Title: Alfuzosin

CAS Registry Number: 81403-80-7

CAS Name: N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarboxamide

Additional Names: N1-(4-amino-6,7-dimethoxyquinazol-2-yl)-N1-methyl-N2-(tetrahydrofuroyl-2)-propylenediamine

Manufacturers’ Codes: SL-77.499

Molecular Formula: C19H27N5O4

Molecular Weight: 389.45

Percent Composition: C 58.60%, H 6.99%, N 17.98%, O 16.43%

Literature References: a1-Adrenoceptor antagonist structurally similar to prazosin, q.v. Prepn: P. M. J. Manoury, DE 2904445; idem, US 4315007 (1979, 1982 both to Synthelabo); and antihypertensive activity in rats: P. M. Manoury et al., J. Med. Chem. 29,19 (1986). Pharmacology: A. G. Ramage, Eur. J. Pharmacol. 129, 307 (1986). HPLC determn in biological fluids: P. Guinebault et al., J. Chromatogr. 353, 361 (1986). Pharmacology in humans: A. H. Deering, Br. J. Clin. Pharmacol. 25, 417 (1988). Clinical evaluation in essential hypertension: S. Leto Di Priolo et al., Eur. J. Clin. Pharmacol. 35, 25 (1988); A. K. Ghosh, S. Ghosh, Ger. Cardiovasc. Med. 1, 81 (1988). Clinical trial in benign prostatic hyperplasia (BPH): C. G. Roehrborn et al., BJU Int. 92, 257 (2003). Review of clinical experience in BPH: D. M. Weiner, F. C. Lowe, Expert Opin. Pharmacother. 4, 2057-2063 (2003).

Alfuzosin hydrochloride (CAS 81403-68-1)

Derivative Type: Hydrochloride

CAS Registry Number: 81403-68-1

Manufacturers’ Codes: SL-77.499-10

Trademarks: Mittoval (Schering AG); Urion (Zambon); UroXatral (Sanofi-Synthelabo); Xatral (Sanofi-Synthelabo)

Molecular Formula: C19H27N5O4.HCl

Molecular Weight: 425.91

Percent Composition: C 53.58%, H 6.63%, N 16.44%, O 15.03%, Cl 8.32%

Properties: Crystals from ethanol + ether, mp 225° (Manoury, 1986), also reported earlier as mp 235° (dec) (Manoury, 1982). pKa 8.13.

Melting point: mp 225° (Manoury, 1986); mp 235° (dec) (Manoury, 1982)

pKa: pKa 8.13

Therap-Cat: Antihypertensive. In treatment of benign prostatic hypertrophy.

Keywords: Antihypertensive; Quinazoline Derivatives; Antiprostatic Hypertrophy; a-Adrenergic Blocker.

Alfuzosin (INN, provided as the hydrochloride salt) is a pharmaceutical drug of the α₁ blocker class. As an antagonist of the α₁adrenergic receptor, it works by relaxing the muscles in the prostate and bladder neck, making it easier to urinate. It is thus used to treat benign prostatic hyperplasia (BPH).^[1]

Alfuzosin is marketed in the United States by Sanofi Aventis under the brand name Uroxatral and elsewhere under the tradenames Xat, Xatral, Prostetrol and Alfural. Alfuzosin was approved by the U.S. FDA for treatment of BPH in June 2003.

Side effects

The most common side effects are dizziness (due to postural hypotension), upper respiratory tract infection, headache, fatigue, and abdominal disturbances. Side effects include stomach pain, heartburn, and congested nose.^[2] Adverse effects of alfuzosin are similar to that of tamsulosin with the exception of retrograde ejaculation.^[3]

Contraindications

Alfuzosin should be used with caution in patients with severe renal insufficiency, and should not be prescribed to patients with a known history of QT prolongation who are taking medications known to prolong the QT interval.

Chemistry

Alfuzosin contains a stereocenter and is therefore chiral. There are two enantiomeric forms, (R)-alfuzosin and (S)-alfuzosin. The drug is used as a racemate, (RS)-alfuzosin, a 1: 1 mixture of the (R)- and (S)-forms.^[4]

