Therapeutic Molecules and Methods-1

Abstract

Methods of inhibiting the cytokine or biological activity of Macrophage Migration Inhibitory Factor (MIF) comprising contacting MIF with a compound of formula (I) as defined herein, is provided. The invention also relates to methods of treating diseases or conditions where MIF cytokine or biological activity is implicated comprising administration of compounds of formula (I), either alone or as part of a combination therapy. Novel heterocyclic compounds are also provided for.

1 . A method of inhibiting cytokine or biological activity of MIF comprising contacting MIF with a cytokine or biological activity inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof 
       
         
           
           
               
               
           
         
       
       wherein
 X is selected from —O—, —S—, —C(R 5 )(R 5′ )— or —N(R 6 )—; 
 Y is selected from —N(R 7 )—, —O—, —S— or —C(R 7 ) 2 —; 
 Z is selected from —C(O)—, —C(S)—, —C(═NR 6 )—, —S(O)— or —S(O) 2 —; 
 R 1  is selected from hydrogen, C 1-3 alkyl, (CR 5 R 5′ ) n OR 7 , (CR 5 R 5′ ) n SR 7 , (CR 5 R 5′ ) n N(R 6 ) 2  and (CR 5 R 5′ ) n halo; 
 R 2  is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, (CR 12 R 12′ ) m C(O)R 9 , (CR 12 R 12′ ) m C(S)R 8 , (CR 12 R 12′ ) m S(O)R 8 , (CR 12 R 12′ ) m S(O) 2 R 8 , (CR 12 R 12′ ) m OR 9 , (CR 12 R 12′ ) m SR 9 , (CR 12 R 12′ ) m NR 10 R 11 , (CR 12 R 12′ ) m C(═NR 24 )R 22  and (CR 12 R 12′ ) m R 13 ; 
 R 3  is selected from hydrogen, C 1 -C 6 alkyl, (CR 16 R 16′ ) p NR 14 R 15 , (CR 16 R 16′ ) p OR 17 , (CR 16 R 16′ ) p SR 17 , (CR 16 R 16′ ) p halo, (CR 16 R 16′ ) p NO 2 , (CR 16 R 16′ ) n C(O)R 28 , (CR 16 R 16′ ) n C(═NR 24 )R 22 , (CR 16 R 16′ )S(O)R 17 , (CR 16 R 16′ ) n S(O) 2 R 17 , (CR 16 R 16′ ) n S(O) 3 R 17  and (CR 16 R 16′ ) p C(R 18 ) 3 ; 
 R 4  is selected from hydrogen, halogen C 1 -C 3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and (CR 12 R 12′ ) n C(R 8 ) 3 ; 
 Each R 5  and R 5′  is independently selected from hydrogen, C 1 -C 3 alkyl, halo, OR 7 , SR 7  and N(R 6 ) 2 ; 
 Each R 6  is independently selected from hydrogen, C 1 -C 3 alkyl and OR 7 ; 
 Each R 7  is independently selected from hydrogen and C 1 -C 3 alkyl; 
 R 8  is selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, OR 19 , SR 19 , N(R 20 ) 2 , [NH—CH(R 21 )—C(O)] q —OR 29 , [sugar] q  and (CR 12 R 12′ ) t R 13 ; 
