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Inhibitors of glutaminyl cyclase

The technology of a compound, azetidine, is applied in the field of azetidinone derivatives, which can solve problems such as undisclosed sequence homology

Active Publication Date: 2021-08-03
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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  • Inhibitors of glutaminyl cyclase
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  • Inhibitors of glutaminyl cyclase

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0425] Compounds were synthesized according to method 1:

[0426] rac1-(1H-benzimidazol-5-yl)-4-phenylazetidin-2-one:

[0427] Step A: 5-aminobenzimidazole (1.33g, 10mmol), benzaldehyde (1.27g, 1.22mL, 12mmol) in 80mL of toluene gave 1.62g of crude product I;

[0428] Step B: I (0.433g, 2mmol), zinc powder (0.262g, 4mmol), TMS-Cl (0.180mL, 1.4mmol), ethyl bromoacetate (0.377mL, 3.4mmol). 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), HPLC99%.

Embodiment 2 and 3

[0430] (R)-1-(1H-Benzo[d]imidazol-6-yl)-4-phenylazetidin-2-one 2

[0431]Example 1 (0.089 g) was subjected to chiral preparative HPLC separation to obtain compound 2. Yield: 0.025g, 1 H-NMR (DMSO-d6): δ12.25 (d, 1H); 8.13 (d, 1H); 7.53 (d, 1H); 7.46-7.30 (m, 6H); 7.12 (d, 1H); t, 1H); 3.63-3.57 (m, 1H); 2.92-2.86 (m, 1H); MS=264 (M+1); HPLC ~ 96.31%: Chiral HPLC ~ 92.48%

[0432] (S)-1-(1H-Benzo[d]imidazol-6-yl)-4-phenylazetidin-2-one 3

[0433] Example 1 (0.089 g) was subjected to chiral preparative HPLC to obtain compound 3. Yield: 0.025g, 1 H-NMR (DMSO-d6): δ12.25 (d, 1H); 8.13 (s, 1H); 7.46-7.30 (m, 7H); 7.12 (bs, 1H); 3.57(m, 1H); 2.90-2.86(m, 1H); MS=264(M+1); HPLC~99.00%: Chiral HPLC~98.35%.

Embodiment 4

[0435] Rac 1-(1H-benzo[d]imidazol-5-yl)-4-(2,6-difluoro-4-methoxyphenyl)azetidin-2-one 4

[0436] Step A: 5-aminobenzimidazole (0.690g, 5.2mmol), 2,5-difluoro-4methoxy-benzaldehyde (1.07g, 6.2mmol) in 80mL of toluene gave 1.66g of crude product I;

[0437] Step B: I (1.15 g, 4 mmol), zinc powder (0.524 g, 8.31 mmol), TMS-Cl (0.360 mL, 2.8 mmol), ethyl bromoacetate (0.754 mL, 6.8 mmol). Yield: 0.022g (1.2%); MS m / z 330.4 (M+H) + ; 1 H NMR (DMSO-d 6 , 400MHz): δ3.25-3.29(m, 1H), 3.63-3.67(m, 1H), 3.76(s, 3H), 5.49-5.51 8m, 1H), 6.80(d, 2H, 3J=11.2Hz) , 7.34 (dd, 1H, 3J = 8.8Hz, 4J = 2Hz), 7.50 (d, 1H, 4J = 2Hz), 7.74 (d, 1H, 3J = 8.8Hz), 9.10 (s, 1H), HPLC [A ]: 100%)

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Abstract

The present invention relates to a compound of formula (I), or its pharmaceutically acceptable salt, solvate or polymorph, including all tautomers and stereoisomers thereof, wherein: A is selected from 1H- Benzimidazolyl and heteroaryl of imidazo[1,2-a]pyridine, and R 1 , R 2 , R 3 , R 4 and R 5 As defined herein, it acts as an inhibitor 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 to pyroglutamic acid (5-oxo-prolyl, pGlu*) with the release of ammonia, and the release of N-terminal glutamic acid residues In the case of water, the intramolecular cyclization becomes pyroglutamic acid.

Description

technical field [0001] The present invention relates to novel azetidinone derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) with improved pharmacokinetic properties. 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, a corresponding enzymatic activity was found in animal pituitary glands (Busby, W.H.J. et al. 1987 J Biol Chem 262, 8532-8536; Fischer, W.H. and Spiess, J. 1987 Proc NatlAcad Sci USA 84, 3628-3632). For mammalian QC, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07D471/04A61K31/4184A61P25/28
CPCC07D403/04C07D471/04A61K31/4184A61P25/28A61K45/06A61K31/437A61P25/00A61P25/16A61P25/24A61P25/22
Inventor U·海泽R·佐默
Owner VIVORYON THERAPEUTICS NV