Use of carbamate compounds for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures
阅读说明：本技术 用于预防、减轻或治疗失神发作或显示失神发作的癫痫的氨基甲酸酯化合物的用途 (Use of carbamate compounds for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures ) 是由 申蕙园 于 2018-11-13 设计创作，主要内容包括：本发明涉及由化学式1表示的氨基甲酸酯化合物,或其药学上可接受的盐,溶剂合物或水合物用于预防、减轻或治疗失神发作或显示失神发作的癫痫的用途。(The present invention relates to the use of a carbamate compound represented by chemical formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof for preventing, alleviating, or treating absence seizures or epilepsy exhibiting absence seizures.)
1. A medicament for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures, comprising a therapeutically effective amount of a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof:
[ formula 1]
Wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, halogen, C1-C8Alkyl, halo-C1-C8Alkyl radical, C1-C8Alkylthio and C1-C8An alkoxy group; and
A1and A2One is CH and the other is N.
2. According to claimThe medicament of claim 1, wherein R1And R2Each independently selected from hydrogen, halogen and C1-C8An alkyl group.
3. The medicament according to claim 1, wherein the carbamate compound of formula 1 is (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate of the following formula 2:
[ formula 2]
。
4. The medicament according to claim 1, wherein a subject suffering from a absence seizure or an epilepsy exhibiting a absence seizure exhibits spike-Slow Wave Discharge (SWD) in an electroencephalogram (EEG).
5. The medicament according to claim 1, wherein the epilepsy exhibiting absence seizures is selected from childhood-type absence epilepsy, epilepsy with myoclonic absence, juvenile-type absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (blepharospasm with absence), hereditary generalized epilepsy with phantom absence and L enox-Gastaut syndrome.
6. The medicament according to claim 1, wherein the absence episode is a typical absence episode.
7. A medicament according to claim 1, wherein the absence episode is an atypical absence episode.
8. A medicament according to any one of claims 1 to 7, prepared for mammalian administration.
9. The medicament according to any one of claims 1 to 7, wherein the therapeutically effective amount of the carbamate compound of formula 1 is administered once daily based on 50 mg to 500 mg in free form.
10. A pharmaceutical composition for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures, comprising a therapeutically effective amount of a carbamate compound of the following formula 1; or a pharmaceutically acceptable salt, solvate or hydrate thereof; and further one or more pharmaceutically acceptable carriers:
[ formula 1]
Wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, halogen, C1-C8Alkyl, halo-C1-C8Alkyl radical, C1-C8Alkylthio and C1-C8An alkoxy group; and
A1and A2One is CH and the other is N.
11. The pharmaceutical composition according to claim 10, wherein R is1And R2Each independently selected from hydrogen, halogen and C1-C8An alkyl group.
12. The pharmaceutical composition according to claim 10, wherein the carbamate compound of formula 1 is (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate of formula 2 below:
[ formula 2]
。
13. The pharmaceutical composition according to claim 10, wherein a subject suffering from a absence seizure or an epilepsy exhibiting a absence seizure exhibits a spike-and-slow-wave discharge (SWD) in an electroencephalogram (EEG).
14. The pharmaceutical composition according to claim 10, wherein the epilepsy exhibiting absence seizures is selected from childhood-type absence epilepsy, epilepsy with myoclonic absence, juvenile-type absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (blepharospasm with absence), hereditary generalized epilepsy with phantom absence and L enox-Gastaut syndrome.
15. The pharmaceutical composition according to claim 10, wherein the absence episode is a typical absence episode.
16. The pharmaceutical composition according to claim 10, wherein the absence episode is an atypical absence episode.
17. A pharmaceutical composition according to any one of claims 10 to 16, which is prepared for mammalian administration.
18. The pharmaceutical composition according to any one of claims 10 to 16, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 mg to 500 mg, based on the free form, administered once daily.
