Inhibitors of glutaminyl cyclase
View Patent ↗The invention relates to a compound of formula (I): Formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein A is heteraryl selected from 1H-benzimidazolyl and imidazo[1,2-a]pyridine, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL). QC and QPCTL catalyze 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, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein:
A is heteroaryl selected from the group consisting of:
R 1 represents hydrogen, alkyl or halogen;
R 2 represents hydrogen, alkyl or halogen;
R 3 represents hydrogen, alkyl or alkoxy;
R 4 represents hydrogen or alkyl; and
R 5 represents hydrogen, alkyl or halogen;
and
wherein the above alkyl or alkoxy groups are optionally substituted by one or more halogen.
2. The compound of formula (I) according to claim 1 , wherein
R 1 represents hydrogen or halogen;
R 2 represents hydrogen or halogen;
R 3 represents hydrogen or alkoxy;
R 4 represents hydrogen; and
R 5 represents hydrogen or halogen;
and
wherein the above alkoxy group is optionally substituted by one or more halogen.
3. The compound of formula (I) according to claim 1 wherein A is:
4. The compound of formula (I) according to claim 1 , wherein R 1 is hydrogen.
5. The compound of formula (I) according to claim 1 , wherein R 1 is halogen.
6. The compound of formula (I) according to claim 1 , wherein R 2 is hydrogen.
7. The compound of formula (I) according to claim 1 , wherein R 2 is halogen.
8. The compound of formula (I) according to claim 1 , wherein R 3 represents —O—C 1-4 alkyl, optionally substituted by one or more halogen.
9. The compound of formula (I) according to claim 1 , wherein R 3 is a member of the group consisting of methoxy, difluoropropoxy and difluorobutoxy.
10. The compound of formula (I) according to claim 1 , wherein R 3 is a member of the group consisting of 2,2-difluoropropoxy and 3,3-difluoropropoxy.
11. The compound of formula (I) according to claim 1 , wherein R 5 is hydrogen.
12. The compound of formula (I) according to claim 1 , wherein R 5 is halogen.
13. The compound of formula (I) according to claim 1 selected from the group consisting of
1 1-(1H-benzo[d]imidazol-5-yl)-4-phenylazetidin-2-one;
2 (R)-1-(1H-benzo[d]imidazol -6-yl)-4-phenylazetidin-2-one;
3 (S)-1-(1H-benzo[d]imidazol-6-yl)-4-phenylazetidin-2-one;
4 1-(1H-benzo[d]imdazol-5-yl)-4-(2,6-difluoro-4-methoxyphenyl)azetidine-2-one;
5 (R)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
6 (S)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
7 (R)-4-(4-(3,3-difluoropropoxy)-2,3-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
8 (S)-4-4-(3,3-difluoropropoxy)-2,3-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
9 (R)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
10 (S)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
11 (R)-4-(4-(2,2-difluoropropoxy)-2-fluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
12 (S)-4-(4-(2,2-difluoropropoxy)-2-fluorophenyl)-1-(1H-benzo[d]imidazol-5-yl) azetidin-2-one;
13 (R)-4-(4-(2,2-difluoropropoxy)-2,3-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
14 (S)-4-(4-(2,2-difluoropropoxy)-2,3-difluorophenyl)-1-(1H-benzo[d]imidazol-5-yl)azetidin-2-one;
15 (R)-4-(4-(2,2-difluoropropoxy)-2,6-difluorophenyl)-1-1H-benzo[d]imidazol-5-yl)azetidin-2-one;
16 (S)-4-(4-(2,2-difluoropropoxy)-2,6- difluorophenyl)-1-1H-benzo[d]imidazol-5-yl)azetidin-2-one;
17 (R)-1-(4H-imidazol[1,2-a]pyridin-7-yl)-4-phenylazetidin-2-one;
18(S)-1-(4H-imidazol[1,2-a]pyridin-7-yl)-4-phenylazetidin-2-one;
19 4-(2,6-difluoro-4-methoxyphenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
20 (R)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
21 (S)-4-(4-(3,3-difluoropropoxy)-2-fluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
22 (R)-4-(4-(3,3-difluoropropoxy)-2,3-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
23 (S)-4-(4-(3,3-difluoropropoxy)-2,3-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
24 (R)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
25 (S)-4-(4-(3,3-difluoropropoxy)-2,6-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
26 (R)-4-(4-(2,2-difluoropropoxy)-2-fluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
27 (S)-4-(4-(2,2-difluoropropoxy)-2-fluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
28 (R-4-(4-(2,2-difluoropropoxy)-2,3-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one;
29 (S-4-(4-(2,2-difluoropropoxy)-2,3-difluorophenyl)-1-(4H-imidazol[1,2-a]pyridin-7-yl)azetidin-2-one; and
a pharmaceutically acceptable salt, solvate, polymorph, tantomer and stereoisomer thereof.
14. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more therapeutically acceptable diluents or carriers.
15. The pharmaceutical composition of claim 14 , which comprises additionally 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 antimultiple sclerosis drugs.
16. The pharmaceutical composition of claim 15 , which comprises additionally at least one compound, selected from the group consisting of PEP-inhibitors, LiCl, inhibitors of inhibitors of DP IV or DI IV-like enzymes, acetylcholinesterase (ACE) inhibitors, MIT 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 27, adapalene), BAY 351677 (interleukin-4), matrix-metalloproteinase-inhibitors, interferon-tau (trophoblastin) and SAIK-MS.
17. A process for the preparation of a compound of claim 1 , which comprises:
(a) reacting a compound of formula (II)
wherein R 1 and R 5 and are as defined in claim 1 for compounds of formula (I), by reacting a compound of formula (II) with bromoacetic acid in the presence of zinc-dust, and a protecting agent; or
(b) reacting a compound of formula (III):
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 for compounds of formula (I), with diethylazodicarboxylate in the presence of triphenylhosphine, and a solvent; and thereafter removing the BOC group.