MX2008008092A - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of epilepsy - Google Patents

Abstract

The present invention is a method for treating, preventing, reversing, arresting or inhibiting the occurrence, development and maturation of seizures or seizure-related disorders. More specifically, the present invention is directed to methods for the use of benzo-fused heterocycle sulfamide derivatives of formula (I) and formula (II) as described herein to therapeutically or prophylactically treat, prevent, reverse, arrest or inhibit epileptogenesis and epilepsy.

Description

USE PE DERIVATIVES OF HETEROCILO SULFAMIDA BENZOFUSIONADOS FOR THE TREATMENT OF EPILEPSY REFERENCE TO RELATED REQUESTS This application claims the benefit of the provisional application of E U A 60/751, 496 filed on December 19, 2005, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to the use of benzofused heterocycle sulfamide derivatives to treat, prevent, reverse, suppress or inhibit the presentation, development and maturation of epileptic seizures or disorders related to epileptic seizures. More specifically, the present invention relates to methods for the use of benzofused heterocycle sulfamide derivatives to treat, prevent, reverse, suppress or inhibit, therapeutically or prophylactically, epileptogenesis and epilepsy BACKGROUND OF THE INVENTION Damage or trauma of various kinds to the central nervous system (CNS) or peripheral nervous system (PNS) can produce profound and long-lasting neurological and psychiatric symptoms and disorders A common mechanism for the production of these effects is the induction of epileptic seizure activity or epileptic crisis-like phenomena in the CNS or in the nerves and ganglia of the PNS Symptomatic or paroxysmal alterations In the electrical activity of the CNS or SNP, epileptic seizures or neurological mechanisms similar to epileptic seizures are considered to be the basis of many of the pathological phenomena in a wide variety of neurological and psychiatric disorders. A severe neurological condition characterized by epileptic 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. Epilepsy describes a condition in which a person has recurrent epileptic seizures due to a chronic underlying process. Epilepsy refers to to a phenomenon clinical rather than a single disease entity, since there are many forms and causes of epilepsy Using a definition of epilepsy as two or more unprovoked epileptic seizures, the incidence of epilepsy is estimated to be approximately 0 3 to 0.5 per hundred of different populations in the world, with a prevalence of epilepsy calculated in 5 to 10 people per 1000 Based on the clinical and encephalographic phenomenon four epilepsy subdivisions are recognized, the epilepsy of the great evil (with generalized, focal, Jacksonian subgroups), epilepsy of the small malignant, psychomotor or temporal lobe epilepsy (with psychomotor subgroups proper or tonic with adverse or torsional movements or masticatory phenomenon, automatic with amnesia or sensory with alutions and states of sleep) and autonomic or diencephalic epilepsy (with rugor, pallor, tachycardia, hypertension, perspiration or other visceral symptoms). Although epilepsy is one of the most notable examples of a seizure-related disorder, a wide variety of neurological and psychiatric symptoms and disorders may have epileptic seizures or neurological phenomena similar to epileptic seizures. In simple terms, an epileptic seizure or a neurological phenomenon similar to a related seizure is a single separate clinical event caused by an excessive electrical discharge from a collection of neurons or a group of neurons susceptible to seizures through a procedure called "ictogenesis". " As such, the ictogenic epileptic seizures can simply be a symptom of a disease. However, epilepsy and other analogous disorders related to epileptic seizures are dynamic and often progressive diseases with a maturation procedure characterized by a complex and poorly understood sequence of pathological changes. The development and maturation of these changes is the "epileptogenesis" procedure in which the largest collection of neurons, that is, the normal brain, is altered and subsequently becomes susceptible to abnormal, spontaneous, sudden, recurrent and excessive electric shocks. say, epileptic seizures. The maturation of Epileptogenic procedure results in the development of an "epileptogenic focus" whereby collections of neurons with abnormal discharges or neurons susceptible to epileptic seizures form localized groups or "epileptogenic zones" interspersed in the cortical tissue. The epileptogenic zones are biochemically interconnected so that an abnormal ictogenic discharge is capable of generating a cascade from one area to another. As epileptogenesis progresses, the involved areas of the nervous system become more susceptible to an epileptic seizure and it becomes easier for an epileptic seizure to be triggered resulting in progressively debilitating symptoms of epileptic seizure or seizure-related disorder. Although the ictogenesis and epileptogenesis may have a common origin in certain biochemical phenomena and common neuronal pathways in various diseases, the two procedures are not identical. The ictogenesis is the beginning and spread of an epileptic crisis in a defined time and space, a fast and definitive electrical / chemical event that occurs in a period of time that varies from seconds to minutes. Comparatively, epileptogenesis is a gradual, biochemical or neuronal restructuring procedure whereby the normal brain is transformed by ictogenic events in an epileptogenically focused brain that has neural circuits that become more sensitive and respond to the ictogenic events by making an individual increasingly susceptible to the recurrence of epileptic seizures spontaneous, episodic, limited time and progressively debilitating symptoms of epileptic crisis or disorders related to epileptic seizure and progressively unable to respond to treatment. The maturation of an "epileptogenic focus" is a slow biochemical and / or structural procedure that is usually carried out for months to years. Epileptogenesis is a two-stage procedure: "Phase 1 epileptogenesis" is the beginning of the epileptogenic procedure before of the first epileptic seizure or symptom of a disorder related to an anal epileptic seizure and is often the result of a certain kind of damage or trauma to the brain, ie, stroke, disease (for example, infection such as meningitis) or trauma such as a seizure accidental of the head or a surgical procedure performed on the brain The "phase 2 epileptogenesis" refers to a procedure during which the brain tissue that is already susceptible to epileptic seizures or phenomena related to epileptic seizures of an analogous crisis-related disorder epileptic becomes even more susceptible to frequent and / or graved epileptic seizures ad increasing and / or becomes less sensitive to treatment Although the procedures involved in epileptogenesis have not been definitively identified, some researchers consider that regulation by increase of excitatory coupling between neurons, mediated by N-receptors, is involved. methyl-D-aspartate (NMDA) Other researchers consider that the regulation of Inhibitory coupling between neurons, mediated by α-aminobutypic acid (GABA) receptors Many other factors may be involved in this procedure in relation to the presence, concentration or activity of NO (nitric oxide) or iron, calcium or zinc ions. epileptic seizures are rarely fatal, a large number of patients require medication to avoid the disruptive and potentially dangerous consequences of epileptic seizures In many cases, the medication used to manage seizures or epileptic symptoms of an analogous seizure related to a seizure Epileptic seizures are required for prolonged periods of time and in some cases the patient must continue to take prescription medication for life., such medications are only effective for the administration of symptoms and have side effects associated with chronic and prolonged use. A wide variety of medications available for the administration of epileptic seizures include older agents such as phenytoin, valproate and carbamazepine (channel blockers). of ions) as well as newer agents such as felbamate, gabapentin, topiramate and tiagabine. In addition, for example, ß-alanine has been reported to have activity against epileptic seizures, NMDA inhibitory activity and stimulatory activity similar to GABA (GABAergica) but it has not yet 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 "epileptic anticrisis" or "anti-ictogenic". These drugs therapeutically suppress epileptic seizures by blocking the start of a single ictogenic event. But of the clinically available AEDs today, they do not prevent the process of epileptogenesis. When treating epileptic seizures or related symptoms of analogous disorders related to epileptic seizures, that is, for diseases and disorders with neurological phenomena similar to epileptic seizures that apparently could be related to epileptic seizure disorders such as mood cycles in bipolar disorder, Impulsive behavior in patients with impulse control disorders or for epileptic seizures resulting from damage to the brain, some AEDs may also be therapeutically useful. However, these now approved AEDs are unable to prevent prophylactically or therapeutically the initial development or progressive maturation of epileptogenesis to an epileptogenic focus that also characterizes analogous disorders related to epileptic seizures. The poorly understood pathological mechanisms underlying epileptogenesis certainly play a role in the development of epilepsy and analogous disorders related to epileptic seizures under a variety of clinical circumstances that include spontaneous development or as a result of damage or trauma of many kinds to the central or peripheral nervous system Current treatment for epilepsy focuses on suppressing epileptic seizure activity when administering AEDs after overt clinical epilepsy has developed Although AEDs have positive effects in suppressing epileptic seizures, those now available universally have not succeeded in preventing epileptogenesis, ie the initial development or progress and worsening of epilepsy and other related diseases similar to epileptic seizures Even treatment with AEDs does not prevent the development of epilepsy after damage or trauma to the nervous system In addition, if treatment with AEDs is stopped, epileptic seizures typically recur and, in unfortunate cases, worsen over time. Currently there is no method available clinically to treat, prevent, reverse, suppress or inhibit the onset and / or progress of epilepsy or other epileptic seizure disorders or the many analogous seizure-related disorders. In addition, it is also considered that mechanisms may be involved. Similar neurological events corresponding to epileptogenesis in the evolution and development of many disorders related to epileptic seizures clinically analogous to epilepsy that do not appear to be "epileptic" in a manifest manner, such as the initial development and progressive worsening observed in the disease state mature in bipolar disorder, impulse control disorders, disorders obsessive-compulsive, schizoaffective disorders, substance abuse or addictive disorders and many other psychiatric and neurological disorders. Thus, despite the large number of drugs available for the treatment of epilepsy (ie, by suppressing epileptic seizures, ie, seizures associated with epileptic seizures) and other disorders related to seizures, there are no medications generally accepted for treat, avoid, reverse, suppress or inhibit the underlying process of epileptogenesis that may be etiological in many devastating neurological and psychiatric disorders such as epilepsy and analogous seizure-related disorders including bipolar disorder. Currently, there are no known methods to inhibit the process. epileptogenic to prevent the development of epilepsy or other analogous disorders related to epileptic seizures in patients who have not yet shown clinically symptoms thereof, but those who have the disease in an unknown way or are at risk of developing the disease In addition, there are no known methods to prevent the development or to reverse the procedure of epileptogenesis, and therefore the conversion of collections of neurons in an area epileptogenic which has been the source or are susceptible or capable of participating in epileptic seizure activity in nervous tissue that does not show abnormal, spontaneous, sudden, recurrent or excessive electric shocks or that are not susceptible or capable of said seizure activity epileptic In addition, no there are drugs that have not been approved or approved which have such anti-epileptogenic properties, that is, truly anti-epileptogenic drugs (AEGD) (See, Schmidt, D and Rogaws i, MA, Epilepsy Research, 2002, 50, 71 -78) Thus, there is a strong need to develop safe and effective AED medicines and treatment methods that treat, prevent, suppress, inhibit and / or effectively reverse epileptogenesis in neurological and / or psychiatric disorders related to crisis epileptic, preferably, in addition to suppressing epileptic seizures or convulsions or symptoms related to epileptic seizures in patients who in advance manifest this type of symptoms BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment, prevention, suppression, inhibition and / or inversion of epileptogenesis, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) where R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl, R4 is selected from the group consisting of hydrogen and lower alkyl, a is an integer from 1 to 2, is selected from the group consisting of where b is an integer from 0 to 4, and where c is an integer from 0 to 2, each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro, with the proviso that when is or then a is 1, or a pharmaceutically acceptable salt thereof. The present invention is further related to a method for the treatment, prevention, suppression, inhibition and / or inversion of epileptogenesis which comprises administering to a subject in need thereof a therapeutically effective amount. of the compound of formula (II) or a pharmaceutically acceptable salt thereof In one embodiment, the present invention relates to methods for the treatment, prevention, suppression, inhibition and / or reversal of epileptogenesis in neurological and / or psychiatric disorders related to epileptic seizures comprising administering a subject in need thereof a therapeutically effective amount of a compound of formula (I) and / or of formula (II) as described herein. In another embodiment, the present invention relates to methods for the treatment, prevention, suppression, inhibition and / or inversion of epileptogenesis in a patient at risk of developing epilepsy, an epileptic seizure disorder or an analogous seizure related to epileptic seizure In another embodiment, the present invention relates to an improved method for treating and preventing epileptic seizures and related disorders. epileptic seizures in a subject in need thereof This method includes the step of administering prophylactically or therapeutically to the subject in need thereof a therapeutically effective amount of the compounds described herein that treat and prevent the occurrence of seizures, seizures or disorders related to epileptic seizures in the subject while simultaneously suppressing the epileptogenesis In the embodiments of the present invention, the subject in need of such treatment is administered a prophylactically or therapeutically effective amount of a pharmaceutical composition to prevent or treat epileptic seizures or seizures or disorders related to epileptic seizures in patients who in advance show the symptoms of said seizures. disorders, comprising one or more of the compounds of formula (I) and / or of formula (II), in admixture with a pharmaceutically acceptable carrier or excipient. In further embodiments, it is a prophylactically or therapeutically effective amount of a pharmaceutical composition. to prevent, treat, reverse, suppress and / or inhibit epileptogenesis comprising one or more of the compounds of formula (I) or of formula (II) in admixture with a pharmaceutically acceptable carrier or excipient, whereby said composition is administered to the subject in need of treatment with an AEGD. Pharmaceutical compositions comprising at least one compound of formula (I) and / or of formula (II) and one or more pharmaceutically acceptable excipients are administered to a subject in need thereof The present invention is further related to methods for the treatment, prevention, suppression, inhibition and / or inversion of epileptogenesis which comprises co-treatment with a therapeutically effective amount of at least one suitable pharmaceutical agent and at least the compounds of formula (I) and / or of formula (II) as described herein DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment and / or prevention of epileptogenesis, epilepsy and related disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein a, R, R2 and R4 are as defined herein The compounds of formula (I) and formula (II) are anticonvulsants and can suppress epileptic seizures. In addition, the compounds of formula (I) and formula (II) are they have unexpectedly found that they are powerfully anti-epileptogenic compounds that can prevent the initial development and maturation of pathological changes in the nervous system that allow epileptic seizures and related phenomena to occur and / or spread. The compounds of formula (I) and formula (II) may also be able to reverse the changes that result from epileptogenesis. In this way, the compounds of formula (I) and of formula (II) of the present invention, as used in the methods of this invention, are truly anti-epileptogenic drugs (AEGD) and have properties that are notoriously different and that do not possess any of the approved AED drugs. so far, the present invention relates to methods for treating, preventing, reversing, suppressing and / or inhibiting epileptogenesis. In some embodiments, these methods comprise administering a prophylactically or therapeutically effective amount of a compound of formula (I) or Formula (II) to the subject in need thereof A person skilled in the art will recognize that prior to the prophylactic or therapeutic administration of any of the compounds described herein for treatment, prevention, inhibition, reversal or suppression of epileptogenesis a determination will be made of whether the subject suffers from epilepsy or an analogous disorder related to epileptic seizure or not epileptic or if you are considered to be at a high risk of developing epileptic seizures or disorders related to epileptic seizures. In one embodiment of the present invention a subject or patient in need of treatment may be a subject who has already shown the symptoms of epilepsy, i.e., seizures or epileptic seizures or it may be a subject who has shown the symptoms of an analogous related disorder. with epileptic seizures before the time of administration In another embodiment of the present invention, a subject or a patient in need of treatment with an anti-epileptogenic medicament (AEGD) can be a subject who has not shown the symptoms of epilepsy or analogous disorders related to epileptic seizures, i.e., seizures or epileptic seizures before the time of administration In another embodiment of the present invention, the subject or patient in need of treatments will be determined to be in risk of developing epilepsy or an analogous disorder related to epileptic seizures at the time of administration and on this basis will be considered to be a patient in need of treatment with an AEGD In one embodiment, the present invention relates to with methods for the treatment, prevention, inhibition, suppression and / or reversal of epileptogenesis, regardless of the initiating and / or underlying cause. In one embodiment, the present invention provides methods for treating, preventing, reversing, suppressing and / or inhibiting epileptogenesis that comprises administering a therapeutically effective amount of a compound of formula (I) or and formula (II) as described herein to a patient who has not developed epilepsy or some type of epileptic seizure disorder or an analogous seizure-related disorder but who may be in a high-risk group for the development of seizures epileptic or an analogous related disorder with epileptic seizures due to damage or trauma to the nervous system that has occurred, including but not limited to brain damage or stroke or that may occur in the future, including but not limited to planned neurosurgical procedures or due to some known predisposition either biochemical or genetic or the finding of a verified biomarker of one or more of these disorders. In treating epileptogenesis, the methods of the invention can control the development of epileptic seizures, particularly epileptic seizures. In this method it can therefore be used to treat and prevent epilepsy and epileptic seizures, reduce the risk of developing epilepsy, suppress the development of epilepsy (particularly in development of neuron collections which are the sources or that are susceptible to epileptic seizures). ictogenic), 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 epileptogenesis procedure in epilepsy. Furthermore, in treating, preventing, inhibiting, suppressing and / or reversing epileptogenesis according to the methods of the present invention, the progress of neurological and / or psychiatric analogous disorders whose etiology is partially or totally based on a mechanism of action similar to epileptic crisis will be treated, avoided, inhibited, suppressed and / or reversed. As used herein, the term "epileptogenesis" means biochemical, genetic, histological or other procedures or changes or structural or functional changes that can revert to nervous tissue, including the central nervous system (CNS), susceptible to epileptic seizures spontaneous and recurrent. In addition, the term "epileptogenesis" is also used in the present in a broader sense to refer to changes and / or procedures that contribute to the clinical progress observed in patients with epilepsy or other epileptic seizure disorder or an analogous seizure-related disorder including, but not limited to: worsening or progress of the disorder and its symptoms or the development of "drug resistance", in which the disorder becomes more difficult to treat as a result of neurobiological changes that result in reduced sensitivity to the drug or recruitment by the epileptogenesis procedure of nerve tissue not susceptible to epileptic seizures. In addition, the term "epileptogenesis" is used herein in its broadest sense to refer to the no less similar ones of progressive worsening over time of the signs and symptoms of apparently non-epileptic disorders including psychiatric disorders whose etiology appears be related to epileptic seizures. As used herein, the term "inhibition of epileptogenesis" refers to preventing, stopping, stopping and / or coating the epileptogenesis process. The term "antiepileptogenic agent or medicament" and the abbreviation "AEGD", as used herein, refers to an agent that is capable of inhibiting epileptogenesis when the agent is administered to a subject in need thereof. As used herein, the terms "seizure disorder" and "epileptic seizure disorder" refer to a disorder 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 conditions, for example seizures due to the administration of a convulsive agent or toxin in the subject As used in the present, the terms "analogous disorders related to epileptic crisis" or "epilepsy related to a neurological phenomenon similar to epileptic crisis" refers to a neurobiological disorder or a psychiatric disorder that may show little or no overt epileptic seizure activity but which it is still considered to be totally or partially the result of neural mechanisms similar to epileptic or related seizures and which are often found to be treatable with AEDs. As used herein, the term "subject" refers to an animal, preferably a mammal, more preferably a human who has been the object of treatment observation or experiment As used herein, the term "subject" or "patient" also includes a subject, preferably a human being, who has not yet has shown the symptoms of epilepsy or an analogous disorder related to epileptic seizures but who may be in a high-risk group. As used herein, the term "a subject in need of treatment with an AEGD" includes any individual with a history or who currently has epilepsy, an epileptic seizure disorder or an epileptic seizure related to an analogous epilepsy similar to a neurological phenomenon or a disorder related to epileptic seizures or any disorder in which the patient's current and clinical condition or prognosis may benefit from the suppression of inhibition of the epileptogenesis procedure to prevent extension, progress, worsening or increased resistance to treatment in any neurological or psychiatric disorder The term "a subject in need of treatment with an AEGD" also includes any individual who does not have epilepsy or an analogous disorder related to epileptic crisis but who may be in the high risk group for the development of epileptic seizures or a disorder related to an epileptic seizure due to damage or trauma to the central nervous system (CNS) or peripheral (SNP) An individual or patient is considered to be at high risk for the development of epileptic seizures or disorders related to epileptic seizures due to ot damage CNS or SNP rabies due to a certain biochemical or genetic predisposition known to epilepsy or an analogous disorder related to epileptic seizures or due to a verified biomarker or associated marker of one or more of these disorders being discovered The term "a subject in need of treatment with an AEGD "also includes any individual whose clinical condition or prognosis may benefit from treatment with an AEGD This includes, but is not limited to any individual who is determined to be at increased risk of developing epilepsy, a disorder of epileptic crisis or an analogous disorder related to epileptic seizure or an epileptic crisis related to epilepsy similar to a neurological phenomenon or an epileptic seizure-related disorder as described above, due to any predisposing factors predisposing factors include, but are not limited to, damage or trauma of any kind to the CNS or SNP, 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 Pepnatal asphyxia, cardiac suppression, therapeutic or diagnostic finger surgical procedures, for example carotid endarterectomy or cerebral angiography, cardiac bypass surgery, spinal cord trauma, hypotension, damage to the CNS due to embolism, hyperperfusion or CNS hypoperfusion, hypoxia affecting to the CNS, known genetic predisposition to disorders known to be nden to the AEGD, lesions occupying the CNS space, brain tumors, for example ghoblastomas, bleeding or hemorrhage in the part surrounding the CNS, for example intracerebral hemorrhages or subdural hematomas, cerebral edema, febrile convulsions hyperthermia, exposure to toxic or poisonous agents , drug intoxication, for example cocaine, family history of epileptic crisis disorders or disorders related to epileptic seizure analogues, history of epileptic states, total treatment with medications that lower the threshold for epileptic seizures, for example lithium carbonate, torazine or clozapine, testing of associated markers or markers that the patient is in need for treatment with an anti-epileptogenic medicament, for example an MRI scan showing sclerosis in the hippocampus or other CNS pathology, elevated serum concentrations of neuronal degradation products. As used herein, unless otherwise indicated , the term "epilepsy" will mean any disorder in which a subject (preferably a human, infant or lactating adult) experiences one or more epileptic seizures and / or tremors. Suitable examples include, but are not limited to epilepsy (including, but which is not limited to related epilepsies such as localization, generalized epilepsies, epilepsies with generalized and local epileptic seizures and the like), epileptic seizures as a complication of a disease or condition (such as epileptic seizures related to encephalopathy, phenylketonuria, juvenile Gaucher's disease, progressive myoclonic epilepsy of Lundborg, stroke, brain trauma, tension, hormonal changes, drug use or suspension of same, alcohol use or suspension thereof, sleep suppression and the like) and the like. It is intended that the terms refer to clinical disorders regardless of the type of epileptic seizure, origin of seizure, seizure progress or underlying cause or etiology. The term "antiepileptic medication" and its abbreviation "AED" will be used in a manner interchangeable with the term "anticonvulsant agent" and as used herein, refer to an agent able to treat, inhibit or prevent epileptic seizure activity or ictogenesis when the agent is administered to a subject or patient. As used herein, the term "a subject in need of treatment with an AED" includes any individual who is known to be ill. of epilepsy or who has epileptic seizures or repeated seizures or who has shown the symptoms of an analogous disorder related to epileptic seizures regardless of the etiology of these symptoms. As used herein, the terms "treat" or "treatment" refer to actions that can cause any sign of success in the prevention or reduction of damage, pathology, symptom or condition, which includes any objective or subjective parameter such as depression, remission, decrease in symptoms that produce the damage, pathology or condition more tolerable for the patient, who slows down the rate of degeneration or decline, who make the final point of degeneracy less debilitating ion or that improves the physical or mental well-being of the subject In this way, the terms "treatment" or "treat" include any action that improves, reverses, reverses, suppresses and / or inhibits the pathological procedures of epileptogenesis as defined in term and how it is used in the present The treatment or decrease of symptoms can be based on objective or subjective parameters, which include the results of a physical examination, a neurological examination and / or psychiatric evaluations. Consequently, the term "treat" or " "treatment" includes the administration of the compounds or agents of the present invention to treat, prevent, reversing, suppressing and / or inhibiting the growth of epileptogenesis In some cases, treatment with the compounds of the present invention will prevent, inhibit and / or suppress the progress of brain dysfunction or cerebral hyperexcitability associated with epilepsy. the present, the term "therapeutic effect" refers to the treatment, inhibition, abatement, reversal and / or prevention of epileptogenesis, the effects or symptoms of epileptogenesis or side effects of epileptogenesis in a subject The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that induces the biological or medicinal response in the animal or human tissue system that is investigated by a researcher, veterinarian, physician or other medical professional which includes the alleviation of symptoms or the disease or disorder that is treated In this way, the terms "therapeutic amount "Effectively effective" or "Therapeutically effective dose", which are used interchangeably herein, means a sufficient amount or dose of one or more compounds or compositions of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of such treatment, inhibition, abatement, reversal and / or prevention of epileptogenesis, the effects or symptoms of epileptogenesis or the side effects of epileptogenesis The range of doses required for these different therapeutic effects they will require according to the characteristics of a subject or patient and the precise nature of the condition to be treated. Wherein the present invention is directed to a combination therapy or treatment, comprising the administration of one or more compounds of formula ( I) or of formula (II) and one or