AVANAFIL

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

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

Molecular Formular: C23H26ClN7O3

Molecular Mass: 483.95064

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

INNOVATOR  —  VIVUS

APPROVED FDA  27/4/2-12

U 155… TREATMENT OF ERECTILE DYSFUNCTION

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:

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.

AVANAFIL

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 sildenafil, tadalafil 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:

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

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

………………………………………………………

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.

AVANAFIL

…………………………….

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
6. • Peterson CA. Hemodynamic effect of avanafil and glyceryl trinitrate coadministration. , Drugs Context , Volume 2013 , 2013 Feb 26
   • Gur S. The Effect of Intracavernosal Avanafil, a Newer Phosphodiesterase-5 Inhibitor, on Neonatal Type 2 Diabetic Rats With Erectile Dysfunction. , Urology , 2013 Dec 9
   • Hill JK. Avanafil for erectile dysfunction. , Ann Pharmacother , Volume 47 , Issue 10 , 2013 Oct
   • Sanford M. Avanafil: a review of its use in patients with erectile dysfunction. , Drugs Aging , Volume 30 , Issue 10 , 2013 Oct
   • Hellstrom WJ. PDE5 inhibitors: considerations for preference and long-term adherence. , Int J Clin Pract , Volume 67 , Issue 8 , 2013 Aug
   • Aversa A. An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. , Expert Opin Pharmacother , Volume 14 , Issue 10 , 2013 Jul
   • Oelke M. Phosphodiesterase inhibitors in clinical urology. , Expert Rev Clin Pharmacol , Volume 6 , Issue 3 , 2013 May
   • Kukreja RC. Sildenafil and cardioprotection. , Curr Pharm Des , Volume 19 , Issue 39 , 2013
   • Day WW. An open-label, long-term evaluation of the safety, efficacy and tolerability of avanafil in male patients with mild to severe erectile dysfunction. , Int J Clin Pract, Volume 67 , Issue 4 , 2013 Apr
   • Tang J. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. , Eur Urol , Volume 63 , Issue 5 , 2013 May

United States	APPROVED 6656935	2012-04-27	EXPIRY 2020-09-13
United States	7501409	2012-04-27	2023-05-05

• Faster-Working Erectile Dysfunction Drug?. CBS News. November 24, 2009.
• Vivus says men taking avanafil were more likely to be ready for sex within 15 minutes. The Gaea Times. January 11, 2010.
• “Avanafil is the New Player in The Erectile Dysfunction Field”. June 28, 2011.

• • 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

Update nov 2015

NEW PATENT     WO 2015177807

WO 2015177807

Suryakant Shivaji Pol; Nitin Sharadchandra Pradhan; Shashikant Balu Padwal; Vihar Raghunath Telange; Nitn Shankar Bondre

Wanbury ltd

The present invention relates to a novel compound of Formula (II), and its use in preparation of Avanafil, [Formula should be inserted here] wherein R is -OH, -CI or -OR¹ and R¹ is C₁ to C₃ alkyl group

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015177807&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

It having been developed and launched by VIVUS and JW Pharmaceutical, under license from Mitsubishi Tanabe Pharma, and Auxilium Pharmaceuticals, for treating ED.

A process for preparation of Avanafil was first disclosed in US 6,797,709 (depicted in Scheme I), wherein 4-chloro-5-ethoxycarbonyl-2-methylthio-pyrimidine is coupled with 3-chloro-4-methoxybenzylamine in presence of triethylamine to provide compound of Formula (A), which on oxidization provides a sulfonyl compound of Formula (B). Said compound of Formula (B) is reacted with L-prolinol and exert compound of Formula (C). The resulting compound of Formula (C) undergoes column chromatographic purification and crystallization, while further subjected to hydrolysis to obtain compound of Formula (D). The compound of Formula (D) is coupled with 2-aminomethylpyrimidine to obtain Avanafil of Formula (I). The final product obtained is purified by column chromatography. The need to purify the intermediate compound of Formula (C) and final product, by column chromatography makes this process cumbersome, time consuming and unviable for large scale production thereby contributing to main disadvantages of the process.

