171596-29-5 Usage
Indications and uses
Cialis (or Tadalafil) was developed by American pharmaceutical company Lilly. It is used to treat erectile dysfunction and belongs to a second generation of PDE5 inhibitors. Studies show that Cialis works very quickly, taking effect in around 15-20 minutes, and has a prolonged effect that can last for up to 36 hours. T1/2 is 17.5h.
Clinical Research
In a study of 348 cases of mild to severe erectile dysfunction, patients were randomly given 20mg of Cialis or a placebo. Results showed that in comparison to the placebo group, patients who took Cialis experienced improved intercourse success in the 24-36 hours following medication, with many patients achieving successful sexual intercourse twice in 36 hours. Side effect rate and severity were also no different from those of the placebo group. Over 5% of patients in the Cialis group experienced headaches and indigestion.
Side effects
Different sources of media describe the Side effects of 171596-29-5 differently. You can refer to the following data:
1. No severe negative reactions. No perceived facial flushing or sight abnormalities following medication. Rare cases of headache and indigestion.
2. Adverse effects related to oral therapy for erectile function are primarily concerned with adverse cardiovascular effects, because PDE5
inhibitors promote vasodilation and, therefore, have an inherent potential to cause hypotension. This is a particular concern for elderly
patients with a preexisting condition.
Warnings and precautions
Patients currently taking nitrates, experiencing angina pectoris, suffering from heart disease, patients who have unregulated hypertension or hypotension, or patients who have had a stroke in the past 6 months should not take Cialis.
Chemical Properties
White to Off-White Cyrstalline Solid
Originator
Lilly/ICOS (US)
Uses
Different sources of media describe the Uses of 171596-29-5 differently. You can refer to the following data:
1. analgesic, norepinephrine uptake blocker, mu-opiod receptor agonist.A phosphodiesterase 5 inhibitor.Tadalafil is used for the treatment of erectile dysfunction.
2. Tadalafil is used for the treatment of erectile dysfunction. A phosphodiesterase 5 inhibitor.
Definition
ChEBI: A pyrazinopyridoindole that is 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione substituted at position 2 by a methyl group and at position 6 by a 1,3-benzodioxol-5-yl group (the 6R,12aR
Brand name
Cialis (Lilly).
General Description
Tadalafil, (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 (Cialis), is a potent PDE5 inhibitor.It received FDA approval for the treatment of erectiledysfunction in December 2003. Because of its half-life of17.5 hours, it is marketed as a 36-hour treatment. Tadalafil ispredominantly metabolized by hepatic enzymes, includingCYP3A4. The concomitant use of CYP3A4 inhibitors suchas ritonavir, indinavir, ketoconazole, as well as moderateCYP3A inhibitors such as erythromycin have been shown toresult in significant increases in tadalafil plasma levels.Much like sildenafil, tadalafil is under clinical investigationfor managing PAH.
Mechanism of action
Tadalafil was the last agent to be released and can be taken on a full stomach without slowing the onset. It has a much longer duration of action, lasting up to 48 hours, compared with sildenafil and vardenafil, which last for approximately 4 hours. The longer half-life of tadalafil results in a lengthened period of responsiveness as compared to sildenafil and vardenafil. This longer therapeutic window requires fewer time constraints for the effectiveness of tadalafil and has been interpreted as being advantageous through providing the option for more spontaneous sexual activity. Because of its long half-life, however, tadalafil, has been detected in plasma even 5 days after oral administration. This suggests the possibility of accumulation if taken regularly and in short intervals, which may result in an increased risk of side effects with the excessive use of this PDE5 inhibitor. The 3,4-methylenedioxy substitution on the phenyl ring was significant for increasing its potency as PDE5 inhibitor. Optimization of the chain on the piperazinedione ring resulted in no significant change in IC50s. Tadalafil is a highly potent PDE5 inhibitor (IC50, 5 nM), with high selectivity for PDE5 versus PDE1 through PDE4. The PDE5/PDE6 selectivity ratio is 85.
