NZ731396B2 - Compositions and methods for the treatment of multiple sclerosis - Google Patents

Abstract

The invention relates to the compounds of formula II or their pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The invention further relates to pharmaceutical compositions comprising an effective amount of compounds of formula II and methods for treating or preventing multiple sclerosis. The compositions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous or parenteral administration, as a syrup, or for injection. Such compositions may be used in the treatment of neurodegenerative diseases and other inflammatory diseases. methods for treating or preventing multiple sclerosis. The compositions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous or parenteral administration, as a syrup, or for injection. Such compositions may be used in the treatment of neurodegenerative diseases and other inflammatory diseases.

Description

(12) Granted patent specificaon (19) NZ (11) 731396 (13) B2 (47) Publicaon date: 2021.12.24 (54) COMPOSITIONS AND METHODS FOR THE TREATMENT OF MULTIPLE SCLEROSIS (51) Internaonal Patent Classificaon(s): C07C 69/60 C07C 271/16 A61K 31/232 A61K 31/27 A61P 25/00 (22) Filing date: (73) Owner(s): 2014.11.20 CELLIX BIO E LIMITED (23) Complete specificaon filing date: (74) t: 2014.11.20 Griffith Hack (30) Internaonal Priority Data: (72) Inventor(s): IN 4873/CHE/2014 2014.09.29 KANDULA, Mahesh (86) Internaonal Applicaon No.: (87) Internaonal Publicaon number: WO/2016/051420 (57) Abstract: The invenon relates to the nds of formula II or their pharmaceucal acceptable salts, as well as polymorphs, solvates, enanomers, stereoisomers and hydrates thereof. The invenon further s to pharmaceucal composions comprising an effecve amount of compounds of formula II and methods for treang or prevenng e sclerosis. The ions may be formulated for oral, buccal, rectal, topical, ermal, transmucosal, intravenous or parenteral administraon, as a syrup, or for injecon. Such composions may be used in the treatment of neurodegenerave diseases and other inflammatory diseases.

NZ 731396 B2 2014/000726 COMPOSITIONS AND METHODS FOR THE TREATMENT OF MULTIPLE SCLEROSIS PRIORITY The present application claims the benefit of Indian Provisional Patent Application No. 4873/CHE/2014 filed on 292014, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION This disclosure generally relates to compounds and compositions for the treatment of multiple sclerosis. More particularly, this invention relates to ng subjects with a aceutically acceptable dose of compounds, stereoisomers, enantiomers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION Multiple sclerosis (MS) is an atory, autoimmune, demyelinating disease of the central nervous system. It generally strikes at an early age, most often the early adult years. Its most freQuent symptoms include numbness, impaired vision, loss of balance, weakness, bladder dysfunction, and psychological changes. Fatigue is an early symptom in MS, often the earliest. The disease can wax and wane for up to 30 years, but in perhaps half of all cases it ly progreSSes to severe disability and premature death.

MS is the most common cause of neurologic disability in young adults. The lesions of demyelination are histopathologically characteristic of the disease. Brain examination by MRI tic resonance imaging) can ely detect these “white matter plaques.” MRI correlates well with the classic histopathology of the lesions, and is progressively a more sensitive tool for detecting the teristic lesiOns of MS in situ, as compared to conventional functional evaluation. Multiple sclerosis is a x disease, perhaps assing more than a single etiopathological entity and very likely subject to actorial etiology. MS prevalenceworldwide is estimated at one million cases; in the United States this number is 250,000—350,000. Although not generally considered life threatening, this disease kills about 3,000 people each year in the United The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism,‘excitotoxicity, and for ive damage is increasingly compelling. It is likely that there is a complex interplay, between these mechanisms.

Mitochondria are the major intracellular source of ‘free radicals, and increased mitochondrial calcium concentrations enhance free radical tion. 'Mitochondrial DNA is particularly susceptible to ive stress, and there is evidence of age- dependent damage and deterioration of respiratory enzyme activities withnormal aging.