Scheme I

Formula (A)

m-CPBA/chloroform

Formula (C) Formula (B)

NaOH/DMSO

Formula (D) Formula (I)

CN 103254179, discloses a process for preparation of Avanafi, wherein 3-chloro-4-methoxybenzylhalide is coupled with cytosine to result compound of Formula (E), later on condensation with L-prolinol yields 4-[(3-chloro-4-methoxy benzyl)amino-2-(2-hydroxymethyl)-l -pyrrolinyl]pyrimidine of Formula (F). The compound of Formula (F) is then condensed with N-(2-pyrimidylmethyl)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme II

Scheme II

Formula (F) Formula (I)

CN 103254180 describes an alternate process for preparation of Avanafil of Formula (I), wherein a substitution reaction on 6-amino-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid, ethyl ester and 3-chloro-4-methoxybenzylchloride provides 6-(3-chloro-4-methoxybenzylamino)-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid, ethyl ester of Formula (G) which on condensation with L-prolinoI generates 6-(3-chloro-4-methoxybenzylamino)-l ,2-dihydropyrimidine-2-keto-5-carboxylic acid ethyl ester of Formula (H). The compound of Formula (H) is then hydrolysed and coupled with N-(2-pyrimidylmethyI)formamide to obtain Avanafil of Formula (I). Process is depicted in Scheme III

Scheme III

Formula (H) Formula (Γ)

In all the prior art discussed above, chiral compound L-prolinol is coupled in molecule in earlier steps of synthesis. This approach seems to be less feasible for large scale production; the insertion of L-prolinol in early stage may need to exert number of purifications for intermediates. Further the main shortcoming in such process is that the chirality of molecule is disturbed by inserting L-prolinol in early stages because there are number of operations in line in process to obtain the target compound.

CN 103483323, discloses a synthetic method for preparation of avanafil, wherein amidation of pyrimidine-5-carbonyl chlorides with 2-(aminomethyl)pyrimidine at temperature ranging from -10 to 5°C resulted an amide (intermediates A); which underwent condensation with 3-chloro-4-methoxybenzylamine at the temperature ranging from 0 -3°C to give 4-[(3-chloro-4-methoxybenzyl)amino]-5-

pyrimidinecarboxamides (intermediates B), which further on condensation with L-prolinol gave avanafil. The disadvantage of this process is the need to maintain the reaction temperature in range of – 10 to 5°C which adds up to cost of process and makes the process complicated. The process is depicted in Scheme IV.

Scheme IV

Intermediate (A)

wherein, R’ & R² are independently, hydrogen, halogen, alkoxy, alkoxyalkyl, cyno group, amino group

Hence, to overcome shortcomings of prior art the inventors of present invention have skillfully designed a process with novel intermediate which concomitantly result Avanafil compound of Formula (I), substantially free from impurities. Further this invention encompass L-proline in last stage of molecule in order to avoid the number of purifications of intermediate which relent the economic significances by taking into account yield of each stage.

Object of the invention

1. The main object of the invention is to provide a novel compound of Formula

(ID-

2. Another object of present invention is to provide a process for preparation of a novel compound of Formula (II).

3. Yet another object of present invention is to provide a process for preparation of Avanafil of Formula (I), in high yield and purity using a novel compound of Formula (II).

4. Yet another object of the present invention to provide simple, economic and industrially scalable process for the preparation of Avanafil o Formula (I).

Summary of the invention

According to an aspect of present invention, there is provided a novel compound of Formula (II).

Formula (II)

wherein R is -OH, -CI or -OR and R is Q to C₃ alkyl group

 

The invention will be specifically described below with reference to Examples but it should not be construed that the scope of the invention is limited thereto. Since the starting compound was produced by a modified method from that described in prior art, it will be described as Referential Example 1 to 3. Here synthesis routes of Referential Example 1 to 3 and Example 1 to 10 are illustrated below in Scheme (V).

Scheme (V)

Formula (I) Referential Examples

Referential Example 1 – Preparation of ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfanyl)pyrimidine-5-carboxylate

To 600ml of methylene dichloride was added l OOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500ml of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30°C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95% of HPLC purity.

Above reaction can also be carried out using ammonia or triethylamine in same reaction conditions and parameters, in place of sodium carbonate.

