MX2008000694A

MX2008000694A - Use of 2-phenyl-l, 2-ethanedi0l-(di) carbamates for treating epileptogenesis and epilepsy

Info

Publication number: MX2008000694A
Application number: MXMX/A/2008/000694A
Authority: MX
Inventors: Boyu Zhao; Roy E Twyman
Original assignee: Janssen Pharmaceutica Nv; Roy E Twyman; Boyu Zhao
Priority date: 2005-07-12
Filing date: 2008-01-14
Publication date: 2008-10-03

Abstract

This invention is directed to methods for preventing, treating, reversing, inhibiting, or arresting epileptogenesis in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of Formula (I) and Formula (II), or a pharmaceutically acceptable salt or ester thereof,:Formula (I) Formula (II) wherein phenyl is substituted at X with one to five halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine;and, R-i, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and CrC4 alkyl;wherein C1-C4 alkyl is optionally substituted with phenyl (wherein phenyl is optionally substituted with substituents independently selected from the group consisting of halogen, CrC4 alkyl, CrC4 alkoxy, amino, nitro and cyano).

Description

METHODS TO TREAT EPILEPTOGENESIS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention is generally related to the fields of pharmacology, neurology and psychiatry. In particular, the present invention provides methods for treating, preventing, reversing, stopping or inhibiting the development and maturation of seizures or disorders related to seizures. More specifically, this invention provides methods for the use of certain carbamate compounds to treat, prevent, reverse, stop or therapeutically or prophylactically inhibit epileptogenesis.

DESCRIPTION OF THE RELATED ART Lesions or trauma of various kinds to the central nervous system (CNS) or the peripheral nervous system (PNS) can produce deep, long-lasting neurological and psychiatric symptoms and disorders. A common mechanism for the production of these effects is the induction of seizure activity or a phenomenon similar to seizures in the CNS or in the nerves and ganglia of the PNS. Symptomatic of paroxysmal disturbances in the electrical activity of the CNS or the PNS, it is believed that seizures or neurological mechanisms similar to seizures are underlying many of the pathological phenomena in a wide range of neurological and psychiatric disorders. A serious neurological condition characterized by seizures is epilepsy. Epilepsy is a common but devastating disorder that affects more than two and a half million people in the United States alone. The term epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable appearance of seizures (See, The Treatment of Epilepsy, Principies &Practice, Third Edition, Elaine Wyllie, MD Editor, Lippincott Williams &Wilkins, 2001; Goodman &Gilman's The Pharmacoloqical Basis of Therapeutics, 9th edition, 1996). Seizures that occur without obvious provocation are classified as epileptic. Typically a subject is considered to suffer from epilepsy after experiencing two or more seizures that occur with a separation of more than 24 hours. Clinically, an epileptic seizure results from a sudden and abnormal electrical discharge that originates from a collection of interconnected neurons in the brain or elsewhere in the nervous system. Depending on the type of epilepsy involved, the resulting nerve cell activity can be manifested by a wide variety of clinical symptoms, such as uncontrollable motor movements, changes in the level of consciousness of the patient and the like.

Based on the clinical and encephalographic phenomenon, four subdivisions of epilepsy are recognized: epilepsy of the great evil (with subgroups: generalized, focal, Jacksonian), epilepsy of the small malignant, psychomotor or temporal lobe epilepsy (with subgroups: psychomotor proper or tonic with adverse or torsional movements or masticatory phenomenon, automatic with amnesia, or sensory with hallucinations or sleep states) and autonomic or diencephalic epilepsy (with blushing, pallor, tachycardia, hypertension, sweating or other visceral symptoms). Although epilepsy is one of the most extreme examples of a seizure-related disorder, a wide variety of neurological and psychiatric symptoms and disorders may have, as its etiology, seizures or a related neurological phenomenon similar to seizures. In simple terms, a convulsion or a related neurological phenomenon similar to seizures, is a single discrete clinical event caused by an excessive electrical discharge from a collection of neurons or a group of neurons susceptible to a seizure through a process called "ictogenesis". " Therefore, the ictogenic convulsions can simply be the symptom of a disease. However, epilepsy and other analogous disorders related to seizures are dynamic and often progressive diseases, with a maturation process characterized by a complex and poorly understood sequence of pathological changes.

The development and maturation of such changes is the process of "epileptogenesis", so the largest collection of neurons that is the normal brain, is altered and then becomes susceptible to abnormal electric shocks, spontaneous, sudden, recurrent, excessive , that is, convulsions. The maturation of the epileptogenic process results in the development of an "epileptogenic focus", so collections of neurons with abnormal discharges or neurons susceptible to seizures, form localized groups or "epileptogenic zones" distributed through the cortical tissue. The epileptogenic zones are interconnected biochemically so that an abnormal ichlogenic discharge is able to be transported in cascade from one zone to another zone. As epileptogenesis progresses, the involved areas of the nervous system become more susceptible to a seizure and it becomes easier for them to trigger a seizure, resulting in progressively debilitating symptoms of the seizure or seizure-related disorder. Although the ictogenesis and epileptogenesis may have a common origin in certain biochemical phenomena and neuronal trajectories common in several diseases, the two processes are not identical. Icytogenesis is the onset and spread of a seizure in discrete time and space, a rapid and definitive electrical / chemical event that occurs over a period of time ranging from seconds to minutes. Comparatively, epileptogenesis is a gradual process of biochemical or neuronal restructuring, so that the normal brain is transformed by the ictogenic events in a brain with epileptogenic foci, which has neuronal circuitry that becomes sensitized and responds to the ictogenic events, making an individual susceptible in an increased manner to the reappearance of spontaneous, episodic, time-limited seizures, resulting in progressively debilitating symptoms of seizure or seizure-related disorder and a lack of progressive response to treatment. The maturation of an "epileptogenic focus" is a slow biochemical and / or structural process that usually occurs for months to years.

Epileptogenesis: A two-phase process "Phase 1 epileptogenesis" is the beginning of the epileptogenic process before the first epileptic seizure or convulsion of an analogous seizure-related disorder, and is often the result of some kind of injury or trauma of the brain, that is, stroke, disease (for example, infection such as meningitis), or trauma, such as an accidental blow to the head or a surgical procedure performed on the brain. "Phase 2 epileptogenesis" refers to the process during which brain tissue that is already susceptible to epileptic seizures or seizures of an analogous seizure-related disorder becomes even more susceptible to seizures of a frequency and / or increased severity and / or responds less to treatment.

Although the processes involved in epileptogenesis have not been definitively identified, some researchers believe that it is involved in the upregulation of excitatory coupling between neurons, mediated by the N-methyl-D-aspartate (NMDA) receptors. Other investigators involve deregulation of inhibitory coupling between neurons mediated by gamma-amino-butyric acid (GABA) receptors. Many other factors may be involved in this process, which are related to the presence, concentration or activity of NO (nitric oxide) or iron, calcium or zinc ions. Although epileptic seizures are rarely fatal, many patients require medication to avoid the disturbing, and potentially dangerous, consequences of seizures. In many cases, the medication used to manage epileptic seizures or seizures of an analogous seizure-related disorder, it is required for extended periods of time, and in some cases, a patient must continue taking such prescription drugs for life. In addition, such drugs can be used only for the management of symptoms and have side effects associated with chronic, prolonged use. A wide variety of drugs available for the management of epileptic seizures include older agents such as phenytoin, valproate and carbamazepine (ion channel blockers), as well as more recent agents such as felbamate, gabapentin, topiramate and tiagabine. In addition, ß-alanine has been reported to have anticonvulsant activity, NMDA inhibitory activity, and GABAergic stimulatory activity, but it has not been used clinically to treat epilepsy. The drugs accepted for the treatment of epilepsy are anticonvulsant agents or more appropriately called antiepileptic drugs (AED), where the term "antiepileptic" is synonymous with "anticonvulsant" or "anti-pathogenic". These drugs suppress seizures therapeutically by blocking the onset of a single ictogenic event. But it is believed that they are not prophylactically or therapeutically effective in influencing epileptogenesis. In the treatment of seizures for analogous seizure-related disorders, that is, for diseases and disorders with a neurological phenomenon similar to seizures that may be apparently related to seizure disorders, such as the state cycles of seizures. mood in Bipolar Disorder, impulsive behavior in patients with Impulse Control Disorders or for seizures resulting from brain injury, some AEDs may also be therapeutically useful. However, they are similarly incapable of prophylactically or therapeutically avoiding the initial development or progressive maturation of epileptogenesis to an epileptogenic focus that also characterizes the analogous disorders related to seizures. Poorly understood pathological mechanisms underlying epileptogenesis certainly play a role in the development of epilepsy and related seizure-related disorders under a variety of clinical circumstances, including spontaneous development or as a result of injury or trauma. of many kinds to the central or peripheral nervous system. The current treatment of epilepsy is focused on the suppression of seizure activity, by administering AED after open clinical epilepsy has developed. Although EDAs have positive effects on the suppression of seizures, they have been universally unsuccessful in preventing epileptogenesis, that is, the development or progression of epilepsy and other related seizure-related diseases. Even pretreatment with AEDs does not prevent the development of epilepsy after injury or trauma to the nervous system. In addition, if the therapy with AED is interrupted, the seizures typically reappear and in unfortunate cases, they worsen over time. Currently, there is no known effective method to treat, prevent, reverse, stop or inhibit the onset and / or progression of epilepsy. In addition, it is also believed that similar neurological mechanisms corresponding to epileptogenesis may be involved in the evolution and development of many seizure-related disorders, clinically analogous to epilepsy, that do not appear to be "epileptic" openly, such as the development Initial and progressive worsening observed in the mature disease state in Bipolar Disorder, Impulse Control Disorders, Obsessive-Compulsive Disorders, Schizoaffective Disorders and other psychiatric disorders. Thus, despite the numerous drugs available for the treatment of epilepsy (ie, through the suppression of stroke epilepticus, ie, seizures associated with epileptic seizures) and other analogous seizure-related disorders, there are no generally accepted drugs to treat, prevent, reverse, stop or inhibit the underlying process of seizures. epileptogenesis, which can be etiological in many devastating neurological and psychiatric disorders, such as epilepsy and analogous seizure-related disorders. Currently, there are no known methods to inhibit the epileptogenic process to prevent the development of epilepsy or other analogous seizure-related disorders in patients who have not yet clinically shown symptoms of seizures, but who unknowingly have the disease or are at risk to develop the disease. In addition, there are no known methods to prevent the development of, or to reverse the process of, epileptogenesis, thus converting the collections of neurons into an epileptogenic zone that has been the source of, or that is susceptible to or capable of participating in the activity. convulsive in nervous tissue that does not exhibit abnormal, spontaneous, sudden, recurrent or excessive electric shocks or that is not susceptible to, or capable of, such seizure activity. In addition, there are no approved or unapproved medications recognized as having such antiepileptogenic properties, ie, truly antiepileptogenic drugs (AEGD) (See, Schmidt, D. and Rogawski, A., Epilepsy Research, 2002, 50; 71-78). Thus, there is a great need to develop safe and effective drugs and treatment methods to effectively treat, prevent, stop, inhibit and reverse epileptogenesis in neurological and / or psychiatric disorders related to seizures.

BRIEF DESCRIPTION OF THE INVENTION This invention relates, in part, to methods and compounds useful for the treatment and / or prevention, arrest, inhibition and reversal of epileptogenesis in a patient who can, but does not need to have, the symptoms of epilepsy and / or a related analogous disorder. with seizures. This invention is based, in part, on the unexpected discovery that certain carbamate compounds, which are effective AEDs and that can suppress epileptic seizures are, in addition, powerful antiepileptogenic and can prevent the onset of development and maturation of pathological changes in the nervous system that allows seizures and related phenomena to develop and / or disperse and can reverse these changes. Thus, the carbamate compounds of the present invention, as used in the methods of this invention, are true AEGD and have properties not possessed by any medication or AED currently available. Therefore, in one aspect, the invention provides a method for treating and preventing seizures and disorders related to seizures in a subject in need thereof. In another aspect, the invention provides a method for stopping, inhibiting and reversing epileptogenesis in a subject. The method includes the step of administering prophylactically or therapeutically to the subject in need thereof, an effective amount of a carbamate compound that treats, prevents, stops, inhibits and reverses epileptogenesis in a subject. In various embodiments, the invention provides methods for treating, preventing, reversing, stopping or inhibiting epileptogenesis. In certain embodiments, these methods comprise administering a prophylactically or therapeutically effective amount of a carbamate compound to the subject. Accordingly, the present invention provides methods for treating, preventing, stopping, inhibiting and reversing epileptogenesis in a subject in need thereof, which comprises administering to the subject a prophylactically or therapeutically effective amount of a composition comprising at least one compound of Formula 1 or Formula 2: Formula 1 Formula 2 or a pharmaceutically acceptable salt or ester form thereof, wherein Ri, R2, R3 and R4 are independently hydrogen or Ci-C4 alkyl, wherein the Ci.C alkyl is unsubstituted or substituted by phenyl, and wherein the phenyl is substituted or unsubstituted with up to five substituents independently selected from halogen, C 4 alkyl, CrC 4 alkoxy, amino (wherein the amino is optionally mono or disubstituted with C 1 -C 4 alkyl), nitro or cyano; and ??, X2, X3, X4 and X5 are independently hydrogen, fluorine, chlorine, bromine or iodine. The embodiments of the present invention include a compound of Formula 1 or Formula 2, wherein? - ?, X2, X3, X4 and X5 is independently selected from hydrogen, fluorine, chlorine, bromine or iodine. In certain embodiments,? - ?, X2, X3, X4 and X5 are independently selected from hydrogen or chlorine. In other embodiments, X1 is selected from fluorine, chlorine, bromine or iodine. In another embodiment, it is chlorine, and X2, X3, X4 and X5 are hydrogen. In another embodiment, RL R2, R3 and R4 are hydrogen.

