68844-77-9 Usage
Uses
Different sources of media describe the Uses of 68844-77-9 differently. You can refer to the following data:
1. Astemizole 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.
2. Nonsedating-type histamine H1-receptor antagonist. Potential for combination therapy with antivancer drugs such as doxorubicin in resistant leukemia. Antihistaminic
3. Astemizole 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.
Description
Astemizole 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 Properties
Crystalline Solid
Originator
Janssen (Belgium)
Definition
ChEBI: 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 Process
A 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 name
Hismanal (Janssen);Alermizol;Astezol;Astol;Histamanal;Novo-nastizol;EISMANAL.
Therapeutic Function
Antiallergic, 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 Activity
Orally 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 Actions
Astermizole 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 Profile
Poison 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.
Synthesis
Astemizole, 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).
References
1) 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
Check Digit Verification of cas no
The CAS Registry Mumber 68844-77-9 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,8,8,4 and 4 respectively; the second part has 2 digits, 7 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 68844-77:
(7*6)+(6*8)+(5*8)+(4*4)+(3*4)+(2*7)+(1*7)=179
179 % 10 = 9
So 68844-77-9 is a valid CAS Registry Number.
InChI:InChI=1/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31)
68844-77-9Relevant articles and documents
Metal-Free Synthesis of Heteroaryl Amines or Their Hydrochlorides via an External-Base-Free and Solvent-Free C-N Coupling Protocol
Fan, Guang-Gao,Jiang, Bo-Wen,Sang, Wei,Cheng, Hua,Zhang, Rui,Yu, Bao-Yi,Yuan, Ye,Chen, Cheng,Verpoort, Francis
, p. 14627 - 14639 (2021/11/01)
Herein, a metal-free and solvent-free protocol was developed for the C-N coupling of heteroaryl halides and amines, which afforded numerous heteroaryl amines or their hydrochlorides without any external base. Further investigations elucidated that the basicity of amines and specific interactions derived from the X-ray crystallography analysis of 3j′·HCl played pivotal roles in the reactions. Moreover, this protocol was scalable to gram scales and applicable to drug molecules, which demonstrated its practical value for further applications.
Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
Kumar, Malkeet,Okombo, John,Mambwe, Dickson,Taylor, Dale,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Fontinha, Diana,Sanches-Vaz, Margarida,Bezuidenhout, Belinda C.,Lauterbach, Sonja B.,Liebenberg, Dale,Birkholtz, Lyn-Marie,Coetzer, Theresa L.,Prudêncio, Miguel,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
, p. 303 - 315 (2019/01/15)
A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of 50 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
Methods of using norastemizole in combination with leukotriene inhibitors to treat or prevent asthma
-
, (2008/06/13)
Methods and pharmaceutical compositions employing norastemizole and a leukotriene inhibitor for the treatment or prevention of inflammation or allergic disorders, such as asthma or the symptoms thereof. Also included are methods and compositions employing norastemizole and a decongestant for the treatment or prevention of inflammation or allergic disorders, such as asthma or the symptoms thereof.
