Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-14
2001-09-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06288108
ABSTRACT:
The present invention deals with the disciplines of medicinal chemistry, neurophysiology, and neuro-pharmacology. Specifically, the present invention is related to increasing levels of acetylcholine by the administration of 2-aryl-3-aryloxybenzo[b]thiophenes.
Cholinergic neurons make up a major neuronal system of the central and peripheral nervous systems. Cholinergic neurons are associated especially with the neurotransmitter acetylcholine. In the central nervous system, acetylcholine is a neurotransmitter and can be found in, among other places, the hippocampus and frontal cortex of the brain.
The hippocampal area of the brain, particularly those areas which are known to involve cholinergic neurons, is believed to have functions associated with cognition, learning, and memory. Degenerative diseases with symptoms such as loss of cognition, learning, and memory, have been linked to a loss in cholinergic neurons. For example, it is known that in patients suffering from Alzheimer's disease, there is a marked decrease in the level of cholinergic neurons in the hippocampus. The progressive loss of these cholinergic neurons appears to mirror the progressive loss in memory and cognitive function in these patients. It is thought that one reason for the decline of these neurons is the loss or decreased function of the neurotransmitter, acetylcholine. Several potential therapies which are designed to increase levels of acetylcholine are being clinically evaluated.
The level of acetylcholine in a neuron is basically determined by where the equilibrium between its bio-synthesis and bio-degradation lies. The enzyme choline acetyltransferase (ChAT) is primarily responsible for its synthesis and acetylcholineesterase (AChE) for its degradation. One therapeutic strategy for increasing the level of acetylcholine is based on blocking its degradation via inhibition of AChE, e.g., using AChE inhibitors such as physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride and the like. Although, there are some encouraging results with the clinical use of AChE inhibitors, especially in early stages of Alzheimer's disease, these agents generally have undesirable side effects, because of their non-specific, systemic action. Currently, tacrine has been approved for the early treatment of Alzheimer's symptoms, (See “Goodman and Gilman's, The Pharmacological Basis of Therapeutics”, Ed. Gilman, et al., Pergamon Press, 8
th
Ed., Chap.7, (1990) and references cited, therein).
Another therapeutic strategy for increasing levels of acetylcholine is based on up-regulating ChAT in the neurons. It has been found that the hormone, estrogen, increases the level of acetylcholine by up-regulating ChAT in the hippocampus of rats (see “Immunochemical demonstration of increased choline acetyltransferase concentration in rat preoptic area after estradiol administration”, Luine, et al., Brain Res., 191:273-277, 1980, “Estradiol Increases Choline Acetyltransferase Activity in Specific Basal Forebrain Nuclei and Projection Areas of Female Rats”, Luine, V.,
Exp. Neurology
, 89:484-490, 1985, “Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats”, Singh, M., et al.,
Brain Res
., 644:305-312, 1994). It, therefore, has been speculated, and preliminary clinical information confirms, that post-menopausal women treated with hormone replacement therapy (estrogen with or without progestins) may be less likely to succumb to Alzheimer's disease or should have existing symptoms alleviated.
However, therapy with estrogen has undesirable side-effects, including uterotrophic effects, a possible increase in breast cancer incidence, bloating, resumption of menses, etc., which limits patient compliance. Thus, the opportunity exists for new and improved therapeutic interventions to increase levels of acetylcholine.
The current invention relates to a method for up-regulating choline acetyltransferase (ChAT) in mammals comprising administering to a mammal in need thereof an effective amount of a compound of formula I:
or a pharmaceutical acid addition salt or solvate thereof; where:
R
1
and R
3
are independently hydrogen, methyl, benzoyl, substituted benzoyl, or C(O)—(C
1
-C
6
alkyl);
R
2
is selected from the group pyrolidin-1-yl, piperidin-1-yl, and hexamethyleneimin-1-yl; where the R
2
group is optionally the N-oxide; and optionally a choline esterase inhibitor.
In addition, the present invention relates to a method for increasing the levels of acetylcholine in the frontal cortex and/or hippocampus regions of the brain in mammals comprising administering to a mammal in need thereof, an effective amount of a compound of formula I, or a pharmaceutical acid addition salt or solvate thereof; and optionally a choline esterase inhibitor.
Further, the present invention relates to a method for inhibiting conditions or detrimental effects caused by a deficiency of choline acetyltransferase and/or acetylcholine in the frontal cortex and/or hippocampus regions of the brain in mammals comprising administering to a mammal in need thereof, an effective amount of a compound of formula I, or a pharmaceutical salt or solvate thereof; and optionally a choline esterase inhibitor.
Moreover, the present invention relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical acid addition salt or solvate thereof, an acetylcholineesterase (AChE) inhibitor; and a pharmaceutical carrier, diluent, or excipient.
The current invention is related to the discovery that a select group of 2-aryl-3-aryloxybenzo[b]thiophenes, i.e., compounds of formula I, are useful for up-regulating ChAT, and, therefore, are useful for increasing levels of acetylcholine in neurons which contain acetylcholine and ChAT.
A preferred embodiment of all methods of the present invention is where the mammal to be administered a compound of formula I is a human, particularly a female human, and most particularly when that human female is estrogen deficient. However, human males are also contemplated under the term “mammal”, particularly males who are testosterone deficient.
Another preferred embodiment of the present invention is where the condition caused by a decrease of choline acetyltransferase and/or acetylcholine in the frontal cortex and/or hippocampus regions of the brain is Alzheimer's disease.
Moreover, another preferred embodiment of all methods of the present invention is the use of a pharmaceutical acid addition salt of a compound of formula I where R
1
is hydrogen, R
3
is methyl, and R
2
is pyrolidin-1-yl. More preferably, the salt is the hydrochloride. This more preferred compound is named 2-(4-methoxyphenyl)-3-(4-[2-(pyrolidin-1-yl) ethoxy]phenoxy-6-hydroxybenzo[b]thiophene hydrochloride.
An even more preferred embodiment of all methods of the present invention is the use of a pharmaceutical acid addition salt of a compound of formula I where R
1
is hydrogen, R
3
is methyl, and R
2
is piperidin-1-yl. Most preferably, the salt is the hydrochloride. This most preferred compound is named 2-(4-hydroxyphenyl)-3-(4-[2-(piperidin-1-yl) ethoxy]phenoxy)-6-hydroxybenzo [b]thiophene hydrochloride.
The present invention contemplates the optional use of currently known AChE inhibitors such as physostigmine salicylate, tacrine hydrochloride, donepezil hydrochloride and the like, as well as agents that are later found to be AChE inhibitors.
As used herein, the term “effective amount” means an amount of a compound of formula I which is capable of up-regulating ChAT and/or increasing levels of acetylcholine in the hippocampus and frontal cortex regions of the brain and/or inhibiting conditions or detrimental effects caused by a decrease of choline acetyltransferase and/or acetyl in mammals. When a compound of formula I is co-administered with an AChE inhibitor the term “effective amount” also means an amount of such an agent capable of inhibiting AChE.
The term “estr
Bryant Henry Uhlman
Glinn Michele Annette
Paul Steven Marc
Wu Xin
Boudreaux William R.
Eli Lilly and Company
Jones Dwayne C.
Voy Gilbert T.
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