139755-83-2 Usage
Uses
Used in Pharmaceutical Industry:
Sildenafil is used as a vasodilator agent for the treatment of erectile dysfunction (ED). It acts as an EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor, increasing the penile response to sexual stimulation by inhibiting the PDE5-mediated degradation of cGMP in smooth muscle.
Used in Erectile Dysfunction Treatment:
Sildenafil is used as a PDE5 inhibitor for the treatment of organic or psychological male erectile dysfunction (ED). It is an orally active selective type 5 cGMP phosphodiesterase inhibitor, enhancing the penile response to sexual stimulation and improving erectile function in men with ED.
Brand Names:
Viagra (Pfizer), Segurex.
What is sildenafil?
Sildenafil (Viagra?) is an oral medication called a phosphodiesterase-5 (PDE5) inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients. The goal of this therapy is to improve exercise ability and delay clinical worsening. Research studies showing the effectiveness of the medication included mostly patients with symptoms that were rated as WHO Functional Class II-III. Sildenafil is marketed as Revatio? for PAH and was approved by the United States Food and Drug Administration (FDA) in 2005. Sildenafil is also marketed as Viagra? which is FDAapproved for the treatment of erectile dysfunction but not for the treatment of PAH.
Indications
Sildenafil Citrate is an oral drug used to treat male erectile dysfunction and is a 5-phosphodiesterase inhibitor developed by the American Pfizer Pharmaceuticals to originally treat cardiovascular disease that was later discovered to improve patients'sex lives. Sildenafil Citrate treats erectile dysfunction and was the first clinical oral drug used to specifically target male erectile dysfunction.
Indications
Sildenafil (Viagra) is a selective
inhibitor of PD-5, an enzyme that inactivates cGMP.
Vardenifil (Levitra) is a particularly effective inhibitor
of PD-5. It has a shorter onset of action and can be used
in smaller doses than sildenafil. Other drugs used in the
treatment of ED exert their effects through other biochemical
pathways, both central and peripheral.
Side effects
Sildenafil is generally well tolerated. The most frequent side effects are:Nose bleedsHeadacheUpset stomach and heartburnFlushing of the skinDifficulty sleepingWorsening shortness of breathNasal congestion.Other side effects include:Fluid retentionNausea and diarrheaPain in the extremity (arm or leg)Temporary muscle achesFeverNumbnessA reduction in blood pressure throughout the body may occur because sildenafil relaxes blood vessels (arteries) throughout the body. Caution must be used in patients with low blood pressure, less than 90/50 mmHg for example. Caution is also needed in patients with dehydration, leftsided heart diseases and certain abnormalities of the body’s nervous system function.Taking certain medications such as nitrates, nitric oxide donors or alpha blockers along with sildenafil can cause a significant drop in blood pressure. This could result in loss of consciousness or even death. You should make certain that you are not taking these medications before starting sildenafil. Use of sildenafil with medications known as nitrates is CONTRAINDICATED.Prolonged erection (greater than four hours) in a male patient is a rare but very serious side effect; if this should happen to you, you should go to an emergency room or contact your doctor immediately.Sudden loss of vision in one or both eyes has occurred in patients on PDE5 inhibitors. Such an event may represent serious dysfunction of the optic nerve and requires immediate medical attention.Sudden loss of hearing may occur and may be accompanied by dizziness and/or ear ringing. Patients should seek prompt medical attention should this occur.https://www.henryford.com/
Side effects
Orally administered sildenafil is an effective and
well-tolerated treatment for men with ED, including
those with diabetes mellitus. It has also been used for
so-called salvage therapy in men who do not respond to
intracorporeal injections of other agents.
Headache is a common side effect, as are flushing
and rhinitis.More serious side effects include definite or
suspected myocardial infarctions and cardiac arrest.
Overdose
Overdose information is limited. In studies with healthy volunteers, of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates and severities were increased.In cases of overdose, standard supportive measures should be adopted as required. Sildenafil blood levels are not clinically useful. Monitor ECG and blood pressure in symptomatic patients. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.Contact the Poisons Information Centre on 13 11 26 for advice on the management of an overdose.https://www.pfizer.com.au/
Genotoxicity
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.
