Bridged bicyclic compounds and derivatives thereof as antiepileptic agents and methods of use thereof

Abstract

The method for preventing or treating seizures and treating epilepsy in an individual includes administering a bridged bicyclic small molecule compound. When administered in a therapeutically effective amount, these compounds exhibit antiepileptic activity in an individual. This method and use of the antiepileptic compound provides protection from seizures at low and high doses of the compound without toxic effects.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 399,312, filed August 19, 2022. The entire disclosure of the above application is incorporated herein by reference.

[0002] [Field of the Invention] The present invention relates generally to the fields of pharmacology, medicine and neurology, and more particularly to methods for treating or preventing seizures and treating epilepsy by administering compounds that exhibit antiepileptic effects.

[0003] [Statement Regarding Federally Sponsored Research] This invention was made with government support under Grant No. GM110651 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0004] Epilepsy is a common condition in the United States, affecting approximately 1.2% of the population. Epilepsy is diagnosed after two or more seizures, which occur when increased neuronal excitability causes confusion, muscle spasms, and sometimes loss of consciousness. Despite its high incidence, few new antiepileptic drugs (AEDs) have been approved by the FDA in recent years, leaving one-third of patients undertreated. Existing medications (e.g., sodium valproate, valproic acid, phenytoin, and levetiracetam) remain effective but are often associated with side effects. Recent literature suggests that 30% of adults with new-onset epilepsy exhibit AED-resistant seizures (Galanopoulou et al., Epilepsia, 2012, 53(3), 571-582; Dalic et al., Neuropsychiatric Disease and Treatment, 2016, 12, 2605; Mohanraj R. and Brodie MJ, Seizure, 2005, 14(5), 318-323). Furthermore, previously treatable patients subsequently develop AED resistance, further highlighting the need for the development of more effective treatments (Loescher et al., 2020, Pharmacol. Rev., 72, 606-638). Therefore, there is an urgent need for new, potent AEDs, particularly from lesser-known compound classes, that can provide alternatives for patients who do not respond to existing medications. The majority of existing FDA-approved AEDs have heterocyclic skeletons with varying degrees of unsaturation. Recent efforts over the past decade have not shown any significant changes to this heterocyclic motif (Oezbek, O.; Guerdere, MB, Med. Chem. Res. 2020, 29, 1553-1578). Summary of the Invention

[0005] Described herein are methods for preventing or treating seizures and treating epilepsy in an individual. The methods include administering to the individual a therapeutically effective amount of a compound that exhibits antiepileptic activity in the individual. These antiepileptic compounds mostly contain saturated, all-carbon bridged bicyclic skeletons, specifically, a highly "three-dimensional" core skeleton and five contiguous chiral centers. In experiments using the methods described herein and the antiepileptic compounds described below, protection from seizures was observed at low and high concentrations of the compounds without evidence of toxic effects. In vivo experiments using the C. elegans assay described below provide evidence that epileptic seizures can be prevented.

[0006] Therefore, here, Equation 1:

[0007] [ka]

[0008] or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, wherein: Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo; X is R 1 or R 2 is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 or arylamino, R 1 and R 2 are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R 3is arylCH=CH, alkylCH=CH, or alkyl; R 4 is H, alkyl, or aryl, and R 5 and R 6 are independently alkyl.

[0009] In this method, the compound is administered in a therapeutically effective amount that exhibits antiepileptic activity in the individual. The therapeutically effective amount is a dose of about 0.001 mg / kg to about 10 mg / kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, or 10.1 mg / kg). In typical embodiments, the individual is a human, but may be any animal (e.g., a mammal, such as a rodent, dog, cat, cow, or non-human primate). In embodiments, administration of the compound to the individual alleviates epileptic symptoms and shortens the duration of seizures without evidence of toxic effects. In embodiments, administering the compound to an individual shortens the recovery time if the individual experiences a seizure. The compound can exhibit antiepileptic activity in the presence of a proconvulsant. In this method, the compound is typically present in a composition that also includes a pharmaceutically acceptable carrier. Typically, the compound is administered to the individual before the onset of a seizure.

