AU2013285126A1 - Compositions and methods for the treatment of moderate to severe pain - Google Patents

Abstract

The invention relates to the compounds of formula 1 or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof The pharmaceutical compositions comprising art effective amount of compounds of formula Ϊ; and methods for treating or preventing moderate to severe pain, may he formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenieral adminisiration, syrup, or injection. Such compositions may be used to treatment of muscle pain, spasticity, neuropathic pain, fibromyalgia, postoperative pain,.muscle spasticity, headache, chronic pain, sub-chronic pain and local pain.

Description

WO 2014/006529 PCT/IB2013/055146 1 COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN PRIORITY [000 1 The present application claims the benefit of Indian Provisional Patent Application No. 2682/CHE/2012 filed on 03-ul-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference. FIELD OF THE INTENTION 100021 This disclosure generally relates to compounds and compositions for the treatment of moderate to severe pain. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, enantiomers, stereoisomers, esters, salts, hydrates, prodrugs, or mixtures thereof BACKGROUND OF T E INVENTION 10003j Pain is a subjective experience, influenced by physical, psychological, social, and spiritual factors. The concept of total pain acknowledges the importance of all these dimensions and that good pain relief is unlikely without attention to each aspect. Pain and diseases such as cancer are not synonymous: at least two thirds of patients experience pain at some time during the course of their illness, and most will need potent analgesics. [00041 Moderate to severe pain is also associated with injury, inflammation, burning of seasonal allergies, eye pain, itchiness, bipolar disorder are a heterogeneous group of diseases of the nervous system., including the brain, spinal cord, and peripheral nerves that have much different aetiology. Many are hereditary some are secondary to toxic or metabolic processes. Free radicals are highly reactive molecules or chemical species capable of independent existence. Generation of highly Reactive Oxygen Species (ROS) is an integral feature of normal cellular function like mitochondrial respiratory chain, WO 2014/006529 PCT/IB2013/055146 2 phagocytosis and arachidonic acid metaboinsm. The release of oxygen free radicals has also been reported during the recovery phases from many pathological noxious stimuli to the cerebral tissues. Some of the pain associated neurological disorders include injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibroimyalgia and lower back pain, [00051 Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease, There is currently a need in the art for new compositions to treatment of moderate to severe pain, SUMMARY OF THE INVENTION 100061 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 moderate to severe pain [00071 The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts, hydrate, solvate, prodrug, enantiomer, or stereoisoier thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of moderate to severe pain and its associated complications, cF NH c R

R>

WO 2014/006529 PCT/IB2013/055146 3 Formula I [00081 In certain embodiments, the present Invention relates to the compounds and compositions of formula I or pharmaceutically acceptable salts, hydrate, solvate, prodrug, enantiomer. or stereoisomer thereof tel CCl NH CI R1 R2 Formula I [00091 Wherein, R1 represents H, D, -OCH, -OCD 3 , 0 0 00 H 0~s 0 0 O 0 O 0 O WO 2014/006529 PCT/IB2013/055146 4

A

0 H H N 0 H H0 H H H N NN O HHH 00 NNN oH H 0/ OO H H R2 represents 0

HO

WO 2014/006529 PCT/IB2013/055146 5 0 0 OH

H

2 N O 0 C7 H 3 0 0 CH-3 0 H1 CH H3

OOH

3 OH N CH 3

NHCOCH

3 HOH 0 OH OHO 0V -\09 WO 2014/006529 PCT/IB2013/055146 6 o 0

CONH

2 Z~ 1c;407 I7 OH 0O OCOCH3 O41 OH N OH 00 H 0H NH OH HN N H HI O H IH HO Nkn OHO H H 0 HN O HO N 0 0 HO OH OH HO

HN

WO 2014/006529 PCT/IB2013/055146 7 0 b 00 0 b b or 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 -01OD, C-C-alkyl, -NH or -COCH3; n is independently 1, 2, 3, 4 or 5. 100101 In the illustrative embodiments, examples of compounds of formula 1 are as set forth below: CI NH o o (1-1) WO 2014/006529 PCT/IB2013/055146 8 c, NH (1-2) 100111 Herein the application also provides a kit conipising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of moderate to severe pain or its related complications. 100121 The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carier and a-y of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administrati on. 10013j Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of moderate to severe pain or its related complications. 100141 The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from moderate to severe pain or its related complications manifested from metabolic conditions, severe diseases or disorders; Hepatology, Cancer, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Neurologi cal or Ocular complications.