The present invention provides enantiomers of Formula 1 or Formula 2 for treating epileptogenesis in a subject in need thereof. In certain embodiments, a compound of Formula 1 or Formula 2 will be in the form of a single enantiomer thereof. In other embodiments, a compound of Formula 1 or Formula 2 will be in the form of an enantiomeric mixture, in which one enantiomer predominates with respect to the other enantiomer. In another aspect, an enantiomer predominates in a range of about 90% or greater. In a further aspect, an enantiomer predominates in a range of about 98% or greater. The present invention also provides methods comprising administering to the subject a prophylactically or therapeutically effective amount of a composition comprising at least one compound of Formula 1 or Formula 2, wherein Ri, R2, R3 and R4 are independently selected from hydrogen or alkyl C4 alkyl; and ??, X2, X3, X and X5 are independently selected from hydrogen, fluorine, chlorine, bromine or iodine. In the embodiments of the present invention, prior to the prophylactic or therapeutic administration of the composition to the subject, a determination will be made as to whether or not the subject suffers from epilepsy or an analogous disorder related to seizures, or if it is considered to be in a high risk of developing such seizures or disorders related to seizures.

The present invention also provides methods for identifying a subject in need of prophylactic or therapeutic administration of an antiepileptogenic composition, wherein the subject suffers from epilepsy or an analogous seizure-related disorder, or is considered to be at a high risk of developing epilepsy, or where the subject is in need of treatment with an AEGD. The present invention provides methods comprising administering prophylactically or therapeutically to the subject, a composition comprising at least one compound having Formula 1 or Formula 2. In certain embodiments of the present invention, a prophylactically or therapeutically effective amount of a compound of Formula 1 or Formula 2 for the treatment of epileptogenesis, is in a range of about 0.01 mg / Kg / dose to about 150 mg / Kg / dose. In certain embodiments, a prophylactically or therapeutically effective amount of a pharmaceutical composition for preventing, treating, reversing, stopping or inhibiting epileptogenesis, comprises one or more of the enantiomers of a compound of Formula 1 or Formula 2, includes a pharmaceutically acceptable salt or ester. acceptable thereof, in admixture with a pharmaceutically acceptable carrier or excipient, whereby such a composition is administered to the subject in need of treatment with an AEGD. Pharmaceutical compositions comprising at least one compound having Formula 1 or Formula 2 and one or more pharmaceutically acceptable excipients are administered to a subject in need thereof.

In certain embodiments, a subject or patient in need of treatment with an AEGD may be one who has not yet shown the symptoms of epilepsy or an analogous seizure-related disorder prior to the time of administration. In another aspect, it will be determined that the subject or patient is at risk of developing epilepsy or an analogous disorder related to seizures at the time of administration, and will therefore be a subject, ie, a patient in need of treatment with an AEGD. In other embodiments, the subject in need thereof is an individual who has shown the symptoms of epilepsy (e.g., open seizures) or an analogous disorder related to seizures (e.g., mood cycles, impulsive behavior and the like. ) before or at the time of administration.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: is a graph that shows the effects of doses that increase TC in the number of neurons in different areas of the hippocampus counted at 14 days after the SE by li-pyl. The values are expressed as the number of neuronal cell bodies in each area of interest ± the S.E.M. Figure 2: is a graph that shows the effects of the doses that increase TC in the number of neurons in different nuclei of the amygdala counted at 14 days after the SE by li-pyl. The values are expressed as the number of neuronal cell bodies in each area of interest ± the S.E.M. Figure 3: is a graph showing the effects of increasing TC doses on the number of neurons in different thalamic nuclei counted at 14 days after the SE by li-pyl. The values are expressed as the number of neuronal cell bodies in each area of interest ± the S.E.M. Figure 4: is a graph that shows the effects of the doses that increase TC in the number of neurons in different areas of the cortex counted at 14 days after the SE by? -pilo. The values are expressed as the number of neuronal cell bodies in each area of interest ± the S.E.M. Figure 5: is a graph that shows the effects of the doses that increase TC in the latency at the first spontaneous seizure. The values are expressed as the average latency in days for each group ± the S.E.M. Figure 6: is a graph that shows the effects of the doses that increase in TC in the frequency of spontaneous seizures recorded with video during a period of 4 weeks. Values are expressed as the mean number of seizures ± S.E.M. The total represents the total number of seizures observed during the 4 weeks of video recording and the average represents the average number of seizures per week. The Anova test demonstrated a treatment effect on the total number of seizures (p = 0.045) and the mean number of seizures per week (p = 0.045). Figure 7: shows the total number of seizures recorded with video for four weeks, plotted against latency for the first spontaneous seizure (SL = short latency, LL = long latency). The values are expressed as the mean number of seizures for each subgroup ± the S.E.M. The ANOVA test shows no significant effect of the treatment. Figure 8: shows the correlation between latency for the first spontaneous seizure and the total number of seizures observed during the following four weeks.

DETAILED DESCRIPTION OF THE INVENTION The Carbamate Compounds of the Invention The present invention provides methods for using monocarbamates and dicarbamates of 2-phenyl-1,2-ethanediol in the treatment / prevention of epileptogenesis. Representative carbamate compounds according to the present invention, include those having Formula 1 or Formula 2: Formula 1 Formula 2 wherein: R-i, R2, 3, and R4 are, independently, hydrogen or C4 alkyl and X1t X2, X3, X4 and X5 are, independently, hydrogen, fluorine, chlorine, bromine or iodine.

"CrC4 alkyl" as used herein, refers to substituted or unsubstituted aliphatic hydrocarbons having from 1 to 4 carbon atoms. Included specifically within the definition of "alkyl" are those aliphatic hydrocarbons which are optionally substituted. In a preferred embodiment of the present invention, the C 1 -C 4 alkyl is unsubstituted or substituted by phenyl. The term "phenyl", as used herein, whether used alone or as part of another group, is defined as a substituted or unsubstituted aromatic hydrocarbon ring group, having 6 carbon atoms. Specifically included within the definition of "phenyl" are those phenyl groups which are optionally substituted. For example, in a preferred embodiment of the present invention, the "phenyl" group is unsubstituted or substituted by halogen, CrC 4 alkyl, C 1 -C 4 alkoxy, amino, nitro or cyano. In a preferred embodiment of the present invention, X-i is fluorine, chlorine, bromine or iodine and X2, X3, X4 and X5 are hydrogen. In another preferred embodiment of the present invention, ??, X2, X3, X4 and X5 are, independently, chlorine or hydrogen. In another preferred embodiment of the present invention, R2) R3, and R4 are all hydrogen. It will be understood that substituents and substitution patterns in the compounds of the present invention can be selected by one of ordinary skill in the art, to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the art, as well as methods provided in the present. Representative 2-phenyl-1, 2-ethanediol monocarbamates and dicarbamates include, for example, the following compounds: Formula 4 Formula 6 Formula 8 Suitable methods for synthesizing and purifying the carbamate compounds, including the carbamate enantiomers, used in the methods of the present invention are well known to those skilled in the art. For example, pure enantiomeric forms and enantiomeric mixtures of the 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates are described in U.S. Patent Nos. 5,854,283, 5,698,588 and 6,103,759, the descriptions of which are incorporated herein by reference. in the present as a reference in its entirety.

The present invention includes the use of the isolated enantiomers of Formula 1 or Formula 2. In a preferred embodiment, a pharmaceutical composition comprising the isolated S enantiomer of Formula 1, is used to treat epileptogenesis in a subject. In another preferred embodiment, a pharmaceutical composition comprising the isolated R-enantiomer of Formula 2, is used to treat epileptogenesis in a subject. In another embodiment, a pharmaceutical composition comprising the isolated S-enantiomer of Formula 1 and the isolated R-enantiomer of Formula 2, can be used to treat epileptogenesis in a subject. The present invention also includes the use of mixtures of enantiomers of Formula 1 or Formula 2. In one aspect of the present invention, an enantiomer will predominate. An enantiomer that predominates in the mixture is one that is present in the mixture in an amount greater than any of the other enantiomers present in the mixture, for example, in an amount greater than 50%. In one aspect, an enantiomer will predominate to the degree of 90% or to the degree of 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% or more. In a preferred embodiment, the enantiomer that predominates in a composition comprising a compound of Formula 1 is the S-enantiomer of Formula 1. In another preferred embodiment, the enantiomer that predominates in a composition comprising a compound of Formula 2 is the R-enantiomer. of Formula 2.

In a preferred embodiment of the present invention, the enantiomer that is present as the sole enantiomer or as the predominant enantiomer in a composition of the present invention, is represented by Formula 3 or Formula 5, wherein X 1 (X 2, X 3, X4l X5, Ri, R2, R3 and R4 are as defined above, or by Formula 7 or Formula 8.

Formula 3 Formula 5 Formula 7 Formula 8 The present invention provides methods for using enantiomers and enantiomeric mixtures of the compounds represented by Formula 1 and Formula 2 or a pharmaceutically acceptable salt or ester form thereof: An enantiomer of the carbamate of Formula 1 or Formula 2 contains a carbon Asymmetric chiral in the benzylic position, which is the aliphatic carbon adjacent to the phenyl ring.

An enantiomer that is isolated is one that is substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is separated via separation techniques or free preparation of the corresponding enantiomer. "Substantially free", as used herein, means that the compound is comprised of a significantly greater proportion of an enantiomer. In preferred embodiments, the compound includes at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound includes at least about 99% by weight of a preferred enantiomer. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or the preferred enantiomers can be prepared by the methods described in the present. Methods for the preparation of preferred enantiomers would be known to one of skill in the art and are described, for example, in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33: 2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Híll, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University Press Notre Dame, Notre Dame, IN 1972). In addition, the compounds of the present invention can be prepared as described in U.S. Patent No. 3,265,728 (the disclosure of which is incorporated herein by reference in its entirety and for all purposes), 3,313,692 (the description of which is incorporated herein by reference). which is incorporated herein by reference in its entirety and for all purposes), and U.S. Patent Nos. 5,854,283, 5,698,588 and 6,103,759 (the disclosures of which are incorporated herein by reference in their entirety and for all purposes). The epileptogenic process usually consists of two phases. The first epileptogenic stage is known as the initial aggression or stage of the injury. The initial injury or injury is commonly an injury that damages the brain caused by one or more of a multitude of possible factors including, for example, traumatic brain injury; CNS infection, such as, for example, bacterial meningitis, viral encephalitis, bacterial brain abscess or neurocysticercosis); cerebrovascular disease (such as stroke or brain tumor, including, for example, malignant gliomas, neurosurgery (such as, for example, craniotomy), and epileptic states In some cases, the initial aggression will be the result of developmental problems before the birth (such as, not exclusively, asphyxia due to birth, intracranial trauma during birth, metabolic disturbances or congenital malformations of the brain), or as the result of genetic determinants.The second epileptogenic stage is known as the latency stage. The methods of the present invention include the prophylactic or therapeutic administration of a carbamate compound of the present invention, in the first or second epileptogenic stage or before these stages, to treat, inhibit, prevent, stop or reverse the subsequent development of epilepsy or other analogous disorder related to seizures in a subject in need thereof. The second epileptogenic stage also includes the process of neuronal restructuring, which is characterized by recurrent seizures (eg, asymptomatic epilepsy), or by symptoms shown in analogous seizure-related disorders. The epileptogenic process can also be observed among people who actually suffer from epilepsy or analogous disorders related to seizures. For example, seizures experienced by people suffering from epilepsy are epileptogenic if they tend to make later seizures more likely. In a similar manner, the related response similar to seizures in neurological or psychiatric disorders analogous to epilepsy may become severe in an increased manner over time or resistant to treatment as the disorder matures. The methods and compounds of the present invention are intended to be used to treat, prevent, stop, inhibit or reverse the process of epileptogenesis in such neurological or psychiatric analogues related to seizures as well. In certain embodiments, phase 1 epileptogenesis can be initiated by factors other than those listed above, such as by ingestion of compounds with an epileptogenic potential, for example, psychotropic medications, such as, for example, tricyclic antidepressants, clozapine and lithium and the similar. The methods and compounds of the present invention are also intended to treat, prevent, arrest, inhibit or reverse the development of epileptogenesis, which has been initiated by factors that tend to increase the potential of a subject to become epileptogenic. Therefore, in the treatment of epileptogenesis, the methods of the invention can prevent the development of seizures, particularly epileptic seizures. Such methods can therefore be used to treat and prevent epilepsy and epileptic seizures, reduce the risk of developing epilepsy, stop the development of epilepsy (particularly, the development of collections of neurons that are the source of, or are susceptible to) to ictogenic seizures), inhibit the development and maturation of epilepsy (particularly, the development of epileptogenic zones and epileptogenic foci), reduce the severity of epilepsy in a subject and reverse the process of epileptogenesis in epilepsy. Furthermore, in treating, preventing, inhibiting, stopping or reversing epileptogenesis according to the methods of the present invention, the development or progression of the analogues of neurological and / or psychiatric disorders whose etiology is partially or completely based on a mechanism of action similar to seizures, will be treated, avoided, inhibited, stopped or reversed.

