TREATMENT OF CHRONIC PA N

PRIORITY jOtiOI ^' l The present application claims the benefit of Indian Provisional Patent Application No. 1857/CHE 2012 filed on j.O-May-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION

[0002] This disclosure generally relates to compounds and compositions for the treatment of chronic pain. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, stereoisomers, enantiomers, polymorphs, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE I VENTION

[0003] 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 rel ief 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 opioid analgesics.

[0004] Opioids are a cornerstone of the management of cancer pain and postoperative pain and are used increasingl for the management of chronic non-cancer pain. Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in younger than 45 years. In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.

|0O05] Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient. Pharmacodynamic and pharmacokinetic differences underlie this variability of response. Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug.

[0006] Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and hetweeu-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial -and-error procedure. j0007j Neurological disorders such as pain 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 (RGS) is an integral feature of normal cellular function like mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. The release of oxygen free radicals has also been reported during the recover)' 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 injur)', migraine, HIV related neuropathic pain, post herpetic neuralgia, diabetic neuropathy, cancer pain, fibromyalgia and lower back pain,

{Oti Sj Managing acute pathology of often reiies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of chronic pain.

SUMMARY OF THE INVENTION

[0009] 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 chronic pain. lOOlO ^' J The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of chronic pain and its associated complications.

Formula I

[0011] In certain embodiments, the present invention relates to the compounds and compositions of formula Ϊ, or pharmaceutically acceptable salts thereof!,

Formula I

Wherein,

R ^l independently represents H, D, CD¾ or CJ¾;

R independently represents H, D, -OCH ₃ , -CH _. s.

R ³ , R ^Cl each independeiitiy represents H, D, -OCH ₃ , -OCD3, carbon l functional

>==o

groups (ketone or aldehyde), *> , -G¾, -OH, -O or -O ^' D;

R ⁴ , R' each independently represents H, D, -QCi¾,







a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6,

c and d are each independently H, D, -OH, -OD, Q-Q-alkyl, - Hj or -COCH3; n is independently 1 , 2, 3, 4 or 5

[0012] Accordingly, in certain embodiments, the present invention also relates to the compounds and compositions of formula II or pharmaceutically acceptable salts thereof,

Formula Π

Wherein.

R independently represents H, D, CD;? , null or C¾;

R ² independently represents H, D, -OCH _¾ -C¾, -CD$,

R' , R" each independently represents H, D, -OCH _¾ . -OCD;?, carbon l functional

:0

groups (ketone or aldehyde). -€H ₃ , -OH, ~0 or -OD;

R ⁴ , R each independently represents H, D, -OCH ₃ , -OCD ₃ .

10

11

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

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

n is independently 1 , 2, 3, 4 or 5.

1001.3} in the illustrative embodiments, examples of compounds of formula ! are as set forth below:

M - l >

j001 | In the iiiustrative embodiments, examples of compounds of formula Π are as set forth below;

(2-1)

{0015| Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of chronic pain or its related complications.

[001.6] The application also discloses a pharmaceutical composition comprising a pharmaceutically accepiable 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.

[001.7] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of chronic pain or its related complications.

[001.8] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from chronic pain or its related complications manifested from metabolic conditions, chronic diseases or disorders; Hepatology, Cancer, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Neurological or Ocular complications. DETAILED DESCRIPTION OF THE INVENTION

Definitions

(001 J 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.

{002 1 The compounds of the present invention can foe present in the form of pharmaceutically acceptabie saits. The compounds of the present invention can also be present in the form of pharmaceutically acceptabie esters (i.e., the meihyi and ethyi esters of the acids of formula I and formula II. to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i.e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula 1 and formula I! (hydration). f 021 Compounds thai 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 axe termed "isomers." Isomers that differ in the anangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiorners. Stereoisomers bearing one or more asymmetric centers that are nors- 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 enant omers is possible. An enantioraer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the - and S-sequencing rales 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 enantioraer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture" . |0022| 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.

[0023] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0024] The phrases "parenteral administration" and "administered parenteralSy" as used herein refer to modes of administration other than enteral and topi cal administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, tntrapericardiai, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, in.raden.nal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemai injection and infusion.

[00251 ^'" '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.