WO 2014/006529 PCT/IB2013/055146 9 DETAILED DESCRIPTION OF THE INVEN TION Definitions [0015 As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art [0016] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e, the methyl and ethyl esters of the acids of formula Ito be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hvdration). 100171 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 isomerss." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantioners." 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 enantionmer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e, as (+) or (-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof A mixture containing equal proportions of the enantiomers is called a "racemic mixture" WO 2014/006529 PCT/IB2013/055146 10 [00181 As used herein, the term "metabolic condition' refers to an inbor errors of metabolism (or genetic metabolic conditions) are Cenetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. 100191 The term polymorphh" as used herein is art-recognized and refers to one crystal structure of a given compound. 100201 The phrases "parenteral administration" and "administered parenterally"2 as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapeural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital. intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. 100211 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. 10022J The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other mateials and/or dosage forms which are, i thin the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 100231 The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, 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 carder must be "acceptable" in the sense of being WO 2014/006529 PCT/IB2013/055146 11 compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate. (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and 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 ethl laurate; (13) agar; (14) bufferig agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [00241 The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. 100251 The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e g, disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e_ it is intended WO 2014/006529 PCT/IB2013/055146 12 to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [00261 The term "predicting" as used herein refers to assessing the probability according to which a neurodegenerative condition or disorder such as Moderate to severe pain related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon. analysis by the method of the present invention. 100271 The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition inclides ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the neurological condition such as Moderate to severe pain of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g, prophylactic), adjunct and palliative treatment. 100281 The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, In certain embodi ments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective WO 2014/006529 PCT/IB2013/055146 13 amount m ay vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation. 100291 In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment, The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for aiy particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervi sing the administration of the compositions. Typicaly, dosing will be determined using techniques known to one skilled in the art. [0030J Additionally, the optimal concentration and/or quantiies or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition. 100311 in certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