 R 9  is selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, (CR 12 R 12′ ) t R 13 , C(O)R 23 , CO 2 R 23 , C(S)R 23 , C(S)OR 23 , S(O)R 23 , S(O) 2 R 23 , [C(O)CH(R 21 )NH] q —R 23  and [sugar] q ; 
 R 10  and R 11  are independently selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, (CR 12 R 12′ ) m R 13 , C(O)R 23 , C(S)R 23 , S(O)R 23 , S(O) 2 R 23 , [C(O)CH(R 21 )NH] q —R 23 , -[sugar] q  and NHC(═NR 25 )—NH 2 ; 
 Each R 12  and R 12′  is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6  alkenyl, C 2 -C 6 alkynyl, OR 24 , SR 24 , halo, N(R 24 ) 2 , CO 2 R 24 , CN, NO 2 , aryl or heterocyclyl; 
 R 13  is selected from OR 25 , SR 25 , halo, N(R 25 ) 2 , C(O)R 31 , CN, C(R 8 ) 3 , aryl or heterocyclyl; 
 R 14  and R 15  are independently selected from hydrogen, C 1 -C 3 alkyl, OR 17 , (CR 16 R 16′ ) p C(R 18 ) 3 ; 
 Each R 16  and R 16′  is independently selected from hydrogen, C 1 -C 3 alkyl, halo, OR 17 , SR 17  and N(R 17 ) 2 ; 
 Each R 17  is independently selected from hydrogen and C 1 -C 3 alkyl; 
 Each R 18  is independently selected from hydrogen and halo; 
 R 19  and each R 20  are independently selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, (CR 26 R 26′ ) t R 27 ; 
 R 21  is the characterising group of an amino acid; 
 R 22  is selected from C 1 -C 6 alkyl, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , OR 29  or SR 29 ; 
 R 23  is selected from hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl (CR 26 R 26′ ) t R 27 ; 
 Each R 24  is independently selected from hydrogen and C 1 -C 6 alkyl; 
 Each R 25  is independently selected from hydrogen, C 1 -C 6 alkyl, C 1-3 alkoxyC 1-3 alkyl, aryl and heterocyclyl; 
 Each R 26  and R 26′  is independently selected from hydrogen, C 1 -C 6  allyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OR 29 , SR 29 , halo, N(R 29 ) 2 , CO 2 R 29 , CN, NO 2 , aryl and heterocyclyl; 
 R 27  is selected from hydrogen, OR 30 , SR 30 , halo, N(R 30 ) 2 , CO 2 R 30 , aryl and heterocyclyl; 
 R 28  is selected from hydrogen, C 1-6 alkyl, OR 29 , SR 29  or N(R 29 ) 2 ; 
 Each R 29  is independently selected from hydrogen and C 1 -C 3 alkyl; 
 Each R 30  is independently selected from hydrogen, C 1 -C 3 alkyl, aryl and heterocyclyl; 
 R 31  is selected from C 1-3 alkyl, OH, C 1-3 alkoxy, aryl, aryloxy, heterocyclyl and heterocyclyloxy; 
 n is 0 or an integer from 1 to 3; 
 m is 0 or an integer from 1 to 20; 
 p is 0 or an integer from 1 to 6; 
 q is an integer from 1 to 5; 
 t is an integer from 1 to 10; 
 wherein alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted. 
 