[0026] 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.

[0027] 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 transport g any subject composition, from one organ, or porti n of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutical !y acceptable carrier 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, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyi oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; 06) pyrogen-free water; (17) isotonic saline; (I S) Ringer's solution; (19) ethyl alcohol; (20) phosphaie bufler solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations 0028] 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 . j 0029 J The term "prophylactic or therapeutic" treatment is art-recognized and includes administratio to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i .e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). 100301 The term "predicting" as used herein refers to assessing the probability related diseases patieni will suffer from abnormalities or compiication and/or terminal platelet aggregation or failure and/οτ 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.

1003]} 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., causina regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the neuroiogicai condition such as acute pain (such as post-operative pain), palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis, non-malignant chronic pain, chemotherapy induced pain, pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder 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. 100321 The phrase "therapeutically effective amount" is an ait-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 admini stered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art ma empirically determine the effective amount of a particular composition without necessitating undue experi mentation.

[0033] 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, inactivaiion. 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.

{0034J 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 di sease or condition.

[0035] 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 (Croax) and the area under the plasma concentration-time curve from time 0 to infinity may be used,

|0036| 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 character stics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may 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.

|0O37] 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 materia! 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 admi istration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes. 0038] 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 reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary of sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being admini stered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

10039 J The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.

10040) This application also discloses a pharmaceutical composition comprisin a pharmaceutically acceptable carrier and the composition of a compound of Formula .1 and formula II may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formul ted 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..

10G41| In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1 and Formula If) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula Ϊ and formula If or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I and formula II or its pharmaceutical acceptabie 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 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. {0042J Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula 1 and formula 11 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. 0043] The concentration and/or amount of any compound of formula I and formula 11 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 microdiaiysis, as reviewed by T. E. Robinso et al., 1991 , microdiaiysis in the neurosciences. Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdiaiysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula J and formula 0 such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dia!ysate 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.

|0044] In certain embodiments, the dosage of the subject compounds of formula I and formula II 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.

{0045| Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas .1 or fonnula 11 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 Ϊ may be administered at a dose o 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 rag/kg/day, or 40 mg/kg day. Compounds of Formula I and formula 11 may also be administered to a human patient at a. dose of, for example, between 0.1 mg and 1000 nig, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. in certain embodiments, the com positions 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 and formula 11 required, for th same therapeutic benefit.

[0046) An effective amount of the compounds of formula 1 and formula II described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

[0047) 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 de yeSi ation and/or elevated reactiv oxidative- nitrosative species and/or abnormalities in neurotransmitter homeostasis' s, in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic {prevention) administration as appropriate. The amount and timing of compositions 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. {0048 J 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 oraliy, topically, parenteral ty, 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 daig delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.

[0049) 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 pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex: silicates, together with 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 tabietting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the 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, eihanol. propylene glycol, glycerin and combinations thereof. The compounds of formula 1 and formula 11 may also comprise enterically coated comprising of various exeipients, as is well known in the pharmaceutical art.

10050} For parenteral administration, solutions of the compositions may he prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration, in this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

[0051 J The formulations, for instance tablets., may contain e.g. 10 to 100. 50 to 2 SO, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, S00 mg of the compounds of formula 1 and formula 11 disclosed herein, for instance, compounds of formula ί and formula H or pharmaceutical acceptable salts of a compounds of Formula I

[0052] Generally, a composition as described herein may be administered orally, or parenteral I y (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder thai 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 tabl ets or lozenges formulated in a conventional manner,

[0053] 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. |0054| illustratively, dosage levels of the administered active ingredients are; intravenous, 0.1 to about 200 mg kg; intramuscul r, 1 to about 500 mg/kg; orally, 5 to about 1000 mg kg; intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 mg/kg of host body weight.

{0055J Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasal I y, pharyngolaryngeally, bronchi ally, intravaginally, rectally, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% vv/v.

{005 j 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.

