JP2015527309A - Compositions and methods for the treatment of moderate to severe pain - Google Patents

Abstract

The present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates. A pharmaceutical composition comprising an effective amount of a compound of formula I. Methods for treatment or prevention of moderate to severe pain can be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral, syrup, or injection . Such compositions can be used to treat muscle pain, spasticity, neuropathic pain, fibromyalgia, postoperative pain, muscle spasticity, headache, chronic pain, subchronic pain and local pain. [Selection figure] None

Description

This application is filed on International Application No. PCT / IB2013 / 055146 filed June 23, 2013 (invention title “Compositions and Methods for the Treatment of Moderate to Severe Pain”, International Publication No. WO / 2014/006529). This international application further claims the priority of Indian Patent Application No. 2682 / CHE / 2012 filed on July 3, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

The present disclosure relates generally to compounds and compositions for the treatment of moderate to severe pain. In particular, the present invention relates to treating a subject with a pharmaceutically acceptable dose of a compound, crystal, enantiomer, stereoisomer, ester, salt, hydrate, prodrug, or mixture thereof.

Pain is a subjective experience that is influenced by physical, psychological, social, and mental factors. All the concepts of total pain recognize the importance of these dimensions, and their superior pain relief is rare without paying attention to each aspect. Diseases such as pain and cancer are not synonymous. At least two-thirds of patients experience pain at some time during their course of illness and need the most powerful analgesics.

From moderate to severe pain also damage, inflammation associated with seasonal allergies, eye pain, itching burning, bipolar disorder, brain, spinal cord, peripheral nerves etc. have many different etiologies A heterogeneous group of diseases. Many are inherited; secondary to several toxic and metabolic processes. Free radicals are highly reactive molecules or species exist independently. High-generation reactive oxygen species (ROS) are essential functions of normal cellular functions such as mitochondrial respiratory chain, phagocytic ability and arachidonic acid metabolism. Oxygen free radical release has also been reported during the recovery phase from many pathological noxious stimuli to brain tissue. In addition to several pain-related neurological disorders, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia Diabetic neuropathy, cancer pain, fibromyalgia and low back pain.

Frequent acute phase management addresses depend on the underlying pathology and symptom of the disease. There is a current need for art of new compositions to treat moderate and severe pain.

The present invention provides compounds and compositions comprising these same compounds and methods for use in therapy, prevention and / or ameliorating the effects of conditions such as moderate to severe pain.

The present invention provides herein a composition comprising Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer or stereoisomer. The present invention also provides a pharmaceutical composition comprising Formula I or an intermediate thereof and one or more compounds of one or more pharmaceutically acceptable carriers, vehicles or diluents. These compositions can be used for moderate treatment of severe pain and associated complications.
Formula I

In certain embodiments, the present invention relates to I and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomers of compounds of formula I and compositions.
Formula I

here,
R1 represents H, D, -OCH3, -OCD3
Or
R2 represents
Or
R1 represents H, D, —OCH3, —OCD3, a independently 2, 3 or 7;
Each b is independently 3, 5 or 6;
e is independently 1, 2, 6;
c and d are each independently

In an exemplary embodiment, as an example of a compound of formula:

The present application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit can include instructions for use in the treatment of moderate to severe pain and related complications.

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

Here, the application further provides a kit comprising a pharmaceutical composition as described herein. The kit may further comprise instructions for use in the treatment of severe pain or its associated complications.

It has several uses for the compositions described herein. The present application provides, for example, a method of treating a patient who is moderately suffering from severe pain or related complications arising from a metabolic condition, severe disease or disorder. Hepatology, cancer, blood, orthopedics, cardiovascular, kidney, skin, neurological or ocular complications.

Definitions As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

The compounds of the present invention can exist in the form of pharmaceutically acceptable salts. The compounds of the invention can also be hydrated, solvated, for example (for example, methyl and ethyl esters of the acids of formula I are used as prodrugs). Solvation can be affected in the course of the manufacturing process, or can be carried out as an example of the hygroscopic nature of the anhydrous compound initially of formula I (hydration).
Illustrative embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings and the like, which refer to like elements.

“Isomers” are compounds that have the same molecular formula but differ in the nature or arrangement of their spatial arrangement, called the bond or of their atoms. 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 that are not enantiomers. Stereoisomers with one or more asymmetric centers that are non-superimposable mirror images of each other when they are called “enantiomers” are compounds that have, for example, an asymmetric center, with four different groups of carbon atoms When attached, a pair of enantiomers is possible. Enantiomers can be characterized by their asymmetric centers or the absolute configuration of the centers, r and dextrorotatory by the manner in which the molecules described by the Cahn, Ingold and Prelog R- and S-sequence rules rotate the plane of polarized light. Or levorotatory (for example, (+) or (-)-isomers, respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing an equal proportion of enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic state” refers to an inborn error of metabolism, which is a genetic disease caused by (genetic metabolic conditions or) one or more metabolic pathway defects; Is affected, either missing or completely present

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

The phrases “parenteral administration” and “parenteral administration” with reference to modes of administration other than enteral and topical administration as used herein, as such injections and limited intravenous, intramuscular, intrathoracic Intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal and sternum Included and infusion without intra-injection.

By “patient”, “subject” or “host” human or non-human animals such as primates, mammals and vertebrates is treated by the methods of the invention.

The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term refers to compositions, polymers and other materials suitable for use in contact with mammalian, human and animal tissues, and / or appropriate medical, without undue toxicity, irritation. Allergic reactions or other problems or complications commensurate with a reasonable benefit / risk ratio including dosage form within the scope of the judgment.

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, a material, composition or pharmaceutically acceptable vehicle, such as another organ or part of the body or As a liquid or solid filler, diluent, solvent or encapsulating material involved in transporting any object from one organ, or body part. Each carrier must be “acceptable” in the sense of being harmful to the patient and compatible with other ingredients of the subject composition. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that may be useful are as pharmaceutically acceptable carriers: (1) sugars such as lactose, glucose and sucrose; (2) corn starch and potato starch; (3) cellulose and sodium carboxymethylcellulose Derivatives of ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt. (6) gelatin; talc; (8) cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; for example, propylene glycol (10) glycol; glycerin (11) polyols such as 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 hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphorus

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

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to one or more hosts of a subject composition. If it was previously administered to a clinical condition of an undesirable condition (eg, host animal disease or other undesirable condition), subsequent treatment protects the host against the development of an unwanted condition, ie, prevention If administered after the onset of an undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize its existing undesirable condition or side effects. )

As used herein, the term “predict” means to assess the probability, and patients suffering from such abnormalities or complications and / or terminal platelet aggregation or disorders and / or death are associated with severe pain A moderate neurodegenerative condition or disorder (ie, mortality within a future defined time window (predictive window)). Mortality can be caused by the central nervous system or complications. The prediction window is the interval during which the subject is developing one or more of the complications according to the predicted probability. The prediction window can be the total remaining life of the subject at the time of analysis by the method of the present invention.

The term “treat” is art-recognized and susceptible to a disease, but a disorder and / or symptom, including preventing a disease, disorder or condition from occurring in an animal, is still diagnosed as having it It has not been. Preventing its progression, such as inhibiting a disease, disorder or condition. And causing regression of the disease, disorder, and / or condition, eg, alleviating the disease, disorder, or condition. Even if the underlying pathophysiology is unaffected, including treating the disease or ameliorating at least one symptom of a particular disease or condition, such agents do not treat the cause of the condition Nevertheless, administration of a drug can treat a neurological condition such as moderate to severe pain in a subject. The terms “treat”, “treat” or “treatment” include sclerosing agents as used herein, including prophylaxis or palliative treatment (eg, prevention).

The phrase “therapeutically effective amount” is a term recognized in the art. In certain embodiments, the term refers to the amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit / risk ratio applicable to any medical treatment. In certain embodiments, the term refers to an amount necessary or sufficient to eliminate or alleviate medical symptoms for a period of time. The effective amount can vary depending on factors such as the disease or condition being treated, he will be administered a particular target construct, the size of the subject, or the severity of the disease or condition. One skilled in the art can empirically determine the effective amount of a particular composition without necessitating undue experimentation.