Definitions As used herein, the term "epileptogenesis" means the biochemical, genetic, histological or other structural or functional processes or changes that make nervous tissue, including the central nervous system (CNS), susceptible to recurrent, spontaneous seizures. In addition, the term "epileptogenesis" is also used herein in a broader sense to refer to the changes and processes that contribute to clinical progression observed in some epilepsies and the development of "drug resistance", in which epilepsy is becomes more difficult to treat as a result of neurobiological changes that result in reduced sensitivity to the drug. Furthermore, the term "epileptogenesis" is used herein in the broadest possible sense to refer to the similar phenomenon of progressive worsening over time of the signs and symptoms of apparently non-epileptic disorders, including psychiatric disorders, the etiology of which It seems to be related to seizures. This is intended to include, but is not limited to, the worsening or progression of, for example: Bipolar disorder over time or as a result of exposure to antidepressants or other drugs, as evidenced by the increased proportion of the cycles, increased severity of the episodes, increased severe psychotic symptoms and / or reduced response to treatment, etc .; Impulse Control Disorders; Obsessive-Compulsive Disorders, certain personality disorders, impulsive or aggressive behavior in neurodegenerative or related disorders. The term "inhibition of epileptogenesis", as used herein, refers to preventing, slowing down, stopping or reversing the process of epileptogenesis. The term "antiepileptogenic agent or drug" (AEGD), as used herein, refers to an agent that is capable of inhibiting epileptogenesis when the agent is administered to a subject. The term "seizure disorder", as used herein, refers to a disorder in a subject, in which the subject suffers from seizures, for example, seizures due to an epileptic seizure. Seizure disorders include, but are not limited to, epilepsy and non-epileptic seizures, for example, seizures due to the administration of a convulsive agent to the subject. As used herein, the terms "analogous seizure-related disorders" or "seizure-related neurological phenomenon related to epilepsy" refers to a neurobiological disorder or a psychiatric disorder that may show little or no overt seizure activity , which is still believed to be totally or partially the result of a related neural mechanism similar to seizures, and which is frequently found to be treatable with AED. Examples of analogous disorders related to seizures include, but are not limited to; Bipolar Disorder, Schizoaffective Disorder, Psychotic Disorders, Impulse Control Disorders and the Spectrum of Disease Related to Impulse Control Disorder, Eating Disorders such as Bulimia or Nervous Anorexia, Obsessive-Compulsive Disorder (OCD), Abuse Disorders of substances, and changes in personality and behavior that occur in patients with Temporary Lobe Epilepsy or in primary personality disorders. As used herein, the term "subject" includes an individual or patient who has not shown the symptoms of epilepsy or the analogous disorder related to seizures, but who may be in a high-risk group. As used herein, the term "a subject in need of treatment with an AEGD" would include an individual who does not have epilepsy or an analogous disorder related to seizures, but who may be in a group at high risk for development of seizures or a disorder related to seizures, due to an injury or trauma to the CNS or PNS or an individual or patient who is considered to be at high risk for the development of such seizures or seizure-related disorders, due to an injury or trauma of the CNS or PNS, due to any known biochemical or genetic predisposition for epilepsy or an analogous disorder related to seizures, or because a verified biomarker or substitute marker of one or more of these disorders has been discovered.

The term "a subject in need of treatment with an AEGD" would also include an individual whose clinical condition or prognosis could benefit from treatment with an AEGD. This would include, but is not limited to, any individual who has been determined to be at an increased risk of developing epilepsy, a seizure disorder or an analogous disorder related to seizures or a neurological phenomenon similar to seizures, related to epilepsy or seizure-related disorder as defined above, due to any predisposing factor. Predisposing factors include, but are not limited to: injury or trauma of any kind to the CNS; CNS infections, for example, meningitis or encephalitis; anoxia; stroke, that is, cerebrovascular accidents (CVA); autoimmune diseases affecting the CNS, for example, lupus; birth injuries, for example, perinatal asphyxia; heart attack; vascular therapeutic or diagnostic surgical procedures, for example, carotid endarterectomy or cerebral angiography; cardiac bypass surgery; trauma of the spinal cord; hypotension; injury to the CNS of embolism, hyper or hypoperfusion of the CNS; hypoxia that affects the CNS; genetic predisposition known to known disorders that respond to AEGD; injuries that occupy space of the CNS; brain tumors, for example, glioblastomas; bleeding or hemorrhage in or around the CNS, for example, intracerebral bleeds or subdural hematomas; cerebral edema; Feverish convulsions; hyperthermia; exposure to toxic or poisonous agents; intoxication with drugs, for example, cocaine; family history of seizure disorders or an analogous disorder related to seizures, history of status epilepticus; current treatment with medications that lower the threshold for seizures, for example, lithium carbonate, torazine or clozapine; evidence of surrogate markers or biomarkers that the patient is in need of treatment with an antiepileptogenic drug, eg, MRI scan showing hippocampal sclerosis or other CNS pathology, elevated serum levels of neuronal degradation products. In addition, the term "a subject in need of treatment with an AEGD" also refers to any individual with a history of, or who currently has epilepsy, a seizure disorder or an analogous neurological phenomenon similar to seizures related to epilepsy or seizure-related disorder, as defined above, or any disorder in which the patient presents a clinical condition or prognosis that may benefit from the suppression or inhibition of the process of epileptogenesis, to prevent extension, progression, or increased resistance to treatment of any neurological or psychiatric disorder. The term "antiepileptic drug" (AED), will be used interchangeably with the term "anticonvulsant agent", and as used herein, both terms refer to an agent capable of inhibiting (e.g., avoiding, slowing down) , stop or reverse) the convulsive activity or ictogenesis when the agent is administered to a subject or patient.

The term "pharmacophore" is known in the art, and as used herein, refers to a molecular moiety capable of exerting a selected biochemical effect, for example, the inhibition of an enzyme, binding to a receptor, chelation of a ion, and the like. A selected pharmacophore may have more than one biochemical effect, for example, it may be an inhibitor of an enzyme and an agonist of a second enzyme. A therapeutic agent may include one or more pharmacophores, which may have the same or different biochemical activities. The term "treat" or "treatment" as used herein, refers to actions that cause any indication of success in the prevention or alleviation of an injury, pathology, symptoms or condition, including any objective or subjective parameters, such as dejection; remission; decrease in symptoms or make the lesion, pathology or condition more tolerable for the patient; slow down the rate of degeneration or decline; make the final point of degeneration less debilitating; or improve the physical or mental well-being of the subject. Thus, the term "treatment" or "treat" is intended to include any action that improves, avoids, reverses, stops or inhibits the pathological process of epileptogenesis, as that term is defined and used herein. The treatment or relief of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neurological examination and / or psychiatric assessments.

Accordingly, the term "treating" or "treatment" includes the administration of the compounds or agents of the present invention to treat, prevent, reverse, arrest or inhibit the process of epileptogenesis. In some cases, treatment with the compounds of the present invention will prevent, inhibit or stop the progression of brain dysfunction or hyperexcitability associated with epilepsy. The term "therapeutic effect", as used herein, refers to the treatment, inhibition, abatement, inversion or prevention of epileptogenesis, symptoms of epileptogenesis, or side effects of epileptogenesis in a subject. The term "a therapeutically effective amount", as used herein, means a sufficient amount of one or more of the compounds of the invention, to produce a therapeutic effect, as defined above, in a subject or patient in need of such treatment, inhibition, abatement, inversion or prevention of epileptogenesis, symptoms of epileptogenesis, or side effects of epileptogenesis. The terms "subject" or "patient" are used interchangeably herein and as used herein, means any mammalian subject or patient to whom the compositions of the invention may be administered. The term "mammal" includes human patients and non-human primates, as well as experimental animals, such as rabbits, rats and mice, and other animals.

In some embodiments, the methods of the present invention will be advantageously used to treat a patient who does not suffer or who knows that he suffers from a condition that is known in the art as being effectively treated with the carbamate compounds or currently known AEDs, including analogous disorders related to seizures. In these cases, the decision to use the methods and compounds of the present invention, would be made based on the determination of whether the patient is a "patient in need of treatment with an antiepileptogenic drug (AEGD)", as the term previously defined . In some embodiments, this invention provides methods for treating, preventing, reversing, stopping or inhibiting epileptogenesis. In certain embodiments, these methods comprise administering a therapeutically effective amount of a carbamate compound to a patient who has not yet developed overt clinical epilepsy, or a seizure-related disorder, but who may be in a high-risk group for development. of seizures or a disorder related to seizures, due to an injury or trauma to the nervous system or due to a known predisposition, either biochemical or genetic or to the finding of a verified biomarker of one or more of these disorders. Thus, in some embodiments, the methods and compositions of the present invention are directed toward the treatment of epileptogenesis in a subject who is at risk of developing epilepsy or a seizure-related disorder or an analogous seizure-related disorder, but who He has not yet developed epilepsy or clinical evidence of seizures. A subject who is at risk of developing epilepsy or an analogous seizure-related disorder, but who has not yet developed epilepsy or an analogous seizure-related disorder, may be a subject who has not yet been diagnosed with epilepsy or an analogous disorder. related to seizures, but that is at a greater risk than the general population of developing epilepsy or an analogous disorder related to seizures. This "higher risk" can be determined by the recognition of some factor in a subject, or their families, medical history, physical examination or test that is indicative of a risk greater than the average of developing epilepsy or an analogous disorder related to seizures. Thus, this determination that a patient may be at a "higher risk" by any means available, can be used to determine whether the patient should be treated with the methods of the present invention. Accordingly, in the exemplary embodiments, subjects who can benefit from treatment by the methods and compounds of this invention can be identified using accepted screening methods to determine the risk factors associated with epileptogenesis. These screening methods include, for example, conventional treatment to determine the risk factors that may be associated with epileptogenesis, including non-exclusively: for example, head trauma, either closed or penetrating, CNS infections, bacterial or viral, cerebrovascular disease, including non-exclusively, stroke, brain tumors, cerebral edema, cysticercosis, porphyria, metabolic encephalopathy, drug abstinence, including non-exclusive, sedative-hypnotic abstinence or alcohol, abnormal perinatal history, including anoxia at birth, birth injury of any kind, cerebral palsy, learning disabilities, hyperactivity, history of febrile convulsions in childhood, history of epileptic status, family history of epilepsy or any disorder related to seizures, inflammatory disease of the brain including lupus, intoxication co n drugs, either direct or by placental transfer, including, but not limited to, cocaine poisoning, parental consanguinity, and treatment with medications that lower the threshold for seizures, including psychotropic medications. In some embodiments, the compounds of the present invention would be used for the manufacture of a medicament for the purpose of treating a patient in need of treatment with an antiepileptogenic drug (AEGD). This would include the manufacture of a medicament for the purpose of treating a patient who currently has, or is at risk of developing epilepsy, a seizure disorder or an analogous disorder related to seizures or a seizure-related neurological phenomenon related to epilepsy or a seizure-related disorder, as defined above, or any disorder in which the patient's clinical condition or clinical prognosis may benefit from suppressing or inhibiting the process of epileptogenesis to prevent extension, worsening, or increased resistance to treatment of any neurological or psychiatric disorder. The determination of which patients can benefit from treatment with an AEGD in patients who do not have clinical signs or symptoms of epilepsy or related disorders, can be based on a variety of "surrogate markers" or "biomarkers". As used herein, the terms "substitute marker" and "biomarker" are used interchangeably and refer to any anatomical, biochemical, structural, electrical, genetic or chemical indicator or marker that can be reliably correlated with the present existence or the future development of a seizure or disorder related to seizures. In some cases, brain imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), can be used to determine if a subject is risk of developing epilepsy or a disorder related to seizures. Suitable biomarkers for the methods of this invention include, but are not limited to: determination by MRI, CT or other imaging techniques, of sclerosis, atrophy or volume loss in the hippocampus or open mesial temporal sclerosis (MTS) or similar relevant anatomical pathology; detection in the blood, serum or tissues of the patient of a molecular species such as a protein or other biochemical biomarker, for example, elevated levels of ciliary neutrophil factor (CNTF) or elevated serum levels of a product of neuronal degradation; or other evidence of surrogate markers or biomarkers that the patient is in need of treatment with an antiepileptogenic drug, for example, an EEG that suggests a seizure disorder or an analogous seizure-related disorder or a neurological phenomenon similar to seizures related to seizures. epilepsy or a disorder related to seizures. It is expected that many more such biomarkers that use a wide variety of detection techniques will develop in the future. It is intended that any such markers or indicators of the existence of the possible future development of a compulsive disorder or a disorder related to seizures, as the latter term is used herein, may be used in the methods of this invention to determine the need of treatment with the compounds and methods of this invention. A determination that a subject has, or may be at risk of developing, epilepsy or an analogous disorder related to seizures would also include, for example, a medical evaluation that includes a complete history, a physical examination and a series of relevant blood tests. It may also include an electroencephalogram (EEG), CT, MRI or PET scan. A determination of an increased risk of developing an analogous disorder related to seizures may also be made by genetic testing, including profiling of gene expression or proteomic techniques. (See, Schmidt, D. Rogawski, M.A. Epilepsy Research 50; 71-78 (2002), and Loscher, W, Schmidt D. Epilepsy Research 50; 3-16 (2002)). For psychiatric disorders that may be "analogous seizure-related disorders", for example, Bipolar Disorder, Impulse Control Disorders, etc., the above tests may include an examination of the present state and a detailed history of the course of the symptoms of the patient, such as the symptoms of mood disorder and psychotic symptoms over time and in relation to other treatments that the patient may have received over time, for example, a clinical history. These and other specialized and routine methods allow the clinician to select patients in need of therapy, using the methods and formulations of this invention. In some embodiments of the present invention, carbamate compounds suitable for use in the practice of this invention will be administered either alone or concomitantly with at least one or more other compounds or therapeutic agents, for example, with other antiepileptic drugs. , anticonvulsant drugs or neuroprotective drugs or electroconvulsive therapy (ECT). In these embodiments, the present invention provides methods for treating, preventing or reversing epileptogenesis in a patient. The method includes the step of administering to a patient in need of treatment, an effective amount of one of the carbamate compounds described herein, in combination with an effective amount of one or more other compounds or therapeutic agents having the ability to of treating or preventing epileptogenesis or the ability to increase the antiepileptic or neuroprotective effects of the compounds of the invention. As used herein, the term "concomitant administration" or "administration in combination" of a compound, therapeutic agent or known drug with a compound of the present invention means the administration of the drug and one or more compounds at such time, that both the drug and the compound will have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. Such concomitant administration may involve concurrent administration (ie, at the same time), before or after the drug with respect to the administration of a compound of the present invention. A person with ordinary skill in the art will have no difficulty in determining the appropriate schedule, sequence and dosages of administration for the particular drugs and compounds of the present invention. The one or more other compounds or therapeutic agents can be selected from compounds having one or more of the following properties: antioxidant activity; NMDA receptor antagonist activity, increased inhibition of endogenous GABA; activity of the NO synthase inhibitor; ability to join iron, for example, an iron chelator; ability to bind to calcium, for example, a chelator of Ca (II); ability to bind zinc, for example, a Zn (II) chelator; the ability to effectively block the sodium or calcium ion channels, or to open the potassium or chloride ion channels in a patient's CNS, so that epileptogenesis is inhibited in the patient. In some preferred embodiments, one or more of the other compounds or therapeutic agents will antagonize NMDA receptors by binding to NMDA receptors (e.g., binding to the glycine binding site of NMDA receptors) and / or the agent will increase the inhibition of GABA by decreasing the uptake of glial GABA. In addition, the one or more of the other compounds or therapeutic agents can be any agent known to suppress seizure activity, even if that compound is not known to inhibit epileptogenesis. Such agents would include, in an exclusive manner, any effective AED known to someone skilled in the art or discovered in the future, for example, suitable agents include, but not limited to; carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotigin, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, retigabine, talampanel, tiagabine, topiramate, valproate, vigabatrin, zonisamide, benzodiazepines, barbiturates or sedative hypnotics. In some embodiments of the present invention, the treatment would be directed to patients having epilepsy or a neurological phenomenon similar to seizures related to epilepsy or an analogous seizure-related disorder, as defined above, and taking advantage of the ability to the compounds of the present invention, to reverse epileptogenesis, would allow the gradual reduction in the dosages of the maintenance medication or the intensity of the treatment used to control the clinical manifestations of epilepsy or the neurological phenomenon similar to seizures related to epilepsy or the analogous disorder related to the patient's seizures, as defined above. Therefore, since treatment with the compounds of the invention results in improvement in the underlying disorder, the patient could be removed from his maintenance measurement, including, but not limited to, the compounds of the present invention themselves, if they are being used. as the only therapy. Thus, to a patient with epilepsy with maintenance therapy of a conventional EDA, EDA can be withdrawn, after treatment with one or more of the compounds of the present invention has reversed the underlying epileptic disorder. In addition, a patient with a seizure-like neurological phenomenon related to epilepsy or an analogous seizure-related disorder, as defined above, including but not limited to, for example, Bipolar Disorder, may be graduated his maintenance medications by example, lithium carbonate, as the treatment with one or more of the compounds progresses. Likewise, if one or more of the compounds are being used as the sole therapy, the dose of this compound can graduate to zero over time. Someone with experience in the technique can determine how quickly to perform the graduation, based on clinical signs and symptoms, including EEG, the progress of seizures or other appropriate biomarkers of the underlying disorder.

