Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors

Journal of Medicinal Chemistry

Volumn 52, Issue 10, 2009, Pages 3174-3183

  Randolph, John T ^a,b   Flentge, Charles A ^a   Huang, Peggy P ^a   Hutchinson, Douglas K ^a   Klein, Larry L ^a,c   Lim, Hock B ^a   Mondal, Rubina ^a   Reisch, Thomas ^a   Montgomery, Debra A ^a   Jiang, Wen W ^a,d   Masse, Sherie V ^a   Hernandez, Lisa E ^a   Henry, Rodger F ^a   Liu, Yaya ^a   Koev, Gennadiy ^a   Kati, Warren M ^a   Stewart, Kent D ^a   Beno, David W A ^a   Molla, Akhteruzzaman ^a   Kempf, Dale J ^a  

^a ABBOTT LABORATORIES   (United States)

^b Antiviral Research   (United States)

^c UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^d MIDWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 OXO 4 PHENYLOXAZOLIDINE 3 CARBOXYLIC ACID [1 (3,3 DIMETHYLBUTYL) 4 HYDROXY 3 (7 METHANESULFONYLAMINO 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 3 YL) 2 OXO 1,2 DIHYDRONAPHTHALEN 1 YL]AMIDE; 4 (3,3 DIMETHYLBUTYL) 3,4 DIHYDROXYNAPHTHALEN 1 (4H) ONE; BENZOTHIADIAZINE DERIVATIVE; N [1 (3,3 DIMETHYLBUTYL) 4 HYDROXY 3 [7 [(METHYLSULFONYL)AMINO] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 3 YL]2 OXO 1,2 DIHYDRONAPHTHALEN 1 YL]BENZAMIDE; N [1 (3,3 DIMETHYLBUTYL) 4 HYDROXY 3 [7 [(METHYLSULFONYL)AMINO] 1,2 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 3 YL] 2 OXO 1,2 DIHYDRONAPHTHALEN 1 YL]ACETAMIDE; N [3 [4 (3,3 DIMETHYLBUTYL) 1,4 DIHYDROXY 3 OXO 3,4 DIHYDRONAPHTHALEN 2 YL] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 7 YL]METHANESULFONAMIDE; N [3 [4 (BENZYLAMINO) 4 (3,3 DIMETHYLBUTYL) 1 HYDROXY 3 OXO 3,4 DIHYDRONAPHTHALEN 2 YL] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 7 YL]METHANESULFONAMIDE; N [3 [4 [(2,6 DIMETHYLBENZYL)AMINO] 4 (3,3 DIMETHYLBUTYL) 1 HYDROXY 3 OXO 3,4 DIHYDRONAPHTHALEN 2 YL] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 7 YL]METHANESULFONAMIDE; N [3 [4 AMINO 1 HYDROXY 4 (3,3 DIMETHYLBUTYL) 3 OXO 3,4 DIHYDRONAPHTHALEN 2 YL] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 7 YL]METHANESULFONAMIDE; N [3 [4 AMINO 4 (3,3 DIMETHYLBUTYL) 1 HYDROXY 3 OXO 3,4 DIHYDRONAPHTHALEN 2 YL] 1,1 DIOXIDO 4H 1,2,4 BENZOTHIADIAZIN 7 YL]METHANESULFONAMIDE TRIFLUOROACETIC ACID; NUCLEOTIDYLTRANSFERASE INHIBITOR; RNA DIRECTED RNA POLYMERASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CHIRALITY; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; GENOTYPE; HEPATITIS C VIRUS; IC 50; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; RAT; REPLICON;

ANIMALS; ANTIVIRAL AGENTS; BACTERIAL PROTEINS; BENZOTHIADIAZINES; ENZYME INHIBITORS; GENOTYPE; HEPACIVIRUS; LIVER; MICROBIAL SENSITIVITY TESTS; RATS; RNA REPLICASE; STRUCTURE-ACTIVITY RELATIONSHIP; TISSUE DISTRIBUTION;

EID: 66249135258     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm801485z     Document Type: Article

References (26)

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13. Inhibitor 1 was modeled in the benzothiadiazine binding site of HCV polymerase (PDB entry 1C2P: Lesburg, C. A.; Cable, M. B.; Ferrari, E.; Hong, Z.; Mennarino, A. F.; Weber, P. C. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat. Struct. Mol. Biol. 1999, 6, 937-943) with docking of 1 based on the reported binding orientation of a quinolinone analog (see ref 9).
14. The Z-oxime analogue was unreactive toward allylation using allylindium. For another example of allylation of methyloximes using allylindium, see the following: Bernardi, L.; Cere, V.; Femoni, C.; Pollicino, S.; Ricci, A. Organometallic reactions in aqueous media: indium-promoted additions to 2-pyridyl and glyoxylic acid oxime ethers. J. Org. Chem. 2003, 68, 3348-3351.
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19. A detailed description of methods used for synthesis and analysis of chiral isoamyl analogues 31-35 is available in the Supporting Information.
20. For information on the formation and reactivity of titanium Ate complexes, see the following: Reetz, M. T. Organotitanium Chemistry. In Organometallics in Synthesis. A Manual, 2nd ed.; Schlosser, M., Ed.; John Wiley & Sons Ltd.: West Sussex, England, 2002; p 832.
21. Krimen, L. I.; Cota, D. J. The Ritter Reaction. In Organic Reactions; Dauben, W. G., Ed.; Robert E. Krieger Publishing Co.; New York, 1969; Vol.17, pp 213-325.
22. For an initial report on the use of chiral oxazolidonones for the resolution of racemic amines, see the following: Pirkle, W. H.; Simmons, K. A. Improved chiral derivatizing agents for the chromatographic resolution of racemic primary amines. J. Org. Chem. 1983, 48, 2520-2527.
23. Molecular modeling studies revealed that the isomer having the S-configuration would properly position the inhibitor such that the isoamyl side chain would project into the hydrophobic pocket (see Figure 2). Given the importance of this group to the activity of the B-ring dialkyl series of inhibitors (see ref 11), it was anticipated that the S-isomer would be the more active isomer in the B-ring amino series.
24. Optical rotation measurement confirmed that 29 was the (-)-enantiomer {[α]D-72° (c 0.5, MeOH)}, which we expected to be the desired S-stereoisomer based on polarimetry studies of chiral isoamyl analogues. Details are available in the Supporting Information.
25. Our initial investigations of B-ring amino thiadiazine inhibitors of HCV polymerase focused on a series of compounds bearing an isoamyl side chain. This initial series of analogues was made prior to the discovery that a neohexyl side chain on the B-ring offered advantages over an isoamyl B-ring side chain as the result of improved metabolic stability.
26. Experimental details for the synthesis of 26b-v can be found in the Supporting Information.