     
     
         2 . A method according to  claim 1  wherein X is selected from the group consisting of —N(H)—, —N(C 1-3 alkyl)-, —N(OH)—, —N(OC 1-3 alkyl)-, —O—, —S—, —CH 2 , —CH(OH)—, —CH(NH 2 )—, —CH(C 1-3 alkyl)-, —CH(halo)-, —CH(SH)—, —CH(OC 1-3 alkyl), —CH(SC 1-3 alkyl)-. 
     
     
         3 . A method according to  claim 1  wherein Y is selected from the group consisting of —NH—, —O—, —S—, —N(C 1-3 alkyl)— or —CH 2 —. 
     
     
         4 . A method according to  claim 1  wherein Z is selected from the group consisting of —C(O)—, —C(S)—, —C(═NH)—, —C(═NC 1-3 alkyl)-, —C(═NOH)— or —C(═NOC 1-3 alkyl). 
     
     
         5 . A method according to  claim 1  wherein R 1  is selected from the group consisting of hydrogen, CH 3 , OH, SH, NH 2 , NHCH 3 , F, Cl or Br. 
     
     
         6 . A method according to  claim 1  wherein R 2  is selected from the group consisting of C 1-20 alkyl, C 1-20 alkenyl, (CR 12 R 12′ ) m heterocyclyl, (CR 12 R 12′ ) m aryl, (CR 12 R 12′ ) m halo, (CR 12 R 12′ ) m OH, (CR 12 R 12′ ) m OC 1-20 alkyl, (CR 12 R 12′ ) m OC 2-20 alkenyl, (CR 12 R 12 ) m OC(O)C 1-20 alkyl, (CR 12 R 12′ ) m OC(O)C 2-20 alkenyl, (CR 12 R 12′ ) m OC(O)aryl, (CR 12 R 12′ ) m O[C(O)CH(R 21 )NH] r —H, (CR 12 R 12′ ) m O[sugar] r , (CR 12 R 12′ ) m NH 2 (CR 12 R 12′ ) m NHC 1-20 alkyl, (CR 12 R 12′ ) m N(C 1-20 alkyl) 2 , (CR 12 R 12′ ) m NHC 2-20 alkenyl, (CR 12 R 12′ ) m N(C 2-20 alkenyl) 2 , (CR 12 R 12′ ) m N(C 1-2 alkyl)(C 2-20 alkenyl), (CR 12 R 12′ ) m NHC(O)C 1-20 alkyl, (CR 12 R 12′ ) m NHC(O)C 2-20 alkenyl, (CR 12 R 12′ ) m NHC(O)aryl, (CR 12 R 12′ ) m NH[C(O)CH(R 21 )NH] r H, (CR 12 R 12′ ) m NH-[sugar] r , (CR 12 R 12′ ) m SO 3 H, (CR 12 R 12′ ) m SO 3 C 1-20 alkyl, (CR 12 R 12′ ) m SO 3 C 2-20 alkenyl, (CR 12 R 12′ ) m C(O)C 1-20 alkyl, (CR 12 R 12′ ) m C(O)C 2-20 alkenyl, (CR 12 R 12′ ) m CO 2 H, (CR 12 R 12′ ) m CO 2 C 1-20 alkyl, (CR 12 R 12′ ) m CO 2 C 2-20 alkenyl, (CR 12 R 12′ ) m C(O)NHC 1-20 alkyl, (CR 12 R 12′ ) m C(O)N(C 1-20 alkyl) 2 , (CR 12 R 12′ ) m C(O)NHC 2-20  alkenyl, (CR 12 R 12′ ) m C(O)N(C 2-20 alkenyl) 2 , (CR 12 R 12′ ) m C(O)N(C 2-20 alkyl)(C 2-20 alkenyl), (CR 12 R 12′ ) m C(O)[NHCH(R 21 )C(O)] r OH, (CR 12 R 12′ ) m C(O)[NHCH(R 21 )C(O)] r OCH 3 (CR 12 R 12′ ) m C(O)[sugar] r , (CR 12 R 12′ ) m SC 1-6 alkyl, C(═N)NHC 1-6 alkyl; wherein each R 12  and R 12′  is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, OH, hydroxyC 1-6 alkyl, OC 1-6 alkyl, CO 2 H, CO 2 C 1-3 alkyl, NH 2 , NHC 1-3 allyl, N(C 1-3 alkyl) 2 , CN, NO 2 , aryl or heterocyclyl; R 21  is the characterising group of an amino acid, m is 0 or an integer from 1 to 20 and r is an integer from 1 to 5. 
     
     
         7 . A method according to  claim 1  wherein R 3  is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, —(CH 2 )NH 2 , —(CH 2 ) n NO 2 , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3  or —(CH 2 ) n —SH wherein n is as defined in  claim 1 . 
     
     
         8 . A method according to  claim 1  wherein R 4  is selected from the group consisting of hydrogen, methyl, ethyl, —CH 2 ═CH 2 , CH 2 CF 3 , fluoro, chloro or bromo. 
     
     
         9 . A method according to  claim 1  wherein at least one of R 5  and R 5′  in each (CR 5 R 5′ ) is hydrogen. 
     
     
         10 . A method according to  claim 1  wherein at least one of R 12  and R 12′  in each (CR 12 R 12′ ) is hydrogen. 
     
     
         11 . A method according to  claim 1  wherein at least one of R 16  and R 16′  in each (CR 16 R 16′ ) is hydrogen. 
     
