- Research and development of a second-generation process for bosentan, an endothelin receptor antagonist
-
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.
-
-
Read Online
- Succinct synthesis of bosentan utilizing glycol Mono-THP ether
-
GRAPHICAL ABSTRACT A concise synthetic method for bosentan, a nonpeptide orally active dual endothelin (ET-1A/B) receptor antagonist used for the treatment of pulmonary artery hypertension (PAH), was developed. We developed a new succinct synthetic route for bosentan by employing an acid-labile tetrahydropyran (THP)-protected glycol. THP group is advantageous over the previously known protection groups used in bosentan synthesis in that it provides a clean and quantitative deprotection. Bosentan was constructed via two parallel reaction pathways, yet the better product yield was obtained from a pathway via 6. Deprotection of THP ether was achieved under a mild acidic condition to afford bosentan.
- Lee, Chung Ryul,Lee, Sang Yeul,Nam, Tae-Gyu
-
-
Read Online
- A preparation method of bosentan monohydrate, novel intermediate useful for the preparation of bosentan monohydrate, and the preparation method thereof
-
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.
- -
-
-
- A method for the treatment of pulmonary arterial hypertension drug preparation method
-
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.
- -
-
Paragraph 0118; 0129; 0138; 0139
(2017/10/07)
-
- METHOD FOR PRODUCING BOSENTAN OR HYDRATE THEREOF
-
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
- -
-
Paragraph 0042; 0043
(2017/01/09)
-
- METHOD FOR PRODUCING BOSENTAN USING DEHYDRATING AGENT OR HYDRATE THEREOF
-
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 are 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 adding sodium hydroxide as a base and further a dehydrating agent; and a hydrate thereof. SELECTED DRAWING: Figure 4 COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0039-0040
(2017/01/12)
-
- PROCESS FOR PREPARATION OF BOSENTAN MONOHYDRATE OF PHARMACEUTICAL PURITY
-
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.
- -
-
Page/Page column 14; 15
(2014/07/21)
-
- An alternate synthesis of bosentan monohydrate, an endothelin receptor antagonist 1
-
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
-
p. 265 - 269
(2014/02/14)
-
- A new efficient synthetic process for an endothelin receptor antagonist, bosentan monohydrate
-
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
-
p. 1021 - 1026
(2013/09/12)
-
- ACID ADDITION SALTS OF BOSENTAN
-
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.
- -
-
-
- New approaches to endothelin receptor antagonist-bosentan
-
An improved and efficient synthetic process developed for an endothelin receptor antagonist, bosentan monohydrate by condensing a key intermediate 4-tert-butyl-N-(6-hydroxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidine-4-yl) benezenesulfonamide 5 with commercially cheaper chloro acetonitrile and α-halo esters. This synthetic approach efficiently provides highly pure bosentan without formation of the major impurity 2 (dimer) and less than 0.15% of Nalkylated impurity 3 and pyrimidinone impurity 5 in the final product. In the present process upon purification of bosentan monohydrate gave overall yield of 62-65%.
- Rebelli, Pradeep,Yerrabelly, Jayaprakash Rao,Yalamanchili, Bharathi Kumari,Kommera, Rajashekar,Ghojala, Venkat Reddy,Bairy, Kondal Reddy
-
p. 364 - 368
(2013/07/26)
-
- PROCESS FOR THE PREPARATION OF BOSENTAN MONOHYDRATE
-
The invention relates to improved processes for the preparation of bosentan monohydrate which provide higher yield and purity.
- -
-
-
- PROCESS FOR THE PREPARATION OF BOSENTAN
-
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.
- -
-
Page/Page column 11
(2014/01/08)
-
- A NOVEL PROCESS FOR PREPARATION OF BOSENTAN
-
A novel ammonium salt of Bosentan of formula (VIII); has been disclosed. The salt may be either crystalline or amorphous or mixture of Crystalline and amorphous form. A novel single pot process for the preparations of ammonium salt of Bosentan has been disclosed. The process comprises reacting the 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'- bipyrimidine with 4-tert-butylbenzenesulfonamide in the presence of solvent and a base; adding ethylene glycol to the reaction mass and isolating the ammonium salt of Bosentan. The ammonium salt of Bosentan is converted into Bosentan and further into Bosentan Monohydrate which are substantially free from dimer impurity and 6-hydroxy impurity.
- -
-
Page/Page column 22-23
(2012/03/09)
-
- PROCESS FOR PREPARATION OF ENDOTHELIAL RECEPTOR ANTAGONIST (BOSENTAN)
-
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).
- -
-
-
- PROCESS FOR THE PREPARATION OF BOSENTAN
-
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.
- -
-
-
- AN IMPROVED PROCESS FOR PREPARING BOSENTAN
-
The present invention relates to an improved process for preparing Bosentan of formula (I).
- -
-
-
- 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
-
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
-
p. 7849 - 7861
(2012/10/29)
-
- A PROCESS FOR THE PREPARATION OF BOSENTAN
-
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.