[0057] 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, polyaikyiene glycols, thermoplastic polyaikyiene 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 carboxym eth l cellulose, cross-linked hydroxypropylcellu!ose, hydroxy-propyl cellulose (HPC), hydroxypropylraethylcellulose (HPMC), hydroxyisopropyleelSulose, hydroxybutylceliulose. hydroxyphenylcellulose, hydroxy ethyl cellulose (HEC), by droxy penty I ceil ulose, hydroxypropy J ethyl ceil dose, hydroxypropylbutylcell lose, and hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable polyaikyiene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyaikyiene oxides include, but are not limited to, poly (ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacryiatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic- acid homopolymers and copolymers such as those commercially available from Noveon Chemicais under the tradename CARBOPOL ^I¾f . 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, gelian gum, maltodextrin, gaiactomannan, pusstulan, laminarm, sclerogiueam gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglam methylart, chitirt, cyclodextrin, chitosan, and mixtures thereof. Examples of suitabie clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium tri silicate; 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 thereo Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrol idane, cross-linked agar, and cross-linked carboxymethylcelluiose sodium, and mixtures thereof.

JOOSSj The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitabie excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glsdants, release-modifying excipients, superdismtegrants, antioxidants, and mixtures thereof,

{005 J Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrol i done and hydroxypropyimethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcelluiose, tara, gum arabic, tragacanth, pectin, xanthan, gelian, gelatin, maltodextrin, gaiactomannan, pusstulan, laminarm, scieroglucaR, inulin, whelan, rhamsan, zooglan, methyl an, chitin, cyclodextrin, chitosan, polyvinyl, pyrrolidine, cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, rnicrocrystaiiine cellulose, and mixtures thereof.

{0060] 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 glidams include, but are not limited to, colloidal silicon dioxide. Suitable release-modi ying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof. 0061] Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water- insoluble polymers include, but are not limited to, efhyleellulose, polyvinyl alcohols, polyvinyl acetate, pol ycaprol actones, cellulose acetate and its derivatives, acryiates, methacrylates, acrylic acid copolymers, copolymers thereof and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated 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, glyceryl palmitostearate, glyceryl monostearate, glyceryl tri stearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyl choline, phosphatidyl serene, phosphotidyl enositol, pliosphoiidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, rnicrocrystaiiine wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super dismtegrants include, but are not limited to, crascarmellose 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 dkintegrant.

|0062] Examples of antioxidants include, bin are not limited to, tocopherols, ascorbic acid, sodium pyrosuifite, butyl.hydroxytoh.iene, butylated hydroxy ani sole, edetie acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.

{0063 j 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.a., from about 250 microns to about 1000 microns. In embodiment, the immediate release coaling is typically compressed at a density of more than about 0.9 g cc, as measured b the weight and volume of that specific layer.

[0064J In one embodiment, the immediate release coating contains a first portion and a second porti on, wherein at least one of the porti ons 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,

{0065} 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 contai ned in the tablet core.

{0066) In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.

|0067| 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 i 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.

[0068] 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 quantit of the active agent with con entional 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).

{0069] Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remingto The Science and Practice of

Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion sy stem typically consists of one of two types of devices, reservoir and matrix, which are we!iknown and described in die art. The matrix devices are generally prepared by compressing the dasg with a slowly dissolving polymer carrier into a tablet form,

[0070] 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. |007l] 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 ca be prepared, for example, by coati ng a drug or a drug-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.

[0072) 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.

{0073 J Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximatel 5 hours to .12 hours, following administration.

[0074] Another dosage form contains a compressed tablet or a. capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose. The deiayed 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.

[0075] 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 solutions, may be prepared.

[0076] Methods of preparing various pharmaceutical compositions with certain amount of one or more compounds of formula ί and formula Π 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., 1 th Edition ( 1995).

[0077] In addition, in certain embodiments, subject compositions of the present application maybe lyopbilized or subjected to another appropriate drying technique such as spray drying. The subject compositions may be admi istered 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.

|007S] Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual ), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration. j0079j 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.

[0080) The compounds of formula ί and formula 11 described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/ , of medicament relative to the total weight of the formulation.

[0081 j 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 pharmaceiiticali 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, carboxyraethylcelluiose, alginates, gelatin, polyvinyl pyrroiidone, 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 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 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 he 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. {0082 J Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, niicroemulsions, 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, isopropyi alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofmyl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0083] Suspensions, in addition; to the subject compositions, may contain suspending agents such as, for example, ethoxyiaied isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, macrocrystalline cellulose., aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof. fOO j Formulations for rectal or vaginal administration may be presented as a suppository, which ma 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.

