5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as potent, orally active, nonsteroidal progesterone receptor agonists: The effect of D-ring substituents

Journal of Medicinal Chemistry

Volumn 41, Issue 3, 1998, Pages 303-310

  Edwards, James P ^a   West, Sarah J ^a   Marschke, Keith B ^a   Mais, Dale E ^a   Gottardis, Marco M ^a   Jones, Todd K ^a  

^a LIGAND PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 (4 CHLOROPHENYL) 1,2 DIHYDRO 2,2,4 TRIMETHYL 5H CHROMENO[3,4 F]QUINOLINE; 5 (4 CHLOROPHENYL) 9 FLUORO 1,2 DIHYDRO 2,2,4 TRIMETHYL 5H CHROMENO[3,4 F]QUINOLINE; 5 ARYL 1,2 DIHYDRO 5H CHROMENO[3,4 F]QUINOLINE; 9 CHLORO 5 (4 CHLOROPHENYL) 1,2 DIHYDRO 2,2,4 TRIMETHYL 5H CHROMENO[3,4 F]QUINOLINE; ESTRADIOL BENZOATE; HORMONE RECEPTOR STIMULATING AGENT; MEDROXYPROGESTERONE ACETATE; MIFEPRISTONE; NORETHISTERONE; ONAPRISTONE; PROGESTERONE; PROGESTERONE RECEPTOR; PROGESTERONE RECEPTOR AGONIST; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG ANTAGONISM; DRUG POTENCY; DRUG STRUCTURE; FEMALE; HORMONE RECEPTOR INTERACTION; HORMONE SUBSTITUTION; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION; UTERUS WEIGHT;

ANIMALS; CELL LINE; FEMALE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; QUINOLINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, PROGESTERONE; STRUCTURE-ACTIVITY RELATIONSHIP; UTERUS;

EID: 0032576698     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9705770     Document Type: Article

References (36)

