JP2015533114A - Compositions and methods for the treatment of neurological disorders - Google Patents

Abstract

The invention relates to the synthesis of Formula I or its pharmaceutically acceptable salts as well as polymorphs, solvates, enantiomers, stereoisomers and their hydroxides. Formulations containing an effective amount of a compound of formula I, and methods for treating or preventing neurological disorders may be formulated, oral, buccal, rectal, topical, transdermal, oral mucosa, intravenous Parenteral administration, syrup or infusion. Such a configuration may be used to treat epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial colorectal adenoma. [Selection figure] None

Description

This application is a national phase application of the Patent Cooperation Treaty (PCT), WIPO filed on January 13, 2013 entitled Application #No. PCT / IB2013 / 050801 entitled “Compositions and Methods for Treatment of Neurological Disorders”. Publication WO / 2013/167989 with publication number #, which further requests priority to parent application 1789 / CHE / 2012 filed in India on May 8, 2012. The entire disclosure of the priority application depends on all purposes and is also incorporated into this application by reference.

This disclosure generally relates to composites and configurations for the treatment of neurological diseases. More particularly, this invention relates to treating the subject with pharmaceutically acceptable doses of compounds, stereoisomers, enantiomers, crystals, esters, salts, hydroxides, prodrugs or mixtures thereof. .

Central nervous system illnesses remain in the illness that is known to mankind and is most insensitive to human movement. This is because neurological diseases are typically devastating to affected patients and their families, often depriving individuals of the attributes we most strongly relate to humans and (neurologic Because most neurodegenerative disorders lack effective treatment). In the 1980s and 1990s, the arrival of molecular genetics mapped and identified in our understanding of the pathogenic basis of a number of important neurological diseases that the disease gene laid the foundation for huge progress Approach to do.

Valproic acid (VPA) is widely used as an anticonvulsant. However, treatment with drugs is related to hepatoxin (either reversible liver dysfunction or irreversible liver failure). Both clinical and empirical studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of fatty acid oxidation and synthesis, and gluconeogenesis, urea synthesis, oxidative phosphorylation and glycine cleavage systems Suppression. Other abnormalities noted include changes in the protein structure of the internal mItochndnal membrane (hyperammonemia) and increased bile flow. It is understood that such a hepatotoxic mechanism is still rare, even if mediated by VPA or its metabolites. Sensitivity to VPA hepatoxin may be enhanced by conditions such as starvation, inborn errors of metabolism of enzymes that cause enzymes, additional neurological diseases and co-administration.

The potential involvement of free radical or oxidative damage in the pathogenesis of human disease has received a great deal of research in the last decade. Free radicals are atoms or molecules with unstructured electrons in their external orbitals that make them highly reactive with the structure of macromolecules that lead to disruption of cell injury and homeostasis. Free radicals are produced as normal metabolic by-products and ingrowth mechanisms exist to reduce their composition or enhance their inactivation. Disruption of oxidant support and antioxidant balance in favor of the former may be a potential underlying mechanism of human disease. A large collection of evidence supports the concept caused by increased free radical production or highlights neuronal wounds and leads to disease. This evidence has also been investigated recently. Treatment aimed at boosting antioxidant defenses or reducing pro-oxidant production with free radical scavengers or antioxidants is in preventing, ameliorating or preventing many neurological diseases It may be effective.

Sharp pathology management, often depends on the underlying pathology and signs of addressing the disease. There is currently a need in the art of new composition to the treatment or delay of neurological diseases and their associated complex progression attacks.

The present invention provides a method of using the same to treat, prevent and / or and / or ameliorate the effects of conditions such as compounds, compositions containing these compounds, and neurological diseases. Offers.

The invention here provides a composition consisting of Formula I or a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, vehicle or diluent Formula I or an intermediate thereof and one or more compounds. These configurations may be used in neurological diseases and their associated complex treatments.

Formula I

In certain embodiments, the present invention relates to a compound and composition of Formula I, or a pharmaceutically acceptable salt thereof,

Formula I
Where R1 represents H (D)? O-, CO- and -CH2CO-CH2-,

R2 says.

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, C1-C6 alkyl, -NH2 or -COCH3.

In an illustrative embodiment, an example of a compound of Formula I is as stated below:

(1-1)

(1-2)

Here, the application provides a kit that further includes any of the pharmaceutical configurations shown here. The kit may contain instructions used in neurological disease or its associated complex treatment.

Its application further indicates the pharmaceutical composition including any of the pharmaceutically acceptable carriers and compositions here. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, infusion, subcutaneous or percutaneous management.

Here, the application further provides a kit containing the pharmaceutical composition described herein. The kit may also contain instructions for use in neurological diseases or related complex treatments.

The configuration described here has several uses. The present application provides a method for treating patients with its associated complexities, metabolic syndrome, chronic neurological illness or illness, eg, manifested from a neurological disease or metabolic condition or illness; epilepsy, depression Bipolar disorder, neuropathic pain, orthopedics, cardiovascular, kidney, skin, duct, visual complications.

Example implementations are illustrated by way of example, not limitations, in which similar references indicate similar elements in the figures of the accompanying drawings:
Shows 1H-NMR results for Formula I.

As used herein, the following terms and phrases shall have the meanings given below: If not defined otherwise, all technical and scientific terms used here have the same meaning as commonly understood by one of the ordinary arts of art.

The compounds of the present invention can exist in the form of pharmaceutically acceptable salts. The compounds of the present invention can also exist in the form of pharmaceutically acceptable esters (ie, methyl and ethyl esters of the Formula I acids used as prodrugs). The compounds of the present invention can also be solvated, ie hydrated. Solvation can be affected or can occur during the manufacturing process, ie first as a result of the hygroscopic nature of the anhydrous compound of formula I (hydration).

Compounds that have the same molecular formula but differ in the bonding nature or sequence of their atoms in space, or the arrangement of their atoms, are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Left-right isomers are stereoisomers with the opposite configuration of one or more asymmetric centers that are not antipodes. Stereoisomers carry one or more asymmetric centers that are non. The mirror images that can be superimposed on each other are named "antipods". If the composite has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a set of enantiomers is possible. Antipodes can be characterized by their asymmetric centers or the absolute configuration of the centers, and are the rules of ordering R and S in Khan, Ingold and Prelog, or clockwise or levorotatory (ie (+) As (... or (-)-isomers, respectively), the molecule is described by a method specified by rotating a plane of polarized light. A chiral compound can exist as one individual enantiomer, or a mixture thereof. A mixture containing equal enantiomers is called a “racemic mixture”.

As used herein, the term “anabolic condition” refers to an inborn error of metabolism (or genetic assimilation condition) ... a genetic disease caused by a defect in one or more metabolic pathways; In particular, the function of the enzyme is affected and is insufficient or completely absent.

In some embodiments, the conjugation of the molecule is R lipoic acid (CAS 1200-22-2), salsalate (CAS 552-94-3), acylcycleIne (CAS 616-91-1), icosapentaenoic acid (CAS 10417-94). -4) and docosahexaenoic acid (CAS 6217-54-5).

The term “polymorph” as used herein is art-recognized and refers to the single crystal structure of a given composite.

Phrases, “parenteral administration”, “and parenterally administered” as used herein, refer to and include modes of administration other than intestinal and topical administration such as infusion, without limitation , Intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraoral, intracardiac, intradenal, intraperitoneal, transconduit, subcutaneous, epidermal, intraarticular, subcapsular, subcapsular Intrathecal injection and infusion under the spinal cord.

“Patient”, “subject” or “host” to be treated by the subject method may mean either humans or non-human animals such as primates, mammals and vertebrates.

"Pharmaceutically acceptable" phrase, art recognized. In one embodiment, the term is used to refer to the composition (mammalian, human, and excessive toxicity, inflammation, allergic reaction or other problem-free animal tissue or complexity (equal to a reasonable benefit-risk ratio)). Suitable for, dosage forms within the scope of sound medical judgment), including polymers and other materials.

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes pharmaceutically acceptable materials, compositions or vehicles, such as liquid or solid blends, diluents, dissolving power Some or encapsulating material, involved in carrying or transporting any subject matter, from one organ, to a body part, to another organ, or body part. Each carrier must be “acceptable” in the sense that it is compatible with other ingredients of the subject matter and not harmful to the patient. In one embodiment, a pharmaceutically acceptable carrier is non-pyrogenic. . Some examples of materials that 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) ground gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8 ) Cocoa butter and suppository wax; (9) Oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) ethylene glycol such as propylene glycol; (11) glycerin and sorbitol Polyvalent, such as mannitol and polyethylene glycol (12) Esters such as ethyl oleate and ethyl laurate; (13) Amakusa; (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen natural water; 17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

The term “prodrug” is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agent of the present invention. A common way to make prodrugs is to include selected halves that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzyme activity of the host animal.

The term “prevent or treat”, treatment is art-recognized and includes the management of one or more hosts in the subject structure. If it is treated prior to clinical symptoms of an undesired condition (eg disease or other undesired condition in the host animal), the treatment prevents, ie it protects the host from developing unwanted conditions To do. However, if it is processed after the manifestation of an unwanted condition, the treatment is a cure (that is, it is intended to reduce, improve or stabilize an existing unwanted condition or its side effects. )

Terminology As used herein, “predict” is a disease that a patient suffers from an abnormal outlook (terminal platelet aggregation) or complexity within a defined time window (prophetic window). )) Or to evaluate that the failure was related in the future. Death may be caused by the central nervous system or complexity. A prophetic window is an interval that develops one or more of the above mentioned complexities by the likelihood that the subject matter was predicted. The prophetic window may be the entire remaining life of the analytical subject according to the method of the present invention.

The term "treating"-is a recognized art and includes preventing, ill, or condition, but still treating it from occurring in an animal that may be leaned to that disease Not diagnosed as having; forbidden disease, confusion or condition, eg, obstructing its progression; and removing disease, confusion or condition (eg, illness, confusion and / or reversal caused by condition). Even if the underlying pathophysiology is not affected to treat epilepsy, treatment of the disease or condition includes improving at least one sign of the particular disease or condition, bipolar disorder, migraine Schizophrenia, cancer, HIV (subject management familial adenomatous adenomatosis even if such agent does not handle the cause of the condition). The term “treat”, “hospitality” or “treatment” as used herein includes therapeutic, prophylactic (eg, prophylactic), adjunct and palliative treatment.

The phrase “therapeutically effective amount” is an art recognized term. In one embodiment, the term refers to the amount of salt or composition that produces the desired effect that is a reasonable benefit-risk ratio applicable to any of the medical treatments shown herein. In one embodiment, the term refers to that amount that is necessary or sufficient to eliminate or reduce the medical signs of a period. The effective amount may vary depending on factors such as the disease or condition being treated, special, targeted, constructing, processing, subject size, or severity of the disease or condition. One of the normal techniques of art may determine an effective amount of a special composition without the need for empirically inappropriate experimentation.

In one embodiment, the pharmaceutical composition described herein is formulated as it was said that the composition would be delivered to the patient in a therapeutically effective amount as part of the preventive or therapeutic treatment. Is done. The composition of the desired amount to be processed by the patient will depend on the absorption, inactivation and excretion rates of the drug as well as the rate of delivery of the salts and composition from the subject composition. It is to be noted that the medication value may change further depending on the severity of the conditions under which it is eased. For any particular subject, it is to be further understood that the specific medicine regimen should be adjusted over time according to the individual needs and professional judgment of the person handling or overseeing the management of the composition. Typically, dosing will be determined using techniques known to one of ordinary skill in the art.

In addition, the optimal concentration, amount or amount of any particular salt or composition may be adjusted to provide for changes in treatment parameters. Such treatment parameters include the clinical application being prepared, eg, the site being treated, the type of patient, eg, human or non-human, adult or child, and the nature of the disease or condition.

In certain embodiments, dosing of the subject composition provided herein may be determined by reference to the therapeutic composition or plasma concentration of other encapsulated material. For example, the maximum plasma concentration (Cmax) and its area under the plasma concentration time curve from time 0 to infinity may be used.

The term “sustained release” is art-recognized when used in reference to pharmaceutical composition or other materials. For example, a subject composition that releases a substance over time may exhibit sustained release characteristics as opposed to a large pill type control where the full amount of the substance is biologically available once. For example, in a specific embodiment, in contact with body fluids, including blood, spinal fluid, mucus secretion, lymph fluid or the like, one of the pharmaceutically acceptable excipients The above may experience a gradual or delayed decline (eg, due to hydrolysis) with an accompanying release of any material ... congruent there, eg, therapeutic and / or biologically active For salt ... or composition, one retained ... or long term (for release from large pills). This release may result in an extended delivery of any of the therapeutically effective amounts of the therapeutic agents shown here.

The phrases "systemic administration", "systematically processed", "peripheral management", "and peripherally processed" art-recognized, therapeutic, including or treated subject composition management Other materials at sites far from illness. Management of the agent for the disease, treatment, the agent may subsequently be systematically distributed, may be named “local”, “maybe” or “local” In addition to administration, directly into the central nervous system, eg, by subcutaneous administration, such as it enters the patient's system and therefore follows metabolism and other similar processes.

The phrase “therapeutically effective amount” is an art recognized term. In one embodiment, the term refers to the amount of salt or composition that produces the desired effect that is a reasonable benefit-risk ratio applicable to any of the medical treatments shown herein. In one embodiment, the term refers to that amount that is necessary or sufficient to eliminate or reduce the medical signs of a period. The effective amount may vary depending on factors such as the disease or condition being treated, special, targeted, constructing, processing, subject size, or severity of the disease or condition. One of the normal techniques of art may determine an effective amount of a special composition without the need for empirically inappropriate experimentation.

The current disclosure further contemplates prodrugs of the composition shown here as well as the pharmaceutically acceptable salts of the prodrugs described above.

This application demonstrates a pharmaceutical composition that further includes a pharmaceutically acceptable carrier. The composition of Formula I compounds may also be formulated for systemic, topical or oral administration. The pharmaceutical composition may also be formulated for oral administration, oral solution, infusion, subcutaneous management or transdermal management. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, blend, binder and lubricant.

In many embodiments, the pharmaceutical composition described herein is in an amount sufficient to deliver a therapeutically effective amount of Formula I or composition to the patient as part of the preventive or therapeutic treatment. It will incorporate the indicated composition and composition (Formula I) that is communicated. The desired concentration of Formula I or its pharmaceutical acceptable salts will depend on the absorption, inactivation and excretion rates of the drug as well as the rate of delivery of the salts and components from the subject composition. It is to be noted that the medication value may change further depending on the severity of the conditions under which it is eased. It is to be further understood that for any particular subject, the specific medicine regimen should be adjusted over time according to the individual needs and professional judgment of the person handling or supervising the management of the composition. Typically, medication will be determined using techniques known to those skilled in the art.