{0085J 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 propellents that may be required. For transdermal administration, the complexes ma include lipophilic and hydrophilic groups to achieve the desired water solubilit and transport properties.

|0086] The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, e cipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poiyarnide powder, or mixtures of such substances. Sprays may additionally contain customar propeJlants, such as ch!orofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0087] 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.

[0088] ^' in another embodiment, a transdermal patch may comprise, a substrate sheet comprising a composite film formed of a resin composition comprising 300 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 styreiie-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer, A method for the manufacture of the above-mentioned substrate sheet compri es preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkylene terephthalate film on one side of the composite film by means of an adhesive layer iherebv forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene terephthalate film.

(0089| Another type of patch comprises incorporating the ding directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The daig should be present at a concentration which wiil not affect the adhesive properties, and at the same time deliver the required clinical dose.

[0090J Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large io be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for iarge-molecule drugs.

|0G9I| Iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an ioiitophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.

|00 2| In some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositi ns such as 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,

10093} 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.

[0094J Methods and compositions tor the treatment of chronic pain. Among other things, herein is provided a method of treating chronic pain, comprising administering to a patient in need thereof a therapeuticall effective amount of compound of Formula 1:

Formula. I

Wherein,

R independently represents H, D, CD < or C¾;

R ³ independently represents H, Ό, -OC¾, -CH _¾ ,

R' , R" each independent! represents H, D, -OCH _¾ . -OCD _:! , carbon l functional groups (ketone or aldehyde), ^ , -Cl , -OH, ~0 or -OD;

R ⁴ , R each independently represents H, D, -OCH ₃ ,





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 _T -OH, ~OD, C Q-alky1, ~NH ₂ or ~COC¾; n is independently 1 , 2, 3, 4 or 5. j0095| Methods and compositions for the treatment of chronic pain. Among other things, herein is provided a method of treating chronic pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula II:

Formula 11

Wherein,

R ¹ independently represents H, D, CDj , null or Q¾;

R ² independently represents H, D, -OCHk, -CH _& -CD¾,

each independently represents H, D, -OQ¾, -OCD ₃ , carbonyl functional groups {ketone or aldehyde), , -€¾, -OH, -O or -OD;

R ⁴ , R' each independently represents H, D, -OCH¾, -OCD¾, 42

43

44

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6,

c and d are each independently H, D, -OH, -OD, Ci-Cs-alky!, -NHj or -COCHb;

n is independently 1, 2, 3, 4 or 5.

Methods for using compounds of formula I and formula 11:

{00961 The invention also includes methods for treating acute pain (such as postoperative pain), palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer, and degenerative conditions such as rheumatoid arthritis, non- malignant chronic pain, chemotherapy induced pain, pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.

METHODS OF MAKING

|0097J Examples of synthetic pathways useful for making compounds of formula I and formula .11 are set forth in example below and generalized in scheme 1 and scheme 2: Scheme I :

1-chloroethyl

j 09S| Step- i : Synthesis of compound 3:

1 2

|0099| A mixture of compound 1 (13.16 g, 44 m mol ), benzyl bromide 2 (9.2 g) and potassium bicarbonate ( 17.6 g) in toluene (200 ml) was heated to reflux for 4 hours, then cooled and filtered. The ft i ir ate was extracted with diiute acetic acid. Immediately, the extract was basified with ammonium hydiOxide to collect compouod 3 (yield: 16.19 95%).

{OOlOOj Step-2: Synthesis of compound 4:

3 4 fOOlOl ) A solution of compound 3 ( 1.1 62 g, 30 mmol), 1-chioroethyi chloroformate (5.52 g _s 37.8 mmol) and proton sponge (1 .1 g) in methylene chloride (80 nil ) was heated at reflux for 2 hours. The reaction mixture was evaporated in vacuo to dryness to obtain a residue. The residue was dissolved in methanol (50 nil), heated to reflux for 30 minutes, basified with ammonium hydroxide., and then evaporated to dryness to obtain compound 4 which was used for next step directly.

J00102J Step-3 : Synthesis of compound 6.

4 β 00103) To the compound 4 was added (chloromethyl)-cycJopropane 5 (5.14 g, 55.6 m o\), sodium carbonate (14.7 g, 139 mmol ), and potassium iodide (4.6 g, 28 mmol) in ethanol (250 ml) and heating was done at reflux for 20 hours. The mixture was cooled and evaporated in vacuo to dryness. The residue was chromatographed on silica gei with an elating solvent system of methanol/ethyl acetate ( 10/90 v/v) to yield compound 6 (10.93 g; 85% yield).

|00104| Step-4: Synthesis of compound 7:

5 ti

[00105] A mixture of compound 6 (1.0 g, 23 mmoi), formi c acid (90%, 60 ml), D.I. water (3 ml), methanol ( 10 nil) and hydrogen peroxide (31%, 3.3 ml) was stirred and heated at 40-50°C for 5 hours. The mixture was allowed to cool then 5% Pd/C (0.5 g) was added, and the mixture was hydrogenated under 25-inch-H.g for 8 hours. The catalyst was filtered off. The residue was evaporated in vacuo. It was dried at 90°C under 25 inch-Hg of vacuum for 4 hours to yield compound 7 (6.8g; 86% yield).

[00106] Step-5: Synthesis of compound 9:

j ^' 00107} Stirring a mixture of a solution of compound 7 ( 18.0 mmol; 1.0 eq) and Lipoic acid 8 ( 1 8 0 mmol; 1 .0 eq) in Dichloromethane (DCM) (200 mL; LR grade); l -ethyl-3- (3'~dimethylaminopropyl)carbodiimtde.HCl (EDCI.HCl) (527.0 mmol; 1.5 eq) and 4- Dimethyiaminopyridine(D AP) (.18.0 mmol, 1 .0 eq) at room temperature (RT) for 24 hours. Reaction was monitored by TLC. On completion of the reaction, the reaciion mixture was diluted with DCM (200 mL), washed with water (2x300 mL) followed by brine solution (300 mL) and dried over anhydrous Ν¾?80,( 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 obtain the final compound 9. Mol . Wt: 529.20 ; Elemental Analysis: C, 63.49; H, 6.66; , 2,64; 0, 15.10; S, 12.11.

Scheme 2:

00108J Step-1 : Sy nthesi s of compound 2

5 h

{00109} A mixture of compound 1 (10 g, 23 nm oi), fonnic acid (90%, 60 ml), D.I. water (3 ml), methanol (10 ml) and hydrogen peroxide (31%, 3.3 ml) was stirred and heated at 4G-5Q°C for 5 hours. The mixture was allowed to cool, then 5% Pd/C (0.5 g) was added, and the mixture was hydrogenated under 25-inch-Hg for 8 hours. The catalyst was filtered off. The residue was evaporated in vacuo to dryness to give a casde product, which is re-oystallized from acetone/water to give a white crystalline solid. t was dried at 90°€ under 25 inch-Hg of vacuum for 4 hours to yield compound 2 (86% yield). jOOOOj Step-2: Synthesis of compound 4:

OOlill Stirring a mixture of a solution of compound 2 (18.0 mmoi; 1.0 eq) and Lipoie acid 3 (IS O mmoi; 1.0 eq) in Dichlorornethane (DCM) (200 mL; LR grade); l-ethyl-3- (3'-dimethylarainopropyl)carbodnmide.HCl (EDCI.HG) (527.0 mmoi; 1.5 eq) and 4- Dimethy)aminopyridine(DMAP) (18.0 mmoi; 1.0 eq) at room temperature ( .T) 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 brine solution (300 mL) and dried over anhydrous a ₃ S0 ₄ and evaporated under reduced pressure. The crude was purified b column chromatography over 100-200 mesh silica gel by using ethyl acetate-pet ether to yield the final compound 4· Mol. Wf : 489.16; Elemental Analysis: C, 61.32; H, 6.38; N, 2.86; (X 16.34; S, 13.10.

100112} 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 centri ugation or cell sorting. Preferably, ceil-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.

EQUIVALENTS 001131 present disclosure provides among other things compositions and methods for treating chronic 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

{ ^' 001. J 4} 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.