Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-29
2002-12-24
Seaman, Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S290000, C546S294000, C514S312000, C514S345000, C514S347000
Reexamination Certificate
active
06498254
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds useful as antiretroviral agents. More particularly, this invention relates to pyridine and quinoline derivatives which inhibit replication of the retroviruses HIV-1, HIV-2 and human cytomegalovirus (HCMV).
BACKGROUND OF THE INVENTION
There are currently about seven nucleoside reverse transcriptase (RT) inhibitors (NRTIs), about three nonnucleoside RT inhibitors (NNRTI) and about six protease inhibitors (PI) officially approved for the treatment of HIV-infected individuals. Reverse transcriptase and protease are virus-encoded enzymes. The clinical efficacy of the individual drugs varies depending on the nature and the molecular target of the drugs.
U.S. Pat. No. 5,268,389 describes certain thiocarboxylate ester compounds that are said to inhibit replication of HIV. It is alleged that the selectivity of these compounds for HIV-1 is due to a highly specific interaction with HIV-1 RT.
U.S. Pat. No. 5,696,151 is directed to certain carbothioamides that inhibit replication of HIV-1 and reverse transcriptase mutants thereof.
The rapid emergence of HIV-1 strains resistant to several HIV-1 -specific RT inhibitors in cell culture and in AIDS patients has caused concern for further development of these inhibitors in the clinic. See, e.g., Balzarini et al, J. Virology 67(9): 5353-5359 (1993) (“Balzarini I”) and Balzarini et al, Virology 192: 246-253 (1993) (“Balzarini II”).
Failure of long-term efficacy of known drugs can be associated with the appearance of dose-limiting and/or long-term side-effects, or more importantly, with the emergence of drug-resistant virus strains. Both RT inhibitors and protease inhibitors tend to select for virus strains that show a reduced susceptibility for the particular drugs. Moreover, a considerable cross-resistance exists between drugs that act against the same target.
Attempts have been made to combine various HIV-1 RT inhibitors to eliminate virus resistance. See, e.g., Balzarini I, supra. However, there is still a need for new compounds for the treatment of HIV that act at a target (either viral or cellular) that is different from those at which the existing drugs act.
It is the purpose of this invention to provide compounds which, by themselves, can inhibit or suppress the emergence of HIV-1, HIV-2 and HCMV.
SUMMARY OF THE INVENTION
This invention relates to the novel compounds 2-[[1-(5-amino-2-methylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 1],1,4-xylyl-bis-2-sulfonyl pyridine-N-oxide [compound 23], 1,4[1,2,4,5-tetramethylbenzyl]-bis-(2′-sulfonylpyridine-N-oxide) [compound 25], 2-(4′-tert-pentylphenylmethylsulfonyl)pyridine-N-oxide [compound 40], 2[1-(9-anthryl)methylsulfonyl]pyridine-N-oxide [compound 51], ethyl-N-[4-(pyridyl-N-oxide-2-sulfonylmethyl)phenylcarbonyl]carbamate [compound 60], 2-[(3-methoxy-4-benzyloxy)phenylmethylsulfonyl]pyridine-N-oxide [compound 61], 2-[[(2-nitro-5-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 62], 2-[[[2,5-bis(1-methylethyl)-4-bromophenyl]methyl]sulfonyl]pyridine-N-oxide [compound 63], 2-[[(3-nitro4-chlorophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 64], 2-[[(3,5-dinitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 65], 2-[[(3-methyl-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 66], 2-[[(3-nitro-4-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 67], 2-[[(2-chloro-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 69], 