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. (Formula (I))
1 . A compound of formula I:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, wherein:
Y is CH or N;
X is CH 2 , O, or S; and
n is 0, 1, or 2.
2 . The compound of claim 1 , wherein the compound is a compound of formula II:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, wherein:
X is CH 2 , O, or S; and
n is 0, 1, or 2.
3 . The compound of claim 2 , wherein the compound is a compound of formula II(a):
4 . The compound of claim 2 , wherein the compound is a compound of formula II(b):
5 . The compound of claim 1 , wherein the compound is a compound of formula III:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, wherein:
X is CH 2 , O, or S; and
n is 0, 1, or 2.
6 . The compound of claim 5 , wherein the compound is a compound of formula III(a):
7 . The compound of claim 5 , wherein the compound is a compound of formula III(b):
8 . The compound of claim 1 , wherein X is CH 2 .
9 . The compound of claim 1 , wherein X is O.
10 . The compound of claim 1 , wherein X is S.
11 . The compound of claim 1 , wherein n is 1 or 2.
12 . The compound of claim 1 , wherein n is 1.
13 . The compound of claim 1 , wherein n is 2.
14 . The compound of claim 1 , selected from:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
15 . A pharmaceutical composition comprising a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, and a pharmaceutically acceptable excipient.
16 . A method for increasing oxygen affinity of hemoglobin in a subject in need thereof, comprising administering to the subject a compound according to claim 1 or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
17 . A method for treating a disorder mediated by hemoglobin in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
18 . The method of claim 16 , wherein the hemoglobin is sickle hemoglobin.
19 . A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
20 . A compound selected from:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.