In addition, the optimal concentration, amount or amount of any particular compound of Formula I may be adjusted to provide for changes in treatment parameters. Such treatment parameters include the clinical application being prepared, eg, the site being treated, the type of patient, eg, human or non-human, adult or child, and the nature of the disease or condition.

The concentration and / or amount of any compound of Formula I is routinely determined in an animal (eg, a mouse) by using appropriate analysis to obscure a series of concentrations and / or the amount of material in question. May be easily identified by inspection. In addition, known methods are available to analyze local tissue concentration, salt or composition prevalence and local blood flow before and after management of the treatment formulation presented here. T. T. et al. e. One such method is microdialysis, as investigated by Robinson et al., 1991, Microdialysis in (Chapter 1) of Neuroscience, Techniques, Volume 7. In short, the method investigated by Robinson may be applied as follows: The mIcrodIallysIs loop is placed in place on the test animal. Dialysate is pumped by the loop. If a compound that is adjacent to the loop and has Formula I like the one shown here is injected, it will be collected in dialysate proportional to their local tissue concentration that has released the drug. The progression of salt or composition diffusion may be determined for that with an appropriate calibration procedure using known concentrations of salts or composition.

In certain embodiments, dosing of the subject compound of Formula I provided herein may be determined by reference to the therapeutic composition or plasma concentration of other encapsulated material. For example, the maximum plasma concentration (Cmax) and its area under the plasma concentration time curve from time 0 to infinity may be used.

In general, in carrying out the methods detailed in this application, an effective amount for a compound of Formula I is from a single (0.01 mg (eg) / kg / day in a single or divided dose to about 50mg / kg / day) or about 100mg / kg / day in divided doses to about 0.01mg / kg / day. The compound of formula I is for example 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, It may be given at a dose of 30 mg / kg / day or less than 40 mg / kg / day. Formula I compounds may also be administered to human patients at a dose, 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, this configuration is 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% of the Formula I compound required for the same therapeutic benefit, or Processed in an amount that is less than 10%.

An effective amount of a compound of Formula I described herein refers to one of the amounts that can inhibit or prevent the aforementioned salts or constituent diseases.

An effective amount is banned, treated, mitigated, ameliorated, stopped, inhibited, slowed, reversed, or nerve damage (high reactive oxidation nItrosatIve May be sufficient in patients at risk of such a complex to reduce the severity of the complex and / or physiologic homeostasis abnormalities caused by demyelIzatIon. Thus, as appropriate, these methods include (sharp) and / or prevent (prevent) management in both medical treatments. The amount and timing of the processed composition will depend, of course, on the subject matter being treated, the severity of the affliction, the manner of management, and the discretion of the defining physician. Therefore, the medication given above is a guideline because of patient patient variability. The physician may also titrate the dose of the drug to achieve a treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance various factors such as the patient's age, the pre-existing presence of the disease, and the presence of other diseases.

The configuration provided by this application may be administered parenterally as a current matter to subjects that require treatment by various conventional routes of administration, including orally, eg intravenously, subcutaneously Or intramedullary. In addition, the composition may be processed intranasally as a rectal suppository (ie using a “flash” formulation), that is, drug treatment can dissolve in the mouth without the need to use water In addition, the composition may be processed into a subject in need of treatment by a controlled release dosage form, placing specific drug delivery, transdermal drug delivery, stereotaxic patch (active / active) (Passive) mediated drug delivery or in nanoparticles.

The composition may be processed either alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent, either in single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or mixtures (sterile solution injections and various organic solvents). Then combine the composition and pharmaceutically acceptable carrier, pharmaceutical composition formed by vehicle or diluent, easy in various dosage forms like tablets, powders, rhombus, syrups, injections etc. Will be processed. These pharmaceutical compositions can include additional ingredients such as seasonings, binders, excipients and the like, if desired. Thus, for oral administration purposes, tablets containing various excipients such as erarginine, sodium citrate, calcium carbonate and calcium phosphate may be used, various, polyvinylpyrrolidone, It breaks down like glue, alginic acid and some complex silicates along with adhesives like sugar, gelatin and acacia. In addition, facilitating agents such as magnesium stearate, sodium lauryl sulfate and talc are often helpful in tabletting the purpose. A similar type of solid composition may also be used as a blend in a soft, hard, full gelatin capsule. Suitable materials include lactose or lactose and high molecular weight polyethylene glycols. When water retention or secrets are desired for oral administration, the essential active ingredients may be combined with various sweeteners or flavoring agents, pigments or dyes, and emulsified if desired. Or suspending agents with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. As is well known in the pharmaceutical arts, Formula I compounds may further include overcoating the various excipients enterIcalli.

For parenteral administration, compositional solutions may be prepared in sesame or peanut oil (for example), may be used in propylene glycol in water, or sterile solution injections not. If necessary, such aqueous solutions should be buffered appropriately, and liquid diluent first made isotonic with sufficient saline or glucose. These special aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, all sterile aqueous solvents used are readily available by standard techniques known to those skilled in the art.

Formulations (e.g. tablets) may include ... 10 (e.g.), 50, 150-500 mg, 350-800 mg (e.g. 10, 50, 100, 300, 500, 700, Formula I shown here, 800 mg of compound) to 250 to 100, for example, a compound of formula I or pharmaceutical ... acceptable salts ... one compound of formula I.

In general, configurations as described herein may be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously, intramedullary). For example, where the patient is suffering from gastrointestinal disease, topical administration may also be indicated, which prevents oral administration or is most often applied to the surface of tissues or organs as determined by the attending physician If always. For example, local administration may also be indicated if a high dose is desired in the target tissue or organ. For cheek management, the active composition may take the form of a tablet or rhombus formulated in a traditional manner.

The treated medication will depend on the identity of the metabolic disease; the type of host included, its age, health and weight, if any, and the type of combination therapy; frequency.

Illustratively, the dosage levels of the treated active ingredient are as follows: intravenous, 0.1 to about 200 mg / kg; intramuscular, 1 to about 500 mg / kg; oral 5 to about 1000 mg / kg; Intranasal instillation (5 to about 1000 mg / kg); and aerosol (5 to about 1000 mg / kg host body weight).

Expressed in terms of concentration, the active ingredient is comprised in the composition of the present invention for topical use with respect to the dermis, intranasally, Pharyngolalyally, bronchially, vaginally, rectally or visually. About 0.01 to about 50% w / w concentration; preferably about 1 to about 20% w / w of the composition; and about 0.05 to about 50% w / v concentration of the composition For parenteral use, and preferably from about 5 to about 20% w / v.

The composition of the present invention consists of a human, tablet, capsule, tablet, powder, granule, suppository, sterile parenteral solution or a unit dosage form such as a retention non-sterile non-contained containing an appropriate amount of the active ingredient. Rather indicated for the management of parenteral and oral solutions to animals or retention and the like. For oral administration, either solid or flowable unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, cellulose derivatives, polyalkylenes / ethylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gels that can be increased Water feed into starch, increasing cross-linked polymer and mixing. Examples of suitable water-enhancing cellulose derivatives include, but are not limited to, sodium carboxymethyl cellulose, cross-linked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyIsopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose (HEC), hydroxypropylenecellulose, hydropropylpropylcellulose, hydropropylpropylcellulose thylcellulose, and the mixture, about it. Examples of suitable polyalkylene ethylene glycol 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 methacrylate divinylbenzene copolymer, polymethyl methacrylate, high molecular weight acrylic acid homopolymer, and copolymers such as those Cross-linked, available from Noveon Chemicals under the trade name CARBOPOLTM. Examples of suitable hydrocolloids include, but are not limited to, algin, amakusa, guar gum, locust bean gum, kappa carrageenin, iota carrageenin, tara, gum arabic, tragacanth gum, pectin, xanthan, gellan gum, maltodextrIn, galactomannan , Pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zoglan, methyllan, chitin, cyclodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, spectItems such as bentonite, kaolin and laponite; magnesium trisilicate; aluminum magnesium silicate; and mixtures thereof. Examples of suitable increasing cross-linked polymers of carboxymethylcellulose include, but are not limited to: cross-linked polyvinyl pyrrolidone, cross-linked amakusa and cross-linked sodium, and blending about it .

The carrier may contain prosthetics suitable for formulating one or more tablets. Examples of suitable excipients include, but are not limited to, blends, adsorbents, binders, disintegrants, lubricants, fluidizers, release modifying excipients, super disintegrants, antioxidants and Its mixed.

Suitable binders include, but are not limited to, water-soluble polymers including hydrocolloids such as polyvinyl pyrrolidone and dry binders such as hydroxypropylmethylcellulose (;) acacia, algin, agar, guar gum, carob, carrageenin, carboxymethylcellulose Wet binders such as tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrIn, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whellan, rhamsan, zoolanc, methylan , Cellulose compound , Sucrose, also starch) also mixtures. Suitable disintegrants include, but are not limited to, sodium glue glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose, starch, microcrystalline cellulose, and blending.

Suitable lubricants include, but are not limited to, long chain fatty acids and their salts such as magnesium stearate and stearic acid, talc, glyceride waxes and mixtures thereof. Suitable fluidizers include, but are not limited to, colloidal silicon dioxide. Prosthetics that modify the appropriate release include, but are not limited to, unresolved edible materials, pH-dependent polymers and mixtures thereof.

Suitable non-obvious edible materials used as prosthetics to modify release include, but are not limited to, water-insoluble polymers and low melting hydrophobic materials, their copolymers and their blends. Examples of suitable water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylate copolymers , Copolymer, about it, and mixing, about it. Suitable low melting point hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes and blends. Examples of suitable fats include but are not limited to hydrogenated vegetable oil, such as cocoa butter, hydrogen combined palm nut oil, hydrogen combined cottonseed oil, hydrogen combined sunflower oil, hydrogenated large Soybean oil, free fatty acids, their salts, and mixtures. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmaltearate, glyceryl monostearate, glyceryl trIstearate, glyceryl trIlaurylate, myrIstate of glyceryl group, GlycoWax-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixed. Examples of suitable phospholipids include phosphoIdyl choline, phosphoIdyl, mild, phosphoIdyl enosItol, phosphoIdIc and about it. Examples of suitable waxes include but are not limited to carnauba wax, whale wax wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and solid paraffin; fat-containing blends such as chocolate and Its mixed. Examples of the best disintegrants include, but are not limited to, croscarmellose sodium, sodium glue glycolate and cross-linked povidone (crospovIdone). In one embodiment, the tablet core contains up to about 5 weight percent of such best disintegrants.

Examples of antioxidants include but are not limited to tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene (hydroxylIsol with butyl groups introduced) (edetic acid, and edetate salts, and mixtures thereof) Examples include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures about it.

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; for example, from about 250 microns to about 1000 microns. In embodiments, immediate release coatings are typically compressed at a density of about 0.9 g / cc or higher, as measured by weight and volume of that particular layer.

In one embodiment, the immediate release coating includes an initial portion and another portion. There, at least one of the parts restrains a second pharmaceutically active agent. In one embodiment, the parts contact each other at the central axis of the tablet. In one embodiment, the first part includes the first pharmaceutically active agent. The second part also includes a second pharmaceutically active agent.

In one embodiment, the first part checks the first pharmacologically active agent. The second part also checks the second pharmacologically active agent. In one embodiment, one of the parts checks the third pharmacologically active agent. In one embodiment, one of its parts contains another immediate release part of the same pharmaceutically active agent as that contained in the tablet core.

In one embodiment, the outer coating is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment, the outer coat portion is included in dry granulation with a pharmaceutically active agent.

It may be possible to combine formulations with different drug release mechanisms described above within a single dosage form or a final dosage form containing multiple units. Examples of numerous units include multi-layer tablets, capsules containing solid tablets, balls or granules, or liquid forms. Typical immediate release formulations include gelatin tablets, compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example. Many methods are known in the art to prepare or cover a coating or to incorporate a drug.

Therapeutically effective amount with immediate release dosage, dosage unit, ie tablets, balls containing many drugs, granules or particles, or coated core dosage form outer layer, conventional pharmaceutical excipients To check out active agents. Immediate release dosing units may or may not be covered, delayed release dosing units or units (mixtures in capsules of granules, particles or balls containing immediate release drugs, delayed release) May or may not be mixed with medicine-containing granules or balls).

For example, the extended release formulation is generally prepared as a diffusion or infiltration system, as described in 20th in "Remington of Pharmacy-Science and Practice". Ed, LIppIncott Williams & Wilkins (Baltimore, Maryland, 2000). Diffusion systems typically consist of one of two types of devices, reservoirs and matrices. As described, matrix devices are generally prepared by compressing and packing a drug with a slowly dissolving polymer carrier into a tablet format.

The immediate release part can be added to the extended release system by either applying an immediate release layer on the extended release core, using a coating or compression process, or including a capsule (extended ) In a complex unit system like an instant release ball.

  A delayed release dosage formulation is created by covering a solid dosage form with a film of a polymer that is unresolvable in the acidic environment of the stomach but is soluble in the neutral environment of the small intestine. Delayed release dosing units can be prepared, for example, by covering a drug or drug containing composition with a selected coating material. The drug-containing composition consists of a tablet for incorporation into either a tablet or capsule, a tablet for incorporation into a capsule, a tablet used as the inner core of a “coated core” dosage form, May be a ball, particle or small particle containing a lot of medicine.

Pulse release dosage forms mimic the complex drug-drinking profile without repeated administration, and are typically shown as at least conventional dosage forms (eg, as a conventional solid dosage form with a resolved or rapid drug release) It allows for a reduction of twice the frequency of medication compared to a given drug. Pulsed release characteristics are characterized by a release (delay time) followed by a rapid drug release or a period without a reduced release.

Each dosage form checks for a therapeutically effective amount of active agent. In one embodiment of a dosage form that mimics a twice daily drug taking profile, approximately 30% to 70% by weight (preferably 40% to 60% by weight) is the total amount of active agent in the dosage form. Will be released in the transmission pulse. Correspondingly, approximately 70% to 3.0% by weight (preferably 60% to 40% by weight) is also released in the second pulse to the total amount of active agents in the dosage form. For a dosage form that mimics a twice daily drug taking profile, the second pulse is released for approximately 3 hours rather than 14 hours, preferably from approximately 5 hours to less than 12 hours following administration.

Another dosage form includes a compressed tablet or capsule having a drug-containing immediate release dosage unit, a delayed release dosage unit, and an optional additional delayed release dosage unit. In this dosage form, the immediate release dosage unit contains many balls, small particles, its release drug, providing an initial dose, essentially immediately following oral administration. The delayed release dosage unit contains many coated balls or granules, which release, take approximately 3 to 14 hours following oral administration to provide the drug, another dose.

