SILDENAFIL

1-[4-ethoxy-3-(6,7-dihydro-1-methyl-
7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)
phenylsulfonyl]-4-methylpiperazine

CAS NO  139755-83-2
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer.^[1]It acts by inhibiting cGMP-specific phosphodiesterase type 5 (PDE5), an enzyme that promotes degradation of cGMP, which regulates blood flow in the penis. Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra)

Erectile dysfunction (or ED), also called male impotence, describes a mans inability to achieve and maintain an erection sufficient for mutually satisfactory sexual intercourse with his partner. By itself, ED is not a disease but more of a signal that something else may be a problem.

Viagra works best if taken 30-60 minutes before sexual activity. Only 1 tablet should be taken per day. It should be taken on an empty stomach. Increasing the dosage beyond the recommended amounts will not improve the response and will only result in greater side effects.

Sildenafil is a vasoactive agent used to treat erectile dysfunction and reduce
symptoms in patients with pulmonary arterial hypertension (PAH).

Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown
via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high
concentrations in the corpus cavernosum, erectile tissue of the penis.

It is also found in the retina and vascular endothelium.

Increased cGMP results in vasodilation which facilitates generation and
maintenance of an erection. The vasodilatory effects of sildenafil also help reduce
symptoms of PAH.
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names,
is adrug used to treat erectile dysfunction and pulmonary arterial
hypertension (PAH).
It was originally developed by British scientists and then brought to market by the
US-basedpharmaceutical company Pfizer. 

It acts by inhibiting cGMP-specific phosphodiesterase type 5, an enzyme that promotes degradation of cGMP, which regulates blood flow in thepenis.

Since becoming available in 1998, sildenafil has been the prime treatment for erectile dysfunction; its primary competitors on the market are tadalafil (Cialis) and vardenafil (Levitra).

VIAGRA® (sildenafil citrate) , an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. VIAGRA (sildenafil citrate) is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

Target is cyclic guanosine monophosphate phosphodiesterase type 5 receptor.

Fluforma is a company which found the genome explorations and target identification
through affymetrix microarrays.

High throughput functional assays of Si Rna’s inhibit the expression of target,
chromatographic techniques, spectrophotometric methods, adsorptive
stripping voltametry.

Gingel et.al showed that a 50mg dose given daily for 28 days consecutively
improved errections in almost 90% of patients.

Structural validation techniques are NMR technique, Infrared spectrum, HPLC, Mass spectroscopy and Liquid chromatography.

Viagra

The chemical name of sildenafil is 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1- methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and its formula is C22H30N6O4S. The melting point of sildenafil is 189-190oC. Its solubility is 3.5 mg/mL in water.
The 1H NMR data of sildenafil is given below. The abbreviations used are s for singlet, d for doublet, t for triplet and q for quartet. The chemical shifts are given in ppm (parts per million) and are followed by the number of Hydrogens the peaks account for: 1H NMR data: peak (ppm) integration multiplicity 0.94 3H t 1.32 3H t 2.15 3H s 2.35 4H broad s 2.76 2H t 2.88 4H broad s 4.14 3H s 4.18 2H q 7.36 1H d 7.80 2H multiplet 12.16 1H broad s
Viagra aims at inhibiting the enzyme phosphodiesterase PDE5. It must therefore have a structure that is similar in some places to the substrate. However, there are many other constraints as there are several different types of PDE enzymes which are found in different parts of the body. Of the 7 types of PDE, three selectively hydrolyse cGMP relative to cAMP. PDE5 itself can be found in several parts of the body : the lungs, platelets and various forms of smooth muscle. Selectivety was a very important factor in the research for an inhibitor of PDE5. The research on a molecule to inhibit PDE type 5 started with the molecule Zaprinast (1) which is shown on the right. The research established that derivatives of pyrazolo[4,3-d]pyrimidin-7-one (2) gave more potent cGMP PDE5 inhibition. The studies carried out compared many molecules by changing the substituents on them and comparing the inhibitory data of these molecules. To establish the selectivity of the compound, the compounds were also screened against the other widespread cGMP enzymes, PDE1 which was isolated from rat liver and PDE3 which was isolated from rat platelet. Further studies showed that sildenafil was the best PDE5 inhibitor. The different functional groups on the molecule were established by comparing the affinities of the molecules to the different PDE enzymes and establishing the selectivity of each compound made. Of course, high selectivity for PDE type 5 was looked for. Viagra mimics the guanosine base of cGMP and the extension of 3-substituent fills a space in the enzyme active site occupied by ribose. Substituents on the 5'-position of the phenyl ring reproduce the role of the phosphate bonding. To improve the solubility of the drug, polar substituents were added which gave compounds with a lower lipophilicity. This was found to also increase the enzyme affinity. Sidenafil gave an excellent combination of enzyme inhibitory potency, selectivity, solubility and in vivo characteristics.
It is interesting to compare the structure of sidenafil with that of cGMP (cyclic guanosine monophosphate), which is the molecule that usually interacts with PDE5. The drug that was being developed by the researchers had to have some similarity so that it could bind to the active site of the enzyme, PDE5. The 2 dimensional structure of cGMP is given above the 3 dimensional picture, however the latter can be used to view the molecule in 2D as well, with any orientation of the molecule. The first figure also shows that cGMP and pyrazolo[4,3-d]pyrimidin-7-one, which is one of the parent molecules of sildenafil, have a similar size, shape and dipole moment. These were characteristics that were looked for in a molecule that would inhibit PDE5. The following molecule is cGMP :

Sildenafil is the active ingredient in Viagra ™ and it is chemically designated as 5-[2- ethoxy-5 -(4-methyl)piperazine- 1 -yl-sulfonyl)phenyl]- 1 -methyl-3-n-propyl- 1 ,6-dihydro- 7H-pyrazolo[4,3-d]pyrimidin-7-one, and the following chemical structure V:

                                                         V

Sildenafil is originally disclosed in US Patent No. 5,250,534 and it has been found to be particularly useful in the treatment of inter-alia male erectile dysfunction. Multi step syntheses for the production of Sildenafil are disclosed in US'534 with a yield of 27%.