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

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

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

The term “sustained release” when used with respect to pharmaceutical compositions or other substances is art-recognized. For example, a subject composition that releases a substance over time that can exhibit sustained release characteristics as opposed to a bolus-type administration in which the entire amount of the substance is made bioavailable at once. For example, in certain embodiments, one or acceptable excipients, such as fluids such as bodily blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc., with simultaneous release (such as by hydrolysis) are slowly Or any pharmaceutically contact (compared to bolus release) that can undergo delayed degradation can be sustained or extended over time, eg, therapeutic and / or biological Incorporated an active salt and / or composition. This release may result in sustained delivery of a therapeutically effective amount of any of the therapeutic agents disclosed herein.

The terms “peripheral administration”, “systemic administration”, “systemic administration”, “peripheral administration” are art-recognized and are intended to treat a subject composition, therapeutic agent or others at a remote site since the disease is treated Administration of these substances. Administration of the drug for the disease is by subcutaneous administration, for example, not directly to the central nervous system, but may be referred to as “local” or “local” or “local” administration. It is subject to metabolism and other similar processes, so that even if you are receiving other treatments, it will thus enter the patient's system and become.

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

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

The application also discloses that pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a composition of a compound of Formula 1 can be formulated for systemic or topical or oral administration. The pharmaceutical composition can be formulated for oral administration, oral solution, injection, subcutaneous administration, or transdermal administration. The pharmaceutical composition can include at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

In many embodiments, a pharmaceutical composition described herein is in an amount sufficient to deliver a therapeutically effective amount of a compound of Formula 1 or a composition thereof to a patient as part of a prophylactic or therapeutic treatment. Will. The desired concentration of one of the formulas or a pharmaceutically acceptable salt thereof will depend on absorption, inactivation and excretion rates, of the drug and the rate of delivery of the salt and composition from the subject's composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. In addition, for any particular subject, it should be understood that the particular dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. Typically, dosing is determined using techniques known to those skilled in the art.

Also, optimal concentrations and / or amounts, or the amount of any particular compound of Formula 1, can be adjusted to accommodate variations in treatment parameters. Such therapeutic parameters include, for example, the formulation placed, clinical use, treatment site, patient type, eg, human or non-human, adult or child, and the nature of the disease or condition.

The concentration and / or amount of any compound of the formula is identified by routine screening in animals, eg, rats, by screening a range of amounts of the substance of interest using easy concentrations and / or appropriate assays. can do. Known methods are also available for assaying local tissue concentrations, salt or composition diffusion rates, and local blood flow after administration of the therapeutic formulations previously disclosed herein. One method such as reviewed by TE Robinson et al., 1991, Neuroscience, Techniques, Microdialysis, Volume 7, Chapter 1, is microdialysis. The method studied by Robinson can be easily applied as follows. Microdialysis loop, microdialysis loop is placed in place in the test animal. Dialysate is pumped by the loop. If a compound that is adjacent to the loop and has Formula 1 like the one shown here is injected, it will be collected in dialysate proportional to their local tissue concentration that has released the drug. The progression of salt or composition diffusion may be determined for that with an appropriate calibration procedure using known concentrations of salts or composition.

In certain embodiments, the dosage of the subject compound of Formula 1 provided herein may be determined by reference to the composition of treatment or the plasma concentration of other encapsulated material. For example, the maximum plasma concentration (Cmax) and its area under the plasma concentration time curve from time 0 to infinity may be used.

In general, in practicing the methods detailed in this application, an effective dosage of a compound of Formula I is about 0 per day, eg, about 0.01, in about 100 milligrams / kilogram / dose or divided doses. Approximately 50 milligrams / kilogram / day / kilogram / day with a single or divided dose of milligrams ranging from 0.01 milligram / kilogram / day. For example, a compound of the formula that can be administered at a dose of less than 0.2 / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 / kg / day 10 mg / kg / day, 20 mg / kg / day, 30 mg / kg, or 40 mg / kg / day. The compound of formula I may also be 100 less than 5 milligrams and less than 80 milligrams, or between 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 0.1 and 1000 milligrams. In between, for example, 300, 400, 500, 800, 1000, 2000, 5000 milligrams per day can be administered to a human patient. In certain embodiments, the composition herein is in an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound. Formula I administered is necessary for the same therapeutic benefit.

Formula I refers to one amount of the same salt or composition that inhibits the effective amount of the compounds listed here or prevents disease. For example moderate to severe pain or other medical conditions.

Effective amounts can be banned, treated, mitigated, ameliorated, stopped, inhibited, slowed, reversed, or nerve damage (such as high reactive oxidation). Species) may be sufficient among patients at risk of such a complex to reduce the severity of complex and / or physiological homeostasis abnormalities resulting from demyelination. Thus, these methods include both medical therapeutic (acute) and / or prophylactic (preventive) administration, as appropriate. The amount is, of course, treated with the severity of the pain, depending on the timing of the composition administered to the subject, the mode of administration and the judgment of the prescribing physician. Therefore, because of patient-to-patient variability, the above dosages are also doctors and titrations for drug dosages to achieve treatment that the physician or doctor considers appropriate for the patient. In view of the desired degree of treatment, the physician must balance the age of the patient, the presence of an existing disease, as well as the presence of other diseases, in a variety of factors.

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

The composition can be administered in either a single dose or multiple doses, alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. If desired, these pharmaceutical compositions can include additional ingredients such as, for example, perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate, for example with starch, alginic acid and the like, together with binders as follows: Polyvinyl pyrrolidone, sucrose, gelatin and acacia that can be used with various disintegrants such as some complex silicates. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules. Suitable materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, agents, emulsifiers or suspensions, where necessary the active ingredient may be various sweeteners or flavors, along with diluents such as water, ethanol, propylene, etc. It may be combined with an agent, coloring substance or pigment, and includes glycol, glycerin and combinations thereof. As is well known in the pharmaceutical art, the compounds of formula I can also include enteric coated claims of various excipients.

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

The formulation can be, for example, a tablet, for example, 10 to 100, 50 to 150 mg of 500, 250, or 350 to 800 mg of Example 10, 50, 100, 300, 500, 700 is formula 1 800 mg of a compound of formula 1 is disclosed herein, for example a compound of formula I or a pharmaceutically acceptable salt

    In general, the compositions described herein may be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration is indicated, for example, for patients suffering from gastrointestinal disorders as determined by the attending physician when oral administration is prevented or when the drug is applied to the surface of the best tissue or organ. May be. Where higher doses are desired for the target tissue or organ, localized administration may also be indicated, for example. Compositions active for buccal administration can take the form of tablets or lozenges formulated in a conventional manner.

Dosages that depend on the identity of the metabolic disease involved, including host type, its age, health and weight. The type of concurrent treatment, if any, and frequency of treatment and treatment ratio.

Illustratively, the dose levels of active ingredient administered are as follows: 0.1 to about 200 milligrams / kilogram intravenous. Intramuscular about 500 milligrams / kilogram 1. Orally, 5 at about 1000 milligrams / kg. Intranasal instillation, from 5 to about 1000 milligrams / kilogram. Aerosol, 5 to about 1000 milligrams / kilogram host weight.

Expressed in terms of concentration, minutes can be present in the compositions of the present invention for use in localized about the dermis, intranasally, phalyngogenicly, bronchial, vagina, rectum, or about 0.01-w / Effective composition of w, at a concentration of about 50% by weight of the composition. Preferably from about 1 to about 20% by weight of the composition / weight. Up to about 50%, w v of a parenteral composition at a concentration from about 0.05, preferably from about 5 to about 20% by weight / volume / volume.

The compositions of the present invention are preferably as, for example, tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile parenteral solutions of suspensions, and oral Solutions or suspensions containing appropriate amounts of the active ingredients indicated for administration to humans and animals in such unit dosage forms. It can be prepared for a solid or liquid unit dosage form for oral administration.

Suitable hydrophilic polymers include, but are not limited to, water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, swelling of gelled cross-linked polymers, and mixtures thereof. . Examples of suitable water-swellable cellulose derivatives include sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), droxyisopropylcellulose, hydroxybutylcellulose, hydroxyisopropylcellulose, hydroxyethylcellulose (HEC), including, but not limited to, hydroxyisopropylcellulose, hydroxypropylethylcellulose, hydroxyisopropylcellulose, and hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly (ethylene oxide). Examples of suitable acrylic polymers include potassium methylacrylate divinylbenzene copolymers, polymethyl methacrylate, high molecular weight cross-linked acrylic acid homopolymers and copolymers such as those commercially available from CARBOPOLTM Noveon Chemicals under such trade names. However, it is not limited to these. Examples of suitable hydrocolloids are limited to alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan Examples include laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, lambsan, zoolan, methyllan, chitin, cyclodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite. Magnesium trisilicate. Magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelled starches include, but are not limited to, starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof, and limited acid hydrolyzed starches. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar and cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

The carrier can include one or more suitable excipients for tablet formulation. Examples of suitable excipients include but are not limited to fillers, adsorbents, binders, disintegrants, lubricants, glidants, modified release these excipients, superdisintegrants, antioxidants, And mixtures thereof.

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

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

It is not limited to insoluble polymers and low melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof, It is not limited to these. Suitable low melting point hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Like hydrogenated vegetable oil. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, Glyceryl myristate, glyco-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl mild, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl mild, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. Its fat-containing chocolate-like mixtures, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In one embodiment, the tablet core comprises up to about 5% by weight of the super disintegrant.

It is not limited to insoluble polymers and low melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof, It is not limited to these. Suitable low melting point hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Like hydrogenated vegetable oil. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, Glyceryl myristate, glyco-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl mild, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl mild, phosphatidyl enositol, phosphoticic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, whale wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax. Its fat-containing chocolate-like mixtures, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In one embodiment, the tablet core comprises up to about 5% by weight of the super disintegrant.

In one embodiment, the immediate release coating has an average thickness of about 2500 microns, such as about 50 microns, at least 50 microns. For example, from about 1000 microns, about 250 microns. In embodiments as measured by weight and the volume of that particular layer, the immediate release coating is typically compressed to a density of more than about 0.9 grams / cc.

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

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

In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment, the outer coating portion is contained in a dry granule that includes a pharmaceutically active agent.

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

Immediate release agents contain a therapeutically effective amount of a plurality of conventional active agents in dosage unit units, ie, tablets, drug-containing beads, granules or particles, or the outer layer of a coated core dosage form. Pharmaceutical excipient. The immediate release dose unit may be uncoated or may be mixed or mixed with a delayed release dose unit or unit, such as in an encapsulated mixture of good or immediate release drug-containing granules, particles or beads Release drug containing granules or beads that may not be delayed).

As described in “Remington, The Science and Practice of Pharmacy”, 20th, extended release formulations are generally prepared, for example, as diffusion or osmotic systems. Ed. Lippincott Williams & Wilkins, Baltimore, Maryland, 2000). Diffusion systems are typically constructed from one of two types of devices, well known in the die technology art, reservoirs and matrices. Matrix devices are generally prepared by compressing a drug with a polymeric carrier that slowly dissolves in the form of a tablet.

The immediate release portion can be added to the sustained release system by either applying an immediate release layer over the sustained release core. Using a coating or compression process such as capsules containing such expanded and immediate release beads or in multiple unit systems.

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

Pulsed-release dosage forms mimic multiple dosing profiles without repeated administration, and typically there is at least a fold decrease in the frequency of administration compared to the drug presented as a conventional dosage form (solution or Conventional solid dosage forms that allow for rapid drug release). A pulsed release profile is characterized by a period of timeless release (lag time) or a reduced release followed by rapid drug release.

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

Other dosage forms include compressed tablets or capsules having a drug-containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads and granulates particles that release drug substantially after oral administration to provide an initial dose immediately. The delayed release dosage unit comprises a plurality of beads or granules coated with the drug for 3 hours up to 14 hours after oral administration to provide an approximately second dose.

For purposes of transdermal (eg, topical) administration, it can be prepared (usually at a concentration of about 0.1% to 5%), otherwise sterile aqueous or Dilute the partially aqueous solution.

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

Furthermore, in certain embodiments, the subject compositions of the present application were probably lyophilized or subjected to another suitable drying technique, such as spray drying. The subject composition may be administered once, or in a number of smaller doses administered by varying the time interval, depending in part on the rate of release of the composition and the desired dosage. It may be divided.

Formulations useful in the methods provided herein include oral, nasal, rectal, vaginal, aerosol and / or parenteral (including buccal and sublingual) topical administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of the composition of the invention that can be combined with a carrier material to produce a single dose that can vary depending on the subject is made therapeutic, and the particular mode of administration.

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

The compounds of formula I described herein can be administered by inhalation or aerosol formulation. Inhalants or aerosol formulations may include one or more agents as such adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is 0.005 to 90 percent of w / w, eg 0.005 to 5 percent of w / w, eg 0.005 to 90 percent, for comparison with the drug in the total weight of the formulation Or from 0.01 to 1.0 percent of w / w.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) the composition of the present invention may comprise one or more pharmaceutically acceptable carriers and / or any of the following: Mixed with heels. (1) Fillers or bulking agents such as, for example, starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) drugs such as paraffin; (6) Absorption enhancers such as quaternary ammonium compounds; (7) Wetting agents such as alcohol and glycerol monostearate, acetyl, (8) Absorbents such as kaolin and bentonite clay; (9) Lubricant, for example Luc, its calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. And (10) a colorant. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Similar types of solid compositions can also use lactose or lactose, fillers in soft and hard filled gelatin capsules, and high molecular weight polyethylene glycols and the like.

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

Suspensions, for example, add stearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth, and mixtures thereof in addition to the compositions of the present invention. Suspending agents such as chemicals may be included.

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

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

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

Methods for delivering a composition or composition via a transdermal patch are known in the art. Typical patches and methods of patch delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239, 180 and 6,103,275.

In another embodiment, the transdermal patch may include: 100 parts by weight of polyvinyl chloride-polyurethane composite and 2-10 with respect to the weight of styrene-ethylene-butylene-styrene copolymer. A first adhesive layer on one side of a composite film including a composite film formed of a resin composition containing parts by weight, and a polyalkylene attached to one side of the composite film via the first adhesive layer A primer layer containing a terephthalate film, a saturated polyester resin, a primer layer formed on the surface of the polyalkylene terephthalate film, and a second adhesive layer containing a styrene-diene-styrene block copolymer containing a pharmaceutical are laminated on the primer layer. . The base sheet manufacturing method is such that a resin composition is formed on a composite film by calendering to prepare the resin composition, and then a polyalkylene terephthalate film is bonded to one side of the composite film using an adhesive. Thereby forming a base material sheet and forming a primer layer containing a saturated polyester resin on the outer surface of the polyalkylene terephthalate film.

Another type of patch is, for example, a polyester backing membrane that incorporates the drug directly into a pharmaceutically acceptable adhesive and laminates the drug-containing adhesive on a suitable backing member. The drug should be present at a concentration that will not affect adhesion and at the same time deliver the required clinical dose.

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

Iontophoresis is a technique used to improve the flux of substances ionized through a membrane by the application of an electric current. An example of iontophoresis, a membrane, is described in US patents. US Pat. No. 5,080,646 to Theeuwes. Iontophoresis is the primary mechanism by enhancing molecular transport across the skin (a) repels charged ions from the same charged electrode, (b) charged pores in response to an applied electric field Increases skin permeability through the convective movement of electroosmotic solvents that generate preferential passage of counter ions through or the application of current by (c).

