AU2013257707A1 - Compositions and methods for the treatment of epilepsy - Google Patents

Abstract

The invention relates to the compounds of formula (I) and formula (II) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I) or formula (II); and methods for treating or preventing neurological diseases may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotoaia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder.

Description

WO 2013/167986 PCT/IB2013/050740 1 COMPOSITIONS AND METHODS FOR THE TREATMENT OF EPILEPSY PRIORITY [00011 The present application claims the benefit of Indian Provisional Patent Application No. 1791/CHE/2012 filed on 08-May-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference, FIELD OF THE INVENTION 100021 This disclosure generally relates to compounds and compositions for the treatment of epilepsy. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, stereoisomers, enantiomers, esters, salts, hydrates, prodrugs, or mixtures thereof. BACKGROUND OF THE INVENTION 100031 Epilepsy is defined as a chronic neurological condition characterized by recurrent, unprovoked seizures. It is one of the most common serious neurological disorders in the United States and often requires long-term management. Each year 150000 people in the United States are newly diagnosed as having epilepsy, with the cumulative lifetime incidence approaching 3%. TIhe incidence is highest during the first year of life and in elderly persons- Although most people with epilepsy become seizure-free with appropriate therapy, 30% to 40% of patients will continue to have seizures despite the use of antiepileptic drugs either alone or in combination. 100041 Patients with uncontrolled seizures experience significant morbidity and mortality and face social stigma and discrimination as well. In the United States, only 17% of patients with new-onset epilepsy are initially seen by a neurologist. Furthermore, primary care physicians provide approximately 40% of the long-terr anagement of epilepsy patients with or without initial consultation with a specialist.

WO 2013/167986 PCT/IB2013/050740 2 [00051 Unfortunately, a survey of general practitioners revealed that only 40% of responders felt confident in their knowledge of epilepsy and two thirds were unfamiliar with the new antiepileptic drugs. A recent survey of 71 patients with epilepsy who are treated exclusively by general practitioners showed that 45% had experienced a seizure within the past year, 68% complained of drowsiness or difficulty in concentration with their current medications, and 28% were prescribed polytherapy. 100061 Prior to 1993, the choice of an anticonvulsant medication was limited to phenobarbital, primidone, phenytoin, carbamazepine, and vailproate. Although these "traditional" anticonvulsants have the advantage of familiarity as well as proven efficacy, many patients are left with refractory seizures as well as intolerable adverse effects. Since 1993, new medications have been approved by the US Food and Drug Administration (FDA), expanding treatment options. The newer antiepileptic drugs offer the potential advantages of fewer drug interactions, unique mechanism s of action, and a broader spectrum of activity. With more options, however, comes the challenge of determining what role the new antiepileptic drugs play in optimizing treatment in addition to understanding important adverse effects and drug interactions of these increasingly prescribed medications. 100071 Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a. need in the art for new compositions to treatment of epilepsy. SUMMARY OF THE INVENTION [00081 The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as epilepsy.

WO 2013/167986 PCT/IB2013/050740 3 [00091 The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceuticallv acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of epilepsy and its associated complications. HaC S N R R2

CH

3 Formula I 100101 In certain embodiments, the present invention relates to the compounds and compositions of fornaula I or pharmaceutically acceptable salts thereof.

H

3 C S N R2 OHO CH3 Formula 1 Wherein, R independently represents H, D, WO 2013/167986 PCT/IB2013/050740 4 0 0 NH, NH0 0 N 0 0 0 NN ANH, H HH HH 00 H

R

2 independently represents Acetyl (CH 3

CO-),

WO 2013/167986 PCT/IB2013/050740 5 00 C OH H OH HO HON 00 NHCH oo 0t HH HO 0 0 WO 2013/167986 PCT/IB2013/050740 6 NIHCOCH 00 C 0 2 H

