Acyclic Thiol Prodrugs
Disclosed herein are acyclic thiol prodrugs, and pharmaceutical compositions thereof. The prodrugs and pharmaceutical compositions thereof may be used to treat or prevent medical disorders such as, for example cystinosis, cystinuria, cancer neurodegenerative disease, Parkinson's disease, Huntington's disease, malaria, nonalcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease or rheumatoid arthritis.
1 . A compound of structural Formula (I):
or pharmaceutically acceptable salts, hydrates or solvate thereof wherein:
R 1 is the residue of a thiol of molecular weight of less than 1000 daltons;
Y is —NR 2 R 3 ;
X is —OR 4 , or —SR 1 ;
R 2 and R 3 are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl or R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkenyl or substituted heterocycloalkenyl ring; and
R 4 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl or substituted heteroarylalkyl;
provided that both R 2 and R are not —H and unless R 2 and R 3 together with the atoms to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkenyl or substituted heterocycloalkenyl ring that one of R 2 and R 3 is —H.
2 . The compound of claim 1 , wherein R 1 is the residue of a thiol of molecular weight of less than 500 daltons.
3 . The compound of claim 1 wherein R 1 is
R 101 -R 103 , R 106 , R 109 , R 116-118 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl; and R 104 , R 105 , R 107 , R 108 , R 110 -R 115 and R 119 -R 129 are independently —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl.
4 . The compound of claim 3 , wherein R 101 -R 103 , R 106 , R 109 , R 116-118 are independently alkyl, or alkenyl and R 104 , R 105 , R 107 , R 108 , R 110 -R 115 and R 119 -R 129 are independently —H, alkyl, or alkenyl.
5 . The compound of claim 1 , wherein R 2 and R 3 are independently —H, substituted alkyl, substituted alkenyl, substituted arylalkyl, substituted arylalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, substituted heteroarylalkyl or substituted heteroarylalkenyl.
6 . The compound of claim 1 , wherein R 2 and R 3 are independently —H, substituted alkyl, substituted alkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl or substituted heteroalkenyl.
7 . The compound of claim 1 , wherein R 2 and R 3 are independently —H, substituted alkyl or substituted alkenyl.
8 . The compound of claim 1 , wherein R 2 and R 3 are independently —H or —CHR 5 CO 2 R 6 ; R 5 is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroaryl or substituted heteroaryl; and R 6 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl.
9 . The compound of claim 1 , wherein R 2 and R 3 are independently —H or —CHR 5 CO 2 R 6 ; R 5 is —H, alkyl, substituted alkyl, alkenyl or substituted alkenyl; and R 6 is alkyl, alkenyl or arylalkenyl.
10 . The compound of claim 9 , wherein are R 2 and R 3 are independently —H, or
11 . The compound of claim 9 , wherein one of R 2 and R 3 are —H, and the other of R 2 and R 3 are
12 . The compound of claim 1 , wherein R 4 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl or substituted heteroarylalkyl.
13 . The compound of claim 1 , wherein R 4 is alkyl, alkenyl, aryl or substituted aryl.
14 . The compound of claim 1 , wherein the compound is selected from the group consisting of
15 . A compound of structural formula:
and pharmaceutically acceptable salts, hydrates or solvates thereof.
16 . A compound of structural formula:
and pharmaceutically acceptable salts, hydrates or solvates thereof.
17 . A compound of structural formula:
and pharmaceutically acceptable salts, hydrates or solvates thereof.
18 . A compound of structural formula:
and pharmaceutically acceptable salts, hydrates or solvates thereof.
19 . A compound of structural formula:
and pharmaceutically acceptable salts, hydrates or solvates thereof.
20 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.
21 . A method of treating cystinosis, cystinuria, cancer neurodegenerative disease, Parkinson's disease, Huntington's disease, malaria, nonalcoholic fatty liver disease, radiation poisoning, arsenic poisoning, radioprotection, Wilson's disease or rheumatoid arthritis comprising administering to the patient in need thereof a therapeutically effective amount of the compound of claim 1 .