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WO2024039435A1 - Composés bicycliques pontés et leurs dérivés en tant qu'agents antiépileptiques, et leurs procédés d'utilisation - Google Patents

Composés bicycliques pontés et leurs dérivés en tant qu'agents antiépileptiques, et leurs procédés d'utilisation Download PDF

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Publication number
WO2024039435A1
WO2024039435A1 PCT/US2023/025444 US2023025444W WO2024039435A1 WO 2024039435 A1 WO2024039435 A1 WO 2024039435A1 US 2023025444 W US2023025444 W US 2023025444W WO 2024039435 A1 WO2024039435 A1 WO 2024039435A1
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Prior art keywords
alkyl
compound
individual
aryl
antiepileptic
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Inventor
Salvatore D. Lepore
Samantha E. STILLEY
Krishna YADAVALLI
Ken Dawson-Scully
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Florida Atlantic University
Nova Southeastern University
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Florida Atlantic University
Nova Southeastern University
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Priority to EP23855286.3A priority Critical patent/EP4572747A1/fr
Priority to JP2025507518A priority patent/JP2025528158A/ja
Priority to KR1020257008754A priority patent/KR20250051729A/ko
Priority to CA3264333A priority patent/CA3264333A1/fr
Publication of WO2024039435A1 publication Critical patent/WO2024039435A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/18—Acetic acid esters of trihydroxylic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms

Definitions

  • the invention relates generally to the fields of pharmacology, medicine, and neurology.
  • the invention relates to methods of treating or preventing seizures and treating epilepsy by administering compounds exhibiting antiepileptic effects.
  • Epilepsy is a prevalent disease in the United States, with about 1.2% of the population being affected. Epilepsy can be diagnosed following two or more seizures that occur oftentimes when there is increased neuronal excitability that causes disturbances and muscle convulsions, and in some, loss of consciousness. Although the occurrence is high, few new antiepileptic drugs (AEDs) have been FDA-approved in recent years and one-third of patients find themselves without sufficient treatment. Existing drugs (e g., sodium valproate, valproic acid, phenytoin, levetiracetam) remain effective, but they are often accompanied by side-effects.
  • AEDs antiepileptic drugs
  • Described herein are methods of preventing or treating seizures and treating epilepsy in an individual.
  • the methods include administration of compounds exhibiting antiepileptic effects to the individual in a therapeutically effective amount to exhibit antiepileptic function in the individual.
  • These antiepileptic compounds contain a mostly saturated all-carbon bridged bicyclic scaffold, specifically, a highly ‘three-dimensional’ core scaffold and the presence of five contiguous chiral centers.
  • protection from seizures was observed at low and higher concentrations of compound without evidence of a toxic effect.
  • the in vivo experiments, using the C. elegans assay, described below provide evidence that an epileptic attack can be prevented.
  • a method of preventing or treating seizures and treating epilepsy in an individual including administering to the individual a compound of Formula 1 : or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • Ar is aryl
  • Y is an ortho, meta, or para aryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo;
  • X is O, S, or NH bonded to R 1 or R 2 ;
  • R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 , or arylamino;
  • R 1 and R 2 are alkylcarbonyl, arylcarbonyl, alkyl, or H, individually;
  • R 4 is H, alkyl, or aryl
  • R 5 and R 6 are alkyl, individually.
  • the compound is administered in a therapeutically effective amount to exhibit antiepileptic function 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, 10.1 mg/kg).
  • the individual is a human, but can be any animal (e.g., mammals such as rodents, canines, cats, bovines, non-human primates, etc.).
  • administering the compound to the individual alleviates epileptic symptoms and decrease duration of seizures without evidence of a toxic effect. In embodiments, administering the compound to the individual decreases time to recovery when the individual experiences a seizure.
  • the compound can exhibit antiepileptic function in the presence of a pro-convulsant.
  • the compound is within a composition also including a pharmaceutically acceptable carrier.
  • the compound is administered to the individual prior to onset of a seizure.
  • alkyl is a saturated hydrocarbon moiety containing up to six carbons; and, aryl is a 5- or 6-membered aryl or heteroaryl group.
  • the compound has the formula: or an enantiomer, or a pharmaceutically acceptable salt thereof.
  • the compound has the formula: or an enantiomer, or a pharmaceutically acceptable salt thereof.
  • the compound has the formula: or an enantiomer, or a pharmaceutically acceptable salt thereof.
  • Also described herein is a method of preventing or treating seizures and treating epilepsy in an individual including administering to the individual a compound of Formula 2: or an enantiomer, diastereomer, racemic mixture, analogue, derivative or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • Ar is aryl
  • Y is an ortho, meta, or para aryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo;
  • X is O, S, or NH bonded to R 1 or R 2 ;
  • R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 , or arylamino;
  • R 1 and R 2 are alkylcarbonyl, arylcarbonyl, alkyl, or H, individually;
  • R 4 is H, alkyl, or aryl
  • R 5 and R 6 are alkyl, individually.
  • the compound can have the formula: or an enantiomer, diastereomer, racemic mixture, analogue or derivative or a pharmaceutically acceptable salt thereof.
  • group means "group,” “functional group,” “pendant group,” “moiety,” “molecular moiety,” or the like are somewhat synonymous in the chemical arts and are used to refer to distinct, definable portions or units of a molecule, and to units that perform some function.
  • Examples of functional groups that are suitable for the compounds described herein include, but are not limited to, aryl or heteroaryl group, alkyoxy, alkylamino, alkylthio, dialkylamino, halo, hydroxy, amino, thiol, arylamino, alkanoyl, arylcarbonyl, arylvinyl, alkylvinyl, or the like.
  • aryl refers to aromatic hydrocarbons such as phenyl and naphthyl that may be substituted with a variety of functional and/or alkyl groups (e.g., C1-C6 alkyl).
  • heteroaryl refers to aromatic cycles where one or more heteroatoms form part of the ring.
  • the heteroaryl ring may also be substituted with a variety of functional and/or alkyl groups (e g., C1-C6 alkyl).
  • alkyl refers to a saturated hydrocarbon fragment.
  • an alkyl can be a saturated hydrocarbon moiety containing up to six carbons (e.g., methyl, ethyl, propyl, isopropyl).
  • alkyoxy refers to a group comprised of an alkyl group connected to an oxygen (e.g., methoxy, ethyoxy)
  • alkylamino refers to a group comprised of an alkyl group connected to a trivalent nitrogen (e.g., methylamino, ethylamino).
  • dialkylamino refers to a group comprised of two alkyl groups (though not necessarily the same) connected to a trivalent nitrogen (e.g., dimethylamino, diethylamino, ethylmethylamino).
  • arylamino refers to an aryl group connected to a trivalent nitrogen.
  • alkanoyl refers an alkyl group connected to a carbonyl.
  • aryl carbonyl refers an aryl group connected to a carbonyl.
  • arylvinyl refers to an aryl group connected to an ethylene group (e.g., phenylvinyl, also abbreviated as CeH CHCH).
  • alkylvinyl refers to an alkyl group connected to an ethylene group (e.g., methylvinyl, also abbreviated as CH3CHCH).
  • halo refers to F, CI, Br, or I.
  • biologically active compound and “bioactive compound” mean a compound having a physiological or biological effect on animals or humans or cells therefrom.
  • antiepileptic compound any compound that exhibits antiepileptic function.
  • an antiepileptic compound is capable of treating (alleviating, mitigating) epilepsy (e.g., protection from seizures) in an individual.
