JP2016508956A - Compositions and treatments for the treatment of local 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. Pharmaceutical compositions comprising an effective amount of a compound of formula I and methods for the treatment of topical pain are oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral, syrup, or It can be formulated for injection. Such compositions include infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia, neuralgia, motor neuron disease Treatment of diabetic neuropathy, postherpetic neuralgia, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, cancer pain, and low back pain Can be used for [Selection figure] None

Description

This application is based on International Application No. PCT / IB2013 / 051268 (Title of Invention “Composition and Treatment for Local Pain”, International Publication No. WO / 2013/168006) filed on Feb. 16, 2013. Domestic transition application. This international application further claims the priority of Indian patent application number 1843 / CHE / 2012 filed on May 10, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

This announcement is widely related to compounds and compositions for the treatment of local pain. More specifically, this intervention depends on the pharmaceutically acceptable dose of the compound, crystal, polymorph, ester, salt, stereoisomer, enantiomer, hydrate, prodrug, and mixtures thereof. Related to treating the subject.

Pain is a subjective experience that is influenced by physical, psychological, social, and mental factors. The concept of holistic pain recognizes the importance of all these aspects and recognizes that excellent pain relief would not be possible without paying attention to each aspect. Diseases such as pain and cancer are not synonymous. This is because at least two-thirds of patients experience pain at some point in their illness, and most require powerful analgesics.

Severe pain, such as pain, depression, fibromyalgia, rheumatoid arthritis, restless leg syndrome, and bipolar disorder, are heterogeneous diseases that have a very different etiology of the nervous system, including the brain, spinal cord, and peripheral nerves It is a gathering of. Many are hereditary and some occur following toxic or metabolic processes. Free radicals are highly reactive molecules or species that can exist independently. The generation of highly reactive oxygen species (ROS) is an essential feature of normal cellular functions such as mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. Oxygen free radical release is also delivered during the recovery phase from many pathologically harmful stimuli to the brain tissue. The neurological disorders associated with pain include injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia, diabetic nerves Disability, cancer pain, fibromyalgia, back pain, etc. may be included.

Managing acute pathology often relies on identifying the underlying pathology and disease symptoms. Currently, there is a need in the art for new compositions for treating local pain.

The present invention provides compounds, compositions containing compounds, and methods for using the same to treat, prevent, ameliorate, or all of the effects of conditions such as local pain .

The present invention provides herein a composition composed of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof. The present invention also provides a pharmaceutical composition composed of one or more compounds consisting of Formula I, its intermediate products, and one or more pharmaceutically acceptable carriers, media or diluents. Offer things. These compositions may be used to treat local pain and related complications.

In certain embodiments, the present invention relates to Formula I and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomeric compounds and compositions thereof. .
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof.
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, -OH, -OD, C1-C6-alkyl, -NH2, or -COCH3.
n is independently 1, 2, 3, 4 or 5.

As a specific example, an example of a compound of formula I is as follows.

The application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit may also include instructions for use in the treatment of local pain or its associated complications.

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

The application further provides kits comprising the pharmaceutical compositions described herein. The kit may further include instructions for use in the treatment of local pain or related complications.

The compositions described herein have several uses. This application provides a way to treat patients suffering from, for example, local pain, related complications manifested by metabolic status, and severe illnesses and disorders. These include complications such as hepatology, cancer, blood, orthopedics, circulatory organs, kidneys, skin, neurology, and eyes.

Brief Description of Shapes: Specific examples are given by way of example and are not meant to limit the shape of the drawings that are shown together with like elements shown for reference.
Among them, FIG. 1 shows ¹³ C-NMR as a result of the chemical formula I.

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 in the art as one universal technique.

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 invention may also be solvated, for example hydrated. Solvation may be affected during the manufacturing process or may be made as a hygroscopic result (hydration) of inherently anhydrous compounds of formula I.

Compounds that have the same molecular formula but differ in their nature, arrangement of bonding of atoms, or spatial arrangement of atoms are called “isomers”. Among them, isomers having different atomic arrangements are called “stereoisomers”. Diastereomers are stereoisomers that have the opposite configuration with respect to one or more chiral centers and that are not enantiomers. Among stereoisomers, stereoisomers with one or more chiral centers that are non-superimposable mirror images of each other are termed “enantiomers”. If the compound has a chiral center, for example when the carbon atom is bonded to 4 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of one or more chiral centers and are represented by the Cahn, Ingold and Prelog R- and S-sequencing rules, or by how the molecule rotates the plane of polarized light. , Dextrorotatory or levorotatory (ie (+) or (−) − isomers in order). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic state” refers to an inborn error of metabolism (or genetic metabolic condition), a genetic disorder resulting from a defect in one or more metabolic pathways. Specifically, the function of the enzyme is affected and is deficient or completely absent.

