Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives
The invention relates to fluorinated compounds and their use as integrin receptor antagonists. Novel fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives and pharmaceutically acceptable salts or solvates thereof and their use are described.
1. A method of treating a condition mediated by increased bone resorption in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein
X is selected from CH and N;
Y is selected from CH and N;
R 1 is C 1 -C 6 alkoxy wherein said C 1 -C 6 alkoxy is substituted with 0, 1, 2, 3, 4, or 5 fluorine atoms; and
R 2 and R 3 are each independently selected from H and F,
or R 2 and R 3 taken together with the carbon atom to which they are attached form a 3- or 4-membered carbocyclic or heterocyclic ring,
provided that the compound of formula I contains at least one fluorine atom.
2. The method of claim 1 , wherein the compound of formula I is of formula II:
3. The method of claim 1 , wherein the compound of formula I is of formula III:
4. The method of claim 1 , wherein the compound of formula I is of formula IV:
5. The method of claim 1 , wherein the compound of formula I is of formula V:
6. The method of claim 1 , wherein the compound of formula I is selected from
7. The method of claim 1 , wherein the condition is selected from osteopenia due to bone metastases, periarticular erosions in rheumatoid arthritis, Paget's disease, and immobilization-induced osteopenia.
8. The method of claim 1 , wherein the condition is osteoporosis induced by estrogen deficiency, immobilization, or glucocorticoid.
9. The method of claim 1 , wherein the condition is senile osteoporosis.
10. The method of claim 1 , wherein the condition is malignant hypercalcemia.
11. A method of alleviating pain associated with an osteolytic lesion in a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein
X is selected from CH and N;
Y is selected from CH and N;
R 1 is C 1 -C 6 alkoxy wherein said C 1 -C 6 alkoxy is substituted with 0, 1, 2, 3, 4, or 5 fluorine atoms; and
R 2 and R 3 are each independently selected from H and F,
or R 2 and R 3 taken together with the carbon atom to which they are attached form a 3- or 4-membered carbocyclic or heterocyclic ring,
provided that the compound of formula I contains at least one fluorine atom.
12. The method of claim 11 , wherein the compound of formula I is of formula II:
13. The method of claim 11 , wherein the compound of formula I is of formula III:
14. The method of claim 11 , wherein the compound of formula I is of formula IV:
15. The method of claim 11 , wherein the compound of formula I is of formula V:
16. The method of claim 11 , wherein the compound of formula I is selected from
17. The method of claim 11 , wherein the disease is osteoporosis, osteodystrophy, Paget's disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, periodontal disease, cholelithiasis, nephrolithiasis, urolithiasis, urinary calculus, sclerosis, arthritis, bursitis, neuritis, or tetany.