  • resveramorph and “RVM” refer to scaffolds that are modified forms of resveratrol natural products that contain a significant amount of three- dimensional character, specifically, a bridged bicycle. As described in Example 1 below, some resveramorphs, including RVM-3, exhibit antiepileptic properties.
  • purified means separated from many other entities (small molecules, compounds, proteins, nucleic acids), and does not require the material to be present in a form exhibiting absolute purity, exclusive of the presence of other entities.
  • a small molecule, compound, protein, nucleic acid or other entity is considered pure (purified) when it is removed from substantially all other entities.
  • to modulate and “modulates” is meant to increase or decrease. These terms can refer to increasing or decreasing an activity, level or function of a molecule (e.g., protein, peptide, nucleic acid, small molecule, metabolite), or effecting a change with respect to one or more biological or physiological mechanisms, effects, responses, functions, pathways or activities in which, for example, seizures are involved.
  • a molecule e.g., protein, peptide, nucleic acid, small molecule, metabolite
  • patient typically a mammal, to be treated, diagnosed, and/or to obtain a biological sample from.
  • 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 epilepsy or seizure treatment is an example of a subject.
  • agent and “therapeutic agent” as used herein refer to a chemical entity or biological product, or combination of chemical entities or biological products, administered to a subject (a mammal such as a human) to treat a disease or condition (e.g., epilepsy, seizures).
  • therapeutic agents include small molecules (compounds) and biologies, which may be referred to herein as a “drug” or “therapeutic drug”.
  • a therapeutic agent e.g., an antiepileptic compound as described herein or composition including an antiepileptic compound
  • therapeutic agents e.g., an antiepileptic compound as described herein or composition including an antiepileptic compound
  • therapeutic agents e.g., an antiepileptic compound as described herein or composition including an antiepileptic compound
  • therapeutic agents e.g., an antiepileptic compound as described herein or composition including an antiepileptic compound
  • therapeutic agents e.g., an antiepileptic compound as described herein or composition including an antiepileptic compound
  • Figure 1 shows the structure of several RVM compounds evaluated for antiseizure activity.
  • Figure 2 is a graph showing recovery time (seconds) for N2 worms (vertical axis) in the presence of M9 or pentylenetetrazol (PTZ) (first two bars). In other experiments, PTZ is combined with either an RVM or sodium valproate.
  • PTZ pentylenetetrazol
  • FIG. 3 left is the structure of RVM-3
  • Figure 3 right is a graph showing recovery time (seconds) for N2 worms (vertical axis) in the presence of M9 or PTZ (first two bars).
  • PTZ is combined with RVM-3 at varying concentrations or sodium valproate.
  • Figure 4 is a schematic of a C. elegcms electroshock assay.
  • 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 I or Formula 2, such that the antiepileptic compound is in a therapeutically effective amount to exhibit antiepileptic function in the individual.
  • antiepileptic compounds RVM-3, RVM-6, RVM-11, and RVM-12 restored function to C. elegcms in the presence of a seizure promoting agent and RVM-3 treatment of animals in the absence of a seizure promoting agent resulted in normal recovery time.
  • treatment with the antiepileptic compounds was not associated with any toxic effect.
  • the experimental results show that the antiepileptic compounds (RVMs) alleviate symptoms and duration of seizure in an in vivo model.
  • a compound of Formula 1 or an enantiomer, diastereomer, racemic mixture or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • Ar is aryl
  • Y is an ortho, meta, or para aryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo;
  • X is O, S, or NH bonded to R 1 or R 2 ;
  • R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 , or arylamino;
  • R 1 and R 2 are alkylcarbonyl, arylcarbonyl, alkyl, or H, individually;
  • R 4 is H, alkyl, or aryl
  • R 5 and R 6 are alkyl, individually.
  • a compound of Formula 2 or an enantiomer, diastereomer, racemic mixture, or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • Ar is aryl
  • Y is an ortho, meta, or para aryl substituent selected from the group consisting of alkyl, alkyloxy, alkylamino, NR 5 R 6 and halo;
  • X is O, S, or NH bonded to R 1 or R 2 ;
  • R is H, alkyl, aryl, OH, alkyloxy, aryloxy, NH2, alkylamino, NR 5 R 6 , or arylamino;
  • R 1 and R 2 are alkylcarbonyl, arylcarbonyl, alkyl, or H, individually;
  • R 4 is H, alkyl, or aryl
  • R 5 and R 6 are alkyl, individually.
  • the compound is administered in a therapeutically effective amount to exhibit antiepileptic function in the individual, typically at a dose of about 0.001 mg/kg to about 10 mg/kg.
  • administering the compound to the individual can alleviate epileptic symptoms and decrease duration of seizures without evidence of a toxic effect.
  • the antiepileptic compounds exhibit antiepileptic function in the presence of a pro-convulsant.
  • administering the compound to the individual can decrease time to recovery when the individual experiences a seizure.
  • An antiepileptic compound can be administered to the individual at one or more time points (e.g., a first time point and a second time point), including prior to onset of a seizure, at onset, or during a seizure.
  • the compounds described herein may exist as different diastereomeric isomers than those exemplified both as racemates as well as non-racemic or enantiopure forms. Analogues and derivatives of the compounds described herein are also encompassed by the invention.
  • an alkyl is a saturated hydrocarbon moiety containing up to six carbons
  • an aryl is a 5- or 6- membered aryl or heteroaryl group.
  • Any suitable alkyl can be used.
  • 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 referring to an aryl substituent, it may be, for example, one that is ortho, meta and/or para substituted.
  • antiepileptic compounds according to Formula 1 used in the methods described herein, and their synthesis are described in U.S. Patent No. 10,759, 735, which is incorporated herein by reference in its entirety.
  • Novel antiepileptic compounds according to Formula 2 can be synthesized from Formula 1, which is itself 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 methods.
