Details for Patent: 7,608,590

Title:	HCV NS-3 serine protease inhibitors
Abstract:	Compounds of the formula ##STR00001## where the variables are as defined in the specification inhibit the NS3 protease of flavivirus such as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.
Inventor(s):	Rosenquist; Asa (Huddinge, SE), Thorstensson; Fredrik (Linkoping, SE), Johansson; Per-Ola (Linkoping, SE), Kvarnstrom; Ingemar (Linkoping, SE), Ayesa; Susana (Huddinge, SE), Classon; Bjorn (Huddinge, SE), Rakos; Laszlo (Huddinge, SE), Samuelsson; Bertil (Huddinge, SE)
Assignee:	Medivir AB (Huddinge, SE)
Filing Date:	Jan 28, 2005
Application Number:	10/572,418
Claims:	1. A compound of formula I': ##STR00212## wherein A is C(.dbd.O)OR.sup.1, or C(.dbd.O)NHSO.sub.2R.sup.2,wherein; R.sup.1 is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; wherein R.sup.2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--R.sub.b, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb, Y--NRaC(.dbd.O)ORb; Y is independently a bond or C.sub.1-C.sub.3alkyl; Ra is independently H or C.sub.1-C.sub.3alkyl; Rb is independently H, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl or C.sub.0-C.sub.3alkylheterocyclyl; p is independently 1 or 2; M is CR.sup.7R.sup.7'; R.sup.7 taken together with R.sup.7' forms a C.sub.3-C.sub.6cycloalkyl ring substituted with J; q is 1 and k is 1; W is --CH.sub.2--, --O--, --OC(.dbd.O)NH, --OC(.dbd.O), --S--, --NH--, --NRa, --NHSO.sub.2--, --NHC(.dbd.O)NH-- or --NHC(.dbd.O)--, --NHC(.dbd.S)NH-- or a bond; R.sup.8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings each of which has 4-7 ring atoms and each of which has 0 to 4 hetero atoms independently selected from S, O and N, the ring system being optionally spaced from W by a C.sub.1-C.sub.3 alkylene group; any of which R.sup.8 groups can be optionally mono-, di-, or tri-substituted with R.sup.9, wherein R.sup.9 is independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2C(.dbd.O)--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb, Y--NRaC(.dbd.O)ORb; wherein said carbocyclyl or heterocyclyl is optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino, amido, sulfonyl, (C.sub.1-C.sub.3 alkyl)sulfonyl, NO.sub.2, OH, SH, halo, haloalkyl, carboxyl; E is --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O).sub.2.sup.-, --S(.dbd.O)--, --C(.dbd.N--Rf)--; Rf is H, --CN, --C(.dbd.O)NRaRb; --C(.dbd.O)C.sub.1-C.sub.3alkyl; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R.sup.7/R.sup.7' cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to three heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R.sup.14; wherein; R.sup.12 is H, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, or C(.dbd.O)R.sup.13; R.sup.13 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; R.sup.14 is independently selected from the group consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, hydroxy, halo, amino, oxo, thio and C.sub.1-C.sub.6thioalkyl; m is 0 ; n is 0; G is --NRy-; Ry is J; R.sup.16 is H; or C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb, Y--NRac(.dbd.O)ORb; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, with the partial structure Ia', Ib' or Iaa': ##STR00213## where e is 1 or 2. 3. A compound according to claim 1, wherein E is --C(.dbd.O)--. 4. A compound according to claim 1, wherein R.sup.16 is H, C.sub.1-C.sub.3 alkyl or C.sub.3-C.sub.6 cycloalkyl. 5. A compound according to claim 1, wherein W is --OC(.dbd.O)--, --NRa--, NHS(O).sub.2--; --NHC(.dbd.O)-- or --OC(.dbd.O)NH--. 6. A compound according to claim 1, wherein W is --S--, a bond or --O--. 7. A compound according to claim 5 or 6 wherein R.sup.8 is optionally substituted C.sub.0-C.sub.3alkylcarbocyclyl or optionally substituted C.sub.0--C.sub.3-alkylheterocyclyl. 