Carcinogenicity
Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUC) for unbound sildenafil and its major metabolite of 35- and 39-times, for male and female rats, respectively, the exposures observed in human males given the maximum recommended human dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the maximum tolerated dose of 10 mg/kg/day, but resulting in total systemic drug exposure for unbound sildenafil and its major metabolite of less than the exposures observed in human males given the MRHD.
Preparation
The first synthetic route of sildenafil accomplished the preparation of its pyrazole derivative from ethyl 3-butyrylpyruvate and hydrazine hydrate in acetic acid, followed by the selective N-methylation of the pyrazole ring with dimethyl sulfate. The carboxylic acid was obtained after alkaline hydrolysis was subjected to nitration, followed by treatment with concentrated ammonium hydroxide solution to sequentially deliver the corresponding carboxamide derivative. The nitro group of the mentioned carboxamide derivative was then reduced to an amino group by stannous chloride/hydrochloric acid in ethanol, leading to the formation of the main 4-aminopyrazole structure. Mild amidation of the aminopyrazole derivative by the appropriate benzoyl chloride was performed, followed by cyclization mediated by hydrogen peroxide under basic environment which led to the formation of pyrimidinone heterocycle ring. Chloro-suIphonylation of pyrimidinone derivative imposed selectively on the 50 position of the phenyl ring, led to the aroyl sulfonyl chloride derivative which was then coupled with N-methylpiperazine to afford sildenafil.synthesis of sildenafil
Therapeutic Function
Vasodilator
Mechanism of action
Sildenafil is readily absorbed after oral administration
and reaches peak plasma levels after about an
hour. It undergoes hepatic metabolism and has a terminal
half-life of about 4 hours.An initial dose of 50 mg is
taken about an hour prior to sexual activity to induce
penile erection.
Clinical Use
Sildenafil is a selective inhibitor of cGMP-specific
PD-5 and therefore inhibits the degradation of cGMP.
PD-5, the predominant type in the corpus cavernosum,
also is present in other tissues (e.g., lungs, platelets, and
eye). The selective inhibition of this enzyme facilitates
the release of nitric oxide and smooth muscle relaxation
of the corpus cavernosa. Sildenafil enhances erection by
augmenting nitric oxide–mediated relaxation pathways.
It has been suggested that sildenafil’s mechanism of
action is due to cross-talk between cGMP- and cAMPdependent
transduction pathways within the cavernous
muscles.
Enzyme inhibitor
Sildenafil is rapidly absorbed and peaks in concentration (127–560 ng/mL) after 0.5 to 2.0 hours, displaying a half-life of 3 to 4 hours
for the full therapeutic dose (25–100 mg). It is 96% bound to plasma proteins and is metabolized by the liver CYP3A4. The
metabolite N-desmethylsildenafil possesses approximately 50% of the activity of the parent molecule.
Drug interactions
Potentially hazardous interactions with other drugs
Alpha-blockers: enhanced hypotensive effect - avoid
for 4 hours after sildenafil.
Antibacterials: concentration increased by
clarithromycin and erythromycin - consider
reducing sildenafil dose or frequency.
Antifungals: concentration increased by ketoconazole
- reduce initial dose for ED and avoid for PAH;
concentration increased by itraconazole - reduce
initial dose of sildenafil.
Antivirals: ritonavir significantly increases sildenafil
concentration - avoid; concentration possibly
increased by saquinavir, fosamprenavir and indinavir
- reduce dose of sildenafil; concentration reduced
by etravirine; side effects possibly increased by
atazanavir; increased risk of ventricular arrhythmias
with saquinavir - avoid; avoid with telaprevir; avoid
with tipranavir for PAH.
Cobicistat: concentration of sildenafil possibly
increased - reduce initial dose for ED and avoid for
PAH.
Nicorandil: enhanced hypotensive effect - avoid.
Nitrates: enhanced hypotensive effect - absolutely
contraindicated.
Riociguat: enhanced hypotensive effect - avoid.
