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US 5,723,490 AGranted
THF-containing sulfonamide inhibitors of aspartyl protease
AssigneeVertex Pharmaceuticals Incorporated
InventorRoger D. Tung
Life of this patent
Estimating the term…
Abstract
The present invention relates to a class of THF-containing sulfonamides which are aspartyl protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention.
Claims18
A pharmaceutical composition comprising:
- a) a pharmaceutically effective amount of a compound of the formula;
- ##STR310## wherein;
- each R.sup.1 is independently selected from the group consisting of --C(O)--, --S(O).sub.2 --, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2, --NR.sup.2 --S(O).sub.2 --, --NR.sup.2 --C(O)-- and --NR.sup.2 --C(O)--C(O)--;
- each Het is independently selected from the group consisting of C.sub.3 -C.sub.7 carbocycle;
- C.sub.6 -C.sub.10 aryl;
- phenyl fused with heterocycle;
- and heterocycle;
- wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, --N(R.sup.2)(R.sup.2), --NHOH, --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R.sup.2)(R.sup.2), --S(O).sub.2 --N(R.sup.2)(R.sup.2), --N(R.sup.2)--C(O)--R.sup.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --R.sup.6, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, --R.sup.6 and --O--R.sup.6 ;
- each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl optionally substituted with R.sup.6 ;
- each R.sup.3 is independently selected from the group consisting of H, Het, C.sub.1 -C.sub.6 alkyl and C.sub.2 -C.sub.6 alkenyl wherein any member of said R.sup.3, except H, may be optionally substituted with one or more substituents selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2)(R.sup.2), Het, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, NR.sup.2 --C(O)--R.sup.2 ;
- each n is independently 1 or 2;
- each D and D' is independently selected from the group consisting of R.sup.6 ;
- C.sub.1 -C.sub.5 alkyl, which may be optionally substituted with one or more groups selected from --OR.sup.2, --R.sup.3, --O--R.sup.6, --S--R.sup.6 and R.sup.6 ;
- C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of --OR.sup.2, --R.sup.3, --O--R.sup.6 and R.sup.6 ;
- C.sub.3 -C.sub.6 carbocycle, which may be optionally substituted with or fused with R.sup.6 ;
- and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted with or fused with R.sup.6 ;
- each E is independently selected from the group consisting of Het;
- --O--Het;
- Het--Het;
- --O--R.sup.3 ;
- --NR.sup.2 R.sup.3 ;
- C.sub.1 -C.sub.6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Het;
- and C.sub.2 -C.sub.6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Het;
- each R.sup.4 is independently selected from the group consisting of --OR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo, --NR.sup.2 --C(O)--R.sup.2 and --CN;
- each R.sup.5 is independently selected from the group consisting of H and C.sub.1 -C.sub.4 alkyl optionally substituted with aryl;
- and
- each R.sup.6 is independently selected from the group consisting of aryl, carbocycle and heterocycle, wherein said carbocycle or heterocycle may be optionally substituted with one or more groups selected from the group consisting of oxo, --OR.sup.5, --R.sup.5, --N(R.sup.5) (R.sup.5), --N(R.sup.5)--C(O)--R.sup.5, --R.sup.5 --OH, --CN, --CO.sub.2 R.sup.5, --C(O)--N(R.sup.5) (R.sup.5), halo and --CF.sub.3 ;
- b) one or more additional agents selected from the group consisting of other anti-viral agents and immunostimulators;
- and
- c) a pharmaceutically acceptable carrier, adjuvant or vehicle,
- wherein said pharmaceutical composition is orally administrable.
