147536-97-8 Usage
Description
Bosentan, also known as Tracleer or Bozentan, is a mixed endothelin receptor antagonist that was the first of its kind to be marketed in the United States. It is a pale yellow to off-white solid and works by competitively blocking the endothelin receptor subtypes ETA and ETB, which in turn prevents the constriction of vascular smooth muscle and the narrowing of blood vessels, thus reducing hypertension. Bosentan is also an inducer of CYP2C9 and CYP3A4, and its use requires monitoring for liver toxicity.
Uses
Used in Pharmaceutical Industry:
Bosentan is used as a vasodilator and antihypertensive agent for the treatment of pulmonary arterial hypertension. It is the first endothelin (ET) receptor antagonist to be launched and has been shown to inhibit the pulmonary arterial vasoconstricting effect of ET-1, predominantly mediated via ETA receptors on smooth muscle cells. In clinical trials, bosentan improved exercise capacity, decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean capillary wedge pressure, and mean right atrial pressure, demonstrating a beneficial selectivity for the pulmonary vasculature.
Used in Clinical Trials:
Bosentan has been used in clinical trials to evaluate its effectiveness in treating pulmonary hypertension. Patients treated with bosentan showed a 20% increase in exercise capacity compared to placebo as measured by the six-minute walk test. The compound is hepatically metabolized into three major metabolites by CYP3A4 and 2C9 and is almost exclusively eliminated in the bile.
Brand Name:
Tracleer (Actelion) is the brand name under which Bosentan is marketed.
Originator
Roche (Switzerland)
Manufacturing Process
4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-
yl]benzenesulphonamide were heated to 100°C, cooled for a further 4 hours,
poured on to ice and adjusted to pH 3 with 1 M tartaric acid. The suspension
obtained was extracted with ethyl acetate, the organic extracts were
combined, washed with water, dried with sodium sulfate and concentrated
under reduced pressure. The residue was chromatographed on silica gel with
CH2Cl2-ethyl acetate 9:1 and yielded 4-t-butyl-N-[6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)-2-(pyrimidin-2-yl)-pyrimidin-4-yl]benzenesulphonamide as
a solid. Sodium salt melted at 195°-198°C.
The 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl)-pyrimidin-
4-yl]benzenesulfonamide was prepared starting from pyrimidine-2-
carboxamidine hydrochloride via rac-5-(2-methoxyphenoxy)-2-(pyrimidin-2-
yl)tetrahydropyrimidine-4,6-dione and 4,6-dichloro-5-(2-methoxyphenoxy)-
2,2'-bipyrimidine.
Therapeutic Function
Endothelin receptor antagonist
Hazard
A reproductive hazard.
Pharmacokinetics
Bosentan is mainly
eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites
have been identified, formed by CYP2C9 and CYP3A4. The pharmacokinetics of bosentan are
dose-proportional up to 500 mg/day (multiple doses). The pharmacokinetics of bosentan in pediatric patients with PAH
are comparable to those in healthy subjects, whereas adult patients with PAH show a twofold increase in clearance.
Severe renal impairment and mild hepatic impairment do not have a clinically relevant influence on its
pharmacokinetics. Bosentan generally should be avoided in patients with moderate or severe hepatic impairment
and/or elevated liver aminotransferases. Inhibitors of CYP3A4 increase the plasma concentration of bosentan as well
as cause an increase in the clearance of drugs metabolized by CYP3A4 and CYP2C9 because of induction of these
metabolizing enzymes. The possibility of reduced efficacy of CYP2C9 and CYP3A4 substrates coadministered with
bosentan is increased. No clinically relevant interaction was detected for P-glycoprotein. Bosentan can increase
plasma levels of ET-1.
Clinical Use
Bosentan is an orally administered, nonselective ET-1 receptor antagonist blocking ETA and ETB receptors and is
approved for the treatment of patients with PAH. Following oral administration, bosentan attains peak plasma
concentrations in approximately 3 hours, with an absolute bioavailability of approximately 50%. Food has no clinically
relevant effect on its absorption recommended doses. Bosentan is approximately 98% bound to albumin, with a volume
of distribution of 30 L. Its terminal half-life after oral administration is 5.4 hours and is unchanged at steady state.
Side effects
Adverse effects include hypotension, headache, flushing, increased liver aminotransferases, leg
edema, and anemia. Bosentan may cause birth defects and, therefore, is contraindicated in pregnancy. It also can
cause liver injury.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antidiabetics: increased risk of hepatoxicity with
glibenclamide - avoid.
Antifungals: fluconazole, ketoconazole and
itraconazole cause large increases in concentration of
bosentan - avoid.
Antivirals: concentration of bosentan increased by
lopinavir and ritonavir - consider reducing bosentan
dose; telaprevir concentration reduced and bosentan
concentration possibly increased; avoid with
tipranavir.
