Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-06
2002-04-02
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S343000, C546S278400, C548S568000
Reexamination Certificate
active
06365621
ABSTRACT:
This application is a 371 of PCT/JP99/04264 filed Aug. 6, 1999.
TECHNICAL FIELD
The present invention relates to a therapeutic or preventive agent for, among other epilepsies, intractable epilepsies, which are difficult to prevent or treat by existing antiepileptics.
BACKGROUND ART
Epilepsy is a chronic brain disease in which epileptic seizures are the predominant feature. Generally, most epilepsies and diseases associated therewith are difficult to treat, since epilepsies are not etiologically elucidated. Thus, administration of an antiepileptic agent is a common approach toward suppressing epileptic seizures or inhibiting propagation of focal seizures to other portions.
At present, more than ten types of antiepileptic agents are available in Japan. Yet, many different intractable epilepsies cannot be successfully suppressed by antiepileptic agents, including so-called “resistant-to-therapy” seizures and cases in which drug compliance cannot be obtained due to side effects despite satisfactory suppression of seizures. Thus, there is still demand for an antiepileptic agent which is more effective than existing ones and which exhibits fewer and less severe side effects (see “Mechanismus of Action Antiepileptics,”
Clinical Psychiatry Courses
, Nakayama-Shoten, authored by Akira TAKAZAWA, et al.).
Therefore, an object of the present invention is to provide a pharmaceutical effective for intractable epilepsies or a seizure associated therewith, for which existing antiepileptics have not exhibited satisfactory efficacy.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive studies, and have found that a pyrrolidinylalkylcarboxylic acid amide derivative represented by formula (I) serves as a pharmaceutical which is efficacious in the treatment or prevention of intractable epilepsies. The present invention has been accomplished based on this finding.
Accordingly, the present invention provides a therapeutic or preventive agent for an intractable epilepsy or a seizure associated therewith comprising as an active ingredient a compound represented by the following formula (I):
R
2
—CH
2
CONH—R
1
(I)
wherein R
1
is a phenyl group or a pyridyl group, either of which may have one or more substituents which may be identical to or different from one another and which are selected from among a C1-C3 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 one or more substituents may be identical to or different from one another and are selected from among a halogen atom, a hydroxyl group, and a C1-C3 alkyl group; a salt thereof; or a hydrate of the compound or the salt.
The present invention also provides an inhibitor which limits a motor seizure associated with an epilepsy (in terms of duration of an epileptic symptom); an inhibitor for propagation of an epileptic seizure; and a therapeutic or preventive agent for epilepsy having a function of raising a seizure-inductive threshold, each of the above three types of agents comprising as an active ingredient a compound represented by the formula (I), a salt thereof, or a hydrate of the compound or salt. The present invention provides use of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt, for producing a therapeutic or preventive agent for an intractable epilepsy or a seizure associated therewith.
The present invention also provides use of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt, for producing a suppresser which limits a motor seizure associated with an epilepsy (in terms of duration of a epileptic symptom); a suppresser for propagation of an epileptic seizure; and a therapeutic or preventive agent for epilepsy having a function of raising a seizure-inductive threshold.
The present invention provides a method for treating an intractable epilepsy or a seizure associated therewith through 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 for treatment for inhibiting a motor seizure associated with an epilepsy (in terms of duration of a epileptic symptom); a method for treatment for preventing propagation of an epileptic seizure; and a method for treating epilepsy involving a function of raising a seizure-inductive threshold, by the administration of a compound represented by the following formula (I); a salt thereof; or a hydrate of the compound or salt.
BEST MODE FOR CARRYING OUT THE INVENTION
The substituents in formula (I) will next be described. R
1
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 R
1
. The one or more substituents for a phenyl group may be identical to or different from one another and are selected from among a C1-C3 alkyl group, a halogen atom, and a hydroxyl group. Of these, a methyl group and a hydroxyl group are preferred. Furthermore, two methyl groups or a combination of two methyl group and one hydroxyl group are preferred, and the preferable positions of substitution are 2- and 6-positions of a phenyl group. Thus, a 2,6-dimethylphenyl group is particularly preferred. The one or more substituents for a pyridyl group may be identical to or different from one another and are selected from among a halogen atom, a C1-C3 alkyl group, an acyl group, etc.
R
2
is a 2-oxo-1-pyrrolidinyl group which may have one or more substituents. The one or more substituents may be identical to or different from one another and are selected from among a halogen atom, a C1-C3 alkyl group, and a hydroxyl group. Of these, a hydroxy-substituted-2-oxopyrrolidinyl group and 2-oxopyrrolidinyl group are particularly preferred.
A typical example of the compound represented by 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 already been disclosed in Japanese Patent Application Laid-Open (kokai) Nos. 56-2960, 61-280470, and 6-65197.
Nefiracetam finds pharmaceutical use as, for example, a cerebovascular dementia-ameliorating agent (Japanese Patent Application Laid-Open (kokai) No. 56-163145), an ameliorating agent for dementia of Alzheimer type (Japanese Patent Application Laid-Open (kokai) No. 5-163144), or a stabilizing agent for the mitochondrial membrane (Japanese Patent Application No. 8-260649). The working mechanism of nefiracetam is partially disclosed in Japanese Patent Application No. 9-249131.
An antiepileptic action provided by nefiracetam has already investigated through a test employing EL mice as models, and potential use as an antiepileptic agent is indicated (the 17th Convention of Japanese Neuroscience Society, 3i, 1993; the 23rd Society for Neuroscience, 1993, 11; and the 26th Society for Neuroscience, Nov. 16, 1996, Washington D.C.).
The model of epilepsy employing EL mice tested in the above reports is a model of epilepsy caused by a congenital genetic disposition formed through mutation. The model exhibits perception-evoked secondary generalization of a seizure and stupor after tonic or clonic convulsion. An electroencephalogram of the model shows characteristic changes corresponding to the above states. In addition, the model of epilepsy is a genetic model, to thereby serve as a useful model for investigating epileptic states induced by genetic disposition.
However, no clinically defined types of epilepsies of humans correspond to the EL mouse model, although efficacy of a pharmaceutical to suppress epilepsy is easily attained for EL mice through administration of a pharmaceutical in a small dose. Therefore, the pharmaceutical is not always clinically effective for humans even though the efficacy is proven for EL mice. Particularly, since a clinical effect of a pharmaceutical on intractable epilepsy of humans st
Murashima Yoshiya
Takazawa Akira
Tanaka Tatsuya
Yoshii Mitsunobu
Davis Zinna Northington
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmaceutical Co., Ltd.
LandOfFree
Remedies or preventives for intractable epilepsy does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Remedies or preventives for intractable epilepsy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Remedies or preventives for intractable epilepsy will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2816297