     
         12 . A method according to  claim 1  wherein at least one of R 26  and R 26′  in each (CR 26 R 26′ ) is hydrogen. 
     
     
         13 . A method according to  claim 1  wherein
 X is selected from the group consisting of —O—, —S—, —C(R 5 ) 2 — or —N(R 6 )—; 
 Y is selected from the group consisting of —N(R 7 )—, —O—, —S—, or —C(R 7 ) 2 —; 
 Z is selected from the group consisting of —C(O)—, —C(S)—, —S(O)— or —C(═NR 6 ); 
 R 1  is selected from the group consisting of hydrogen, CH 3 , OH, SH, NH 2 , NHCH 3 , F, Cl or Br; 
 R 2  is selected from the group consisting of C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, (CR 12 R 12′ ) m C(O)R 5 , —(CR 12 R 12′ ) m C(S)R 8 , —(CR 12 R 12′ ) m S(O)R 8 , —(CR 12 R 12′ ) m S(O) 2 R 8 , —(CR 12 R 12′ ) m OR 9 , —(CR 12 R 12′ ) m SR 9 , —(CR 12 R 12′ ) m NR 10 R 11 , (CR 12 R 12′ ) m C(═NR 24 )R 22  or (CR 12 R 12′ ) m R 3  where m, R 7 , R 3 , R 9 , R 10 , R 11 , R 12 , R 12′ , R 13 , R 22  and R 24  are as defined in  claim 1 ; 
 R 3  is hydrogen, halogen, C 1-6 alkyl, —(CH 2 )NH 2 , —(CH 2 ) n NO 2 , —(CH 2 ) n —OH, —(CH 2 )CF 3  or —(CH 2 ) n SH where n is as defined in  claim 1 ; and 
 R 4  is hydrogen, halogen, methyl, ethyl, CH 2 CF 3  or —CH 2 ═CH 2 . 
 
     
     
         14 . A method according to  claim 1  wherein
 X is —N(R 6 )—; 
 Y is —N(R 7 )— or —C(R 7 ) 2 —; 
 Z is —C(O)—, —C(S)—, —S(O)— or —C(═NH); 
 R 1  is hydrogen, CH 3 , NH 2 , NIHCH 3 , F, Cl or Br; 
 R 2  is as defined in  claim 1 ; 
 R 3  is hydrogen, halogen, C 1-3 alkyl, (CH 2 )NH 2 , —(CH 2 ) n NO 2 , (CH 2 )OH or (CH 2 ) n CF 3  where n is defined in  claim 1 ; and 
 R 4  is hydrogen, halogen, methyl, ethyl, CH 2 CF 3  or —CH 2 ═CH 2 . 
 
     
     
         15 . A method according to  claim 1  wherein the compound of formula (I) is a benzimidazole compounds having the formula (II): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, CH 3 , NHCH 3 , F, Cl or Br; 
 R 2  is as defined in  claim 1 ; 
 R 3  is hydrogen, halogen, C 1 -C 3 alkyl, (CH 2 )NH 2 , —(CH 2 )NO 2 , (CH 2 ) n OH, CH 2 C(O)CH 3 , or (CH 2 ) n CF 3  where n is as defined in  claim 1 ; and 
 R 4  is hydrogen, F, Cl or Br, methyl, ethyl, CH 2 CF 3  or —CH 2 ═CH 2 . 
 
     
     
