Benzofuran based PDE4 inhibitors

Bioorganic and Medicinal Chemistry

Volumn 7, Issue 6, 1999, Pages 1131-1139

  McGarry, D G ^a   Regan, J R ^a   Volz, F A ^a   Hulme, C ^a   Moriarty, K J ^a   Djuric, S W ^a   Souness, J E ^b   Miller, B E ^a   Travis, J J ^a   Sweeney, D M ^a  

^a Departments of Medicinal Chemistry and Inflammation Biology   (United States)

^b Rhone Poulenc Rorer Essex RM107XS ^*  (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOFURAN DERIVATIVE; PHOSPHODIESTERASE IV INHIBITOR;

ARTICLE; ASTHMA; CONTROLLED STUDY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; INFLAMMATION; METHODOLOGY; NONHUMAN;

3',5'-CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; ANIMALS; BENZOFURANS; ENDOTOXEMIA; ENZYME INHIBITORS; MALE; MICE; MICE, INBRED BALB C; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033049376     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(99)00038-3     Document Type: Article

References (36)

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23. The first use of a benzofuran ring system to replace the 3,4-dialkoxy-phenyl subunit of rolipram was reported by the Glaxo group: Stafford, J. A.; Feldman, P. L.; Marron, B. E.; Schoenen, F. J.; Valvano, N. L.; Unwalla, R. J.; Domanico, P. L.; Brawley, E. S.; Leesnitzer, M. A.; Rose, D. A.; Dougherty, R. W. Bioorg. Med. Chem. Lett. 1994, 4, 1855. More recently, a number of groups have published patent applications describing the use of benzofurans and dihydrobenzofurans for this purpose. For a short summary of the patent literature in this area see Exp. Opin. Ther. Patents 1998, 8, 899. See also Gutterer, B.; Flockerzi, D.; Amschler, H.; Ulrich, W.; Bar, T.; Martin, T.; Hatzelmann, A.; Boss, H.; Beume, R.; Hafner, D.; Kley, H-P. Byk Gulden Lomberg: European patent application 819688, 1998; Chem. Abst. 1998, 128, 140616.
24. The first use of a benzofuran ring system to replace the 3,4-dialkoxy-phenyl subunit of rolipram was reported by the Glaxo group: Stafford, J. A.; Feldman, P. L.; Marron, B. E.; Schoenen, F. J.; Valvano, N. L.; Unwalla, R. J.; Domanico, P. L.; Brawley, E. S.; Leesnitzer, M. A.; Rose, D. A.; Dougherty, R. W. Bioorg. Med. Chem. Lett. 1994, 4, 1855. More recently, a number of groups have published patent applications describing the use of benzofurans and dihydrobenzofurans for this purpose. For a short summary of the patent literature in this area see Exp. Opin. Ther. Patents 1998, 8, 899. See also Gutterer, B.; Flockerzi, D.; Amschler, H.; Ulrich, W.; Bar, T.; Martin, T.; Hatzelmann, A.; Boss, H.; Beume, R.; Hafner, D.; Kley, H-P. Byk Gulden Lomberg: European patent application 819688, 1998; Chem. Abst. 1998, 128, 140616.
25. The first use of a benzofuran ring system to replace the 3,4-dialkoxy-phenyl subunit of rolipram was reported by the Glaxo group: Stafford, J. A.; Feldman, P. L.; Marron, B. E.; Schoenen, F. J.; Valvano, N. L.; Unwalla, R. J.; Domanico, P. L.; Brawley, E. S.; Leesnitzer, M. A.; Rose, D. A.; Dougherty, R. W. Bioorg. Med. Chem. Lett. 1994, 4, 1855. More recently, a number of groups have published patent applications describing the use of benzofurans and dihydrobenzofurans for this purpose. For a short summary of the patent literature in this area see Exp. Opin. Ther. Patents 1998, 8, 899. See also Gutterer, B.; Flockerzi, D.; Amschler, H.; Ulrich, W.; Bar, T.; Martin, T.; Hatzelmann, A.; Boss, H.; Beume, R.; Hafner, D.; Kley, H-P. Byk Gulden Lomberg: European patent application 819688, 1998; Chem. Abst. 1998, 128, 140616.
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30. Compound 18 is the 2-alkyl-7-methoxy-benzofuranyl analogue of the Celltech clinical candidate CDP 840 (structure 30) (a) Warrellow, G. J.; Alexander, R. P.; Boyd, E. C.; Eaton, M. A.; Head, J. C.; Higgs, G. A. presented at the 8th RSC-SCI Medicinal Chemistry Symposium, Cambridge, U. K. 1995.
31. (b) Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223 and references therein.
32. For the synthesis of 26d and 26g, the required heterocycles, 5-hydroxy-2-methyl-pyridine and 2-hydroxy-4-methyl-pyridine, were protected as their t-butyldiphenylsilyl ethers.
33. Turner, N. C.; Wood, L. J.; Burns, F. M.; Gueremy, T.; Souness, J. E. Br. J. Pharmacol. 1993, 108, 876.
34. 50 obtained for rolipram under the same assay conditions.
35. 50=0.2 nM). This compound we prepared from 2-allyl-3-hydroxy-4-methoxy-benzoic acid methyl ester in 9 steps.
36. This compound was prepared in the same way as 26a, except using 3-cyclopentoxy-4-methoxy-benzaldehyde as starting material instead of 9c.