- 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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- 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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Paragraph 0076
(2014/09/30)
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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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Paragraph 14-15
(2013/05/09)
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- PROCESS FOR PREPARATION OF ENDOTHELIAL RECEPTOR ANTAGONIST (BOSENTAN)
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The present invention relates to processes for the preparation of an endothelial receptor antagonist. The present invention particularly relates to synthesis of 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (bosentan).
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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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Page/Page column 20
(2011/04/14)
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- PROCESS FOR PREPARATION OF BOSENTAN
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The present invention provides improved processes for preparing Bosentan. The present invention provides novel intermediates like 4,6-dihydroxy-5-(2-methoxy phenoxy)[2,2'] bipyrimidine of formula (II) and N-(6-Chloro-5-(2- ethoxyphenoxy)[2,2'-bipyrimidinyl]-4-t-butyl benzenesulfonamide cesium salt and process for preparation thereof. The invention also disclosed novel polymorphic form of the intermediates.
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Page/Page column 6; 14-15; 24
(2010/04/25)
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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 11-12
(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 18; 21
(2009/09/05)
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- ENDOTHELIN RECEPTOR ANTAGONISTS
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This invention relates to novel endothelin receptor antagonists, derivatives, acceptable acid addition salts, solvates, hydrates and polymorphs thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by compounds that block the endothelin signaling pathway that leads to vasoconstriction and in particular those diseases or conditions beneficially treated by endothelin receptor antagonists.
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Page/Page column 28
(2008/12/07)
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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; 34
(2008/12/07)
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- The use of sulfonylamido pyrimidines incorporating an unsaturated side chain as endothelin receptor antagonists
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A series of compounds structurally related to bosentan 1 featuring an unsaturated side chain at position 6 of the core pyrimidine have been studied for their potential to block the ETA and ETB receptor. Incorporation of a 2-butyne-1,4-diol linker bearing a pyridyl carbamoyl moiety led to in vitro highly potent endothelin receptor antagonists (e.g., 70 and 75). The propargyl derivative 26 significantly reduced blood pressure in in vivo model studies with hypertensive salt-sensitive Dahl rats.
- Bolli, Martin H.,Boss, Christoph,Clozel, Martine,Fischli, Walter,Hess, Patrick,Weller, Thomas
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p. 955 - 959
(2007/10/03)
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- Research and development of a second-generation process for bosentan, an endothelin receptor antagonist
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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%.
- Harrington, Peter J.,Khatri, Hiralal N.,DeHoff, Brad S.,Guinn, Martin R.,Boehler, Mark A.,Glaser, Karl A.
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p. 120 - 124
(2013/09/06)
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- Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists
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In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ETA -selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ETA binding affinity and ETA selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3 mg /kg with a duration of > 6.5 h. Compound 6e also exhibited a potent antagonisti activity in the pithed rats. Copyright
- Harada, Hironori,Kazami, Jun-ichi,Watanuki, Susumu,Tsuzuki, Ryuji,Sudoh, Katsumi,Fujimori, Akira,Sanagi, Masanao,Orita, Masaya,Nakahara, Hideaki,Shimaya, Jun,Tsukamoto, Shin-ichi,Tanaka, Akihiro,Yanagisawa, Isao
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p. 2955 - 2968
(2007/10/03)
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- Preparation of sulfonamides
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The present invention provides a process for preparing 1,2-diheteroethylene sulfonamide of the formula: by reacting a pyrimidine monohalide of the formula: with a mono-protected 1,2-diheteroethylene anion of the formula M1XCH2CH2YR5 and removing the protecting group, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Z, X, Y, M, M1 and W are defined herein.
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- Discovery of Ro 48-5695: A potent mixed endothelin receptor antagonist optimized from Bosentan
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Implementation of a pyridylcarbamoyl group and an isopropylpyridylsulfonamide substituent as key components in the scaffold of Bosentan resulted in the identification of the potent orally active endothelin receptor antagonist Ro 48-5695. It shows affinities for ET(A) and ET(B) receptors in the low nanomolar range and high functional antagonistic potency in vitro.
- Neidhart, Werner,Breu, Volker,Burri, Kaspar,Clozel, Martine,Hirth, Georges,Klinkhammer, Uwe,Giller, Thomas,Ramuz, Henri
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p. 2223 - 2228
(2007/10/03)
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- Development of a process to prepare 2-cyanopyrimidine on commercial scale
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2-Chloropyrimidine is converted to 2-cyanopyrimidine under very mild conditions in nearly quantitative yield using 1,4-diazabicyclo[2.2.2]octane as catalyst. The development of the process for commercial batch production of 2-cyanopyrimidine regarding processing of the materials in technical equipment, process safety, conservation, economic raw material use and work load is described.
- Goehring, Wolfgang,Schildknecht, Juerg,Federspiel, Muriel
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p. 538 - 543
(2007/10/03)
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