In some cases it may be desirable to administer in the form of a kit and may include containers for containing separate compositions such as such divided bottles or divided foil packets. Typically, the kit includes instructions for administration of the separate components. The kit form is particularly advantageous when different components are preferably administered in different dosage forms (eg, oral and parenteral) where titration of the individual components of the combination is desired by the prescribing physician. Or when administered at intervals.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs consist of a sheet of relatively hard material covered with a foil of plastic material, which may generally be transparent. A depression is formed in the plastic foil during the process during packaging. The recesses must be packed in the size and shape of the tablet or capsule. The tablet or capsule is then placed in a recess and a sheet of relatively hard material is sealed against the plastic foil with the foil surface opposite to the direction in which the depression was formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments, the strength of the sheet is such that the tablet or capsule can be manually removed from the blister pack by applying pressure to a recess formed in the sheet where the opening is a recess. . The tablet or capsule can then be removed through the opening.

Methods and compositions for the treatment of moderate to severe pain. In particular, administering a therapeutically effective amount of a compound of formula I herein to a patient in need thereof provides a method of treating moderate to severe pain.
Formula I

here,
R1 represents H, D, -OCH3, -OCD3
Or
R2 represents
a is independently 2, 3 or 7;
Each b is independently 3, 5, or 6.
e is independently 1, 2, or 6;
c and d are each independently H, D, -OH, -OD, C1-C6 alkyl, -NH2, or -COCH3.
n is independently 1, 2, 3, 4 or 5.
A method of using a compound of formula I.
The present invention also includes a method for pain in the treatment of pain injury, including postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain Post-herpetic neuralgia, diabetic neuropathy, bipolar depression, depression, stress, cancer pain, fibromyalgia and any other medical conditions related to low back pain or severe pain.
Production method

Scheme-1

Step-1: Synthesis of Compound 2:

As shown in FIG. 2, 60 ml of glacial acetic acid 6 dichloroaniline 1 (76 grams, 0.047 mmol) was added dropwise to a mechanically stirred solution of acetyl chloride (36 ml, 0.5 mmol). After the addition is complete, the reaction mixture is heated at 90 ° C. for 20 minutes. The solution forms a white precipitate and is poured into ice water (500 milliliters). The solid is washed with water (91.8 grams, 96%, white solid 179-180 ° C, lit melting point glacial acetic acid to 180-181 ° C melting point), product 2 is dried and filtered.

Step 2: Synthesis of Compound 4:

Compound 2 was dissolved in 15 grams of bromo 150 3, 5 milliliters of 5 and half gram of calcined potassium carbonate and 0.5 grams of copper powder, and the added mixture was removed by a water separator to form a water-cooled 4 days At reflux, the residue subjected to steam distillation is extracted with 200 ml of ether, the ether solution is filtered through Hyflo and the residue is concentrated to dryness under 11 torr. The residue is dissolved in 60 ml of ethanolic potassium hydroxide and the solution is refluxed for 3 hours. The solution is then concentrated to dryness at 40 under 11 Torr. 10 milliliters of water is then added to the residue extracted with 100 milliliters of ether. The ether solution was removed and extracted with 20 milliliters of water. The ether solution is dried over sodium sulfate and concentrated to dryness under 11 torr. The residue was obtained as a yellow oil at 115 I / O C / 0.01 Torr and distilled under high vacuum.

Step-3: Synthesis of Compound 6:

40 grams of freshly distilled chlorochloride 5 grams of compound 4 was refluxed for 1 hour. The dark solution was evaporated at 11 Torr at 50 OC bath temperature. The residue is dissolved in ether, 70 ml / ethyl acetate, 1: 1 This solution is dried over 10 ml of 2N potassium bicarbonate solution, water, sodium sulfate, evaporated under 11 torr and extracted with 10 ml did. Compound 6 was recrystallized from methanol, MP 143 OC.

Step 4: Synthesis of Compound 7:

Compound 6 is thoroughly mixed with 4 grams of aluminum chloride, 4 grams and heated at 160 OC for 2 hours. The melt was cooled and poured over about 50 grams of ice while still warm. The separated oil was dissolved in 50 ml of chloroform. The chloroform solution was dried over water, sodium sulfate, concentrated under 11 Torr and washed with 10 ml. The residue was distilled. The resulting compound 7 was crystallized from methanol, MP 126 OC.

Step-5: Synthesis of Compound 8:

A 40 gram solution of compound 7 in 420 ml of 280 ml of ethanol in 1 N sodium hydroxide solution was refluxed for 2 hours. The clear solution was cooled and ethanol was distilled off at 11O Torr and 40 bath temperatures. The aqueous residue was extracted with 100 milliliters of ether. The ether was removed and the aqueous solution was cooled by adding about 50 grams of externally cooled ice from 5 ° C. 2N hydrochloric acid was added with stirring until the pH of the solution was about 6. The precipitated acid was taken up in 400 ml of ether, the ether solution was separated and the aqueous solution was extracted again with 200 ml of ether. The ether solution is dried over sodium sulfate, concentrated and combined under 11 torr without heating and washed with 50 milliliters of water. After compound 8 is crystallized into a concentrated ether solution and petroleum ether is added. After crystallization from ether / petroleum ether, re-melting at 156-158 OC.

Step-6: Synthesis of Compound 10:

Compound 8 (10 mmol) and SOCl 2 were refluxed for 2 hours to obtain 5 milliliters of acid chloride. Excess SOCl 2 was distilled off and the acid chloride was used directly. Compound 9 was 0 OC and the comment was suspended in additional DIPEA (12 mmol) DCM. The reaction mixture was stirred for 30 minutes and then acid chloride in DCM was added dropwise to the reaction mixture at 0 OC. The reaction mixture was stirred for 4 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with DCM and added water. The layers were separated and the organic layer was washed with saturated NaHCO 3 and then evaporated to give a residue. The residue was purified through a column to obtain the MF of compound 10: C22H23Cl2NO3S2. Mole. Weight: 483.05. Elemental analysis: C, 54.54; H, 4.79; Cl, 14.64. N, 2.89. , 9.91, O. S, 13.24.

Scheme 2:
Step 1: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid (2)

To 1-stirred solution (2,6-dichloro-phenyl) -1,3-dihydro-indol-2-one 1 (10 grams, 0.03 mmol) in toluene (340 milliliters) was added the aqueous solution. NaOH at room temperature (2N, 34 ml)). The resulting mixture was stirred at 90 ° C. for 16 hours. After completion, the clear solution was cooled in an ice bath and acidified by fraud. hydrochloric acid. The precipitated solid was washed with ethanol and dried under vacuum to obtain 9.0 grams (84.4% yield) of compound 2 as an off-white solid and filtered. Used in the next step without further purification. Mass: 294.1 (M-H). 1 H-NMR (400 MHz, DMSO): 12.70 (single, 1H), 7.53 to 7.51 (d, J = 8.0 Hz, 2H), 7.24 to 7.16. (M, 3H), 7.08 to 7.03 (M, 1H), 6.87-6.83 (m is 1H), 6.28 to 6.26 (d, J = 7.8 Hz) 1H), 3.69 (multiple possible, 2H). 13C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76 115.95, 37.74.

Step 2: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-tert-butoxycarbonylaminoethyl ester (4):

To the stirred solution was added [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid] 2 (4.0 grams, 0.01 mmol, 1 equiv) and N-BOC-ethanolamine in DCM (2 .39 grams, 0.01 mmol) (70 milliliters) of DMAP was added at room temperature (0.16 grams, 0.001 mmol). To this mixture was added DCC (5.5 grams, 0.02 mmol) in DCM (30 milliliters) and the resulting mixture was stirred dropwise at 0-5 ° C. for 1 hour at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in water (100 ml) and extracted with DCM (2 × 50 ml). The combined organic layers were dried over anhydrous Na 2 SO 4, washed with hexane (2 × 20 ml), and the resulting crude compound was evaporated under reduced pressure to yield compound 4 and cyclized compound 1 as an off-white solid. Dried to obtain 6.0 grams of crude. This mixture was used in the next step without further purification. Mass: 439.3 (M + H).

