KR840001106B1 - Method for the preparation of pyridine derivatives - Google Patents
Method for the preparation of pyridine derivatives Download PDFInfo
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- KR840001106B1 KR840001106B1 KR1019840003540A KR840003540A KR840001106B1 KR 840001106 B1 KR840001106 B1 KR 840001106B1 KR 1019840003540 A KR1019840003540 A KR 1019840003540A KR 840003540 A KR840003540 A KR 840003540A KR 840001106 B1 KR840001106 B1 KR 840001106B1
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
Description
본 발명은 항부정맥 작용 및 혈소판 응집 억제 작용을 갖는 피리딘 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a pyridine derivative having an antiarrhythmic action and platelet aggregation inhibitory action.
본 발명의 방법에 의하여 제조되는 신규의 피리딘 유도체는 하기 일반식(Ⅰ)로 표시된다.The novel pyridine derivatives produced by the process of the invention are represented by the following general formula (I).
(식중, 피리딘 치환체 B는 피리딘환의 제2, 3 또는 4위 중의 어느 하나의 위치에 치환되며, R1는 탄소원자 1 내지 10개를 갖는 직쇄 또는 측쇄의 포화 또는 불포화 알킬기 또는 지환족기이며, R2와 R3는 탄소원자 1 내지 6개를 직쇄 또는 측쇄의 알킬기 또는 지환족기 이거나, 그렇지 않으면 R2와 R3는 질소원자와 결합되어 제2의 복소원자와 1개 이상의 치환체, 특히 1개 이상의 알킬기를 갖일 수 있는 5 내지 7개의 환을 갖는 복소환을 형성하며, n는 2, 3, 또는 4이다).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).
본 화합물(Ⅰ)은 유기 또는 무기산과 함께 가용성염을 형성한다. 본 발명에 따른 화합물은 하기 공정식의 방법에 의하여 얻을 수가 있다.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.
아세토니트릴피리딜 1을 할로겐쇄(X=할로겐)의 존재하에 제1알킬화반응 시켜 니트릴을 얻는다. 다음에 이 니트릴을 R1X(X=할로겐)로 표시되는 화합물의 존재하에 제2의 알킬화 반응시켜 니트릴을 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.
하기에 실시예들을 열거하여 본 발명의 제조방법에 대하여 상세하게 서술 하겠으며, 본 발명은 이들 실시예들만으로 한정되는 것은 아니다.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.
[실시예 1]Example 1
2-(2-디이소프로필아미노에틸) 2-(2-피리딜) 4-메틸 4-펜탄아미드(CM 403 48)2- (2-Diisopropylaminoethyl) 2- (2-pyridyl) 4-methyl 4-pentanamide (CM 403 48)
a) 4-디이소프로필아미노 2-(2-피리딜) 부탄니트릴.a) 4-diisopropylamino 2- (2-pyridyl) butanenitrile.
플라스크내에 2-피리딜 아세토니트릴 8g, 1-클로로 2-디이소프로필아미노에탄 8.81g 및 벤질트리에틸염화암모늄 0.27g을 주입시키고, 35℃ 미만의 온도로 유지하면서 50% 소다 35cm3를 첨가하였다. 혼합물을 35℃에서 5시간 가열한 후 실온으로 다시 냉각시킨 다음 혼합물을 물로 희석하고 에테르로 추출하였다. 유기층을 황산나트륨 상에서 건조 시킨 다음 용매를 증발 건고 시켰다. 잔사를 증류하여 황색액체 9.36g을 얻었다. 비점 132 내지 134℃/0.6mmHgInto 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-디이소프로필아미노에틸) 2-(2-피리딜) 4-메틸 4-펜텐니트릴b) 2- (2-diisopropylaminoethyl) 2- (2-pyridyl) 4-methyl 4-pentenenitrile
질소 가스 분위기 하의 삼구 플라스크중에 수소화나트륨(55 내지 60% 유분산액) 및 디메틸포름아미드(DMF) 60ml를 주입 시켰다. DMF 30ml 중에 상기 니트릴 7.35g을 용해시킨 용액을 실온에서 적가하였다. 이 혼합물을 실온에서 30분간 교반한 다음, DMF 30ml 중에 2-메틸 3-클로로프로펜 3g을 용해시킨 용액을 첨가하였다. 이 혼합물을 실온에서 1시간 교반한 다음 DMF를 감압증발시켰다. 잔사를 물에 용해하고 에테르로 추출하였다. 유기층을 황산나트륨 상에서 건고 시킨 다음 증발 건고하였다.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.