Carbamate Compounds as Pharmaceutical Compounds The present invention provides isolated enantiomeric and enantiomeric mixtures of Formula 1 and / or Formula 2 as pharmaceuticals. The carbamate compounds are formulated as pharmaceuticals to treat epileptogenesis, for example, to prevent, inhibit, reverse or arrest the development of epilepsy in a subject. In general, the carbamate compounds of the present invention can be administered as pharmaceutical compositions by any method known in the art for administering therapeutic drugs, including oral, buccal, topical, systemic (e.g., transdermal, intranasal or suppository), or parenteral (for example, intramuscular, subcutaneous or intravenous injection). Administration of the compounds directly to the nervous system may include, for example, administration to routes of intracerebral, intraventricular, intacerebroventricular, intrathecal, intracysternal, intraspinal or peri-spinal delivery by intracranial or intravertebral needles or catheters with or without pumping devices . The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols or any other suitable composition; and comprising at least one compound of this invention in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to those of ordinary skill in the art, and the same, and methods of formulating the compositions, can be found in standard references such as Alfonso AR: Reminqton's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton PA, 1985, the description of which is incorporated herein by reference in its entirety and for all purposes. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution and glycols. The carbamate compounds can be provided as aqueous suspensions. The aqueous suspensions of the invention may contain a carbamate compound in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include, for example, a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum, and dispersing agents or humectants, such as natural phosphatide (e.g. , lecithin), a condensation product of alkylene oxide with a fatty acid (for example, polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecaethylene oxicetanol), a product of condensation of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (for example, polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. The formulations can be adjusted for osmolarity. Oily suspensions for use in the present methods can be formulated by suspending a carbamate compound in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281: 93-102, 1997. The pharmaceutical formulations of the invention may also be in the form of oil-in-water emulsions. The oil phase may be vegetable oil or a mineral oil, described above, or mixtures thereof. Suitable emulsifying agents include natural gums, such as acacia gum and tragacanth gum, natural phosphatides, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the products of condensation of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulgent, a preservative or a coloring agent. The compound of choice, alone or in combination with other suitable components, can be made in aerosol formulations (ie, they can be "nebulized") to be administered via inhalation. The aerosol formulations can be placed in acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen and the like. Formulations of the present invention suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, can include sterile, aqueous and non-aqueous, sterile injection solutions. , which may contain antioxidants, buffers, bacteriostats, and solutes that return to the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. Among the acceptable vehicles and solvents that can be used are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile, fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be used, including mono or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. Where the compounds are sufficiently soluble, they can be dissolved directly in normal physiological saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. The dispersions of the finely divided compounds can be constituted in aqueous starch or solution of sodium carboxymethylcellulose, or in a suitable oil, such as peanut oil. These formulations can be sterilized by conventional well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH-adjusting agents and buffers, agents that adjust for toxicity, eg, sodium acetate, sodium chloride, potassium chloride, chloride of calcium, sodium lactate and the like. The concentration of a carbamate compound in these formulations can vary widely, and will be selected based primarily on fluid volumes, viscosities, body weight and the like, according to the particular mode of administration selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique, using those suitable dispersing or wetting agents or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in diluents or a non-toxic parenterally acceptable solvent, such as a solution of 1,3-butanediol. Enrichment formulations may be presented in sealed containers of multiple dose unit doses, such as ampoules and vials. Solutions and suspensions for injection can be prepared from sterile powders, granules and tablets of the kind previously described. A carbamate compound suitable for use in the practice of this invention can, and preferably is orally administered. The amount of a compound of the present invention in the composition can vary widely, depending on the type of composition, the size of a unit dosage, the type of excipient and other factors well known to those of ordinary skill in the art. In general, the final composition can comprise, for example, 0.000001 weight percent (% by weight) to 10% by weight of the carbamate compound, preferably 0.00001% by weight to 1% by weight, with the remainder being the excipient or excipients. Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers allow the pharmaceutical formulations to be formulated into unit dosage forms, such as tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, watered pastes, suspensions, etc., suitable for ingestion by the patient . Formulations suitable for oral administration may consist of (a) liquid solutions, such as an effective amount of the packaged nucleic acid suspended in diluents, such as water, physiological saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, such as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Pharmaceutical preparations for oral use can be obtained through the combination of the compounds of the present invention with a solid excipient, optionally comminuting a resulting mixture, and processing the mixture of granules, after adding the appropriate additional compounds, if desired, to obtain cores of tablets or dragees. Suitable solid carriers are carbohydrate or protein fillers and include, but are not limited to, sugars, including lactose, sucrose, mannitol or sorbitol; starch of corn, wheat, rice, potatoes or other plants; cellulose such as methyl cellulose, hydroxymethyl cellulose, hydroxypropylmethylcellulose or sodium carboxymethyl cellulose; and gums including arabica and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. The tablet forms may include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and others. excipients, dyes, fillers, binders, diluents, buffers, wetting agents, preservatives, flavoring agents, dyes, disintegrating agents and pharmaceutically compatible carriers. The tablet forms may comprise the active ingredient in a flavor, for example, sucrose, as well as troches comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels and the like, containing , in addition to the active ingredient, carriers known in the art. The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the present invention can also be administered by intranasal, intraocular, intravaginal and intrarectal routes, including suppositories, insufflation, powders and aerosol formulations (for the examples of spheroidal inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187- 193, 1995; Tjwa, Ann., Allergy Asthma Immunol., 75: 107-111, 1995). The compounds of the present invention can be delivered transdermally, via a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols. The encapsulating materials can also be used with the compounds of the present invention and the term "composition" can include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release in the body. In one embodiment, the microspheres can be administered via intradermal injection of the drug, microspheres containing (e.g., mifepristone), which are released slowly subcutaneously (see, Rao, J. Biomater Sci. Polym, Ed. 7: 623-645, 1995; as biodegradable and injectable gel formulations (see, for example, Gao, Pharm, Res. 12: 857-863, 1995); or, as microspheres for oral administration (see, for example, Eyles, J. Pharm, Pharmacol 49: 669-674, 1997). Both the transdermal and intradermal routes provide a constant supply for weeks or months. Capsules can also be used in the delivery of the compounds of the present invention. In another embodiment, the compounds of the present invention can be delivered by the use of liposomes that fuse with the cell membrane or are endocytocytized, i.e., employing ligands attached to the liposome that bind to the membrane protein receptors of the surface of the cells, resulting in endocytosis. By using liposomes, particularly where the surface of the liposome carries ligand specific for the target cells, or is otherwise directed, preferentially to a specific organ, one can focus the supply of the carbamate compound towards the target cells in vivo. (See, for example, Al-Muhammed, J. Microencapsul 13: 293-306, 1996, Chonn, Curr Opin Biotechnol 6: 698-708, 1995, Ostro, Am. J. Hosp. Pharm 46: 1576-1587, 1989). The pharmaceutical formulations of the invention can be provided as a salt and can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be more soluble in aqueous solvents or other protonic solvents than the corresponding free base forms. In other cases, the preferred preparation may be a lyophilized powder which may contain, for example, any or all of the following: histidine 1 mM-50 mM, sucrose 0.1% -2%, mannitol 2% -7%, a a pH range of 4.5 to 5.5, which is combined with a buffer before use. The pharmaceutically acceptable salts and esters refer to the salts and esters which are pharmaceutically acceptable and which have the desired pharmacological properties. Such salts include salts that can be formed in which the acidic protons present in the compounds are capable of reacting with the inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, for example, sodium and potassium, magnesium, calcium and aluminum. Suitable organic salts include those formed with the organic bases, such as the amine bases, for example, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. The pharmaceutically acceptable salts may also include acid addition salts formed from the reaction of the amine portions in the parent compound with inorganic acids (eg, hydrochloric and hydrobromic acids) and organic acids (eg, acetic acid, citric acid, maleic acid and the alean and arenesulfonic acids, such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from the carboxy, sulfonyloxy and phosphonoxy groups present in the compounds. When there are two acid groups present, a pharmaceutically acceptable salt or ester can be a monosal or ester or a disal or monoacid ester; and similarly, where there are more than two acid groups present, some or all of such groups may be salified or esterified. The compounds named in this invention may be present in unsalified or unesterified form, or in salified and / or esterified form, and the nomenclature of such compounds is intended to include both the original compound (non-salified and non-esterified) and their salts and esters pharmaceutically acceptable The present invention includes the pharmaceutically acceptable salt and ester forms of Formula 1 and Formula 2. More than one crystalline form of an enantiomer of Formula 1 or Formula 2 may exist and, therefore, are also included in the present invention. A pharmaceutical composition of the invention may optionally contain, in addition to a carbamate compound, at least one additional therapeutic agent useful in the treatment of a disease or condition associated with epileptogenesis. Methods for formulating the pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets. Second edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications. Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems. Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc, the description of which is incorporated herein as a reference in its entirety and for all purposes. The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with the Good Manufacturing Practice (GMP) regulations of the Food and Drug Administration of E.U.A.