Step 3: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-aminoethyl ester (5)

[2- (2,6-Dichloro-phenylamino) -phenyl] -acetic acid DCM (50 ml), TFA was added and 2-tert-butoxycarbonylaminoethyl ester 4 (5.3 grams, 0.01 mmol) (Ml in a stirred solution of 5.3) at 0 ° C. The resulting mixture was stirred for 16 hours at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with aqueous sodium bicarbonate and extracted with DCM (2 x 50 ml). The combined organic layers were dried over any Na 2 SO 4 and evaporated under reduced pressure. To obtain the crude compound, 1.0 gram of compound purified by silica gel column chromatography using methanol and DCM (5:95) was obtained as a brown solid (24.4% yield). Mass: 339.0 (M + H).

Step 4: [2- (2,6-Dichloro-phenylamino) -phenyl] -acetic acid 2- [3-((R) -2,4-dihydroxy-3,3-dimethyl-butyrylamino) -propionylamino]- Synthesis of ethyl ester (CLX-SYN-G18-C01):

3 in a stirred solution of-((R) -2,4-dihydroxy-3,3-dimethyl-butyrylamino) -propionic acid 6 (0.2 grams, 0.0007 mmol, 1 equivalent) in DMF (4 ml) Triethylamine (0.31 grams, 0.003 mmol), EDC. HCl (0.22 grams, 0.001 mmol) HOBt (0.15 grams, 0.001 mmol) and [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-aminoethyl ester 5 At room temperature (0.26 grams, 0.0007 mmol, 1 equiv). The resulting mixture was stirred for 16 hours at room temperature and monitored by TLC. After completion, the reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2 × 20 ml). The combined organic layers were dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give methanol and DCM to obtain 0.11 gram (26.4% yield) of CLX-SYN-G18-C01 as off-white. Purified by silica gel column chromatography using (3:97) solid; mass: 539.9 [M + H].
Equivalent

This disclosure is provided in other moderately moderate-treatment methods for other compositions and severe pain and its complications. While specific embodiments of the present disclosure have been described, the above specification is illustrative and not restrictive. Many variations of the systems and methods 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 equivalents, and the specification, along with such variations.
Replenishment by quotation

All publications and patents, including these items above, are described in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference as described herein. Incorporated herein by reference. In case of conflict, the present application, including any definitions herein, will control.

This application is filed on International Application No. PCT / IB2013 / 055146 (Composition and Method for the Treatment of Moderate to Severe Pain), International Publication Number WO / 2014/006529). This international application further claims the priority of Indian Patent Application No. 2682 / CHE / 2012 filed on July 3, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

  The present disclosure relates generally to compounds and compositions for the treatment of moderate to severe pain. In particular, the invention relates to treating a subject with a pharmaceutically acceptable dose of a compound, crystal, enantiomer, stereoisomer, ester, salt, hydrate, prodrug, or mixture thereof.

  Pain is a subjective experience that is affected by physical, psychological, social, and mental factors. The concept of total pain recognizes the importance of all these aspects, but good pain relief often does not pay much attention to each aspect. Diseases such as pain and cancer are not synonymous. : At least two-thirds of patients experience pain at some point in their illness process, and many require powerful analgesics.

  Moderate to severe pain is also associated with injury, inflammation, burning of seasonal allergies, eye pain, itching, and bipolar disorder includes the brain, spinal cord, and peripheral nerves with a completely different etiology, A heterogeneous group of neurological diseases. Some are hereditary; some occur after toxicity and metabolic processes. Free radicals are very reactive to molecules and species that can exist independently. Generation of highly reactive oxygen species (ROS) is an essential function of normal cellular functions such as mitochondrial respiratory chain, phagocytic ability and arachidonic acid metabolism. Oxygen free radical release has been reported during the recovery phase from numerous pathological noxious stimuli to brain tissue. Injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia, diabetic neuropathy, cancer pain, fiber There are also pains associated with neurological disorders, including myalgia and back and back pain.

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

  The present invention provides compounds, compositions containing them, and methods of using them to treat, prevent, and / or ameliorate the effects of moderate to severe pain conditions.

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

In certain embodiments, the present invention relates to compounds and compositions of formula I or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomers.
Formula I

here,
R ¹ represents H, D, —OCH ₃ , —OCD ₃ ;
Or
R ² represents:
Or
Each b is independently 3, 5 or 6;
e is independently 1, 2, 6;
c and d are each independently H, D, —OH, —OD, C ₁ -C ₆ -alkyl, NH ₂ or —COCH ₃ ;
n is 1, 2, 3, 4 or 5, respectively.

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

  The present application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit can include instructions for use in the treatment of moderate to severe pain and its associated complications.

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

  Here, the present application further provides a kit comprising the pharmaceutical composition described herein. The kit may further comprise instructions for use in the treatment of moderate to severe pain or its associated complications.

  It has several uses for the compositions described herein. This application describes, for example, moderate to severe pain or related complications arising from metabolic conditions, severe diseases or disorders; liver, cancer, blood, orthopedics, cardiovascular, kidney, skin, neurological or ocular complications A method of treating a patient suffering from illness is provided.

Definitions As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

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

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

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

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

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

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

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

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, transporting any object from one organ or part of the body to another organ or part of the body and A pharmaceutically acceptable substance, composition or vehicle is included as a liquid or solid filler, diluent, solvent or encapsulating material involved in transport. Each carrier must be “acceptable” in the sense of being harmless to the patient and compatible with the ingredients of other subject compositions. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of substances that can be provided as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) carboxymethylcellulose sodium (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository wax; (9) peanut oil, cottonseed oil Oils such as sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) ethyl oleate and Esters such as ethyl phosphate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline. (18) Ringer's solution; (19) Ethyl alcohol; (20) Phosphate buffer; and (21) Other non-toxic affinity substances are used in pharmaceutical formulations.

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

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

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

  The term “treat” is art-recognized and refers to a disease, disorder, or condition that occurs in an animal that may have a predisposition to a disease, disorder, and / or symptom, but has not yet been diagnosed as having it. Prevention; including inhibiting a disease, disorder or condition, ie preventing its progression, and reducing a disease, disorder, or condition, ie, causing regression of the disease, disorder, and / or condition. To treat a disease or condition includes epilepsy, bipolar disorder, trigeminal neuralgia, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limbs Neurological conditions such as syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, congenital myotony, post-traumatic stress disorder in subjects At least one of a particular disease or condition, even if the underlying pathophysiology is not affected, such as treatment by administering the drug, even if the drug being administered does not address the cause of the condition Includes remission of symptoms. As used herein, the term “treating”, “treat” or “treatment” includes cure, prevention (eg, prevention), preventive aids and palliative treatment.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The compositions provided by this application can be administered to a subject in need of treatment by various conventional routes of administration, including oral, topical, parenteral, eg, intravenous, subcutaneous or intramedullary administration. In addition, the composition may be administered intranasally such that the drug can be dissolved in the mouth without the need for water, ie, using a rectal suppository, or “flash” formulation. Further, the composition may be administered by controlled release dosage forms, site-specific drug delivery, transdermal drug delivery patch (active / passive) mediated drug delivery, stereotactic injection, or to a subject in need of treatment with nanoparticles. it can. The composition can be administered either in a single dose or in multiple doses, alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. If desired, these pharmaceutical compositions can include additional ingredients such as, for example, perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as, for example, L-arginine, sodium citrate, calcium carbonate, and calcium phosphate are available in various forms such as starch, alginic acid, and certain complex silicates. Can be used with other disintegrants and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules. Suitable materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredients therein are various sweetening or flavoring agents, coloring substances or pigments, optionally emulsifying or suspending agents, water, You may combine with diluents, such as ethanol, propylene glycol, glycerol, and those combination. As is well known in the pharmaceutical art, the compounds of Formula I and Formula II may also include enteric coatings of various excipients.