This may contribute to the delayed onset and age ence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in ophic lateral sclerosis, Multiple sis, Huntington’s disease, Parkinson’s. disease, and Alzheimer’s disease. [0006‘] Inflammation is a self-defensive reaction aimed at eliminating or neutralizing ' injurious i, and restoring tissue integrity.»~ In neurodegenerative diseases ' inflammation occurs as a local response driven by microglia, in the e of leukocyte infiltration. Like peripheral inflammation, neuroinflammation‘ may become a harmful process, and it is now widely accepted that it may contribute to the pathogenesis of many central nervous system disorders, ineluding chronic neurodegenerative diseases such as Multiple sis.

Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of multiple sclerosis and its associated complications ssion.

SUMMARY OF THE INVENTION [0008) The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as multiple sclerosis. [0008A] In one aspect there is provided a compound of Formula II: Formula II or a ceutically acceptable salt, e, solvate, enantiomer, or stereoisomer thereof; R1, R3 are each independently null: R2 is ; and R4 represents 17897439_1 (GHMatters) P109613.NZ [0008B] In another aspect there is provided a pharmaceutical composition comprising a compound as defined herein and a pharmaceutically acceptable carrier. [0008C] In another aspect there is provided use of a compound as defined herein for the manufacture of a medicament for the treatment of egenerative diseases, le sclerosis, psoriasis and inflammatory diseases. [0009) The invention herein provides itions comprising of formula I or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of a I or intermediates thereof and one or more of ceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of multiple sclerosisand its associated complications.

Formula I (0010] In n embodiments, the present invention relates to the compounds and compositions of formula I, or pharmaceutically able salts thereof, 3a followed by Page 4 17897439_1 (GHMatters) P109613.NZ 2014/000726 Formula I Wherein, Rl R3each independently represents —CH3CO-, acetyl, D, H, CD3CO-, 0is, Rome/z:OH 2;:\/\S/\/“\; or flown/[Lg R2, R4each independently represents H, D, WO 51420 WO 51420 2014/000726 NHCOCH3 o o C65“ (1‘32“ CONH “‘5‘ 2 0;; ’ OH o OCOCH3 0&7. ’ ’ ‘55f CH3 CH 0 CH3 6" OH 77 o A ° HN NH HO H H u H2N OH 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.

The invention herein also provides compositions comprising of a II or pharmaceutical acceptable salts f. The invention also provides pharmaceutical compositions comprising one or more compounds of formula II or intermediates thereof and one or more of pharmaceutically'acceptable carriers; vehicles or ts. These compositions may be used in the treatment of multiple sclerosis and its associated V complications.

ANXM Formula II Accordingly, in certain embodiments, the present invention relates to the compounds and cOmpositions of formula II, or phannaceutically able salts thereof, 0/ \R4 Formula II Wherein Rl R3each independently represents H, D, '0' o ,\O:4" WO 51420 R2, R4 each ndently represents D, CH3CO, CD3CO, 2014/000726 0 o O H3C/ \n/\/U\O/ HO O O a /3: .

O 15: HO 0H 0 , , 2014/000726 NHCOCH3 WO 51420 ”N ' NH HO 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-alky1, -NH2 or ~COCH3.

In the rative embodiments, examples of compounds of formula I are as set forth below: O 0 o 0 /\=/\._./\=/\_—J\=W xfiJKONo/NM‘a H (1-1) ‘ 0 o o 0 - ._ _— " __ “\L-N/fl\ H ‘\\ . o O s V \S (1-2) .

In the rative embodiments, exemples of compounds of formula II are as set forth below: WO 51420 91 £1 01 L 61 '— ___f O — "' _‘ —- O 0__\\—-N/u\ o MO\ H O (2-1) Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may'comprise instructions for use in the treatment of le sisor its related complications.

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

Herein, the application additionally es kits comprising the pharmaceutical compositions described herein The kits may further comprise instructions for use in the treatment of multiple sclerosisor its related complications.

The compositions described herein have several uses. The present application provides, for example, methods of treating a t sufiering from multiple sclerosisor its related complications manifested from neurodegeneration, neurological dysfunction, lic conditions or disorders, metabolic syndrome, chronic diseases or disorders; Hyperinsulinemia, Insulin ance, Glucose intolerance, Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Nephrological, or Ocular complications.