Metabolism
In vitro metabolism studies for sildenafil have shown that the primary metabolite, N-desmethylsildenafil, and the minor metabolite, oxidative opening of the piperazine ring, are mediated by CYP3A4, CYP2C9, CYP2C19, and CYP2D6. The estimated relative contributions to clearance were 79% for CYP3A4, 20% for CYP2C9, and less than 2% for CYP2C19 and CYP2D6. These results demonstrate that CYP3A4 is the primary cytochrome mediating N-demethylation and that drugs inhibiting CYP3A4 likely impair sildenafil biotransformation and clearance. The pharmacokinetics of radiolabeled sildenafil were consistent with rapid absorption, first-pass metabolism, and primarily fecal elimination of N-demethylated metabolites. The absorption of sildenafil following oral administration was rapid (~92%), whereas the oral bioavailability was approximately 38% as a result of first-pass metabolism.
Check Digit Verification of cas no
The CAS Registry Mumber 139755-83-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,9,7,5 and 5 respectively; the second part has 2 digits, 8 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 139755-83:
(8*1)+(7*3)+(6*9)+(5*7)+(4*5)+(3*5)+(2*8)+(1*3)=172
172 % 10 = 2
So 139755-83-2 is a valid CAS Registry Number.
InChI:InChI=1/C22H30N6O4S/c1-5-7-17-19-20(27(4)25-17)22(29)24-21(23-19)16-14-15(8-9-18(16)32-6-2)33(30,31)28-12-10-26(3)11-13-28/h8-9,14H,5-7,10-13H2,1-4H3,(H,23,24,29)
139755-83-2Relevant articles and documents
Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil
Baxendale, Ian R.,Ley, Steven V.
, p. 1983 - 1986 (2000)
Sildenafil 1 (Viagra(TM)), a well known and commercially important pharmaceutical drug, has been prepared using polymer-supported reagents in a multi-step, convergent process resulting in a clean and efficient preparation without the need for conventional purification methods. (C) 2000 Elsevier Science Ltd.
Molecular and crystal structure of sildenafil base
Stepanovs, Dmitrijs,Mishnev, Anatoly
, p. 491 - 494 (2012)
Sildenafil citrate monohydrate, well known as Viagra , is a drug for the treatment of erectile dysfunction. Here we present the X-ray crystal structure of the sildenafil base, C22H30N 6O4S. The compound crystallizes in the monoclinic system, space group P21/c with the unit cell parameters a = 17:273(1), b=17:0710(8), c=8:3171(4) A° , β =99:326(2), Z = 4, V = 2420:0(3) A°3. A comparison with the known crystal structures of sildenafil citrate monohydrate and sildenafil saccharinate is also presented.
α-Keto Acids as Triggers and Partners for the Synthesis of Quinazolinones, Quinoxalinones, Benzooxazinones, and Benzothiazoles in Water
Huang, Jian,Chen, Wei,Liang, Jiazhi,Yang, Qin,Fan, Yan,Chen, Mu-Wang,Peng, Yiyuan
, p. 14866 - 14882 (2021/10/25)
A general and efficient method for the synthesis of quinazolinones, quinoxalinones, benzooxazinones, and benzothiazoles from the reactions of α-keto acids with 2-aminobenzamides, benzene-1,2-diamines, 2-aminophenols, and 2-aminobenzenethiols, respectively, is described. The reactions were conducted under catalyst-free conditions, using water as the sole solvent with no additive required, and successfully applied to the synthesis of sildenafil. More importantly, these reactions can be conducted on a mass scale, and the products can be easily purified through filtration and washing with ethanol (or crystallized).
Improved, gram-scale synthesis of sildenafil in water using arylacetic acid as the acyl source in the pyrazolo[4,3-d]pyrimidin-7-one ring formation
Laha, Joydev K.,Gulati, Upma,Saima,Gupta, Anjali,Indurthi, Harish Kumar
, p. 2643 - 2648 (2021/02/16)
An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction, has been developed. Unlike the previous literature, the current method demonstrates the use of arylacetic acid as an acyl source, a cheap oxidant K2S2O8, and water as the reaction medium in the key step of pyrrazolo[4,3-d]pyrimidin-7-one ring formation. As well as being a green and benign approach, the current method reduces the cost by half compared to our previous strategy. In addition, the general relevance of the method has been demonstrated in the synthesis of a variety of quinazolinone and benzothiazole derivatives with excellent functional group tolerance.
