Synthesis and evaluation of CCR5 antagonists containing modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane

Shah, Shrenik K.; Chen, Natalie; Guthikonda, Ravindra N.; Mills, Sander G.; Malkowitz, Lorraine; Springer, Martin S.; Gould, Sandra L.; DeMartino, Julie A.; Carella, Anthony; Carver, Gwen; Holmes, Karen; Schleif, William A.; Danzeisen, Renee; Hazuda, Daria J.; Kessler, Joseph; Miller, Michael D.; Emini, Emilio A.; MacCoss, Malcolm

doi:10.1016/j.bmcl.2004.12.044

Cited by 24 publications

(16 citation statements)

References 14 publications

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“…ethyl 3-(3-ethoxy-3-oxopropyl)-4-oxopiperidine-1-carboxylate, (6), following a literature procedure (Shah et al, 2005), which was converted in a three-step synthesis (68% yield) to thiolactam (8-1) (see Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

Preparation and structural analysis of (±)-cis-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate and (±)-trans-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate

et al. 2014

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Bicycle ring closure on a mixture of (4aS,8aR)- and (4aR,8aS)-ethyl 2-oxodecahydro-1,6-naphthyridine-6-carboxylate, followed by conversion of the separatedcisandtransisomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate, C11H18N2O2S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z′ = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate, C10H16N2O3, was also accomplished in good overall yield. Here the five-membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.

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Section: Resultsmentioning

confidence: 99%

Preparation and structural analysis of (±)-cis-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate and (±)-trans-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate

et al. 2014

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“…The structure of 58 was assigned by x-ray analysis of its hydrochloride salt 20. Significantly, the heterocyclic scaffolds present in 57 and 58 are found in compounds that are chemokine CCR5 receptor antagonists37 and inhibitors of dipeptidyl peptidase IV (DPP-IV) 38. Of course, 56 and related compounds may be transformed by other dipolar cycloaddition reactions, and such efforts are in progress.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of diverse heterocyclic scaffolds via tandem additions to imine derivatives and ring-forming reactions

2009

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A novel strategy has been developed for the efficient syntheses of diverse arrays of heterocyclic compounds. The key elements of the approach comprise a Mannich-type, multicomponent coupling reaction in which functionalized amines, aromatic aldehydes, acylating agents, and π-and organometallic nucleophiles are combined to generate intermediates that are then further transformed into diverse heterocyclic scaffolds via a variety of cyclization manifolds. Significantly, many of these scaffolds bear functionality that may be exploited by further manipulation to create diverse collections of compounds having substructures found in biologically active natural products and clinically useful drugs. The practical utility of this strategy was exemplified by its application to the first, and extraordinarily concise synthesis of the isopavine alkaloid roelactamine.

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“…For example, the octahydro-1H-pyrrolo[3,2- c ]pyridine scaffold present in 2 is represented in the CCR5 antagonist 3 14 and the bradykinin receptor antagonist martinellic acid ( 4 ). 15 Moreover, the privileged 2-arylpiperidine substructure present in 1 and 2 can be found in the substance P antagonist 5 16 and the neurokinin 1 receptor antagonist 6 .…”

Section: Introductionmentioning

confidence: 99%

Multicomponent, Mannich-type assembly process for generating novel, biologically-active 2-arylpiperidines and derivatives

Hardy

Martin

2014

Tetrahedron

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A multicomponent, Mannich-type assembly process commencing with commercially available bromobenzaldehydes was sequenced with [3+2] dipolar cycloaddition reactions involving nitrones and azomethine ylides to generate collections of fused, bicyclic scaffolds based on the 2-arylpiperidine subunit. Use of the 4-pentenoyl group, which served both as an activator in the Mannich-type reaction and a readily-cleaved amine protecting group, allowed sub-libraries to be prepared through piperidine N-functionalization and cross-coupling of the aryl bromide. A number of these derivatives displayed biological activities that had not previously been associated with this substructure. Methods were also developed that allowed rapid conversion of these scaffolds to novel, polycyclic dihydroquinazolin-2-ones, 2-imino-1,3-benzothiazinanes, dihydroisoquinolin-3-ones and bridged tetrahydroquinolines.

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Synthesis and evaluation of CCR5 antagonists containing modified 4-piperidinyl-2-phenyl-1-(phenylsulfonylamino)-butane

Cited by 24 publications

References 14 publications

Preparation and structural analysis of (±)-cis-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate and (±)-trans-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate

Preparation and structural analysis of (±)-cis-ethyl 2-sulfanylidenedecahydro-1,6-naphthyridine-6-carboxylate and (±)-trans-ethyl 2-oxooctahydro-1H-pyrrolo[3,2-c]pyridine-5-carboxylate

Synthesis of diverse heterocyclic scaffolds via tandem additions to imine derivatives and ring-forming reactions

Multicomponent, Mannich-type assembly process for generating novel, biologically-active 2-arylpiperidines and derivatives

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