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Novel inhibitors

A technology of solvates and compounds, applied in the field of halogenated oxazolidinone derivatives, can solve problems such as undisplayed sequence homology

Active Publication Date: 2016-01-20
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 structures of QCs from papaya with those of highly conserved QCs 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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] The invention also relates to racemates and R-stereoisomers of the compounds of the invention:

[0379]

[0380] General Synthesis Description:

[0381] Method A: Examples 1–3

[0382]

[0383] step 1:

[0384] A mixture of the corresponding fluorine-substituted 4-hydroxybenzonitrile (1 equiv), the corresponding 4-chloro-2-butanol (3 equiv) and potassium carbonate (2 equiv) in acetonitrile was refluxed for 20 h. The reaction was cooled to room temperature, then filtered. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude intermediate MA-S1.

[0385] Step 2:

[0386] 2-Iodosobenzoic acid (9 equiv) was added to a solution of MA-S1 (crude, 1 equiv) in dichloromethane and dimethyl sulfoxide and stirred at room temperature for 18 h. The reaction was filter...

Embodiment 21

[0460] Method M: Examples 21–22

[0461]

[0462] step 1:

[0463] (R)-3-Hydroxypyrrolidine (1.5 eq) was added to a stirred solution of the corresponding 4-fluorobenzonitrile (1 eq) and potassium carbonate (1 eq) in dimethylformamide, and the mixture was heated at 80 Stir overnight at °C. The reaction was filtered, washed with ethyl acetate and the filtrate was evaporated in vacuo. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude intermediate. Purify by column chromatography on neutral alumina to obtain MN-S1.

[0464] Step 2:

[0465] Class 1 :

[0466] Dess-martin periodinane (2 equiv) was added to a solution of MM-S1 (1 equiv), and the mixture was stirred for 15 h. The reaction was filtered through celite and washed with dichloromethane. The filtrate was washed with water, brine; dried over anhydrous sodium sulfate...

Embodiment 18

[0473] Method N: Examples 18–22

[0474]

[0475] step 1:

[0476] At -30°C, n-butyllithium in hexane (2.2M; 2 eq.) was added to a stirred solution of methyltriphenylphosphonium bromide (2 eq.) in THF, and the mixture was heated at 0-5 Stir for 30 min at °C. A solution of the corresponding intermediate ML-S5 or MM-S4 (1 equiv) in THF was added dropwise at -30°C. The temperature was allowed to warm to room temperature, and the mixture was stirred for 2 h. The reaction was quenched with acetic acid and the pH was adjusted to ~5. The solution was extracted with ethyl acetate. The combined organic layers were washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude intermediate. Purification by column chromatography on silica gel afforded MN-S1.

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Abstract

The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein R1, R2, R3, R4 and R5 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 halogenated oxazolidinone derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5) having 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] Glutamyl cyclase (QC, EC2.3.2.5) catalyzes the intramolecular cyclization of N-terminal glutamine residues to pyroglutamate (pGlu*), releasing ammonia. QC was first isolated from the latex of tropical plant papaya (Caricapapaya) by Messer in 1963 (Messer, M.1963Nature4874, 1299). After 24 years, a 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 ProcNatlAcadSciUSA84, 3628-3632). For mammalian ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61K31/437A61P25/00
CPCC07D413/04A61K31/422C07D413/14A61P1/04A61P1/14A61P1/18A61P15/00A61P15/08A61P17/06A61P19/02A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/26A61P25/28A61P29/00A61P3/00A61P35/00A61P35/04A61P37/02A61P39/02A61P43/00A61P5/00A61P7/00A61P9/10A61K31/4184A61K45/06
Inventor U·海泽M·布赫霍尔茨R·佐默H-U·德穆特A·迈耶
Owner 维沃永治疗公众有限公司
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