Modifications and structure–activity relationships at the 2-position of 4-sulfonamidopyrimidine derivatives as potent endothelin antagonists

Morimoto, Hiroshi; Shimadzu, Hideshi; Hosaka, Toshihiro; Kawase, Yasushi; Yasuda, Kōsuke; Kikkawa, Kohei; Yamauchi-Kohno, Rikako; Yamada, Kazuo

doi:10.1016/s0960-894x(01)00682-5

Cited by 14 publications

(5 citation statements)

References 12 publications

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“…In this way, a variety of O-, S-, N-, and C-nucleophiles can be bound to the oxacalixarene platform (Scheme , Table ). To be able to perform S N Ar reactions on oxacalix[4]arene 1 , the 2-(methylsulfanyl) groups have to be activated for nucleophilic displacement by oxidizing them to their methylsulfonyl analogues. 10a, Oxacalix[4]arene 1 was oxidized to bis(methylsulfonyl)oxacalixarene 4 nearly quantitatively (96%), and without the need of chromatography, using m -CPBA as an oxidant.…”

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confidence: 99%

Efficient Post-Macrocyclization Functionalizations of Oxacalix[2]arene[2]pyrimidines

et al. 2008

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Diversely functionalized oxacalix[2]arene[2]pyrimidines have been synthesized starting from a bis(methylsulfanyl)-substituted oxacalix[4]arene by two efficient post-macrocyclization pathways. Functionalized aryl groups were introduced on the pyrimidine building block via Liebeskind-Srogl cross-coupling reactions, while a variety of O-, S-, N-, and C-nucleophiles were inserted on the calixarene skeleton by nucleophilic aromatic substitution reactions on the bis(methylsulfonyl)oxacalix[4]arene analogue.

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confidence: 99%

Efficient Post-Macrocyclization Functionalizations of Oxacalix[2]arene[2]pyrimidines

et al. 2008

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“…This encouraged us to further evaluate the sulfamide series with scaffolds lacking a substituent in position 2 of the core pyrimidine. We therefore prepared a number of 2-unsubstituted pyrimidine derivatives incorporating a selection of 5-substituents that were known to lead to potent ET receptor antagonists. − Some examples are compiled in Table . As shown with compounds 52 and 53 , a 3-methoxyphenoxy rather than a 2-methoxyphenoxy substituent led to an increase in potency on ET A but left the affinity for ET B unchanged.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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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 ET(A) 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.

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“…The same synthetic protocol was used to obtain 2-substituted 4,6-dichloro-5-(p-tolyl)pyrimidines 53b-f, which are useful intermediates in the synthesis of potential endothelin ET A antagonists 54b-f (Scheme 30). 100 A wide range of 2-amino-substituted 4-(hetero)arylpyrimidines were obtained from 2-chloropyrimidine (23a) and organolithium compounds 55 by a multistep reaction sequence (Scheme 31). 98,[100][101][102][103][104] Compounds 57 are agonists of the Wnt-b-catenin cellular messaging system, 102,103 while their structural analogues 58 exhibit properties of the serotonin 5-HT receptor ligands.…”

Section: Scheme 29 2-substituted 46-dichloropyrimidines Through S N mentioning

confidence: 99%

“…100 A wide range of 2-amino-substituted 4-(hetero)arylpyrimidines were obtained from 2-chloropyrimidine (23a) and organolithium compounds 55 by a multistep reaction sequence (Scheme 31). 98,[100][101][102][103][104] Compounds 57 are agonists of the Wnt-b-catenin cellular messaging system, 102,103 while their structural analogues 58 exhibit properties of the serotonin 5-HT receptor ligands. 98,104 For a better understanding of the use of organolithium compounds in the nucleophilic…”

Section: Scheme 29 2-substituted 46-dichloropyrimidines Through S N mentioning

confidence: 99%

Recent Advances in Direct C–H Functionalization of Pyrimidines

et al. 2017

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Data spanning the period 2000–2017 on the direct C–H functionalization of pyrimidines are collected and discussed in this review. This demonstrates the surge of interest and creativity that this field of chemistry has experienced during the last two decades. Plausible applications of highly functionalized pyrimidines are also discussed.1 Introduction2 Transition-Metal-Catalyzed C–H Functionalization of Pyrimidine Derivatives3 Transition-Metal-Free Direct C–H Functionalization of Pyrimidine Derivatives4 Deprotonative Metalation of Pyrimidine Derivatives5 Conclusions

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Modifications and structure–activity relationships at the 2-position of 4-sulfonamidopyrimidine derivatives as potent endothelin antagonists

Cited by 14 publications

References 12 publications

Efficient Post-Macrocyclization Functionalizations of Oxacalix[2]arene[2]pyrimidines

Efficient Post-Macrocyclization Functionalizations of Oxacalix[2]arene[2]pyrimidines

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

Recent Advances in Direct C–H Functionalization of Pyrimidines

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