Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-24
2002-08-27
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S300000
Reexamination Certificate
active
06441006
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions, and 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, and particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.
Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al.
N. Engl. J. Med
. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al.,
Brain Res
. 624:295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al.,
J. Neurochem
. 43:1593 (1984); Rapier et al.,
J. Neurochem
. 50:1123 (1988); Sandor et al.,
Brain Res
. 567:313 (1991) and Vizi, Br.
J. Pharmacol
. 47:765 (1973). Release of norepinephrine by neurons upon administration of nicotine has been reported by Hall et al.,
Biochem. Pharmacol
. 21:1829 (1972). Release of serotonin by neurons upon administration of nicotine has been reported by Hery et al.,
Arch. Int. Pharmacodyn. Ther
. 296:91 (1977). Release of glutamate by neurons upon administration of nicotine has been reported by Toth et al.,
Neurochem Res
. 17:265 (1992). In addition, nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain disorders. See, Sanberg et al.,
Pharmacol. Biochem
. &
Behavior
46:303 (1993); Harsing et al.,
J. Neurochem
. 59:48 (1993) and Hughes,
Proceedings from Intl. Symp. Nic
. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, Decina et al.,
Biol. Psychiatry
28:502 (1990); Wagner et al.,
Pharmacopsychiatry
21:301 (1988); Pomerleau et al.,
Addictive Behaviors
9:265 (1984); Onaivi et al.,
Life Sci
. 54(3):193 (1994); Tripathi et al.,
JPET
221: 91-96 (1982) and Hamon,
Trends in Pharmacol. Res
. 15:36.
Various nicotinic compounds have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al.
DN
&
P
7(4):205-227 (1994), Arneric et al.,
CNS Drug Rev
. 1(1):1-26 (1995), Arneric et al.,
Exp. Opin. Invest. Drugs
5(1):79-100 (1996), Bencherif et al.,
JPET
279:1413 (1996), Lippiello et al.,
JPET
279:1422 (1996), Damaj et al.,
Neuroscience
(1997), Holladay et al.,
J. Med. Chem
40(28): 4169-4194 (1997), Bannon et al.,
Science
279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Pat. Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al. 5,604,231 to Smith et al. and 5,852,041 to Cosford et al. Nicotinic compounds are reported as being particularly useful for treating a wide variety of Central Nervous System (CNS) disorders.
CNS disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
It would be desirable to provide a useful method for the prevention and treatment of a condition or disorder by administering a nicotinic compound to a patient susceptible to or suffering from such a condition or disorder. 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 which interacts with nicotinic receptors, such as those which have the potential to effect the functioning of the CNS, but which compound when employed in an amount sufficient to effect the functioning of the CNS, does not significantly effect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle sites).
SUMMARY OF THE INVENTION
The present invention relates to aryloxyalkylamines, including pyridyloxylalkylamines and phenoxyalkylamines. Exemplary compounds include dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3-pyridyloxy)ethylamine, 4-(3-pyridyloxy)butylamine, methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(2-(3-pyridyloxy)ethyl)amine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, (3-(3-methoxyphenoxy)propyl)methylamine, (3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine, dimethyl(3-(3-pyridyloxy)propyl)amine, 3-(3-pyridyloxy)propylamine, methyl(4-(3-pyridyloxy)butyl)amine, 3-(5-chloro-3-pyridyloxy)propylamine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl)methylamine, methyl(3-(5-(phenyl methoxy)(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl)amine, benzyl(3-(3-pyridyloxy)propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine, methyl(3-(3-nitrophenoxy)propyl)amine, 1-(3-chloropropoxy)-3-nitrobenzene, (3-(3-aminophenoxy)propyl)methylamine, dimethyl(3-(3-(methylamino)-propoxy)phenyl)amine, methyl(3-tricyclo[7.3.1.0<5,13>]-tridec-2-yloxypropyl)amine, (3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine, 3-(4-piperidinyloxy)pyridine, 3-((3S)-3-pyrrolidinyloxy)pyridine, (2-(5-bromo(3-pyridylthio))ethyl)methylamine, (2-(5-bromo(3-pyridylthio))isopropyl)-methylamine, (2-(5-bromo(3-pyridylthio))-propyl)methylamine and (3-(5-bromo(3-pyridylthio))propyl)-methylamine. The present invention also relates to prodrug derivatives of the compounds of the present invention.
The present invention also relates to methods for the prevention or treatment of a wide variety of conditions or disorders, and particularly those disorders characterized by disfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release. The present invention also relates to methods for the prevention or treatment of disorders, such as central nervous system (CNS) disorders, which are characterized by an alteration in normal neurotransmitter release. The present invention also relates to methods for the treatment of certain conditions (e.g., a method for alleviating pain). The methods involve administering to a subject an effective amount of a compound of the present invention.
The prese
Consilvio Michael B.
Dull Gary Maurice
Hadimani Srishailkumar B.
Wagner Jared Miller
Aulakh Charanjit S.
Targacept, Inc.
Womble Carlyle Sandridge & Rice PLLC
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