Heterocylcic derivatives as inhibitors of glutaminyl cyclase

A compound, heterocyclic group technology, applied in the field of new pyrrolidine derivatives, can solve problems such as undisplayed sequence homology

Active Publication Date: 2012-09-26
维沃永治疗公众有限公司
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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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  • Heterocylcic derivatives as inhibitors of glutaminyl cyclase
  • Heterocylcic derivatives as inhibitors of glutaminyl cyclase
  • Heterocylcic derivatives as inhibitors of glutaminyl cyclase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0730] Example 1: 5-tert-butyl-1-(1H-benzo[d]imidazol-5-yl) imidazolidin-2-one

[0731] The compound in the hydrochloride salt form was synthesized by the following method.

[0732] Dissolve phenyl chloroformate (0.98 mL, 7.8 mmol) in CH 2 Cl 2 , cooled to 0°C and slowly added 5-aminobenzimidazole (0.865g, 6.5mmol). The mixture was maintained at 0°C for 30 min, then the mixture was allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulting solid was aspirated, dried and added to a small amount of DMF. 1-Amino-3,3-dimethylbutan-2-one (0.986, 6.5 mmol) and TEA (2.73 mL, 19.5 mmol) were added to the solution. The mixture was kept at 40 °C for 2 h. Solvent was removed and purified by preparative HPLC. The residue was redissolved in MeOH and a small amount of HCl (1-2%) was added. The solution was hydrogenated (PdC, 10% on charcoal, 4 bar, 60° C.) for 4 h. pass The catalyst was removed by pad filtration, and the residue ...

Embodiment 2

[0734] Example 2: 1-(1H-benzo[d]imidazol-5-yl)-5-cyclohexylimidazolidin-2-one

[0735] From 5-aminobenzimidazole (0.59g, 4.4mmol), cyclohexanecarbaldehyde (0.45g, 0.485mL, 4mmol), TMSCN (0.5mL, 4mmol), PdC (10%, 0.05g ), bis-(imidazol-1-yl)methanone (0.64 g, 3.92 mmol) to start the synthesis of this compound as the trifluoroacetate salt. The product was purified by preparative HPLC using a water-acetonitrile gradient containing 0.04% trifluoroacetic acid.

[0736] Yield: 0.089g (5.6%); MS m / z 285.1 (M+H) + ; 1 H NMR(DMSO,400MHz):δ0.82-0.91(m,H);0.97-1.16(m,4H);1.39-1.42(m,H);1.52-1.69(m,5H);3.24-3.27( m,H);3.42-3.46(m,H);4.48-4.52(m,H);6.92(s,H);7.56-7.59(dd,H, 3 J=9.1Hz, 4 J=2.1Hz);7.73-7.75(d,H, 3 J=9.1Hz);7.94-7.95(d,H, 4 J=2.1Hz);9.24(s,H),HPLC(λ=214nm,[B]:rt 8.64min(99%).

Embodiment 3

[0737] Example 3: 1-(1H-benzo[d]imidazol-5-yl)-5-phenylimidazolidin-2-one

[0738] As described in method 2, from 5-aminobenzimidazole (1.46g, 10mmol), benzaldehyde (1.06g, 10mmol), TMSCN (1.25mL, 10mmol), PdC (10%, 0.05g), bis-(imidazole -1-yl)methanone (1.73, 12 mmol) was used to start the synthesis of this compound.

[0739] Yield: 0.303g (10.9%); MS m / z 279.3 (M+H) + ; 1 H NMR(DMSO,400MHz):δ3.08-3.11(m,H);3.85-3.89(m,H);5.54-5.58(m,H);7.19-7.33(m,6H);7.51-7.54( m,H);7.60(d,H,J=8.7Hz);7.84(d,H,4J=1.7Hz);9.15(s,H),HPLC(λ=214nm,[B]:rt 7.36min( 96%).

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Abstract

The invention relates to novel pyrrolidine derivatives of formula (I), wherein R1, R2 and R3 are as defined herein, 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 pyrrolidine derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamic acid (5-oxo-prolyl, pGlu*) upon release of ammonia, and the N-terminal glutamic acid residues upon release of water. Intramolecular cyclization to pyroglutamic acid. Background technique [0002] Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamate (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 US A 84,3628-3632 ). For mammalian QC, the conversion of Gln to pGlu by QC can be confirme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/00A61P25/28C07D403/14C07D405/14C07D413/04C07D413/14C07D417/14C07D471/04A61K31/437A61K31/4184
CPCC07D235/06C07D471/04C07D417/14C07D413/04C07D413/14C07D403/04C07D405/14C07D403/14A61K31/4184A61K31/422A61K31/427A61K31/437A61K31/454A61K31/496A61K31/5355A61K31/5377A61K45/06C07D401/14C07D417/04A61P1/18A61P15/08A61P17/06A61P19/02A61P25/00A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00A61P3/00A61P3/04A61P35/00A61P35/04A61P37/00A61P37/02A61P37/06A61P43/00A61P5/00A61P7/00A61P9/00A61P9/10
Inventor U·海泽R·佐默D·拉姆斯贝克A·迈耶T·赫夫曼L·伯厄勒H-U·德穆特
Owner 维沃永治疗公众有限公司
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