8. A compound according to claim 7, wherein the C.sub.0-C.sub.3 alkyl moiety is methylene or a bond. 9. A compound of formula I': ##STR00214## wherein A is C(.dbd.O)OR.sup.1, or C(.dbd.O)NHSO.sub.2R.sup.2, wherein; R.sup.1 is hydrogen, C.sub.1-C.sub.6alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.0C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; wherein R.sup.2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--R.sub.b,Y--C(.dbd.O)Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb, Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)ORb, Y--NRaC(.dbd.O)ORb; Y is independently a bond or C.sub.1-C.sub.3alkyl; Ra is independently H or C.sub.1-C.sub.3alkyk; Rb is independently H, C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl or C.sub.0-C.sub.3alkylheterocyclyl; p is independenly 1 or 2; M is CR.sup.7R.sup.7'; R.sup.7 taken together with R.sup.7' forms a C.sub.3-C.sub.6cycloalkyl ring substituted with J; q is 1 and k is 1; W is --O--, --OC(.dbd.O)NH, --OC(.dbd.O), --S--, --NRa, --NHSO.sub.2--, --NHC(.dbd.O)--, or a bond; R.sup.8 is C.sub.0-C.sub.3alkylaryl, or C.sub.0-C.sub.3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R.sup.9, wherein; R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, NO.sub.2, OH, halo, trifluoromethyl, amino, amido optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylaryl, C.sub.0-C.sub.3alkylheteroaryl, carboxyl, aryl or heteroaryl being optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, sulfonylC.sub.1-C.sub.6alkyl, NO.sub.2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl; E is --C(.dbd.O)--, --C(.dbd.S)--, --S(.dbd.O).sub.2, --S(.dbd.O)--, C(.dbd.N--Rf)--; Rf is H, --H, --CN, --C(.dbd.O)NRaRb; --C(.dbd.O) C.sub.1-C.sub.3alkyl; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain that extends from the R.sup.7/R.sup.7' cycloalkyl to G and forms a macrocycle, which chain is optionally interrupted by one to thee heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, and wherein 0 to 3 carbon atoms in the chain are optionally substituted with R.sup.14; wherein; R.sup.12 is H, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, or C(.dbd.O)R.sup.13; R.sup.13 is C.sub.1-C.sub.6, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; R.sup.14 is independently selected from the group consisting of H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, hydroxyl, halo, amino, oxo, thio and C.sub.1-C.sub.6thioalkyl; m is 0; n is 0; G is --NRy-; Ry is J; R.sup.16 is H; or C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, any of which can be substituted with halo, oxo, nitrile, azido, nitro, C.sub.1-C.sub.6, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl, NH.sub.2CO--, Y--NRaRb, Y--O--Rb, Y--C(.dbd.))Rb, Y--(C.dbd.O)NRaRb, Y--NRaC(.dbd.O)Rb, Y--NHSO.sub.pRb, Y--S(.dbd.O).sub.pRb,Y--S(.dbd.O).sub.pNRaRb, Y--C(.dbd.O)Orb, Y--NRac(.dbd.O)Orb; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 9 wherein R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, amino, di-(C.sub.1-C.sub.3 alkyl)amino, C.sub.1-C.sub.3alkylamide, aryl or heteroaryl, the aryl or heteroaryl being optionally substituted with R.sup.10; wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino, mono- or di-C.sub.1-C.sub.3 alkylamino, amido, halo, trifluoromethyl, or heteroaryl. 11. A compound according to claim 10, wherein, R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di substituted with C.sub.1-C.sub.3 alkyl, amido, C.sub.1-C.sub.3-alkylamide, halo, or heteroaryl. 12. A compound according to claim 11 wherein R.sup.10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with C.sub.1-C.sub.3 alkyl, amido, or C.sub.1-C.sub.3alkyl thiazolyl. 13. A compound according to claim 8, wherein R.sup.8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-naphthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R.sup.9. 14. A compound according to claim 13 wherein R.sup.8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R.sup.9. 