[0010] In some embodiments of the antiepileptic compound, alkyl is a saturated hydrocarbon moiety containing up to 6 carbons and aryl is a 5- or 6-membered aryl or heteroaryl group. In some embodiments, alkyl is alkyloxy, alkylamino, alkylCH=CH, or alkylcarbonyl. In one embodiment, the compound has the formula:

[0011] [ka]

[0012] or an enantiomer or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has the formula:

[0013] [ka]

[0014] or an enantiomer or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has the formula:

[0015] [ka]

[0016] or an enantiomer or a pharmaceutically acceptable salt thereof.

[0017] Also, here, Equation 2:

[0018] [ka]

[0019] or an enantiomer, diastereomer, racemic mixture, analog, derivative, or pharmaceutically acceptable salt or solvate thereof, wherein: Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo; X is R 1 or R 2 is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 or arylamino, R 1 and R 2 are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R 3 is arylCH=CH, alkylCH=CH, or alkyl; R 4 is H, alkyl, or aryl, and R 5 and R 6 are independently alkyl.

[0020] In an embodiment of such a method, the compound has the formula:

[0021] [ka]

[0022] or an enantiomer, diastereomer, racemic mixture, analog or derivative or pharmaceutically acceptable salt thereof.

[0023] Terms such as "group," "functional group," "pendant group," "moiety," and "molecular moiety" are somewhat synonymous in the chemical arts and are used to refer to distinct and definable portions or units of a molecule and units that exhibit some function. Examples of functional groups suitable for the compounds described herein include, but are not limited to, aryl or heteroaryl groups, alkoxy, alkylamino, alkylthio, dialkylamino, halo, hydroxy, amino, thiol, arylamino, alkanoyl, arylcarbonyl, arylvinyl, alkylvinyl, and the like.

[0024] The term "aryl" as used herein refers to aromatic hydrocarbons such as phenyl and naphthyl, which may be substituted with various functional groups and / or alkyl groups (eg, C1-C6 alkyl).

[0025] The term "heteroaryl" as used herein refers to an aromatic ring in which one or more heteroatoms form part of the ring, and the heteroaryl ring may be substituted with various functional groups and / or alkyl groups (e.g., C1-C6 alkyl).

[0026] As used herein, the term "alkyl" refers to a saturated hydrocarbon fragment. For example, in one embodiment, an alkyl can be a saturated hydrocarbon moiety containing up to 6 carbons (e.g., methyl, ethyl, propyl, isopropyl).

[0027] The term "alkoxy," as used herein, refers to a group consisting of an alkyl group attached to an oxygen (eg, methoxy, ethoxy).

[0028] The term "alkylamino," as used herein, refers to a group consisting of an alkyl group attached to a trivalent nitrogen (e.g., methylamino, ethylamino).

[0029] The term "dialkylamino" as used herein refers to a group consisting of two alkyl groups (not necessarily the same) attached to a trivalent nitrogen (e.g., dimethylamino, diethylamino, ethylmethylamino).

[0030] The term "arylamino," as used herein, refers to an aryl group attached to a trivalent nitrogen.

[0031] The term "alkanoyl" as used herein refers to an alkyl group linked to a carbonyl.

[0032] The term "arylcarbonyl," as used herein, refers to an aryl group attached to a carbonyl.

[0033] The term "arylvinyl," as used herein, refers to an aryl group attached to an ethylene group (e.g., phenylvinyl, also abbreviated as CHCHCH).

[0034] The term "alkylvinyl," as used herein, refers to an alkyl group attached to an ethylene group (e.g., methylvinyl, also abbreviated as CH3CHCH).

[0035] The term "halo" or "halogen" as used herein refers to F, Cl, Br, or I.

[0036] The terms "biologically active compound" and "bioactive compound," when referring to a compound herein, mean a compound that has a physiological or biological effect on animals or humans, or cells derived therefrom.

[0037] The term "antiepileptic compound" refers to any compound that exhibits antiepileptic function. Typically, an antiepileptic compound is capable of treating (alleviating, reducing) epilepsy (e.g., protecting against seizures) in an individual. In some embodiments, the antiepileptic compound has Formula 1:

[0038] [ka]

[0039] or a pharmaceutically acceptable salt or solvate thereof, wherein Ar=aryl, Y=alkyl, alkyloxy, alkylamino, R 5 R 6 N, and aryl substituents selected from the group consisting of halo (ortho, meta, or para), X=O, N, or S, R=H, alkyl, aryl, OH, alkyloxy, aryloxy, NH, alkylamino, R 5 R 6 N, or arylamino, R 1 and R 2 = independently alkylcarbonyl, arylcarbonyl, alkyl, or H(R 1 and R 2 may be the same group or different groups), R 3 = Aryl CH=CH, alkyl CH=CH, alkyl, R 4= H, alkyl, or aryl, and R5 and R6 = independently alkyl (R 5 and R 6 may be the same group or different groups).

