- A method for the treatment of pulmonary arterial hypertension drug preparation method
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The invention provides a preparation method of a therapeutic medicine for treating pulmonary arterial hypertension and particularly provides a preparation method of a key intermediate compound as shown in a formula (IV). According to the method, the compound as shown in the formula (IV) is obtained by means of reaction of a compound as shown in a formula (II) and a compound as shown in a formula (III). The preparation method is easily available in raw materials, low in cost, mild in condition and suitable for industrialized production. The formulae (IV), (II) and (III) are as shown in the specification.
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- Metabolism study and biological evaluation of bosentan derivatives
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Bosentan, the first-in-class drug used in treatment of pulmonary arterial hypertension, is principally metabolized by the cytochromes P450, and it is responsible for cytochromes induction and drug-drug interaction events with moderate to severe consequences. A strategy to reduce drug-drug interactions consists of increasing the metabolic stability of the perpetrator, and fluorinated analogues are often designed to block the major sites of metabolism. In this paper bosentan analogues were synthesized, and their metabolism and biological activity were evaluated. All synthesized compounds showed an improved metabolic stability towards CYP2C9, with one maintaining a moderate antagonist effect towards the ETA receptor.
- Lepri, Susan,Goracci, Laura,Valeri, Aurora,Cruciani, Gabriele
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p. 658 - 670
(2016/07/06)
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- An alternate synthesis of bosentan monohydrate, an endothelin receptor antagonist 1
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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.
- Pradeep, Rebelli,Jayaprakash Rao, Yerrabelly,Kumari Bharathi, Yalamanchili,Subbanarsimulu, Porala,Venkat Reddy, Ghojala,Kondal Reddy, Bairy
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supporting information
p. 265 - 269
(2014/02/14)
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- ACID ADDITION SALTS OF BOSENTAN
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The present invention relates to the stable acid addition salts of Bosentan that are useful for the purification of Bosentan base. In particular, the Bosentan acid addition salt is selected from Bosentan citrate and Bosentan tartrate.
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- PROCESS FOR PREPARATION OF BOSENTAN MONOHYDRATE OF PHARMACEUTICAL PURITY
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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.
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Page/Page column 13; 14
(2014/07/21)
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- PROCESS FOR THE PREPARATION OF BOSENTAN
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The present invention relates to a process for the preparation of Bosentan (Formula 1) or pharmaceutically acceptable salts or hydrates thereof which results the product substantially free of impurities like ethylene glycol bis-sulfonamide dimer and 6-hydroxy sulfonamide. The process according to present invention is also producing Bosentan sodium and Bosentan ammonium which gives Bosentan or pharmaceutically acceptable salts or hydrates thereof in improved yield and quality as compared to prior art processes.
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Page/Page column 8
(2014/01/08)
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- ACID ADDITION SALTS OF BOSENTAN
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The present invention relates to the stable acid addition salts of Bosentan that are useful for the purification of Bosentan base. In particular, the Bosentan acid addition salt is selected from Bosentan citrate and Bosentan tartrate.
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- A new efficient synthetic process for an endothelin receptor antagonist, bosentan monohydrate
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A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl) benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.
- Rebelli, Pradeep,Yerrabelly, Jayaprakash Rao,Yalamanchili, Bharathi Kumari,Kommera, Rajashekar,Ghojala, Venkat Reddy,Bairy, Kondal Reddy
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p. 1021 - 1026
(2013/09/12)
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- The discovery of N -[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy] ethoxy]-4-pyrimidinyl]- N ′-propylsulfamide (macitentan), an orally active, potent dual endothelin receptor antagonist
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Starting from the structure of bosentan (1), we embarked on a medicinal chemistry program aiming at the identification of novel potent dual endothelin receptor antagonists with high oral efficacy. This led to the discovery of a novel series of alkyl sulfamide substituted pyrimidines. Among these, compound 17 (macitentan, ACT-064992) emerged as particularly interesting as it is a potent inhibitor of ETA with significant affinity for the ET B receptor and shows excellent pharmacokinetic properties and high in vivo efficacy in hypertensive Dahl salt-sensitive rats. Compound 17 successfully completed a long-term phase III clinical trial for pulmonary arterial hypertension.