BRIEF DESCRIPTION OF FIGURES: Example embodiments are illustrated by way of example and not limitation in the figures of theaccompanying drawings, in which like references indicate similar elements and in which: . 1 shows the 1H —NMR results for Formula 11.

FIGURE. 2 shows the 13C —NMR s for Formula II.

DETAILED DESCRIPTION OF THE INVENTION 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 g as commonly understood to one of ordinary skill in the art.

The compounds. of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically able esters (i.e., the methyl and ethyl esters of the acids of formula I and a II to be used as gs). The compounds of the t invention can also be solvated, i.e. hydrated. The l9dentate19 can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I and formula II (hydration).

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space aretermed “stereoisomers.” Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not omers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed iomers.” When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute ration of its asymmetric center or centers and is described by the R— and S-sequencing rules iof Cahn, lngold and , or by the manner in which the molecule rotates the plane of polarized light and ated as dextrorotatory or levorotatory (i.e., as (+) or (-)—isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbom errors of metabolism (or genetic metabolic cOnditions) are genetic disorders that result from a defect in one or more metabolic ys; specifically, the function Of an enzyme is affected and is either deficient or completely absent.

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

The phrases teral administration” and “administered parenterally” as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation‘intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- ‘ lar, subcapsular, subarachnoid, intraspinal and intrastemal injection and infilsion.

A “patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

The phrase aceutically acceptable” is art-recognized. In certain ments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical nt, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase f‘pharmaceutically able carrier” is art-recognized, and includes, for example, ceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, 21dentate, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a ceutically acceptable r is rogenic.

Some examples of materials which may serve as pharmaceutically acceptable carriers include: ( 1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) ose, and its derivatives, such as sodium ymethyl cellulose, ethyl ose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) tale; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, oliVe oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;-( 13) agar; (l4) buffering agents, such as magnesium hydroxide and um hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) ic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The term ug” . is ed to encompass nds that, under physiologiCal conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological ions to reveal the desired 7. molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the t compositions. If it is administered prior to clinical manifestation of the ed condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted cOndition, whereas if it is administered afier station of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, rate, or ize the exiSting unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probability related; diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous System or complication. The tive window is an interval in which the subject will develop one or more of the said complications according to the predicted ility. The predictive window may be the entireremaining lifespan of the subject upon analysis by the method of the present invention.

The term “treating” is art —recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, er, or condition, e.g., causing regression of the disease, disorder and/or condition.

Treating the disease or condition includes ameliorating at least one symptom of the particular e or condition, even if the underlying pathophysiology is not affected, such as treating the neurological condition such as multiple sclerosis and other diseases related to ive stress such as renal diseases of a t by administration ofan agent even though such agent does not treat the cause of the condition. The term “treating”, “treat” or ment” as Used herein es curative, preventative (e.g., prophylactic), t and palliative treatment.

The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces. some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In n embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or cendition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without itating undue experimentation.

In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a eutically effective amount, as part‘of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a t will depend on absorption, inactivation, and excretion rates of thedrug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the stration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or s of any ular salt or composition may be ed to accommodate variations in the . treatment parameters. Such treatment include the clinical use to which the _ parameters preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For examme, the maximum plasma - concentration (Cmax) and the area under the plasma concentration-time curve from time 0 tr) infinity may be used. [0038‘] When used with respect to a pharmaceutical composition or other material, the term “sustained release” is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained e characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may o gradual or delayed ation '(e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or ed period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.

The phrases “systemic administration,7, 6‘administered systemically,39 6‘peripheral administration” and “administered peripherally” are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be termed “local” or “topical” or “regional” administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient’s system and, thus, is subject to lism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term. t In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary Or sufficient to eliminate or reduce l symptoms for a period of time. The ive amount may vary ing on such factors as the disease or condition being treated, the particular ed constructs being administered, the size of the t, or the severity of the disease or ionf One of ordinary skill in the art may cally determine the effective amount of a particular composition without necessitating undue mentation.

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

This application also discloses a pharmaceutical ition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I and formula II may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also ated for oral administration, oral solution, injection, subdermal administration, or ermal administration. The pharmaceutical composition may further se at least one of a pharmaceutically acceptable stabilizer, 26dentate, surfactant, filler, binder, and lubricant.

In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I and Formula II) to be delivered in an amount sufficient to deliver to a t a therapeutically effective amount of a compound of formula I and formula II or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I and a II or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the t compositions. It is to be noted that dosage values may also vary with the ty of the ion to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or ising the administration of the compositions. Typically, dosing will be determined ’using techniques known to one skilled in the art. onally, the optimal concentration and/or quantities or amounts of any particular compound Vof formula I and formula II may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

The concentration and/or amount of any nd of formula I and formula 11 may be readily identified by routine screening in animals, e.g., rats, by ing a range of concentration and/or amounts of the material in question using appropriate assays.

Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is ialysis, as reviewed by T. E. Robinson et al., 1991, microdialysis in the neurosciences, Techniques, V ‘The volume 7, Chapter 1. methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is. pumped through the loop. When compounds with formula I and formula II such as those disclosed herein are injected adjacent to the loop, released drugs arecolleCted in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the salts or itions may be determined y .with le calibration procedures using known concentrations of salts or compOsitions.

In certain embodiments, the dosage of the subject compounds Of formula I and formula 11 ed herein may be determined by reference to the plasma concentrations of the therapeutic .composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration- time curve from time 0 to infinity may be used.

Generally, in ng out the s detailed in this application, an effective dosage for the compounds of Formulas I is inthe range‘of about 0.01 day to about 100 day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Fortnulas I may be administered at a dose of, for e, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of Formula I and formula 11 may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an Mount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I and formula 11 required for the same therapeutic benefit.

An effective amount of the compounds of formula I and formula 11 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a cation resulting from nerve damage or demyelization and/or elevated reactive ivenitrosative species and/or abnormalities in neurotransmitter homeostasis’s, in patients who are‘at risk for Such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions stered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to—patient variability, the dosages given above are a ine and the ian may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.

In ering the degree of treatment desired, the physician must e a y of factors such as age of the patient, ce of preexisting disease, as well as presence of other diseases.

The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, ing orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary.

Further, the compositions may be administered intranasally, as a rectal suppository, or using a “flash” formulation, i.e., allowing the medication to dissolve in the mouth t the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic ion, or in nanoparticles.

The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitablepharmaceutical carriers, vehicles and diluents e inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically . able carriers, vehicles or diluents are then readily stered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.

These pharmaceutical itions can, if desired, contain onal ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as nine, sodium e, calcium carbonate and calcium phosphate may be employed along with various egrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, n and . Additionally, lubricatingagents such as magnesium stearate, sodium lauryl sulfate and talc are ofien useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in sofi and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are ‘ desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, ng matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof. The compounds of formula I and formula Il may also comprise enterically coated comprising of s excipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such s solutions should be suitably buffered if necessary and the liquid 30 dentate first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially le for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

The formulations, for instance s, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg ofthe compounds of formula I and formula II disclosed herein, for instance, nds of formula I and formula II or pharmaceutical acceptable salts of a compounds of Formula I.

Generally, a composition as described herein may be administered orally, or parenterally (e.g., enous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering frOm gastrointestinal er that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.

Localized administration may also be indicated, for example, when a high dose is d at the target tissue or organ. For buccal administration the active ition may take the form of tablets or lozenges formulated in aconventional .

The dosage administered will be ent upon the identity of the neurological disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight.

Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a tration of from about 0.01 to about 50% w/‘w of the composition; preferably about 1- to about % w/w ofthe composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v ofthe ition and preferably from about 5 to about 20% w/v. , The compositions of the present ion are preferably presented for administration to humans and animalsin unit dosage forms, such as tablets, capsules, pills, powders, es, suppositories, sterile parenteral solutions or sions, sterile non-parenteral solutions of suspensions, and oral ons or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared. . [0059] As discussed above, the tablet core contains one or more hilic polymers.

