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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

AVANAFIL

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Jan 252014
 

File:Avanafil.svg

AVANAFIL

A phosphodiesterase (PDE5) inhibitor, used to treat erectile dysfunction.

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Avanafil is a new phosphodiesterase-5 inhibitor that is faster acting and more selective than other drugs belonging to the same class. Chemically, it is a derivative of pyrimidine and is only available as the S-enantiomer. FDA approved on April 27, 2012.

CAS RN: 330784-47-9
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

(S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-pyrimidinylmethyl)carbamoyl]pyrimidine
4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide
TA 1790

Molecular Formular: C23H26ClN7O3

Molecular Mass: 483.95064

  • Stendra
  • TA 1790
  • TA-1790
  • UNII-DR5S136IVO
  • NDA 202276

INNOVATOR  —  VIVUS

APPROVED FDA  27/4/2-12

Patent No Patent Expiry patent use code
6656935 Sep 13, 2020 U-155
7501409 May 5, 2023

U 155… TREATMENT OF ERECTILE DYSFUNCTION

Exclusivity Code Exclusivity_Date
NCE Apr 27, 2017

Stendra (avanafil) was given the green light by the US Food and Drug Administration 27/4/2012, but there has been no launch yet as Vivus has been seeking a partner. The latest data should be attractive to potential suitors and could help Stendra take on other phosphodiesterase type 5 (PDE5) inhibitors, notably Pfizer’s Viagra (sildenafil) but also Eli Lilly’s Cialis (tadalafil) and Bayer’s Levitra (vardenafil).

read all at

http://www.pharmatimes.com/Article/13-06-20/Vivus_ED_drug_gets_to_work_in_less_than_15_mins.aspx

STENDRA (avanafil) is a selective inhibitor of cGMP-specific PDE5.

Avanafil is designated chemically as (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2pyrimidinylmethyl)-5-pyrimidinecarboxamide and has the following structural formula:

STENDRA™ (avanafil)Structural Formula Illustration

Avanafil occurs as white crystalline powder, molecular formula C23H26ClN7O3 and molecular weight of 483.95 and is slightly soluble in ethanol, practically insoluble in water, soluble in 0.1 mol/L hydrochloric acid. STENDRA, for oral administration, is supplied as oval, pale yellow tablets containing 50 mg, 100 mg, or 200 mg avanafil debossed with dosage strengths. In addition to the active ingredient, avanafil, each tablet contains the following inactive ingredients: mannitol, fumaric acid, hydroxypropylcellulose, low substituted hydroxypropylcellulose, calcium carbonate, magnesium stearate, and ferric oxide yellow.

2D image of a chemical structureAVANAFIL

Avanafil is a PDE5 inhibitor approved for erectile dysfunction by FDA on April 27, 2012 [1] and by EMA on June 21, 2013.[2] Avanafil is known by the trademark names Stendra and Spedra and was developed by Vivus Inc. In July 2013 Vivus announced partnership with Menarini Group, which will commercialise and promote Spedra in over 40 European countries plus Australia and New Zealand.[3] Avanafil acts by inhibiting a specificphosphodiesterase type 5 enzyme which is found in various body tissues, but primarily in the corpus cavernosum penis, as well as the retina. Other similar drugs are sildenafiltadalafil and vardenafil. The advantage of avanafil is that it has very fast onset of action compared with other PDE5 inhibitors. It is absorbed quickly, reaching a maximum concentration in about 30–45 minutes.[4] About two-thirds of the participants were able to engage in sexual activity within 15 minutes.[4]

Avanafil is a highly selective PDE5 inhibitor that is a competitive antagonist of cyclic guanosine monophosphate. Specifically, avanafil has a high ratio of inhibiting PDE5 as compared with other PDE subtypes allowing for the drug to be used for ED while minimizing adverse effects. Absorption occurs quickly following oral administration with a median Tmax of 30 to 45 minutes and a terminal elimination half-life of 5 hours. Additionally, it is predominantly metabolized by cytochrome P450 3A4. As such, avanafil should not be co-administered with strong cytochrome P450 3A4 inhibitors. Dosage adjustments are not warranted based on renal function, hepatic function, age or gender. Five clinical trials suggest that avanafil 100 and 200 mg doses are effective in improving the Sexual Encounter Profile and the Erectile Function Domain scores among men as part of the International Index of Erectile Function. A network meta-analysis comparing the PDE5 inhibitors revealed avanafil was less effective on Global Assessment Questionnaire question 1 while safety data indicated no major differences among the different PDE5 inhibitors. The most common adverse effects reported from the clinical trials associated with avanafil were headache, flushing, nasal congestion, nasopharyngitis, sinusitis, and dyspepsia.

