Inhibitors
Novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu*) under liberation of ammonia and the intramolecular cyclization of N-terminal glutamate residues into pyroglutamic acid under liberation of water.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers thereof wherein:
R 1 represents -aryl,
in which aforesaid aryl may optionally be substituted by one or more groups selected from nitro, halogen, cyano, and hydroxyl;
R 2 represents C 1-6 alkyl or C 1-6 haloalkyl; and
R 3 represents C 1-6 alkyl or C 1-6 haloalkyl.
2. A compound according to claim 1 , wherein R 1 represents phenyl optionally substituted by one or more groups selected from nitro, halogen, cyano, and hydroxyl.
3. A compound according to claim 1 , wherein R 1 represents phenyl optionally substituted by one or more halogen groups.
4. A compound according to claim 3 , wherein R 1 represents 2,3-difluorophenyl.
5. A compound according to claim 3 , wherein R 2 represents C 1-6 haloalkyl.
6. A compound according to claim 5 , wherein R 2 represents trifluoromethyl.
7. A compound according to claim 3 , wherein R 2 represents C 1-6 alkyl.
8. A compound according to claim 7 , wherein R 2 represents methyl, ethyl, propyl or isopropyl.
9. A compound according to claim 8 , wherein R 2 represents methyl.
10. A compound according to claim 3 , wherein R 3 represents C 1-6 haloalkyl.
11. A compound according to claim 10 , wherein R 3 represents 2,2,2-trifluoromethyl or 2,2,3,3-tetrafluoropropyl.
12. A compound according to claim 3 , wherein R 3 represents C 1-6 alkyl.
13. A compound according to claim 12 , wherein R 3 represents methyl or ethyl.
14. A compound or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers, selected from the group consisting of:
15. A compound according to claim 1 , which is 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 1 , which is (R)-1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 1 , which is (S)-1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according to claim 1 , optionally in combination with one or more therapeutically acceptable diluents or carriers.
19. The pharmaceutical composition according to claim 18 , wherein the compound is selected from the group consisting of:
20. The pharmaceutical composition of claim 18 , which comprises additionally 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.
21. The pharmaceutical composition of claim 18 , which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCI, 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), IR 208, NBI 5788/MSP 771 (tiplimotide), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.
22. A method of treatment of:
(i) a disease selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease; or
(ii) a disease selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis;
the method comprising administering to a subject an effective amount of a compound according to claim 1 , optionally in combination with one or more therapeutically acceptable diluents or carriers.
23. The method of treatment according to claim 22 , wherein the disease is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, Familial British Dementia, Familial Danish Dementia, neurodegeneration in Down Syndrome and Huntington's disease.
24. The method of treatment according to claim 22 , wherein the disease is selected from the group consisting of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.
25. A process for preparation of a compound of formula (I) according to claim 1 , which comprises:
(a) preparing a compound of formula (I) from a compound of formula (II)
wherein R 1 and R 2 are as defined in claim 1 ;
(b) interconversion of compounds of formula (I); and/or
(c) deprotecting a compound of formula (I) which is protected.