YM-018
milrinone
CAS: 78415-72-2
Molecular Formula: C12H9N3O
YM-018 - Names and Identifiers
| Name | milrinone |
| Synonyms | YM-018 Milrila Primacor Corotrope Milrinone milrinone Milirinone MilrinoneUsDmf 3-CYANO-6-METHYL-5-(4-PYRIDYL)-2-PYRIDONE 6-METHYL-5-(4-PYRIDYL)-2-PYRIDONE-3-CARBONITRILE 6-Methyl-2-oxo-5-pyridin-4-yl-1H-pyridine-3-carbonitrile 1,6-DIHYDRO-2-METHYL-6-OXO-3,4-BIPYRIDINE-5-CARBONITRILe 1,2-DIHYDRO-6-METHYL-2-OXO-5-(4-PYRIDINYL)-NICOTINONITRILE 1,6-DIHYDRO-2-METHYL-6-OXO-(3,4'-BIPYRIDINE)-5-CARBONITRILE 6-Dihydro-2-methyl-6-oxo-(3,4'-bipyridine)-5-carbonitrile 2-METHYL-6-OXO-1,6-DIHYDRO-3,4'-BIPYRIDINE-5-CARBONITRILE(MILRINONE) 4'-bipyridine)-5-carbonitrile,1,6-dihydro-2-methyl-6-oxo-( win47203 1,2-DIHYDRO-6-METHYL-2-OXO-5-(4-PYRIDINYL)- NICOTINONITRILES(MILRINONE) |
| CAS | 78415-72-2 |
| EINECS | 278-903-6 |
| 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) |
| InChIKey | FYEJSUDMDUIMKJ-UHFFFAOYSA-N |
YM-018 - Physico-chemical Properties
| Molecular Formula | C12H9N3O |
| Molar Mass | 211.22 |
| Density | 1.1922 (rough estimate) |
| Melting Point | >3000C |
| Boling Point | 350.9°C (rough estimate) |
| Water Solubility | Soluble in DMSO. Insoluble in water. |
| Solubility | DMSO : 50 mg/mL (236.72 mM; Need ultrasonic);H2O : < 0.1 mg/mL (insoluble) |
| Appearance | Crystallization |
| Color | off-white |
| Merck | 14,6197 |
| pKa | 7.21±0.10(Predicted) |
| Storage Condition | 2-8°C |
| Stability | Stable. Incompatible with strong oxidizing agents. |
| Refractive Index | 1.5700 (estimate) |
| MDL | MFCD00133539 |
| Physical and Chemical Properties |
|
| Use | Cardiac medicine, with enhanced myocardial contractility and direct dilation of blood vessels |
YM-018 - Risk and Safety
| Risk Codes | R23/24/25 - Toxic by inhalation, in contact with skin and if swallowed. R26/27/28 - Very toxic by inhalation, in contact with skin and if swallowed. |
| Safety Description | S36/37/39 - Wear suitable protective clothing, gloves and eye/face protection. S45 - In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.) S22 - Do not breathe dust. |
| UN IDs | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | DW1762000 |
| HS Code | 29337900 |
| Hazard Class | 6.1(b) |
| Packing Group | III |
YM-018 - Nature
Open Data Verified Data
crystallized from dimethylformamide monohydrate or from ethanol, melting point> 300 °c.
Last Update：2024-01-02 23:10:35
YM-018 - Preparation Method
Open Data Verified Data
4 A methyl pyridine dissolved in anhydrous ether. A solution of phenyllithium in diethyl ether was added dropwise with stirring under nitrogen protection at room temperature, and the reaction was continued after the addition. The reaction was carried out by dropwise addition of hexyl acetate. It is then acidified with concentrated hydrochloric acid to a pH of 1 to 2. Separate the aqueous layer, alkaline to pH 9 with saturated sodium carbonate, precipitate oil, extract several times with chloroform, dry, distill chloroform, vacuum fractionation, that is, 1-(4 pyridyl) acetone. 1-(4-pyridyl) acetone, acetonitrile and n. N-= methylformamide dimethyl acetal are refluxed together, and the post-treated product is heated to reflux with cyanoacetamide, sodium methoxide and dimethylformamide, the solvent was distilled off under reduced pressure, and the resulting material was dissolved by warming with acetonitrile and treated to obtain milrinone. Or 4 pyridyl acetone as raw material, after condensation with triethyl orthoformate, and 2 cyanoacetamide reaction, that is, milrinone. It can also be obtained by reacting pyridyl acetone with 2,2-= cyanovinyl ethyl ether.