         16 . A method according to  claim 1  wherein the compound of formula (I) is a compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         X is —O—, —NH— or —CH 2 —; 
         Y is —NH—, —O—, —S— or —CH 2 —; 
         Z is —C(O)—, —C(S)— or —S(O)—; 
         R 101  is selected from hydrogen, C 1-3 alkyl, OH, SH, NH 2 , NHC 1-3 alkyl, F, Cl or Br; 
         R 102  is selected from C 1-20 alkyl, C 20 alkenyl, CO 2 H, CO 2 R 105 , —NH 2 , F, Cl, Br, (CH 2 ) w R 106 , C(O)N(R 107 ) 2 , C(═N)NHC 1-6 alkyl, SO 2 C 1-6 alkyl, C(O)[NHCH(R 108 )C(O)] q —OR 109 , C(O)sugar, CONH(CH 2 ) n aryl, NHC(O)(CH 2 ) n Sheterocyclyl, C(O)SC 1-6 alkyl, C(O)(CH 2 ) n CO 2 H, SO 2 OC 1-10 alkyl, and SO 2 NHC 1-10 alkyl; 
         R 103  is selected from hydrogen, F, Cl, Br, C 106 alkyl, —(CH 2 ) n NH 2 , —(CH 2 ) n NO 2 , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , —(CH 2 )C(O)C 1-3 alkyl or —(CH 2 ), —SH; 
         R 104  is selected from hydrogen, methyl, ethyl, CH 2 C(R 110 ) 3 , C(R 110 ) 3 , —CH 2 ═CH 2 , fluoro, chloro or bromo; 
         R 105  is selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl or (CH 2 ) t OC 1-3 alkyl; 
         R 106  is selected from SH, SC 1-6 alkyl, OH, OC 1-6 alkyl, sugar, CO 2 H, NH 2 , heterocyclyl or aryl; 
         Each R 107  is independently selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl, (CH 2 ) t aryl and (CH 2 ) t heterocyclyl; 
         R 108  is the characterising group of an amino acid; 
         R 109  is hydrogen, C 1-3 alkyl; 
         Each R 110  is independently selected from hydrogen and halo; and 
         n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6; t is an integer from 1 to 10; wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted. 
       
     
     
         17 . A method according to  claim 1  wherein the compound of formula I is a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein
 R 101  is selected from hydrogen, CH 3 , OH, SH, NH 2 , NHCH 3 , F, Cl or Br; 
 R 102  is selected from C 1-20 alkyl, C 2-20 alkenyl, CO 2 H, CO 2 R 105 , —NH 2 , F, Cl, Br, (CH 2 ) w R 106 , C(O)N(R 107 ) 2 , C(═N)NHC 1-6 alkyl, SO 2 C 1-6 alkyl, C(O)[NHCH(R 108 )C(O)] q —OR 109 , C(O)sugar, CONH(CH 2 ) n aryl, NHC(O)(CH 2 )Sheterocyclyl, C(O)SC 1-6 alkyl, C(O)(CH 2 ) n CO 2 H, SO 2 OC 1-10 alkyl, and SO 2 NHC 1-10 alkyl; 
 R 103  is selected from hydrogen, F, Cl, Br, C 1-6 alkyl, (CH 2 ) n NH 2 , —(CH 2 ) n NO 2 , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , CH 2 C(O)CH 3  or —(CH 2 ) n —SH; 
 R 104  is selected from hydrogen, methyl, ethyl, CH 2 CF 3 , —CH 2 ═CH 2  fluoro, chloro or bromo; 
 R 105  is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, (CH 2 ) t OC 1-3 alkyl; 
 R 106  is selected from SH, SC 1-6 alkyl, OH, OC 1-6 alkyl, sugar, CO 2 H, NH 2 , heterocyclyl or aryl; 
 Each R 107  is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, (CH 2 ) t aryl and (CH 2 ) t heterocyclyl; 
 R 108  is the characterising group of an amino acid; 
 R 109  is hydrogen, C 1-3 alkyl; 
 Each R 110  is independently selected from hydrogen and halo; and 
 n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6, t is an integer from 1 to 10; wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted. 
 
     
     