An improved process for its preparation is described in a later application i.e. US Patent No. 5,955,611 which consisting the preparation of 5-chlorosulfonyl-2-ethoxybenzoic acid and converting it into 2-ethoxy-5-(4-methylpiperazin-l-ylsulfonayl)benzoic acid. The acid is then condensed with 4-amino-l-methyl-3-n-propylpyrazole-5-carboxyamide in the presence of N,N'-carbonyldiimidazole, and the resulting 4-[2-ethoxy-5-(4- methylpiperzin-l-ylsulfonyl)benzamido]-l-methyl-3-n-propylpyrazolo-5-carboxyamide is cyclized in an alkaline, neutral or acid solution to yield Sildenafil with about 47% yield.

Patent application number WO 2001/22918 describes the process for the preparation of Sildenafil wherein the process involves the reaction step between 2-ethoxy-5-(4-methyl- piperazine- 1 -sulfonyl)benzaldehyde and 4-amino- 1 -methyl-S-n-propyl-pyrazole-S- carboxamide to form an intermediate which is further cyclised to form Sildenafil.

Patents/ patent applications US6204383, US20030069422, US20030144530, US 20040106796, US 20040110948, EP 0812845, EP 1002798, EP 1077214, WO 01/19827, WO 04/31134 also discloses several processes for the preparation of Sildenafil citrate.

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil citrate has most recently been utilized as the basis for an oral therapy for erectile dysfunction and has been marketed by Pfizer Labs under the trademark Viagra^®. Publications relating to benign visual side-effects (e.g., blue-shift in vision, light-sensitivity, and blurring noted to occur in some patients) of sildenafil prompted the FDA to insist on product insert warnings.

Sexual dysfunction

The primary indication of sildenafil is treatment of erectile dysfunction (inability to sustain a satisfactory erection to complete intercourse). Its use is now standard treatment for erectile dysfunction in all settings, including diabetes.^[2]

People on antidepressants may experience sexual dysfunction, either as a result of their illness or as a result of their treatment. A 2003 study showed that sildenafil improved sexual function in men in this situation.^[3] Following up reports from 1999,^[4] the same researchers found that sildenafil improved sexual function in female patients on antidepressants as well.^[5]

Pulmonary hypertension

As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This, in turn, reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the United States Food and Drug Administration (FDA), and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.^[6]

The synthesis of sildenafil citrate was first reported in the Bioorganic & Medicinal Chemistry Letters, Vol 6, pp. 1819, 1824, 1996. The reaction scheme is reproduced below. Sildenafil was reported in this journal as "a potent and selective inhibitor of type 5 PDE with utility for the treatment of male erectile dysfunction". The first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product. This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5'-position of the phenyl ring. This can then couple with an amine to give sildenafil (7). The yield of each step is given on the reaction scheme.  This is the original synthesis which was reported in the literature when the molecule was first synthesised. A variant of the synthesis was published but the changes it involved only consisted in the change of a few reactants, and no major changes were reported. This synthesis appeared in the January 1999 issue of Chemistry in Britain. This journal only reported the original discovery synthesis and said that the synthesis used commercially had not been published. The drug is commercially manufactured by an alternative route. The reaction scheme is described in the patent which was published on 17 decembre 1997. However, the synthesis used in the commercial manufacture could be different to this. The patent was filed by the Pfizer Research and Development Company. The scheme is reproduced below. The synthesis was described in a lot of detail, including the solvents that were the best to use, however, these details have not been reproduced here. These and further details about the synthesis can be found on the original patent document. The reaction pathway is explained in more detail below. Compound 2 can be prepared by the chlorosulphonation of 2-ethoxybenzoic acid (1). The conversion of compound 2 to compound 4 is achieved by N-sulphonation of 1-methylpiperazine and may be conducted in a one or two step procedure. Coupling of compound 4 with compound 6 can be achieved by any of the known amide bond-forming reactions. The aminopyrazole (6) is obtainable by the conventional reduction of the corresponding nitropyrazole (5). The resulting solution of compound 6 may be used directly after filtration in the coupling reaction with compound 4. The cyclisation of compound 7 to give sildenafil has been achieved in yields up to 95%. Thus the overall yield of sildenafil based on compound 1 as a starting material, depending on whether the one or two step sulphonylation procedure is used can be as high as 51.7% or 47.8% respectively. This compares favourably with the first synthesis in which the overall yield is 27.6%. The cyclisation of compound 7 to sildenafil can be conducted under neutral or acidic conditions. Under neutral conditions, compound 7 is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or mechanical water removal system. Under acidic conditions, the reaction is carried out with a prolic acid or Lewis acid optionally in the presence of a solvent. The reagents employed in the reactions can vary, but the following are among the ones recommended by the submitters of the patent: The first step is the chlorosulphonylation of 2-ethoxybenzoic acid. This can be achieved by reacting 1 equivalent mole of thionyl chloride with 4 equivalent mole of chlorosulphonic acid. Addition of 1-methylpiperazine to an aqueous suspension of compound 2 is a suitable reaction to obtain compound 4 in one step. The carboxylic function of compound 4 can be activated using a 5% excess of N,N'-carbonyldiimidazole in ethyl acetate. This intermediate can then be reacted with imidazolide and compound 6. Compound 6 is obtainable by reduction of the corresponding nitropyrazole 5 for example by using palladium catalysed hydrogenation in ethyl acetate. Compound 7 is then cyclised to complete the reaction scheme and give sildenafil. Information about the synthesis used to manufatcure Viagra was not available, and the two presented above are only the ones which were published. It is not surprising that the commercial manufacture of the drug is by a pathway that is not published. ........................................................ SYNTHESIS EP2024369

SCHEME2

Example 1

Preparation of 2- hydroxy-5-(4 methyl)-l-piperazinyl sulphonyl) benzoic acid Step-1: Preparation of 5-Chlorosulfonyl-2-hydroxy benzoic acid

To the chilled chlorosulfonic acid (1012 g), salicylic acid (200 g) was added at 0-5⁰C over a period of 1 hour 40 min. The temperature of the reaction mixture was maintained at 20-25⁰C for 2 hrs. Then thionyl chloride (172.4 g) was added over a period of 15 min and maintained for 12 hrs. The product formed was poured onto ice and maintained for lhr. The product was filtered and washed with DM water to get 5-Chlorosulfonyl-2- hydroxy benzoic acid.

