Revisiting the Ullmann-ether reaction: A concise and amenable synthesis of novel dibenzoxepino[4,5-d]pyrazoles by intramolecular etheration of 4,5-(o,o′-halohydroxy)arylpyrazoles

Journal of Organic Chemistry

Volumn 67, Issue 21, 2002, Pages 7215-7225

  Olivera, Roberto ^a,b   SanMartin, Raul ^a   Churruca, Fátima ^a   Domínguez, Esther ^a  

^a UNIVERSITY OF THE BASQUE COUNTRY UPV EHU   (Spain)

^b FAES FARMA SA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ETHERATION;

CATALYSIS; CHEMICAL BONDS; ETHERS; HYDROLYSIS; KETONES; PALLADIUM; SUBSTITUTION REACTIONS; SYNTHESIS (CHEMICAL);

NITROGEN COMPOUNDS;

BRAIN RECEPTOR; BROMINE; COPPER; DIBENZOXEPINO[4,5 D]PYRAZOLE; KETONE; PALLADIUM; PHENYLACETIC ACID DERIVATIVE; PHENYLHYDRAZINE; PYRAZOLE DERIVATIVE; SALICYLALDEHYDE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CATALYSIS; CHEMICAL REACTION; CYCLIZATION; HYDROLYSIS; REACTION ANALYSIS; RECEPTOR BINDING; STEREOCHEMISTRY; SYNTHESIS; TECHNIQUE;

DIBENZOXAZEPINES; ETHERS; INDICATORS AND REAGENTS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037131141     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo025767j     Document Type: Article

References (112)

1. Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem. 1982, 25, 1065-1070.
2. For a review, see: Missir, A.; Limban, C.; Stecoza, C.; Morusciag, L.; Chirita, I. Farmacia 1998, 46, 17-30.
3. (a) Bischoff, S. In Novel Antipsychotic Drugs, Meltzer: New York, 1992, pp. 117-134.
4. (b) Storni, A. Actual Chim. Ther. 1989, 16, 143-150.
5. (a) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G. Pure Appl. Chem. 1999, 71, 2039-2046.
6. (b) Sperling, W.; Demling, J. Drugs Today 1997, 33, 95-102.
7. (c) Claghorn, J.; Lesem, M. D. Prog. Drug Res. 1996, 46, 243-262.
8. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
9. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
10. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
11. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
12. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
13. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
14. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
15. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
16. For lead references on the synthesis and biological evaluations of ORG 4428 (Beloxepin) and ORG 5222 and patent claims, see: (a) Prinsse, E. P. M.; Koek, W.; Kleven, M. S. Eur. J. Pharmacol. 2000, 388, 57-67. (b) Miguel-Hidalgo, J. J. Drugs 2000, 2, 85-92. (c) Van Bemmel, A. L.; Vermeeren, M. T. G.; Ruigt, G.; Sennef, C. Neuropsychobiology 1999, 40, 107-114. (d) Andrews, J. S. Patent WO 9932108 (Chem. Abstr. 131, 54031). (e) van Delft, A. M. L.; Ruigt, G. S. F.; van Proosdij, J. N. Neuropsychopharmacology 1994, 10, (Suppl. Part 2), 24. (f) Delbressine, L. P. C.; Wieringa, J. H. Patent WO 9523600. (g) Room, P.; Tielemans, A. J. P. C.; de Boer, T.; VanDelft; A. M. L.; Jeroen, J. A. D. M. Eur. J. Pharmacol. 1991, 205, 233-240. (h) Costall, B.; Domeney, A. M.; Kelly, M. E.; Naylor, R. J.; Tomkins, D. M. Pharmacol. Biochem. Behav. 1990, 35, 607-615. (i) Ruigt, G. S. F.; van Proosdij, J. N. Eur. J. Pharmacol. 1990, 183, 1467-1468.
17. 2-dopamine receptor antagonists: Power, P. L.; Rakhit, S. U.S. Patent 5703072 (Chem. Abstr. 128, 88936).
18. 2-dopamine receptor antagonists: Power, P. L.; Rakhit, S. U.S. Patent 5703072 (Chem. Abstr. 128, 88936).
19. Few natural products containing an oxepine ring have been isolated to date. For example, see: (a) Pacharin, a constituent of the heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of a bioactive dihydrobenzodioxepin from Juncus effusus: Della-Greca, M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochemistry 1993, 34, 1182-1184. Isolation and characterization of new natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of Artocarpus rigida have recently been achieved. Several of them have exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung, M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang, J.-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D: Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron Lett. 2001, 42, 5269-5270.
20. Few natural products containing an oxepine ring have been isolated to date. For example, see: (a) Pacharin, a constituent of the heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of a bioactive dihydrobenzodioxepin from Juncus effusus: Della-Greca, M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochemistry 1993, 34, 1182-1184. Isolation and characterization of new natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of Artocarpus rigida have recently been achieved. Several of them have exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung, M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang, J.-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D: Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron Lett. 2001, 42, 5269-5270.
21. Few natural products containing an oxepine ring have been isolated to date. For example, see: (a) Pacharin, a constituent of the heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of a bioactive dihydrobenzodioxepin from Juncus effusus: Della-Greca, M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochemistry 1993, 34, 1182-1184. Isolation and characterization of new natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of Artocarpus rigida have recently been achieved. Several of them have exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung, M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang, J.-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D: Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron Lett. 2001, 42, 5269-5270.
