Vardenafil

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Vardenafil
Vardenafil.svg
Systematic (IUPAC) name
4-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one
Clinical data
Trade names Levitra, Staxyn, Vivanza
AHFS/Drugs.com monograph
MedlinePlus a603035
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 15%
Protein binding 95%
Metabolism Hepatic (CYP3A4)
Half-life 4–5 hours
Excretion Biliary
Identifiers
CAS number 224785-90-4 YesY
ATC code G04BE09
PubChem CID 110634
DrugBank DB00862
ChemSpider 99300 YesY
UNII UCE6F4125H YesY
ChEMBL CHEMBL1520 YesY
Chemical data
Formula C23H32N6O4S 
Mol. mass 488.604 g/mol
 YesY (what is this?)  (verify)

Vardenafil (INN) is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra (Bayer AG, GSK, and SP), Staxyn in India, and Vivanza in Italy.

History[edit]

Vardenafil was co-marketed by Bayer Pharmaceuticals, GlaxoSmithKline, and Schering-Plough under the trade name Levitra. As of 2005, the co-promotion rights of GSK on Levitra have been returned to Bayer in many markets outside the U.S. In Italy, Bayer sells vardenafil as Levitra and GSK sells it as Vivanza. Thus, because of European Union trade rules, parallel imports might result in Vivanza sold next to Levitra in the EU.

An orally disintegrating form, marketed as Staxyn, has been gaining approvals in countries such as the United States[1] and Canada.[2]

Clinical use[edit]

Main article: PDE5 inhibitor

Vardenafil's indications and contra-indications are the same as with other PDE5 inhibitors; it is closely related in function to sildenafil citrate (Viagra) and tadalafil (Cialis). The difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom's position and the change of sildenafil's piperazine ring methyl group to an ethyl group. Tadalafil is structurally different from both sildenafil and vardenafil. Vardenafil's relatively short effective time is comparable to but somewhat longer than sildenafil's.

Beyond its indications for erectile dysfunction, vardenafil may be effective in the treatment of premature ejaculation, where it may significantly increase the time from penetration to ejaculation.[3]

Adverse drug reactions[edit]

The common, adverse drug reactions (side-effects) are the same as with other PDE5 inhibitors. The frequent vardenafil-specific side-effect is nausea; the infrequent side-effects are abdominal pain, back pain, photosensitivity, abnormal vision, eye pain, facial edema, hypotension, palpitation, tachycardia, arthralgia, myalgia, rash, itch, and priapism.

One possibly serious, but rare, side-effect with vardenafil is heart attack. Also, in rare cases, vardenafil use may cause priapism, a very painful emergency condition that can cause impotence if left untreated.[4]

On 18 October 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible deafness (sudden hearing loss) would be added to the drug labels of Vardenafil, and other PDE5 inhibitors.[5]

Drug interactions[edit]

Vardenafil, as with all PDE5 inhibitors, should not be used by men taking nitrate medications, because combining them with vardenafil might provoke potentially life-threatening hypotension (low blood pressure).

Further, Vardenafil causing lengthening of the QT interval. Therefore it should not be taken by men taking other medications that affect the QT interval (such as amiodarone).

Dose forms[edit]

Levitra 20mg Oral Tablet

It is available in 2.5 mg, 5 mg, 10 mg, and 20 mg doses in round orange tablets. The normal starting dose is 10 mg[6] (roughly equivalent to 50 mg of sildenafil). Vardenafil should be taken 1 to 2 hours prior to sexual activity, with a maximum dose frequency of once per day. In some territories, such as the UK, only certain doses may be available.

Vardenafil is also available under the name Staxyn as a tablet which dissolves on the tongue rather than being swallowed in the form of a pill.[7]

Synthesis[edit]

1[edit]

  1. 2-hydroxybenzonitrile is alkylated with EtBr.
  2. Addition of ammonia to the nitrile functionality using AlMeCINH2, generated in situ by reacting NH4Cl with AlMe3, to give amidine.
  3. D,L-alanine was acylated with butyryl chloride which underwent a Dakin-West reaction with ethyl oxalyl chloride to furnish the intermediate α-oxoamino ester 2.
  4. The carboximidohydrazide 1 is formed in situ by addition of hydrazine hydrate to the amidine.
Bayer synthesis of Vardenafil (Bay-38-9456):[8][9] U.S. Patent 6,362,178
  1. A solution of crude 2 in ethanol was added to 1 and the mixture was heated at 70°C for 4 hours to give the condensation product.
  2. The above intermediate was cyclized to the imidazotriazinone using POCl3 to give product in in 28% yield without isolation of intermediate compounds.
  3. Reaction with chlorosulfonic acid provided the sulfonyl chloride, which was treated with N-ethylpiperazine to furnish vardenafil.

2[edit]

A modified synthesis of vardenafil on a multi-kilogram scale was recently reported by a group from Bayer.

Bayer large scale synthesis of vardenafil: EP 1345939 

Benzamidine was prepared in a different manner than previously described, ∵ it is difficult to use Al2Me6 on a large scale.

Thus, 2-ethoxybenzamide was dehydrated with SOCl2 to give 2-ethoxybenzonitrile, which was treated with hydroxyl amine hydrochloride to afford the N-hydroxybenzamidine. Catalytic hydrogenation provided benzamidine.

Notes[edit]

  1. ^ http://www.pharmpro.com/News/Feeds/2010/06/pharmaceutical-companies-bayer-new-erectile-dysfunction-treatment-staxyn-approve/
  2. ^ http://www.newswire.ca/en/story/832217/staxyn-new-innovation-in-erectile-dysfunction-helps-younger-men-rise-to-the-occasion
  3. ^ A Aversa et al. "Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation". Retrieved 2010-12-14. 
  4. ^ Schools of Pharmacy (Glen L. Stimmel, Pharm.D., and Mary A. Gutierrez, Pharm.D.) and Medicine (Glen L. Stimmel, Pharm.D.), University of Southern California, Los Angeles, California. "Counseling Patients About Sexual Issues: Drug-Induced Priapism". Medscape. Retrieved 2010-12-06. 
  5. ^ "FDA Announces Revisions to Labels for Cialis, Levitra and Viagra". Food and Drug Administration. 2007-10-18. Retrieved 2009-08-06. 
  6. ^ "How Do I Take Levitra". HealthExpress. Retrieved 2014-02-18. 
  7. ^ "Vardenafil". Medicine Net. Retrieved 2014-02-18. 
  8. ^ Haning, H.; Niewöhner, U.; Schenke, T.; Es-Sayed, M.; Schmidt, G.; Lampe, T.; Bischoff, E. (2002). "Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors". Bioorganic & Medicinal Chemistry Letters 12 (6): 865. doi:10.1016/S0960-894X(02)00030-6.  edit
  9. ^ Drugs of the Future, 2001,26, 141-144.

External links[edit]