Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters

a monoamine neurotransmitter and azabicyclo[3.1.0]hexane technology, applied in the field of compounding comprising (1r, 5s)(+)1(naphthalen2yl)3azabicyclo3 . 1 . 0hexane, can solve the problems of low educational attainment, difficulty in functioning, and under achievement in vocational and educational pursuits, and achieve the effects of inhibiting norepinephrine, preventing, preventing

Inactive Publication Date: 2014-07-24
OTSUKA AMERICA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]It is shown herein that use of (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof is effective in treating, preventing, alleviating, or moderating disorders affected by monoamine neurotransmitters or biogenic amines, specifically disorders that are alleviated by inhibiting norepinephrine and / or dopamine and / or serotonin reuptake.

Problems solved by technology

Major symptoms in adults include inattention, disorganization, lack of concentration and to some extent impulsivity, which result in difficulty functioning, low educational attainment, under achievement in vocational and educational pursuits, and poor social and family relations (Biederman et al., 2006; Barkely et al., 2006).
However, major concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines (Berman et al., 2009).
The abuse potential of stimulants is particularly problematic in adults because substance abuse is a common co-morbidity with adult ADHD (Levin and Kleber, 1995; Ohlmeier, 2008).
However, atomoxetine has lower efficacy and takes 2-4 weeks for onset of action (Spencer et al., 1998; Newcorn et al., 2008).

Method used

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  • Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters
  • Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters
  • Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters

Examples

Experimental program
Comparison scheme
Effect test

example i

Preparation of (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane

[0107](1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be prepared as follows:

Step 1: Synthesis of [(1S2R)-2-(aminomethyl)-2-(2-naphthyncyclopropyl]methan-1-ol, p-toluenesulfonic Acid Salt

[0108]500 g (2.99 mol, 1.0 eq) of 2-naphthylacetonitrile was charged to a 12 L 3-neck round bottom flask equipped with overhead stirrer, addition funnel, thermocouple, nitrogen inlet, cooling bath and drying tube. 3.0 L of tetrahydrofuran was added and stirred at room temperature to dissolve all solids. 360 g (3.89 mol, 1.30 eq) (S)-(+)-epichlorohydrin was added and then the solution was cooled to an internal temperature of −25° C. 3.0 L of a 2 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (6.00 mol, 2.0 eq) was added to the reaction mixture via addition funnel at a rate such that the internal temperature of the reaction mixture is maintained at less than −15° C. After completion of the addit...

example ii

Inhibition of Monoamine Uptake by (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane

[0113]The ability of (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane for inhibiting transport of norepinephrine (NE) and / or dopamine (DA) and / or serotonin (5-HT) was evaluated using cell lines (such as the HEK 293 cell line) that stably express recombinant human NE, DA, and 5-HT transporters, respectively. Techniques for stably transfecting mammalian cell lines with neurotransmitter transporters and measuring the effects of drugs on amine uptake have been described in the literature (e.g., Eshleman A J, J Pharmacol Exp Ther 289:877-885, 1999) and are well known to those skilled in the art

[0114]Monoamine uptake was determined in MDCK, CHO-K1, and HEK-293 cell lines respectively transfected with NE, DA, and 5-HT uptake transporters by MDS Pharma Services (Taipei, Taiwan 112, R. O. C.). The cells were incubated in 5 mM Tris-HCl, and 7.5 mM HEPES buffer, pH 7.1, containing 120 mM NaCl, 5...

example iii

Effect of (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane on Monoamine Transporters In Vivo

[0117]To evaluate the effect of (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane on monoamine uptake transporters in vivo, microdialysis studies were performed in rat brain regions.

[0118]Microdialysis studies were conducted using male Wistar rats (250-300 g) bred at the Institute of Pharmacology, the Polish Academy of Sciences, Krakow, Poland. The rats (250-300 g) were housed on a 12 h / 12 h light / dark cycle at a constant temperature and humidity, and were provided with food and water ad libitum. The microdialysis procedure has been previously described (Popik et al., 2006). Briefly, the rats were anaesthetized with ketamine (75 mg / kg IM) and xylazine (10 mg / kg IM), placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, Calif., USA) with their skulls exposed. Small holes were drilled in the skull for insertion of the vertical microdialysis probes into the prefron...

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Abstract

The present invention relates to (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and pharmaceutical compositions thereof, and methods employing their use in the treatment of conditions affected by monoamine neurotransmitters, including ADHD and substance abuse.

Description

RELATED APPLICATIONS[0001]This application claims priority benefit of U.S. Provisional patent application Ser. No. 61 / 574,231, filed Jul. 30, 2011, the disclosure of which are incorporated herein in its entirety by reference.TECHNICAL FIELD[0002]The present invention relates to compositions comprising (1R,5S)-(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and methods for use of these compositions for treatment and prevention of central nervous system disorders and other conditions affected by monoamine neurotransmitters.BACKGROUND OF THE INVENTION[0003]Attention-deficit hyperactivity disorder (ADHD) is a central nervous system (CNS) disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity (Buitelaar et al., 2010; Spencer et al., 2007). ADHD is one of the most common developmental disorders in children with 5-10% prevalence (Scahill et al., 2000; Polanczyk et al., 2007). While ADHD was once regarded as only a childhood disorder, it can co...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/403A61K45/06
CPCA61K45/06A61K31/403
Inventor MCKINNEY, ANTHONY ALEXANDERBYMASTER, FRANK
Owner OTSUKA AMERICA PHARMA INC
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