AU2013257727A1 - Compositions and methods for the treatment of local pain - Google Patents

Abstract

The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of local pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postheipetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and Sower back pain.

Description

WO 2013/168006 PCT/IB2013/051268 1 COMPOSITIONS AND METHODS FOR THE TREATMENT OF LOCAL PAIN PRIORITY [0001 The present application claims the benefit of Indian Provisional Patent Application No. 1843/CHE/2012 filed on .1 0-May-201 2, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference, FIELD OF THEINNENTION 100021 This disclosure generally relates to compounds and compositions for the treatment of local pain More particularly, this invention relates to treating subjects with a pharmaceutical acceptable dose of compounds, crystals, polymorphs, esters, salts, stereoisomers, enantiomers, hydrates, prodrugs, or mixtures thereof. BACKGROUJ ND OF TBHE 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 Severe Pain such as pain, depression, fibromyalgia, rheumatoid arthritis, restless leg syndrome, 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 WO 2013/168006 PCT/IB2013/051268 2 normal cellular function like mitochondrial respiratory chain, phagocytosis and arachidotnic acid metabolism. The release of oxven 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, fibronalgia and lower back pain. 100051 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 local 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 local pain. [00071 The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts, hydrate, solvate, prodrug, enantiom er, or stereoisomer 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 local pain and its associated complications. H N N

R

WO 2013/168006 PCT/IB2013/051268 3 Formula I [00081 In certain embodiments, the present invention relates to the compounds and compositions of formula [, or pharmaceutically acceptable salts, hydrate, solvate, prodrug. enantiomer or stereoisomer thereof, H N R -- R2 Foimla I \Wherein,

R

1 independently represents D -CHt -OCHE H

NH

2 Q o o 0 0 WO 2013/168006 PCT/IB2013/051268 4 -o H H NN 0 0 0 HH or H R independently represents 0 O S 0 O, 0-1 s 0 WO 2013/168006 PCT/IB2013/051268 5 0 0 020 O 0 N CH. O C NHCOCH3 0 OH NN HoH O O 0 OHCO2H CHCONH2 OH 0CH.3olOH OO OH O0 H NH2 WO 2013/168006 PCT/IB2013/051268 6 b HO ne Nd 0 OH HH nN * O ab 0 0 0 H 0N a b d oo a is independently 2 3 or 7; each b is indepen den t y 3 5 or 6; e is independently 1, 2 or 6; c and d are each independently H. D, -OH, -OD, C-C-alkvl. -NH 2 or -COCH 3 ; n is independently 1, 2, 3, 4 or 5 [00091 In the illustrative embodiments, examples of compounds of formula I are as set forth below:

H

WO 2013/168006 PCT/IB2013/051268 7 (1I- 1) H N 0 (1-2) 1001.01 Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. TIhe kit may comprise instructions for use in the treatment of local pain or its related complications. 100111 The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects. the pharmaceutical composition is formulated. for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration. 100121 Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of local pain or its related complications. 100131 The compositions described herein have several uses. The present application provides, for example, methods of treating a patient sufTering from local pain or its related complications manifested from metabolic conditions, severe diseases or disorders; Hepatology, Cancer, Hematoogical, Orthopedic, Cardiovascular, Renal, Skin, Neurological or Ocul ar complications.

WO 2013/168006 PCT/IB2013/051268 8 DETAILED DESCRIPTION OF THE INVEN TION Definitions [00141 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 [0015] 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). 100161 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 "enantiomers." When a. compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enaniomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing 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 2013/168006 PCT/IB2013/051268 9 100171 As used herein, the term "metabolic condition" refers to an inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent, [0018J In some embodiments, a molecular conjugate comprises of compounds selected from the group consisting of R-lipoic acid (CAS No. 1200-22-2), salsalate (CAS No. 552-94-3), acetylcysteine (CAS No. 616-91-1), Eicosapentaenoic acid (CAS No- 10417 94-4), Docosahexaenoic acid (CAS No. 6217-54-5). [001,91 The term polymorphh" as used herein is art-recognized and refers to one crystal structure of a given compound. [00201 The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital. intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subeuticular, intra articular, subcapsular, subarachnoid, intraspinal and intrastenal 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. 100221 The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

WO 2013/168006 PCT/IB2013/051268 10 [00231 The phrase "pharrnaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solve ent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurioLs 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 sodi um carboxym ethyl 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) polvols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxlde; (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 pharni aceutical form ul ati on s. 100241 The term "prodrug" is intended to enconipass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A comnimon 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 WO 2013/168006 PCT/IB2013/051268 11 administered prior to clinical manifestation of the unwanted condition (e.g, disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side etfects thereof) 100261 The term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention. [0027J The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it, inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g, causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as local anesthesia including infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia 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.

WO 2013/168006 PCT/IB2013/051268 12 [00281 The phrase "therapeutically effective amount" is an art-recognized term, In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically detennine the effective amount of a particular composition without necessitating undue experimentation. [0029J In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions, It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. [00301 Additionally, the optimal concentration and/or quantities or amounts Of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

WO 2013/168006 PCT/IB2013/051268 13 [00311 In certain embodiments, the dosage of the subject compositions provided ierein 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. [0032J 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 pharnaceutically 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. 100331 The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripheralfly" 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, eg., 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 aim-recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed WO 2013/168006 PCT/IB2013/051268 14 herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation, [0035J The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs. 100361 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. 100371 In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula. I or composition as part of a prophylactic or therapeutic treatment. The desired concentration of form ula 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 ie 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 WO 2013/168006 PCT/IB2013/051268 15 adninisteing or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art. 100381 Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I may be adjusted to accommodate variations in the treatment parameters, Such treatment parameters include the clinical use to which the preparation is put, e., the site treated, the type of patient, e.g., human or non-hanan, adult or child, and the nature of the disease or condition. [0039] The concentration and/or amount of any compound of formula I may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed by T- E, Robinson et al-, 1991., microdialysis in the neuroscience, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in. brief, as follows. A. microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula I such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialyate 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. 10040j In certain embodiments, 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 plasm.a concentration (Coax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

WO 2013/168006 PCT/IB2013/051268 16 [0041.1 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 rng/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/dav, L0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of Formula I may also be administered to a human patient at a dose of for example, between 0.1 nmg and 1000 mg, between 5 mg and 80 mg, or less than 1 .0, 90, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I required for the same therapeutic benefit. [00421 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. [00431 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 resuming from nerve damage or demyelization and/or elevated reactive oxidative nitrosative species and/or abnormalities in physiological 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 WO 2013/168006 PCT/IB2013/051268 17 factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases. 100441 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 using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles 10045J The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These phannaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and 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 WO 2013/168006 PCT/IB2013/051268 18 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, emulsift'ing 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. 100461 For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluenit first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intraMu secular, 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. [00471 The formulations, for instance tablets, may contain e.g 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 n e g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula 1. [00481 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.

WO 2013/168006 PCT/IB2013/051268 19 [00491 The dosage administered will be dependent upon the identity of the metabolic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio. 100501 Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mgikg; intramuscular, I to about 500 mg/kg; orally, 5 to about 1000 in gkg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 ig/kg of host body weight. 100511 Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of from about 001. to about 50% w/w of the coinposition; 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. 100521 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. [00531 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, polvakylen e glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof Examples of suitable water swellable celhdlose derivatives include, but are not limited to, sodium carboxymethyl cellulose. cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), WO 2013/168006 PCT/IB2013/051268 20 hy droxy isopropvlcellul ose, hydroxybutyCellOs, hy droxyphenylcellulose, hvdroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethyl cellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glvcol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide) Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, highimolecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL' T' 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, gaiactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures thereof Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and 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 E xamples of suitable swelling cross-fIinked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxynmethylcellulose sodium, and mixtures thereof 100541 The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipients 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 pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, WO 2013/168006 PCT/IB2013/051268 21 carrageenan, carboxymethvIcellulose, tara, gum arabic., tragacanti, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, lainnarin, scleroglucan, inulin, whelan, rhamsan, zooglan, inethylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxvmethylcellulose, starches, microcrystalline cellulose, and mixtures thereof 100561 Suitable lubricants include, but are not limited to, long chain fatty acids and. their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, p--dependent polyrners, and mixtures thereof. 100571 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 palin 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, glyceryl behenate, glyceryI palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax 932, lauroyl macrogol-32 glycerides, stearoyl in acrogol-32 glycerides, and mixtures thereof Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl WO 2013/168006 PCT/IB2013/051268 22 serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax. microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof Examples of super disintegrants include, but are not limited to. croscarmellose sodium, sodium starch glycolate and cross linked povidone (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, butylhydroxytoluene, 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, mnalic acid, acetic acid, benzoic acid, and sorbic acid, and inixtures thereof. 100591 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. hi 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 otie 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 WO 2013/168006 PCT/IB2013/051268 23 embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core 100621 In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharn aceutically 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 iutil layer tablets, capsules containing tablets, beads, or granules in. a solid or liquid form. Ty pical, 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). 100651 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 polymer carrier into a tablet form.

WO 2013/168006 PCT/IB2013/051268 24 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. [0067J 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 drog-contaiing 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 dng-containing beads, particles or granules, for incorporation into either a tablet or capsule. [0068] 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. 100691 Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt.. % to 70 wt %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt % to 3.0 vt. %, preferably 60 wt, % to 40 vt. %, 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 WO 2013/168006 PCT/IB2013/051268 25 than 14 hours, and more preferably approximately 5 hours to 12 hours, following admi nistration. [00701 Another dosage form contains a compressed tablet or a capsule having a drug containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately foll owing oral administration to provide an initial dose, The delayed release dosage unit contains a plurality of coated beads or granules, which release dnig approximately 3 hours to 14 hours following oral administration to provide a second dose. [00711 For purposes of transdermal (e.g, topical.) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral so utions, may be prepared. [00721 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, Nlack 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 subj ect 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. [00741 Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The fornulations may conveniently be presented in unit WO 2013/168006 PCT/IB2013/051268 26 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. 100751 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 therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0005-90% w/w, for instance 0 005-50%, 0.005-5% w/w, or 0.0 1-L .0% w/w, of medicament relative to the total weight of the formulation. [00771 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, carboxymethycellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) hunectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calciurn carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, 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 polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring WO 2013/168006 PCT/IB2013/051268 27 agents. In the case of capsules, tablets and pills, the pharmaceutical compositions ma also comprise suffering agents- Solid compositions of a similar type may also be employed as fillers in sot and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. 100781 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, peanuL, sunflower, soybean, olive, castor, and sesame oils), glycerol., tetrahydrofuryi alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof f00791 Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, nicrocrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, and mixtures thereof 100801 Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and 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.

WO 2013/168006 PCT/IB2013/051268 28 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 pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and. hydrophilic groups to achieve the desired water solubility and transport properties. 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, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or fixtures thereof Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polvam ide powder, or mixtures of such substances. Sprays may additionally contain custom arv propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. 100831 Methods of delivering a composition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch delivery are described in U S Patent Nos. 6,974,588. 6,564,093, 6,312,716. 6,440,454, 6,267,983, 6,239,180, and 6, 103,2 75. [00841 In another embodiment, a transdernial 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 filn, 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 WO 2013/168006 PCT/IB2013/051268 29 saturated polyester resin and is formed on the surface of the polvalkylene terephthalate fili and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises 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 filn 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. [0085J Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and latminating 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 Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitrogl ycerine 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. [0087J 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 iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the WO 2013/168006 PCT/IB2013/051268 30 preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current. [00881 In some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e~g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician, 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 stiff material covered with a foil of a plastic material that may be transparent. [0090J Methods and compositions for the treatment of local pain. Among other things, herein is provided a method of treating local pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula I: H N N Formula I WO 2013/168006 PCT/IB2013/051268 31 Wherein, R' each independently represents D, -CH -OCH3 H 0 0 H2 O O H H 00 NNN NO H H N O N 0 O0 WO 2013/168006 PCT/IB2013/051268 32 O A N H R independently represents S s 20 WO 2013/168006 PCT/IB2013/051268 33 N CH HO NHCOCH 3 0 OH HO OHI 0 0 OH CO2H CH

CONH

2 OH OCOCH OHO 0 0~ HOH 0o WO 2013/168006 PCT/IB2013/051268 34 0 H OH H N __ HO Sa b 00 HN NH H H 0 a ,or 00 b cd a is independently 2,3 or 7; each b is independently 3, 5 or 6; e is i independently 1, 2 or 6; c and d are each independently H D, -01, -OD, C-Qs-alkyl, -NI2 or -COCHt; n is independently 1, 2, 3, 4 or 5. Me thods for uxsng compounds afformlda I: 1009Il The invention also includes methods for treating local pain including infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpefic neuralgia and neuralgia. METHODS OF MAKING 100921 Examples of synthetic pathways useful for making compounds of formula i are set forth in. example below and generalized in scheme 1: WO 2013/168006 PCT/IB2013/051268 35 Scheme - I: Oxaloyl chloride 0 OH .HC O DCM, DMF H H N 20-26C,4.5h N N- Raney Ni/l N M. CH0H H 1NH 2 Pyrdine 3 CHCOOH 4 2 DCM 50 0C.30 h -5" KCO, H H& N'+ H + CI o DMF O OH HOS 90 *C, 5h 6 7 EDIHC H DMAP N DCM rt24h 100931 Step-i : Synthesis of com pound 3: Oxatyl chloride 0 OH HO DCM,ODMF 6 -'N20-25 0 C, 45 hN N XH0 NH2 Pyrdine DCM 100941 A three neck round bottom flask equipped with mechanical stirrer, dropping runnel and condenser, under argon atmosphere was charged with 19.4 g. of 2-picolinic acid hydrochloride, 0.3 ml of NN--dimethylfornnamide and 225 ml of dichloromethane. Then, a solution of 11, ml of oxalyl chloride (1.05 equiv) in 4 ml of dichloromethane was added to the mixtre in a period of 30 min at 20-25C. The reaction mixture was kept at 20-25" C with vigorous stirring for additional 4.5 hours and then cooled to -5* C. A WO 2013/168006 PCT/IB2013/051268 36 solution of 15 ml of 2,6-xylidine (. .0 equiv) and 20 nil of pyridine (2.0 equiv) in 15 ml dichloromethane was added in a period of I hour at the same temperature. The reaction mixture was stirred for I hour at -5 to Ct warmed to 20" C and maintained for an additional 1 hour for the completion of the reaction. To the reaction mass 200 ml of water were added, stirred for additional 1 5 min and the mixture was transferred to a separatory funnel. The organic layer was separated and washed with 100 ml of water. The aqueous layers were combined and extracted once with 50 ml ofdichloronethane. The two organic layers were combined, dried over MgSO4, filtered and the solvents were removed in a rotary evaporator. The crude solid mass obtained (-32g.) was recrystallized with 75 ml of cyclohexane, filtered and the crystals were washed with 15 ml of cyclohexane to provide after drying 26.0 g. of slightly yellowish crystals of pipecolic 2-acid-2%6'-xylidide 3 in -94 % yield. M.P.1042- 104.50C. f00951 Step-2: Synthesis of compound 4: H jjj RaneyNUH 2 H N ____ N N X CH 3 0H 0 H C HICOOH 3 4 50 *C,30 h 100961 To an SS reaction bottle equipped with a mechanical stirrer 2 5 g of picolinic-2 acid-2t6' xylidide 3, 625 ml of methanol, 63 ml of acetic acid and 15 g. of Ranev nickel were added. Then, in the mixture argon was passed through for 5 nin, sealed and charged with hydrogen at 18 Kg/cm (260 psi). The reaction mixture was heated at 504C and maintained under the same pressure and temperature for .28-30 hours until completion of reaction. The reaction mass was filtered to remove the catalyst and mother liquor was concentrated in a rotary evaporator. The crude reaction mass was dissolved in 250 ml of toluene, transferred to a separatory funnel, 250 ml of water was added and basitfied with 50 ml of 20% aqueous sodium hydroxide, The organic layer was separated and the aqueous layer was extracted twice with 100 nil of toluene. The combined organic layer after extraction was dried over MgSO 4 and concentrated in a WO 2013/168006 PCT/IB2013/051268 37 rotary evaporator. The crude solid mass obtained was recrystallized from 70 ml of toluene to provide 18.5 g of slightly pink solid of compound 4 in 72 % yield, M.P 116 * C. [00971 Step-3: Synthesis of compound 6: H H N NK2CO + N r 5 DMF o 4 g" 6 100981 A dry suspension of potassium carbonate (7.2 mmol), 4 (4.8 mmol) and 3 chloropropane-1-ol 5 (5.3 mmol in DMINF was heated to 90 C' for 5 h, The reaction mixture was filtered over a glas microfibre filter and the filtrate was concentrated. The residue was purified by silicagel column chromatography to provide 6. [00991 Step-4: Synthesis of compound 8: o EDCLHC N N- DMAP N + HO DA S-S DCM 6 rt, 24 h H -(N 0 0 8 [001001 Stirring a mixture of a solution, of compound 6 (18.0 mmol; 1 .O eq) and R-(+) Lipoic acid (18.0 mmol; 1.0 eq) in Dichloromethane (DCM) (200 mL; LR grade); I ethyli-3-(3 -dimethylai inopropyl)carbodi imide. H1Cl. (EDCIl HG) (527.0 mmol; 1.5 eq) and 4-Dimethylaminopyridine(DMAP) (18.0 mmol; .0 eq) at room temperature (RT) for 24 hours. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was diluted with DCM (200 mL), washed with water (2x300 mL) followed by WO 2013/168006 PCT/IB2013/051268 38 bfine solution (300 mL) and dried over anhydrous Na 2

