78415-72-2 Usage
Description
Milrinone, also known as 1,6-dihydro-2-methyl-6-oxo-3,4'-bipyridine-5-carbonitrile (Primacor), is a dipyridine phosphodiesterase F-III inhibitor with pharmacological properties similar to amrinone. It is a selective phosphodiesterase inhibitor that exerts a positive inotropic effect on the heart and a peripheral vasodilatory effect. Milrinone is used for its strong positive inotropic effect, which is about 20 to 50 times that of amrinone, and its significant effect on expanding smooth muscle, reducing the load on the heart and improving kidney and muscle blood supply.
Uses
Used in Pharmaceutical Industry:
Milrinone is used as a bronchodilator for the treatment of respiratory conditions.
Milrinone is used as a selective phosphodiesterase inhibitor with vasodilating and positive inotropic activity for the short-term management of severe heart failure, particularly intravenously as the lactate form. It inhibits the action of phosphodiesterase-3, preventing the degradation of cAMP, leading to increased activation of protein kinase A and improved cardiac function.
Milrinone is used as a cardiotonic agent to increase the force of cardiac muscle contraction and improve cardiac output, pulmonary capillary wedge pressure, and vascular resistance without significant effects on heart rate.
Milrinone is used for the treatment of severe heart failure, such as chronic heart failure and congestive heart failure, due to its ability to reduce the load on the heart and improve blood supply to vital organs.
Chemical Properties:
Milrinone is a crystalline solid that can be crystallized from dimethyl formamide monohydrate or ethanol, with a melting point greater than 300°C.
Brand Names:
Primacor (Sterling Winthrop) and Corotrope.
Positive Inotropic drugs
Milrinone, also known as bipyridine ketone, methyl cyanide topiramate ketone, is a drug for the treatment of heart failure ,it is a homolog of amrinone, having positive inotropic and vasodilatory effects, its mechanism of action is the same as ammonia milrinone , but the strength of its effect is 10 to 30 times of amrinone,without side effects of reducing platelets,it is well tolerated. Oral or intravenous way has a good effect, it can increase cardiac output and cardiac index, reduce left ventricular end diastolic pressure, pulmonary wedge pressure and right atrial pressure, it has no significant effect on blood pressure and heart rate,it takes effect within 0.5 hours after oral administration,and achieves to maximum effect after 1 to 3 hours , the half-life is 2 hours, the effect can be maintained for 4-6 hours, it is mainly metabolically inactivated in the liver , 80% of it is excreted unchanged in the urine. It is clinically used in the treatment of various acute and chronic heart failure,it is effective in digitalis and diuretics invalid refractory heart failure . This product is the same as amrinone, significant short-term effect, long-term efficacy remains to be further confirmed, but the side effects are little.
Compared with amrinone, milrinone has the following characteristics:
1, small doses mainly have positive inotropic effect, vasodilator effect is gradually enhanced while increasing the dose ,its positive inotropic effect accounts for 1/3 of the total effect in the treatment of heart failure, vasodilation effect accounts for2/3 of the total effect.
2,not significantly increasing myocardial oxygen consumption.
3, to improve peripheral circulatory disorders in heart failure, to increase exercise capacity of patients with heart failure and improve their quality of life.
4, for cardiac β receptors in a low-key and reduced β agonistssusceptibility heart failure patients, the drug is still valid.
5, the positive inotropic effect does not produce tachyphylaxis phenomenon.
6, no significant effect on blood pressure and heart rate.
The above information is edited by the lookchem of Tian Ye.
Mechanism
Milrinone is non-digitalis, non-catecholamines cardiac drug , it is representative drug of phosphodiesterase inhibitor,selectively inhibiting phosphodiesterase in myocardial cells, increasing intracellular cyclic adenosine monophosphate, alter intracellular calcium transport, thereby increasing myocardial contractility and expanding peripheral vessel . An increase in myocardial oxygen consumption caused by Milrinone increasing myocardial contractility may be offset by its vasodilator effect. Milrinone is an ideal drug for the treatment of coronary artery stenosis, decompensated heart failure led by myocardial ischemia . Because milrinone hasβ receptor down features, it is an ideal drug for the treatment of decompensated heart failure in patients applying β-blocker . Because milrinone has effect on expanding small arteries and veins, it is more beneficial than dobutamine for the traetment of decompensated heart failure with severe pulmonary hypertension .
Dosage
First dose is slow intravenous injection (50 μg/kg, intravenous injection after dilution, time is not less than 10 min), then with 0.375~0.750 μg/(kg · min), continuous intravenous drip. The maximum daily dose is 1.13 mg/kg. Patients with renal insufficiency reduce the use according to creatinine clearance level, for example, creatinine clearance rate is 20 ml/(min · 1.73 m2), intravenously at a dose of 0.28 μg/(kg · min). 80% of Milrinone is excreted from the kidneys, in general,for renal insufficiency patients, the dose should be halved.
Drug Interactions
Patients already receiving angiotensin-converting enzyme inhibitor therapy using milrinone can further improve hemodynamics, but also increase the side effects caused by the blood vessels dilation. Milrinone combinated with mid-dose dobutamine, can enhance the positive inotropic effect, further reducing left ventricular end-diastolic pressure. When there is low blood pressure, milrinone can theoretically combine a larger dose dopamine.
Precautions
1, showing ventricular arrhythmia, supraventricular arrhythmias; few are headache, ventricular arrhythmias, weakness, low platelet count, etc; overdose may lead to low blood pressure, tachycardia; occasionally bronchospasm, fever .
2, acute myocardial infarction patients are disabled.
3, patients with hypotension, tachycardia, renal insufficiency, atrial fibrillation or flutter, electrolyte imbalance, drug-induced arrhythmias, kidney disease, severe aortic or pulmonary valve disease , pregnant women, lactating women should use with caution.
