KR840001106B1 - Method for the preparation of pyridine derivatives - Google Patents

Abstract

R2,R3=C1-6 alcyclic, R2,R3=forming 5-7 membered hetero cycle contg. N; n=2-4) having antiasrrhythmic activity, were prepd. in 3 steps. a)acetonitrile pyridyl II was alkylated by X-(CH2)n-N(R2)R3. b) The resulting product of a was alkylated again with R1XR1=unsate. alkyl). c)The nitrile group of the resulting product of b was hydrolysed to corresponding amide to give I.

Description

Method for preparing pyridine derivative

The present invention relates to a method for producing a pyridine derivative having an antiarrhythmic action and platelet aggregation inhibitory action.

The novel pyridine derivatives produced by the process of the invention are represented by the following general formula (I).

Wherein the pyridine substituent B is substituted at any one of the second, third or fourth positions of the pyridine ring, R ₁ is a straight or branched chain saturated or unsaturated alkyl group having 1 to 10 carbon atoms or an alicyclic group, and R is ₂ and R ₃ are linear or branched alkyl or alicyclic groups of 1 to 6 carbon atoms, or R ₂ and R ₃ are bonded to a nitrogen atom to form a second heteroatom and at least one substituent, in particular at least one To form a heterocycle having 5 to 7 rings which may have an alkyl group, n is 2, 3, or 4).

Compound (I) forms soluble salts with organic or inorganic acids. The compound which concerns on this invention can be obtained by the method of the following process formulas.

(X=할로겐)의 존재하에 제1알킬화반응 시켜 니트릴

을 얻는다. 다음에 이 니트릴

을 R₁X(X=할로겐)로 표시되는 화합물의 존재하에 제2의 알킬화 반응시켜 니트릴

을 얻는다. 마지막으로 알콜수용액의 칼륨 존재하에서 생성니트릴을 가수 분해시킴으로서 본 화합물을 얻는다.Halogen chain of acetonitrile pyridyl 1

Nitrile by first alkylation in the presence of (X = halogen)

Get This nitrile

To a second alkylation reaction in the presence of a compound represented by R ₁ X (X = halogen)

Get Finally, the compound is obtained by hydrolyzing the resulting nitrile in the presence of potassium in an aqueous alcohol solution.

The production method of the present invention will be described in detail with reference to the following examples, and the present invention is not limited only to these examples.

Example 1

2- (2-Diisopropylaminoethyl) 2- (2-pyridyl) 4-methyl 4-pentanamide (CM 403 48)

a) 4-diisopropylamino 2- (2-pyridyl) butanenitrile.

Into the flask, 8 g of 2-pyridyl acetonitrile, 8.81 g of 1-chloro 2-diisopropylaminoethane and 0.27 g of benzyltriethylammonium chloride were added, and 50% soda 35 cm ³ was added while maintaining the temperature below 35 ° C. . The mixture was heated at 35 ° C. for 5 hours and then cooled back to room temperature, then the mixture was diluted with water and extracted with ether. The organic layer was dried over sodium sulfate and then the solvent was evaporated to dryness. The residue was distilled off to obtain 9.36 g of a yellow liquid. Boiling Point 132-134 ℃ / 0.6mmHg

b) 2- (2-diisopropylaminoethyl) 2- (2-pyridyl) 4-methyl 4-pentenenitrile

In a three-necked flask under nitrogen gas atmosphere, 60 ml of sodium hydride (55-60% oil dispersion) and dimethylformamide (DMF) were injected. A solution of 7.35 g of the nitrile in 30 ml of DMF was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes and then a solution of 3 g of 2-methyl 3-chloropropene in dissolve in 30 ml of DMF was added. The mixture was stirred at room temperature for 1 hour and then DMF was evaporated under reduced pressure. The residue was dissolved in water and extracted with ether. The organic layer was dried over sodium sulfate and then evaporated to dryness.

Thus, 10.2 g of liquid with organic color was obtained and used for the operation.

c) CM 40348

10.2 g of the compound obtained above, 36 g of potassium, 150 ml of 95% ethanol, and 200 ml of water were heated to reflux for 86 hours, the alcohol was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated to dryness. The residue was separated by a chromatography on an alumina column using a mixture of pentane and ethyl acetate as a first developer and then using ethyl acetate as a second developer to obtain 4.73 g of a white solid. Recrystallization Melting Point 92-93 ° C in hexane

According to the method of the present invention, the compounds of Table 1 may be prepared.