Dosage regimens The present invention provides methods for treating epileptogenesis in a mammal using carbamate compounds. The amount of the carbamate compound necessary to treat epileptogenesis is defined as a therapeutically or pharmaceutically effective dose. The dosage schedule and the effective amounts for this use, i.e., the dosage or dosing regimen, will depend on a variety of factors, including the stage of the disease, the physical condition of the patient, age and the like. In the calculation of the dosing regime for a patient, the mode of administration is also taken into account. A person of ordinary skill in the art will be able without undue experimentation, with respect to that experience and this description, to determine a therapeutically effective amount of a particular substituted carbamate compound for the practice of this invention (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols 1-3, 1992), Lloyd, 1999, The Art, Science and Technology of Pharmaceutical Compounding, and Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also one in which any toxic or harmful side effects of the active agent are overcome in clinical terms by beneficial therapeutic effects. It is further noted that for each particular subject, the specific dosage regimens should be evaluated and adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compounds. For treatment purposes, the compositions or compounds described herein may be administered to the subject in a single bolus delivery, via continuous delivery for an extended period of time, or in a repeated administration protocol (eg, by a administration protocol repeated every hour, daily or weekly). The pharmaceutical formulations of the present invention can be administered, for example, one or more times a day, 3 times a week or weekly. In one embodiment of the present invention, the pharmaceutical formulations of the present invention are administered orally once or twice a day. A treatment regimen with the compounds of the present invention can begin, for example, after a subject suffers from a brain-damaging injury or other initial aggression, but before the subject is diagnosed with epilepsy, eg, before that the subject has a first and second seizure. In one embodiment, a subject who is being treated with a compound having an epileptogenic potential, for example, a psychotropic drug, or a subject having a disease associated with a risk of developing epilepsy, for example, autism, may begin a regimen of treatment with a carbamate compound of the present invention. In certain embodiments, the carbamate compound can be administered daily for a fixed period of time (week, month, year) after the onset of the injury that damages the brain or the initial aggression. A physician attending will know how to determine that the carbamate compound has reached a therapeutically effective level, for example, a clinical examination of a patient, or by measuring the levels of the drug in the blood or cerebrospinal fluid. In this context, a therapeutically effective dosage of the biologically active agent may include repeated doses with a prolonged treatment regimen that will provide clinically meaningful results to avoid, reverse, stop or inhibit the development of epilepsy. The determination of effective dosages in this context is typically based on studies of animal models, followed by clinical trials in humans, and followed by the determination of effective dosages and administration protocols that significantly reduce the occurrence or severity of the symptoms or exposure conditions selected in a subject. Suitable models in this regard include, for example, murines, rats, portions, felines, non-human primates and other subjects of accepted animal models known in the art. Alternatively, effective dosages can be determined in vitro models (eg, immunological and histopathological assays). Using such models, only ordinary calculations and adjustments are typically required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the biologically active agents (eg, amounts that are intranasally effective, transdermally effective, intravenously effective or intramuscularly effective to cause a desired answer). In an exemplary embodiment of the present invention, the unit dosage forms of the compounds are prepared for the standard administration regimens. In this way, the composition can be easily subdivided into smaller doses with the direction of the physician. For example, the unit dosages can be made in powders, vials or packaged ampoules, and preferably in the form of a capsule or tablet. The active compound present in these unit dosage forms of the composition, may be present in an amount of, for example, from about 10 mg to about one gram or more, for a single or multiple daily administration, according to the particular need of the patient. At the start of the treatment regimen with a minimum daily dose of about one gram, the blood levels of the carbamate compounds can be used to determine if a larger or smaller dose is indicated.

The effective administration of the carbamate compounds of this invention can be administered, for example, at an oral or parenteral dose of about 0.01 mg / kg / dose to about 150 mg / kg / dose. Preferably, the administration will be from about 0.1 mg / kg / dose to about 25 mg / kg / dose, more preferably from about 0.2 to about 18 mg / kg / dose. Therefore, the therapeutically effective amount of the active ingredient contained per dosage unit as described herein, may be, for example, from about 1 mg / day to about 7000 mg / day for a subject having, for example, an average weight of 70 kg.

Equipment for use in the treatment of epileptogenesis After a pharmaceutical product comprising a carbamate compound has been formulated in a suitable carrier, it can be placed in an appropriate container and labeled for the treatment of epileptogenesis. In addition, another pharmaceutical compound comprising at least one other therapeutic agent useful in the treatment of epileptogenesis, epilepsy or other disorder or condition associated with epileptogenesis, may also be placed in the container, and labeled for the treatment of the indicated disease. Such labeling can include, for example, instructions regarding the amount, frequency and method of administration of each pharmaceutical product.

Although the above invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the skilled person that certain changes and modifications are encompassed by the description, and may be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration and not limitation. The following examples are provided to illustrate the specific aspects of the invention, and are not intended to be limitations.

EXAMPLES The activity of an isolated S-enantiomer of Formula 1 (e.g., Formula 7), referred to herein as the "test compound" or TC, is evaluated in the following experiments to determine the efficacy of the compound for neuroprotection and in the Treatment of epileptogenesis in the model of epilepsy of the temporal lobe induced by lithium and pilocarpine in the rat.

EXAMPLE 1 The lithium-pilocarpine model in temporal lobe epilepsy The model induced in rats by pilocarpine associated with lithium (Li-Pilo), reproduces most of the clinical and neurophysiological characteristics of human temporal lobe epilepsy (Turski et al. , 1989, Synapse 3: 154-171, Cavalheiro, 1995, Ital J Neurol Sci 16: 33-37). In adult rats, the systemic administration of pilocarpine leads to an epileptic state (SE). The lethality ratio reaches 30-50% during the first days. In surviving animals, neuronal damage predominates within the formation of the hippocampus, the piriform and entorhinal cortex, the thalamus, the amygdaloid complex, the neocortex, and the substantia nigra. This period of acute seizures is followed by a "silent" seizure-free phase with an average duration of 14-25 days, after which all animals exhibit spontaneous recurrent seizures at the usual frequency of 2 to 5 per week (Turski et al. al., 1989, Synapse 3: 154-171, Cavalheiro, 1995, Ital J Neurol Sci 16: 33-37, Dube et al., 2001, Exp Neurol 167: 227-241).

Lithium-pilocarpine and treatments with the test compound Male Wistar rats weighing 225-250 g, provided by Janvier Breeding Center (Le Genest-St-lste, France), were housed under controlled standard conditions (light / dark cycle, 7.00 am-7.00 pm, lights on), with food and water available ad libitum. All animal experimentation was carried out in accordance with the rules of the Directive of the Council of European Communities of November 24, 1986 (86/609 / EEC), and the French Department of Agriculture (License No. 67-97). For the electrode implant, the rats were anesthetized by i.p. of 2.5 mg / kg of diazepam (DZP, Valium, Roche, France) and 1 mg / kg of ketamine hydrochloride (Imalgene 1000, Rhone Merrieux, France). Four recording electrodes from a single contact were placed on the skull, on the parietal cortex, two on each side.

Induction of status epilepticus Treatment with the test compound and occurrence of spontaneous recurrent seizures (SRS) All rats received lithium chloride (3 meq / kg, i.p., Sigma, St Louis, Mo, E.U.A.); approximately 20 hours later, the animals were placed in plexiglass boxes, in order to record the cortical EEG of the baseline. Metilcocolamine bromide (1 mg / kg, s.c., Sigma) was administered to limit the peripheral effects of the convulsant. SE was induced by injecting pilocarpine hydrochloride (25 mg / kg, s.c., Sigma) 30 minutes after methylcopolamine. Bilateral cortical activity of the EEG was recorded throughout the duration of the SE and changes in behavior were noted. The effects of the increasing doses of the test compound were studied in 3 groups of rats. The animals of the first group received 10 mg / kg of the test compound, ip, 1 hour after the start of SE (pilo-TC10), while the animals of groups 2 and 3 received 30 and 60 mg / kg of the compound of test (pilo-TC30 and pilo-TC60), respectively. Another group was injected with 2 mg / kg of diazepam (DZP, i.m.) at 1 hour after the onset of SE, which is our standard treatment to improve survival of animals after SE (pilo-DZP). The control group received physiological saline in place of the pilocarpine and the test compound (physiological saline-saline). Pilot rats-test compound rats surviving the SE were then injected approximately 10 hours after the first injection of the test compound with a second i.p. of the same dose of the test compound, and were maintained under a twice daily treatment with the test compound for an additional 6 days. Pilo-DZP received a second injection of 1 mg / kg of DZP on the day of the SE at approximately 0 hours after the first. Subsequently, the rats with Pilo-DZP and physiological serum-saline received an equivalent volume of physiological saline twice a day. The effects of the test compound on the EEG and on the latency for the appearance of the SRS were investigated by a daily video recording of the animals for 10 hours per day, and the recording of the electrographic activity twice a week for 8 hours. hours.

Quantification of cell densities Quantification of cell densities was performed 6 days after ES in 8 rats with pilo-DZP, 8 with pilo-TC10, 7 with pilo-TC30, 7 with pilo-TC60, and 6 with serum physiological-physiological serum. At 14 days after the SE, the animals were deeply anesthetized with 1.8 g / kg of pentobarbital (Dolethal®, Vetoquinol, Lure, France). The brains were removed and frozen. Sections of 20 μm in series were cut in a cryostat, air dried for several days before staining with thionin. The quantification of cell densities was performed with a microscopic grid of 10 x 10 boxes of 1 cm2 in the coronal sections according to the stereotaxic coordinates of the atlas of the rat brain (Paxinos and Watson, 1986). The cell counts were performed twice in a blind manner and were the average of at least 3 values of 2 adjacent sections in each individual animal. The counts involved only cells larger than 10 pm, the small ones are considered glial cells.

Staining with Timm At 2 months after the onset of spontaneous recurrent seizures, the emergence of mossy fibers was examined in the rats in the chronic period exposed to the test compound or DZP and in 3 rats of physiological saline-serum. The animals were deep anesthetized and perfused transcardially with physiological saline followed by 100 ml of 1.15% Na2S (weight / volume) in 0.1 M phosphate buffer, and 100 ml of 4% formaldehyde (volume / volume) in phosphate buffer 0.1 M. The brains were removed from the skull, they were postfixed in 4% formaldehyde for 3-5 hours and sections of 40 μ? t were cut? in a sliding vibratome and mounted on slides coated with gelatin. The next day, the sections were developed in the dark in a solution at 26 ° C of 50% (w / v) arabic gum (160 ml), sodium citrate buffer (30 ml), 5.7% hydroquinone (weight / volume) (80 ml) and 10% (weight / volume) silver nitrate (2.5 ml) for 40-45 minutes. The sections were then rinsed with tap water at 40 ° C for at least 45 minutes, quickly rinsed with distilled water and allowed to dry. They were dehydrated in ethanol and covered with a coverslip. The emergence of mossy fibers was evaluated according to the criteria previously described in the dorsal hippocampus (Cavazos et al., 1991, J Neurosci 1: 2795-2803.), Which is as follows: 0 - no granules between the tips and the crests of DG1 1 - scarce granules in the supragranular region in an unequal distribution between the tips and the crest of DG; 2 - more numerous granules in a continuous distribution between the tips and the crest of DG; 3 - prominent granules in a continuous pattern between the tips and the crest, with occasional areas of confluent granules between the tips and the crest; 4 - prominent granules that form a dense laminar band confluent between the tips and the crest and 5 - dense laminar band confluent of granules that extends into the inner molecular layer.

Analysis of the data For the comparison of the characteristics of the SE in the animals with pilo-physiological serum and pilo-test compound, we used an unpaired Student's t-test. The comparison between the number of rats convulsing in both groups was carried out by means of a Chi square test. For neuronal damage, statistical analyzes between groups were performed using an ANOVA followed by a Fisher's test for multiple comparison, using a Statview program (Fisher RA, 1946a, Statistical Methods for Research Workers (10th edition) Oliver &Boyd , Edinburgh, Fisher RA, 1946b, The Design of Experiments (4th edition) Oliver &Boyd, Edinburgh).

Characteristics of behavior and EEG status epilepticus by lithium-pilocarpine A total number of Sprague-Dawley rats weighing 250-330 g underwent SE induced by Li-pilo. The behavior characteristics of SE were identical in the groups of pilo-physiological serum and pilo-compound test. Within 5 minutes after injection of pilocarpine, the rats developed diarrhea, piloerection and other signs of cholinergic stimulation. During the following 15-20 minutes, the rats exhibited wobbling head, scratching, chewing and exploratory behavior. Recurrent seizures started approximately 15-20 minutes after administration of pilocarpine. These seizures with associated episodes of myoclonus of the head and bilateral forelimbs with erecting and drooping progressed to SE at about 35-40 minutes after pilocarpine, as previously described (Turski et al., 1983, Behav Brain Res. 9: 315-335.).

Patterns of the EEG during the SE During the first hour of the SE, in the absence of pharmacological treatment, the amplitude of the EEG increased progressively while the frequency decreased. Within 5 minutes after injection of pilocarpine, normal background EEG activity was replaced with fast low-voltage activity in the cortex while the theta rhythm (5-7 Hz) appeared in the hippocampus. At 15-20 minutes, rapid high-voltage activity superimposed on the theta rhythm of the hippocampus and isolated high voltage peaks were recorded only in the hippocampus, while the activity of the cortex did not change substantially. At 35-40 minutes after injection of pilocarpine, the animals developed typical electrographic seizures with rapid high-voltage activity present in the hippocampus and cortex, which occurred first as bursts of activity preceding seizures, and followed by continuous trains of high voltage peaks and policos that last until the administration of DZP or the test compound. At approximately 3-4 hours of the SE, the EEG of the hippocampus was characterized by periodic electrographic discharges (PED, approximately one / second) in the group with pilo-DZP and with pilo-10 in the hippocampus and cortex. The amplitude of the activity of the EEG background was low in the animals with pilo-TC60. At 6-7 hours of the SE, peak activity was still present in the cortex and hippocampus in rats treated with DZP and TC10, while the EEG amplitude decreased and returned to baseline levels in the hippocampus. of the rats with TC30 and in both structures of the rats treated with TC60. There was no difference between the groups with TC10, TC30 and TC60. At 9 o'clock SE, the isolated peaks were still recorded in the hippocampus of the rats treated with the test compound, and occasionally in the cortex. In both structures, fund activity was very low at that time.

Mortality induced by the SE During the first 48 hours after the SE, the mortality rate was similar in the rats with pilo-DZP (23%, 5/22), the rats with p10-TC10 (26%, 6 / 23), and rats with pilo-TC30 (20%, 5/25). The proportion of mortality was greatly reduced in the rats with pilo-TC60, in which it only reached 4% (1/23). The difference was statistically significant (p <0.01).

