Pyrazolopyrimidine Derivatives or Pharmaceutically Acceptable Salts Thereof

Abstract

A pyrazolopyrimidine derivative represented by formula (1) and pharmaceutically acceptable salt thereof exhibit excellent inhibitory activity against MAPKAP-K2. Accordingly, medicines containing this compound as an active ingredient are expected to be effective for treating diseases mediated by MAPKAP-K2 such as, for example, inflammatory disorder, autoimmune diseases, destructive osteopathy, cancer and/or tumor growth.

1 . A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1): 
     
       
         
         
             
             
         
       
       [wherein, 
       R 1  represents a hydrogen atom or a halogen; 
       R 2  represents a hydrogen atom or a halogen; 
       R 3  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR 5 ; 
       R 5  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R 6 ; 
       R 6  represents an optionally substituted C1-C8 alkyl group; 
       n represents 0 or 1, or n represents 0 when R 3  is —OR 5 ; 
       R 4  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted heterocyclylalkyl group or an optionally substituted C7-C16 aralkyl group; 
       the substituents in the optionally substituted C6-C14 aryl group as R 4  are one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , —CHO, —OH, —COOH, optionally substituted C1-C8 alkyl group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl group, —O—(CH 2 ) m —W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)—R 133 , —O—C(═O)R 26 , —C(═O)OR 27 , —NR 28 C(═O)R 29 , —NR 30 R 31 , —C(═O)NR 32 R 33 , —NR 34 C(═X 1 )OR 35 , —NR 36 C(═X 2 )NR 37 R 38 , —NR 39 —SO 2 R 40 , —S(O) r —R 41  and —SO 2 NR 42 R 43 , wherein X 1  or X 2  represents O, S, N—CN or NH and r represents 0 to 2; 
       W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group, and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group, —NR 150 R 151  or an optionally substituted phenoxy group and in this case m represents 1 to 4; 
       R 26  to R 43 , R 133 , R 150  and R 151  may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclylalkyl group, or, when R 30  and R 31 R 32  and R 33 R 37  and R 38 , R 42  and R 43  or R 150  and R 151  are optionally substituted alkyl groups, the substituents in each combination may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; 
       -A-B- represents —CH 2 —CH(-Z 1 )-, —(CH 2 ) p —, —CH 2 —CH═CH—CH 2 —, —CH═C(-Z 2 )— or —(CH 2 ) q —C(═O)—; 
       p represents 3 or 4 and q represents 1 or 2; 
       Z 1  and Z 2  may be identical or different and each represents a hydrogen atom or —CH 2 —OR 11 ; and 
       R 11  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or a substituted silyl group.] 
     
   
   
       2 . A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1): 
     
       
         
         
             
             
         
       
       [wherein, 
       R 1  represents a hydrogen atom or a halogen; 
       R 2  represents a hydrogen atom or a halogen; 
       R 3  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR 5 ; 
       R 5  represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R 6 ; 
       R 6  represents an optionally substituted C1-C8 alkyl group; 
       n represents 0 or 1 or n represents 0 and when R 3  is —OR 5 ; 
       R 4  represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted C7-C16 aralkyl group; 
       the substituents in the optionally substituted C6-C14 aryl group as R 4  are one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , optionally substituted C1-C8 alkyl group, —O—(CH 2 ) m —W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR 7 , —NR 8 C(═O)R 9 , —NR 10 R 127 , —C(═O)NR 128 R 129  and —SO 2 NR 130 R 131 ; 
       W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group or an optionally substituted phenoxy group and in this case m represents 1 to 4; 
       R 7  to R 10  and R 127  to R 131  may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group, or, when R 10  and R 127 , R 128  and R 129  or R 130  and R 131  are optionally substituted alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; 
       -A-B- represents —CH 2 —CH(-Z 3 )-, —(CH 2 ) p —, —CH 2 —CH═CH—CH 2 —, —CH═C(-Z 4 )— or —(CH 2 ) q —C(═O)—; 
       p represents 3 or 4 and q represents 1 or 2; 
       Z 3  and Z 4  may be identical or different and each represents a hydrogen atom or —CH 2 —OR 11 ; and 
       R 11  represents a hydrogen atom or an optionally substituted C1-C8 alkyl group.] 
     
   
   
       3 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 1  is a hydrogen atom. 
   
   
       4 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 2  is a hydrogen atom. 
   
   
       5 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 2  is a halogen. 
   
   
       6 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 3  is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group. 
   
   
       7 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 3  is an unsubstituted C1-C4 alkyl group, a substituted C1-C4 alkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, phenyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, —CN, —CHO, —OH, —(C═O)OH, —(C═O)OR 86 —(C═O)NR 87 R 88  and —NR 89 R 90 ; R 86  represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group or a phenyl group; R 87  and R 88  may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl group; R 89  represents a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a benzyl group; R 90  represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, or, when R 89  and R 90  are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond; further this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which R 89  and R 90  bond), an unsubstituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —OH, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkoxy group and —NR 91 R 92 , wherein R 91  represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R 92  represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), an unsubstituted heterocyclic group or a substituted heterocyclic group (wherein, when carbon atom(s) in the substituted heterocyclic group are substituted, the substituent(s) are 1 to 3 substituents selected from the group consisting of halogen, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, phenyl group, benzyl group, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR 93 R 94 , wherein R 93  represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R 94  represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, wherein, when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group). 
   
