WO2001035959A1

WO2001035959A1 - Use of thiazole derivatives for treatment/prevention of p38 kinase mediated disorders

Info

Publication number: WO2001035959A1
Application number: PCT/SE2000/002252
Authority: WO
Inventors: Magnus Ingelman-Sundberg; Anastasia Simi; Niclas Tindberg
Original assignee: Astrazeneca Ab
Priority date: 1999-11-18
Filing date: 2000-11-15
Publication date: 2001-05-25
Also published as: AU1653101A; SE9904177D0

Abstract

The present invention relates to the use of a compound of general formula (I) or (II) wherein R1 is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF3; R2 and R3 are independently H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl, (a), with the proviso that one of R2 or R3 is (b) wherein W is O, S, NH or N-lower alkyl; R4 is H, lower alkyl or lower acyl; R5 is H, lower alkyl, aryl-lower alkyl, cyclopropyl or lower perfluoroalkyl; Ar is phenyl, furyl, thienyl, naphthyl, pyridyl or pyrrolyl, optionally substituted by R6; R6 is one or more groups selected from lower alkyl, lower acyl, halogen, lower alkoxy, CF3, OH, NO2 or NR7R8, wherein R7 and R8 independently are H, lower alkyl or lower acyl; R9 is CH2-halogen, CH3 or COOH; R10 is H, OH or =O; R11 is H or OH; geometrical and optical isomers, tautomers and racemates thereof where such isomers or tautomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof, for the preparation of a medicament for the treatment and/or prevention of p38 MAP kinase mediated disorders.

Description

USE OF THIAZOLE DERIVATIVES FOR TREATMENT PREVENTION OF P38 KINASE MEDIATED DISORDERS

Field of the invention s The present invention is related to the use of thiazole derivatives in the treatment and/or prevention of p38 kinase mediated disorders.

Background of the Invention

Mitogen-activated protein kinases (MAP kinases) are a family of proline-directed

10 serine/threonine kinases, to date including extracellular regulated kinases (ERKs), c-jun N- terminal kinases (JNKs) and p38 MAP kinases. The catalytic mechanism of MAP kinases involves initial phosphorylation of a threonine residue and a tyrosine residue, binding of substrate and subsequently binding of adenosine triphosphate deep in the catalytic cleft. Next, transfer of phosphate to the bound protein substrate occurs. Activation of MAP is kinases takes place when upstream regulatory protein kinases are stimulated by e.g. growth factors, inflammatory agents and neurotransmitters to phosphorylate MAP kinases.

The p38 MAP kinase family consists of at least five isoforms, named p38α, p38β, p38β2, p38γ and p38δ. Alternatively, the p38 MAP kinase proteins have been named stress- o activated protein kinases (SAPK), together with the c-jun N-terminal kinase family. The p38 MAP kinases are specifically activated by bacterial lipopolysaccharide, osmotic stress, alkylating agents, pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNFα) as well as by the neurotransmitter glutamate. Numerous substrates of p38 MAP kinases have been identified, including transcription factors (e.g. ATF-2, Elk- 5 1, SAP-1, CHOP and MEF2C) as well as other kinases (MAPKAP kinases-2. -3, -5,

MNKs-1, -2 and PRAK). Besides the direct substrates, the activity of other proteins such as the transcription factor NFKB can be indirectly affected. The regulation of numerous cellular genes has been shown to be dependent, at least in part, on p38 MAP kinase. Examples of affected genes and proteins are c-fos, c-jun, interleukin-1, cyclooxygenase-2 o and phosphoenolpyruvate carboxykinase (PEPKC). p38 MAP kinases have been implicated to be of importance in numerous human disorders and pathological conditions. These include disorders, which are clearly inflammatory in nature, such as rheumatoid arthritis, asthma and Crohn's disease. In addition, it has recently become evident that p38 MAP kinases have pronounced roles in, for example, ₅ cerebral infarction or haemorrhage as well as cardiac infarction. Specifically, several independent lines of evidence have demonstrated that p38 MAP kinases have regulatory roles, for example on apoptotic responses, as well as during hypoxia and ischaemia, affecting cells of the central nervous system or cardiac myocytes.

