- Novel N-acylated heterocycles
-
Described are compositions comprising a muscarinic receptor antagonist and an N-acylated heterocycle derivative having affinity for serotonergic receptors, and enantiomers, diastereoisomers, N-oxides, polymorphs, solvates and pharmaceutically acceptable salts thereof. The combination of a muscarinic receptor antagonist and an N-acylated heterocycle, or an enantiomer, diastereoisomer, N-oxide, polymorph, solvate or pharmaceutically acceptable salt thereof, is useful in the treatment of patients with neuromuscular dysfunction of the lower urinary tract and diseases related to 5-HT1A receptors.
- -
-
-
- NAPHTHALENE AMIDES HAVING LEUKOTRIENE-ANTAGONISTIC ACTION
-
Naphthalene amides of formula (I) wherein the substituent containing A is bound to the 6- or 7- position of the 2-naphthol system; the substituent containing B is bound to the benzene ring at any free position; R is hydrogen or methyl; R is hydrogen, fluorine, chlorine or -OCH3, which is bound to the naphthalene system at any positions except the 2- and the one occupied by the other substituent; R is hydrogen, fluorine, chlorine or bromine; A- is -CO-NR- or -NR-CO- group, wherein R is hydrogen or methyl; B is a 5-tetrazolyl or -COOR group, wherein R is hydrogen, a (C1-C4)-alkyl or a phenylalkyl group of less than 10 carbon atoms; m is 0 or 1; n and p are integers from 0 to 6, with the proviso that n + p is less or equal to 6; as well as the solvates and pharmaceutically acceptable salts thereof, have leukotriene antagonistic action.
- -
-
-
- Synthesis and SAR of a novel, potent and structurally simple LTD4 antagonist of the quinoline class
-
The two geminal ethyl groups in the succinic acid moiety of CGP57698 (4- [3-(7-fluoro-2-quinolinylmethoxy)phenyl-amino]-2,2-diethyl-4-oxo-butanoic acid) are responsible for the high in vitro and in vivo potency of this peptidoleukotriene antagonist of the quinoline type. The synthesis and structure activity relationships of CGP57698 and its analogs are described.
- Von Sprecher, Andreas,Gerspacher, Marc,Beck, Andreas,Kimmel, Sabine,Wiestner, Hansruedi,Anderson, Gary P.,Niederhauser, Ulrich,Subramanian, Natarajan,Bray, Michael A.
-
p. 965 - 970
(2007/10/03)
-
- Development of a novel series of styrylquinoline compounds as high- affinity leukotriene D4 receptor antagonists: Synthetic and structure- activity studies leading to the discovery of (±)-3-[[[3-[2-(7-chloro-2- quinolinyl)-(E)-ethenyl]phenyl][[3-(dimethylamino)-3- oxopropyl]thio]methyl]thio]propionic acid
-
Based on LTD4 receptor antagonist activity of 3-(2-quinolinyl-(E)- ethenyl)pyridine (2) found in broad screening, structure-activity studies were carried out which led to the identification of 3-[[[3-[2-(7-chloro-2- quinolinyl)-(E)-ethenyl]phenyl][[3-(dimethylamino)-3- oxopropyl]thio]methyl]thio]propionic acid (1, MK-571) as a potent and orally active LTD4 receptor antagonist. These studies demonstrated that a phenyl ring could replace the pyridine in 2 without loss of activity, that 7-halogen substitution in the quinoline group was optimal for binding, that the (E)- ethenyl linkage was optimal, that binding was enhanced by incorporation of a polar acidic group or groups in the 3-position of the aryl ring, and that two acidic groups could be incorporated via a dithioacetal formed from thiopropionic acid and the corresponding styrylquinoline 3-aldehyde to yield compounds such as 20 (IC50 = 3 nM vs [3H]LTD4 binding to the guinea pig lung membrane). It was found that one of the acidic groups could be transformed into a variety of the amides without loss of potency and that the dimethylamide 1 embodied the optimal properties of intrinsic potency (IC50 = 0.8 nM on guinea pig lung LTD4 receptor) and oral in vivo potency in the guinea pig, hyperreactive rat, and squirrel monkey. The evolution of 2 to 1 involves the increase of >6000-fold in competition for [3H]LTD4 binding to guinea pig lung membrane and a >40-fold increase in oral activity as measured by inhibition of antigen-induced dyspnea in hyperreactive rats.
- Zamboni,Belley,Champion,Charette,DeHaven,Frenette,Gauthier,Jones,Leger,Masson,McFarlane,Metters,Pong,Piechuta,Rokach,Therien,Williams,Young
-
p. 3832 - 3844
(2007/10/02)
-
- Quinoline dioic acids and amides
-
Compounds having the formula are antagonists of leukotrienes and inhibitors of their biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.
- -
-
-
- 2-substituted quinoline dioic acids and pharmaceutical compositions
-
Compounds having the formula: STR1 are antagonists of leukotrienes and inhibitors of their biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.
- -
-
-
- ASYMMETRIC DITHIOACETALS III: THE PREPARATION OF THE ENANTIOMERS OF 3-((((3-(2-(7-CHLOROQUINOLIN-2-YL)-(E)-ETHENYL)PHENYL)-3-DIMETHYLAMINO-3-OXOPROPYLTHIO)METHYL)THIO)PROPIONIC ACID (L-660,711) (MK-571), AN ANTAGONIST OF LEUKOTRIENE D4
-
The application of a novel method for the preparation of chiral dithioacetals to the synthesis of the enantiomers of L-660,711, an antagonist of leukotriene D4, is described.Reaction of 3-(t-butyldiphenylsilyloxymethyl)benzaldehyde or isophthal
- Young, Robert N.,Gauthier, Jacques Yves,Therien, Michel,Zamboni, Robert
-
p. 967 - 978
(2007/10/02)
-
- 2-Substituted quinoline dioic acids
-
Compounds having the formula: are antagonists of leukotrienes and inhibitors of their biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents.
- -
-
-
