Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance

a technology monoaminergic substance, which is applied in the field of combined action of nicotinic acetylcholine receptor agonist and monoaminergic substance, can solve the problems of window of vulnerability during which the patient might not be able to comply with therapy, and achieve the effect of increasing the success rate and accelerating the onset of action

Inactive Publication Date: 2007-11-15
OLSEN GUNNAR M +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] According to the invention it has now been found that the action of a nicotinic acetylcholine receptor agonist potentiate the monoaminergic action, so the combination of a nicotinic acetylcholine receptor agonist and a monoamine agonist or antagonist or a monoamine reuptake inhibitor for use in the treatment of affective disorders may result in a faster onset of action and an increased success rate. The invention therefore resides in the combined action of a nicotinic acetylcholine receptor agonist and a monoamine agonist or antagonist or a monoamine reuptake inhibitor, or the dual action of a substance possessing both nicotinic acetylcholine receptor agonist activity and monoamine agonist or antagonist activity or monoamine reuptake inhibiting activity, for the treatment of affective disorders.

Problems solved by technology

However, their most severe drawback is that while the side effects set in almost immediately, no substantial antidepressant effect will be seen within the first 2 to 4 weeks, leaving a window of vulnerability during which the patient might be non-compliant with therapy.

Method used

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  • Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance
  • Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance
  • Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparatory Example

General

[0159] All reactions involving air sensitive reagents or intermediates were performed under nitrogen and in anhydrous solvents. Magnesium sulphate was used as drying agent in the workup-procedures and solvents were evaporated under reduced pressure.

Method A

1-(5-Bromo-3-pyridyl)-piperazine Fumaric Acid Salt (Compound 1A1)

[0160] A mixture of 3,5-dibromopyridine (100 g, 422 mmol) and piperazine (72.7 g, 844 mmol) was stirred at 130° C. for 100 hours. Water (400 ml) was added and the pH was adjusted to 7 by adding hydrochloric acid (4 M). The aqueous phase was washed three times with ethyl acetate (3×600 ml). The aqueous mixture was made alkaline by adding sodium hydroxide (200 ml, 4 M). The aqueous mixture was extracted four times with diethyl ether (4×500 ml). The product was isolated as free base.. Yield 44 g (43%). The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp 185.0° C.

1...

example 2

Preparatory Example

General

[0192] All reactions involving air sensitive reagents or intermediates were performed under nitrogen and in anhydrous solvents. Magnesium sulphate was used as drying agent in the workup-procedures and solvents were evaporated under reduced pressure.

9-Methyl-3,9-diazabicyclo-[4.2.1]-nonane

[0193] was prepared according to [Michaels R J & Zaugg H E; J. Org. Chem. 1960 25 637].

(±) 3-(2-Naphthalyl)-9-methyl-3,9-diazabicyclo-[4.2.1]-nonane Fumaric Acid Salt (Compound 2A)

[0194] A mixture of 2-bromonaphtalene (5.0 g; 24.1 mmol), 9-Methyl-3,9-diazabicyclo[4.2.1]-nonane (3.38 g; 24.1 mmol) and palladacycle (0.045 g; 0.048 mmol) [Angew. Chem. Int. Ed. Engl. 1995 34 1844] was stirred for two days at 150° C. Sodium hydroxide (50 ml; 1 M) was added at room temperature. The mixture was extracted with diethyl ether (2×100 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound. The corresponding salt was ...

example 3

Biological Activity

Mouse Forced Swim Test

[0206] Systemic administration of a classical antidepressant (Desipramine) induces an increase in the forced swim distance performed by mice in a small water pool. The Forced Swim Test therefore is considered predictive of a potential antidepressant pharmacological effect.

[0207] Female NMRI mice (of 20-25 g) are habituated to the laboratory (a 12 hour light / dark cycle) for at least 16 hours before the experiment.

[0208] 30 minutes after s.c. injection of either vehicle or drug, the mouse is placed in a glass beaker (d=16 cm; 5000 ml) with water (24° C.) up till 10 cm from the top edge. For the subsequent 6 minutes the duration of immobility defined as swim speed less than 2.5 cm / minute, and forced swim distance defined as distance swum with a speed above 5 cm / minute, is recorded. There are 8 mice in each group.

[0209] The activity of the mouse is tracked by the View Point system for the measurement of distance, immobility, and speed.

[0210...

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Abstract

This invention relates to use of the combined action of a nicotinic acetylcholine receptor agonist and a monoaminergic substance for the treatment of affective disorders, as well as to pharmaceutical compositions comprising these substances and chemical substances for use according to the invention.

Description

[0001] This application is a divisional of U.S. application Ser. No. 10 / 380,653 filed Mar. 17, 2003, which is the national phase under 35 U.S.C. ∅ 371 of PCT Application No. PCT / DK01 / 00661 filed Oct. 10, 2001, which designated the United States of America and claims priority from Denmark Application PA2000-01535 filed Oct. 13, 2000 and U.S. application Ser. No. 60 / 242,146 filed Oct. 23, 2000 The disclosures of the foregoing applications are incorporated by reference herein.TECHNICAL FIELD [0002] This invention relates to use of the combined action of a nicotinic acetylcholine receptor agonist and a monoaminergic substance for the treatment of affective disorders, as well as to pharmaceutical compositions comprising these substances and chemical substances for use according to the invention. BACKGROUND ART [0003] Selective monoamine reuptake inhibitors, and in particular serotonin reuptake inhibitors (SSRI's), are the gold standard for treating depression. However, their most severe ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61K31/397A61K31/501A61P25/00A61P25/24C07D205/12C07D295/00C07D401/00A61K31/00A61K31/4439A61K31/455A61K31/46A61K31/497A61K31/519A61K31/551A61K45/00A61K45/06A61P25/20A61P25/22A61P43/00C07D213/74C07D237/20C07D241/20C07D401/04C07D403/04C07D451/02C07D487/08
CPCA61K31/00A61K31/4439C07D487/08C07D451/02C07D403/04C07D241/20C07D237/20C07D213/74A61K45/06A61K31/551A61K31/519A61K31/455A61K31/46A61K2300/00A61K31/439C07D213/61C07D213/65C07D237/12C07D241/16C07D401/04A61P23/00A61P25/00A61P25/04A61P25/18A61P25/20A61P25/22A61P25/24A61P25/26A61P25/34A61P3/04A61P43/00
Inventor OLSEN, GUNNAR M.PETERS, DANNIELSEN, ELSEBET OSTERGAARD
Owner OLSEN GUNNAR M
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