- 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
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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.
- 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.
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- Novel asymmetric synthesis of a bicyclo[3.1.0]hexane derivative by an efficient retro-Diels-Alder strategy
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The first preparation of enantiomerically pure bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester (1), a valuable synthetic intermediate, is described. The synthesis features a retro-Diels-Alder reaction as a key step. Conditions which allow for a high yielding thermal conversion of 3 to 4 are described.
- Moher, Eric D.
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- C3′-cis-Substituted carboxycyclopropyl glycines as metabotropic glutamate 2/3 receptor agonists: Synthesis and SAR studies
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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
- 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.
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- TMG catalyzed cyclopropanation of cyclopentenone. Illustration by a simple synthesis of bicyclo[3.1.0]hexane-2-one derivatives
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The catalytic preparation of bicyclo[3.1.0]hexane-2-one-6-carboxylic acid ethyl ester 1 is described by cyclopropanation of cyclopentenone using 1,1,3,3-tetramethylguanidine (TMG) as a catalyst in high yield and high diastereoselectivity. This process has been applied to an efficient synthesis of the important intermediate, β-hydroxyl cyclopentanone 2.
- Zhang, Fuyao,Moher, Eric D.,Zhang, Tony Y.
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- Stereoselective cyclopropanation of enones with ethyl dimethylsulfonium acetate bromide in the presence of DBU
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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.
- Collado, Ivan,Dominguez, Carmen,Ezquerra, Jesus,Pedregal, Concepcion,Monn, James A.
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- Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase
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The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; siali-dase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.
- Colombo, Cinzia,Podlipnik, ?rtomir,Presti, Leonardo Lo,Niikura, Masahiro,Bennet, Andrew J.,Bernardi, Anna
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- 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)
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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.
- Rasmy, Ossama M.,Vaid, Radhe K.,Semo, Michael J.,Chelius, Erik C.,Robey, Roger L.,Alt, Charles A.,Rhodes, Gary A.,Vicenzi, Jeffery T.
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- ISOXAZOLE CARBOXYLIC ACIDS AS LPA ANTAGONISTS
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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.
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(2021/01/22)
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- TRIAZOLE CARBOXYLIC ACIDS AS LPA ANTAGONISTS
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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.
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(2021/01/22)
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- PRODRUG OF AMINO ACID DERIVATIVE
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Provided is an amino acid derivative prodrug represented by general formula (I-A) that is a prodrug form of an amino acid derivative which is a group 2 metabotropic glutamate receptor antagonist, or a pharmaceutically acceptable salt thereof. More specifically, provided is an amino acid derivative prodrug represented by general formula (I-A) that is a preventive or therapeutic drug for mood disorders (including depression and bipolar disorder), anxiety disorder, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscular rigidity, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, brain infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord disorders, head trauma, inflammation and immune- related diseases, and so on.
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Paragraph 0181
(2017/11/14)
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- 1,4,5,6-TETRAHYDRO-PYRIMIDIN-2-YLAMINE COMPOUNDS
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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/
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(2012/02/15)
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- 1,4,5,6-TETRAHYDRO-PYRIMIDIN-2-YLAMINE COMPOUNDS
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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/
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(2012/03/09)
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- Constrained cycloalkyl analogues of glutamic acid: Stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) and its 6-phosphonic acid analogue
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A new stereocontrolled synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2.6- dicarboxylic acid (LY354740) 1, a potent and selective 2mGluR agonist, has been accomplished in four steps with an overall yield of 27% starting from the enantiopure (+)-(R)-2-(p-tolylsulfinyl)cyclopent-2-enone 3. The key steps include asymmetric cyclopropanation of 3 with (dimethylsulfuranylidene)acetate (EDSA) and removal of the chiral p-tolylsulfinyl auxiliary from the cycloadduct ent-4c upon treatment with iso-propylmagnesium chloride. The stereoselective hydantoin formation from the bicyclic ketone 6 formed (Bucherer-Bergs reaction) and subsequent hydrolysis completed the synthesis of 1. The same reaction sequence has been applied in the first synthesis of enantiopure (+)-2-amino-6-phosphonobicyclo[3.0.1]hexane-2-carboxylic acid 2, a structural 6-phosphono analogue of 1. The starting bicyclic ketophosphonates 9-11 have been obtained by asymmetric cyclopropanation of (-)-(S)-3 with phosphoryl sulfonium ylides, producing only two endo-isomers. The major endo-isomer (+)-11a containing the 6-diisopropoxyphosphoryl group has been converted in three steps into (+)-endo-2 in 46% overall yield.
