38070-79-0Relevant articles and documents
Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold
Zscherp, Robert,Baumeister, S?ren,Schepmann, Dirk,Wünsch, Bernhard
, p. 397 - 404 (2018)
It has been reported that benzo [7]annulen-7-amines bearing electron withdrawing substituents such as 3d with a 2-Cl or 3e with a 2-NO2 moiety show very high affinity towards the ifenprodil binding site of GluN2B subunit containing NMDA receptors. Therefore, bioisosteres of 3 with an electron deficient pyridine ring instead of the chloro- or nitrobenzene ring were envisaged. Starting from pyridine-2,3-dicarboxylic acid (5) a five-step synthesis of the key intermediate, the ketone 10, was developed. Reductive amination with various primary amines and NaBH(OAc)3 led to the homologous secondary amines 11a-c. Subsequent methylation yielded the tertiary amines 12b and 12c. Receptor binding studies with [3H]ifenprodil revealed Ki-values above 100 nM for the most active phenylpropyl- and phenylbutylamines 11b and 11c. The >100-fold reduced GluN2B affinity of pyridines 11b and 11c compared to the GluN2B affinity of the corresponding chloro- and nitrobenzene derivatives 3d and 3e indicates that the pyridine ring is not tolerated as bioisosteric replacement of the chloro- or nitrobenzene ring in this type of compounds.
IDO/TDO Inhibitor
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Paragraph 0334-0336; 0497; 0498, (2020/08/19)
A compound of formula (I) given below or a pharmaceutically acceptable salt of the compound is useful as an IDO/TDO inhibitor. Thus, the compound of formula (I) or the pharmaceutically acceptable salt of the compound can be used as, for example, a therapeutic agent for a disease or a disorder selected from tumor, infectious disease, neurodegenerative disorder, cataract, organ transplant rejection, autoimmune disease, postoperative cognitive impairment, and disease related to women's reproductive health [in the following formula (I), ring A represents an aromatic ring, an aliphatic ring, a heterocyclic ring, or a condensed ring of two or more rings selected from an aromatic ring, an aliphatic ring and a heterocyclic ring; X, R1 and R2 represent a substituent on a ring atom constituting ring A; m represents an integer of 0 to 6; X represents, for example, a halogen atom; and R1 and R2 are the same or different and are selected from, for example, the group consisting of groups of formula (a) or formula (b); and in the following formula (a) and formula (b), Y is selected from the group consisting of O, S, and Se, Z is selected from the group consisting of O, S, and Se, n represents an integer of 1 to 8, r represents an integer of 1 to 8, s represents an integer of 1 to 8, R4 represents, for example, —C(═NH)—HN2, and R6 represents, for example, a substituted or unsubstituted aryl group].
Coplanar tetracyclic π-excess σ2P ligands
Niaz, Basit,Iftikhar, Fatima,Kindermann, Markus K.,Jones, Peter G.,Heinicke, Joachim
, p. 4220 - 4227 (2013/09/12)
The acid-catalyzed reactions of 5-methyl-2-phosphanylaniline (1) with dialdehydes were studied. Whereas the reaction with glyoxal provides a mixture of two 1H-1,3-benzazaphospholes, 2 and 3, by concomitant reduction of a CHO group and C-C bond cleavage, respectively, the reaction with o-phthalic dicarbaldehyde provided in excellent yield the tetracyclic planar benzazaphosphole 4, which was characterized by crystal structure analysis. The active hydrogen atoms, delivered by aromatization of a dihydrobenzazaphosphole intermediate, forms an N-CH2 bridge by reductive N-alkylation. Pyridine-2,6-dicarbaldehyde reacts analogously but not chemoselectively and, thus, gives two isomers 5 and 6. Condensation with pyridine-2,6-dicarbaldehyde afforded the bis(benzazaphosphole)pyridine pincer ligand 7, but along with 2-(benzazaphospholyl)-6-tolylpyridine (8) by partial P-C bond cleavage. The high upfield 31P NMR chemical shift of 4 compared to those of normal benzazaphospholes indicates it to be a particularly π-rich σ2P ligand. Aromatization-driven acid-catalyzed condensations of the N,P-diprimary compound 1 with dialdehydes are coupled with hydrogen transfer reactions. With glyoxal and pyridine-2,6-dicarbaldehyde this gives rise to side products, but with o-C6H4(CHO)2, high yields of 4 are obtained. π-Delocalization through the coplanar aryl rings causes high π-density at the phosphorus atom.
