306960-78-1Relevant articles and documents
Pyrazolo[3,4-b]pyridine compounds, and their use as a PDE4 inhibitors
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Page/Page column 148, (2009/05/28)
The invention provides a compound of formula (I) or a salt thereof: wherein R2 is H, C1-3alkyl, n-butyl, C1-2fluoroalkyl, cyclopropyl, cyclobutyl, (cyclopropyl)methyl-, —CN, or —CH2OH; R3 is inter alia optionally substituted C4-7cycloalkyl or an optionally substituted heterocyclic group (aa), (bb) or (cc); Ra is H, methyl or ethyl; Rb is H or methyl; R4 is H, methyl, ethyl, n-propyl, —C(O)-Me, or —C(O)—C1fluoroalkyl; and R5 is: —C(O)—(CH2)n—Ar, —C(O)-Het, —C(O)—C1-6alkyl, —C(O)—C1 fluoroalkyl, —C(O)—(CH2)2—C(O)—NR15bNR15b, —C(O)—CH2—C(O)—NR15bNR15b, —C(O)—NR15b—(CH2)m1—Ar, —C(O)—NR15b—Het, —C(O)—NR15b—C1-6alkyl, —C(O)—NR5aR5b, —S(O)2—(CH2)m2—Ar, —S(O)2-Het, —S(O)2—C1-6alkyl, or —CH2—Ar; or R4 and R5 taken together are —(CH2)p1—, —(CH2)2—X5—(CH2)2—, —C(O)—(CH2)p2—, —C(O)—N(R15)—(CH2)p3—; or NR4R5 is of sub-formula (y), (y1), (y2) or (y3). The invention provides the use of the compounds as inhibitors of phosphodiesterase type IV (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as COPD and the like.
Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].
Palanki,Erdman,Gayo-Fung,Shevlin,Sullivan,Goldman,Ransone,Bennett,Manning,Suto
, p. 3995 - 4004 (2007/10/03)
We investigated the structure-activity relationship studies of N-[3, 5-bis(trifluoromethyl)phenyl][2-chloro-4-(trifluoromethyl)pyrimidin-5 -yl]carboxamide (1), an inhibitor of transcription mediated by both NF-kappaB and AP-1 transcription factors, with the goal of improving its potential oral bioavailability. Compounds were examined for cell-based activity, were fit to Lipinski's rule of 5, and were examined for potential gastrointestinal permeability using the intestinal epithelial cell line, Caco-2. Selected groups were substituted at the 2-, 4-, and 5-positions of the pyrimidine ring using solution-phase combinatorial methodology. The introduction of a fluorine in the place of 2-chlorine of 1 resulted in a compound with comparable activity. However, other substitutions at the 2-position resulted in a loss of activity. The trifluoromethyl group at the 4-position could be replaced with a methyl, ethyl, chlorine, or phenyl without a substantial loss of activity. The carboxamide group at the 5-position is critical for activity. If it was moved to the 6-position, the activity was lost. The 2-methyl analogue of 1 (81) showed comparable in vitro activity and improved Caco-2 permeability compared to 1.