22. Few natural products containing an oxepine ring have been isolated to date. For example, see: (a) Pacharin, a constituent of the heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of a bioactive dihydrobenzodioxepin from Juncus effusus: Della-Greca, M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochemistry 1993, 34, 1182-1184. Isolation and characterization of new natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of Artocarpus rigida have recently been achieved. Several of them have exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung, M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang, J.-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D: Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron Lett. 2001, 42, 5269-5270.
23. Few natural products containing an oxepine ring have been isolated to date. For example, see: (a) Pacharin, a constituent of the heartwood of Bauhinia racemosa lamk: Comber, M. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1990, 5, 1371-1373. (b) Isolation of a bioactive dihydrobenzodioxepin from Juncus effusus: Della-Greca, M.; Fiorentino, A.; Molinaro, A.; Monaco, P.; Previtera, L. Phytochemistry 1993, 34, 1182-1184. Isolation and characterization of new natural dibenzo[b,f]oxepines (Artocarpols) from the root bark of Artocarpus rigida have recently been achieved. Several of them have exhibited potent antiinflammatory effects: (c) Artocarpol A: Chung, M.-I.; Ko, H.-H.; Yen, M.-H.; Lin, C.-N.; Yang, S.-Z. Tsao, L.-T.; Wang, J.-P. Helv. Chim. Acta 2000, 83, 1200-1204. (d) Artocarpols C and D: Ko, H.-H.; Lin, C.-N.; Yang, S.-Z. Helv. Chim. Acta 2000, 83, 3000-3005. (e) Artocarpol F: Ko, H.-H.; Yang, S.-Z.; Lin, C.-N. Tetrahedron Lett. 2001, 42, 5269-5270.
24. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
25. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
26. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
27. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
28. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
29. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
30. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
31. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
32. Diverse applications of dibenzoxepino-fused heterocycles have been claimed: (a) Analgesic agents: Martin, L. L.; Setescak, L. L. U.S. Patent 4576960 (Chem. Abstr.: 104, 224840). (b) Antiarthritic agent: Cherkofsky, S. C.; Sharpe, T. R. U.S. Patent 4198421 (Chem. Abstr. 93, 71783). (c) Antihistamine agents: Kumazawa, T.; Ohsima, E.; Obase, H. Patent JP 61152673 (Chem. Abstr. 106, 4904). (d) Antiespasmodic agents: Bracaccio, G.; Lettieri, G.; Monforte, P.; Larizza, A. Farmaco 1982, 37, 711-718. (e) Anti-neurodegenerative agents: Zimmermann, K.; Roggo, S.; Betschart, C. Patent WO 9745422 (Chem. Abstr. 128, 61439). (f) Antioxidants: Jinno, S.; Okita, T. Heterocycles 1999, 51, 303-314. (g) Tracheal smooth muscle relaxants: Yamashita, S.; Takeo, J.; Jinno, S.; Kogure, Y.; Onuki, H.; Okita, T.; Hata, J.; Fukuda, Y.; Ohtsuka, N. Patent WO 9725985 (Chem. Abstr. 127, 149089). (h) Antipsychotic, cardiovascular and gastroprotectors: Gil-Lopetegui, P.; Fernández-Gadea, F. J.; Meert, T. F. Patent WO 97338991, and (i) Antiasthmatic and respiratory tract hypersensitiviness inhibitors: Jinno, S.; Okita, T.; Ohtsuka, N.; Yamashita, S.; Hata, J.; Takeo, J. Patent WO 0075127 (Chem. Abstr. 134, 29329).
33. These type of compounds have also exhibited efficiency for the treatment of diseases such as: (a) Asthma: Lever, O. W.; King, A. N.; Harfenist, M.; Chao, E. Y. H. Patent WO 9015599 (Chem. Abstr. 16, 20960). (b) Arteriosclerosis: Nakazawa, H.; Ando, K.; Kuge, Y.; Sugaya, T.; Kasai, M.; Tomioka, S. Patent JP 06306070 (Chem. Abstr. 122, 160492). (c) Cancers related to estrogen regulation disorders: Kanamaru, T.; Hida, T.; Muroi, M. Patent EP 342665 (Chem. Abstr. 113, 5954).
34. These type of compounds have also exhibited efficiency for the treatment of diseases such as: (a) Asthma: Lever, O. W.; King, A. N.; Harfenist, M.; Chao, E. Y. H. Patent WO 9015599 (Chem. Abstr. 16, 20960). (b) Arteriosclerosis: Nakazawa, H.; Ando, K.; Kuge, Y.; Sugaya, T.; Kasai, M.; Tomioka, S. Patent JP 06306070 (Chem. Abstr. 122, 160492). (c) Cancers related to estrogen regulation disorders: Kanamaru, T.; Hida, T.; Muroi, M. Patent EP 342665 (Chem. Abstr. 113, 5954).
35. These type of compounds have also exhibited efficiency for the treatment of diseases such as: (a) Asthma: Lever, O. W.; King, A. N.; Harfenist, M.; Chao, E. Y. H. Patent WO 9015599 (Chem. Abstr. 16, 20960). (b) Arteriosclerosis: Nakazawa, H.; Ando, K.; Kuge, Y.; Sugaya, T.; Kasai, M.; Tomioka, S. Patent JP 06306070 (Chem. Abstr. 122, 160492). (c) Cancers related to estrogen regulation disorders: Kanamaru, T.; Hida, T.; Muroi, M. Patent EP 342665 (Chem. Abstr. 113, 5954).