Suitable hilic polymers include, but are not limited to, water ble cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, olloids, clays, gelling starches, swelling cross—linked polymers, and mixtures thereof. Examples of suitable water Swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropleellulose, hydroirypropyl cellulose (HPC), ypropylmethylcellulose (HPMC), hydroxyisopropylcellulOse, ‘ hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HBO), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof.

Examples of suitable polyalkylene s include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides e, but are, not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, olecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOLTM. Examples of suitable olloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum 32 denta, ' tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, glucan, gum 32denta, inulin, pectin, gelatin, 32denta, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and ~ mixtures f. Examples of le clays inelude, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate, and mixtures thereof. Examples of suitable gelling starches e, but are not limited to, acid hydrolyzed es, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swelling linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross—linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable entsfor the formulation of s. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, idants, and mixtures f.

Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including olloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum 32 denta, tragacanth, pectin, xanthan, , gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, 33 denta, rhamsan, zooglan, methylan‘, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures f. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked ymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium te and stearic acid, talc, glycerides waxes, and mixtures thereof. Suitable ts include, but are not limited to, colloidal silicon dioxide.

Suitable e-modifying excipients include, but are not limited to, insoluble edible materials, Ph-dependent polymers, and mixtures thereof. le insoluble edible materials for use as release-modifying excipients include, but are not limited to, water~insoluble rs and low-melting hydrophobic materials, copolymers thereof, and mixtures f. Examples of suitable water- ble polymers include, but are not‘ limited to, ethylcellulose, nyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof.

Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated er oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof.

Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, ylbehenate, glycerylpalmitostearate, glycerylmonostearate, glyceryltristearate, yltrilaurylate, glycerylmyristate, GlycoWax—932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 ides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidylenositol, otidic acid, and mixtures thereof.

Examples of suitable waxes include, but are not limited to, a wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and n wax; fat- containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not d to, croscarrnellose sodium, sodium starch glycolate and cross-linked povidone ovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.

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

In one embodiment, the immediate release g has an average thickness of at least 50 microns, such as fiom about 50 microns to about 2500 microns; e.g., from about ’ '250 s to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume ofthat specific layer.

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

In one embodiment, the first n contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one Of the portions contains a second immediate release portion of the same pharmaceutically active agent as that ned 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 included of a driedgran‘ulation including the pharmaceutically active agent.

Formulations with different drug release isms bed above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in 'a solid or liquid form. Typical, immediate release formulations e compressed s, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin e. Many methods for preparing gs, covering or incorporating drugs, are known. in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, es or particles, or an outer layer of a coated core dosage form, contains‘a therapeutically ive quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug—containing granules or beads).

Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in “Remington—~The Science and Practice of Pharmacy”, 20‘“. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are 2014/000726 wellknown' and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.

] An immediate release portion can be added to the extended release system by means of either applying an ate release layer on top of the extended release core; using coating or compression processes or in a le unit system such as a capsule containing extended and immediate release beads.

Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the h, but soluble in the neutral environment of small intestines; The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected g material. The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage fOrm, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.

A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a tional dosage form (e.g., as a on or prompt drugéreleasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release ’followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of active agent. In one ment of dosage forms that mimic a twice daily dosing profile, approximately wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %,'of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released imately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following- administration.

‘ Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the ate release dosage unit contains a plurality of beads, granules particles that e drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% tration), ise similar to the above parenteral ons, may be prepared. s of ing various pharmaceutical compositions with a certain amount of one or more compounds of a I and formula II or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositiOns, see Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject itions of the present application. maybe lyophilized or subjected to another appropriate drying technique such as spray drying. The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending ~ in part on the release rate of the compositions and the d dosage.

Formulations useful in the methods provided herein include those suitablefor 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 ed by any methods well known in the art of pharmacy.

The amount of a subject composition which may be combined with a r material to produce a single dose may vary ing upon the subject being treated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the step of bringing into association subject itions with the r and, optionally, one or more accessory ingredients. In general, the formulations are prepared by unifome and tely bringing into association a subject composition with liquid rs, or finely divided solid rs, or both, and then, if necessary, shaping the product.