Ciclosporin: When ciclosporin and bosentan are
co-administered, initial trough concentrations of
bosentan are 30 times higher than normal. At steady
state, trough levels are 3-4 times higher than normal.
Blood concentrations of ciclosporin decreased by
50% - avoid.
Cytotoxics: concentration of bosutinib possibly
reduced - avoid.
Guanfacine: concentration of guanfacine possibly
reduced - increase guanfacine dose.
Lipid lowering agents: concentration of simvastatin
reduced by 45% - monitor cholesterol levels and
adjust dose of statin.
Oestrogens, progestogens and ulipristal: may be
failure of contraception - use alternative method.
Metabolism
Upon multiple dosing, plasma concentrations of bosentan
decrease gradually to 50%-65% of those seen after single
dose administration. This decrease is probably due to
auto-induction of metabolising liver enzymes. Steadystate conditions are reached within 3-5 days.
Bosentan is eliminated by biliary excretion following
metabolism in the liver by the cytochrome P450
isoenzymes, CYP2C9 and CYP3A4. Bosentan
forms three metabolites and only one of these is
pharmacologically active. This metabolite is mainly
excreted unchanged via the bile. In adult patients, the
exposure to the active metabolite is greater than in healthy
subjects. In patients with evidence of the presence of
cholestasis, the exposure to the active metabolite may be
increased.
Check Digit Verification of cas no
The CAS Registry Mumber 147536-97-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,7,5,3 and 6 respectively; the second part has 2 digits, 9 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 147536-97:
(8*1)+(7*4)+(6*7)+(5*5)+(4*3)+(3*6)+(2*9)+(1*7)=158
158 % 10 = 8
So 147536-97-8 is a valid CAS Registry Number.
InChI:InChI=1/C27H29N5O6S/c1-27(2,3)18-10-12-19(13-11-18)39(34,35)32-23-22(38-21-9-6-5-8-20(21)36-4)26(37-17-16-33)31-25(30-23)24-28-14-7-15-29-24/h5-15,33H,16-17H2,1-4H3,(H,30,31,32)
147536-97-8Relevant articles and documents
Research and development of a second-generation process for bosentan, an endothelin receptor antagonist
Harrington, Peter J.,Khatri, Hiralal N.,DeHoff, Brad S.,Guinn, Martin R.,Boehler, Mark A.,Glaser, Karl A.
, p. 120 - 124 (2002)
A second-generation manufacturing process from 5-(2-methoxyphenoxy)-[2,2′-bipyrimidine]-4,6-(1H,5H)-dione to bosentan is based on the synthesis and deprotection of the tert-butyl ether of bosentan using available and inexpensive ethylene glycol mono-tert-butyl ether. This new strategy triggered a cascade of process improvements. Isolations are reduced from six to three, and drying operations, from five to two. Process solvents are reduced from six to two. The isolations of two sensitizers are eliminated. Toluene is used in place of methylene chloride. Two aqueous waste streams are eliminated by replacing DMF and ethylene glycol by toluene. Two methanol - isopropyl acetate recrystallizations of bosentan are replaced by the decantation of a suspension of bosentan formate monoethanolate in ethanol - toluene. Finally, the overall yield is increased from 67 to 84% and the final product purity improved from 99.3 to 99.7%.
A preparation method of bosentan monohydrate, novel intermediate useful for the preparation of bosentan monohydrate, and the preparation method thereof
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Paragraph 0130-0143, (2019/10/08)
The present invention provides a method for preparing bosentan monohydrate, a novel intermediate used therefor, and a method for preparing same. The novel intermediate composition of the present invention is produced at a high yield and high purity, and by using said intermediate composition, high-purity bosentan monohydrate can be economically mass produced at a high yield.
METHOD FOR PRODUCING BOSENTAN OR HYDRATE THEREOF
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Paragraph 0042; 0043, (2017/01/09)
PROBLEM TO BE SOLVED: To produce: high purity bosentan by suppressing the formation of 4-tert-butyl-N-[6-hydroxy-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide which is a reaction by-product or a hydrate thereof. SOLUTION: There is produced high purity bosentan by suppressing the formation of a reaction by-product by carrying out a reaction between 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(pyrimidine-2-yl)pyrimidine-4-yl]benzenesulfonamide and ethylene glycol by using alkali metal salt of disilazane as a base and a dehydrating agent or a hydrate thereof. SELECTED DRAWING: Figure 4 COPYRIGHT: (C)2016,JPOandINPIT
PROCESS FOR PREPARATION OF BOSENTAN MONOHYDRATE OF PHARMACEUTICAL PURITY
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Page/Page column 14; 15, (2014/07/21)
A process for the preparation of bosentan monohydrate of pharmaceutical purity is characterized by that crude bosentan is suspended in methyl alcohol / dichloromethane mixture at a volume ratio from 8:1 to 1:2, the mixture is stirred at room temperature, crystalline bosentan monohydrate is isolated, dried to constant weight and optionally crystallized to obtain appropriate crystal shape.