2-[(2,5-dimethylphenyl)chloromethylsulfonyl]-6-methylpyridine-N-oxide [compound73], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-6-chloropyridine-N-oxide [compound 76], 2-(2,5-dimethylphenylmethylsulfonyl)-6-chloropyridine-N-oxide [compound 77], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-4,6-dimethylpyridine-N-oxide [compound 81], 2[(2,5-dimethylphenyl)chloromethylsulfonyl]pyridine [compound 106], 8-ethyl-4-methyl-2-[(1-phenylethyl)sulfonyl]quinoline [compound 107], 2-[[1 -(2,5-dimethylphenyl)-2-methoxyethyl]sulfonyl]pyridine [compound 123], 3-chloro-2-[[1-(2,5-dimethylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 124], 3-chloro-2-[[chloro-(2,5-dimethylpbenyl)methyl]sulfonyl]pyridine-N-oxide [compound 125], 3-chloro-2-[(phenylmethyl)thio]pyridine-N-oxide [compound 132], 3-chloro-2-[[(2,5-dimethylphenyl)methyl]thio]pyridine-N-oxide [compound 133], 4-(1,1 -dimethylethyl)-2-[(4-methoxyphenyl)methylthio]pyridine-N-oxide [compound 134], 3-chloro-2-[(phenylmethyl)sulfinyl]pyridine-N-oxide [compound 136], 2-[[(2,6-dichlorophenyl)methyl]thio]-3-methyl-pyridine-N-oxide [compound 137], 2-[[(2,6-dichlorophenyl)methyl]sulfinyl]-3-methyl-pyridine-N-oxide [compound 138], 2-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-methyl-pyridine-N-oxide [compound 139], 2[[(2,5-dimethylphenyl)methyl]thio]-1-methylpyridinium chloride [compound 142], 2-benzylthio-3-nitropyridine [compound 146], 2-((2,5-dimethylphenyl)methylthio) pyridine [compound 148], 6-chloro-(2-benzylthio)pyridine-N-oxide [compound 149], 2-(2,5-dimethylbenzylsulfonyl)pyridine [compound 150], 5-chloro-2(benzylthio) pyridine-N-oxide [compound 151], 2-(N-methyl-3-piperidylmethylthio)pyridine-N-oxide [compound 156], 2-(2,5-dimethylphenylmethylthio)pyridine hydrochloride [compound 157], 2-(1-cyano-2-phenylethenethio) pyridine-N-oxide [compound 158], 2-[1-cyano-2-(p-methoxyphenyl)ethenethio]pyridine-N-oxide [compound 159], 2-[1-cyano-2-(3,4,5-trimethoxyphenyl)ethenethio]pyridine-N-oxide [compound 160], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]pyridine [compound 161], 2-[[1-(2,5-dimethylphenyl)ethyl]thio]-4-methylquinoline [compound 162] and 2-(2,5-dimethylphenyl)methylsulfinyl)pyridine [compound 163], and pharmaceutically acceptable salts thereof
The compounds of this invention are useful for inhibiting replication of HIV-1, HIV-2 and HCMV in vitro and in vivo. The compounds are also useful in the therapeutic or prophylactic treatment of diseases caused by these viruses.
This invention additionally relates to pharmaceutical compositions containing one or more of the above recited compounds and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to the following novel compounds: 2-[[1-(5-amino-2-methylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 1], 1,4-xylyl-bis-2-sulfonyl pyridine-N-oxide [compound 23], 1,4[1,2,4,5-tetramethylbenzyl]-bis-(2′-sulfonylpyridine-N-oxide) [compound 25], 2-(4′-tert-pentylphenylmethylsulfonyl)pyridine-N-oxide [compound 40], 2[1-(9-anthryl)methylsulfonyl]pyridine-N-oxide [compound 51], ethyl-N-[4-(pyridyl-N-oxide-2-sulfonylmethyl)phenylcarbonyl]carbamate [compound 60], 2-[(3-methoxy-4-benzyloxy)phenylmethylsulfonyl]pyridine-N-oxide [compound 61], 2-[[(2-nitro-5-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 62], 2-[[[2,5-bis(1-methylethyl)4-bromophenyl]methyl]sulfonyl]pyridine-N-oxide [compound 63], 2-[[(3-nitro-4-chlorophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 64], 2-[[(3,5-dinitrophenyl)me
Brewer Arthur D.
Cantor Stephen E.
Dekeyser Mark A.
Doweyko Arthur M. P.
Harris John W.
Jones Mary Louise
Reitenbach Daniel
Seaman Margaret
Uniroyal Chemical Company, Inc.
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