~CONH

2 0C00 H OH OCC3a A

CH

3 e, OH 0 0

CH

NHCOH

3 K-C

H

3 C-N0

H

3 0 OH 3

H

3 CHX H - o HC CH CH OH 0 NH) 0 Hb or d a is Independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH, -OD, CI-C%-alky], -NH or -COCH 100111 In the illustrative embodiments, examples of compounds of formula I are as set forth below: WO 2013/167986 PCT/IB2013/050740 7 S NO

H

3 C & 0 o CHa (.1-i) [0012] Accordingly, the invention also provides pharmaceutical compositions comprising one or more compounds of formula 11 or inermediatesthereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents These compositions may be used in the treatment of epilepsy and its associated complications. 0 H R, NR2 H O N Formula II Wherein, R' independently represents, -ydrogei 0 0 0 WO 2013/167986 PCT/IB2013/050740 8 o j--o-[ <XN \ o 0 0 0O N Ho c H 00 t / H NN NH NH, HO HH N N O O OI HH 00 OHO H H N NjO or H R2 independently represents Acetyl (CH3CO-), SH OH S-C N te HH NHIN

OH

WO 2013/167986 PCT/IB2013/050740 9 0 00

H

2 N OO NN o"O 0 HO HO

NHCOCH

5 C02H CONH2 KOH

OCOCH

3 WO 2013/167986 PCT/IB2013/050740 10

OH

3 C OH 0 3 0

OH

3

+

3

-

a1 N

H

3 NH

OH

3 IH OHtQ CH3O 0 0H O b b Ora a is independently 23or 7; each b is independently 3, ) 5 o--r 6; e is independently 1, 2 or 6; c and d are each independently H D, -OH, -OD, CjC-alkyI, -NH or -COCH [00131 In the illustrative emibodim-ents, examples of compounds of form-ula I are as set forth below: H H H N O / H 0 N (2-1) WO 2013/167986 PCT/IB2013/050740 11 H N H 0 N (2-2) 100.1,41 Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of epilepsy or its related complications [00.1,51 The application also discloses a pharmaceutical composition comprising a pharmaceutical y acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systenic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration. 100161 Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of epilepsy or its related complications. [0017J The compositions described herein have several uses. 'The present application provides, for example, methods of treating a patient suffering from epilepsy or its related complications manifested from metabolic conditions, chronic diseases or disorders; Hepatology, Cancer, Neurological, Heniatological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications.

WO 2013/167986 PCT/IB2013/050740 12 DETAILED DESCRIPTION OF THE INVEN TION Definitions [00181 As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art [0019J The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e, the methyl and ethyl esters of the acids of formula I and formula 11 to be used as prodrugs). The compounds of the present invention can also be solvated, i.e, hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I and formula 11 (hydration). 100201 Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers " Isomers that difTer in the arrangement of their atoms in space are termed !!stereoisoiers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing riles of Cahn, ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e,, as (+) or (-)-isomers respectively). A chiral compound WO 2013/167986 PCT/IB2013/050740 13 can exist as either individual enantioner or as a mixture thereof. A. mixture containing equal proportions of the enantioniers is called a "racemic mixture". 100211 As used herein, the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. 100221 In sonic embodiments, a molecular conjugate comprises of compounds selected from the group consisting of R-hpoic acid (CAS No. 1200-22-2), salsalate (CAS No. 552-94-3), acetylcysteine (CAS No. 616-91-1), Eicosapentaenoic acid (CAS No 10417 94-4), Docosahexaenoic acid (CAS No. 6217-54-5), [0023] The term "poly.morph" as used herein is art recognized and refers to one crystal structure of a given compound, [00241 The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbitaP. intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion, 100251 A "patient," "subject" or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates. 100261 The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive WO 2013/167986 PCT/IB2013/050740 14 toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [00271 The phrase pharmaceuticallyy acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppositoty waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean, oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. 100281 TIe term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired rmolecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

