3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: A new class of anticonvulsant agents

Journal of Medicinal Chemistry

Volumn 39, Issue 9, 1996, Pages 1898-1906

  Reddy, P Amruta ^a   Hsiang, Bonnie C H ^a   Latifi, Tammy N ^a   Hill, Matthew W ^a   Woodward, Karen E ^b   Rothman, Steven M ^a,c   Ferrendelli, James A ^b   Covey, Douglas F ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c ST LOUIS CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 PYRROLIDONE DERIVATIVE; 3 BENZYL 2 PYRROLIDINONE; 3 BENZYL 3 ETHYL 2 PYRROLIDINONE; 3 BENZYL 3 METHYL 2 PYRROLIDINONE; 3,3 DIETHYL 2 PYRROLIDINONE; 4 AMINOBUTYRIC ACID; ALPHA ISOPROPYL ALPHA METHYL GAMMA BUTYROLACTONE; ANTICONVULSIVE AGENT; ETHOSUXIMIDE; PENTETRAZOLE; PHENOBARBITAL; PICROTOXIN; SULFUR 35; TERT BUTYLBICYCLOPHOSPHOROTHIOATE; UNCLASSIFIED DRUG; VALPROIC ACID;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTICONVULSANT ACTIVITY; ARTICLE; CHLORIDE CURRENT; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG ANTAGONISM; ELECTRIC SHOCK; HIPPOCAMPUS; MOUSE; NERVE CELL; NONHUMAN; SEIZURE;

ANIMALS; ANTICONVULSANTS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MICE; NEURONS; PYRROLIDINONES;

EID: 0029882080     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9600196     Document Type: Article

References (51)