For the purpose of transcutaneous (eg topical) management, aseptic, thinned, water or partially aqueous solution (usually at about 0.1% to a concentration of 5%) (not above Otherwise similar to oral solution) may be prepared.

Methods for preparing various pharmaceutical compositions with a certain amount of one or more compounds of Formula I or other active agents are known or known to those skilled in the art. It will be clear in light of the disclosure. For an example of how to prepare a pharmaceutical composition, see Remington's Pharmacy, Mac Publishing, Easton, Pennsylvania, 19th Edition (1995).

Further, in some embodiments, the subject matter configuration of this application, perhaps lyophilized or exposed to another, applies a drying technique such as spray drying. The subject composition may be processed once, or it may be divided into a number of lower doses that are administered at the desired dosage depending on the release rate of the composition, with varying time intervals.

Formulations useful for the methods provided here include appropriate people for oral, nasal, topical (including buccal and sublingual glands), rectal, vagina, aerosol and / or parenteral Administration. The formulation may be shown as convenient in unit dosage forms, or may be prepared by any method well known in the pharmaceutical arts. The amount of subject composition combined with the carrier material to produce a single dose may vary depending on the subject being treated and the particular mode of administration.

Methods to prepare these formulations or compositions include steps that lead to an association theme composition with a carrier and optionally one or more accessory ingredients. In general, the formulation is prepared by bringing the subject structure with a liquid carrier, a nicely divided solid carrier, or both to the association uniformly in detail, then shaping the product if necessary. The

Formula I compounds described here may be processed with an inhalation formulation or an aerosol formulation. An inhalation formulation or aerosol formulation may include one or more drugs, such as adjuvants, diagnostics, contrast agents or therapeutics useful for inhalation therapy. The final aerosol formulation would be, for example, 0.005-90% w / w (eg 0.005-50%, 0.005-5% w / w, 0) for drugs related to the total weight of the formulation .01-1.0% w / w).

  In solid dosage forms for oral administration (capsules, tablets, tablets, dragees, powders, granules, etc.), the subject composition is mixed with one or more pharmaceutically acceptable carriers and / or any of the following: Matches: (1) Mixtures or diluents such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) Binders such as carboxymethylcellulose (algin, gelatin, polyvinyl (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca glue, alginic acid, certain silicates and sodium carbonate; ) Solution dyeing agent like paraffin; (6) Quaternary ammonium compound (7) wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbent materials such as kaolin and bentonite clay; (9) lubricants, such as Talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and tablets, the pharmaceutical composition may further include buffering the agent. A similar type of solid composition may also be used as a blend in flexible, difficult filled gelatin capsules using lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, retention, syrups and secrets. In addition to the subject composition, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, solubilizers, and ethyl alcohol, isopropyl alcohol, ethyl carbonate, May contain emulsifiers such as ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3 butylene glycol, oil (in items and cottonseed, corn, peanuts, sunflower, in soybeans) not. Polyethylene glycol and fatty acid ester of olive, castor and sesame oil, glycerin, tetrahydrofuranyl alcohol, sorbItan and mixtures thereof.

The suspension may contain a suspending agent in addition to the subject composition, eg, isostearyl alcohol, polyoxyethylene ethoxylated. (Sorbitol, sorbItan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth rubber, and mixtures thereof)

Formulation for rectal or vaginal administration may be indicated as a suppository, mixing the subject composition with one or more suitable non-irritating carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate May also be prepared by a solid at room temperature, but a fluid at body temperature, and therefore will dissolve in an appropriate body cavity and release encapsulated composition and composition. Formulations suitable for vaginal administration further include pessaries, tampons, creams, gels (pastes), foams, or sprays containing carriers as known to be appropriate in the art. Formalization.

Dosage forms for transdermal management include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The subject composition may be mixed with a pharmaceutically acceptable carrier under sterile conditions, any preservatives, buffers or propellants that may be required. For transdermal management, the complex may contain lipophilic and hydrophilic groups to achieve the desired water solubility and transport volume.

Ointments, pastes, creams and gels are in addition to the subject composition, other carriers such as animal and vegetable oils, oils, waxes, paraffIns, glue, tragacanth gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, May contain talc and zinc oxide, or mixtures thereof. Powders and sprays may contain prosthetics such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or a mixture of such substances, in addition to the subject composition. Hmm. The spray may also contain conventional propellants such as chlorofluorohydrocarbons, and volatile unsubtutted hydrocarbons such as butane and propane.

Methods that convey composition (s) by transdermal application are known in the art. Typical 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.

In another embodiment, the transdermal patch may include: polychlorinated by weight of styrene-ethylene-butylene-styrene copolymer (the first adhesive layer next to the composite film). A substrate sheet comprising a composite film made of a vinyl polyurethane composite and a resin composition comprising 100 parts by weight of 2-10 parts, and also a polyalkylene terephthalate film is synthesized by the first adhesive layer Adhered to one side of the film (a finer layer containing a saturated polyester resin and formed on the surface of a polyalkylene terephthalate film); of styrene-diene-styrene and a finer layer Another adhesive layer containing a block copolymer that controls the pharmaceutical agent layered above. The method for manufacturing a substrate sheet as described above forms a resin composition into a composite film by a calendar process, then forms a substrate sheet, and is saturated on the outer surface of the polyalkylene terephthalate film. It involves preparing the above resin composition to form a more elegant layer containing polyester resin and adhere to it to one side polyalkylene terephthalate film of the composite film with adhesive layer.

Another type of patch involves incorporating the drug directly into a pharmaceutically acceptable adhesive and tearing the adhesive containing the drug on a suitable retracting member (eg, a polyester that supports the film) into a thin layer. The drug must be present at a concentration that does not affect adhesion and at the same time does not convey the required clinical dose.

Transcutaneous patches may be passive or active. Passive transdermal drug delivery systems such as nicotine, estrogen and nitroglycerin patches currently available deliver small molecule drugs. Many new and highly developed protein and peptide drugs are too large to be transmitted through passive transcutaneous patches, and techniques such as electrical assist (iontophoresis) are used for macromolecular drugs May be told.

Iontophoresis is a technique used to enhance the outflow of substances ionized by a thin film by applying an electric current. One example of an iontophoretic thin film is given by a tap in the United States. No. 5,080,646 to Theeuwes. The primary mechanism by which iontophoresis enhances molecular transport across the skin is by (a) repelling intense ions from the same charged electrode, (b) electro-osmosis, the transmissible transfer of the resulting solvent, 1. Preferential passage of counterion or (c) increased skin permeability by application of current when imposed, responsive and deliberate, electric field is applied.

In some cases, it may be desirable to process in the form of a kit, which may include containers for containing individual components such as divided bottles or divided foil packets. Typically, the kit includes instructions for the management of individual components. The kit format is particularly advantageous when individual components are rather processed in different dosage forms (eg, oral or parenteral), different dosage intervals, or titrations of individual components of the combination specify the internal Processed as desired by the physician.

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 packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs consist of a piece of relatively stiff material that is generally covered with a foil of plastic material that may be transparent.

Methods and configurations for the treatment of neurological diseases. Among other things, comprising treating a patient in need thereof, a method of treating a neurological disorder, comprising a therapeutically effective amount of a compound of formula I:

Formula I
Where R1 independently represents H (D)? O-, CO- and -CH2CO-CH2-,

R2 says independently.

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, C1-C6 alkyl, —NH2 or —COCH3.

A method of using a compound of formula I.
The present invention includes Alzheimer's disease, cancer, HIV and familial adenomatous polyposis, including methods for treating epilepsy, bipolar disorder, migraine, schizophrenia, depression.

Examples of synthetic pathways useful for making formal compounds, I, described below in the examples and generalized in Scheme 1 and Scheme 2:
Scheme 1:

Step-1: Synthesis of Compound 3:

0.06 mole of TBABr was added to a solution of 8 g NaOH (0.2 mole) in 30 ml H2O. The resulting mix was also heated at about 80oC until complete dissolution. After cooling to 60 ° C, 61.5 g of n-propyl bromide 2 and 6.5 g (0.5 mole) (0.05 mole) of ethyl acetoacetate 1 were added simultaneously to the mix. The resulting biphasic system was maintained under active movement at 71oC for 39 hours. A solution of 30.7 g n-propyl bromide (0.249 mol) and 2.2 g (0.057) mol of NaOH in 5 ml H2O was added. Also, the resulting mixture was left to react under the conditions described above for an additional 6 hours. The excess propyl bromide was distilled and recovered, thereby giving a biphasic reaction mixture whose organic phase consisted of ethyl 2 (two dipropyl acetoacetates used directly in the subsequent reaction). To this mixture, including, 2 dipropyl acetoacetates (solution of 8 g NaOH (0.2 mol) in 10 ml H2O) was added to ethyl 2 and also reacted at 80oC for 20 hours The resulting mixing left for. This finished mixture was diluted with water and extracted with DCM. Following the separation of the acidified layer of water phae, PH = 1.3 with 3 extracted times with 33% HCl and ethyl acetate. The ethyl acetate layer was dried over Na2SO4 and concentrated on drying to 3.1 g synthetic compound3.

  Step-2: Synthesis of Compound 5:

To the synthetic solution, 3 (1.0 mmol) of dry DCM (1.8 ml) was additional N, N-diisopropylethylamine (2.0 mmol) (stirred at the same temperature of 30 mIn-10 Following the wise addition of 1-chloroethylchloroform by reduction at ° Cand.) (4 (1.1 mmol) was allowed to run at 0 ° C for 1 h at the same temperature and reaction mixture). Upon completion of the reaction (monitored by TLC), the reaction mixture and solvent evaporated. In addition, the natural product was purified through a column to obtain compound 5.

Step-3: Synthesis of Compound 7:

In the RB flask, acid 6 (1.2 mmol) & anhydrous K2CO3 (1.1 mmol) were obtained in dry DMF (Volume 10), run at room temperature of 30 mIn and then cooled to -10 oC Composite 5 was slowly added, dropped, wise & then allowed to run at room temperature for 12 h. The reaction was monitored by TLC. In completing the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 × 5 ml). The combined organic layers were washed with water (2 x 5 mL) followed by brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The natural product was purified by column chromatography on 100-200 mesh silica gel to obtain product 7.

Scheme 2:

Step-1: Synthesis of Compound 3:

To an agitated solution of valproic acid 1 (20 g, 0.138 mol) in dichloromethane (200 mL) (1-2 drops of DMF) (additional oxallyl chloride (18.8 mL, 0.208 mol, 1.5 eq) .) Was wisely dropped by a dropping funnel at 0 ° C under N2 atmosphere for 20 minutes) The ice bath was removed and allowed to room temperature. The reaction mixture was then stirred at RT for another 2h. After completion of the reaction (by TLC) volatIles, it was concentrated under N2 atmosphere. The resulting native acid chloride-2 was the equivalent of acetonitrile (220 mL) to acetaldehyde (21.36 mL, 0.4159 mol, 3 eq.) And sodium iodide (52 g, 0.3446 mol, 2.5) at 00C. To the stirred mixture. After stirring at 0-5 for 2 h at 0-5, it was extracted with hexane (2 × 200 mL) and poured into ice water (200 mL). The combined organic extracts were washed with 5% sodium thiosulfate solution (2x100ml) in water followed by 5% sodium bicarbonate solution (50mL) and finally with brine solution (2x50ml). The combined organic layers were filtered and dried over anhydrous sodium sulfate and evaporated under reduced pressure ... gave 3 g (71% yield) to the composition as an oil.

Step-2: Synthesis of Compound 5:

(5Z, 8Z, 11Z, 14Z, 17Z) -ethyl icosa-5,8,11,14,17-pentaenoate (4 and 10 g, 00302 mol, one equivalent) is dissolved in ethanol (200 ml) and NaOH aqueous solution (11.98g, 0.299mol, 9.9, legitimate, 50ml H2O) was added. The reaction mixture was then stirred for 2 h at room temperature. After completion of the reaction, volatIles evaporated under reduced pressure on the work directory evaporator. The resulting crude product was diluted with water (50 ml), extracted with ethyl acetate (2 × 300 ml) and acidified with 3N HCI. The combined organic extracts were washed with brine (2 x 100 mL), filtered, dried over anhydrous sodium sulfate and concentrated on drying. Purification on silica gel (20% EtOAc in hexanes) gave compound 5 (9 g, 90% yield); bulk (m / z): 301 (M−H).

Step-3: Synthesis of Compound 6:

To the EPA's awakened solution, 5 of ethyl acetate (50 mL) (5 g, 0.0165 mol, one equivalent) was added ... triethylamine (4.7 mL, 0.033 mol, two equivalents) ) Sodium iodide (0.49 g, 0.0033 mol, equivalent of 0.2) and Compound-3 (7.37 g, 0.0248 mol, equivalent of 1.5) followed by 2 mIn of N2 atmosphere Falls wisely at room temperature. After that, the reaction temperature was raised to 500C and moved overnight. After completion of the reaction (based on TLC analysis), the reaction mixture was diluted with ethyl acetate and water. The organic layer was filtered and concentrated to dryness, separated over anhydrous sodium sulfate and dried. Purification on silica gel (3% EtOAc in hexane) yielded 6 (7.6 g, 97% yield) to the composition as a pale yellow liquid.

Example:
Effects of valproic acid and Formula I (1-1) on markers of cell viability, necrosis and oxidative stress in rat liver cells:
At 24 h, after plating of hepatocytes, the medium was sounded and replaced with fresh HepatoZYME-SFM medium ... streptomycin (100 lg / ml) supplementing ed with penicillin (100 U / ml) L-glutamine (2 mM). Hepatocytes were treated with VPA (24 h Formula I (1-1) at various concentrations). In another experiment, 1-amInobenzotrIazole, hepatocytes were pretreated (0.5 mM), or VPA (1 mM in WST-1, analyzing and 12 mM during analysis of LDH and DCF) or medium (vehicle) Medium (vehicle control) 30mIn prior to control. After 24 hours, cytotoxicity analysis was performed. Treatment of rat hepatocytes with 24 h VPA leads to the greatest or almost the greatest result among the various indices of hepatotoxicity. Formula I (1-1), valproic acid molecule conjugation and R lipoic acid, treatment for 24 hours showed the very least toxic effect among the various indices of hepatotoxicity.

The term “sample” refers to a sample of body fluid, a sample of separated cells, or a sample from a tissue or organ. More preferably, the bodily fluid sample is obtained by a well-known technique and may rather include a blood, plasma, serum or urine sample, a blood, plasma or serum sample.

