Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
J Org Chem ; 84(12): 8006-8018, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31124362

RESUMEN

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.


Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Amidas/química , Técnicas de Química Sintética , Lactamas/química , Fenol/química
2.
J Org Chem ; 84(8): 4780-4795, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30475616

RESUMEN

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.


Asunto(s)
Antivirales/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Estructura Molecular , Estereoisomerismo , Proteínas no Estructurales Virales/metabolismo
3.
Antimicrob Agents Chemother ; 60(8): 4830-9, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27246784

RESUMEN

Oxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16- to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.


Asunto(s)
Antibacterianos/farmacología , Ciclooctanos/farmacología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , ADN-Topoisomerasas de Tipo II/metabolismo , Inhibidores de Topoisomerasa II/farmacología , Animales , Línea Celular , ADN Bacteriano/genética , Perros , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Ratas , Ratas Wistar , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/genética
4.
J Am Chem Soc ; 137(43): 13728-31, 2015 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-26414910

RESUMEN

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

5.
J Med Chem ; 65(8): 6001-6016, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35239336

RESUMEN

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.


Asunto(s)
Inhibidores Enzimáticos , Éteres Cíclicos , Amidas , Ciclización , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo
6.
J Org Chem ; 75(23): 8330-2, 2010 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-21047088

RESUMEN

A mild Negishi cross-coupling of 2-heterocyclic organozinc reagents and aryl chlorides is described. The use of Pd(2)(dba)(3) and X-Phos as a ligand provides high yields for many examples. An efficient method to generate the organozinc reagents at room temperature is also demonstrated.


Asunto(s)
Hidrocarburos Clorados/química , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Reactivos de Enlaces Cruzados , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Estructura Molecular
7.
Org Lett ; 22(4): 1648-1654, 2020 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-31990565

RESUMEN

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)-C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

8.
J Org Chem ; 74(14): 5111-4, 2009 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-19485353

RESUMEN

A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purification. In addition, the iodination works on both 2- and 4-hydroxypyridines and -hydroxyquinolines.


Asunto(s)
Piridinas/química , Cromatografía Líquida de Alta Presión , Halogenación , Hidroxiquinolinas/química , Estructura Molecular
9.
J Med Chem ; 61(9): 3984-4003, 2018 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-29681153

RESUMEN

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Farmacorresistencia Viral/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Perros , Genotipo , Hepacivirus/genética , Hepacivirus/metabolismo , Masculino , Ratas , Distribución Tisular
10.
Chem Sci ; 8(4): 2841-2851, 2017 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-28553522

RESUMEN

Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.

11.
J Med Chem ; 60(1): 290-306, 2017 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-27808515

RESUMEN

We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Polimorfismo Genético , Pirrolidinas/química , Pirrolidinas/farmacología , Tiazoles/química , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Línea Celular , Perros , Haplorrinos , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Tiazoles/farmacocinética
12.
Org Lett ; 4(20): 3481-4, 2002 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-12323049

RESUMEN

The palladium-catalyzed N-(hetero)arylation of a number of heteroarylamines including 2-aminopyridines, 2-aminothiazoles, and their analogues has been realized using Xantphos as the ligand. Weak bases such as Cs(2)CO(3), Na(2)CO(3), and K(3)PO(4) were used in most cases to allow for the introduction of functional groups. Choice of the base and solvent was critical for the success of these reactions. [reaction: see text]

13.
Org Lett ; 6(9): 1465-8, 2004 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-15101768

RESUMEN

[reaction: see text] Directly mixing primary, secondary, and tertiary alcohols with nC(4)F(9)SO(2)F-NR(3)(HF)(3)-NR(3) in THF or MeCN results in convenient conversion to the corresponding fluorides in high yields. The readily available reagents are easy to handle, and the mild, almost neutral reaction conditions allow for excellent functional group compatibility. A NR(3)(HF)(3)/NR(3) ratio of

Asunto(s)
Alcoholes/síntesis química , Fluoruros/síntesis química , Acetonitrilos/química , Alcoholes/química , Hidrocarburos Fluorados/química , Estructura Molecular
14.
Org Lett ; 16(10): 2716-9, 2014 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-24786635

RESUMEN

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.


Asunto(s)
Anisoles/síntesis química , Pirrolidinas/síntesis química , Aminación , Aminas/química , Anisoles/química , Catálisis , Cloruros/química , Ciclohexanos , Estructura Molecular , Pirrolidinas/química , Estereoisomerismo , Compuestos de Zinc/química
15.
Org Lett ; 14(13): 3458-61, 2012 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-22725839

RESUMEN

A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.


Asunto(s)
Azepinas/síntesis química , Triazoles/síntesis química , Azepinas/química , Azepinas/farmacología , Estructura Molecular , Receptores de Orexina , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología
16.
J Org Chem ; 63(17): 5726-5727, 1998 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-11672160
17.
Org Lett ; 11(15): 3194-7, 2009 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-19572567

RESUMEN

Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.


Asunto(s)
Inhibidores de Integrasa VIH/química , Pirimidinonas/química , Cristalografía por Rayos X , Ciclización , Diseño de Fármacos , Inhibidores de Integrasa VIH/síntesis química , Estructura Molecular , Pirimidinonas/síntesis química , Pirrolidinonas/química , Raltegravir Potásico
18.
J Am Chem Soc ; 129(6): 1816-25, 2007 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-17284010

RESUMEN

TpMo(CO)2(5-alkenyl-eta-2,3,4-pyranyl) diene complexes function as excellent chiral scaffolds for the efficient regio- and enantiocontrolled synthesis of highly functionalized 1-oxadecaline derivatives through a novel transition metal-mediated Diels-Alder reaction. Very good to excellent yields and excellent levels of endo selectivity are obtained, and the reaction gives products with complete retention of enantiomeric purity when carried out with chiral, nonracemic scaffolds. A subtle structural modification on the diene (replacement of an H by a trans-CH3 group) leads to a complete change of regiochemistry, which is discussed from a mechanistic point of view. The role of the eta3-coordinated TpMo(CO)2 moiety is also critical to the further functionalization of the [4 + 2] cycloadducts, as illustrated by the preparation of 20 variously functionalized 1-oxadecaline derivatives (>98% ee when carried out with high enantiopurity scaffolds).


Asunto(s)
Alquenos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Cromanos/síntesis química , Molibdeno/química , Compuestos Organometálicos/química , Piranos/química , Ciclización , Estereoisomerismo
19.
J Org Chem ; 72(12): 4554-7, 2007 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-17500567

RESUMEN

Pyridine N-oxides were converted to 2-aminopyridines in a one-pot fashion using Ts2O-t-BuNH2 followed by in situ deprotection with TFA. The amination proceeded in high yields, excellent 2-/4-selectivity, and with good functional group compatibility. 2-Amino (iso)quinolines were also obtained in the same manner. Combined with the simple oxidation of pyridines to pyridine N-oxides, this method provides a general and efficient way for amination of 2-unsubstituted pyridines.


Asunto(s)
Aminopiridinas/síntesis química , Aminoquinolinas/síntesis química , Piridinas/química , Quinolinas/química , Aminación
20.
J Org Chem ; 71(2): 840-3, 2006 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-16409008

RESUMEN

[reaction: see text] Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of protected alpha-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with alpha-alkoxy ketones and other compounds via Felkin-Ahn control.


Asunto(s)
Efedrina/análogos & derivados , Efedrina/síntesis química , Aminas , Hidrocarburos Aromáticos , Indicadores y Reactivos , Cetonas , Modelos Moleculares , Conformación Molecular , Solventes , Estereoisomerismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA