Astemizole

Astemizole Basic information
Uses
Product Name:Astemizole
Synonyms:1-((4-fluorophenyl)methyl)-n-(1-(2-(4-methoxyphenyl)ethyl)-4-piperidinyl)-1h-b;r45312;retolen;ASTEMIZOLE;1-[(4-FLUOROPHENYL)METHYL]-N-[1-[2-(4-METHOXYPHENYL)ETHYL]-4-PIPERIDINYL]-1H-BENZIMIDAZOL-2-AMINE;(1-[4-FLUOROBENZYL]-2-[1-(4-METHOXYPHENETHYL)PIPERIDIN-4-YL] AMINOBENZIMIDAZOLE;Astemisan;R 43512
CAS:68844-77-9
MF:C28H31FN4O
MW:458.57
EINECS:272-441-9
Product Categories:ASCABIOL;Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Histamine receptor
Mol File:68844-77-9.mol
Astemizole Structure
Astemizole Chemical Properties
Melting point 172.9°C
Boiling point 627.3±65.0 °C(Predicted)
density 1.1587 (estimate)
storage temp. 2-8°C
solubility DMSO: >20mg/mL
pkapKa 4.85(H2O t=25.0 I=0.025) (Uncertain);8.69(H2O t=25.0 I=0.025) (Uncertain)
form powder
color Crystals
Water Solubility It is soluble in DMSO (25 mg/ml ), ethanol (25 mg/ml), chloroform, methanol, and water (partly miscible).
Stability:Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
Safety Information
Hazard Codes Xn
Risk Statements 22-36/37/38
Safety Statements 26-36
RIDADR UN 2811 6.1 / PGII
WGK Germany 3
RTECS DD8968000
HS Code 2933992600
Hazardous Substances Data68844-77-9(Hazardous Substances Data)
ToxicityLD50 orl-rat: >2560 mg/kg AIPTAK 251,39,81
MSDS Information
ProviderLanguage
Astemizole English
SigmaAldrich English
Astemizole Usage And Synthesis
UsesAstemizole is a histamine H1-receptor antagonist with IC50 of 4.7 nM. Astemizole is also a potent inhibitor of ether à-go-go 1 (Eag1) and Eag-related gene (Erg) potassium channels. Astemizole has antineoplastic and antipruritic effects.
DescriptionAstemizole belongs to the second-generation class of non-sedating, non-anticholinergic antihistamines. Its non-sedating properties appear to result from its poor penetration of the blood brain barrier. As a result it shows no potentiation of CNS depressants, including alcohol. Its long half-life allows once-daily dosing.
Chemical PropertiesCrystalline Solid
OriginatorJanssen (Belgium)
UsesAstemizole is used for preventing and treating severe seasonal and chronic allergic rhinitis, allergic conjunctivitis, hives, Quinke’s edema, other allergic conditions and dermatitis. Synonyms of this drug are hismanal, histazol, and others.
Usesscabicide
UsesNonsedating-type histamine H1-receptor antagonist. Potential for combination therapy with antivancer drugs such as doxorubicin in resistant leukemia. Antihistaminic
DefinitionChEBI: A piperidine compound having a 2-(4-methoxyphenyl)ethyl group at the 1-position and an N-[(4-fluorobenzyl)benzimidazol-2-yl]amino group at the 4-position.
Manufacturing ProcessA mixture of 2.3 parts of 2-(4-methoxyphenyl)ethyl methanesulfonate, 4.9 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2- amine dihydrobromide, 3.2 parts of sodium carbonate, 0.1 part of potassium iodide and 90 parts of N,N-dimethylformamide is stirred overnight at 70°C. The reaction mixture is poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 2.2 parts (48%) of 1- (4-fluorophenylmethyl)-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1Hbenzimidazol- 2-amine, MP 149.1°C.
Brand nameHismanal (Janssen);Alermizol;Astezol;Astol;Histamanal;Novo-nastizol;EISMANAL.
Therapeutic FunctionAntiallergic, Antihistaminic
World Health Organization (WHO)The first clinically interesting histamine ti-antagonists were introduced in the late forties and early fifties. Several histamine ti-antagonists have a similar cardiac effect to that seen with astemizole and terfenadine. Serious cardiovascular adverse reactions have been reported when used concomitantly with imidazole antifungals and macrolide antibiotics.
Biological ActivityOrally active, potent histamine H 1 antagonist (IC 50 = 4 nM) that displays 20-fold, > 250-fold and > 250-fold selectivity over 5-HT, dopamine and muscarinic acetylcholine receptors respectively. Exhibits antimalarial activity in multidrug resistant strains in vitro (IC 50 = 227 - 734 nM). Also potent hERG K + channel blocker (IC 50 = 0.9 nM) that displays cardiotoxicity in vivo .
Biochem/physiol ActionsAstermizole is a potent hERG potassium channel blocker (IC50 of 0.9 nM) and may used as a pharmacological chaperone to correct folding defects and restore protein function for some mutated forms of hERG channels. It has also been studied for treatment of malaria, hERG and hEAG channel function in cancer and as a second generation antihistamine H-1 antagonist.
Safety ProfilePoison by subcutaneous andintravenous routes. Moderately toxic by ingestion. Humansystemic effects by ingestion: arrhythmias, coma, nauseaor vomiting, somnolence. When heated to decompositionit emits toxic fumes of F?? and NOx.
SynthesisAstemizole, 1-[(4-fluorophenyl)methyl]-N-[1-[2-(4-methoxyphenyl) ethyl]-4- piperidinyl]-benzimidazol-2-amine (16.1.31), is synthesized in a multi-stage synthesis from 1-carbethoxy-4-aminopiperidine and 2-nitroisothiocyanobenzol, from which a derivative of thiourea (16.1.26) is synthesized upon their reaction. The nitro group of the product is reduced and the further S-methoxided. In reaction conditions intermolecular cyclization into a derivative of benimidazol, N-[1-[2-(4-carethoxy)]-4-piperidinyl]benzimidazol-2-amine (16.1.28) occurs. The obtained aminobenzimidazole derivative is alkylated with 4-fluorobenzylchoride into 1-[(flurophenyl)methyl]-N-[1-[2-(4-carethoxy)]-4-piperidinyl] benzimidazol- 2-amine (16.1.29). The carbethoxyl group of the resulting compound (16.1.29) is hydrolyzed by hydrobromic acid, forming a non-substituted on the nitrogen atom derivative of piperidine (16.1.30), the alkylation of which with 2-(4-methoxyphenyl)ethylmetanesulfonate leads to the formation of astemizole (16.1.31).