WO 2014/006529 PCT/IB2013/055146 14 [00321 When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the phannaceutically acceptable excipients may undergo gradual or delayed degradation (e.g,, through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein. 10033J The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other m material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes. 100341 The phrase "therapeutically effective amount" is an artrecognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such. factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the WO 2014/006529 PCT/IB2013/055146 15 effective aniount of a particular composition without necessitating undue experimentation. [00351 The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs. [00361 This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent. surfactant, filler, binder, and lubricant. 10037] In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula I) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formal ia I 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 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 judgmnent of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. [00381 Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula 1 may be adjusted to accommodate variations in the treatment parameters, Such treatment parameters include the clinical use to which the WO 2014/006529 PCT/IB2013/055146 16 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. 100391 The concentration and/or amount of any compound of formula I may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein, One such method is microdialysis, as reviewed by T. E. Robinson et a]., 1991, microdialvsis in the neurosciences, Techniques, volume 7., Chapter . The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal Dialysis fluid is pumped through the loop. When compounds with formula I such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions. [00401 In certain enibodiments, the dosage of the subject compounds of formula I provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve front time 0 to infinity may be used. 100411 Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas I is in the range of about 0.01 mg/kg/day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 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 WO 2014/006529 PCT/IB2013/055146 17 Formula I may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 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 ng per day, In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula 1 required for the same therapeutic benefit. 100421 An effective amount of the compounds of formula I described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease. For example Moderate to severe pain or any other medical condition. [0043J An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt., restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or deniyelization and/or elevated reactive oxidative nitrosative species and/or abnormalities in neurotransmitter homeostasis', in patients who are at risk, for such complications- As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases. [0044J The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g , intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal suppository, or WO 2014/006529 PCT/IB2013/055146 18 using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic nj ection, or in nanoparticles. 100451 The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses, Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents, The pharmaceutical compositions formed by combing the compositions and the pharnmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges., syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like Thus, for purposes of oral administration, tablets containing various recipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes,. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water. ethanol, propylene glycol, glycerin and combinations thereof. The compounds of formula I may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art- WO 2014/006529 PCT/IB2013/055146 19 [00461 For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut OiL, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably butfered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration, In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. 100471 The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mug, or 350 to 800 rg e.g. 10, 50, 100, 300, 500, 700, 800 mng of the compounds of formula I disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula I. 100481 Generally, a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ, For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner. 100491 The dosage administered will be dependent upon the identity of the neurological disease; the type of host involved, including its age, health and weight.; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio. [00501 Illustratively, dosage levels of the administered active ingredients are: intravenous, 0. 1 to about 200 mg/kg; intramuscular, I to about 500 mgkg; orally, 5 to WO 2014/006529 PCT/IB2013/055146 20 about 1000 mg/kg, intranasal instillation. 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight. [0051I 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, intravagi nail y, rectally, or ocularly in a concentration of from about 0.01 to about 50% wi/w of the composition; preferably about I to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v, [0052J The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared. [0053J As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polvalkylene glycols, thennoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches. swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HIPC), hvdroxvpropylmethylcell ulouse (HI PMC), hydroxyisopropylcellulose, hydroxybutylcellu lose, hydroxyphenylcellulose, hydroxyethyl cellulose (HEC), hydroxypentylcellulose, hydroxypropylethvlcellulose, hydroxypropylbutylcellulose, and hvdroxypropylethylcellulose, and mixtures thereof Examples of suitable poly alkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are WO 2014/006529 PCT/IB2013/055146 21 not I mitted to, potassiun methacrylatedi vinylbenzene cool ymer, polymethylmethacrylate, high-molecular wvveight crosslinked acrylic acid homopolyimers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOLIt Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhaisan, zooglan., methylan, chitin, cyclodextrin, chitosan, and mixtures thereof Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponiite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof Examples of suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof 100541 The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipits Include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof 100551 Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrroli done and hydroxypropy I m ethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar guni, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked WO 2014/006529 PCT/IB2013/055146 22 polyvinylpyrroidone, cross-linked carboxymethylceiiulose, starches, microcrystalline cellulose, and mixtures thereof [00561 Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, tale, glycerides waxes, and mixtures thereof Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable release-nodifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof 10057] Suitable insoluble edible materials for use as release-modifying recipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolyniers thereof, and mixtures thereof Examples of suitable water insoluble polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated paln kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceril behenate, glycery pal mitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax 932, lauroyl macrogol-32 glycerides, stearoy] macrogol-32 glycerides, and mixtures thereof Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax. microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to., croscarmellose sodium, sodium starch glycolate and cross- WO 2014/006529 PCT/IB2013/055146 23 linked povidone (crospovidone), in one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant. 100581 Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylbydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof Examples of preservatives inclUde, but are not limited to, citric acid, tartaric acid, lactic acid, amalic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof [0059] In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g, from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer. 100601 In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent. 100611 In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core. [0062J 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 WO 2014/006529 PCT/IB2013/055146 24 coating portion is included of a dried granulation including the piarmaceutically active agent. 100631 Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art 100641 The immediate release dosage, unit of the dosage form, i.e, a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads). [00651 Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington.The Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are wellknown and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polvmer carrier into a tablet form. 100661 An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

WO 2014/006529 PCT/IB2013/055146 25 100671 Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drg-containing composition with a selected coating material, The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. [0068J A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release. [00691 Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 tvi. % to 70 wt %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt .% to 40 wt, %, of the total amount of active agent in the dosage form is released in the second pulse, For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration. 100701 Another dosage form contains a compressed tablet or a capsule having a drug containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage WO 2014/006529 PCT/IB2013/055146 26 unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose. 100711 For purposes of transdernal (e.g, topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared. [0072J Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I 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). 100731 In addition, in certain embodiments, subject compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage. 100741 Formulations useful in the methods provided herein include those suitable fur oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount. of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.

