KR860001339B1 - Process for preparation of pyridazinone derivatives - Google Patents
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- KR860001339B1 KR860001339B1 KR1019830002710A KR830002710A KR860001339B1 KR 860001339 B1 KR860001339 B1 KR 860001339B1 KR 1019830002710 A KR1019830002710 A KR 1019830002710A KR 830002710 A KR830002710 A KR 830002710A KR 860001339 B1 KR860001339 B1 KR 860001339B1
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Abstract
Description
본 발명은 의약품으로서 유용한 피리다지논 유도체의 제조방법에 관한 것으로서, 더욱 상세히 말하면, 5위치에서 치환된 3-피리다지논의 제조방법에 관한 것이다.The present invention relates to a method for preparing a pyridazinone derivative useful as a medicine, and more particularly, to a method for preparing 3-pyridazinone substituted at the 5-position.
지난 수십년간에 걸쳐 아주 많은 종류의 3-피리다지논 이 제조되어 왔으며 이들의 대부분은 고혈압 치료제로서 심장혈관계통에 대하여 작용을 나타낼 뿐 아니라 다른 분야, 즉, 진통, 염증, 충추신경계통에 대하여 작용을 나타냈다. 또한 제조된 화합물은 절반이상이 제초제로서도 연구되어 왔다.Over the last few decades, a great number of 3-pyridazinones have been produced, most of which act on the cardiovascular system as a therapeutic agent for hypertension, as well as on other fields: analgesic, inflammation, and impulse nervous system. Indicated. More than half of the prepared compounds have also been studied as herbicides.
종래에도 피리다진환에서 여러가지 치환이 행하여졌지만 5-위치에서의 치환은 일어나기 힘들기 때문에 5-위치에서 치환된 화합물은 얼마되지 않았다. 따라서 본 발명의 목적은 다음 일반식(I)로 표시되는 5-아릴리덴-(2H, 4H)-3-피리다지논을 포함한 신규의 피리다니존 유도체의 제조방법을 제공하는 데에 있다.Conventionally, various substitutions have been made in the pyridazine ring, but since the substitution at the 5-position is difficult to occur, there are very few compounds substituted at the 5-position. It is therefore an object of the present invention to provide a process for the preparation of novel pyridanezone derivatives comprising 5-arylidene- (2H, 4H) -3-pyridazinone represented by the following general formula (I).
이때, R1은 H, F, Cl, NO2또는 CH3,Wherein R 1 is H, F, Cl, NO 2 or CH 3 ,
R2는 H, Cl, NO2, CF3또는 OCH3,R 2 is H, Cl, NO 2 , CF 3 or OCH 3 ,
R3는 H, F Cl, CH3, NO2, OCH3또는 OH,R 3 is H, F Cl, CH 3 , NO 2 , OCH 3 or OH,
R4는 H 또는 OCH3, R5는 H 또는 Cl이고,R 4 is H or OCH 3 , R 5 is H or Cl,
R1내지 R5모두가 동시에 수소원자일수는 없으며,R 1 to R 5 may not all be hydrogen atoms at the same time,
R2와 R3는 -O-CH2-O로써 결합될 수 있으며,R 2 and R 3 may be combined as -O-CH 2 -O,
R6는 -CH=나-CHOH-이다.R 6 is -CH = I-CHOH-.
본 발명에 따른 화합물 중 R6가 -CH=인 화합물이나 R6가 -CHOH-인 경우에는 R2및 R4가 수소원자인 화합물이 바람직하다. 이들 유도체중에서Among the compounds according to the present invention, when R 6 is -CH = or R 6 is -CHOH-, R 2 and R 4 are preferably hydrogen. Among these derivatives
R1이 H나 Cl, R2가 H, Cl 또는 CF3,R 1 is H or Cl, R 2 is H, Cl or CF 3 ,
R3가 H, Cl 또는 NO2,R 3 is H, Cl or NO 2 ,
R4가 H나 Cl이고R 4 is H or Cl
더우기 R1및 R5가 Cl일 때 R2, R3 Furthermore, when R 1 and R 5 are Cl, R 2 , R 3
R4가 H인 유도체를 사용함으로써 상당히 유용하게 된다.It is quite useful by using derivatives in which R 4 is H.