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; from about 250 microns to about 1000 microns. In embodiments, the immediate release coating is typically compressed to a density of about 0.9 g / cc or greater, as measured by the weight and volume of the particular layer.

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

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

In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment, the outer coating portion is contained in a dry granule that includes a pharmaceutically active agent.

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

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

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

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

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

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

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

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

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

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

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

Formulations useful in the methods provided herein include methods suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of the composition of the invention that can be combined with a carrier material to produce a single dosage that can vary depending on the subject depends on the subject to be treated and the particular mode of administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are typically composed of a relatively stiff sheet covered with a foil of a permeable plastic material.
During the packaging process, depressions are formed in the plastic foil. The recess must be the size and shape of the tablet or capsule to be packed. The tablet or capsule is then placed in the recess and a sheet of relatively hard material is sealed against the plastic foil with the foil surface opposite to the direction in which the depression was formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments, the strength of the sheet allows the tablet or capsule to be removed from the blister pack by manually applying pressure on the recess to form an opening in the recess on the sheet. The tablet or capsule can then be removed through the opening.

Methods and compositions for the treatment of moderate to severe pain. In particular, there is provided a method of treating moderate to severe pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I

here,
R ¹ represents H, D, —OCH ₃ , —OCD ₃ ;
Or
R ² represents:
a is independently 2, 3 or 7;
Each b is independently 3, 5, or 6;
e is independently 1, 2, or 6;
c and d are each independently H, D, —OH, —OD, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ ;
n is independently 1, 2, 3, 4 or 5.
Methods of using compounds of formula I:
The present invention also provides pain, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, neuropathic pain associated with HIV, postherpetic neuralgia, diabetic neuropathy, Includes methods for the treatment of pain due to bipolar depression, depression, stress, cancer pain, fibromyalgia and back pain or any other health condition associated with severe pain.
Production method

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

Step-1: Synthesis of Compound 2:

  To a mechanically stirred solution of 2,6-dichloroaniline 1 (76 g, 0.047 mmol) in 60 mL of glacial acetic acid was added dropwise acetyl chloride (36 mL, 0.5 mmol). After completion of the addition, the reaction mixture was heated at 90 ° C. for 20 minutes. The solution was poured into ice water (500 mL) and a white precipitate formed. The solid was filtered, washed with water and dried to give product 2 (91.8 g, 96%, white solid, mp 179-180 ° C., lit. 180-181 ° C. from mp glacial acetic acid).

Step 2: Synthesis of Compound 4:

  15 g of compound 2 is dissolved in 150 mL of bromobenzene 3, 5.5 g of calcined potassium carbonate and 0.5 g of copper powder are added, the mixture is refluxed for 4 days, the water formed is removed by a water separator, Cooled and subjected to steam distillation. The residue was extracted with 200 mL ether. The ether solution is filtered through Hyflo and the residue is concentrated to dryness under 11 torr. The residue is dissolved in 60 mL of ethanolic potassium hydroxide and the solution is refluxed for 3 hours. The solution is then concentrated to dryness under 40 torr. 10 mL of water is added to the residue, which is then extracted with 100 mL of ether. The ether solution was removed and extracted with 20 mL of water. The ether solution is dried over sodium sulfate and concentrated to dryness under 11 torr. The residue was distilled under high vacuum (115 ° C./0.01 torr) to obtain compound 4 as a yellow oil.

Step-3: Synthesis of Compound 6:

  4 g of compound 4 and freshly distilled 40 mL of chloroacetyl chloride 5 were refluxed for 1 hour. The dark solution was evaporated under 11 torr at a bath temperature of 50 ° C. The residue was dissolved in 70 mL ethyl acetate / ether (1: 1). This solution was extracted with 10 mL of 2N potassium bicarbonate solution, 10 mL of water was dried over sodium sulfate and evaporated under 11 torr. Compound 6 was recrystallized from methanol (melting point: 143 ° C.).

Step 4: Synthesis of Compound 7:

  4 g of compound 6 and 4 g of aluminum chloride were mixed well and heated at 160 ° C. for 2 hours. The melt was cooled and poured onto about 50 g of ice while still warm. The separated oil was dissolved in 50 mL of chloroform. The chloroform solution was washed with 10 mL of water, dried over sodium sulfate and concentrated under 11 torr. The residue was distilled. The obtained compound 7 was crystallized from methanol (melting point: 126 ° C.).

Step-5: Synthesis of Compound 8:

  A solution of 40 g of compound 7 in 280 mL of 1N sodium hydroxide solution and 420 mL of ethanol were refluxed for 2 hours. The clear solution was cooled and ethanol was distilled at 40 bath temperature under 11 torr. The aqueous residue was extracted with 100 mL of ether. The ether was removed and the aqueous solution was cooled by adding about 50 g of ice and further cooled to 5 ° C. 2N hydrochloric acid was added with stirring until the pH of the solution was about 6. The precipitated acid was taken up in 400 mL ether, the ether solution was separated and the aqueous solution was extracted again with 200 mL ether. The ether solution was washed with 50 mL of water, dried over sodium sulfate, and concentrated under 11 torr without heating. After adding petroleum ether to the concentrated ether solution, 8 crystallized. After recrystallization from ether / petroleum ether melts at 156-158 ° C.

Step-6: Synthesis of Compound 10:

Compound 8 (10 mmol) and 5 mL of SOCl ₂ were refluxed for 2 hours to obtain the acid chloride. Excess SOCl ₂ was distilled and the acid chloride was used directly. Compound 9 was kept in DCM at 0 ° C. and DIPEA (12 mmol) was added. The reaction mixture was stirred for 30 minutes and then the acid chloride in DCM was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred for 4 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with DCM and water was added. The layers were separated and the organic layer was washed with saturated NaHCO ₃ and evaporated to give a residue. The residue was purified through a column to obtain compound 10. M.M. _{F: C 22 H 23 C l2} NO 3 S 2; Mol. Wt. : 483.05; Elemental analysis: C, 54.54; H, 4.79; Cl, 14.64; N, 2.89; O, 9.91; S, 13.24.

The term “sample” refers to a sample of body fluid, a sample of separated cells, or a sample from a tissue or organ. The body fluid sample is obtained by known techniques, preferably the body fluid sample comprises a blood, plasma, serum or urine sample, more preferably a blood, plasma or serum sample. Tissue or organ samples can be obtained from any tissue or organ, for example, by biopsy. Separated cells can be obtained from body fluids or tissues or organs by separation techniques such as centrifugation or cell sorting. Preferably, the cell, tissue or organ sample can be obtained from a cell, tissue or organ that expresses or produces a peptide as described herein.
Equivalent

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

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

This application is filed on International Application No. PCT / IB2013 / 055146 (Composition and Method for the Treatment of Moderate to Severe Pain), International Publication Number WO / 2014/006529). This international application further claims the priority of Indian Patent Application No. 2682 / CHE / 2012 filed on July 3, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

  The present disclosure relates generally to compounds and compositions for the treatment of moderate to severe pain. In particular, the invention relates to treating a subject with a pharmaceutically acceptable dose of a compound, crystal, enantiomer, stereoisomer, ester, salt, hydrate, prodrug, or mixture thereof.

  Pain is a subjective experience that is affected by physical, psychological, social, and mental factors. The concept of total pain recognizes the importance of all these aspects, but good pain relief often does not pay much attention to each aspect. Diseases such as pain and cancer are not synonymous. : At least two-thirds of patients experience pain at some point in their illness process, and many require powerful analgesics.

  Moderate to severe pain is also associated with injury, inflammation, burning of seasonal allergies, eye pain, itching, and bipolar disorder includes the brain, spinal cord, and peripheral nerves with a completely different etiology, A heterogeneous group of neurological diseases. Some are hereditary; some occur after toxicity and metabolic processes. Free radicals are very reactive to molecules and species that can exist independently. Generation of highly reactive oxygen species (ROS) is an essential function of normal cellular functions such as mitochondrial respiratory chain, phagocytic ability and arachidonic acid metabolism. Oxygen free radical release has been reported during the recovery phase from numerous pathological noxious stimuli to brain tissue. Injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia, diabetic neuropathy, cancer pain, fiber There are also pains associated with neurological disorders, including myalgia and back and back pain.

