78415-72-2 Usage
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.
Chemical Properties
Different sources of media describe the Chemical Properties of 78415-72-2 differently. You can refer to the following data:
1. Crystallization From Dimethyl formamide monohydrate or ethanol, the melting point> 300 ℃.
2. Crystalline Solid
Uses
Different sources of media describe the Uses of 78415-72-2 differently. You can refer to the following data:
1. New non-glycosides non-catecholamines cardiac drug , its function is similar to amrinone ,positive inotropic effect is strong and about 20 to 50 times of amrinone, and it has significant effect on expanding smooth muscle,it can reduce the load on the heart, it can also improve kidney and muscle blood supply. Oral and intravenous are valid, no serious adverse reactions. It is used For severe heart failure such as chronic heart failure and congestive heart failure.
2. bronchodilator
3. Selective phosphodiesterase inhibitor with vasodilating and positive inotropic activity. Cardiotonic
4. It is used (particularly intravenously, as the lactate) for the short-term management of severe heart failure. Milrinone inhibits the action of phosphodiesterase-3 preventing degradation of cAMP. The corresponding increase in cAMP levels leads to increased activation of protein kinase A. It is a selective phosphodiesterase inhibitor with vasodilating and positive inotropic activity.
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.
Description
Different sources of media describe the Description of 78415-72-2 differently. You can refer to the following data:
1. Milrinone, an inhibitor of phosphodiesterase selective for fraction III PDE, exerts a
positive inotropic effect on the heart as well as a peripheral vasodilatory effect. Milrinone
given intravenously produces significant improvements on cardiac output, pulmonary
capillary wedge pressure and vascular resistance without significant effects on the heart
rate.
2. Milrinone is an inhibitor of type 3 phosphodiesterases (PDEs), inhibiting recombinant PDE3A and PDE3B with IC50 values of 0.45 and 1 μM, respectively. It is selective for PDE3 over PDE1, PDE2, PDE4, PDE5, and PDE7 (IC50s = 263, >300, 17.5, 49.1, and 58.3 μM, respectively). Milrinone (0.1-1 mg/kg) has positive inotropic effects, increasing cardiac contractile force in anesthetized dogs with a concomitant increase in heart rate but not blood pressure. It also increases contractile force in models of propranolol- and verapamil-induced heart failure in anesthetized dogs when administered at an initial dose of 30 μg/kg followed by a continuous 3 μg/kg per minute infusion. Milrinone has vasodilatory effects as well, decreasing mean aortic pressure and increasing venous compliance in anesthetized dogs when administered at an initial dose of 10 μg/kg followed by a continuous 1.7-2.4 μg/kg per minute infusion. Formulations containing milrinone have been used in the treatment of heart failure.
Originator
Eastman Kodak (Sterling) (USA)
Brand name
Primacor (Sterling Winthrop);Corotrope.
General Description
Milrinone, 1,6-dihydro-2-methyl-6-oxo-3,4＇-bipyridine-5-carbonitrile (Primacor), is another dipyridinephosphodiesterase F-III inhibitor that possesses pharmacologicalproperties similar to those of amrinone. The inhibitionof the degradation of cAMP results in an increase in the cardiacmuscle’s force of contraction.
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 process of milrinone
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Paragraph 0114-0119, (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.
Synthesis method of milrinone
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Paragraph 0045-0066, (2021/10/13)
The invention discloses a synthesis method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is taken as a raw material to react with alpha-(N, N-dimethylamine methylene) malononitrile, so as to obtain an off-white solid milrinone. The method for synthesizing milrinone is simple and convenient to operate, 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.
Milrinone intermediate compound
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, (2020/10/14)
The invention provides a milrinone intermediate compound, discloses a preparation method of the milrinone intermediate compound, and belongs to the technical field of medicine synthesis. Alpha-substituted acetyl acetaldehyde (SM-1) reacts with 4-pyridylboronic acid (alkyl) (SM-2) so as to obtain the milrinone intermediate compound I. A method of using the milrinone intermediate compound to preparea milrinone agricultural product is simple and convenient to operate, high in safety, high in yield and suitable for industrial scale-up production, and the appearance and purity of the obtained high-purity milrinone finished product both reach the standards.
