Prodrugs of 2,4-pyrimidinediamine compounds and their uses
The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.
1. A method of inhibiting the release and/or synthesis of cytokines in a cell, the method comprising contacting the cell with a metabolite of the compound of formula (I):
or a salt, solvate, hydrate or N-oxide thereof, wherein:
Y is O;
Z 1 and Z 2 are each, independently of one another, CH or N;
R 2 is lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, or a heteroaryl group, each of which is optionally substituted;
R 5 is halo, cyano, nitro, or trihalomethyl;
R 17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R 17 taken together with R 18 are an oxo (═O) group;
R 18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R 18 taken together with R 17 are an oxo (═O) group;
R 19 hydrogen or lower alkyl, or, alternatively, R 19 taken together with R 20 are an oxo (═O) group;
R 20 is hydrogen or lower alkyl, or, alternatively, R 20 taken together with R 19 are an oxo (═O) group;
R 21 , R 22 and R 23 are each, independently of one another, hydrogen or R P ;
R 24 is hydrogen, lower alkyl or R P , with the proviso that at least one of R 21 , R 22 , R 23 and R 24 is R P ; and
each R P is, independently of the others, —(CR d R d ) y —O—P(O)(OR i )(OR i ), —(CR d R d ) y —O—P(O)(OR i )(OH), —(CR d R d ) y —O—P(OR i )(OR i ) or —(CR d R d ) y —O—P(OR i )(OH), where each R i is, independently of the others, lower unsubstituted alkanyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
each R d is, independently of the other, hydrogen, cyano, optionally substituted (C 1 -C 20 ) alkyl, (C 1 -C 20 ) perfluoroalkyl, optionally substituted (C 7 -C 30 ) arylalkyl or optionally substituted 6-30 membered heteroarylalkyl, where each optional substituent is, independently of the others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroalkyl, or, alternatively, two R d taken together with the carbon atom to which they are bonded are a (C 3 -C 5 ) cycloalkyl; and
y is 1, 2, or 3, and
wherein the metabolite is the product of cleavage of the R p group from the compound of formula (I).
2. The method of claim 1 in which R 5 is fluoro.
3. The method of claim 1 in which R 2 is a phenyl optionally substituted with one or more of the same or different R 8 groups.
4. The method of claim 3 in which R 2 is 3,4,5 tri(lower alkoxy)phenyl.
5. The method of claim 4 in which R 2 is 3,4,5-(trimethoxy)phenyl.
6. The method of claim 1 in which R 17 and R 18 are each methyl and R 19 and R 20 are taken together to form an oxo group.
7. The method of claim 6 in which R 2 is a phenyl optionally substituted with one or more of the same or different R 8 groups.
8. The method of claim 7 in which R 2 is 3,4,5-tri(lower alkoxy)phenyl.
9. The method of claim 8 in which R 2 is 3,4,5-(trimethoxy)phenyl.
10. The method of claim 9 in which only R 21 is R P .
11. The method of claim 10 in which R P is selected from the group consisting of an ester, a thioester, an ether, a thioether, a silyl ether, a thiosilyl ether, a carbonate, a thiourea, an amide, a thioamide, a carbamate and a urea linkage.
12. The method of claim 11 in which R 3 , together with the heteroatom, A, to which it is bonded, is a phosphate group.
13. The method of claim 12 in which R P has the formula —(CR d R d )—O—P(O)(OH) 2 , or a salt thereof, where each R d is, independently of the others, selected from the group consisting of optionally substituted lower alkyl, optionally substituted (C 6 -C 14 ) aryl and optionally substituted (C 7 -C 20 ) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C 6 -C 14 ) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R d bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms.
14. The method of claim 10 in which R P comprises a phosphate ester group.
15. The method of claim 14 in which R P is selected from the group consisting of —(CR d R d )—O—P(O)(OR e )(OH), —(CR d R d )—O—P(OR e )(OR e ),
and salts thereof, wherein each R e is, independently of the others, selected from the group consisting of substituted or unsubstituted lower alkyl, substituted or unsubstituted (C 6 -C 14 ) aryl, substituted or unsubstituted (C 7 -C 20 ) arylalkyl, —(CR d R d ) y —OR f , —(CR d R d ) y —O—C(O)R f , —(CR d R d ) y —O—C(O)OR f , —(CR d R d ) y —S—C(O)R f , —(CR d R d ) y —S—C(O)OR f , —(CR d R d ) y —NH—C(O)R, —(CR d R d ) y —NH—C(O)OR f and —Si(R d ) 3 , wherein each R f is, independently of the others, selected from the group consisting of unsubstituted or substituted lower alkyl, substituted or unsubstituted (C 6 -C 14 ) aryl, and substituted or unsubstituted (C 7 -C 20 ) arylalkyl;
each R g is, independently of the others, selected from the group consisting of hydrogen and lower alkyl; each R h is, independently of the others, selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloheteroalkyl, substituted or unsubstituted (C 6 -C 14 ) aryl, substituted or unsubstituted (C 7 -C 20 ) arylalkyl and substituted or unsubstituted 5-14 membered heteroaryl; y is an integer ranging from 1 to 3; z is an integer ranging from 0 to 2; and
each R d is independently of the others, selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted (C 6 -C 14 ) aryl and optionally substituted (C 7 -C 20 ) arylalkyl; where the optional substituents are, independently of one another, selected from hydroxyl, lower alkoxy, (C 6 -C 14 ) aryloxy, lower alkoxyalkyl, and halogen, or, alternatively, two R d bonded to the same carbon atom are taken together with the carbon atom to which they are bonded to form a cycloalkyl group containing from 3 to 8 carbon atoms.
16. The method according to claim 1 , wherein the compound is
or a pharmaceutically acceptable salt and/or hydrate thereof.
17. The method of claim 16 , wherein the compound or the pharmaceutically acceptable salt thereof is in the form of a hydrate.
18. The method of claim 17 , wherein the compound is a free acid.
19. The method of claim 17 , wherein the compound is a pharmaceutically acceptable salt.
20. The method of claim 19 , wherein the pharmaceutically acceptable salt is an alkali metal salt.
21. The method of claim 20 , wherein the pharmaceutically acceptable salt is a sodium salt.
22. The method of claim 21 , wherein the pharmaceutically acceptable salt is a disodium salt.
23. The method of claim 19 , wherein the pharmaceutically acceptable salt is an alkaline earth metal salt.
24. The method of claim 23 , wherein the pharmaceutically acceptable salt is a calcium salt.