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 or preventing a disease or condition selected from the group consisting of macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO) 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 or solvate 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 R and R′ are each H.
3. The method of claim 1 , wherein Q is
4. The method of claim 3 , wherein X is N and Y is CH.
5. The method of claim 3 , wherein X and Y are each CH.
6. The method of claim 3 , wherein X and Y are each N.
7. The method of claim 3 , wherein R 1 is straight chain C 1 -C 4 or branched C 3 -C 4 alkyl, and is substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms.
8. The method of claim 3 , wherein R 1 is methyl substituted with 1, 2, or 3 fluorine atoms.
9. The method of claim 3 , wherein R 1 is straight chain C 1 -C 6 or branched C 3 -C 6 alkoxy, and is substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms.
10. The method of claim 9 , wherein R 1 is methoxy substituted with 0, 1, 2, or 3 fluorine atoms.
11. The method of claim 3 , wherein Z is
R and R′ are each H; and R 1 is methyl substituted with 1, 2, or 3 fluorine atoms or methoxy substituted with 0, 1, 2, or 3 fluorine atoms.
12. The method of claim 11 , wherein X is N and Y is CH; and R 1 is OCHF 2 .
13. The method of claim 11 , wherein X and Y are each N; and R 1 is CF 3 .
14. The method of claim 3 , wherein Z is
R and R′ are each H; X is N and Y is CH; and R 1 is methoxy substituted with 0, 1, 2, or 3 fluorine atoms.
15. The method of claim 1 , wherein the compound of formula I is of formula II:
or a pharmaceutically acceptable salt or solvate thereof.
16. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.
17. The method of claim 1 , wherein the αv integrin is an αvβ3 or αvβ5 integrin.
18. The method of claim 1 , further comprising administering a second therapy.
19. The method of claim 18 , wherein the second therapy comprises administering an agent selected from the group consisting of a) an antagonist of integrin α5β1, b) a cytotoxic/antiproliferative agent, c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factor, d) an inhibitor of VEGF, e) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tic-1, and f) an inhibitor of phosphoinositide 3-kinase, and a mixture thereof.