36. Drug Data Rep. 2000, 22, 376-378.
37. (a) A number of synthetic pharmacophores, with the activities indicated as follows, are based upon a diaryl-substituted pyrazole motif: (a) Neuropsychiatric disorders. Application of corticotropin releasing factor (CRF) as receptor modulators: Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641-1660. (b) Application of ER-38930, a retinoic acid receptor (RARa) agonist for dermatologic and immunological diseases: Hibi, S.; Tagami, K.; Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also: Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622. Likewise, particularly appealing is the potency exhibited by this kind of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.; BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J. R.; Madar, D. J.; Sciotti, R. J.; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron, S.; Bauch, J.; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy, T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J. M.; Warrior, U.; Wegner, C. D.; Carter, G. W. J. Med. Chem. 2000, 43, 2975-2981.
38. (a) A number of synthetic pharmacophores, with the activities indicated as follows, are based upon a diaryl-substituted pyrazole motif: (a) Neuropsychiatric disorders. Application of corticotropin releasing factor (CRF) as receptor modulators: Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641-1660. (b) Application of ER-38930, a retinoic acid receptor (RARa) agonist for dermatologic and immunological diseases: Hibi, S.; Tagami, K.; Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also: Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622. Likewise, particularly appealing is the potency exhibited by this kind of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.; BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J. R.; Madar, D. J.; Sciotti, R. J.; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron, S.; Bauch, J.; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy, T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J. M.; Warrior, U.; Wegner, C. D.; Carter, G. W. J. Med. Chem. 2000, 43, 2975-2981.
39. (a) A number of synthetic pharmacophores, with the activities indicated as follows, are based upon a diaryl-substituted pyrazole motif: (a) Neuropsychiatric disorders. Application of corticotropin releasing factor (CRF) as receptor modulators: Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641-1660. (b) Application of ER-38930, a retinoic acid receptor (RARa) agonist for dermatologic and immunological diseases: Hibi, S.; Tagami, K.; Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also: Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622. Likewise, particularly appealing is the potency exhibited by this kind of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.; BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J. R.; Madar, D. J.; Sciotti, R. J.; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron, S.; Bauch, J.; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy, T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J. M.; Warrior, U.; Wegner, C. D.; Carter, G. W. J. Med. Chem. 2000, 43, 2975-2981.
40. (a) A number of synthetic pharmacophores, with the activities indicated as follows, are based upon a diaryl-substituted pyrazole motif: (a) Neuropsychiatric disorders. Application of corticotropin releasing factor (CRF) as receptor modulators: Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641-1660. (b) Application of ER-38930, a retinoic acid receptor (RARa) agonist for dermatologic and immunological diseases: Hibi, S.; Tagami, K.; Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also: Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622. Likewise, particularly appealing is the potency exhibited by this kind of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.; BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J. R.; Madar, D. J.; Sciotti, R. J.; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron, S.; Bauch, J.; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy, T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J. M.; Warrior, U.; Wegner, C. D.; Carter, G. W. J. Med. Chem. 2000, 43, 2975-2981.
