PYRIMIDINONE COMPOUNDS FOR THE TREATMENT OF ACUTE INFLAMMATION

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt or tautomer thereof, in which X represents O or OH; L is -(CH2) m CH2CH2-, -(CH2) m Y(CH2) p -, -(CH2) m C(O)(CH 2)P -, -(CH2) m C(O)O(CH2) Р -, -(CH2) m C(O)NR 2 (CH2) P - or -(CH2) m NR 2 C(O)(CH2) P ; represents O, N or S(O) q ; R 1 is C6-C 10 aryl or heteroaryl in which aryl and heteroaryl are substituted by R a and R b and optionally substituted by one or more R e ; R 2 is H or C1-C6 alkyl; one of R a and R b is hydrogen and the other is -(CH2) r CO2R x, -OCH2CO2R x , -(CH2) r tetrazole, -(CH2) r oxadiazolone, -(CH2) r tetrazolone, -(CH2) r dihydrotetrazolone, -(CH2) r thiadiazolol, -(CH2) r isoxazol-3-ol, -(CH2) r P(O(OH)OR x , -(CH2) r S(O)2OH, -(CH2) r C(O)NHCN or -(CH2) r C(O)NHS(O)2alkyl; R c represents H, C1-C6alkyl, C1-C6haloalkyl, halogen, -CN, -OR x , -CO2R x or NO2; R d represents methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle; every R x independently in each case represents hydrogen or C1-C6 alkyl; every R e independently represents C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -OR y , C1-C6haloalkyl, -NHR Z , -OH or -CN; R f is H or absent; every R y and R z independently represents hydrogen, C1-C6alkyl or C1-C6haloalkyl; each m and p are independently equal to 0, 1, or 2 if m+p<3; q is 0, 1 or 2; r is 0 or 1; and the dotted line represents an optional double bond; provided that R c does not represent hydrogen or -CN if X is O, L is -SCH2- and R d is optionally substituted phenyl, R c is not C1-C6alkyl if X is O, L is SCH2- and R d is methyl and that R c is not -CN if X is O, L is -SCH2- and R d is 2-furyl; for use in the treatment of acute inflammatory conditions.

2. A compound for use according to claim 1, wherein the compound is represented by formula (Ia) or a pharmaceutically acceptable salt or tautomer thereof.

3. A compound for use according to claim 1 or 2, wherein the compound is represented by formula (Ib): or a pharmaceutically acceptable salt thereof, where n is 0, 1, 2 or 3.

4. A compound for use according to any one of paragraphs 1-3, in which one of R a and R b is hydrogen and the other is CO2R x , CH2CO2R X , tetrazole or oxadiazolone; R c is a halogen, -CN, -OR x or C1-C6alkyl; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle; and R x represents hydrogen or C1-C6 alkyl; every R e independently represents C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogen, -OR y , C1-C6haloalkyl, -NHR Z , -OH or -CN; every R y and R z independently represents hydrogen, C1-C6alkyl or C1-C6haloalkyl; and n is 0, 1, 2, or 3; provided that R c does not represent hydrogen or -CN if R d is optionally substituted phenyl and that R c does not represent CN if R d is 2-furyl.

5. A compound for use according to any one of claims 1 to 3, wherein the compound is represented by formula (II): or its pharmaceutically acceptable salt.

6. A compound for use according to claim 5, wherein R c is a halogen, -CN, -OR x or C1-C6alkyl, Rd represents methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered carbocycle and R x represents hydrogen or C1-C6 alkyl.

7. A compound for use according to any one of paragraphs 1-6, in which R c represents -CN or halogen.

8. A compound for use according to any one of claims 1 to 7, wherein R d is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl or thienyl.

9. A compound for use according to any one of claims 1 to 7, wherein R d represents methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl or optionally substituted phenyl.

10. A compound for use according to any one of claims 1 to 4, wherein R a is hydrogen, CH2CO2H, tetrazole or oxadiazolone (1,2,4-oxadiazol-5(4H)-one).

11. A compound for use according to any one of claims 1 to 4, wherein R bis hydrogen, CH2CO2H, tetrazole or oxadiazolone (1,2,4-oxadiazol-5(4H)-one).

12. A compound for use according to any one of claims 1 to 4, wherein n is 0.

13. A compound for use according to claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. A compound for use according to claim 1, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

15. A compound for use according to claim 1, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

16. A compound for use according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

17. A compound for use according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

18. A compound for use according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

19. A compound for use according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

20. A compound for use according to any one of claims 1-19, wherein the acute inflammatory condition is a systemic inflammatory condition.

21. A compound for use according to any one of claims 1 to 19, wherein the acute inflammatory condition is an organ-specific condition.

22. A compound for use according to any one of claims 1-19, wherein the acute inflammatory condition is cytokine storm or hypercytokinemia, systemic inflammatory response syndrome (SIRS), graft versus host disease (GVHD), acute respiratory distress syndrome (ARDS), severe acute respiratory distress syndrome (SARS), catastrophic antiphospholipid syndrome, viral infections, bacterial infections, fungal infections, influenza, pneumonia, shock and sepsis.

23. A compound for use according to any one of claims 1 to 19, wherein the acute inflammatory condition is acute pancreatitis, hepatitis, a respiratory disease or enterocolitis.

24. A compound for use according to any one of claims 1 to 23, wherein the pro-inflammatory cytokine is reduced or the anti-inflammatory cytokine is increased.

25. A compound for use according to claim 24, wherein the proinflammatory cytokine is IL-1β, IL-6, IL-18, TNF-α or TGF-β.

26. A compound for use according to claim 24, wherein the proinflammatory cytokine is MCP-1, TNF-α or IL-1β.

27. A compound for use according to claim 24, wherein the proinflammatory cytokine is IL-6.

28. A compound for use according to claim 24, wherein the anti-inflammatory cytokine is IL-10.

29. A compound for use according to any one of claims 1-23, wherein the expression of the sod2, tfam, ddal genes modulated by sirtuin-1 is increased in the liver.