more "suitable pharmaceutical agents", the term "therapeutically effective amount" will mean that amount of the combination of the agents taken together such that the combined effect inducing the desired biological or medicinal response . For example, the therapeutically effective amount of therapy comprises administration of a compound of formula (I) or formula (II) and at least one suitable pharmaceutical agent will be the amount of the compound of formula (I) or formula (II) and the amount of the appropriate pharmaceutical agent that, when taken together or sequentially they have a combined effect that is therapeutically effective. In addition, it will be recognized by a person skilled in the art that in case of therapy with a therapeutically effective amount, as in the previous example, the amount of the compound of formula (I) or formula (II) and / or the amount of the appropriate pharmaceutical agent individually may or may not be therapeutically effective. As used herein, the terms "therapy" and "combination therapy" (combination treatment or combination therapy) means a treatment of a subject in need thereof by administration of one or more compounds of formula (I) or formula (II) in combination with one or more suitable pharmaceutical agents, wherein one or more of the compounds of formula (I) or formula (II) and one or more of the pharmaceutically suitable agents are administered by any suitable means simultaneously, sequentially, separately or in a pharmaceutical formulation When one or more of the compounds of formula (I) or of formula (II) and one or more of the suitable pharmaceutical agents are administered in separate dosage form, the number of dosages administered per day for each compound may be the same or different One or several of the compounds of formula (I) or formula (II) and one or more suitable pharmaceutical agents can be administered by the same or different administration routes Examples of suitable methods of administration include, but are not limited to, are limited to oral, intravenous (iv), intramuscular (im), subcutaneous (se), transdermal and rectal. Compounds can also be administered directly to The nervous system including, but not limited to intracerebral, intraventricular, intracerebroventricular, intrathecal, intracranial, intraspina, and / or penospinal routes of administration by intracranial or intra-vertebral I delivery with needles and / or catheters or probes with or without Pumping One or several of the compounds of formula (I) or formula (II) and one or more suitable pharmaceutical agents can be administered according to the simultaneous or alternating regimes, at the same or different times during the course of the treatment, concurrently in divided or unique forms As used herein, unless otherwise indicated, the term "suitable pharmaceutical agent" is intended to mean any pharmaceutical agent having one or more of the following properties antioxidant activity, NMDA receptor antagonist activity, increase of inhibition of endogenous GABA; inhibitory activity of NO synthase; iron binding capacity, for example an iron chelator, calcium ion capacity, for example a Ca (II) chelator, zinc binding capacity, for example a Zn (ll) chelator, the ability to block effectively the sodium or calcium ion channels or to open the channels of potassium or chloride ions in the CNS of a patient, which include the known AEDs or which are useful therapeutic agents in the treatment of abuse and addiction to substances that include, but which are not limited to methadone, disulfiram, bupropion, antipsychotics, antidepressants, benzodiazepines, buspirone, naloxone or naltrexone Preferably, the appropriate pharmaceutical agent antagonizes NMDA receptors by binding to NMDA receptors (for example by binding to the glycine binding site of NMDA receptors) and / or the agent that increases the inhibition of GABA by decreasing the uptake of GABA in the ga In addition, the "suitable pharmaceutical agent" can be any agent that knows its prime epileptic seizure activity even if said compound is not known to inhibit epileptogenesis. Such agents can be but are not limited to any EDA or effective anticonvulsant known to those skilled in the art or to be discovered in the future, for example Suitable agents include, but are not limited to: carbamazepine, clobazan, clonazepam, ethosuximide, felbamate, gabapentin, lamotigin, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, retigabine, talampanel, tiagabine, topiramate, valproate, vigabatrin, zonisamide, benzodiazepines, barbiturates or hypnotic sedatives. The term "epilepsy" refers to a disorder of brain function characterized by the periodic and unpredictable presentation of epileptic seizures (see The Treatment of Epilepsy, Principies &Practice, Third Edition, Elaine Wyllie, MD Editor, Lippincott Williams & Wilkins, 2001; Goodman &Gilman's The Pharmacological Basis of Therapeutics ninth edition, 1996) (both references incorporated herein by reference in this document). Epileptic seizures that occur without evident provocation are classified as epileptic. Epilepsy can be idiopathic or it can be related to some kind of damage, malformation or damage to the central nervous system at any stage of life. Every subject is typically considered to suffer from epilepsy when experiencing two or more epileptic seizures that occur more than 24 hours apart. 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 patient's level of consciousness and the like Epilepsies and epileptic seizures and syndromes can be classified in a variety of ways (see, The Treatment of Epilepsy, Principies &Practice, Third Edition, Elaine Wyllie, MD Editor, Lippincott Williams & Wilkins, 2001). However, as used herein, the terms "epilepsy", "epileptic seizure" and "epileptic syndromes" mean the inclusion of all known types of seizures and epileptic syndromes including partial epileptic seizures including simple epileptic seizure, complex and partial that evolves into generalized tonic-clonic seizures of generalized epileptic seizures, both convulsive and non-convulsive and unclassified seizures. The terms "epileptogenesis" of the "epileptogenic process" generally consists of two phases. The methods of the present invention are intended to include the prophylactic and / or therapeutic administration of any of the compounds described herein either in the first or second epileptogenic stage or these steps precede to treat, inhibit, prevent, suppress or reverse the subsequent development of epilepsy or other analogous disorders related to epileptic seizure in a subject in need of it The first epileptogenic stage is known as the initial attack or damage stage The initial attack or damage is commonly damage harming the brain caused by one or more of a length of possible factors including, for example, traumatic damage to the brain. brain, which includes shallow and penetrating cephalic trauma or a neurosurgical procedure; 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 craniotomies) and epileptic In some cases, the initial attack will be the result of developmental problems before birth (such as, but not limited to asphyxia at birth, intracranial trauma during birth, metabolic alterations or congenital malformations in brains) as a result of genetic determinants. Second epileptogenic stage is known as the "latency stage" The second epileptogenic stage includes the neuronal restructuring process which is characterized by recurrent epileptic seizures (eg symptomatic epilepsy) or by symptoms shown in analogous seizures related to seizures The epileptogenic procedure It can also be observed among people who currently suffer from epilepsy or similar disorders related to epileptic seizures. The epileptic seizures experienced by people suffering from epilepsy themselves are epileptogenic since they tend to make the presentation of subsequent epileptic seizures more likely or of a larger area of nervous tissue that undergoes seizure activity or that makes seizure disorder more resistant to treatment The consequences of this process for a patient who has an epileptic seizure disorder is that epileptic seizures they tend to become more frequent and more severe and often more resistant to treatment with conventional AEDs In a similar way, the response similar to epileptic seizure related in neurological or psychiatric disorders analogous to epilepsy can become increasingly serious with the passage of time or resistant to the treatment according to the mature disorder Phase 1 of epileptogenesis can be initiated by factors other than those indicated above, such as the ingestion of compounds with epileptogenic potential, for example psychotropic drugs such as, for example, antipyretic drugs, clozapine and lithium and the like The methods of the present invention are also designed to treat, avoid, suppress, inhibit or reverse the development of epileptogenesis which has been initiated by factors which tend to increase the potential for a subject to become epileptogenic The compounds of formula (I) and formula (II), as described herein are useful in the treatment of epilepsy and analogous disorders related to epileptic seizure. Furthermore, the compounds of formula (I) and of formula (II) described herein are useful for suppressing, controlling and preventing the resulting epileptogenesis process. in the worsening, clinical progress or increased resistance to the treatment of epilepsy and disorders related to epileptic seizures or de novo onset of these disorders and their symptoms as a result of some form of damage or trauma to the nervous system Thus, in one embodiment, the present invention relates to methods which allow a physician to treat the symptoms of epilepsy, another epileptic seizure disorder and / or symptoms of analogous disorders related to epileptic seizure and simultaneously to inhibit the epileptogenic process which is responsible of the deterioration, progress, extension or increase of resistance to the treatment of the underlying disease process. The method comprises the prophylactic or therapeutic administration to the subject in need thereof of an effective antiepileptogenic amount or dose of a compound of formula (I) and / or of formula (II) as described herein to the subject who simultaneously treats and avoids epileptic seizures or other symptoms of the disorder and, moreover, that is capable of suppressing, inhibiting and reversing the process of epileptogenesis in the subject. In some embodiments, the subject or patient in need of treatment (preferably the subject or patient in need of treatment with an AEGD) may be a subject who has already shown symptoms of epilepsy, i.e., seizures or epileptic seizures or a subject or patient which has shown the symptoms of an analogous disorder related to epileptic seizures (eg, cyclic mood swings, impulsive behavior, addictive behavior and the like) before or at the time of administration. Therefore, in one aspect, the present invention provides an improved method for treating or preventing epileptic seizures and the symptoms of epileptic crisis related disorders in a subject in need thereof. The method includes the stage of administering prophylactics or therapeutically to the subject in need thereof a therapeutically effective amount of a compound of formula (I) and / or of formula (II) as described herein that treats and prevents the occurrence of seizures, seizures or disorders related to epileptic seizures . In some other embodiments, the subject or patient in need of treatment (preferably the subject or patient in need of treatment with an AEGD) may be a subject who has not shown the symptoms of epilepsy, i.e., seizures or convulsions or the symptoms of an analogous disorder related to epileptic crisis before the moment of administration. In this modality, the subject or patient will be determined to be at risk of developing epilepsy or an analogous disorder related to epileptic seizures at the time of administration or on this basis will be considered to be a patient in need of treatment with an AEGD. In this regard, the invention provides a method for suppressing, inhibiting and / or reversing epileptogenesis. The method includes the step of administering prophylactically or therapeutically to the subject in need thereof a prophylactically or therapeutically effective amount of any of the compounds described herein to the subject to treat, prevent, suppress, inhibit and reverse epileptogenesis. By suppressing the process of epileptogenesis, the development of an epileptic seizure disorder or a related disorder in a subject who has sustained some form of prejudice or damage to the nervous system or in some way or other at risk can be avoided. In consecuense, The present invention provides methods for treating, preventing, suppressing, inhibiting and / or reversing epileptogenesis in a subject in need thereof, comprising administering to the subject a prophylactically or therapeutically effective amount of a composition comprising at least one compound of formula (I) and / or of formula (II) In one embodiment of the present invention, the method is advantageously used to treat a patient who does not suffer from or is known to suffer from a condition that is known in the art to be effectively treated with currently known anticonvulsant or antiepileptic (AED) medications These conditions include but are not limited to analogous disorders related to epileptic seizures In these cases the sion to use the methods and compounds of the present invention will be made based on the determination of whether the patient is a "patient in need of treatment with an antiepileptogenic medicine (AEGD)", in the manner in which the term is defined in the above In another embodiment, the present invention provides methods useful for the treatment and / or prevention of epileptic seizures in patients with epilepsy or other epileptic seizure disorders and / or analogous symptoms in disorders related to epileptic seizures while simultaneously inhibiting the process of epileptogenesis and thus avoiding the extension or worsening of the underlying disease process or the recrudescence by the epileptogenesis procedure of nervous tissue not susceptible to epileptic seizures The methods of the present invention are directed to the treatment of epileptogenesis in a subject who is at risk of developing epilepsy or a disorder related to epileptic seizures or an analogous disorder related to epileptic seizures but who does not have epilepsy or clinical epileptic seizure tests. subject who is at risk of developing epilepsy or an analogous disorder related to epileptic seizures but who does not present with epilepsy or other epileptic seizure disorder or an analogous seizure related to epileptic seizures may be a subject who has not yet been diagnosed with epilepsy or with an analogous disorder related to epileptic seizures but who is at a greater risk than the general population of developing epilepsy or an analogous disorder related to epileptic seizure This "higher risk" can be determined by the recognition of any of the factors in the subject or in your medical history co-relatives, in a physical examination or in tests that are indicative of a greater than average risk for developing epilepsy or an analogous disorder related to epileptic seizures Therefore, this determination that a patient is in a "major risk" for an available means can be used to determine whether the patient should be treated with the methods of the present invention Patients who are at a greater risk include, but are not limited to those who have not suffered damage or prejudice in their central nervous system but that they have a high probability of such harm or prejudice either because of their medical condition or their ambient. This may include, but is not limited to patients with a history of transient ischemic attacks (TIA) or known carotid artery stenosis or simply known significant arteriosclerosis as well as patients close to undergoing a neurosurgical procedure. In addition, individuals who are likely to suffer from neurological damage due to wars or sports injuries may be administered prophylactically the compounds of the invention; This can include soldiers in periods of war or athletes in violent contact sports such as boxing. Subjects who can benefit from the treatment by the methods of the present invention can be identified using accepted screening methods to determine risk factors related to epileptogenesis, epilepsy or other seizure disorders or an analogous seizure related to seizure. A determination that a subject has or may be at risk of developing epilepsy, another epileptic seizure disorder or an analogous seizure related to seizure disorder may 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), computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET). A determination of an increased risk of developing epilepsy or an analogous disorder related to epileptic seizure can also be made by means of genetic tests that include determination of gene expression profile or proteomic techniques (see Schmidt, D Rogawski, M to Epilepsy Research 50, 71 -78 (2002) and Loscher, W, Schmidt D Epilepsy Research 50, 3-16 (2002)) These methods of screening include, for example, conventional medical treatments for determining risk factors that may be related to epileptogenesis including, but not limited to, for example, head trauma, either closed or penetrating, procedures neurosurgical, CNS, bacterial or viral infections, trigeminal neuralgia, cerebrovascular disease that includes but is not limited to stroke or a history of TIA, brain tumors, cerebral edema, cysticercosis, porphyria, metabolic encephalopathy, suspension in the supply of drugs that include but are not limited to sedative-hypnotic suspension or alcohol, abnormal pennatal history that include anoxia at birth or damage at birth any kind, cerebral palsy, learning disability, hyperactivity, history of febrile seizures, history of epileptic status, family history of epilepsy or any disorder related to epileptic seizures, inflammatory diseases of the brain or blood vessels including lupus, drug intoxication, whether direct or by placental transfer that includes but is not limited to cocaine and methamphetamine toxicity, parental consanguinity, and treatment with medications that lower the threshold to epileptic seizures including psychotropic medications such as antidepressant or antipsychotic medications The determination of which patients can benefit from treatment with a AEGD in a patient who does not have clinical signs or symptoms of epilepsy or other epileptic seizure disorder or an analogous seizure related to seizures can be based on a variety of "Substitute markers" and a "biomarker" Such biomarkers include, but are not limited to, gene or protein expression profiles in tissue, blood, or CSF or in the presence of genetic markers such as SNO As used herein, " "substitute markers" and "biomarker" are used as interchangeable terms and refer to any anatomical, biochemical, structural, electrical, genetic or chemical indicator or marker that can be easily related to the current existence or future development of epilepsy or a crisis disorder epilepticus or an analogous disorder related to epileptic crisis In some cases, brain imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) or other neurological imaging techniques can be used to determine if a The subject is at risk of developing one of the above disorders. Examples of suitable biomarkers for the methods of this invention include, but are not limited to, MRI, CT or other imaging techniques of sclerosis, atrophy or loss of volume. in the hippocampus or the presence of medium temporal sclerosis (MTS) or similar relevant anatomical pathology, the detection in the blood, serum or tissues of the patient of some molecular species such as a protein or other biochemical biomarker, for example high concentrations of ciliary neurotrophic factor (CNTF) or elevated serum concentrations of a degradation product neuronal or other evidence of surrogate markers or biomarkers that the patient is in need of treatment with an anti-epileptogenic drug, for example an EEG suggestive of an epileptic seizure disorder or an analogous disorder related to epileptic seizure or a seizure-related epilepsy. neurological phenomenon similar to epileptic crisis or a disorder related to epileptic crisis It is expected that in the future many more biomarkers will be developed using a wide variety of detection techniques. It is intended that any of said markers or indicators in existence or possible in future development of an epileptic seizure disorder, epilepsy or an analogous disorder related to epileptic seizure, are ultimately used herein and can be used in the methods of this invention to determine the need for treatment with the compositions and methods of this invention. embodiment of the present invention The treatment is directed to patients who have epilepsy or a neurological phenomenon of epilepsy related to epileptic seizure or an analogous disorder related to epileptic seizure, as defined above, and which take advantage of the capacity of the compounds of the present invention. for Reversing epileptogenesis which can generate a gradual reduction of maintenance medication dosages or treatment intensity that is required to control the clinical manifestations of patient epilepsy or epilepsy related to neurological phenomena similar to epileptic seizures or analogous seizure-related disorders epileptic, as defined in the foregoing Thus, since treatment with the methods of the present invention results in an improvement in the underlying disorder, the patient can be removed from the maintenance medication that includes but is not limited to compounds of the present invention in themselves if these are used as a single treatment In this way, a patient with epilepsy in a maintenance treatment of a conventional AED may be withdrawn from the AED supply after treatment with one or more of the compounds of the present invention when they have reversed the underlying epileptic disorder. A person skilled in the art will be able to determine with how quickly to carry out this suppression based on clinical signs and symptoms that include EEGs, sudden epileptic seizures or any other appropriate biomarker of the underlying disorder The present invention relates to methods for treatment, prevention, suppression, elimination and / or inhibition of epileptogenesis comprising administering to a subject in need thereof, preferably a subject in need of treatment with an AEGD, a therapeutically and / or prophylactically effective amount of a compound of formula (I) and / or of formula (II) as described herein. In one embodiment of the present invention, R1 is selected from the group consisting of hydrogen and methyl. another embodiment of the present invention, R 2 is selected from the group consisting of hydrogen and methyl In another embodiment of the present invention, R 1 and R 2 are each hydrogen or R 1 and R 2 are each methyl In one embodiment of the present invention - (CH2) a- is selected from the group consisting of -CH2- and -CH2-CH2- In another embodiment of the present invention, - (CH2) a- is -CH2- In one embodiment of the present invention, R4 is selected of the group consisting of hydrogen and methyl, preferably R 4 is hydrogen In one embodiment of the present invention a is 1 In one embodiment of the present invention b is an integer from 0 to 2 In another embodiment of the present invention c is a number whole from 0 to 2 In another m The embodiment of the present invention b is an integer from 0 to 1. In another embodiment of the present invention, c is an integer from 0 to 1. In another embodiment of the present invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1 In another additional embodiment of the present invention, b is an integer from 0 to 2 and c is 0 In an embodiment of the present invention is selected from the group consisting of In another embodiment of the present invention, is selected from the group consisting of In one embodiment of the present invention, is selected from the group consisting of 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- (benzo [1,3] d? oxol? lo) , 3- (3,4-d? H? Dro-benzo [1,4] d? Oxep? N? Lo), 2- (6-chloro-2,3-d? H? Dro-benzo [1, 4] d? Ox? N? Lo), 2- (6-fluoro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (chromanyl), 2 - (5-fluoro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (7-chloro-2,3-d? H? Drobenzo [ 1, 4] d? Ox? N? Lo), 2- (6-chloro-benzo [1,3] d? Oxol? Lo), 2- (7-n? Tro-2,3-d? H? drobenzo [1,4] d? ox? n? lo), 2- (7-met? l-2,3-d? h? dro-benzo [1, 4] d? ox? n? lo) , 2- (5-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (6-bromo-2,3-d? benzo [1,4] d? ox? n? lo), 2- (6J-d? chloro-2,3-d? h? dro-benzo [1, 4] d? ox? n? lo), 2 - (8-chloro-2,3-d? H? Drobenzo [1,4] d? Ox? N? Lo), 2- (2,3-d? H? Dro-naphtho [2,3- b] [1, 4] d? ox? n? lo) and 2- (4-met? l-benzo [1, 3] d? oxol? lo) In another embodiment of the present invention, is selected from the group consisting of 2- (benzo [1,3] d? oxol? lo), 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo) , 2- (6-chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (7-chloro-2,3-d? Hydro? benzo [1, 4] d? ox? n? lo), 2- (7-met? l-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2 - (6-bromo-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo) and 2- (6J-d? Chloro-2,3-d? benzo [1,4] d? ox? n? lo) In another embodiment of the present invention, is selected from the group consisting of 2- (2,3-d? h? dro-benzo [1, 4] diox? n? lo), 2- (7-met? l-2,3-d? h? dro-benzo [1, 4] d? ox? n? lo) and 2- (6-bromo-2,3-d? h? dro-benzo [1,4] d? ox? n? lo) In a embodiment of the present invention, R5 is selected from the group consisting of halogen and lower alkyl. In another embodiment of the present invention, R5 is selected from chloro, fluoro, bromo and methyl. In one embodiment of the present invention, the stereo-center in the compound of formula (I) is in the S configuration. In another embodiment of the present invention, the stereo-center of the compound of formula (I) is in the R configuration. In one embodiment of the present invention, the compound of Formula (I) is present as an enantiomepically enriched mixture, wherein the% enantiomepco enrichment (% ee) is greater than about 75%, preferably greater than about 90%, more preferably greater than about 95% and much more preferagreater than about 98%. Additional embodiments of the present invention include those wherein the substituents are selected from one or more of the varia defined herein (i.e., R1, R2, R3, R4, XY and A) which are independently selected to be any individual substituents or any subset of substituents that are selected from the complete list as defined herein The representative compounds of the present invention are as include in the list of Table 1 below. The additional compounds of the present invention are included in Table 3. In the following Tables 1 and 2 the columns headed "stereo" define the stereo-configuration on the carbon atom of the heterocycle attached to the bond. with an asterisk When a designation is not included, the compound is prepared as a mixture of stereo-configurations When an "R" or "S" designation is indicated, the stereo-configuration is based on the enantiomatically enriched initial material TABLE 1 Representative compounds of formula (I) TABLE 2 Additional compounds of the present invention As used herein, unless otherwise indicated, the term "halogen" means chlorine, bromine, fluorine and iodine. As used herein, unless otherwise indicated by the term "alkyl" and either used alone or as part of a substituent group includes straight and branched chains For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sectbutyl, tertbutyl, pentyl and the like Unless otherwise indicated, "lower", when used with alkyl means a carbon chain composition of 1 -4 carbon atoms. As used herein, unless otherwise indicated, "alkoxy" shall mean an oxygen ether radical of the straight or branched chain alkyl groups described above For example, methoxy, ethoxy, n-propoxy, secbutoxy, terbutoxy, n-hexyloxy and the like As used herein, the notation "*" indicates the presence of a stereo center When a particular group is "substituted" (eg, alkyl, aplo, etc.), that group may have one or more substituents, preferably one to five substituents, more preferably one to three substituents, much more preferably from one to two substituents that are independently selected from the list of substituents With reference to substituents, the term "independently" means that when more than one of said substituents are possible, the substituents may be the same or different from s Under the standard nomenclature used in this description, the terminal portion of a designated side chain is first described, followed by functionality adjacent to the point of attachment. Thus, for example, a "phenylalkylcarbonylalkyl" substituent refers to a group of formula The abbreviations used in the specification, particularly in the schemes and examples are the following DCC = dicyclohexylcarbodnmide DCE dichloroethane DCM dichloromethane DIPEA or DIEA dnsopropylethylamine DMF N, Nd? Met? Lformamide DMSO dimethyl sulfoxide EDC ethylcarbodiimide Et3N or TEA triethylamine Et20 diethyl ether EA or EtOAc ethyl acetate EtOH ethanol IPA 2-propanol Hept heptane HOBT 1 -hydroxybenzotriazole CLAP high pressure liquid chromatography LAH lithium aluminum hydride M or MeOH methanol NMR nuclear magnetic resonance Pd-C palladium carbon catalyst CLAP RP reverse phase high pressure liquid chromatography t.a. room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC = thin layer chromatography When the compounds according to this invention have at least one chiral center, they can accordingly exist as enantiomers. When the compounds possess two or more chiral centers, these can additionally exist as diastereoisomers. It should be understood that all of said isomers and mixtures thereof are encompassed within the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs and, as such, it is intended that they be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. with hydrates) or common organic solvents and said solvates are also intended to be encompassed within the scope of this invention. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be useful in the preparation of compounds according to this invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as the acids: hydrochloric, sulfuric, fumaric, maleic, succinic , acetic, benzoic, citric, tartaric, carbonic or phosphoric. In addition, when the compounds of the invention have an acidic portion, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts.; alkaline earth metal salts, for example calcium or magnesium salts and salts formed with suitable organic ligands, for example quaternary ammonium salts. In this manner, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dichlorohydrate, edetate, edisilate, estolate , esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsilate, nitrate, ammonium salt of N-methylglucamine, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Representative acids and bases which can be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-acid aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) - camphoric acid, camphor sulfonic acid, (+) - (1 S) -camfor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethane sulfonic acid, formic acid, fumaric acid, galactárico acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-acid glucuronic, L-glutamic acid, a-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) - L-lactic acid, (±) -DL-lactic acid ico, lactobionic acid, maleic acid, (-) - L-malic acid, malonic acid, (±) -DL-mandelico acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, acid 1 -hydroxy-2-naphthoic, acid nicotinic, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid , (+) - L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases, which include ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. The compounds of formula (I) can be prepared according to the procedure indicated in Scheme 1.

SCHEME 1 (??: I) Accordingly, a suitably substituted compound of formula (X), a known compound or a compound prepared by the known methods, is reacted with sulfamide, a known compound, preferably wherein the sulfonamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane and the like, preferably at an elevated temperature in the range of about 50 ° C to about 100 ° C, more preferably about the reflux temperature, to provide the corresponding compound of formula (la). Alternatively, a suitably substituted compound of formula (X), a known compound or a compound prepared by known methods is reacted with a suitably substituted compound of formula (XI), a known compound or a compound prepared by known methods, in presence of a base such as TEA, DIPEA, pyridine and the like in an organic solvent such as DMF, DMSO and the like, to provide the corresponding compound of formula (I). Compounds of formula (X) wherein is can be prepared according to the procedure limited in Scheme 2. SCHEME 2 !For! Accordingly, a suitably substituted compound of formula (XII), a known compound or a compound prepared by a known method (for example as described in Scheme 3 above) is reacted with NH OH, a known compound, optionally in an organic solvent such as acetonitrile and the like, to provide the corresponding compound of formula (XIII). The compound of formula (XIII) is reacted with a suitably selected reducing agent such as LAH and the like, and the like, in an organic solvent such as THF, diethylether and the like, to provide the corresponding compound of formula (Xa). Compounds of formula (X) wherein is selected from they can be prepared according to the process indicated in Scheme 3.