Last Update：2022-01-01 09:10:11
YM-018 - Standard
Authoritative Data Verified Data
This product is 1, 6-dihydro-2-methyl-6-oxo-[3,4 '-bipyridine]-5-carbonitrile. Calculated as dry product, containing C12H9N30 shall not be less than 98.5%.
Last Update：2024-01-02 23:10:35
YM-018 - Trait
Authoritative Data Verified Data
- This product is white crystalline powder; Odorless.
- This product is almost insoluble in water or ethanol, slightly soluble in dilute hydrochloric acid.
Last Update：2022-01-01 11:54:07
YM-018 - Use
Open Data Verified Data
The new non-glycoside non-catecholamine cardiotonic drug, phosphodiesterase inhibitor, is similar to amrinone. Its mechanism of action is the same as amrinone, and the tolerance is good. Has the expansion of vascular smooth muscle function, can reduce the load on the heart, but also can improve the kidney and muscle blood supply. No serious adverse reactions. Applicable to Digitalis, diuretics, vasodilators ineffective or ineffective treatment of various causes of acute and chronic refractory congestive heart failure.
Last Update：2022-01-01 09:10:12
YM-018 - Differential diagnosis
Authoritative Data Verified Data
- take about 20mg of this product, add 2ml of 1 mol/L hydroxylamine hydrochloride propylene glycol solution and 2ml of 1 mol/L potassium hydroxide propylene glycol solution, boil in water bath for 2 minutes, add 1 drop of ferric chloride test solution, should be red to magenta
- take about 50mg of this product, add 2ml of pyridine to dissolve, and add 4ml of silver nitrate test solution to generate white precipitate.
- take about 20mg of this product, add 0401 of lactic acid to dissolve it, dilute it with water to make a solution containing about 6Jug per lm l, and measure it by UV-Vis spectrophotometry (general rule), there is a maximum absorption at 266mn and 325nm wavelengths.
- The infrared absorption spectrum of this product should be consistent with that of the control (Spectrum set 749).
Last Update：2022-01-01 11:54:08
YM-018 - Exam
Authoritative Data Verified Data
clarity and color of sodium hydroxide solution
take 1.0g of this product, Add 10ml of sodium hydroxide solution to dissolve, the solution should be clear and colorless (General rule 0902 first method); If the color, comparison with yellow No. 2 Standard Colorimetric solution (General rule 0901 first method), not deeper.
Related substances
take an appropriate amount of this product, accurately weigh it, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 2mg per 1mL (if necessary, heat in a water bath at 80°C to dissolve), as a test solution; Take 1ml of the solution accurately, put it in a 100ml measuring flask, dilute it to the scale with mobile phase, shake it, take 1ml of the solution accurately and put it in a 10ml measuring flask, dilute to the scale with mobile phase, shake, as a control solution; Take appropriate amount of impurity I reference substance, precise weighing, dissolve and quantitatively dilute with mobile phase to make a solution containing about 2ug per 1ml, as a reference solution; An appropriate amount of milrinone and impurity I control was taken, dissolved and diluted with mobile phase to prepare a solution containing 20ug each in 1ml as a system applicable solution. According to the high performance liquid chromatography (General rule 0512) determination, with octyl silane bonded silica gel as filler, with dipotassium hydrogen phosphate solution (take dipotassium hydrogen phosphate 2.7g, add water to dissolve 2.4, add triethylamine, adjust the pH value with phosphoric acid to 7.5)-acetonitrile (80:20) as mobile phase, the detection wavelength is 220nnn, and the system applicable solution 20u1 is injected into the liquid chromatograph, the retention time of impurity I peak relative to milrinone peak is about 0.6, and the separation degree between impurity I peak and milrinone peak should be greater than 4.0, the control solution and the reference solution were injected with 20 u1 respectively, and the chromatogram was recorded to 2 times of the retention time of the main component peak. In the chromatogram of the test solution, if there is a chromatographic peak consistent with the retention time of impurity I, the peak area shall be calculated by the external standard method, and shall not exceed 0.1%; other single impurity peak area shall not exceed 0.5 times (0.05%) of the main peak area of the control solution, and the sum of other impurity peak areas shall not be greater than the main peak area of the control solution (0.1%).