Pharmacokinetics
Tadalafil is different in structure from both sildenafil and vardenafil. It is rapidly absorbed and peaks in concentration (378 μg/L after a
20-mg dose) after 2 hours, displaying a long half-life of 17.5 hours. It also is metabolized by the liver (CYP3A4). Notably, its
pharmacokinetics is not clinically influenced by alcohol or food intake or by factors such as diabetes or impaired hepatic or renal
function.
Clinical Use
Tadalafil is one of the two new PDE5 inhibitors launched for the oral
treatment of male erectile dysfunction. Tadalafil is a b-carboline derivative and it is
structurally distinct from vardenafil (Levitraw) and sildenafil (Viagraw), both of
which are PDE5 inhibitors based on a fused pyrimidine core structure. Tadalafil is
synthesized in three steps starting from D-tryptophan methyl ester, by first
condensing with piperonal in a Pictet-Spengler cyclization reaction to form the
tetrahydro-β-carboline derivative, which is followed by chloroacetylation of the
piperidine ring nitrogen and cyclization with methylamine. Tadalafil is a potent and
highly selective inhibitor of PDE5 (IC50=1 nm). It shows ＞10,000-fold selectivity
for PDE5 versus PDE1, 2, 3, 4, 7, 8 and 9, and ＞700-fold selectivity versus PDE6.
Typically administered at 10 and 20 mg doses, tadalafil is rapidly absorbed and has a
tmax of 2 h, which is slightly longer than those of sildenafil (1 h) and vardenafil
(0.75 h). Clinically, all of these agents appear to have efficacy for many men within
30–60 min. However, tadalafil distinguishes itself from other PDE5 inhibitors in
terms of significantly longer duration of action. The half-life of tadalafil dosed at
20 mg is 17.5 h as compared with 3.8 h for sildenafil (100 mg) and 4.7 h for
vardenafil (20 mg). In clinical studies, significant rates of response were reported up
to 36 h following drug ingestion. Tadalafil is predominantly metabolized in the liver
by CYP3A4 to entities that are not active against PDE5 and excreted mainly as
metabolites in the feces and the urine. The pharmacokinetics of tadalafil are
unaffected by factors such as intake of food and alcohol, age, the presence of
diabetes, and mild or moderate hepatic insufficiency. The most common drug-related
adverse events are headache, back pain, dyspepsia, and myalgia. At 10 and 20 mg
doses, Tadalafil does not have a significant effect on blood pressure and heart rate
and does not result in increased instances of myocardial infarction. Rare reports of
prolonged erections greater than 4 h and priapism have been noted with the use of
tadalafil. Priapism, if not treated properly, can result in irreversible damage to the
erectile tissue. Patients who have an erection lasting greater than 4 h are advised
to seek emergency medical attention. Tadalafil has a modest synergistic effect on the nitrate-induced reduction in blood pressure and, as with sildenafil and
vardenafil, it is contraindicated for use in patients on nitrate therapy. In diabetic
patients, improvement of erectile function by tadalafil is irrespective of the type of
diabetes and the type of diabetic therapy.
Synthesis
D-(-)-Tryptophan methyl ester (175) and 1,3-
benzodioxole-5-carboxaldehyde (176) were subjected to a
modified Pictet-Spengler reaction to form cis- and transtetrahydro-
β-carboline tricyclic compounds. The ciscompound
177 was isolated as a white solid in 42% yield.
The basic nitrogen in the piperidine ring of 177 was acylated
with chloroacetyl chloride (179) to give compound 180 in
93% yield. Finally, the diketonepiperazine ring was formed
by adding 180 to 33% methylamine in ethanol under
refluxing conditions and yielded tadalafil (XXII) in 77% as
a white solid.
Drug interactions
Potentially hazardous interactions with other drugs
Alpha-blockers: enhanced hypotensive effect - avoid
concomitant use.
Antibacterials: concentration possibly increased by
clarithromycin and erythromycin; concentration
reduced by rifampicin - avoid.