10 Previously, imidazole derivatives (e.g. 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5- (4-pyridyl)lH-imidazole, SB 203580), pyrrole derivatives, and pyrrolopyridines (e.g. 6- amino-2-(4-fluorophenyl)-4-methoxy-3- (4-pyridyl)-lH-pyrrolo[2, 3-b]pyridine, RWJ 68354), pyrazole derivatives and bisarylureas have been shown to be potent inhibitors of p38 MAP kinase isoforms, with IC₅₀ values in cellbased assays in the range of is approximately 0, 1- 1 μM, see e.g. Henry JR et al. (1998): Potent inhibitors of the MAP kinase p38, Bioorganic and Medicinal Letters 8:3335-3340; De Laszlo SE (1998): Pyrroles and other heterocycles as inhibitors of p38 kinase, Bioorganic and Medicinal Letters 8:2689-2694; Henry JR et al. (1998): 6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4- pyridyl)-lH-pyrτolo(2,3-δ pyridine (RWJ 68354): A potent and selective p38 kinase o inhibitor. Journal of Medicinal Chemistry 41: 4196-4198; Gallagher TF et al (1995): 2,4,5-Triarylimidazole inhibitors of IL-1 biosynthesis, Bioorganic and Medicinal Chemistry Letters 5: 1171-1176; and Adams JL et al (1998): Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased function of hepatic cytochrome P450 enzymes, Bioorganic and Medicinal Chemistry Letters 8: 3111-3116, W098/52937, ₅ WO98/52940, W098/52941 , W098/52558, WO99/00357 and W099/32463. The imidazole, pyrrole and pyrrolopyridine derivatives previously described are all believed to inhibit p38 MAP kinase activity by inhibiting binding of adenosine triphosphate to the kinase. In 1999, a new type of p38 MAP kinase inhibitor, LL-Z1640-2, was described by Takehana K, Sato S, Kobayasi T, Maeda T (1999): A Radicilol-related macrocyclic o nonaketide compound, antibiotic LL-Z1640-2, inhibits the JNK/p38 pathways in signal- specific manner, Biochem Biophvs Res Comm 257:19-23. This compound acts as an inhibitor of events upstream of p38 MAP kinase activation as it has been described to inhibit the phosphorylation of p38 MAP kinase, in response to anisomycin, but not to tumor necrosis factor-α. When inhibition of expression of genes downstream of p38 MAP kinase by the above mentioned imidazole-derivative SB 203580 has been evaluated, expression of response genes such as c-fos or c-jun has been inhibited to 60 - 80%.

Brief Description of the Invention

The thiazole compounds of general formula I or II below according to the present invention are found to show usefulness in the treatment and/or prevention of p38 MAP kinase mediated disorders. The thiazole compounds are found to inhibit p38 MAP kinase pathways by a mechanism distinctly different from that of imidazole derivatives, such as SB 203580, and therefore provides new therapeutic potential. Another object of the invention is a pharmaceutical formulation comprising said thiazole compounds. Still another object of the invention is a combination treatment in the form of a thiazole compound according to the invention and another p38 MAP kinase inhibitor, which acts through a different mechanism, and therefore also affords a new therapeutic possibility.

These thiazole compounds have the general formula I or II

(I) (II)

wherein Rj is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF3;

R2 and R3 are independently H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl,

WR₄

/ CF„ or C — Ar

\

with the proviso that one of R2 or R3 is

WR₄ C — Ar

\

wherein W is O, S, NH or N-lower alkyl;

R₄ is H, lower alkyl or lower acyl; R5 is H, lower alkyl, aryl-lower alkyl, cyclopropyl or lower perfluoroalkyl;

Ar is phenyl, furyl, thienyl, naphthyl, pyridyl or pyrrolyl, optionally substituted by

R is one or more groups selected from lower alkyl, lower acyl, halogen, lower alkoxy, CF3, OH, NO2 or NR Rg, wherein R7 and R% independently are H, lower alkyl or lower acyl;

R₉ is CH₂-halogen, CH3 or COOH; RlO is H, OH or =0;

geometrical and optical isomers, tautomers and racemates thereof where such isomers or tautomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof, for the preparation of a medicament for the treatment and/or prevention of p38 MAP kinase mediated disorders.