In some examples, the molecular conjugate is R lipoic acid (CAS number 1200-22-2), salsalate (CAS number 552-94-3), acetylcysteine (CAS number 616-91-1), It consists of a compound selected from icosapentaenoic acid (CAS number 10417-94-4) and docosahexaenoic acid (CAS number 6217-54-5).

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”, as used herein, refer to dosage forms other than enteral and topical administration, and without limitation, intravenous, intramuscular, intrathoracic, Intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal Including injections and infusions.

“Patient”, “subject”, “host” to be treated by the subject methods will mean either humans or non-human animals such as primates, mammals and vertebrates.

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

The phrase “pharmaceutically acceptable carrier” is pharmaceutically recognized in the art, eg, pharmaceutically acceptable substances, compositions, or media, liquid or solid fillers, diluents, solvents or capsules The chemical material carries the composition of interest from one organ or body part to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is harmful to the patient, does not compete with other components of the subject composition, and is not invasive to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can serve are: (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, 3) Cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) 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 (10) glycols such as propylene glycol (11) polyols such as sorbitol, mannitol and polyethylene glycol (12) ethyl oleate and La 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) ethanol, (20) phosphate buffer solution, (21) other non-toxic non-competitive substances used in pharmaceutical formulations.

The term “prodrug” is intended to include compounds that are converted under physiological conditions to an active agent for treatment according to the present invention. A common method for producing prodrugs is to include selected moieties that have been hydrolyzed under physiological conditions to reveal the desired molecule. In another embodiment, the prodrug is converted by the activity of the host animal enzyme.

The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to a host having one or more of the subject compositions. If it is administered before clinical signs of an undesired situation (eg, host animal disease or other unwanted condition), the treatment is a preventive measure, that is, it progresses to an undesirable condition Protect your host from doing. On the other hand, if it is administered after an indication of an undesirable situation, it is a therapeutic measure. (Example: It is intended to suppress, improve, and stabilize existing unwanted conditions and their side effects.)

As used in this application, the term “predict” refers to abnormalities or complications and / or terminal platelet aggregation, disability and / or death (ie death) within a set period of time (predicted period). Rate) to assess the probability associated with the disease that the patient will suffer. It can be caused by this mortality rate, central nervous system or complications. This prediction period is a period during which one or more of the aforementioned complications are progressing according to the predicted probability of the subject. In the analysis by the method of the present invention, the prediction period may be the entire remaining life of the target.

The term “treating” is art-recognized. Preventing a disease, disorder or condition that occurs in an animal that may have a predisposition to the disease, disorder, and / or symptom but has not yet been diagnosed with it, eg, slowing its progression, disease, disorder or condition And causing regression of the disease, disorder, and / or condition, eg, alleviating the disease, disorder, or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected. Specifically, anesthesia, nerve block, epidural anesthesia, intrathecal anesthesia, pain, severe pain, chronic pain, including local infiltration of the subject, even though such drugs do not treat the cause of the condition , Chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia, administration of drugs for neuralgia, and the like. As used in this application, the terms “treating”, “treat” or “treatment” include curative treatment, prophylactic treatment (eg, prophylactic treatment), preventive adjuvant treatment, and palliative treatment. It is.

The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to the amount that the salt or composition provided herein 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 medical symptoms for a period of time. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 to reach a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of composition administered to a patient depends on absorption, inactivation and excretion rates of the drug, as well as the rate of transfer of salt and composition from the subject composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

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 containing substance. For example, the maximum plasma concentration (Cmax) or the area under the plasma concentration-time curve from time 0 to infinity may be used.

When used with respect to pharmaceutical compositions or other substances, the term “sustained release” is art-recognized. In contrast to a bolus-type administration in which the entire amount of the substance is made bioavailable at one time, for example, a subject composition that releases the substance over time can exhibit a sustained release characteristic. For example, in one embodiment, one or more pharmaceutically acceptable excipients may be associated with any substance, eg, therapeutic, when contacted with a bodily fluid such as blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc. And / or slow release (eg compared to release from a bolus) of sustained or prolonged (eg hydrolysis) by concomitant release of and / or biologically active salts and / or compositions ). This release can result in sustained delivery of a therapeutically effective amount to any therapeutic agent disclosed in this application.

The phrases “systemic administration”, “administered systemically”, “peripheral administration”, “administered peripherally” are recognized in the art, and the subject composition, therapeutic agent or other substance can be administered to the treatment site. Administration to a site away from the body. Administration of the drug for the disease being treated is that if the drug is subsequently diffused systemically, but not directly into the central nervous system, for example, it enters a system within the patient's body and is subject to metabolism and other similar processes. Depending on the subject's subcutaneous administration, etc., it may be referred to as “local” administration.

The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to the amount that the salt or composition provided herein 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 medical symptoms for a period of time. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 and prodrugs.