The. compounds of formula I and formula II described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol ations may se one or more agents, such as adjuvants, diagnostic agents, g agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90%'w/w, for instance COOS—50%, 0.005—5% w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, ‘alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as ol; (4) disintegrating agents, such as agar-agar, calcium ate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quatemary‘ammonium compounds; (7) wetting agents, such as, for example, acetyl l and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) ants, such a talc, calcium stearate, magnesium te, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring . In the case of capsules, tablets and pills, the pharmaceutical compositions may ' also se buffering agents. Solid compositions of a similar type may also be employed as fillers in sofi and hard-filled gelatin capsules using lactose or milk_ sugars, 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 on to the subject compositions, the liquid dosage forms may n inertdiluents ly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl e, benzyl alcohol, benzyl benzoate, propylene glycol, 01,3-butylene glycol, oils (in particular, - cottonSeed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofiiryl alcohol, hylene glycols and fatty acid esters of sorbitan, and ' mixtures thereof. sions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.’ Formulations for rectal or vaginal stration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non—irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a itory wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and e the encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such'carriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. ’ A subject composition may be mixed under sterile conditions with a pharmaceutically able carrier, and with any preservatives, buffers, or prOpellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, .silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, ents such as e, talc, silicic acid, um ide, calcium silicates and ide powder, or mixtures of such nces.

Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and le tituted hydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transderrnal patch are known in the art. Exemplary s 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 r embodiment, a transdermal patch may comprise: a substrate sheet comprising a ite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a , styrene-ethylene-buty1ene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive layer sing a styrene-diene-styrene block eopolymer containing a pharmaceutical agent layered on the primer layer. A method, for the manufacture of the above~mentioned substrate sheet ses preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkylene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a ted polyester resin on the outer surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a le g member, e.g. a polyester backing membrane. The drug should be t at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

Transdermal s may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transderrnal patches and may be red using technology such as electrical assist (iontophoresis) for large-molecule drugs.

, Iontophoresis is a technique ed for ing the flux of ionized substances, through membranes by application of electric current. One example of an horetic membrane is given in US. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular trémsport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective nt of solvent that occurs h, a charged pore in se the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.

In some cases, it may be desirable to ster in the form of a kit, it may comprise a container for containing the {separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components ofthe combination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs are well known in the ing industry and are widely used for the ing of ‘ pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally 2014/000726 consist of a sheet ‘of relatively stiff al covered with a foil of a plastic material that may be arent.

Methods and compositions for the treatment of multiple sclerosis. Among other things, herein is provided a method of treatingmultiple sclerosis, comprising administering to a patient in need thereof a therapeutically eflective amount of compound ofFormula I: Formula I Wherein, Rl , R3 each independently represents fCH3C0-, acetyl, D, H, CD3CO-, O O Trio 0371/. Eli; §\J\/2‘L R2 , R4 each ndently represents H, D, WO 51420 WO 51420 WO 51420 “a; 0 How dit \ ~ ,HZN OH ,JKMJIelf O \ e, _ AIM/N, 7 3 NH O a is independently 2,3 or 7; each h 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 £00m.

Accordingly, in another aspect the methods and compositions for the treatment of multiple sclerosis. Among other things, herein is provided a method of ng multiple WO 51420 sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula II: Formula II Wherein Rl R3 each independently represents H, D, NH2 NH2 fWK/‘KW‘LLE—o—E £52”N\/\’/\/N5\ xx”k /\O/\/“\§\, E-JK/E, “ax/NA;swat3 gnws/Vnyf or ENE/waif: R2 R4 each independently represents D, CH3CO, CD3CO, WO 51420 WO 51420 O 0 ,/ 9v“\ 0 HO 0 \ , H ' H2N NH2 - OH 0271/ HO OH O 9 , WO 51420 16‘ OH ' OH 2014/000726 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-C5-alkyl, -NH2 or —COCH3.

