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Pharmaceutical compositions and methods for use

a technology of nicotinic cholinergic receptor and composition, applied in the field of pharmaceutical compositions, can solve the problems of subtypes with the potential to induce undesirable side effects, no significant associated side effects, etc., and achieve the effects of preventing and suppressing symptoms, no appreciable adverse side effects, and increasing blood pressure and heart ra

Inactive Publication Date: 2010-07-13
TARGACEPT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention relates to certain compounds, called diazabicyclic compounds, and particularly N-aryl diazabicyclic compounds. These compounds have shown potential therapeutic benefit in the prevention and treatment of various conditions and disorders, particularly those involving dysfunction of nicotinic cholinergic neurotransmission. The invention also includes prodrug derivatives of these compounds. The compounds have the potential to interact with relevant nicotinic receptor sites and modulate neurotransmitter secretion, thereby alleviating symptoms associated with these disorders. The pharmaceutical compositions of the invention are safe and effective and are believed to have minimal adverse side effects."

Problems solved by technology

It would be highly beneficial to provide individuals suffering from certain disorders (e.g., CNS diseases) with interruption of the symptoms of those disorders by the administration of a pharmaceutical composition containing an active ingredient having nicotinic pharmacology and which has a beneficial effect (e.g., upon the functioning of the CNS), but which does not provide any significant associated side effects.
It would be highly desirable to provide a pharmaceutical composition incorporating a compound with interacts with nicotinic receptors, such as those which have the potential to effect the functioning of the CNS, but, when employed in an amount sufficient to effect the fimctioning of the CNS, does not significantly effect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at cardiovascular and skeletal muscle sites).

Method used

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  • Pharmaceutical compositions and methods for use
  • Pharmaceutical compositions and methods for use
  • Pharmaceutical compositions and methods for use

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0109]Sample No. 1 is (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane hernigalactarate, which was prepared in accordance with the following techniques:

3-Bromo-5-(4-methoxyphenoxy)pyridine

[0110]To a stirred suspension of sodium hydride (3.0 g of 80% in mineral oil, 100 mmol) in DMF (95 mL) in an ice water bath, 4-methoxyphenol (12.2 g, 96 mmol) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (15.6 g of 98%, 65 mmol) was added and the mixture was then heated at 85° C. (bath temperature) for 32 h. The mixture was cooled, diluted with water (120 mL), poured into 5N sodium hydroxide (15 mL), and extracted with ether (3×150 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, to give a light-yellow oil (21.9 g). The oil was diluted with ethanol and rotary evaporated (twice) to remove residual DMF and then diluted with et...

example 2

[0115]Sample No. 2 is (1S,4S)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane hernigalactarate, which was prepared in accordance with the following techniques:

3-Bromo-5-(3-methoxyphenoxy)pyridine

[0116]Following a procedure similar to that described for the preparation of 3-bromo-5-(4-methoxyphenoxy)pyridine, 3-bromo-5-(3-methoxyphenoxy)pyridine was prepared using 3-methoxyphenol (2.79 g, 0.023 mole), 75% sodium hydride suspension in oil (0.72 g, 0.023 mol) in dimethyl-formamide (20 mL) and 3,5-dibromopyridine (3.55 g, 0.015 mol). The reaction was worked up using water (50 mL), 5 N NaOH solution (5 mL), and diethyl ether (3×50 mL), and a yellow oil (4.6 g) was obtained as crude product. This oil was purified by column chromatography on silica gel, eluting with cyclohexane-ethyl acetate (92.5:7.5, v / v). Selected fractions containing the product were concentrated via rotary evaporation to give 2.3 g (55%) of a yellow oil.

(1S,4S)-5-(5-(3-Methoxyphenoxy)-3-pyridyl)-2-(t...

example 3

[0121]Sample No. 3 is (1S,4S)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride, which was prepared in accordance with the following techniques:

3-Bromo-5-(4-fluorophenoxy)pyridine

[0122]Sodium hydride (1.53 g of 80% in mineral oil, 51 mmol) was slowly added to a solution of 4-fluorophenol (5.6 g, 50 mmol) in DMF (100 mL) as it was stirred and cooled (ice water bath) under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (5.9 g, 25 mmol) was added and the mixture was then heated at 90° C. (bath temperature) for 62 h. The mixture was cooled, diluted with water (150 mL), poured into 5N sodium hydroxide (150 mL), and extracted with diethyl ether (2×150 mL). The combined ether extracts were washed with water, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using 5% ethyl acetate: hexane as eluent, to yield 1.4...

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Abstract

The present invention relates to diazabicyclic compounds, preferably to N-aryl diazabicyclic compounds. Of particular interest are 2-pyridinyl diazabicyclic compounds, such as (1S,4S)-2-(5-(3-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. Other exemplary compounds of the present invention include (1S,4S)-2-(5-(4-methoxyphenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, (1S,4S)-2-(5-(3-thienyl)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, (1S,4S)-2-(5-(4-fluorophenoxy)-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane, and (1S,4S)-2-(5-benzoyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane. The present invention also relates to prodrug derivatives of the compounds of the present invention.

Description

RELATED APPLICATION[0001]This application is a CIP of U.S. patent application Ser. No. 09 / 578,768, filed May 25, 2000, now U.S. Pat. No. 6,440,970, the disclosure of which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION[0002]The present invention relates to pharmaceutical compositions, particularly pharmaceutical compositions incorporating compounds that are capable of affecting nicotinic cholinergic receptors. More particularly, the present invention relates to compounds capable of activating nicotinic cholinergic receptors, for example, as agonists of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.[0003]Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al., N. Engl. J. Med. 330:811 (1994). Certain o...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D487/08C07D209/00A61K31/40A61P25/00A61K31/407A61K31/439A61P25/26A61P43/00C07D471/08
CPCC07D487/08A61P25/00A61P25/26A61P43/00
Inventor MILLER, CRAIG HARRISONDULL, GARY MAURICEMIAO, LANLYNM, DWOSCHMITT, JEFFREY DANIELCLARK, THOMAS JEFF
Owner TARGACEPT INC
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