- Krysiak, Jerzy,Midura, Wanda H.,Wieczorek, Wanda,Sieron, Leslaw,Mikolajczyk, Marian
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experimental part
p. 1486 - 1493
(2010/11/04)
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- Synthesis of the potent anticancer agents ottelione A and ottelione B in both racemic and natural optically pure forms
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(Chemical Equation Presented) The powerful antitumor agents ottelione A and B were synthesized in racemic form by a method that relies on selective ring closing metathesis. Optically pure natural (+)-ottelione A was then made from D-ribose, via an α-keto cyclopropane. A key feature of the route is that the cyclopropyl group controls the stereochemistry in the attachment of the ArCH2 unit and is then converted by the action of SmI2 into a vinyl group, so that the substituents on the resulting five-membered ring have the required trans relationship. Epimerization of an intermediate gave access by the same method to the trans ring fused isomer (-)-ottelione B.
- Clive, Derrick L. J.,Liu, Dazhan
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p. 3078 - 3087
(2008/09/19)
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- Steric control in the thermal rearrangement of a bicyclo[3.1.0]hex-2-ene substituted at a radical-nonstabilizing position
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Introduction into the long-known bicyclo[3.1.0]hex-2-ene system of a large substituent in an electronically inactive, interconnected pair of positions brings to light the importance of sterics as a major factor in the determination of products. Far from the "flat" surface that so well describes the caldera of diradicals of the archetype, a "bumpy" surface is required as the conceptual scheme. The relief of "compressional" strain serves to explain the dramatic effect on kinetics and composition at equilibrium.
- Doering, William Von Eggers,Zhao, Xin
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p. 6430 - 6437
(2008/12/22)
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- Synthesis of the otteliones A and B: Use of a cyclopropyl group as both a steric shield and a vinyl equivalent
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(Chemical Equation Presented) To A and B: The extremely powerful antitumor agents ottelione A and B have been synthesized from D-ribose. Key steps in the synthesis involve the use of a cyclopropane unit fused onto a five-membered ring to control the stere
- Clive, Derrick L. J.,Liu, Dazhan
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p. 3738 - 3740
(2008/02/14)
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- Asymmetric sulfonium ylide mediated cyclopropanation: Stereocontrolled synthesis of (+)-LY354740
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The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate. 60°C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantio-selectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95% ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.
- Aggarwal, Varinder K.,Grange, Emma
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p. 568 - 575
(2008/09/21)
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- Excitatory amino acid receptor modulators
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Compounds of the formula (I) in which: R1 is (CH2)nY; n is 1 or 2; Y is NHSO2R2 or X1—W—X2—R3; X1 is O or NH; W is C═O, C═S, C═NH, or SO2; X2 is O or NH, provided that X1 and X2 are not both O; R2 is C1-10 alkyl; C2-10 alkenyl; C2-10 alkynyl; aryl; aryl-C1-10 alkyl; aryl-C2-10 alkenyl; aryl-C2-10alkynyl; C3-8 cycloalkyl or C3-8-cycloalkyl-C1-10 alkyl; and R3 is hydrogen, C1-10alkyl; C2-10 alkenyl; C2-10 alkynyl; aryl; aryl-C1-10 alkyl; aryl-C2-10 alkenyl; aryl-C2-10 alkynyl; C3-8 cycloalkyl; or C3-8-cycloalkyl-C1-10 alkyl; or a salt or ester thereof, modulate metabotropic glutamate receptor function and are useful in treating disorders of the central nervous system.