Step-2: Preparation of 2-hydroxy-5-(4-methyI)-l-piperazinylsulphonyl)benzoic acid

5-Chlorosulfonyl-2-hydroxy benzoic acid (40Og) obtained in step 1 was dissolved in acetone (1200 ml) and cooled to 5-10⁰C. To this clear solution N-methyl piperazine (254 g) was added and maintained for 2 hrs. The product formed was filtered, washed with water and purified in methanol to get 308 g of the titled compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 2.78 (3H, s), 3.17 (8H, brs), 6.85(1H, d, J = 8.7),

7.52 - 7.56 (IH, dd, J=8.7, 2.7), 7.95 (IH, d, J = 2.7)

¹³C-NMR (75 MHz in DMSO-d₆): δ 41.98, 43.36, 51.60, 117.58, 118.33, 119.46,

130.28, 132.01, 167.63, 170.35.

Melting point: 268-272⁰C

Purity by HPLC: 99.4% Example 2

Preparation of 4-[2-hydroxy-5-(4-methyI-l-piperazinyIsulphonyl)benzamido]-l- methyl-3-n-propyl-lH-pyrazole-5-carboxamide

2-Hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzoic acid (10Og) was dissolved in dichloromethane (500 ml) and triethylamine (50 ml) followed by distillation to get residual mass. The residual mass was dissolved in dichloromethane (1500ml) followed by the addition of 1,3-dicyclohexylcarbodiimide (75.6 g) and 1-hydroxybenzotriazole (45g). The reaction mixture was stirred at 27-28⁰C and then 4-amino-l-methyl-3-n-propyl- pyrazole-5-carboxamide (60.6 g) was added. The reaction mixture was heated to reflux temperature and maintained for 3 hours. Filtered the undissolved material at hot and washed the cake with dichloromethane (200ml). The filtrate was distilled out completely to get residue. Dissloved the residue in methanol (300ml) at 4O⁰C and then cooled the mass to 27-28⁰C and stirred overnight. Further, cooled the mass to 5-7⁰C and stirred for lhr. Filtered the product and washed the cake with chilled methanol (100ml) and dried to get 130 g of title compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.87 (3H, t, J = 7.5), 1.53-1.60 (2H, m), 2.39- 2.46(5H, m), 2.72 (4H, brs), 2.96 (4H, brs), 3.17 (3H, s), 3.91 (3H, s), 6.93 (H, d, J = 8.7), 7.57-7.61 (H, dd, J=8.7 & 2.1), NH2-(2H, brs, J =7.69 & 7.72), 8.15 (IH, d, J=2.1) 11.5 (OH, br).

¹³C-NMR (75 MHz in DMSO-(I₆): 613.80, 21.37, 27.45, 44.05, 44.75, 48.60, 52.87, 116.37, 118.06, 119.67, 120.03, 130.64, 132.17, 132.38, 146.16, 160.83, 166.33, 166.89.

Purity by HPLC: 97.5%

Example 3

Preparation of 5-[2-hydroxy-5-(4-methylpiperazinyl-l-yl-sulphonyl)phenyl]-l- methyl -3-n- propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one Sodium hydroxide (34 g) was added into diethylene glycol (780ml) and then heated to 110-115⁰C. 4-[2-hydroxy-5-(4-methyl-l-piperazinylsulphonyl)benzamido)-l-methyl-3-n- propyl-lH-pyrazole-5-carboxamide (130 g) obtained from example 2 was added to the above reaction mixture. The reaction mixture was maintained at 125-13O⁰C for 4-6 hrs. The reaction mixture was cooled to room temperature and then DM water (1300ml) was added slowly over 20min at 25⁰C and maintained at this temperature for 1 hour. Filtered the mass and filtrate pH was adjusted to 6.5-7.5 with dilute hydrochloric acid at room temperature and stirred at room temperature for 2-3hrs. Product was filtered and slurried the cake with excess DM Water followed by purification in methanol to get 91 g of titled compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.96 (3H, t, J=7.2), 1.71-1.83 (2H, m), 2.41 (3H, s), 2.78-2.83 (6H, m), 2.99 (4H, brs), 4.15 (3H₃ s), 6.93 (IH, d, J=8.7), 7.54-7.57 (IH, dd, J=8.7, 2.1), 8.47 (lH, d, J=2.1).

¹³C-NMR (75MHz in DMSO-d₆): 513.84, 21.52, 27.20, 37.80, 43.94, 44.72,- 52.80, 115.97, 119.82, 120.19, 124.48, 128.71, 131.13, 136.46, 143.82, 151.26, 154.05, 167.24.

Purity by HPLC: 97.8%

Example 4

Preparation of 5-[2-ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyI)phenyl]- l-methyI-3n-propyI-l,6-dihydro-7H-pyrazolo-[4,3-d]pyrimidin-7-one

5-[2-hydroxy-5-(4-methylpiperazinyl-l -yl-sulphonyl)phenyl]- 1 -methyl-3 -n- propyl- 1 ,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (90 g) obtained from example 3 was dissolved in dichloromethane (360 ml) and added triethyl amine (41 ml) at room temperature and stirred for 10 min. The reaction mixture was cooled to 0-5⁰C and followed by the addition of ethyl chloro formate (24ml) over 30 min under nitrogen atmosphere. The temperature of the reaction was raised slowly to 28-3O⁰C and maintained for 24 hrs. The reaction mixture was cooled to 0-5⁰C and kept it for 1 hr. The product formed was filtered, washed with dichloromethane, dried and purified from methanol (270ml) to obtain 81 g of the title compound.

NMR Data:

¹H-NMR (300 MHz in DMSO-d₆): δ 0.92 (3H, t, J=7.2), 1.17 (3H, t, J=7.2), 1.68-1.75 (2H, m), 2.16 (3H, s), 3.99 (4H, br), 2.73 (2H, t, J=7.0), 4.12-4.19 (2H, t, J=6.9), 4.15 (3H, s), 7.71 (IH, d, J = 8.7), 7.93-7.97 (IH, dd, J=8.7 & 2.1), 8.01 (IH, d, J=2.0)

¹³C-NMR (75 MHz in DMSO-d₆): 513.47, 13.80, 21.57, 27.03, 37.90, 45.72, 53.49, 65.12, 124.51, 127.65, 130.14, 130.61, 132.82, 137.30, 144.96, 146.51, 151.38, 151.66, 154.36.