A “phosphodiesterase type 5 inhibitor” or “PDE5 inhibitor” refers to an agent that blocks the degradative action of phosphodiesterase type 5 on cyclic GMP in the arterial wall smooth muscle within the lungs and in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. PDE5 inhibitors are used for the treatment of pulmonary hypertension and in the treatment of erectile dysfunction. Examples of PDE5 inhibitors include, without limitation, tadalafil, avanafil, lodenafil, mirodenafil, sildenafil citrate, vardenafil and udenafil and pharmaceutically acceptable salts thereof.

“Avanafil” refers to the chemical compound 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, and its pharmaceutically acceptable salts. Avanafil is described in Limin M. et al., (2010) Expert Opin Investig Drugs, 19(11):1427-37. Avanafil has the following chemical formula:

Figure US20120269898A1-20121025-C00005

Avanafil is being developed for erectile dysfunction. Avanafil currently has no trademarked term associated with it but it is being developed by Vivus Inc.

…………………………………

DESCRIPTION IN A PATENT

US6797709

EXAMPLE 92-145

The corresponding starting compounds are treated in a similar manner to give the compounds as listed in the following Table 7.

TABLE 7
Figure US06797709-20040928-C00234
Figure US06797709-20040928-C00248 Figure US06797709-20040928-C00249 Amorphous MS(m/z): 484(MH+)

ENTRY 98 IS AVANAFIL

…………………………………………………….

/CN103254180A

The invention discloses a preparation method of Avanafil (Avanafil, I), which comprises the following steps: carrying out a substitution reaction on 6-amino-1, 2-dihydro pyrimidine-2-keto-5-carboxylic acid ethyl ester (XII) and 3-chloro-4-methoxy benzyl chloride (XIII) so as to obtain 6-(3-chloro-4-methoxy benzyl amino)-1, 2-dihydro pyrimidine-2-keto-5-carboxylic acid ethyl ester (IXV); carrying out condensation on the compound (IXV) and S-hydroxymethyl pyrrolidine (II) so as to generate 4-[(3-chloro-4-methoxy benzyl) amino]-2-[2-(hydroxymethyl)-1-pyrrole alkyl] pyrimidine-5-carboxylic acid ethyl ester (XI); and carrying out hydrolysis on the compound (XI) and then carrying out an acylation reaction on the compound (XI) and the compound (XI) so as to obtain Avanafil (I). The preparation method is simple in process, economic and environmental-friendly, suitable for the requirements of industrialization amplification.

……………………………………………………

/CN103265534A

The invention discloses a method for preparing avanafil (Avanafil, I). The method comprises the steps of taking cytosine as an initial material; and orderly carrying out replacement, halogen addition and condensation reaction on a side chain 3-chlorine-4-methoxy benzyl halide (III), N-(2-methylpyrimidine) formamide (IV) and S-hydroxymethyl pyrrolidine (II), so as to obtain a target product avanafil (I). The preparation method is available in material, concise in technology, economic and environment-friendly, and suitable for the demands of industrial amplification.

…………………………………………………….

SYNTHESIS

Avanafil can be synthesized from a benzylamine derivative and a pyrimidine derivative REF 5:Yamada, K.; Matsuki, K.; Omori, K.; Kikkawa, K.; 2004, U.S. Patent 6,797,709

Avanafil synthesis.png
………………………………………………………
SYNTHESIS
A cutting that phenanthrene by a methylthio urea ( a ) and ethoxy methylene malonate ( 2 ) cyclization of 3 , chloride, phosphorus oxychloride get 4 , 4 with benzyl amine 5 occurred SNAr the reaction product after oxidation with mCPBA 6 . In pyrimidine, if the 2 – and 4 – positions are active simultaneously the same leaving group in the case, SNAr reaction occurs preferentially at 4 – position, but does not guarantee the 2 – side reaction does not occur. Here is an activity of the poor leaving group sulfide spans 2 – bit, and a good leaving group active chlorine occupy four – position, thus ensuring a high regioselectivity of the reaction. 4 – position after completion of the reaction, then the 2 – position of the group activation, where sulfide sulfoxide better than the leaving group. Amino alcohols 7 and 6 recurrence SNAr reaction 8 , 8 after alkaline hydrolysis and acid alpha amidation get that phenanthrene.
A cutting that phenanthrene (Avanafil) -2012 April FDA-approved treatment for ED medication
AVANAFIL
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Links
  1. FDA approves Stendra for erectile dysfunction” (Press release). Food and Drug Administration (FDA). April 27, 2012.
  2.  http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002581/human_med_001661.jsp&mid=WC0b01ac058001d124
  3.  http://ir.vivus.com/releasedetail.cfm?releaseid=775706
  4. Kyle, Jeffery; Brown, Dana (2013). “Avanafil for Erectile Dysfunction”Annals of Pharmacotherapy (Sage Publishing). doi:10.1177/1060028013501989. Retrieved 28 September 2013.
  5.  Yamada, K.; Matsuki, K.; Omori, K.; Kikkawa, K.; 2004, U.S. Patent 6,797,709
United States APPROVED 6656935 2012-04-27 EXPIRY 2020-09-13
United States                  7501409 2012-04-27             2023-05-05
  • • Hatzimouratidis, K., et al.: Drugs, 68, 231 (2008)
  • US7927623 4-20-2011 Tablets quickly disintegrated in oral cavity
    US2010179131 7-16-2010 Combination treatment for diabetes mellitus
    US2009215836 8-28-2009 Roflumilast for the Treatment of Pulmonary Hypertension
    US2008027037 1-32-2008 Cyclic compounds
US5242391 Oct 30, 1991 Sep 7, 1993 ALZA Corporation Urethral insert for treatment of erectile dysfunction
US5474535 Jul 19, 1993 Dec 12, 1995 Vivus, Inc. Dosage and inserter for treatment of erectile dysfunction
US5773020 Oct 28, 1997 Jun 30, 1998 Vivus, Inc. Treatment of erectile dysfunction
US6656935 Aug 10, 2001 Dec 2, 2003 Tanabe Seiyaku Co., Ltd. Aromatic nitrogen-containing 6-membered cyclic compounds

