EP2882427A2 - Compositions and methods for the treatment of neurological disorders - Google Patents

Abstract

The invention relates to the compounds of formula (I) 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), and methods for treating or preventing neurological disorders may be formulated for oral, buccal, rectal, topical, transdermal, transrnucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial adenomatous polyposis.

Description

COMPOSITIONS AND METHODS FOR THE

TREATMENT OF NEUROLOGICAL DISORDERS

PRIORITY

[0001 j The present application claims the benefit of Indian Provisional Patent Application No. 1789/CHE/2012 filed on 08~May~20I2, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION j^'0002| This disclosure generally relates to compounds and compositions for the treatment of neurological disorders More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, stereoisomers, enantiomers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION jOOOS] Diseases of the central nervous system remain among the most compelling maladies known to humankind. This is because neurological disorders are typically devastating to affected patients and their families, often robbing individuals of the quaiities that we most strongly associate with being human, and because the vast majority of neurological and neurodegenerative disorders lack effective therapies. In the 1980s and 1990s, the advent of molecuiar genetics approaches to map and identiiy disease genes laid the foundation for a prodigious advance in our understanding of the pathogenic basi of numerous important neurological disorders,

|Ό004) Valproic acid (VPA) is widely used as an anticonvulsant, but therapy with the drug has been associated with hepatotoxicity, either reversible hepatic dysfunction or irreversible hepatic failure. Both clinical and experimental studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of the oxidation and synthesis of fatty acids and inhibition of gluconeogenesis, urea synthesis, oxidative phosphorylation, and the glycine cleavage system. Other abnormalities noted include alteration in the protein conformation of the internal mitochondnal membrane, hyperammonemia, and increased bile flow. The mechanisms of such hepatotoxicity, whether mediated by VPA or by its metabolites, are still little understood. Susceptibility to VPA hepatotoxicity may be enhanced by such conditions as starvation, inborn errors of metabolism, additional neurological disease, and concomitant administration of enzyme-i nducing drags .

|0005| The pote ti l involvement of free radical or oxidative damage in the pathogenesis of human disease has received an enormous amount of study in the last decade. Free radicals are atoms or molecules with unpaired electrons in their outer orbits, making them highly reactive with macromolecular structures, leading to cellular injury and homeostatic disruption. Free radicals are produced as a byproduct of normal metabolism, and endogenous mechanisms exist to reduce their formation or enhance their inactivation. Disruption of the prooxidant and antioxidant balance in favor of the former may be a potential fundamental mechanism of human disease. A large body of evidence supports the concept that increased production of free radicals causes or accentuates neuronal injur}_' and leads to disease, and this evidence has recently been reviewed. Therapy aimed at boosting antioxidant defenses or reducing pro-oxidant production with free radical scavengers or antioxidants may be efficacious in preventing, ameliorating, or arresting many neurologic diseases,

|0 06^'} 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 or delay of the onset of neurological disorders and its associated complications progression. SUMMARY OF TH E INVENTION

{0007] The present: invention provides compoiinds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as neurological disorders.

{OOOSj The invention herein provides compositions comprising of formula 1 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 pharmaceutically acceptable carriers, vehicles or diluents. These compositions may he used in the treatment of neuroiogical disorders and its associated complications.

Formula Ϊ

[0009] In certain embodiments, the present invention relates to the compounds compositions of formula L or pharmaceutically acceptable salts thereof.

Formula 1 





a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and ά are each independently H, D, -OH, -OD, Cj-Ce-alkyl, -Ν¾ or -COCH3. fOOlOj In the illustrative erabodiraeiits, examples of compounds of formula } are as set forth below;

( 1 -1 )

(1 -2)

|00111 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 neurological disorders or its related complications.

[0012] The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

10013| Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of neurological disorders or its related complications.

|001 ] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering fro neurological disorder or its related complications manifested from metabolic conditions or disorders, metabolic syndrome, chronic neurological diseases or disorders; epilepsy, depression, bipolar disorder, neuropathic pain. Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications. DETAI LED DESCRIPTION OF THE ^'INVENTION

Definitions

|0015] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, ail technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

|0016^'] 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 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 1 (hydration).

|0017] 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 differ in the arrangement of their atoms in space are termed "stereoisomers," 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 - and S-sequencing rules of Calm, 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 can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture" . [0018) As used herein, the term "metabolic conditi n" refers to an inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect i one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. 001.91 some embodiments, a molecular conjugate comprises of compounds selected from the group consisting of R-lipoie acid (CAS No, 1200-22-2), salsalate (CAS No. 552-94-3). acetylcysteine (CAS No. 61 -91-.1 ), Eieosapentaenoic acid (CAS No. 10417- 94-4), Docosahexaenoic acid (CAS No. 6217-54-5).

