| Identification | More | [Name]
Ivabradine hydrochloride | [CAS]
148849-67-6 | [Synonyms]
Ivabradine HCl
Ivabradine hydrochloride
3-[3-[[(8S)-3,4-Dimethoxy-8-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one hydrochloride
3-[3-[[[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one Hydrochloride
Corlentor
Procoralan
S-16257 | [EINECS(EC#)]
638-798-3 | [Molecular Formula]
C27H36N2O5.HCl | [MDL Number]
MFCD00929899 | [Molecular Weight]
505.05 | [MOL File]
148849-67-6.mol |
| Chemical Properties | Back Directory | [Melting point ]
193-196?C | [alpha ]
58921 +7.8°; 36521 +27.8° (c = 1% in DMSO) | [storage temp. ]
2-8°C | [solubility ]
H2O: ≥5mg/mL (warmed) | [form ]
powder | [color ]
white to beige | [Optical Rotation]
[α]/D +5 to +9°, c = 1 in DMSO | [Water Solubility ]
H2O: ≥5mg/mL (warmed) | [Usage]
Selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node. Antianginal | [Merck ]
14,5247 | [InChIKey]
HLUKNZUABFFNQS-ZMBIFBSDSA-N | [SMILES]
C([C@H]1CC2=CC(OC)=C(OC)C=C12)N(C)CCCN1CCC2=CC(OC)=C(OC)C=C2CC1=O.Cl |&1:1,r| | [CAS DataBase Reference]
148849-67-6(CAS DataBase Reference) |
| Hazard Information | Back Directory | [Description]
In an effort to develop angina agents without the unwanted negative
inotropic and hypotensive effects associated with b-adrenergic blockers and
calcium channel blockers, a new class of heart-rate reducing compounds that act
specifically on the sinoatrial (SA) node has been explored. These bradycardic
agents interact directly with the pacemaking cell of the SA node and the hyperpolarization-
activated If , the primary pacemaking current. Ivabradine has
evolved as a specific inhibitor of If current through its contact with f-channels on
the intracellular side of the plasma membrane. As a consequence, ivabradine
reduces the speed of diastolic depolarization and decreases heart rate. It has been
approved for the treatment of chronic stable angina and provides a viable
alternative to patients with a contraindication or intolerance of b-blockers. Evaluation
is also underway for the potential treatment of ischemic heart disease.
Using a patch-clamp technique on rabbit sinoatrial node cells, inhibition of If
current ranged from 6% (0.03 mM) – 80% (10 mM).
. | [Chemical Properties]
White to Off-White Solid | [Originator]
Servier (France) | [Uses]
angina therapeutic | [Uses]
Ivabradine HCl, a new If inhibitor with IC 50 of 2.9 μM which acts specifically on the pacemaker activity of the sinoatrial node, is a pure heart rate lowering agent | [Uses]
Selective bradycardic agent with direct effect on the pacemaker If current of the sinoatrial node. Antianginal | [Definition]
ChEBI: A hydrochloride obtained by combining ivabradine with one molar equivalent of hydrochloric acid. Used to treat patients with angina who have intolerance to beta blockers and/or heart failure. | [Brand name]
Procoralan | [Biochem/physiol Actions]
Ivabradine is used to treat chronic heart failure. | [Clinical Use]
Symptomatic treatment of chronic stable angina pectoris
in patients with sinus rhythm
Treatment of mild to severe chronic heart failure | [Synthesis]
1. 567 g of (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1H-benzo[d]azepin-2(3H)-one was added to a reaction flask. 2. 2.55 L of glacial acetic acid and 141 g of palladium-carbon was added with thorough stirring and cooled to 20±5°C. 3. After evacuation, replace the nitrogen gas 3 times. 4. Control the temperature at 15~25°C and react under atmospheric pressure of hydrogen for 23 h. 5. Filter the reaction mixture through diatomaceous earth, and rinse the filter cake with glacial acetic acid. 6. Mix the filtrate with purified water and ethyl acetate, and mix thoroughly. 7. Adjust the pH to 9-10 with sodium hydroxide solution. 8. Separate the liquids, and the aqueous phase was extracted with ethyl acetate, and the organic phase was combined. 9. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn. 10. The organic phase was dried overnight, filtered, and the filter cake was rinsed with ethyl acetate. 11. The filtrate was dried by rotary evaporation to give 403.9 g of ivabradine, with a yield of 70.9% and a purity of 96.3% by HPLC. 12. To a 10L reaction flask, 402 g of ivabradine and 6L of ethyl acetate were added and stirred. 13. 6L of ethyl acetate was added to a 10L reaction flask, stirred until complete dissolution, and cooled to 0~10°C. 13. 172.2g of 20wt% hydrogen chloride isopropanol solution was added, and a large amount of white solid precipitate was observed. 14. After stirring for 1 hour, it was filtered, and the filter cake was rinsed with ethyl acetate. 15. The solid was dried in vacuum for 15 hours, and 405.1g of white solid Ivabradine HCL was obtained, with the yields of 93.5% and HPLC purity of 99.3%. 16. HPLC purity was 99.8%. | [Drug interactions]
Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone and disopyramide.
Antibacterials: concentration possibly increased by
clarithromycin and telithromycin - avoid; increased
risk of ventricular arrhythmias with erythromycin -
avoid.
Antifungals: concentration increased by ketoconazole
- avoid; concentration increased by fluconazole -
reduce initial ivabradine dose; concentration possibly
increased by itraconazole - avoid.
Antimalarials: increased risk of ventricular
arrhythmias with mefloquine.
Antipsychotics: increased risk of ventricular
arrhythmias with pimozide.
Antivirals: concentration possibly increased by
ritonavir - avoid.
Beta-blockers: increased risk of ventricular
arrhythmias with sotalol.
Calcium-channel blockers: concentration increased
by diltiazem and verapamil - avoid.
Grapefruit juice: ivabradine concentration increased.
Pentamidine: increased risk of ventricular
arrhythmias.
St John’s wort: ivabradine concentration reduced -
avoid. | [Metabolism]
Ivabradine is extensively metabolised by the liver
and the gut by oxidation through cytochrome P450
3A4 (CYP3A4) only. The major active metabolite is
N-desmethyl-ivabradine (S 18982) with an exposure
about 40% of that of the parent compound. This active
metabolite undergoes further metabolism by CYP3A4.
Excretion of metabolites occurs to a similar extent via
faeces and urine. | [storage]
Store at -20°C | [References]
[1] Patent: CN108424390, 2018, A. Location in patent: Paragraph 0057; 0059-0062; 0063-0069
[2] Patent: WO2011/138625, 2011, A1. Location in patent: Page/Page column 44-45
[3] Patent: WO2014/188248, 2014, A1
[4] Patent: WO2017/138017, 2017, A1. Location in patent: Page/Page column 16 |
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