  • an antiepileptic compound according to Formula 1 the compound has the formula (and its enantiomer):
  • an antiepileptic compound according to Formula 1 the compound has the formula (and its enantiomer):
  • an antiepileptic compound according to Formula 1 the compound has the formula (and its enantiomer):
  • an antiepileptic compound according to Formula 2 the compound has the formula (and its enantiomer)
  • an antiepileptic compound as described herein encompasses any other combinations of the structural features described herein.
  • compositions including an antiepileptic compound according to any embodiments described herein typically also include a pharmaceutically acceptable carrier.
  • the individual is suffering from a seizure or seizures or is susceptible to suffering from a seizure(s).
  • the antiepileptic compounds and compositions described herein may be used to treat, reduce or prevent any type of seizure, e.g., seizures caused by anything that interrupts the normal connections between neurons in the brain. Examples of pathologies, in addition to epilepsy, that cause seizures include drug and alcohol withdrawal, fever, stroke, meningitis, etc.
  • any suitable methods of administering an antiepileptic compound or composition as described herein to an individual may be used.
  • the compounds and compositions can be administered to an individual by any suitable route, e.g., oral, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), and topical (i.e., both skin and mucosal surfaces, including airway surfaces), administration.
  • an antiepileptic compound or composition may be administered systemically by intravenous injection.
  • an antiepileptic compound or composition may be administered directly to a target site, by, for example, surgical delivery to an internal or external target site (e.g., brain) or by catheter to a site accessible by a blood vessel.
  • an internal or external target site e.g., brain
  • the compound or composition may be administered in a single bolus, multiple injections, or by continuous infusion (e.g., intravenously, by peritoneal dialysis, pump infusion).
  • the compound or composition is preferably formulated in a sterilized pyrogen-free form.
  • an antiepileptic compound or composition as described herein may be in a form suitable for sterile injection.
  • the suitable active therapeutic agent(s) e.g., a therapeutically effective amount of an antiepileptic compound
  • a parenterally acceptable liquid vehicle e.g., water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3 -butanediol, Ringer's solution, and isotonic sodium chloride solution and dextrose solution (D5W, 0.9% sterile saline).
  • the aqueous formulation may also contain one or more preservatives (e.g., methyl, ethyl or n-propyl p-hydroxybenzoate).
  • preservatives e.g., methyl, ethyl or n-propyl p-hydroxybenzoate.
  • a dissolution enhancing or solubilizing agent can be added, or the solvent may include 10-60% w/w of propylene glycol or the like.
  • the compounds and compositions described herein may be administered to an individual (e.g., rodents, humans, nonhuman primates, canines, felines, ovines, bovines, insects) in any suitable formulation according to conventional pharmaceutical practice (see, e.g.
  • the therapeutic methods described herein in general include administration of a therapeutically effective amount of the antiepileptic compounds and compositions described herein to an individual (e.g., human) in need thereof, particularly a human.
  • Such treatment will be suitably administered to individuals, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof (e.g., epilepsy, seizures). Determination of those individuals "at risk” can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider.
  • the methods described herein can include measuring antiepileptic effects of an antiepileptic compound. In these methods, any suitable protocol and/or model can be used to measure the antiepileptic effects of a compound, including the C. elegans electroshock model described in Example 1.
  • the antiepileptic compounds and compositions described herein are preferably administered to an individual in need thereof (e.g., human with epilepsy) in an effective amount, that is, an amount capable of producing a desirable result in a treated individual. Desirable results include but are not limited to one or more of the following: restoring function (neurological, behavioral), achieving normal recovery time, preventing a seizure(s), etc. Such a therapeutically effective amount can be determined according to standard methods. Toxicity and therapeutic efficacy of the antiepileptic compounds and compositions utilized in the methods described herein can be determined by standard pharmaceutical procedures.
  • a delivery dose of an antiepileptic composition as described herein is typically between about 0.001 mg/kg of antiepileptic compound to about 10 mg/kg (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 mg/kg) of antiepileptic compound and can be determined based on preclinical efficacy and safety
  • a dosage amount for an individual may be based on achieving drug concentrations at the cellular level required for the cells involved to
  • Example 1 BRIDGED BICYCLIC COMPOUNDS AND THEIR DERIVATIVES AS ANTIEPILEPTIC AGENTS
  • RVMs resveramorphs
  • RVMs alleviate symptoms and duration of seizure. It is expected that a pharmacological intervention based on RVMs will provide relief from epileptic events at low dosages.
  • the C. elegans seizure assay includes placing L4 C. elegans into a small tube that is capped on both sides by copper wires. A shock of 47 V for three seconds is then administered. The worms demonstrate a stiff paralysis state and uncoordinated rigid unilateral body bends. This suggests muscle convulsions as seen in high temperature seizures. Recovery is recorded when the animals present with coordinated three sinusoidal movements, which is then characterized as normal swimming activity.
  • PTZ Pentylenetetrazole
  • This C. elegans assay offers a new model for the evaluation of electroconvulsive seizures (Figure 4).
  • There are few previous reports that describe seizure susceptibility in worms (Pandey et al., Seizure 2010, 19(7), 439 - 442) and none that examine electroconvulsive seizures.
  • This assay allows for quick and efficient evaluation of the antiepileptic efficacy of compounds.
  • approximately 10 worms are inserted into a clear tube containing an M9 saline solution. Copper wire attached to a square pulse generating stimulator plugs each side of the tube, allowing for 1 cm between electrodes.
  • the M9 saline solution allows for an even conductance of current.

