Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides
摘要:
N-1-Phenyl-3,5-dinitro-N-4,N-4-di-n-propylsulfanilamide (1) and N-1-phenyl-3,5-dinitro-N-4,N-4-di-n-butylsulfanilamide (2) show potent in vitro antimitotic activity against kinetoplastid parasites but display poor in vivo activity. Seventeen new dinitroaniline sulfonamide and eleven new benzamide analogs of these leads are reported here. Nine of the sulfonamides display in vitro IC50 values under 500 nM against African trypanosomes, and the most active antikinetoplastid compounds also inhibit the in vitro assembly of purified leishmanial tubulin with potencies similar to that of 2. While several of the potent compounds are rapidly degraded by rat liver S9 fractions in vitro, N-1-(3-hydroxy)phenyl-3,5-dinitro-N-4,N-4-di-n-butylsulfanilamide (21) displays an IC50 value of 260 nM against African trypanosomes in vitro and is more stable than 2 in the in vitro metabolism assay. (c) 2006 Elsevier Ltd. All rights reserved.
Selected substituted piperidine compounds are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving activation of the melanocortin receptor. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Selected substituted piperazine compounds are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving activation of the melanocortin receptor. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
[EN] SUBSTITUTED PIPERAZINES AS MODULATORS OF THE MELANOCORTIN RECEPTOR<br/>[FR] PIPERAZINES SUBSTITUEES COMME MODULATEURS DU RECEPTEUR DE MELANOCORTINE
申请人:AMGEN INC
公开号:WO2003009850A1
公开(公告)日:2003-02-06
Selected substituted piperazine compounds are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving activation of the melanocortin receptor. The subject invention also relates to processes For making such compounds as well as to intermediates useful in such processes.
The present invention provides, among other things, new benzylamine compounds, compositions comprising benzylamine compounds, methods of making benzylamine compounds, and methods of using benzylamine compounds for treating or preventing a variety of conditions or diseases associated with lipoprotein metabolism.
Disclosed is a compound represented by the formula (1) below, a prodrug thereof or a pharmaceutically acceptable salt of either, which is useful as a therapeutic, preventive or ameliorating agent for diabetes and the like.
(In the formula, R
3
represents an optionally substituted carbamoyl group or the like; X represents a hydroxyl group or the like; W
1
and W
2
independently represent a single bond or methylene; R
7
and R
8
independently represent a hydrogen atom, an optionally substituted alkyl group or the like; and Ar represents an optionally substituted aryl group or the like.)