Purity by HPLC: 98.6%

Example 5

Preparation of 5-[2-ethoxy-5-(4-methyl piperazine-l-ylsulfonyl)phenyl]-l-methyl-3- n-propyl-1 ,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (Sildenafil base)

5-[2-Ethoxycarbonyloxy-5-(4-methylpiperazin-l-yl-sulfonyl)phenyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (50g) was dissolved in ethanol (750ml) in an autoclave and then added dicyclohexylcarbodimide (29.8g). The reaction temperature was raised to HO⁰C with internal pressure of 1.8-4.0 kg/cm and maintained for 6 hours followed by cooling to room temperature. The solvent was distilled off to get the crude Sildenafil base. The base thus obtained was dissolved in dichloromethane (380ml), filtered and filtrate was distilled out completely to get solid material, which is again dissolved in a mixture dichloromethane and isopropyl ether. The crude obtained was recrystallized from ethanol (260ml) to obtain 17.4gm of pure Sildenafil base.

Purity by HPLC: 99.77% Example 6

Preparation of 5-[2-Ethoxy-5-(4-methylpiperazine-l-yI-sulfonyl)phenyl]-l-methyl- 3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one citrate (Sildenafil Citrate)

Sildenafil base (50 g) was dissolved in acetone (850 ml) at 55⁰C and then slowly added citric acid solution (20 g in 100 ml acetone) over 45 min and maintain the reaction mixture for about 30 min. The reaction mixture was cooled, filtered and dried to get 65 g of Sildenafil citrate.

Purity by HPLC: 99.85%

Chemical synthesis

The preparation steps for synthesis of sildenafil are as follows:^[45]

1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate
2. Hydrolysis with aqueous NaOH to free acid
3. Nitration with oleum/fuming nitric acid
4. Carboxamide formation with refluxing thionyl chloride/NH₄OH
5. Reduction of nitro group to amino
6. Acylation with 2-ethoxybenzoyl chloride
7. Cyclization
8. Sulfonation to the chlorosulfonyl derivative
9. Condensation with 1-methylpiperazine.

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Patent issues and expirations

European Union

Pfizer's patent on sildenafil citrate expired in some member countries of the EU, Austria, Denmark, France, Germany, Ireland, Italy, The Netherlands, Spain, Sweden, United Kingdom as well as Switzerland on 21 June 2013.^[60][61][62] A UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.^[63][64]

United States

In 1992 Pfizer filed a patent covering the substance sildenafil and its use to treat cardiovascular diseases.^[65] This patent was published in 1993 and expired in 2012. In 1994 Pfizer filed a patent covering the use of sildenafil to treat erectile dysfunction.^[66] This patent was published in 2002 and will expire in 2019. Teva sued to have the latter patent invalidated, but Pfizer prevailed in an August 2011 federal district court case.^[67]

The patent on Revatio (indicated for pulmonary arterial hypertension rather than erectile dysfunction) expired in late 2012. Generic versions of this low-dose form of sildenafil have been available in the U.S. from a number of manufacturers including Greenstone, Mylan and Watson, since early 2013.^[68] There is no legal barrier to doctors prescribing this form of sildenafil "off label" for erectile dysfunction, although the dosage typically required for treating ED requires patients to take multiple pills.

Canada

In Canada, Pfizer's patent 2,324,324 for Revatio (sildenafil used to treat pulmonary hypertension) was found invalid by the Federal Court in June 2010, on an application by Ratiopharm Inc.^[69][70]

On November 8, 2012 the Supreme Court of Canada ruled that Pfizer's patent 2,163,446 on Viagra was invalid from the beginning because the company did not provide full disclosure in its application. The decision, Teva Canada Ltd. v. Pfizer Canada Inc., pointed to section 27(3)(b) of The Patent Act which requires that disclosure must include sufficient information "to enable any person skilled in the art or science to which it pertains" to produce it. It added further: "As a matter of policy and sound statutory interpretation, patentees cannot be allowed to 'game' the system in this way. This, in my view, is the key issue in this appeal."^[71]

Teva Canada launched Novo-Sildenafil, a generic version of Viagra, on the day the Supreme Court of Canada released its decision.^[72][73][74] To remain competitive, Pfizer then reduced the price of Viagra in Canada.^[75] However, on November 9, 2012, Pfizer filed a motion for a re-hearing of the appeal in the Supreme Court of Canada,^[76] on the grounds that the court accidentally exceeded its jurisdiction by voiding the patent.^[77] Finally, on April 22, 2013, The Supreme Court of Canada invalidated Pfizer's patent altogether.^[78]

India

Manufacture and sale of sildenafil citrate drugs known as "generic viagra" is common in India, where Pfizer's patent claim does not apply. Trade names include Kamagra (Ajanta Pharma), Silagra (Cipla), Edegra (Sun Pharmaceutical), Penegra (Zydus Cadila), and Zenegra (Alkem Laboratories).

China

Manufacture and sale of sildenafil citrate drugs known as "generic viagra" is common in China, where Pfizer's patent claim is not widely enforced.

Other countries

Egypt approved Viagra for sale in 2002, but soon afterwards allowed local companies to produce generic versions of the drug, citing the interests of poor people who would not be able to afford Pfizer's price.^[79]

Pfizer's patent on sildenafil citrate expired in Brazil in 2010.^[80]

