Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H- imidazo[4,5,1-ij]quinolin-5-amine and its metabolites

Journal of Medicinal Chemistry

Volumn 40, Issue 5, 1997, Pages 639-646

  Heier, Richard F ^a   Dolak, Lester A ^a   Duncan, J Neil ^a   Hyslop, Deborah K ^a   Lipton, Michael F ^a   Martin, Iain J ^b   Mauragis, Michael A ^a   Piercey, Montford F ^a   Nichols, Nanette F ^a   Schreur, Peggy J K D ^a   Smith, Martin W ^a   Moon, Malcolm W ^a  

^a PFIZER INC   (United States)

^b Astra Pharmaceuticals Ltd   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

5,6 DIHYDRO N,N DIMETHYL 4H IMIDAZO[4,5,1 IJ]QUINOLIN 5 AMINE; IMIDAZOQUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; DEMETHYLATION; DOPAMINERGIC TRANSMISSION; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG STABILITY; DRUG SYNTHESIS; LIVER MICROSOME; NONHUMAN; RAT; SEROTONINERGIC SYSTEM;

AMINOQUINOLINES; ANIMALS; DOPAMINE AGONISTS; IMIDAZOLES; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; METHYLAMINES; MICE; MICROSOMES, LIVER; MOLECULAR STRUCTURE; RABBITS; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, DOPAMINE; RECEPTORS, SEROTONIN; SEROTONIN AGONISTS; STEREOISOMERISM;

EID: 15144348177     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960360q     Document Type: Article

References (31)