Equivalent current disclosures provide for the treatment of neurological diseases and their complexities during other incident configurations and methods. Although specific embodiments of subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the system and method will now be apparent to those skilled in the art of examining this specification. The full range of systems and methods required should be determined by reference to the claims in addition to those full ranges of equivalents and specifications in addition to such changes.

All incorporated publications and patents by reference include those items mentioned, listed, and thus incorporated by reference in their entirety as if they were individual publications or patents As if each was specifically shown to be individually incorporated by reference. In case of conflict, the current application, including any definitions here, will control.

This application is based on International Application No. PCT / IB2013 / 050801 filed on January 13, 2013 (Title of Invention “Composition and Method for Treatment of Neurological Diseases”, International Publication No. WO / 2013/166799). Is a domestic transition application. This international application further claims the priority of Indian Patent Application No. 1789 / CHE / 2012 filed on May 8, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

The present disclosure relates generally to compounds and compositions for the treatment of neurological diseases. In particular, the present invention treats a subject with a pharmaceutically acceptable dose of a compound, crystal, polymorph, ester, salt, stereoisomer, enantiomer, hydrate, prodrug, or mixture thereof. About.

Central nervous system diseases continue to be the most difficult-to-resistance disease known to mankind. This is because neurological disorders are typically devastating to patients and their families, often depriving individuals of the traits that are most strongly associated with being humans, and are major neurological and neurodegenerative disorders. This is because the part lacks effective treatment. The emergence of molecular genetic approaches to the mapping and identification of disease genes in the 1980s and 1990 laid the foundation for enormous progress in our understanding of the pathogenic basis of many important neurological diseases.

Valproic acid (VPA) is widely used as an anticonvulsant. However, treatment with this drug is associated with hepatoxin (either reversible liver dysfunction or irreversible liver failure). Both clinical and empirical studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of fatty acid oxidation and synthesis, and gluconeogenesis, urea synthesis, oxidative phosphorylation and the glycine cleavage system Suppression. Other notable abnormalities include changes in the protein structure of the inner mitochondrial membrane, hyperammonemia, and increased bile flow. Such hepatotoxic mechanisms, whether possessed by VPA or its metabolites, are still poorly understood. Sensitivity to VPA hepatoxin can be enhanced by conditions such as starvation, inborn errors of metabolism, additional neurological diseases, and co-administration of enzyme-inducing agents.

The potential involvement of free radicals or oxidative damage in human disease pathogenesis has been extensively studied over the last decade. A free radical is an atom or molecule that has an unpaired electron in its external orbital and is highly reactive to the macromolecular structure by the unpaired electron, leading to disruption of cell damage and homeostasis. Free radicals are produced as a by-product of normal metabolism, and ingrowth mechanisms exist to reduce their composition or enhance their inactivation. The disruption of the pro-oxidant and antioxidant balance that supports the former may be a potential fundamental mechanism of human disease. Much of the evidence supports the notion that increased free radical production causes or accelerates neuronal damage leading to injury, and the basis for this has been reviewed recently. Treatments aimed at boosting antioxidant defenses or reducing pro-oxidant production with free radical scavengers or antioxidants are in preventing, ameliorating or preventing many neurological diseases It may be effective.

Addressing acute pathology often relies on addressing the underlying pathology and signs of the disease. There is a current need in the art for new compositions for the treatment of neurological diseases.

  The present invention provides compounds, compositions comprising these compounds, and methods of using them to treat, prevent, and / or ameliorate the effects of neurological diseases.

The present invention provides herein a composition comprising Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer or stereoisomer. The present invention also provides pharmaceutical compositions comprising one or more compounds of formula I, or intermediates thereof, and one or more pharmaceutically acceptable carriers, solvents or diluents. These compositions can be used to treat mucositis and related complications.
Formula I

In certain embodiments, the present invention relates to compounds and compositions of formula I or pharmaceutically acceptable salts,
Formula I
Here, R ¹ represents H, D, —O—, —CO—, —CH ₂ CO—CH ₂ —,
R ² represents:
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, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ .

In an exemplary embodiment, examples of compounds of formula I are those shown below. :
(1-1)

  The present application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit can include instructions for use in the treatment of a neurological disorder and its associated complications.

  The present application also discloses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some embodiments, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, oral administration, injection, subcutaneous administration, or transdermal administration.

  Here, the present application further provides a kit comprising the pharmaceutical composition described herein. The kit may further comprise instructions for use in the treatment of a neurological disease or its related complications.

The compositions described herein have several uses. This application covers, for example, neurological diseases or metabolic conditions, metabolic syndrome, chronic neurological diseases or related complications manifested from disease; epilepsy, depression, bipolar disorder, neuropathic pain, orthopedics, cardiovascular A method of treating a patient suffering from kidney, skin, neurological or ocular complications is provided.

Definitions 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 by one of ordinary skill in the art.

The compounds of the present invention can exist in the form of pharmaceutically acceptable salts. The compounds of the present invention can also exist in the form of pharmaceutically acceptable esters (ie, methyl and ethyl esters of the acids of formula I used as prodrugs). The compounds of the present invention can also be soluble, eg, water soluble. Solubility can be affected during the manufacturing process or can occur, for example, as a result of hygroscopicity of formula I (hydration), which was initially an anhydrous compound.

Compounds with the same molecular formula but different properties, atomic bonding processes, and spatial arrangements are called “isomers”. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Diastereomers are stereoisomers with the opposite configuration at one or more chiral centers that are not enantiomers. One or more stereoisomers with asymmetric centers that are non-overlapping mirror images are called “optical isomers”. For example, when a compound has one asymmetric center, if a carbon atom is bonded to four different groups, a set of optical isomers is formed. Optical isomers are characterized by the absolute composition of their asymmetric center (s) and by the R- and S-arrangement rules of Cahn, Ingold, and Prelog, or the molecules rotate their plane of polarization. And a method of selecting dextrorotatory or levorotatory (respectively (+) or (−)-isomer). A chiral compound can exist as a single optical isomer or as a mixture thereof. A mixture containing an equal proportion of optical isomers is called a “racemic mixture”.

As used herein, the term “metabolic state” (or genetic metabolic state), which refers to an inherited abnormality of metabolism, is a genetic disorder caused by a defect in one or more metabolic pathways; specifically, the function of an enzyme Is affected and is missing or completely lacking functionality.

In some embodiments, the molecular complex comprises R lipoic acid (CAS 1200-22-2), salsalate (CAS 552-94-3), acetylcysteine (CAS 616-91-1), eicosapentaenoic acid (CAS 10417). -94-4), a compound selected from the group consisting of docosahexaenoic acid (CAS 6217-54-5).

The term “polymorph” as used herein is art-recognized and refers to one crystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally” as used herein refer to modes of administration other than topical administration such as enteral and injection, including but not limited to intravenous, intramuscular. Intrathoracic, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, spinal cord Includes intra- and intra-sternal injections and infusions.

“Patient”, “subject” or “host” to be treated by the methods of the invention means either a human or non-human animal, such as a primate, mammal, vertebrate, and the like.

The phrase “pharmaceutically acceptable” is recognized in the art. In certain embodiments, the term is in contact with mammals, humans and animal tissues, without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the scope of appropriate medical judgment. Including compositions, polymers and other materials and / or dosage forms suitable for use or in a reasonable benefit / risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, transporting any object from one organ or part of the body to another organ or part of the body and A pharmaceutically acceptable substance, composition or vehicle is included as a liquid or solid filler, diluent, solvent or encapsulating material involved in transport. Each carrier must be “acceptable” in the sense of being harmless to the patient and compatible with the ingredients of other subject compositions. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of substances that can be provided as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) carboxymethylcellulose sodium (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository wax; (9) peanut oil, cottonseed oil Oils such as 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) ethyl oleate and Esters such as ethyl phosphate; (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; and (21) Other non-toxic affinity substances are used in pharmaceutical formulations.

The term “prodrug” is intended to include compounds that are converted under physiological conditions to the therapeutically active agents of the present invention. A common method for producing prodrugs is to include a selected moiety that is hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to one or more of the subject compositions. If treated before a clinical condition of an undesirable condition (eg, a host animal disease or other undesirable condition), the treatment is prophylactic and protects the host from developing into an undesirable condition . On the other hand, treatment is therapeutic if administered after an undesirable clinical condition. That is, it is intended to reduce, improve or stabilize existing undesirable conditions or side effects.

  As used herein, the term “predict” refers to an abnormality or complication and / or terminal platelet aggregation or disorder and / or death (ie, mortality) within a future defined time window (prediction window). To assess the probability associated with a disease in a patient who will be affected. Mortality can be caused by the central nervous system or complications. The prediction window is the interval during which the subject progresses one or more of the complications according to the predicted probability. The prediction window can be the total remaining life of the subject at the time of analysis by the method of the present invention.

The term “treat” is art-recognized and refers to a disease, disorder, or condition that occurs in an animal that may have a predisposition to a disease, disorder, and / or symptom, but has not yet been diagnosed as having it. Prevention; including inhibiting a disease, disorder or condition, ie preventing its progression, and reducing a disease, disorder, or condition, ie, causing regression of the disease, disorder, and / or condition. To treat a disease or condition, a drug that is administered causes the condition, such as a mucositis or mucosal disorder in the subject, or a condition such as inflammation and ulceration with gastrointestinal lining and oral cavity. Ameliorating at least one symptom of a particular disease or condition, even when the underlying pathophysiology is not affected, such as treating by administering a drug without addressing. As used herein, the term “treating”, “treat” or “treatment” includes cure, prevention (eg, prevention), preventive aids and palliative treatment.

The phrase “therapeutically effective amount” is a term recognized in the art. In certain embodiments, the term refers to the 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 an amount necessary or sufficient to eliminate or alleviate a medical condition for a period of time. An effective amount can vary depending on factors such as the disease or condition being treated, the particular targeting construct being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular composition without necessitating undue experimentation.

In certain embodiments, a pharmaceutical composition described herein is formulated such that the pharmaceutical composition is delivered to a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of composition administered to a subject depends on the delivery rate of the salt and composition from the subject composition and the rate of absorption, inactivation and excretion of the drug. It should be noted that dosage values can also be varied to reduce the severity of the condition. Furthermore, for any particular subject, it should be understood that the particular dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. Typically, dosing is determined using techniques known to those skilled in the art.

Also, optimal concentrations and / or amounts, or the amount of any particular salt or composition, can be adjusted to accommodate variations in treatment parameters. Such therapeutic parameters include, for example, the clinical site in which the formulation is placed, such as treatment site, patient type, human or non-human, adult or child, and the nature of the disease or condition.

In certain embodiments, the dosage of the compositions of the invention provided herein can be determined by reference to the plasma concentration of the therapeutic composition or other encapsulating material. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

The term “sustained release” when used with respect to pharmaceutical compositions or other substances is art-recognized. For example, a subject composition that releases a substance over time may exhibit sustained release characteristics as opposed to a bolus-type administration in which the entire amount of the substance is made bioavailable at once. For example, in certain embodiments, when in contact with bodily fluids, including bodily blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc., over a sustained or extended period (compared to bolus release), or Multiple acceptable excipients can be combined with any material, for example, slow or delayed degradation with simultaneous release of therapeutically and / or biologically active salts and / or compositions ( Subject to hydrolysis). This release can result in sustained delivery of a therapeutically effective amount of any of the therapeutic agents disclosed herein.

The phrases “systemic administration”, “systemic administration”, “peripheral administration”, “peripheral administration” are art-recognized and are intended compositions, therapeutic agents in locations away from where the disease is treated Or administration of other substances. Administration of a drug for a disease is a systemic distribution of the drug unless it is administered directly to the central nervous system where it enters the patient's tissues and follows a process such as metabolism, such as by subcutaneous administration. In some cases, it may be referred to as “local” or “topical” or “regional” administration.

The phrase “therapeutically effective amount” is a term recognized in the art. In certain embodiments, the term refers to the 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 an amount necessary or sufficient to eliminate or alleviate medical symptoms for a period of time. The effective amount can vary depending on factors such as the disease or condition, the particular targeting construct being treated, the size of the subject, or the severity of the disease or condition being administered. One skilled in the art can empirically determine the effective amount of a particular composition without necessitating undue experimentation.

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

The application also discloses pharmaceutical compositions comprising a pharmaceutically acceptable carrier that can be formulated for systemic, topical or oral administration and a composition of a compound of formula I. The pharmaceutical composition can be formulated for oral administration, oral solution, injection, subcutaneous administration, or transdermal administration. The pharmaceutical composition can further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

In many embodiments, a pharmaceutical composition described herein is in an amount sufficient to deliver a therapeutically effective amount of a compound of formula I or as a part of a prophylactic or therapeutic treatment to a patient. Incorporates the disclosed compounds and compositions (formula I) to be delivered. The desired concentration of Formula I or a pharmaceutically acceptable salt thereof will depend on absorption, inactivation and excretion rates, the drug and the delivery rate of the salt and composition from the compositions of the present invention. It should be noted that dosage values can also be varied to reduce the severity of the condition. In addition, for any particular subject, it should be understood that the particular dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. Typically, dosing is determined using techniques known to those skilled in the art.

Also, the optimal concentration and / or amount or amount of any particular compound of Formula I can be adjusted to accommodate variations in treatment parameters. Such therapeutic parameters include, for example, the formulation placed, clinical use, treatment site, patient type, eg, human or non-human, adult or child, and the nature of the disease or condition.

The concentration and / or amount of any compound of formula I can be easily identified by routine screening in animals such as rats by screening the range of concentration and / or amount of the relevant material using appropriate tests. I can do it. Known methods are also available for assaying local tissue concentrations, salt or composition diffusion rates, and local blood flow before and after administration of the therapeutic formulations disclosed herein. T. T. et al. E. One such method is microdialysis, as referenced in Robinson et al., 1991, Neuroscience Microdialysis, Technology, Chapter 7, Chapter 1. The method reviewed by Robinson can be easily applied as follows. The microdialysis loop is placed in place in the test animal. Permeabilized fluid is pumped through the loop. For example, when a compound of formula I, such as that disclosed herein, is injected adjacent to the loop, the released drug is recovered in the dialysate in proportion to the local tissue concentration at that location. The The progress of the diffusion of the salt or composition can be determined by a suitable calibration procedure using known concentrations of the salt or composition.

In certain embodiments, the dosage of a compound of the invention of formula I provided herein can be determined by reference to the plasma concentration of the therapeutic composition or other encapsulating material. For example, the maximum plasma concentration (in Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

In general, in performing the methods detailed in this application, an effective dosage of a compound of formula I is in the range of about 0.01 mg / kg / day to 100 mg / kg / day, such as a single dose or The range is about 0.01 mg / kg / day to 50 mg / kg / day in divided doses. Compounds of formula I can be administered in a single dose, for example, 0.2 / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 It can be administered at mg / kg / day, 30 mg / kg / day, or less than 40 mg / kg / day. Compounds of formula I may also be between 0.1 and 1000 mg, between 5 mg and 80 mg, or 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, per day, Less than 100, 300, 400, 500, 800, 1000, 2000, 5000 mg may be administered to human patients. In certain embodiments, the compositions herein are 95%, 90%, 80%, 70%, 60%, 50%, 40% of the compounds of formula I required for the same therapeutic benefit, Administered in an amount that is less than 30%, 20%, or 10%.

