The invention generally relates to Pharmacology. More specifically, it relates to a
novel antiepileptic compound. The present invention further relates to the therapeutically effective dosage of the novel antiepileptic compound.
BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Epilepsy is a condition of the brain marked by a susceptibility to recurrent seizures. There are numerous causes of epilepsy such as birth trauma, perinatal infection, anoxia, infectious diseases, ingestion of toxins, tumors of the brain, inherited disorders or degenerative disease, head injury or trauma, metabolic disorders, cerebro-vascular accident and alcohol withdrawal. Epilepsy is one of the most common chronic diseases of the nervous system in the world, which affects both children and adults. According to WHO, epilepsy affects about 50 million people, which is about 0.5-1% of the world's population. Annually around 2.5 million new cases are diagnosed in the world. There are many drugs available for the treatment of epilepsy in the market such as lamotrigine, topiramate, oxcarbazepine, levetiracetam, tiagabine, gabapentin, pregabalin, zonisamide, valproate and carbamazepine. The available drugs are able to prevent the seizures but suffer from many limitations such as Side effects, High cost, unclear mode of action and inability to cure refractory epilepsy (Refractory epilepsy is a type of epilepsy in which medicine cannot bring seizures under control).
[0004] A large amount of research work is going on in the field of treating epilepsy. EP3309150 discloses Biphenyl-Ethyl-Pyrrolidine derivatives for the treatment of epilepsy and other cognitive disorders. EP3311666 discloses P-diketone, y- diketone or y- hydroxyketone or salts or analogs for the treatment of epilepsy. WO2002098418 discloses an antiepileptic composition comprising of P-glycoprotein (P-gp) inhibitor and an antiepileptic drug selected

from phenytoin (5,5- diphenyl-2,4- imidazolidinedione), carbamazepine, lamotrigine, gabapentin, oxcarbazepin, valproic acid, and topiramate. JP20066534798 discloses an antiepileptic compound namely N- [Heteroalyl (Piperidin-2- yl) Methyl] Benzamide. EP20090382051 discloses a derivative of a non-commercial monacolin J compound, specifically (lS,2S,6R,8S,8aR)-l,2,6,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-l-naphthalenyl-2-ethylbutyrate for the treatment for epilepsy. WO2016203239 discloses a Cannabidiol (CBD) for use in the treatment of focal seizures and epilepsy. BRI0607017 discloses an antiepileptic composition comprising of NMDAr antagonist and an acetylcholinesterase inhibitor (AChel). KR2017/011596 discloses a composition containing syringaresinol or preventing or treating neurological and mental disorders such as epilepsy. US2018050029 discloses a composition
comprising a selective connexin hemi-channels blocker compounds useful in the treatment of epilepsy in combination with other antiepileptic compounds. WO2006/033947 discloses use of 2-phenyl- 1, 2-ethanediol- (di) carbamates for treating epileptogenesis and epilepsy. RU2650523 discloses use of derivatives of pyridoxine having anti-epileptic activity. WO 2017021881 discloses use of 2-(5smethyl-2-oxo-4r-phenylpyrrolidin-l-yl)-acetamide in the treatment of seizures and epilepsy. IN-201717045509 discloses compounds viz., l,l,l-Trifuoro-3-Hydroxypropan-2-yl -carbamate derivatives and 1,1,1- trifluoro-4-hydroxybutan -2yl-carbamate derivatives as anti-epileptic drugs.
[0005] Though pathophysiology of epilepsy is well understood and a number of drugs are available in the market but still the existing antiepileptic drugs are not effective, cannot cure refractory epilepsy, have side effects, are not economical and have failed to cure the epilepsy completely. There is, therefore, a need to develop new anti-epileptic compounds, which can overcome deficiencies associated with the known arts. The inventors have addressed the above problems in a very innovative manner by providing a novel compound which can cure refractory epilepsy.
OBJECTS OF THE INVENTION
[0006] An object of the present invention is to disclose a novel anti-epileptic compound which overcomes the deficiencies associated with conventional anti-epileptic compounds.

[0007] An object of the present invention is to disclose a novel anti-epileptic compound which
is very effective in treating refractory epilepsy.
[0008] Another object of the present invention is to disclose a novel anti-epileptic compound and
its therapeutically effective dosage.
[0009] Another object of the present invention is to disclose a novel anti-epileptic compound
which does not have side effects.
[0010] Another object of the present invention is to disclose a novel anti-epileptic compound
which is economical and can cure epilepsy completely.
SUMMARY OF THE INVENTION
[0011] This summary is provided to introduce a selection of concepts in a simplified form
that are further described below in Detailed Description section. This summary is not intended to
identify key features or essential features of the claimed subject matter, nor is it intended to be
used as an aid in determining the scope of the claimed subject matter.
[0012] The present invention relates to Pharmacology. Specifically, the present invention
relates to a novel antiepileptic compound.
[0013] In one aspect, the present invention relates to a novel anti-epileptic compound
which is very effective in treating refractory epilepsy.
[0014] In another aspect, the present invention relates to a novel anti-epileptic compound
which is economical and can cure epilepsy completely.
[0015] In another aspect, the present invention relates to a novel anti-epileptic compound
which does not have side effects.
[0016] In another aspect, the present invention relates to a novel anti-epileptic compound,
wherein the novel anti-epileptic compounds is Diethyl dithiocarbamic acid sodium salt trihydrate
(DDA).
[0017] In another aspect, the present invention relates to a novel anti-epileptic compound
and its therapeutically effective dosage.
[0018] In another aspect, the present invention relates to a novel anti-epileptic compound,
wherein the therapeutically effective dosage in animals is 75-150 mg/kg.
[0019] In one aspect, the present invention relates to relates to a novel anti-epileptic
compound, which can be given to the patients in oral form.

[0020] In one aspect, the present invention relates to relates to a novel anti-epileptic
compound, which can be given to the patients in any dosage form such as tablets, syrups, sustained release capsules, extended release capsules etc.
[0021] Other aspects of the invention will be set forth in the description which follows, and
in part will be apparent from the description, or may be learnt by the practice of the invention.
BRIEF DESCRIPTION OF DRAWINGS THE INVENTION
[0022] The following drawings form part of the present specification and are included to further
illustrate aspects of the present disclosure. The disclosure may be better understood by reference
to the drawings in combination with the detailed description of the specific embodiments
presented herein.
Figure 1: Effect of antiepileptic compound Diethyl dithiocarbamic acid sodium salt trihydrate
(DDA) on pentylenetetrazol induced kindled seizures (epilepsy) in mice.
Figure 2: Effect of anti epileptic compound Diethyl dithiocarbamic acid sodium salt trihydrate
(DDA) on pilocarpineinducedstatus epilepticus (epilepsy) in mice.
Figure 3: Histopathological studies of mice brain hippocampus
A. Control group (Only saline/ vehicle)
B. Pilocarpine +Vehicle (saline) group
C. Pilocarpine+Diethyl dithiocarbamic acid sodium salt trihydrate (DDA)
D. Pentylenetetrazole+ Vehicle( saline)
E. Pentylenetetrazole + Diethyl dithiocarbamic acid sodium salt trihydrate (DDA)
DETAILED DESCRIPTION
[0023] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims. [0024] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is

inconsistent or contrary to the definition of that term provided herein, the definition of that term
provided herein applies and the definition of that term in the reference does not apply.
[0025] Reference throughout this specification to "one embodiment" or "an embodiment"
means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. [0026] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0027] As used in the description herein and throughout the claims that follow, the meaning
of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.
[0028] Unless the context requires otherwise, throughout the specification which follow, the
word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense that is as "including, but not limited to."
[0029] The recitation of ranges of values herein is merely intended to serve as a shorthand
method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were

individually recited herein. All methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g. "such as") provided with respect to certain
embodiments herein is intended merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No language in the specification
should be construed as indicating any non-claimed element essential to the practice of the
invention.
[0030] Groupings of alternative elements or embodiments of the invention disclosed herein
are not to be construed as limitations. Each group member can be referred to and claimed
individually or in any combination with other members of the group or other elements found
herein. One or more members of a group can be included in, or deleted from, a group for reasons
of convenience and/or patentability. When any such inclusion or deletion occurs, the
specification is herein deemed to contain the group as modified thus fulfilling the written
description of all Markush groups used in the appended claims.
[0031] The description that follows, and the embodiments described therein, is provided by
way of illustration of an example, or examples, of particular embodiments of the principles and
aspects of the present disclosure. These examples are provided for the purposes of explanation,
and not of limitation, of those principles and of the disclosure.
[0032] It should also be appreciated that the present disclosure can be implemented in
numerous ways, including as a system, a method or a device. In this specification, these
implementations, or any other form that the invention may take, may be referred to as processes.
In general, the order of the steps of the disclosed processes may be altered within the scope of
the invention.
[0033] The headings and abstract of the invention provided herein are for convenience only
and do not interpret the scope or meaning of the embodiments.
[0034] The following discussion provides many example embodiments of the inventive
subject matter. Although each embodiment represents a single combination of inventive
elements, the inventive subject matter is considered to include all possible combinations of the
disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second
embodiment comprises elements B and D, then the inventive subject matter is also considered to
include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0035] Various terms as used herein are shown below. To the extent a term used in a claim
is not defined below, it should be given the broadest definition persons in the pertinent art have
given that term as reflected in printed publications and issued patents at the time of filing.
[0036] Though pathophysiology of epilepsy is well understood and a number of drugs are
available in the market but still the existing antiepileptic drugs are not effective, cannot cure
refractory epilepsy, have side effects, are not economical and have failed to cure the epilepsy
completely.
[0037] The inventors have addressed the above problems in a very innovative manner by
providing a compound Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) and its
effective dose which can cure refractory epilepsy. The said compound acts at molecular level and
leads to cure refractory epilepsy by inhibiting transcriptional factor kappa- B (NF-KB). The NF-
KB regulates the induction of genes involved in seizures and epilepsy (status epilepticus
condition).
[0038] The present invention relates to Pharmacology. Specifically, the present invention
relates to a novel antiepileptic compound.
[0039] In one aspect, the present invention relates to a novel anti-epileptic compound
which is very effective in treating refractory epilepsy.
[0040] In another embodiment, the present invention relates to a novel anti-epileptic
compound which is economical and can cure epilepsy completely.
[0041] In another embodiment, the present invention relates to a novel anti-epileptic
compound which does not have side effects.
[0042] In another embodiment, the present invention relates to a novel anti-epileptic
compound, wherein the novel anti-epileptic compounds is Diethyl dithiocarbamic acid sodium
salt trihydrate (DDA).
[0043] In another embodiment, the present invention relates to a novel anti-epileptic
compound and its therapeutically effective dosage.
[0044] In another embodiment, the present invention relates to a novel anti-epileptic compound,
wherein the therapeutically effective dosage in animals is 75-150 mg/kg.
[0045] In one embodiment, the present invention relates to relates to a novel anti-epileptic
compound, which can be given to the patients in oral form.

[0046] In one embodiment, the present invention relates to relates to a novel anti-epileptic
compound, which can be given to the patients in any dosage form such as tablets, syrups,
sustained release capsules, extended release capsules etc.
[0047] In another embodiment, the disclosed anti-epileptic compound can be used to prepare
antiepileptic formulations in syrup, tablet or any dosage form at commercial scale in
Pharmaceutical industries.
[0048] In another embodiment, the present invention relates to a novel anti-epileptic
compound, wherein the therapeutically effective dosage in humans is 6-12 mg/kg.
[0049] In one embodiment, the present invention relates to relates to a novel anti-epileptic
compound, wherein the compound is administered intravenously.
[0050] While the foregoing describes various embodiments of the disclosure, other and
further embodiments of the disclosure may be devised without departing from the basic scope
thereof. The scope of the invention is determined by the claims that follow. The invention is not
limited to the described embodiments, versions or examples, which are included to enable a
person having ordinary skill in the art to make and use the invention when combined with
information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0051] The present invention is further explained in the form of following examples.
However, it is to be understood that the following examples are merely illustrative and are not to
be taken as limitations upon the scope of the invention.
[0052] Example 1: Induction of epilepsy in mice: The epilepsy was induced in mice by two
methods viz.
i. By administering pentylenetetrazole for kindled seizures. (Kindling refer to the
phenomenon whereby repeated chemical stimulation of the brain with initially subconvulsive
doses results in the progressive development of partial and secondarily generalized seizures,
resembling or reflecting epileptogenesis).
ii. By administering pilocarpine for status epilepticus with spontaneous recurrent seizure (Status
epilepticus (SE) is a single epileptic 5 seizure lasting more than five minutes or two or more
seizures within a five-minute period without the person returning to normal between them).
Induction of the pentylene tetrazole mediated epilepsy in mice Male inbred Swiss albino mice
weighing 25±2g maintained on standard laboratory diet having free access to tap water were

used for the study. The mice were divided into 4 groups of 10 each and were administered i.p. (intra-peritoneal) saline, Pentylenetetrazole and Diethyl Dithiocarbamic Acid Sodium Salt Trihydrate (DDA) for 15 days as given in Table 1.
Table 1: Effect of administration of Antiepileptic compound in treating epilepsy in mice

Groups Treatments (mg/kg on every alternate day)

Vehicle (saline) Pentylenetetrazole (PTZ)
(Seizure Inducing Drug) Diethyl
Dithiocarbamic Acid Sodium Salt Trihydrate
(Compound of present invention) Observations (After Day 15)
I(Control) 10 0 0 No seizures
II 10 40 0 Progressive Increase in seizures
III 10 40 75 Significant suppression of seizures
IV 10 40 150 Almost complete suppression of seizures
The administration of saline alone did not cause any seizures in Group I, while administration of
Pentylenetetrazole (seizure causing drug) on alternate days for 15 days caused seizures in mice which increased with each progressive day 5 in Group II. In Group III, the administration of 75 mg/kg of antiepileptic compound viz. Diethyl Dithiocarbamic Acid Sodium Salt Trihydrate (DDA) with Pentylenetetrazole resulted in significant suppression of seizures while in Group IV, administration of 150 mg /kg antiepileptic compound viz. Diethyl Dithiocarbamic Acid Sodium Salt Trihydrate (DDA) with 10 Pentylenetetrazole (40mg/kg) resulted in almost complete suppression of seizures (Figure 1).
ii. Induction of the status epilepticus with spontaneous recurrent seizure activity in mice
The mice were divided into 4 groups of 10 each and were administered saline, pilocarpine and DDA for 31 days (alternate days) as given in Table 2. In order to avoid peripheral cholinergic 15 side effects, hyoscine butylbromide (1 mg/kg i.p.) was administered 20 minutes prior to the

application of pilocarpine.
Table 2: Effect of administration of Antiepileptic compound in treating epilepsy in mice

Groups Treatments (mg/kg)

Vehicle (Saline) Pilocarpine
(Seizure Inducing Drug) (After 30 mins of DDA) Diazepam
(After 40 mins of seizures) Diethyl
Dithiocarbamic Acid Sodium Salt Trihydrate (DDA)
(Prior 30 mins of pilocarpine) Observations (After Day 31)
I (Control) 10 0 3 0 No seizures
II(Seizure inducing drug) 10 100 3 0 Progressive Increase in seizures
III (Seizure inducing drug + 75 mg per kg ofthe novel drug) 10 100 3 75 Significant Suppression of seizures
IV (Seizure inducing drug + 150mg per kg ofthe novel drug) 10 100 3 150 Complete suppression of seizures
The administration of saline alone did not cause any seizures in Group I, while administration of Pilocarpine (seizure causing drug) on alternate days for 31 days caused seizures in mice which increased with each progressive day in Group II. 5 In Group III, the administration of 75 mg/kg of antiepileptic compound viz. Diethyl Dithiocarbamic Acid Sodium Salt Trihydrate (DDA with Pilocarpine) resulted in significant suppression of seizures while in Group IV, administration of 150 mg/kg antiepileptic compound viz. Diethyl Dithiocarbamic Acid Sodium Salt Trihydrate (DDA) with Pilocarpine resulted in almost complete suppression of seizures (Figure 2).
Example 2: Evaluation of the antiepileptic activity of the compound of present invention

The evaluation was done by Biochemical analysis and Pathological examination of brain tissues.
Biochemical analysis
The animals were sacrificed by cervical dislocation. The brains were removed and homogenized
in phosphate buffer (pH 7.4, 10% w/v) using a homogenizer. The clear supernatant obtained after
centrifugation at 3000 rpm for 15 min, was used for biochemical analysis. Pilocarpine induced
status epilepticus & repeated treatment of sub convulsive dose of Pentylenetetrazol e produced
significant increase in seizures.
Result
The administration of Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) increased the
levels of harmful Thiobarbituric acid reactive substances (TBARS) and increased the level of
Glutathione (GSH) which clearly demonstrates ability of the compound to treat the epilepsy.
The results are summarized in Table 3.
Table 3. Biochemical analysis of mice brain after administration of Antiepileptic compound

Groups Thiobarbituric acid (TBA) Glutathione
I (Control No effect No effect
II (Seizure inducing drug) Increased Decreased
III (Seizure inducing drug + 75mg per kg of the novel drug) Decreased Increased
IV (Seizure inducing drug + 150mgpernkg of the novel drug) Decreased Increased
High TBA levels means more neurotoxicity due to membrane damage. TBA levels are measured by the Thiobarbituric-acid assay which is a method to detect levels of lipid peroxidation. Lipid peroxidation is one of the major outcomes of free radical-mediated injury that directly damages 10 membranes and generates a number of secondary products that possess epileptic and neurotoxic activity. High Glutathione levels mean high protective effect against neurotoxicity. Glutathione is the brain's master antioxidant and plays an important protective role in the brain. The neuroprotective and memory enhancing drugs should increase the glutathione level).

Example 3: Histopathological studies
3 mice from every group mentioned above, were anesthetized with pentobarbital sodium (50 mg/kg) and the brains were trans-cardially perfused with phosphate buffer solution (PBS, pH 7.4), followed by 4% paraformaldehyde in PBS (pH 7.4). The brains were removed and kept overnight in phosphate buffer solution containing 4% paraformaldehyde at 4°C and embedded in paraffin. Sections of 5-um thickness were stained with hematoxylin and eosin dyes. {Hematoxylin is used to stain nuclei blue, while eosin stains cytoplasm and the extracellular connective tissue matrix pink). The lesions of brain tissues were observed with light microscope and the images were collected by image analysis system.
Pilocarpine and Pentylenetetrazole administration produced significant alterations in hippocampus, striatum and frontal cortex. Neurons appeared shrunken with a fusiform shape with a typical picnotic conformation which shows deformation in brain. Treatment with Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) showed remarkable recovery and neurons appeared to be regaining from fusiform shape. It was thus confirmed that DDA attenuates the effect of pilocarpine and Pentylenetetrazole on neuronal texture and configuration (Fig 3). Thus, the compound of present invention when administered in mice 75-150 mg/kg can cure refractory epilepsy. Equivalent human dose was found to be 6-12 mg/kg (intravenous).
The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
ADVANTAGES OF THE PRESENT INVENTION
[0053] The present invention provides a novel antiepileptic compound.
[0054] The present invention provides a novel antiepileptic compound which is very effective in
treating refractory epilepsy.
[0055] The present invention a novel anti-epileptic compound and its therapeutically effective
dosage.
[0056] The present invention a novel anti-epileptic compound which does not have side effects.

[0057] The present invention a novel anti-epileptic compound which is economical and can cure epilepsy completely.

WE Claim:

1.A novel antiepileptic compound, effective in treating refractory epilepsy, wherein the antiepileptic effect is achieved by inhibiting transcriptional factor kappa- B (NF-KB).
2. The novel antiepileptic compound, as claimed in claim 1, wherein the novel antiepileptic compound is Diethyl dithiocarbamic acid sodium salt trihydrate (DDA).
3. The novel antiepileptic compound, as claimed in claim 1, which does not have any side effects and can cure refractory epilepsy.
4. The therapeutic dosage of the novel antiepileptic compound, as claimed in claim 1.
5. The therapeutic dosage of the novel antiepileptic compound, as claimed in claim 1, wherein the dosage for treating epilepsy in animals is 75-150 mg/kg.
6. The therapeutic dosage of the novel antiepileptic compound, as claimed in claim 1, wherein the compound is administered as tablets, syrups, sustained release capsules, extended release capsules and the like.
7. The therapeutic dosage of the novel antiepileptic compound, as claimed in claim 1, wherein the dosage for treating epilepsy in humans is 6-12 mg/kg.
8. The therapeutic dosage of the novel antiepileptic compound, as claimed in claim 7, wherein the compound is administered intravenously.