Diltiazem hydrochloride

Diltiazem hydrochloride Basic information
Product Name:Diltiazem hydrochloride
Synonyms:(2S-cis)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one monohydrochloride;1,5-benzothiazepin-4(5h)-one,2,3-dihydro-3-(acetyloxy)-5-(2-(dimethylamino)eth;2,3-dihydro-3-(acetyloxy)-5-(2-(dimethylamino)ethyl)-2-(4-methoxyphenyl)-5-benzothiazepin-4(5h)-one;altiazem;anginyl;angizem;masdil;monohydrochloride,cis-(+)-yl)-2-(4-methoxyphenyl)
CAS:33286-22-5
MF:C22H27ClN2O4S
MW:450.98
EINECS:251-443-3
Product Categories:Cardiovascular APIs;Ion Channels;Intermediates & Fine Chemicals;Pharmaceuticals;Calcium channel;Aromatics;Active Pharmaceutical Ingredients;Chiral Reagents;Sulfur & Selenium Compounds;33286-22-5
Mol File:33286-22-5.mol
Diltiazem hydrochloride Structure
Diltiazem hydrochloride Chemical Properties
Melting point 212-214 °C
alpha D24 +98.3 ± 1.4° (c = 1.002 in methanol)
density 1.30 g/cm3
refractive index 118 ° (C=1, H2O)
Fp 2℃
storage temp. 2-8°C
solubility Freely soluble in water, in methanol and in methylene chloride, slightly soluble in anhydrous ethanol.
form Powder
color White to off-white
PHpH (10g/l, 25℃) : 4.3~5.3
Water Solubility soluble
Merck 13,3226
BRN 4228706
Stability:Stable for 1 year from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20°C for up to 3 months.
CAS DataBase Reference33286-22-5(CAS DataBase Reference)
EPA Substance Registry System1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, hydrochloride (1:1), (2S,3S)- (33286-22-5)
Safety Information
Hazard Codes Xn,Xi,F
Risk Statements 22-40-36/37/38-36-20/21/22-11
Safety Statements 36-45-36/37-26-16
RIDADR 3249
WGK Germany 3
RTECS DL0310000
8-10
HazardClass 6.1(b)
PackingGroup III
HS Code 29349990
ToxicityLD50 in male, female mice, male, female rats (mg/kg): 61, 58, 38, 39 i.v.; 260, 280, 520, 550 s.c.; 740, 640, 560, 610 orally (Nagao, 1972)
Diltiazem hydrochloride Usage And Synthesis
DescriptionDiltiazem HCl (33286-22-5) is a?non-dihydropyridine-type blocker of L-type Ca2+ channels.1,2 Reduces Ca2+ oscillations in subcellular compartments in vascular smooth muscle cells.3?Also blocks P-type Ca2+ channels in freshly dissociated rat cerebellar Purkinje neurons.4 Clinically useful antihypertensive agent.5?Cell permeable.
Chemical PropertiesDiltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. It has a molecular weight of 450.98. Diltiazem hydrochloride injection is a clear, colorless, sterile, nonpyrogenic solution. It has a pH range of 3.7 to 4.1.
OriginatorHerbesser,TANABE SEIYAKU,Japan,1974
UsesDiltiazem Hydrochloride is a calcium channel blocker with vasodilating activity. Anti-anginal; anti-hypertensive; anti-arrhythmic (class IV).
Usesantihypertensive, sedative, antibacterial
UsesPeripheral Vasodilator
UsesAn antianginal, antihypertensive. Regulates Calcium release from intracellular stores in neutrophils
DefinitionChEBI: Diltiazem hydrochloride is a hydrochloride salt resulting from the reaction of equimolar amounts of diltiazem and hydrogen chloride. A calcium-channel blocker and vasodilator, it is used in the management of angina pectoris and hypertension. It has a role as an antihypertensive agent, a vasodilator agent and a calcium channel blocker. It contains a diltiazem(1+). It is an enantiomer of an ent-diltiazem hydrochloride.
Manufacturing Processβ-Diethylaminoethyl chloride is condensed with 2-(4-methoxyphenyl)-3- hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in a first step. Then a mixture of 1.5 grams of 2-(4-methoxyphenyl)-3-hydroxy-5-(βdimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 20 ml of acetic anhydride was heated on a water bath for 5 hours. The reaction mixture was evaporated under reduced pressure to remove acetic anhydride and the concentrated product was poured into ice water. The resulting mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The chloroform layer was dried and evaporated to remove the solvent. The residue was dissolved in acetone, and an ethanol solution containing hydrogen chloride was added thereto producing 1.53 grams of 2-(4-methoxyphenyl)3- acetoxy-5-(β-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride having a melting point from 187° to 188°C.
The starting material is made by reacting 4-methoxybenzaldehyde with ethyl chloroacetate; that product with sodium ethoxide; and that product with 2- aminothiophenol.
Brand nameCardizem (Biovail); Cartia (Andrx); Dilacor (Watson); Diltzac (Apotex); Taztia (Andrx); Tiazac (Biovail).
Therapeutic FunctionCoronary vasodilator
General DescriptionDiltiazem hydrochloride is a calcium ion cellular influx inhibitor. It was developed and introduced inJapan as a cardiovascular agent to treat angina pectoris. Itwas observed to dilate peripheral arteries and arterioles. Thedrug increases myocardial oxygen supply by relieving coronaryartery spasm and reduces myocardial oxygen demandby decreasing heart rate and reducing overload. Diltiazemhydrochloride is used in patients with variant angina. Thedrug has electrophysiological properties similar to those ofverapamil and is used in clinically similar treatment conditionsas an antiarrhythmic agent, but it is less potent.
The drug is absorbed rapidly and almost completely fromthe digestive tract. It reaches peak plasma levels within 1hour after administration in gelatin capsules. Oral formulationson the market are sustained-release preparations providingpeak plasma levels 3 to 4 hours after administration.
Biological ActivityAntihypertensive and cardioprotective agent; an inhibitor of L-type Ca 2+ channels.
Biochem/physiol ActionsProduct does not compete with ATP.
Clinical UseCalcium-channel blocker:
Prophylaxis and treatment of angina
Hypertension