1. Klunk, W. E.; McKeon, A. C.; Covey, D. F.; Ferrendelli, J. A. Alpha-Substituted γ-Butyrolactones: New Class of Anticonvulsant Drugs. Science 1982, 217, 1040-1042.
2. Klunk, W. E.; Covey, D. F.; Ferrendelli, J. A. Anticonvulsant Properties of α-, γ-, and α,γ-Substituted γ-Butyrolactones. Mol. Pharmacol. 1982, 22, 438-443.
3. Klunk, W. E.; Covey, D. F.; Ferrendelli, J. A. Comparison of Epileptogenic Properties of Unsubstituted and β-Alkyl-Substituted γ-Butyrolactones. Mol. Pharmacol. 1982, 22, 431-437.
4. (a) Peterson, E. M.; Xu, K.; Holland, K. D.; McKeon, A. C.; Rothman, S. M.; Ferrendelli, J. A.; Covey, D. F. α-Spirocyclopentyl- and α-Spirocyclopropyl-γ-Butyrolactones: Conformationally Constrained Derivatives of Anticonvulsant and Convulsant α,α-Disubstituted γ-Butyrolactones. J. Med. Chem. 1994, 37, 275-286.
5. (b) Canney, D. J.; Holland, K. D.; Levine, J. A.; McKeon, A. C.; Ferrendelli, J. A.; Covey, D. F. Synthesis and Structure-Activity Studies of Alkyl-Substituted γ-Butyrolactones and γ-Thiobutyrolactones: Ligands for the Picrotoxin Receptor. J. Med. Chem. 1991, 34, 1460-1467.
6. Levine, J. A.; Ferrendelli, J. A.; Covey, D. F. Alkyl-Substituted Thiolo-, Thiono-, and Dithio-γ-Butyrolactones: New Classes of Convulsant and Anticonvulsant Agents. J. Med. Chem. 1986, 29, 1996-1999.
7. Holland, K. D.; Naritoku, D. K.; McKeon, A. C.; Ferrendelli, J. A.; Covey, D. F. Convulsant and Anticonvulsant Cyclopentanones and Cyclohexanones. Mol. Pharmacol. 1990, 37, 98-103.
8. (a) Holland, K. D.; McKeon, A. C.; Covey, D. F; Ferrendelli, J. A. Binding Interactions of Convulsant and Anticonvulsant γ-Butyrolactones and γ-Thiobutyrolactones with the Picrotoxin Receptor. J. Pharmacol. Exp. Ther. 1990, 254, 578-583.
9. (b) Levine, J. A.; Ferrendelli, J. A.; Covey, D. F. Convulsant and Anti-convulsant Gammabutyrolactones Bind at the Picrotoxinin/tert-Butylbicyclophosphorothionate (TBPS) Receptor. Biochem. Pharmacol. 1985, 34, 4187-4190.
10. 35S]TBPS Binding to a GABA-Linked Chloride Ionophore. Eur. J. Pharmacol. 1984, 105, 195-196.
11. A Receptor Complex Brain Res. 1993, 615, 170-174.
12. A Receptor Channel-Lining Residues Probed by Cysteine Mutants. Biophys. J. 1995, 69, 1858-1867.
13. (b) Yoon, K.-W.; Covey, D. F.; Rothman, S. M. Multiple Mechanisms of Picrotoxin Block of GABA-Induced Currents in Rat Hippocampal Neurons. J. Physiol. 1993, 464, 423-439.
14. (c) Holland, K. D.; Yoon, K.-W.; Ferrendelli, J. A.; Covey, D. F.; Rothman, S. M. γ-Butyrolactone Antagonism of the Picrotoxin Receptor: Comparison of a Pure Antagonist and a Mixed Antagonist/Inverse Agonist. Mol. Pharmacol. 1991, 39, 79-84.
15. (a) Holland, K. D.; Ferrendelli, J. A.; Covey, D. F.; Rothman, S. M. Physiological Regulation of the Picrotoxin Receptor by γ-Butyrolactones and γ-Thiobutyrolactones in Cultured Hippocampal Neurons. J. Neurosci. 1990, 10, 1719-1727.
16. (b) Zorumski, C. F.; Yang, J.; Baker, K.; Covey, D. F.; Clifford, D. B. Convulsant γ-Butyrolactones Block GABA Currents in Cultured Chick Spinal Cord Neurons. Brain Res. 1989, 484, 102-110.
17. (c) Baker, K.; Yang, J.; Covey, D. F.; Clifford, D. B.; Zorumski, C. F. α-Substituted Thiobutyrolactones Potentiate GABA Currents in Voltage-Clamped Chick Spinal Chord Neurons. Neurosci. Lett. 1988, 87, 133-138.
18. Holland, K. D.; Mathews, G. C.; Bolos-Sy, A. M.; Tucker, J. B.; Reddy, P. A.; Covey, D. F.; Ferrendelli, J. A.; Rothman, S. M. Dual Modulation of the γ-Aminobutyric Acid Type A Receptor/Ionophore by Alkyl-Substituted γ-Butyrolactones. Mol. Pharmacol. 1995, 47, 1217-1223.
19. A Receptor Distinct from the Picrotoxin Site. Soc. Neurosci. Abstr. 1995, 21, 1026.
20. Menezes, R.; Smith, M. B. A Mild and Facile Route to ω-Amino Esters. Synth. Commun. 1988, 18, 1625-1636.
21. (a) Kametani, T.; Ihara, M.; Honda, T. The Alkaloids of Corydalis pallida var. tenuis (Yatabe) and the Structures of Pallidine and Kikemanine. J. Chem. Soc. C 1970, 1060-1064.
22. (b) Cummings, W. A. W.; Davis, A. C. The Synthesis and Rearrangement of 3-Vinyl-2-pyrrolidone. J. Chem. Soc. 1964, 4591-4604.
23. 16
24. Ibarzo, J.; Ortuno, R. M. 1,2-Dibromoethane in the Synthesis of 2-Bromoesters: Bromination vs Alkylation. Tetrahedron 1994, 32, 9825-9830.
25. (a) Osby, J. O.; Heinzman, S. W.; Ganem, B. Studies on the Mechanism of Transition-Metal-Assisted Sodium Borohydride and Lithium Aluminium Hydride Reductions. J. Am. Chem. Soc. 1986, 108, 67-72.
