Design and synthesis of a new indazole library: direct conversion of N-methoxy-N-methylamides (Weinreb amides) to 3-keto and 3-formylindazoles

Crestey, François; Stiebing, Silvia; Legay, Rémi; Cailly, Thomas; Rault, Syl­vain

doi:10.1016/j.tet.2006.10.063

Cited by 26 publications

(18 citation statements)

References 69 publications

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“…The 3-acetyl-1 H -indazole intermediate was synthesized from 1 H -indazole-3-carboxylic acid by initial conversion into Winreb amide using the one-pot reaction: mixed anhydride method followed by nucleophilic attack of N , O -dimethylhydroxylamine hydrochloride. The Winreb amide thus formed was further treated with methyl magnesium bromide to yield 3-acetyl-1 H -indazole [26]. The 3-acetyl-1 H -indazole was converted to α,γ-diketo ester 14 and further converted to compound 14a as described above.…”

Section: Resultsmentioning

confidence: 99%

“…Following a prenominal variation in the reported procedure [26], isobutyl chloroformate (0.79 g, 5.88 mmol) and N -methylmorpholine (0.59 g, 5.88 mmol) were added to a solution of 1 H -indazole-3-carboxylic acid (0.6 g, 3.70 mmol) in anhydrous THF (15 mL) under nitrogen atmosphere at −20°C, and the mixture was stirred for 4 h. To this mixture was added N , O -dimethylhydroxylamine hydrochloride (0.54 g, 5.55 mmol) suspended in 5 mL triethylamine. The reaction was then stirred at room temperature for 6 h, concentrated under vacuum and suspended in 20 mL n- hexane.…”

Section: Methodsmentioning

confidence: 99%

“…m.p. 184 – 186° C) [26]; R f = 0.71 ( n- hexane:EtOAc 70:30); 1 H NMR (400 MHz; CDCl 3 ; TMS) δ 13.85 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 2.65 (s, 3H).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Bhatt

Gurukumar

Basu

et al. 2011

European Journal of Medicinal Chemistry

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Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Here we report the synthesis and biological evaluation of a new series of α,γ-diketo acids (DKAs) as NS5B polymerase inhibitors. We initiated structure-activity relationship (SAR) optimization around the furan moiety of compound 1a [IC50 = 21.8 μM] to achieve more active NS5B inhibitors. This yielded compound 3a [IC50 = 8.2 μM] bearing the 5-bromobenzofuran-2-yl moiety, the first promising lead compound of the series. Varying the furan moiety with thiophene, thiazole and indazole moieties resulted in compound 11a [IC50 = 7.5 μM] bearing 3-methylthiophen-2-yl moiety. Finally replacement of the thiophene ring with a bioisosteric phenyl ring further improved the inhibitory activity as seen in compounds 21a [IC50 = 5.2 μM] and 24a [IC50 = 2.4 μM]. Binding mode of compound 24a using glide docking within the active site of NS5B polymerase will form the basis for future SAR optimization.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Bhatt

Gurukumar

Basu

et al. 2011

European Journal of Medicinal Chemistry

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“…10 Nucleophilic addition of Grignard or lithiated reagents to new Weinreb amides efficiently gave the corresponding ketones and allowed the design and synthesis of a new indazole library. 11 A rapid library-generation via liquid-phase multiple-parallel synthesis of 2-(substituted)benzyl-1-benzopyrano [4,3-c]pyrazol-3(2H)-ones, bearing two points of diversity, under microwave irradiation has been successfully performed using chromenone-3-carboxylic acids as starting materials. Compared to an identical library generated by conventional parallel synthesis, microwave-assisted parallel synthesis dramatically decreased reaction times from an average of 16 h to 13 min, and the yields of products and intermediates were improved in most cases.…”