MetabolismDiltiazem is almost completely absorbed from the gastrointestinal tract after oral doses, but undergoes extensive first-pass hepatic metabolism resulting in a bioavailability of about 40%. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4; one of the metabolites, desacetyldiltiazem, has been reported to have 25-50% of the activity of the parent compound
About 2-4% of a dose is excreted in urine as unchanged diltiazem with the remainder excreted as metabolites in bile and urine.
storageStore at RT
Mode of actionDiltiazem Hydrochloride is a benzothiazepine calcium channel blocking agent. Diltiazem hydrochloride inhibits the transmembrane influx of extracellular calcium ions into select myocardial and vascular smooth muscle cells, causing dilatation of coronary and systemic arteries and decreasing myocardial contractility. Because of its vasodilatory activity, this agent has been shown to improve the microcirculation in some tumors, thereby potentially improving the delivery of antineoplastic agents to tumor cells.
References1) Kraus?et al.?(1998),?Molecular mechanism of diltiazem interaction with L-type Ca2+ channels; J. Biol. Chem.,?273?27205 2) Godfraind?et al. (1986),?Calcium antagonism and calcium entry blockade; Pharmacol. Rev.,?38?321 3) Fedoryak?et al.?(2004),?Spontaneous Ca2+ oscillations in subcellular compartments of vascular smooth muscle cells rely on different Ca2+ pools; Cell Res.,?14?379 4) Ishibashi?et al. (1995),?Block of P-type Ca2+ channels in freshly dissociated rat cerebellar Purkinje neurons by diltiazem and verapamil; Brain Res.,?695?88 5) Chaffman and Bogden (1985),?Diltiazem. A review of its pharmacological properties and therapeutic efficacy; Drugs,?29?387
Ethanol Ethyl pyruvate Ethyl formate Sibutramine hydrochloride 3-Dimethylaminopropylamine Anisole Ethylparaben m-Anisyl alcohol (Trifluoromethoxy)benzene Diltiazem ISOXADIFEN-ETHYL p-Anisidine 1-AdaMantanethylaMine Ethyl acetate Methoxyacetic acid p-Anisaldehyde Ethyl acrylate Ethyl cyanoacetate Diltiazem Hcl

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