SCHEME 3 :? ? v) (XV) (Xb) Accordingly, a suitably substituted compound of formula (XIV), a known compound or a compound prepared by known methods, is reacted with NH OH, in the presence of a coupling agent such as DCC and the like, optionally in a organic solvent such as acetonitrile and the like to provide the corresponding compound of formula (XV). The compound of formula (XV) is reacted with a suitably selected reducing agent such as LAH and the like, in an organic solvent such as THF, diethylether and the like to provide the corresponding compound of formula (Xb).

Compounds of formula (X) wherein is selected from and where a is 2, they can be prepared according to the process indicated in Scheme 4.

SCHEME 4 Accordingly, a suitably substituted compound of formula (XVI) wherein J1 is a suitable leaving group such as Br, Cl, I, tosyl, mesyl, triflyl and the like, a known compound or a compound prepared by known methods (e.g. activation of the corresponding compound wherein J1 is OH), is reacted with such a cyanide such as potassium cyanide, sodium cyanide and the like in an organic solvent such as DMSO, DMF, THF and the like, to provide the corresponding compound of formula (XVII). The compound of formula (XVII) is reduced according to known methods, for example by reacting with a suitable reducing agent such as LAH, borane and the like to provide the corresponding compound of formula (Xc). Compounds of formula (X) wherein is selected from and where a is 1, they can be prepared according to the process indicated in Scheme 5.

SCHEME S Accordingly, a suitably substituted compound of formula (XVIII), a known compound or a compound prepared by known methods is activated, according to a known method, to provide the corresponding compound of formula (XIX), wherein J2 is a group suitable salient, such as tosylate, Cl, Br, I, mesylate, triflate and the like. The compound of formula (XIX) is reacted with a salt of phthalimide, such as potassium phthalimide, sodium phthalimide and the like, in an organic solvent such as DMF, DMSO, acetonitrile and the like, preferably at an elevated temperature in the range from 50 ° C to about 200 ° C, more preferably at about the reflux temperature, to provide the corresponding compound of formula (XX).

The compound of formula (XX) is reacted with N 2 H, a known compound in an organic solvent such as ethanol, methanol and the like, preferably at an elevated temperature in the range of about 50 ° C to about 100 ° C, more preferably. preferable at about reflux temperature and the like, to provide the corresponding compound of formula (Xd). A person skilled in the art will recognize that the compounds of formula (X) wherein is selected from they can be similarly prepared according to known methods or, for example, according to the processes indicated in Schemes 2 to 5 above, by selecting and replacing the corresponding naphthyl fused compounds by the benzofused starting materials. A person skilled in the art will further recognize that where a single enantiomer (or a mixture of enantiomers in which one enantiomer is enriched) of a compound of formula (X) is desired, the above process, as described in Schemes 1 to 5 can be applied by substituting the corresponding single enantiomer (or enantiomer mixture in which one enantiomer is enriched) by the appropriate initial material. A person skilled in the art will recognize that where a reaction step of the present invention can be carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems. When the process for the preparation of the compounds according to the invention gives rise to a mixture of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. The compounds can be prepared in racemic form or individual enantiomers can be prepared either by enantiospecific synthesis or by resolution. For example, the compounds can be resolved into their constituent enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an acid optically active such as (-) - di-p-toluoyl-D-tartaric acid and / or (+) - di-p-toluoyl-L-tartaric acid followed by fractional recrystallization and regeneration of the free base. The compounds can also be resolved by formation of diastereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral CLAP column. During any of the processes for preparation of the compounds of the present invention it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules involved. This can be carried out by means of conventional protecting groups such as those described in Protective Groups in Orqanic Chemistry. ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Orqanic Synthesis, John Wiley & Sons, 1991. Protective groups can be removed in a convenient subsequent step using methods known in the art. The present invention provides methods for treating epileptogenesis, regardless of the underlying cause or stage of development, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or formula (II) as is described in the present. The methods of this invention therefore provide the ability to suppress epileptic seizures, convulsions or the symptoms of an analogous disorder related to an epileptic seizure and simultaneously prevent the process of epileptogenesis so as to avoid the progress or worsening of the underlying disease or recruitment by the process of epileptogenesis of a nervous tissue not susceptible to epileptic seizure. In order to accomplish this objective, the compounds or compositions of this invention must be used in a therapeutically effective amount or dose, as described in the following. The optimal dosages and protocols to be administered can be readily determined by a person skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration and the progress of the condition. of disease. In addition, the factors associated with the particular patient being treated, which include patient age, weight, diet and time of administration, will result in the need for dosage adjustments. In one embodiment of the present invention, the treatment regimen with a compound of formula (I) and / or formula (II) can start in a subject or in a patient with whom he has already experienced epileptic seizures sufficient to justify a diagnosis of epilepsy. In this embodiment, the compounds of the invention can be used simultaneously as EDA to suppress epileptic seizures in a patient with a recognized epileptic seizure disorder or epilepsy. However, in this context, according to the methods of the invention, these compounds are used in the appropriate dosage ranges in order that, in addition, they provide an antiepileptogenic effect (AEGD effect) and that they avoid the extension or expansion of nervous tissue subjected to epileptic seizure activity and the consequent worsening of the disease. In another embodiment, the treatment regimen with the compounds of the present invention may begin, for example, after a subject suffering from damage harming the brain or other initial attack but before the subject is diagnosed with epilepsy, for example, before the subject has the first or second epileptic seizures. In one embodiment, it is a subject that is treated with a compound having epileptogenic potential, for example, a psychotropic drug or a subject having a disease associated with a risk of developing epilepsy, for example autism, a treatment regimen with a compound of formula (I) or formula (II) as described herein. In another modality, the treatment regimen with the compounds of the present invention can begin before any damage or prejudice to the nervous system has occurred but at a time when such damage or prejudice can be expected to be likely to occur. For example, said treatment regimen may begin before a subject undergoes a neurosurgical procedure or is likely to suffer from other forms of head or brain trauma, for example, in a war, in violent sports or in races. , in recurring attacks, TIA, etc.

In another embodiment, the compounds as described herein can be administered daily for a set period of time (week, month, year) after the presentation of the initial damage or attack that damages the brain. The attending physician will know how to determine that the compound of formula (I) or of formula (II), as described herein, has reached the therapeutically effective level, for example, a clinical examination of the patient or by measuring the concentrations of the drug in the blood or cerebrospinal fluid A person skilled in the art will be able to determine the maximum tolerable dose by means of physical examination to determine the presence and severity of side effects such as sputtering, lethargy or damaged coordination. The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and / or of formula (II) with a pharmaceutically acceptable carrier The pharmaceutical compositions Euticas contain one or more of the compounds of the invention described herein as the active ingredient can be prepared by thoroughly mixing the compound or compounds with a pharmaceutical carrier in accordance with conventional pharmaceutical compounding techniques. The carrier can acquire a broad range of variety of forms depending on the desired route of administration (eg oral, parenteral) Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, sabotagents , preservatives, stabilizers, coloring agents and the like, for solid oral preparations such as powders, capsules and tablets suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations can also be coated with substances such as sugars or can be enteric coated so that the main absorption site is controlled For parenteral administration, the carrier will usually consist of sterile water and other ingredients that can be added to increase solubility or preservation The suspensions or solutions Injectables can also be prepared using aqueous carriers together with appropriate additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient are mixed perfectly with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, carrier which can acquire a wide variety of forms depending on of the form of the desired preparation for administration, for example, oral or parenteral such as intramuscular When preparing the compositions in oral dosage form, any of the usual pharmaceutical means can be used. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, gels, oils, alcohols, flavoring agents, preservatives, coloring agents and the like, for solid oral preparations such as, for example, powders, capsules, tablets, gelatin capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used. If desired, the tablets may be coated with sugar or enteric coated by standard techniques. For parenteral substances, the carrier usually comprises sterile water although other ingredients may be included, for example, for purposes of assisting in solubility or for preservation. Injectable suspensions may also be prepared in which case suitable liquid carriers, agents that improve the suspension and the like may be used. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, for example, tablet, capsule, powder, suppository injection, teaspoon and the like of about 0.1-1000 mg and can be administered in a dosage from about 0.01-200.0 mg / kg. day, preferably from about 0.1 to 100 mg / kg / day, more preferably from about 0.5-50 mg / kg / day, so more preferably about 1.0-25.0 mg / kg / day or any intermediate range. However, the dosages may vary depending on the requirement of the patients, the severity of the condition to be treated and the compound to be used. The use of daily administration or post-periodic dosing may be employed. Preferably, these compositions are in unit dosage form for example, as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosol dispensed sprays, or liquids, drops, ampoules, autoinjector devices or suppositories; for parenteral, intranasal, sublingual or rectal oral administration or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as the decanoate salt, can be adapted to provide a deposition preparation for intramuscular injection. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum and other pharmaceutical diluents, for example water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof.

When referring to these preformulation compositions as homogeneous, it is required to indicate that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preform composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 to about 1000 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or they can form compounds in some other way to provide a dosage form that provides the long-acting advantage. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact to the duodenum or to be delayed in its release. A variety of materials can be used for such enteric layers or coatings, said materials include numerous polymeric acids with such materials as lacquer, cetyl alcohol and cellulose acetate. Liquid forms in which the novel compositions of the present invention can be incorporated for oral administration by injection include aqueous solutions, flavored syrups suitably, aqueous or oily suspensions and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia gum, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. The method for treating depression described in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg of the compound and can be constituted in any suitable form for the mode of administration that is selected. Carriers include necessary and inert pharmaceutical excipients and include, but are not limited to binders, suspension improving agents, lubricants, flavors, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each includes immediate release, synchronized release and sustained release formulations), granules and powders and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Useful forms for parenteral administration include sterile solutions, emulsions and suspensions. Advantageously, the compounds of the present invention can be administered in a single daily dose or the total daily dosage can be administered in divided doses of two, three or four times a day. In addition, the compounds of the present invention can be administered in an intranasal form via topical use of suitable intranasal vehicles or via transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the administration dosage, of course, will be continuous rather than intermittent during the dosing regimen. For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable and inert carrier such as ethanol, glycerol, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia gum, tragacanth gum or sodium oleate, sodium stearate, magnesium stearate , sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in the suitably flavored suspension or dispersing agents such as synthetic and natural gums, for example, tragacanth, acacia gum, methylcellulose and the like. For parenteral administration, suspensions and sterile solutions are desired. Isotonic preparations which generally contain suitable preservatives are used when intravenous administration is desired. The compounds of this invention can be administered in any of the above compositions and in accordance with the dosage regimens established in the art whenever the depression treatment so requires. The daily dosage of the products can vary over a wide range from 0.01 to 200 mg / kg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5 ,. 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage for the patient to be treated. An effective amount of the medicament is usually supplied at a dosage level from about 0.01 mg / kg to about 1500 mg / kg of body weight per day. Preferably, the range is from about 0.1 to about 100.0 mg / kg of body weight per day, more preferably, from about 0.5 mg / kg to about 50 mg / kg, more preferably, from about 1.0 to about 25.0 mg / kg of body weight per day. The compounds can be administered in a regimen of 1 to 4 times a day. A person skilled in the art will recognize that a therapeutically effective dosage of the compounds of the present invention may include repeated doses within a prolonged treatment regimen that will provide clinically meaningful results to prevent, reverse, suppress or inhibit epileptogenesis. A person skilled in the art will recognize that both assays, in vivo and in vitro using suitable and known cellular models and / or animals, are generally predictive elements of the ability of a test compound to treat or prevent a given disorder. A person skilled in the art will further recognize that clinical trials in humans can be completed which include trials first in human, determination of dose range and efficacy in healthy patients and / or those suffering from a given disorder, according to methods well known in clinical and medical techniques. The determination of effective dosages is typically based on studies in animal models followed by clinical trials in humans and are guided by determining effective dosages of administration protocols that significantly reduce the presentation or severity of symptoms or target exposure conditions in the subject. In this respect, suitable models include, for example, models in mouse, rat, pig, cat, non-human primate and other models accepted animals known in the art. Alternatively, effective dosages can be determined using in vitro models (eg, immunological and histopathological analysis). Using such models, typically only calculations and customary adjustments are required to determine an appropriate concentration and dose to administer a therapeutically effective amount of one or more biologically active agents (e.g., amounts that are effective intranasally, transdermally, intravenously or intramuscularly to induce a desired response). The following examples are set forth in order to assist in understanding the invention and are not intended to be construed as limiting in any way the invention set forth in the claims that follow thereafter.

EXAMPLE 1 ((3,4-dihydro-2H-benzofblf1, 41dioxepin-3-yl) methyl) sulfamide (Compound # 3) Catechol (5.09 g, 46.2 mmol) and potassium carbonate in acetonitrile are combined and heated at reflux for one hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) is added and the reaction continues to reflux for 24 hours. The solution is cooled to room temperature and filtered. The filtrate is evaporated and the residue is diluted with water and extracted with diethyl ether 3 times. The combined organic solution is dried over MgSO4 and concentrated. Chromatography (2% ethyl ether in hexane) provides 3-methylene-3,4-dihydro-2H-benzo [b] [1,4] dioxepin as a colorless oil. MS (ESI): 163.2 (M + H +) 1 H-NMR (300 MHz, CDCl 3), d: 6.94 (m, 4 H), 5.07 (s, 2 H), 4 J 6 (s, 4 H). Dissolve 3-methylene-3,4-dihydro-2H-benzo [b] [1,4] dioxepine (5.00 g, 30.8 mmol) in 100 mL dry THF. At 0 ° C borane-THF (1.0 M in THF, 10.3 ml) the reaction is stirred at r.t. for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) is added. The reaction is heated to reflux overnight. The solution is cooled to room temperature and aqueous sodium hydroxide (3.0 M, 100 ml) is added. The solution is extracted with ethyl acetate (100 ml, 3 times). The combined organic solution is dried over MgSO4. The solution is concentrated under vacuum and purified by chromatography (2% to 8% methanol in dichloromethane) to provide ((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3-yl) methyl) amine as a colorless oil. MS (ESI): 180.1 (M + H +) NMR 'H (300 MHz, DMSO), d: 6.92 (m, 4H), 4.21 (m, 2H), 4.07 (m, 2H), 3.33 (broad, 2H), 3.16 (d, J = 4 Hz, 1 H), 2J2 (d, J = 4 Hz, 1 H), 2.30 (m, 1 H). Combine ((3,4-dihydro-2H-benzo [b] [1,4] dioxepin-3) il) methyl) amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) in 60 ml of dry dioxane and heated at reflux overnight. Chloroform is added and the precipitate is separated by filtration. The filtrate is concentrated under vacuum and purified by chromatography (2% to 8% acetone in dichloromethane) to give the title compound as an off white solid. MS (ESI): 258.8 (M + H +) 1 H NMR (300 MHz, DMSO), d: 6.92 (m, 4H), 6.71 (broad, 1 H), 6.59 (broad, 2H), 4.19 (m, 2H). , 4.04 (m, 2H), 3.00 (m, 2H), 2.39 (m, 1 H). EXAMPLE 2 N- (2,3-Dihydro-benzo [1,4-dioxin-2-ylmethyl) -sulfamide (Compound # 1) 2,3-Dihydro-1,4-benzodioxin-2-ylmethylamine (4.4 g, 26 mmoles) racemic and sulfamide (5.1 g, 53 mmol) in 100 ml of 1,4-dioxane and refluxed for 2 h. The reaction is cooled to room temperature and a small amount of the solid is filtered and discarded. The filtrate is evaporated in vacuo and the residue is purified using flash column chromatography (DCM: methanol-10: 1) to give a white solid. The solid recrystallized from DCM to give the title compound as a white solid, m.p .: 97.5-98.5 ° C Elemental Analysis: Calculated Analysis: C, 44.25; H, 4.95; N, 1 1.47; S, 13.13 Analysis Found: C, 44.28; H, 4.66; N, 11.21; S, 13.15 EXAMPLE 3 (Benzof 1, 31-dioxol-2-ylmethyl) sulfamide (Compound # 2) Catechol (10.26 g, 93.2 mmol), sodium methoxide are combined (25% by weight in methanol, 40.3 g, 186 mmol) and methyl dichloroacetate (13.3 g, 93.2 mmol) in 100 ml of dry methanol. The solution is heated to reflux overnight. The reaction is cooled to room temperature, acidified by the addition of concentrated hydrochloric acid and then reduced in volume under vacuum to about 50 ml. Water is added and the mixture is extracted with diethyl ether (100 ml, 3 times). The combined organic solution is dried with MgSO 4, concentrated to a brown solid and chromatographed (2% ethyl acetate in hexane) to give the benzo [1,3] dioxol-2-carboxylic acid methyl ester as an oil. colorless. MS (ESI): 195.10 (M + H +) 1 H-NMR (300 MHz, CDCl 3), d: 6.89 (broad, 4H), 6.29 (s, 1 H), 4.34 (c, J = 7 Hz, 2H), 1.33. (t, J = 7 Hz, 3H). To the benzo [1,3] dioxol-2-carboxylic acid methyl ester (7.21 g, 40. 0 mmol) is added ammonium hydroxide (29% in water, 10 ml) and enough acetonitrile to make the mixture homogeneous (~ 5 ml). The solution is stirred for 2 hours at room temperature and then distilled water is added. The benzo [1, 3] dioxol-2-carboxylic acid amide precipitates as a white solid and is collected by filtration and used without further purification. MS (ESI): 160.00 (M + H +) 1 H NMR (300 MHz, DMSO), d: 7.99 (s, broad, 1 H), 7J 2 (s, broad, 1 H), 6.94 (m, 2 H), 6.86. (m, 2H), 6.30 (s, 1 H). Benzo [1, 3] dioxol-2-carboxylic acid amide (5.44 g, 32.9 mmol) is dissolved in tetrahydrofuran (THF, 100 ml). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) is slowly added to the solution at room temperature. The reaction is stirred at room temperature for 24 hours. Distilled water is added to destroy the excess LAH. Aqueous sodium hydroxide (3.0 M, 100 ml) is added and the solution is extracted with ethyl acetate (100 ml, 3 times). The combined organic solution is washed with water and dried over MgSO4. The solvent is evaporated to give C-benzo [1,3] dioxol-2-yl-methylamine as a colorless oil. MS (ESI): 152.10 (M + H +) 1 H NMR (300 MHz, CDCl 3), d: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1 H), 3.13 (d, J = 4 Hz , 2H) Combine C-benzo [1,3] dioxol-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3 J4 g, 38.9 mmol) in 50 mL of dry dioxane and the solution is refluxed for the night. The reaction is concentrated and the residue is chromatographed (2% to 10% acetone in dichloromethane) to give the title compound as a white solid MS (ESI) 230 0 (M + H +) 1 H NMR (300 MHz, CDCl 3), d 6 87 (m , 4H), 6 25 (t, J = 4 Hz, 1 H), 4 79 (broad, 1 H), 4 62 (wide, 1 H), 3 64 (d, J = 4 Hz, 2H) EXAMPLE 4 (2SH -) - N- (2,3-dihydro-benzoyl-1, 41-dioxin-2-ylmethyl) -sulfamide (Compound # 4) Catechol (13 2 g, 0 12 mol) and potassium carbonate are stirred (16 6 g, 0 12 mol) in 250 ml of DMF and (2R) -gl? Cyl (2 8), 0 10 mol) tosylate is added and the reaction is stirred at 60 ° C for 24 hours. hours The reaction is cooled to room temperature and diluted with 1 l of ice water and extracted with diethyl ether 4 times The combined organic solution is washed 3 times with 10% potassium carbonate, once with water, once with brine and evaporate in vacuo to provide a white solid which is purified by flash column chromatography (DCM Methanol-50 1) to provide ((2S) -2,3-d? h? dro-benzo [1,4] d? ox? n-2-? l) -methanol as a solid The solid (13.3 g, 68 mmol) is dissolved in 85 ml of pyridine, cooled to 0 ° C, p-toluenesulfonyl chloride (13.0 g, 68 mmol) is added and the reaction mixture is stirred at room temperature for 20 minutes. h. The reaction is diluted with 1 l of diethyl ether and 1.2 l of 1 N HCl. The organic layer is separated and washed 2 times with 500 ml of 1 N HCl, 4 times with 150 ml of water, once with brine, dried with MgSO 4 and evaporated in vacuo to provide a white solid which is purified by flash column chromatography (HeptEA-2: 1) to give the ester (2S) -2,3-dihydro-benzo [1,4] dioxin 2-Ethyl toluene-4-sulfonic acid as a white solid. The white solid is combined with potassium phthalimide (14.4 g, 78 mmoles) in 250 ml of DMF and refluxed for 1 h, cooled to room temperature and poured into 1.5 l of vigorously stirred water, and stirred for 30 min. The white solid is filtered and the solid is washed several times with water, 2% NaOH and water again and allowed to air dry to provide (2S) -2- (2,3-dihydro-benzo [1,4] dioxin- 2-olmethyl) -isoindole-1,3-dione as a white powdery solid. The pulverulent white solid is combined with hydrazine (2.75 g, 86 mmol) in 225 ml of EtOH and refluxed for 2 h, cooled to room temperature and 1 N HCl is added to pH 1.0 and stirred for 15 min. The white solid is filtered and washed with fresh EtOH (the solid is discarded) and the filtrate is evaporated in vacuo to a solid which is divided between diethyl ether and dilute aqueous NaOH. The diethyl ether solution is dried with Na 2 SO 4 and evaporated in vacuo to give a light yellow oil. The oil is purify by flash column chromatography (DCM MeOH-10 1) to provide an oil. A portion of the oil (4.82 g, 29 mmol) in 250 ml of 2-propanol is treated with 30 ml of 1 N HCl and heated in a steam bath until homogeneous and then allowed to cool to room temperature After 3 h, the mixture is cooled with ice for 2 h. A white flaky solid is filtered off (the corresponding HCl salt of (2S) -C- (2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-? L) -met? Lam? Na) and then recrystallized again from 2-propanol to give a solid White. [α] D = -69 6 (c = 1 06, EtOH) The white solid is partitioned between DCM and dilute NaOH and the DCM is dried with NaS04 and evaporated under vacuum to provide (2S) -C- (2.3 -d? h? dro-benzo [1, 4] d? ox? n-2-? l) -met? lam? na as an oil [a] D = -57 8 (c = 1 40, CHCl3) oil (2 1 g, 12 7 mmoles) and sulfamide (2 44 g, 4 mmoles) are refluxed in 75 ml of dioxane for 2 h and the crude product is purified by flash column chromatography (DCM MeOH 10 1) to give a white solid which is recrystallized from DCM to give the title compound as a white crystalline solid mp 102-103 ° C [a] D = -45 1 ° (c = 1 05 M), 1 H NMR (DMSOd 6) d 6 86 (m, 4H), 6 81 (broad s, 3H, NH), 4. 3 (m, 2H), 3.97 (dd, J = 6.9, 1.4 Hz, 1 H), 3.20 (dd, J = 5.5, 13.7 Hz, 1 H), 3.10 (dd, J = 6.9, 13J Hz, 1 H) Elemental Analysis: Calculated Analysis: C, 44.25; H, 4.95; N, 1 1 .47; S, 13.13 Analysis Found: C, 44.20; H, 4.69; N, 1 1 .40; S, 13.22 EXAMPLE 5 N- (2,3-dihydrobenzori, 41-dioxin-2-ylmethyl) -N ', N'-dimethylsulfamide (Compound # 6) Race 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine is combined (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) in 10 ml of DMF and cooled in an ice bath as dimethylsulphamoyl chloride (1.44 g, 10 mmol) is added. The reaction mixture is then stirred for 3 h with continuous cooling. The reaction mixture is partitioned between ethyl acetate and water, and the ethyl acetate solution is washed with brine, dried with MgSO 4 and evaporated in vacuo to provide an oil. The oil is purified using flash column chromatography (ethyl acetate: heptane -1: 1) to give a white solid, which recrystallizes (ethyl acetate). ethyl / hexane) to provide the title compound as a white floccular solid. p.f. 76-79 ° C EM 273 (MH +) Elemental Analysis: Calculated Analysis: C, 48.52; H, 5.92; N, 10.29; S, 1 1.78 Analysis Found: C, 48.63; H, 5.62; N, 10.20; S, 11.90 1 H NMR (CDCl 3) d 6.87 (m, 4 H), 4.59 (broad m, 1 H, NH), 4. 35 (m, 1 H), 4.27 (dd, J = 2.3, 1.4 Hz, 1 H), 4.04 (dd, J = 7.0, 1.4 1.4 H), 3.36 (m, 2H), 2.82 (s, 6H) EXAMPLE 6 N- (2,3-dihydro-benzof1, 41-dioxin-2-ylmethyl) -N-methylsulfamide (Compound # 7) Dissolve racemic 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine (825 mg, 5 mmol) in 15 ml of ethyl formate, reflux for 30 min and evaporate in vacuo to give N- ( 2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -formamide as an oil. The oil in 25 ml of diethyl ether is treated with 1 M LAH and THF (9.0 ml, 9.0 mmol) at 0 ° C and stirred for 5 h at room temperature.

The reaction is cooled in an ice bath and suspended with 0.50 ml of water, followed by 0.50 ml of 3N NaOH and 0.50 ml of water. The mixture is then stirred at room temperature for 1 h. The solid is filtered and the filtrate is evaporated in vacuo to provide a residue which is divided between 1 N HCl and diethyl ether. The aqueous phase is gasified with 1N NaOH and extracted with diethyl ether. The organic phase is dried with MgSO 4 and evaporated in vacuo to provide (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -methylamine as an oil. MS 180 (MH +) 1 H NMR (CDCl 3) d 6.85 (m, 4 H), 4.30 (m, 2 H), 4.02 (dd, J = 7.9, 11. 6 Hz, 1 H), 2.85 (m 2 H, 2.50 (s, 3 H) .The oil (380 mg, 2.1 mmol) and sulfonamide (820 mg, 8.5 mmol) are combined in 15 ml of dioxane, refluxed for 1.5 h and evaporated in vacuo to provide a crude residue The residue is purified by column chromatography (ethyl acetate / heptane 1: 1) and the resulting solid recrystallized from ethyl acetate / hexane to give the title compound as a white solid, mp 97-98 ° C MS 257 (MH +) Elemental Analysis: Calculated Analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 Analysis Found: C, 46.48; H, 5.65; N, 10.90; S, 12.07 1 H NMR (CDCl 3) d 6.86 (m, 4 H), 4.52 (broad s, 2 H), 4.46 (m, 1 H), 4.29 (dd, J = 2.3, 1 1.5 Hz, 1 H), 4.05 (dd, J = 6.5, 1 1.5 Hz, 1 H), 3.51 (dd, J = 67, 14.9 Hz, 1 H), 3.40 (dd, J = 5.9, 14.9 Hz, 1 H), 2.99 (s, 3H).

EXAMPLE 7 (2S) - (-) - N- (6-Chloro-2,3-dihydro-benzop, 41-dinoxy-2-ylmethyl) -N-sulfamide (Compound # 8) Following the procedure indicated in Example 4 above, 4-chlorocatechol is reacted to provide a mixture of (2S) -C- (7-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) methylamine and (2S) -C- (6-chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine (approximate ratio of 3: 1 to 6-chloro: 7-chloro isomers, as determined by CLAP The mixture is dissolved in 100 ml of 2-propanol and 1 N HCl in diethylether is added until a pH = 1.0 is obtained The hydrochloride salt which precipitates is filtered (2.65 g) and recrystallized from methanol / IPA to provide white crystals The white crystals are divided between DCM and dilute NaOH The DCM is dissolved and evaporated under vacuum to provide (2S) -C- (6-chloro-2,3-dihydro-benzo [1,4] dioxin -2-yl) -methylamine purifies as an oil. [A] D = -67.8 (c = 1.51, CHCl3) 7.75 mmol of the oil and sulfamide (1.50 g, 5.5 mmol) are combined in 50 ml of dioxane and refluxed for 2.0 h, cooled to room temperature and evaporated in vacuo to provide a solid. The product is purified via flash column chromatography using DCM / methanol 20: 1 to provide the title compound as a white solid. MS 277 (M "1) [a] D = -59.9 ° (c = 1.11, M) 1 H-NMR (CDCl 3) d 6.90 (d, J = 2.2 Hz, 1 H), 6.81 (m, 2 H), 4.76 ( m, 1 H), 4.55 (s, 2H), 4.40 (m, 1 H), 4.29 (dd, = 2.4, 1 1.5 Hz, 1 H), 4.05 (dd, J = 7.1, 11.5 Hz, 1 H) , 3.45 (m, 2H) Elemental Analysis: Calculated Analysis: C, 38.78; H, 3.98; N, 10.05 Analysis Found: C, 38.80; H, 3.67; N, 9.99 Filters of the crystallized hydrochloride salt of (2S) - C- (6-Chloro-2,3-dihydro-benzo [1,4] dioxin-2-yl) -methylamine prepared in the above is recovered (approximately 1: 1 of 6-chloro: 7-chloro isomers) and evaporate in vacuo to give a solid which is divided between 200 ml of DCM and dilute NaOH (0.5 M, 50 ml) The DCM solution is washed once with brine, dried with Na2SO and evaporated in vacuo to give an oil which is purified via reverse phase CLAP (ACN with 10-50% with TFA 0.16% in water with 0.20% TFA) to provide (2S) -C- (7-chloro-2,3-dihydro-benzo [1, 4] dioxin-2-yl) -methylamine as a residue.

The residue is combined with sulfonamide (0.90 g, 9.4 mmol) in 25 ml of dioxane and refluxed for 2.5 h, cooled to room temperature and evaporated in vacuo to provide an oil. The oil is purified by flash column chromatography using DCM / methanol = 10: 1 to provide (2S) - (-) - N- (7-chloro-2,3-dihydro-benzo [1,4] dioxin) 2-ylmethyl) -sulfamide as a white solid. MS 277 (M'1) 1H-NMR (CDCl3 / CD3OD) d 6.88 (d, J = OJ Hz, 1 H), 6.81 (m, 2H), 4.37 (m, 1 H), 4.30 (dd, J = 2.3) , 11.6 Hz, 1 H), 4.04 (dd, J = 7.0, 1 1.6 Hz, 1 H), 3.38 (m, 2H). EXAMPLE 8 Chroman-2-ylmethylsulfamide (Compound # 10) Combine chroman-2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) in 40 ml of DCM and 10 ml of DMF. At room temperature, dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added and the reaction mixture was stirred for 30 min. Ammonium hydroxide (2.26 ml, 33.4 mmol) is added and the reaction mixture is stirred for 16 h. The reaction mixture is partitioned with 50 ml of DCM and 50 ml of water and adjusted to the pH of the mixture to approximately pH = 3.0 with 1 N HCl. The DCM is separated and the aqueous phase is extracted twice with DCM.