residual solvent
take this product about 0.1g, precision weighing, put 10ml measuring flask, add dimethyl sulfoxide dissolved and diluted to the scale, shake, as a test solution; Other ethyl acetate, methanol, dichloromethane, N, N-dimethylformamide, acetic acid in appropriate amount, precision weighing, dissolving and quantitatively diluting with dimethyl sulfoxide to prepare 50ug of ethyl acetate, 30ug of methanol, 6ug of dichloromethane, N per lml, A mixed solution of N-dimethylformamide 8.8UG and acetic acid 50ug was used as a control solution. According to the determination method of residual solvent (General 0861 second method), the capillary column with polyethylene glycol (PEG-20M) as stationary liquid is used as the chromatographic column, the starting temperature is 40°C, and the retention time is 8 minutes, the temperature was raised to 200°C at 20°C per minute for 4 minutes; The inlet temperature was 250°C and the detector temperature was 250°C. The separation degree of each component peak shall meet the requirements. Take 1ul of each of the reference solution and the test solution, respectively inject the human gas chromatograph, and record the chromatogram. According to the external standard method based on peak area, the residues of ethyl acetate, methanol, dichloromethane, N-dimethylformamide and acetic acid shall meet the requirements.
nitride
take 1.0g of this product, add 50ml of water, fully shake, filter, take 25ml of filtrate, check according to law (General rule 0801), If turbidity occurs, not more concentrated (0.014%) than the control solution made of 7ml of standard sodium chloride solution.
loss on drying
take this product, dry to constant weight at 105°C, weight loss shall not exceed 1.0% (General rule 0831).
ignition residue
l.Og of this product shall be taken for inspection according to law (General rule 0841), and the residual Tongtong shall not exceed 0.1%.
Heavy metals
The residue left under the item of burning residues shall not contain more than 20 parts per million of heavy metals after examination by law (General rule 0821, Law II).
Last Update：2022-01-01 11:54:09
YM-018 - Content determination
Authoritative Data Verified Data
take about 0.16g of this product, precision weighing, Add 30ml of glacial acetic acid, heat below 60°C to dissolve, cool, add 1 drop of crystal violet indicator solution, and use perchloric acid titration solution (0.1 mol/L) titration until the solution shows blue color, and the titration result is corrected by blank test. Each 1 ml of perchloric acid titration solution (0.1 mol/L) corresponds to 21.12mg of C12H9N30.
Last Update：2022-01-01 11:54:09
YM-018 - Category
Authoritative Data Verified Data
cardiotonic drugs.
Last Update：2022-01-01 11:54:09
YM-018 - Storage
Authoritative Data Verified Data
sealed and stored in a dry place.
Last Update：2022-01-01 11:54:10
YM-018 - Milrinone injection
Authoritative Data Verified Data
This product is a sterilized aqueous solution made of milrinone and lactic acid. Milrinone-containing (C12H9N30) shall be between 95.0% and 105.0% of the labeled amount.
trait
This product is colorless and clear liquid.
identification
- take 10ml of this product, put it on a water bath to dry, add 2ml of 1 mol/L hydroxylamine hydrochloride propylene glycol solution and lml of 1 mol/L potassium hydroxide propylene glycol solution to the residue, put it on a water bath to heat, that is, there was obvious yellow color. After cooling and filtering, the filtrate was added with 1 drop of ferric chloride solution, which turned red to purple.
