Patent EA-001221-B1 (EA)
Title: Thf-containing sulfonamide inhibitors of aspartyl protease
Inventor: TUNG ROGER D
IPC: A61K38/00
Filed: 1996-04-18
Abstract: 1. A pharmaceutical composition, comprising: a) pharmaceutically acceptable amount of protease inhibitor - compounds of formula I wherein:   each R<1> is independently selected from the group consisting of -C(O)-, -S(O)2-, -C(O)-C(O)-,  -O-C(O)-, -O-S(O)2, -NR<2>-S(O)2-, -NR<2>-C(O) - and -NR<2>-C(O)-C(O) - ; each Het is independently selected from the group consisting of C3-C7 carbocycle; C6-C10 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<2>, -R<2>, -N(R<2>)(R<2>), -NHOH, -R<2>-OH, -CN, -CO2R<2>, -C(O)-N(R<2>)(R<2>), -S(O)2-N(R<2>)(R<2>), -N(R<2>)-C(O)-R<2>, -C(O)-R<2>, -S(O)n-R<2>, -OCF3, -S(O)n-R<6>, -N(R<2>)-S(O)2(R<2>), halo, -CF3, -NO2, -R<6> and -O-R<6>;  each R<2> is independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with R<6>;  each R<3> is independently selected from the group consisting of H, Het, C1-C6alkyl and C2-C6 alkenyl wherein any member of said R<3>, except H, may be optionally substituted with one or more substituents selected from the group consisting of -OR<2>, -C(O)-NH-R<2>, -S(O)n-N(R<2>)(R<2>), Het, -CN, -SR<2>, -CO2R<2>, -NR<2>-C(O)-R<2>;  each n is independently 1 or 2;  each D and D' is independently selected from the group consisting of R<6>; C1-C5 alkyl, which may be optionally substituted with one or more groups selected from -OR<2>, -R<3>, -O-R<6>, -S-R<6> and R<6>; C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of -OR<2>, -R<3>, -O-R<6> and R<6>; and C3-C6 carbocycle, which may be optionally substituted with or fused with R<6>; and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with R<6>; each E is independently selected from the group consisting of Het; -O-Het; Het-Het; -O-R<3>; -NR<2>R<3>; C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R<4> and Het; and C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R<4> and Het; each R<4> is independently selected from the group consisting of -OR<2>, -C(O)-NHR<2>, -S(O)2-NHR<2>, halo, -NR<2>-C(O)-R<2> and -CN; each R<5> is independently selected from the group consisting of H and C1-C4 alkyl optionally substituted with aryl; and  each R<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<5>, -R<5>, -N(R<5>)(R<5>), -N(R<5>)-C(O)-R<5>, -R<5>-OH, -CN, -CO2R<5>, -C(O)-N(R<5>)(R<5>), halo and -CF3.  b) one or more additional anti-viral agents and immunostimulators, independently selected from the group consisting of (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimidine-2-one (3 TC, lamivudine, Epivir(RTM)), [4-(1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-yl)phenoxy] acetic acid (935U83), sulphate salt (2:1) (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl-2-cyclopentene-1-methanol (1592U89, abakavir, Ziagen(RTM)), 4-amino-5-phluoro-1-[(2R, 5S)-2-hydroxymethyl)-1,3-oxothiolane-5-yl]-2(1H)-pyrimidinone (524W91), piperazine-1-[3-[(1-methylethyl)amino]-2-piridinyl]-4-[[5-methylsulphonyl)-amino]-1H-indole-2-yl]carbonyl]monomethansulphonate (delavirdine, U90) and 4-[(2-formyl-3-hydroxyphenoxy)methyl]-benzoic acid (tuscarazole); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor. 2. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) one or more additional anti-viral agents and immunostimulators, independently selected from the group consisting of (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimidine-2-one (3 TC, lamivudine, Epivir(RTM)), [4-(1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-yl)phenoxy] acetic acid (935U83), sulphate salt (2:1) (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl-2-cyclopentene-1-methanol (1592U89, abakavir, Ziagen(RTM)), 4-amino-5-phluoro-1-[(2R, 5S)-2-hydroxymethyl)-1,3-oxothiolane-5-yl]-2(1H)-pyrimidinone (524W91), piperazine-1-[3-[(1-methylethyl)amino]-2-pyridinyl]-4-[[5-methylsulphonyl)-amino]-1H-indole-2-yl]carbonyl] monomethansulphonate (delavirdine, U90) and 4-[(2-formil-3-hydroxyphenoxy)methyl]-benzoic acid (tuscarazole); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor. 3. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimidine-2-one (3 TC, lamivudine, Epivir(RTM)); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor.   4. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) sulphate salt (2:1) (1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-yl-2-cyclopentene-1-methanol (1592U89, abakavir, Ziagen(RTM)); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor. 5. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) [4-(1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-yl)phenoxy] acetic acid (935U83); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor. 6. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) 4-amino-5-phluoro-1-[(2R, 5S)-2-hydroxymethyl)-1,3-oxothiolane-5-yl]-2(1H)-pyrimidinone (524W91); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor. 7. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) piperazine-1-[3-[(1-methylethyl)amino]-2-pyridinyl]-4-[[5-methylsulphonyl)-amino]-1H-indole-2-yl]carbonyl] monomethansulphonate (delavirdine, U90); and c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor.   8. The pharmaceutical composition, comprising: a) a pharmaceutically acceptable amount of 4-amino-N-((2 sin, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran-3-yloxycarbonylamino)butyl)-N-isobutylbenzolsulphonamide (compound 168); b) 4-[(2-formil-3-hydroxyphenoxy)methyl]-benzoic acid (tuscarazole); and  c) pharmaceutically acceptable carrier, adjuvant or vehicle; provided that the composition does not comprise the second protease inhibitor.   9. The pharmaceutical composition according to any of claims 1-8, wherein said pharmaceutical composition is orally administrable.  10. A method for preventing HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to any of  claims 1-9. 11. A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to any of  claims 1-9.