{002 1 The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0021] The phrases "parenteral administration" and "administered parenteral! " 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, intraorbital, intracardiac, intrademial, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intra sternal injection and infusion.

[0022] 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.

[0023] 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 toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. |0024| The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a. liquid or solid .filler, diluent, so! ent 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 he "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 carhoxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com 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 ethyi lattrate; (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 soiutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations.

[00251 The 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 hydro!yzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal . j0026^'| he term "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).

|0027] 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 i nvention .

|002S] 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 epilepsy, bipolar disorder, migraine, schizophrenia, cancer, HIV, familial adenomatous polyposis 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 (e.g., prophylactic), adjunct and palliative treatment.

|0029] The phrase "therapeutically effective amount" is an art-recognized term, in certain embodiments, the term refers to an amount of a salt or composition di closed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to an 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 admini stered, 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.

|0030] 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.

[0031 ] 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 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 0032] In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference t 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. {0033) 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 accepiable exeipients may undergo gradual or deiayed 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. 0034) 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 erf an agent for the disease being treated, even if the agent is subsequently distributed systemicaily, 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.

{0035) The phrase "therapeutically effective amount" is a art-recognized term, in certai 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.

[0036] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.

[0037] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formul 1 may be formulated for systemic or topical or oral administration. The pharmaceutical 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.

[0038] In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula 1 or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I or its pharmaceutical acceptable salts will depend on absorption, inacti vation, 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 perso administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0039] Additionally, the optima! concentration and/or quantities or amounts of any particular compound of formula I 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.

[0040] The concentration and/or amount of any compound of formula I 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. E. Robinson et aL 1991 , microdialysis in the oeurosciences. Techniques, volume 7, Chapter 1. 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 such as those disclosed herein are injected adjacent to the ioop, 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.

[0041] In certain embodiments, the dosage of the subject compounds of formula Ϊ provided herein may be determined by reference to the plasm 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.

[0042] Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas I is in the range of about 0.0.1 mg kg day to about 100 mg/kg/day in single or divided doses, for instance 0.0Ί mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas Ϊ may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 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 may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 rag 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 rag 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 1.0% of the compound of formula 1 required for the sam therapeutic benefit. f0043| An effective amount of the compounds of formula 1 described herein refers to the amount of one of said salts or compositi ons which is capable of inhibiting or preventing a disease.

[0044J 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 damage or demyelization and/or elevated reactive o idative- nitrosative species and/or abnormalities in physiological 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 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.

[0045] The com positions 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, parentera!ly, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasal] y, 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 nanoparticies

|0046| The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple 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, T hese 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 bindi g agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabietting 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 essentia! active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and. if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. The compounds of formula Ϊ may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art. 10047] 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.

|004R| The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 rag e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I disclosed herein, or instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula ^'! .

100 91 Generally, a composition as described herein may be administered orally, or parenteral ly (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also foe 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 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.

{ 0050 J The dosage administered will be dependent upon the identity of the metabolic 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.

|0051^'J Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg kg; intramuscular, 1 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. |0052] 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, pbaryngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of from about 0.0 ί 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. f0053| 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 non-parenterai 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.

{0054] As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water svvellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof Examples of suitable water svvellable cellolose derivatives include, but are not limited to, sodium carboxymethylcelluiose, cross-linked hydroxypropylcelluiose, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), hydroxyisopropylcellulose, hydroxy butyl cell lose, hydroxyphenylcellulose, hydroxyethylcellutose (HEC), hydroxy pentylce!hilose, hydroxypropylethylceUuiose, hydroxypropyibutylcellulose, and hydroxypropylethylcellulose, 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, po!y(ethy1ene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacryiatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslhiked acrylic acid honiopolymers and copolymers such as those commercially available from oveon Chemicals under the tradename CARBOPOL^m Examples of suitabie 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, gei!an gum, maltodestrin, gakctomannan, pusstulan, lamioarin, scleroglucan, gum arabic, itiulin, pectin, gelatin, whe!an, rhamsan, zooglaii, methylan, chitin, cydodextrin, chitosari, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium tnsilicate; magnesium aluminum silicate; and mixtures thereof. Examples of suitabie gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked poly vinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcelluiose sodium, and mixtures thereof. 0055) The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitabie excipients include, but are not limited to, fillers, adsorbents, binders, di si integrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof. 0056] Suitabie binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropyi ethylcellijlose; 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, ge!lan, gelatin, maltodextrin, galactomannan, pusstulan, laminarm, scleroglucan., inulin, wheian. rhamsan, zooglan, methylan. chitin, cydodextrin, chiiosan, polyvinyl pyrrolidone, celSulosics, sucrose, and starches; and mixtures thereof. Suitable dismtegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyiceliulose, starches, niierocrystaSlhie cellulose, and mixtures thereof.

{005? j Suitabie 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 exci ients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof,

[0058] 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, ethylcelliilose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylafces, methacrylafces, acrylic acid copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not liniiied to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogen ated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sun Slower 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-, dk and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl triiaurylate, glyceryl m ri state, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphatidyl choline, phosphatidyl serene, phosphatidyl enositol, phosphotidic acid, and mixtures thereof Examples of suitable waxes include, but are not limited to, camauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, macrocrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disi tegrants include, but are not. limited to, croscarmeiiose sodium, sodium starch glycol ate and cross- linked povidone (crospovidone). in one embodiment the tablet core contains up to about 5 percent by weight of such super di mtegrarit,

[0059] Examples of antioxidants include, but are not limited to, tocopherols, ascorbic add, sodium pyrosuifite, but Ih droxy toluene, butylated hydroxyanisole, edetic acid, and edetaie 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.

[0060] 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,

[006.1] In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contai ns 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 pharaiaceutically active agent and the second portion includes the second pharmaceutically active agent.

{006 1 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.

10063) 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 pharmaceutically active agent,

[0064] 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 known in the art

[0065] 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 exeipients. The immediate release dosage unit may or may not be coated, and may or may not be adinixed 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),

[0066] Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington— The Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are weSiknown and described in die art. The matrix devices are generally prepared by compressing the drag with a slowly dissolving polymer carrier into a tablet form.

[0067] 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.

{0068] Delayed release dosage formulations are created by coaling 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 ma 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 int either a tablet or capsule.

|0069J A pulsed release dosage form is one thai 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.

{007 1 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. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 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 forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 1 hours, and more preferably approximately 5 hours to 12 hours, following administration.

[0071] 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 administration 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 1.4 hours following oral admin stration to provide a second dose. |0072 For iloses 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 he prepared.

[0073] Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formul 1 or other active agents are known, or will be apparent in Sight 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, Easton, Pa., 19th Edition (1995).

[0074] In addition, in certain embodiments, subject compositions of the present application maybe lyophilized 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.

[0075] 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.

[0076] Methods of preparin 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. {0077] The compounds of formula ί 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 0,01-1.0% w/w, of medicament relative to the total weight of the formulati n.

10078] in sol id dosage forms for oral administration (capsules, tablets, pi Us. dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (I) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, earboxymethyl cellulose, alginates, gelatin, polyvinyl pyirolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, a!ginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, or example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentomte 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 buffering 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.

{0079] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, in addition to the subject compositions, the liquid dosage forms may contain inert, diluents commonly used in the art, such as, for example, water or other solvents, sol bili zing agents and emu! sifters, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-mitylene glycol, oils (in particular. cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol , tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol, and mi tures thereof.

[0080] Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxy!ated tsosteary) alcohols, potyoxyethylene sorbitol, and sorbkan esters, microcrystallme cellulose, aluminum metahydroxide, bentoiiite, agar- agar and iragacanth, and mixtures thereof.

[0081 ] 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, coco 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 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.

[0082] 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 propellarits that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

[0083] 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, bentomtes, silicic acid, talc 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.

(008 | 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, J 80, and 6,103,275. 0085J In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-poiyurethane composite and 2-10 parts by weight of a styrene-ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyaikyiene terephthaiate 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 polyaikyiene terephthaiate 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 compri ses preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyaikyiene terephthaiate 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 polyaikyiene terephthaiate film.

1 0861 Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating 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.

|O087J 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 dmgs. 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 (iontophoresi ) for large-molecule drugs.

{00881 Iontophoresis is a technique employed for enhancing the flu of ionized substances through membranes by application of electric current. One example of an i ontophoretic 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, (b) electroosmosis, 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 permeabil ity due to application of electrical current.

[0089] 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.

1009 1 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.

[0091] Methods and compositions for the treaifneni of neurological disorders. Among other things, herein is provided a method of treating neurological disorders, comp.ris.ing administering to patient in need thereof a therapeutically effective amount of compound of Formula i

Formula I

Wherein, * independently represents H, D, -0-,-CO-, -CH2-CO-CH2-,

32



a is independently 2,3 or 7;

each b is independentl 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OH, -OD, CpCc-alkyl, - H₂ or -COC¾.

Methods for using compounds of formula I:

|0092J The invention also includes methods for treating epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial adenomatous po!yposi s.