본 발명에 따른 신규한 약물은 신경진정작용은 약하지만 대퇴골의 혈류에 있어서 실질적인 증가의 효과가 있는 바, 이러한 약물에는 하나이상의 본 발명에 따른 피리다지논 유도체가 유효량만큼 함유되어 있는 것으로 특징지워지고, 특히 6-메틸-5-(2', 6'-디클로로-1'-벤질리덴)-(2H, 4H)-3-피리다지논이나 6-메틸-5-(2', 6'-디클로로-1'-페닐 하이드록시메틸)-4, 5-디히이드로 (2H)-3-피리다지논의 약리학적 활성부위를 함유하는 약물인 경우 유용하다.The novel drug according to the present invention is characterized by a weak neurosettling effect but a substantial increase in the blood flow of the femur, which drug is characterized in that it contains an effective amount of one or more pyridazinone derivatives according to the present invention. Especially 6-methyl-5- (2 ', 6'-dichloro-1'-benzylidene)-(2H, 4H) -3-pyridazinone or 6-methyl-5- (2', 6'-dichloro- Useful in the case of drugs containing pharmacologically active sites of (2H) -3-pyridazinone in 1'-phenyl hydroxymethyl) -4, 5-dihydride.
본 발명에 따른 화합물은 4-아릴-3-아세틸 부타놀 라이드로부터 제조될 수 있는 바, 이것은 다음과 같은 방법에 의해 방향족 알데히드와 α-안겔리카락톤 사이에서의 축합반응으로 얻어질 수 있으며 그 반응식은 다음과 같다.The compounds according to the invention can be prepared from 4-aryl-3-acetyl butanolide, which can be obtained by the condensation reaction between aromatic aldehydes and α-angelicalactone by the following methods The scheme is as follows.
R6가 -CHOH-인 본 발명에 따른 화합물을 얻기 위해 원료물질로서 사용되는 상기 화합물은 극성 유기용매중에서 하이드라진 수화믈과 반응시키며 이런 형태의 화합물을 탈수시키면 R6가 -CH=인 대응하는 화합물이 얻어지게 된다.The compound used as a starting material to obtain a compound according to the invention wherein R 6 is -CHOH- is reacted with hydrazine hydrate in a polar organic solvent and dehydrating this type of compound gives a corresponding compound wherein R 6 is -CH =. Is obtained.
이하 본 발명을 실시예에 의거 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail with reference to Examples.
[실시예 1 : 4-아릴-3-아세틸-4-부타놀라이드(또는-4(2', 6'-디클로로 페닐)-3-아세틸-4-부타놀라이드)의 제조]Example 1 Preparation of 4-aryl-3-acetyl-4-butanolide (or-4 (2 ', 6'-dichloro phenyl) -3-acetyl-4-butanolide)
1ℓ 용량의 반응용기에 염화메틸렌 200ml에 안겔리카락톤 0.05몰 및 2, 6-디클로 벤즈알데히드 0.05몰을 용해시켜서된 용액을 넣고, 실온에서 염화메틸렌 100ml에 보론 트리플루오라이드 에테레이트 0.05몰을 용해시켜서된 용액을 30분간에 걸쳐 교반하면서 적가한 후 70시간이상 유지시킨다.In a 1 L reaction vessel, 0.05 ml of angelicalactone and 0.05 mol of 2,6-dichlorobenzaldehyde were dissolved in 200 ml of methylene chloride, and 0.05 mol of boron trifluoride etherate was dissolved in 100 ml of methylene chloride at room temperature. The solution was added dropwise with stirring over 30 minutes and then maintained for at least 70 hours.
다음에 포화된 염화나트륨용액 300ml를 격렬하게 교반하면서 첨가하고, 용액이 혼탁해지면 15분간 더 교반을 계속한다. 내용물은 분리깔대기에 옮겨서 2개의 층을 분리시킨다. 유기층은 황산나트륨상에서 건조시킨 후 용매를 저압하에 증발시키고, 유상잔사(oily residue)를 비이커에 옮겨서 저온(-20℃)에서 에탄올의 존재하에 결정화시킨다. 이러한 조생성물(raw product)을 에탄올에서 재결정시킨다.Next, 300 ml of saturated sodium chloride solution is added with vigorous stirring, and stirring is continued for 15 minutes when the solution becomes cloudy. The contents are transferred to a separatory funnel to separate the two layers. The organic layer is dried over sodium sulfate and the solvent is evaporated under low pressure, the oily residue is transferred to a beaker and crystallized in the presence of ethanol at low temperature (-20 ° C.). This raw product is recrystallized in ethanol.