METHODS OF MAKING Examples of tic pathways fiseful for making compounds of formula II are Set forth in example below and generalized in scheme 1: Scheme-1: ‘l’ 0 V 0 DCC.DMAP, / OH L- . 5N HCI, 0 HOJK/Z\COZMe—————> 07W COzMe. 1 DCM’ rt, 2“ c H o )V Dioxane, rt, 1-2h C5H1203 " Mol M1010 , 0“”.160“ , MoI.WL:132,16 ' " - Step-1 » _ Mol.Wt..244.2ft Step-2 o a . OH Ho/fiflo COzMe — A , HO 4 + . , "0'5on . DCM,rt,2h C H O - . 20 so 2 'Mol. \th.1:220§l.18 Mol. Wt.: 302.45 Step-3 MOWOWCOZMe_ _ 0' . DCC.DMAP, - O7 _. _________) Mol. Wt.: 488.61 ~ DCM, rt, 2h 0 Step-4 Mol. M: 130.10 CsaH4401o Mol. Wt.: 600.70 Step-l: Synthesis ofcompound 3: I O DCC, DMAP, O O/Y\OJJ\/\002Me OH . o -H0 COM6 DCM, rt. 2h )VO 3 1 2 C6H1203 C5HBO4 . C11H1606 ' MOI. \Nt.: 132.16 MOI. VVt.'. 130.10 MOI. VVt.2 244.24 To a solution of INT-1 (30g, 0.22 mol), INT-2 (38g, 0.29 mol), DMAP (26g, 0.22 mol) in Dichloromethane (200 ml) was added drop wise the solution of DCC (50g, 0.24 mol) in Dichloromethane (100 ml) under nitrogen atmosphere at 25°C. After the on, reaction mixture was d for 2—3 h at 25°C. The Progress of reaction was monitored by TLC. Reaction mixture was filtered to remove DCU byproduct and bed washed with Dichloromethane (2 x 20ml). The collected filtrate was washed with DM water (1 x 150 ml), 5% hydrochloric acid solution (1 x 50 ml), sat. Sodium onate solution (1 x 100 ml), washed with 10% brine solution (1 x 50 ml). The ted organic layer was dried (anh. NaZSO4) filtered and distilled off under reduced pressure at 40- 45°C. The crude was dissolved in hexane (600 ml) filtered immediately to remove insoluble impurities (DCU). Collected filtrate was concentrated under reduced pressure to m volume (~50-100 ml). Filtered product and bed washed with, hexane (2 x 50 ml), air dried product at 35-40°C to afford INT- 3 (40g, 74%) as off white powder.

Stepe2: Synthesis ofcompound 4: M O o/TO 5N HCI, )T 3 COzMe_________> Ho/WAOMCOWIG Dioxane, rt, 1-2h HO 4 C11 H1606 CsH1206 Mol. Wt.§244.24 MOI. \Nt.: 204.18 To a solution of INT-3 (20g, 0.08 mol) in Dioxane (100 ml) was added drop wise 5N Hydrochloric acid (100 ml) at 25°C. The reaction mixture was d for 1h at 25°C and Progress of reaction was monitored by TLC. After starting al was consumed completely, the reaction mixture was neutralized by addition of solid sodium carbonate until Ph was basic (~Ph 8) and crude mass was filtered off to remove inorganic materials.

The filtrate was concentrated under reduced pressure to remove dioxane and aqueous layer was extracted with Ethyl acetate (2 x 100 ml) and combined organic extracts were dried (NaZSO4), filtered and‘concentrated under d pressure at 40-45°C. The crude residue was stirred in di-isopropyl ether (100 ml) for 4-6h and the suspension was d. Isolated product was air dried at 40-50°C to afford TNT-4 (10g, 60%) as off white solid.

