- Novel imidazobenzazepine derivatives as dual H1/5-HT 2A antagonists for the treatment of sleep disorders
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A novel imidazobenzazepine template (5a) with potent dual H 1/5-HT2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R1-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]- 2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H1/5-HT2A receptor antagonist activities and good developability profiles.
- Gianotti, Massimo,Corti, Corrado,Fratte, Sonia Delle,Di Fabio, Romano,Leslie, Colin P.,Pavone, Francesca,Piccoli, Laura,Stasi, Luigi,Wigglesworth, Mark J.
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supporting information; experimental part
p. 5069 - 5073
(2010/10/20)
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- IMIDAZOBENZAZEPINE COMPOUNDS FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM (CNS) DISEASES
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This invention relates to novel novel imidazobenzazepine derivatives of formula (I) or a pharmaceutically acceptable salt thereof, for treating diseases and conditions of the central nervous system (CNS), in particular sleep disorders.
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Page/Page column 26
(2010/12/29)
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- Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors
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Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase activity of leukotriene A4 hydrolase (E.C. 3.3.2.6). Several compounds showed Ki values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
- Albrecht, Sebastien,Defoin, Albert,Salomon, Emmanuel,Tarnus, Celine,Wetterholm, Anders,Haeggstroem, Jasper Z.
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p. 7241 - 7257
(2007/10/03)
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- SUBSTITUTED PYRIDINONES
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Disclosed are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.
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Page/Page column 311-312
(2008/06/13)
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- Unexpected enhancement of thrombin inhibitor potency with o-aminoalkylbenzylamides in the P1 position
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Thrombin inhibitors incorporating o-aminoalkylbenzylamides in the P1 position were designed, synthesized and found to have enhanced potency and selectivity in several different structural classes. X-ray crystallographic analysis of compound 24 bound in the α-thrombin-hirugen complex provides an explanation for these unanticipated results.
- Rittle, Kenneth E.,Barrow, James C.,Cutrona, Kellie J.,Glass, Kristen L.,Krueger, Julie A.,Kuo, Lawrence C.,Lewis, S. Dale,Lucas, Bobby J.,McMasters, Daniel R.,Morrissette, Matthew M.,Nantermet, Philippe G.,Newton, Christina L.,Sanders, William M.,Yan, Youwei,Vacca, Joseph P.,Selnick, Harold G.
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p. 3477 - 3482
(2007/10/03)
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: wherein R3 is hydrogen or halogen, and u is N or CH.
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- Thrombin inhibitors
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Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, e.g. where R3 is —CH2NH2, —CH2CH2NH2, or —CH2NHC(O)OC(CH3)3.
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- Tripeptidylpeptidase inhibitors
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A compound of formula wherein the substituents are defined as in the specification and salts or hydrates thereof is disclosed as well as a method of treating disorders associated with the inactivation or excessive degradation of cholecystokinin.
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- Substituted sulfonamides, process of preparation and medicines containing same
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The present invention concerns new substituted sulfonamides, and the physiologically acceptable salts possibly in the form of complexes, esters and amides thereof, represented by the formula: STR1
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- 4-Amido-2-carboxytetrahydroquinolines. Structure-Activity Relationships for Antagonism at the Glycine Site of the NMDA Receptor
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trans-2-Carboxy-5,7-dichloro-4-amidotetrahydroquinolines, evolved from the lead 5,7-dichlorokynurenic acid, have been synthesized and tested for in vitro antagonist activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor.Optimization of the 4-substituent has provided antagonists having nanomolar affinity, including the urea trans-2-carboxy-5,7-dichloro-4-amino>-1,2,3,4-tetrahydroquinoline (35; IC50 = 7.4 nM vs glycine binding; Kb = 130 nM for block of NMDA responses in the rat cortical slice), which is one of the most poten t NMDA antagonists yet found.The absolute stereochemical requirements for binding were found to be 2S,4R, showing that, in common with other glycine-site NMDA receptor ligands, the unnatural configuration at the α-amino acid center is required.The preferred conformation of the trans-2,4-disubstituted tetrahydroquinoline system, as shown by X-ray crystallography and 1H NMR studies, places the 2-carboxyl pseudoequatorial and the 4-substituent pseudoaxial.Modifications of the 4-amide show that bulky substituents are tolerated and reveal the critical importance for activity of correct positioning of the carbonyl group.The high affinity of trans-2-carboxy-5,7-dichloro-4--1,2,3,4-tetrahydroquinoline (55; IC50 = 6 nM) suggests that the Z,Z-conformer of the phenyl urea moiety in 35 is recognized by the receptor.Molecular modeling studies show that the 4-carbonyl groups of the kynurenic acids, the tetrahydroquinolines, and related antagonists based on N-(chlorophenyl)glycine, can interact with a single putative H-bond donor on the receptor.The results allow the establishment of a three-dimensional pharma cophore of the glycine receptor antagonist site, incorporating a newly defined bulk tolerance/hydrophobic region.
- Leeson, Paul D.,Carling, Robert W.,Moore, Kevin W.,Moseley, Angela M.,Smith, Julian D.,et al.
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p. 1954 - 1968
(2007/10/02)
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- Optimization of the Quinoline and Substituted Benzyl Moieties of a Series of Phenyltetrazole Leukotriene D4 Receptor Antagonists
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This report describes the development of a series of highly potent quinoline-based leukotriene D4 (LTD4) receptor antagonists containing an N-benzyl-substituted phenyltetrazole moiety.They were designed to provide both the correct positioning of the acidic function and secondary lipophilic domain required for strong receptor binding.Members of this series possess high activity in blocking LTD4-induced contractions of isolated guinea pig ileum.Compound 32, LY287192 (2-phenyl>-2H-tetrazol-2-yl>methyl>-5-fluorobenzoic acid sodium salt), blocked contraction with a pKB value of 9.1+/-0.3.Qualitative structure-activity studies have demonstrated specific requirements for the best activity.In particular, ortho substitution of the benzyl group with an acidic function was crucial for maximum potency.In cases similar to 32, where the benzyl group possesses an ortho carboxylate, the N-2-substituted tetrazole isomer showed 100-fold greater activity relative to the corresponding N-1 isomer.This pattern was reversed when the acid was substituted at the para position.The quinoline unit may be replaced by other nitrogen-containing heterocycles.
- Sawyer, J. Scott,Baldwin, Ronald F.,Rinkema, Lynn E.,Roman, Carlos R.,Fleisch, Jerome H.
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p. 1200 - 1209
(2007/10/02)
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- Synthesis of Chalcogeno Lactones. II. 3,4-Dihydro-1H-2-benzothiin-3-one, 3,4-Dihydro-1H-2-benzoselenin-3-one and 3,4-Dihydro-1H-2-benzotellurin-3-one
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The synthesis of 3,4-dihydro-1H-benzothiin-3-one and its selenium and tellurium analogs is reported from o-bromomethylphenylacetyl chloride and sodium hydrogen chalcogenates, via phase-transfer catalysis.
- Lemaire, Ch.,Luxen, A.,Christiaens, L.,Guillaume, M.
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p. 811 - 812
(2007/10/02)
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- 2,5-Inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-5-iodo-PGF1 compounds
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The present invention provides 2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-5-iodo-PGF1 compounds. These compounds are intermediates for preparing 2,5-inter-o-phenylene-3,4-dinor-prostacyclin analogs, which are useful for pharmacological purpo
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- Cephalosporin antibiotics
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Novel cephalosporin antibiotic derivatives.
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