WO 2013/167986 PCT/IB2013/050740 15 100291 The tern "prophylactic or therapeutic" treatment is art-recognized and Includes administration to the host of one or more of the subject compositions. if it is administered prior to clinical manifestation of the unwanted condition (e.g, disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e, it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition. the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof), [0030J The term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention. 100311 The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it, inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g, causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the neurological condition such as epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain. disorder, neuromyotoia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress WO 2013/167986 PCT/IB2013/050740 16 disorder of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (eg., prophylactic), adjunct and palliative treatment, 100321 The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation. f0033] In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount. as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, Typically, dosing will be determined using techniques known to one skilled in the art. 100341 Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the WO 2013/167986 PCT/IB2013/050740 17 preparation is put, e-.g, the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition. 100351 In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used. [0036J When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable recipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein. 10037 The phrases "systemic administration),""administered systemically," "peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

WO 2013/167986 PCT/IB2013/050740 18 [00381 The phrase "therapeutically effective amount" is an ar-recognized term.. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, In certain embodiments, the tern refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation. [0039J The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said piodrugs. 100401 This application also discloses a pharmaceutical composition comprising a pharmacetlically acceptable cancer and the composition of a compound of Formula I and formula IHI may be fJonulated for systemic or topical or oral administration. The pharmicetiical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant. 100411 In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I and Formula 1I) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I and formula II or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula. I and formula II or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the WO 2013/167986 PCT/IB2013/050740 19 subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. [00421 Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I and formula II may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which. the preparation is put, e.g, the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition. 100431 The concentration and/or amount of any compound of formula I and formula II may be readily identified by routine screening in animals, e.g-, rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed by T. [ Robinson et at., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter I The methods reviewed by Robinson may be applied, in brief, as follows. A. microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula I and formula 11 such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions. 100441 In certain embodiments, the dosage of the subject compounds of formula 1 and formula II provided herein may be determined by reference to the plasma concentrations WO 2013/167986 PCT/IB2013/050740 20 of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration time curve from time 0 to infinity may be used. 100451 Generally, in carrying out the methods detailed in this application, an efTective dosage for the compounds of Formulas I is in the range of about 0,01 mgfkc/day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 10 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of Formula. I and formula Ill may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0. 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the coin pound of formula 1 and formula I required for the same therapeutic benef t. [00461 An effective amount of the compounds of formula I and formula H described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease. [00471 An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve darnage or demvelization and/or elevated reactive oxidative nitrosative species and/or abnormalities in neurotransmitter homeostasis's, in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate, The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient WO 2013/167986 PCT/IB2013/050740 21 variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases. 100481 The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g , intravenously, subcutaneously or intrarneduillary Further, the compositions may be administered intranasally, as a rectal suppository, or using a "flash." formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles. 100491 The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents. in either single or inultiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers. vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia, Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and tale are often useful for tabletting WO 2013/167986 PCT/IB2013/050740 22 purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emnulsifyin or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof The compounds of formula I and formula 11 may also comprise enterically coated comprising of various excipients, as is well known in the pharnaceutical art. 100501 For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, Intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. 100511 The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 ng, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I and formula Il disclosed herein, for instance, compounds of formula I and formula Il or pharmaceutical acceptable salts of a compounds of Formula I. 100521 Generally, a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired WO 2013/167986 PCT/IB2013/050740 23 at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner. [00531 The dosage administered will be dependent upon the identity of the neurological disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio, 100541 Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, I to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight 100551 Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v. 100561 The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile nonparenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient For oral administration either solid or fluid unit dosage forms can be prepared. 100571 As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water swvellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof Examples of suitable water swellable cellulose derivatives include, but are not WO 2013/167986 PCT/IB2013/050740 24 Jiited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropy Imethyicell ul ose (HPMC), hydroxyisopropylcellulose, hydroxy butv cellul ose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethvlcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcelulose, and mixtures thereof Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivi nylbenzene copolymer, polymethyl methacryl ate, high-molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from. Noveon Chemicals under the tradename CARBOPOL 7 Examples of suitable hydrocolloids include, but are not limited to, alginates, agar., guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, gal actomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures thereof Examples of suitable clays include, but are not limited to. smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate, and mixtures thereof Examples of suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof, Lxamples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof [00581 The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable recipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof WO 2013/167986 PCT/IB2013/050740 25 100591 Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethyl cell lose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic. tragacanth, pectin, xanthan, gellian, gelatin. maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethvlcellulose, starches, microcrystalline cellulose, and mixtures thereof [0060J Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable release-modifying recipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof. 100611 Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kenel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl WO 2013/167986 PCT/IB2013/050740 26 monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myri state, GlycoWax 932, lauroyl macrogol-32. glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof Examples of suitable phospholipids include phosphotidyl choline., phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof Examples of suitable waxes include., but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross linked povidone (crospovi.done). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant. 100621 Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butyihydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof [00631 In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g, from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer, 100641 In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.

