USES OF 4'-DESFERRITHIOCIN ANALOGS
Macular degeneration, closed head injury, stroke, irritable bowel disease, and reperfusion injury are all associated with biological injury due to reactive oxygen species, probably due to focal iron overload in many instances. The present invention provides methods and pharmaceutical compositions for treating these diseases and conditions using desferrithiocin analogs of Formula (I). In certain embodiments, the analogs include a polyether moiety at the 4′-position of the phenyl ring of the compound.
1 . A method of treating macular degeneration in a subject comprising administering to the subject a therapeutically effective amount of Formula (I):
wherein:
R 1 is hydrogen, alkyl, or acyl;
R 2 is hydrogen, alkyl, or —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y —R′;
R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, arylalkyl, or —OR 10 ;
R 6 , R 7 , and R 8 are each independently hydrogen, halogen, alkyl, or —OR 12 ;
R 9 is —OR 11 or —SR 11 ;
R 10 is hydrogen, alkyl, or acyl;
R 11 is hydrogen or alkyl;
R 12 is hydrogen or alkyl;
R′ is alkyl;
each occurrence of n is independently an integer from 1 to 8, inclusive;
x is an integer from 1 to 8, inclusive; and
y is an integer from 0 to 8, inclusive;
or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or polymorph thereof.
2 . The method of claim 1 , wherein the compound is of the Formula (III):
3 . The method of claim 1 , wherein R 9 is —OR 11 .
4 . The method of claim 1 , wherein R 9 is —OH.
5 . The method of claim 1 , wherein R 8 is —CH 3 .
6 . The method of claim 1 , wherein R 6 and R 7 are each hydrogen.
7 . The method of claim 1 , wherein R 3 , R 4 , and R 5 are each hydrogen.
8 . The method of claim 1 , wherein R 1 , R 3 , R 4 , and R 5 are each hydrogen.
9 . The method of claim 1 , wherein R 2 is —[(CH 2 ) n —O] x —R′; n is 2 to 4; and x is 1 to 4.
10 . The method of claim 1 , wherein R 2 is —[(CH 2 ) n —O] x —R′; n is 2; x is 3; and R′ is —CH 3 .
11 . The method of claim 1 , wherein R 2 is —[(CH 2 ) n —O] x —R′; n is 2; x is 2; and R′ is —CH 3 .
12 . The method of claim 1 , wherein the compound is of the Formula (III-A):
13 . The method of claim 1 , wherein the compound is of the Formula (III-B) or (III-C):
14 . (canceled)
15 . The method of claim 1 , wherein the compound is of the Formula (IV-A):
16 . The method of claim 1 , wherein the compound is of the Formula (IV-B) or (IV-C):
17 . (canceled)
18 . The method of claim 1 , wherein the compound is of the Formula (V-A), (V-B), or (V-C):
19 - 20 . (canceled)
21 . A method of treating a closed head injury in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
wherein:
R 1 is hydrogen, alkyl, or acyl;
R 2 is hydrogen, alkyl, or —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y —R′;
R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, arylalkyl, or —OR 10 ;
R 6 , R 7 , and R 8 are each independently hydrogen, halogen, alkyl, or —OR 12 ;
R 9 is —OR 11 or —SR 11 ;
R 10 is hydrogen, alkyl, or acyl;
R 11 is hydrogen or alkyl;
R 12 is hydrogen or alkyl;
R′ is alkyl;
each occurrence of n is independently an integer from 1 to 8, inclusive;
x is an integer from 1 to 8, inclusive; and
y is an integer from 0 to 8, inclusive;
or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or polymorph thereof.
22 - 44 . (canceled)
45 . A method of treating stroke in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
wherein:
R 1 is hydrogen, alkyl, or acyl;
R 2 is hydrogen, alkyl, or —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y —R′;
R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, arylalkyl, or —OR 10 ;
R 6 , R 7 , and R 8 are each independently hydrogen, halogen, alkyl, or —OR 12 ;
R 9 is —OR 11 or —SR 11 ;
R 10 is hydrogen, alkyl, or acyl;
R 11 is hydrogen or alkyl;
R 12 is hydrogen or alkyl;
R′ is alkyl;
each occurrence of n is independently an integer from 1 to 8, inclusive;
x is an integer from 1 to 8, inclusive; and
y is an integer from 0 to 8, inclusive;
or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or polymorph thereof.
46 - 66 . (canceled)
67 . A method of treating irritable bowel disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
wherein:
R 1 is hydrogen, alkyl, or acyl;
R 2 is hydrogen, alkyl, or —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y —R′;
R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, arylalkyl, or —OR 10 ;
R 6 , R 7 , and R 8 are each independently hydrogen, halogen, alkyl, or —OR 12 ;
R 9 is —OR 11 or —SR 11 ;
R 10 is hydrogen, alkyl, or acyl;
R 11 is hydrogen or alkyl;
R 12 is hydrogen or alkyl;
R′ is alkyl;
each occurrence of n is independently an integer from 1 to 8, inclusive;
x is an integer from 1 to 8, inclusive; and
y is an integer from 0 to 8, inclusive;
or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or polymorph thereof.
68 - 86 . (canceled)
87 . A method of treating reperfusion injury in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):
wherein:
R 1 is hydrogen, alkyl, or acyl;
R 2 is hydrogen, alkyl, or —[(CH 2 ) n —O] x —[(CH 2 ) n —O] y —R′;
R 3 , R 4 , and R 5 are each independently hydrogen, alkyl, arylalkyl, or —OR 10 ;
R 6 , R 7 , and R 8 are each independently hydrogen, halogen, alkyl, or —OR 12 ;
R 9 is —OR 11 or —SR 11 ;
R 10 is hydrogen, alkyl, or acyl;
R 11 is hydrogen or alkyl;
R 12 is hydrogen or alkyl;
R′ is alkyl;
each occurrence of n is independently an integer from 1 to 8, inclusive;
x is an integer from 1 to 8, inclusive; and
y is an integer from 0 to 8, inclusive;
or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, or polymorph thereof.
88 - 111 . (canceled)