- in the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
- take 0.6ml of this product, put it in a 0.17% measuring flask, add 2.5ml of 0401 lactic acid solution, dilute it with water to the scale, shake it well, and measure it by UV-visible spectrophotometry (general rule). The maximum absorption was measured at a wavelength of 266nm and 325nm.
examination
- the pH value should be 2.8 to 3.5 (General 0631).
- lactic acid: take this product as a test solution; Take an appropriate amount of sodium lactate reference substance, weigh it accurately, add water to dissolve and quantitatively dilute it to make it contain about 1 per 1 ml. 0 mg solution, as a control solution. According to the high performance liquid chromatography (General 0512) test, silica gel bonded with eighteen alkyl silane was used as the filler, and formic acid-dicyclohexylammonium-water (0.1:0.1:100) was used as the mobile phase, the detection wavelength was 210nm. Appropriate amounts of sodium lactate and sodium acetate were added, dissolved and diluted with water to make a mixed solution containing about 1 mg per 1 ml, which was used as a system applicable solution. 20ul was injected into the liquid chromatograph and the chromatogram was recorded. The number of theoretical plates shall not be less than 2000 calculated by lactic acid peak, and the separation degree of lactic acid peak and acetic acid peak shall meet the requirements. Then, 20 u1 of the test solution and the reference solution are accurately weighed, respectively injected into the human liquid chromatograph, and the peak area is calculated by the external standard method, and the calculated result is multiplied by 0.7948. The amount of lactic acid contained in each lml should be 85.0% to 115.0% of the prescribed amount.
- Related Substances: take this product as a test solution; Take appropriate amount with precise volume, and quantitatively dilute it with mobile phase to prepare a solution containing about 2ug of milrinone per 1 ml, which is used as a control solution; in addition, appropriate amounts of each reference substance of impurity I and impurity II were accurately weighed, dissolved and quantitatively diluted with mobile phase to prepare a solution containing about 1ug each in 1 ml, which was used as a reference solution. According to the chromatographic conditions under the content determination item, 20 u1 of the test solution, the control solution and the reference solution are respectively injected into the liquid chromatograph, the chromatogram was recorded to 3 times of the retention time of the main component peak. If there are chromatographic peaks in the chromatogram of the test solution that are consistent with the retention time of impurity I peak and II peak, the peak area shall be calculated according to the external standard method, and the peak area shall not exceed 0.1% of the labeled amount of milrinone, the Peak area of other single impurity shall not exceed 0.5 times (0.1%) of the main peak area of the control solution, and the sum of the peak areas of other impurities shall not be greater than the main peak area of the control solution (0.2%).
- osmolality the osmolality ratio should be 0.90 to 1.10 (General 0632).
- bacterial endotoxin take this product, according to the inspection (General 1143), the amount of endotoxin per 1 mg milrinone should be less than 12EU.
- others should comply with the relevant provisions under injection (General 0102).
Content determination
- measured by high performance liquid chromatography (General 0512).
- chromatographic conditions and system applicability test using eighteen alkyl silane bonded silica gel as filler; Water-methanol-Sodium Borate Buffer (take boric acid 31G, add water 800ml, slowly add the appropriate amount of 20% sodium hydroxide solution, fully shake the boric acid to dissolve completely, adjust the pH value to 20% with 7.0 sodium hydroxide solution, dilute to 1000ml with water, and shake to obtain. The new system (725:250:25) was used as mobile phase, and the detection wavelength was 254nm. Take the appropriate amount of milrinone, impurity I and impurity II control, dissolve and dilute with mobile phase to make a mixed solution containing about lOOug in each lml, as the system applicable solution, 20u1 was injected into human liquid chromatograph, and the chromatogram was recorded. The degree of separation of the impurity I peak from the milrinone peak should be greater than 4.0.