References

1. ^ Jump up to:^a b Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (June 1996). "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction". Int. J. Impot. Res. 8 (2): 47–52.PMID 8858389.
2. Jump up^ Vardi M, Nini A (2007). "Phosphodiesterase inhibitors for erectile dysfunction in patients with diabetes mellitus". In Vardi, Moshe. Cochrane Database Syst Rev (1): CD002187.doi:10.1002/14651858.CD002187.pub3. PMID 17253475.
3. Jump up^ Nurnberg HG, Hensley PL, Gelenberg AJ, Fava M, Lauriello J, Paine S (January 2003)."Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial". JAMA 289 (1): 56–64. doi:10.1001/jama.289.1.56. PMID 12503977.
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26. Jump up^ Sildenafil Will Not Affect Libido - Fact!
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32. Jump up^ Teri Thompson, Christian Red, Michael O'Keefffe, and Nathaniel Vinton (10 June 2008)."Source: Roger Clemens, host of athletes pop Viagra to help onfield performance". Daily News (Daily News). Retrieved 2009-02-10.
33. Jump up^ Busbee J (2012-11-28). "Bears’ Brandon Marshall says some NFL players use Viagra … ON THE FIELD". Yahoo! Sports. Retrieved 2012-11-28.
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38. Jump up^ FDA letter to Libidus distributor
39. Jump up^ FDA Warns Consumers About Dangerous Ingredients in "Dietary Supplements" Promoted for Sexual Enhancement
40. Jump up^ Hidden Risks of Erectile Dysfunction "Treatments" Sold Online
41. Jump up^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1552–1553.http://www.biomedicalpublications.com/dt9.pdf
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52. Jump up^ Devine, Amy (September 29, 2008). "Chemists plan to sell Viagra on the internet". Daily Record. Retrieved 2012-04-30.
53. Jump up^ "Urban Dictionary: Vitamin V". Urban Dictionary. January 16, 2009. Retrieved 2013-12-27.
54. Jump up^ Keith A (2000). "The economics of Viagra". Health Aff (Millwood) 19 (2): 147–57.doi:10.1377/hlthaff.19.2.147. PMID 10718028.
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57. Jump up^ Berenson, Alex (December 4, 2005). "Sales of Impotence Drugs Fall, Defying Expectations". The New York Times. Retrieved 2013-12-27.
58. Jump up^ "Over-the-counter Viagra piloted". BBC News. BBC News. 11 February 2007. Retrieved 2009-02-10.
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60. Jump up^ "Actavis Launches Generic Viagra in Europe as Patents Expire". Retrieved 2013-10-25.
61. Jump up^ Jim Edwards (October 21, 2009). "What Will Happen When Viagra Goes Generic?". AccessRx.com. Retrieved 2013-12-27.
62. Jump up^ "Is Viagra about to lose its pulling power in the UK?". The Guardian. Retrieved 13 June 2013.
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External links

• 
  Official Viagra Website
• Official Viagra UK Website
• Official Revatio Website
• prescribing information for Viagra and prescribing information for Revatio from Pfizer
• FDA Information
• MedlinePLUS information, including side effects
• U.S. National Library of Medicine: Drug Information Portal – Sildenafil
• Viagra bound to proteins in the PDB
• Viagra at The Periodic Table of Videos (University of Nottingham)

Lodenafil Carbonate … an Erectile Dysfunction Drug in Phase III « New Drug Approvals

Lodenafil Carbonate … an Erectile Dysfunction Drug in Phase III « New Drug Approvals:



'via Blog this'

Mirodenafil 米罗那非 标准品 ………..An erectogenic agent.

Mirodenafil, 米罗那非 标准品

SYNTHESIS WILL BE UPDATED SOON

SK-3530

UNII-504G362H0H

862189-96-6 DIHYDROCHLORIDE
862189-95-5 (free base)

FORMULA	C26H37N5O5S
MOL. MASS	531.666 g/mol

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

5-ethyl-2-f-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-phenylg -7-propoxypropyl-3,5-dihydropyrrolo-[3,2-d]-pyrimidin-4-one

5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one 

2-(5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;

Launched – 2007

In2Gen (Originator)
SK Chemicals (Originator)

Treatment of
Treatment of Erectile Dysfunction , hypertention

Mirodenafil belongs to a class of drugs called PDE5 inhibitors, which many other erectile dysfunction drugs such as sildenafil, tadalafil, andvardenafil also belong to. It was developed by SK Chemicals Life Science and is marketed under the trade name of Mvix tab which comes in different doses (50 mg, 100 mg).

Mirodenafil is also available under the name of Mvix S ODF 50 mg as an orally dissolving film (ODF) which dissolves on the tongue without water. It is the first licensed medicine for the treatment of erectile dysfunction as a dosage form of film.

Mirodenafil is a newly developed oral phosphodiesterase type 5 inhibitor, currently under investigation as a treatment for erectile dysfunction (ED).

MIRODENAFIL米罗那非 标准品

Mirodenafil hydrochloride is a high selective PDE5 inhibitor commercialized by SK Chemicals which had been in early clinical development for the treatment of erectile dysfunction (ED). Early clinical studies had also been ongoing for the treatment of hypertension in patients taking amlodipine; however, no recent development has been reported for this research. The development of compound started in 1998 jointly by SK Chemicals and a bio-venture In2Gen.

Several clinical trials were conducted,[1][2][3] but mirodenafil has not been approved for use in the United States by the U.S. Food and Drug Administration.

CLINICAL STUDIES

http://clinicaltrials.gov/search/intervention=Mirodenafil

Mirodenafil dihydrochloride CAS No: 862189-96-6 Synonyms: 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 hydrochloride Chemical Formula: C26H39Cl2N5O5S Molecular Weight: 604.59

The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs.

 European patent applications EP-A-0463756 and EP-A-0526004 disclose certain pyrazolo 4,3-dpyrimidin-7-ones as cGMP PDE inhibitors, useful in the treatment of cardiovascular disorders such as angina, hypertension and heart failure. International application WO 94/28902 discloses their use for the treatment of impotence. 0017The present inventors have recently disclosed a series of pyrazolo4,3-dpyrimidin-7-one derivatives as PDE V inhibitors (Appln. No. KR 98-60436 and KR 99-7580). Herein a new series of pyrrolo4,33,2d-pyrimidin-74-one derivatives are prepared as PDE V inhibitors

Korean Patent No. 358083 discloses pyrrolopyrimidinone derivatives having good inhibition activity against PDE-5, a method of its preparation thereof, an intermediate compound used to prepare the same and their use for prevention and treatment of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive pulmonary disease, benign prostatic hypertrophy and lower urinary tract diseases.

Of the pyrrolopyrimidinone derivatives disclosed in Korean Patent No. 358083, 5-ethyl-2-{5-[4- (2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-l-3,5-dihydro-4 H-pyrrolo[3,2-d]pyrimidin-4-one (hereinafter, “SK-3530″) represented by the following formula (1 ) is an excellent selective inhibitor PDE-5 over other PDEs and is under clinical trial for the treatment of erectile dysfunction after passing through the preclinical stage.