Enantiomers of alfuzosin
CAS number: 123739-69-5	CAS number.: 123739-70-8

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
23680-84-4	C10H10ClN3O2	4-amino-2-chloro-6,7-dimethoxyquinazoline	4-Quinazolinamine, 2-chloro-6,7-dimethoxy-
5004-88-6	C9H12N2O3	2-amino-4,5-dimethoxybenzamide	Benzamide, 2-amino-4,5-dimethoxy-
541-41-3	C3H5ClO2	chloroformic acid ethyl ester	Carbonochloridic acid, ethyl ester
72104-44-0	C9H14N2O2	2-cyano-N-methyl-N-tetrahydrofuroylethylamine	2-Furancarboxamide, N-(2-cyanoethyl)tetrahydro-N-methyl-
27631-29-4	C10H8Cl2N2O2	2,4-dichloro-6,7-dimethoxyquinazoline	Quinazoline, 2,4-dichloro-6,7-dimethoxy-
28888-44-0	C10H10N2O4	2,4-dihydroxy-6,7-dimethoxyquinazoline	2,4(1H,3H)-Quinazolinedione, 6,7-dimethoxy-
20357-25-9	C9H9NO5	4,5-dimethoxy-2-nitrobenzaldehyde	Benzaldehyde, 4,5-dimethoxy-2-nitro-
4959-60-8	C9H10N2O5	4,5-dimethoxy-2-nitrobenzamide	Benzamide, 4,5-dimethoxy-2-nitro-
28888-44-0	C10H10N2O4	6,7-dimethoxyquinazoline-2,4-dione	2,4(1H,3H)-Quinazolinedione, 6,7-dimethoxy-
541-41-3	C3H5ClO2	ethyl chloroformate	Carbonochloridic acid, ethyl ester
693-05-0	C4H8N2	3-(methylamino)propanenitrile	Propanenitrile, 3-(methylamino)-
81403-67-0	C9H18N2O2	N1-methyl-N2-tetrahydrofuroyltrimethylenediamine	2-Furancarboxamide, tetrahydro-N-[3-(methylamino)propyl]-
16874-33-2	C5H8O3	(±)-tetrahydrofuran-2-carboxylic acid	2-Furancarboxylic acid, tetrahydro-
167391-50-6	C8H12O5	tetrahydro-2-furancarboxylic acid anhydride with ethyl hydrogen carbonate	2-Furancarboxylic acid, tetrahydro-, anhydride with ethyl hydrogen carbonate
57-13-6	CH4N2O	urea	Urea
120-14-9	C9H10O3	veratraldehyde	Benzaldehyde, 3,4-dimethoxy-

Trade Names

Country	Trade Name	Vendor	Annotation
D	Alfunar	Apogepha
	Alfusin	TAD Pharma
	Urion	Sanofi-Aventis
	Uroxatral	Sanofi-Aventis
F	Urion	Zambon
	Xatral	Sanofi-Aventis
GB	Xatral	Sanofi-Aventis
I	Mittoval	Sanofi-Aventis
	Xatral	Sanofi-Aventis

Formulations

• film tabl. 2.5 mg; retard tabl. 10 mg (hydrochloride)

References

• • Manoury, P.M. et al.: J. Med. Chem. (JMCMAR) 29, 19 (1986).
  • US 4 315 007 (Synthelabo; 9.2.1982; F-prior. 6.2.1978, 29.12.1978).
  • DE 2 904 445 (Synthelabo; appl. 16.8.1979; F-prior. 6.2.1978, 29.12.1978).

• synthesis of 6,7-dimethoxyquinazoline-2,4-dione:

  • Althuis, T.H.; Hess, H.J.: J. Med. Chem. (JMCMAR) 20, 146 (1977).

SYN

Mathias Scheer, “Alfuzosin tablets and synthesis.” U.S. Patent US20060062845, issued March 23, 2006.

US20060062845

Syn,  DOI: 10.1021/jm00151a003 NB: (WO2009001369)

FTIR spectrum of alfuzosin hydrochloride 

CLIP

Add the following:

Alfuzosin Hydrochloride

C19H27N5O4·HCl 425.91

2-Furancarboxamide, N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-, monohydrochloride (±).
(±)-N-[3-[(4-Amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furamide monohydrochloride [81403-68-1].

» Alfuzosin Hydrochloride contains not less than 99.0 percent and not more than 101.0 percent of C19H27N5O4·HCl, calculated on the anhydrous basis.

Packaging and storage— Preserve in tight, well-closed containers, protected from light and humidity. Store at room temperature.

USP Reference standards 11— 
USP Alfuzosin Hydrochloride RS.
USP Alfuzosin System Suitability Mixture RS.

Identification—

A: Infrared Absorption 197K.

B: It meets the requirements of the test for Chloride 191.

pH 791: between 4.0 and 5.5

Test solution: 20 mg per mL, in carbon dioxide-free water.

Optical rotation 781: 0.10 to +0.10

Test solution: 20 mg per mL, in carbon dioxide-free water.

Water, Method I 921: not more than 0.5%.

Residue on ignition 281: not more than 0.1%.

Related compounds—

Solution A— Dilute 5.0 mL of perchloric acid in 900 mL of water, adjust with 2 M sodium hydroxide solution to a pH of 3.5, and dilute with water to 1000 mL.

Mobile phase— Prepare a filtered and degassed mixture of Solution A, acetonitrile, and tetrahydrofuran (80:20:1). Make adjustments if necessary (see System Suitability under Chromatography 621).

System suitability solution— Dissolve an accurately weighed quantity of USP Alfuzosin System Suitability Mixture RS in Mobile phase, and dilute quantitatively with Mobile phase to obtain a solution containing about 0.4 mg per mL.

Test solution— Dissolve 40.0 mg of Alfuzosin Hydrochloride in Mobile phase, and dilute with Mobile phase to 100.0 mL.

