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Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
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A technology of heterocyclic groups and compounds, applied in the field of new heterocyclic derivatives, can solve problems such as undisclosed sequence homology
Active Publication Date: 2012-11-21
VIVORYON THERAPEUTICS NV
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However, comparison of the primary structure of the QC from papaya with that of the highly conserved QC from mammals did not reveal any sequence homology (Dahl, S.W. et al. 2000 Protein Expr Purif 20, 27-36)
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Embodiment 1
[0369] Example 1: 1-(1H-benzo[d]imidazol-6-yl)-5-cyclohexyl-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one
[0370] From KOH (15eq in water), N-methyl-N-nitroso-p-toluenesulfonamide (8eq), ethylene glycol / Et 2 O(1 / 2v / v, 30ml), 1-(1H-benzo[d]imidazol-6-yl)-5-cyclohexyl-3-hydroxy-4-methyl-1H-pyrrole-2(5H) - Ketone (1.00g, 3.22mmol, 1eq) and MeOH (10ml) started to synthesize the compound; Yield: 0.250g (25%); MS m / z: 326.1[M+H] + ; 1 H-NMR: (400MHz, DMSO-D 6 )δ:1.05(d,3H),1.40(d,2H),1.65-1.60(m,4H),2.05(s,3H),4.03(s,3H),4.40(s,1H),7.05(s ,1H),7.62(s,1H),7.63(s,1H),7.82(s,1H);HPLC (method [A]):rt 11.25min(98.78%)
Embodiment 2
[0371] Example 2: 1-(1H-benzo[d]imidazol-6-yl)-5-isopropyl-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one
[0372] From KOH (15eq in water), N-methyl-N-nitroso-p-toluenesulfonamide (8eq), ethylene glycol / Et 2 O(1 / 2v / v, 30ml), 1-(1H-benzo[d]imidazol-6-yl)-5-isopropyl-3-hydroxy-4-methyl-1H-pyrrole-2(5H )-ketone (0.500g, 1.83mmol, 1eq) and MeOH (10ml) started to synthesize the compound; Yield: 0.040g (7.6%); MS m / z: 286.1[M+H] + ;1H-NMR: (400MHz, DMSO-D 6 )δ:0.54(d,3H),0.94-0.92(q,3H),1.95(t,3H),3.86(s,1H),4.73(s,1H),7.26-7.15(m,1H),7.65 -7.51(m,2H),8.22(d,1H),12.46(d,1H);HPLC(method [A]):rt 8.32min(96.64%)
Embodiment 3
[0373] Example 3: 1-(1H-benzo[d]imidazol-5-yl)-5-(2,6-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrole-2 (5H)-Kone
[0374] From KOH (15eq in water), N-methyl-N-nitroso-p-toluenesulfonamide (5eq), ethylene glycol / Et 2 O(3 / 1v / v), 1-(1H-benzo[d]imidazol-6-yl)-5-(2,6-difluorophenyl)-3-hydroxy-4-methyl-1H- Pyrrol-2(5H)-one (0.189g, 0.5mmol, 1eq) and MeOH / H 2 O(90 / 10v / v) started to synthesize the compound; Yield: 0.058g(32.6%); MS m / z:356.3[M+H] + ; 1 H-NMR: (400MHz, DMSO-D 6 )δ:1.65-1.81(s,3H),3.83-3.93(s,3H),6.14(s,1H),6.83-7.78(m,6H),8.15(s,1H),12.07-12.07(bs, 1H); HPLC (method [A]): rt 11.24min (99%)
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technical field [0001] The present invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of the N-terminal glutamine residue to pyroglutamate (5-oxo-prolyl, pGlu) with the release of ammonia * ), and the intramolecular cyclization of the N-terminal glutamate residue to pyroglutamate upon release of water. Background technique [0002] Glutamyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (pGlu * ), releasing ammonia. QC was first isolated from the latex of the tropical plantCarica papaya by Messer in 1963 (Messer, M.1963 Nature 4874, 1299). After 24 years, corresponding enzymatic activity was found in animal pituitary (Busby, W.H. J.et al.1987 J Biol Chem 262,8532-8536; Fischer, W.H.and Spiess, J.1987 Proc Natl Acad Sci U S A 84,3628-3632 ). For mammalian QC, the conversion of Gln to pGlu by QC can be...
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