Table 1

Antiarrhythmic effect test

Test Methods :

The antiarrhythmic activity of the compounds according to the present invention was measured in animals with ventricular arrhythmias as samples. The hybrid dog was anesthetized, the metal cone was inserted into the tubular bed by the retrograde catheter method, and the frequency modulated micro transmitter was attached to the back of the animal and connected to two front chest electrodes. Animals that once returned to these boxes showed signs of progressive thrombosis of the preventricular septal defect artery. In other words, local and intrawall infarction of the myocardium (generative of abnormal repetitive electrical activity: mental and poor).

Under these conditions, the drug was orally administered and the actual development time of dysrhytmia was tracked by a telemeter device. By continually calculating the sum of sino-auricular and pathological contractile complexes by the electron method, the superiority and persistence of the activity of the compound could not be measured.

result :

Table 2 lists the results for various target compounds.

의 비율로 나타났다.The activity of the compound against psychotic pulmonary disease was either improved or significantly improved in the sinus rhythm.

Appeared in the ratio.

Table 2

In the human body, CM 7857 50mg was administered once orally, which showed a recovery effect of oriental rhythm.

Test Methods :

In vitro and in vivo assays were carried out by Boron's turbidity method for the aggregation inhibitory activity of the compounds. In vitro tests were performed on human platelet-rich plasma. The test compound was dissolved in an isotonic solution of sodium chloride and the compound was incubated at 37 ° C. for 5 minutes in the presence of platelet rich plasma before the addition of the aggregation inhibitor.

)에 섭식시키고, 생체의 시험을 행하였다. 공시 화합물을 50mg/kg의 약양으로 경구투여하였다. 공시 화합물을 투여하기 전에 혈액시료를 채취한 다음, 투여 후 1,2,3 및 24시간후에 혈소판의 응집현상의 분석을 행하였다. 그 결과를 대조용(응집율 100%)에 대하여 혈소판응집 억제 백분율로 나타내었다.Rub water the day before the test.

) And the test of the living body. The test compound was orally administered in a dose of 50 mg / kg. Blood samples were taken before administration of the test compounds, and then platelet aggregation was analyzed 1,2,3 and 24 hours after administration. The results are expressed as percentage platelet aggregation inhibition relative to the control (coagulation rate 100%).

As a result of in vitro tests on platelet-rich human plasma, it was found that CM 7857 was able to inhibit platelet aggregation by collagen. The required concentration of 50% inhibition of platelet aggregation was about 80 μm.

After the oral administration of the drug of the present invention 50mg / kg to five baboons was tested in vivo. This drug resulted in 30% inhibition of platelet aggregation by ADP. In humans, CM 7857 was orally administered at a dose of 50 mg / kg, resulting in platelet aggregation.

From the above results, it can be seen that the compound according to the present invention not only has a strong activity against the distritmere but also has an excellent activity as a platelet aggregation inhibitor.

Therefore, the compound (I) of the present invention can be used as a myocardial protective agent for the treatment of disorders caused by platelet aggregation as well as ventricular rhythm disorders caused by ischemic disorders. The compound according to the present invention can be formulated as a herbal medicine for oral administration (tablets, gels) and parenteral administration (ampoules for injection).

When the compound according to the present invention is used in the human body as a platelet aggregation inhibitor and an oriental rhythm recovery agent, it can be administered orally about 400 to 800 mg per day.

An example of preparation of a herbal preparation is described below.

Claims (1)

a) general formula

Acetonitrile of General Formula

Alkylation with a compound of (X = halogen), b) a second alkylation reaction of the reaction product with a compound of the general formula R ₁ X (R ₁ = unsaturated alkyl group), and c) hydrolysis of the nitrile group of the obtained product. A process for preparing a compound of formula (I), characterized in that to yield the corresponding amide.

Wherein the -pyridine substituent is substituted at any one of the second, third or fourth positions of the pyridine ring, -R ₁ is a straight or branched chain saturated or unsaturated alkyl group or alicyclic group having 1 to 10 carbon atoms,- R ₂ and R ₃ may be a linear or branched alkyl or alicyclic group having 1 to 6 carbon atoms, or R ₂ and R ₃ may be bonded to a nitrogen atom to have a second hetero atom and one or more substituents. Forms a heterocycle having 5 to 7 rings, where -n is 2, 3 or 4.