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- An intramolecular organocatalytic cyclopropanation reaction
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Nucleophilic tertiary amines catalyze an intramolecular cyclopropanation reaction to give [n.1.0]bicycloalkanes in good yield (see scheme). The reaction is tolerant of a wide range of functional groups and is highly diastereoselective. Furthermore, when a
- Bremeyer, Nadine,Smith, Stephen C.,Ley, Steven V.,Gaunt, Matthew J.
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p. 2681 - 2684
(2007/10/03)
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- PRODRUGS OF EXCITATORY AMINO ACIDS
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This invention relates to synthetic excitatory amino acid prodrugs and processes for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds for the treatment of neurological disorder
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- Method of resolving 2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivatives
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There is disclosed a method of resolving 2-oxobicyclo[3.1.0]hexane-6-carboxylates having the following relative configuration of formula (1): wherein X1, X2, R1, R2and R3have the same meanings as defined below, into one enantiomer ester thereof and the other enantiomer acid, which is characterized by contacting an enzyme having an ability to preferentially hydrolyze one enantiomer ester contained in 2-oxobicyclo[3.1.0]hexane-6-carboxylate of formula (1) as defined above, with 2-oxobicyclo[3.1.0]hexane-6-carboxylates of formula (1) as defined above to obtain one enantiomer as an acid and the other enantiomer as an ester.
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- Excitatory amino acid receptor modulators
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Compounds of formula (I) in which R1is halo-C1-10alkyl; halo-C2-10alkenyl; or (CH2)nY in which n is 1 or 2 and Y is OH, CN, N3, OR3, SH, S(O)pR4, S(O)3H, NH2, NHR5, NR6R7, NHCOR8, NO2, CO2H, CONHR9, 1H-tetrazol-5-yl, 5-phenyltetrazol-2-yl or PO3H2; R3, R5, R6, R7, R8and R9are each selected independently from C1-4alkyl, aryl and aryl-C1-4alkyl; R4is selected from C1-4alkyl, aryl, aryl-C1-4alkyl, and 1H-tetrazol-5-yl, carboxy-(1-4C)alkyl and 1H-tetrazol-5-yl-C1-4alkyl; and p is 0, 1, 2 or 3; or a salt or ester thereof, provided that R1is not methoxymethyl, modulate metabotropic glutamate receptor function and are useful in treating disorders of the central nervous system.
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- Excitatory amino acid receptor modulators
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The present invention relates to compounds of the formula ???in which R1 is defined in the specification, and non-toxic metabolically labile esters and amides thereof are useful as modulators of metabotropic glutamate receptor function.
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- EXCITATORY AMINOACID RECEPTOR MODULATORS
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Compounds of the formula STR1 in which R 1 and R 2 are as defined in the specification, and non-toxic metabolically labile ester and amides thereof are useful as modulators of metabotropic glutamate receptor function.
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- Asymmetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)
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The assymetric synthesis of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) 1, a potent and selective group 2 mGluR agonist, has been accomplished starting from the readily available enantiomerically pure cyclopentenone 4. Thus, cyclopropanation with ethyl(dimethylsulfuranylidene)acetate generated in situ with DBU, followed by deketalization gave rise to the dihydroxy bicyclic ketone 9. After protecting the ketone as 1,3-dioxolane and its transformation to the orthoformate 11, this was pyrolytically deoxygenated in a sealed tube to the bicyclic enone 13. The synthesis was completed after hydrogenation, stereoselective Bucherer-Bergs reaction and hydantoin hydrolysis, yielding LY354740 (+)-1 with an e.e. ≤98%. reserved.
- Dominguez, Carmen,Ezquerra, Jesus,Prieto, Lourdes,Espada, Modesta,Pedregal, Carmen
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p. 511 - 514
(2007/10/03)
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