134176-18-4Relevant articles and documents
Design, synthesis, and pharmacological characterization of (+)-2- aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): A potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties
Monn, James A.,Valli, Matthew J.,Massey, Steven M.,Wright, Rebecca A.,Salhoff, Craig R.,Johnson, Bryan G.,Howe, Trevor,Alt, Charles A.,Rhodes, Gary A.,Robey, Roger L.,Griffey, Kelly R.,Tizzano, Joseph P.,Kallman, Mary J.,Helton, David R.,Schoepp, Darryle D.
, p. 528 - 537 (1997)
2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (τ1 and τ2) which determine the relative positions of the α- amino acid and distal carboxyl functionalities are constrained where τ1 = 166.9°or 202°and τ2 = 156°, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (±)-9, its C2-diastereomer (±)-16, and its enantiomers (+)- 9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (±)-9 (EC50 = 0.086 ± 0.025 μM) and its enantiomer (+)-9 (EC50 = 0.055 ± 0.017μM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 μM. Importantly, the mGluR agonist effects of (+)- 9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.
C3′-cis-Substituted carboxycyclopropyl glycines as metabotropic glutamate 2/3 receptor agonists: Synthesis and SAR studies
González, Rosario,Collado, Iván,López De Uralde, Beatriz,Marcos, Alicia,Martín-Cabrejas, Luisa M.,Pedregal, Concepción,Blanco-Urgoiti, Jaime,Pérez-Castells, Javier,Fernández, M. Alejandro,Andis, Sherri L.,Johnson, Bryan G.,Wright, Rebecca A.,Schoepp, Darryle D.,Monn, James A.
, p. 6556 - 6570 (2005)
The synthesis of a series of C3′-cis-substituted carboxycyclopropyl glycines bearing a wide variety of functional groups is described, and the structure-activity relationship for this series as agonists of group II metabotropic glutamate receptors is repo
Stereoselective cyclopropanation of enones with ethyl dimethylsulfonium acetate bromide in the presence of DBU
Collado, Ivan,Dominguez, Carmen,Ezquerra, Jesus,Pedregal, Concepcion,Monn, James A.
, p. 2133 - 2136 (1997)
The cyclopropanation reaction of α, β-unsaturated ketones 1a-c with ethyl (dimethyl sulfuranylidene) acetate (EDSA), generated in situ from the corresponding sulfonium bromide salt and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in toluene, leads exclusively to the exo adduct 2a-c (d.e. = 100%). Acyclic enones 1d-g, give mainly the 'trans' cyclopropanes 4d-g with a high degree of stereocontrol (d.e. 380%). Changing the solvent to CHCl3 affords a 2:1 mixture of 'trans' and 'cis' cyclopropanes 4d-g and 5d-g respectively. The 'cis' isomers 5d-g can be epimerizated to the alternative 'trans' isomers 6d-g under basic conditions.
Process development of (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (LSN344309)
Rasmy, Ossama M.,Vaid, Radhe K.,Semo, Michael J.,Chelius, Erik C.,Robey, Roger L.,Alt, Charles A.,Rhodes, Gary A.,Vicenzi, Jeffery T.
, p. 28 - 32 (2006)
Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Buecherer-Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-α- methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.
TRIAZOLE CARBOXYLIC ACIDS AS LPA ANTAGONISTS
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Page/Page column 96, (2021/01/22)
The present invention provides compounds of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
1,4,5,6-TETRAHYDRO-PYRIMIDIN-2-YLAMINE COMPOUNDS
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Page/Page column 55, (2012/02/15)
This invention relates to compounds of the formula wherein R1 to R9 are as described below, or to pharmaceutically acceptable salts thereof. These compounds are BACE2 inhibitors and can be used as medicaments for the therapeutic and/