Referential Example 2 – Preparation of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid

To 600ml of methanol was added l OOg of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate (Referential Example 1) and an aqueous solution of sodium hydroxide (15g of NaOH in 140ml of water). The reaction mixture was heated to reflux temperature. After completion of reaction, the pH of mixture was adjusted to 1 -2 using concentrated hydrochloric acid followed by stirring the mixture for 1 hour at 10-15°C. The solid product obtained was filtered, washed sequentially with water and methanol, and dried overnight at 70-75°C to get 87g of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid.

Referential Example 3 – Preparation of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III)

To a mixture of 400ml of toluene and 0.5ml of dimethyl formamide was added 50g of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylic acid (Referential Example 2) and 70g of thionyl chloride, and the reaction mixture was refluxed for 2.5 hours. After completion of reaction, solvent was distilled under vacuum and the residue was stripped with toluene to obtain yellow solid mass. The solid mass thus obtained, was cooled to 15-20°C followed by addition of 1 75ml of methylene dichloride, 36. l g of 2-amino methyl pyrimidine mesylate and 35.55g of triaethylamine. The reaction mixture was stirred overnight at 25-30°C. After completion of reaction, methylene dichloride was distilled out to get residue. The residue was washed sequentially with 2.5% sodium carbonate solution and water. The residue was then treated with methanol to obtain 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III) having HPLC purity of more than 95% (yield: 80%)

Referential Example 4 – Preparation of 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)-l -pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide (Avanafil)

Step i)

To 200ml of dichloromethane was added lOg of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyI)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide and 6.5g of m-chloro per benzoic acid and the mixture was stirred for 1 hour at 25-30°C. After completion of reaction, the reaction mixture was washed with aqueous solution of sodium carbonate and water. The resulting dichloromethane layer comprising compound of Formula (IV) was taken to next step.

Step ii)

To the dichloromethane layer obtained in step i), was added 2.57g of triethylamine followed by slow addition of 125ml solution of L-prolinol in dichloromethane (2.46g of L-prolinol in 125ml of dichlromethane). The reaction mixture was maintained overnight. After completion of reaction, the reaction mixture was washed with water followed by evaporation of dichloromethane to obtain an oily mass. The oily mass thus obtained was treated with methanol to yield 8g of Avanafil.

Examples

Example 1 : Preparation of Compound of Formula (II) (wherein R is -OH)

Step i)

To 200ml of methylene dichloride was added lOg of 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxiamide of Formula (III) and 6.5g of m-chloro per benzoic acid and the mixture was stirred for 1 hour at 25-30°C. After completion of reaction, the reaction mixture was washed with aqueous solution of sodium carbonate and water. The resulting methylene dichloride layer comprising compound of Formula (IV) was taken to next step.

Step ii)

To the methylene dichloride layer comprising compound of Formula (IV) obtained in step i), was added 5g of triethylamine followed by slow addition of 125ml solution of L-proline in methylene dichloride (2.8g of L-proline in 125ml of methylene dichloride). The reaction mixture was maintained overnight. After completion of reaction, the reaction mixture was washed with water and 5% sodium carbonate solution, followed by evaporation of methylene dichloride to obtain an oily mass. The oily mass obtained was stripped with 50ml acetone to yield 9g of compound of Formula (II) having HPLC purity 98%.

Example 2: Preparation of Compound of Formula (II) (wherein R is -OC₂H₅)

To 100ml of ethanol was added 0.5ml of sulphuric acid and l Og of compound of Formula (II) obtained in example 1 , and the reaction mixture was maintained at reflux temperature till completion of reaction. The reaction mixture was then cooled to 25-30°C and the pH of reaction mixture was adjusted to 7-8 using sodium carbonate. Filter the reaction mixture and collect filtrate containing product. The ethanol in filtrate is completely distilled out to isolate 10.45g of esterified compound of Formula (II).

Example 3 : Preparation of Compound of Formula (II) (wherein R is -CI)

To a mixture of 400ml of toluene and 0.5ml of dimethylformamide was added 50g of compound of Formula (II) obtained in example 1 , and 70g of thionyl chloride. The reaction mixture was refluxed for 2.5 hours. After completion of reaction, solvent was distilled under vacuum and the residue was stripped with toluene to obtain 50.5g of oily carboxylic acid chloride compound of Formula (II).