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

  The present invention provides compounds, compositions containing them, and methods of using them to treat, prevent, and / or ameliorate the effects of moderate to severe pain conditions.

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

In certain embodiments, the present invention relates to compounds and compositions of formula I or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomers.
Formula I

here,
R ¹ represents H, D, —OCH ₃ , —OCD ₃ ;
Or
R ² represents:
Or
Each b is independently 3, 5 or 6;
e is independently 1, 2, 6;
c and d are each independently H, D, —OH, —OD, C ₁ -C ₆ -alkyl, NH ₂ or —COCH ₃ ;
n is 1, 2, 3, 4 or 5, respectively.

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

  The present application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit can include instructions for use in the treatment of moderate to severe pain and its associated complications.

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

  Here, the present application further provides a kit comprising the pharmaceutical composition described herein. The kit may further comprise instructions for use in the treatment of moderate to severe pain or its associated complications.

  It has several uses for the compositions described herein. This application describes, for example, moderate to severe pain or related complications arising from metabolic conditions, severe diseases or disorders; liver, cancer, blood, orthopedics, cardiovascular, kidney, skin, neurological or ocular complications A method of treating a patient suffering from illness is provided.

Definitions As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

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

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

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

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

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

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

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

The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, the transfer of any object from one organ or part of the body to another organ or part of the body. A pharmaceutically acceptable substance, composition or vehicle is included as a liquid or solid filler, diluent, solvent or encapsulating material involved in transport. Each carrier must be “acceptable” in the sense of being harmless to the patient and compatible with the ingredients of other subject compositions. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of substances that can be provided as pharmaceutically acceptable carriers are: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) carboxymethylcellulose sodium Cellulose and its derivatives such as ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository wax; (9) peanut oil, cottonseed oil Oils such as sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) ethyl oleate and laurin Ethyl acid (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18 Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic affinity substances are used in pharmaceutical formulations.

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

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

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

  The term “treat” is art-recognized and refers to a disease, disorder, or condition that occurs in an animal that may have a predisposition to a disease, disorder, and / or symptom, but has not yet been diagnosed as having it. Prevention; including inhibiting a disease, disorder or condition, ie preventing its progression, and reducing a disease, disorder, or condition, ie, causing regression of the disease, disorder, and / or condition. To treat a disease or condition includes epilepsy, bipolar disorder, trigeminal neuralgia, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limbs Neurological conditions such as syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, congenital myotony, post-traumatic stress disorder in subjects At least one of a particular disease or condition, even if the underlying pathophysiology is not affected, such as treatment by administering the drug, even if the drug being administered does not address the cause of the condition Includes remission of symptoms. As used herein, the term “treating”, “treat” or “treatment” includes cure, prevention (eg, prevention), preventive aids and palliative treatment.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The compositions provided by this application can be administered to a subject in need of treatment by a variety of conventional routes of administration, including oral, topical, parenteral, eg, intravenous, subcutaneous or intramedullary administration. Further, the composition may be administered intranasally such that the drug can be dissolved in the mouth without the need for water, ie, using a rectal suppository, or “flash” formulation. Further, the composition may be administered by controlled release dosage forms, site-specific drug delivery, transdermal drug delivery patch (active / passive) mediated drug delivery, stereotactic injection, or to a subject in need of treatment with nanoparticles. it can. The composition can be administered either in a single dose or in multiple doses, alone or in combination with a pharmaceutically acceptable carrier, vehicle or diluent. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. If desired, these pharmaceutical compositions can include additional ingredients such as, for example, perfumes, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as, for example, L-arginine, sodium citrate, calcium carbonate, and calcium phosphate are available in various forms such as starch, alginic acid, and certain complex silicates. Can be used with other disintegrants and binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules. Suitable materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredients therein are various sweetening or flavoring agents, coloring substances or pigments, optionally emulsifying or suspending agents, water, You may combine with diluents, such as ethanol, propylene glycol, glycerol, and those combinations. As is well known in the pharmaceutical art, the compounds of Formula I and Formula II may also include enteric coatings of various excipients.

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; from about 250 microns to about 1000 microns. In embodiments, the immediate release coating is typically compressed to a density of about 0.9 g / cc or greater, as measured by the weight and volume of the particular layer.

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

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

In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment, the outer coating portion is contained in a dry granule that includes a pharmaceutically active agent.

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

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

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

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

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

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

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

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

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

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

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

Formulations useful in the methods provided herein include methods suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. The amount of the composition of the present invention that can be combined with a carrier material to produce a single dose that can vary depending on the subject depends on the subject to be treated and the particular mode of administration.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs are typically composed of a relatively stiff sheet covered with a foil of a permeable plastic material. During the packaging process, depressions are formed in the plastic foil. The recess must be the size and shape of the tablet or capsule to be packed. The tablet or capsule is then placed in the recess and a sheet of relatively hard material is sealed against the plastic foil with the foil surface opposite to the direction in which the depression was formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments, the strength of the sheet allows the tablet or capsule to be removed from the blister pack by manually applying pressure on the recess to form an opening in the recess on the sheet. The tablet or capsule can then be removed through the opening.

Methods and compositions for the treatment of moderate to severe pain. In particular, there is provided a method of treating moderate to severe pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I

here,
R ¹ represents H, D, —OCH ₃ , —OCD ₃ ;
Or
R ² represents:
a is independently 2, 3 or 7;
Each b is independently 3, 5, or 6;
e is independently 1, 2, or 6;
c and d are each independently H, D, —OH, —OD, C ₁ -C ₆ alkyl, —NH ₂ or COCH ₃ ;
n is independently 1, 2, 3, 4 or 5.

Methods of using compounds of formula I:
The present invention also provides pain, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, neuropathic pain associated with HIV, postherpetic neuralgia, diabetic neuropathy, Includes methods for the treatment of pain due to bipolar depression, depression, stress, cancer pain, fibromyalgia and back pain or any other health condition associated with severe pain.
Production method

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

Step-1: Synthesis of Compound 2:

  To a mechanically stirred solution of 2,6-dichloroaniline 1 (76 g, 0.047 mmol) in 60 mL of glacial acetic acid was added dropwise acetyl chloride (36 mL, 0.5 mmol). After completion of the addition, the reaction mixture was heated at 90 ° C. for 20 minutes. The solution was poured into ice water (500 mL) and a white precipitate formed. The solid was filtered, washed with water and dried to give product 2 (91.8 g, 96%, white solid, mp 179-180 ° C., lit. 180-181 ° C. from mp glacial acetic acid).

Step 2: Synthesis of Compound 4:

  15 g of compound 2 is dissolved in 150 mL of bromobenzene 3, 5.5 g of calcined potassium carbonate and 0.5 g of copper powder are added, the mixture is refluxed for 4 days, the water formed is removed by a water separator, Cooled and subjected to steam distillation. The residue was extracted with 200 mL ether. The ether solution is filtered through Hyflo and the residue is concentrated to dryness under 11 torr. The residue is dissolved in 60 mL of ethanolic potassium hydroxide and the solution is refluxed for 3 hours. The solution is then concentrated to dryness under 40 torr. 10 mL of water is added to the residue, which is then extracted with 100 mL of ether. The ether solution was removed and extracted with 20 mL of water. The ether solution is dried over sodium sulfate and concentrated to dryness under 11 torr. The residue was distilled under high vacuum (115 ° C./0.01 torr) to obtain compound 4 as a yellow oil.