19. Use of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for preparing a medicament for preventing, alleviating, or treating absence seizures or epilepsy exhibiting absence seizures:
[ formula 1]
Wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, halogen, C1-C8Alkyl, halo-C1-C8Alkyl radical, C1-C8Alkylthio and C1-C8An alkoxy group; and
A1and A2One is CH and the other is N.
20. Use according to claim 19Wherein R is1And R2Each independently selected from hydrogen, halogen and C1-C8An alkyl group.
21. The use according to claim 19, wherein the carbamate compound of formula 1 is (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate of the following formula 2:
[ formula 2]
。
22. The use according to claim 19, wherein a subject suffering from a absence seizure or an epilepsy exhibiting a absence seizure exhibits a spike-and-Slow Wave Discharge (SWD) in an electroencephalogram (EEG).
23. Use according to claim 19, wherein the epilepsy exhibiting absence seizures is selected from childhood absence epilepsy, epilepsy with myoclonic absence, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (blepharospasm with absence), hereditary generalized epilepsy with phantom absence and L enox-Gastaut syndrome.
24. Use according to claim 19, wherein the absence episode is a typical absence episode.
25. Use according to claim 19, wherein the absence episode is an atypical absence episode.
26. The use according to any one of claims 19-25, wherein the medicament is for mammalian administration.
27. The use according to any one of claims 19-25, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 mg to 500 mg, based on the free form, administered once daily.
28. A method for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a carbamate compound of formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
[ formula 1]
Wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, halogen, C1-C8Alkyl, halo-C1-C8Alkyl radical, C1-C8Alkylthio and C1-C8An alkoxy group; and
A1and A2One is CH and the other is N.
29. The method according to claim 28, wherein R1And R2Each independently selected from hydrogen, halogen and C1-C8An alkyl group.
30. The method according to claim 28, wherein the carbamate compound of formula 1 is (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate of formula 2 below:
[ formula 2]
。
31. The method according to claim 28, wherein a subject suffering from a absence seizure or an epilepsy exhibiting a absence seizure exhibits spike-Slow Wave Discharge (SWD) in an electroencephalogram (EEG).
32. The method according to claim 28, wherein the epilepsy exhibiting absence seizures is selected from childhood absence epilepsy, epilepsy with myoclonic absence, juvenile absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (blepharospasm with absence), hereditary generalized epilepsy with phantom absence and L enox-Gastaut syndrome.
33. The method according to claim 28, wherein the absence episode is a typical absence episode.
34. The method according to claim 28, wherein the absence episode is an atypical absence episode.
35. The method according to claim 28, wherein the subject for administration is a mammal.
36. The method according to claim 28, wherein the therapeutically effective amount of the carbamate compound of formula 1 is administered once daily, based on 50 mg to 500 mg in free form.
Technical Field
The present invention relates to the use of a carbamate compound of the following formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures:
[ formula 1]
Wherein the content of the first and second substances,
R1、R2、A1and A2As defined herein.
Background
All symptoms caused by transient and irregular abnormal excitation of nerve cells are collectively called seizures (seizure). Epilepsy refers to a group of diseases in which chronic seizures occur even when there are no abnormalities in the body that can cause seizures, such as specific causative factors, e.g., electrolyte imbalance, acid-base abnormality, uremia, alcohol withdrawal, loss of severe sleep, etc. It is well known that in the case of two or more episodes, the treatment must be continued with the drug.
Epileptic seizures are classified based on clinical symptoms and electroencephalogram (EEG) detection. According to this classification, seizures are largely divided into local seizures and generalized seizures. A local attack refers to an hyperexcitability (hyperexcitability) attack of nerve cells starting in a part of the cerebral cortex, while a systemic attack refers to an attack starting in a wide range of two cerebral hemispheres. Types of systemic seizures include systemic tonic-clonic seizures, absence seizures (mini-seizures), myoclonic seizures and dystonic seizures. Types of local seizures include simple local seizures, complex local seizures, and secondary systemic seizures resulting from local seizures (source: korea institute of epilepsy).
Of these, absence episodes (petit episodes) are characterized by sudden cessation of action and symptoms of disorganized fixation or low first approximately 5 to 10 seconds. Sometimes, slight vibrations around the eyes or mouth can be observed. These symptoms usually appear at the time of dyspnea (origin: korea academy of epilepsy). The two most typical features of a seizure are the clinical symptoms of impaired consciousness and electroencephalograms (EEG) showing spike-and-Slow Wave Discharges (SWD). Types of epilepsy with symptoms of absence seizures include childhood-type absence epilepsy, epilepsy with myoclonic absence, juvenile-type absence epilepsy and juvenile myoclonic epilepsy.
Absence episodes can be classified as typical absence and atypical absence. In the case of a typical absence, the episode will usually end in 2 to 10 seconds and rarely last for more than 30 seconds. Thus, the patient himself, let alone others, sometimes does not know whether they have had an attack. After the episode, the patient returns to the action or situation they were doing just before the episode without realizing that he has the episode. Atypical loss of consciousness includes loss of consciousness, full eye gaze, eyelid blinking, licking the lips, chewing behavior or finger touch. The frequency of these symptoms may decrease before and after puberty, but most tend to develop into grand mal seizures.
Valproic Acid or Ethosuximide are used predominantly, lamotrigine may also be used, but are known to be less effective (Glaser et al (2010) "Ethosuximide, Valproic Acid, and L amotrine in Childhood Absence epissy," New England and Journal of Medicine,362 (9): 790-9.) however, other antiepileptics such as carbamazepine, vigabatrin, Tiagabine, oxcarbazepine, phenytoin, phenobarbital, gabapentin and pregabalin are contraindicated in patients with Absence seizures ("NICE guidelphines" 2014 11/3/d; Knake et al (1999 8/d) "diagnosis-induced 317 and European style 314).
Carboxamido dibenzoazepine based drugs are used to treat topical seizures, but such drugs are known to exacerbate generalized seizures, especially absence seizures.
Disclosure of Invention
Technical problem to be solved
The present invention aims to provide a method for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures.
The present invention is also directed to the use of a carbamate compound of the following formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures:
[ formula 1]
Wherein the content of the first and second substances,
R1、R2、A1and A2As defined herein.
[ solution to problems ]
The present invention provides a medicament for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures, which comprises a therapeutically effective amount of a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof:
[ formula 1]
Wherein the content of the first and second substances,
R1and R2Each independently selected from hydrogen, halogen, C1-C8Alkyl, halo-C1-C8Alkyl radical, C1-C8Alkylthio and C1-C8An alkoxy group; and
A1and A2One is CH and the other is N.
In addition, the present invention provides a pharmaceutical composition for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures, comprising a therapeutically effective amount of the carbamate compound of formula 1 above, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further one or more pharmaceutically acceptable carriers.
In addition, the present invention provides a method for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures in a subject, which comprises administering to the subject a therapeutically effective amount of a carbamate compound of formula 1 above, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In addition, the present invention provides the use of the carbamate compound of formula 1 above, or a pharmaceutically acceptable salt, solvate, or hydrate thereof for preventing, alleviating, or treating absence seizures or epilepsy exhibiting absence seizures.
In one embodiment of the present invention, in the above formula 1, R1And R2Each independently selected from hydrogen, halogen and C1-C8An alkyl group.
In one embodiment of the invention, halo C1-C8Alkyl is perfluoroalkyl.
In another embodiment according to the present invention, the carbamate compound of the above formula 1 is (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate of the following formula 2:
[ formula 2]
。
The carbamate compounds of the above formulae 1 and 2 can be easily prepared by one of ordinary skill in the art of compound synthesis using known compounds or compounds that can be easily prepared therefrom. In particular, methods for preparing the compounds of formula 1 above are described in detail in PCT publications WO2006/112685a1, WO2010/150946a1 and WO2011/046380a2, the disclosures of which are incorporated herein by reference. The compound of the above formula 1 can be chemically synthesized by any method described in the above documents, but these methods are merely exemplary methods, and the order of unit operations and the like can be selectively changed if necessary. Accordingly, the above methods are not intended to limit the scope of the present invention.
The carbamate compound of the above formula 1 can be used for preventing, alleviating or treating absence seizures or epilepsy exhibiting absence seizures.
According to one embodiment of the present invention, absence episodes may be broadly divided into typical absence and atypical absence. In the case of a typical absence, the episode will usually end in 2 to 10 seconds and rarely last for more than 30 seconds. Thus, the patient himself, let alone others, sometimes does not know whether they have had an attack. After the episode, the patient returns to the action or situation they were doing just before the episode without realizing that he has the episode. Atypical loss of consciousness includes loss of consciousness, full eye gaze, eyelid blinking, licking the lips, chewing behavior or finger touch. The frequency of these symptoms may decrease before and after puberty, but most tend to develop into grand mal seizures.
According to an embodiment of the present invention, the epilepsy showing absence seizures may be one or more selected from childhood-type absence epilepsy, epilepsy with myoclonic absence, juvenile-type absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (blepharospasm with absence), hereditary generalized epilepsy with phantom absence and L enox-Gastaut syndrome.
According to one embodiment of the invention, the absence episode may be a typical absence or an atypical absence. Absence episodes may also include all episodes with spike-Slow Wave Discharge (SWD) characterized by EEG.
The carbamate compound of the above formula 1 can be applied to absence seizures or epilepsy showing absence seizures by its ability to inhibit Spinodal Wave Discharge (SWD).
The efficacy of the carbamate compound of formula 1 above for absence seizures or epilepsy exhibiting absence seizures can be confirmed using known models. For example, The GAERS (hereditary absence epilepsy rat from Strasbourg) model is a type of rat that, due to its genetic characteristics, exhibits spontaneous spike-Slow Wave Discharge (SWD) and absence seizure behavior, and is therefore an experimental animal model that is being used as a means to demonstrate The efficacy of agents for treating absence seizures (Depaulis et al, The genetic absence epsilon, from Strasbourg as a model to deacidipherythe neural and network mechanisms of generalized diabetic epilepsy, JNeeurosic Methods, 2016 Feb15;260: 159-74).
In rats in this disease model, SWD is characteristically observed by cerebral cortical EEG recordings and occurs approximately 45 to 60 times per hour for approximately 17 to 25 seconds each. This SWD is also associated with a cessation of activity, which is a behavioral characteristic of absence episodes. It is well known that SWD in GAERS model rats is also inhibited by valproate, ethosuximide, etc., similarly to human patients, and that many drugs do not inhibit or some drugs adversely worsen SWD (Dedewaerder et al, fluent and constant activity inhibition in vitro with genetic and acquired expression. Seizure.2011 Jan;20(1):72-9; New et al, Cerebriety metabolism with genetic expression system is not affected by the biological activity of biological metabolism, yield-reaction, reaction, the effective of systematic and intracritical administration of phyton in two genetic models of absence EPILEPYS. Br J Pharmacol. 2006 Aug;148(8) 1076-82; Vartan et al, Activity profile of pregabalin in cadent models of EPILEPYS and ataxia. EPILEPYS Res. 2006 Mar;68(3) 189-).
Thus, this disease model is considered to be a useful model for predicting the effect on absence seizures (Klitgarget, Use of epidemic animals for adaptive effect testing. Epilepsy Res.2002 Jun;50(1-2):55-65; van L uijtelaar E L, Drinkenburg WH, van Rijn CM, CoenenAM. Rat models of genetic absence epsy EEG, what has do spike-wave discrete absence devicesMethods Find Exp Clin Pharmacol. 2002;24 Suppl D:65-70)。
The dose of the carbamate compound of formula 1 for preventing, alleviating or treating the above-mentioned diseases may generally vary depending on the severity, body weight and metabolic condition of the disease of the subject. A "therapeutically effective amount" for an individual patient refers to an amount of active compound sufficient to achieve the pharmacological effects described above (i.e., the therapeutic effects described above). A therapeutically effective amount of a compound of formula 1 is 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300 mg, 50 to 200 mg, or 100 to 200 mg, in free form and administered once daily to a human.
The compounds of the present invention may be administered by any conventional method for administering therapeutic agents, for example, oral, parenteral, intravenous, intramuscular, subcutaneous, or rectal administration.
A medicament or pharmaceutical composition according to one embodiment of the present invention may comprise a therapeutically effective amount of a compound selected from the group consisting of the carbamate compounds of the present invention, pharmaceutically acceptable salts, solvates, hydrates thereof, and combinations thereof.
Examples of the pharmaceutically acceptable salts of the carbamate compounds of formula 1 above independently include acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camphorsulfonate, carbonate, citrate, edetate, edisylate, etolate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolylated para-aminophenylarsenate, hexylresorcinate (hexylresorcinate), hydrabamine (hydrabamine), hydrobromide, hydrochloride, bicarbonate, hydroxynaphthoate (hydroxynaphthoate), iodide, isethionate, lactate, lactobionate (lactobionate), malate, maleate, mandelate, methanesulfonate, methylnitrate, methylsulfate, mucate (mucate), naphthalenesulfonate, nitrate, pamoate (pamoate), pantothenate, phosphate/diphosphate, calcium acetate, camphorate, menthyl nitrate, methyl sulfate, galactonate, napsylate (mucoate), napsylate (pamoate), pamoate, pantothenate, phosphate/diphosphate, and the like, Polygalacturonate, salicylate, stearate, subacetate, succinate or hemisuccinate, sulfate or hemisulfate, tannate, tartrate, oxalate or hemitartrate, theachlorate (teoclate), triiodonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium, and zinc.
The medicament or pharmaceutical composition according to one embodiment of the present invention may be administered orally or parenterally. Parenteral administration may include intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intravaginal administration, intrapulmonary administration, rectal administration, and the like. In the case of oral administration, the pharmaceutical composition according to one embodiment of the invention may be formulated as a plain tablet (uncoated tablet) or such that the active agent is coated or protected from degradation in the stomach. Furthermore, the composition can be administered by any device capable of transferring the active agent to the target cell. The route of administration may vary according to the general condition and age of the subject to be treated, the nature of the condition being treated and the active ingredient selected.
The appropriate dose of the drug or pharmaceutical composition according to one embodiment of the present invention may vary depending on factors such as formulation method, administration method, age, body weight and sex of the patient, pathological conditions, diet, administration times, administration route, excretion rate and response sensitivity, and a physician having ordinary skill can easily determine and prescribe a dose effective for the desired treatment or prevention. The pharmaceutical composition according to one embodiment may be administered in one or more doses, e.g., 1-4 times per day. A pharmaceutical composition according to one embodiment may comprise a compound of formula 1 in an amount of 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300 mg, 50 to 200 mg, or 100 to 200 mg, based on the free form.
The medicament or pharmaceutical composition according to one embodiment of the present invention may be formulated according to methods that can be easily performed by those having ordinary skill in the art, using pharmaceutically acceptable carriers and/or excipients, so as to be prepared in unit dosage form, or contained in a multi-dose container. The above formulation may be a solution, suspension or emulsion (emulsified solution), extract, powder, granule, tablet or capsule in an oil or aqueous medium, and may further include a dispersing or stabilizing agent. In addition, the pharmaceutical composition may be administered in the form of suppositories, sprays, ointments, emulsions, gels, inhalants or skin patches. The pharmaceutical compositions may also be prepared for administration to a mammal, more preferably for administration to a human.
The pharmaceutically acceptable carrier may be a solid or a liquid, and may be one or more selected from the group consisting of fillers, antioxidants, buffers, bacteriostats, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release control agents, wetting agents, stabilizers, suspending agents, and lubricants. In addition, the pharmaceutically acceptable carrier may be selected from the group consisting of saline, sterile water, ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.
In one embodiment, suitable fillers include, but are not limited to, sugars (e.g., glucose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, and xylitol), starch hydrolysates (e.g., dextrins and maltodextrins), cellulose or cellulose derivatives (e.g., microcrystalline cellulose), or mixtures thereof.
In one embodiment, suitable binders include, but are not limited to, povidone, copovidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch, or mixtures thereof.
In one embodiment, suitable preservatives include, but are not limited to, benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, gallates, hydroxybenzoate, EDTA, or mixtures thereof.
In one embodiment, suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch, microcrystalline cellulose, or a mixture thereof.
In one embodiment, suitable sweeteners include, but are not limited to, sucralose (sucralose), saccharin, sodium saccharin, potassium saccharin, calcium saccharin, potassium acesulfame or sodium cyclamate, mannitol, fructose, sucrose, maltose, or mixtures thereof.
In one embodiment, suitable glidants include, but are not limited to, silicon dioxide, colloidal silicon dioxide, talc, and the like.
In one embodiment, suitable lubricants include, but are not limited to, long chain fatty acids and salts thereof, such as magnesium stearate and stearic acid, talc, glyceride waxes, or mixtures thereof.
As used herein, the terms "preventing", "preventing" and "prevention" refer to reducing or eliminating the likelihood of disease.
As used herein, the terms "alleviate", "alleviating" and "alleviating" refer to ameliorating, in whole or in part, a disease and/or its attendant symptoms.
As used herein, the terms "treating", "treating" and "treatment" refer to the complete or partial elimination of a disease and/or its attendant symptoms.
As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc.), most preferably a human, who is the subject of treatment, observation or experiment.
As used herein, the term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medical response in a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" encompasses a product comprising the specified amounts of the specified ingredients and any product which results, directly or indirectly, from combination of the specified amounts of the specified ingredients.
[ Effect of the invention ]
The medicament and the pharmaceutical composition according to the present invention can effectively treat and prevent absence seizures or epilepsy showing absence seizures.
Drawings
Fig. 1 shows the results of electroencephalogram (EEG) measurements observed under baseline conditions for the gas model used in the examples. It can be seen that spontaneous SWD occurred.
Fig. 2 shows the results of analyzing the effect of valproate used as a positive control on the number of occurrences of SWD produced in the GAERS model by electroencephalogram (EEG) analysis. The efficacy of two doses, 150 mg/kg and 200 mg/kg, was analyzed. The number of SWD occurrences in the baseline period immediately before the administration of the drug and the number of SWD occurrences in a total of 80 minutes from 10 minutes to 90 minutes after the administration of the drug are shown.
Figure 3 shows the results of an EEG analysis to analyze the effect of test compounds on the number of occurrences of SWD generated in the gas model. Four doses of 5, 10, 20 and 30 mg/kg were analyzed for efficacy. The number of SWD occurrences in the baseline period immediately before 20 minutes of test compound administration and the total 80 minutes from 10 minutes to 90 minutes after test compound administration are shown.
Figure 4 shows the number of SWD occurrences from 10 to 70 minutes, for a total of 60 minutes, following drug or test compound administration. Differences in effects among the vehicle-administered group, the test compound-administered group, and the valproate-administered group can be confirmed.
Figure 5 shows the results of analysis of the effect of valproate as a positive control on the cumulative duration of SWD produced in the gas model over time by EEG analysis. The efficacy of two doses, 150 mg/kg and 200 mg/kg, was analyzed. The cumulative duration of SWD in the baseline period immediately prior to dosing for 20 minutes and the cumulative duration of SWD at 20 minute unit intervals from 10 minutes to 90 minutes after dosing are shown.
Figure 6 shows the results of analysis of the effect of test compounds on the cumulative duration of SWD produced in the gas model over time by EEG analysis. Four doses of 5, 10, 20 and 30 mg/kg were analyzed for efficacy. The cumulative duration of SWD in the baseline period immediately prior to 20 minutes of test compound administration and the cumulative duration of SWD at 20 minute unit intervals from 10 minutes to 90 minutes after test compound administration are shown.
Fig. 7 shows the cumulative duration of SWD at 20 minute unit intervals from 10 to 70 minutes, for a total of 60 minutes, following drug or test compound administration. Differences in effects among the vehicle-administered group, the test compound-administered group, and the valproate-administered group can be confirmed.
Detailed Description
Hereinafter, the present invention will be explained in more detail by working examples. However, the following working examples are intended only to illustrate one or more embodiments and are not intended to limit the scope of the invention.
Preparation examples: synthesis of (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate
(R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl carbamate (test compound) was prepared according to the method described in preparation example 50 of PCT publication No. WO 2010/150946.
Example (c): efficacy test for prevention and treatment of absence seizures using the GAERS (hereditary absence epilepsy rat from Strasbourg) model
The GAERS (hereditary absence of epilepsy from Strasbourg) model is a type of rat that exhibits spontaneous SWD due to genetic effects. The GAERS model has typical behavioral, electrophysiological and pharmacological characteristics of absence seizures and has therefore been used as a disease model for absence seizures for about 20 years (Depaulis et al, The genetic anaerobic approach from Strsbourg as a model to The defibrillator The neurological and cybernechanics of genetic refractory approaches, J Neurosci methods, 2016 Feb15;260: 159-74).
Laboratory animal
Twelve 5-week-old GAERS model rats were purchased from the Grenobel Institute of neurosciens, France. After purchase, rats were housed at a temperature of 21 ± 2 ℃ under free access to food and water and controlled light (8 am to 8 pm lighting) and maintained in conditions for 2 months prior to surgery.
Electrode implantation for EEG measurements
EEG electrodes were implanted into twelve 3-month-old GAERS rats. Stereotactic implantation was performed under anesthesia with isoflurane (2% concentration in oxygen). Rats were fixed on a stereotactic frame and operated while observing body temperature. Ophthalmic gels are used to prevent drying of the cornea. After cutting the hair at the incision site, it was sterilized with povidone, and after the incision, four holes were drilled in the frontal and apical cortex positions of the two hemispheres of the open skull with a drill. Monopolar electrodes are placed in these holes and then connected to a female connector fixed to the skull for EEG recording. The incision site is then sutured. After surgery, buprenorphine was injected subcutaneously at a dose of 0.1 mg/kg, and anesthesia was removed and observed until consciousness was restored. Thereafter, the rats were housed in cages for one week.
Animal screening for drug efficacy testing
One week after electrode implantation, a1 hour preliminary EEG measurement was performed on all 12 animals, and 10 animals were selected that showed sufficient signal-to-noise ratio to detect SWD production.
Drug delivery
Test compounds and positive control drugs were prepared immediately prior to administration. Carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl-ethyl ester prepared in the above preparation example was used as test compound, dissolved in 30% (v/v) PEG300(81164-14, Sigma-Aldrich), and the positive control valproate (P4543, Sigma-Aldrich) was dissolved in 0.9% sterile saline (Cooper, France). Both drugs were administered intraperitoneally at a dose of 5 ml/kg. 30% PEG300 was used for vehicle administration as a negative control.
The test was performed using a cross-over method with a minimum interval of 71 hours between each administration in order to wash out the drug. In the first stage of the test, the following conditions were employed.
Medium (30% PEG300)
200 mg/kg of valproate
5 mg/kg of test compound
10 mg/kg of test compound
Test compound 20 mg/kg
In the second stage of the test, the following conditions were employed.
-valproate 150 mg/kg
30 mg/kg of test compound
EEG recording
For EEG recordings, 10 GAERS rats were placed in the recording chamber and then connected to the lead wires for EEG recordings. After one hour of acclimation, EEG recordings were made of free-moving animals. As a baseline phase, recordings were made 20 minutes prior to dosing and 90 minutes after dosing using systempis Evolution (Micromed). During the recording, the animals were kept in a resting wake.