   
       8 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 3  is an unsubstituted heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted saturated heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in the heterocycle and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group and tert-butoxycarbonyl group), a C1-C4 alkyl group substituted with one amino group or a C3-C8 cycloalkyl group substituted with one amino group. 
   
   
       9 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 3  is a piperidyl group, a pyrrolidinyl group or a cyclohexyl group substituted with an amino group. 
   
   
       10 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein n is 0. 
   
   
       11 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group. 
   
   
       12 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH 2 ) m —W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR 7  and —C(═O)NR 9 R 10 . 
   
   
       13 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group and —O—(CH 2 ) m —W. 
   
   
       14 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group and the substituents are one or more —O—(CH 2 ) m —W, wherein W is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted heterocyclic group or an optionally substituted C1-C8 alkoxy group. 
   
   
       15 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, optionally substituted C6-C14 aryl group and optionally substituted heterocyclic group. 
   
   
       16 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —C(═O)OR 7  and —C(═O)NR 9 R 10 . 
   
   
       17 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH 2 ) m —W and —C(═O)OR 113 , wherein W represents a hydrogen atom, an optionally substituted C1-C4 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted monocyclic or bicyclic heterocyclic group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4, and R 113  represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted phenyl group). 
   
   
       18 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted phenyl group (wherein the substituent is one —O—(CH 2 ) m —W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4). 
   
   
       19 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, optionally substituted phenyl group and optionally substituted monocyclic or bicyclic heterocyclic group). 
   
   
       20 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, —C(═O)OR 113  and —C(═O)NR 118 R 119 , wherein R 113 , R 118  and R 119  may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group; and when R 118  and R 119  are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which they bond). 
   
   
       21 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted heterocyclic group. 
   
   
       22 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted bicyclic heteroaryl group (wherein, when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, C1-C8 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C8 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, phenyl group, monocyclic or bicyclic heterocyclic group, —C(═O)OR 122 , —NR 123 R 124  and —C(═O)NR 125 R 126 , wherein R 123  represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, R 124  represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, R 122  represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and R 125  and R 126  may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group; when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group). 
   
   
       23 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted bicyclic heteroaryl group (wherein the bicyclic heteroaryl group means a bicyclic heteroaryl group wherein a phenyl group is fused with an aromatic heterocycle containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens; when nitrogen atom(s) in the heterocycle are substituted, the substituent represents one or more C1-C4 alkyl group). 
   
   
       24 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C7-C16 aralkyl group or an optionally substituted heterocyclylalkyl group. 
   
   
       25 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein R 4  is an optionally substituted heterocyclylalkyl group. 
   
   
       26 . The pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2 , wherein -A-B- is —CH 2 —CH 2 —, —(CH 2 ) p —, —CH 2 —CH═CH—CH 2 — or —CH═CH—. 
   
   
       27 . A pyrazolopyrimidine derivative represented by formula (2): 
     
       
         
         
             
             
         
       
       [wherein, R 1 , R 2 , R 3 , R 4 , n and -A-B- are as defined in either  claim 1  or  2 , and Boc represents tert-butoxycarbonyl]. 
     
   
   
       28 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 1  and R 2  are a hydrogen atom. 
   
   
       29 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 1  is a hydrogen atom and R 2  is a halogen. 
   
   
       30 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 3  is an optionally substituted C1-C8 alkyl group, an optionally substituted cyclohexyl group or an optionally substituted heterocyclic group (wherein the heterocyclic group means a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S). 
   
   
       31 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 3  is an unsubstituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in a saturated heterocyclic group and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group), a C1-C4 alkyl group substituted with an amino group or a C3-C8 alkyl group substituted with an amino group. 
   
   
       32 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 4  is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group. 
   
   
       33 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 4  is an optionally substituted phenyl group or an optionally substituted bicyclic heteroaryl group. 
   
   
       34 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 4  is an optionally substituted phenyl group (wherein the substituents are one or more —O—(CH 2 ) m —W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4, or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4). 
   
   
       35 . The pyrazolopyrimidine derivative according to  claim 27 , wherein R 4  is an optionally substituted bicyclic heteroaryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens.). 
   
   
       36 . The pyrazolopyrimidine derivative according to  claim 27 , wherein -A-B- is —CH 2 —CH 2 —, —(CH 2 ) p —, —CH 2 —CH═CH—CH 2 — or —CH═CH—. 
   
   
       37 . The pyrazolopyrimidine derivative according to  claim 27 , wherein n is 0. 
   
   
       38 . A pharmaceutical composition comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2  and a pharmaceutically acceptable carrier. 
   
   
       39 . A MAPKAP-K2 inhibitor comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2  as an active ingredient. 
   
   
       40 . A therapeutic agent comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to  claim 1  or  2  as an active ingredient for neurodegenerative and/or neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma or chronic obstructive pulmonary disease (COPD). 
   
   
       41 . The therapeutic agent according to  claim 40 , wherein the autoimmune disease is rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, graft-versus-host disease, diabetes mellitus or Crohn's disease.