[0040] In other embodiments, the antiepileptic compound has Formula 2:

[0041] [ka]

[0042] or an enantiomer, diastereomer, racemic mixture, or pharmaceutically acceptable salt or solvate thereof, wherein Ar is aryl and Y is alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo, and X is an ortho, meta, or para aryl substituent selected from the group consisting of R 1 or R 2 and R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 or arylamino, and R 1 and R 2 are independently alkylcarbonyl, arylcarbonyl, alkyl, or H, and R 3 is arylCH=CH, alkylCH=CH, or alkyl, and R 4 is H, alkyl, or aryl, and R 5 and R 6 are independently alkyl.

[0043] The terms "resveramorph" and "RVM," as shown in Figure 1, refer to a skeleton that is a modified form of the resveratrol natural product, containing distinctive three-dimensional features, specifically a bridged bicyclic ring. As described in Example 1 below, some resveramorphs, including RVM-3, exhibit antiepileptic properties.

[0044] The term "purified" means separated from many other entities (small molecules, compounds, proteins, nucleic acids), and does not require that the material be present in a form that exhibits absolute purity, excluding the presence of other entities. In some embodiments, a small molecule, compound, protein, nucleic acid, or other entity is considered pure (purified) when it has been removed from substantially all other entities.

[0045] The terms "modulating" and "modulate" mean to increase or decrease. These terms can refer to an increase or decrease in the activity, concentration, or function of a molecule (e.g., a protein, peptide, nucleic acid, small molecule, metabolite), or to effecting a change in one or more biological or physiological mechanisms, effects, responses, functions, pathways, or activities involving, for example, seizures.

[0046] The terms "patient," "subject," and "individual" are used interchangeably herein and refer to a subject, typically a mammal, for treatment, diagnosis, and / or collection of biological samples. Subjects include, but are not limited to, humans, non-human primates, horses, cows, sheep, pigs, rats, mice, insects, dogs, and cats. A human in need of treatment for epilepsy or seizures is one example of a subject.

[0047] As used herein, the terms "pharmaceutical agent" and "therapeutic agent" refer to a chemical or biological product, or a combination of chemical or biological products, that is administered to a subject (a mammal such as a human) to treat a disease or condition (e.g., epilepsy, seizures). Examples of therapeutic agents include small molecules (compounds) and biologics, which may be referred to herein as "drugs" or "therapeutic agents."

[0048] The terms "therapeutic treatment" and "treatment," as used herein, are defined as the application or administration of a therapeutic agent (e.g., an antiepileptic compound described herein, or a composition comprising an antiepileptic compound) to a patient having a disease, a symptom of a disease, or a predisposition to a disease, for the purpose of curing, alleviating, mitigating, altering, treating, ameliorating, or affecting the disease, symptom of a disease, or predisposition to a disease.

[0049] Although methods, compounds, and compositions similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods, compounds, and compositions are described below. All publications, patent applications, and patents mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. The specific embodiments described below are for illustrative purposes only and are not limiting. [Brief explanation of the drawings]

[0050] [Figure 1] 1 shows the structures of several RVM compounds evaluated for antiepileptic activity. [Figure 2] Graph (first two bars) showing the recovery time (seconds) of N2 nematodes (vertical axis) in the presence of M9 or pentylenetetrazole (PTZ). In other experiments, PTZ is combined with either RVM or sodium valproate. [Figure 3] On the left is the structure of RVM-3, and on the right is a graph (first two bars) showing the recovery time (seconds) of N2 nematodes (vertical axis) in the presence of M9 or PTZ. In other experiments, PTZ was combined with RVM-3 or sodium valproate at various concentrations. [Figure 4] FIG. 1 is a schematic diagram of the C. elegans electroshock assay. DETAILED DESCRIPTION OF THE INVENTION

