171599-83-0 Usage
Description
Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE5) with IC50 values of 3.6 and 3 nM for PDE5 activity in isolated rabbit platelets and human corpus cavernosum, respectively. It is selective for PDE5 over PDE1 and PDE3 (IC50s = 0.26 and 65 μM, respectively). Sildenafil reverses glucose-induced decreases in angiopoietin 1 (ANG1) expression and reduction of capillary-like tube formation by mouse dermal endothelial cells in vitro and increases the number of functional blood vessels and regional blood flow in the sciatic nerve in a db/db mouse model of diabetic peripheral neuropathy. It increases the ratio of maximum intracavernosal pressure to mean arterial blood pressure (ICP/MAP), a measure of erectile function, in castrated rats when administered at a dose of 20 mg/kg per day. Sildenafil (0.5 mg/kg) also reduces cardiac arrest and resuscitation-induced increases in angiotensin II , angiotensin converting enzyme (ACE), ACE2, and various angiotensin receptors and increases survival in a porcine model of ischemia/reperfusion injury. Formulations containing sildenafil have been used in the treatment of erectile dysfunction, pulmonary arterial hypertension, and high-altitude pulmonary edema associated with altitude sickness.
Chemical Properties
White Solid
Originator
Alsigra,Alembic Ltd.,India
Uses
Sildenafil citrate is an orally active selective type 5 cgmp phosphodiesterase inhibitor that is used in the treatment of erectile dysfunction and primary pulmonary hypertension.
Definition
ChEBI: Sildenafil citrate is the citrate salt of sildenafil. It has a role as a vasodilator agent and an EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor. It contains a sildenafil.
Manufacturing Process
A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 0.132
mol) (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568) and
dimethyl sulfate (16.8 g, 0.133 mol) were heated to 90°C for 2.5 h. The
mixture was dissolved in dichloromethane and the solution washed with
sodium carbonate solution. The organic phase was separated, dried (MgSO4)
and evaporated under vacuum to give a solid. Chromatography on silica gel
(300 g), eluting with dichloromethane gave the 1-methyl-3-n-propylpyrazole-
5-carboxylic acid ethyl ester as a colourless oil (20.4 g, 79%).1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol)
was suspended in 6 N aqueous sodium hydroxide solution (50 ml, 0.30 mol).
The mixture was heated to 80°C for 2 h then diluted with water (50 ml) and
acidified with concentrated hydrochloric acid (25 ml). Filtration gave the 1-
methyl-3-n-propylpyrazole-5-carboxylic acid as pale brown crystals (12.3 g,
71%), melting point 150°-154°C.1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added
portionwise to a mixture of oleum (13 ml) and fuming nitric acid (11 ml),
keeping the temperature below 60°C. After the addition, the mixture was
heated at 60°C overnight and then cooled to room temperature before being
poured onto ice. Filtration of the precipitate gave the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxylic acid as a white solid (11.5 g, 75%), melting point
124°-127°C.1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) was
added to thionyl chloride (50 ml) and the resulting mixture heated under
reflux for 3 h. The reaction mixture was then cooled and excess thionyl
chloride removed by evaporation under vacuum. The oily residue was
dissolved in acetone (50 ml) and the solution cautiously added to a mixture of
ice (50 g) and concentrated aqueous ammonium hydroxide solution (50 ml).
The precipitate was collected by filtration to provide the 1-methyl-4-nitro-3-npropylpyrazole-
5-carboxamide as a pale yellow solid (8.77 g, 78%), melting
point 141°-143°C.1-Methyl-4-nito-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and
stannous chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol and
the mixture heated under reflux for 2 h. The resulting solution was cooled to
room temperature, basified to pH 9 by the addition of 2 N aqueous sodium
hydroxide solution and extracted with dichloromethane (3 x 150 ml). The
organic extracts were combined, dried (MgSO4) and evaporated under
vacuum. Trituration of the residue with ether gave the 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide as an off-white solid (2.77 g, 94%), melting
point 98°-101°C.A solution of 2-ethoxybenzoyl chloride (6.1 g, 33.0 mmol) in dichloromethane
(50 ml) was added to a stirred solution of 4-amino-1-methyl-3-npropylpyrazole-
5-carboxamide (3.0 g, 16.4 mmol), 4-dimethylaminopyridine
(0.02 g, 0.1 64 mmol) and triethylamine (3.34 g, 33.0 mmol) in
dichloromethane (50 ml) at 0°C. The resulting mixture was allowed to warm
to room temperature and stirred for a further 2 h. The solvent was evaporated
under vacuum, the residue dissolved in a 19:1 mixture of dichloromethane
and methanol (250 ml), and then the solution washed with 1 N hydrochloric
acid (100 ml), dried (MgSO4) and evaporated under vacuum. The crude
material was chromatographed on silica gel (200 g), eluting with a 97:3
mixture of dichloromethane and methanol, to give a pink solid; crystallisation
from ethyl acetate-hexane gave the 4-(2-ethoxybenzamido)-1-methyl-3-npropylpyrazole-
5-carboxamide as a pale pink solid (2.2 g, 40%), melting point
153°-155°C.4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g,
0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g,
1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml).