4, 5-디하이드로(2H)-3-피리다지논은 저급 알코올인 극성유기용매중에서 하이드라진 수화물과 반응시킨 4-아릴-3-아세틸-4-부타놀라이드로부터 제조된다.4,5-Dihydro (2H) -3-pyridazinone is prepared from 4-aryl-3-acetyl-4-butanolide reacted with hydrazine hydrate in a polar alcohol, a lower alcohol.
[실시예 2 : 6-메틸-(2', 6'-디클로로-1'-페닐하이드록시메틸)-4, 5-디하이드로(2H)-3-피리다지논의 제조][Example 2: Preparation of 6-methyl- (2 ', 6'-dichloro-1'-phenylhydroxymethyl) -4, 5-dihydro (2H) -3-pyridazinone]
250ml의 용량을 가진 밸륜플라스크에서 2', 6'-디클로로-4-페닐-3-아세틸-4-부타놀라이드 0.01몰을 최소량의 에탄올에 뜨거운 상태에서 용해시켜 완전히 용해시킨 후 하이드라진 수화물 0.01몰을 첨가한 다음이 용액을 가열하고, 2시간동안 교반하면서 환류시키고 냉각시키면 대응하는 피리다지논이 침전된다. 때때로 용매의 일부를 미리 증발시킬 필요가 있으며, 조생성물은 에탄올에서 재결정화시킨다.In a 250 ml ballwheel flask, 0.01 mol of 2 ', 6'-dichloro-4-phenyl-3-acetyl-4-butanolide was dissolved in hot water in a minimum amount of ethanol to completely dissolve, followed by 0.01 mol of hydrazine hydrate. After addition, the solution is heated, refluxed with stirring for 2 hours and cooled to precipitate the corresponding pyridazinone. Sometimes some of the solvent needs to be evaporated beforehand, and the crude product is recrystallized in ethanol.
수율은 90%, 분자량은 287, 융점은 211℃이다. C12H12O2N2Cl2에 대한 원소분석 :The yield is 90%, molecular weight is 287 and melting | fusing point is 211 degreeC. Elemental Analysis for C 12 H 12 O 2 N 2 Cl 2 :
양자 핵자기공명(NMR)의 결과는 제안된 구조식과 일치된다.The results of quantum nuclear magnetic resonance (NMR) are consistent with the proposed structural formula.
4, 5-디하이드로(2H)-3-피리다지논들이 실시예 1에 따라 제조된 대응하는 부타놀라이드로부터 실시예 2의 방법에 따라 제조된다.4, 5-dihydro (2H) -3-pyridazinones are prepared according to the method of Example 2 from the corresponding butanolides prepared according to Example 1.
제조된 4, 5-디하이드로(2H) 피리다지논은 탈수에 의해 5-아릴리덴(2H, 4H)-3-피지다지논으로 전환될 수 있다.The prepared 4, 5-dihydro (2H) pyridazinone may be converted to 5-arylidene (2H, 4H) -3-fizidazinone by dehydration.
이 조작은 탈수제의 존재하에 보다 효율적으로 이루어진다.This operation is made more efficient in the presence of a dehydrating agent.
[실시예 3 : 6-메틸-5-(2', 6-디클로로-1'-벤질리덴) (2H, 4H)-3-피다지논의 제조]Example 3 Preparation of 6-Methyl-5- (2 ', 6-dichloro-1'-benzylidene) (2H, 4H) -3-pyridinone
100ml의 용량을 가진 비이커에서 실시예 1의 방법에 따라 제조된 하이드록시메틸-3-피리다지논 0.01몰을 진한황산 30ml 중에 현탁시키고 수분간 교반하여 생성물을 용해시킨 후 용액을 빙수 100ml를 함유한 비이커에 옮긴 다음, 5-아릴리덴피리다지논 침전물을 여과하여 건조한 후 에탄올에서 재결정화시킨다.In a beaker having a capacity of 100 ml, 0.01 mol of hydroxymethyl-3-pyridazinone prepared according to the method of Example 1 was suspended in 30 ml of concentrated sulfuric acid, stirred for several minutes to dissolve the product, and then the solution containing 100 ml of ice water. After transferring to a beaker, the 5-arylidenepyridazinone precipitate is filtered off, dried and recrystallized from ethanol.
