- Trityl losartan
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The title compound (systematic name: (2-butyl-4-chloro-1-[2-(2-trityl-2H- tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazol-5-yl}methanol), C 41H37ClN6O, crystallizes in the centrosym-metric space group P1 with two independent molecules in the asymmetric unit. These molecules differ significantly only in the relative orientations of the rings in the biphenylyltetrazole moieties. One of the molecules shows disorder for three C atoms in the n-butyl group. Hydrogen bonds link the molecules in an infinite chain along the a axis.
- Sieron, Leslaw,Nagaraj,Prabhuswamy,Yathirajan,Nagaraja,Narasegowda,Gaonkar
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- Mechanistic Studies of the Suzuki Cross-Coupling Reaction
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The key step in the synthesis of the drug substance losartan is a palladium-catalyzed cross-coupling reaction of an aryl bromide and a boronic acid.The reaction scheme was defined in kinetic studies using HPLC, and computer simulation served to depict the
- Smith, George B.,Dezeny, George C.,Hughes, David L.,King, Anthony O.,Verhoeven, Thomas R.
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- Continuous Synthesis and Separation ofp-Bromobenzyl Bromide Using Atom-Efficient Bromination ofp-Bromotoluene without Any Organic Effluent: Potential for Green Industrial Practice
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This work focuses on the bromination ofp-bromotoluene (PBT) using different brominating agents such as liquid Br2, NaBr-NaBrO3, NaBr-NaBrO3-NaCl, NaBr-H2O2, and HBr-H2O2. NaBr-NaBrO3-NaCl is an eco-friendly brominating agent obtained from a bromine recovery plant. Both NaBr-NaBrO3and NaBr-NaBrO3-NaCl were found to be nonhazardous and efficient brominating agents. Pure NaBr-NaBrO3resulted in the best PBT conversion with 79.7% Br atom efficiency in water and 98.2% average Br atom efficiency using dichloroethane as a solvent. Dichloroethane is de facto no longer used in the US and Europe and is not eco-friendly; the process with water as a solvent is the best. The substrate to active bromine molar ratio of 3:1 was found to be sufficient to get the maximum selectivity ofp-bromobenzyl bromide (PBBB). The low-temperature crystallization method was used for separation cum purification of the product. Unreacted PBT was recycled along with the dibromo byproduct obtained. The dibromo product, which was built up gradually in the reaction mixture over 10 successive batches, was converted back into PBBB/PBT through NaBH4treatment of the mother liquor. This continuous process is highly sustainable and produces zero organic waste, making it potentially attractive toward green industrial implementation.
- Sancheti, Sonam V.,Yadav, Ganapati D.
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p. 2071 - 2080
(2021/09/13)
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- Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor
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Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.
- Meyer, Maxime,Foulquier, Sébastien,Dupuis, Fran?ois,Flament, Stéphane,Grimaud, Linda,Henrion, Daniel,Lartaud, Isabelle,Monard, Gérald,Grillier-Vuissoz, Isabelle,Boisbrun, Michel
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p. 334 - 352
(2018/09/22)
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- New losartan-hydrocaffeic acid hybrids as antihypertensive-antioxidant dual drugs: Ester, amide and amine linkers
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We report new examples of a series of losartan-hydrocaffeic hybrids that bear novel ester, amide and amine linkers. These compounds were made by linking hydrocaffeic acid to the side chain of losartan at the C-5 position of the imidazole ring through different strategies. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect and have increased antioxidant ability. Most of them reduced arterial pressure in rats better or as much as losartan.
- García, Gonzalo,Serrano, Isabel,Sánchez-Alonso, Patricia,Rodríguez-Puyol, Manuel,Alajarín, Ramón,Griera, Mercedes,Vaquero, Juan J.,Rodríguez-Puyol, Diego,álvarez-Builla, Julio,Díez-Marqués, María L.
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experimental part
p. 90 - 101
(2012/07/13)
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- PROCESS FOR THE PREPARATION OF LOSARTAN AND ITS SALTS
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The invention relates to the preparation of losartan and its salts (e.g., losartan potassium). More particularly, the invention relates to the preparation of losartan and its salts (e.g., losartan potassium) in a simplified process that provides higher purity losartan potassium and losartan potassium having larger crystal sizes. The invention further includes formulating losartan, its salts (e.g., losartan potassium ) and/or in vivo cleavable prodrugs thereof (collectively "the compounds of the invention") into readily usable dosage units for the therapeutic treatment (including prophylactic treatment) of mammals, including humans.
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Page/Page column 11-12
(2008/06/13)
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- A process for the preparation of losartan derivatives by chlorination and reduction of the respective 1H-imidazole-5-carbaldehydes
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The invention provides a process for the preparation of a sartan derivative of formula (I): wherein R = C2-C7 straight or branched alkyl or C3-C9 cycloalkyl, or a pharmaceutically acceptable salt thereof, comprising the steps of chlorinating and reducing, in any order, a compound of formula (III): wherein R is defined as above to form a compound of formula (VI), wherein R is defined as above and then deprotecting said compound of formula (VI) to obtain the sartan derivative of formula (I), and optionally converting said sartan derivative into one of its pharmaceutically acceptable salts. A preferred embodiment of this invention is a process for the preparation of losartan and, particularly, its potassium salt.