Ethanol (700 ml) was added and the resulting mixture heated under reflux for
2.5 h, cooled, then evaporated under vacuum. The resulting solid was treated
with 2 N hydrochloric acid (380 ml), with external cooling, and the mixture
was extracted with dichloromethane (1 x 700 ml, 3 x 200 ml). The combined
organic extracts were washed successively with saturated aqueous sodium
carbonate solution (3 x 400 ml) and brine (300 ml), then dried (Na2SO4) and
evaporated under vacuum. Chromatography of the residue on silica gel (1000
g), using a methanol in dichloromethane elution gradient (0-1%), followed by
trituration of the crude product with ether (300 ml), gave the 5-(2-
ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-one as a colourless solid (152.2 g, 72%), melting point 143°-146°C.5-(2-Ethoxyphenyl)-1-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one (10.0 g, 32.1 mmol) was added portionwise to
chlorosulfonic acid (20 ml) at 0°C under a nitrogen atmosphere. After being
stirred overnight, the reaction solution was cautiously added to ice-water (150ml) and the aqueous mixture extracted with a 9:1 mixture of dichloromethane
and methanol (4 x 100 ml). The combined extracts were dried (Na2SO4) and
evaporated under vacuum to give the required 5-(5-chlorosulphonyl-2-
ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-
7-one as a white solid (12.8 g, 97%), melting point 179°-181°C.4-Methylpiperidine was added to a stirred suspension of 5-(5-chlorosulphonyl-
2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one in ethanol at room temperature. The resulting mixture was
stirred for 4 days before removing the solvent by evaporation under vacuum.
The residue was dissolved in a 9:1 mixture of dichloromethane and methanol
and the solution washed with saturated aqueous sodium carbonate solution.
The aqueous phase was further extracted with dichloromethane-methanol
mixtures (3 x 100 ml) and all the organic fractions were combined, dried
(MgSO4) and evaporated under vacuum to give a solid. Crystallisation from a
mixture of methanol-dimethylformamide gave the 5-[2-ethoxy-5-(4-
methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[
4,3-d]-pyrimidin-7-one as an off-white solid, melting point 187°-
189°C.After addition of citric acid to the 5-[2-ethoxy-5-(4-
methylpiperidinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7Hpyrazolo[
4,3-d]-pyrimidin-7-one (sildenafil) the it's salt is obtained, namely
sildenafil citrate.
Brand name
Viagra (Pfizer).
Therapeutic Function
Vasodilator
General Description
Sildenafil Citrate is the citrate salt form of sildenafil, an orally bioavailable pyrazolopyrimidinone derivative structurally related to zaprinast, with vasodilating and potential anti-inflammatory activities. Upon oral administration, sildenafil selectively targets and inhibits cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), thereby inhibiting the PDE5-mediated degradation of cGMP found in smooth muscle and increasing cGMP availability. This results in prolonged smooth muscle relaxation in the corpus cavernosum of the penis, thereby causing vasodilation, blood engorgement and a prolonged penile erection. ?In the smooth muscle of the pulmonary vasculature, the increase in cGMP results in smooth muscle relaxation, vasodilation of the pulmonary vascular bed, relieving pulmonary hypertension and increasing blood flow in the lungs. In addition, sildenafil may reduce airway inflammation and mucus production.
Biological Activity
Orally active, potent inhibitor of phosphodiesterase 5 (PDE5) (IC 50 = 4 nM). Enhances nitric oxide-dependent relaxation of human corpus cavernosum in vitro .