Detailed Description of the Invention

The present invention provides thiazole compounds having the general formula I or II for the treatment and/or prevention of p38 MAP kinase mediated disorders

(I) (II)

geometrical and optical isomers, tautomers and racemates thereof where such isomers or tautomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof, wherein Rj is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF3;

WR„

/

CF₃ or C - -Ar

V

ith the proviso that one of R2 or R3 is

wherein W is O, S, NH or N-lower alkyl;

R4 is H, lower alkyl or lower acyl;

R5 is H, lower alkyl, aryl-lower alkyl, cyclopropyl or lower perfluoroalkyl;

Rζ is one or more groups selected from lower alkyl, lower acyl, halogen, lower alkoxy, CF3, OH, NO2 or NR₇Rg, wherein R7 and Rg independently are H, lower alkyl or lower acyl;

R₉ is CH₂-halogen, CH3 or COOH; Rin is H, OH or =0; Rπ is H or OH.

The following definitions shall apply throughout the specification and the appended claims.

In the present context lower alkyl may be a straight or branched Cj-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl or isohexyl.

In the present context lower alkoxy may be a straight or branched Ct-Cό alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, t-pentyloxy. neopentyloxy, n-hexyloxy or isohexyloxy.

In the present context halogen may be fluoro, chloro, bromo or iodo.

In the present context aryl may be phenyl or naphthyl.

In the present context lower acyl may be lower alkyl-CO, aryl-CO or aryl-lower alkyl-CO.

The expression "pharmaceutically acceptable acid addition salts" is intended to include but is not limited to such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulphate, dihydrogen phosphate, ethanedisulphonate, mesylate, fumarate, maleate, succinate, tartrate, citrate, lactate and malate.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all geometrical and optical isomers, tautomers and racemates thereof where such isomers or tautomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as for instance hydrates.

Rl is preferably H or lower alkyl.

R2 and R3 are preferably independently H, lower alkyl or

WR₄

/ C — Ar

\

with the proviso that one of R2 or R3 is

WR₄

/ C — Ar

\ W is preferably O or NH.

R4 is preferably H.

R5 is preferably H, lower alkyl or lower perfluoroalkyl.

Ar is preferably phenyl or furyl optionally substituted with halogen.

R9 is preferably CH₂- halogen.

RlO and Rj ₁ are preferably H.

The most preferred compounds of formula I and II according to the present invention arel-(4- methyl-5-thiazolyl)- 1 -phenylmethylamine and 5-(2-chloroethyl)-4-methylthiazole (clomethiazole), respectively. The compounds of general formula I and II may be prepared according to any methods described in GB 847 520, WO92/03134, WO95/01967, WO95/01968, WO95/01979, J. Am. Chem. Soc. 1935, 57, 1876-1881, Xenobiotica 1975, 5, 687-696, Dokl. Akad. Nauk SSSR 1971, 347-350 and J. Org. Chem. 1988, 53, 1748- 1761.

Pharmaceutical Formulations

The administration of the thiazole compounds according to this invention alone or in combination with another p38 MAP kinase inhibitor, that acts through a different mechanism, may conveniently be oral, rectal, nasal, parenteral or by inhalation at a dosage level of, for example, about 1 to 3000 mg/kg, preferably about 10 to 1000 mg/kg and especially about 25 to 300 mg/kg and may be administered on a regime of 1 to 4 times a day. The dose will depend on the route of administration, a preferred route being by oral administration and a particularly preferred route being by intravenous infusion of an aqueous solution containing the compound of general formula I or II, in which case a steady state plasma concentration of between 0.1 and 500 μM will be achieved. It will be appreciated that the severity of the disorder, the age of the patient and other factors normally considered by the attending physician will influence the individual regime and dosage most appropriate for a particular patient.

5

The other p38 MAP kinase inhibitor, which acts through a different mechanism, may be for example an imidazole derivative, a pyrrole derivative, a pyrrolopyridine derivative, a pyrazole derivative, a bisarylurea or a macrocyclic nonaketide compound.

lo The present compounds may also be used in co-therapies for the treatment of neurological disorders, such as together with tissue plasminogen activators, glutamate receptor antagonists, calcium-channel antagonists, other cation channel blockers, NOS inhibitors, radical scavengers, other kinase inhibitors, chemokine antagonists, purinergic antagonists or protease inhibitors.