An effective amount of a compound of formula I as described herein means one amount of the salt or composition capable of inhibiting or preventing the disease.

  Effective doses may determine the severity of complications resulting from nerve damage, or demyelination and / or increased reactive oxidative-nitrosated species, and / or abnormal physiological homeostasis, and the risk of such complications. In some patients, the amount may be sufficient to be banned, treated, alleviated, ameliorated, stopped, inhibited, delayed, or reversed or reduced. Thus, these methods include both medical treatment (acute) and / or prophylactic (preventive) administration, as appropriate. The amount and timing of the composition administered will, of course, depend on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. Thus, due to patient-to-patient variability, the above dosage is a guide and the dosage of the drug can be titrated to achieve a treatment that the physician deems appropriate for the patient. Considering the desired degree of treatment, the physician must balance various factors such as the age of the patient, the presence of an existing disease, as well as the presence of other diseases.

  The compositions provided by the present application can be administered to a subject in need of treatment by various conventional routes, including oral, topical, parenteral, eg, intravenous, subcutaneous or intramedullary administration. Further, the composition may be administered intranasally such that the drug dissolves in the mouth without the need for water, ie, a rectal suppository or “flash” formulation is used. Further, the composition may be administered by controlled release dosage forms, site-specific drug delivery, transdermal drug delivery patch (active / passive) mediated drug delivery, stereotaxic injection or to a subject in need of treatment with nanoparticles. it can.

The composition can be administered either in a single dose or in multiple doses, alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. If desired, these pharmaceutical compositions can include additional ingredients such as, for example, perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as, for example, L-arginine, sodium citrate, calcium carbonate, and calcium phosphate are available in various forms such as starch, alginic acid, and certain complex silicates. Can be used with other disintegrants and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules. Suitable 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 ingredients therein are various sweetening or flavoring agents, coloring substances or pigments, optionally emulsifying or suspending agents, water, You may combine with diluents, such as ethanol, propylene glycol, glycerol, and those combination. As is well known in the pharmaceutical art, the compounds of formula I may also include enteric coatings of various excipients.

For parenteral administration, a solution of the composition can be prepared (for example) in sesame oil or peanut oil, in aqueous propylene glycol, or in a sterile aqueous solution. Such aqueous solutions should be suitably buffered when necessary, and the liquid diluent is first made isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, all sterile aqueous media used are readily available by standard techniques known to those skilled in the art.

Formulations (eg tablets) are for example 10-100, 50-250, 150-500 mg, or 350-800 mg, for example 10, 50, 100, 300, 500, 700, 800 mg of the formula I disclosed herein. Of a compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I.

In general, the compositions described herein may be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may refer to cases where the patient has a gastrointestinal disorder that prevents oral administration, or where the attending physician determines that the drug is best applied to the surface of cells or organs. . For example, local administration may indicate when a high dose is desired for the target tissue or organ. Active compositions for buccal administration can take the form of tablets or troches formulated in a conventional manner.

The dosage will depend on the characteristics of the inflammation and lipid disorders, the type of patient, including age, health and weight, the type of concomitant therapy, if any, and the frequency of the treatment to therapy ratio.

Illustratively, the dose levels of active ingredient administered are as follows (relative to host weight): Intramuscular, 0.1 to about 200 mg / kg; intravenous, 1 to about 500 mg / kg; oral, 5 to about 1000 mg / kg; intranasal instillation, 5 to about 1000 mg / kg; aerosol, 5 to about 1000 mg / Kg.

Expressed in terms of concentration, preferably at a concentration of about 0.01 to about 50% by weight of the composition for topical use on the dermis, intranasal, intrapharyngeal, bronchial, vagina, rectum, or eye; preferably Is present at a concentration of about 1 to about 20% by weight of the composition; for parenteral use at a concentration of about 0.05 to about 50% by weight of the composition; preferably at a concentration of about 5 to about 20% by weight. it can.

The compositions of the present invention preferably contain an appropriate amount of the active ingredient, eg tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, suspensions It exists for administration to humans and animals in sterile parenteral solutions and in unit dose forms such as oral. Solid or liquid unit volume forms can be prepared for oral administration.

As mentioned above, the tablet core includes one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelled starches, swollen crosslinked polymers, and mixtures thereof. Is included. Examples of suitable water-swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenyl Examples include cellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, 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, poly (ethylene oxide). Examples of suitable acrylic polymers include CARBOPOL ™, methacrylate divinylbenzene potassium copolymer, polymethyl methacrylate, high molecular weight cross-linked acrylic acid homopolymers and copolymers commercially available from Noveon Chemicals. It is not limited to. Examples of suitable hydrocolloids include alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pushtulan, laminarin, scre Examples include, but are not limited to, loglucan, gum arabic, inulin, pectin, gelatin, wean, ramsan, zoolan, 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 gelled starches include, but are not limited to, swellable starches such as acid hydrolyzed starch, sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar and cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

The carrier can include one or more suitable excipients for tablet formulation. Examples of suitable excipients include fillers, adsorbents, binders, disintegrants, lubricants, glidants, release modifiers, super disintegrants, antioxidants, and mixtures thereof, It is not limited to these.

Suitable binders include dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose; acacia, alginate, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, cod, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin Water-soluble, including hydrocolloids such as maltodextrin, galactomannan, pustulan, minarin, scleroglucan, inulin, whelan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose, sucrose, and starch Wet binders such as polymers; and mixtures thereof, including but not limited to. Suitable disintegrants include, but are not limited to, sodium glue glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose, starch, microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fatty acids and their salts such as magnesium stearate and stearic acid, talc, glyceride waxes and mixtures thereof. Suitable glidants include, but are not limited to colloidal silicon dioxide. Suitable modified release excipients include, but are not limited to, insoluble edible substances, pH dependent polymers, and mixtures thereof.

  Insoluble edible substances suitable for use as modified release excipients include, but are not limited to, water insoluble polymers and low melting point hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof, It is not limited to these. Suitable low melting point 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, cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Like hydrogenated vegetable oil. 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 monostearate, glyceryl tristearate, glyceryl trilaurate, Examples include glyceryl myristate, glyco-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl selenium, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. A fat-containing mixture such as chocolate and mixtures thereof; Examples of superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In one embodiment, the tablet core comprises up to about 5% by weight of the super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, sorbic acid, and mixtures thereof.

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; from about 250 microns to about 1000 microns. In embodiments, the immediate release coating is typically compressed to a density of about 0.9 g / cc or greater, as measured by the weight and volume of the particular layer.

In one embodiment, the immediate release coating includes a first portion and a second portion, at least one of which contains a second pharmaceutically active agent. In one embodiment, the portions contact each other at the central axis of the tablet. In one embodiment, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent.

In one embodiment, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent. In one embodiment, one of the moieties contains a third pharmaceutically active agent. In one embodiment, one of the portions comprises a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

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 contained in a dry granule that includes a pharmaceutically active agent.

Formulations with different drug release mechanisms described above can be combined into a final dosage form containing single or multiple units. Examples of multiple units include multi-layer tablets, capsules, etc. that include tablets, beads, or granules in solid or liquid form. Typically, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, such as in gelatin capsules. Many methods for preparing coatings, covers or combined agents are known in the art.

The immediate release agent has a therapeutically effective amount of the active agent in a unit volume form, i.e., a tablet, multiple drug-containing beads, granules or particles, or a coated core volume form, along with conventional pharmaceutical excipients. include. Immediate release dosage units may or may not be coated or mixed with delayed release volume unit (s) (immediate release drug-containing granules, particles or bead capsules) In the combined mixture and in the delayed release drug-containing granules or beads).

For example, extended release formulations are generally prepared as diffusion or osmotic systems, as described in “Remington-Pharmacology and Practice,” 20th, Lippincott Williams and Wilkins, Baltimore, Maryland, 2000. A diffusion system typically consists of one of two types of devices, a reservoir and a matrix, well known in the dyeing art. Matrix devices are generally prepared by compressing a drug with a polymeric carrier that slowly dissolves in the form of a tablet.

The immediate release portion is sustained by either introducing an immediate release layer on the sustained release core or by using a coating or compression process or multiple unit systems such as capsules containing expansion and immediate release beads. Can be added to the discharge system.

Delayed release dosage formulations are made by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach but soluble in the neutral environment of the small intestine. Delayed release dosage units can be prepared by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition comprises a plurality of drug-containing beads, particles or granules for incorporation into either a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a tablet or capsule. It may be.

Pulsed-release dosage forms mimic multiple dosage profiles without repeated administration, and typically include, for example, drugs presented as conventional dosage forms (solution or immediate drug release, or conventional solid dosage forms As a result, the frequency of administration is at least half as low. The pulse release profile is characterized by a reduced release followed by a rapid drug release (period delay time without release).

Each dosage form contains a therapeutically effective amount of the active agent. In one embodiment of a dosage form that mimics the twice daily dosing characteristics, it is released in an initial pulse of about 30% to 70%, preferably 40% to 60% by weight of the total amount of active agent in the dosage form. The Then, about 70% to 3.0%, preferably 60% to 40% by weight of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms that mimic twice daily dosage characteristics, the second pulse is preferably released from about 3 hours to less than 14 hours, more preferably from about 5 hours to 12 hours after administration.

Other dosage forms include compressed tablets or capsules 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 comprises a plurality of beads, granules, particles that substantially release the drug immediately after oral administration to provide a nascent dose. The delayed release dosage unit comprises a plurality of coated beads or granules that release the drug from about 3 hours to 14 hours after oral administration to provide a second dose.

For transdermal (eg, topical) administration purposes, sterile aqueous or partially aqueous diluted solutions (usually at a concentration of about 0.1% to 5%) can be prepared, but otherwise Similar to parenteral solutions can be prepared.

Methods of preparing various pharmaceutical compositions containing a certain amount of one or more compounds of Formula I, or other active agent, are known or will be apparent to those skilled in the art in light of this disclosure. For an example of how to prepare a pharmaceutical composition, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 19th Edition (1995).

Further, in certain embodiments, the subject compositions of the present application are perhaps used with another suitable drying technique, such as lyophilization or spray drying. The subject compositions may be administered once, or the volume administered by varying the time interval can be reduced to multiple small doses, depending in part on the rate of release of the composition and the desired dosage. You may divide into.

Formulations useful in the methods provided herein include methods 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 method well known in the pharmaceutical arts. The amount of the composition of the invention that can be combined with a carrier material to produce a single dosage that can vary depending on the subject depends on the subject to be treated and the particular mode of administration.

The methods of preparing these formulations or compositions comprise the step of binding to a composition of the invention with a carrier and optionally one or more auxiliary ingredients. In general, formulations are prepared by synthesizing the subject composition uniformly and intimately with a liquid carrier, a finely divided solid carrier, or both, and if necessary shaping the product.

The compounds of formula I described herein can be administered by inhalation or aerosol formulation. Inhalants or aerosol formulations may include one or more agents as such adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is, for example, 0.005 to 90% w / w of the drug compared to the total weight of the formulation, for example 0.005 to 50% w / w, 0.005 to 5% w / w, or 0.01 to 1.0% w / w may be included.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition comprises one or more pharmaceutically acceptable carriers and / or any of the following: Mixed. (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) paraffins, etc. (6) Absorption promoters such as quaternary ammonium compounds; (7) Wetting agents such as acetyl alcohol and glycerol monostearate; (8) Absorbents such as kaolin and bentonite clay; (9) Talc. Calcium stearate, steari (10) coloring agents; magnesium acid, solid polyethylene glycols, absorbents such as sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Similar types of solid compositions can also use lactose or lactose as a filler in soft and hard filled gelatin capsules, as well as high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compositions of the present invention, the liquid dosage form contains inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol Benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol And solubilizers and emulsifiers such as fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the compositions of the present invention, include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and their Suspending agents such as mixtures may be included.

Formulations for rectal or vaginal administration are prepared by mixing the composition of the invention with one or more suitable nonirritating carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes, or salicylates. Can be provided as a suppository to obtain. And they are solid at room temperature but become liquid at body temperature, thus melting in the appropriate body cavity to release the encapsulated compound (s) and composition (s) . Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers as are known in the art to be suitable.

Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The compositions of the invention may be mixed under sterile conditions with a pharmaceutically acceptable carrier, or with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complex may contain lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

Ointments, pastes, creams and gels, in addition to the subject composition, for example animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and Other carriers such as zinc oxide, or mixtures thereof may be included. Powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures thereof, in addition to the subject composition. The spray may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Methods for delivering a single composition or multiple compositions via a transdermal patch are known in the art. Typical patch and patch delivery methods are described in US Pat. Nos. 6,974,588, 6564093, 6312716, 6440454, 6267983, 6239180, and 6103275.

In another embodiment, the transdermal patch may comprise: a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2 to 10 parts by weight of a styrene-ethylene-butylene-styrene copolymer. A composite film comprising a composite film formed by: a first adhesive layer on one side of the composite film; and a polyalkylene terephthalate film attached to one side of the composite film via the first adhesive layer; A second adhesive layer comprising a saturated polyester resin, a primer layer formed on the surface of the polyalkylene terephthalate film, and a styrene-diene-styrene block copolymer containing a pharmaceutical laminated on the primer layer. The base sheet manufacturing method is such that a resin composition is formed on a composite film by calendering to prepare the resin composition, and then a polyalkylene terephthalate film is bonded to one side of the composite film using an adhesive. Including doing. This involves preparing a base sheet and preparing the resin composition described above to adhere to the polyalkylene terephthalate film phthalate film.

Another type of patch includes, for example, incorporating a drug directly into a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive on a suitable backing member such as a polyester backing. The drug is present at a concentration that does not affect adhesion, while at the same time delivering the required clinical dose.

The transdermal patch may be passive or active. Currently available passive transdermal drug delivery systems such as nicotine, estrogen and nitroglycerin patches deliver small molecule drugs. Many of the newly developed protein and peptide drugs are too large to be delivered via passive transdermal patches, and for large molecule drugs, using techniques such as electro-assist (iontophoresis) Can be delivered.