Step-3: Synthesis of compound 5: bMOHDCC DMAP Ho/YO COzMe *“ — 7‘ ——-—'———’> HO 4 + DCM, n, 2h 0 H 0 C EfiAo20 so 2 M01. €Vt.1:22064.18 Mol, Wt: 302.45 Step-3 WCOZW—' _ O CzaH4007 MOI. Wt: 488.61 To a solution of TNT-4 (10 g, 0.04 mol), EPA (16.2 g, 0.05 mol), DMAP (2.9g, 0.02 mol) in Dichloromethane (400 ml) was added the solution of DCC (109 g, 0.05 ‘mol) in Dichloromethane (100 m1) under nitrogen atmosphere at 25°C. After the addition, reaction mixture was d for 1-2 h at 25°C. The Progress of reaction was monitored by TLC. Reaction mixture was filtered to remove DCU byproduct and bed washed with Dichloromethane (2 x 25 ml). The collected filtrate was washed with DM water (1 x 150 m1), 5% hloric acid on (1 x 50 ml), sat. Sodium bicarbonate solution (1 x 100 ml), washed with 10% brine solution (1 x 50 ml). The organic layer was dried (Na2804), filtered and solvent was distilled off at reduced pressure at 40-45°C. The crude was purified by passing over silica gel column (60-120 mesh) by eluting with 15-20% Ethyl acetate: Hexane to afford INT-5 (11g, 46%).

] Step-4: Synthesis of compound 6: Ofl/OWI/Vcozwle O V O Cst4007 Mol. Wt.: 488.61 DCC, DMAP, HOMCOZMe V DCM. rt, 2h 2 ' Step-4 . C5H504 MOI. Wt: 130.10 o COzMe C331444010 0 MOI. VW; 600.70 ] To a solution of INT-5 (11 g, 24mmol), MMF (3.8 g, 29 mmol), DMAP (2.9 g, 24 mmol) in Dichloromethane (80 ml) was added the sclution of DCC (4.9 g, 24 mmol) in Dichloromethane (30 ml) under nitrogen atmosphere at 25°C. After the addition, reaction mixture was stirred for 1-2 h at 25°C. The Progress of on was monitored by TLC. Reaction mixture was filtered to remove DCU byproduct and bed washed with Dichloromethane (2 x 15 ml). The collected filtrate was washed with DM Water (1 x 100 ml), 5% hydrochloric acid solution (1 x 25 ml), sat. Sodium bicarbonate solution (1 x 25 ml), washed with 10% brine solution (1 x 25 ml). The organic layer was dried (NaZSO4), filtered and t'was distilled ofi‘ at reduced pressure at 40-45°C. The crude was purified by passing over silica gel column (60-120 mesh) by eluting with 10-13% Ethyl acetate: Hexane to afford final compound 6 (10g, 73%).

WO 51420 The term “sample” refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well—knowntechniques and include, preferably, s of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ- by, e.g., biopsy. ted cells may be obtained from the body fluids or the tissues or organs by separating techniques such as fugation or cell sorting.

EQUIVALENTS The present di5closure provides among other things compositions and. methods for treating multiple sclerosis and their complications. While specific embodiments of the subject disclosure have been discussed, the above speCification‘is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed s and s should be detemrined by reference to the claims, along with their full scope of lents, and the specification, alongwith such variations.

INCORPORATION BY REFERENCE ' ‘ All publications and patents mentioned herein, .including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was ispecifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any ions herein, will control.

Claims (7)

WE CLAIM :

1. A compound of Formula II: Formula II or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, or stereoisomer thereof; wherein R1, R3 are each independently null : R2 is ; and R4 represents 17897448_1 ters) P109613.NZ

2. A nd of claim 1, wherein the compound has the chemical structure of:

3. A compound of claim 1, wherein the compound has the chemical structure of:

4. A pharmaceutical composition comprising a compound of any of claims 1 to 3 and a pharmaceutically acceptable r.

5. The pharmaceutical ition of claim 4, which is formulated for oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

6. The pharmaceutical composition of claim 4, which is formulated for use in the treatment of neurodegenerative es, multiple sis, psoriasis and inflammatory diseases.

7. Use of a compound of any of claims 1 to 3 for the manufacture of a medicament for the treatment of neurodegenerative diseases, le sclerosis, psoriasis and inflammatory diseases. 17897448_1 (GHMatters) P109613.NZ