
The animal was anesthetized with bentoparbital sodium (KFC) and artificial respiration was performed. 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 aortic blood flow (ITV), which was used as an approximate index of cardiac output (CO). A catheter tip manometer was inserted into the left ventricle to measure the left ventricular pressure, and the rate of change in left ventricular pressure (dp/dt) was determined electrically. A strain measuring gauge was attached to the right ventricular wall, and the contractile force (Cont) % of the right ventricular muscle was measured. Systemic blood pressure was measured from the left femoral artery. The heart rate was measured by electrocardiogram (Mn# conductor), and the compound dissolved in the solvent was intravenously administered through the left femoral vein.

When the above-mentioned pharmacological tests were conducted, all of the cardiotonic drugs of the present invention increased the contractile force of papillary muscles of dogs and left atrial muscles of guinea pigs, and the maximum rate of change in left ventricular pressure (dp) during anesthesia.
/dtmhx).

Cont, caused an increase in Co, i.e. an increase in cardiac contractility. Rate of increase in canine papillary muscle contraction force when these compounds were administered at 7θOpf/-, 10-"77ml
Table 1 shows the rate of increase in left atrial contractile force in guinea pigs when administered with 30 μSL/kp′i and the rate of increase in dp/dt wax, Coat, CO in anesthetized dogs when administered with 30 μSL/kp′i.

Table I Increase rate book for each measurement value) Continuation of page 1 0 shots Akita Kiyota 1) Good Yokohama City Midori Ward Laboratory

Claims (1)

[Claims] (1) The following general formula CI) (Y represents an oxy group, a thio group, or an imino group, R
, a hydrogen atom, an amino group, a q~noble alkylamino group,
Represents a dialkylamino group of q~-. ). ] Pyridine derivative or its salts represented by