Iontophoresis is a technique used to improve the flux of substances ionized through a membrane by the application of an electric current. An example of an iontophoretic membrane is described in US Pat. No. 5,080,646 to Theeuwes. The main mechanism of iontophoresis by enhancing molecular transport across the skin is: (a) repel charged ions from the same charge electrode, and (b) charge cells in response when an electric field is applied. The convective motion of the electroosmotic solvent that causes the preferential passage of counterions through the pores, and (c) increase the skin permeability due to the application of current.

In some forms, it may be desirable to administer in the form of a kit and may include a container for containing separate compositions such as divided bottles or divided foil packets. Typically, the kit includes instructions for administration of the separate components. When it is preferred that separate compositions be administered in different dosage forms (eg, oral and parenteral) and for different periods of time, or when it is desired by the prescribing physician to titrate the individual compositions in the combination The kit form is particularly advantageous.

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 packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are typically composed of a relatively stiff sheet covered with a foil of a permeable plastic material.

Methods and compositions for the treatment of neurological diseases. In particular, there is provided a method of treating mucositis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I
Here, R ¹ independently represents H, D, —O—, —CO—, —CH ₂ —CO—CH ₂ —,
R ² independently represents:
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, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ .
Process for the preparation of compounds of formula I

The invention further includes methods for the treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial adenomatous polyposis.

Examples of synthetic routes useful in making the compounds of formula I are set forth below and are discussed generally in Scheme 1.
Scheme 1:

Step-1: Synthesis of Compound 3:

TBABr 0.06 mol was added to a solution of 8 g NaOH (0.2 mol) in 30 ml H ₂ O and the resulting mixture was heated at about 80 ° C. until completely dissolved. After cooling to 60 ° C., 261.5 g (0.5 mol) of n-propyl bromide and 16.5 g (0.05 mol) of ethyl acetoacetate were simultaneously added to the mixture. The resulting two-layer system was kept vigorously stirred at 71 ° C. for 39 hours. 30.7 g (0.249 mol) n-propyl bromide, and a solution of 2.2 g (0.057 mol) NaOH in 5 ml H ₂ O were added and the above mixture was reacted under the conditions described above to react. I left it for another 6 hours. Excess propyl bromide was distilled off to give a two-layer reaction mixture in which the organic layer consisted of ethyl 2,2 dipropyl acetoacetate. The organic layer was used directly in the subsequent reaction. To this mixture containing ethyl 2,2 dipropyl acetoacetate was added 8 g (0.2 mol) NaOH solution in 10 ml H ₂ O and the resulting mixture was left at 80 ° C. for reaction for 20 hours. . After completion, the mixture was diluted with water and extracted with DCM. The separated aqueous layer was then acidified with 33% HCl to pH = 1 and extracted three times with ethyl acetate. The ethyl acetate layer was dried over Na ₂ SO ₄ and concentrated to anhydrous yielding 3.1 g of compound 3.

Step-2: Synthesis of Compound 5:

To compound 3 (1.0 mmol) in dry DCM (1.8 ml) was added N, N-diisopropylethylamine (2.0 mmol) at −10 ° C. and stirred at the same temperature for 30 minutes, then 1-chloroethylchlorocarbonic acid. Salt 4 (1.1 mmol) was added dropwise at the same temperature and the reaction mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction (monitored by TLC), the solvent of the reaction mixture was evaporated and the crude product was purified through a column to give compound 5.

Step-3: Synthesis of Compound 7:

In an RB flask, acid 6 (1.2 mmol) and anhydrous K ₂ CO ₃ (1.1 mmol) are taken up in dry DMF (10 vol), stirred at room temperature for 30 minutes and cooled to −10 ° C. to give compound 5 The solution was slowly added dropwise and then stirred at room temperature for 12 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 × 5 ml). The combined organic layers were washed with water (2 × 5 mL) then brine solution (10 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on 100-200 mesh silica gel to obtain product 7.
Example

Effects of valproic acid and Formula I (1-1) on markers of cell viability, necrosis and oxidative stress in rat liver cells:
Twenty-four hours after hepatocyte plating, the medium was aspirated and replaced with fresh HepatoZYME-SFM medium supplemented with penicillin (100 U / ml), streptomycin (100 lg / ml), and L-glutamine (2 mM). Hepatocytes were treated with VPA, various concentrations of Formula I (1-1) for 24 hours. In another example, hepatocytes were pretreated with 1-aminobenzotriazole (0.5 mM) or pre-loaded with VPA (1 mM during WST-1 analysis and 12 mM during LDH and DCF analysis) 30 minutes before. Administered medium or medium (solvent control). After 24 hours, cytotoxicity analysis was performed. Treatment of rat liver cells with 24 hours of VPA resulted in the greatest or nearly the maximum of the various indices of hepatotoxicity. Formula I (1-1), a molecular complex of valproic acid and R lipoic acid, treatment for 24 hours showed the least toxic effect among the various indices of hepatotoxicity.

The term “sample” refers to a sample of body fluid, a sample of separated cells, or a sample from a tissue or organ. The body fluid sample is obtained by known techniques, preferably the body fluid sample comprises a blood, plasma, serum or urine sample, more preferably a blood, plasma or serum sample.
Equivalent

The present disclosure provides, inter alia, compounds and methods for the treatment of moderate to severe pain and related conditions. While specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the arrangements and methods herein will become apparent to those skilled in the art upon reference to this specification. The full scope of the claims and methods should be determined with reference to the claims, their equivalents, and the specification, along with variations thereof.
Replenishment by quotation

All publications and patents mentioned in this specification, including those listed above, are expressly incorporated by reference as if individual publications or patents were shown explicitly and each incorporated by reference. Incorporated throughout. In case of conflict, the present application, including any definitions herein, will control.

This application is based on International Application No. PCT / IB2013 / 050801 filed on January 13, 2013 (Title of Invention “Composition and Method for Treatment of Neurological Diseases”, International Publication No. WO / 2013/166799). Is a domestic transition application. This international application further claims the priority of Indian Patent Application No. 1789 / CHE / 2012 filed on May 8, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

The present disclosure relates generally to compounds and compositions for the treatment of neurological diseases. In particular, the present invention treats a subject with a pharmaceutically acceptable dose of a compound, crystal, polymorph, ester, salt, stereoisomer, enantiomer, hydrate, prodrug, or mixture thereof. About.

Central nervous system diseases continue to be the most difficult-to-resistance disease known to mankind. This is because neurological disorders are typically devastating to patients and their families, often depriving individuals of the traits that are most strongly associated with being humans, and are major neurological and neurodegenerative disorders. This is because the part lacks effective treatment. The emergence of molecular genetic approaches to the mapping and identification of disease genes in the 1980s and 1990 laid the foundation for enormous progress in our understanding of the pathogenic basis of many important neurological diseases.

Valproic acid (VPA) is widely used as an anticonvulsant. However, treatment with this drug is associated with hepatoxin (either reversible liver dysfunction or irreversible liver failure). Both clinical and empirical studies have revealed several VPA-related biochemical abnormalities in the liver: inhibition of fatty acid oxidation and synthesis, and gluconeogenesis, urea synthesis, oxidative phosphorylation and the glycine cleavage system Suppression. Other notable abnormalities include changes in the protein structure of the inner mitochondrial membrane, hyperammonemia, and increased bile flow. Such hepatotoxic mechanisms, whether possessed by VPA or its metabolites, are still poorly understood. Sensitivity to VPA hepatoxin can be enhanced by conditions such as starvation, inborn errors of metabolism, additional neurological diseases, and co-administration of enzyme-inducing agents.

The potential involvement of free radicals or oxidative damage in human disease pathogenesis has been extensively studied over the last decade. A free radical is an atom or molecule that has an unpaired electron in its external orbital and is highly reactive to the macromolecular structure by the unpaired electron, leading to disruption of cell damage and homeostasis. Free radicals are produced as a by-product of normal metabolism, and ingrowth mechanisms exist to reduce their composition or enhance their inactivation. The disruption of the pro-oxidant and antioxidant balance that supports the former may be a potential fundamental mechanism of human disease. Much of the evidence supports the notion that increased free radical production causes or accelerates neuronal damage leading to injury, and the basis for this has been reviewed recently. Treatments aimed at boosting antioxidant defenses or reducing pro-oxidant production with free radical scavengers or antioxidants are in preventing, ameliorating or preventing many neurological diseases It may be effective.

Addressing acute pathology often relies on addressing the underlying pathology and signs of the disease. There is a current need in the art for new compositions for the treatment of neurological diseases.

  The present invention provides compounds, compositions comprising these compounds, and methods of using them to treat, prevent, and / or ameliorate the effects of neurological diseases.

The present invention provides herein a composition comprising Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer or stereoisomer. The present invention also provides pharmaceutical compositions comprising one or more compounds of formula I, or intermediates thereof, and one or more pharmaceutically acceptable carriers, solvents or diluents. These compositions can be used to treat mucositis and related complications.
Formula I

In certain embodiments, the present invention relates to compounds and compositions of formula I or pharmaceutically acceptable salts,
Formula I
Here, R ¹ represents H, D, —O—, —CO—, —CH ₂ CO—CH ₂ —,
R ² represents:
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, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ .

In an exemplary embodiment, examples of compounds of formula I are those shown below. :
(1-1)

  The present application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit can include instructions for use in the treatment of a neurological disorder and its associated complications.

  The present application also discloses pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some embodiments, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, oral administration, injection, subcutaneous administration, or transdermal administration.

  Here, the present application further provides a kit comprising the pharmaceutical composition described herein. The kit may further comprise instructions for use in the treatment of a neurological disease or its related complications.

The compositions described herein have several uses. This application covers, for example, neurological diseases or metabolic conditions, metabolic syndrome, chronic neurological diseases or related complications manifested from disease; epilepsy, depression, bipolar disorder, neuropathic pain, orthopedics, cardiovascular A method of treating a patient suffering from kidney, skin, neurological or ocular complications is provided.

Exemplary embodiments are shown by way of illustration and not limitation with the drawings. In the drawings, like reference numerals refer to like elements.
1H shows the 1H-NMR result for Formula I.

Definitions 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 by one of ordinary skill in the art.

The compounds of the present invention can exist in the form of pharmaceutically acceptable salts. The compounds of the present invention can also exist in the form of pharmaceutically acceptable esters (ie, methyl and ethyl esters of the acids of formula I used as prodrugs). The compounds of the present invention can also be soluble, eg, water soluble. Solubility can be affected during the manufacturing process or can occur, for example, as a result of hygroscopicity of formula I (hydration), which was initially an anhydrous compound.

Compounds with the same molecular formula but different properties, atomic bonding processes, and spatial arrangements are called “isomers”. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Diastereomers are stereoisomers with the opposite configuration at one or more chiral centers that are not enantiomers. One or more stereoisomers with asymmetric centers that are non-overlapping mirror images are called “optical isomers”. For example, when a compound has one asymmetric center, if a carbon atom is bonded to four different groups, a set of optical isomers is formed. Optical isomers are characterized by the absolute composition of their asymmetric center (s) and by the R- and S-arrangement rules of Cahn, Ingold, and Prelog, or the molecules rotate their plane of polarization. And a method of selecting dextrorotatory or levorotatory (respectively (+) or (−)-isomer). A chiral compound can exist as a single optical isomer or as a mixture thereof. A mixture containing an equal proportion of optical isomers is called a “racemic mixture”.

As used herein, the term “metabolic state” (or genetic metabolic state), which refers to an inherited abnormality of metabolism, is a genetic disorder caused by a defect in one or more metabolic pathways; specifically, the function of an enzyme Is affected and is missing or completely lacking functionality.

In some embodiments, the molecular complex comprises R lipoic acid (CAS 1200-22-2), salsalate (CAS 552-94-3), acetylcysteine (CAS 616-91-1), eicosapentaenoic acid (CAS 10417). -94-4), a compound selected from the group consisting of docosahexaenoic acid (CAS 6217-54-5).

The term “polymorph” as used herein is art-recognized and refers to one crystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally” as used herein refer to modes of administration other than topical administration such as enteral and injection, including but not limited to intravenous, intramuscular. Intrathoracic, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, spinal cord Includes intra- and intra-sternal injections and infusions.

“Patient”, “subject” or “host” to be treated by the methods of the invention means either a human or non-human animal, such as a primate, mammal, vertebrate, and the like.

The phrase “pharmaceutically acceptable” is recognized in the art. In certain embodiments, the term is in contact with mammals, humans and animal tissues, without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the scope of appropriate medical judgment. Including compositions, polymers and other materials and / or dosage forms suitable for use or in a reasonable benefit / risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, transporting any object from one organ or part of the body to another organ or part of the body and A pharmaceutically acceptable substance, composition or vehicle is included as a liquid or solid filler, diluent, solvent or encapsulating material involved in transport. Each carrier must be “acceptable” in the sense of being harmless to the patient and compatible with the ingredients of other subject compositions. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of substances that can be provided as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) carboxymethylcellulose sodium (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository wax; (9) peanut oil, cottonseed oil Oils such as 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) ethyl oleate and Esters such as ethyl phosphate; (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; and (21) Other non-toxic affinity substances are used in pharmaceutical formulations.

The term “prodrug” is intended to include compounds that are converted under physiological conditions to the therapeutically active agents of the present invention. A common method for producing prodrugs is to include a selected moiety that is hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to one or more of the subject compositions. If treated before a clinical condition of an undesirable condition (eg, a host animal disease or other undesirable condition), the treatment is prophylactic and protects the host from developing into an undesirable condition . On the other hand, treatment is therapeutic if administered after an undesirable clinical condition. That is, it is intended to reduce, improve or stabilize existing undesirable conditions or side effects.

  As used herein, the term “predict” refers to an abnormality or complication and / or terminal platelet aggregation or disorder and / or death (ie, mortality) within a future defined time window (prediction window). To assess the probability associated with a disease in a patient who will be affected. Mortality can be caused by the central nervous system or complications. The prediction window is the interval during which the subject progresses one or more of the complications according to the predicted probability. The prediction window can be the total remaining life of the subject at the time of analysis by the method of the present invention.

The term “treat” is art-recognized and refers to a disease, disorder, or condition that occurs in an animal that may have a predisposition to a disease, disorder, and / or symptom, but has not yet been diagnosed as having it. Prevention; including inhibiting a disease, disorder or condition, ie preventing its progression, and reducing a disease, disorder, or condition, ie, causing regression of the disease, disorder, and / or condition. To treat a disease or condition, a drug that is administered causes the condition, such as a mucositis or mucosal disorder in the subject, or a condition such as inflammation and ulceration with gastrointestinal lining and oral cavity. Ameliorating at least one symptom of a particular disease or condition, even when the underlying pathophysiology is not affected, such as treating by administering a drug without addressing. As used herein, the term “treating”, “treat” or “treatment” includes cure, prevention (eg, prevention), preventive aids and palliative treatment.