15

The present compounds may also be used in co-therapies for the treatment of inflammatory disorders, such as together with steroids, cyclooxygenase-2 inhibitors, NSAEDs, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB₄ antagonists and LTA₄ hydrolase inhibitors. o

The pharmaceutical formulations comprising the compound of this invention may conveniently be tablets, pills, capsules, powders or granules for oral administration; sterile parenteral solutions or suspensions for parenteral administration; or as suppositories for rectal administration. 5

Medical and Pharmaceutical Use

Compounds of formula I or II would be useful for, but not limited to, the treatment of any disorder or disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated p38 MAP kinase activation in such a mammal. Accordingly, the o present invention provides a method of treating a p38 MAP kinase mediated disorder, which comprises administration of an effective p38 MAP kinase-interfering amount of a compound of formula, I or II, or a pharmaceutically acceptable salt thereof.

Compounds of formula I or II would be useful for, but not limited to, the treatment of 5 inflammation in a subject.

Compounds of the invention would be useful to treat neurological disorders, including but not limited to cerebral ischaemia, stroke including cerebral infarction, cerebral haemorrhage and embolization to the vessels of the brain, multiple sclerosis, viral or to bacterial infection and other inflammatory states of the central nervous system.

Compounds of the invention would be useful to treat hepatic diseases, including but not limited to alcoholic liver disease, liver cirrhosis, viral infections of the liver including infections with hepatitis viruses HAV, HBV, HCV, HDV and HEV.

15

Compounds of the invention would also be useful to treat arthritis, pulmonary disorders or lung inflammation, asthma, viral and bacterial infections and bone resoφtion diseases such as osteoporosis.

o Compounds of the invention would also be useful to treat cachexia, cachexia secondary to infection or malignancy, including but not limited to cachexia secondary to acquired immunodefiency syndrome (AIDS), AIDS related complex (ARC), pneumonia, herpesvirus and hepatitisvirus.

5 Compounds of the invention would also be useful to treat autoimmune diseases, including but not being limited to rheumatoid arthritis, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), Sjόgren's syndrome, psoriasis, sarcoidosis, and graft-versus- host reactions.

o Compounds of the invention would be useful to treat endotoxic shock, toxic shock syndrome, reperfusion injury, cardiovascular diseases including atherosclerosis, nephritis, myalgia related to infection, gastrointestinal conditions including inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

Compounds of the invention would be useful to treat ophthalmic diseases, neoplasia, metastasis, diabetic nephropathy, cardiomyopathy and disorders of the female reproductive system such as endometriosis.

Besides being useful for human treatment, these compounds may also be useful for veterinary treatment including mammals.

As used herein, the term "p38 MAP kinase mediated disorders" refers to any and all disorders and disease states in which p38 MAP kinases play a role, either by control of p38 MAP kinase itself, or by p38 MAP kinase causing another factor to be released, such as, but not limited to, IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38 MAP kinase, would therefore be considered a disorder mediated by p38 MAP kinase.

PHARMACOLOGY

Biological evaluation

The present thiazole compounds have been evaluated biologically 1) in rat cortical glial cultures, 2) in human neuroblastoma cell lines and 3) in in vitro immunocomplex kinase assays

The results showed that the imidazole derivative 4-(4-fluorophenyl)-2-(4- methylsulfιnylphenyl)-5-(4-pyridyl)lH-imidazole (SB 203580), but not 5-(2-chloroethyl)- 4-methyl thiazole (clomethiazole) or l-(4-methyl-5-thiazolyl)-l-phenylmethylamine, inhibited p38 MAP kinase in this assay. The results demonstrate that the thiazole compounds of the invention and imidazole derivatives such as 4-(4-fluorophenyl)-2-(4- methylsulfinylphenyl)-5-(4-pyridyl)lH-imidazole act by different mechanisms when interfering with p38 MAP kinase pathways.