수율은 87%, 분자량은 269, 융점은 256℃이다.The yield is 87%, molecular weight is 269 and melting point is 256 degreeC.
C12H10ON2Cl2에 대한 원소분석 :Elemental Analysis for C 12 H 10 ON 2 Cl 2 :
양자 핵자기공명의 결과는 제안된 구조식과 일치된다.The result of quantum nuclear magnetic resonance is consistent with the proposed structural formula.
적외선스펙트럼을 이용하여 본 결과 3,400cm-1부근에 위치한 OH밴드가 사라지고 1,660cm-1부근에 위치한 락탐의 카보닐피크는 계속 존재하였다.The results using infrared spectrum is OH band in the vicinity of 3,400cm -1 it disappears and the carbonyl peak of the lactam in the vicinity of 1,660cm -1 was still present.
더우기 진동 v(c=c)에 해당하는 1,600cm-1의 인접피크의 강도가 현저히 증가한다.Furthermore, the intensity of adjacent peaks of 1,600 cm −1 corresponding to the vibration v (c = c) increases significantly.
개에서 연구된 6-메틸-5-(2', 6'-디클로로-1'-벤질리덴) (2H, 4H)-3-피리다지논 화합ㅁ루은 혈액동력학적 매개변수의 약간의 변동도 없이 필수적으로 혈관계작용을 나타내며, 특히 대퇴부혈류에서의 선택적인 증가, 경미한 심장흥분 및 동맥혈압의 적은 변동이 주목된다.6-Methyl-5- (2 ', 6'-dichloro-1'-benzylidene) (2H, 4H) -3-pyridazinone compound studied in dogs without any fluctuations in hemodynamic parameters Essentially, it exhibits vascular system activity, in particular a selective increase in femoral blood flow, slight cardiac excitation, and small fluctuations in arterial blood pressure are noted.
이외에 쥐의 경우에는 진정효과가 주목되나 강직중(强直 t-10 )은 높은 용량에서만 나타난다.In addition, sedation effects are noted in rats, but rigid weight (强直 t-10) appears only at high doses.
고려되고 있는 화합물은 혈관질환, 특히 동매질환의 치료를 위해 인체약품에 적용시키는 것으로 알려져 있다. 5-아닐리덴(2H, 4H)-3-피라다지논 화합물의 예는 실시예 3의 방법에 따라 제조된다.The compounds under consideration are known to be applied to human pharmaceuticals for the treatment of vascular diseases, particularly isoplastic diseases. Examples of 5-anilidene (2H, 4H) -3-pyradazinone compounds are prepared according to the method of Example 3.
[실시예 4 : 경구투여에 의한 독성실험]Example 4 Toxicity Test by Oral Administration
실시예 3에 따른 화합물을 0.5% 셀룰로오즈 용액에 현탁시키고, 이 현탁액을 증가된 용량으로 20±2g의 쥐에게 위 소식자를 사용하여 투여하였으며 각 용략을 여섯마리의 동물에 투여하였다.The compound according to Example 3 was suspended in 0.5% cellulose solution, and this suspension was administered to the 20 ± 2 g rats at increased dose using the gastric mediator and each solution was administered to six animals.
그 결과, 경구 투여에 의하여 800mg/kg 부근에서 대략 LD50이 설정될 수 있었다.As a result, approximately LD50 could be set around 800 mg / kg by oral administration.