28 more elements
A method of treating or preventing HIV infection in a mammal comprising the steps of:
- a) administering to the mammal a composition comprising:
- (i) a pharmaceutically effective amount of a compound of the formula:
- ##STR311## wherein:
- each R.sup.1 is independently selected from the group consisting of --C(O)--, --S(O).sub.2 --, --C(O)--C(O)--, --O--C(O)--, --O--S(O).sub.2, --NR.sup.2 --S(O).sub.2 --, --NR.sup.2 --C(O)-- and --NR.sup.2 --C(O)--C(O)--;
- each Het is independently selected from the group consisting of C.sub.3 --C.sub.7 carbocycle;
- C.sub.6 -C.sub.10 aryl;
- phenyl fused with heterocycle;
- and heterocycle;
- wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, --OR.sup.2, --R.sup.2, N(R.sup.2) (R.sup.2), --NHOH, --R.sup.2 --OH, --CN, --CO.sub.2 R.sup.2, --C(O)--N(R)(R.sup.2), --S(O).sub.2 --N(R.sup.2)(R.sup.2), --N(R.sup.2)--C(O)--R.sup.2, --C(O)--R.sup.2, --S(O).sub.n --R.sup.2, --OCF.sub.3, --S(O).sub.n --R.sup.6, --N(R.sup.2)--S(O).sub.2 (R.sup.2), halo, --CF.sub.3, --NO.sub.2, --R.sup.6 and --O--R.sup.6 ;
- each R.sup.2 is independently selected from the group consisting of H and C.sub.1 -C.sub.3 alkyl optionally substituted with R.sup.6 ;
- each R.sup.3 is independently selected from the group consisting of H, Het, C.sub.1 -C.sub.6 alkyl and C.sub.2 -C.sub.6 alkenyl wherein any member of said R.sup.3, except H, may be optionally substituted with one or more substituents selected from the group consisting of --OR.sup.2, --C(O)--NH--R.sup.2, --S(O).sub.n --N(R.sup.2)(R.sup.2), Het, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, NR.sup.2 --C(O)--R.sup.2 ;
- each n is independently 1 or 2;
- each D and D' is independently selected from the group consisting of R.sup.6 ;
- C.sub.1 -C.sub.5 alkyl, which may be optionally substituted with one or more groups selected from --OR.sup.2, --R.sup.3, --O--R.sup.6, --S--R.sup.6 and R.sup.6 ;
- C.sub.2 -C.sub.4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of --OR.sup.2, --R.sup.3, --O--R.sup.6 and R.sup.6 ;
- C.sub.3 -C.sub.6 carbocycle, which may be optionally substituted with or fused with R.sup.6 ;
- and C.sub.5 -C.sub.6 cycloalkenyl, which may be optionally substituted with or fused with R.sup.6 ;
- each E is independently selected from the group consisting of Het;
- --O--Het;
- Het--Het;
- --O--R.sup.3 ;
- --NR.sup.2 R.sup.3 ;
- C.sub.1 -C.sub.6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Het;
- and C.sub.2 -C.sub.6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Het;
- each R.sup.4 is independently selected from the group consisting of --OR.sup.2, --C(O)--NHR.sup.2, --S(O).sub.2 --NHR.sup.2, halo, --NR.sup.2 --C(O)--R.sup.2 and --CN;
- each R.sup.5 is independently selected from the group consisting of H and C.sub.1 -C.sub.4 alkyl optionally substituted with aryl;
- and
- each R.sup.6 is independently selected from the group consisting of aryl, carbocycle and heterocycle, wherein said carbocycle or heterocycle may be optionally substituted with one or more groups selected from the group consisting of oxo, --OR.sup.5, --R.sup.5, --N(R.sup.5)(R.sup.5), --N(R.sup.5)--C(O)--R.sup.5, --R.sup.5 --OH, --CN, --CO.sub.2 R.sup.5, --C(O)--N(R.sup.5)(R.sup.5), halo and --CF.sub.3 ;
- and
- ii) a pharmaceutically acceptable carrier, adjuvant or vehicle,
- wherein said pharmaceutical composition is orally administrable;
- and
- b) concurrently or sequentially administering to the mammal one or more additional agents selected from the group consisting of other anti-viral agents and immunostimulators.
30 more elements
Dependencies are inferred from the claim text.