1. Evans, R. M. The Steroid and Thyroid Hormone Receptor Superfamily. Science 1988, 240, 889.
2. (a) McDonnell, D. P.; Vegeto, E.; Gleeson, M. A. G. Nuclear Hormone Receptors as Targets for New Drug Discovery. Bio / Technology 1993, 11, 1256-1261.
3. (b) Rosen, J.; Day, A.; Jones, T. K.; Jones, E. T. T.; Nadzan, A. M.; Stein, R. B. Intracellular Receptors and Signal Transducers and Activators of Transcription Superfamilies: Novel Targets for Small-Molecule Drug Discovery. J. Med. Chem. 1995, 38, 4855.
4. (a) Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344.
5. (b) Fuller, P. J. The Steroid Receptor Superfamily: Mechanisms of Diversity. FASEB J. 1991, 5, 3092.
6. (c) O'Malley, B. W.; Tsai, S.; Bagchi, M.; Weigel, N. L.; Schrader, W. T.; Tsai, M.-J. Molecular Mechanism of Action of a Steroid Hormone Receptor. Recent Prog. Horm. Res. 1991, 47, 1-26.
7. (d) Tsai, M.-J.; O'Malley, B. W. Molecular Mechanisms of Action of Steroid/Thyroid Receptor Superfamily Members. Annu. Rev. Biochem. 1994, 63, 451-486.
8. Savouret, J. F.; Misrahi, M.; Loosfelt, H.; Atger, M.; Bailly, A.; Perrot-Applanat, M.; Vu Hai, M. T.; Guiochon-Mantel, A.; Jolivet, A.; Lorenzo, F.; Logeat, F.; Pichon, M. F.; Bouchard, P.; Milgrom, E. Molecular and Cellular Biology of Mammalian Progesterone Receptors. Recent Prog. Horm. Res. 1989, 45, 65-120.
9. (a) The Pharmacological Basis of Therapeutics, 8th ed.; Gilman, A. G.; Rail, T. W., Nies, A. S., Taylor, P., Eds.; Pergamon Press: New York, 1990; Chapter 58, pp 1397-1412.
10. (b) Savouret, J. F.; Chauchereau, A.; Misrahi, M.; Lescop, P.; Mantel, A.; Bailly, A.; Milgrom, E. The Progesterone Receptor. Biological Effects of Progestins and Antiprogestins. Hum. Reprod. 1994, 9 (Suppl. 1), 7-11.
11. Collins, D. C. Sex Hormone Receptor Binding, Progestin Selectivity, and the New Oral Contraceptives. Am. J. Obstet. Gynecol. 1994, 170, 1508-1513.
12. (a) Casper, R. F.; Chapdelaine, A. Estrogen and Interrupted Progestin: A New Concept for Menopausal Hormone Replacement Therapy. Am. J. Obstet. Gynecol. 1993, 168, 1188-1196.
13. (b) Lobo, R. A. The Role of Progestins in Hormone Replacement Therapy. Am. J. Obstet. Gynecol. 1992, 166, 1997-2004.
14. (a) Satyaswaroop, P. G.; Mortel, R. Hormonal Treatment of Endometrial Carcinoma: An Overview and New Development in Biology. J. Steroid Biochem. Mol. Biol. 1990, 37, 997-1001.
15. (b) Horwitz, K. B.; Wei, L. L.; Sedlacek, S. M.; D'arville, C. N. Progestin Action and Progesterone Receptor Structure in Human Breast Cancer: A Review. Recent Prog. Horm. Res. 1985, 41, 249-316.
16. (c) Haller, D. G.; Glick, J. H. Progestational Agents in Advanced Breast Cancer: An Overview. Semin. Oncol. 1986, 13 (Suppl. 4), 2-8.
17. (d) Santen, R. J.; Manni, A.; Harvey, H. A.; Redmond, C. Endrocrine Treatment of Breast Cancer in Women. Endocrinol. Rev. 1990, 11, 221-265.
18. (a) Pollow, K.; Juchem, M.; Grill, H.-J.; Elger, W.; Beier, S.; Henderson, D.; Schmidt-Gollwitzer, K.; Manz, B. Gestodene: A Novel Synthetic Progestin-Characterization of Binding to Receptor and Serum Proteins. Contraception 1989, 40, 325-341.
19. (b) Darney, P. D. The Androgenicity of Progestins. Am. J. Med. 1995, 98 (1a), 104s-110s.
20. Berger, T. S.; Parandoosh, Z.; Perry, B. W.; Stein, R. B. Interaction of Glucocorticoid Analogues with the Human Glucocorticoid Receptor. J. Steroid Biochem. Mol. Biol. 1992, 41, 733-738.
21. (a) Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.; Torres, A.; Goldman, M. E. Nonsteroidal Human Progesterone Receptor Modulators from the Marine Alga Cymopolia Barbata. Mol. Pharm. 1995, 47, 630-635.
22. (b) Hamann, L. G.; Farmer, L. J.; Johnson, M. G.; Bender, S. L.; Mais, D. E.; Wang, M.-W.; Crombie, D.; Goldman, M. E.; Jones, T. K. Synthesis and Biological Activity of Novel Nonsteroidal Progesterone Receptor Antagonists Based on Cyclocymopol Monomethyl Ether. J. Med. Chem. 1996, 39, 1178.