Characteristics of the EEG of the silent phase and appearance of spontaneous recurrent seizures EEG patterns during the silent period were similar in the rats with pilo-DZP and pilo-TC10, 30 or 60. At 24 and 48 hours after the SE, the EEG of the baseline was still characterized by the appearance of PEDs in which waves or large peaks can overlap. Between 1 and 8 hours after injection of the test compound or injection of the vehicle, there was no change in the groups with pilo-DZP or pilo-TC10. In the rats with TC30 and TC60, the frequency and amplitude of the PEDs decreased as early as 10 minutes after the injection and were replaced by large amplitude peaks in the TC30 group and low amplitude peaks in the TC60 group. At 4 hours after the injection, the EEG had returned to the baseline levels in the last two groups. At 6 days after the SE, the EEG was still of lower amplitude than before the injection of pilocarpine and in most of the groups, peaks could still be recorded, occasionally in the rats with pilo-DZP, -TC10 and -TC30 . In rats with pilo-TC60, the frequency of large amplitude peaks was higher than in all other groups. After injection of the test compound or the vehicle, the EEG recording was not affected by injection of the pilo-DZP and pilo-TC10 groups. In the rats with pi-TC30, the injection induced the appearance of slow waves in the EEG of the hippocampus and the cortex and a decreased frequency of the peaks in the pilo-TC60 rats.

All rats exposed to DZP, TC10 and TC30 and studied up to the chronic phase, developed SRS with a similar latency. The latency was 18.2 ± 6.9 days (n = 9) in the rats with pilo-DZP, 15.4 ± 5.1 days (n = 7) in the rats with pilo-TC10, 18.9 ± 9.0 days (n = 10) in the rats with pilo-TC30. In the group of rats subjected to TC60, a subgroup of rats became epileptic with a latency similar to that of the other groups, ie 17.6 ± 8.7 days (n = 7), while another group of rats became epileptic with a much longer delay ranging from 109 to 191 days post-SE (149.8 ± 36.0 days, n = 4), and a rat did not become epileptic in a delay of 9 months post-SE. The difference in latency at SRS between rats with pilo-DZP, pilo-TC10, pilo-TC30 and the first subgroup with pilo-TPM60 is not statistically significant. None of the rats with saline-saline solution (n = 5) developed SRS. To calculate the frequency of SRS in the rats exposed to pilocarpine, the severity of the seizures was considered and a distinction was made between the seizures of stage III (clonic convulsions of the facial muscles and the forelimbs) and stage IV-V (erecting and fall). The frequency of SRS stage III per week in the rats with pilo-DZP and pilo-compound test was variable between the groups. It was low, constant in the groups with pilo-DZP and pilo-TC60 (with an early onset of SRS) during the first 3 weeks and had disappeared during the 4th week in the group with pilo-DZP. The frequency of the SRS of stage III was higher in the group with pilo-TC10, where it increased significantly with respect to the values with pilo-DZP during weeks 3 and 4. The frequency of the SRS of the stage IV-V more severe, was higher during the first week in most groups, except with pilo-TC30 and TC60, with the late onset of seizures, where the frequency of SRS was constant during all 4 weeks in the group with TC30 and during the first two weeks in the group with pilo-TC60 with a late onset of SRS, in which no convulsion of stage IV-V was recorded after the second week. The frequency of SRS of stage IV-V was significantly reduced in the groups with TC10, TC30 and TC60 (with an early onset of SRS) (2.3-6.1 SRS per week), compared with the group with pilo-DZP (11.3 SRS per week) during the first week. During weeks 2-4v the frequency of SRS of stage IV-V was reduced in all groups compared to the first week, reaching values of 2-6 seizures per week, except in the group with pilo-TC60, with an early onset of SRS, where the frequency of seizures was significantly reduced to 0.6-0.9 seizures per week compared with the group with pilo-DZP, in which the frequency of the SRS varied from 3.3 to 5.8.

Cellular densities in the hippocampus, thalamus and cortex In rats with pilo-DZP compared to rats with saline-physiological saline, the number of cells decreased massively in the CA1 region of the hippocampus (70% cell loss in the cell layer pyramidal), whereas the CAS region was less extensively damaged (54% cellular loss in CA3a and 31% in CA3b). In the dentate gyrus, the pilo-DZP rats experienced extensive cell loss in the hilum (73%), whereas the granular cell layer showed no visible damage. Similar damage was seen in the ventral hippocampus, but cell counts were not performed in this region. Extensive damage to the lateral thalamic nucleus (91% of cell loss) was also recorded, while the mediodorsal thalamic nucleus was moderately damaged (56%). In the piriform cortex, cell loss was total in the III-IV layers that were no longer visible, and reached 53% in layer II in the rats with pilo-DZP. In the dorsal entorhinal cortex, layers II and III-IV suffered slight damage (9 and 15%, respectively). Layer II of the ventral entorhinal cortex was completely preserved, while layers III-IV suffered 44% cell loss. In the hippocampus of animals with pilo-test compound, cell loss was reduced compared to rats with pilo-DZP in pyramidal layer CA1, in which cell loss reached 75% in animals with pilo-DZP and 35 and 16% with pilo-TC30 or pilo-TC60, respectively. This difference was statistically significant at the two doses of the test compound. In the pyramidal CAS layer, the test compound did not provide any protection in the CA3a area, whereas the 60 mg / kg dose of the test compound was significantly neuroprotective in CA3b. In the dentate gyrus, cell loss in the hilum was similar in the animals with pilo-test compound (69-72%) and with pilo-DZP (73%). In the two thalamic nuclei, the dose of 60 mg / kg was also protective to reduce neuronal damage by 65 and 42% in the lateral and mediodorsal nuclei, respectively. In the cerebral cortex, treatment with the test compound provided neuronal protection compared to DZP only at the highest dose, 60 mg / kg. At the two lowest doses, 10 and 30 mg / kg, the total cell loss and disorganization of the tissue, observed in the III-IV layers of the piriform cortex, were identical in the rats with pilo-DZP and the rats with pilo-test compound, and did not allow any counting in any of the groups. In layers II and III-IV of the piriform cortex, treatment with TC60 reduced the neuronal damage recorded in rats with pilo-DZP by 41 and 44%, respectively. In the ventral entorhinal cortex, neuroprotection was induced by the administration of TC60 in layers III-IV and reached 31% in comparison with rats with pilo-DZP. In the entorhinal cortex, there was a slight worsening of cell loss in the pilo-TC10 rats compared to the rats with pilo-DZP in the III-IV layers of the dorsal entorhinal cortex (28% more damage) and the lll-IV layers. -IV of the ventral entorhinal cortex (35% more damage). At the other doses of the test compound, the cell loss in the entorhinal cortex was similar to that recorded in the rats with pilo-DZP.

Emergence of mossy fibers in the hippocampus All rats exhibiting SRS in the groups with pilo-DZP and pilo-TPM showed a similar intensity of staining with Timm in the inner molecular layer of the dentate gyrus (grades 2-4). Staining with Timm was present in the upper and lower teeth of the dentate gyrus. The mean value of the Timm score in the upper tooth reached 2.8 ± 0.8 in the rats with pilo-DZP (n = 9), 1.5 + 0.6 in the rats with pilo-TC10 (n = 7), 2.6 ± 1.0 in the rats with pilo-TC30 rats (n = 10), and 1.5 ± 0.7 in the complete group of rats with pilo-TC60 (n = 11). When the group of pilo-test compound at 60 mg / kg was subdivided according to the latency to the SRS, the subgroup with the initial appearance of SRS showed a Timm score of 1.8 ± 0.6 (n = 6) and the subgroup of rats with a late onset or absence of SRS had a Timm rating of 1.2 ± 0.6 (n = 5) . The values recorded in the rats with pilo-DZP were statistically significantly different from the values in the subgroup with pilo-TC10 (p = 0.032) and the pilo-TC60 with late seizures or without seizures (p = 0.016).

Discussion and conclusions The results of the present study show that a 7-day treatment with the test compound, starting 1 hour after the start of SE, is able to protect some areas of the brain from neuronal damage, for example, in the layer of pyramidal cells of the CA1 and CA3b area, the mediodorsal thalamus, layers II and 11 MV of the piriform cortex and the III-IV layers of the ventral entorhinal cortex, but only at the highest dose of the test compound, ie 60 mg / kg. The last dose of the test compound is also capable of delaying the onset of SRS, at least in a subgroup of animals that become epileptic with an average delay that was approximately 9 times longer than in the other groups of animals and an animal he did not become epileptic in a delay of 9 months after the SE. These results show that a compound with anti-chronic properties, which are the classic properties of most of the antiepileptic drugs marketed, is also capable of delaying epileptogenesis, that is, it is antiepileptogenic. The data of the present study also show that the treatment with the test compound, whatever the dose used, decreases the severity of the epilepsy, since it decreases the number of convulsions of stage IV-V, mainly during the first week of appearance and throughout the 4 week observation period with the treatment with the test compound at 60 mg / kg. In addition, in the group with TC10, there was a shift towards an increase in the appearance of less severe seizures of stage III, which are more numerous than in the group with pilo-DZP.

EXAMPLE TWO The purpose of the present project was to continue the study reported in Example one above on the potential neuroprotective and antiepileptogenic properties of the test compound (TC) in the lithium-pilocarpine (Li-Pilo) model of temporal lobe epilepsy. In the first study, it was demonstrated that the CT was able to protect the CA1 and CA3 areas of the hippocampus, the piriform cortex and ventral entorhinal of the neuronal damage induced by the epileptic state (SE) by Li-Pilo. The majority of these neuroprotective properties occurred at the highest dose studied, 60 mg / kg and the treatment was able to delay the onset of spontaneous seizures in 36% (4 of 1) of the rats. In the present example, the consequences of treatment with the highest doses of CT in neuronal damage and epileptogenesis are studied.

The lithium-pilocarpine model of temporal lobe epilepsy The model of epilepsy induced in rats by pilocarpine associated with lithium (Li-Pilo) reproduces most of the clinical and neurophysiological characteristics of human temporal lobe epilepsy (Turski et al. al., 1989; Cavalheiro, 1995). In adult rats, systemic administration of pilocarpine leads to SE, which may last up to 24 hours. The lethality ratio reaches 30-50% during the first days. In surviving animals, neuronal damage predominates within the formation of the hippocampus, the piriform and entorhinal cortices, the thalamus, the amygdaloid complex, the neocortex, and the substantia nigra. This period of acute seizures is followed by a "silent" seizure-free phase with an average duration of 14-25 days, after which all animals exhibit recurrent spontaneous seizures at the usual frequency of 2 to 5 per week (Turski et al., 1989; Cavalheiro, 1995; Dubé et al., 2001). Current antiepileptic drugs do not prevent epileptogenesis and are only transiently efficient in recurrent seizures. In our previous study, we studied the potential neuroprotective and antiepileptogenic effects of doses that increase TC, given in monotherapy, and compared with our standard treatment with diazepam (DZP), given mainly to avoid a high mortality. These data show that a 7-day treatment with 10, 30 or 60 mg / kg of CT, starting at 1 hour after the start of the SE, is able to protect some areas of the brain from neuronal damage. This effect is statistically significant in the layer of the pyramidal cells of the CA1 and CA3b areas, the mediodorsal thalamus, layers II and III-IV of the piriform cortex and the III-IV layers of the ventral entorhinal cortex, but only highest dose of TC, that is, 60 mg / kg. Furthermore, it seems that the last dose of the CT is also the only one that is capable of delaying the appearance of SNS, at least in a subgroup of animals that became epileptic with a mean delay that was approximately 9 times longer than that in the other groups of animals, and an animal did not become epileptic in a delay of 9 months after the SE. In the present study, the effects of different doses of CT, ie 30, 60, 90 and 120 mg / kg (TC30, TC60, TC90 and TC120) were tested using the same design as in the previous study. The treatment was started one hour after the start of the SE and the animals were treated with a second injection of the same dose of the drug. This initial treatment of the SE was followed by a 6-day treatment with the CT. This report is related to the effects of the four different doses of CT on neuronal damage, assessed in the hippocampus, the parahippocampal cortex, the thalamus and the amygdala at 14 days after the ES and in the latency and frequency of the lesions. spontaneous epileptic seizures.

Methods Animals Adult male Sprague-Dawley rats provided by Janvier Breeding Center (Le Genest-St-lsle, France) were housed under standard controlled conditions, without overcrowding at 20-22 ° C (dark light cycle, 7.00 am-7.00 pm, lights lit), with food and water available ad libitum. All animal experimentation was carried out in accordance with the rules of the Directive of the Council of European Communities of November 24, 1986 (86/609 / EEC), and the French Department of Agriculture (License No. 67-97).

Induction of epileptic status, treatment with CT and appearance of SRS All rats received lithium chloride (3 meq / kg, i.p., Sigma, St Louis, Mo, E.U.A.); approximately 20 hours later, all animals also received methylcopolamine bromide (1 mg / kg, s.c., Sigma) which was administered to limit the peripheral effects of the convulsant. SE was induced by injecting pilocarpine hydrochloride (25 mg / kg, s.c., Sigma) 30 minutes after methylcopolamine. The effects of doses that increase TC were studied in 5 groups of rats. The animals received either 2.5 mg / kg of DZP, i.m., or 30, 60, 90 or 120 mg / kg of TC (TC30, TC60, TC90, TC120), i.p., at 1 hour after the onset of SE. The control group received the vehicle instead of the pilocarpine and the CT. The rats surviving the SE were then injected approximately 10 hours after the first CT injection with a second i.p. of 1.25 mg / kg of DZP for the group with DZP or the same dose of TC as in the morning and were maintained under TC treatment twice a day (sc) for an additional 6 days, while the rats with DZP received an injection of the vehicle. The effects of DZP and the 4 doses of TC on epileptogenesis were investigated by daily video recording of the animals for 10 hours per day. Video recording was performed during 4 weeks, during which the appearance of the first seizure was recorded, as well as the total number of seizures during the entire period. The animals were removed from the video recording system and kept for an additional 4 weeks in our animal facilities before they were slaughtered, after a total period of 8 weeks of epilepsy. Rats that did not exhibit seizures were sacrificed after 5 months of video recording.

