Efficient Synthesis of Losartan, A Nonpeptide Angiotensin II Receptor Antagonist

Larsen, Robert D.; King, Anthony O.; Chen, Cheng Y.; Corley, Edward G.; Foster, Bruce S.; Roberts, F. E.; Yang, Chunhua; Lieberman, David; Reamer, Robert A.; Tschaen, David M.; Verhoeven, Thomas R.; Reider, Paul J.; Young, Sophia; Rossano, Lucius T.; Brookes, Sidney; Meloni, David; Moore, James R.; Arnett, John F.

doi:10.1021/jo00100a048

Cited by 179 publications

(75 citation statements)

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“…Diese sind wertvolle Bausteine unter anderem in der Synthese hochkomplexer Naturstoffe [21] oder Arzneimittel (z. B. das Antihypertonikum Losartan ® [22] oder das Antibiotikum Vancomycin [23]) in Forschung und Industrie (Abbildung 2).…”

Section: Suzuki-kupplungunclassified

Organometall‐Reaktionen in Wasser

Seßler¹,

Schatz

2012

Chemie in nserer Zeit

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Vorteile von Wasser als Lösungsmittel liegen auf der Hand: Es ist ungiftig und nicht brennbar, während organische Lösungsmittel oft giftig, teuer und leicht entflammbar sind und noch dazu aus Kohlenstoffquellen gewonnen werden müssen [8,9] [3].Es ist somit nicht verwunderlich, dass diese -zumindest in Industriestaaten -gut verfügbare, billige und in guter Reinheit zu erhaltene Verbindung auch als Lösungs-mittel in chemischen Prozessen eingesetzt wird. Gerade in den letzten Jahren ist das Interesse am Lösungsmittel Wasser und insbesondere an Synthesen "in water" [4], "on water" [5] oder "in the presence of water" signifikant gestiegen, wobei auf diese Detailunterschiede im Rahmen dieser Zusammenstellung nicht näher eingegangen werden soll [6,7]. 48

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Section: Suzuki-kupplungunclassified

Organometall‐Reaktionen in Wasser

Seßler¹,

Schatz

2012

Chemie in nserer Zeit

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“…Cette réac-tion a suscité un grand intérêt dans la communauté des chimistes organiciens et connaît de nombreuses applications aussi bien dans le milieu académique qu'industriel [3]. Un exemple d'application industrielle de ces réactions de couplage est la synthèse du Losartan, médicament de la famille des sartans (antagonistes des récepteurs AT1 de l'angiotensine II) développé par la Société DuPont et utilisé dans le traitement de l'hypertension artérielle ( Figure 1B) [4].…”

Section: Palladium Et Synthèse Organique Une Précieuse Rencontre Récounclassified

Palladium et synthèse organique

Bouyssi

Balme

2010

Med Sci (Paris)

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“…The first line therapy for the treatment of hypertension is angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. The biphenyl-tetrazole is the key substrate [3][4][5], which belongs to a group of angiotensin II-receptor antagonists generally referred to as "sartans". These include Losartan, Valsartan and Candesartan which are useful in the treatment of hypertension, heart diseases, and bladder diseases and work by blocking the action of angiotensin II on its receptor ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Tetrazole Regioisomers of Biphenyl as ACE Inhibitors

Meti¹,

Kamble²,

Kumbar³

et al. 2017

MOCR

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Abstract. Novel angiotensin converting enzyme (ACE) inhibitors were designed based on the structure of commercially available sartans and synthesized by N-alkylation of 5-substituted-1H-tetrazole with 4'-(bromomethyl)-biphenyl-2-carbonitrile gave 1,5-and 2,5-regioisomers of tetrazole. The nitrile group appended to biphenyl nucleus was converted into tetrazole and later the tetrazole was ring transformed into 1,3,4-oxadiazole. The synthesized compounds were screened for the ACE inhibition and some of the compounds exhibited significant results.Keywords: Biphenyl, tetrazole, N-alkylation, regioisomers, 1,3,4-Oxadiazole, ring transformation, ACE inhibition IntroductionAll the cardiovascular diseases in the present era are caused mainly by "lifestyle disorder", a term coined to redefine hypertension. Although the causes of cardiovascular disease are many, hypertension stands to be the crucial one. A recent study suggests that hypertensive patients are more prone to develop type II diabetes [1]. Thus, these chronic diseases coexist, with increasing risk of coronary artery disease, kidney damage, vision problems, enlarging of heart, stroke and heart failure. Many drugs have been developed to treat such chronic diseases with reduced risk of side effects. Thus, the efficacy of hypertensive medications involves many etiologies and disease mechanisms to treat the hypertensive related chronic disease [2]. The first line therapy for the treatment of hypertension is angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. The biphenyl-tetrazole is the key substrate [3][4][5], which belongs to a group of angiotensin II-receptor antagonists generally referred to as "sartans". These include Losartan, Valsartan and Candesartan which are useful in the treatment of hypertension, heart diseases, and bladder diseases and work by blocking the action of angiotensin II on its receptor ( Figure 1). Tetrazole is a heterocyclic moiety that functions as a carboxylic acid bioisostere with greater metabolic stability. It forms two hydrogen bonds with peptide residues in a biological target site which facilitates the binding interaction [6]. The negative charge of the tetrazolic anion is delocalized over all four nitrogens which play a major role in the clog P value and thus resulting in better oral bioavailability and cell penetration. It also exhibits many biological activities like antihypertensive [7,8], anti-inflammatory [9], endocannabinoid metabolism inhibitor, antibiotic [10] and anticonvulsant [11]. 1,3,4-Oxadiazole is a biologically active nucleus which shows a broad spectrum of pharmacological activities such as antimicrobial [12], antiprotozoal [13], anti-inflammatory [14], anti-tubercular [15] etc. Thus, the combination of two biological active moieties enhances the biological activities of the novel template.Considering all the above observations, we intended to synthesize novel scaffolds by N-alkylation of 5-substituted-1H-tetrazole 2a-d with 4'-(bromomethyl)-biphenyl-2-carbonitrile 1, there by aff...

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Efficient Synthesis of Losartan, A Nonpeptide Angiotensin II Receptor Antagonist

Cited by 179 publications

References 10 publications

Organometall‐Reaktionen in Wasser

Organometall‐Reaktionen in Wasser

Palladium et synthèse organique

Synthesis of Tetrazole Regioisomers of Biphenyl as ACE Inhibitors

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