Inhibitors of glutaminyl cyclase

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein:

R 1 represents

 or

imidazolyl-C 1-4 alkyl wherein the imidazole ring is optionally substituted by methyl;

R 2 represents (i) phenyl which is optionally substituted by one or more groups selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, halogen, and hydroxyl; or (ii) phenyl substituted by phenyl;

R 3 represents H;

R 4 represents H or —C 1-4 alkyl;

X represents O or S; and

Y represents O or S.

2. A compound according to claim 1 , wherein R 1 represents:

3. A compound according to claim 1 , wherein R 1 represents:

wherein A represents

an unbranched or branched C 1-4 alkylene chain or

a branched C 1-4 alkylene chain; and

R 11 , R 12 and R 13 independently represent H or methyl.

4. A compound according to claim 1 represented by the formula:

wherein R 2 , R 3 , R 4 , X and Y are as defined in claim 1 .

5. A compound according to claim 1 , wherein R 2 is -biphenyl-4-yl.

6. A compound according to claim 1 , wherein R 2 represents phenyl optionally substituted by one, two, or three substituents, which may be the same or different and are chosen from halogen, OH, C 1-3 alkyl, C 1-3 haloalkyl, and C 1-3 alkoxy.

7. A compound according to claim 6 , wherein R 2 is phenyl substituted by n-propyloxy.

8. A compound according to claim 1 , wherein R 4 represents H.

9. A compound according to claim 1 , wherein X represents O.

10. A compound according to claim 1 , wherein Y represents O.

11. A compound according claim to 1 , wherein the compound of formula (I) is represented by

wherein R 2 and R 3 are as defined in claim 1 .

12. A compound according to claim 1 selected from the group consisting of:

1-(1H-benzo[d]imidazol-5-yl)-5-phenylimidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(2-hydroxy-5-methylphenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(2-fluoro-5-trifluoromethylphenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(2-bromo-5-fluorophenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(4-chloro-3-trifluoromethylphenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(3-fluoro-4(trifluoromethyl)phenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(3-hydroxy-4-methoxyphenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(2-hydroxy-3-methoxyphenyl)imidazolidine-2,4-dione;

1-(1H-benzimidazol-5-yl)-5-(1,1′-biphenyl-4-yl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(3-chlorophenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(4-chlorophenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(2-chlorophenyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-(4-fluorophenyl)imidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-phenylimidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-(2-bromo-4-fluorophenyl)imidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-(4-propoxyphenyl)imidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-(3-fluoro-4-(trifluoromethyl)phenyl) imidazolidine-2,4-dione;

1-[3-(1H-imidazol-1-yl)propyl]-5(4-biphenyl)imidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-(3-chlorophenyl)imidazolidine-2,4-dione;

1-(3-(1H-imidazol-1-yl)propyl)-5-(2-chlorophenyl)imidazolidine-2,4-dione;

1-(3-(5-methyl-1H-imidazol-1-yl)propyl)-5-phenylimidazolidine-2,4-dione;

5(2-bromo-5-fluorophenyl)-143(5-methyl-1H-imidazol-1-yl)propyl)imidazolidine-2,4-dione;

1-(3-(5-methyl-1H-imidazol-1-yl)propyl)-5-(4-propoxyphenyl)imidazolidine-2,4-dione;

1-[3-(5-methyl-1H-imidazol-1-yl)propyl]-5-(4-phenylphenyl)imidazolidine-2,4-dione;

5(3-chlorophenyl)-1-(3-(5-methyl-1H-imidazol-1-yl)propyl)imidazolidine-2,4-dione;

1-(3-(4-methyl-1H-imidazol-1-yl)propyl)-5-phenylimidazolidine-2,4-dione;

1-[3-(4-methyl-1H-imidazol-1-yl)propyl]-5(4-biphenyl)imidazolidine-2,4-dione;

5(3-chlorophenyl)-1-(3-(4-methyl-1H-imidazol-1-yl)propyl)imidazolidine-2,4-dione;

1-(1H-benzo[d]imidazol-5-yl)-5-phenyl-2-thioxoimidazolidin-4-one;

1-(1H-benzimidazol-5-yl)-5-(1,1′-biphenyl-4-yl)-2-thioxoimidazolidin-4-one;

1-(1H-benzo[d]imidazol-5-yl)-5-(3-hydroxy-4-methoxyphenyl)-2-thioxoimidazolidin-4-one;

1-(1H-benzo[d]imidazol-5-yl)-5-phenyl-4-thioxoimidazolidin-2-one;

1-(1H-benzimidazol-5-yl)-5-(1,1′-biphenyl-4-yl)-4-thioxoimidazolidin-2-one;

1-(1H-benzo[d]imidazol-5-yl)-5-(2,3,4-trifluorophenyl)-4-thioxoimidazolidin-2-one;

1-(1H-benzo[d]imidazol-6-yl)-5-(4-bromo-2-fluorophenyl)-4-thioxoimidazolidin-2-one;

1-(1H-benzo[d]imidazol-5-yl)-5-(2,3-difluoro-4-methylphenyl)-4-thioxoimidazolidin-2-one;

1-(1H-benzo[d]imidazol-5-yl)-5-(4-chloro-3-methylphenyl)-4-thioxoimidazolidin-2-one; and

1-(H-imidazo[1,2-a]pyridin-7-yl)-5-phenylimidazolidine-2,4-dione; or

a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

13. A compound according to claim 1 which is 1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidine-2,4-dione, having a structure of:

14. A process for the preparation of a compound of claim 1 comprising one of:

a) reacting a compound of formula (II) by converting an imine to a carbonyl under aqueous conditions to give a compound of formula (I) wherein X is O and R 4 is H; R 1 , R 2 , R 3 and Y are as defined in claim 1 ; and R represents alkyl

b) reacting a compound of formula (II) with a source of sulfide ions to give a compound of formula (I) wherein X is S and R 4 is H; or

c) reacting a compound of formula (VIII), wherein R 1 and R 4 are as defined in claim 1 ;

with a compound of formula (IX), wherein R 2 is as defined in claim 1 ;

to give a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 and Y are as defined in claim 1 ; and X represents O; or

d) reacting a compound of formula (XIII), wherein R 1 , R 2 and R 3 are as defined in claim 1 ;

with a compound of formula (XIV), wherein (i) J and K both represent H; (ii) J and K both represent a leaving group; or (iii) J represents alkoxy and K represents a halogen;

to give a compound of formula (I) wherein R 1 , R 2 R 3 , R 4 and Y are as defined above and X represents O.

15. A pharmaceutical composition comprising:

a compound according to claim 1 ; and

one or more pharmaceutically acceptable diluents or carriers.

16. A pharmaceutical composition according to claim 15 further comprising at least one compound selected from the group consisting of neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

17. A pharmaceutical composition according to claim 15 further comprising at least one compound selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DP IV-like enzymes, acetylcholinesterase (ACE) inhibitors, PIMT enhancers, inhibitors of beta secretases, inhibitors of gamma secretases, inhibitors of neutral endopeptidase, inhibitors of Phosphodiesterase-4 (PDE-4), TNFalpha inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulatory agents, immunosuppressive agents or an agent selected from the group consisting of antegren (natalizumab), Neurelan (fampridine-SR), campath (alemtuzumab), NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636 (mesopram), Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.