[0051] Methods for preventing or treating seizures and treating epilepsy in an individual are described herein. The methods include administering to the individual an antiepileptic compound of Formula 1 or Formula 2, or a composition containing an antiepileptic compound of Formula 1 or Formula 2, at a therapeutically effective amount such that the antiepileptic compound exhibits antiepileptic function in the individual. In the C. elegans electroshock experiments described below, the antiepileptic compounds RVM-3, RVM-6, RVM-11, and RVM-12 restored C. elegans function in the presence of a seizure-promoting agent, while RVM-3 treatment of animals in the absence of a seizure-promoting agent resulted in a normal recovery time. In these experiments, treatment with the antiepileptic compounds was not associated with any toxic effects. Experimental results demonstrate that the antiepileptic compounds (RVMs) alleviate the symptoms and duration of seizures in an in vivo model.

[0052] In an embodiment of this method, an individual in need thereof (e.g., an individual having a seizure, an individual prone to seizures, an individual with epilepsy) is administered a dose of Formula 1:

[0053] [ka]

[0054] or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo; X is R 1 or R 2 is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 or arylamino, R 1 and R2 are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R 3 is arylCH=CH, alkylCH=CH, or alkyl; R 4 is H, alkyl, or aryl, and R 5 and R 6 are independently alkyl.

[0055] In another embodiment of this method, an individual in need thereof (e.g., an individual experiencing seizures, an individual prone to seizures, an individual with epilepsy) is administered a dose of Formula 2:

[0056] [ka]

[0057] or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, wherein Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo; X is R 1 or R 2 is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 or arylamino, R 1 and R 2 are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R 3 is arylCH=CH, alkylCH=CH, or alkyl; R 4is H, alkyl, or aryl, and R 5 and R 6 are independently alkyl.

[0058] The compound is administered in a therapeutically effective amount that exhibits antiepileptic activity in an individual, typically at a dose of about 0.001 mg / kg to about 10 mg / kg. In this method, administering the compound to an individual can alleviate epileptic symptoms and shorten the duration of seizures without evidence of toxic effects. As described in Example 1, the antiepileptic compound exhibits antiepileptic activity in the presence of a proconvulsant. Also, in this method, administering the compound to an individual can shorten the recovery time if the individual experiences a seizure. The antiepileptic compound can be administered to an individual at one or more time points (e.g., a first time point and a second time point), including before, at, or during the onset of a seizure.

[0059] The compounds described herein may exist as diastereomeric isomers different from those exemplified, both as racemic, non-racemic or optically pure forms. Analogs and derivatives of the compounds described herein are also encompassed by the present invention.

[0060] In one embodiment of the antiepileptic compound according to Formula 1 or Formula 2, alkyl is a saturated hydrocarbon moiety containing up to six carbons, and aryl is a five- or six-membered aryl or heteroaryl group. Any suitable alkyl can be used. Examples of alkyl-containing substituents that can be used in the antiepileptic compounds described herein include alkyloxy, alkylamino, alkylCH═CH, and alkylcarbonyl. Similarly, any suitable aryl can be used. Examples of aryl-containing substituents that can be used in the compounds described herein include arylcarbonyl, arylamino, and arylvinyl. When an aryl substituent is referred to, it can be, for example, ortho-, meta-, and / or para-substituted.

[0061] The antiepileptic compounds of formula 1 used in the methods described herein and their synthesis are described in U.S. Patent No. 10,759,735, the entire contents of which are incorporated herein by reference. The novel antiepileptic compounds of formula 2 can be synthesized from formula 1, which itself can be obtained using previously reported methods (e.g., U.S. Patent No. 10,759,735). The conversion of formula 1 to formula 2 can be achieved by an alkene addition reaction (e.g., hydrogenation). The antiepileptic compounds can be synthesized using any suitable method.

[0062] In one embodiment of the antiepileptic compound of Formula 1, the compound has the following formula (and its enantiomers):

[0063] [ka]

[0064] In another embodiment of the antiepileptic compound of Formula 1, the compound has the following formula (and its enantiomers):

[0065] [ka]

[0066] In another embodiment of the antiepileptic compound of Formula 1, the compound has the following formula (and its enantiomers):

[0067] [ka]

[0068] In one embodiment of the antiepileptic compound of Formula 2, the compound has the following formula (and its enantiomers):

[0069] [ka]

[0070] In some embodiments, the antiepileptic compounds described herein include any other combination of structural features described herein.