The application also discloses that a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a composition of a compound of formula I can be formulated for systemic administration, topical administration and oral administration. Yes. 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, the pharmaceutical compositions described herein are delivered in an amount sufficient to deliver a therapeutically effective amount of a compound of formula I to a patient as part of a prophylactic or therapeutic treatment In order to incorporate the disclosed compounds and compositions (Formula I). The desired concentration of Formula I or a pharmaceutically acceptable salt thereof depends on the absorption, inactivation, excretion rate of the drug, the salt from the composition of interest and the rate of transmission of the composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

Concentration and / or amount of any compound of Formula I is facilitated by routine screening of animals such as rats by screening the concentration and / or amount range of the substance of interest using an appropriate assay. Can be identified. Also, well-known methods are 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. . One such method is described in T.W. E. Microdialysis reviewed in Techniques, Chapter 7, Chapter 1 in Robinson et al., “Microdialysis in the neurosciences” (1991). Briefly, the method reviewed by Robinson can be adapted as follows. The microdialysis loop is placed in situ in the test animal. Dialysate is forced through the loop. When a compound having Formula I as disclosed in this application is injected along the loop, the released drug is recovered in the dialysate in proportion to their local tissue concentration. The progress of diffusion of the salt or composition can be determined by following appropriate adjustment procedures using known concentrations of the salt or composition.

In certain embodiments, the dosage of a subject compound of Formula I in this application can be determined by reference to the plasma concentration of the therapeutic composition or other containing substance. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity can 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 about 100 mg / kg / day in single or divided doses. For example, from 0.01 mg / kg / day to about 50 mg / kg / day, a single dose or divided doses are used. Compounds of formula I may be, for example, less than 0.2 mg / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 / kg / day, 10 mg / kg / day, 20 mg / day It can be administered in a volume such as kg / day, 30 / kg / day, or 40 mg / kg / day. Formula I is for human patients, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0 mg per day, 9.0 mg, 12.0 mg, 20.0 mg, 50.0 mg 75.0 mg, 100 mg, 300 mg, 400 mg, 500 mg, 800 mg, 1000 mg, 2000 mg, 5000 mg. In certain examples, the compositions of this application comprise less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% of the compound of Formula I, respectively. The required amount was administered for the same therapeutic effect.

An effective amount of a compound of formula I as described in this application indicates the amount of a salt or composition described above that can inhibit or prevent the disease.

Effective doses prevent the severity of complications resulting from nerve damage or demyelination and / or high temperature reactive oxidative nitrosated species and / or abnormal physiological homeostasis in patients at risk of such complications May be sufficient to treat, reduce, improve, stop, inhibit, slow down, reverse or reduce progression. Thus, these methods include both medical therapeutic (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 variability between patients, the above dosage is merely a guideline, and the doctor can determine the dosage of the drug to achieve the treatment that the doctor considers appropriate for the patient. Considering the degree of treatment desired, the physician must balance various factors such as the age of the patient, the presence of pre-existing conditions, and the presence of other diseases.

The compositions provided in this application may be administered to a subject in need of treatment through various conventional routes of administration including, for example, oral, topical and parenteral, such as intravenous, subcutaneous or intramedullary. it can. Further, the composition may be administered intranasally, as a rectal suppository, or as a “flash” formulation, ie, an agent that dissolves in the mouth without the need for water. In addition, the composition may be administered by controlled release drugs, site-specific drug delivery, transdermal drug delivery patches (active / passive), mediated drug delivery, stereotactic injection, or to subjects in need of treatment with nanoparticles. Can do.

The composition can be administered either alone 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. The pharmaceutical composition formed by combining the composition, pharmaceutically acceptable carrier, vehicle or diluent can then be in various dosage forms such as tablets, powders, troches, syrups, injectable solutions, etc. Easy to administer. 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 can be used, such as starch, alginic acid, and certain complex silicates. It can be used with various disintegrants and with 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 or 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 may be combined with various sweetening or flavoring agents, coloring materials or dyes, optionally with emulsifiers or suspensions, Can be combined with diluents such as ethanol, propylene glycol, glycerin and combinations thereof. As is well known in the pharmaceutical arts, the compound of Formula I can also include various excipients coated enterically.

For parenteral administration, a solution of the composition can be prepared (for example) in sesame or peanut oil, aqueous propylene glycol, or used in a sterile aqueous solution. Such aqueous solutions should be buffered appropriately as needed, 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 in the art.

    Formulations such as tablets are, for example, 10-100 mg, 50-250 mg, 150-500 mg, or 350-800 mg, such as 10 mg, 50 mg, 100 mg, 300 mg, 500 mg, 700 mg, 800 mg, compounds of formula I or compounds of formula I The pharmaceutically acceptable salts of the compounds of formula I disclosed herein may be included.