METHODS OF MAKING

0093] Examples of synthetic pathways useful for making compounds of formula I are set forth in example below and generalized in scheme 1 :

Scheme 1:

1)TBA&

[0094) Step-1 : Synthesis of compound 3 :

1)TSABr

|0095| 0 06 moies of TBABr were added to a solution of 8 g (0.2 moles) of NaOH in 30 ml H20 and the resulting mixture was heated at about 80 °C till complete dissolution. After cooling to 60 °C, 6.1.5 g (0.5 moles) of n-propyl bromide 2 and 6.5 g (0.05 moles) of ethyl acetoacetate I were simultaneously added to the mixture. The resulting bi-phasic system, was kept under vigorous stirring for 39 hours at 71 X. 30.7 g (0,249 moles) of n- propyl bromide and a solution of 2.2 g(0.057) moles of NaOH in 5 ml ¾0 were added and the resulting mixture was left to react under the aforesaid conditions for further si hours. The excess propyl bromide was distilled off and recovered, thus giving bi hasic reaction mixture whose organic phase consisted of ethyl 2,2-dipropyl acetoacetate which was directly used in the subsequent reaction. To this mixture comprising the of ethyl 2,2- di propyl acetoacetate, a solution of 8 gC^'0.2 moles) of NaOH in 10 ml ϊ¾0 was added and the resulting mixture left to react at SO oC for 20 hours. This end mixture was diluted with water and extracted with D M. Following the separation of layers the water phae was acidified to P^H~^:! with 33%HCI and extracted three times with ethy acetate. The ethyl acetate layer was dried over a^SO.} and concentrated to dryness yeilding 3.1 g of compound 3.

{0096] Step-2: Synthesis of compound 5:

3 4

-10 °c 5 0 97] To a solution of compound 3 ( 1 .0 mmol) in dry DOM (1 .8 ml) was added N, N- diisopropylethylamiiie (2.0 mmol) at -,10°Caiid stirred at same temperature for 30 min, followed by drop wise addition of l -chloroei yiciiloroformate 4 (1.1 mmol) at the same temperature and the reaction mixture was allowed to stir for 1 h at 0°€. On completion of the reaction (monitored by TLC), the reaction mixture the solvent was evaporated and the crude was purified through column to get compound 5, 0098J Step-3 : Synthesis of compound 7;

[0099| in a RB flask the acid 6 (1.2 mmol) & anhydrous K2CO3 (LI mmol) was taken in dry DMF (10 vol) stir at room temperature for 30 min and then cooled to -10 "C, compound 5 was added slowly drop wise & then allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2x5 ml). The combined organic layers were washed with water (2 x SmL) followed by brine solution (10 mL), dried over anhydrous a-2S<) and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to get the product

EXAMPLES jOO!OOj Effect of Valproic acid and formula I ( 1-1 ) on markers of cell viability, necrosis, and oxidative stress in Rat Hepatocytes:

At 24 h after plating of hepatocytes, culture medium was aspirated and replaced with fresh HepatoZYME-SFM medium supplemented with penicillin ( 100 U/tnl), streptomycin ( 100 lg/nil), and L-glutamine (2 m M). Hepatocytes were treated with VP A, formula I (1 -1 ) for 24 h at the various concentrations. In another experiment, hepatocytes were pretreated with l-aminobenzotriazole (0.5mM) or culture medium (vehicle control) 30 min prior to the administration of VPA (IniM in the WST-1 assay and I2mM in the LDH and DCF assays) or culture medium (vehicle control). At 24 1i thereafter, cytotoxicity assays were performed. Treatment of rat hepatocytes with VTA for 24 h leads to maxima! or near-maximal effects in various indices of hepatocyte toxicity. Formula Ϊ (1 -1 ), a molecular conjugate of valproic acid and R-lipoic acid, treatment for 24 rs showed very minimal toxic effects in various indices of hepatocyte toxicity.

(00101 j 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, seaim, or urine, more preferably, samples of blood, plasma or serum.

EQUIVALENTS

j 0102| The present disclosure provides among other things compositions and methods for treating neurological disorders and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many 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

(00103J 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

1. A compound of formula I:

Formula 1

or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof;

Wherein, 1 independently represenis H, D, -0-,-CO-, -CHrCO-CHj-,

40

42

a is independently 2,3 or 7;

each b is independentl 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OH, -OD, Ci-Ce-alkyl, -N¾ or -COC¾,

2. A Pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administrati n, delayed release or sustained release, Iransmucosal, syrup, topical, parenteral administration, injection, suhdermai, oral solution, rectal administration, buccal administration or transdermal administration.

4. Compounds and compositions of claim 3 are formulated for the treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer' s disease, cancer, HIV and familial adenomatous polyposis.

5. A molecular conjugate of val roic acid and R-Li oic acid.

6. A molecuiar conjugate of vaiproic acid and eicosapentaenoic acid.

7. A molecular conjugate of valproic acid and docosahexaenoic acid.

8. A molecuiar conjugate of valproic acid and acetyl cysteine.

9. A molecuiar conjugate of valproic acid and sal sal ate.