Step-3: Synthesis of Compound 6:

  4 g of compound 4 and freshly distilled 40 mL of chloroacetyl chloride 5 were refluxed for 1 hour. The dark solution was evaporated under 11 torr at a bath temperature of 50 ° C. The residue was dissolved in 70 mL ethyl acetate / ether (1: 1). This solution was extracted with 10 mL of 2N potassium bicarbonate solution, 10 mL of water was dried over sodium sulfate and evaporated under 11 torr. Compound 6 was recrystallized from methanol (melting point: 143 ° C.).

Step 4: Synthesis of Compound 7:

  4 g of compound 6 and 4 g of aluminum chloride were mixed well and heated at 160 ° C. for 2 hours. The melt was cooled and poured onto about 50 g of ice while still warm. The separated oil was dissolved in 50 mL of chloroform. The chloroform solution was washed with 10 mL of water, dried over sodium sulfate and concentrated under 11 torr. The residue was distilled. The obtained compound 7 was crystallized from methanol (melting point: 126 ° C.).

Step-5: Synthesis of Compound 8:

  A solution of 40 g of compound 7 in 280 mL of 1N sodium hydroxide solution and 420 mL of ethanol were refluxed for 2 hours. The clear solution was cooled and ethanol was distilled at 40 bath temperature under 11 torr. The aqueous residue was extracted with 100 mL of ether. The ether was removed and the aqueous solution was cooled by adding about 50 g of ice and further cooled to 5 ° C. 2N hydrochloric acid was added with stirring until the pH of the solution was about 6. The precipitated acid was taken up in 400 mL ether, the ether solution was separated and the aqueous solution was extracted again with 200 mL ether. The ether solution was washed with 50 mL of water, dried over sodium sulfate, and concentrated under 11 torr without heating. After adding petroleum ether to the concentrated ether solution, 8 crystallized. After recrystallization from ether / petroleum ether melts at 156-158 ° C.

Step-6: Synthesis of Compound 10:

Compound 8 (10 mmol) and 5 mL of SOCl ₂ were refluxed for 2 hours to obtain the acid chloride. Excess SOCl ₂ was distilled and the acid chloride was used directly. Compound 9 was kept in DCM at 0 ° C. and DIPEA (12 mmol) was added. The reaction mixture was stirred for 30 minutes and then the acid chloride in DCM was added dropwise to the reaction mixture at 0 ° C. The reaction mixture was stirred for 4 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with DCM and water was added. The layers were separated and the organic layer was washed with saturated NaHCO ₃ and evaporated to give a residue. The residue was purified through a column to obtain compound 10. M.M. _{F: C 22 H 23 C l2} NO 3 S 2; Mol. Wt. : 483.05; Elemental analysis: C, 54.54; H, 4.79; Cl, 14.64; N, 2.89; O, 9.91; S, 13.24.

Scheme 2:
Step 1: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid (2):

To a stirred solution of 1- (2,6-dichloro-phenyl) -1,3-dihydro-indol-2-one 1 (10 g, 0.03 mmol) in toluene (340 mL) was added aqueous NaOH (2N, 34 mL). Added at room temperature. The resulting mixture was stirred for 16 hours at 90 ° C. After completion, the clear solution was cooled in an ice bath and acidified with concentrated hydrochloric acid. The precipitated solid was filtered, washed with ethanol and dried under reduced pressure to give 9.0 g of compound 2 (84.4% yield) as an off-white solid. Used in the next step without further purification. Mass: 294.1 (M−H); ¹ H-NMR (400 MHz, DMSO): 12.70 (s, 1H), 7.53 to 7.51 (d, J = 8.0 Hz, 2H), 7 .24 to 7.16 (M, 3H), 7.08 to 7.03 (m, 1H), 6.87 to 6.83 (m, 1H), 6.28 to 6.26 (d, J = 7.8 Hz, 1 H), 3.69 (s, 2 H); ¹³ C-NMR (400 MHz; DMSO): 173.86, 142.66, 137.11, 130.89, 130.04, 129.17, 127.51, 125.56, 123.89, 120.76, 115.95, 37.74.

Step 2: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-tert-butoxycarbonylaminoethyl ester (4):

[2- (2,6-Dichloro-phenylamino) -phenyl] -acetic acid] 2 (4.0 g, 0.01 mmol, 1 eq) and N-BOC-ethanolamine (2.39 g, 0 in DCM (70 mL). .01 mmol) was added DMAP (0.16 g, 0.001 mmol) at room temperature. To this mixture was added DCC (5.5 g, 0.02 mmol) in DCM (30 mL) dropwise at 0-5 ° C. and the resulting mixture was stirred for 1 hour at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in water (100 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude compound, which was washed with hexane (2 × 20 mL) to obtain 6.0 g of crude compound 4. The compound 1 was crystallized as an off-white solid. This mixture was used in the next step without further purification. Mass: 439.3 (M ⁺ + H).

Step 3: Synthesis of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-aminoethyl ester (5):

To a stirred solution of [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid and 2-tert-butoxycarbonylaminoethyl ester 4 (5.3 g, 0.01 mmol) in DCM (50 mL) was added TFA ( 5.3 mL) was added at 0 ° C. The resulting mixture was stirred for 16 hours at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was neutralized with aqueous sodium bicarbonate and extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. To obtain 1.0 g (24.4% yield) of compound 5 as a brown solid, it was purified by silica gel column chromatography using methanol and DCM (5:95). Mass: 339.0 (M ⁺ + H).

Step 4: [2- (2,6-Dichloro-phenylamino) -phenyl] -acetic acid 2- [3-((R) -2,4-dihydroxy-3,3-dimethyl-butyrylamino) -propionylamino]- Synthesis of ethyl ester (CLX-SYN-G18-C01):

To a stirred solution of 3-((R) -2,4-dihydroxy-3,3-dimethyl-butyrylamino) -propionic acid 6 (0.2 g, 0.0007 mmol, 1 eq) in DMF (4 mL) was added triethylamine (0. 31 g, 0.003 mmol), EDC. HCl (0.22 g, 0.001 mmol), HOBt (0.15 g, 0.001 mmol) and [2- (2,6-dichloro-phenylamino) -phenyl] -acetic acid 2-aminoethyl ester 5 (0.26 g) , 0.0007 mmol, 1 eq) was added at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain 0.11 g (26.4% yield) of CLX-SYN-G18-C01 as an off-white solid. Purified by silica gel column chromatography using methanol and DCM (3:97). Mass: 539.9 [M + H].

Equivalent

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

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

Claims (9)

Compounds of formula I:
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer, characteristic thereof
R1 represents H, D, -OCH3, -OCD3
R2 represents
Each a is independently 2, 3 or 7;
Each b is independently 3, 5, or 6;
Each e is independently 1, 2, or 6;
Each c and d is independently H, D, —OH, —OD, C1-C6 alkyl, —NH 2 or —COCH 3.
And each n is independently 1, 2, 3, 4 or 5. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition feature according to claim 2, characterized in that the pharmaceutical composition is formulated to treat the underlying pathogenesis of an effective amount to be administered to a patient in need thereof by oral administration, delayed release or sustained release, transmucosal, Syrup, topical, parenteral, injection, subcutaneous, oral solution, rectal, buccal or transdermal. Compound and Composition of Claim 3 The compound and composition comprise severe pain, muscle pain, spasticity, neuropathic pain, fibromyalgia, postoperative pain, muscle spasticity, headache, chronic pain, subchronic pain and local pain. Be prescribed for the treatment of. Pharmaceutical composition comprising molecular complex 2- (2-((2,6-dichlorophenyl) amino) phenyl) acetic acid and R lipoic acid, salsalate, eicosapentaenoic acid and carboxylic acid compound selected from the group consisting of docosahexaenoic acid It is.     The molecular complex according to claim 5 and the carboxylic acid compound are R-α-lipoic acid. The molecular complex according to claim 5 and the carboxylic acid compound are eicosapentaenoic acid. The molecular complex according to claim 5 and the carboxylic acid compound are docosahexaenoic acid. The molecular complex according to claim 5 and the carboxylic acid compound are salsalates.