Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-14
2003-05-13
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S413000, C544S143000, C546S167000, C546S200000, C546S269700, C546S270400, C546S271400, C546S276700, C548S131000, C548S136000, C548S142000, C548S143000, C548S214000, C548S225000, C548S227000, C548S228000, C548S229000, C548S181000, C548S236000, C548S248000, C548S312100, C548S453000
Reexamination Certificate
active
06562816
ABSTRACT:
FIELD OF INVENTION
Nicotinic acetylcholine receptors (nAChRs) play a large role in central nervous system (CNS) activity. Particularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, one of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety. The present invention relates to molecules that have a greater effect upon the &agr;7 nAChRs as compared to other closely related members of this large ligand-gated receptor family. Thus, the invention provides compounds that are active drug molecules with fewer side effects.
BACKGROUND OF THE INVENTION
Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The &agr;7 nAChR is one receptor system that has proved to be a difficult target for testing. Native &agr;7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar,
J. Neurochem
., 1997, 68 (5):2140-51). Another feature that makes functional assays of &agr;7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the &agr;7 nAChR (Eisele et al.,
Nature
, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT
3
receptor expressed well in
Xenopus oocytes
while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the &agr;7 nAChR receptor and the C-terminus of the mouse form of the 5-HT
3
gene. However, under physiological conditions the &agr;7 nAChR is a calcium channel while the 5-HT
3
R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken &agr;7 nAChR/ mouse 5-HT
3
R behaves quite differently than the native &agr;7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT
3
R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
U.S. Pat. No. 6,255,490 B1 discloses 7-azabicyclo[2.2. 1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,117,889 discloses discloses 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as analgesics and anti-inflammatory agents.
U.S. Pat. No. 6,060,473 discloses 7-azabicyclo[2.2.1]-heptane and -heptene derivatives as cholinergic receptor ligands.
U.S. Pat. No. 6,054,464 discloses azabicyclic esters of carbamic acids useful in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of intermediates in synthesis.
U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the &agr;7 receptor subtype with little or no activation of the &agr;4&bgr;2 or other receptor subtypes.
U.S. Pat. No. 5,712,270 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT
1A
receptors and dopamine D
2
receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 5,624,941 discloses pyrazole derivatives useful in pharmaceuticals in which cannabis is known to be involved.
U.S. Pat. No. 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic, acid ester or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
U.S. Pat. No. 5,510,478 discloses a group of 2-aroylaminothiazole derivatives which bind to and stimulate central muscarinic acetylcholine receptors and are useful agents for treating symptoms of cognitive disorders, specifically the impaired memory associated with a decrease in the neurotransmitter, acetylcholine. Some of the compounds of this invention also bind to 5HT
1A
receptors and dopamine D
2
receptors, making them useful as antipsychotic agents.
U.S. Pat. No. 5,364,863 discloses bicyclic carboxylic esters and amides, their pharmaceutical formulations, and a method for their use in treating migraine, emesis, gastrointestinal disorders, schizophrenia, or anxiety in mammals.
U.S. Pat. No. 5,106,843 discloses heterocyclic compounds useful as 5-HT
3
antagonists.
U.S. Pat. No. 5,057,519 discloses 5-HT
3
antagonists as being useful in reducing opiate tolerance.
U.S. Pat. No. 5,039,680 discloses 5-HT
3
antagonists in preventing or reducing dependency on dependency-inducing agents.
U.S. Pat. No. 4,988,691 discloses isoxazole-containing compounds exhibiting anti-serotonin activity.
U.S. Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT
3
antagonists.
U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
U.S. Pat. No. 4,605,652 discloses a method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes, and the pharmaceutically acceptable acid addition salts, hydrates and alcoholates thereof.
WO 01/60821 discloses novel biarylcarboxamides.
WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
WO 01/29304 discloses quinuclidine acrylamides.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the &agr;7 nAChR and the 5-HT
3
R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the &agr;7 nAChR.
WO 97/30998 discloses azabicyclic esters of carbamic acids useful in therapy.
WO 95/01793 discloses 5-HT
3
antagonists as topical medicaments for treatment of peripheral disorders associated with pain.
WO 92/15579 discloses multicyclic tertiary amine polyaromatic squalene synthase inhibitors and method of treatment for lowering serum cholesterol levels using the compounds.
DE 3810552 A1 discloses esters and amides of indolyl-, benzo[b]thiophenyl-, benzo[b]furancarboxylic acids or 4-amino-2 methoxy-benzoic acids with N-heterocyclic or N-heterobicyclic alcohols or amines. The compounds disclosed have activity against pain especially migraine, as an anti-arrhythmic for gastrointestinal disturbances, stomach disturbances, gastritis ulcer, gall bladder, spastic colon, Crohn's disease, ulcerative colitis, carcinoid syndrome, diarrhea of various types. The compounds are also disclosed as speeding stomach
Bodnar Alice L.
Corbett Jeffrey W.
Groppi, Jr. Vincent E.
Jacobsen Eric Jon
Myers Jason K.
Hosley Mary J.
Pharmacia & Upjohn Company
Ramsuer Robert W.
LandOfFree
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