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Page/Page column 11
(2008/06/13)
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- Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients
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The present invention relates to the use, for the preparation of drugs to increase the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amount of an angiotension II receptor antagonist compound, such as the class of substituted imidazoles represented by formula (I) and in particular by losartan potassium, 2-butyl-4-chloro-[(2′-tetrazol-5-yl)biphenyl-4-il]methyl]-5-(hydroxymethyl)imidazole potassium salt.
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- INSULIN SENSITIVITY WITH ANGIOTENSIN II RECEPTOR BLOCKING IMIDAZOLES
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This invention relates to a novel method of using an Angiotensin II antagonist for the improvement of insulin sensitivity alone or in conjunction with the treatment of hypertension. Angiotensin II antagonists such as the class of substituted imidazoles represented by formula I: STR1 and specifically by Losartan, 2-butyl-4-chloro-1-[(2'-tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(hydroxymethyl)imidazole potassium salt.
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- Polymorphs of losartan and the process for the preparation of form II of losartan
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Polymorphic forms of Losartan (Formula I) STR1 and a process for the preparation of Form II of Losartan. Losartan is known to be useful in the treatment of hypertension.
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- Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
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A method of treatment for atherosclerosis and/or reducing cholesterol using an angiotensin II antagonist. This method of treatment can be used in conjunction with the treatment of hypertension. Substituted imidazoles such as STR1 are useful as angiotensin II receptor antagonists for this method of treatment. A method of treatment for atherosclerosis and/or reducing cholesterol using an angiotensin II receptor antagonist in combination with an HMG-Co A reductase inhibitor. A method of treatment for atherosclerosis and/or reducing cholesterol using an angiotensin II receptor antagonist in combination with an HMG-Co A reductase inhibitor and an angiotensin converting enzyme inhibitor. Also within the scope of this invention are pharmaceutical compositions for this method of use.
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- Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist
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A highly efficient, convergent approach to the synthesis of the angiotensin II receptor antagonist losartan (1) is described. Directed ortho-metalation of 2-trityl-5-phenyltetrazole provides the key boronic acid intermediate 10 for palladium-catalyzed biaryl coupling with bromide 5 obtained from the regioselective alkylation of the chloroimidazole 2. This methodology overcomes many of the drawbacks associated with previously reported syntheses.
- Larsen,King,Chen,Corley,Foster,Roberts,Yang,Lieberman,Reamer,Tschaen,Verhoeven,Reider,Lo,Rossano,Brookes,Meloni,Moore,Arnett
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p. 6391 - 6394
(2007/10/02)
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- PROCESS FOR PREPARING BIPHENYLTETRAZOLE COMPOUNDS
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Method for the preparing biphenyltetrazole compounds which are angiotensin II receptor antagonists or which are useful intermediates to prepare angiotensin II receptor antagonists. An illustrative biphenyl tetrazole compound is 2-n-butyl-4-chloro-1-[(2'-(tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imi dazole-5-methanol, potassium salt.
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- Practical Synthesis and Regioselective Alkylation of Methyl 4(5)-(Pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate To Give DuP 532, a Potent Angiotensin II Antagonist
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DuP 532 (2), which is a potent angiotensin II receptor antagonist, has been prepared by two different routes.One route, which is more practical for large-scale synthesis, required the preparation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate (9).This imidazole was synthesized in five steps from commercially available 11 in 32percent overall yield.Alternate perfluoroalkylation methods of the iodoimidazole precursor 14 are presented.Imidazole 9 is remarkably stable to basic conditions and is alkylated by 2--4'-(bromomethyl) -1,1'-biphenyl (8), giving only the desired regioisomer.A comparison of the alkylation of the trisubstituted precursors and analogues to 9 with 8 indicate that even under mildly basic conditions (K2CO3/DMF), the mechanism is SE2cB (anionic), except for 2-propyl-4(5)-(hydroxymethyl)imidazole (11) which alkylates as a neutral species (SE2')
- Pierce, Michael E.,Carini, David J.,Huhn, George F.,Wells, Gregory J.,Arnett, John F.
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p. 4642 - 4645
(2007/10/02)
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- Tetrazolylphenylboronic acid intermediates for the synthesis of AII receptor antagonists
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Novel tetrazolylphenylboronic acids, methods for their preparation, and their use in the syntheses of angiotensin II receptor antagonists are disclosed.
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- Nonpeptide Angiotensin II Receptor Antagonists: The Discovery of a Series of N-(Biphenylylmethyl)imidazoles as Potent, Orally Active Antihypertensives
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A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared.These N-(biphenylylmethyl)imidazoles, e.g. 2-butyl-1--4-chloro-5-(hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously.It has been found that the acidic group at the 2'-position of the biphenyl is essential.Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency.The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective.The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
- Carini, David J.,Duncia, John V.,Aldrich, Paul E.,Chiu, Andrew T.,Johnson, Alexander L.,et al.
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p. 2525 - 2547
(2007/10/02)
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