이와 같이하여 유기색상을 띈 액체 10.2g을 얻은 다음 조작에 사용하였다.Thus, 10.2 g of liquid with organic color was obtained and used for the operation.
c) CM 40348c) CM 40348
상기에서 얻은 화합물 10.2g, 칼륨 36g, 95% 에탄올 150ml 및 물 200ml를 86시간동안 가열환류 시키고 알콜을 증발시킨 다음, 혼합물을 초산에틸로 추출하였다. 유기층을 황산나트륨 상에서 건조하고 용매를 증발건고시켰다. 잔사를 제1전개제로서 펜탄과 초산에틸과의 혼합물을 사용하고, 다음에 제2전개제로서 초산에틸을 사용하는 알루미나칼럼상의 분배크로마토그래피에 의해 분리시킴으로서 백색의 고상물 4.73g을 얻었다. 헥산에서 재결정 융점 92 내지 93℃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
본 발명의 방법에 따라 하기 표 1의 화합물이 제조될 수 있다.According to the method of the present invention, the compounds of Table 1 may be prepared.
제1표Table 1
항부정맥 작용시험Antiarrhythmic effect test
시험 방법 :Test Methods :
본 발명에 따른 화합물의 항부정맥 활성에 대하여 심실성 부정맥을 갖고 있는 동물을 시료로 하여 측정하였다. 잡종개를 마취시키고, 금속제원추를 역행성의 카테테르법에 의해 관상 베드에 꽂음과 동시에, 주파수 변조 마이크로 송신기를 동물의 등에 부착시켜 2개의 전흉부전극에 접속시켰다. 이들 상자로 일단 다시 돌아온 동물은 전심실 중격 결손 동맥의 진행성 혈정증의 증세를 나타내었다. 환언하면, 심근의 국부적이고 벽내경색(비정상적인 반복 전기 활성의 발생기 : 심신성 빈박)이 나타났다.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).
이와 같은 상태하에서 약을 경구 투여하고, 텔리미터장치에 의해 디스리트미어 (dysrhytmia)의 실제의 전개시간을 추적하였다. 동방간(洞房間, sino-auricular) 및 병적 수축성 복합체의 합계를 전자(電子) 방법에 의해 영속적으로 산정함으로써 본 화합물에 대한 활성의 우수성과 지속성을 측정할 수가 없었다.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.
결과 :result :
각종의 목적 화합물에 대한 결과를 제2표를 기재하였다.Table 2 lists the results for various target compounds.
심신성 빈박에 대한 본 화합물의 활성이 동방간(洞房間) 리듬의 회복이나 또는 상당히 개선된의 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.
제2표Table 2
인체의 경우 CM 7857 50mg을 1회 경구투여한 결과 동방간리듬의 회복효과가 나타났다.In the human body, CM 7857 50mg was administered once orally, which showed a recovery effect of oriental rhythm.
시험방법 :Test Methods :
본 화합물의 응집 억제 활성에 대하여 보론(Born)씨의 비탁법(比濁法)에 의한 시험관내 및 생체의 측정시험을 행하였다. 시험관내 시험은 인체의 혈소판이 풍부한 혈장에 대하여 행하였다. 공시화합물을 염화나트륨의 등장액중에 용해시키고, 응집 억지제를 첨가시키기 전에 본 화합물을 혈소판이 풍부한 혈장의 존재하에서 5분간 37℃에서 항온처리하였다.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.
시험하기 전날 물을 비비()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%).
혈소판이 풍부한 인체혈장에 대하여 행한 시험관내 시험의 결과 CM 7857은 교원질에 의한 혈소판 응집을 억제할 수 있음이 발견되었다. 혈소판 응집의 50% 억제율의 소요 농도는 80μm정도이었다.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.
비비 5마리에 본 본 발명 50mg/kg의 약양을 경구투여한 후 생체의 시험을 행하였다. 이 약양에 의하여 ADP에 의한 혈소판응집의 억제율이 30%로 나타났다. 인체의 경우에는 CM 7857을 50mg/kg의 약양으로 경구 투여한 결과, 혈소판 응집에 의한 장해가 일어났다.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.
상기 결과들로 부터 본 발명에 따른 화합물은 디스리트미어에 대한 활성이 강할 뿐만 아니라 혈소판응집 억지제로서 활성이 우수함을 알 수가 있다.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.
따라서 본 발명의 화합물(Ⅰ)은 국소빈혈 장애로 일어나는 심실리듬 장해뿐만 아니라 혈소판 응집으로 일어나는 장해의 치료용 심근 보호제로서 사용할 수가 있다. 본 발명에 따른 화합물은 경구 투여용(정제, 겔제) 및 비경구 투여용(주사제용 앰푸울)의 생약제로 제제할 수가 있다.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).
본 발명에 따른 화합물을 혈소판 응집 억지제 및 동방간 리듬회복제로서 인체에 사용할 경우에는 1일 400 내지 800mg 정도로 경구 투여할 수가 있다.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.
하기에 생약제제의 제조 1예를 기술한다.An example of preparation of a herbal preparation is described below.
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KR1019840003540A KR840001106B1 (en) | 1980-10-10 | 1984-06-22 | Method for the preparation of pyridine derivatives |
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KR1019800003884A KR840001105B1 (en) | 1980-10-10 | 1980-10-10 | Method for the preparation of pyridine derivatives |
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1980
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1984
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