EXTRAS

A “phosphodiesterase type 5 inhibitor” or “PDE5 inhibitor” refers to an agent that blocks the degradative action of phosphodiesterase type 5 on cyclic GMP in the arterial wall smooth muscle within the lungs and in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. PDE5 inhibitors are used for the treatment of pulmonary hypertension and in the treatment of erectile dysfunction. Examples of PDE5 inhibitors include, without limitation, tadalafil, avanafil, lodenafil, mirodenafil, sildenafil citrate, vardenafil and udenafil and pharmaceutically acceptable salts thereof. In one aspect, the PDE5 inhibitor is tadalafil.

“Tadalafil” or “TAD” is described in U.S. Pat. Nos. 5,859,006 and 6,821,975. It refers to the chemical compound, (6R-trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione and has the following chemical formula:

Figure US20120269898A1-20121025-C00004

Tadalafil is currently marketed in pill form for treating erectile dysfunction (ED) under the trade name Cialis® and under the trade name Adcirca® for the treatment of PAH.

“Avanafil” refers to the chemical compound 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide, and its pharmaceutically acceptable salts. Avanafil is described in Limin M. et al., (2010) Expert Opin Investig Drugs, 19(11):1427-37. Avanafil has the following chemical formula:

Figure US20120269898A1-20121025-C00005

Avanafil is being developed for erectile dysfunction. Avanafil currently has no trademarked term associated with it but it is being developed by Vivus Inc.

“Lodenafil” refers to the chemical compound, bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate and has the following chemical formula:

Figure US20120269898A1-20121025-C00006

More information about lodenafil is available at Toque H A et al., (2008) European Journal of Pharmacology, 591(1-3):189-95. Lodenafil is manufactured by Cristália Produtos Químicose Farmacêuticos in Brazil and sold there under the brand-name Helleva®. It has undergone Phase III clinical trials, but is not yet approved for use in the United States by the U.S. FDA.

“Mirodenafil” refers to the chemical compound, 5-Ethyl-3,5-dihydro-2-[5-([4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl)-2-propoxyphenyl]-7-propyl-4H-pyrrolo[3,2-d]pyrimidin-4-one and has the following chemical formula:

Figure US20120269898A1-20121025-C00007

More information about mirodenafil can be found at Paick J S et al., (2008) The Journal of Sexual Medicine, 5 (11): 2672-80. Mirodenafil is not currently approved for use in the United States but clinical trials are being conducted.

“Sildenafil citrate,” marketed under the name Viagra®, is described in U.S. Pat. No. 5,250,534. It refers to 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine and has the following chemical formula:

Figure US20120269898A1-20121025-C00008

Sildenafil citrate, sold as Viagra®, Revatio® and under various other trade names, is indicated to treat erectile dysfunction and PAH.

“Vardenafil” refers to the chemical compound, 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 and has the following chemical formula:

Figure US20120269898A1-20121025-C00009

Vardenafil is described in U.S. Pat. Nos. 6,362,178 and 7,696,206. Vardenafil is marketed under the trade name Levitra® for treating erectile dysfunction.

“Udenafil” refers to the chemical compound, 3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide and has the following chemical formula:

Figure US20120269898A1-20121025-C00010

More information about udenafil can be found at Kouvelas D. et al., (2009) Curr Pharm Des, 15(30):3464-75. Udenafil is marketed under the trade name Zydena® but not approved for use in the United States.

 

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ANTHONY MELVIN CRASTO

THANKS AND REGARD’S

DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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