The dihydrochloride salt (2HCI) of SK-3530 has been under investigation through the preclinical and clinical stages.

The SK-3530 dihydrochloride salt has good solubility and can be easily stabilized for pharmaceutical preparation. But, it has the following drawbacks.

First, because the SK-3530 dihydrochloride salt is hygroscopic, it easily absorbs moisture from the atmosphere and becomes discolored when the moisture content is high. And, due to the hygroscopic property, an anhydrous solvent condition and a dry air condition have to be provided to obtain a stable product. Second, the SK-3530 dihydrochloride salt should be kept at a temperature lower than room temperature because it does not show enough stability at room temperature. In particular, the SK-3530 dihydrochloride salt is labile to heat or light, and thus any prolonged exposure to heat or light results in various impurities.

Third, the SK-3530 dihydrochloride salt could corrode the punch during tablet ting due to its somewhat corrosive properties. This is because the SK-3530 dihydrochloride salt is a simple amorphous salt rather than being a stable crystalline acid addition salt or hydrate form. Thus, one of the two hydrochloric acid groups with a relatively weak ionic bond character may leave the molecule under severe conditions. As aforementioned, the SK-3530 dihydrochloride salt may be endowed with a sufficient stability for pharmaceutical preparation. But, some additional techniques and costs are needed due to the deficiency in intrinsic physicochemical property and stability of the compound.

MIRODENAFIL米罗那非 标准品

…………………………

US6962911

The invention relates to a series of pyrrolopyrimidinone derivatives of the formula (1):

R1 ETHYL

R2=H

R3= PROPYL

R4 = PROPYL

R5=R5=SO2NR6R7,  NR6R7 is 4-(3-hydroxypropyl)piperazinyl) IS  MIRODENAFIL

ANALOGOUS METHOD

BELOW IS CUT PASTE OF R1 METHYL ANALOGUE ……………..R1 =METHYL AND NOT ETHYL   ….CAUTION

Example 39 Preparation of

5-(5-(4-(2-hydroxyethyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one hydrochloride (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(2-hydroxyethyl)piperazinyl)

The titled compound was prepared as described in Example 2 by using 5-(5-(4-(2-hydroxyethyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one in place of 5-(2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one.

yield: 99%

mp 66.5° C. dec;

IR (neat) 3332 (NH and OH), 1676 (C═O), 1166 (SO2) cm−1;

1H NMR (DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.2 Hz, 3H, OCH2CH2CH3), 1.56-1.80 (m, 4H, 2 CH2CH2CH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.91 (br t, J=11.7 Hz, 2H, 2 SO2NCHax), 3.12-3.27 (m, 4H, NCH2CH2 and 2 SO2NCHeq), 3.58 (br d, J=11.7 Hz, 2H, 2 +HNCHax), 3.68-3.85 (m, 4H, CH2CH2OH and 2 +HNCHeq), 4.00 (s, 3H, NCH3), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.66 (br s, 1H, OH), 7.28 (s, 1H, H-2), 7.44 (d, J=9.0 Hz, 1H, H-3′), 7.89 (dd, J=9.0 Hz, 2.4 Hz, 1H, H-4′), 8.01 (d, J=2.4 Hz, 1H, H-6′), 10.85 (br s, 1H, NH+), 12.01 (br s, 1H, NH).

Example 42 Preparation of

5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(3-hydroxypropyl)piperazinyl)

The titled compound was prepared as described in Example 1 by using 5-(5-chlorosulfonyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one and 1-(3-hydroxypropyl)piperazine in place of 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one and 1-methylpiperazine.

yield: 94%

mp 162.5° C. dec (EtOAc/hexanes);

IR (neat) 3484, 3302 (NH and OH), 1669 (C═O), 1170 (SO2) cm−1;

1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.20 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.64-1.80 (m, 4H, CH2CH2CH2OH and CH2CH2CH3), 1.99-2.11 (m, 2H, OCH2CH2CH3), 2.58-2.64 (m, 6H, NCH2CH2 and 2 NCH2), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.08 (br s, 4H, 2 SO2NCH2), 3.71 (t, J=5.4 Hz, 2H, CH2CH2OH), 4.08 (s, 3H, NCH3), 4.26 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.28 (br s, 1H, OH), 6.88 (s, 1H, H-2), 7.14 (d, J=8.7 Hz, 1H, H-3′), 7.77 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 8.87 (d, J=2.7 Hz, 1H, H-6′), 10.69 (br s, 1H, NH); MS (FAB) m/z 532 (MH+).

Example 43 Preparation of

5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one hydrochloride (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(3-hydroxypropyl)piperazinyl)

The titled compound was prepared as described in Example 2 by using 5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one in place of 5-(2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one.

yield: 99%

mp 62.5° C. dec;

IR (neat) 3347, 3321 (NH and OH), 1689 (C═O), 1168 (SO2) cm−1;

1H NMR (DMSO-d6) δ 0.93 (t, J=7.5 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.57-1.87 (m, 6H, CH2CH2CH2OH and 2 CH2CH2CH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.89 (br t, J=11.7 Hz, 2H, 2 SO2NCHax), 3.01-3.19 (m, 4H, NCH2CH2 and 2 SO2NCHeq), 3.44 (t, J=6.0 Hz, 2H, CH2CH2OH), 3.52 (br d, J=11.7 Hz, 2H, 2 +HNCHax), 3.79 (br d, J=11.7 Hz, 2H, 2 +HNCHeq), 4.00 (s, 3H, NCH3), 4.15 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.71 (br s, 1H, OH), 7.29 (s, 1H, H-2), 7.44 (d, J=8.7 Hz, 1H, H-3′), 7.89 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.02 (d, J=2.4 Hz, 1H, H-6′), 11.13 (br s, 1H, NH+), 12.05 (br s, 1H, NH).