4,the elimination half-life of this product is significantly prolonged in patients with renal insufficiency , it should be reduced in patients with renal insufficiency, and the infusion rate should be slow . Elderly patients do not need to adjust the dose.
production method
Method 1: 4-methylpyridine is dissolved in anhydrous diethyl ether, under protection of nitrogen, a solution of phenyl lithium in diethyl ether is added dropwise with stirring at room temperature, the reaction is continued. Nitrogen is stopped, cool to 0 ℃, ethyl acetate is added dropwise at below 10 ℃. With concentrated hydrochloric acid to Ph = 1~2, the aqueous layer is separated, basify with saturated sodium carbonate to Ph = 9, precipitate oil , extract several times with chloroform, dry, chloroform is distilled off, vacuum distillation, collecting 130-132 ℃/1.47kPa of fractions, namely, 1-(4-pyridyl) acetone.
1-(4-pyridyl) acetone, acetonitrile, and N, N-dimethylformamide dimethyl acetal are refluxed together. The solvent is distilled off under reduced pressure, the residue is dissolved in an appropriate amount of chloroform and an alumina column (Soxhlet)is heated at reflux for extraction, concentrate extract, with carbon tetrachloride-cyclohexane (4: 1) recrystallize to give 1-(4-pyridyl)-2-(dimethylamino) ethenyl methyl ketone.
1-(4-pyridyl)-2-(dimethylamino) ethenyl methyl ketone, cyano acetamide, sodium methoxide and dimethyl formamide are heated under reflux, the solvent is distilled off under reduced pressure, the residue is added acetonitrile, warm to dissolve , cool to 10 ℃; the precipitated solid is filtered, dissolve with amount of water, decolorize with charcoal, and acidify with hydrochloric acid 6mol/L to Ph = 6.5~7, the precipitated solid is recrystallized from dimethylformamide to give pale yellow granular crystals, which are milrinone, mp> 300 ℃.
Method 2: use 4-pyridyl acetone as a raw material, after condensation with triethyl orthoformate, it reacts with 2-cyanoacetamide, to obtain milrinone.
Method 3: pyridyl acetone reacts with 2,2-cyano-vinyl ethyl ether reaction to generate milrinone.
Originator
Eastman Kodak (Sterling) (USA)
Biological Activity
Potent cAMP phosphodiesterase inhibitor (IC 50 = 56 nM for inhibition of PDE III). Has inotropic and vasodilator effects following oral or intravenous administration in vivo . Also available as part of the Phosphodiesterase Inhibitor Tocriset? .
Biochem/physiol Actions
Phosphodiesterase type III inhibitor; cAMP-specific, cGMP-inhibitable; potent cardiotonic, positive inotropic vasodilator.
references
[1] tang km1, jang ek, haslam rj. photoaffinity labelling of cyclic gmp-inhibited phosphodiesterase (pde iii) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors. eur j pharmacol. 1994 jun 15;268(1):105-14.[2] cheung p1, yang g, boden g. milrinone, a selective phosphodiesterase 3 inhibitor, stimulates lipolysis, endogenous glucose production, and insulin secretion. metabolism. 2003 nov;52(11):1496-500.
Check Digit Verification of cas no
The CAS Registry Mumber 78415-72-2 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,8,4,1 and 5 respectively; the second part has 2 digits, 7 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 78415-72:
(7*7)+(6*8)+(5*4)+(4*1)+(3*5)+(2*7)+(1*2)=152
152 % 10 = 2
So 78415-72-2 is a valid CAS Registry Number.
InChI:InChI=1/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)
78415-72-2Relevant articles and documents
Preparation method of 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one
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, (2021/10/13)
The invention discloses a preparation method of a compound 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and belongs to the technical field of medicine synthesis. The method comprises the following steps: reacting a solid compound intermediate I with N, N-dimethylformamide dimethyl acetal to obtain 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one; the invention also provides a method for preparing milrinone by using 4-(dimethylamino)-3-(pyridine-4-yl) butyl-3-ene-2-one, and the method is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and purity of the obtained milrinone finished product reach the standard.
Preparation process of milrinone
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, (2021/10/13)
The invention discloses a preparation method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is used as a raw material and is subjected to a heating reaction with alpha-(substituted methylene) cyanoacetamide under an alkaline condition, and milrinone is obtained. The method for preparing milrinone is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.
Preparation method of medical intermediate milrinone
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, (2020/08/18)
The invention discloses a preparation method of a medical intermediate milrinone. The preparation method comprises the following steps: S1, sequentially adding 4-methylpyridine and acetic anhydride into a reaction bottle, dropwise adding concentrated sulfuric acid, stirring and reacting for 20-30 minutes, continuing reaction at 40-60 DEG C, completely reacting by TLC (Thin Layer Chromatography), cooling in an ice bath, dropwise adding ethanol, stirring for 1 hour, heating and refluxing for 6-8 hours, extracting dichloromethane, drying, filtering, carrying out rotary evaporation on filtrate toremove a solvent dichloromethane, distilling out 4-methylpyridine by reduced pressure distillation, cooling, and carrying out reduced pressure distillation to obtain 1-(4-pyridyl)-acetone; S2, mixing1-(4-pyridyl)-acetone, triethyl orthoformate, glacial acetic acid and acetic anhydride, adding alpha-cyanoacetamide, and performing cyclization under the alkaline condition to obtain crude milrinone;and S3, adding DMF into the crude milrinone obtained in the S2, stirring until the solid is dissolved, adding a decolorizing agent, stirring and refluxing for 8-20 minutes, filtering, and cooling thefiltrate to separate out refined milrinone. According to the method, the raw material cost is saved, and the product purity, yield and color degree are improved.
