Modulators of hemoglobin
The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of hemoglobin, and methods for their use in treating disorders mediated by hemoglobin.
1. A compound of formula I:
or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof, wherein:
X is CH or N;
Y is CH or N;
Z is absent, CH 2 , O, or S; and
R 1 is mono-hydroxy-(C 1-4 alkyl), di-hydroxy-(C 1-4 alkyl), —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CN, or
2. The compound of claim 1 , wherein X is CH.
3. The compound of claim 1 , wherein X is N.
4. The compound of claim 1 , wherein Y is CH.
5. The compound of claim 1 , wherein Y is N.
6. The compound of claim 1 , wherein Z is absent, CH 2 , or O.
7. The compound of claim 1 , wherein Z is absent.
8. The compound of claim 1 , wherein Z is CH 2 .
9. The compound of claim 1 , wherein Z is O.
10. The compound of claim 1 , wherein Z is S.
11. The compound of claim 1 , wherein R 1 is —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CN, or
12. The compound of claim 1 , wherein R 1 is —CH 2 OH or —CH 2 CH 2 OH.
13. The compound of claim 1 , wherein R 1 is mono-hydroxy-(C 1-4 alkyl) or di-hydroxy-(C 1-4 alkyl).
14. The compound of claim 1 , wherein R 1 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, or 2-hydroxy-2-methylpropyl.
15. A compound of formula:
or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.
16. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable excipient.
17. A method for increasing oxygen affinity of hemoglobin S in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
18. A method for treating a disorder mediated by hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
19. The method of claim 18 , wherein the hemoglobin is sickle hemoglobin.
20. A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .