MXPA01001326A

MXPA01001326A - Remedies or preventives for intractable epilepsy

Info

Publication number: MXPA01001326A
Application number: MXPA/A/2001/001326A
Authority: MX
Inventors: Mitsunobu Yoshii; Tatsuya Tanaka; Akira Takazawa; Yoshiya Murashima
Original assignee: Daiichi Pharmaceutical Co Ltd
Priority date: 1998-08-06
Filing date: 2001-02-02
Publication date: 2001-12-13

Abstract

Remedies and preventives for intractable epilepsy which contain as the active ingredient compounds represented by the general formula (I):R2-CH2-CONH-R1 wherein R1 represents optionally substituted pyridyl or phenyl;and R2 represents optionally substituted 2-oxo-1-pyrrolidinyl.

Description

AGENTS TO ALLEVIATE AND PREVENT INTRATABLE EPILEPSY TECHNICAL FIELD The present invention relates to a therapeutic or preventive agent for intractable epilepsies, among others, which are difficult to prevent or treat with the existing antiepileptics.

ANTECEDENTS OF THE TECHNIQUE Epilepsy is a chronic brain disease in which epileptic seizures are the predominant feature. Generally, most epilepsies and diseases associated with it are difficult to treat, since epilepsies do not have a clear etiology. Thus, the administration of an antiepileptic agent is a common approach towards the suppression of epileptic seizures or the inhibition of the spread of focal seizures to other portions. Currently, more than 10 types of antiepileptic agents are available in Japan. Even many different intractable epilepsies can not be successfully suppressed by antiepileptic agents, including attacks known as "therapy resistant" and cases where compliance with the prescribed drug regimen can not be achieved due to side effects, despite satisfactory suppression. of the attacks Thus, there is still a demand for an antiepileptic agent that is more effective than existing ones and exhibits fewer collateral effects and less seriousness (see "Mechanismus of Action Antiepileptics," Clinical Psychiatry Courses, Nakayama-Shoten, by Akira TAKAZAWA , et al.). Therefore, an object of the present invention is to provide an effective pharmaceutical agent for intractable epilepsies or an attack associated therewith, for which existing antiepileptic drugs have not shown satisfactory efficacy.

DESCRIPTION OF THE INVENTION The present inventors have made extensive studies and have discovered that a pyrrolidinyl alkylcarboxylic acid amide derivative represented by the formula (I) functions as a pharmaceutical which is effective in the treatment or prevention of intractable epilepsies. The present invention has been achieved based on these findings. In this manner, the present invention provides a therapeutic or preventive agent for an intractable epilepsy or an attack associated therewith which comprises as an active ingredient a compound represented by the following formula (I) R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents which may be identical or different from each other and which are selected from an alkyl group of C-1-C3 and a hydroxyl group, and R2 is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents, wherein said one or more substituents may be identical or different from each other and are selected from a halogen atom, a hydroxyl group and a C1 alkyl group -C3; a salt of them; or a hydrate of the compound or salt. The present invention also provides an inhibitor that limits an motor attack associated with an epilepsy (in terms of duration of an epileptic symptom); an inhibitor of the spread an epileptic attack; and a therapeutic or preventive agent for epilepsy having a function of raising the threshold of induction of the attack, each of the three mentioned types of agents comprises as active ingredient a compound represented by the formula (I), a salt thereof, or a hydrate of the compound or salt. The present invention provides the use of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt, to produce a therapeutic or preventive agent for an intractable epilepsy or an attack associated therewith. The present invention also provides the use of a compound represented by the following formula (I); a salt thereof; or a compound hydrate or salt, to produce a suppressant that limits an motor attack associated with an epilepsy (in terms of duration of a symptom epileptic); a suppressor of the spread of an epileptic seizure and a therapeutic or preventive agent for epilepsy having a function of raising the threshold of attack induction. The present invention provides a method for treating an intractable epilepsy or an attack associated therewith through the administration of a compound represented by the following formula (I); a salt thereof or a hydrate of the compound or salt. The present invention also provides a method of treatment for inhibiting an motor attack associated with an epilepsy (in terms of duration of an epileptic symptom); a method of treatment to prevent the spread of an epileptic seizure; and a method for treating epilepsy that involves the function of raising the threshold for induction of attack, by administering a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt.

DETAILED DESCRIPTION OF THE INVENTION The substituents in the formula (I) will be described below. R1 represents a pyridyl group, a substituted pyridyl group, a phenyl group or a substituted phenyl group. Of these, a phenyl group or a substituted phenyl group is preferred as R1. The substituent (s) for a phenyl group can be identical or different from each other and are selected from a C 1 -C 3 alkyl group, a halogen atom, and a hydroxyl group. Of these, prefers a methyl group and a hydroxyl group. Additionally, two methyl groups or a combination of two methyl groups and one hydroxyl group is preferred, and the preferred positions of substitution are the 2- and 6- positions of a phenyl group. In this way, a particular preference is given to a 2,6-dimethyiphenyl group. The substituent (s) for a pyridyl group can be identical or different from each other and are selected from a halogen atom, a C 1 -C 3 alkyl group, an acyl group, etc. R2 is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents. The substituent (s) can be identical or different from each other selected from a halogen atom, a C 1 -C 3 alkyl group and a hydroxyl group. Of these, special preference is given to the hydroxy-substituted-2-oxopyrrolidinyl group and the 2-oxopyrrolidinyl group. A typical example of the compound represented by the formula (I) is N- (2,6-dimethylphenyl) -2- (2-oxo-1-pyrrolidinyl) acetamide (generic name: nefiracetam), a salt thereof and a hydrate of the compound or salt. A process for producing nefiracetam has been described in the Japanese patent application that remains open (kokai) Nos. 56-2960, 61-280470, and 6-65197. Nefiracetam finds pharmaceutical use, for example as a cerebrovascular agent to mitigate dementia (Japanese patent application open to the public (kokai) No. 56-1631450), an agent to mitigate Alzheimer's type dementia (Japanese patent application open to the public (kokai) No. 5-163144), or a stabilizing agent for the membrane mitochondrial (Japanese patent application No. 8-260649). The mechanism of operation of nefiracetam is partially described in Japanese patent application No. 9-249131. An antiepileptic action provided by nefiracetam has already been investigated using a test using EL mice as models, and potential use as an antiepileptic agent is indicated (XVII Convention of the Society of Japanese Neuroscience, 3i, 1993, XXIII Society for Neuroscience, 1993 , 11, and XXVI Society for Neuroscience, November 16, 1996, Washington DC). The model of epilepsy using EL mice tested in previous reports is a model of epilepsy caused by a congenital genetic disposition formed through mutation. The model exhibits a secondary generalization evoked by the perception of an attack and stupor after a tonic or clonic seizure. An electroencephalogram of the model shows characteristic changes corresponding to the mentioned states. further, the model of epilepsy is a genetic model, to function in this way as a useful model for the investigation of epileptic states induced by genetic disposition. However, no clinically defined type of epilepsies in humans corresponds to the EL mouse model, although the efficiency of the pharmaceutical agent to suppress epilepsy is easily obtained for EL mice through the administration of a pharmaceutical agent in a low dose. Therefore, the pharmaceutical agent is not always clinically effective for humans, although efficacy has been proven for EL mice. Particularly, because a clinical effect of a pharmaceutical agent in human intractable epilepsy still involves an unknown point, the model is not suitable for the evaluation of the prospective clinical effect. In view of the foregoing, the present inventors have conducted formal studies, and have found that the compound represented by the formula (I), suppresses not only the focal attack, but also a generalized secondary attack in a model of focal epilepsy, which has presented a complicated treatment by the use of a conventional therapeutic agent. Thus, an objective of the present invention is to provide a suppressor for focal epilepsies; a suppressor for secondary generalization; and a therapeutic or preventive agent for intractable epilepsies. In this manner, the present invention relates to a therapeutic or preventive agent for intractable epilepsies. First, an explanation of "intractable epilepsy" will be given below. The characteristics of intractable epilepsy include 1) a high incidence of partial seizure followed by a generalized seizure (particularly temporal lobe epilepsy); 2) a high incidence in symptomatic epilepsy caused by a lesion in the brain; 3) a long term with no treatment from the beginning to the consultation of a specialist and a high incidence of attacks; and 4) a high incidence of epileptic states in the anamnesis. In other words, the temporal lobe It is probably a portion of the brain responsible for intractable epilepsy. It is indicated that epilepsy becomes more intractable changing the nature of it and evolving while repeated attacks are acquired. The intractable epilepsy is classified into three clinical types, ie, a) epilepsies and syndromes related to the location, b) epilepsies and generalized syndromes, and c) epilepsies and syndromes not determined, either focal or generalized. Examples of (a) epilepsies and syndromes related to location include temporal lobe epilepsies, frontal lobe epilepsies, and multiple-lobed epilepsies. Temporal lobe epilepsies and frontal lobe epilepsies are typical examples of intractable epilepsy. Epilepsies in several lobes are considered to be caused by two or more lobes. Examples of (b) epilepsies and generalized syndromes include Lennox-Gastaut syndrome, West syndrome, and myoclonic syndrome. Examples of (c) epilepsies and syndromes not determined, either focal or generalized, include severe myoclonic epilepsy in childhood, which exhibits a variety of types of attacks. In particular, tonic-clonic seizures occur frequently, thus leading to an epileptic state. Thus, a special treatment indicated by a specialist for the treatment of epilepsy is of great importance (Masako WATANABE, et al., Igakuno Ayumi, 183 (1): 103-108, 1997).

Attacks associated with intractable epilepsy are classified into a variety of types, for example, tonic attacks, tonic-clonic seizures, atypical absence attacks, stunned attacks, myoclonic attacks, clonic seizures, partial simple seizures, partial complex seizures, and secondary seizures. generalized Among these, special attention should be paid to tonic and atonic attacks with respect to injuries resulting from falls. In addition, partial complex attacks can cause an accident caused by the behavior during the alteration of consciousness. In intractable epilepsies, "partial complex attacks" associated with temporal lobe epilepsies and frontal lobe epilepsies occur with a relatively high frequency in adults. Although such attacks occur with a low frequency in children, the attacks are also intractable in the case of adults (Progress of Epileptology, No. 2, Haruo AKIMOTO and Toshio YAMAUCHI, Iwanami Gakujutsu Shuppan, 1991, pages 51-85). In the present description, the term "intractable epilepsy" refers to epilepsies or attacks associated with it corresponding to the following four types of epilepsy or attack associated with it: 1) difficult to treat epilepsies where the suppression of attacks associated with it does not can be controlled through a conventional pharmaceutical treatment (Masako WATANABE, et al., Igaku-no Ayumi, 183 (1): 103-108, 1997; 2) epilepsies corresponding to the following types (a) to (c): a) epilepsies related to the location, such as temporal lobe epilepsies and cortical epilepsies; b) generalized epilepsies and syndromes such as Lennox-Gastaut syndrome, West syndrome and myoclonic epilepsy; c) epilepsies and syndromes not determined, either focal or generalized, such as severe myoclonic epilepsy in childhood; 3) attacks associated with the intractable epilepsies described above, including tonic attacks, tonic-clonic attacks, atypical absence attacks, atonic attacks, myoclonic attacks, clonic attacks, partial simple attacks, partial complex attacks and generalized secondary attacks; and 4) epilepsies such as epilepsies after brain surgery, traumatic epilepsies and recurrent epilepsies after surgery for epilepsy. The antiepileptic agent of the present invention is effective for the four mentioned types of intractable epilepsies. Of these, the anti-epileptic agent of the present invention is particularly effective for the location-related epilepsies corresponding to (2) (a); attacks such as generalized secondary attacks, partial complex attacks and epileptic states corresponding to (3) and epileptic states; and epilepsies after brain surgery, traumatic epilepsies and recurrent epilepsies after an epilepsy surgery corresponding to (4). The antiepileptic agent of the present invention has an effect possibly excellent with epilepsies such as epilepsies related to location, temporal lobe epilepsies and cortical epilepsies. "Temporal lobe epilepsy," which is a type of intractable epilepsy, will be described below. Temporal lobe epilepsy is an epilepsy that has a focus of attack in the temporal lobe and is classified in the context of symptomatic epilepsies and related to the location, which also includes epilepsies of the frontal lobe, epilepsies of the parietal lobe, epilepsies of the lobe occipital, based on the international classification of epilepsies. The temporal lobe epilepsy syndromes vary according to a site of localized focus and type of spread of attacks, in which the temporal lobe has an anatomically complex structure including the neocortex, allocortex, and paleocortex. Temporal lobe epilepsy, as previously defined as psychomotor attack primarily causes partial complex attacks such as clinically observed seizures, and also causes simple partial seizures, generalized secondary seizures, and combinations of seizures. Simple partial attacks include autonomic and mental symptoms and symptoms related to the senses such as smell, hearing or vision, sometimes they are concomitant with symptoms of experience such as deja-vu and jamais-v ?. Partial complex attacks often present a halt in movement followed by automatism in the eating function, and are divided into amygdala-hippocampal attacks and seizures.

Temporary lateral lobe in accordance with the location. In the case of epilepsy of the temporal lobe, from 70 to 80% of the attacks are hippocampal attacks, where aura, high movement, lip automatism and loss of consciousness are presented successively until amnesia is reached. When the focus is in the amygdala, autonomic symptoms such as dysphoria in the epigastrium, phobia and olfactory hallucination are caused. Attacks of the lateral temporal lobe include auditory illusion, hallucinations and a state of drowsiness, and alterations in speech when the focus is on the dominant hemisphere. Temporal lobe epilepsy exhibits a state similar to long-term psychosis in addition to other symptoms and recognition and memory disorders more frequently than other epilepsies (Medical Dictionary, Nazando). The treatment of temporal lobe epilepsy is carried out through pharmacotherapy using a maximum dose of a combination of drugs or through surgical treatment. "Bark epilepsy," which is a type of intractable epilepsy, will be described below. Bark epilepsy is an epilepsy that has a focus in the cerebral cortex and is classified as symptomatic epilepsy that belongs to epilepsies and location-related syndromes (focal) in the international classification of epilepsy. In the international classification, attacks associated with bark epilepsy are classified as partial simple attacks, which are particular attacks without diminished consciousness. In this way, an electroencephalogram taken during an attack associated with epilepsy of Bark (not always recorded on the scalp) exhibits a contralateral electrical shock located from the corresponding cortical field. The ratio of attacks associated with bark epilepsy to the completeness of attacks associated with epilepsies is approximately 15%, and about 2/3 of them are focal motor attacks including Jacksonian attacks (Wada et al.). Bark epilepsies are mainly caused by a brain tumor, a side effect of a cephalothorax, etc; or damage during a perinatal period (Medical dictionary, Nazando). Based on the focus, bark epilepsy is classified as temporal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy. The "traumatic epilepsy" which is a type of intractable epilepsy will be described below. Traumatic epilepsy in a broad sense, is divided into two epilepsies, ie, "early epilepsy" and "late epilepsy." "Early epilepsy" is caused by seizure-induced brain stimulation within a week of suffering from a trauma, and is not a true epilepsy. In contrast, "late epilepsy" is a real epilepsy that is caused within one or more weeks after suffering from a trauma. Japan produces between 100,000 and 200,000 candidates for traumatic epilepsy per year (Shinya MANAKA, Kyukyu Iryo, 17: 1076-1077). Most traumatic epilepsies are caused by the formation of a focus of a traumatically damaged portion of the cortex if they are considered to be typical examples of partial epilepsies. This Thus, the treatment of it is mainly based on a pharmacotherapy that is generally used for the treatment of epilepsy. However, because the onset and procedure of individual symptoms are diverse, in many cases epilepsy becomes treatable by administration of an antiepileptic agent, as reported by Nihon Saigai Igakukai Kaishi, 32 (6): 453-460, 1984. Meanwhile, the surgical treatment that has been used to treat currently untreatable symptoms in which the control of an attack is difficult (Yoshifumi MATSUMOTO, Neurotraumatology, 17: 101-106, 1994). "A generalized secondary attack" which is one of the symptoms associated with intractable epilepsy, will be described below. The generalized secondary attack is a type of partial attack, which exhibits a clinical syndrome and a characteristic in the electroencephalogram observed as the excitation of the neurons that shows the beginning of an attack in a limited portion of a cerebral hemisphere. The generalized secondary attack begins as a simple partial attack (without deterioration of consciousness) or a partial complex attack (with deterioration of consciousness), and develops into a general convulsion induced through secondary generalization. The main symptom of this is the seizure as a tonic / clonic attack, a tonic attack or a clonic attack (Kazuyoshi WATANABE, the 22nd Nou-no Igaku Seíbutsugaku Kenkyuukai, 1997. 1. 18).

"A partial complex attack," which is one of the symptoms associated with intractable epilepsy, will be described below. The partial complex attack refers to a partial attack with deterioration of consciousness, and is similar to an attack that has conventionally been called psychomotor or an attack associated with temporal lobe epilepsy. In the International classification project (1981), the partial complex attack is defined as an attack "with deterioration of consciousness exhibiting an electroencephalogram during an attack, in which a unilateral or bilateral electrical discharge is attributed to a focus in a diffuse portion. or a temporary or frontal-temporal ". Currently, the neuromechanism responsible for previous type of attacks is considered to include the amygdala, the hippocampus, the hypothalamus, the parolfative cortex, etc., in addition to the frontal and temporal lobes. Typically, attacks last between 1 and 2 minutes or a little longer, and the start and end of the attack are not abrupt, but gradual. Examples of partial complex attacks include (1) attacks with reduced consciousness (gradually evolving deterioration of consciousness, interruption of movement, speech and reaction, and amnesia); (2) cognitive attacks (deja-vu, jamais-vu, ideas attacks); (3) emotional attacks (fear, anger, emptiness, strangeness, joy, joy); (4) psychosensory attacks (visual, auditory, gustatory, olfactory, and kinesthetic hallucinations); and (5) psychomotor attacks (autonomatism, licking lips, chewing, stereotyping). The onset of attacks can be observed mainly between and 25 years of age, but can occur at any age (Epilepsy, Nihon, Bunkakagaku-sha, 49-51, 1996, edited by Haruo AKIMOTO). The "status epilepticus", which is a type of intractable epilepsy, will be described below. In the epileptic state consciousness is not amenable to rehabilitation during an attack associated with epilepsy that lasts for 30 minutes or more or is repeated. Any type of attack can evolve to an epileptic state. The most common case is a tonic-clonic attack and the status epilepticus is fatal and should be treated immediately. In many cases the suspension of an antiepileptic agent induces an epileptic state. In this way, an antiepileptic agent is administered intravenously while the disorder in the central nervous system and the conditions of the whole body are monitored and controlled, and the elucidation of the cause and treatment thereof advances (Nanzando, Medical Dictionary). As it is already known that an epileptic seizure causes intractable epilepsy, an immediate and adequate action is required for the diagnosis and first aid of a seizure in an epileptic state. The suppression of a seizure in the first stage is an important key for subsequent care (Teruyuki OGAWA, Clinical Pediatrics; 47 (12): 2673-2681, 1994). Clinical models for intractable epilepsy in humans are produced through the use of animals. Examples of such animal models they include an "ignition" model and a model of "attacks induced by Kainic acid". Next, the "ignition" model that functions as a model for intractable epilepsy will be described. When a weak electrical stimulus is applied to a certain portion of the brain repeatedly at intervals, an evolution from a partial attack to a generalized attack is observed. This phenomenon is called ignition. The epileptic origin is formed in the brain while the ignition lasts a long time after interrupting the stimulus and sometimes causes a spontaneous epileptic seizure. Although the ignition is a long-term phenomenon, a large-scale morphological change of the brain has not been found. In this way, the ignition model functions as a typical experimental model for epilepsy where a non-specific epileptic origin is acquired that does not involve damage to brain tissue and persists for a long time. By using such a model, a process of potentiation of acquired epileptic origin in relation to intractable epilepsy can be investigated, and investigation of specific pathological stages such as the initiation, continuation and interruption of attacks can be carried out; a stage after the attack, and a stage of absence of attacks (Mitsumoto SATO, the 22 th Igaku Seibutsugaku Kenkyuukai, summary of readings, 1997. 1. 18). A variety of epilepsy models can be produced from an ignition model, where a portion of stimulation can be selected. The most sensitive portion is the amygdala, which is stimulated repeatedly at a later discharge threshold (minimum stimulation intensity) (generally one daily), to present attack stages as indicated below: stage 1 (chewing); stage 2 (tilt the head); stage 3 (upper extremities clonus); stage 4 (stand up); and stage 5 (stand up and fall). Stages 1 and 2 correspond to a partial complex attack of human epilepsy of the temporal lobe, and stages 3 to 5 are considered as stages of a generalized secondary attack. Stage 5 is observed as an ignition establishment stage. Once ignition is established, the susceptibility to electrical stimulation is maintained almost for life. Ignition is similar to human epilepsy, not only in terms of attack symptoms, but also in the evaluation of an effect of an antiepileptic agent and the like. This way of lighting is a useful means to understand the epileptic phenomenon by using an ignition model that has a focus on the limbic system or on the cortex, a variety of phenomena can be ensured, for example, an effect on an attack partial; an effect at a stage of development from a partial attack to a generalized secondary attack; its mechanisms of action (such as the action for the acquisition of epileptogenesis, and a neuromechanism in relation to the generalization of an attack in the limbic system); and an effect on clinical symptoms. A pharmaceutical effect during an ignition development process toward the establishment of a generalized attack is called a "prevention effect", which is evaluated by an effect of prevention of a pharmaceutical agent on the acquisition of epileptogenesis. A pharmaceutical effect during an ignition development process that involves repeated stimulation after the establishment of a generalized attack is called "therapeutic effect" (Juhn A. Wada, Mitsumoto SATO, and Kiyoshi Morimoto, Neuroscientific Mechanism of Epilepsy Studied with a Kindling Model, p 225-241, 1993). In this way, an ignition model is known as an excellent animal model for temporal lobe epilepsy resistant to treatment with a partial complex attack, a generalized secondary attack of a human. The inventors of the present invention have studied the effects of nefiracetam in a procedure of development of amygdaloid attacks of ignition and on the establishment of the ignition through a method described below, and have determined the efficacy of nefiracetam. The ignition evolution process is tested using rats, in which electrodes are placed in the amygdala and firing stimulation is applied (50 Hz sinusoidal waves, one second duration, once a day) at specific intervals for recovery. On the first day, a subsequent discharge - challenge threshold is determined without the administration of a pharmaceutical agent. From the second day on, the stimulation of ignition having the intensity of subsequent discharge - threshold of provocation is applied to the rats administered with a specimen in a variety of administration doses, to investigate thus an effect of the specimen in the evolution process of ignition.

The use of nefiracetam as a specimen under such conditions enabled investigation of the effect of nefiracetam on parameters such as an attack stage and duration of subsequent discharge on a stimulated side of the amygdala during a spread of amygdala firing attack. The results of such investigation revealed that a group of rats given nephiracetam in an amount of 180 mg / kg included a number of rats that did not reach stage 5 even though the duration of the subsequent discharge was extended, and that a group of rats given nefiracetam in an amount of 90 mg / kg exhibits a stable inhibition of induction from stage 5. Although typically the "subsequent discharge threshold" is expected to decrease with the evolution of the ignition, Importantly, approximately half of the rats given nephracetam in an amount of 90 mg / kg exhibited a surprise increase in the threshold of subsequent discharge in a process from stage 3 to stage 5. Afterwards, the effects of nephiracetam in an establishment of amygdala firing attacks were investigated with respect to the attack stage, the duration of subsequent discharge and duration of motor attack, as indicated. To further clarify the response to the pharmaceutical agent, the intensity of the firing stimulation was used 1 to 3 times that of the generalized attack threshold (GST) where stage 5 is constantly being developed.

The results of such investigation revealed that the administration of nefiracetam (120 mg / kg) exhibits a strong and strong suppression effect in all parameters under the intensity equivalent of GST stimulation. In the case of a group of rats stimulated in a double GST intensity equivalent, a parameter in relation to the duration of the subsequent discharge was restored to a level value without administration, and the attack stage and duration of the motor attack they were suppressed in an important way. In the case of a group of rats stimulated with a triple GST intensity equivalent, the duration of the subsequent discharge was restored, and a tendency towards the restoration of the attack stage and the duration of the motor attack was proved. As described above, the effects of nephracetam depend on the intensity of the stimulation. Thus, the effect on the suppression of an ignition attack is indicated that involves two factors, ie the increase of the threshold subsequent to the discharge to an attack inducing portion and the suppression of the spread of the attack to the whole brain. An antiepileptic action of the compound represented by formula (I) was investigated by using another model, "attacks induced by kainic acid (model of kainate)", functioning as a model for intractable epilepsy. The kainate model is an epileptic model in which kainic acid, which is one of the exciting amino acids found in the brain, is injected into the nucleus (amygdala, hippocampus, etc.) in the system limbic in a micro-quantity to induce focal epilepsy. The model of kainate works as a model for an epileptic seizure; particularly, as a model for the epileptic state induced from the limbic system in the acute phase, and as a model for the evolution of a spontaneous limbic attack to a generalized secondary attack in the chronic phase. In this way, the kainate model is recognized as a model for intractable epilepsy. In addition, the model is also used as a model for intractable human temporal lobe epilepsy in which the model satisfies the following conditions: a) existence of a focus of epilepsy in the tissue (amygdala, hippocampus, etc.) in the limbic system; b) change in the tissue equivalent to hardening of the hippocampus; c) repeated and continuous development of the spontaneous partial complex attack (attack of the limbic system); and d) no therapeutic effect provided by a usual pharmaceutical agent (edited by Tatsuya TANAKA, Frontier of Epileptic Research, page 14, 1994, Ist Japan Winter Conference on Brain Research, Life-Science Publishing). The kainate model can also be used as a model of bark epilepsy by injecting kainic acid into the cortex (sensorimotor field). Additionally, since local blood flow increases during an epileptic seizure, the correlation between glucose metabolism during limbic system status epilepticus and local brain blood flow can be investigated by autoradiography with the use of the model, and an effect The epileptic seizure in cell damage can also be investigated.

Although the mechanism of attack development in the kainato model has not been completely elucidated, the following mechanism is proposed. That is, a proposed mechanism comprising a) the continuation of epileptic stimulation induced by the abnormal accumulation of glutamate due to the binding of kainate to the glutamate receptors; b) the synergy of kainate and glutamate released from presynaptic terminals; and c) the release of a toxic amount of glutamate or aspartate due to the stimulation of the kainate receptors contained in the presynapses (edited by Tatsuya TANAKA, Frontier of Epileptic Research, page 18, 1994, 1st Japan Winter Conference on Brain Research, Life -Science Publishing). Along with clinical epileptic symptoms, the kainate model corresponds to a model for intractable temporal lobe epilepsy (injection to the amygdala or hippocampus) and to a model for intractable cortex epilepsy (injection in the sensory motor field (Tatsuya TANAKA, BIO Clinical, 11 (9), 695-697.) The excellent antiepileptic action of nefiracetam has been proven through the injection of rats of the kainate model, one of the models of intractable epilepsy.A high dose of nefiracetam clinically suppressed the attack of amygdala induced by kainate and an attack of focal cortex, and the suppression of observed in an electroencephalogram.The degree of suppression is greater in relation to the attack of focal cortex.The model of kainate identical, proves that the administration of nefiracetam suppresses hypermetabolism in the brain and the spread of an attack from a focus. suppression is greater in the cortex. Since the nefiracetam depending on the dose suppressed the propagation of the hypermetabolism related to the attack, the mechanism of nephiracetam attack suppression is based on the suppression of the attack propagation. Additionally, the above action corresponds to an action suppressing glucose metabolism in the brain predominantly in the cortex, where the nefiracetam exhibits a sedative action to the rats. Kainic acid, a strong neuroextracting amino acid, is known to induce a seizure attack through systemic administration or local administration to the brain. The injection of kainic acid in a micro-quantity on one side of the amygdala of an animal, like a cat or rat, induces the epileptic status of epilepsy of the limbic system in an acute phase and an attack of the spontaneous limbic system in a chronic phase, to thus make a model for epilepsy similar to epilepsy of the human temporal lobe. The status epilepticus of an amygdala attack induced by kainate in a water phase is very serious, and only a high concentration of zonisamide among the known antiepileptic agents has proven a suppression effect. Nefiraceam exhibited a suppression effect on the amygdala attack induced by kainate in a dose as high as 200 mg / kg. However, the suppression effect was temporary and lasted for a few minutes or hours, and an attack appeared again. Meanwhile nephracetam exhibited a significant suppression effect in a focal barium attack induced by kainate for all rats tested through the administration in an amount of 100 mg / kg, and the suppression of attack was maintained immediately after the administration of nefiraceam so that the attack never appeared again. In this way, nefiracetam revealed that it exhibits a suppression effect in the amygdala attack induced by kainate and a focal barium attack induced by kainate, and the suppression effect revealed to be stronger in a focal cortex attack. In addition, in both models, the nephracetam was injected intravenously to rats to provide sedation, and algodiafolia and callasia were observed in the rooms. This indicated that nefiracetam suppresses functions throughout the cortex. Additionally, research regarding the change in local glucose metabolism during an attack revealed that administration of nefiracetam in an amount of 100 mg / kg decreases glucose metabolism throughout the brain in the case of a tonsil attack and in the case of a focal cortex attack. Particularly, the glucose metabolism decreased to below a normal level in portions of the cortex and basal ganglia on the non-focal side. When the dose of nefiracetam was increased, the evolution of a domain of hypermetabolism with spread of attacks was suppressed dependent on the dose. A domain of hypermetabolism was limited in one focus in the amygdala through administration of 200 mg / kg. Such effects on glucose metabolism during an attack indicated that nephiracetam suppresses the spread of an attack. In addition, the source of suppression of Cerebral glucose metabolism and basal ganglia indicated that nefiracetam is more effective in the ratio of a focal attack of the cortex than in relation to a systemic limbic attack, as shown by observing an electroencephalogram. A sedative action nefiracetam at a high concentration is considered to be attributed to an affinity thereof to the cortex. The manner of administration of the antiepileptic agents for the intractable epilepsies of the present invention is not particularly limited and the agents may be administered to humans perorally or parenterally. The newly described compound represented by the formula (I), an active ingredient of the pharmaceutical agents of the present invention, can be administered directly. However, typically, a pharmaceutical composition that is prepared by use of the compound represented by formula I and one or more pharmaceutically acceptable additives is preferably administered perorally or parenterally. The dosage of the pharmaceutical agent of the present invention is not particularly limited, and is suitably selected in accordance with the manner of administration, severity of a symptom of epilepsy or attacks, frequency of attacks, purpose of administration, for example preventive or therapeutic , and patient's age and weight. For example, the daily dose of the compound represented by the formula (I) for an adult is 200 to 2000 mg, preferably about 300 to 900 mg, and the daily dose can be divided. The separation of the administration of the pharmaceutical agent from the The present invention can also be suitably selected. If the pharmaceutical agent is administered before the onset of epileptic symptoms or attacks, they function as an antiepileptic agent. Examples of the manner of formulation suitable for peroral administration include tablets, capsules, powders, granules, liquids and syrups. Examples of the formulation form suitable for parenteral administration include subcutaneous, intravenous and intramuscular injections; drops, inhalants, percutaneous or permucosal absorption formulations; suppositories and cataplasms. Examples of pharmaceutically acceptable additives include excipients, disintegrants, disintegration aids, binders, lubricants, coatings, dyes, diluents, bases, solubilizers or solubilization aids, sotonic agents, pH regulators, propellants and tackifiers. For example, pharmaceutically acceptable additives can be incorporated into formulations suitable for peroral and percutaneous administration or permucosal administration. Examples of the additives include excipients such as glucose, D-mannitol, starch and crystalline cellulose; disintegrators or disintegration aids such as calcium carboxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and gelatin; lubricants such as magnesium stearate and talc; coatings such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol and titanium oxide; and base as Vaseline, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water and hard fat.

Additionally, the formulations can be produced by the incorporation of propellants such as fron, diethyl ether and compressed gas. Adhesion agents such as sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene and polybutene; and base fabric such as cotton fabric and plastic sheets. Additives for the formulation can be incorporated into formulations suitable for injection and drops, for example, solubilizers or solubilization aids that function as a component of injections that are aqueous or should be made soluble before use. Examples thereof include distilled water for injection, sodium chloride for injection and propylene glycol. Sotonic agents such as glucose, sodium chloride, D-mannitol and glycerin and pH regulators such as organic and inorganic acids and organic and inorganic bases can also be added. Nefiracetam, a typical pharmaceutical agent of the present invention has an acute toxicity of 2,005 mg / kg (in male mice, peroral administration) and therefore, it is very safe (Japanese patent application open to the public (kokai) No. 5- 163144).

EXAMPLES The present invention will now be described in greater detail by way of example, which should not be construed as limiting the invention.

Method for preparing an ignition model Wistar male rats (weight: 200-250 g, Tokyo Jíkken Dobutsu) were used, and pentobarbital anesthetic agent (50 mg / kg, Dinabot) and ketamine (50 mg / kg, Sankyo Co was used ., Ltd). Each anesthetized rat was placed in a stereotactic apparatus (type SR-6, Narishige Ikakiki K.K.), and the scalp of the rat was removed to expose the cranial bone. A small incision was made in the cranial bone using an electric drill (model C-201, Urawa Kohgyo K.K.). Subsequently, in accordance with the brain atlas of Paxinos, G., Watson, C. (The rat Brain in Stereotaxic Coordinators, Academic Press, New York, 1986), an electrode for chronic stimulation and registration (made of stainless steel with Teflon coating, with an outer diameter of approximately 250 μm, Nippon Koku Denshí) was implanted in the amygdala (shown on the left side of the brain atlas), and fixed firmly on the cranial bone using dental glue to prevent disconnection of the same. Subsequently, after a recovery period of one to two weeks an ignition stimulation was initiated. An ignition stimulation was performed during a second diary with an intensity of 200 μA with a 50 Hz sine wave. The apparatus that was used for electrical stimulation is produced by Nihon Kohden Kogyo Co .; Cat No. 8-6207A.). A rat that exhibited an attack in stage 5 for 3 or more consecutive days was considered a fully "lit" rat. The generalized attack threshold (GST, for its acronym in English) where stage 5 of Attack was shown constant was obtained from each of the fully ignited rats.

EXAMPLE 1 A dose response of nefiracetam (15-180 mg / kg) with respect to an ignition attack induced a stimulation intensity of GST was evaluated in terms of the following parameters: stage of attack and duration of subsequent discharge in the stimulated amygdala and duration of motor attack. The results are shown in tables 1 to 3. In accordance with the method of Racine et al. (Modification of Seizure Activity by Electrical Stimulation: Seizure II Motor, Electroencephalograpy Clin Neurophysiol, 1972. 32: 281-294), the attacks were classified into the following five stages: stage 1 (chewing); stage 2 (tilt the head); stage 3 (upper extremities clonus); stage 4 (stand up) and stage 5 (stand up and fall). The duration of the motor attack (seconds) was represented by the total duration of stages 3 to 5. Stage 1 or stage 2 is an attack symptom of the limbic system, and stage 3, 4 or 5 is observed as a motor attack (Sato, M. Racine, RJ, McIntyre, D.C., Kindlin: basic mechanisms and clinical validity, Electroencephalography Clin.Neurophysiol., 1990, 76: 459-472).

The duration of the subsequent discharge (seconds) was recorded with the use of a recording electrode and was represented by the attack-discharge duration shown on an electroencephalogram, which is induced by an ignition stimulation. Nefiracetam was dissolved in a solvent (0.5% carboxymethylcellulose) and the solution was administered orally 90 minutes before stimulation of GST, where the amount of nefiracetam was classified in various stages within a range of 15 to 180 mg / kg.

TABLE 1 Effect of nephiracetam in stages of attack in rats initiated completely in tonsil Quantity Standard Error Change Number Value p Mg / kg samples stages% 15 5 80.0 20.0 .3739 30 5 100.0 0.0 .0000 60 6 80.0 16.3 .2752 90 5 76.0 4.0 .0039 ** 120 6 13.3 9.9 .0003 ** 180 5 36.0 22.3 .0453 * Change of stage (%): percentage of an attack stage after the administration of nefiracetam, with an attack stage before administration of the same taken as 100. Amount: the amount of nefiracetam administered. P value: proven value T of the exchange rate with respect to the value before the administration of nefiracetam (compared to test t).

* Refers to p < 0.05; ** refers to p < 0.01.

TABLE 2 Effect of nefiracetam on the duration of motor attack (MSD) in rats initiated completely in amygdala Quantity Standard Error Change Number Value p Mg / kg MSD samples% 15 5 76.4 20.2 .3072 30 5 96.0 9.4 .6955 60 6 81.7 17.1 .3321 90 5 78.0 19.8 .3286 120 6 0.6 0.6 < 0001 ** 180 5 21.3 14.3 .0054 ** Change of MSD (%): percentage of MSD after administration of nefiracetam, MSD before administration thereof taken as 100. Amount: the amount of nefiraceta administered. P value: proven value T of the rate of change with respect to the value before the administration of nefiracetam (compared to the T test.

** Refers to p < 0.01.

TABLE 3 Effect of nephiracetam on the duration of subsequent discharge (ADD) in rats initiated completely in amygdala Quantity Standard Error Change Number Value p Mg / kg samples ADD% 15 5 81.7 19.4 .3997 30 5 99.9 7.9 .9923 60 6 83.9 17.2 .3898 90 5 82.3 21.9 .4652 120 6 25.0 12.7 .0020 ** 180 5 24.8 16.0 .0094 ** Change in ADD (%): percentage of ADD after administration of nefiracetam, with ADD before administration of the same taken as 100. Amount: the amount of nefiracetam administered. P-value: the proven value T of the rate of change with respect to the value before the administration of nefiracetam (compared with the test t). ** Refers to p < 0.01. For the rats receiving nefiracetam, a dose-dependent inhibition was recognized in all three parameters: attack stage (table 1), duration of motor attack (table 2), and duration of subsequent discharge (table 3). The least squares method was obtained a regression curve of the effect of nefiracetam in an attack stage, and the regression curve was used to obtain 114 mg / kg of ED50.

EXAMPLE 2 Method The rats that were used in this example were of the same type in terms of source of acquisition, body weight and age (in weeks).

Each rat, in the same way as for example 1 was anesthetized, an electrode was implanted in the amygdala, the electrode was fixed in the cranial bone, and an ignition stimulation was applied (50 Hz, sinusoidal wave). For rats that did not receive the administration of nefiracetam and the rats that received the administration of nefiracetam (120 mg / kg), the effect of the administration was evaluated when the intensity of GST stimulation was increased by a factor of two (GST 2) or three (GST 3) the effect of 120 mg / kg of nefiracetam on ignition attacks induced by simple, double and triple GTS stimulation was evaluated in terms of the following parameters: attack stage, duration of motor attack and duration of the subsequent discharge. The results are shown in tables 4 to 6.

TABLE 4 Effect of nephiracetam on atagitic eaters in rats initiated completely in tonsil with different stimulation intensities Intensity Error Change Number Value p of GST samples stages% standard Simple 6 16.7 16.7 .0041 ** Double 5 14.7 14.7 .0066 ** Triple 5 52.0 13.6 .0240 * Stage change (%): percentage of an attack stage after administration of nefiracetam, with an attack stage before of the administration taken as 100.

P value: test value of T of the exchange rate with respect to the value before administration of nefiracetam (compared to the test t) - * Refers to p < 0.05; ** refers to p < 0.01.

TABLE 5 Effect of nefiracetam on the duration of motor atack (MSD) in rats initiated completely in tonsil with different intensities of stimulation Intensity of Number of Change of, _. . . , -C-G *. , c p / 11M Standard error Value p GST samples MSD (%) Simple 6 1 1.1 1 1.1 .0005 ** Double 5 15.2 9.5 .0009 ** Triple 5 43.8 14.0 .0159 * Change in MSD (%): percentage of MSD after administration of nefiracetam with MSD before administration of the same taken as 100. Value p: proven value T of the rate of change with respect to the value before the administration of nefiracetam (compared to the T test).

* Refers to p < 0.05; ** refers to p < 0.01.

TABLE 6 Effect of nephiracetam on the duration of subsequent discharge (ADD) in rats initiated completely in tonsil with different intensities of stimulation Intensity Error Change Number Value p of GST samples ADD% standard Simple 6 24.9 19.4 .0118 * Double 5 91.8 21.0 .7171 Triple 5 95.5 7.0 .5555 Change of ADD (%): percentage of ADD after administration of nefiracetam, with ADD before administration of it taken as 100. Value p: value with T test of the rate of change with respect to the value before administration of nefiracetam (purchased with the T test). * Refers to p < 0.05, which indicates that the result is not important.

In the case of the simple GST stimulation intensity, a strong and important inhibition was shown in all the parameters: attack stage, duration of motor attack, and duration of subsequent discharge. In the case of double GST stimulation intensity, significant inhibition was shown in the attack stage and in the duration of the motor attack, but an effect on the duration of the subsequent discharge was reduced. In the case of triple GST stimulation intensity, significant inhibition was shown in the attack stage and in the duration of the motor attack, but the effect was reduced compared to the effect in the case of single or double GST stimulation intensity. . In the case of double GST intensity and in the case of triple GST stimulation intensity, some show maintained very low attack stages or no behavioral attacks, although the duration of subsequent discharge almost returned to the value before the administration of nefiracetam. From the results described above, the effect of nefiracetam on the ignition attack can be related to the following two mechanisms: the increase of the threshold of subsequent discharge at the site where the attack was induced, and the inhibition of the dispersion of the attack on all brain. Thus, nefiracetam can increase the attack threshold at the central site of the attack, and inhibit the spread of the attack, and inhibit the expression of an attack. Therefore, the drug of the present invention is effective for an intractable generalized secondary attack generated from the temporal lobe.

EXAMPLE 3 In this test, the following parameters were evaluated: attack stage in the amygdala firing development process and duration of subsequent discharge in the stimulated amygdala.

Method Male Wistar rats (5 to 6 weeks of age, weight: 200-250 g, Tokyo Jikken Dobutsu) were used. For each rat, similarly to that of Example 1, anesthesia was performed, an electrode was placed in the amygdala and the electrode was fixed in the cranial bone. After a recovery period of at least two weeks, firing stimulation was initiated. The ignition stimulation was carried out for one second per day with a sine wave of 50 Hz. On the first day, the threshold of subsequent discharge was determined, and from the second day on stimulation of ignition was carried out at the intensity of the threshold . The first day, nephiracetam was not administered to determine the threshold. For 20 days from the second day, a dose of nefiracetam (45, 90 or 180 mg / kg) was administered orally, and then firing stimulation was carried out 90 minutes after administration. After administering nefiracetam for 20 days, firing stimulation was carried out without administration for an additional 7 days. TABLE 7 Effect of nefiracetam on the establishment of an ignition coupling (change in the subsequent discharge threshold) Number of samples Number of samples showing stage 5 show an increase in the intermittent discharge threshold / subsequent samples / total total samples Test 1 Control sample 0/5 0/5 Nefiracetam 90 mg / kg 4/6 3 / 6 Test 2 Control sample 0/5 0/5 Nefiracetam 45 mg / kg 0/4 0/4 Nefiracetam 180 mg / kg 5/6 2/6 TABLE 8 Effect of administration of nefiracetam (90 mg / kg) on the development of a binding stage (a typical example) Day 1 2 3 4 5 6 7 8 9 10 Stimulation intensity (μA) 50 50 50 50 50 50 50 50 50 50 Control samples 0 0 1 1 3 4 4 4 5 5 Stimulation intensity (μA) 50 50 50 50 50 50 50 50 50 50 Nephiracetam administration 0 0 0 0 0 1 3 4 4 5 Day 11 12 13 14 15 16 17 18 19 20 Stimulation intensity (μA) 50 50 50 50 50 50 50 50 50 50 Control samples 5 5 5 5 5 5 5 5 5 5 Stimulation intensity (μA) 150 50 100 75 75 75 50 50 100 125 Administration of nefiracetam 4 4 0 4 4 4 4 4 5 0 Day 21 22 23 24 25 26 27 28 Stimulation intensity (μA) 50 50 50 50 50 50 50 50 Control samples 5 5 5 5 5 5 5 5 Stimulation intensity (μA) 100 50 50 50 50 50 50 50 Administration of nefiracetam 5 5 5 5 5 5 5 5 On day 22 and after this day, an underlined number refers to the case in which nefiracetam was not administered. Table 8 shows the attack development process in a typical example of a rat to which nefiracetam was not administered and a rat to which nephiracetam (90 mg / kg) was administered in this test. As is evident from Table 8, in the case of a control rat to which nefiracetam was not administered, a stage began to progress on the third day and reached stage 5 on the fifth day. Subsequently, a rat to which nefiracetam was not administered remained in stage 5 until day 28, the last day of the proof. Rats to which nefiracetam was not administered, did not show examples of increased subsequent discharge threshold (see table 7). In contrast, in the case of a rat administered nephiracetam (90 mg / kg), one stage began to progress on the sixth day, and continued to progress as in the case of the rat to which nefiracetam was not administered, and it reached stage 5 on the tenth day (see table 8). In one case of a rat administered nephracetam, no further discharge was induced despite stimulation of the subsequent discharge threshold. In this case, the electrical stimulation was increased in steps of 25 μA until further discharge was shown. On day 11 further discharge was shown at 150 μA and the attack stage was 4. Subsequently, the subsequent discharge threshold changed, and the increase and fall of the threshold was repeated several times (see table 8). Such an increase in the subsequent discharge threshold was not shown in the cases of nephiracetam administration of 90 and 180 mg / kg (see Table 7). As is evident from Table 7, even in the case that there was no increase in the subsequent discharge threshold, in one case stage 5 was expressed intermittently. As described above, after the end of stage 5 there was an evident difference between rats to which nefiracetam was not administered and rats to which nefiracetam was administered, in the change of stage and in the threshold (see table 7). In this test, no difference was observed between rats given nefiracetam and control rats that were not administered, in the number of stimulations until the end of stage 5. However, after the end of step 5, the rats given nefiracetam showed "the return" of an attack stage more frequently than the control rats. In the normal process of attack development, once the attack reached stage 5, this stage was expressed constantly. It is known that the subsequent discharge threshold decreases according to the development of attack in the normal process of attack development. However, as a result of the administration of nefiracetam, the subsequent discharge threshold apparently increased during the expression of stages 3 to 5; that is, the expression of an engine attack. Such a phenomenon has not been exhibited in the case of administration of known drugs. Additionally, administration of nefiracetam prevented the expression of step 5, even though the subsequent discharge threshold did not increase. As described above, the nefiracetam comprises a new mechanism which affects the ignition development process.

EXAMPLE 4-1 The antiepileptic action of nefiracetam was studied by using two models of partial attack; that is, models for amygdala attacks and focal cortical attacks, both caused by local injection of kainic acid. Specifically, effects on clinical attack, on electroencephalogram observations and on glucose metabolism in the brain during an attack were studied. f.-Study of tonsil attacks induced by kainate: effects of suppressive attack of nephracetam on amygdala attacks, and changes in electroencephalogram observations were studied.

Method for measuring an electrophysiological effect The next operation was carried out using 19 Wistar male mice (Japan SLC Co.), each weighing 250-350 g. Each rat was anesthetized by pentobarbital and fixed in a stereotaxic apparatus. A stainless steel cannula with an outside diameter of 0.6 mm was inserted into the bilateral left amygdala of the rat, to inject kainic acid (Pellegrino, AS, Cushman, AJ, A Stereotaxic Atlas of the Rat Brain, Plenum Press, New York, 1979, insertion position: A, +5.0, L, +5/0, D, -3.0). Subsequently, a bipolar depth electrode with a diameter of 0.2 mm was inserted into the bilateral amygdala (A, +5.0; L, + -5.0; D, -3.0) and hippocampus (A, +3.0; L, + -3.2; D, +1.5). Screw electrodes were placed in the left sensorimotor area (A, +1.0 (from bregam), L, + -2.5, D, 0.5 (from dura)), frontal sinus and occipital median. The electrodes were connected to receptacles, and the cannula, electrodes and receptacles were fixed to the skull using dental glue. Seven days after the operation, 1μl of a solution of dissolved kainic acid was injected into a pH buffer of phosphoric acid (1 mg / ml), measured by the cannula (range: 0.8-1.0 ml / min) (n = 12), to induce attacks in the limbic system. The electrodes were connected to an electroencephalogram, and the behavior of the rat within the a cage. An electroencephalogram was recorded, using the electrode in the frontal sinus serving as a neutral electrode and the electrode in the occipital median serving as earth. The behavior and electroencephalogram were recorded simultaneously using an electroencephalogram video recorder, based on an electroencephalogram (SYNAFIT 1000, NEC San-eI Instruments, LTD.). One or two hours after the injection of kainic acid, when the attack on the limbic system was in epileptic state, nefiracetam dissolved in saline (10 mg / ml), was slowly injected into the caudal vein in an amount selected from 10. , 50, 100 and 200 mg / kg (n = 12). The same amount of saline was injected into a rat vein of the control group (n = 7). Subsequently, rat behavior and electroencephalograms were recorded continuously for at least 8 hours, followed by a 2 hour record, after 24 hours, 48 hours and 72 hours. Changes in clinical attack and electroencephalogram observations were measured just after the injection of the nephiracetam or saline solution, and the occurrence of electroencephalogram attacks and observations after 24, 48 and 72 hours were measured, and the results were evaluated by comparison .

Results After the injection of kainic acid in the amygdala during rest and during waking at rest, multiple pulses of amplitude appeared it goes down in 20 minutes, and multiple pulses continued to appear. In a short time, high amplitude rhythmic pulses appeared with clinical attacks, and the attack waves reached the hippocampus on the same side, and the amygdala and hippocampus on the other side. The clinical attacks were typical limbic system attacks, exhibiting symptoms such as turning the head to the right, attention response, akinesis, sialorrhea and prosopospam. Subsequently, the attacks reappeared at intervals of 5 to 10 minutes, and progressed in epileptic state. Rats injected intravenously with nefiracetam in an amount of 10, 50 or 100 mg / kg during status epilepticus, showed no apparent changes in paroxysmal behavior, or electroencephalograms (tables 9 and 10). However, the rats injected in an amount of 100 mg / kg, sedated, closed their eyes and their limbs relaxed. At that time, the rats showed no reaction to pain stimulation, and the sedative action continued for 30-60 minutes after the injection. In 5 of 8 rats injected in an amount of 200 mg / kg, the attacks disappeared just from the injection until minutes or 4 hours more, and then the attacks reappeared (box 9). In 4 of the 5 rats, pulses corresponding to the amygdala disappeared from an electroencephalogram. In the remaining rat, the pulses corresponding to the amygdala on the other side and those corresponding to the hippocampus on both sides disappeared, and the pulses corresponding to the amygdala on the injected side remained. Although the attacks of a rat disappeared just after the nephiracetam injection, the rat he died 25 minutes later. In two rats, pulses corresponding to the amygdala disappeared after 24, 48, and 72 hours (Table 10). In 3 of the 8 rats, the attacks were not suppressed in terms of behavior and an electroencephalogram, even when the rats were injected with 200 mg / kg of nephiracetam. In the three rats, pulses corresponding to the amygdala remained after 24, 48 and 72 hours. The 8 rats injected in an amount of 200 mg / kg, and the rats injected in an amount of 100 mg / kg, were sedated for approximately 60-90 minutes starting just after injection, and awoke after attack waves they were repeated on the electroencephalogram. Said sedative action was not observed in the case of injection of nefiracetam in an amount of 10 or 50 mg / kg.

TABLE 9 Suppressive effect of nefiracetam on amygdala ligations induced by kainate Rat Dose Disappearing Period of action sedative nefiracetam of attacks disappearance of just after injection attacks after intravenous injection intravenous C1 NS - ND - C2 NS - ND - C3 NS - ND - C4 NS - ND - C5 NS - ND - C6 NS - ND - C7 NS - ND - N1 200 mg / kg + 2 h 33 min + N2 200 - ND + N3 200 - ND + N4 200 - ND + N5 200 + (died after + 25 min) N6 200 + 5 min . + N7 200 + 4 h 32 min. + N8 200 + 35 min. + N9 100 - ND + N10 100 - ND + N11 50 - ND - N12 10 - ND - C1 - C7: control group, N1 - N10: group to which nefiracetam was administered, NS: saline, ND: no data, (+) cash, (-): ineffective, h: hours, min: minutes TABLE 10 Effects of nefiracetam on the change in the electroencephalogram observations of the amygdala corresponding to the amygdala attachments induced by kainate Rat Dose Pulse Pulses Pulse Pulses of the nephiracetam amygdala amygdala amygdala amygdala just after after after after 24 h 48 h 72 h intavenous injection C1 'NS + + + + C2 NS + + + - C3 NS + + + - C4 NS + + + + C5 NS + + + + C6 NS + + - - C7 NS + + - - N1 200 mg / kg - - - - N2 200 + - - - N3 200 + + + + N4 200 + + + + N5 200 - ND ND N6 200 - + + + N7 200 - - - - N8 200 + + ND ND (the pulses disappeared outside the focal point) N9 100 + + ND ND N10 100 + + ND ND amplitude declination) N1 1 50 + + ND ND N12 10 + + ND ND C1-C7: control group, N1-N10: group to which nephiracetam was administered, NS: saline solution, ND: no data, (+) effective, (-): ineffective, h: hours EXAMPLE 4-2 1-2 Study of change in local cerebral glucose metabolism Effects of nefiracetam on local cerebral glucose metabolism during an amygdala attack were studied.

Method for measurement of cerebral glucose metabolism Cannulas were inserted for injection of cainic acid at an assigned position on the left side of the amygdala of 18 male Wistar rats, and fixed through the same procedure described in example 1-1. Seven days after the operation, polyethylene catheters were placed and fixed to the femoral artery and vein on one side under halothane anesthesia, and the lower half of the body of each rat was placed in plaster to avoid removal of the catheter. Upon awakening from narcotism, the same solution of kainic acid described in 1-1 (1 μl) was injected through the cannula to induce seizures. 90 minutes after the injection of kainic acid, when the attacks of the limbic system were in epileptic state, 50, 100 or 200 mg / kg of nephiracetam were injected intravenously, while saline was injected to two rats of the control group . 60 minutes later, 25 μCi of deoxyglucose [14C] was injected intravenously. After the tracer was injected, blood was continuously collected from the artery for 45 minutes. When the shot was over, the heads Brains were removed immediately and snap frozen with hexane (-25 ° C) cooled by dry ice. Frozen brain slices were made in a cryostat (-20 ° C) to produce frozen coronary serial sections with a thickness of 20 μm. Subsequently, the sections were dried and placed on high-speed X-ray film with a standard [1 C], followed by seven days of exposure on a cassette to thereby obtain an autoradiogram. The blood samples collected from the artery were centrifuged to collect plasma, the radioactivity [14C] was measured by the use of a liquid scintillation counter, and the concentration of glucose in the plasma was measured. The optical density of the intracerebral structure of each section was measured from the autoradiogram using a densitometer, and a ratio of glucose utilization of each intracerebral structure was calculated by using the Sokoloff formula (Sokoloff, L., Reívich, M ., Kennedy, C, er al., J Neurochemistry, 28: 897-916, 1977) based on [14C] radioactivity and plasma glucose concentration. The data obtained were compared quantitatively and statistically with those of the control group, through the Mann-Whitney U test.

Results Table 11 shows the rate of local glucose metabolism of each intracerebral structure of the control group (group to which nefiracetam was not administered) and the group to which 100 mg / kg of nefiracetam during tonsil attacks. In the control group, glucose metabolism in the occipitoparietal cortex, temporal lobe cortex, sensorimotor area and caudatum-putamen on the focal side; the limbic system, such as the amygdala and the hippocampus on both sides; and the thalamus and black matter on the focal side were accelerated compared to the glucose metabolism of normal rats. When 100 mg / kg of nefiracetam is administered, the glucose metabolism shows no change in the sensorimotor area, caudatum-putamen, amygdala and hippocampus on the focal side. In contrast, in almost all other regions, where the glucose metabolism shows a high velocity in the group to which no dose was applied, the promotion of glucose metabolism is suppressed (Table 12). In addition, glucose metabolism is suppressed in all regions of the cerebral cortex, thalamus, hypothalamus and reticular formation of the brain stem on the non-focal side, where almost no changes are observed, even in the control group, ie the local glucose metabolism in these regions is lower than in normal rats. Said suppression of cerebral glucose metabolism caused by the nephracetam can be described as follows; when 50 mg / kg of nephiracetam are administered, the amygdala, hippocampus and cerebral cortex on the non-focal side are suppressed slightly; when 100 mg / kg of nephiracetam is administered, suppression of glucose metabolism is also observed in the hippocampus and in the cerebral cortex on the focal side; and when 200 mg / kg of nephiracetam are administered, the amygdala on the focal side is the only region in the that the metabolism accelerates. In other words, nefiracetam suppresses extension of the area in which glucose metabolism is high, in a dose-responsive manner. In addition, when 100 or 200 mg / kg of nephiracetam were administered to a rat, the same sedative action described in 1-1 was observed.

TABLE 11 Rate of local glucose metabolism in each intracerebral structure during amygdala atacks induced by kainate (comparison of group to which nefiracetam was administered and group to which it was not administered). with administration of nefiracetam (100 mg / kg, 1 group 7 heads without administration of nefiracetam (1 group 7 heads) average data ± standard error (u mol / min / g) * P <0 05, ** P <0 01 (Mann-Whitney U test) TABLE 12 ?: without changes ? i: decreased in a low degree I: decreased to a moderate degree 1 1: decreased to a high degree EXAMPLE 5-1 II. Study of focal cortical seizures induced by kainate: The effects of suppression of nephiracetam attack on focal cortical attacks and changes in electroencephalogram observations were studied.

Method for measuring an electrophysiological effect A stereotactic operation was carried out in the same manner described in 1-1, using male Wistar rats. A cannula was inserted into the left sensory-motor area for injection of kainic acid, and the cannula was used simultaneously as an electrode. A bipolar depth electrode was placed in the bilateral caudate, and screw electrodes were placed in the right sensomotor area, frontal sinus and occipital bone. Seven days after the operation, 1 μl (2 mg / ml) of kainic acid solution was injected to induce focal cortical attacks. After 1-2 hours from the injection of kainic acid, the same solution of nefiracetam described in 1-1 (100 mg / kg) was injected intravenously, and the behavior and electroencephalogram were recorded using a video recorder. electroencephalogram. Suppression of attacks just after administration of nefiracetam, changes in electroencephalograms, occurrence of attacks after and observations of electroencephalograms, were compared with those of the control group.

Results After the injection of kainic acid into the cortex of the left sensory area during rest and during awake at rest, multiple pulses of low amplitude appeared in 20 minutes in the left sensorimotor area and the caudatum-putamen, and multiple pulses continued to appear. In a short time, rhythmic pulses of high amplitude appeared, and simultaneously, clonic attacks began to occur in the right upper extremity and in the face. The attack waves instantly reached the sensory-motor area and the caudatum-putamen on the other side. Subsequently, the attacks reappeared at intervals of 5 to 10 minutes, and tonic attacks on the right upper extremity and generalized secondary attacks were also observed. When said partial seizures were in an epileptic state, the rat was injected intravenously with nephiracetam (100 mg / kg). As a result, the attacks disappeared immediately and the frequency of the pulses in the electroencephalograms decreased remarkably. In one rat, the pulses corresponding to the right sensorimotor area on the other side and those corresponding to the right caudatum-putamen almost disappeared (table 13). In addition, just after the intravenous injection of nefiracetam, the rats sedated, closed their eyes and their limbs relaxed, and then awoke at 60 minutes, in the same way as in the I experiment. However, the attacks did not They appeared after waking up. In addition, only interictal discharges appeared in the electroencephalogram, and the frequency of discharges gradually decreased. After 24 hours, similarly to the case of the control group, myoclonic attacks corresponding to pulses on an electroencephalogram were observed in a rat. In contrast, the attacks completely disappeared in two other rats.

TABLE 13 Suppressive effect of nefiracetam on focal cortical attachments induced by kainate Rats Disappearance Reappearance of Decreased Pulses Action of attacks attacks of pulses after sedative 24 hours CC1 + CC2 - - + - CC3 + DC1 + + + DC2 + - + + + DC3 + + + + CC1-CC3: control group DC1-DC3: group given nefiracetam (+): effective, (-): ineffective EXAMPLE 5-2 II-2 Study of change in cerebral glucose metabolism The effects of nefiracetam on local cerebral glucose metabolism during a focal cortical attack were studied.

Method A cannula was placed in the left sensomotor area of rats, and kainic acid was injected to induce seizures in the same manner described in the 1-1 experiment. Subsequently, a solution of nefiracetam (100 mg / kg) was injected intravenously to each rat. 60 minutes later, deoxyglucose [14C] was injected intravenously, and autoradiograms were produced by the same procedure described in the I-2 experiment. A ratio of glucose utilization of each intracerebral structure was compared with that of the control group.

Results During focal cortical attacks induced by kainate, the local glucose metabolism accelerates in the sensorimotor area, which is the focal region; and in the cortex of the frontal lobe and the parietal lobe on the same side, both connected to the sensorimotor area. Cerebral glucose metabolism also accelerates in the caudatum-putamen, thalamus and hippocampus on both sides. Moreover, glucose metabolism accelerates in the sensorimotor area on the non-focal side of a rat. In the case in which nefiracetam (100 mg / kg) is injected intravenously during attacks, hypermetabolism is remarkably suppressed in the sensorimotor area, caudatum-putamen and thalamus on the non-focal side and in the hippocampus or both sides . In addition, nephracetam suppresses extension of the area, where glucose metabolism increases in the cortex of the focal side (Table 14). From Similar to the case of amygdala attacks, glucose metabolism is suppressed throughout the brain. Especially, the metabolism is strongly suppressed in a distant region.

TABLE 14 Effects of nefiracetam on the rate change of local cerebral glucose metabolism during focal cortical attachment Intracerebral structure Nefiracetam (100 mg / kg) Focal side non-focal side Frontal lobe cortex 4F F Parietal lobe cortex F FF Occipital lobe cortex 4F F Temporal lobe cortex 1 F Sensomotor area cortex 41 F Corpus callosum 4 4 Candatum-putamen F FF Amygdala 4F 4F Hippocampus FF FF Septal area 41 4F Thalamus - > ? F Hypothalamus f F Substance black? 4F Reticular formation of brainstem 4? 4F Brain cortex 4 4 4: no change 4F: decreased in a low degree F: decreased to a moderate degree FF: decreased to a high degree INDUSTRIAL APPLICATION The drugs of the present invention are effective for intractable human epilepsy, specifically for temporal lobe epilepsy, bark epilepsy, location-related epilepsy, recurrent epilepsy after surgery for epilepsy, epilepsy after brain surgery or traumatic epilepsy. In addition, the drugs are effective for attacks associated with epilepsy, such as generalized secondary attacks, complex partial seizures, and epileptic status.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A therapeutic or preventive agent for an intractable epilepsy or an attack associated therewith, comprising as active ingredient a compound represented by the following formula (I): R -CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents, which may be identical or different from each other, and which are selected from a C1-C3 alkyl group and a hydroxyl group, and R2 is a 2- group oxo-1-pyrrolidinyl, which may have one or more substituents, wherein said substituent or substituents may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate.

2. A therapeutic or preventive agent as claimed in claim 1, wherein the intractable epilepsy is a location-related epilepsy, a generalized epilepsy or its syndromes.

3. A therapeutic or preventive agent as claimed in claim 2, wherein location-related epilepsy and generalized epilepsy are ideophatic or symptomatic.

4. - A therapeutic or preventive agent as claimed in claim 3, wherein the epilepsy related to the location is cortical epilepsy or temporal lobe epilepsy.

5. A therapeutic or preventive agent as claimed in claim 2, wherein the generalized epilepsy or a syndrome thereof is the West syndrome, Lennox syndrome or a child symptomatic syndrome.

6. A therapeutic or preventive agent as claimed in claim 4, wherein the cortical epilepsy is a frontal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy.

7. A therapeutic or preventive agent as claimed in claim 1, wherein the attack associated with the intractable epilepsy is a secondary generalized attack or a complex partial attack.

8. A therapeutic or preventive agent as claimed in claim 1, wherein the intractable epilepsy or the attack associated with the intractable epilepsy is status epilepticus.

9. A therapeutic or preventive agent as claimed in claim 1, wherein the intractable epilepsy is an epilepsy after a brain surgery, a traumatic epilepsy or a recurrent epilepsy after intractable epilepsy surgery.

10. A therapeutic or preventive agent as claimed in claim 1, wherein the intractable epilepsy or the attack associated with intractable epilepsy, is an epilepsy related to the intractable location, an intractable secondary generalized attack, an intractable complex partial attack or an intractable status epilepticus.

1 1. An inhibitor which limits the duration of an epileptic seizure (a motor attack), suppressant comprising as active ingredient a compound represented by the following formula (I): R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents, which may be identical or different from each other, and which are selected from a C1-C3 alkyl group and a hydroxyl group, and R2 is a 2-oxo-1-pyrrolidinyl group, which may have one or more substituents, wherein said substituent or substituents may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and an alkyl group of C1 -C3; a salt thereof; or a compound or salt hydrate.

12. An inhibitor against the propagation of an epileptic attack, suppressor comprising as active ingredient a compound represented by the following formula (I): R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents, which may be identical or different from each other, and which are selected from a C 1 -C 3 alkyl group and a hydroxyl group, and R 2 is a 2-oxo-1 group pyrrolidinyl, which may have one or more substituents, wherein said substituent or substituents they may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate.

13. A therapeutic agent or preventive for an epileptic attack, whose agent has a function of raising an attack-provoking threshold, and comprises as active ingredient a compound represented by the following formula (I): R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents, which may be identical or different from each other, and which are selected from a C1-C3 alkyl group and a hydroxyl group , and R2 is a 2-oxo-1-pyrrolidinyl group, which may have one or more substituents, wherein said substituent or substituents may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate.

14. An inhibitor, a therapeutic agent or a preventive agent as claimed in any of claims 1-13, wherein epileptic see is an intractable epileptic see.

15. A therapeutic agent, a preventive agent or a suppressant, as claimed in any of the claims 1-14, wherein the compound represented by the formula (I) is N- (2,6-dimethylphenyl) -2- ( 2-oxo-1- pyrrolidinyl) acetamide, a salt thereof, or a hydrate of the compound or salt.

16. The use of a compound represented by the following formula (I): R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents which may be are identical or different from each other, and which are selected from a C 1 -C 3 alkyl group and a hydroxyl group, and R 2 is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents, wherein said substituent or substituents may be identical or different from each other, and are selected from a hydrogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate; for the production of a therapeutic or preventive agent for an intractable epilepsy or an attack associated therewith.

17. The use of a compound as claimed in claim 16, wherein the intractable epilepsy is a location-related epilepsy, a generalized epilepsy or its syndromes.

18. The use of a compound as claimed in claim 17, wherein location-related epilepsy and generalized epilepsy are idiopathic or symptomatic.

19. - The use of a compound as claimed in claims 17 or 18, wherein the epilepsy related to the location is cortical epilepsy or temporal lobe epilepsy.

20. The use of a compound as claimed in claim 17, wherein the generalized epilepsy or a syndrome thereof, is West syndrome, Lennox syndrome or a child symptomatic syndrome.

21. The use of a compound as claimed in claim 19, wherein the cortical epilepsy is a frontal lobe epilepsy, parietal lobe epilepsy or occipital lobe epilepsy.

22. The use of a compound as claimed in claim 16, wherein the attack associated with intractable epilepsy is a secondary generalized attack or a complex partial attack.

23. The use of a compound as claimed in claim 16, wherein the intractable epilepsy or the attack associated with the intractable epilepsy is status epilepticus.

24. The use of a compound as claimed in claim 16, wherein the intractable epilepsy is an epilepsy after brain surgery, a traumatic epilepsy or a recurrent epilepsy after surgery for intractable epilepsy.

25. The use of a compound as claimed in claim 16, wherein the intractable epilepsy or the attack associated with the intractable epilepsy, is an intractable epilepsy of related localization, a secondary intractable generalized attack, an intractable complex partial attack, or an intractable status epilepticus.

26. The use of a compound represented by the following formula (I): wherein R.sup.1 is a phenyl group or a pyridyl group, any of which may have one or more substituents which they can be identical or different from each other, and which are selected from a C 1 -C 3 alkyl group and a hydroxyl group, and R 2 is a 2-oxo-1-pyrrolinyl group, which can be Having one or more substituents, wherein said substituent or substituents may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof or a hydrate of the compound or salt, for the production of a suppressant which limits the duration of an epileptic seizure (a motor attack).

The use in the production of a suppressor against the propagation of an epileptic attack, of a compound represented by the following formula (I): R2-CH2CONH-R1 (I) *. wherein R1 is a phenyl group or a pyridyl group, any of which 20 may have one or more substituents, which may be identical or different from each other, and which are selected from a C 1 -C 3 alkyl group and a hydroxyl group, and R 2 is a 2-oxo-1-pyrrolidinyl group, which may have one or more substituents, wherein said substituent or substituents they may be identical or different from each other, and are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate.

28.- The use in the production of a therapeutic or preventive agent for an epilepsy, which has a function of raising an inductive threshold of attack, of a compound represented by the following formula (I): R2-CH2CONH-R1 (I) wherein R1 is a phenyl group or a pyridyl group, any of which may have one or more substituents, which may be identical or different from each other, and which are selected between a C1-C3 alkyl group and a hydroxyl group, and R2 is a 2-oxo-1-pyrrolidinyl group, which may have one or more substituents, wherein said substituent or substituents may be identical or different from each other, and they are selected from a halogen atom, a hydroxyl group and a C1-C3 alkyl group; a salt thereof; or a compound or salt hydrate.

29. The use of a compound as claimed in any of claims 26-38, wherein the epileptic attack is an intractable epileptic attack.

30. The use of a compound as claimed in any of claims 16-29, wherein the compound represented by the formula (I) is N- (2,6-dimethylphenyl) -2- (2-oxo) -1-pyrrolidinyl) acetamine, a salt thereof, or a hydrate of the compound or salt.