         18 . A method according to  claim 1  wherein the compound of formula I is selected from the group consisting of:
 benzimidazole-2-one-5-n-pentanoate, 
 5-[2-(1-oxy-2-hydroxyethyl)ethyl]benzimidazol-2-one-5-carboxylate, benzimidazole-2-one-5-methanoate, 
 benzimidazole-2-one-5-ethanoate, 
 3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl-benzimidazole-2-one-5-carboxylate, 
 5-bromo-6-methylbenzimidazol-2-one, 
 5-hydroxy-6-methylbenzimidazol-2-one, 
 5-dodecanylbenzoimidazol-2-one, 
 4,5,7-tribromo-6-methylbenzimidazol-2-one, 
 4,5,6,7-tetrabromobenzimidazol-2-one, 
 5-methyl-6-nitrobenzimidazol-2-one, 
 5-amino-6-methylbenzimidazol-2-one, 
 N-(6-methylbenzimidazol-5-yl)-2-pyrimidin-2-yl-sulfanyl-acetamide, pentyl-benzimidazol-2-one-5-carbothioate, 
 5-(benzimidazol-2(3H)-one-6-yl)-5-oxopentanoic acid, 
 2(3H)-benzimidazolone-5-sulfonic acid pentyl ester, 
 2(3H)-benzimidazolone-5-sulfonic acid pentyl amide, 
 N-butyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboximidamide, 
 5-heptanoylbenzofuran-2(3H)-one, 
 methyl 3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}propanoate, 
 3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}propanoic acid, 
 methyl 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoate, 
 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoic acid, and 
 N-(3,4-dihydroxyphenethyl)-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboxamide. 
 
     
     
         19 . A method of treating, preventing or diagnosing a disease or condition wherein MIF cytokine or biological activity is implicated comprising the administration of a treatment, prevention or diagnostic effective amount of a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof to a subject in need thereof. 
     
     
         20 . A method according to  claim 19  wherein the disease or condition is selected from autoimmune diseases, solid or haemopoitic tumours and chronic or acute inflammatory diseases. 
     
     
         21 . A method according to  claim 19  wherein the disease or condition is selected from the group consisting of Rheumatic diseases, spondyloarthropathies, crystal arthropathies, Lyme disease, connective tissue diseases, vasculitides, glomerulonephritis, interstitial nephritis, inflammatory bowel disease, peptic ulceration, gastritis, oesophagitis, liver disease, autoimmune diseases, pulmonary diseases, cancers whether primary or metastatic, atherosclerosis, disorders of the hypothalamic-pituitary-adrenal axis, brain disorders, corneal disease, iritis, iridocyclitis, cataracts, uveitis, sarcoidosis, diseases characterised by modified angiogenesis, endometrial function, psoriasis, endotoxic (septic) shock, exotoxic (septic) shock, infective (true septic) shock, other complications of infection, pelvic inflammatory disease, transplant rejection, allergies, allergic rhinitis, bone diseases, atopic dermatitis, UV(B)-induced dermal cell activation, malarial complications, diabetes mellitus, pain, inflammatory consequences of trauma or ischaemia, testicular dysfunctions and wound healing. 
     
     
         22 . A method according to  claim 21  wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis, Reiter's syndrome, gout, pseudogout, calcium pyrophosphate deposition disease, systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjögren's syndrome, polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, ulcerative colitis, Crohn's disease, cirrhosis, hepatitis, diabetes mellitus, thyroiditis, myasthenia gravis, sclerosing cholangitis, primary biliary cirrhosis, diffuse interstitial lung diseases, pneumoconioses, fibrosing alveolitis, asthma, bronchitis, bronchiectasis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, colon cancer, lymphoma, lung cancer, melanoma, prostate cancer, breast cancer, stomach cancer, leukemia, cervical cancer and metastatic cancer, ischaemic heart disease, myocardial infarction, stroke, peripheral vascular disease, Alzheimer's disease, multiple sclerosis, diabetic retinopathy, parturition, endometriosis, osteoporosis, Paget's disease, sunburn and skin cancer. 
     
     
         23 . A method of  claim 19  wherein the subject is a human subject. 
     
     
         24 . A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier, diluent or excipient 
     
     
         25 . A pharmaceutical composition according to  claim 24  further comprising a glucocorticoid. 
     
     
         26 . A method of treating or preventing a disease or condition wherein MIF cytokine or biological activity is implicated comprising:
 administering to a mammal a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof and a second therapeutic agent.   
     
     
         27 . A method according to  claim 26  wherein the second therapeutic agent is a glucocorticoid. 
     