- Bolli, Martin H.,Boss, Christoph,Binkert, Christoph,Buchmann, Stephan,Bur, Daniel,Hess, Patrick,Iglarz, Marc,Meyer, Solange,Rein, Josiane,Rey, Markus,Treiber, Alexander,Clozel, Martine,Fischli, Walter,Weller, Thomas
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supporting information
p. 7849 - 7861
(2012/10/29)
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- AN IMPROVED PROCESS FOR PREPARING BOSENTAN
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The present invention relates to an improved process for preparing Bosentan of formula (I).
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Page/Page column 10
(2012/06/16)
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- PROCESS FOR THE PREPARATION OF BOSENTAN
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The invention concerns a new process for the preparation of bosentan or bosentan monohydrate by reaction of compound of Formula II with ethylene glycol in the presence of potassium bases and the potassium salt of bosentan.
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Page/Page column 2
(2012/03/08)
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- A PROCESS FOR THE PREPARATION OF BOSENTAN
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The present invention relates to an improved process for the preparation of Bosentan or its salt. The present invention also relates to an improved process for the deprotection of hydroxy protected Bosentan. The present invention further relates to a pharmaceutical composition comprising Bosentan of formula I with excipients.
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Page/Page column 16
(2012/05/19)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN
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The present application provides purification of Bosentan crude by making its crystalline potassium salt, which is further converted to Bosentan (I) with bis-sulfonamide (VIII) and deshydroxyethyl (IX) impurities to less than 0.2% by HPLC analysis.
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- Facile one-pot process for large-scale production of highly pure bosentan monohydrate, an endothelin receptor antagonist
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Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′- bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.
- Niphade, Navnath C.,Jagtap, Kunal M.,Gaikawad, Chandrashekhar T.,Jachak, Madhukar N.,Mathad, Vijayavitthal T.
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experimental part
p. 1382 - 1387
(2012/01/11)
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- IMPROVED PROCESS FOR THE PREPARATION OF 4-(1,1-DIMETHYLETHYL)-N-[6-(2-HYDROXYETHOXY)-5-(2-METHOXYPHENOXY)[2,2'-BIPYRIMIDIN]-4-YL]BENZENESULFONAMIDE
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The present invention relates to improved process for the preparation of 4-(1,1-dimethylethyl)-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy) [2,2'-bipyrimidin]-4-yl] benzene sulfonamide monohydrate. Formula (I)
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Page/Page column 19-20
(2011/04/13)
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- PROCESS FOR THE PREPARATION OF BOSENTAN
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The invention concerns a new process for the preparation of bosentan or bosentan monohydrate and a new salt of bosentan.
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Page/Page column 5; 6
(2010/10/03)
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- PROCESSES FOR THE PREPARATION OF BOSENTAN AND ITS INTERMEDIATES THEREOF
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The present invention relates to processes for the preparation of bosentan and compounds that can be used as structurally novel intermediates for the synthesis thereof, and a pharmaceutical composition of the same.
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Page/Page column 12
(2010/10/19)
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- IMPROVED AND NOVEL PROCESS FOR THE PREPARATION OF BOSENTAN
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The present invention relates to an improved and novel process for the preparation of bosentan compound of formula (1). The present invention also relates to a crystalline form of bosentan and its intermediates.
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Page/Page column 23
(2009/09/05)
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- SUBSTITUTED PYRIMIDINES
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Disclosed herein are substituted pyrimidine-based endothelin modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 32-33; 34
(2008/12/07)
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- Bis-sulfonamides as endothelin receptor antagonists
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Modification of the structure of bosentan 1, the first marketed endothelin receptor antagonist (Tracleer), by introduction of a second sulfonamide function at the alkoxy side chain, led to bis-sulfonamides 2. This allowed to prepare dual ETA/ETB as well as ETB receptor selective antagonists, which could serve as tools to investigate the pharmacological consequences of selective ETB receptor blockade.
- Boss, Christoph,Bolli, Martin H.,Weller, Thomas,Fischli, Walter,Clozel, Martine
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p. 951 - 954
(2007/10/03)
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- Butyne diol derivatives
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The present invention relates to novel butyne diol derivatives of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists.
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