European Journal of Medicinal Chemistry p. 816 - 829 (2008)
Update date:2022-08-04
Topics:
Raboisson, Pierre
Schultz, Dominique
Muller, Christian
Reimund, Jean-Marie
Pinna, Guillaume
Mathieu, Romain
Bernard, Philippe
Do, Quoc-Tuan
DesJarlais, Renee L.
Justiano, Helene
Lugnier, Claire
Bourguignon, Jean-Jacques
A series of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines were considered as a bioisosteric replacement for the 9-substituted adenine derivatives resulting in the discovery of 8-(2-methoxybenzyl)-4-(N-methylamino)-2-n-propylpyrazolo[1,5-a]-1,3,5-triazine (14d) and 2-trifluoromethyl-8-(2-methoxybenzyl)-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14e) as a new structural class of potent phosphodiesterase type 4 inhibitors (IC50 = 13 nM and 11 nM, respectively) with high isoenzyme selectivity. An original tandem of reactions involving a palladium-mediated cross-coupling reaction (PMCCR) of the readily available 8-iodo-2-methyl-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine (11a) and arylboronic acids or alkynes followed by the displacement of the N-methyl-N-phenylamino group constitute the key steps in a novel synthetic approach developed herein. The treatment of 11a-c with n-BuLi and selected aldehydes represents an interesting alternative to the PMCCR for the synthesis of benzylic derivatives 14a-i. Preliminary biological testing has shown that compounds 14d and 14e strongly inhibit LPS-induced TNFα release from human mononuclear cells from healthy subjects. These two compounds were selected for further biological evaluation.
View MoreContact:+86-571-86491666
Address:SHI XIANG ROAD
Contact:0512-63006287
Address:no.88.YISHENG Road,etdz-WUJIANG,SUZHOU,CHINA
Changzhou Welton Chemical Co., Ltd,
Contact:0086-519-85910828,85920537,85912897
Address:No.8 Jinlong Road, Binjiang Park, Changzhou, Jiangsu, China.
Guangxi Shanyun Biochemical Science and Technology Co., Ltd
Contact:+86-0772--6828887
Address:#2 Industrial Park of Luzhai County, Liuzhou, Guangxi, China
Chengdu D-Innovation Pharmaceutical Co., Ltd
Contact:86-28-85105536
Address:1001, B6, No.88 Keyuan South Road, Chengdu Hi-Tech Zone
Doi:10.1021/jo701443c
(2007)Doi:10.1021/om034045v
(2003)Doi:10.1016/S0020-1693(00)86245-3
(1977)Doi:10.1021/jm030908a
(2003)Doi:10.1002/anie.201506579
(2015)Doi:10.1002/anie.200351793
(2003)