41. (a) A number of synthetic pharmacophores, with the activities indicated as follows, are based upon a diaryl-substituted pyrazole motif: (a) Neuropsychiatric disorders. Application of corticotropin releasing factor (CRF) as receptor modulators: Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641-1660. (b) Application of ER-38930, a retinoic acid receptor (RARa) agonist for dermatologic and immunological diseases: Hibi, S.; Tagami, K.; Kikuchi, K.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Bioorg. Med. Chem. Lett. 2000, 10, 623-625. See also: Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tai, K.; Hida, T.; Tokuhara, N.; Yamauchi, T.; Nagai, M. Med. Chem. Lett. 2000, 10, 619-622. Likewise, particularly appealing is the potency exhibited by this kind of heterocycle as (c) estrogen receptor a-selective agonists: Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934-4947. (d) Interleukine-2 (IL-2) inhibitors: Djuric, S. W.; BaMaung, N. Y.; Basha, A.; Liu, H.; Luly, J. R.; Madar, D. J.; Sciotti, R. J.; Tu, N. P.; Wagenaar, F. L.; Wiedeman, P. E.; Zhou, X.; Ballaron, S.; Bauch, J.; Chen, Y.-W.; Chiou, X. G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G. C.; Marsh, K. C.; Mollison, K. W.; Pong, M.; Shaughnessy, T. K.; Sheets, M. P.; Smith, M.; Trevillyan, J. M.; Warrior, U.; Wegner, C. D.; Carter, G. W. J. Med. Chem. 2000, 43, 2975-2981.
42. Nagaoka; H.; Kamino, S.; Onuki, H. Patent JP 10204079 (Chem. Abstr. 129, 189246).
43. Rosowsky, A. In The Chemistry of Heterocyclic Compounds: 7-membered Heterocyclic Compounds containing Oxygen and Sulfur; Weissberger, A., Taylor, E. C., Eds., Wiley-Interscience: New York, 1972; pp 154-176 and references therein.
44. (a) Olivera, R.; SanMartin, R.; Domínguez, E. J. Org. Chem. 2000, 65, 6398-6411.
45. (b) Olivera, R.; SanMartin, R.; Domínguez, E. J. Org. Chem. 2000, 65, 7010-7019.
46. (c) Olivera, R.; SanMartin, R.; Domínguez, E. Synlett 2000, 7, 1028-1030.
47. (a) de la Fuente, M. C.; Castedo, L.; Domínguez, D. Tetrahedron 1996, 52, 4917-4924.
48. (b) Burden, P. M.; Capper, H. R.; Allan, R. D.; Johnston, G. A. R. J. Chem. Soc., Perkin Trans. 1 1991, 3291-3294.
49. (a) Sawyer, J. S. Tetrahedron 2000, 56, 5045-5065.
50. (b) Theil, F. Angew. Chem., Int. Ed. 1999, 111, 2345-2347.
51. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 111, 2046-2067.
52. (d) Chiu, C. K.-F. In Comprehensive Organic Functional Groups Transformations, Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: Cambridge, 1995; Vol. 2, Chapter 2.13, pp 683-685.
53. (a) Kuwabe, S.-I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202-12206.
54. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 10776-10781.
55. (c) Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907-12908.
56. (d) Cundy, D. J.; Forsyth, A. S. Tetrahedron Lett. 1999, 39, 7979-7982.
57. (e) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63, 9594-9596.
58. (f) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933-2936.
59. (g) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395-3396.
60. (h) Lindley, J. Tetrahedron 1984, 40, 1433-1456.
61. (a) Pleier, A.-K.; Glas, H.; Grosche, M.; Sirsch, P.; Thiel, W. R. Synthesis 2001, 55-62.
62. (b) Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000, 1822-1824.
63. (a) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2000, 2, 4181-4184.
64. (b) Müller, T. J. J.; Braun, R. U.; Ansorge, M. Org. Lett. 2000, 2, 1967-1970.
65. (c) Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Aelterman, W.; De Kimpe, N. Tetrahedron 2000, 56, 7313-7318.
66. (d) Dawood, K. M.; Kandeel, Z. E.; Farag, A. M. Heteroatom Chem. 1999, 10, 417-422.
67. (e) Bejan, E.; Aït-Hadou, H.; Daran, J.-C.; Balavoine, G. G. A. Eur. J. Org. Chem. 1998, 2907-2912.
68. 13C NMR analysis of chromatographed fractions provided clear evidence for the structure of 6. GC/MS spectrum showed a concordance of 99% when compared with the authentic one contained in a Wiley MS database.
69. Pelter, A.; Ward, R. S.; Ashdown, D. H. J. Synthesis 1978, 843-846 and references therein.
70. Kuntz, H.; Waldman, H. In Comprehensive Organic Synthesis; Trost; B. M., Fleming, I., Schreiber, S. L., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter 3.1, pp 643-663.
71. Kocienski, P. J. In Protecting Groups, 2nd ed.; Enders, D., Noyori, R., Trost, B. M., Eds.; Thieme: Stuttgart, 1994; pp 21-85.
72. Syntheses of α-aminonitriles and corresponding starting ortho-iodinated aldehydes were performed according to the method reported in ref 14a.
73. Under a variety of related conditions, 4-nitro-2-phenylsulfonyloxybenzaldehyde 7d failed to give the corresponding alcohol, leading to gummy, crude mixtures of difficult manipulation.
74. Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1972, 51, 2289-2299. Attempts to perform bromination of the so-obtained alcohols with HBr in acetic acid yielded mainly the acetyl derivatives as a result of the high reactivity of the desired bromomethyl compounds. Concretely, when 5-chloro-2-(phenylsulfonyloxy)phenyl]methanol 9b was submitted to such conditions, a mixture of the target bromide 10b (23% yield) and 5-chloro-2-(phenylsulfonyloxy)phenyl]-methyl acetate 10e (41% yield) was afforded.