[0071] Compositions comprising an antiepileptic compound according to any of the embodiments described herein typically also include a pharmaceutically acceptable carrier.

[0072] In some embodiments, the individual suffers from or is prone to suffer from seizures.The antiepileptic compounds and compositions described herein can be used to treat, alleviate, or prevent any type of seizure, such as seizures caused by something that disrupts the normal connections between neurons in the brain.In addition to epilepsy, examples of conditions that can cause seizures include drug and alcohol withdrawal, fever, stroke, meningitis, etc.

[0073] Any suitable method of administering the antiepileptic compounds or compositions described herein to an individual can be used. In these methods, the compounds and compositions can be administered to an individual by any suitable route, for example, oral, buccal (e.g., sublingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), and topical (i.e., both cutaneous and mucosal surfaces, including respiratory tract surfaces) administration. In one embodiment, the antiepileptic compound or composition can be administered systemically by intravenous injection. In another embodiment, the antiepileptic compound or composition can be administered directly to the target site, for example, by surgical delivery to an internal or external target site (e.g., the brain) or by a catheter to a vascularly accessible site. When administered intravenously, the compound or composition can be administered by a single bolus, multiple injections, or continuous infusion (e.g., intravenous, peritoneal dialysis, pump infusion). For parenteral administration, the compound or composition is preferably formulated in a sterile, pyrogen-free form.

[0074] As mentioned above, the antiepileptic compounds or compositions described herein may be in a form suitable for sterile injection. To prepare such compositions, a suitable active therapeutic agent (e.g., a therapeutically effective amount of an antiepileptic compound) is dissolved or suspended in a parenterally acceptable liquid vehicle. Acceptable vehicles and solvents that can be used include water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, and dextrose solution (D5W, 0.9% sterile saline). Aqueous formulations may also contain one or more preservatives (e.g., methyl, ethyl, or n-propyl p-hydroxybenzoate). If the therapeutic agent (one or more antiepileptic compounds) is poorly or slightly soluble in water, a solubility enhancer or solubilizer may be added, or the solvent may contain 10-60% w / w propylene glycol, etc. The compounds and compositions described herein can be administered to individuals (e.g., rodents, humans, non-human primates, dogs, cats, sheep, cattle, insects) in any suitable formulation in accordance with conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (21st ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, (3rd ed.) eds. J. Swarbrick and J.C. Boylan, Marcel Dekker, CRC Press, New York (2006), standard texts in this field, and USP / NF). Descriptions of exemplary pharmaceutically acceptable carriers and diluents, as well as pharmaceutical formulations, can be found in Remington, supra. Other substances may be added to stabilize and / or preserve the compounds and compositions.

[0075] The therapeutic methods described herein generally involve administering a therapeutically effective amount of the antiepileptic compounds and compositions described herein to an individual (e.g., a human) in need thereof, particularly a human. Such treatment is suitably administered to an individual, particularly a human, who is afflicted with, suffering from, susceptible to, or at risk for a disease, disorder, or symptom thereof (e.g., epilepsy, seizures). Determination of an "at risk" individual can be made by diagnostic testing or by objective or subjective determination by the subject or a healthcare provider's opinion. The methods described herein can include measuring the antiepileptic efficacy of the antiepileptic compound. These methods can use any suitable protocol and / or model to measure the antiepileptic efficacy of the compound, including the C. elegans electroshock model described in Example 1.

