Alfuzosin hydrochloride

Description

Alfuzosin (SL-77499) (I), a quinazoline derivative which is a uroselective alpha-1 adrenoreceptor antagonist, has been developed and launched worldwide by Sanofi-Synthelabo, for the treatment of benign prostate hyperplasia (BPH). In November 2003, alfuzosin (I) was launched as an extended release formulation in the US as Uroxatral utilizing Skyepharma’s oral controlled release technology.

Chemical properties

White to Off-White Solid

The Uses of Alfuzosin hydrochloride

α1-Adrenoceptor antagonist structurally similar to Prozosin. Antihypertensive. Alfuzosin hydrochloride is used in treatment of benign prostatic hypertrophy.

The Uses of Alfuzosin hydrochloride

a-1- Adrenoceptor antagonist structurally similar to prozosin

The Uses of Alfuzosin hydrochloride

Antihypertensor;Alpha 1- adrenergic antagonist

What are the applications of Application

Alfuzosin hydrochloride is an α 1 adrenoceptor antagonist

brand name

Uroxatral (Sanofi Aventis).

General Description

Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.

Biological Activity

Functionally uro-selective α 1 adrenoceptor antagonist that does not discriminate between α 1 subtypes. Inhibits increases in intraurethral pressure caused by phenylephrine-induced contraction by 81% with minor cardiovascular effects. Also relaxes corpus cavernosum tissue (pIC 50 = 7.64) in vitro .

Biochem/physiol Actions

Alfuzosin hydrochloride is an alpha-adrenergic blocker used to treat benign prostatic hyperplasia (BPH). It works by relaxing the muscles in the prostate and bladder neck, making it easier to urinate.

Clinical Use

Alpha-blocker:
Treatment of benign prostatic hyperplasia
Treatment of acute urinary retention

Synthesis

Although syntheses of alfuzosin (I) have appeared in several reports, an optimized route used for the manufacture of the compound does not appear in the literature. The synthesis reported by the Sanofi group for alfuzosin will be described and is shown in the scheme. The commercially available 4- amino-2-chloro-6,7-dimethoxyquinazoline (1) was treated with 3-methylaminopropionitrile (2) in isoamyl alcohol and refluxed for 5 hrs. Filtration of the precipitated product and washing with ethanol gave nitrile 3 in 62% yield. Hydrogenation of the nitrile was done in 15% ammonia solution in ethanol with Raney nickel as catalyst at 70??C and 1000 psi to obtain the corresponding amine free base. Conversion of the free base to the hydrochloride salt was done in ethanol to give the HCl salt 4 in 52% yield. The final acylation of amine 4 was done with the imidazolyl anhydride of furan 5. Thus, 2-carboxyfuran was treated with carbonyldiimidazole in THF at 40??C for 1 hr and then cooled to 10??C. Addition of amine 4 in THF in the presence of triethylamine at 10??C, then refluxing the reaction for 1 hr, and aqueous workup gave the alfuzosin free base. After conversion to the hydrochloride salt and recrystallization from 2-propanol alfuzosin hydrochloride (I) was obtained in 44% yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Antidepressants: enhanced hypotensive effect with MAOIs.
Antivirals: concentration possibly increased by ritonavir - avoid; avoid with telaprevir.
Avanafil, vardenafil, sildenafil and tadalafil: enhanced hypotensive effect, separate administration by 4-6 hours.
Beta-blockers: enhanced hypotensive effect; increased risk of first dose hypotensive effect.
Calcium-channel blockers: enhanced hypotensive effect; increased risk of first dose hypotensive effect.
Cobicistat: concentration of alfuzosin possibly increased - avoid.
Diuretics: enhanced hypotensive effect; increased risk of first dose hypotensive effect.
Moxisylyte: possibly severe postural hypotension.

Metabolism

Extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4, to inactive metabolites that are mainly excreted in faeces via the bile.