     
         28 . A method of prophylaxis or treatment of a disease or condition for which treatment with a glucocorticoid is indicated, said method comprising:
 administering to a mammal a glucocorticoid and a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof.   
     
     
         29 . A method of treating a steroid-resistant disease or condition comprising:
 administering to a mammal a glucocorticoid and a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof.   
     
     
         30 . A method of enhancing the effect of a glucocorticoid in mammals comprising administering a compound of formula (I) as defined in  claim 1  or a pharmaceutically acceptable salt or prodrug thereof simultaneously, separately or sequentially with said glucocorticoid. 
     
     
         31 . A compound of formula (III) or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 X is —O—, —NH— or —CH 2 —; 
 Y is —NH—, —O—, —S— or —CH 2 —; 
 Z is —C(O)—, —C(S)— or —S(O)—; 
 R 101  is selected from hydrogen, C 1-3 alkyl, OH, SH, NH 2 , NHC 1-3 alkyl, F, Cl or Br; 
 R 102  is selected from C 1-20 alkyl, C 2-20 alkenyl, CO 2 H, F, Cl, Br, CO 2 R 105 , (CH 2 ) w R 106 , C(O)N(R 107 ) 2 , C(═N)NHC 1-6 alkyl, SO 2 C 1-6 alkyl, C(O)[NHCH(R 108 )C(O)] q —OR 109 , NH 2 , C(O)sugar, CONH(CH 2 ) n aryl, NHC(O)(CH 2 ) n Sheterocyclyl, C(O)SC 1-6 alkyl, C(O)(CH 2 ) n CO 2 H, SO 2 OC 1-10 alkyl and SO 2 NHC 1-10 alkyl; 
 R 103  is selected from hydrogen, F, Cl, Br, C 1-6 alkyl, —(CH 2 ) n NH 2 , —(CH 2 ) n NO 2 , —(CH 2 )—OH, —(CH 2 ) n —CF 3 , —(CH 2 ) n C(O)C 1-3 alkyl or —(CH 2 ) n —SH; 
 R 104  is selected from hydrogen, methyl, ethyl, CH 2 C(R 110 ) 3 , C(R 110 ) 3 , —CH 2 ═CH 2 , fluoro, chloro or bromo; 
 R 105  is selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl or (CH 2 ) t OC 1-3 alkyl; 
 R 106  is selected from SH, SC 1-6 alkyl, OH, OC 1  ialkyl, sugar, CO 2 H, NH 2 , heterocyclyl or aryl; 
 Each R 107  is independently selected from hydrogen, C 1-20 alkyl, C 2-20 alkenyl, (CH 2 ) t aryl and (CH 2 ) t heterocyclyl; 
 R 108  is the characterising group of an amino acid; 
 R 109  is hydrogen, C 1-3 alkyl; 
 Each R 110  is independently selected from hydrogen and halo; and 
 n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6; t is an integer from 1 to 10; wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted. 
 
     
     
         32 . A compound of formula (IV) or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 101  is selected from hydrogen, CH 3 , OH, SH, NH 2 , NHCH 3 , F, Cl or Br; 
 R 102  is selected from C 1-20 alkyl, C 2-20 alkenyl, CO 2 H, F, Cl, Br, CO 2 R 105 , (CH 2 ) w R 106 , C(O)N(R 107 ) 2 , C(═N)NHC 1-6 alkyl, SO 2 C 1-6 alkyl, C(O)[NHCH(R 108 )C(O)] q —OR 109 , NH 2 , C(O)sugar, CONH(CH 2 ) n aryl, NHC(O)(CH 2 ) n Sheterocyclyl, C(O)SC 1-6 alkyl, C(O)(CH 2 ) n CO 2 H, SO 2 OC 1-10 alkyl and SO 2 NHC 1-10 alkyl. 
 R 103  is selected from hydrogen, F, Cl, Br, C 1-6 alkyl, (CH 2 ) n NH 2 , —(CH 2 ) n NO 2 , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , CH 2 C(O)CH 3  or —(CH 2 ) n —SH; 
 R 104  is selected from hydrogen, methyl, ethyl, CH 2 CF 3 , —CH 2 ═CH 2  fluoro, chloro or bromo; 
 R 105  is selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, (CH 2 ) t OC 1-3 alkyl; 
 R 106  is selected from SH, SC 1-6 alkyl, OH, OC 1-6 alkyl, sugar, CO 2 H, NH 2 , heterocyclyl or aryl; 
 Each R 107  is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, (CH 2 ) t aryl and (CH 2 )theterocyclyl; 
 R 108  is the characterising group of an amino acid; 
 R 109  is hydrogen, C 1-3 alkyl; 
 Each R 110  is independently selected from hydrogen and halo; and 
 n is 0 or an integer from 1 to 3, q is an integer from 1 to 5, w is an integer from 1 to 6, t is an integer from 1 to 10; wherein each alkyl, alkenyl, alkynyl, aryl and heterocyclyl may be optionally substituted. 
 