26. (b) Heinzman, S. W.; Ganem, B. The Mechanism of Sodium Borohydride-Cobaltous Chloride Reductions. J. Am. Chem. Soc. 1982, 104, 6801-6802.
27. In the case of substrates 6c and 6i, the reaction mixture was stirred under reflux for 72 h prior to workup to ensure the complete cyclization of the intermediate amino esters.
28. Stamm, H.; Woderer, A.; Wiesert, W. Reactions with Aziridines. XXII. One Step Synthesis of Pyrrolidones by Amidoethylation of Simple Esters with N-Acylaziridines. Chem. Ber. 1981, 114, 32-48.
29. Najer, H.; Giudicelli, R.; Sette, J. Guanidines with Antihypertensive Activity. IV. N-(β-Guanidinoethyl)azaspiroalkanes. 1. Bull. Soc. Chim. Fr. 1964, 2572-2581.
30. (a) Werry, J.; Stamm, H.; Lin, P. -Y.; Falkenstein, R.; Gries, S.; Irngartinger, H. Reactions with Aziridines. Part 50. Homolytic Aziridine Opening (Aza Variant of Cyclopropylcarbinyl-Homoallyl Rearraangement) by Addition of Tributyltin Radical to N-Acylaziridines. Factors Contributing to the Regioselectivity. Tetrahedron 1989, 45, 5015-5028.
31. (b) Bentz, G.; Besbes, N.; Laurent, A.; Stamm, H. Intramolecular Radical Trapping in "Set" Ring Opening of N-Enoyl Aziridines. A New Mechanistic Probe and a New Synthesis of Pyrrolidones. Tetrahedron Lett. 1987, 28, 2511-2512.
32. MacPhee, J. A.; Dubois, J.-E. Steric Limits to Ester Alkylation; Synthesis of Highly Hindered Esters via Hexamethylphosphoramide-Favoured Enolization. J. Chem. Soc., Perkin Trans. 1 1977, 694-696.
33. Ipaktschi, J. Reduction of Oximes with Sodium Borohydride in the Presence of Transition Metal Compounds. Chem. Ber. 1984, 117, 856-858.
34. Wrobel, J.; Dietrich, A.; Gorham, B. J.; Sestanj, K. Conformationally Rigid Analogues of Aldose Reductase Inhibitor, Tolrestat. Novel Syntheses of Naphthalene-Fused γ-, δ-, and ε-Lactams. J. Org. Chem. 1990, 55, 2694-2702.
35. A Receptors. FASEB J. 1990, 4, 1469-1480.
36. A Receptor Channels: From Subunits to Functional Entities. Curr. Opin. Neurobiol. 1992, 2, 263-269.
37. A Receptor Channels. Ann. Rev. Neurosci. 1994, 17, 569-602.
38. (a) Hawkins, J. E., Jr.; Sarett, L. H. On the Efficacy of Asparagine, Glutamine, γ-Aminobutyric Acid and 2-Pyrrolidinone in Preventing Chemically Induced Seizures in Mice. Clin. Chim. Acta 1957, 2, 481-484.
39. (b) Lightowler, J. E.; MacLean, J. A. R. Studies on Some Analogues of Gamma-Aminobutyric Acid. Arch. Int. Pharmacodyn. 1963, 145, 233-242.
40. (a) Holland, K. D.; McKeon, A. C.; Canney, D. J.; Covey, D. F.; Ferrendelli, J. A. Relative Anticonvulsant Effects of GABAmimetic and GABA Modulatory Agents. Epilepsia 1992, 33, 981-986.
41. (b) Ferrendelli, J. A.; Holland, K. D.; McKeon, A. C.; Covey, D. F. Comparison of the Anticonvulsant Activities of Ethosuximide, Valproate, and a New Anticonvulsant, Thiobutyrolactone. Epilepsia 1989, 30, 617-622.
42. (a) Chen, G.; Portman, R.; Ensor, C. F.; Bratton, A. C., Jr. The Anticonvulsant Activity of α-Phenyl Succinimides. J. Pharmacol. Exp. Ther. 1951, 103, 54-61.
43. 1-α-Phenylsuccimides. J. Am. Chem. Soc. 1951, 73, 4895-4898.
44. (c) Chen, G.; Weston, J. K.; Bratton, A. C., Jr. Anticonvulsant Activity and Toxicity of Phensuximide, Methsuximide and Ethosuximide. Epilepsia 1963, 4, 66-76.
45. Loscher, W.; Schmidt, D. Which Animal Models Should be Used in the Search for New Antiepileptic Drugs? A Proposal Based on Experimental and Clinical Considerations. Epilepsy Res. 1988, 2, 145-181.
46. Lion, C.; Dubois, J. E. Alkylation of Some Carbonyl Compounds by Tertiary Alkyl Groups. Utilization of the Friedel-Crafts Reaction in the Synthesis of Sterically Crowded Esters and Ketones. Tetrahedron 1981, 37, 319-323.
47. Spencer, R. W.; Tam, T. F.; Thomas, E.; Robinson, V. J.; Krantz, A. Ynenol Lactones: Synthesis and Investigation of Reactions Relevant to their Inactivation of Serine Proteases. J. Am. Chem. Soc. 1986, 108, 5589-5597.
48. 33 bp 105-110 °C (0.5 mmHg).
49. Colombo, M.; De Amici, M.; De Micheli, C.; Pitre, D ; Carrea, G.; Riva, S. Chemoenzymatic Synthesis of the Enantiomers of Iopanoic Acid. Tetrahedron: Asymmetry 1991, 2, 1021-1030.
50. Desert, S.; Metzner, P. Diastereoselectivity of the Thio-Claisen Rearrangement of Acyclic Precursors bearing a Chiral Center Adjacent to Carbon 6. Tetrahedron 1992, 48, 10327-10338.
51. This aldehyde rapidly rearranges to uncharacterized oxidation products upon standing in air. Analytical data could not be obtained until the compound was converted to the stable oxime derivative.