23. For previous attempts to prepare nonsteroidal hPR modulators, see: (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. (b) Combs, D. W.; Reese, K.; Cornelius, L. A.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteriodal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884. (c) Neelima; Seth, M.; Bhaduri, A. P. Progesterone Receptor Binding of Steroidal and Nonsteroidal Compounds. Prog. Drug Res. 1986, 30, 151-188. (d) Tatsuta, K.; Yasuda, S.; Kurihara, K.-i.; Tanabe, K.; Shinei, R.; Okonogi, T. Total Synthesis of Progesterone Receptor Ligands, (-)-PF1092A, B, and C. Tetrahedron Lett. 1997, 38, 1439-1443.
24. For previous attempts to prepare nonsteroidal hPR modulators, see: (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. (b) Combs, D. W.; Reese, K.; Cornelius, L. A.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteriodal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884. (c) Neelima; Seth, M.; Bhaduri, A. P. Progesterone Receptor Binding of Steroidal and Nonsteroidal Compounds. Prog. Drug Res. 1986, 30, 151-188. (d) Tatsuta, K.; Yasuda, S.; Kurihara, K.-i.; Tanabe, K.; Shinei, R.; Okonogi, T. Total Synthesis of Progesterone Receptor Ligands, (-)-PF1092A, B, and C. Tetrahedron Lett. 1997, 38, 1439-1443.
25. For previous attempts to prepare nonsteroidal hPR modulators, see: (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. (b) Combs, D. W.; Reese, K.; Cornelius, L. A.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteriodal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884. (c) Neelima; Seth, M.; Bhaduri, A. P. Progesterone Receptor Binding of Steroidal and Nonsteroidal Compounds. Prog. Drug Res. 1986, 30, 151-188. (d) Tatsuta, K.; Yasuda, S.; Kurihara, K.-i.; Tanabe, K.; Shinei, R.; Okonogi, T. Total Synthesis of Progesterone Receptor Ligands, (-)-PF1092A, B, and C. Tetrahedron Lett. 1997, 38, 1439-1443.
26. For previous attempts to prepare nonsteroidal hPR modulators, see: (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. (b) Combs, D. W.; Reese, K.; Cornelius, L. A.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteriodal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884. (c) Neelima; Seth, M.; Bhaduri, A. P. Progesterone Receptor Binding of Steroidal and Nonsteroidal Compounds. Prog. Drug Res. 1986, 30, 151-188. (d) Tatsuta, K.; Yasuda, S.; Kurihara, K.-i.; Tanabe, K.; Shinei, R.; Okonogi, T. Total Synthesis of Progesterone Receptor Ligands, (-)-PF1092A, B, and C. Tetrahedron Lett. 1997, 38, 1439-1443.
27. Zhi, L.; Tegley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K. 5-Aryl-1,2-dihydrochromeno-[3,4-f]quinolines: A Novel Class of Nonsteroidal Human Progesterone Receptor Agonists. J. Med. Chem. 1998, 41, 291-302.
28. Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.; Snieckus, V.; Josephy, P. D. Sequential Directed Ortho Metalation-Boronic Acid Cross-Coupling Reactions. A General Regiospecific Route to Oxygenated Dibenzo[b,d]pyran-6-ones Related to Ellagic Acid. J. Org. Chem. 1991, 56, 3763-3768.
29. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. The Palladium-Catalyzed Cross-Coupling Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases. Synth. Commun. 1981, 11, 513-519.
30. (b) Suzuki, A. Synthetic Studies via the Cross-coupling Reaction of Organoboron Derivatives with Organic Halides. Pure Appl. Chem. 1991, 63, 419-422.
31. Alternatively, direct coupling of 3 with 2-bromo-5-nitrobenzoic acid obviated the need for the hydrolysis step, and 5b was prepared in this way; however, in practice the methyl esters were easier to purify and handle.
32. Manske, R. H. F.; Kulka, M. The Skraup Synthesis of Quinolines. Organic Reactions; 1953; Vol. 7, Chapter 2.
33. Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J.; Neuenschwander, K. Conversion of Lactones into Ethers. J. Org. Chem. 1981, 46, 2417-2419.
34. The preparation, resolution, and biological evaluation of enantiomerically pure compounds from this series will be the subject of a future report.
35. Vegeto, E.; Allan, G. F.; Schrader, W. T.; Tsai, M. J.; McDonnell, D. P.; O'Malley, B. W. The Mechanism of RU 486 Antagonism Is Dependent on the Conformation of the Carboxy-Terminal Tail of the Human Progesterone Receptor. Cell 1992, 69, 703-713.
36. The general experimental as well as the materials and methods for the biological assays can be found in ref 13.