Synthesis_68844-77-9

storageStore at +4°C
References1) Richards et al. (1984), Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy; Drugs, 28 38 2) Laduron et al. (1982), In vitro and in vivo binding characteristics of a new long-acting histamine H1 antagonist, astemizole; Mol. Pharmacol., 21 294
Astemizole Preparation Products And Raw materials
Raw materialsIodomethane-->Bromoethane-->1,4-Dimethoxybenzene-->norastemizole-->Sodium carbonate
Cisapride 2-(AMINOMETHYL)-1-METHYLIMIDAZOLE 1-BENZYL-1H-BENZOIMIDAZOL-2-YLAMINE 1-ETHYL-1H-BENZOIMIDAZOL-2-YLAMINE norastemizole DESMETHYL ASTEMIZOLE 2-AMINO-1-((4-FLUOROPHENYL)METHYL)BENZI& DESMETHYL ASTEMIZOLE HYDROCHLORIDE 1-PHENETHYL-PIPERIDIN-4-YLAMINE O-Desmethyl Astemizole 1-BENZYL-1H-IMIDAZOL-2-YLAMINE 1-(4-METHOXYPHENETHYL)-4-AMINOPIPERIDINE 4-AMINO-1-(1-PROPYL)-PIPERIDINE ASTEMIZOLE, [METHYL-3H]- Astemizole Benzene astemizole tetrachlorocuprate(II) 2-AMINO-1-METHYLBENZIMIDAZOLE

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