Unlock instant, AI-driven research and patent intelligence for your innovation.

7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors

A compound, C1-C4 technology, applied in biochemical equipment and methods, medical preparations containing active ingredients, enzymes, etc., can solve problems such as hepatotoxicity, reduction of therapeutic effective dose, limited functionalization of compounds, etc.

Active Publication Date: 2014-09-03
UNIV DE ROUEN (FR)
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds have still been shown to produce hepatotoxicity, so it is critical to reduce the effective dose required for treatment
The huperzine alpha derivatives described in WO 97 / 13754 offer some structural arrangement possibilities, but the functionalization of these compounds is limited

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors
  • 7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors
  • 7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

no. 1 approach

[0085] In a first embodiment, the method of the present invention comprises the following steps:

[0086] a) contacting a diketone of formula 1 with an α-haloester,

[0087]

[0088] to obtain the compound of formula 2

[0089]

[0090] where R' is C 1 -C 4 Alkyl;

[0091] b) converting the alcohol group on the compound of formula 2 into a leaving group to give the compound of formula 3

[0092]

[0093] wherein R" is a leaving group;

[0094] b') converting the compound of formula 3 into a compound of formula 4;

[0095]

[0096] c) contacting the compound of formula 4 with the compound of formula 5

[0097]

[0098] where R a , R b , R c and R d is as defined in formula I, and R e is CN or COOH to give compounds of formula HUP.

[0099]

[0100] where R' is C 1 -C 4 Alkyl and R 10 is NH 2 or Cl.

[0101] In a second embodiment, the method of the present invention comprises the following steps:

[0102] a) contacting a diketone of formula 1 w...

Embodiment 1

[0141] Example 1: Ethyl (12-amino-3-chloro-6,7,10,11-tetrahydro-7,11-methylenecyclooctano[b]quinolin-9-yl)acetate (HUP 1)

[0142] Preparation of tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate

[0143] A mixture of 1,1,3,3-tetramethoxypropane (32.8 g, 0.20 mol) and 2M hydrochloric acid (100 mL) was stirred at room temperature for 1.5 hours. To this mixture cooled to 0° C. was added sequentially and carefully 5M aqueous NaOH (pH=8) (within 30 min) and methanol (100 mL). At 0°C, dimethyl-3-oxoglutaric acid (69.6 g, 0.40 mol) was added followed by methanol (70 mL). The reaction mixture was warmed to room temperature and stirred for 3 days. The reaction mixture was acidified to pH=3 with 10M HCl. Fractions were filtered, washed with water, and dried in a desiccator to afford the desired tetraester as a white solid (39.2 g, 51%).

[0144] Preparation of bicyclo[3.3.1]nonane-3,7-dione (1)

[0145] Tetramethyl 3,7-dihydroxybicyclo[3.3.1]nona-...

Embodiment 2

[0169] Example 2: 2-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methylenecyclooctano[b]quinolin-9-yl)ethanol (HUP 2)

[0170]

[0171] To cold (0°C) anhydrous LiAlH 4 (400 mg, 10 mmol) in anhydrous THF (50 mL) was added dropwise to a solution of ester (HUP 1 ) (1.78 g, 5.0 mmol) in anhydrous THF (15 mL). The solution was stirred for 1 h (0° C. to room temperature) and then carefully quenched at 0° C. by the addition of water (1.75 mL), followed by 5M NaOH solution (1.75 mL) followed by water (5 mL). The reaction mixture was stirred at room temperature for 10 min, then washed with Na 2 SO 4 dry. Filtration and concentration gave the desired huperzine alpha complex (HUP 2) (1.60 g, quantitative) as a very pale yellow solid. Recrystallization from acetone gave a white solid.

[0172] Rf (AcOEt / MeOH 8 / 2, v / v) = 0.15.

[0173] m.p.=174℃(decomposition).

[0174] IR(KBr): ν=3352, 3252, 2894, 1645, 1609, 1573, 1490, 1424, 1373, 1309, 1285, 1046, 928, 818, 770cm -1 .

[...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to novel highly functionalizable huperzine alpha derivatives of formula I, processes for their preparation and their use in the treatment of neurological disorders in which acetylcholine levels are affected, such as Alzheimer's disease.

Description

technical field [0001] The present invention relates to novel highly functionalizable huperzine alpha derivatives (Huprine) derivatives and processes for the preparation of these compounds. Huperzine alpha derivatives are acetylcholinesterase inhibitors, and for this reason, the derivatives are promising candidates for the treatment of neurological diseases in which acetylcholine levels are affected, such as Alzheimer's disease. Background technique [0002] Alzheimer's disease is a major public health problem today with economic and human impacts that tend to increase as the population ages. Among the different solutions that have been investigated for the treatment of neurodegenerative diseases, especially Alzheimer's disease, the only treatment that has resulted in and currently commercialized an effective compound is a symptomatic therapy of cholinergic deficiency: acetylcholine esters The enzyme (AchE), which is a key enzyme in terminating the process of nerve impulse ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D221/22C07D401/08C07D401/14A61K31/473A61P25/28
CPCC07D221/22C07D401/08C07D401/14A61P25/00A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28C12N9/18C12Y301/01008
Inventor C·龙科P·Y·勒纳尔L·让F·纳赫翁A·罗米厄
Owner UNIV DE ROUEN (FR)