US2015259306A1PendingUtilityA1
Desazadesferrothiocin analogues as metal chelation agents
Est. expiryMay 4, 2030(~3.8 yrs left)· nominal 20-yr term from priority
Inventors:James W. Malecha
A61P 35/02A61P 3/10A61P 43/00A61P 39/04A61P 7/06A61P 31/12A61P 7/00A61P 31/14A61P 37/06C07D 277/56C07D 233/28C07D 277/12A61P 1/16C07D 263/16C07D 231/14
39
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Claims
Abstract
Disclosed herein are new compounds of desazadesferrothiocin polyether (DADFT-PE) analogues, as well as pharmaceutical compositions comprising them and their application as metal chelation agents for the treatment of disease. Methods of chelation of iron and other metals in a human or animal subject are also provided for the treatment of metal overload and toxicity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula III:
or a salt thereof, wherein:
each dashed line represents a second bond which may be present or absent;
X 1 -X 3 are each chosen from CR 12 , NR 13 , O, and S, provided that when X 3 is N, R 13 is null, and R 11 is methyl or hydrogen, then X 1 is not S;
Z is chosen from OR 1 , NR 2 R 3 , morpholine and optionally substituted piperazine;
R 1 is chosen from [(CH 2 ) m —O] x —[(CH 2 ) n —O] y —R 4 , [(CH 2 ) m —NH] x —[(CH 2 ) n —NR 4 ] y -R 5 , and [(CH 2 ) m —O] x —[(CH 2 ) n —NR 4 ] y —R 5 ;
R 2 is chosen from hydrogen, alkyl, [(CH 2 ) m —O] x —[(CH 2 ) n —O] y —R 4 , [(CH 2 ) m —NH] x -[(CH 2 ) n —NR 4 ] y —R 5 , and [(CH 2 ) m —O] x —[(CH 2 ) n —NR 4 ] y —R 5 ;
R 3 is chosen from hydrogen and alkyl;
each m and each n is, independently, an integer from 1 to 8;
x is an integer 0 to 8;
y is an integer from 1 to 8;
R 4 and R 5 are independently chosen from hydrogen, alkyl, and acyl;
R 6 is chosen from hydrogen, alkyl and alkoxy;
R 7 is chosen from OR 8 and N(OH)R 9 ;
R 8 is chosen from hydrogen, alkyl and aralkyl;
R 9 is chosen from an alkyl group and —(CH 2 ) p —N(OH)C(O)R 10 ;
p is an integer from 1 to 8;
R 10 is an alkyl group;
R 11 is chosen from hydrogen and alkyl.
each R 12 is independently chosen from null, hydrogen, and lower alkyl; and
each R 13 is independently chosen from null, hydrogen, and lower alkyl.
2 . The compound as recited in claim 1 , wherein Z is OR 1 .
3 . The compound as recited in claim 2 , wherein R 1 is [(CH 2 ) m —O] x —[(CH 2 ) n —O] y —R 4 .
4 . The compound as recited in claim 3 , wherein:
each m and each n is, independently, an integer from 1 to 4; x is an integer from 0 to 4; and y is an integer from 1 to 4.
5 . The compound as recited in claim 4 , wherein R 4 is alkyl.
6 . The compound as recited in claim 5 , wherein:
each n is, independently, an integer from 2 to 3; x is 0; and y is an integer from 1 to 4.
7 . The compound as recited in claim 6 , wherein R 4 is lower alkyl.
8 . The compound as recited in claim 7 , wherein R 7 is OR 8 .
9 . The compound as recited in claim 8 , wherein:
each n is 2; x is 0; y is an integer from 2 to 3; and R 4 is methyl.
10 . The compound as recited in claim 9 , wherein R 8 is hydrogen.
11 . The compound as recited in claim 1 , having a structural formula chosen from Ma, IIIb, IIIc and IIId:
12 . The compound as recited in claim 11 , having a structural formula chosen from IIla1, IIIa2, IIIa3, IIIb1, IIIb2, IIIb3, IIIc1, IIIc2, IIIc3, IIId1, IIId2, and IIId3:
13 . The compound as recited in claim 12 , wherein Z is OR 1 .
14 . The compound as recited in claim 13 , wherein R 1 is [(CH 2 ) m —O] x —[(CH 2 ) n —O] y —R 4 .
15 . The compound as recited in claim 14 , wherein:
each m and each n is, independently, an integer from 1 to 4; x is an integer from 0 to 4; and y is an integer from 1 to 4.
16 . The compound as recited in claim 15 , wherein R 4 is alkyl.
17 . The compound as recited in claim 16 , wherein:
each n is, independently, an integer from 2 to 3; x is 0; and y is an integer from 1 to 4.
18 . The compound as recited in claim 17 , wherein R 4 is lower alkyl.
19 . The compound as recited in claim 18 , wherein R 7 is OR 8 .
20 . The compound as recited in claim 19 , wherein:
each n is 2; x is 0; y is an integer from 2 to 3; and R 4 is methyl.
21 . The compound as recited in claim 20 , wherein R 8 is hydrogen.
22 . A compound chosen from:
23 . The compound as recited in claim 22 , chosen from:
24 . A pharmaceutical composition comprising the compound as recited in claim 1 , together with at least one pharmaceutically acceptable excipient.
25 . A method of treating a metal-mediated condition in a subject comprising administering to the subject a therapeutically effective amount of a compound as recited in claim 1 .
26 . The method as recited in claim 25 wherein said metal is iron.
27 . The method as recited in claim 26 wherein said condition is iron overload.
28 . The method as recited in claim 26 wherein said condition is the result of mal-distribution or redistribution of iron in the body.
29 . The method as recited in claim 28 wherein said condition is chosen from atransferrinemia, aceruloplasminemia, and Fredreich's ataxia.
30 . The method as recited in claim 26 wherein said condition is the result of transfusional iron overload.Cited by (0)
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