Claims

1. The use of a compound of general formula I or II

wherein:

R_l is H, lower alkyl, lower alkoxy-lower alkyl, aryl-lower alkyl or CF3;

WR₄

/ CF„ or C — Ar

\

with the proviso that one of R2 or R3 is

WR₄

/ C — Ar

\

wherein W is O, S, NH or N-lower alkyl;

RO;

Rg is one or more groups selected from lower alkyl, lower acyl, halogen, lower alkoxy, CF3, OH, NO₂ or NR₇Rg, wherein R7 and Rg independently are H, lower alkyl or lower acyl;

R9 is CH₂-halogen, CH₃ or COOH;

Rπ is H or OH; geometrical and optical isomers, tautomers and racemates thereof where such isomers or tautomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof, for the preparation of a medicament for the treatment and/or prevention of p38 MAP kinase mediated disorders.

2. The use of a compound of general formula I according to claim 1 characterized in that R_l is H or lower alkyl.

3. The use of a compound of general formula I according to any one of claims 1 or 2 characterized in that R2 and R3 are independently H, lower alkyl or

WR,

/ C — Ar

'5

with the proviso that one of R2 or R3 is WR„

/

4. The use of a compound of general formula I according to any one of claims 1 to 3 characterized in that W is O or NH.

5. The use of a compound of general formula I according to any one of claims 1 to 4 characterized in that R4 is H.

6. The use of a compound of general formula I according to any one of claims 1 to 5 characterized in that R5 is H, lower alkyl or lower perfluoroalkyl.

7. The use of a compound of general formula I according to any one of claims 1 to 6 characterized in that Ar is phenyl or furyl optionally substituted with halogen.

8. The use of a compound of general formula II according to claim 1 characterized in that R9 is CH2- halogen.

9. The use of a compound of general formula II according to any one of claims 1 or 8 characterized in that RIQ and Ri 1 are H.

10. The use of a compound of general formula I according to any one of claims 1 to 7 characterized in that the compound is l-(4-methyl-5-thiazolyl)-l-phenylmethylamine.

11. The use of a compound of general formula II according to any one of claims 1 or 8 to 9 characterized in that the compound is 5-(2-chloroethyl)-4-methylthiazole.

12. The use according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prevention of inflammation, neurological disorders, multiple sclerosis, viral or bacterial infection and other inflammatory states of the central nervous system.

5 13. The use according to claim 12 in the manufacture of a medicament for the treatment and/or prevention of cerebral ischaemia, stroke including cerebral infarction, cerebral haemorrhage and embolization to the vessels of the brain.

14. The use according to any one of claims 1 to 11 in the manufacture of a medicament for lo the treatment and/or prevention of hepatic diseases.

15. The use according to claim 14 in the manufacture of a medicament for the treatment and/or prevention of alcoholic liver disease, liver cirrhosis, viral infections of the liver including infections with hepatitis viruses HAV, HBV, HCV, HDV and HEV.

15

16. The use according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prevention of arthritis, pulmonary disorders or lung inflammation, asthma, viral and bacterial infections and bone resoφtion diseases such as osteoporosis.

0 17. The use according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prevention of cachexia, cachexia secondary to infection or malignancy, including cachexia secondary to acquired immunodefiency syndrome (AIDS), AIDS related complex (ARC), pneumonia, heφesvirus and hepatitisvirus.

5 18. The use according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prevention of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), Sjόgren's syndrome, psoriasis, sarcoidosis, and graft-versus-host reactions.

o 19. The use according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment and/or prevention of endotoxic shock, toxic shock syndrome, reperfusion injury, cardiovascular diseases including atherosclerosis, nephritis, myalgia related to infection, gastrointestinal conditions including inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

20. The use according to any one of claims 1 to 11 in the manufacture of a medicament for 5 the treatment and/or prevention of ophthalmic diseases, neoplasia. metastasis, diabetic nephropathy, cardiomyopathy and disorders of the female reproductive system such as endometriosis.

21. A method for the treatment and/or prevention of p38 MAP kinase mediated disorders to by administering to a mammal including man in need of such a treatment a therapeutically effective amount of a compound defined in any one of claims 1 to 11.

22. A method according to claim 21 for the treatment and/or prevention of inflammation, neurological disorders, multiple sclerosis, viral or bacterial infection and other s inflammatory states of the central nervous system.

