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Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)

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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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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)

Method used

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  • Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
  • Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)
  • Heterocyclic inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5)

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The invention relates to 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.

Description

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 plant Carica 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...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D403/10C07D405/10A61K31/4184A61K31/5377A61K31/454A61K31/4709C07D401/04C07D403/14A61P1/04A61P25/18A61P25/28A61P29/00A61P31/04A61P35/00
CPCC07D401/14C07D403/04C07D405/14C07D403/14A61P1/04A61P1/18A61P15/00A61P17/00A61P17/06A61P19/02A61P25/00A61P25/14A61P25/18A61P25/20A61P25/28A61P29/00A61P31/04A61P35/00A61P35/04A61P37/06A61P5/00A61P7/00A61P9/10A61K31/4025A61K31/4184C07B2200/13
Inventor U·海泽U-T·格特纳H-U·德穆特
Owner VIVORYON THERAPEUTICS NV
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