EEG data analysis
The resulting SWD was analyzed using recorded EEG data and all data analysis was performed by blinding. SWD analysis was performed for a baseline period of 20 minutes and for a total period of 80 minutes from 10 to 90 minutes after dosing. The 80 minutes were analyzed by dividing them into 20-minute intervals, and the number of occurrences of SWD and the accumulated SWD duration (accumulated duration of SWD) were analyzed.
Statistical analysis
Results are expressed as mean ± standard error and were statistically analyzed using prism (graphpad). For the number of SWD occurrences and cumulative duration of SWD over time, two-way ANOVA (2-way ANOVA) was used. For comparison to the baseline period, to the negative control administered with vehicle, and to the positive control administered with valproate, the paired comparison method of Bonferroni was used. Regarding the total effect 1 hour after drug administration, for replicate measurements, one-way analysis of variance (1-way ANOVA) was used, and the paired comparison method of Bonferroni was used for comparison with the negative control administered with vehicle and for comparison with the positive control administered with valproate. The criterion for statistical significance was defined as p < 0.05.
Test results
In one of the 10 GAERS rats used for EEG recording, the number of baseline SWDs produced was low, making it unsuitable for analysis, and data for that one was excluded from the final analysis.
1) Test Compounds for Effect on the number of SWD occurrences
The results of the two-factor analysis of variance for measurements at unit intervals of every 20 minutes are as follows.
At any time point, the vehicle-administered group as a negative control showed no difference compared to baseline.
The valproate-administered group as a positive control showed the effect of reducing the number of occurrences of SWD by valproate administration. The 150 mg/kg dose group showed a statistically significant decrease in the number of occurrences of SWD at intervals of 10-30 minutes and 30-50 minutes after the administration, compared to the vehicle dose group. In addition, the 200 mg/kg-dosed group showed a significant reduction in the number of occurrences of SWD over the entire time period (between 10 and 90 minutes) after dosing compared to the negative control.
The test compound-dosed groups at doses of 10, 20 and 30 mg/kg showed a significant reduction in the number of occurrences of SWD compared to the vehicle-dosed group. The 10 mg/kg dose showed significance at intervals of 30 to 50 minutes after administration, the 20 mg/kg dose showed significance at intervals of 30 to 90 minutes after administration, and the 30 mg/kg dose showed significance throughout the period after administration. In terms of duration of effect, the test compound showed a longer duration than valproate as a positive control.
With respect to the total effect at 1 hour after the administration, the results of the one-way anova showed that the test compound-administered groups at the doses of 20 and 30 mg/kg significantly reduced the number of occurrences of SWD compared to the vehicle-administered group, and showed effects similar to those of the valproate-administered group at the doses of 150 and 200 mg/kg.
2) Effect of test Compounds on cumulative duration of SWD
The results of the two-factor analysis of variance for the cumulative value of SWD duration per 20 minute unit interval are as follows.
At any time point, the vehicle-administered group as a negative control showed no difference compared to baseline.
The valproate-administered group as a positive control showed a decreasing effect of the cumulative duration of SWD by valproate administration. The 150 mg/kg dose group showed significant reduction in the intervals of 10-30 min, 30-50 min and 50-70 min after the administration, while the 200 mg/kg dose group showed significant reduction in the entire time period (10-90 min) after the administration as compared with the negative control.
The test compound-dosed groups at doses of 10, 20 and 30 mg/kg showed a significant reduction in the cumulative duration of SWD compared to the vehicle-dosed group. The 10 mg/kg dose showed significant reduction in the 30-50 and 50-70 minute intervals after administration, the 20 mg/kg dose showed significant reduction in the 30-90 minute intervals after administration, and the 30 mg/kg dose showed significant reduction throughout the period after administration. In terms of duration of effect, the test compound showed a longer duration than valproate as a positive control.
With respect to the total effect 1 hour after the administration, the results of the one-way anova showed that the test compound-administered group at the doses of 20 and 30 mg/kg significantly reduced the cumulative duration of SWD compared to the vehicle-administered group, and showed effects similar to those of the valproate-administered group at the doses of 150 and 200 mg/kg.