SO

4 and evaporated under reduced pressure. The crude was purified 'by column chromatography over 100-200 mesh silica gel by using ethyl acetate-pet ether to get compound 8. MoL Wt: 47823: Elemental Analysis: C, 62.72; H, 8.00; N, 5,85; 0, 10.03; S, 13.40. EXAMPLES 1001011 Pharmacokinetic Evaluation of Rupivacaine (BU) and Formula I (1-1) in free Sprague-Dawley rats: 1001021 Male specific pathogen-free Sprague-Dawley rats weighing 300-350g were obtained from the Laboratory. The animals had free access to food and water. The rat was anaesthetized with urethane 1.Og/mL and chloralose 0. ig/niL (.1mL/kg,i.p.) before surgery. The femoral vein was cannulated for further drug administration, and the rat's body temperature was maintained by heating pad during the experiment. All rats remained anaesthetized during the experimental period over which the Formula 1 (1-1) and BU concentrations in blood, brain and bile were monitored, and they were euthanized by overdose C02 under the anaesthetic after the experimental endpoint. 001031 Bupivacaine (3mg/nL) was prepared in 0. 9%(w/v) sodium chloride. Formula 1(1-1) equivalent of BU 3mg/mL Rats were divided into the following groups (n 5 for each group) and received drugs intravenously: group I treated with (20 mg/kg) 10min before BU (3mg/kg~administrafion, group 2 treated with Formula 1 (I - I) (3mg/kg). 1001041 The chromatographic system consisted of a PM-80 chromatographic pump (BAS, West Lafayette, IN, USA), an off-line injector (CM A'140, Stockholm, Sweden) equipped with a 20L sample loop injector (Rheodyncmodel7125) and a UV-Vis detector (Soma, Tokyo, Japan) that operated at room temperature (25+2 C). Separation was achieved on a LiChrosphere6ORP- select B column (4.6mm250mmn, 5m, Merck). The mobile phase for plasma, brain homogenate, blood dialysate and brain dialysate was WO 2013/168006 PCT/IB2013/051268 39 comprised of 10mNl potassium dihvdrogenphosphate-- acetoniie triethy I anine (67:33:001). adjusted to pH4.3 with H-3P04. i'le mobile phase for bile dialysate consisted of 10mM potassium dihydrogen phosphate acetoni trial e- tri ethyl amine (60:40:0,01), adjusted to pH6.0 with H 3 P0 4 . The flow rate was set ati.OmL/min for both mobile phases. [00105] Results: The pharmacokinetic parameters of BU and Formula 1 (1-1) in both blood and brain was as follows Blood PK Parameters BU1 Fomiula 1 (1 -1) AUC (min ug/mi) 82 i 16 98 * 29 T1/2 (min) 4± 2 7 t 6 Brain PK Parameters BU Formula 1 (1-1) AUC (min ug/mL) 15±4 23 ± 7 Cmax (ug/mL) 0. 56 0.13 0.78 * 0.40 1001061 The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ by, e.g& biopsy. Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting Preferably, cell-, tissue- or organ. samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein WO 2013/168006 PCT/IB2013/051268 40 EQUIVALENTS [001071 The present disclosure provides among other things compositions and methods for treating local 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 1001081 All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. in case of conflict, the present application, including any definitions herein, will control.

Claims (9)

1. 3. The pharmaceutical composition of claim 2, which is formulated to treat the underlying etiology with an efTective 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. WO 2013/168006 PCT/IB2013/051268 46
2. 4. A method of treating local pain related diseases as the underlying etiology, the method comprising administering to a patient in need thereof an effective amount of claim 3.
3. 5. The method of claim 4, wherein the local pain as the underlying etiology is selected from infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain. 6& A pharmaceutical composition conpising a molecular conjugate of bupivacaine and R-Lipoic acid.
4. 7. A pharmaceutical composition comprising, a molecular conijugate of bupivacaine and eicosapentaenoic acid.
5. 8. A pharmaceutical composition comprising a molecular conjugate of bupivacaine and docosahexaenoic acid.
6. 9. A pharmaceutical composition comprising a molecular conijugate of bupivacaine and salsalate.
7. 10. A pharmaceutical composition comprising a niolecular conjugate of bupivacaine and acetylsalicylic acid.
8. 11. A pharmaceutical composition comprising a molecular conjugate of bupivacaine and pantothenic acid.
9. 12. A pharmaceutical composition comprising a molecular conjugate of bupivacaine and pyridoxamine.