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Compounds with activity on muscarinic receptors

a technology of muscarinic receptors and compounds, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of limited clinical utility of tacrine, cholinergic side effects of tacrine, and limited doses of tacrin

Inactive Publication Date: 2008-05-08
BRANN MARK +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0023] The present invention further provides pharmaceutical compositions comprising an effective amount of a compound of formula (I).
[0024] Further provided are methods of treating the symptoms of a disease or condition associated with reduced levels of acetylcholine, said method comprising administering a therapeutically effective amount of a composition comprising a compound of formula (I).
[0025] In yet a further embodiment, the present invention provides a method of treating the symptoms of a disease or condition associated with increased intraocular pressure, such as, for example, glaucoma, where the method comprises administering a therapeutically effective amount of a composition comprising a muscarinic receptor agonist, preferably an m1 selective agonist, preferably selected from the compounds of formula (I).

Problems solved by technology

On the other hand, tacrine has been found to have cholinergic side effects due to the peripheral acetylcholine stimulation.
The adverse effects of tacrine have severely limited its clinical utility.
m2 and / or m3 activity is therefore a significant drawback for the muscarinic agonists proposed until now for the treatment of Alzheimer's disease, severely limiting the doses of the drugs which it has been possible to administer to patients who may therefore have received sub-optimal doses.
Furthermore, the lack of subtype selectivity and low potency of the currently tested cholinergic compounds appear to favor the negative peripheral side effects and have limited cognitive effects because of weak and / or opposing actions in the brain.

Method used

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  • Compounds with activity on muscarinic receptors
  • Compounds with activity on muscarinic receptors
  • Compounds with activity on muscarinic receptors

Examples

Experimental program
Comparison scheme
Effect test

example i

4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine (5)

[0193] 1-Benzyl-4-n-butylidenepiperidine (2). A 500 mL 3-necked flask fitted with a stirrer, was charged with sodium hydride (1.61 g, 67 mmol) and DMSO (40 mL). The resulting suspension was heated to 90° C. for 30 min, until the evolution of hydrogen ceased. The suspension was cooled on an ice-bath for 20 min followed by addition of a slurry of butyltriphenylphosphonium bromide (26.6 g, 67 mmol) in DMSO (70 mL). The red mixture was stirred for 15 min at rt. 1-Benzyl-4-piperidone 1 (14.0 g, 74 mmol) was slowly added over 30 min, and the mixture was stirred at room temperature over night. H2O (200 mL) was added to the reaction mixture followed by extraction with heptane (4×100 mL) and ethyl acetate (2×100 mL). The combined organic phases were dried and evaporated to dryness, producing 38.1 g of a yellow oil. The oil was distilled to give 14.9 g (88%) of 2, bp 101-105° C. (0.1 mm Hg). 1H NMR (CDCl3) δ 0.90-0.95 (t, 3H), 1.25-...

example ii

3-Hydroxymethyl-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine (7)

[0197] 4-(3-Hydroxymethyl-piperidin-1-yl)-butyronitrile (6). In an oven-dried 25 mL flask was placed piperidine-3-yl-methanol (1.12 g, 10 mmol) in acetonitrile (10 mL), followed by addition of potassium carbonate (1.38 g, 10 mmol) and 4-bromobutyronitrile (0.90 mL, 9 mmol). The reaction mixture was stirred at rt. for 12 h. The mixture was filtered and evaporated to dryness. Addition of H2O (20 mL) was followed by extraction with ethyl acetate (3×20 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce 1.50 g of crude 6 which was used without further purification in the synthesis of compound 7.

[0198] 3-Hydroxymethyl-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine (7). In a 50 mL oven-dried flask was added Mg turnings (780 mg, 32 mmol), which were activated by the use of a heat-gun under vacuum, followed by addition of anhydrous THF (7 mL). Under inert atmosphere was added a suspension...

example iii

2-Propyl-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine (9)

[0199] 4-(2-propyl-piperidin-1-yl)-butyronitrile (8). A mixture of 2-propylpiperidine (550 mg, 4.3 mmol), 4-bromobutyronitrile (430 mg, 3.0 mmol) and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (5 mL) was stirred at rt for 12 h., followed by addition of a saturated brine (25 mL). The reaction mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce crude 8. The crude product was subjected to CC [eluent: CH2Cl2:MeOH (99:1)] to give pure 8 (0.48 g, 83%); LC-MS [M+H]+ 194 (cald. 194.2).

[0200] 2-Propyl-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine (9). In a 10 mL oven-dried flask was added Mg turnings (97 mg, 4.1 mmol) which were activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 2-iodotoluene (380 μl, 2.8 mmol) in Et2O (3 mL) and the reaction mixture was allowed to reflux for 1 hour. A mixtu...

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Abstract

Compounds and methods are provided for the alleviation or treatment of diseases or conditions in which modification of muscarinic m1 receptor activity has a beneficial effect. In the method, a therapeutically effective amount of a selective muscarinic m1 agonist compound is administered to a patient in need of such treatment.

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel compounds which are selective for muscarinic acetylcholine receptor subtypes, as well as to methods for activating muscarinic receptors and for treating or alleviating diseases in which modification of muscarinic receptor activity is beneficial. BACKGROUND OF THE INVENTION [0002] Muscarinic acetylcholine receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Cloning has established the presence of five distinct muscarinic receptor subtypes (termed m1-m5) (cf. T. I. Bonner et al, Science 237, 1987, pp. 527-532; T. I. Bonner et al., Neuron 1, 1988, pp. 403-410). It has been found that m1 is the predominant subtype in the cerebral cortex and is believed to be involved in the control of cognitive functions, m2 is predominant in heart and is believed to be involved in the control of heart rate, m3 is believed to be involved...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/5377C07D211/26C07D211/20C07D265/32A61K31/445C07D211/00C07D211/22C07D213/50C07D295/108
CPCC07D211/00C07D211/20C07D211/22C07D295/108C07D213/50C07D265/32C07D211/26A61P25/00
Inventor BRANN, MARKMESSIER, TERRICURRIER, ERIKADUGGENTO, KATESPALDING, TRACYFRIBERG, MIKAELSKJAERBAEK, NIELS
Owner BRANN MARK
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