The phrase “therapeutically effective amount” is a term recognized in the art. In certain embodiments, the term refers to the 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 an amount necessary or sufficient to eliminate or alleviate a medical condition for a period of time. An effective amount can vary depending on factors such as the disease or condition being treated, the particular targeting construct being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular composition without necessitating undue experimentation.

In certain embodiments, a pharmaceutical composition described herein is formulated such that the pharmaceutical composition is delivered to a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of composition administered to a subject depends on the delivery rate of the salt and composition from the subject composition and the rate of absorption, inactivation and excretion of the drug. It should be noted that dosage values can also be varied to reduce the severity of the condition. Furthermore, for any particular subject, it should be understood that the particular dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. Typically, dosing is determined using techniques known to those skilled in the art.

Also, optimal concentrations and / or amounts, or the amount of any particular salt or composition, can be adjusted to accommodate variations in treatment parameters. Such therapeutic parameters include, for example, the clinical site in which the formulation is placed, such as treatment site, patient type, human or non-human, adult or child, and the nature of the disease or condition.

In certain embodiments, the dosage of the compositions of the invention provided herein can be determined by reference to the plasma concentration of the therapeutic composition or other encapsulating material. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

The term “sustained release” when used with respect to pharmaceutical compositions or other substances is art-recognized. For example, a subject composition that releases a substance over time may exhibit sustained release characteristics as opposed to a bolus-type administration in which the entire amount of the substance is made bioavailable at once. For example, in certain embodiments, when in contact with bodily fluids, including bodily blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc., over a sustained or extended period (compared to bolus release), or Multiple acceptable excipients can be combined with any material, for example, slow or delayed degradation with simultaneous release of therapeutically and / or biologically active salts and / or compositions ( Subject to hydrolysis). This release can result in sustained delivery of a therapeutically effective amount of any of the therapeutic agents disclosed herein.

The phrases “systemic administration”, “systemic administration”, “peripheral administration”, “peripheral administration” are art-recognized and are intended compositions, therapeutic agents in locations away from where the disease is treated Or administration of other substances. Administration of a drug for a disease is a systemic distribution of the drug unless it is administered directly to the central nervous system where it enters the patient's tissues and follows a process such as metabolism, such as by subcutaneous administration. In some cases, it may be referred to as “local” or “topical” or “regional” administration.

The phrase “therapeutically effective amount” is a term recognized in the art. In certain embodiments, the term refers to the 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 an amount necessary or sufficient to eliminate or alleviate medical symptoms for a period of time. The effective amount can vary depending on factors such as the disease or condition, the particular targeting construct being treated, the size of the subject, or the severity of the disease or condition being administered. One skilled in the art can empirically determine the effective amount of a particular composition without necessitating undue experimentation.

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

The application also discloses pharmaceutical compositions comprising a pharmaceutically acceptable carrier that can be formulated for systemic, topical or oral administration and a composition of a compound of formula I. The pharmaceutical composition can be formulated for oral administration, oral solution, injection, subcutaneous administration, or transdermal administration. The pharmaceutical composition can further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

In many embodiments, a pharmaceutical composition described herein is in an amount sufficient to deliver a therapeutically effective amount of a compound of formula I or as a part of a prophylactic or therapeutic treatment to a patient. Incorporates the disclosed compounds and compositions (formula I) to be delivered. The desired concentration of Formula I or a pharmaceutically acceptable salt thereof will depend on absorption, inactivation and excretion rates, the drug and the delivery rate of the salt and composition from the compositions of the present invention. It should be noted that dosage values can also be varied to reduce the severity of the condition. In addition, for any particular subject, it should be understood that the particular dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. Typically, dosing is determined using techniques known to those skilled in the art.

Also, the optimal concentration and / or amount or amount of any particular compound of Formula I can be adjusted to accommodate variations in treatment parameters. Such therapeutic parameters include, for example, the formulation placed, clinical use, treatment site, patient type, eg, human or non-human, adult or child, and the nature of the disease or condition.

The concentration and / or amount of any compound of formula I can be easily identified by routine screening in animals such as rats by screening the range of concentration and / or amount of the relevant material using appropriate tests. I can do it. Known methods are also available for assaying local tissue concentrations, salt or composition diffusion rates, and local blood flow before and after administration of the therapeutic formulations disclosed herein. T. T. et al. E. One such method is microdialysis, as referenced in Robinson et al., 1991, Neuroscience Microdialysis, Technology, Chapter 7, Chapter 1. The method reviewed by Robinson can be easily applied as follows. The microdialysis loop is placed in place in the test animal. Permeabilized fluid is pumped through the loop. For example, when a compound of formula I, such as that disclosed herein, is injected adjacent to the loop, the released drug is recovered in the dialysate in proportion to the local tissue concentration at that location. The The progress of the diffusion of the salt or composition can be determined by a suitable calibration procedure using known concentrations of the salt or composition.

In certain embodiments, the dosage of a compound of the invention of formula I provided herein can be determined by reference to the plasma concentration of the therapeutic composition or other encapsulating material. For example, the maximum plasma concentration (in Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

In general, in performing the methods detailed in this application, an effective dosage of a compound of formula I is in the range of about 0.01 mg / kg / day to 100 mg / kg / day, such as a single dose or The range is about 0.01 mg / kg / day to 50 mg / kg / day in divided doses. Compounds of formula I can be administered in a single dose, for example, 0.2 / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 It can be administered at mg / kg / day, 30 mg / kg / day, or less than 40 mg / kg / day. Compounds of formula I may also be between 0.1 and 1000 mg, between 5 mg and 80 mg, or 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, per day, Less than 100, 300, 400, 500, 800, 1000, 2000, 5000 mg may be administered to human patients. In certain embodiments, the compositions herein are 95%, 90%, 80%, 70%, 60%, 50%, 40% of the compounds of formula I required for the same therapeutic benefit, Administered in an amount that is less than 30%, 20%, or 10%.

An effective amount of a compound of formula I as described herein means one amount of the salt or composition capable of inhibiting or preventing the disease.

  Effective doses may determine the severity of complications resulting from nerve damage, or demyelination and / or increased reactive oxidative-nitrosated species, and / or abnormal physiological homeostasis, and the risk of such complications. In some patients, the amount may be sufficient to be banned, treated, alleviated, ameliorated, stopped, inhibited, delayed, or reversed or reduced. Thus, these methods include both medical treatment (acute) and / or prophylactic (preventive) administration, as appropriate. The amount and timing of the composition administered will, of course, depend on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. Thus, due to patient-to-patient variability, the above dosage is a guide and the dosage of the drug can be titrated to achieve a treatment that the physician deems appropriate for the patient. Considering the desired degree of treatment, the physician must balance various factors such as the age of the patient, the presence of an existing disease, as well as the presence of other diseases.

  The compositions provided by the present application can be administered to a subject in need of treatment by various conventional routes, including oral, topical, parenteral, eg, intravenous, subcutaneous or intramedullary administration. Further, the composition may be administered intranasally such that the drug dissolves in the mouth without the need for water, ie, a rectal suppository or “flash” formulation is used. Further, the composition may be administered by controlled release dosage forms, site-specific drug delivery, transdermal drug delivery patch (active / passive) mediated drug delivery, stereotaxic injection or to a subject in need of treatment with nanoparticles. it can.

The composition can be administered either in a single dose or in multiple doses, alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. If desired, these pharmaceutical compositions can include additional ingredients such as, for example, perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as, for example, L-arginine, sodium citrate, calcium carbonate, and calcium phosphate are available in various forms such as starch, alginic acid, and certain complex silicates. Can be used with other disintegrants and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules. Suitable 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 ingredients therein are various sweetening or flavoring agents, coloring substances or pigments, optionally emulsifying or suspending agents, water, You may combine with diluents, such as ethanol, propylene glycol, glycerol, and those combination. As is well known in the pharmaceutical art, the compounds of formula I may also include enteric coatings of various excipients.

For parenteral administration, a solution of the composition can be prepared (for example) in sesame oil or peanut oil, in aqueous propylene glycol, or in a sterile aqueous solution. Such aqueous solutions should be suitably buffered when necessary, and the liquid diluent is first made isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, all sterile aqueous media used are readily available by standard techniques known to those skilled in the art.

Formulations (eg tablets) are for example 10-100, 50-250, 150-500 mg, or 350-800 mg, for example 10, 50, 100, 300, 500, 700, 800 mg of the formula I disclosed herein. Of a compound of formula I, or a pharmaceutically acceptable salt of a compound of formula I.

In general, the compositions described herein may be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may refer to cases where the patient has a gastrointestinal disorder that prevents oral administration, or where the attending physician determines that the drug is best applied to the surface of cells or organs. . For example, local administration may indicate when a high dose is desired for the target tissue or organ. Active compositions for buccal administration can take the form of tablets or troches formulated in a conventional manner.

The dosage will depend on the characteristics of the inflammation and lipid disorders, the type of patient, including age, health and weight, the type of concomitant therapy, if any, and the frequency of the treatment to therapy ratio.

Illustratively, the dose levels of active ingredient administered are as follows (relative to host weight): Intramuscular, 0.1 to about 200 mg / kg; intravenous, 1 to about 500 mg / kg; oral, 5 to about 1000 mg / kg; intranasal instillation, 5 to about 1000 mg / kg; aerosol, 5 to about 1000 mg / Kg.

Expressed in terms of concentration, preferably at a concentration of about 0.01 to about 50% by weight of the composition for topical use on the dermis, intranasal, intrapharyngeal, bronchial, vagina, rectum, or eye; preferably Is present at a concentration of about 1 to about 20% by weight of the composition; for parenteral use at a concentration of about 0.05 to about 50% by weight of the composition; preferably at a concentration of about 5 to about 20% by weight. it can.

The compositions of the present invention preferably contain an appropriate amount of the active ingredient, eg tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, suspensions It exists for administration to humans and animals in sterile parenteral solutions and in unit dose forms such as oral. Solid or liquid unit volume forms can be prepared for oral administration.

As mentioned above, the tablet core includes one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelled starches, swollen crosslinked polymers, and mixtures thereof. Is included. Examples of suitable water-swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenyl Examples include cellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, 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, poly (ethylene oxide). Examples of suitable acrylic polymers include CARBOPOL ™, methacrylate divinylbenzene potassium copolymer, polymethyl methacrylate, high molecular weight cross-linked acrylic acid homopolymers and copolymers commercially available from Noveon Chemicals. It is not limited to. Examples of suitable hydrocolloids include alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pushtulan, laminarin, scre Examples include, but are not limited to, loglucan, gum arabic, inulin, pectin, gelatin, wean, ramsan, zoolan, 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 gelled starches include, but are not limited to, swellable starches such as acid hydrolyzed starch, sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar and cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

The carrier can include one or more suitable excipients for tablet formulation. Examples of suitable excipients include fillers, adsorbents, binders, disintegrants, lubricants, glidants, release modifiers, super disintegrants, antioxidants, and mixtures thereof, It is not limited to these.

Suitable binders include dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose; acacia, alginate, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, cod, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin Water-soluble, including hydrocolloids such as maltodextrin, galactomannan, pustulan, minarin, scleroglucan, inulin, whelan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulose, sucrose, and starch Wet binders such as polymers; and mixtures thereof, including but not limited to. Suitable disintegrants include, but are not limited to, sodium glue glycolate, cross-linked polyvinyl pyrrolidone, cross-linked carboxymethyl cellulose, starch, microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fatty acids and their salts such as magnesium stearate and stearic acid, talc, glyceride waxes and mixtures thereof. Suitable glidants include, but are not limited to colloidal silicon dioxide. Suitable modified release excipients include, but are not limited to, insoluble edible substances, pH dependent polymers, and mixtures thereof.

  Insoluble edible substances suitable for use as modified release excipients include, but are not limited to, water insoluble polymers and low melting point hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof, It is not limited to these. Suitable low melting point 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, cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Like hydrogenated vegetable oil. 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 monostearate, glyceryl tristearate, glyceryl trilaurate, Examples include glyceryl myristate, glyco-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl selenium, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. A fat-containing mixture such as chocolate and mixtures thereof; Examples of superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In one embodiment, the tablet core comprises up to about 5% by weight of the super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, sorbic acid, and mixtures thereof.

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; from about 250 microns to about 1000 microns. In embodiments, the immediate release coating is typically compressed to a density of about 0.9 g / cc or greater, as measured by the weight and volume of the particular layer.

In one embodiment, the immediate release coating includes a first portion and a second portion, at least one of which contains a second pharmaceutically active agent. In one embodiment, the portions contact each other at the central axis of the tablet. In one embodiment, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent.

In one embodiment, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent. In one embodiment, one of the moieties contains a third pharmaceutically active agent. In one embodiment, one of the portions comprises a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

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 contained in a dry granule that includes a pharmaceutically active agent.

Formulations with different drug release mechanisms described above can be combined into a final dosage form containing single or multiple units. Examples of multiple units include multi-layer tablets, capsules, etc. that include tablets, beads, or granules in solid or liquid form. Typically, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, such as in gelatin capsules. Many methods for preparing coatings, covers or combined agents are known in the art.

The immediate release agent has a therapeutically effective amount of the active agent in a unit volume form, i.e., a tablet, multiple drug-containing beads, granules or particles, or a coated core volume form, along with conventional pharmaceutical excipients. include. Immediate release dosage units may or may not be coated or mixed with delayed release volume unit (s) (immediate release drug-containing granules, particles or bead capsules) In the combined mixture and in the delayed release drug-containing granules or beads).

For example, extended release formulations are generally prepared as diffusion or osmotic systems, as described in “Remington-Pharmacology and Practice,” 20th, Lippincott Williams and Wilkins, Baltimore, Maryland, 2000. A diffusion system typically consists of one of two types of devices, a reservoir and a matrix, well known in the dyeing art. Matrix devices are generally prepared by compressing a drug with a polymeric carrier that slowly dissolves in the form of a tablet.

The immediate release portion is sustained by either introducing an immediate release layer on the sustained release core or by using a coating or compression process or multiple unit systems such as capsules containing expansion and immediate release beads. Can be added to the discharge system.

Delayed release dosage formulations are made by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach but soluble in the neutral environment of the small intestine. Delayed release dosage units can be prepared by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition comprises a plurality of drug-containing beads, particles or granules for incorporation into either a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a tablet or capsule. It may be.

Pulsed-release dosage forms mimic multiple dosage profiles without repeated administration, and typically include, for example, drugs presented as conventional dosage forms (solution or immediate drug release, or conventional solid dosage forms As a result, the frequency of administration is at least half as low. The pulse release profile is characterized by a reduced release followed by a rapid drug release (period delay time without release).

