RESUMO
N-Nitrosamines are strictly regulated in pharmaceutical products due to their carcinogenic nature. Therefore, the ability to rapidly and reliably identify the N-nitroso functionality is urgently needed. Unfortunately, not all ionized N-nitroso compounds produce diagnostic fragment ions and hence tandem mass spectrometry based on collision-activated dissociation (CAD) cannot be used to consistently identify the N-nitroso functionality. Therefore, a more reliable method was developed based on diagnostic functional-group selective ion-molecule reactions in a linear quadrupole ion trap mass spectrometer. 2-Methoxypropene (MOP) was identified as a reagent that reacts with protonated N-nitrosamines in a diagnostic manner by forming an adduct followed by the elimination of 2-propenol (CH3C(OH)âCH2]). From 18 protonated N-nitrosamine model compounds studied, 15 formed the diagnostic product ion. The lack of the diagnostic reaction for three of the N-nitrosamine model compounds was rationalized based on the presence of a pyridine ring that gets preferentially protonated instead of the N-nitroso functionality. These N-nitrosamines can be identified by subjecting a stable adduct formed upon ion-molecule reactions with MOP to CAD. Further, the ability to use ion-molecule reactions followed by CAD to differentiate protonated O-nitroso compounds with a pyridine ring from analogous N-nitrosamines was demonstrated This methodology is considered to be robust for the identification of the N-nitroso functionality in unknown analytes. Lastly, HPLC/MS2 experiments were performed to determine the detection limit for five FDA regulated N-nitrosamines.
Assuntos
Nitrosaminas , Espectrometria de Massas em Tandem , Íons/química , Preparações Farmacêuticas , Piridinas , Espectrometria de Massas em Tandem/métodosRESUMO
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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Piperidinas/química , Piperidinas/síntese química , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Amidas/química , Técnicas de Química Sintética , Lactamas/química , Fenol/químicaRESUMO
We report the discovery of novel N,N'-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catalysts afford substantial improvements in enantioselectivity and reaction rate for intramolecular spirocyclization reactions with catalyst loadings as low as 0.3â mol% under mild conditions.
Assuntos
Alcaloides de Cinchona/química , Alcaloides de Cinchona/síntese química , Catálise , Estrutura Molecular , Compostos de Espiro , EstereoisomerismoRESUMO
Matrix metalloproteinase-9 (MMP-9) has been implicated in the breakdown of the blood-brain barrier during cerebral ischemia. As a result, inhibition of MMP-9 may have utility as a therapeutic intervention in stroke. Towards this end, we have synthesized a series of 1-hydroxy-2-pyridinones that have excellent in vitro potency in inhibiting MMP-9 in addition to MMP-2. Representative compounds also demonstrate good efficacy in the mouse transient mid-cerebral artery occlusion (tMCAO) model of cerebral ischemia.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Piridonas/síntese química , Piridonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Piridonas/química , Piridonas/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Zinco/química , Zinco/metabolismoRESUMO
An unusual in-source fragmentation pattern observed for 14 doubly quaternized cinchona alkaloid-based phase-transfer catalysts (PTC) was studied using (+)-ESI high resolution mass spectrometry. Loss of the substituted benzyl cation (R1 or R2) was found to be the major product ion [M2+ - R1+ or R2+]+ in MS spectra of all PTC compounds. A Hofmann elimination product ion [M - H]+ was also observed. Only a small amount of the doubly charged M2+ ions were observed in the MS spectra, likely due to strong Columbic repulsion between the two quaternary ammonium cations in the gas phase. The positive voltage in the MS inlet but not the ESI probe was found to induce this extensive fragmentation for all PTC diboromo-salts. Compound 1 was used as an example to illustrate the proposed in-source fragmentation mechanism. The mechanism of formation of the Hofmann elimination product ion [M - H]+ was further investigated using HRMS/MS, H/D exchange, and DFT calculations. The proposed formation of 2b as the major Hofmann elimination product ion was supported both by HRMS/MS and DFT calculations. Formation of product ion 2b through a concerted unimolecular Ei elimination pathway is proposed rather than a bimolecular E2 elimination pathway for common solution Hofmann eliminations. Graphical Abstract á .
RESUMO
An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.
Assuntos
Antagonistas dos Receptores de Orexina , Piperidinas/síntese química , Piperidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Catálise , Estrutura Molecular , Piperidinas/químicaRESUMO
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.
Assuntos
Aminopiridinas/síntese química , Aminoquinolinas/síntese química , Piridinas/química , Quinolinas/química , AminaçãoRESUMO
A series of novel carboxylic acid-based alpha-sulfone MMP inhibitors have been synthesized and the in vitro enzyme SAR is discussed. A potential binding mode in the active site of the MMP-9 homology model was highlighted. These compounds are potent MMP-9 inhibitors and are selective over MMP-1.
Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Enxofre/química , Animais , Ácidos Carboxílicos/síntese química , Concentração Inibidora 50 , Metaloproteinases da Matriz/química , Metaloproteinases da Matriz/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.