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US 5,691,372 AGranted
Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
AssigneeVertex Pharmaceuticals Incorporated
InventorsRoger D. Tung, Govinda Rao Bhisetti
Life of this patent
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Abstract
The present invention relates to a novel class of 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.
Claims46
A compound of formula I:
- ##STR71## 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 A is a 6 membered non-aromatic monocyclic oxygenated heterocycle containing 2 endocyclic oxygens, optionally attached through a C.sub.1 -C.sub.3 alkyl linker;
- each Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 carbocycle;
- and C.sub.6 -C.sub.10 aryl;
- wherein any member of said Ht is 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, --S--CH.sub.3 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, Ht, 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, is 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), Ht, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, and 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 is optionally substituted with one or more groups selected from --OR.sup.2, --R.sup.3, --S--R.sup.6, --O--R.sup.6 and R.sup.6 ;
- C.sub.2 -C.sub.4 alkenyl, which is 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 ;
- and C.sub.3 -C.sub.6 carbocycle, which is optionally substituted with or fused with R.sup.6 ;
- each E is independently selected from the group consisting of Ht;
- --O--Ht;
- Ht--Ht;
- --O--R.sup.3 ;
- --NR.sup.2 R.sup.3 ;
- C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht;
- C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht;
- and phenyl fused with a 5-7 membered carbocycle;
- 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, and carbocycle, each 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.
22 more elements
A compound of formula I:
- ##STR72## 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 A is independently selected from the group consisting of a 6 membered monocyclic heterocycle, containing 2 endocyclic oxygens, which is methylated at the point of attachment and optionally attached through a C.sub.1 -C.sub.3 alkyl linker;
- each Ht is independently selected from the group consisting of C.sub.3 -C.sub.7 carbocycle;
- and C.sub.6 -C.sub.10 aryl;
- wherein any member of said Ht is 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, --S--CH.sub.3 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, Ht, 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, is 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), Ht, --CN, --SR.sup.2, --CO.sub.2 R.sup.2, and 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 is optionally substituted with one or more groups selected from --OR.sup.2, --R.sup.3, --S--R.sup.6, --O--R.sup.6 and R.sup.6 ;
- C.sub.2 -C.sub.4 alkenyl, which is 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 ;
- and C.sub.3 -C.sub.6 carbocycle, which is optionally substituted with or fused with R.sup.6 ;
- each E is independently selected from the group consisting of Ht;
- --O--Ht;
- Ht--Ht;
- --O--R.sup.3 ;
- --NR.sup.2 R.sup.3 ;
- C.sub.1 -C.sub.6 alkyl, which is optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht;
- C.sub.2 -C.sub.6 alkenyl, which is optionally substituted with one or more groups selected from the group consisting of R.sup.4 and Ht;
- and phenyl fused with a 5-7 membered carbocycle;
- 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, and carbocycle, each 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.
22 more elements
A compound selected from the group consisting of:
- N-Cyclopentylmethyl-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-4-methox y-benzenesulfonamide;
- 4-Amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenes ulfonamide;
- 4-Amino-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl -benzenesulfonamide;
- 3-Amino-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-1,3-dioxan-5-yl-oxycarbonylamino)butyl-N-isobutyl -benzenesulfonamide;
- and
- 3-Amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-hydroxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl-benzenes ulfonamide.
3 more elements
Dependencies are inferred from the claim text.