[0076] [Effective dose] The antiepileptic compounds and compositions described herein are preferably administered to an individual in need thereof (e.g., a human suffering from epilepsy) in an effective amount, i.e., an amount capable of producing a desired outcome in the treated individual. Desired outcomes include, but are not limited to, one or more of: restoration of function (neurological, behavioral), achieving a normal recovery time, preventing seizures, etc. Such therapeutically effective amounts can be determined according to standard methods. The toxicity and therapeutic efficacy of the antiepileptic compounds and compositions used in the methods described herein can be determined by standard pharmaceutical procedures. As is well known in the medical and veterinary fields, the dosage for an individual will depend on many factors, including the individual's size, body surface area, age, the particular composition administered, the time and route of administration, general health, and other drugs administered concomitantly. The delivered dose of the antiepileptic compositions described herein is typically between about 0.001 mg / kg of the antiepileptic compound and about 10 mg / kg of the antiepileptic compound (e.g., 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.1) and can be determined based on preclinical efficacy and safety. The individual dose may be determined based on achieving the cellular drug concentration required for the cells involved to achieve normal function (i.e., cellular homeostasis). In the C. elegans experiments described here, animals were immersed in a drug solution. Even at very dilute concentrations (e.g., 10 picomolar), RVM-3 clearly exhibited an antiepileptic effect. This effect was at least 10,000 times more potent than drugs such as valproic acid and levetiracetam. Based on these results, the dose range for animals was estimated to be 0.001 mg / kg to approximately 10 mg / kg. The usual starting dose of levetiracetam is 10 mg / kg. Levetiracetam is considered one of the most potent antiepileptic drugs. [Example]

[0077] The present invention is further illustrated by the following specific examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. [Example]

[0078] [Bridged bicyclic compounds and their derivatives as antiepileptic drugs] The compound known as resveramorph (RVM) (Figure 1) is used in the method described here as a highly potent antiepileptic agent, as measured in electroshock experiments in C. elegans (see below). The structure of these RVMs consists of a fully saturated, all-carbon bridged bicyclic backbone, a motif unprecedented in the AED literature. At concentrations of 100 μM, RVM-3, RVM-6, RVM-11, and RVM-12 restored function in C. elegans in the presence of the seizure-promoting agent PTZ (Figure 2). Further evaluation of RVM-3 revealed that normal recovery times were achieved at 10 pM compared to C. elegans animals not pretreated with PTZ (Figure 3). Protection was observed even at significantly higher concentrations, such as 100 μM, without evidence of toxic effects. Sodium valproate, an FDA-approved AED used as a control in these experiments, showed a relatively slow recovery of recovery times, even at concentrations of 3 mM (3000 μM). These data demonstrate that RVM reduces the symptoms and duration of seizures, and it is anticipated that RVM-based pharmacological interventions may provide seizure relief at low doses.

[0079] In the C. elegans seizure assay, L4 C. elegans are placed in a small tube capped on both sides with copper wire. A 47V shock is then administered for 3 seconds. The worms become rigidly paralyzed and exhibit irregular unilateral stiffening and flexion of their body, suggesting the muscle spasms seen in hyperthermic seizures. Recovery is recorded when the animals demonstrate three equal sinusoidal movements, which are then characterized as normal swimming movements. GABA AThe use of the receptor antagonist pentylenetetrazole (PTZ) enhances the seizure-like phenotype seen in C. elegans. Application of PTZ prevents the binding of GABA to this receptor, and because GABA is an inhibitory neurotransmitter, this generates a large excitatory signal, causing seizure-like behavior in the animals (Thapliyal, S.; Babu, K, Bio-protocol, 2018, 8(17), e2989). Previous studies have demonstrated that using this method on loss-of-function mutants, unc-25 and unc-49, requires significantly longer recovery times compared to wild-type mutants. unc-25 encodes the GABA biosynthetic enzyme GAD, and unc-49 encodes the GABA biosynthetic enzyme GAD. A This gene encodes a receptor, which reduces the inhibitory signal to the muscle, leading to the results observed here. Importantly, additional administration of PTZ to these animals increases their sensitivity to electric shock. However, treating the mutant animals with antiepileptic drugs such as retigabine, Keppra (levetiracetam), or sodium valproate restores this increased sensitivity. Therefore, this method is a proven model for screening AEDs.