Antifungals: concentration increased by ketoconazole
- avoid; concentration possibly increased by
itraconazole.
Antivirals: concentration possibly increased by
fosamprenavir and indinavir; increased by ritonavir -
avoid; increased risk of ventricular arrhythmias with
saquinavir - avoid; avoid high doses of tadalafil with
telaprevir.
Cobicistat: concentration of tadalafil possibly
increased - reduce dose of tadalafil.
Nicorandil: possibly enhanced hypotensive effect -
avoid concomitant use.
Nitrates: enhanced hypotensive effect - avoid
concomitant use.
Riociguat: enhanced hypotensive effect - avoid
concomitant use.
Metabolism
Tadalafil is metabolised in the liver mainly by the cytochrome
P450 isoenzyme CYP3A4. The major metabolite, the
methylcatechol glucuronide, is inactive. Tadalafil is excreted,
mainly as metabolites, in the faeces (61% of the dose), and to
a lesser extent the urine (36% of the dose).
References
https://www.drugs.com/tadalafil.html
https://www.drugbank.ca/drugs/DB00820
Roehrborn, C. G., et al. "Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study." Journal of Urology 180.4(2008):1228.
Rosano, Giuseppe M. C., et al. "Chronic Treatment with Tadalafil Improves Endothelial Function in Men with Increased Cardiovascular Risk." European Urology 47.2(2005):214-222.
Check Digit Verification of cas no
The CAS Registry Mumber 171596-29-5 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 6 respectively; the second part has 2 digits, 2 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 171596-29:
(8*1)+(7*7)+(6*1)+(5*5)+(4*9)+(3*6)+(2*2)+(1*9)=155
155 % 10 = 5
So 171596-29-5 is a valid CAS Registry Number.
InChI:InChI=1/C22H23N3O3/c1-24-8-9-25-17(22(24)26)11-15-14-4-2-3-5-16(14)23-20(15)21(25)13-6-7-18-19(10-13)28-12-27-18/h2-7,10,15,17,20-21,23H,8-9,11-12H2,1H3/t15?,17-,20?,21-/m1/s1
171596-29-5Relevant articles and documents
Preparation method of tadalafil
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Paragraph 0052-0054; 0056; 0059; 0061; 0064; 0066, (2022/01/12)
The invention provides a preparation method of tadalafil, and relates to the technical field of medicines. The preparation method comprises the steps of taking D-cis-carboline hydrochloride as an initial raw material, carrying out acylating chlorination reaction on the D-cis-carboline hydrochloride and chloroacetyl chloride under the action of an acid-binding agent, carrying out primary refining on an obtained chloroacetylate intermediate crude product, carrying out aminolysis cyclization reaction on the obtained high-purity chloroacetylate intermediate and methylamine, adding a pulping solvent into the obtained tadalafil crude product for pulping, carrying out solid-liquid separation, washing the obtained solid product, and drying to obtain the high-purity tadalafil. Moreover, the D-cis-carline hydrochloride raw material is cheap, easy to obtain and stable in quality, the D-cis-carline hydrochloride raw material is used as a starting raw material, the production period of tadalafil is short, and the production cost is low.
Preparation method of tadalafil
-
, (2022/03/27)
The invention discloses a preparation method of tadalafil. According to the method, a compound I is adopted as a starting material, the tadalafil is obtained through condensation, Fisher indole synthesis reaction, Pictet-Spengler reaction, acylation and ring closing in sequence, and dangerous reagents (n-butyllithium and the like) are not used during ring closing. The reaction route is simple, the reaction condition is mild, the purity is high, the cost is relatively low, the operation is simple and convenient, and industrial production is easy.
Preparation method of phosphodiesterase inhibitor
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Paragraph 0016; 0056-0070, (2021/11/03)
The invention discloses a preparation method of a phosphodiesterase inhibitor and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: starting the raw material 1 and methanol to prepare the intermediate I without adding organic solvent crystallization. After the series of centrifugation, washing and drying, the intermediate II is directly condensed and cyclized with piperonal, and a final product tadalafil is prepared by chloroacetylation, aminolysis and refining steps. The method improves the product yield and quality, greatly shortens the reaction period, reduces the operation steps and the production cost, and is suitable for industrial mass production.