23. A method according to claim 21 for the treatment and/or prevention of cerebral ischaemia, stroke including cerebral infarction, cerebral haemorrhage and embolization to the vessels of the brain. 0

24. A method according to claim 21 for the treatment and/or prevention of hepatic diseases.

25. A method according to claim 21 for the treatment and/or prevention of alcoholic liver ₅ disease, liver cirrhosis, viral infections of the liver including infections with hepatitis viruses HAV, HBV, HCV, HDV and HEV.

26. A method according to claim 21 for the treatment and/or prevention of arthritis, pulmonary disorders or lung inflammation, asthma, viral and bacterial infections and bone o resoφtion diseases such as osteoporosis.

27. A method according to claim 21 for the treatment and/or prevention of cachexia, cachexia secondary to infection or malignancy, including cachexia secondary to acquired immunodefiency syndrome (AIDS), AIDS related complex (ARC), pneumonia, heφesvirus and hepatitisvirus.

28. A method according to claim 21 for the treatment and/or prevention of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), Sjδgren's syndrome, psoriasis, sarcoidosis, and graft-versus- host reactions.

10

29. A method according to claim 21 for the treatment and or prevention of endotoxic shock, toxic shock syndrome, reperfusion injury, cardiovascular diseases including atherosclerosis, nephritis, myalgia related to infection, gastrointestinal conditions including inflammatory bowel disease, such as Crohn's disease and ulcerative colitis.

15

30. A method according to claim 21 for the treatment and/or prevention of ophthalmic diseases, neoplasia, metastasis, diabetic nephropathy, cardiomyopathy and disorders of the female reproductive system such as endometriosis.

0 31. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1-11 optionally in association with diluents, excipients or inert carriers.

32. A pharmaceutical formulation according to claim 31 for use in the treatment of 5 p38 MAP kinase mediated disorders.

33. A pharmaceutical formulation according to any one of claims 31 or 32 for use in the treatment and/or prevention of neurological disorders, multiple sclerosis, viral or bacterial infection and other inflammatory states of the central nervous system, cerebral ischaemia, o stroke including cerebral infarction, cerebral haemorrhage and embolization to the vessels of the brain, hepatic diseases, alcoholic liver disease, liver cirrhosis, viral infections of the liver including infections with hepatitis viruses HAV, HBV, HCV, HDV and HEV, arthritis, pulmonary disorders or lung inflammation, asthma, viral and bacterial infections and bone resoφtion diseases such as osteoporosis, cachexia, cachexia secondary to infection or malignancy, including cachexia secondary to acquired immunodefiency syndrome (AIDS), AIDS related complex (ARC), pneumonia, heφesvirus and hepatitisvirus, autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), Sjδgren's syndrome, psoriasis, sarcoidosis, and graft-versus-host reactions, endotoxic shock, toxic shock syndrome, reperfusion injury, cardiovascular diseases including atherosclerosis, nephritis, myalgia related to infection, gastrointestinal conditions including inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, ophthalmic diseases, neoplasia, metastasis, diabetic nephropathy, cardiomyopathy and disorders of the female reproductive system such as endometriosis.

34. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1-11 in combination with another p38 MAP kinase inhibitor, that acts through a different mechanism, optionally in association with diluents, excipients or inert carriers.

35. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1-11 in combination with a compound for the treatment of neurological disorders optionally in association with diluents, excipients or inert carriers.

36. A pharmaceutical formulation according to claim 35 wherein the compound for the treatment of neurological disorders is selected from the group tissue plasminogen activators, glutamate receptor antagonists, calcium-channel antagonists, other cation channel blockers, NOS inhibitors, radical scavengers, other kinase inhibitors, chemokine antagonists, purinergic antagonists or protease inhibitors.

37. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of any one of claims 1-11 in combination with an anti- inflammatory compound, optionally in association with diluents, excipients or inert carriers.

38. A pharmaceutical formulation according to claim 37 wherein the anti-inflammatory compound is a steroid, a cyclooxygenase-2 inhibitor, a NSAID, an immunosuppressive agent, a 5-lipoxygenase inhibitor, a LTB antagonist or a LTA₄ hydrolase inhibitor.