192767-12-7

Upstream product

• 151103-08-1 4-difluoromethoxy-3-hydroxybenzaldehyde 
• 127842-54-0 3,4-bis-(difluoromethoxy)-benzaldehyde 
• 192767-03-6 2-(4-bromophenyl)-2-[2-(trimethylsilyl)ethoxymethoxy]-1,1,1,3,3,3-hexafluoropropane 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 76513-69-4 (2-trimethylethylsilylethoxy)methyl chloride 
• 2402-72-4 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol 
• 106-37-6 1.4-dibromobenzene 

Downstream Products

• 192767-14-9 3-(3,4-bis-difluoromethoxy-phenyl)-2-pyridin-4-yl-3-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-propionic acid ethyl ester 
• 491869-01-3 4-[2-(3,4-bisdifluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]ethyl]-3-methylpyridine-1-oxide 
• 192767-02-5 2-{4-[1-(3,4-bis-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol 
• 524775-39-1 2-(4-{1-(3,4-bis-difluoromethoxy-phenyl)-2-[3-(1-hydroxy-ethyl)-1-oxy-pyridin-4-yl]-ethyl}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol 
• 524774-95-6 4-(2-(3,4-bis-difluoromethoxy-phenyl)-2-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-ethyl)-2-methyl-pyridine 
• 524774-86-5 4-(2-(3,4-bis-difluoromethoxy-phenyl)-2-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-ethyl)-3-methyl-pyridine 
• 604806-79-3 4-(2-(3,4-bis-difluoromethoxy-phenyl)-2-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-ethyl)-pyridine-3-carbaldehyde 
• 524774-90-1 4-(2-(3,4-bis-difluoromethoxy-phenyl)-2-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-ethyl)-3-ethyl-pyridine 
• 604806-63-5 [4-(2-(3,4-bis-difluoromethoxy-phenyl)-2-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-ethyl)-pyridin-3-yl]-methanol 

Relevant academic research and scientific papers

Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: Prevention of reactive intermediate formation and covalent binding

A detailed study directed towards metabolic stability optimization of the alkoxy substituents on the catechol moiety of CDP-840 is reported. Replacement of the methoxy and cyclopentyloxy substituents by cyclobutyloxy and/or difluromethoxy groups resulted in the discovery of potent and selective PDE4 inhibitors where the formation of reactive metabolites that could covalently bind to microsomal protein was significantly reduced or eliminated.

Discovery of L-791,943: a potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor.

Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.

Substituted 4-(2,2-Diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.