Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-20
2001-10-16
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S275000, C514S218000, C514S226800, C514S227200, C514S318000, C514S341000, C514S342000, C514S343000, C546S193000, C546S270700, C546S271400, C546S274700, C546S279100, C544S033000, C544S055000, C540S553000
Reexamination Certificate
active
06303638
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to modulation of the neuronal nicotinic acetylcholine receptor (nAChR). More particularly, the invention relates to novel heterocyclic compounds, specifically substituted pyridine compounds, as modulators of the mammalian nAChR (m-nAChR). The invention additionally relates to methods for synthesizing the novel compounds, to methods for using the novel compounds to modulate the m-nAChR, and to pharmaceutical formulations containing an m-nAChR modulator of the invention as a therapeutic agent.
BACKGROUND
There are a myriad of neurotransmitters and neurotransmitter receptors, each influencing a specific activity within an organism. One type of neurotransmitter receptor is the nAChR, which in humans is found throughout the nervous system in healthy individuals. The nAChR is an acetylcholine receptor that can bind to nicotine and its analogs (i.e., nicotinic agonists). The receptor is known to perform critical functions in humans and is involved in several central nervous system (CNS) disorders, including Alzheimer's disease, AIDS-associated dementia, Tourette's syndrome, cognitive dysfunction (e.g., disorders of attention, focus and concentration, such as “Attention Deficit Disorder” (ADD) and “Attention Deficit Hyperactivity Disorder” (ADHD)) and possibly Parkinson's disease; see, e.g., Halladay et al. (1997)
J. Med. Chem
. 40:4169-4194, U.S. Pat. No. 5,736,560 to Cosford et al., and U.S. Pat. No. 5,922,723 to Bencherif et al.
When nicotine itself is administered into the human blood stream, both central and peripheral effects of nicotine are seen such as fever, increased heart rate, trembling, nausea, increased blood pressure and convulsions, even when the drug is administered in relatively small amounts; nicotine can in fact be fatal when taken orally at doses of 250-350 mg. However, it has been suggested that certain nicotine analogs may, by contrast, be beneficial in the treatment of many diseases (Lin et al. (1994)
J. Med Chem
. 37:3542). That is, it has been proposed that certain nicotinic agents could modulate the nAChR as desired, but without significantly affecting those receptors that have the potential to induce undesirable side effects.
The 6-chloro-3-pyridinyl moiety has been found to confer high potency to several types of compounds acting at the nAChR, resulting in selective antinociceptive or non-opiate analgesic effects. See, for example, Badio et al. (1994)
Mol. Pharmacol
. 45:563-569, and Houghtling et al. (1995)
Mol. Pharmacol
. 48:280-287. This moiety can also confer insecticidal activity, as in the case of imidacloprid, a compound that acts selectively at the insect versus the mammalian nAChR (Kagabu et al. (1997)
Rev. Toxicol
. 1:75-129).
Surprisingly, it has been found that the N-desnitro metabolite of imidacloprid, 1-[(6-chloro-3-pyridinyl)methyl]-2-imidazolidine, is selective for the mammalian versus the insect nAChR and is similar in potency to that of (−)-nicotine (Chao et al. (1997)
Pestic. Biochem. Physiol
. 58:77-88).
There remains a need in the art, however, for additional compounds that modulate the nAChR, particularly the mammalian nAChR. Such compounds are useful to treat conditions, diseases and disorders that are responsive to the activity of m-nAChR modulators, including CNS disorders, pain, inflammation and inflammatory diseases, diseases caused by smooth muscle contractions, and withdrawal symptoms associated with cessation of chemical substance abuse.
SUMMARY OF THE INVENTION
In one aspect of the invention, then, novel compounds are provided that are useful as modulators of the m-nAChR. The compounds are substituted pyridines having the general structure of formula (I)
wherein:
R is selected from the group consisting of
R
1
is halo or alkyl;
R
2
is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, halo and nitro;
R
3
is hydrogen or alkyl;
R
4
, R
5
and R
6
are independently linear, branched or cyclic alkyl;
X is selected from the group consisting of —CHR
7
═CHR
8
—, —CR
7
R
8
—CR
9
R
10
—(CR
11
R
12
)
p
—(CR
13
R
14
)
q
—, —CR
7
R
8
—NH—CR
9
R
10
—, —CR
7
R
8
—N(CH
3
)—CR
9
R
10
—, CR
7
R
8
—O—CR
9
R
10
— and —CR
7
R
8
—S—CR
9
R
10
— wherein R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are independently hydrogen or alkyl and p and q are independently zero or 1;
Y is selected from the group consisting of CR
15
R
16
, NR
17
, O and S, wherein R
15
and R
16
are independently hydrogen or alkyl, and R
17
is hydrogen, alkyl, alkenyl or alkynyl;
Q
−
is an organic or inorganic anion; and
n is 1, 2 or 3.
In another aspect of the invention, a method is provided for synthesizing compounds having the structure of formula (I), using compound (II)
as a starting material. The substituent L is a leaving group that is generally displaceable by a nucleophile, and may be, for example, halo, particularly chloro.
In another aspect of the invention, methods are provided for using compounds having the structure of formula (I) as modulators of the mammalian nAChR receptor. A first method involves contacting the receptor with the compound of formula (I), e.g., in the context of treating a mammalian individual suffering from a condition, disease or disorder that is responsive to administration of an m-nAChR modulator. Such conditions, diseases and disorders include, for example: CNS disorders such as Alzheimer's disease, AIDS-associated dementia, Tourette's syndrome, ADD and ADHD; pain; inflammation and inflammatory diseases; diseases caused by smooth muscle contractions; and withdrawal symptoms associated with the cessation of chemical substance abuse. The compounds are potent in terms of their therapeutic effectiveness, while the occurrence of undesirable side effects is minimal. A second method involves using the novel compounds as nAChR probes, in order to study the function of the nAChR in mammals.
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Nomenclature
Before the present compounds, compositions and methods are disclosed and described, it is to be understood that unless otherwise indicated this invention is not limited to specific molecular structures, synthetic procedures, therapeutic uses, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to use of “a compound of formula (I)” includes use of two or more compounds of formula (I), reference to “a substituent” as in a compound substituted with “a substituent” includes the possibility of substitution with more than one substituent, wherein the substituents may be the same or different.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
The term “alkyl” as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, hexyl, octyl, and the like, as well as cycloalkyl groups of from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term “alkenyl” as used herein refers to a branched, unbranched or cyclic hydrocarbon group of 2 to 8 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, and the like. The specific term “cycloalkenyl” intends a cyclic alkenyl group of three to eight, preferably five or six, carbon atoms.
The term “alkynyl” as used herein refers to a branched, unbranched or cyclic hydrocarbon group of 2 to 8 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, octynyl, and th
Casida John E.
Latli Bachir
Fan Jane
Reed Dianne E.
Reed & Associates
The Regents of the University of California
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