WO 2014/006529 PCT/IB2013/055146 27 [00751 Methods of preparing these formulations or compositions include the step of bringing Into association subject compositions with the carrier and, optionally, one or more accessory ingredients. In general. the formulations are prepared by Uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. 100761 The compounds of formula I described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeu tic agents useful in inhalation therapy. The final aerosol forniulation may for example contain 0,005-90% w/w, for instance 0 005-50%, 0.005-5% w/w, or 0.01-l.0% w/w, of medicament relative to the total weight of the formulation. 100771 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, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia, (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraiabsorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polvethylene glycols, sodium lauryI sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

WO 2014/006529 PCT/IB2013/055146 28 [00781 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof 100791 Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxyl ated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluninum metahydroxi de, bentonite, agar agar and tragacanth, and mixtures thereof. [00801 Formulations for rectal or vaginal administration may be presented as a. suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritati ng carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and composition( s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate. 100811 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 pharmnaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required For WO 2014/006529 PCT/IB2013/055146 29 transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties. 100821 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, tr-agacanth, 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, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propell ants, such as chl orofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [00831 Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplar,' 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. 100841 In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive layer comprising a sty rene-di en e-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, WO 2014/006529 PCT/IB2013/055146 30 and then adhering a polyalkylene terephithalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene terephthalate film. 100851 Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose. 100861 Transdernal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs. 100871 lontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which lontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current. 100881 In some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the WO 2014/006529 PCT/IB2013/055146 31 separate components. The kit firn is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g, oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. 100891 An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like)- Blister packs generally consist of a sheet of relatively stitT material covered with a foil of a plastic material that may be transparent. During the packaging process recesses are formed in the plastic fil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet, In some embodiments the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [00901 Methods and compositions for the treatment of moderate to severe pain. Among other things, herein is provided a method of treating moderate to severe pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula I: ci NH CI R1 R2 WO 2014/006529 PCT/IB2013/055146 32 Formula I 100911 Wherein, R' represents H , -OC. -CD, O 0 0 0 NH2 OXO H H H HH N Nj QA H 0H Oj O WO 2014/006529 PCT/IB2013/055146 33 ON 00 0 OH H H NN or H R2 represents 0 O N0

H

2 N HO O 00 OH 0 CH3 0OCH SHC 0 OH

OH

WO 2014/006529 PCT/IB2013/055146 34 0 02 HO NHCOCH 3 SOHOH N qHOGH OHI O 0

OHCONH

2 N2 OH 0000H OHO 0 0 HN H OO NN OH OH HO H N N HO H 0 WO 2014/006529 PCT/IB2013/055146 35 0 o HN NH OH H H 0 HN 0 H OH H HO HO O N OH O H O 0 O 0O 00 b n b or d a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1., 2 or 6; e and d are each independently H, D, -OH., -OD, C-C-alkyl, -NH. or -COCHt; a is independently L, 2, 3, 4 or 5.

WO 2014/006529 PCT/IB2013/055146 36 Methods for using c /opown tformulai .1: The invention also includes methods for treating pain, pain due to injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related nieuropathic pain, post herpetic neuralgia, diabetic neuropathy, bipolar depression, depression, stress, cancer pain, fibromyalgia and lower back pain or any other medical condition related to severe pain. METHODS OF MAKING [00921 Examples of synthetic pathways useful for making compounds of formula I are set forth in example below and generalized in scheme 1 Scheme-I C1 C1 Br Cu powder C H

