Methods for treatment of diseases related to activated lymphocytes
The present invention relates to inhibiting proliferation and inducing apoptosis in activated lymphocytes, including T cells and B cells. The invention also provides compositions and methods for inhibiting proliferation and inducing apoptosis in activated lymphocytes, as well methods for treating diseases associated with activated lymphocytes by administering 5-HT receptor antagonists.
1. A method of inducing apoptosis in an immune cell, the method comprising contacting the immune cell with a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is independently selected at each occurrence from hydrogen, halogen, (C 1 -C 6 )alkyl; (C 1 -C 6 )alkenyl; (C 1 -C 6 )alkoxy; OH; NO 2 ; C≡N; C(═O)OR 7 ; C(═O)NR 7 2 ; NR 7 2 ; NR 7 C(═O)(C 1 -C 6 )alkyl; NR 7 C(═O)O(C 1 -C 6 )alkyl; NR 7 C(═O)NR 7 2 ; NR 7 SO 2 (C 1 -C 6 )alkyl; SO 2 NR 7 2 ; OC(═O)(C 1 -C 6 )alkyl; O(C 2 -C 6 )alkylene-NR 7 2 ; (C 2 -C 6 )alkylene-OR 7 ; and (C 1 -C 3 )perfluoroalkyl;
R 2 is independently selected at each occurrence from hydrogen, halogen, (C 1 -C 6 )alkyl; (C 1 -C 6 )alkenyl; (C 1 -C 6 )alkoxy; OH; NO 2 ; C≡N; C(═O)OR 7 ; C(═O)NR 7 2 ; NR 7 2 ; NR 7 C(═O)(C 1 -C 6 )alkyl; NR 7 C(═O)O(C 1 -C 6 )alkyl; NR 7 C(═O)NR 7 2 ; NR 7 SO 2 (C 1 -C 6 )alkyl; SO 2 NR 7 2 ; OC(═O)(C 1 -C 6 )alkyl; O(C 2 -C 6 )alkylene-NR 7 2 ; (C 2 -C 6 )alkylene-OR 7 ; and (C 1 -C 3 )perfluoroalkyl;
R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;
A 1 is CH 2 or NR 4 ;
A 2 is CH or N;
provided that if A 1 is CH 2 , then A 2 is N, and if A 2 is CH, then A 1 is NR 4 ;
R 4 is (CH 2 ) p NHC(O)R 5 ; (CH 2 ) p O(CH 2 ) p OR 7 ; (CH 2 ) p O(CH 2 ) p NR 7 2 ; (CH 2 ) p NR 4 (CH 2 ) p NR 7 2 ; (CH 2 ) p O(CH 2 ) p NHC(O)R 5 ; (CH 2 ) p NR 7 (CH 2 ) p NHC(O)R 5 ; (CH 2 ) q C(═O)OR 7 ; (CH 2 ) q C(═O)NR 7 2 ; (CH 2 ) p O(CH 2 ) q C(═O)OR 7 ; (CH 2 ) p O(CH 2 ) q C(═O)NR 7 2 ; (CH 2 ) p NR 7 (CH 2 ) q C(═O)OR 7 ; or (CH 2 ) p NR 7 (CH 2 ) q C(═O)NR 7 2 ;
R 5 is (C 1 -C 6 )alkyl; NR 7 C(═O)(C 1 -C 6 )alkyl; NR 7 C(═O)O(C 1 -C 6 )alkyl; NR 7 C(═O)NR 7 2 ; CH(R 6 )NR 7 2 ; CH(R 6 )NR 7 C(═O)(C 1 -C 6 )alkyl; or CH(R 6 )NR 7 C(═O)O(C 1 -C 6 )alkyl;
R 6 is H, (C 1 -C 6 )alkyl; (C 2 -C 6 )alkylene-OR 7 ; (CH 2 ) q C(═O)OR 7 ; or (CH 2 ) q C(═O)NR 7 2 ;
R 7 is independently selected at each occurrence from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
m is independently at each occurrence 1, 2, or 3;
n is 0, 1, or 2;
p is independently at each occurrence 2 or 3; and
q is independently at each occurrence 1 or 2.
2. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of:
3. A method of inducing apoptosis in a lymphocyte, the method comprising contacting the lymphocyte with a compound of formula I.
4. The method of claim 3 , wherein the lymphocyte is selected from the group consisting of a T cell and a B cell.
5. The method of claim 4 , wherein the B cell is a plasma cell.
6. The method of claim 5 , wherein the plasma cell is a multiple myeloma cell.
7. A method of inhibiting proliferation of a lymphocyte, the method comprising contacting the lymphocyte with a compound of formula I.
8. The method of claim 7 , wherein the lymphocyte is selected from the group consisting of a T cell and a B cell.
9. The method of claim 8 , wherein the B cell is a plasma cell.
10. The method of claim 9 , wherein the plasma cell is a multiple myeloma cell.
11. The method of claim 1 , wherein the compound of formula I is