Section: Solution-phase Synthesismentioning

confidence: 99%

Combinatorial Chemistry Online

Terrett

2007

Combinatorial Chemistry - an Online Journal

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1. Current literature highlights 1.1. Pyrazole CCK 1 receptor antagonists Cholecystokinin (CCK) is an endogenous 33 amino acid peptide hormone first identified by its pharmacological actions early in the last century, and later purified and sequenced in the 1970s. Subsequently, it was shown that CCK was released in response to food intake and that it regulates gallbladder contraction, pancreatic enzyme secretion, gastric acid secretion, and colonic motility amongst other pharmacological effects. CCK is abundant in the CNS and is believed to be involved in aspects of nociception, satiety and anxiogenesis.The biological actions of CCK are mediated through two G-protein coupled receptors, CCK 1 and CCK 2 , and a number of CCK 1 antagonists have been evaluated in the clinic for pancreatic disorders, IBS and biliary colic. Encouraging clinical results from a phase II trial of constipation-dependent IBS with a peptide derived CCK 1 antagonist has given encouragement to pursue non-peptide antagonists of CCK 1 . 1In this recent work, efforts were undertaken to modify an HTS lead (i) that was identified as a potent and selective antagonist of the CCK 1 receptor (pK i 7.6). This compound displayed promising physical properties and represented a novel chemical scaffold for SAR investigations undertaken by the construction of a solution phase library. The synthetic scheme involved varying positions around aromatic centers B and C giving antagonists of CCK 1 with pK i values between 6.2 and 8.1.During the course of these studies, a novel method for the evaluation of SAR in combinatorial matrices was explored. This new methodology provided for a quantitative assessment of additive and non-additive relationships in the SAR, allowing one to identify potential changes in the binding modes of these antagonists. The assumption with additive SAR models is that one variable in the structure does not affect the binding or conformation of the second variable. However, in many documented cases this assumption is invalid, thus limiting the predictive power of additive models. With the advent of combinatorial methods, a full matrix of compounds can be readily accessed synthetically, and the presence of non-additive relationships in the full matrix can suggest either a different binding mode in the biological target or direct interactions between different parts of a ligand. The results from this study indicate that all compounds tested bind to the receptor in a similar binding mode. N N O OH O (i) A B C Aminopyrrolidinetricarboxylic acids: new group III metabotropic glutamate receptor-selective antagonistsThe glutamate neurotransmitter plays a critical role in many disease processes. Glutamate exerts its effects through two families of receptors: metabotropic (mGlu) and ionotropic (iGlu) receptors. mGlu receptors have been further divided in three groups according to their sequence homologies, pharmacological properties and signal transduction pathways.Group III mGlu receptors include mGlu4, mGlu6, mGlu7 and mGlu8 receptors, which are neg...

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“…The indazole nucleus is a pharmaceutically important and emerging heterocycle with a broad spectrum of activities, including anti‐inflammatory , antitumor , anti‐HIV , antimicrobial , contraceptive , and have also been used as nNOS inhibitors . Therefore, a number of methods have been reported for the synthesis of indazole derivatives . Nevertheless, the development of new synthetic methods for the efficient preparation of heterocycles containing indazole ring fragment is therefore an interesting challenge.…”

Section: Introductionmentioning

confidence: 99%

Ionic Liquid Catalyzed One‐Pot Synthesis of 2H‐Pyridazino[1,2‐a]indazole‐1,6,9(11H)‐triones Via Three‐Component Reaction under Solvent‐Free Conditions

Ding

Guo

2016

Journal of Heterocyclic Chem

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Design and synthesis of a new indazole library: direct conversion of N-methoxy-N-methylamides (Weinreb amides) to 3-keto and 3-formylindazoles

Cited by 26 publications

References 69 publications

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Synthesis and SAR optimization of diketo acid pharmacophore for HCV NS5B polymerase inhibition

Combinatorial Chemistry Online

Ionic Liquid Catalyzed One‐Pot Synthesis of 2H‐Pyridazino[1,2‐a]indazole‐1,6,9(11H)‐triones Via Three‐Component Reaction under Solvent‐Free Conditions

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