- determination of precision take 5ml of this product, put it in a 50ml measuring flask, dilute to the scale with mobile phase, shake well, as a test solution, take 20 u1 for precision measurement, note human liquid chromatograph, record chromatogram; Another milrinone reference substance, precision weighing, plus mobile phase dissolution and quantitative dilution to make about 0 per 1 ml. lmg solution, the same method for determination. According to the external standard method to calculate the peak area, that is.
category
cardiotonic drugs.
specification
5ml:5mg
storage
sealed and stored in a dry place.
Last Update：2022-01-01 11:54:11
YM-018 - Reference Information
| positive inotropic drugs | milrinone, also known as dipyridone, cimyrapidone and milidone, is a drug for the treatment of cardiac insufficiency. it is a homolog of pyridone and has positive inotropic and vasodilation effects. the mechanism of action is the same as amrinone, but the intensity of action is 10 to 30 times that of amrinone, and there is no side effect of reducing platelets, and it is well tolerated. Oral or intravenous drip has a good effect, which can increase cardiac output and cardiac index, reduce left ventricular end-diastolic pressure, pulmonary wedge pressure and right atrial pressure, and have no obvious effect on arterial pressure and heart rate. It takes effect within 0.5 hours after oral administration, reaches the maximum effect at 1 to 3 hours, and has a half-life of 2 hours. The effect can be maintained for 4 to 6 hours, mainly in the inactivation of liver metabolism, 80% is excreted from urine in its original shape. It is clinically suitable for the treatment of various acute and chronic heart failure, and has a positive effect on refractory heart failure that is ineffective in digitalis and diuretics. This product is the same as amrinone, the short-term effect is obvious, the long-term effect needs to be further confirmed, but the side effects are small. compared with amrinone, milrinone has the following characteristics: 1, small dose mainly shows positive inotropic effect, when the dose increases, the vasodilator effect gradually increases, when the treatment of heart failure, its positive inotropic effect accounts for 1/3 of the total effect, and vasodilation accounts for 2/3 of the total effect. 2, no significant increase in myocardial oxygen consumption. 3, improve the peripheral blood circulation disorder of heart failure, increase the exercise ability and improve the quality of life of patients with heart failure. 4, this drug is still effective for heart failure patients with low-key cardiac β receptor and reduced sensitivity to β stimulants. 5, there is no rapid drug resistance in positive inotropic effect. 6, no significant effect on arterial pressure and heart rate. |
| mechanism of action | milrinone is a non-digitalis and non-catecholamine cardiotonic drugs, which are representative drugs of phosphodiesterase inhibitors. by selectively inhibiting phosphodiesterase in myocardial cells, it increases intracellular cyclic adenosine monophosphate and changes the transport of calcium inside and outside the cell, so as to increase myocardial contractility and expand peripheral blood vessels. The increase in myocardial oxygen consumption caused by milrinone's increased myocardial contractility can be offset by its vasodilator effect. Milrinone is an ideal drug for the treatment of decompensated cardiac insufficiency caused by coronary artery stenosis and myocardial ischemia. Because milrinone has the property of downregulating β receptors, it is also an ideal drug for the treatment of decompensated cardiac insufficiency patients who are using β-blockers. Because milrinone has the effect of dilating arterioles and veins, it is more beneficial than dobutamine in treating decompensated cardiac insufficiency with severe pulmonary hypertension. |
| usage and dosage | the first dose is slowly injected intravenously (50 μ g/kg, diluted intravenously for a time of not less than 10 min), then 0.375~0.750 μ g/(kg min) is used for continuous intravenous drip. The maximum daily dose is 1.13 mg/kg. For patients with renal insufficiency, the creatinine clearance rate is reduced, for example, the creatinine clearance rate is 20 ml/(min · 1.73 m2), and the intravenous drip dose is 0.28 μg/(kg · min). Milrinone 80% is excreted from the kidneys. Generally speaking, the dose for patients with renal insufficiency should be halved. |