The combined DCM phase is dried with Na2SO and evaporated in vacuo to provide an oil which is purified by flash column chromatography (ethyl acetate) to provide an oil. The oil (5.35 g, 30 mmol) in 90 mL of THF is stirred as 1 M LAH in THF (36 mL, 36 mmol) is added and the reaction mixture is then stirred at room temperature for 20 h. The reaction is suspended in water, stirred for 2 hours, the solution is decanted, dried with Na 2 SO and evaporated in vacuo to give C-chroman-2-yl-methylamine as an oily amine. The oily amine (1.63 g, 10 mmol) and the sulfonamide (1.92 g, mmol) are combined in 50 ml of dioxane and refluxed for 2 h.

The solution is cooled and evaporated in vacuo to provide an oil which is purified via column chromatography (DCM: methanol 10: 1) to give a white solid. The solid recrystallized from ethyl acetate / hexane to give chroman-2-ylmethylsulfamide as a white solid. p.f. 100-101 ° C EM 241 (M ~ 1) Elemental Analysis Calculated Analysis: C, 49.57; H, 5.82; N, 1 1 .56; S, 13.23 Analysis Found: C, 49.57; 5.80; N, 1.75; S, 13.33 EXAMPLE 9 2- (2,3-Dihydro-benzo [1141-dioxin-2-ylmethyl) -ethylsulfamide (Compound # 16) Potassium cyanide (2 05 g, 31.5 mmol) is added to 2-bromomet? L- (2,3-d? H? Drobenzo [1,4] d? Ox? Na) (6 87 g, 30 mmol). in 90 ml of DMSO and stirred at room temperature for 20 h. The reaction mixture is then diluted with 250 ml of water and extracted twice with diethyl ether. Diethylether is washed with water, washed twice with brine, dried with Na 2 SO 4 and evaporated in vacuo to give 2-c? Anomet? L- (2,3-d? H? Drobenzo [1,4] d? Ox? Na) as a white solid 1 H NMR (CDCl.sub.3) d 6 89 ( m, 4H), 4 50 (m, 1 H), 4 31 (dd, J = 2 3, 1 1 5 Hz, 1 H), 4 08 (dd, J = 6 2 Hz, H), 2 78 ( d, J = 6 1, 2H) The 2-c? anomet? l- (2,3-d? h? drobenzo [1,4] d? ox? na) is dissolved in 50 ml of THF and BH3 is added 1 M in THF (80 mL, 80 mmol) and the reaction mixture is refluxed for 5 h, then stirred at room temperature for 16 h. With cooling in an ice bath, 2N HCl is added until it is obtained a pH = 1 0 The reaction mixture is then stirred for 1 h at room temperature. The oil is partitioned between 3N NaOH and diethylether and the diethylether solution is washed with brine, dried with Na 2 SO 4 and evaporated. under vacuum to provide crude 2- (2,3-dihydrobenzo [1,4] dioxin-2-yl) ethylamine. MS (M + H) + 180 The crude 2- (2,3-dihydrobenzo [1,4] dioxin-2-yl) ethylamine in 100 ml of dioxane is combined with sulfamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The solution is cooled and evaporated in vacuo to provide an orange solid which is purified by column chromatography (DCM: MeOH-10: 1) to give a white solid. The solid recrystallized from DCM to give the title compound as an MS solid (M-1) 257 p.f. 101-103 ° C (corr) 1 H-NMR (CDCl 3): d 6.86 (m, 4 H), 4.70 (m, 1 H), 4.52 (s, 2 H), 4.30 (m, 2 H), 3.94 (dd, J = 7.4, 1 1 .3 Hz, 1 H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9, 2H). Measured Elementary Analysis: C, 46.48; H, 5.60; N, 10.81; S, 12.41 Calculated: C, 46.50; H, 546; N, 10.85; S, 12.41 EXAMPLE 10 (2S) - (-) - (6,7-dichloro-2,3-dihydro-benzo [1,4-dinoxy-2-ylmethyl) -sulfamide (Compound # 29) 4.5-Dichlorocatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) are stirred in 200 ml of DMF. (2R) -glycidyl tosylate (9.12 g, 40 mmol) is added and the reaction mixture is stirred at 60 ° C for 24 h. The reaction mixture is cooled to room temperature and then diluted with 600 ml of ice water and extracted with diethyl ether 4 times. The combined organic solution is washed 3 times with 10% potassium carbonate, 2 times with brine, dried with MgSO 3 and evaporated in vacuo to give a viscous oil of (2S) -2- (6J-dichloro-2,3- dihydro-benzo [1,4] dioxin) methanol. The oil of (2S) -2- (6J-dichloro-2,3-dihydro-benzo [1,4] dioxin) methanol (6.4 g, 27 mmol) is dissolved in 50 ml pyridine and cooled to 0 ° C. Then p-toluenesulfonyl chloride (5.2 g, 27 mmol) is added and the reaction mixture is stirred at room temperature for 20 h. The reaction mixture is diluted with diethyl ether and 750 ml of 1 N HCl and the organic layer is separated and washed 2 times with 250 ml of 1 N HCl, once with 150 ml of water, 2 times with brine, dried with MgSO4 and evaporate to vacuum to give a light yellow solid of (2S) -6J-d? chloro-2,3-d? h? dro-benzo [1,4] d? ox? n-2-? lmethyl acid of toluene -2-sulfon? Co 1 H-NMR (CDCl 3) d 7 79 (d, J = 8 3 Hz, 2 H), 7 36 (d, J = 8 0 Hz, 2 H), 6 94 (s, 1 H), 6 83 (s, 1 H), 4 73 (m, 1 H), 4 2 (m, 3 H), 4 03 (dd, J = 6 3, 1 1 7 Hz, 1 H), 2 47 (s, 3 H) ) The (2S) -6J-d? Chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N-2-? Lmethyl ester of toluene-4-sulfon? (8.0 g, 20.5 mmol) is combined with potassium phthalimide (6.1 g, 33 mmol) in 75 ml of DMF and heated to reflux for 1 h, cooled to room temperature and poured into 0 5 I of water vigorously stirred and then stirred for 30 min. The white solid is filtered and the solid is washed several times with water, 2% NaOH and water again and then allowed to air dry to provide (2S) -2- (6J-d chloro-2, 3-d? h? dro-benzo [1,4] d? ox? n-2-? lmet? l)? so-ddol-1,3-dione (6 0 g, 80 %) as a powdery white solid Powdery white solid is combined with hydrazine (1 06 g, 33 mmole) in 80 ml of EtOH and refluxed for 2 h, then cooled to room temperature. 1 N HCl is added to adjust the pH of the reaction mixture to pH 10 and the reaction mixture is then stirred for 15 min. A white solid is filtered and washed with fresh EtOH (the solid is discarded) and the filtrate is evaporated in vacuo to a solid, which is divided between diethyl ether and dilute aqueous NaOH. The diethyl ether solution is dried with Na 2 SO and evaporated in vacuo to give a viscous oil of (2S) -2-amomethyl (6J-d-chloro-2,3-d? H? Dro-benzo [ 1, 4] d? Ox? Na) 1 H-NMR (CDC): d 6.98 (s, 1 H), 6.96 (s, 1 H), 4.25 (dd, J = 2.0, 11.2 Hz, 1 H), 4.15 (m, 1 H), 4.0 (m, 1 H), 2.97 (d, J = 5.5 Hz, 2H) A portion of the oil (3.8 g, 16 mmol) and sulfamide (3.1 g, 32.4 mmol) is refluxed in 100 ml of dioxane for 2 h and the crude product purify by flash column chromatography (DCM: MeOH 20: 1) to provide the title compound as a white solid which recrystallizes from ethyl acetate / hexane to give the title compound as a white crystalline solid. MS [MH] "31 1.0 pf 119-12 ° C [a] D = -53.4 ° (c = 1.17, M) 1H NMR (DMSOd6): d 7.22 (s, 1 H), 7.20 (s, 1 H) , 6.91 (s broad, 1 H), 6.68 (broad s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 1 1.5 Hz, 1 H), 3.15 (m, 2H) Measured Elemental Analysis : C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24 Calculated: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35 EXAMPLE 11 (2S) - (-) - N- (7-amino-2,3-dihydro-benzo [1,41-dioxan-2-ylmethyl] -sulfamide (Compound # 36) Prepare (2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide (1.2 g, 4.15 mmol) from 4-nitrocatechol according to the procedure indicated in example 4. The (2S) - (-) - N- (2,3-dihydro-7-nitro-benzo [1,4] dioxin-2-ylmethyl) -sulfamide is then combined with 10% Pd / C in 120 ml of methanol and stirred under a hydrogen atmosphere (2.7 MPa (39 pounds per square inch)) at room temperature for 3 h. The solids are filtered and washed with 10% M in DCM and the filtrate is evaporated in vacuo to provide the crude product. The crude product is dissolved in 25 ml of 0.2 N HCl, freeze and lyophilize to provide the title compound as a white flaky solid, such as the corresponding hydrochloride salt. MS (M + H) + 260 1 H NMR (DMSO 6): d 10.2 (broad s, 3H), 6.86 (m, 1 H), 6.85. (s, 1 H), 6.74 (dd, J = 2.5, 8.4 Hz, 1 H), 4.22 (m, 2H), 3.88 (dd, J = 6.7, 11.4 Hz, 1 H), 3.04 (m, 2H) EXAMPLE 12 (2S) - (-) - N -7-methyl-2,3-dihydro-benzori, 41-dioxin-2-ylmethyl) -sulfamide (Compound # 19) The title compound is prepared according to the procedure described in Example 4 above, starting with 4-methylcatechol to give a white solid, which recrystallizes from ethyl acetate / hexane to give the title compound as a white solid. . MS [MH] "257 1 H NMR (CDCl 3): d 6.76 (m, 1 H), 6.66 (m, 2 H), 4.80 (m, 1 H), 4.57 (broad s, 1 H), 4.40 (m, 1 H), 4.28 (m, 1 H), 4.03 (dd, J? 6.9, 11.4 Hz, 1 H), 3.45 (m, 2H), 2.25 (s, 3H), Calculated Elemental Analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41 Found: C, 46.65; H, 6.50; N, 10.84; S, 12.61.

