Disulfide masked prodrug compositions and methods
View Patent ↗The present invention relates to disulfide masked prodrug compounds of formula I, compositions and methods that are amenable to bioactivation by a reducing agent such as glutathione: W—P(V)LG (Formula I), wherein P(V)LG is a pentavalent phosphorus leaving group; and W is: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the specification. Such disulfide based compounds, compositions, and methods can be useful, for example, in providing novel prodrugs for use as therapeutics. Once administered, the prodrug is metabolized in vivo into an active metabolite in a process termed bioactivation.
1. A compound comprising having the Formula III:
wherein,
W is:
wherein
R 1 is H, OH, C 1-6 alkyl, C 1-6 alkyl substituted with one or more hydroxyl groups, or C 1-6 alkyl substituted with one or more halo groups;
R 4 is S or O covalently attached to P;
each R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are independently halo or hydrogen;
each R 9 is individually C 1-6 alkyl;
R 12 is H, halo, C 1-6 alkoxyl, C 1-6 alkenyl, C 1-6 alkenyl substituted with one or more hydroxyl groups, C 1-6 alkenyl substituted with one or more halo groups, or —OR 15 ;
R 13 is H, —O-trityl, —O-trityl substituted with one or more hydroxyl or —O—C 1-6 alkyl groups, —O-pixyl (9-phenylxanthenyl), —O-pixyl (9-phenylxanthenyl) substituted with one or more hydroxyl or —O—C 1-6 alkyl groups, S-pixyl (9-phenylxanthenyl), S-pixyl (9-phenylxanthenyl) substituted with one or more hydroxyl or —O—C 1-6 alkyl groups, halo, C 1-6 alkoxyl, C 1-6 alkenyl, C 1-6 alkenyl substituted with one or more hydroxyl groups, C 1-6 alkenyl substituted with one or more halo groups, a phosphate group, a phosphodiester, or —OR 15 ;
R 14 is O, S, CH 2 , S═O, CHF, or CF 2 ;
R 15 is H, triisopropylsilylOCH 2 —, tert-butyldimethylsilylOCH 2 —, triethylsilylOCH 2 —, trimethylsilylethylOCH 2 —, triisopropylsilyl-, tert-butyldimethylsilyl-, trimethylsilylethyl-, triethylsilyl-, trimethylsilyl-, or trimethylsilylOCH 2 —; and
B is H, 9-adeninyl, 9-guaninyl, 1-uracilyl, 1-cytosinyl, 1-thyminyl, inosinyl, xanthinyl, hypoxanthinyl, isocytosinyl, isoguaninyl, 2-amino-9-adeninyl, 5-methylcytosinyl, 2,6-diaminopurinyl, phenyl, naphthyl, 3-nitropyrrolyl, 5-nitroindolyl, nebularinyl, pyridonyl, or difluorotolyl.
2. The compound of claim 1 , wherein R 1 and R 4 of W are in trans as shown in Formula Wt:
3. The compound of claim 1 having the following formula:
4. The compound of claim 3 , wherein R 1 is O-propargyl or S-propargyl.
5. The compound of claim 3 , wherein R 12 is H, halo, C 1-6 alkoxyl, or —OR 15 ; wherein R 15 is H, triisopropylsilylOCH 2 , tert-butyldimethylsilylOCH 2 O, triethylsilylO-CH 2 , trimethylsilylethylO-CH 2 , triisopropylsilyl, tert-butyldimethylsilyl, trimethylsilylethyl or triethylsilyl.
6. The compound of claim 3 , wherein R 13 is H, —O— trityl or substituted —O-trityl.
7. The compound of claim 3 , wherein R 14 is O or S.
8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.