[0080] This C. elegans assay provides a novel model for assessing electroconvulsive seizures (Figure 4). Few previous reports have described the seizure susceptibility of C. elegans (Pandey et al., Seizure 2010, 19(7), 439-442), and none have examined electroconvulsive seizures. This assay allows for rapid and efficient evaluation of the antiepileptic effects of compounds. In this assay, approximately 10 C. elegans worms are inserted into a transparent tube containing M9 saline. Both sides of the tube are blocked with copper wires attached to a square-wave pulse generator, with the electrodes spaced 1 cm apart. The M9 saline ensures uniform current conduction. For tests involving RVM and PTZ (72 mM), the test compound is added directly to the M9 solution, and the worms are incubated in the RVM solution for 30 minutes before testing. A 47V electric shock is administered for 3 seconds, causing the worms to become rigidly paralyzed, with one side stiffening and bending. This suggests muscle spasms, which are seen in hyperthermic seizures. Recovery was recorded when the animals exhibited three sinusoidal movements, after which they were characterized as normal swimming movements. These analyses were performed under a microscope equipped with a camera and attached recording device, allowing for subsequent further evaluation. In this seizure model, we observed that the time to recovery was shortened when animals were treated with various concentrations of RVM.

[0081] [Other embodiments] Any modifications may be made to some or all of the antiepileptic compounds, compositions, and method steps. All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference. Any examples provided herein or the use of exemplary language (such as "e.g.," "etc.", etc.) are intended to clarify the invention and do not limit the scope of the invention, unless specifically recited in the claims. Any statements herein regarding the nature or advantages of the invention or preferred embodiments are not intended to be limiting, and the appended claims should not be deemed to be limited by such statements. More generally, no language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. The invention includes all modifications and equivalents (such as analogs and derivatives) of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of all possible variations of the above-described elements is encompassed by the invention unless otherwise stated herein or clearly contraindicated by context.

Claims

1. Formula 1: 【Chemical 1】 or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, to the individual, Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR ５ R ６ and halo; X is R １ or R ２ is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH ２ , alkylamino, NR ５ R ６ or arylamino, R １ and R ２ are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R ３ is arylCH═CH, alkylCH═CH, or alkyl; R ４ is H, alkyl, or aryl, and R ５ and R ６ are independently alkyl, The compound is administered in a therapeutically effective amount that exhibits antiepileptic activity in the individual.

2. 10. The method of claim 1, wherein the therapeutically effective amount is a dose of about 0.001 mg / kg to about 10 mg / kg.

3. The compound has the formula: 【Chemistry 2】 10. The method of claim 1, wherein the compound has the formula:

4. 10. The method of claim 1, wherein administering the compound to an individual alleviates epileptic symptoms and reduces seizure duration without evidence of toxic effects.

5. 10. The method of claim 1, wherein the compound exhibits antiepileptic activity in the presence of a convulsant.

6. 10. The method of claim 1, wherein administering the compound to an individual reduces recovery time if the individual suffers a seizure.

7. 10. The method of claim 1, comprising administering the compound to the individual before the onset of a seizure.

8. The method of claim 1 , wherein the compound is contained within a composition comprising a pharmaceutically acceptable carrier.

9. The method of claim 1 , wherein the individual is a mammal.

10. Formula 2: 【Chemistry 3】 or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, to the individual, Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR ５ R ６ and halo; X is R １ or R ２ is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH ２ , alkylamino, NR ５ R ６ or arylamino, R １ and R ２ are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R ３ is arylCH═CH, alkylCH═CH, or alkyl; R ４ is H, alkyl, or aryl, and R ５ and R ６ are independently alkyl, The compound is administered in a therapeutically effective amount that exhibits antiepileptic activity in the individual.

11. formula: 【Chemistry 4】 1. A method of preventing or treating seizures and treating epilepsy in an individual comprising administering to the individual a compound having the formula: The compound is administered in a therapeutically effective amount that exhibits antiepileptic activity in the individual.

12. Formula 2: 【Chemistry 5】 or an enantiomer, diastereomer, racemic mixture, or pharmaceutically acceptable salt or solvate thereof, Ar is aryl; Y is alkyl, alkyloxy, alkylamino, NR ５ R ６ and halo; X is R １ or R ２ is O, S, or NH bonded to R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH ２ , alkylamino, NR ５ R ６ or arylamino, R １ and R ２ are independently alkylcarbonyl, arylcarbonyl, alkyl, or H; R ３ is arylCH═CH, alkylCH═CH, or alkyl; R ４ is H, alkyl, or aryl, and R ５ and R ６ are independently alkyl; The compound, or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof.

13. formula: 【Chemistry 6】 13. The compound of claim 12, having the formula:

14. 13. A composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.

15. The compound has the formula: 【Chemistry 7】 15. The composition of claim 14, having the formula:

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