147536-97-8 Usage
Description
Bosentan was introduced in the US as a twice-daily oral treatment for pulmonary
arterial hypertension. It can be synthesized in five steps via condensation of diethyl (2-
methoxyphenoxy)malonate with pyrimidine-2-carboxamidine to give the precursor of the
symmetrical central dichloropyrimidine ring which is then successively treated with the
potassium salt of 4-tert-butylbenzenesulfonamide and the sodium salt of ethylene gycol.
Bosentan is the first endothelin (ET) receptor antagonist to be launched. ET-1, the most
potent endogenous vasoconstrictor known, has been demonstrated to play a major role in
the functional and structural changes observed in pulmonary hypertension. Bosentan is a
mixed ETA and ETB receptor antagonist that inhibits the pulmonary arterial vasoconstricting
effect of ET-1 predominantly mediated via ETA receptors on smooth muscle cells. In a
hypoxia-induced model of pulmonary hypertension in rat, it reduced the development of
pulmonary hypertension as well as right ventricular hypertrophy and prevented pulmonary
arterial remodeling. In clinical trials, patients treated with bosentan showed a 20% increase
in exercise capacity compared to placebo as measured by the six minute walk test.
Bosentan not only improved the distance walked by patients but also significantly
decreased mean pulmonary artery pressure, mean pulmonary vascular resistance, mean
capillary wedge pressure and mean right atrial pressure. It demonstrated a beneficial
selectivity for the pulmonary vasculature since it had no significant effect on mean aortic
blood pressure and systolic vascular resistance. The compound is hepatically metabolized
into three major metabolites by CYP3A4 and 2C9 and almost exclusively eliminated in the
bile. Although large interspecies differences in systemic plasma clearance was observed
(1.5 mL/min/kg in dogs to 72 mL/min/kg in rabbits), a satisfactory systemic clearance (2
mL/min/kg) was measured in human. The most frequent adverse effect was reversible
elevation of liver transaminases. This adverse reaction appears to be due to intracellular
accumulation of cytotoxic bile salts resulting from inhibition of the hepatocanalicular bile
salt export pump by bosentan.
Chemical Properties
Pale Yellow to Off-White Solid
Originator
Roche (Switzerland)
Uses
Different sources of media describe the Uses of 147536-97-8 differently. You can refer to the following data:
1. A mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.
2. Bosentan is a mixed endothelin receptor antagonist. Used as a vasodilator. Antihypertensive.
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.
Brand name
Tracleer (Actelion).
Therapeutic Function
Endothelin receptor antagonist
General Description
Bosentan, N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-yl-pyrimidin-4-yl]-4-tertbutyl-benzenesulfonamide (Tracleer, Bozentan), was thefirst endothelin receptor antagonist marketed in the UnitedStates. Bosentan works by competitively blocking the endothelinreceptor subtypes ETA and ETB. In binding to thereceptors, it blocks the effects of endothelin, which includeconstriction of the vascular smooth muscle, which leads tonarrowing of the blood vessels and hypertension. Althoughit is not selective for the ETA receptors, it does have a higheraffinity for that subtype over ETB. However, the clinical significanceof selectivity over preferential receptor bindinghas not been demonstrated. Bosentan is an inducer ofCYP2C9 and CYP3A4, and patients using bosentan must bemonitored for liver toxicity.
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
-
, (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
-
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
An alternate synthesis of bosentan monohydrate, an endothelin receptor antagonist 1
Pradeep, Rebelli,Jayaprakash Rao, Yerrabelly,Kumari Bharathi, Yalamanchili,Subbanarsimulu, Porala,Venkat Reddy, Ghojala,Kondal Reddy, Bairy
, p. 265 - 269 (2014/02/14)
An alternate synthesis of an endothelin receptor antagonist bosentan monohydrate is reported. This new synthetic route involves the coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)(2,2′-bipyrimidin)-4-yl] benzene sulfonamide with commercially available raw material (2,2-dimethyl-1,3-dioxolan-4-yl)methanol as the key step. Attractive features of this approach are its versatileness, commercial availability of raw materials, usage of eco-friendly reagents, and it efficiently provides the desired bosentan monohydrate free from reported impurities such as dimer, N-alkylated, and pyrimidinone impurities. Georg Thieme Verlag Stuttgart, New York.