- -
-
Page/Page column 16
(2012/05/19)
-
- CRYSTALLINE FORMS OF BOSENTAN SALTS AND PROCESSES FOR THEIR PREPARATION
-
The present invention relates to crystalline forms of bosentan salts and processes for their preparation.(FORMULA)
- -
-
Page/Page column 6
(2012/11/13)
-
- PROCESS FOR PREPARING BOSENTAN MONOHYDRATE AND ITS INTERMEDIATES
-
The present invention relates to a process for preparing Bosentan Monohydrate; in particular, the present invention provides the preparation of the novel 4-tert- butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)- pyrimidin-4-yl]-benzenesulfonamide sodium salt as an ethylene glycol solvate (Bosentan sodium salt ethylene glycol solvate), which is a useful intermediate for obtaining Bosentan Monohydrate in a pure form.
- -
-
Page/Page column 12
(2012/04/17)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF BOSENTAN
-
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.
- -
-
-
- IMPROVED PROCESS FOR THE PREPARATION OF 4-(1,1-DIMETHYLETHYL)-N-[6-(2-HYDROXYETHOXY)-5-(2-METHOXYPHENOXY)[2,2'-BIPYRIMIDIN]-4-YL]BENZENESULFONAMIDE
-
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)
- -
-
-
- CRYSTALLINE FORMS OF BOSENTAN SALT AND PROCESSES FOR THEIR PREPARATION
-
The present invention relates to crystalline forms of bosentan salts and processes for their preparation.
- -
-
Page/Page column 17; 18
(2011/06/16)
-
- Methods for predicting the response to statins
-
The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
- -
-
-
- Facile one-pot process for large-scale production of highly pure bosentan monohydrate, an endothelin receptor antagonist
-
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.
-
experimental part
p. 1382 - 1387
(2012/01/11)
-
- PROCESS FOR THE PREPARATION OF BOSENTAN
-
The present invention provides a novel process for obtaining Bosentan, with few synthesis steps, by coupling the intermediate pyrimidine compound of formula I with the sulfonamide compound of formula II. The use of said efficient process prevents the use of hazardous chemicals and thus it is of considerable interest for obtaining Bosentan in a large industrial scale. The invention also refers to the novel intermediates of formula II and to a process for its production.
- -
-
Page/Page column 30-31
(2011/10/13)
-
- Process for the preparation of bosentan
-
The present invention provides a novel process for obtaining Bosentan, with few synthesis steps, by coupling the intermediate pyrimidine compound of formula I with the sulfonamide compound of formula II. The use of said efficient process prevents the use of hazardous chemicals and thus it is of considerable interest for obtaining Bosentan in a large industrial scale. The invention also refers to the novel intermediates of formula II and to a process for its production.
- -
-
Page/Page column 16
(2011/10/12)
-
- PROCESS FOR THE PREPARATION OF ENDOTHELIN RECEPTOR ANTAGONISTS
-
The present invention relates to a process for the preparation of endothelin receptor antagonists, in particular bosentan, in which a compound of formula (II) reacts with an alkylating agent X-R formula (II), wherein R is either -CH2CH2OH or a group that can be transformed into - CH2CH2OH; X is a leaving group; and R2 is a 4-terf-butylbenzenesulfonamido group or a group that can be transformed into 4-terf-butylbenzenesulfonamido group; and further transforming the resulting product into bosentan. Useful intermediates are disclosed, its use for the preparation of bosentan, as well as pharmaceutical compositions comprising the product obtained by the above process.
- -
-
Page/Page column 15
(2010/04/03)
-
- PROCESSES FOR THE PREPARATION OF BOSENTAN AND ITS INTERMEDIATES THEREOF
-
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.
- -
-
Page/Page column 12
(2010/10/19)
-
- PROCESS FOR THE INTRODUCTION OF HYDROXYETHOXY SIDE CHAIN IN BOSENTAN
-
The present invention relates to an improved process for the preparation of bosentan. In particular it relates to a process for preparing bosentan substantially free from the dimer impurity of formula (II) and the 6-hydroxy impurity of formula (III). The invention also relates to a pharmaceutical composition comprising bosentan and its use in the treatment of endothelin-receptor mediated disorders.
- -
-
Page/Page column 8
(2010/10/19)
-
- PROCESS FOR THE PREPARATION OF BOSENTAN
-
The invention concerns a new process for the preparation of bosentan or bosentan monohydrate and a new salt of bosentan.
- -
-
Page/Page column 7
(2010/10/03)
-
- PROCESS FOR PREPARATION OF BOSENTAN
-
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.
- -
-
Page/Page column 6; 21; 25
(2010/04/25)
-
- PROCESS FOR THE PREPARATION OF BOSENTAN
-
The present invention provides a novel process for obtaining Bosentan, with few synthesis steps, by coupling the intermediate pyrimidine derivative of formula I with the sulfonamide derivative of formula II. The use of said process prevents the protection of the hydroxyl group of the sulfonamide II and thus is of considerable interest for obtaining Bosentan in a large industrial scale. The invention also refers to the intermediates of formula II and to a process for its production.