NH

2 C H 01C0 NHCOCH, N CGaCOOH C1 refux 4 days I rt9O C 20 min 23 6 C IC IN aqNaOH C CH2CICOc N AC1-3 N 0C Ethanol N 1 eti 1 h00 C 160 C2 reflux 2 HCOOH S7 DCM 0 Ct,4 h 1 100931 Step-1: Synthesis of compound 2: CO C1 NH2 CH ,COCf NHCOCH3 CIGladal (Cl CH3,COOH irt-90 ":C, 20 min 2 WO 2014/006529 PCT/IB2013/055146 37 [00941 To a mechanically stirred solution of 2, 6-dichloroaniline 1 (76 g, .047 mol) in 60 mL of glacial acetic acid is added dropwise acetyl chloride (36 mL, 0.5 mol). After the addition is complete, the reaction mixture is heated at 90* C for 20 minutes, The solution is poured into ice water (500 muL), forming a white precipitate. The solids are filtered, washed with water and dried to give the product 2 (91.8 g, 96%, white solid, m.p. 179 180' C, lit, mp. 180-18 P C from glacial acetic acid), 100951 Step-2: Synthesis of compound 4: Ci Br Cu powder C H NHCOCH3 Cl reflux, 4 days 2 3 100961 15 g of compound 2 are dissolved in 150 ml of bromobenzene 3, Five and a half grams of calcinated potassium carbonate and 0.5 g of copper powder are added The mixture is refIluxed for 4 days the water formed being removed by a water separator cooled and subjected to steam distillation The residue is extracted with 200 ml of ether The ether solution is filtered through Hyflo and the residue is concentrated to dryness under 11 torr. The residue is dissolved in 60 ml of ethanolic potassium hydroxide and the solution is refluxed for 3 hours. The solution is then concentrated to dryness at 40 wider II torr Ten milliliters of water are added to the residue which is then extracted with 100 ml of ether- The ether solution is removed and extracted with 20 ml of water. The ether solution is then dried with sodium sulfate and concentrated to dryness under .1 tor. The residue was distilled under high vacuum to yield compound 4 as yellow oil at 115 C/ 0.01 torr. [0097 Step-3 Synthesis of compound 6: c H 51 'N ~'N CH 2 CIOCC 'NN 4 WO 2014/006529 PCT/IB2013/055146 38 [00981 4 g of compound 4 and 40 ml of freshly distilled chloroacetyI chloride 5 were refluxed for I hour. The dark solution was evaporated under 11 torr at a bath temperature of 50 "C The residue was dissolved in 70 ml of ethyl acetate /ether 1:1, This solution was extracted with 10 ml of 2 N potassium bicatbonate solution and 10 ml of water dried over sodium sulfate and evaporated under I1 torr. The compound 6 was recry stall ised from methano0 MP 143 "C. 100991 Step-4: Synthesis of cornpound 7 N AICI3 C 0 160 C, 2 h X 6 7 1001001 4 g of compound 6 and 4 g of aluminium chloride are well mixed and heated for 2 hours at 160 "C. The melt was cooled and poured onto about 50 g of ice while still warn The oil which separates was dissolved in 50 nl of chloroform. The chloroform solution was washed with 10 ml of water dried over sodium sulfate and concentrated under 1, 1 torr. The residue was distilled. Compound 7 obtained was crystallised from methanol NP 126 *C 1001011 Step-5: Synthesis of compound 8: cI d Naq.NaOH Cl ~N Ci Ethanol . CI I COOH reflux, 2 h 7 [001021 A solution of 40 g of compound 7 in 280 ml of I N sodium hydroxide solution and 420 ml of ethanol was refluxed for 2 hours. The clear solution was cooled and the ethanol was distilled off at a bath temperature of 40 under I I torr. The aqueous residue was extracted with 1.00 ml of ether. The ether was removed and the aqueous solution was cooled by the addition of ice about 50 g and external cooling to 54C . 2 N of hydrochloric WO 2014/006529 PCT/IB2013/055146 39 acid was then added while stIrring until the pH of the solution was about 6. The precipitated acid was taken up in 400 ml of ether, the ether solution was separated and the aqueous solution was again extracted with 200 ml of ether. The ether solutions are washed with 50 ml of water combined dried over sodium sulfate and concentrated under 11 torr without heating. After adding petroleum ether to the concentrated ethereal solution the compound 8 crystallizes. After recrysallisation from ether, petroleum ether it melts at 156-158 *C. 1001031 Step-6i: Synthesis of compound 10: Cl - OH )SOC12 NH C-- reflux, 2 h COOH 2) DIPEA 8 0 CM h H0 *C-t, 4 h 0 0 CI 10 1001041 Compound 8 (10 mmol) and 5 ml of SOC12 were refluxed for 2 h to get acid chloride. Excess SOC 2 was distilled off and the acid chloride was directly used. Compound 9 was suspended in DCM at 0 "C and added DIPEA (12 nmol). The reaction mixture was stirred for 30 min and then added acid chloride in DCM to the reaction mixture dropwise at 0 *C, The reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was diluted with DCM and added water. The layers were separated and the organic layer was washed with saturated NaHCO 3 and evaporated to get the residue. The residue was purified through column to get compound 10. MF: CH3C N03S 2 ; Molt Wt.: 483.05; Elemental Analysis: C, 54.54; Ht 4.79; Cl, 14,64, N, 2.89; 0, 9.91; S, 13.24.

