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Substituted quinolone carboxylic acids, their derivatives, site of action, and uses thereof

Substituted quinolone carboxylic acids, their derivatives, site of action, and uses thereof description/claims

This application claims priority to U.S. provisional application Ser. No. 60/380,641, filed on May 14, 2002.

This invention is in the field of medicinal chemistry. In particular, the invention relates to substituted quinolone carboxylic acids and their derivatives, which modulate, via a unique site, the effect of γ-aminobutyric acid (GABA) on the GABAA receptor complex in a therapeutically relevant fashion and may be used to ameliorate CNS disorders amenable to modulation of the GABAA receptor complex.

GABA is the most abundant inhibitory neurotransmitter in the mammalian brain. GABA controls brain excitability by exerting inhibitory functions on neuronal membranes by altering their permeability to specific ions. Binding of GABA to the GABAA-type (GABAA) receptor increases the permeability of neuronal membranes to chloride ions (Cl−). In most neurons the relative Cl− ion concentration is greater outside than the inside the membrane. Thus, selective permeability to Cl− initiated by GABA binding allows Cl− to flow down its electrochemical gradient into the cell. The majority of fast inhibitory synaptic transmission is a result of GABA binding to the GABAA receptors. GABAA receptors are ubiquitously expressed throughout the CNS with almost all neurons staining for their presence. The GABAA receptor is a hetero-pentameric protein structure of the nicotinic acetylcholine receptor superfamily. Native GABAA receptors are formed from at least 19 related subunits. The subunits are grouped into α, β, δ, ε, π, and ρ families. The most prevalent combination of GABAA receptors is a stoichiometric combination of the 2×α, 2×β, and 1×γ subunits, with the remaining subunits relegated to substituting for the γ subunit during specific development expression or in highly specific brain region localization. The adult brain predominately express the α1β2γ2 subunit combination (60%) with the α2β3γ2 and α3βnγ2 subunits comprising the majority (35%) of the remaining receptors. The relative effects of GABA are influenced by the GABAA receptor subunit expressed in a specific brain region or neuronal circuit.

The neurophysiological effects of GABA result from a conformational change that occurs when GABA binds to the GABAA receptor. The GABAA receptor and the associated ion channel complex (GRC) is a ligand-gated ion channel which recognizes many compounds that allosterically modulate the ability of GABA to bind to the GABAA receptor. The allosteric modulators have distinct sites on the GRC. These sites are separate and unique from the site that recognizes GABA. The most widely studied and characterized class of allosteric modulator of the GRC is that which interact with the benzodiazepine (BZ)-site.

Alternative sites for modulating the GRC have been described. For example, neuroactive steroids are non-hormonal steroids that bind and functionally modulate the GRC. The current role of neuroactive steroids in GABAA receptor pharmacology is supported by overwhelming evidence. Electrophysiological and biochemical techniques have confirmed the capacity of neuroactive steroids to allosterically modulate the GRC through a unique site of action. Experimentally neuroactive steroids exhibit a pharmacological profile similar, but not identical, to the benzodiazepines. Neuroactive steroids produce anxiolytic, anticonvulsant, and sedative-hypnotic properties.

Certain antibacterial fluoroquinolone antibiotics have been implicated in clinical reports as the cause of convulsions in humans (Ball P (1986) Journal of Antimicrobial Chemotherapy. 18 Suppl D 187-193; Simpson K J, Brodie M J (1985) Lancet ii. 161, 1985; Hori S, et al. (1987) Program and Abstracts of the Twenty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, New York 1987. Abstract 30, pg 101). Experimentally, fluoroquinolones have been demonstrated to produce convulsions and death in mice. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) and their by-products have been reported to clinically and experimentally potentiate the convulsive effects of the fluoroquinolones. Concerns about the convulsant side-effects of fluoroquinolone antibacterial agents have led to an interest in the interaction of fluoroquinolones with the GABAA receptor. Convincing evidence has accumulated that suggests that they interact with the GRC to inhibit GABA action. Fluoroquinolones antagonize [3H]muscimol and [3H]GABA binding to the GRC with high micromolar potency. Electrophysiological studies have demonstrated that fluoroquinolones alone weakly reduce GABA-evoked currents. As well, radioligand binding assays have shown that fluoroquinolones, in combination with NSAIDs, induce a conformational change in the GABAA receptor-chloride channel complex that is indicative of a pharmacologically relevant response consistent with functional antagonism of GABA.

It is well-documented that modulation of the GRC can ameliorate anxiety, seizure activity, and insomnia. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs) such as Valium) produce their therapeutically useful effects by interacting with specific modulatory sites on the GRC. None of the known drugs, however, are selectively potent at the α-2 subunit of the GABA receptor. Thus, they exhibit undesirable side effects of sedation, and in the case of fluoroquinolones, convulsions. There is presently a need for GRC modulators that are active without side effects.

The present invention relates to molecules that modulate the GRC with selective potency at the α-2 subunit of GABA to produce therapeutically useful effects without side effects. The present invention further relates to substituted quinolones represented by Formula I that act as enhancers of GABA-facilitated Cl− flux mediated through the GABAA receptor complex (GRC).

The invention also relates to methods of treating disorders responsive to enhancement of GABA action on GABA receptors in a mammal by administering an effective amount of a compound of Formula I and by activation of the novel site which mediates the action of a compound of Formula I as described herein. The novel site is defined by exclusion criteria where a compound of Formula I does not act on known sites of the GRC which include the sites for GABA, benzodiazepines, neuroactive steroids, t-butylbicyclophosphorothionate/picrotoxin, barbiturates, 4′-chlorodiazepam, antibacterial quinolones, ivermectin, loreclezole/mefanamic acid, furosemide and propofol (E. R. Korpi, G. Grunder, H. Luddens, Progress Neurobiology 67:113-159, 2002).

The compounds of the present invention, being ligands for a unique site on the GRC, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; acute and chronic pain; cognitive disorders; insomnia; migraine; and depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder.

Another aspect of the present invention is directed to the use of the site that mediates the activity of compounds of Formula I as enhancers or inhibitors of GABA-facilitated Cl− conductance mediated through the GABAA receptor complex. Enhancement of GABA-mediated chloride conductance is useful for the treatment and prevention of such disorders as anxiety and stress related disorders, depression and other affective disorders, epilepsy and other seizure disorders, insomnia and related sleep disorders, and acute and chronic pain. Inhibition of GABA-mediated chloride conductance is useful for the treatment and prevention of disorders related to learning and memory such as mild cognitive impairment, age related cognitive decline, senile dementia, Alzheimer's disease, sleep disorders involving reduced wakefulness such as narcolepsy and idiopathic hypersomnia.

Also, an aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the enhancement GABA-facilitated Cl− flux mediated through the GRC, containing an effective amount of a compound of Formula I in a mixture with one or more pharmaceutically acceptable carriers or diluents.

Compounds useful in the present invention have not been heretofore reported. Thus, the present invention is also directed to novel substituted quinolones having the structure of Formula I.

Further, the present invention is directed to 3H, 35S, 36Cl, 125I, 131I and 14C radiolabeled compounds of Formula I and their use as a radioligand for their binding site on the GRC.

Additional embodiments and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

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