Mixed inhibitors of aminopeptidase n and of neprilysine

A compound and cyclic compound technology, applied in the field of mixed inhibitors of aminopeptidase N and enkephalinase

Active Publication Date: 2015-07-22
智腾大中华区有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, none of the combination inhibitors disclosed to date have low doses that can be used for extended infusions in clinically suitable vehicles following intravenous administration in acutely painful situations (postoperative, cancer, trauma, dental, etc.) Obtain a rapid, intense analgesic response with a sufficiently long duration of action

Method used

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  • Mixed inhibitors of aminopeptidase n and of neprilysine
  • Mixed inhibitors of aminopeptidase n and of neprilysine
  • Mixed inhibitors of aminopeptidase n and of neprilysine

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Embodiment

[0245] The invention is further elucidated below, but it is not limited in any way to the following examples.

[0246] 1. Synthesis of NEP–APN Mixed Inhibitors

[0247] 1.1 Synthesis of NEP inhibitors

[0248] 1.1.1 step 1 : Synthesis of (R)–2–Bromocarboxylic Acid

[0249]

[0250] The (R)-configuration amino acid (39.3 mmol) was dissolved in 50 mL of water. At 0°C, KBr (3.5eq, 31.8g) and then H 2 SO 4 (7.73 mL), while maintaining the temperature below 5°C. The mixture was cooled to -10 °C and NaNO dissolved in 17 mL of water was added dropwise 2 (1.3eq, 3.59g). The mixture was stirred at -5°C for 2 hours.

[0251] After returning to room temperature, CH 2 Cl 2 (2 x 50 mL) to extract the mixture. with H 2 O, saturated NaCl washing organic phase, NaCl 2 SO 4 Drying afforded the expected (R) configuration product.

[0252] 3a R 2 =CH 2 Ph: pale yellow oil; (yield: 50%); Rf(CH 2 Cl 2 / MeOH):0.62

[0253] NMR (abbreviated as RMN in French) (CDCl 3 ,200MH...

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Abstract

Mixed inhibitors of aminopeptidase N and of neprilysine are described. Pharmaceutical compositions containing at least one of these compounds, used alone or in combination with morphine and derivatives thereof, endocannabinoids and inhibitors of the metabolism thereof, GABA derivatives such as gabapentin or pregabalin, duloxetine or methadone, can be used as an analgesic, anxiolytic, antidepressant or anti-inflammatory.

Description

technical field [0001] The present invention relates to combined inhibitors of aminopeptidase N and enkephalinase, the enzyme involved in the degradation of enkephalins. Background technique [0002] Enkephalins, Tyr–Gly–Gly–Phe–Met(Leu), are endogenous ligands for the opioid receptors μ and δ, and are involved in the regulation of pain impulses in the central and peripheral nervous systems. However, despite their affinity for opioid receptors similar to morphine, these peptides induce only a very transient analgesic response when administered intracerebroventricularly in rodents due to their very rapid inactivation in vivo (including humans) (Mosnaim et al. (2008) Neurochem. Res., 33, 81–86). Two metallopeptidases cause this inactivation: aminopeptidase N (APN, EC 3.4.11.2) and enkephalinase (NEP, EC 3.4.24.11), which cleave the Tyr 1 –Gly 2 Keys and Gly 3 –Phe 4 bond, thus leading to inactive metabolites (Roques et al. (1993) Pharmacol. Rev., 45, 87-146). [0003] Mi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/58A61K31/10A61P25/00A61P27/00
CPCC07C2101/14C07C2102/08C07C323/56C07C323/61C07C2101/08C07C2601/08C07C2601/14C07C2601/16C07C2602/08A61K31/216A61K31/221A61K31/27A61P25/00A61P25/04A61P25/22A61P25/24A61P27/00A61P29/00A61P43/00A61K45/06C07C321/14
Inventor B·P·罗克M-C·富尼耶-扎武斯基H·波拉什
Owner 智腾大中华区有限公司
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