Thiazolopyrimidines useful as TNFα inhibitors
View Patent ↗The invention provides derivatives of thiazolo[4,5-d1]pyrimidine and their use as inhibitors of proinflammatory cytokines.
1. A pharmaceutical composition comprising a compound of formula (I):
wherein R 1 is —Z-A wherein Z is (a) C 1 –C 7 alkyl, optionally comprising 1–2 double bonds, 1–2 nonperoxide O or 1–2 NR wherein R is individually H, phenyl, benzyl, C 2 –C 4 alkanoyl or C 1 –C 6 alkyl; (b) C 3 –C 6 cycloalkyl; (c) C 3 –C 6 cycloalkyl C 1 –C 3 alkyl; (d) C 6 –C 10 aryl; or (e) C 1 –C 3 alkyl;
A is N(R) 2 , C 2 –C 4 acyloxy, SO 3 H, PO 4 H 2 , N(NO)(OH), SO 2 NH 2 , PO(OH)NH 2 , OH, SO 2 R 3 , tetrazolyl, or COOR 3 wherein R 3 is H, phenyl, benzyl or C 1 –C 6 alkyl optionally substituted with 1–2 OR, heteroaryl, C 6 –C 10 aryl, C 2 –C 4 alkenyl, phenyl, tetrazolyl or an amino acid residue formed by the removal of a hydrogen atom from the —COOH group of an amino acid;
R 2 is a C 1 –C 6 alkyl, C 2 –C 4 alkenyl, C 6 –C 10 aryl C 1 –C 2 alkyl or heteroaryl C 1 –C 2 alkyl;
X is H, halo, OR, SR, N 3 or N(R) 2 ; or a pharmaceutically acceptable salt thereof,
in combination with a carrier; wherein the composition is suitable for oral administration.
2. The composition of claim 1 wherein Z is (C 2 –C 6 )alkyl or phenyl.
3. The composition of claim 1 or 2 wherein A is CO 2 R 3 .
4. The composition of claim 3 wherein R 3 is H or (C 1 –C 6 )alkyl, optionally substituted with OH, C 6 –C 10 heteroaryl or the amino acid residue.
5. The composition of claim 4 wherein the amino acid is an L-valine residue or L-glycine residue.
6. The composition of claim 4 wherein R 3 is (C 1 –C 6 )alkyl. substituted with 4-pyridyl.
7. The composition of claim 1 or 2 wherein -Z-A is ethoxycarbonylpropyl.
8. The composition of claim 1 or 2 wherein X is NH 2 .
9. The composition of claim 1 or 2 wherein R 2 is CH 3 , CH 2 CH 3 , or CH 2 CH 2 CH 3 .
10. The composition of claim 1 or 2 wherein the composition is a suspension, a gelatin capsule, or compressed into a tablet.
11. The composition of claim 1 wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof.
12. The composition of claim 1 wherein compound has the formula:
or a pharmaceutically acceptable salt thereof.