Reference solution— Quantitatively dilute an accurately measured volume of the Test solution by a factor of 1000 with Mobile phase.

Chromatographic system (see Chromatography 621)— The liquid chromatograph is equipped with a detector set at 254 nm and a 4.6-mm × 15-cm column that contains 5-µm packing L1. The flow rate is about 1.5 mL per minute. Chromatograph the System suitability solution, and record the peak responses as directed for Procedure: the peak-to-valley ratio is at least 5. [NOTE—The peak-to-valley ratio is determined as the ratio of the height above the baseline of the impurity A peak to the height above the baseline of the lowest point of the curve separating this impurity peak from the peak due to alfuzosin.]

Procedure— Separately inject equal volumes (about 10 µL) of the Reference solution and the Test solution, record the chromatograms, and measure the peak responses. Calculate the percentage of each impurity in the portion of Alfuzosin Hydrochloride taken by the formula:

100[rU / (1000 rS)]

in which 100 is the percentage conversion factor; rU is the peak response for any impurity obtained from the Test solution; 1000 is the dilution factor; and rS is the peak response for alfuzosin obtained from the Reference solution: the limits are as shown in the accompanying table. Disregard any peak with an area less than 0.05%.

Compound	Relative  Retention Time	Limit  (%)
Alfuzosin	1.0	—
Impurity A1	1.2	*
Impurity D2	0.5	0.20
Any individual unspecified impurity	—	0.10
Total impurities	—	0.30
1  N-[3-[(4-Amino-6,7-dimethoxyquinazolin-2-yl)(methyl)amino]propyl]furan-2-carboxamide. 2  N-(4-Amino-6,7-dimethoxyquinazolin-2-yl)-N-methylpropane-1,3-diamine. *  Impurity A, a component of USP Alfuzosin System Suitability Mixture RS, is not a specified impurity.

Assay— Dissolve about 300 mg of Alfuzosin Hydrochloride, accurately weighed, in a mixture of 40 mL of anhydrous acetic acid and 40 mL of acetic anhydride. Titrate with 0.1 M perchloric acid, determining the endpoint potentiometrically. Each mL of 0.1 M perchloric acid is equivalent to 42.59 mg of C19H27N5O4·HCl.USP32

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Daniel K. Bempong, Ph.D. Senior Scientist 1-301-816-8143	(MDPS05) Monograph Development-Pulmonary and Steroids
Reference Standards	Lili Wang, Technical Services Scientist 1-301-816-8129 RSTech@usp.org

USP32–NF27 Page 1449

Pharmacopeial Forum: Volume No. 34(1) Page 69

Chromatographic Column—

ALFUZOSIN HYDROCHLORIDE

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.

References

1. Jump up^ Lepor, Herbert (2016). “Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia”. Urologic Clinics of North America. 43 (3): 311–23. doi:10.1016/j.ucl.2016.04.009. PMC 2213889 . PMID 27476124.
2. Jump up^ “Alfuzosin”. MedlinePlus. United States National Library of Medicine. April 15, 2016.
3. Jump up^ Hills, Robert K; Liu, Chenli; Zeng, Guohua; Kang, Ran; Wu, Wenqi; Li, Jiasheng; Chen, Kang; Wan, Show P. (2015). “Efficacy and Safety of Alfuzosin as Medical Expulsive Therapy for Ureteral Stones: A Systematic Review and Meta-Analysis”. PLOS ONE. 10 (8): e0134589. doi:10.1371/journal.pone.0134589. ISSN 1932-6203. PMC 4526635 . PMID 26244843. This article incorporates text available under the CC BY 4.0 license.
4. Jump up^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, S. 159, ISBN 978-3-946057-10-9.

External links

• Uroxatral (alfuzosin HCl) Extended-Release Tablets Prescribing Information
• Alfuzosin (General information from the NIH)

Alfuzosin

Clinical data
Pronunciation	/ælˈfjuːzoʊsɪn/ al-FEW-zoh-sin
Trade names	Uroxatral, others
AHFS/Drugs.com	Monograph
MedlinePlus	a64002
Pregnancy category	AU: B2 US: B (No risk in non-human studies)
Routes of administration	By mouth (tablets)
ATC code	G04CA01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	49%
Protein binding	82–90%
Metabolism	Liver (CYP3A4-mediated)
Elimination half-life	10 hours
Excretion	Feces (69%) and Urine (24%)
Identifiers
IUPAC name[show]
CAS Number	81403-80-7
PubChem CID	2092
IUPHAR/BPS	7109
DrugBank	DB00346
ChemSpider	2008
UNII	90347YTW5F
KEGG	D07124
ChEBI	CHEBI:51141
ChEMBL	CHEMBL709
ECHA InfoCard	100.108.671
Chemical and physical data
Formula	C19H27N5O4
Molar mass	389.46 g·mol−1
3D model (JSmol)	Interactive image

/////////////////塩酸アルフゾシン, Uroxatral, alfuzosin

COC1=C(OC)C=C2C(N)=NC(=NC2=C1)N(C)CCCNC(=O)C1CCCO1