[실시예 5 : 진전작용의 측정]Example 5: Measurement of tremor
실시예 3에 따른 화합물의 진정작용은 쥐에서 펜토바르비탈에 의해 유도된 수면잠재력의 실험에 의해 설명되어질 수 있는 바, 열마리의 쥐로 된 배취(batch)를 형성한 후 실시예 3에 따른 화합물의 0.5% 메틸셀룰로오즈 현탁액을 위소식자에 의해 증가된 용량으로 각 배취에 투여하고 펜토바르비탈나트륨은 (50mg/kg)의 용량으로 복강내주사에 의해 30분후에 투여하였다. 이러한 조건하에서 바르비탈산염에 의해 유도된 수면기간은 화합물 40번의 100mg/kg을 투여한 동물의 경우의 두배로 증가하였다.The sedation of the compound according to Example 3 can be explained by the experiment of sleep potential induced by pentobarbital in rats, after forming a batch of ten rats followed by the compound according to Example 3 0.5% methylcellulose suspension of was administered to each batch at increased doses by gastrointestinal and pentobarbital sodium was administered 30 minutes later by intraperitoneal injection at a dose of (50 mg / kg). Under these conditions, the duration of sleep induced by barbitalate was doubled for animals receiving 100 mg / kg of Compound 40.
이와 비슷한 결과는 실시예 2의 화합물 22번과 31번일 때 4∼6mg의 용량에서 얻어졌다.Similar results were obtained at doses of 4-6 mg at compound 22 and 31 of Example 2.
[실시예 6 : 심장혈관계에 대한 작용]Example 6 Actions on the Cardiovascular System
실시예 3에 따른 유도체 40번을 혈액동력학적 효과를 연구할 목적으로 마취된 개에게 정맥내주사로 투여하였다. 변수로서는 다음의 8가지가 고려되었는 바, 심장박동수, 좌심실혈압, 시간에 대한 좌심실 혈압(dp/dt)의 유도, 동맥혈류량, 동맥혈압, 관상동맥혈류량, 대퇴부동맥혈류량, 대퇴부동맥혈압 등이다.Derivative 40 according to Example 3 was administered intravenously to anesthetized dogs for the purpose of studying hemodynamic effects. The following eight variables were considered: heart rate, left ventricular blood pressure, induction of left ventricular blood pressure (dp / dt) over time, arterial blood flow, arterial blood pressure, coronary blood flow, femoral artery blood flow, and femoral arterial blood pressure.
3가지 용량, 즉 kg당 0.3, 1 및 3mg을 주사하였으며 각 용량은 폴리에틸렌글리콜(PEG) 및 생리학적 혈청용액 5mg에 용해시켰고, 상술한 용량은 저용량으로부터 높은 용량으로 누진적으로 투여하였다.Three doses, 0.3, 1 and 3 mg per kg, were injected and each dose was dissolved in 5 mg of polyethylene glycol (PEG) and physiological serum solution, with the above doses progressively administered from low to high doses.
0.3mg/kg의 용량에서 관찰된 효과는 대단히 단기적이였고 용매의 것과 다른 바 없었으며 대퇴부 혈류량의 경우 일정하지만 아주 경미한 고혈압과 관련된 관상대동맥혈류량의 경우 변동이 있는 혈류량에 증가가 관찰되었다. 또한 1mg/kg의 용량에서 혈류량에 아주 뚜렷한 증가가 있었고 모든 혈류량은 비교되는 방법에서 영향을 받았으며 비교치보다 약 4배가 더 높아졌고, 최고치는 최초 1분의 끝에 위치하였다. 변동은 관상 대동맥혈류량의 경우 일시적이었으며 대퇴부혈류량의 경우 평균적으로 13분간 지속되었고, 이 효과는 혈압에서 약간의 변동에 의해 이뤄지지 않았다. 한편 일시적인 심동지완(心動遲緩)은 주사완료후 바로 감지되었으며 동물 중 하나의 경우 심동휴지를 일이켰다. 시간과 좌심실 혈압(dp/dt)은 1분간 실험예의 50%에서 증가되었고, 효과는 용량이 3mg/kg으로 증가되었을 때 다른 바 없었다.The effect observed at the dose of 0.3 mg / kg was very short-lived and was not different from that of the solvent, and a constant but very slight increase in femoral blood flow was observed in the fluctuating blood flow in the case of coronary aortic blood flow associated with mild hypertension. There was also a significant increase in blood flow at the dose of 1 mg / kg and all blood flows were affected by the comparison method, approximately four times higher than the comparison, with the peak at the end of the first minute. The fluctuations were transient for coronary aortic blood flow and lasted 13 minutes on average for femoral blood flow, and this effect was not caused by slight fluctuations in blood pressure. On the other hand, transient heart palpitations were detected immediately after the injection was completed, and one of the animals caused heart palpitations. Time and left ventricular blood pressure (dp / dt) were increased in 50% of the experiments for 1 minute, and the effect was no different when the dose was increased to 3 mg / kg.
