Disulfide masked prodrug compositions and methods

Patent metadata

Field	Value
Publication number	US-9884886-B2
Application number	US-201314648716-A
Country	US
Kind code	B2
Filing date	Dec 2, 2013
Priority date	Dec 6, 2012
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Butora Gabor

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C07H19/207

  the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide · CPC title

• C07F9/655363

  the sulfur atom being part of a six-membered ring · CPC title