1. Moon, M. W.; Morris, J. K.; Heier, R. F.; Chidester, C. G.; Hoffmann, W. E.; Piercey, M. F.; Althaus, J. S.; VonVoigtlander, P. F.; Evans, D. L.; Figur, L. M.; Lahti, R. A. Dopaminergic and Serotonergic Activities of Imidazoquinolines and Related Compounds. J. Med. Chem. 1992, 35, 1076-1092.
2. Moon, M. W.; Morris, J. K.; Heier, R. F.; Hsi, R. S. P.; Manis, M. O.; Royer, M. E.; Walters, R. R.; Lawson, C. F.; Smith, M. W.; Lahti, R. A.; Piercey, M. F.; Sethy, V. H. Medicinal Chemistry of Imidazoquinolinone Dopamine Receptor Agonists. Drug Des. Discovery 1992, 9, 313-322.
3. Civelli, O.; Bunzow, J. F.; Grandy, D. K. Molecular Diversity of the Dopamine Receptors. Annu. Rev. Pharmacol. Toxicol. 1993, 32, 281-307.
4. 3) as a Novel Target for Antipsychotics. Biochem. Pharmacol. 1992, 43, 659-666.
5. A preliminary communication of this work has been made; see: Moon, M. W.; Heier, R. F.; Duncan, J. N.; Martin, I. J.; Harris, D. W.; Piercey, M. F.; Smith, M. W.; Nichols, N. F.; Schreur, P. J. K. D. Division of Medicinal Chemistry, ACS National Meeting, Chicago, IL, Aug. 20-25, 1995; Abstract 127.
6. A brief description of the synthesis of (R)-1 and (R)-2 from quinoline has already been presented without experimental details (ref 2). The synthesis shown in Scheme 2 has several improvements over that published. Preparation of the bromohydrin makes isolation of the epoxide 9 unnecessary and also provides an improved procedure for preparation of the epoxide if isolation of this product is desired. The one-step, base-induced cyclization of (R)-15 to (R)-16 is also a significant improvement over the three-step procedure described to effect a similar conversion in ref 2.
7. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
8. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
9. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
10. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
11. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
12. Minter, D. E.; Stotter, P. L. Efficient Conversions of Quinolines to N-(Carboalkoxy)-1,2-dihydroquinolines. J. Org. Chem. 1981, 46, 3965-3970. Katayama, H.; Ohkoshi, M.; Yasue, M. A Convenient Preparation of N-Acyl-1,2-dihydroquinoline. Chem. Pharm. Bull. 1980, 28, 2226-2228. Braude, E. A.; Hannah, J.; Linstead, R. Hydrogen transfer. Part XVI. Dihydrides of Nitrogenous Heterocycles as Hydrogen Donors. J. Chem. Soc. 1960, 3249-3257. Birch, A. J.; Lehman, P. G. 1,4-Dihydroquinoline. J. Chem. Soc., Perkin Trans. I 1973, 2754-2759. Natsume, M.; Kumadaki, S.; Kanda, Y.; Kiuchi, K. Reduction of Quinoline with Sodium Hydride. Tetrahedron Lett. 1973, 2335-2338. Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. On the Mechanism of Disproportionation Reactions of 1,2-Dihydroquinoline. Can. J. Chem. 1985, 63, 412-417.
13. Under the conditions described in the Experimental Section, the byproduct 1,4-dihydroquinoline does not react with di-tert-butyl dicarbonate.
14. Dalton, D. R.; Dutta, V. P.; Jones, D. C. Bromohydrin Formation in Dimethyl Sulfoxide. J. Am. Chem. Soc. 1968, 90, 5498.
15. (a) Carlock, J. T.; Mack, M. P. A Mild Quantitative Method for the Synthesis of a Variety of Heterocyclic Systems. Tetrahedron Lett. 1978, 52, 5153-5156.
16. (b) Pfister, J. R. A One-Pot Synthesis of Aziridines from 2-Aminoethanols. Synthesis 1984, 969.
17. Beak, P.; Lee, W.-K. α-Lithioamine Synthetic Equivalents from Dipole Stabilized Carbanions. The t-BOC Group as an Activator for α-Lithiation of Carbamates. Tetrahedron Lett. 1989, 30, 1197-1200.
18. This alkylation reaction also works well for the related 3-dipropylamino compound (see ref 1) but fails when applied to the close analogue tert-butyl 3-(dimethylamino)-1(2H)-quinolinecarboxylate. The dimethylamine analogue undergoes deprotonation at the 2- and 4-positions followed by elimination of the dimethylamine substituent to form olefin 7a and its 1,4-dihydro isomer instead of undergoing deprotonation at C-8 (M. W. Moon, unpublished results).
19. Hypothermia produced by 10 mg of (R)-6 is completely blocked by sulpiride (100 mg); we thank Dr. A. H. Tang for this unpublished information.
20. Ungerstedt, U.; Arbuthnott, G. W. Quantitative Recording of Rotational Behavior in Rats after 6-Hydroxydopamine Lesions of the Nigrostriatal Dopamine System. Brain Res. 1970, 24, 485-493.
21. Rose, J.; Castagnoli, N., Jr. The Metabolism of Tertiary Amines. Med. Res. Rev. 1983, 3, 73-88.
22. Chalmers, A. H.; Knight, P. R.; Atkinson, M. R. Conversion of Azathioprine into Mercaptopurine and Mercaptoimidazole Derivatives in Vitro and During Immunosuppressive Therapy. Aust. J. Exp. Biol. Med. Sci. 1967, 45, 681-691.
23. Lelo, A.; Kjellen, G.; Birkett, D. J.; Miners, J. O. Paraxanthine Metabolism in Humans: Determination of Metabolic Partial Clearances and Effects of Allopurinol and Cimetidine. J. Pharmacol. Exp. Ther. 1989, 248, 315-319.
24. 1A Receptor Agonists with Various Degrees of Metabolic Stability. J. Med. Chem. 1995, 38, 725-734.
25. 1A Receptor Agonist with Good Oral Activity. J. Med. Chem. 1993, 36, 2208-2218.
26. 3H]U-91356). J. Labelled Compds. Radiopharm. 1992, 31, 933-943.
27. 2 Dopamine Receptors. Mol. Pharmacol. 1994, 45, 51. Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.; Caron, M. G.; Lefkowitz, R. J. The Genomic Clone G-21 Which Resembles a β-Adrenergic Receptor Sequence Encodes the 5-HT1A Receptor. Nature 1988, 335, 358.
28. 2 Dopamine Receptors. Mol. Pharmacol. 1994, 45, 51. Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.; Caron, M. G.; Lefkowitz, R. J. The Genomic Clone G-21 Which Resembles a β-Adrenergic Receptor Sequence Encodes the 5-HT1A Receptor. Nature 1988, 335, 358.
29. 2 Dopamine Receptors. Mol. Pharmacol. 1994, 45, 51. Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.; Caron, M. G.; Lefkowitz, R. J. The Genomic Clone G-21 Which Resembles a β-Adrenergic Receptor Sequence Encodes the 5-HT1A Receptor. Nature 1988, 335, 358.
30. 50) of an Enzymatic Reaction. Biochem. Pharmacol. 1973, 22, 3099.
31. 50 and Confidence Interval Determination. Statistic Methods in Biological Assay; Hafner Publishing Co.: New York, 1952; p 524.