……………………………

Synthesis from patent and some construction by me

you can synthesize as follows, A CHEMIST CAN PICK THIS UP, this is not available clearly anywhere

 Chlorosulfonation of the  methyl salicylate  with ClSO3H in SOCl2 affords the Methyl 3-Chlorosulfonyl-6-hydroxybenzoate described below

EP1362858A1

THESE INTERMEDIATES FROM PATENT MAY HELP YOU

methyl salicylate

X=CL, R8=ME

Methyl 3-Chlorosulfonyl-6-hydroxybenzoate

Example 1 EP1362858A1

Methyl 3-Chlorosulfonyl-6-hydroxybenzoate
• To a cooled solution of SOCl2 (156 g, 1. 31 mol) and ClSO3H (460 g, 3.94 mol) at 0°C was added slowly methyl salicylate (200 g, 1.31 mol) for 30 minutes, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured slowly into the ice (2 kg) and H2O (3 L) mixture, and the resulting white precipitates were collected by filtration. The filtered solid was washed with H2O (3 L), air-dried for 2 days and then dried under vacuum at 40°C for 2 days to afford the titled product (232 g, 93%) as a white solid.
  mp 76.5-77.5 °C (toluene/hexanes);
  IR (neat) 1699 (C=O) cm-1;
  1H NMR (CDCl3/TMS) δ 3. 90 (s, 3 H, OCH3), 6. 93 (d, J= 8. 7 Hz, 1 H, H-3), 7. 70 (dd, J= 8. 7 Hz, 2. 4 Hz, 1 H, H-4), 8. 03 (d, J= 2. 4 Hz, 1 H, H-6).

Example 2 EP1362858A1

Methyl 2-Hydroxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]benzoate
• 1-(2-hydroxyethyl)piperazine
• R8=ME, W=N, n=2
• Methyl 2-Hydroxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]benzoate
• To a mixture of 1-(2-hydroxyethyl)piperazine (27 mg, 0. 21 mmol) and K2CO3 (33 mg, 0. 24 mmol) in DMF (5 mL) was added methyl 3-chlorosulfonyl-6-hydroxybenzoate (50 mg, 0. 20 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O (10 mL), and the aqueous layer was further extracted with 5% MeOH in CH2Cl2 (20 mL). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (5% MeOH in CH2Cl2) to afford the titled compound (59 mg, 86%) as white solid.
  mp 152 °C (dec) (CH2Cl2/ether);
  IR (neat) 1685 (C=O) cm-1;
  1H NMR (CDCl3/TMS) δ 2. 30 (br s, 1 H, CH2OH), 2. 63 (t, J = 5. 4 Hz, 2 H, NCH 2CH2O), 2. 70 (m, 4 H, 2 NCH2), 3. 12 (m, 4 H, 2 SO2NCH2), 3. 64 (t, J= 5. 4 Hz, 2 H, NCH2CH 2O), 4. 01 (s, 3 H, OCH3), 7. 12 (d, J= 8. 7 Hz, 1 H, H-3), 7. 81 (dd, J= 8. 7 Hz, 2. 4 Hz, 1 H, H-4), 8. 26 (d, J = 2. 4 Hz, 1 H, H-6), 11. 26 (br s, 1 H, OH);
  MS (FAB) m/z 345 (MH+).

Example 3 EP1362858A1

Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate

• To a mixture of methyl 2-hydroxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzoate (800 mg, 2. 32 mmol) and K2CO3 (482 mg, 3. 49 mmol) in DMF (5 mL) was added 1-bromopropane (253 µL, 2.79 mmol), and the mixture was stirred at 60°C overnight. The reaction mixture was evaporated to dryness under reduced pressure, washed with H2O (10 mL), and the aqueous layer was further extracted with CH2Cl2 (50 mL x 2). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (309 mg, 80%) as a white solid.
  mp 88-89 °C (EtOAc/hexanes);
  IR (neat) 3242 (OH), 1741 (C=O) cm-1;
  1H NMR (CDCl3/TMS) δ 1. 09 (t, J = 7. 5 Hz, 3 H, OCH2CH2CH 3), 1. 84-1. 95 (m, 2 H, OCH2CH 2CH3), 2. 23 (br s, 1 H, CH2OH), 2. 54 (t, J= 5. 4 Hz, 2 H, NCH 2CH2O), 2. 60 (m, 4 H, 2 NCH2), 3. 04 (m, 4 H, 2 SO2NCH2), 3. 58 (t,J = 5. 4 Hz, 2 H, NCH2CH 2O), 3. 91 (s, 3 H, OCH3), 4. 08 (t, J= 6. 6 Hz, 2 H, OCH 2CH2CH3), 7. 07 (d, J = 9. 0 Hz, 1 H, H-3), 7. 82 (dd, J = 9. 0 Hz, 2. 4 Hz, 1 H, H-4), 8. 15 (d, J = 2. 4 Hz, 1 H, H-6);
  MS (FAB) m/z 387 (MH+).

• FURTHER INFO OTHER THAN ABOVE PATENT

• HYDROLYSE Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate TO -COOLi SALT using LiOH

• CONDENSE WITH 3-amino-1-ethyl-4-propyl-1H-pyrrole-2-carboxamide USING HOBt AND DMAP/ PYRIDINE

9……….Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate R8= ME, R4=PROPYL, W=N, n=2

10……….3-amino-1-ethyl-4-propyl-1H-pyrrole-2-carboxamide R1=ETHYL, R2=H, R3=PROPYL,  IN ABOVE

YOU WILL GET A COMPD

R1 ETHYL

R2=H

R3= PROPYL

R4 = PROPYL

W=N

n=2

IS  MIRODENAFIL precursor ie n-1 compund

•  CYCLIZE THIS WITH BuOK/tBuOH AND USE ACID TO GET FINAL PRODUCT MIRODENAFIL
• A cyclization reaction is generally carried out by heating at an elevated temperature, for example 50-150° C., in the presence of an acid or a base in a suitable solvent such as an aqueous C1-C4 alkanol, water, a halogenated hydrocarbon, or acetonitrile. Thus, for example, the cyclization may be affected by treatment of a compound with an inorganic or organic base such as sodium hydroxide, potassium carbonate or potassium tert-butoxide, in an alcoholic aqueous medium, preferably potassium tert-butoxide in tert-butanol at 60° C. to reflux temperature.