Quantification of cell densities The quantification of cell densities was performed at two moments after the SE: a first group was studied 14 days after the SE and was composed of 7 rats with DZP, 8 with TC30, 1 with TC60, 10 with TC90 , 8 with TC120 and 8 control, not subject to SE. A second group used for the study of SRS latency was sacrificed at 8 weeks after the first SRS or at 5 months, when no SRS could be observed in that delay, and was composed of 14 rats with DZP, 8 with TC30, 10 with TC60, 11 with TC90, 9 with TC120. At the moment, the neural count is still in progress in the second group of animals studied for epileptogenesis and the long-term count and the data related to that part of the study will not be included in this report. For neuronal counting, the animals were deeply anesthetized with 1.8 g / kg pentobarbital (Dolethal®, Vétoquinol, Lure, France). The brains were then removed and frozen. Sections were cut in series of 20 μ? in a cryostat, air-dried for several days before thionine staining. The quantification of the cell densities was performed with a microscopic grid with 10 x 10 boxes of 1 cm2 in the coronal sections according to the stereotaxic coordinates of the atlas of the rat brain (Paxinos and Watson, 1986). The counting grid was placed in a well-defined area of the brain structure of interest and the count was carried out with a microscopic amplification of 200 or 400 times, defined for each unique brain structure. Cell counts were performed twice on each side of three adjacent sections for each region, by a single observer without knowledge of the treatment of the animals. The number of cells obtained in the 12 fields counted in each brain structure was averaged. This procedure was used to minimize the potential errors that can result from a double count that leads to overestimation of the number of cells. The neurons that touch the lower and right edges of the grid were not counted. The counts involved only neurons with cell bodies greater than 10 μ? T ?. Cells with small cell bodies were considered glial cells and were not counted.

Data analysis For neuronal damage and epileptogenesis, a statistical analysis was performed between the groups, by means of a one-way analysis of variance, followed by a Dunnet or Fisher post-hoc test, using the Statistica program.

Results Characteristics of the behavior of status epilepticus by lithium-pilocarpine A total number of 143 Sprague-Dawley rats weighing 250-330 g underwent SE induced by lithium-pilocarpine (Li-pilo). In this number, 10 did not develop SE, whereas 133 rats developed an SE by completely characteristic Li-pilo. The characteristics of SE behavior were identical in both groups with li-pyl-DZP and li-pyl-TC. Within 5 minutes after injection of pilocarpine, the rats developed diarrhea, piloerection and other signs of cholinergic stimulation. During the following 15-20 minutes, the rats exhibited wobbling head, scratching, chewing and exploratory behavior. Recurrent seizures were initiated approximately 15-20 minutes after the administration of pilocarpine. These seizures, whose associated episodes of myocardium of the head and bilateral forelimbs, with erecting and drooping, progressed to SE approximately 35-40 minutes after pilocarpine, as previously described (Turski et al., 1989; Dubé et al. al., 2001, André et al., 2003). The control group not subjected to SE and which received lithium and physiological saline was composed of 20 rats. In the group of 57 animals dedicated to cell counting at 14 days after the SE, a total number of 13 rats died during the first 48 hours after the SE. The degree of mortality varied with: 36% (4/1 1) of the rats with DZP, 33% (4/12) of the rats with TC30, 8% (1/12) of the rats with TC60, 0% (0/10) of rats with TC90 and 33% (4/12) of rats with TC120 died. In the group with DZP, all 4 rats died in the first 24 hours after the SE. In the group of rats with TC30, one rat died on the day of the SE, one rat died 24 hours after the SE and two rats at 48 hours. In the group of rats with TC60, one rat died 48 hours after the SE. In the group of rats with TC120, two rats died at 24 hours and two at 48 hours after the SE. In the group of 55 animals dedicated to the study of latency for SRS and late cell count, the degree of mortality during the first 48 hours after the SE was as follows: 7% (1/14) of the rats with DZP, 27% (3/1) of the rats with TC30, 0% (0/10) of the rats with TC60, 0% (0/11) of the rats with TC90 and 0% (0/9) of the rats with TC120 died. In the group of rats with DZP, one rat died during the first 24 hours after the SE. In the TC30 group, two rats died at 24 hours and one at 48 hours after the SE.

Cellular densities in the hippocampus and cortex in the initial phase (14 days after the SE) In the rats with DZP compared to the control rats, the number of neurons massively decreased in the CA1 region of the hippocampus (85% suppression in the pyramidal cell layer), whereas the CA3 region was damaged less extensively (40% loss) (Table 1 and Figure 1). In the dentate gyrus, the rats with DZP experienced extensive neuronal loss in the hilum (65%), whereas the granular cell layer did not show open damage. The same distribution of damage was observed in the ventral hippocampus, but cell counts were not performed in this region. In the thalamus, the neuronal loss was moderate in the central and lateral mediodorsal nuclei, the dorsal mid dorsolateral and in the middle central (18, 24, 40 and 34% of suppression, respectively), more marked in the mediodorsal nucleus (49% ) and greater in the lateral ventral division of the dorsolateral nucleus (90%) (Table 1 and Figure 2). In the amygdala, the neuronal loss was moderate in the posterior ventral middle nucleus (38%) or more marked in the basolateral and anterior dorsal midbrains (73 and 53% suppression)., respectively). There was no neuronal damage in the central nucleus (Table 1 and Figure 3). In the piriform cortex, neuronal loss was almost complete in layer III (94%) that was no longer truly visible and reached 66 and 89% in dorsal and ventral layer II, respectively in rats with DZP, compared with rats treated with physiological saline, control. In the dorsal entorhinal cortex, layers II and III-IV suffered slight damage (18 and 24%, respectively) and in the ventral layers II and III / IV, the damage reached 22 and 74%, respectively (Table 1 below). Figure 4).

TABLE 1 Effects of increasing TC doses on the number of neuronal cell bodies in the hippocampus, thalamus, amygdala and cerebral cortex of rats subjected to SE by li-pyl * p < 0.05, ** p < 0.01, statistically significant difference between rats with pilo-TC and with physiological li-serum control ° p < 0.05, 00 p < 0.01, statistically significant differences between the rats with pilo-TC and with pilo-DZP In the hippocampus of animals treated with CT, cell loss was significantly reduced compared to rats with DZP in a layer of CA1 pyramidal cells. This reduction was marked in the rats with TC30, 60 or 90 (36-47% of cell loss) and was prominent in the TC120 group (12% of cell loss). The differences were statistically significant at all TC doses (Table 1 and Figure 1). In the CA3 pyramidal layer, there was a tendency towards a slight neuroprotection induced by RWJ, only at the dose of 120 mg / kg, but the difference with the DZP group was not significant. In the dentate gyrus, the cellular loss in the hilum was similar in the groups of DZP and TC30, 60 and 90 (61-66% suppression) and there was a slight tendency to a reduced damage in the group of TC120 (53% of neuronal loss) compared to animals with DZP (66% suppression). None of these differences was statistically significant. In the thalamus, the neuronal loss was similar in the rats with DZP and TC30 and TC60. CT was significantly protective at the dose of 60 mg / kg in the dorsolateral mid dorsal nucleus and at the two highest doses, 90 and 120 mg / kg in all the thalamic nuclei, although the difference does not reach significance in the mid-dorsal central nuclei and central means in rats with TC90. In rats with TC120, neuronal suppression was considerably reduced compared to rats with DZP. It varied from 4-19% and the number of neurons was not significantly different from the control animals, except in the dorsolateral mid dorsal nuclei (Table 1 and Figure 2). In the amygdala, CT was significantly protective at the 30 mg / kg dose in the basolateral nucleus and at the 60 mg dose, also in the middle dorsal anterior nucleus. At the highest dose, the CT was quite neuroprotective; the number of neurons was no longer significantly different from the control level and reached 86-99% of the control level in all the nuclei of the amygdala (Table 1 and Figure 3). In the cerebral cortex, treatment with CT does not significantly protect any cortical area compared to treatment with DZP at a dose of 30 mg / kg. At 60 mg / kg, CT significantly reduced neuronal loss only in layer II of the dorsal piriformis cortex (25% suppression compared to 66% in the DZP group). At 90 and 120 mg / kg, the CT significantly protected all three areas of the piriformis cortex compared to the treatment with DZP and at the highest dose of TC, 120 mg / kg, the neuronal density reached 78-96 % of control levels, including in the piriform cortex, dorsal layer II and layer III, where the neuronal population was almost completely depleted in the DZP group. In all the layers of the dorsal and ventral entorhinal cortex, the two lowest doses of CT, 30 and 60 mg / kg did not provide any neuroprotection. The dose of 90 mg / kg of TC significantly protected layers II and III / IV of the ventral entorhinal cortex (4 and 17% of damage remaining in layers II and II / IV of the dorsal part and in layer II of the ventral part, compared to 19 and 73% in the DZP group). At the highest dose of TC, 120 mg / kg, all parts of the entorhinal cortex, both dorsal and ventral, were protected and the number of neurons in these areas was no longer significantly different from the level in the controls (85-94 % of surviving neurons, compared to 27-81% in the DZP group).Latency and frequency of recurrent seizures The latency of spontaneous seizures reached a mean value of 15.5 ± 2.3 days in the DZP group (14 rats) and was similar (11.6 ± 2.5 days) in the TC30 group (8 rats). At higher TC concentrations, animals can be subdivided into subgroups with short and long latencies.

A short latency was considered as any duration shorter than 40 days after the SE. Some rats exhibited a latency for the first spontaneous seizure that was similar to that recorded in the groups with DZP and TC, but the number of rats exhibiting these short latency values decreased progressively with the increase in TC concentration. Thus, at 30 mg / kg, 70% of the rats (7/10) had short latencies for the seizures, while at 90 and 120 mg / kg, this percentage reached 36% (4/1 1) and the 1 1% (1/9), respectively (Table 2 below and Figure 5).

TABLE 2 Effect of doses increasing TC on latency for spontaneous seizures ** p < 0.01, * p < 0.05, statistically significant differences compared to the group with pilo-DZP 00 p < 0.01, ° p < 0.05, statistically significant differences compared to the short latency group In the groups of TC60, 90 and 120, the mean value of the rats with long latencies was similar and ranged from 52 to 85 days. Finally, at the two highest doses of CT, we were able to identify a percentage of rats that did not develop any seizures for a duration of 150 days post-ES. The percentage of non-epileptic rats reached 45% at both doses of CT. The frequency of spontaneous seizures was similar during the four weeks of registration. It showed a tendency to be higher in the groups with DZP and TC30, while it was lower in the groups with TC60, 90 and 120 (Figure 6). These differences do not reach statistical significance at the level of each individual weekly frequency, but reach significance for the total or average number of seizures during the four weeks. The number of seizures was also plotted according to the duration of latency for the first spontaneous seizure. Animals with a short latency showed a tendency to show 2-3 times more seizures during the four weeks of registration than rats with a long latency period. No statistical analysis could be performed since the ANOVA did not show any significance, most likely because there was only one animal in the short latency subgroup of the animals with TC120 (Figure 7). However, when all latency values were plotted against the number of seizures, there was a significant inverse correlation leading to a straight line with a correlation coefficient of - 0.4 (Figure 8). To complete this analysis, two more measurements will be made. The first is cell counting in animals that were recorded on video and followed for 2 months after the first spontaneous seizure or sacrificed at 5 months to study the potential correlation between the degree and location of brain damage and the appearance of , and / or latency for spontaneous seizures. The second will be a one-year follow-up of the occurrence of seizures in a group of rats to study whether or not the animals we declare "non-epileptic" at 5 months will remain free of seizures. The results of the present study show that a treatment with CT that starts 1 hour after the onset of SE induced by Li-pilo has neuroprotective properties in the CA1 pyramidal cell layer of the hippocampus, and in all layers of the piriform and entorhinal cortex ventral and dorsal. The CT also protects the nuclei of the thalamus and amygdala. However, CT is not protective at a dose of 30 mg / kg, except for CA1, a thalamic nucleus and one of the amygdala. At the dose of 60 mg / kg, layer II of the dorsal piriform cortex and a second nucleus of the amygdala are also protected. At 90 and 120 mg / kg, the drug protects most of the brain regions studied, except that of the CA3 hippocampus and the hilum of the dentate gyrus. The last two structures plus the dorsal dorsolateral dorsal thalamic nucleus are the only regions where the number of neurons remains significantly different from the controls at the dose of 120 mg / kg of TC. From these data, the extremely powerful neuroprotective properties of CT appear clearly. The molecule seems to prevent neuronal death in most of the regions that belong to the limbic epilepsy circuit induced by Li-pilo, that is, the cortexes of the hippocampus, thalamus, amygdala and parahippocampus. These are all regions in which we have detected an MRI signal in the course of epileptogenesis in rats treated with Li-pilo (Roch et al., 2002a). The only two regions that are not efficiently protected by CT are the CA3 pyramidal cell layer and the hilum of the dentate gyrus. The last region suffers rapid and massive cellular damage (André et al., 2001; Roch et al., 2002a) and none of the neuroprotection we used in previous studies has been able to protect this structure. Also, based on previous studies, we have identified this structure as a key area in the initiation and maintenance of epileptic seizures in the Li-pilo model (Dubé et al., 2000). Obviously, the present data show that epileptogenesis can be prevented even if the damage remains very marked in this area. The long-term cell count in the group of animals that is registered with video will be able to show whether the degree of damage in this region is critical or not for epileptogenesis in this model.