| drug interaction | the addition of milrinone to patients who have received angiotensin converting enzyme inhibitor therapy can further improve hemodynamics, but also increase side effects caused by vasodilation. The combined application of milrinone and moderate dose dobutamine can strengthen the positive inotropic effect and further reduce the left ventricular end diastolic pressure. When there is hypotension, milrinone can theoretically be combined with a larger dose of dopamine. |
| precautions | 1, ventricular arrhythmia, supraventricular arrhythmia, etc. A few have headache, ventricular arrhythmia, weakness, platelet count reduction, etc. Hypotension and tachycardia may occur when overdose. Occasionally bronchospasm and fever are seen. 2, patients with acute myocardial infarction are contraindicated. 3, patients with hypotension, tachycardia, renal insufficiency, atrial fibrillation or flutter, electrolyte disturbance, drug-induced arrhythmia, kidney disease, severe aortic or pulmonary valve disease, pregnant women, lactating women with caution. 4, the elimination half-life of this product in patients with renal insufficiency is significantly prolonged, so patients with renal insufficiency should reduce the dose and slow down the infusion speed. Elderly patients do not need to adjust the dose. |
| chemical properties | crystallized from dimethylformamide monowater or from ethanol, melting point> 300 ℃. |
| use | new non-glycoside non-catecholamine cardiotonic drugs, the effect is similar to that of amrinone, the positive inotropic effect is strong, about 20-50 times that of amrinone, and has obvious effect of dilating vascular smooth muscle, which can reduce heart load, it can also improve the blood supply to the kidneys and muscles. Both oral and intravenous were effective without serious adverse reactions. It is used for severe heart failure such as chronic heart failure and congestive heart failure. cardiotonic drugs have the effects of enhancing myocardial contractility and directly dilating blood vessels cardiotonic drugs have the effects of enhancing myocardial contractility and directly dilating blood vessels. |
| production method | method 1:4-methylpyridine is dissolved in anhydrous diethyl ether, protected by nitrogen, and the diethyl ether solution of phenyl lithium is added dropwise at room temperature under stirring, and the reaction is continued after addition. Stop nitrogen, cool to 0 ℃, add ethyl acetate dropwise, and react below 10 ℃. Acidified with concentrated hydrochloric acid to Ph = 1~2, separated into water layer, alkalized with saturated sodium carbonate to Ph = 9, precipitated oil, extracted with chloroform several times, dried, evaporated to chloroform, fractionated under reduced pressure, collected fraction of 130~132 ℃/1.47kPa, namely 1-(4-pyridyl) acetone. 1-(4-pyridyl) acetone, acetonitrile and N,N-dimethylformamide dimethyl acetal are refluxed together. The solvent is evaporated under reduced pressure, the residue is dissolved with an appropriate amount of chloroform, heated and refluxed with an alumina column (Soxhlet extractor), the extract is concentrated, and carbon tetrachloride-cyclohexane (4:1) is used to recrystallize to obtain 1-(4-pyridyl)-2-(dimethylamino) vinyl methyl ketone. 1-(4-pyridyl)-2-(dimethylamino) vinyl methyl ketone, cyanoacetamide, sodium methoxide and dimethylformamide are heated and refluxed, the solvent is distilled under reduced pressure, and the remaining is heated and dissolved with acetonitrile, and cooled to 10 ℃; precipitate solid, filter, dissolve with appropriate amount of water, decolorize activated carbon, acidify with 6mol/L hydrochloric acid to Ph = 6.5~7, precipitate solid, recrystallize with dimethylformamide to obtain light yellow granular crystal, it is milrinone, melting point> 300 ℃. Method 2: 4-pyridyl acetone was used as raw material, condensed with triethyl orthoformate, and then reacted with 2-cyanoacetamide to obtain milrinone. Method 3: The reaction of pyridyl acetone and 2, 2-dicyanovinylethyl ether can produce milrinone. |
Last Update：2024-04-09 21:01:54
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Multiple SpecificationsSpot supply
Product Name: Milrinone Visit Supplier Webpage Request for quotationCAS: 78415-72-2
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
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