- -
-
Page/Page column 15-16
(2010/04/03)
-
- PROCESS FOR INTRODUCTION OF HYDROXYETHOXY SIDE CHAIN IN BOSENTAN
-
The present invention relates to an improved process for the preparation of bosentan. In particular it relates to a process for preparing bosentan substantially free from the dirner impurity of formula (II) and the 6-hydroxy impurity of formula (III). The invention also relates to a pharmaceutical composition comprising bosentan and its use in the treatment of endothelin-receptor mediated disorders.
- -
-
Page/Page column 16
(2009/03/07)
-
- BOSENTAN SALTS
-
Stable acid addition salts of bosentan useful for the purification of bosentan base; the salts are in solid state and the starting acid has a pKa lower than 3.
- -
-
Page/Page column 4
(2009/12/05)
-
- Process for the Preparation of Bosentan
-
A process for the preparation of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-benzenesulfonamide, bosentan, comprising the reaction of a compound of formula (II) or a salt thereof, wherein Z is an optionally protected hydroxy group, with a compound of formula (III), in the presence of a base; and, if necessary, the removal of the hydroxy-protecting group, and/or, if desired, the conversion of a compound of formula (I) to a salt thereof, or vice versa; and novel intermediates useful for its synthesis.
- -
-
Page/Page column 6
(2009/07/03)
-
- NOVEL POLYMORPHS OF BOSENTAN
-
Disclosed herein are novel polymorphic forms of bosentan, processes for preparation, pharmaceutical compositions, and method of treating thereof.
- -
-
Page/Page column 31
(2009/05/30)
-
- PROCESS FOR PREPARING BOSENTAN
-
The present invention relates to a novel intermediate useful in the preparation of bosentan and to processes for the preparation of said intermediate and bosentan. The invention further relates to compositions comprising bosentan prepared according to the processes of the invention and their use in the treatment of endothelin-receptor mediated disorders.
- -
-
Page/Page column 16-17
(2009/10/09)
-
- IMPROVED AND NOVEL PROCESS FOR THE PREPARATION OF BOSENTAN
-
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.
- -
-
Page/Page column 18; 27
(2009/09/05)
-
- PROCESSES FOR THE PREPARATION OF BOSENTAN AND RELATED COMPOUNDS USING NOVEL INTERMEDIATES
-
Provided herein are novel, commercially viable and industrially advantageous processes for the preparation of substantially pure ethylene glycol sulfonamide compounds such as bosentan using novel intermediates.
- -
-
-
- METHOD OF SYNTHESIS OF BOSENTAN, ITS POLYMORPHIC FORMS AND ITS SALTS
-
The present invention relates to alkaline earth metal salts of bosentan, anhydrous bosentan, polymorphic forms thereof, amorphous bosentan and processes for preparing them. The present invention further relates to a process for the preparation of bosentan and its pharmaceutically acceptable salts.
- -
-
Page/Page column 22
(2009/08/14)
-
- Process for the preparation of bosentan
-
A process for the preparation of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yl]-benzenesulfonamide, bosentan, comprising the reaction of a compound of formula (II) or a salt thereof, wherein Z is an optionally protected hydroxy group, with a compound of formula (III), in the presence of a base; and, if necessary, the removal of the hydroxy-protecting group, and/or, if desired, the conversion of a compound of formula (I) to a salt thereof, or vice versa; and novel intermediates useful for its synthesis.
- -
-
Page/Page column 9
(2009/07/17)
-
- SUBSTITUTED PYRIMIDINES
-
Disclosed herein are substituted pyrimidine-based endothelin modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
Page/Page column 33
(2008/12/07)
-
- NOVEL POLYMORPHIC FORMS
-
Novel polymorphic forms of bosentan and processes for their preparation are disclosed. Further, pharmaceutical compositions comprising said polymorphicforms and the use of said compositions in the treatment of patientssuffering from endothelin receptor mediated disorders, for example,cardiovascular disorders such as hypertension, pulmonary hypertension, ischemia, vasospasm and angina pectoris are disclosed.
- -
-
Page/Page column 20
(2009/01/20)
-
- Use of endothelin inhibitors for treatment or prevention of fibrotic disorders
-
The use of endothelin inhibitors for the preparation of drugs for treatment or prevention of fibrotic disorders.
- -
-
-
- Preparation of sulfonamides
-
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.
- -
-
-
- Discovery of Ro 48-5695: A potent mixed endothelin receptor antagonist optimized from Bosentan
-
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
-
p. 2223 - 2228
(2007/10/03)
-
- SULFONAMIDES
-
The novel sulfonamides of formula I, STR1 in which the symbols R. sup.1-R 9, R a, R b, X, Y and n have the significance given in the description and salts thereof can be used for the treatment of circulatory disorders, especially hypertension, ischemia, vasopasms and angina pectoris.
- -
-
-