Biochem/physiol Actions
Sildenafil is a potent, selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5). Sildenafil is used to treat erectile dysfunction and pulmonary arterial hypertension. NO activates guanylate cyclase, which results in increased levels of cGMP, producing smooth muscle relaxation. Sildenafil enhances the effect of NO by inhibiting PDE5, which is responsible for degradation of cGMP.
Safety Profile
A poison by ingestion. Human systemic effects. When heated to decomposition it emits toxic vapors of NOx and SOx.
Veterinary Drugs and Treatments
Sildenafil may be of benefit in the adjunctive treatment of pulmonary
hypertension in small animals.
In humans, sildenafil is indicated for erectile dysfunction or pulmonary
hypertension.
structure and hydrogen bonding
Sildenafil citrate (SC) has been widely used for the treatment of erectile disorder. A detailed study concerning solid-state structure of this compound is very important for understanding enzyme (PDE5)-inhibitor (sildenafil) interaction. It is also of interest to determine sildenafil’s protonation sites, as they may be responsible for its binding to the phosphodiesterase acidic amino acids.
Sildenafil citrate (Viagra) and sildenafil base in pure form were characterized by 1H, 13C, 15N NMR spectroscopy in solution, solid-state, and pharmaceutical dosage forms.42 The analysis of chemical shifts showed that: (i) N6-H forms intramolecular hydrogen bonds, (ii) N25 is protonated in the salt, and (iii) intermolecular OH. . .N hydrogen bonds involving N2 and N4 are present in the solid sildenafil citrate. The 13C CPMAS spectra of the tablets containing different amounts of sildenafil citrate were recorded and showed that chemical shifts of sildenafil citrate in pure form and in pharmaceutical dosage forms are the same. SC is easily detected in the pharmaceutical dosage forms since only two of its carbon resonances (OCH2 and quaternary carbon of the citrate anion) fall into carbohydrate-type region of the excipient.
Solid-state 13C and 15N MAS NMR have recently been used to investigate how water interacts with SC.43 When the humidity is altered, the water concentration in the solid compound changes but does not reach a stoichiometric (e.g., 1:1) ratio to form a true hydrate. Only one set of 15N and 13C signals was observed for each humidity level indicating that water incorporated into the crystal lattice of SC is very mobile and exchanges rapidly between various sites. The 13C data showed the formation of a hydrogen bond between water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the conformation of the propyl group. Additionally, 15N dipolar dephasing (DD) experiments confirmed that the sildenafil molecule is only protonated in the piperazine ring.
Check Digit Verification of cas no
The CAS Registry Mumber 171599-83-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,7,1,5,9 and 9 respectively; the second part has 2 digits, 8 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 171599-83:
(8*1)+(7*7)+(6*1)+(5*5)+(4*9)+(3*9)+(2*8)+(1*3)=170
170 % 10 = 0
So 171599-83-0 is a valid CAS Registry Number.
InChI:InChI=1/C21H28N6O4S/c1-4-6-16-18-19(25-24-16)21(28)23-20(22-18)15-13-14(7-8-17(15)31-5-2)32(29,30)27-11-9-26(3)10-12-27/h7-8,13H,4-6,9-12H2,1-3H3,(H,24,25)(H,22,23,28)
171599-83-0Relevant articles and documents
Preparation method of sildenafil citrate
-
, (2018/06/16)
The invention belongs to the field of chemical drugs, and in particular relates to a preparation method of sildenafil citrate. The invention provides the preparation method of sildenafil citrate. Thepreparation method comprises the following steps: a) adding a compound of a structure as shown in a formula (I) and thionyl chloride into chlorosulfonic acid, and carrying out a sulfonation reaction to generate a compound of a structure as shown in a formula (II); b) dissolving the compound of the structure as shown in the formula (II) in dichloromethane and adding N-methyl piperazine to carry outa substitution reaction at 20-30 DEG C to obtain sildenafil; and c) adding citric acid into a sildenafil aqueous solution to adjust the pH value for a salt forming reaction so as to obtain the sildenafil citrate. Experimental results verify that the sildenafil citrate prepared by the preparation method is high in yield and high in purity.
This product is a nationally controlled contraband, and the Lookchem platform doesn't provide relevant sales information.