15. A compound according to claim 14 wherein R.sup.8 is ##STR00215## wherein R.sup.9a is C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6alkoxy; thioC.sub.1-C.sub.3alkyl; amino optionally substituted with C.sub.1-C.sub.6alkyl; C.sub.0-C.sub.3alkylaryl; or C.sub.0-C.sub.3alkylheteroaryl, C.sub.0-C.sub.3alkylheterocyclyl, said aryl, heteroaryl or heterocycle being optionally substituted with R.sup.10 wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylC.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C1-C6alkyl, amido, C1-C3 amide; and R.sup.9b is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-alkoxy, amino, di(C.sub.1-C.sub.3alkyl)amino, (C.sub.1-C.sub.3alkyl) amide, NO.sub.2, OH, halo, trifluoromethyl, carboxyl. 16. A compound according to claim 15, wherein R.sup.9a is aryl or heteroaryl, either of which is optionally substituted with R.sup.10. 17. A compound according to claim 16 , wherein R.sup.9a is selected from the group consisted of: ##STR00216## wherein R.sup.10 is H, C.sub.1-C.sub.6alkyl, or C.sub.0-C.sub.3alkylcycloalkyl, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, (C.sub.1-C.sub.3alkyl)amide. 18. A compound according to claim 16, wherein R.sup.9a is phenyl, optionally substituted with C.sub.1-C.sub.6alkyl; C.sub.1-C.sub.6alkoxy; or halo. 19. A compound according to claim 15, wherein R.sup.8 is: ##STR00217## wherein R.sup.10a is H, C.sub.1-C.sub.6alkyl, or C.sub.0-C.sub.3alkylcarbocyclyl, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, amido, heteroaryl or heterocyclyl; and R.sup.9b is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6-alkoxy, amino, di(C.sub.1-C.sub.3 alkyl)amino, amido, NO.sub.2, OH, halo, trifluoromethyl, or carboxyl. 20. A compound according to claim 15, wherein R.sup.9b is C.sub.1-C.sub.6-alkoxy. 21. A compound according to claim 1, wherein A is C(.dbd.O)NHSO.sub.2R.sup.2. 22. A compound according to claim 21, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl. 23. A compound according to claim 21, wherein R.sup.2 is optionally substituted C.sub.3-C.sub.7cycloalkyl. 24. A compound according to claim 21, wherein R.sup.2 is optionally substituted C.sub.0-C.sub.6alkylaryl. 25. A compound according to claim 1, wherein A is C(.dbd.O)OR.sup.1. 26. A compound according to claim 25, wherein R.sup.1 is H or C.sub.1-C.sub.6 alkyl. 27. A compound according to claim 1, wherein R.sup.7 and R7' together define a spiro-cyclopropyl. 28. A compound according to claim 1, wherein J is a 3 to 8-membered saturated or unsaturated alkylene chain optionally containing one to two heteroatoms independently selected from: --O--, --S-- or --NR.sup.12--, wherein R.sup.12 is H, C.sub.1-C.sub.6alkyl, or --C(.dbd.O)C.sub.1-C.sub.6alkyl. 29. A compound according to claim 28, wherein J is a 4 to 7-membered saturated or unsaturated, all carbon alkylene chain. 30. A compound according to claim 28, wherein J is saturated or mono-unsaturated. 31. A compound according to claim 28, wherein J is dimensioned to provide a macrocycle of 14 or 15 ring atoms. 32. A pharmaceutical composition comprising a compound as defined in claim 1, and a pharmaceutically acceptable carrier therefor. 33. A pharmaceutical composition according to claim 32, further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon. 34. A compound according to claim 1 with formula Ihe': ##STR00218## or pharmaceutically acceptable salt thereof wherein R.sup.16 is H, or C.sub.1-C.sub.6alkyl; J is a single 3 to 10-membered saturated or partially unsaturated alkylene chain; q is 1 and k is 1; A is C(.dbd.O)OR.sup.1, or C(.dbd.O)NHSO.sub.2R.sup.2, wherein R.sup.1 is hydrogen or C.sub.1-C.sub.6alkyl; R.sup.2 is C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylcarbocyclyl, C.sub.0-C.sub.3alkylheterocyclyl; W is --O-- or --OC(.dbd.O)NH--; R.sup.8 is C.sub.0-C.sub.3alkylaryl or C.sub.0-C.sub.3alkylheteroaryl, either of which is optionally mono, di, or tri substituted with R.sup.9, wherein; R.sup.9 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, NO.sub.2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, C.sub.0-C.sub.3alkylaryl, C.sub.0-C.sub.3alkylheteroaryl, carboxyl, said aryl or heteroaryl being optionally substituted with R.sup.10;wherein R.sup.10 is C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.7cycloalkyl, C.sub.1-C.sub.6alkoxy, amino optionally mono- or di-substituted with C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.3alkyl amide, sulfonylC.sub.1-C.sub.3alkyl, NO.sub.2, OH, halo, trifluoromethyl, carboxyl or heteroaryl. 35. A compound according to claim 34, wherein J is a single 5-8 membered saturated or partially unsaturated alkylene chain. 36. A compound according to claims 34, wherein J is monounsaturated. 37. A compound according to claim 36, wherein J has one double bond spaced one carbon atom from the cyclopropyl group depicted in the formula Ihe'. 38. A compound according to claim 34, wherein R.sup.8 is the group ##STR00219## wherein R.sup.9a is C.sub.0-C.sub.3alkylaryl, C.sub.0-C.sub.3alkylheteroaryl, or C.sub.0-C.sub.3alkylheterocyclyl; said aryl, heteroaryl or heterocyclyl being optionally substituted with R.sup.10 wherein R.sup.10 is C.sub.1-C.sub.6alkyl, amino, amino mono- or disubstituted with C.sub.1-C.sub.6alkyl or NHC(.dbd.O)C.sub.1-C.sub.6alkyl; and R.sup.9b is C.sub.1-C.sub.6alkoxy; or R.sup.8 is C.sub.0-C.sub.3alkylaryl wherein the aryl group is optionally substituted with 1-2 substituents selected from C.sub.0-C.sub.3alkylheterocyclyl and trifluoC.sub.1-C.sub.6alkyl; and wherein the C.sub.0-C.sub.3alkylheterocyclyl is optionally substituted with R.sup.10. 39. A compound according to claim 38, wherein R.sup.9a is phenyl, ##STR00220## wherein R.sup.10 is H, C.sub.1-C.sub.6alkyl, amino, amino mono or disubstituted with C.sub.1-C.sub.3alkyl. 40. A compound according to claim 34, wherein A is C(.dbd.O)NHS(.dbd.O).sub.2R.sup.2. 41. A compound according to claim 40, wherein R.sup.2 is optionally substituted cycloalkyl. 42. The compound according to claim 41 wherein R.sup.2 is optionally substituted cyclopropyl. 43. A compound according to claim 4, wherein R.sup.16 is methyl. 44. A compound according to claim 9, wherein W is --O--. 45. A compound selected from the group consisting of: 19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2, 16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4,14-dicarboxyl- ic acid 4-ethyl ester 14-methyl ester; 19-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyc- lo[15.3.0.0*4,6*]icos-7-ene-3,14-dicarboxylic acid 3-ethyl ester; 14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-quinolin-4- -yloxy)-2,16-dioxo-3, 15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene-4-carboxylic acid 3-ethyl ester; 14-[(Cyclohexyl-methylcarbamoyl-methyl)-19-(7-methoxy-2-phenyl-qui- nolin-4-yloxy)-2,16-dioxo-3,15,17-triaza-tricyclo[15.3.0.0*4,6*]icos-7-ene- -4-carboxylic acid; [14-Cyclopropanesulfonylaminocarbonyl-17(7-methoxy-2-phenyl-quinolin-4-yl- oxy)-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.0*4,6*]octadec-7-en-13-yl]-- carbamic acid ter.butyl ester; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyc- lo[13.3.0.0.*4,6*]octadec-7-ene-4-carboxylic acid ethyl ester; 17-(7-Methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,13,15-triaza-tricyc- lo[13.30.0.*4,6*]octadec-7-ene-4-carboxylic acid; or a pharmaceutically acceptable salt thereof. 46. A pharmaceutical composition comprising a compound as defined in claim 45, and a pharmaceutically acceptable carrier therefor. 47. A pharmaceutical composition comprising a compound as defined in claim 10, and a pharmaceutically acceptable carrier therefor.