192767-13-8

Upstream product

• 192767-03-6 2-(4-bromophenyl)-2-[2-(trimethylsilyl)ethoxymethoxy]-1,1,1,3,3,3-hexafluoropropane 
• 151103-08-1 4-difluoromethoxy-3-hydroxybenzaldehyde 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 127842-54-0 3,4-bis-(difluoromethoxy)-benzaldehyde 
• 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 
• 192767-12-7 (3,4-bis-difluoromethoxy-phenyl)-{4-[2,2,2-trifluoro-1-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-ethyl]-phenyl}-methanol 

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 
• 604806-82-8 1-[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]-ethanol 

Relevant academic research and scientific papers

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.

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.