TADALAFIL SYNTHESIS METHOD
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Page/Page column 11-22, (2020/11/03)
?The invention relates to a new one-pot continuous method for the synthesis of tadalafil from methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate and methylamine in aprotic solvent. The method allows to obtain high-quality tadalafil (I) with the high yield at low temperature in a short time.
Method for preparing Tadalafil by one-pot method
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Paragraph 0031; 0033; 0034; 0036; 0037; 0039; 0040; 0042, (2020/03/06)
The invention discloses a method for preparing Tadalafil by a one-pot method. The method for preparing the Tadalafil by the one-pot method comprises the steps that D-Tryptophan methyl ester hydrochloride and piperonal are used as starting materials, and a single-configuration high-purity compound I hydrochloride is obtained through a Pictet-Spengler reaction; the compound I hydrochloride is subjected to an acylation reaction with chloroacetyl chloride in an organic base system of an aprotic solvent to obtain a mixed reaction solution; and the mixed reaction solution is directly added to a methylamine solution to undergo an aminolysis cyclization reaction without treatment, and the mixture is subjected to cooling crystallization to obtain the Tadalafil after the reaction. According to the method for preparing the Tadalafil by the one-pot method, the usage amount of the solvent is reduced, the amount of waste liquid discharge is effectively controlled, and environmental protection is facilitated; the production cycle is shortened, and the process efficiency is improved; and the yield is improved, and the cost is reduced. Compared with an existing process route, the method for preparing the Tadalafil by the one-pot method is more environmentally friendly, more efficient and lower in cost, and is more suitable for industrial production.
Tadalafil preparation method
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Paragraph 0054-0055; 0058; 0068-0075, (2020/02/10)
The invention belongs to the field of chemical synthesis, and particularly relates to a tadalafil preparation method. According to the method, easily-available piperonyloyl chloride and the like are used as raw materials; the prepared intermediate 1 and sarcosine are subjected to an amidation reaction; under specific reaction conditions, high-purity tadalafil can be prepared at a high yield; and the whole synthesis process is only divided into two steps, and the product can be prepared in a one-pot boiling mode. Compared with the method in the prior art, the method of the invention significantly reduces the complex reaction steps, is simple in operation, and is suitable for large-scale industrial production of tadalafil.
Production process of tadalafil bulk drug
-
, (2020/07/02)
The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
Preparation method of tadalafil and intermediate of tadalafil
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Paragraph 0083-0088, (2019/11/20)
The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.
Preparation method of tadalafil
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Paragraph 0010; 0011; 0012, (2019/08/12)
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of tadalafil. The preparation method comprises the following steps: subjecting (1R,3R)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxy phenyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (compound A) and a methylamine aqueous solution to a temperature controlled reaction inthionyl chloride, adding purified water for crystallization, and then performing centrifugation to obtain tadalafil. Organic solvent residues meet pharmacopeia standards without the need of recrystallization. According to the method, the yield of tadalafil is greatly increased, the operation is simplified, the dosage of an organic solvent is reduced, the purification operation is reduced, and themethod is suitable for industrial production.
Method for synthesizing tadalafil
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, (2019/10/02)
The invention discloses a method for synthesizing tadalafil. Tadalafil is synthesized from D-tryptophan and a compound of formula 1. The method for preparing tadalafil of the invention can effectivelyprepare tadalafil. In addition, the starting material piperonyl dimethyl acetal of the preparation method is easy to obtain as a non-controlled material, the procurement and management are not restricted, the use of the controlled material piperonyl is effectively avoided, the management and procurement are convenient, the process steps are short, the production cost is greatly reduced, and the preparation method is more suitable for large-scale and industrial production of tadalafil.