EXAMPLE 13 Amygdala Sensitization Analysis in vivo The development of amygdala sensitization is an established model of epileptogenesis (Amano K, Hamada K. Yagi K, Seino M. Antiepileptic effects of topiramate on amygdaloid kindiing in. Epulepsy Res. 1998 Jul; 31 (2): 123-8; Barton ME, White HS, The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindiing acquisition and expression, Epilepsy Res. 2004 Mar; 59 (1): 1 -12; Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (ucb L059) in the kindiing model of temporal lobe epilepsy J. Pharmacol Exp Ther 1998, 284 (2): 474-9; McNamara JO Analyzes of the molecular basis of kindiing Psychiatry Clin Neurosci, 1995 June; 49 (3): S175-8 Review, Morimoto K, Katayama K, Inoue K, Sato K, Effects of competitive and noncompetitive NMDA receptor antagonists on kindiing and LTP Pharmacol Biochem Behav. Dec; 40 (4): 893-9; Racine, RJ 1972. Modification of seizure activity by electrical stimulation. r seizure, Electroencephalogr. clin. Neurophysiol. 32, 281-294). The kindled rat model of partial epilepsy is an accepted model of epileptogenesis (McNamara JO, Analyzes of the Molecular Basis of Kindly Development, Psychiatry Clin Neurosci, 1995 Jun; 49 (3): S175-8, Review.). Briefly, the analysis procedure is efficient. Adult male Sprague-Dawley rats are obtained with a weight between 250-300 g from Charles River, Wilmington, MA. All animals were housed in a 12:12 light-dark cycle and were allowed free access to both food (Prolab RMH 3000) and water, except when extracted from the source cage for experimental procedures. Care was taken with the animals regarding the material consistent with the recommendations detailed in the National Research Council Publication, "Guide for the Care and Use of Laboratory Animáis" in a temperature-controlled and pesticide-free facility. Sensitization stimulations were carried out routinely between 9 AM - 2PM to avoid any circadian variation. Compound # 8 is ground in a small volume of 0.5% methylcellulose, sonicated for 10 min and brought to a final volume with 0.5% methylcellulose. Compound # 8 is administered systemically (i.p.) in a volume of 0.04 ml / 10 g body weight and all tests were carried out at a predetermined time of maximum effect of 0.5 hours after i.p. The ability of compound # 8 to block the expression of epileptic seizures sensitized in amygdala was determined as follows. The rats were anesthetized with a combination of ketamine (120 mg / kg, i.p.) and xylazine (12 mg / kg, i.p.). Under aseptic conditions, a bipolar electrode (Plástic One, Roanoke, VA) was implanted stereotaxically in the right lateral bass amygdala (AP -2.2, ML -4.1, DV -8.7, Paxinos and Watson). The anteroposterior and lateral measurements were performed by Bregma, while the dorsal-ventral measurement was made from the surface of the scalp. Sterile screws were implanted in the scalp (3-4) for the indifferent reference electrodes. The electrodes were fixed using dental cement and acrylic. The wound was then closed using sterile Michel 18/8 suture clasps (Roboz, Gaithersburg, MD). Neomycin antibiotic ointment was applied to the wound in a single dose of penicillin (60,000 IU, im, AgriLabs) which was administered to each rat before returning it to the clean cages for a one-week postoperative recovery period. Subsequently it was performed in the amygdala sensitization according to the following protocol. After a brief acclimatization (<; 5 minutes) in the recording chamber the initial EEG records were obtained (MP 100, Bipac Systems Inc., Goleta, CA). Rats were then randomly distributed to receive vehicle (methylcellulose 0.5%) or compound # 8 (75 mg / kg, i.p.) (n = 10 rats per group). On the day of the experiment, a single dose was given in compound # 8 or 0.5% methylcellulose 30 minutes before the stimulation of the amygdala (200 μA for 2 seconds). The rating of the behavioral epileptic seizure and the duration of AD for rats in each treatment group were recorded. The scores of behavioral epileptic seizures were determined using the racine scale, that is, 0 = no response; stage 1 = grooming / hyperactivity; stage 2 = pitching / trembling; stage 3 = clone of the anterior limbs unilateral; stage 4 = backward clone; and stage 5 = tonic-clonic epileptic seizure generalized with regression and fall (Racine, 1972). Activity after discharge (AD) was recorded digitally up to 180 seconds after the stimulation train and the duration of primary AD was measured. The rats were considered completely sensitized when they showed five consecutive epileptic seizures of stage 4 or 5. The daily stimulations continued for up to 13 consecutive days in all three groups until the rats in the vehicle-treated group were fully sensitized ( that is, five consecutive epileptic seizures of stage 4 or 5). At this time all the rats were allowed a stimulus of one week and a period free of medication; after which they were again exposed in the absence of medication with the same stimulus used during the acquisition phase (ie, lanes 1-13). The rats treated with compound # 8 were subsequently stimulated once a day until they reached a fully sensitized state. The duration after discharge (AD) in both vehicle-treated groups and compound # 8 showed a progressive increase in the course of the acquisition phase of sensitization. No statistical difference was observed between the treatment groups. Compound # 8 prevented the acquisition of a fully generalized sensitized epileptic seizure. This conclusion is based on the finding that the epileptic seizure score at the end of the drug-free and stimulus-free period remains significantly lower than that of the rats in the vehicle-treated group (compound # 8 = 1.4 ± 0.40 vs. vehicle = 4 6 ± 0 24) Additionally, when stimulated in the absence of medication, the rating of the epileptic seizure of rats in the group under the treatment of compound # 8 increased at a rate that was parallel to that observed in rats treated with vehicle - substantiating the conclusion that compound # 8 delays the acquisition of sensitization in a few days The results of this study demonstrate that compound # 8 possesses the ability to modify the development of sensitization in rat model sensitized to amygdala partial epilepsy These results agree with the conclusion that compound # 8 has disease modifying effects This conclusion is based on the finding that epileptic seizure qualification, at the conclusion of the drug-free period and stimulation of rats in the group under treatment with compound # 8 remains significantly lower than in the group of rats treated with In addition, once the stimulation protocol is resumed in the absence of medication, the epileptic seizure score progresses at a rate that is parallel to the vehicle-treated group. The finding that the epileptic seizure score but not the duration after discharge (ADD) in the compound treatment group one week after the stimulus and the stimulus-free week is markedly less than that of the vehicle-treated group, suggesting that compound # 8 avoid the acquisition of the generalized epileptic seizure in a secondary manner but not the focal epileptic crisis EXAMPLE 14 As a specific embodiment of an oral composition, 100 mg of compound # 8 prepared as in example 7 is formulated with enough finely diluted lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. The above specification describes the principles of the present invention, with examples that are provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the variations, adaptations and / or modifications which are within the scope of the invention. following claims and their equivalents.

Claims (10)

NOVELTY OF THE INVENTION
1. The use of a compound of formula (I) wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; It is selected from the group consisting of: wherein b is an integer from 0 to 4, and where c is an integer from 0 to 2, each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro, with the proviso that when is or then a is 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful for the treatment of epileptogenesis in a patient 2. The use as claimed in claim 1, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl R4 is selected from the group consisting of hydrogen and lower alkyl, a is an integer from 1 to 2, It is selected from the group consisting of: where b is an integer from 0 to 2; and where c is an integer from 0 to 1; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; with the condition that when it is or then a is 1; or a pharmaceutically acceptable salt thereof. 3 - The use as claimed in claim 2, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; is selected from the group consisting of wherein b is an integer from 0 to 2 and wherein c is 0, each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro, with the proviso that when is then a is 1, or a pharmaceutically acceptable salt thereof. The use as claimed in claim 3, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl, R4 is selected from the group consisting of hydrogen and methyl, a is an integer from 1 to 2, is selected from the group consisting of 2- (2,3-d? h? dro-benzo [1,4] d? ox? n? lo),
2. 2- (benzo [1,3] d? oxol? lo) ,
3. 3- (3,
4. 4-d? H? Dro-benzo [1,4] d? Oxep? N? Lo), 2- (2,3-d? H? Drobenzo [1,4] d? Ox? nol, 2- (6-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- (6-fluoro-2,3-d? h) ? dro-benzo [1, 4] d? ox? n? lo), 2- (chroman? lo), 2- (5-fluoro-2,3-d? benzo [1,4] d? ox? n? lo), 2- (7-chloro-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2- ( 6-chloro-benzo [1,3] d? Oxole), 2- (7-n? Tro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo) , 2- (7-met? L-2,3-d? H? Dro? Benzo [1,4] d? Ox? N? Lo), 2- (
5. 5-chloro-2,3-d? H? dro-benzo [1,4] d? ox? n? lo), 2- (6-bromo-2,3-d? h? dro-benzo [1,4] d? ox? n? lo), 2 - (6J-d? Chloro-2,3-d? H? Dro-benzo [1,4] d? Ox? N? Lo), 2- (8-chloro-2,3-d? benzo [1, 4] d? ox? n? lo), 2- (2,3-d? h? dro-naphtho [2,3-b] [1,4] d? ox? n? lo) and 2- (4-met? L-benzo [1, 3] d? Oxol? Lo), with the proviso that is 2- (3,4-d? -hydro-2H-benzo [1,4] d? oxep? n? lo), then a is 1, or a pharmaceutically acceptable salt thereof 5 Use as claimed in Claim 4, wherein R1 and R2 are each independently selected from the group consisting of hydrogen and methyl, R4 is selected from the group consisting of hydrogen and methyl, a is an integer from 1 to 2, is selected from the group consisting of 2- (benzo [1,3] d? oxol? lo), 2- (2,3-d? h? drobenzo [1,4] d? ox? n? lo), 2 - (2,3-d? H? Drobenzo [1, 4] d? Ox? N? Lo), 2- (6-chloro-2,3-d? H? Drobenzo [1 4] d? Ox? N ? lo), 2- (7-chloro-2,3-d? h? drobenzo [1,4] d? ox? n? lo), 2- (7-met? l-2,3-d? h) Drobenzo [1, 4] d? ox? n? lo) 2- (6-bromo-2,3-d? h? drobenzo [1 4] d? ox? n? lo) and 2- (6J-d) ? chloro-2,3-d? h? drobenzo [1, 4] d? ox? n? lo), or a pharmaceutically acceptable salt thereof
6. 6 -. 6 - The use as claimed in claim 1, wherein the compound of formula (I) is selected from the group consisting of (2S) - (-) - N- (6-chloro-2), 3-d? H? Drobenzo [1, 4] d? Ox? N-2? Lmet? L) -sulfamide, and pharmaceutically acceptable salts thereof 7 Use as claimed in claim 1, wherein one or several predisposing factors that make a patient in need of treatment with an antiepileptogenic drug (an AEGD) are selected from the group consisting of injury or trauma of any kind to the CNS, neurosurgical procedures, activities where it is put at risk of harm to the SNC, for example combat activities, car or horse races and contact sports that include boxing spinal cord trauma, CNS infections, anoxia, stroke (CVA), history of transient ischemic attacks (TIA), carotidia stenosis , history of artepoesclerotic vessel disease, history of pulmonary embolism, peripheral vascular disease, autoimmune diseases affecting the CNS, for example lupus, birth injury, for example, asphyxia pennatal, arrest cardiac, therapeutic or diagnostic vascular surgical procedures, for example carotidia endoarterectomy or cerebral angiography, hypotension, embolism CNS damage, hyperperfusion or hypoperfusion, hypoxia, known genetic predisposition to disorders known to respond to AEGD, lesions occupying CNS spaces , brain tumors, for example glioblastomas, bleeding or hemorrhaging in or surrounding the CNS, for example intracerebral hemorrhages or
7. Subdural hematomas, cerebral edema, febrile seizures, hyperthermia, exposure to toxic or poisonous agents, drug intoxication or suppression, for example of cocaine, methamphetamines or alcohol, family history of epileptic seizure disorders or an epileptic crisis related to epilepsy similar to a neurological disorder or a disorder related to epileptic crisis, history of status epilepticus, current treatment with drugs that lower the threshold for epileptic seizures eg lithium carbonate, thoracine or clozapine test substitute markers or biomarkers that the patient is in need of treatment with an antiepileptogenic drug, for example MRI scan showing hippocampal sclerosis, elevated serum concentrations of neuronal degradation products, high concentrations of ciliary neurotrophic factor (CNTF) or an EEG suggestive of epileptic seizure disorders or a disorder non-neurological similar to epileptic crisis related to epilepsy or an analogous disorder related to epileptic seizure
8. 8 - Use as claimed in claim 1, wherein one or more of the predisposing factors turn the patient in need of treatment with a medication antiepileptogenico (a AEGD) are selected from the group consisting of closed head trauma or penetrating neurosurgical procedures, carotidia stenosis, stroke or other cerebrovascular accidents (CVA), status epilepticus and lesions occupying spaces of the CNS
9. 9 -. 9 - The use as claimed in claim 1, wherein one or several predisposing factors are closed head trauma or penetrating head trauma or a neurosurgical procedure
10. 10 - The use as claimed in claim 1, wherein one or more spans of predisposing factors are stroke, other stroke (CVA), presence of carotid stenosis or transient ischemic attacks 1 1 Use as claimed in claim 1, wherein the predisposing factor is status epilepticus 12 The use of a compound that is selected from the group consisting of (2S) - (-) - N- (6-chloro-2,3-d? h? drobenzo [1,4] d? ox? n-2-? lmet? l) - sulfam? da, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament useful for treating epileptogenesis in a patient 13 The use as claimed in claim 1 2, wherein one or several predisposing factors that make a patient in need of treatment with a medicament or antiepileptogenico (a AEGD) are selected from the group consisting of damage or trauma of any kind to the CNS, neurosurgical procedures, activities where the SNC is put at risk of harm, for example combat activities, car or horse races and contact sports that include boxing, spinal cord trauma, CNS infections, anoxia, stroke (CVA), history of transient ischemic attacks (TIA), carotid stenosis, history of artherosclerotic disease, history of pulmonary embolisms; peripheral vascular disease; autoimmune diseases affecting the CNS, for example lupus, damage at birth, for example, asphyxia pennatal, cardiac arrest, therapeutic or diagnostic vascular surgical procedures, for example endarterectomy carotidia or cerebral angiography, hypotension, damage to the CNS of embolism, hyperperfusion or hypoperfusion , hypoxia, known genetic predisposition to disorders known to respond to AEGD, lesions occupying CNS spaces, brain tumors, for example ghoblastomas, bleeding or hemorrhaging into or surrounding the CNS, for example intracerebral hemorrhages or subdural hematomas, cerebral edema, seizures febrile, hyperthermia; exposure to toxic or poisonous agents, drug intoxication or suspension of drugs, for example cocaine, methamphetamine or alcohol, family history of epileptic seizure disorders or a neurological disorder similar to epileptic crisis related to epilepsy or an epileptic seizure-related disorder, history of status epilepticus; current treatment with drugs that lower the epileptic seizure threshold, for example lithium carbonate, thoracine or clozapine, substitute markers test or biomarkers that the patient is in need of treatment with an antiepileptogenic drug, for example MRI scan showing sclerosis of hippocampus, elevated serum concentrations of neuronal degradation products, high concentrations of ciliary neurotrophic factor (CNTF) or an EEG suggestive of epileptic seizure disorders or a neurological disorder similar to seizures epileptic related to epilepsy or an analogous disorder related to epileptic seizure 14 The use as claimed in claim 12, wherein one or more of the predisposing factors that make the patient in need of treatment with an antiepileptogenic drug (an AEGD) is they select from the group consisting of closed or penetrating head trauma, neurosurgical procedures, carotid stenosis, stroke or other cerebrovascular accidents (CVA), epileptic status and lesions occupying spaces of the CNS 15 - The use as claimed in claim 12, wherein one or more predisposing factors are closed head trauma or penetrating head trauma or a neurosurgical procedure 16 - The use as claimed in claim 12, wherein one or more of the predisposing factors are stroke, another stroke (CVA), presence of carotid stenosis or transient ischemic attacks os 17 Use as claimed in claim 12, wherein the predisposing factor is status epilepticus 18 - The use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament useful for treating epileptogenesis in a patient 19 - The use as claimed in claim 1, wherein the patient has not developed epilepsy at the time of administration 20 - The use as claimed in claim 1, wherein the patient is at risk of developing epilepsy at the time of administration 21 - The use as claimed in claim 12, wherein the patient has not developed epilepsy at the time of administration 22 - The use as claimed in claim 12, wherein the patient is at risk of developing epilepsy at the time of administration