SYNTHESIS OF 1-(2-hydroxyethyl)piperazine needed for MIRODENAFIL SYNTHESIS

Compounds of the formula (29) can be prepared from the compounds of the formula (30):

wherein X and P are as previously defined.

note X=N ATOM, n = 2

…………………………….

MIRODENAFIL

METHODS OF ANALYSIS

Two methods were published for the determination of mirodenafil in biological fluids. Choi et al. (2009) describe an isocratic reversed-phase liquid chromatographic method for simultaneous analysis of mirodenafil and its two main metabolites, SK3541 and SK3544, in rat plasma, urine, and tissue homogenates. The authors used a simple deproteinization procedure for sample preparation, and the compounds were separated on a C18 column (250 mm x 4.6 mm, i.d.; 5 µm particle size; Shiseido, Tokyo, Japan). The mobile phase was constituted with 0.02 M ammonium acetate buffer (pH 6):acetonitrile (52:48, v/v) at a flow rate of 1.4 mL/min. UV detection was at 254 nm.

Lee et al. (2009) developed a study with the proposed method to determine sildenafil and mirodenafil in the plasma and corpus cavernosum tissue of rats using LC–MS/MS. A CapcellPak phenyl column (2.1mm x 150 mm, 5µm) maintained constant at 40 ºC was used for the separation. The mobile phase consisted of 90% acetonitrile in 5 mM ammonium formate (pH 6.0). A gradient program was used for the LC separation with a flow rate of 0.2 mL/min.

References

1.  Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC, Kim SW, Lee SW, Min KS, Moon KH, Park JK, Park K, Park NC, Suh JK, Yang DY, Jung HG (November 2008). “Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction”. The Journal of Sexual Medicine 5 (11): 2672–80. doi:10.1111/j.1743-6109.2008.00945.x. PMID 18638004.
2.  Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, Shin SG, Jang IJ, Yu KS (June 2009). “Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: a single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea”.Clinical Therapeutics 31 (6): 1234–43. doi:10.1016/j.clinthera.2009.06.008. PMID 19695390.
3.  Shin KH, Kim BH, Kim TE, Kim JW, Yi S, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (December 2009). “The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: an open-label, one-sequence, three-period, three-treatment crossover study”.Clinical Therapeutics 31 (12): 3009–20. doi:10.1016/j.clinthera.2009.12.012. PMID 20110038.
4. Synthesis of 5-ethyl-2-[5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl]-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]-[2-14C]pyrimidin-4-one·2 HCl (14C-SK3530·2 HCl)J Label Compd Radiopharm 2006, 49(13): 1141
5. More information about mirodenafil can be found at Paick J S et al., (2008) The Journal of Sexual Medicine, 5 (11): 2672-80.
6. PDE-5 inhibitor that came into the market recently (Choi et al., 2009; Lee et al., 2009).not currently approved for use in the United States but clinical trials are being conducted.
7. Crystal forms of SK-3530.
   Song HO, Sohn YT.Arch Pharm Res. 2010 Dec;33(12):2033-6. doi: 10.1007/s12272-010-1220-3. Epub 2010 Dec 30.
8. Looking to the future for erectile dysfunction therapies.Hatzimouratidis K, Hatzichristou DG.Drugs. 2008;68(2):231-50. Review.
9. • Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC, Kim SW, Lee SW, Min KS, Moon KH, Park JK, Park K, Park NC, Suh JK, Yang DY, Jung HG (November 2008). “Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction”. The Journal of Sexual Medicine 5 (11): 2672–80. doi:10.1111/j.1743-6109.2008.00945.x. PMID 18638004.
   •  Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, Shin SG, Jang IJ, Yu KS (June 2009). “Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: a single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea”. Clinical Therapeutics 31 (6): 1234–43.doi:10.1016/j.clinthera.2009.06.008. PMID 19695390.
   •  Shin KH, Kim BH, Kim TE, Kim JW, Yi S, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (December 2009). “The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: an open-label, one-sequence, three-period, three-treatment crossover study”. Clinical Therapeutics 31 (12): 3009–20.doi:10.1016/j.clinthera.2009.12.012. PMID 20110038.
   •  Matheny, C., et al., Drug Metab. Dispos., 32, 1008 (2004)
     Gupta, M., et al., J. Clin. Pharmacol., 45, 987 (2005)
     Ek, M., et al., Biochem. Pharmacol., 74, 496 (2007)
     Lee, H., et al., Xenobiotica, 38, 21 (2008)

PATENTS

1 WO 2001060825

2.WO 2013085276

3 KR 2013086771

4 WO2008/4796 A1

WO2006018088A1 *	Jul 15, 2005	Feb 23, 2006	Switch Biotech Ag	Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders
KR20010083637A *				Title not available

EP2038282A1

US6962911 *	Feb 15, 2001	Nov 8, 2005	Sk Chemicals Co., Ltd.	Pyrrolopyrimidinone derivatives, process of preparation and use
US20100069632 *	Jul 3, 2007	Mar 18, 2010	Sk Chemicals Co., Ltd	Salts of pyrrolopyrimidinone derivatives and process for preparing the same
EP2038282A1 *	Jul 3, 2007	Mar 25, 2009	SK Chemicals, Co., Ltd.	Salts of pyrrolopyrimidinone derivatives and process for preparing the same

Sweet success for bio-battery

An enzyme cascade strips electrons from glucose and turns it into electricity that could be used to power a mobile phone © NPG

Sugar is an excellent source of energy. Most living cells generate their energy from glucose by passing it down an enzymatic chain that converts it into different sugars. This enzymatic cascade provides the necessary energy to create an electrochemical gradient. This, in turn, can be used to power an enzyme that synthesises adenosine triphosphate (ATP) – the universal biological energy currency. However, extracting this energy from a sugar if you’re not a biological organism is tricky – short of combustion, which is impractical to power handheld electronics.

To fuel their battery the team used maltodextrin – a polymer made up of glucose subunits. They then created an entirely new synthetic enzymatic pathway to extract energy from the sugar. Using 13 different enzymes they were able to strip, on average, 24 electrons from a single glucose molecule, which can then be harnessed to power an electrical device.

http://www.rsc.org/chemistryworld/2014/01/sweet-success-bio-battery-sugar-power-phones

DASANTAFIL « New Drug Approvals

DASANTAFIL « New Drug Approvals:



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