Patent EA-000906-B1 (EA)
Title: Oxygenated heterocycle containing sulfonamide inhibitors of aspartyl protease
Inventor: TUNG ROGER
IPC: C07D309/12
Filed: 1996-04-18
Abstract: 1. A compound of formula I:   wherein:  each R1 is independently selected from the group consisting of -C(O)-, -S(O)2-, -C(O)-C(O)-and -O-C(O)-; each A is dioxanyl; each Het is independently selected from the group consisting of C6-C10-aryl; phenyl fused with C6 -C10 -heterocycle; and C6 -C10 -heterocycle, where any member of said Het can 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-C6 alkyl and C2-C6 alkenyl where any member of said R<3>, except H, can 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 is C1-C5 alkyl, which can be optionally substituted with one or more groups selected from -OR<2>, -R<3>, -S-R<6>, -O-R<6> and R<6>; or C2-C4-alkenyl, which can be optionally substituted with one or more groups selected from the group consisting of -OR<2>, -R<3>, -O-R<6> and R<6>; each D' is selected from the group, including C1-C6-alkyl, which can be optionally substituted with R<6>; each E is 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-C3 alkyl; each R<6> is independently selected from the group consisting of aryl, 3-6-membered carbocycle and 5-6 -membered heterocycle, wherein said aryl, carbocycle or heterocycle can 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; where "aryl" refers to a C6-C10-carbocyclic aromatic radical;"carbocycle" refers to a stable non-aromatic 5-7-membered carbon ring which can be saturated, mono-unsaturated or poly-unsaturated; and "heterocycle" refers to a stable 5-7 membered monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic ring which is either saturated or unsaturated (optionally benzofused if it is monocyclic), and consists of one or more carbon atoms and of one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.  2. The compound according to claim 1, wherein A is 1,3-dioxanyl.  3. The compound according to claim 2, wherein A is 1,3-dioxan-5-yl.  4. The compound according to claim 1, wherein R<1> is -O-C(O)- or -C(O)-. 5. The compound according to claim 4, wherein R<1> is -O-C(O)-.  6. The compound according to claim 1, wherein D is methyl substituted with a substituent selected from the group C2-C5 alkyl, C3-C7 carbocycle and phenyl, which can be optionally substituted with -O-R<5> or -S-phenyl.  7. The compound according to claim 6, wherein D is selected from the group consisting of benzyl, isobutyl and cyclohexylmethyl.  8. The compound according to claim 1, wherein D' is selected from the group consisting of isobutyl, cyclopentylmethyl and cyclohexylmethyl.  9. The compound according to claim 1, wherein: each E is independently phenyl optionally substituted with one or more substituents selected from the group consisting of -OR<2>, -R<2>, -N(R<2>)(R<2>), -N(R<2>)-C(O)-R<2>, -R<2>-OH, -CN, -CO2R<2>, -C(O)-N(R<2>)(R<2>), halo and  -CF3; or phenyl fused with a 5-7 membered heterocycle or carbocycle; each R<2> is independently selected from the group consisting of H and C1-C3-alkyl optionally substituted with R<6>; each R<6> is independently selected from the group consisting of aryl, 3-6-membered carbocycle and 5-6-membered heterocycle, where said aryl, carbocycle or heterocycle can 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; and each R<5> is independently selected from the group consisting of H and C1-C3 alkyl. 10. The compound according to claim 9, where E is phenyl substituted with one more substituents selected from the group consisting of -OH, -OCH3, -NH2, -NHCOCH3, -S-CH3, and -CH3; or phenyl fused with 5-6-membered heterocycle or carbocycle. 11. The compound according to claim 10, where E is phenyl substituted with -NH2 at the meta- or para-position.  