WO 2013/167986 PCT/IB2013/050740 27 100651 In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core. 100661 In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. in another embodiment the outer coating portion is included of a dried granulation including the phaimaceutically active agent. 100671 Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units, Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example. in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are knownri in the art. 100681 The immediate release dosage, unit of the dosage form, i.e, a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads), 100691 Extended release forniulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington-Tfhe Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A WO 2013/167986 PCT/IB2013/050740 28 diffusion system typically consists of one of two types of devices. reservoir and matrix, which are wellknow-n and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. [0070J An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads. [00711 Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a. drug or a drug-containing composition with a selected coating material. The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. 100721 A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form), A pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release. [0073J Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %. preferably 40 wt. % to 60 wt. %4 of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 WO 2013/167986 PCT/IB2013/050740 29 wt. % to 3.0 wt- %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse. For dosage oris mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration. 100741 Another dosage form contains a compressed tablet or a capsule having a drug containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral admim stration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose. 100751 For purposes of transdermal (e.g, topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared. 100761 Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I and formula II or other active agents are knoVn, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Paston, Pa., 19th Edition (1995). 100771 i addition, in certain embodiments, subject compositions of the present application maybe iyophlIized or subjected to another appropriate drying technique such as spray drying. The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

WO 2013/167986 PCT/IB2013/050740 30 [00781 Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration, The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration. [0079] Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally. one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product, 100801 The compounds of formula - and formula I described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%. 0.005-5% w/w, or 0.01~ 0% w/w, of medicament relative to the total weight of the fonriulation. 100811 In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like) the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, al ginates, gelatin, polyvinyl pyrrolidone. sucrose and/or acacia; (3) hunectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch. alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption WO 2013/167986 PCT/IB2013/050740 31 accelerators, such as quaternary anmiumurn compounds (7) wetting agents, such as, for example, acetyl alcohol and glycerol moiostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composItions may also comprise suffering agents, Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [00821 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrIps and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents conumonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn., peanut., sunflower, soybean., oline, castor, and sesame oils), glycerol, tetrahydrofuryi alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof [00831 Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum netahydroxide, bentonite, agar agar and tragacanth, and mixtures thereof. [00g41 Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol" a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and WO 2013/167986 PCT/IB2013/050740 32 release the encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate. 100851 Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties. 100861 The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, tale and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. 100871) Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440 454, 6,267,983, 6,239,180, and 6,103,275. 100881 In another embodiment, a transdennal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by WO 2013/167986 PCT/IB2013/050740 33 weight of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-ethlvene-butvlene-styren e copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet conpises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkylene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on. the outer surface of the polyalkylene terephthalate film. 100891 Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and I ami nati ng the drug-containing adhesive onto a suitable backing member, e g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose. 100901 Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs, Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs. 100911 onrtophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an WO 2013/167986 PCT/IB2013/050740 34 iontophoretic membrane is given in U.S_ Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (Ib) electroosm osis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current. 100921 In some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components, The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. [00931 An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent. [00941 Methods and compositions for the treatment of epilepsy. Among other things, herein is provided a method of treating epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula I: WO 2013/167986 PCT/IB2013/050740 35 HaC $ S N R R2 cO

CH

3 Formula I Wherein, Ri independently represents. Hydrogen, D 0 0 O0 0 0 0O NHH 0 0 0 0 0 0 HH No WO 2013/167986 PCT/IB2013/050740 36 0 H H N Nj NN 0 0 N0 OH 0 H H N NON or H R2 independently represents Acetyl (CH 3 CO-) SH o H

H

3 C N N HO OOH 00 HN

C,

WO 2013/167986 PCT/IB2013/050740 37 NOH 4 7 10 13 16 N H OH HO H N NOH HOO

NHCOCH

3

CO

2 H CONH> OHOH COCH O 0 VfCH3 CH, OH 0 0 H3C CH H O

CH

3 , OH 3 HNAOH 0O WO 2013/167986 PCT/IB2013/050740 38 H NH2 a N a b or b cd a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, ASH, -OD, C-Cf,-alkyl, ~NH 2 or -COCHI; [00951 Accordingly, Methods and compositions for the treatment of epilepsy Among other things, herein is provided a method of treating epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula Il: H N R-R, H

O

WO 2013/167986 PCT/IB2013/050740 39 Formula 11 Wherein, R' independently represents, Hydrogen, D. 0 0 OS 0 00 0 / H

NH

2 NN N H0p H Ol O/ OOO WO 2013/167986 PCT/IB2013/050740 40 0 H H N SN o SOr H R indepen dent ly represents Acety (CiCO~) SH 0 H H 0 H2HH 0

H

3 0 N < H H r 00

H

2 N N 1-3 4 0 WO 2013/167986 PCT/IB2013/050740 41 4 7 1 3 16 0 N CH3 H OH HH N OH HO N) 0 0 NHCOCH3 00 OH 0% OHCCHsOH 0O

SH

3 OH

K-H

3 0-N0

H

3 0 0 OK

CHK

3 CH-, OH 0 HN NH H S

NH

WO 2013/167986 PCT/IB2013/050740 42 b HO b a is independently 213 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H, D, -OH. -OD, Cj-C 6 -alkyl, -NH or -COCH- 3 Methods for using compounds offormnua I and formula I: 100961 The invention also includes methods for treating epilepsy and neurological disorders such as convulsions, partial seizures, or as an adjunctive therapy for partial, myoclonic, tonic-clonic seizures, mood-stabilizing agent, bipolar disorder, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, trigeminal neuralgia. It is also used for a variety of indications, including attention-deficit hyperactivity disorder, schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome., paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, Mvotonia congenita and post-traunatic stress disorder.

WO 2013/167986 PCT/IB2013/050740 43 METHODS OF MAKING 100971 Examples of synthetic pathways usefd for making compounds of formula I and formula II are set forth in example below and generalized in scheme I through scheme 2: Scheme-: 1) Br(CH2)OOOEtN n-BuL -70 "C, 2.5 h EtO 2) 1N HC+ 5-10C 2 3 Br KI (catalytic) UOH H0 Acetone 0 THFH O(1 1) s OH rt 44 h 5 0 rt 4h 6 0 HOOC H b0C H benzene _ 7 0 "C 4h S OH + $ 01" G 2 9 0 0 6SH 0_ WO 2013/167986 PCT/IB2013/050740 44 [00981 Step-1: Synthesis of compound 2: 1) Br(CH)jCOOEt n-Bu 70 *C, 2.5 h Br U S Et 2 O $ 2)IN HCI S 1 5-100C 2 3 -Br [0099J A mixture of n-butyllithium (44 mL, 0.11 mol, 2.5 M) and anhydrous Et 2 O (60 mL) was placed on an ice bath, A solution of 2-broo-3-inethvlthiophene (17.7g, 0.10 mol) in anhydrous Et 2 O (25 mL) was added within 30 min while the temperature was kept at 5-10 'C. Stirring was continued at 10 C for another 15 muin before the mixture was cooled to -70 0 C. A solution of ethyl 4-bromobutyrate (7.8 g, 0.040 mol) in anhydrous Et 2 O (25 iL) was added at such a rate to the 2-lithio-3~methylthiophere 2 that the temperature was kept below -65 *C. When the addition was complete the mixture was stirred at -70 T for 2.5 h. Cold water (30 ml..) and cold aqueous 1 N 110(15 mL) were introduced successively while the temperature was kept below 0 "C. The reaction mixture was stirred for 15 min to allow the temperature to rise above 0 "C, and the phases were separated. The aqueous phase was extracted with Et2O (50 niL) and the combined orgamc phases were washed with cold water (25 mL) and brine (25 nmL). After the solution was dried over anhydrous Na 2 SO4, the solvent was evaporated in vacuo to an oil which was dissolved in 2-propanol (100 mL. A 20% aqueous HSO4 solution (10 nL) was added, and the mixture was stirred at room temperature for 3 h. The solvents were evaporated in vacuo to give a residue which was partitioned between CH2CI12 (200 mL) and a saturated NaH-1C03 solution (50 niL). The phases were separated, and the aqueous phase (with pH 8-9) was extracted further with CH2Cl2 (50 mL), The combined organic phases were washed with water (50 nil), brine (50 inL), and dried (Na:2SO4). The solvent was evaporated in vacuo to give an oil which was purified on a silica gel column) to provide 3 (77% yield from ethyl 4-bromobutyrate) as an oil. 1001001 Step-2: Synthesis of compound 5: WO 2013/167986 PCT/IB2013/050740 45 0 K 2 CO + HN KI (catalyct ic) Br Acetone S t 3 rt 44 h 5 0 100101.1 Compound 3 (0.02 mol) was dissolved in acetone (50 ml..,), and ethyl 3 piperidine carboxylate 4 (0,02 mol), KI (0-002 mol), and K 2

CO

3 (0.02 mol) were added to give a slurry which was stirred at ambient temperature for 44 h The reaction mixture was filtered, and the filtrate was washed with acetone, the combined filtrate was concentrated in vacuo to afford the desired ester 5 as gunr 1001021 Step-3: Synthesis of compound 6: N' K UOFH 2 C 0 N O HLO H S O THF:H 2 0(1:1) S OH 5 0 rt, 4h 6 0 1001031 Compound 6(lmmol) was taken in RB and added THF, water (11) 4+4 ml) and Lithium hydroxide monohydrate 2 minol at room temperature and stirred the reaction mixture at T for 4h. After completion of the reaction as indicated by TLC the mixture was acidified with 10% aqueous citric acid and added ethyl acetate. The layers were separated and the organic layer was dried over Na 2

SO.

4 and removed the solvent to get the product 6. [00104] Step-4: Synthesis of compou-nd 8: 0 HHOO SOC H S- benzene 3 7 0 *C, 4h WO 2013/167986 PCT/IB2013/050740 46 1001051 Acid 7 (10 mmol) was taken in a RB added benzene and cooled to 0 "C and added thionyl chloride (13 mmol) dropwise and stirred the reaction mixture at same temperature for 4 h. After completion of the reaction as indicated by TLC, benzene was distilled and the crude acid chloride 8 was used for the next step. [00106] Step-5: Synthesis of compound 9: OH + 0 0N N H

N

S~ 9 [001071 In a RB acid 6 (1.0 mmol) & anhydrous K 2

CO

3 (3.0 mmol) were suspended in dry DNIF (10 vol) stir at room temperature for 30 min and then cooled to -10 C., acid chloride 8 ( L mmol) was added slowly drop wise over then was allowed to stir at room temperature for 12 h. Reaction was monitored by T.LC. On completion of the reaction, the reacti on. mixture was poured into water (10 mL) and extracted with diethyl ether (2 x 5 ml). The combined organic layers were washed with water (2 x 5 mL) followed by brine solution (10 mL), dried over anhydrous Na 2 SO4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to get the compound 9.

WO 2013/167986 PCT/IB2013/050740 47 Scheme-2: TBAB NHH 0,K5 KOH OD O +N DM 0 N Toluene ,_ OH KOn 1 2 t80% KNn 4 3 HCI 4 12 h, 76% CCOO Et Ek 3 N THF O O O*C ,30 LOd N N06 ..........

oS~c............... -------------- N NOHNH + Cl O QN H U

NH

4 0 H .T2H2 DCM: -bCN (1:1) 0*C>-t 12 h 0 *CAt 85% 5 6 overnight7 07 H 00 HO H O20% H 0 ~ 0- DMF 0 t> t -10 t-c 0 S 1001081 Step-1 : Synthesis of com pound 3: NH2 KOH C N OH + KH Toluene OH 1 2 rt, 12 h, 80% 3 1001091 To a cold 04C solution of compound 1 (0122 mol) in toluene (80 ml) was added anhydrous sodium sulphate (0.129 mol) and the mixture stirred at this temperature for lh. Powdered potassium hydroxide (0.335 mol) was gradually added followed by drop-wise addition of 4-chlorobutyryl chloride 2 (0. 122 mol) with vigorous stirring After WO 2013/167986 PCT/IB2013/050740 48 completion of the reaction, the reaction mixture is filtered through celite. Organic extracts were dried over Na 2

SO

4 and concentrated in vacuo to give compound 3. [001101 Step-2: Synthesis of compound 4: TBAB KOH N DCM N UA VOH KMnO 4 OH 3 HCI 4 0 12 h, 76% [001111 Aqueous potassium hydroxide (0.017 rot in 10 ml water), tetra-n-butyl amnionium bromide (0.0062 mol) and compound 3 (0.0063 mol) in DCM (10 ri) was stirred for 30 min. at room temperature and then added potassium permanganate (0.094 mol)and continued the stirring, After completion of reaction filtered through celite bed and washed with water (10 ml). The aqueous later Pi was adjusted to 3 using HCt (2 ml), added sodium phosphate(0.0152 mol) and toluene (25 mi). The reaction mixture was extracted with DCM (2X25 ml), The organic layer was dried with Na:S0 4 and distilled under reduced pressure to compound 4 as oil. To this toluene (10 ml) was added and stirred at 0 C for about 30 min. The solid was filtered and washed with toluene (5 ml) to afford the pure compound 4. [001121 Step-3 Synthesis of compound 5: CICOOEt, EtN_ THF N 0 3 3m H O N04C , 30 mnin OH NH 4 HNH2 0 0 C-rt, 12 h 4 65% 5 1001131 To a cold 0 T solution of acid 4 (0,292 mol) and EtN (0307 mol) in anhydrous THF (20 ml) was added ethyl chloroformate ( 0.304 mol) and the mixture stirred at 0 "C for 30 min. Ammonium hydroxide (25% w/v aqueous solution, 19 WO 2013/167986 PCT/IB2013/050740 49 ml36.0 Onil) was added and the reaction mixture was stirred at room temperature for 12h. After the addition of K 2 COs (30.0 niol), the mixture was filtered and the volatile material ( solvent and Et 3 N) distilled of? in vacuo. The solid residue was extracted with DCM (3'x50 ml) and combined extracts were dried over Na 2

SO

4 and concentrated in vacuo, recrystallization from acetone gave compound 5 as white solid, [00114] Step-4: Synthesis of compound 7: H H 0 0 0> NO0 UOBUIN NH + C1 o C - ( N H C1 DCM cH 3 CN (1:1 Ci O 5 6 ovemight 7 1001151 Compound 5 (1 mmol) in 2,5 ml of DCM and 2.5 ml of CH 3 CN is cooled to 0 C . 'Lithium t-butoxide (L.OM in hexanes, .I mmol) was added and the mixture was stirred at 0 "T for 15 min and then at room temperature for 10 min. The reaction mixture is re cooled to 0 T and added 1-chloroethyl chloro formate 6 (12 mmol) dropwise, The reaction mixture is stirred at 0 C for 15 min and then allowed to stir at room temperature overnight. After completion of reaction, the mixture is diluted with. DCM and added water and the layers were separated. The organic layer is washed with water and brine, dried over NaSO4 and concentrated in. vacuo. Purification by silica gel chromatography afforded the compoLnd 7. [00.1161 Step-5: Synthesis of compound 9:

H

0 o -10 0C 78 oN-k / H Aa 9 0 WO 2013/167986 PCT/IB2013/050740 50 [001171 In a RB flask the acid 8 (1L2 mmol) & anhydrous K 2 CO3 (3.0 mmol) was taken in dry DMF (10 vol) stir at room temperature for 30 min and then cooled to -10 C, compound 7 (in DMF) was added slowly drop wise over 10 min. & then was allowed to stir at room temperature for 12 i. Reaction was monitored by TLC, On completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with diethyl ether (10 ml). The combined organic layers were washed with water (2 x 5mL) followed by brine solution (10 mL) dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to yield the product 9. EXAMPLES [00118] Blood and cerebrospinal fluid pharmacokineties in comparison of the levetiracetam and Formula 11 (2-1) in rats The temporal pharmacokinetic interrelationship of levetiracetam and Formula II (2- 1) in blood and cerebrospinal fluid (CSF) was studied after acute intraperitoneal administration of levetiracetam and Formula II (2-1), (20, 40 and 80 ng/kg), using an animal model that permits concurrent blood and CSF sampling in freely moving rats. After administration, levetiracetan and Formula 11 rapidly appeared in both senn (time to maximum concentration (Tmnax) mean range 0.25-050 h and 0.47-0.89 respectively) and CSF (Tmax mean range 1.33-1.92 h and 2.14-2.831h respectively), suggesting ready penetration of the blood brain barrier. Both serum and CSF levetiracetam and Formula 11 (2-1) concentrations rose essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate limiting. Test Compounds Elimination half-life i]2) Elimination half-life t0/2) Serum (Mean) Hours -CSF (Mean) Ilours levetiracetam 1.8 - 2.8 4.4 - 4.9 Formula(2-i) 23-3.4 4.8 - 5 6 WO 2013/167986 PCT/IB2013/050740 51 [001191 The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ by, e.g, biopsy. Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting, Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein. EQUIVALENTS [00120] The present disclosure provides among other things compositions and methods for treating epilepsy and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Mary variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. INCORPORATION BY REFERENCE 1001,21.1 All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in. their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the Present application, including any definitions herein, will control

Claims (7)

1. 3. A Pharmaceutical composition comprising a compound of claim I and a pharmaceutically acceptable carrier
2. 4. A Pharmaceutical composition comprising a compound of claim 2 and a pharmaceitically acceptable carrier The phanrmaceutical composition of claim 3, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by WO 2013/167986 PCT/IB2013/050740 61 oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal. oral solution, rectal administration, buccal administration or transdermal administration, 6, The pharmaceutical composition of claim 4, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or tran sdermal administration, 7, Compounds and compositions of claim 5 are formulated for the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, internittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder. 8& Compounds and compositions of claim 6 are formulated for the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, auusin, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuronotonia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder.
3. 9. A molecular conjugate of (R)-1-14,4-bis(3-m ethylthiophen-2-yl)but-3-enyl]I piperidine-3-carboxylic acid and R-Lipoic acid.
4. 10. A molecular conjugate of (R)-1-[4,4-bis(3-methylthiophen-2-yl )but-3-envlI piperidine-3-carboxylic acid and eicosapentaenoic acid. WO 2013/167986 PCT/IB2013/050740 62
5. 11. A molecular conugate of (R)-144-bis(3~mehyihiophen-2-yl)bu-3-enyl] piperidine-3-carboxylic acid and docosahexaenoic acid.
6. 12. A molecular conjugate of (S)-2-(2-oxopyrrolidin I -I)butanami de and R-Lipoic acid. 13 A molecular conj ugate of (S)-2-(2-oxopyrroidin-I-yi)butanami de and eicosapentaenoic acid.
7. 14. A molecular conijugate of (S)-2-(2-oxopyrrolidin- 1 -y)butanami de and docosahexacnoic acid.