Therapeutic molecules and methods-1

1. A method of inhibiting activity of MIF comprising contacting MIF with an MIF activity-inhibiting effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof

wherein

X is —N(R 6 )—;

Y is —N(R 7 )—;

Z is —C(O)—;

R 1 is selected from hydrogen, or (CR 5 R 5′ ) n halo;

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 8 , (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′ ) n 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 halo, and (CR 16 R 16′ ) p NO 2

R 4 is hydrogen, or halogen;

Each R 5 and R 5 is independently hydrogen,

R 6 is hydrogen, or C 1 -C 3 alkyl;

R 7 is hydrogen or C 1 -C 3 alkyl;

R 8 is selected from the group consisting of 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 , pyranosyl and (CR 12 R 12′ ) t R 13 ;

R 9 is hydrogen;

R 10 and R 11 are independently selected from hydrogen, and C(O)R 23 ;

Each R 12 and R 12′ is independently hydrogen;

R 13 is selected from OR 25 , SR 25 , halo, N(R 25 ) 2 , and C(O)R 31 ;

R 14 and R 15 are each hydrogen;

Each R 16 and R 16′ is hydrogen;

R 17 is hydrogen;

R 19 and each R 20 are independently selected from hydrogen, C 1 -C 20 alkyl, and, (CR 26 R 26′ ) t R 27 ;

R 21 is the characterising group of an amino acid wherein the amino acid is alanine, phenylalanine, serine, homoserine or norvaline;

R 22 is NH(C 1-6 alkyl);

R 23 is (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, and C 1 -C 6 alkyl;

Each R 26 and R 26′ is independently hydrogen;

R 27 selected from, OR 30 , SR 30 , and aryl;

Each R 29 is independently selected from hydrogen and C 1 -C 3 alkyl;

Each R 30 is independently selected from, C 1 -C 3 alkyl, and heterocyclyl;

R 31 is 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 —N(H)—, Y is —N(H)—, and Z is —C(O)—.

3. A method according to claim 1 wherein the compound of formula 1 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.

4. A method of treating rheumatoid arthritis wherein MIF activity is implicated comprising the administration of a treatment effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof to a subject in need thereof.

5. A method of claim 4 wherein the subject is a human subject.

6. A method of treating rheumatoid arthritis wherein MIF activity is implicated comprising: administering to a mammal a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a second therapeutic agent.

7. A method according to claim 6 wherein the second therapeutic agent is a glucocorticoid.

8. A method of treatment of rheumatoid arthritis 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 thereof.

9. A method of treating a steroid-resistant rheumatoid arthritis comprising: administering to a mammal a glucocorticoid and a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

10. A method according to claim 1 wherein

R 1 is hydrogen or (CR 5 R 5′ ) n halo;

R 2 is selected from C 1-20 alkyl, (CR 12 R 12′ ) m C(O)R 8 , (CR 12 R 12′ ) m S(O) 2 R 8 , (CR 12 R 12′ ) n 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 1-6 alkyl, (CR 16 R 16′ ) p NR 14 R 15 , (CR 16 R 16′ ) p OR 17 , (CR 16 R 16′ ) p halo and (CR 16 R 16′ ) p NO 2 ;

R 4 is hydrogen or halogen;

Each R 5 and R 5′ is independently hydrogen;

R 8 is selected from C 1 -C 20 alkyl, OR 19 , SR 19 , N(R 20 ) 2 , [NH—CH(R 21 )—C(O)] q —OR 29 , pyranosyl and (CR 12 R 12′ )R 13 ;

R 9 is hydrogen;

R 10 and R 11 are independently selected from hydrogen and C(O)R 23 ;

Each R 12 and R 12′ is independently hydrogen;

R 13 is selected from OR 25 , SR 25 , halo, N(R 25 ) 2 and C(O)R 31 ;

R 14 and R 15 are each hydrogen;

Each R 16 and R 16′ is hydrogen;

R 17 is hydrogen;

R 19 and each R 20 are independently selected from hydrogen, C 1 -C 20 alkyl, and (CR 26 R 26′ ) t R 27 ;

R 21 is the characterising group of phenylalanine or serine;

R 22 is NH(C 1-6 alkyl);

R 23 is (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 and C 1 -C 6 alkyl;

Each R 26 and R 26′ is independently hydrogen;

R 27 is selected from OR 30 , SR 30 and aryl;

Each R 29 is independently selected from C 1 -C 3 alkyl and heterocyclyl; and

R 31 is heterocyclyloxy.

11. A method according to claim 10 wherein

n is 0;

m is 0;

p is 0;

q is 0; and

t is 1 or 2.

12. A method according to claim 1 wherein the compound of formula (I) is benzimidazole-2-one-5-n-pentanoate.