12. A compound claimed in claim 1, selected from the group consisting of:  N-cyclopentylmethyl-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)-4-methoxy-benzenesulfonamide (compound 1);  4-amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)benzenesulfonamide (compound 3), 4-amino-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)-N-isobutyl-benzenesulfonamide (compound 4); 3-amino-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)-N-isobutylbenzenesulfonamide (compound 5); 3-amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl)benzenesulfonamide (compound 6); 13. The compound according to claim 12 selected from the group consisting of:  4-amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)benzenesulfonamide (compound 3), 4-amino-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)-N-isobutyl-benzenesulfonamide (compound 4); 3-amino-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino)butyl)-N-isobutylbenzenesulfonamide (compound 5); 3-amino-N-cyclopentylmethyl-N-((2 syn, 3S)-2-oxy-4-phenyl-3-(1,3-dioxan-5-yl-oxycarbonylamino))butyl)benzenesulfonamide (compound 6); 14. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to of claims 1 or 12 and a pharmaceutically acceptable carrier, adjuvant or filler. 15. The pharmaceutical composition according to claim 14, wherein said pharmaceutical composition is orally administrable.  16. The pharmaceutical composition according to claim 14, wherein that additionally comprises one or more additional agents selected from the group consisting of other anti-viral agents and immunostimulators. 17. The pharmaceutical composition according to claim 16, wherein said other anti-viral agent or agents are protease inhibitors or reverse transcriptase inhibitors.  18. The pharmaceutical composition according to claim 17, wherein said inhibitor or protease inhibitors are HIV protease inhibitors.  19. The pharmaceutical composition according to claim 18, wherein said inhibitor or HIV protease inhibitors are selected from the group, including N-tert-butyldecahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)carboxamide (sahinavir; Ro 31-8959), N-(2(R)-hydroxy-1(S)-indanyl-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(tert-butylcarboxamido)piperazinyl)pentanamide (MK639), (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)valinyl)-amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-, hydroxyhexane (ABT 538; A80538), [3-(3R,4aR,8aR,2'S,3'S)]-2-[2'-hydroxy-3'-pentylthiomethyl-4'-aza-5'-oxo-5'-(2''-methyl-3''-hydroxyphenyl)pentyl]-decahydroisoquinolyne-3-N-tert-butylcarboxamide (AG 1343), N,N'-di-m-aminobenzyl-4,7-dibenzyl-5,6-dihydroxy-1,3-diazacyclohept-2-one (XM 450) and 1,1-dimethylethyl ether [1S-[1R,2S(2S,3R)]]-3-[[3-[[(1,1- dimethylethoxy)carbonyl]amino]-2-hydroxy-4-(4-[2-(4-morpholinyl)ethoxy]-phenyl]butyl]amino]-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid (BMS 186318). 20. The pharmaceutical composition according to claim 17, wherein said inhibitor or reverse transcriptase inhibitors are nucleoside analogs.  21. The pharmaceutical composition according to claim 20, wherein said nucleoside analog or analogs are selected from the group, including 3'-azido-2',3'-dideoxythymidine (zidovudine; AZT), dideoxycytidine (ddC), didanosine (ddI), 1-(2,3-dideoxy-β-D-glyceropent -2-enofuranozyl)thymine (stavudine; d4T), (2'R-cis)-2-deoxy-3'-thiacytidine (3TC), 5-chloro-2',3'-dideoxy-3'-pluorouridine (935U83), (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H- purine -9-yl]-2-cyclopentene-1-methanol (1592U89) and (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine (524W91). 22. The pharmaceutical composition according to claim 17, wherein said inhibitor or reverse transcriptase inhibitors are non-nucleoside analogs.  23. The pharmaceutical composition according to claim 22, wherein said non-nucleoside reverse transcriptase inhibitor or inhibitors are 1-(5-methansulfonamidoindolyl-2-carbonyl)-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (delavirdine; U90) or 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one (nevirapine). 24. A method for inhibiting aspartyl protease activity or method for reversibly binding an aspartyl protease comprising the step of contacting an aspartyl protease with the compound according to claim 1 or 12. 25. A method for reversibly binding an aspartyl protease according to claim 24, comprising the step of contacting an aspartyl protease with the compound according to claim 1 or 12, where said compound being covalently bound to a solid matrix. 26. A method for preventing HIV infection or 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 14, 15 or 16.  27. A method of treating HIV infection according to claim 26, additionally comp