Each dosage form contains a therapeutically effective amount of the active agent. In one embodiment of a dosage form that mimics the twice daily dosing characteristics, it is released in an initial pulse of about 30% to 70%, preferably 40% to 60% by weight of the total amount of active agent in the dosage form. The Then, about 70% to 3.0%, preferably 60% to 40% by weight of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms that mimic twice daily dosage characteristics, the second pulse is preferably released from about 3 hours to less than 14 hours, more preferably from about 5 hours to 12 hours after administration.

Other dosage forms include compressed tablets or capsules 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 comprises a plurality of beads, granules, particles that substantially release the drug immediately after oral administration to provide a nascent dose. The delayed release dosage unit comprises a plurality of coated beads or granules that release the drug from about 3 hours to 14 hours after oral administration to provide a second dose.

For transdermal (eg, topical) administration purposes, sterile aqueous or partially aqueous diluted solutions (usually at a concentration of about 0.1% to 5%) can be prepared, but otherwise Similar to parenteral solutions can be prepared.

Methods of preparing various pharmaceutical compositions containing a certain amount of one or more compounds of Formula I, or other active agent, are known or will be apparent to those skilled in the art in light of this disclosure. For an example of how to prepare a pharmaceutical composition, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 19th Edition (1995).

Further, in certain embodiments, the subject compositions of the present application are perhaps used with another suitable drying technique, such as lyophilization or spray drying. The subject compositions may be administered once, or the volume administered by varying the time interval can be reduced to multiple small doses, depending in part on the rate of release of the composition and the desired dosage. You may divide into.

Formulations useful in the methods provided herein include methods 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 method well known in the pharmaceutical arts. The amount of the composition of the invention that can be combined with a carrier material to produce a single dosage that can vary depending on the subject depends on the subject to be treated and the particular mode of administration.

The methods of preparing these formulations or compositions comprise the step of binding to a composition of the invention with a carrier and optionally one or more auxiliary ingredients. In general, formulations are prepared by synthesizing the subject composition uniformly and intimately with a liquid carrier, a finely divided solid carrier, or both, and if necessary shaping the product.

The compounds of formula I described herein can be administered by inhalation or aerosol formulation. Inhalants or aerosol formulations may include one or more agents as such adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is, for example, 0.005 to 90% w / w of the drug compared to the total weight of the formulation, for example 0.005 to 50% w / w, 0.005 to 5% w / w, or 0.01 to 1.0% w / w may be included.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject composition comprises one or more pharmaceutically acceptable carriers and / or any of the following: Mixed. (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) paraffins, etc. (6) Absorption promoters such as quaternary ammonium compounds; (7) Wetting agents such as acetyl alcohol and glycerol monostearate; (8) Absorbents such as kaolin and bentonite clay; (9) Talc. Calcium stearate, steari (10) coloring agents; magnesium acid, solid polyethylene glycols, absorbents such as sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Similar types of solid compositions can also use lactose or lactose as a filler in soft and hard filled gelatin capsules, as well as high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the compositions of the present invention, the liquid dosage form contains inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol Benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol And solubilizers and emulsifiers such as fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the compositions of the present invention, include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and their Suspending agents such as mixtures may be included.

Formulations for rectal or vaginal administration are prepared by mixing the composition of the invention with one or more suitable nonirritating carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes, or salicylates. Can be provided as a suppository to obtain. And they are solid at room temperature but become liquid at body temperature, thus melting in the appropriate body cavity to release the encapsulated compound (s) and composition (s) . Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers as are known in the art to be suitable.

Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The compositions of the invention may be mixed under sterile conditions with a pharmaceutically acceptable carrier, or with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complex may contain lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

Ointments, pastes, creams and gels, in addition to the subject composition, for example animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and Other carriers such as zinc oxide, or mixtures thereof may be included. Powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures thereof, in addition to the subject composition. The spray may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Methods for delivering a single composition or multiple compositions via a transdermal patch are known in the art. Typical patch and patch delivery methods are described in US Pat. Nos. 6,974,588, 6564093, 6312716, 6440454, 6267983, 6239180, and 6103275.

In another embodiment, the transdermal patch may comprise: a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2 to 10 parts by weight of a styrene-ethylene-butylene-styrene copolymer. A composite film comprising a composite film formed by: a first adhesive layer on one side of the composite film; and a polyalkylene terephthalate film attached to one side of the composite film via the first adhesive layer; A second adhesive layer comprising a saturated polyester resin, a primer layer formed on the surface of the polyalkylene terephthalate film, and a styrene-diene-styrene block copolymer containing a pharmaceutical laminated on the primer layer. The base sheet manufacturing method is such that a resin composition is formed on a composite film by calendering to prepare the resin composition, and then a polyalkylene terephthalate film is bonded to one side of the composite film using an adhesive. Including doing. This involves preparing a base sheet and preparing the resin composition described above to adhere to the polyalkylene terephthalate film phthalate film.

Another type of patch includes, for example, incorporating a drug directly into a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive on a suitable backing member such as a polyester backing. The drug is present at a concentration that does not affect adhesion, while at the same time delivering the required clinical dose.

The transdermal patch may be passive or active. Currently available passive transdermal drug delivery systems such as nicotine, estrogen and nitroglycerin patches deliver small molecule drugs. Many of the newly developed protein and peptide drugs are too large to be delivered via passive transdermal patches, and for large molecule drugs, using techniques such as electro-assist (iontophoresis) Can be delivered.

Iontophoresis is a technique used to improve the flux of substances ionized through a membrane by the application of an electric current. An example of an iontophoretic membrane is described in US Pat. No. 5,080,646 to Theeuwes. The main mechanism of iontophoresis by enhancing molecular transport across the skin is: (a) repel charged ions from the same charge electrode, and (b) charge cells in response when an electric field is applied. The convective motion of the electroosmotic solvent that causes the preferential passage of counterions through the pores, and (c) increase the skin permeability due to the application of current.

In some forms, it may be desirable to administer in the form of a kit and may include a container for containing separate compositions such as divided bottles or divided foil packets. Typically, the kit includes instructions for administration of the separate components. When it is preferred that separate compositions be administered in different dosage forms (eg, oral and parenteral) and for different periods of time, or when it is desired by the prescribing physician to titrate the individual compositions in the combination The kit form is particularly advantageous.

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 packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are typically composed of a relatively stiff sheet covered with a foil of a permeable plastic material.

Methods and compositions for the treatment of neurological diseases. In particular, there is provided a method of treating mucositis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I
Here, R ¹ independently represents H, D, —O—, —CO—, —CH ₂ —CO—CH ₂ —,
R ² independently represents:
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, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ .
Process for the preparation of compounds of formula I

The invention further includes methods for the treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial adenomatous polyposis.

Examples of synthetic routes useful in making compounds of Formula I are shown below and are discussed generally in Scheme 1, Scheme 2.
Scheme 1:

Step-1: Synthesis of Compound 3:

TBABr 0.06 mol was added to a solution of 8 g NaOH (0.2 mol) in 30 ml H ₂ O and the resulting mixture was heated at about 80 ° C. until completely dissolved. After cooling to 60 ° C., 261.5 g (0.5 mol) of n-propyl bromide and 16.5 g (0.05 mol) of ethyl acetoacetate were simultaneously added to the mixture. The resulting two-layer system was kept vigorously stirred at 71 ° C. for 39 hours. 30.7 g (0.249 mol) n-propyl bromide, and a solution of 2.2 g (0.057 mol) NaOH in 5 ml H ₂ O were added and the above mixture was reacted under the conditions described above to react. I left it for another 6 hours. Excess propyl bromide was distilled off to give a two-layer reaction mixture in which the organic layer consisted of ethyl 2,2 dipropyl acetoacetate. The organic layer was used directly in the subsequent reaction. To this mixture containing ethyl 2,2 dipropyl acetoacetate was added 8 g (0.2 mol) NaOH solution in 10 ml H ₂ O and the resulting mixture was left at 80 ° C. for reaction for 20 hours. . After completion, the mixture was diluted with water and extracted with DCM. The separated aqueous layer was then acidified with 33% HCl to pH = 1 and extracted three times with ethyl acetate. The ethyl acetate layer was dried over Na ₂ SO ₄ and concentrated to anhydrous yielding 3.1 g of compound 3.

Step-2: Synthesis of Compound 5:

To compound 3 (1.0 mmol) in dry DCM (1.8 ml) was added N, N-diisopropylethylamine (2.0 mmol) at −10 ° C. and stirred at the same temperature for 30 minutes, then 1-chloroethylchlorocarbonic acid. Salt 4 (1.1 mmol) was added dropwise at the same temperature and the reaction mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction (monitored by TLC), the solvent of the reaction mixture was evaporated and the crude product was purified through a column to give compound 5.

Step-3: Synthesis of Compound 7:

In an RB flask, acid 6 (1.2 mmol) and anhydrous K ₂ CO ₃ (1.1 mmol) are taken up in dry DMF (10 vol), stirred at room temperature for 30 minutes and cooled to −10 ° C. to give compound 5 The solution was slowly added dropwise and then stirred at room temperature for 12 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (2 × 5 ml). The combined organic layers were washed with water (2 × 5 mL) then brine solution (10 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography on 100-200 mesh silica gel to obtain product 7.

Scheme 2:

Step-1: Synthesis of Compound 3:

To a stirred solution of valproic acid 1 (20 g, 0.138 mol) in dichloromethane (200 mL) (1-2 drops of DMF) was added oxalyl chloride (18.8 mL, 0.208 mol, 1.5 eq) for 20 minutes in N ₂ atmosphere. It was added dropwise at 0 ° C. with a dropping funnel. Removed from ice bath and returned to room temperature. The reaction mixture was then stirred at room temperature for a further 2 hours. After completion of the reaction (by TLC), the volatiles were concentrated under N ₂ atmosphere. The resulting crude acid chloride 2 was added to a stirred solution of acetaldehyde (21.36 mL, 0.4159 mol, 3 eq) and sodium iodide (52 g, 0.3446 mol, 2.5 eq) in acetonitrile (220 mL) at 0 ° C. added. After stirring at 0-5 ° C. for 2 hours, the mixture was poured into ice water (200 mL) and extracted with hexane (2 × 200 mL). The combined organic extracts were washed with 5% aqueous sodium thiosulfate solution (2 × 100 ml), then with 5% aqueous sodium bicarbonate solution (50 mL) and finally with brine solution (2 × 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 30 g (71% yield) of compound 3 as an oil.

Step-2: Synthesis of Compound 5:

(5Z, 8Z, 11Z, 14Z, 17Z) -ethyl icosa-5, 8, 11, 14, 17-pentanonate (4, 10 g, 00302 mol, 1 eq) is dissolved in ethanol (200 ml) and an aqueous NaOH solution (11 .98 g, 0.299 mol, 9.9 eq, 50 ml of H ₂ O) was added. The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the volatiles were evaporated under reduced pressure on a rota evaporator. The resulting crude product was diluted with water (50 ml), acidified with 3N HCl and extracted with ethyl acetate (2 × 300 ml). The combined organic extracts were washed with brine (2 × 100 mL), filtered, dried over anhydrous sodium sulfate and concentrated to anhydrous. Purification on silica gel (20% EtOAc in hexane) yielded compound 5 (9 g, 90% yield). Mass (m / z): 301 (M−H)

Step-3: Synthesis of Compound 6:

EPA5 (5 g, 0.0165 mol, 1 eq) in ethyl acetate (50 mL) to triethylamine (4.7 mL, 0.033 mol, 2 eq), then sodium iodide (0.49 g, 0.0033 mol, 0.2 eq) and compound 3 (7.37 g, 0.0248 mol, 1.5 eq) was added dropwise at room temperature under N ₂ atmosphere for 2 minutes. The reaction temperature was then raised to 50 ° C. and stirred overnight. After completion of the reaction (based on TLC analysis), the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to anhydrous. Purification on silica gel (3% EtOAc in hexanes) yielded compound 6 (7.6 g, 97% yield) as a pale yellow liquid.
Example

Effects of valproic acid and Formula I (1-1) on markers of cell viability, necrosis and oxidative stress in rat liver cells:
Twenty-four hours after hepatocyte plating, the medium was aspirated and replaced with fresh HepatoZYME-SFM medium supplemented with penicillin (100 U / ml), streptomycin (100 lg / ml), and L-glutamine (2 mM). Hepatocytes were treated with VPA, various concentrations of Formula I (1-1) for 24 hours. In another example, hepatocytes were pretreated with 1-aminobenzotriazole (0.5 mM) or pre-loaded with VPA (1 mM during WST-1 analysis and 12 mM during LDH and DCF analysis) 30 minutes before. Administered medium or medium (solvent control). After 24 hours, cytotoxicity analysis was performed. Treatment of rat liver cells with 24 hours of VPA resulted in the greatest or nearly the maximum of the various indices of hepatotoxicity. Formula I (1-1), a molecular complex of valproic acid and R lipoic acid, treatment for 24 hours showed the least toxic effect among the various indices of hepatotoxicity.

The term “sample” refers to a sample of body fluid, a sample of separated cells, or a sample from a tissue or organ. The body fluid sample is obtained by known techniques, preferably the body fluid sample comprises a blood, plasma, serum or urine sample, more preferably a blood, plasma or serum sample.
Equivalent

The present disclosure provides, inter alia, compounds and methods for the treatment of moderate to severe pain and related conditions. While specific embodiments of the present disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the arrangements and methods herein will become apparent to those skilled in the art upon reference to this specification. The full scope of the claims and methods should be determined with reference to the claims, their equivalents, and the specification, along with variations thereof.
Replenishment by quotation

All publications and patents mentioned in this specification, including those listed above, are expressly incorporated by reference as if individual publications or patents were shown explicitly and each incorporated by reference. Incorporated throughout. In case of conflict, the present application, including any definitions herein, will control.

Claims (10)

Formula I compounds:
Formula I
Or a pharmaceutically acceptable salt, hydroxide, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof;
Where R1 independently represents H (D)? O-, CO- and -CH2CO-CH2-,
R2 says independently.
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, C1-C6 alkyl, —NH2 or —COCH3. A 2A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. Formulated to treat the underlying etiology of an effective amount to be administered to a patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subcutaneous, oral, The pharmaceutical composition solution according to claim 2, rectal administration, buccal administration or transdermal administration. The compound and the composition of claim 3 are formulated for treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial colorectal adenoma. The compound comprises formula I.
A molecular complex of valproic acid and R lipoic acid. Molecular complex of valproic acid and eicosapentaenoic acid. Molecular complex of valproic acid and docosahexaenoic acid. A molecular complex of valproic acid and acetylcysteine. Conjugation of valproic acid and salsalate molecule.