[실시예 7 : 심장혈관계에 대한 작용]Example 7 Action on Cardiovascular System
실시예 2에 따른 유도체 24번을 마취된 개에게 두여하여 실시예 6에 기술된 바와같은 기술적 조건하에 실험하였다. 실시예 3의 화합물의 실험에서 얻어진 결과와 비교해서 대략 8배가 더 많은 용량, 즉 작용개시의 경우 kg당 3mg 및 최대작용의 경우 20mg/kg일 때 동일한 혈액동력학적 작용이 얻어졌다.Derivative 24 according to Example 2 was placed in anesthetized dogs and tested under technical conditions as described in Example 6. The same hemodynamic action was obtained at approximately 8 times more dose, 3 mg per kg for initiation and 20 mg / kg for maximal action, compared to the results obtained in the experiments of the compound of Example 3.
[실시예 8 : 실시예 3에 따른 화합물의 임상실험]Example 8: Clinical Trials of Compounds According to Example 3
이 실험은 하지의 동맥순환부전으로 고통을 받고 있는 환자에 대해 실시되었으며 하지의 동맥혈류에 대한 실시예 3에 따른 화합물의 효과를 측정하기 위해 실시하였다.This experiment was conducted on patients suffering from arterial circulation failure in the lower extremities and to determine the effect of the compound according to Example 3 on arterial blood flow in the lower extremities.
실험은 플라시보의 사용을 포함한 이중맹검법(doubleblind technique)에 따라 실시하였으며 2회의 연속실험기간 중 각 환자에게 실시예 3에 따른 화합물 또는 무작위로 플라시보의 1회 경구용량을 투여하였다. (교차실험)The experiment was conducted according to the doubleblind technique involving the use of placebo and each patient received a single oral dose of the compound according to Example 3 or randomly placebo in two consecutive trial periods. (Cross experiment)
동맥혈류량은 다음의 두 가지 방법으로 흡수식 플레티스모그라피(페리플로우-쟌센 SI)에 의해 측정되었다.Arterial blood flow was measured by absorption pletismographie (Ferriflow-Bussen SI) in two ways.
휴식상태에서 동맥혈류량의 연속 측정에 의한 2개의 엄지 발가락중 하나의 수준Level of one of the two big toes by continuous measurement of arterial blood flow at rest
뇌졸증후 반응성 다혈중의 연속 측정에 의한 중지발가락의 수준에서 얻어진 결과는 다음 표에 나타난 바와 같다.Post-stroke reactivity The results obtained at the level of stop toe by continuous measurement in blood are shown in the following table.
따라서, 실시예 3에 따른 화합물은 혈류량과 맥박에 증가를 일으키는 말초혈관에 대한 활동작용이 있으며 심장박동수에서의 동시변화는 관찰되지 않았다.Therefore, the compound according to Example 3 has an active action on peripheral blood vessels causing an increase in blood flow and pulse rate, and no simultaneous change in heart rate was observed.
그러므로 실시예 3에 따른 화합물은 하지의 동맥순환부전의 치료에 유익하다.The compound according to example 3 is therefore beneficial for the treatment of arterial circulatory failure of the lower extremities.
다음 실시예는 본 발명에 따른 화합물의 인체치료에서의 응용, 특히 하지의 동맥질환의 치료에 대한 응용에 관한 것이다.The following examples relate to the application of the compounds according to the invention in the treatment of humans, in particular for the treatment of arterial diseases of the lower extremities.
[실시예 9 : 재형 : 캡슐제]Example 9 Reform: Capsule
인체치료용 캡슐제는 다음의 조성을 가진 것이 사용될 수 있다.Capsules for human treatment may be used having the following composition.