     
     
         33 . A compound according to  claim 32  wherein R 101  is hydrogen, F, Cl or Br. 
     
     
         34 . A compound according to  claim 32  wherein R 102  is C 1-20 alkyl, halogen, NH 2 , CO 2 H, CO 2 C 1-10 alkyl, C(O)sugar, CO 2 (CH 2 ) n OC 1-6 alkyl, CONHC 1-10 alkyl, CONH(CH 2 ) n aryl, CO[NHCH(R 107 )CO]—OH, CO[NHCH(R 107 )CO]OC 1-3 alkyl, NHC(O)(CH 2 ) n Sheterocyclyl, C(O)SC 1-6 alkyl, C(O)(CH 2 ) n CO 2 H, SO 2 OC 1-10 alkyl, SO 2 NHC 1-10 alkyl or C(═NH)NHC 1-6 alkyl. 
     
     
         35 . A compound according to  claim 32  wherein R 103  is hydrogen, halogen, C 1-3 alkyl, (CH 2 ) n NH 2 , (CH 2 ) n NO 2 , (CH 2 )NH 2 , (CH 2 ) n OH or (CH 2 ) n CF 3 . 
     
     
         36 . A compound according to  claim 32  wherein R 104  is hydrogen, F, Cl or Br. 
     
     
         37 . A compound according to  claim 32  wherein R 107  is the characterising group from serine (CH 2 OH) or phenylalanine (CH 2 Ph). 
     
     
         38 . A compound of formula (I) selected from the group consisting of:
 benzimidazole-2-one-5-n-pentanoate,   5-[2-(1-oxy-2-hydroxyethyl)ethyl]benzimidazol-2-one-5-carboxylate,   benzimidazole-2-one-5-methanoate,   benzimidazole-2-one-5-ethanoate,   3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl-benzimidazole-2-one-5-carboxylate,   5-bromo-6-methylbenzimidazol-2-one,   5-hydroxy-6-methylbenzimidazol-2-one,   5-dodecanylbenzoimidazol-2-one,   4,5,7-tribromo-6-methylbenzimidazol-2-one,   4,5,6,7-tetrabromobenzimidazol-2-one,   5-methyl-6-nitrobenzimidazol-2-one,   5-amino-6-methylbenzimidazol-2-one,   N-(6-methylbenzimidazol-5-yl)-2-pyrimnidin-2-yl-sulfanyl-axetamide,   pentyl-benzimidazol-2-one-5-carbothioate,   5-(benzimidazol-2(3H)-one-6-yl)-5-oxopentanoic acid,   2(3H)-benzimidazolone-5-sulfonic acid pentyl ester,   2(3H)-benzimidazolone-5-sulfonic acid pentyl amide,   N-butyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboximidamide,   5-heptanoylbenzofuran-2(3H)-one,   methyl 3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimiidazol-5-yl)carbonyl]amino}propanoate,   3-hydroxy-2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}propanoic acid,   methyl 2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoate,   2-{[(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-5-yl)carbonyl]amino}-3-phenyl propanoic acid, and   N-(3,4-dihydroxyphenethyl)-2-oxo-2,3-dihydro-1H-1,3-benzimidazole-5-carboxamide.