Fluorinated integrin antagonists
The present invention relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing the fluorinated compounds of the invention, and methods of treating macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof.
1. A method of treating diabetic retinopathy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Z is
R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring;
Q is
X is CH or N;
Y is CH or N;
R 1 is C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 6 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; and
R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H,
provided that the compound of formula I contains at least one fluorine atom.
2. The method of claim 1 , wherein the compound contains at least one fluorine in the R 1 substituent.
3. The method of claim 1 , wherein R and R′ are each H.
4. The method of claim 2 , wherein R and R′ are each H.
5. The method of claim 1 , wherein Q is
6. The method of claim 4 , wherein Q is
7. The method of claim 1 , wherein X is N and Y is CH.
8. The method of claim 5 , wherein X is N and Y is CH.
9. The method of claim 6 , wherein X is N and Y is CH.
10. The method of claim 1 , wherein R 1 is straight chain C 1 -C 6 or branched C 3 -C 6 alkoxy, and is substituted with 1, 2, 3, 4, 5, 6, or 7 fluorine atoms.
11. The method of claim 5 , wherein R 1 is straight chain C 1 -C 6 or branched C 3 -C 6 alkoxy, and is substituted with 1, 2, 3, 4, 5, 6, or 7 fluorine atoms.
12. The method of claim 9 , wherein R 1 is straight chain C 1 -C 6 or branched C 3 -C 6 alkoxy, and is substituted with 1, 2, 3, 4, 5, 6, or 7 fluorine atoms.
13. The method of claim 1 , wherein R 1 is methoxy substituted with 1, 2, or 3 fluorine atoms.
14. The method of claim 5 , wherein R 1 is methoxy substituted with 1, 2, or 3 fluorine atoms.
15. The method of claim 9 , wherein R 1 is methoxy substituted with 1, 2, or 3 fluorine atoms.
16. The method of claim 1 , wherein R 1 is OCHF 2 .
17. The method of claim 5 , wherein R 1 is OCHF 2 .
18. The method of claim 9 , wherein R 1 is OCHF 2 .
19. The method of claim 4 , wherein the compound of formula I is of formula II:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 6 , wherein the compound of formula I is of formula II:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 18 , wherein the compound of formula I is of formula II:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the compound is
24. The method of claim 22 , further comprising administering a second therapy.
25. The method of claim 24 , wherein the second therapy comprises an inhibitor of VEGF.