화합물 22번 100mg100 mg of compound 22
부형제 적당량 1캡슐Excipient 1 capsule
용량은 1일에 2∼6캡슐로 변동할 수 있다.Dosage can vary from 2 to 6 capsules per day.
[실시예 10 : 제형 : 정제]Example 10 Formulation: Tablet
인체치료용 정제는 다음의 조성을 가진 것이 사용될 수 있다.Human therapeutic tablets may be used having the following composition.
화합물 30번 100mg100 mg of compound 30
부형제 적당량 1정1 tablet of excipient
1일 용량은 2∼6정이다.The daily dose is 2-6 tablets.
[실시예 11 : 제형 : 주사용용액]Example 11 Formulation: Injection Solution
인체치료용 주사제는 다음의 조성을 가진 것이 사용될 수 있다.Injections for human treatment may be used having the following compositions.
실시예 3의 화합물 40번 50mg50 mg of the compound of Example 3
주사제용 용제 적당량 10ml10ml solvent for injection
용량은 근욕 또는 정맥주사로 50mg씩, 하루에 1회 또는 2회이다.The dose is 50 mg, once or twice daily, in a soak or intravenous injection.
실시예 12 : 제형 : 점적용 농축용액Example 12 Formulation: Concentrated Solution for Dropping
인체치료용 점적용 농축용액은 다음의 조성을 가진 것이 사용될 수 있다.Concentrated solution for human treatment drops can be used with the following composition.
실시예 3의 화합물 40번 200mg200 mg of compound 40 of Example 3
주사제용 용제 적당량 20mlInjectable solvent 20ml
용량은 3시간 동안 정맥내로 점적되는 동장액 500ml 중에 실시예 3의 화합물을 200∼400mg 함유시킨다.The dose contains 200-400 mg of the compound of Example 3 in 500 ml of copper fluid that is intravenously dipped for 3 hours.
본 발명은 상술한 실시예에 국한되지 않고 당해 기술분야의 종사자에 의해 변형될 수 있는 것도 본 발명의 범위에 속하게 됨을 밝혀둔다.It is to be understood that the present invention is not limited to the above-described embodiments but may be modified by those skilled in the art to be within the scope of the present invention.
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FR8210630 | 1982-06-18 | ||
FR8210630A FR2528837A1 (en) | 1982-06-18 | 1982-06-18 | ARYLACETYL BUTANOLIDES AND THEIR PYRIDAZINONE DERIVATIVES AS MEDICAMENTS, AND METHODS FOR THEIR MANUFACTURE |
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KR1019830002710A KR860001339B1 (en) | 1982-06-18 | 1983-06-17 | Process for preparation of pyridazinone derivatives |
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JP (1) | JPS5910571A (en) |
KR (1) | KR860001339B1 (en) |
BE (1) | BE897085A (en) |
CH (1) | CH657125B (en) |
DE (1) | DE3321772A1 (en) |
FR (1) | FR2528837A1 (en) |
GB (1) | GB2122195A (en) |
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US4666902A (en) * | 1983-06-20 | 1987-05-19 | Cassella Aktiengesellschaft | Tetrahydropyridazinone derivatives, processes for their preparation and their use |
EP0210530A1 (en) * | 1985-07-27 | 1987-02-04 | MERCK PATENT GmbH | 6-Arylalkenyl pyridazinones |
JPS63220512A (en) * | 1987-03-09 | 1988-09-13 | 松下電器産業株式会社 | Electrode foil for electrolytic capacitor |
JPH04100106U (en) * | 1991-02-12 | 1992-08-28 | ||
JPH0776050B2 (en) * | 1991-07-25 | 1995-08-16 | 実 近藤 | Work transfer device |
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1982
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1983
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IT1194281B (en) | 1988-09-14 |
BE897085A (en) | 1983-12-19 |
JPS5910571A (en) | 1984-01-20 |
DE3321772A1 (en) | 1983-12-22 |
KR840005105A (en) | 1984-11-03 |
NL8302087A (en) | 1984-01-16 |
GR78284B (en) | 1984-09-26 |
IT8321684A0 (en) | 1983-06-17 |
CH657125B (en) | 1986-08-15 |
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