Example 4: Preparation of Avanafil of Formula (I)

In an inert atmosphere, a solution of 30g of compound of Formula (II) obtained in example 1 or 2, in 150 ml of tetrahydrofuran was dropwise added to 180ml of suspension of 1.0M lithium aluminium hydride solution in tetrahydrofuran, The reaction mixture was refluxed for 5 hours. After completion of reaction, the mixture was cooled in ice-bath and saturated aqueous solution of sodium sulfate was added to decompose excess of lithium aluminium hydride. The mixture was then diluted with 200ml of methylene dichloride and thus formed organic layer was separated. The organic layer was washed with water (3 ^χ 100 ml), dried over MgS04 and concentrated to collect crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 22.8g of Avanafil of Formula (I) having HPLC purity of 99.20%.

Example 5 : Preparation of Avanafil of Formula (I)

To a mixture of 1.3g sodium borohydride, 1 ml methanesulfonic acid and 50ml ethanol was added l Og of compound of Formula (II) obtained in example 1 or 2, and the mixture was stirred at 25-30°C for 5 hours. After completion of reaction, 100ml water was added and the mixture was extracted with 1 00ml methylene dichloride (50ml X 2). The methylene dichloride layer obtained was evaporated under reduced pressure to get an oily mass. The oily mass was stripped with ethyl acetate at 45- 50°C. To the oily residue formed was added 50ml of ethyl acetate and the mixture was cooled to 0-5°C. The solid obtained was filtered, washed with ethyl acetate and dried to yield crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 7g of Avanafil of Formula (I) having HPLC purity of 99%.

Example 6 to Example 8

The procedure is carried out as in example 5 except for instead of methanesulfonic acid other reducing agents are used in combination with sodium borohydride. The results are given in Table I

Table I

Example 9: Preparation of Avanafil of Formula (I)

To 100ml of ethanol was added 0.5ml of sulphuric acid and l Og of compound of Formula (II) obtained in example 1 , and the reaction mixture was maintained at reflux temperature till completion of reaction. The reaction mixture was then cooled to 25-30°C and the pH of reaction mixture was adjusted to 7-8 using sodium carbonate. Filter the reaction mixture and collect filterate containing product. To the fi Iterate was added 1.2g of sodium borohydride and 2.6g of lithium bromide, and the mixture was stirred for 5 hours. After complete conversion of ester to final product, l OOml water was added and the mixture was extracted with 100ml methylene dichloride (50ml X 2). The methylene dichloride layer obtained was evaporated under reduced pressure to get an oily mass. The oily mass was stripped with 25ml ethyl acetate at 45-50°C. To the oily residue formed was added 50ml of ethyl acetate and the mixture was cooled to 0-5°C. The solid obtained was filtered, washed with ethyl acetate and dried to yield crude Avanafil of Formula (I) which was subjected to purification using methanol as solvent to yield 7.5g of Avanafil of Formula (I) having HPLC purity of 99%.

Example 10: Preparation of Avanafil of Formula (I) from Compound of Formula (II) (wherein R is -CI)

To a mixture of 400ml of tetrahydrofuran and 50g of carboxylic acid chloride compound of Formula (II) obtained in example 3, was added 12g sodium borohydride at 0-5°C. After completion of reaction, water was added to reaction mixture to decompose excess of sodium borohydride present. The reaction mixture was then concentrated and a solution of 30g of potassium hydroxide in 200 ml of water was added. The mixture was heated to 60-70°C and maintained for 15-18 hours. The mixture was then cooled to 25-30°C and 500 ml of methylene dichloride was added. The organic layer thus formed, was separated and evaporated to yield crude Avanafil

of Formula (I) which was then subjected to purification using methanol as solvent to obtain 40g of Avanafil of Formula (I) having HPLC purity of 99.01%.

 

Mr. K. Chandran
		Wholetime Director & Vice Chairman

 

 

 

 

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:

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:

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:

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:

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:

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:

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:

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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