The treatment does not affect the latency for the first spontaneous seizure at the dose of 30 mg / kg. At the 3 highest doses, a percentage of animals developed epilepsy as fast as rats with DZP or TC30, but the relative importance of this subgroup was inversely related to the dose of CT used. Another subgroup, of constant size (2-4 animals per group) developed epilepsy after latency 4-6 times longer, while at the two highest doses of the drug, 4-5 rats had not become epileptic after 5 days. months, that is, approximately 10 times the duration of the short latency and 2-3 times that of the long latency. This delay in the onset of epilepsy can be correlated with the number of protected neurons in the basal cortices in animals. This assumption is based on the fact that we noticed some heterogeneity in the degree of neuroprotection in the basal cortices of the animals subjected to the short-term neural count at 14 days after the SE. However, for the moment, we have not performed a neuronal count in the animals used for the study of epileptogenesis and therefore, we can not draw a conclusion about a potential relationship between the number of surviving neurons in the basal cortices and the proportion or even the appearance of epileptogenesis. The data obtained in the present study is in agreement with the previous study of this group that reports that the dose of 60 mg / kg of TC protected the hippocampus and the basal cortices of the neuronal damage and delayed the appearance of recurrent seizures (see the previous report, 2002).

They confirm that the protection of the basal cortices can be a key factor in the induction of a disease, modifying the effect in the lithium-pilocarpine model of epilepsy. The key role of basal cortices as initiators of the epileptic process was previously demonstrated by our group in the lithium-pilocarpine model (André et al., 2003, Roch et al., 2002a, b). In conclusion, this study shows that the test compound (TC) has very promising antiepileptogenic effects.

References for Example 2 André V, Marescaux C, Nehlig A, Fritschy JM (2001) Alterations of the hippocampal GABAergic system contribute to the development of spontaneous recurrent seizures in the lithium-pilocarpine model of temporal lobe epilepsy. Hippocampus 11: 452-468. André V, Rigoulot MA, Koning E, Ferrandon A, Nehlig A (2003) Long-term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat. Epilepsy 44: 893-903. Cavalheiro EA (1995) The pilocarpine model of epilepsy. Ital J Neurol Sci 16: 33-37. Dubé C, Marescaux C, Nehlig A (2000) A metabolic and neuropathological approach to the understanding of plastic changes occurring in the immature and adult rat brain during lithium-pilocarpine induced epileptogenesis. Epilepsy 41 (Suppl 6): S36-S43. Dubé C, Boyet S, Marescaux C, Nehlig A (2001) Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat. Exp Neurol 167: 227-241. Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Coordinates, 2nd ed. Academic Press, San Diego. Roch C, Leroy C, Nehlig A, Namer IJ (2002a) Contribution of magnetic resonance imaging to the study of the lithium-pilocarpine model of temporal lobe epilepsy in adult rats. Epilepsy 43: 325-335. Roch C, Leroy C, Nehlig A, Namer IJ (2002b) Predictive valué of cortical injury for the development of temporal lobe epilepsy in P21-day-old rats: a MRI approach using the lithium-pilocarpine model. Epilepsy 43: 1129-1136. Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3: 154-171.

References cited All references cited herein are incorporated by reference in their entirety and for all purposes, to the same degree as if each publication or patent or individual patent application was specifically and individually indicated as being incorporated as a reference in its entirety for all purposes. The discussion of references herein is intended simply to summarize the claims made by their authors and no admission is made that any reference constitutes the prior art. The applicants reserve the right to question the accuracy and pertinence of the cited references. The present invention is not limited in terms of the particular embodiments described in this application, which are intended as unique illustrations of the individual aspects of the invention. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The functionally equivalent methods and apparatus within the scope of the invention, in addition to those enumerated herein, will be apparent to those skilled in the art, from the foregoing description and the accompanying drawings. Such modifications and variations are intended to fall within the scope of the appended claims. The present invention is limited only by the terms of the appended claims, together with the full scope of equivalents to which such claims are entitled.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - The use of a compound, or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of Formula (I) and Formula (II): Formula (I) Formula (II) wherein, the phenyl is substituted at X with one to five halogen atoms, selected from the group consisting of fluorine, chlorine, bromine and iodine and, R-i, R2, F > R5 and F * 6 are independently selected from the group consisting of hydrogen and C4 alkyl; wherein the C 1 -C 4 alkyl is optionally substituted with phenyl (wherein the phenyl is optionally substituted with substituents, independently selected from the group consisting of halogen, CRC 4 alkyl, C 4 alkoxy, amino, nitro and cyano) , to prepare a medicament useful for treating epileptogenesis in a patient in need of treatment with an antiepileptogenic drug (an AEGD). 2. - The use claimed in claim 1, wherein X is chlorine. 3. The use claimed in claim 1, wherein X is substituted in the ortho position of the phenyl ring. 4. The use claimed in claim 1, wherein R-, R2, R3, R, R5 and R6 are selected from hydrogen. 5. The use of an enantiomer, or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of Formula (I) and Formula (II) or an enantiomeric mixture, wherein an enantiomer is selected from the group which consists of Formula (I) and Formula (II) predominates: Formula (I) Formula (II) wherein, the phenyl is substituted at X with one to five halogen atoms, selected from the group consisting of fluorine, chlorine, bromine and iodine and, Ri, R2, R3, 4, R5 and R6 are independently selected from the group consisting of hydrogen and C1-C4 alkyl; wherein the C 1 -C 4 alkyl is optionally substituted with phenyl (wherein the phenyl is optionally substituted with substituents, independently selected from the group consisting of halogen, C 1 -C 4 alkyl, Ci-C 4 alkoxy, amino, nitro and cyano), to prepare a medicament useful for treating epileptogenesis in a patient in need of treatment with an antiepileptogenic drug (an AEGD). 6. The use claimed in claim 5, wherein X is chlorine. 7. The use claimed in claim 5, wherein X is substituted in the ortho position of the phenyl ring. 8. - The use claimed in claim 5, wherein R-? , R2, R3, R4, R5 and R6 are selected from hydrogen. 9. The use claimed in claim 5, wherein an enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the degree of about 90% or greater. 10. The use claimed in claim 5, wherein an enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates to the degree of approximately 98% or greater. 1 . - The use claimed in claim 5, wherein the enantiomer selected from the group consisting of Formula (I) and Formula (II) is an enantiomer selected from the group consisting of Formula (Ia) and Formula ( Na): Formula (Ia) Formula (Ha) wherein, the phenyl is substituted at X with one to five halogen atoms, selected from the group consisting of fluorine, chlorine, bromine and iodine and, Ri, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and C4 alkyl; wherein the C 1 -C 4 alkyl is optionally substituted with phenyl (wherein the phenyl is optionally substituted with substituents, independently selected from the group consisting of halogen, C 4 alkyl, CrC 4 alkoxy, amino, nitro and cyano) . 12. The use claimed in claim 11, wherein X is chlorine. 13. The use claimed in claim 11, wherein X is substituted in the ortho position of the phenyl ring. 14. - The use claimed in claim 11, wherein R ^ R2l R3, R4. 5 and R6 are selected from hydrogen. 15. The use claimed in claim 11, wherein an enantiomer selected from the group consisting of Formula (Ia) and Formula (lia) predominates to the degree of about 90% or greater. 16. - The use claimed in claim 11, wherein an enantiomer selected from the group consisting of Formula (Ia) and Formula (lia) predominates to the degree of about 98% or greater. 17. The use claimed in claim 5, wherein the enantiomer selected from the group consisting of Formula (I) and the Formula (II) is an enantiomer selected from the group consisting of Formula (Ib) and Formula (llb) or a pharmaceutically acceptable salt or ester thereof: Formula (Ib) Formula (llb) 18. The use claimed in claim 17, wherein an enantiomer selected from the group consisting of Formula (Ib) and Formula (llb) predominates to the degree of about 90% or higher. 19. The use claimed in claim 17, wherein an enantiomer selected from the group consisting of Formula (Ib) and Formula (llb) predominates to the degree of about 98% or greater. 20. The use claimed in claims 1 or 5, wherein the predisposing factors that make the patient in need of treatment with an antiepileptogenic drug (an AEGD), are selected from the group consisting of: injury or trauma of any class to the CNS; CNS infections; anoxia; stroke (CVA); autoimmune diseases affecting the CNS, for example, lupus; birth injuries, for example, perinatal asphyxia; heart attack; vascular therapeutic or diagnostic surgical procedures, for example, carotid endarterectomy or cerebral angiography; trauma of the spinal cord; hypotension; injury to the CNS of embolism, hyper or hypoperfusion; hypoxia; known genetic predisposition to disorders known to respond to AEGD; injuries that occupy space of the CNS; brain tumors, for example, glioblastomas; bleeding or hemorrhage in or surrounding the CNS, for example, intracerebral bleeds or subdural hematomas; cerebral edema; Feverish convulsions; hyperthermia; exposure to toxic or poisonous agents; intoxication with drugs, for example, cocaine or alcohol; family history of seizure disorders or a neurological phenomenon similar to seizures related to epilepsy or a seizure-related disorder, history of status epilepticus; current treatment with medications that lower the threshold for seizures, for example, lithium carbonate, torazine or clozapine; evidence of surrogate markers or biomarkers that the patient is in need of treatment with an antiepileptogenic drug, eg, MRI scan showing hippocampal sclerosis, elevated serum levels of neuronal degradation products, elevated levels of ciliary neurotrophic factor (CNTF) ) or an EGG that suggests a seizure disorder or a neurological phenomenon similar to seizures related to epilepsy, or an analogous disorder related to epilepsy. 21. The use claimed in claim 20, wherein the predisposing factors that make the patient in need of treatment with an antiepileptogenic drug (an AEGD), are selected from the group consisting of: head trauma or penetrating; stroke or other cerebrovascular accident (CVA); epileptic state and injuries that occupy space of the CNS. 22. The use claimed in claim 21, wherein the predisposing factors are head trauma or penetrating. 23. - The use claimed in claim 21, wherein the predisposing factors are apoplexy and another cerebral vascular accident (CVA). 24. The use claimed in claim 23, wherein the predisposing factor is status epilepticus. 25. - The use claimed in claims 1 or 5, wherein said medicament is formulated to be administrable in combination with one or more other compounds or therapeutic agents. 26. The use claimed in claim 25, wherein one or more of the other compounds or therapeutic agents are selected from the group consisting of compounds having one or more of the following properties: antioxidant activity; N-DA receptor antagonist activity, ability to increase inhibition of endogenous GABA; activity of the NO synthase inhibitor; ability to join iron, for example, an iron chelator; ability to bind to calcium, for example, a chelator of Ca (II); ability to bind zinc, for example, a Zn (II) chelator; the ability to effectively block the sodium or calcium ion channels, or to open the potassium or chloride ion channels in a patient's CNS, so that epileptogenesis is inhibited in the patient. 27. The use claimed in claim 26, wherein one or more compounds can also be selected from the group consisting of antiepileptic drugs (AED). 28. The use claimed in claim 27, wherein the antiepileptic drug (AED) is selected from the group consisting of: carbamazepine, clobazam, clonazepam, ethosuximide, felbamate, gabapentin, lamotigin, levetiracetam, oxcarbazepine, phenobarbital, phenytoin , pregabalin, primidone, retigabine, talampanel, tiagabine, topiramate, valproate, vigabatrin, zonisamide, benzodiazepines, barbiturates or sedative hypnotics. 29. A pharmaceutical composition for treating epileptogenesis, comprising a pharmaceutically effective amount of an enantiomer, or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of Formula (I) and Formula (II) or a enantiomeric mixture, wherein an enantiomer selected from the group consisting of Formula (I) and Formula (II) predominates: Formula (I) Formula (II) wherein, the phenyl is substituted in X with one to five halogen atoms, selected from the group consisting of fluorine, chlorine, bromine and iodine and, R-, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen and CC alkyl; wherein the C 1 -C 4 alkyl is optionally substituted with phenyl (wherein the phenyl is optionally substituted with substituents, independently selected from the group consisting of halogen, CrC 4 alkyl, CrC 4 alkoxy) amino, nitro and cyano ), and a pharmaceutically acceptable carrier or excipient. 30. A kit, comprising therapeutically effective dosage forms of the pharmaceutical composition according to claim 29, in an appropriate package or container, together with information or instructions for the appropriate use thereof. 31. The use claimed in claims 1 or 5, wherein the medicament is formulated to be administrable in an amount of about 0.01 mg / kg / dose to about 100 mg / kg / dose. 32. - The use claimed in claims 1 or 5, wherein the patient has not developed epilepsy at the time of administration. 33. - The use claimed in claims 1 or 5, wherein the patient is at risk of developing epilepsy at the time of administration. 34. - The use claimed in claims 1 or 5, wherein the patient has developed epilepsy at the time of administration. 35. The use claimed in claims 1 or 5, wherein the amount of said compound (or enantiomer) or a pharmaceutically acceptable salt or ester thereof is progressively decreased as the treatment of the epileptogenic process progresses in the patient. 36. The use claimed in claims 25, 26, 27 or 28, wherein the amount of one or more other compounds or therapeutic agents administered in combination with said medicament is progressively decreased as the treatment of the epileptogenic process progresses in the patient.