75. In our hands (see ref 14a), when using 2-iodobenzyl chloride as alkylating agent, inverse addition of the electrophile was necessary to optimize the yield of 4a.
76. 1H NMR and 13C NMR spectra of the crude reaction, assignable to H-2 and C-1.
77. Shashidhar, M.; Bhatt, M. V. J. Chem. Soc., Chem. Commun. 1987, 654-656.
78. (a) Wähäla, K.; Hase, T. A. J. Chem. Soc., Perkin Trans. 1991, 3005-3008.
79. (b) Anstead, G. M.; Katzenellenboguen, J. A. J. Med. Chem. 1988, 31, 1754-1761.
80. Domínguez, E.; Lete, E.; Villa, M. J.; Iriondo, C. Heterocycles 1984, 22, 1217-1224.
81. Scandium trifiate has been reported as an excellent catalyst for F-C acylation, see: Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.-I. J. Org. Chem. 1997, 62, 6997-7005.
82. Illi, V. O. Tetrahedron Lett. 1979, 26, 2431-2432.
83. Proposed synthetic pathway for the formation of isoflavone 14a. The formation of isoflavones was suppressed by starting from benzoylated deoxybenzoins 13a-c. All the same, the partial lability of this protecting group on deoxybenzoins 13b and 13a upon enaminomethylation conditions was made clear, as shown by the isolation of the corresponding isoflavones 14a,b as minor products in 10 and 16% yield, respectively.
84. Tupper, D. E.; Ray, M. R. Synthesis 1997, 337-341.
85. (a) Bordwell, F. G.; Boutan, P. J. J. Am. Chem. Soc. 1957, 79, 717-722.
86. (b) Wolff, S.; Hoffmann, H. M. R. Synthesis 1988, 760-763.
87. (c) Civitello, E. R.; Rapoport, H. J. Org. Chem. 1994, 59, 3775-3782.
88. (d) Theuns, H. G.; Lenting, H. B. M.; Salemink, C. A.; Tanaka, H.; Shibata, M. Heterocycles 1984, 22, 1995-2005.
89. (e) Belanger, P. C.; Scheigetz, J.; Young, R. N. Can. J. Chem. 1983, 61, 2177-2182.
90. (f) Levacher, V.; Adolfsson, H.; Moberg, C. Acta Chern. Scand. 1996, 50, 454-457.
91. (a) Neuville, L.; Bois-Choussy, M.; Zhu, J. Tetrahedron Lett. 2000, 41, 1747-1751 and references therein.
92. (b) Malnar, I.; Sih, C. J. Tetrahedron Lett. 2000, 41, 1901-1911.
93. (a) Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J. Org. Chem. 2001, 66, 633-634.
94. (b) Evans, D. E.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937-2940.
95. (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860.
96. (b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818.
97. Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron Lett. 1998, 39, 543-546.
98. (a) Parrish, C. A.; S.-I.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498-2500.
99. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224-3225.
100. (c) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378.
101. (d) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6787-6795.
102. Control experiments were conducted in the same solvent mixture in the absence of a palladium catalyst, but none of the desired products were detected, and starting halide was completely recovered (>90%).
103. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005-8008.
104. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333-10334.
105. Marcoux, J.-F.; Poye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10538-10540.
106. Zhang, S.; Zhang, D.; Liebeskind, Chem. 1997, 62, 2312-2313.
107. Evans, D. A.; Ellmann, J. A. J. Am. Chem. Soc. 1989, 111, 1063-1072.
108. NAr mainly occurs with activated fluoro and chloroarenes; see: Paradisi, C. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991; Vol. 4, p 423. Control experiments were carried out in the absence of copper species (Table 6, entry 10), leading to the full recovery of starting phenolates, ruling out the operativity of this reaction pathway.
109. Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974, 43, 679.
110. Grimmett, M. R.; Iddon, B. Heterocycles 1994, 37, 2087-2149.
111. Bellón, R. F.; Carrasco, R.; Milián, V.; Rodés, L. Synth. Commun. 1995, 25, 1077-1083.
112. Alternative substitutive nomenclature of dibenzoxepino[4,5-d]-pyrazoles 1 as azulene derivatives may also be accepted. According to this, the systematic names of the synthesized tetracycles 1 are as follows: la, 1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1b, 7-chloro-1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1c: 5,7-dichloro-1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h] azulene; 1d, 10,11-dimethoxy-1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h] azulene; 1e, 10-diethylamino-1-phenyl-1H-8-oxa-1,2-diazadibenzo[e,h]azulene; 1g, 1-phenyl-5,6,9,10-tetramethoxy-1H-8-oxa-1,2-diazadibenzo[e,h] azulene; 1h, 1-phenyl-5,6,10,12-tetramethoxy-1H-8-oxa-1,2-diazadibenzo[e,h] azulene.