CCR2 receptor antagonists and uses thereof
The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.
1. A method for treating a neurologic disease selected from inflammatory and neuropathic pain, comprising administering an effective amount of a compound of Formula I to a patient in need thereof to treat the neurologic disease, wherein Formula I is represented by:
or an acid addition salt thereof with a pharmacologically acceptable acid; wherein:
R 1 is a group selected from among —H, -halogen, —CN, —O—C 1 -C 4 -alkyl, —C 1 -C 4 -alkyl, —CH═CH 2 , —C≡CH, —CF 3 , —OCF 3 , —OCF 2 H, and —OCFH 2 ;
R 7 is a ring selected from among phenyl and —C 5 -C 6 -heteroaryl, wherein the ring R 7 is optionally substituted with one or more groups selected from among —CF 3 , —O—CF 3 , —S—CF 3 , —CN, —C 1 -C 6 -alkyl, —C(CH 3 ) 2 —CN, and -halogen, or wherein the ring R 7 is optionally substituted with one or more groups selected from among —O—C 1 -C 6 -alkyl and —C 3 -C 6 -cycloalkyl;
R 2 is selected from among —H, -halogen, —CN, —O—C 2 -C 4 -alkyl, —C 1 -C 4 -alkyl, —CH═CH 2 , —C≡CH, —CF 3 , —OCF 3 , —OCF 2 H, and —OCFH 2 ;
R 3 is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH 3 , —CF 3 , and —CN;
n is 1 or 2;
G and E are N;
Z is C;
R 4 denotes —H, and R 5 is -L 1 -R 18 , wherein L 1 is selected from among —NH—, —N(C 1 -C 4 -alkyl)-, and a bond, and R 18 is —C 3 -C 8 -heterocyclyl, wherein R 18 is optionally substituted by one or more groups selected from among halogen, —CF 3 , —OCF 3 , —CN, —OH, —O—C 1 -C 4 -alkyl, —C 1 -C 6 -alkyl, —NH—C(O)—C 1 -C 6 -alkyl, —N(C 1 -C 4 -alkyl)—C(O)—C 1 -C 6 -alkyl, and —C(O)—C 1 -C 6 -alkyl; and
R 6 is selected from among —H, —C 1 -C 4 -alkyl, —OH, —O—C 1 -C 4 -alkyl, -halogen, —CN, —CF 3 , and —OCF 3 .
2. The method of claim 1 , wherein L 1 is —NH—.
3. The method of claim 1 , wherein R 18 is —C 3 -C 8 —heterocyclyl substituted by one or more groups selected from among halogen, —CF 3 , —OCF 3 , —CN, —OH, —O—C 1 -C 4 -alkyl, and —C 1 -C 6 -alkyl.
4. The method of claim 2 , wherein R 18 is —C 3 -C 8 -heterocyclyl substituted by one or more groups selected from among halogen, —CF 3 , —OCF 3 , —CN, —OH, —O—C 1 -C 4 -alkyl, and —C 1 -C 6 -alkyl.
5. The method of claim 1 , wherein R 7 is phenyl optionally substituted with one or more groups selected from among —CF 3 , —O—CF 3 , —CN, —C 1 -C 6 -alkyl, —C(CH 3 ) 2 —CN, and halogen.
6. The method of claim 4 , wherein R 7 is phenyl optionally substituted with one or more groups selected from among —CF 3 , —O—CF 3 , —CN, —C 1 -C 6 -alkyl, —C(CH 3 ) 2 —CN, and halogen.
7. The method of claim 1 , wherein R 1 is a group selected from among —H, and R 2 is —C 1 -C 4 -alkyl.
8. The method of claim 6 , wherein R 1 is —H, and R 2 is —C 1 -C 4 -alkyl.
9. The method of claim 8 , wherein R 6 is —H.
10. The method of claim 2 , wherein the neurologic disease is inflammatory pain.
11. The method of claim 4 , wherein the neurologic disease is inflammatory pain.
12. The method of claim 9 , wherein the neurologic disease is inflammatory pain.
13. The method of claim 2 , wherein the neurologic disease is neuropathic pain.
14. The method of claim 4 , wherein the neurologic disease is neuropathic pain.
15. The method of claim 9 , wherein the neurologic disease is neuropathic pain.
16. The method of claim 15 , wherein the neuropathic pain is selected from the group consisting of low back pain, hip pain, and leg pain.
17. The method of claim 15 , wherein the neuropathic pain is low back pain.
18. The method of claim 15 , wherein the neuropathic pain is trigeminal neuralgia.
19. The method of claim 15 , wherein the neuropathic pain is nerve injury induced pain.
20. The method of claim 15 , wherein the neuropathic pain is due to chemotherapy caused nerve injury.
21. The method of claim 19 , wherein the compound is
or an acid addition salt thereof with a pharmacologically acceptable acid.
22. The method of claim 20 , wherein the compound is
or an acid addition salt thereof with a pharmacologically acceptable acid.
23. A method for treating trigeminal neuralgia, comprising administering an effective amount of a compound having the following formula to a patient in need thereof to treat the trigeminal neuralgia:
or an acid addition salt thereof with a pharmacologically acceptable acid.
24. The method of claim 15 , wherein the patient is a human.
25. The method of claim 21 , wherein the patient is a human.
26. The method of claim 22 , wherein the patient is a human.
27. The method of claim 23 , wherein the patient is a human.
28. The method of claim 24 , wherein said compound is administered orally to the patient.
29. The method of claim 25 , wherein said compound is administered orally to the patient.
30. The method of claim 26 , wherein said compound is administered orally to the patient.
31. The method of claim 27 , wherein said compound is administered orally to the patient.