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Abstract

Des procédés de prévention ou de traitement de crises d'épilepsie et de traitement de l'épilepsie chez un individu comprennent l'administration de composés à petites molécules bicycliques pontés. Ces composés présentent une fonction antiépileptique chez l'individu lorsqu'ils sont administrés en dose thérapeutiquement efficace. L'utilisation des procédés et des composés antiépileptiques assure une protection contre les crises d'épilepsie à des doses faibles et supérieures du composé sans effets toxiques.
PCT/US2023/025444 2022-08-19 2023-06-15 Composés bicycliques pontés et leurs dérivés en tant qu'agents antiépileptiques, et leurs procédés d'utilisation Ceased WO2024039435A1 (fr)

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EP23855286.3A EP4572747A1 (fr) 2022-08-19 2023-06-15 Composés bicycliques pontés et leurs dérivés en tant qu'agents antiépileptiques, et leurs procédés d'utilisation
JP2025507518A JP2025528158A (ja) 2022-08-19 2023-06-15 抗てんかん剤としての架橋二環式化合物およびその誘導体ならびにその使用方法
KR1020257008754A KR20250051729A (ko) 2022-08-19 2023-06-15 항간질제로서의 가교형 바이사이클릭 화합물 및 이의 유도체 및 이의 사용 방법
CA3264333A CA3264333A1 (fr) 2022-08-19 2023-06-15 Composés bicycliques pontés et leurs dérivés en tant qu'agents antiépileptiques, et leurs procédés d'utilisation

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190284123A1 (en) * 2018-03-14 2019-09-19 Florida Atlantic University Board Of Trustees Bridged bicyclic compounds and their derivatives as neuroprotrctive agents and methods of use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190284123A1 (en) * 2018-03-14 2019-09-19 Florida Atlantic University Board Of Trustees Bridged bicyclic compounds and their derivatives as neuroprotrctive agents and methods of use thereof

Non-Patent Citations (3)

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