WO 2014/006529 PCT/IB2013/055146 40 [001051 The term "saniple" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ by, e.g, biopsy. Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting. Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein. EQUIALENTS [00106] The present disclosure provides among other things compositions and methods for treating moderate to moderate to severe pain and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and. not. restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. INCORPORATION BY REFERENCE [001071 All publications and patents menti oned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims (8)

1. A compound of formula .1: CCI NH C R1 R2 Formula I or a pharmaceutically acceptable salt hydrate, polymorph, solvate, prodnig, enantiomer, or stereoisomer thereof: Wherein R' represents H- D. -OC , -OCD 3 O-O NH;, O O 0 O O 0 0 a WO 2014/006529 PCT/IB2013/055146 42 0 0 00 NH 2 NH 2 N>I H H NN -N N O H HH Ny N Nj \AAN 00 H H NN OH H0 00 00 WO 2014/006529 PCT/IB2013/055146 43 0 O H, O H 0 0~ Chej O OHH OHH 44 7 - 1: 131 N C Ht 0 OH HO O OH 0 0 C02 AZ~ ry 0 ' CONH 2 OHK>0 000H t WO 2014/006529 PCT/IB2013/055146 44 oo N OO KIV 00 H OH HN NH H H H HO N 0 0 OH H OH H 0 HN HO HO 0H HO~aHJS d di a b3 WO 2014/006529 PCT/IB2013/055146 45 0 b a6 b or c d a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is independently 1, 2 or 6; c and d are each independently H D, -01-, -01, C-C-alkyl, -Ni or -COCH; n is independently 1, 2, 3, 4 or 5.

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

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

4. Compounds and compositions of claim 3 are formulated for the treatment of severe pain, muscle pain, spasticity, neuropathic pain, fibromvalgia, post-operative pain, muscle spasticity, headache, chronic pain, sub-chronic pain and local pain.

5. A pharmaceutical composition comprising a niolecular conjugate of 2-(2-((2,6 dichl oropheny l)ami no)phenyl)acetic acid and R-Lipoic acid.

6, A pharmaceutical composition comprising a molecular conjugate of 2424(2,6 dichl orophenyl')amino)phenyl)aceti c acid and salsalate.

7. A pharmaceutical composition comprising a molecular conjugate of 2-(2-((2,6 dichl oropheny I )ami no)phenyl)acetic acid and eicosapentaenoic acid.

8. A pharmaceutical composition comprising a molecular conjugate of 242((2,6 dichlorophenyl )amiino)phenyi)acetic acid and docosahexaenoic acid.