Improved synthesis process of sildenafil
-
Paragraph 0039-0042; 0050-0052, (2021/06/21)
The invention discloses an improved synthesis process of sildenafil, belonging to the technical field of preparation of drug intermediates. In the process, high-concentration chlorosulfonic acid is prevented from being used as a reaction solvent and reagent, and 3-5 equivalent chlorosulfonic acid is used as a reaction reagent. Compared with the prior art, the process has the characteristics of economical performance, environmental protection, safety and the like, for example, equipment cannot be corroded, the post-treatment of reaction becomes simpler, the solvent is single and can be reused, product purity is high, and the like.
Preparation method of sildenafil citrate
-
, (2021/04/07)
The invention discloses a preparation method of sildenafil. The method comprises the following steps: activating an intermediate compound B in an aprotic solvent by using thionyl chloride, reducing with 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-formamide in a zinc powder-ammonium chloride system in the presence of an acid-binding agent to obtain an intermediate compound E, and condensing to obtain an intermediate compound C; and cyclizing the intermediate compound C in an alcohol solvent under an alkaline condition to prepare sildenafil. The preparation method disclosed by the invention is short in reaction time, greatly shortens the production period so as to reduce the production cost, and is simple in operation and suitable for large-scale production.
Sulphonated graphene oxide catalyzed continuous flow synthesis of pyrazolo pyrimidinones, sildenafil and other PDE-5 inhibitors
Karra, Purushotham Reddy,Mahajan, Bhushan,Pabbaraja, Srihari,Singh, Ajay K.,Sthalam, Vinay Kumar
, p. 326 - 330 (2022/01/19)
Sulphonated graphene oxide was used for cascade condensation and cyclization reactions towards accessing substituted pyrazolo pyrimidinones. Further, sulphonation and amination reactions were integrated through continuous flow chemistry to access PDE-5 inhibitors. Herein, we report a simple continuous synthetic platform that reduce tedious manual operations and accelerate the synthesis of several potent inhibitors of phosphodiesterase type-5. The developed platform enabled us to perform one-flow multi-step, multi-operational process to synthesize the PDE-5 inhibitors such as sildenafil and its analogues in 32.3 min of the reaction time, with minimal human intervention and single solvent.
Preparation method of sildenafil
-
Paragraph 0038; 0042-0043; 0047-0048; 0052-0053; 0057-0058, (2020/10/04)
The invention provides a preparation method of sildenafil. The preparation method comprises the following steps: dissolving a compound III in an organic solvent I, adding a compound II for amidation reaction, washing and drying to obtain a compound IV; directly adding the solution obtained in the step S1 into a chlorosulfonic acid-thionyl chloride mixture for chlorosulfonation reaction without separation and purification, pouring ice water after the reaction is finished, layering, taking an organic phase, washing and drying to obtain a compound V; adding the compound V obtained in the S2 intoN-methyl piperazine, carrying out N-sulfonation reaction for 0-4 hours, concentrating, adding alkali and an organic solvent II, heating to carry out cyclization reaction for 2-6 hours, adding water for cooling, adding hydrochloric acid for acidification, and filtering to obtain a target compound I. A continuous method is adopted for synthesis, and the production efficiency is improved.
Efficient and Practical Synthesis of Sulfonamides Utilizing SO2 Gas Generated on Demand
Chung Leung, Gulice Yiu,Ramalingam, Balamurugan,Loh, Gabriel,Chen, Anqi
, p. 546 - 554 (2020/04/22)
A simple and practical protocol was developed for the synthesis of sulfonamides by reacting organometallic reagents with SO2 gas generated on demand. SO2 was generated from readily available reagents safely in a highly contained and controlled fashion. The protocol allows the synthesis of sulfonamides without using either atom-inefficient SO2 surrogates or a SO2 cylinder that requires stringent storage regulations in the laboratory. The protocol was successfully applied to the synthesis of sildenafil.
Method for preparing sildenafil citrate
-
, (2020/05/30)
The invention discloses a method for preparing sildenafil citrate. The preparation method comprises the following steps: (a) adding a compound II into chlorosulfonic acid for a reaction to generate anintermediate III; (b) reacting the intermediate III with N-methyl piperazine to generate a crude sildenafil product; (c) recrystallizing the crude sildenafil product to obtain a pure sildenafil product; and (d) carrying out a salifying reaction on the pure sildenafil product to obtain sildenafil citrate. The method is beneficial for industrial production.
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