In general, the compositions described herein can be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be suggested, for example, when the patient suffers from a gastrointestinal disorder and cannot be administered orally, or when the physician determines that the drug is most effective at the surface of the tissue or organ. Local administration may be indicated if high dose administration is desired for the target tissue or organ. Compositions active for buccal administration can take the form of tablets or troches formed in a conventional manner.

The dosage depends on the identity of the metabolic disease, ie the type of host involved, including age, health, weight, etc., the type of concurrent treatment, if any, the frequency of treatment and the rate of treatment.

Illustratively, the dosage levels of the active ingredient to be administered are as follows. 0.1 to about 200 mg / kg for intravenous, about 500 mg / kg for intramuscular, 5 to about 1000 mg / kg for oral, relative to host body weight (kg), intranasal instillation 5 to about 1000 mg / kg for aerosols and 5 to about 1000 mg / kg for aerosols.

Expressed in concentration, the active ingredient in the composition of the present invention is about 0 to the composition in concentration for topical use in the dermis, intranasal, throat, larynx, bronchus, vagina, rectum, or eye. 0.01 to about 50% w / w, preferably about 1 to about 20% w / w, for parenteral use at a concentration of about 0.05 to about 50% w / v to the composition, preferably It can be present at about 5 to about 20% w / v.

The compositions of the present invention are preferably presented in unit dosage form for administration to humans and animals, eg, tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions Alternatively, it contains an appropriate amount of the active ingredient, such as a suspension, a sterile parenteral solution, an oral solution or suspension of the suspension. For oral administration, solid or liquid unit dosage forms can be prepared.

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 the like A mixture of Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxy Examples include phenyl cellulose, hydroxyethyl cellulose (HEC), hydroxy pentacellulose, hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose, and hydroxypropyl ethyl cellulose, 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, but are not limited to, high molecular weight such as potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, such as those commercially available from Noveon Chemicals under the CARBOPOL ^™ name. Cross-linked acrylic acid homopolymers and copolymers are mentioned. Examples of suitable hydrocolloids include, but are not limited to, alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galacto Mannan, pustulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, wilan, 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. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

The carrier may contain one or more suitable excipients for tablet formulation. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, controlled release excipients, super disintegrants, antioxidants, And mixtures thereof.

Suitable binders include, but are not limited to, dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, or acacia, alginate, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, cod, gum arabic, Water-soluble polymers including hydrocolloids such as tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, inulin, weelan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan, Wet binders such as polyvinylpyrrolidone, cellulose, sucrose, and starch, and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch 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 such as magnesium stearate and stearic acid and salts thereof, 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.

Suitable insoluble edible materials for use as modified release excipients include, but are not limited to, water insoluble polymers and low melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and Of the mixture. 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 vegetable oils such as hydrogenated soybean oil, free fatty acids and their salts, And mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, monoglycerides, diglycerides, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glycerin tris. Laurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl selenium, phosphatidylinositol, phosphatidic 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, paraffin wax, fat-containing mixtures such as chocolate, and mixtures thereof. It is done. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In some embodiments, the tablet core contains superdisintegrants up to about 5% of its weight.

Examples of antioxidants include, but are not limited to, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylhydroxyanisole, 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 certain embodiments, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns, such as, for example, from about 250 microns to about 1000 microns. In the examples, the immediate release coating is typically compressed to a density of about 0.9 grams / cc or greater as measured by the weight and volume of that particular layer.

In certain embodiments, 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, each portion contacts each other on the central axis of the tablet. In certain embodiments, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent.

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

In certain embodiments, 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 could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multi-layer tablets, capsules, etc. comprising 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, for example, in gelatin capsules. Many methods are known in the art for preparing, coating, covering, or incorporating drugs.

As a dosage unit, ie as an outer layer of a tablet, multiple drug-containing beads, granules or particles, or a coated core dosage form, an immediate release agent, together with conventional pharmaceutical excipients, is therapeutically effective. Contains an amount of active ingredient. The immediate release dosage unit may or may not be coated (as in an encapsulated mixture of granules, particles or beads containing immediate release drug and granules or beads containing delayed release drug. ) May or may not be mixed with delayed release dosage units.

Sustained release formulations are generally available as diffusion or osmotic systems, for example, Lippincott Williams & Wilkins “Remington-The Science and Practice of Pharmacy” 20th edition (2001, Baltimore, Mary (Land)). A diffusion system is typically composed of one of two types of devices, a reservoir and a matrix, as is well known and described in the art. Matrix devices are generally prepared by compressing the drug into a tablet form with a polymeric carrier that slowly dissolves the drug.

Immediate release parts apply multiple release systems such as applying an immediate release layer over a sustained release core, utilizing a coating or compression process, or encapsulating sustained release and immediate release beads Or can be added to the sustained release system using any method.

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 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. A drug-containing composition is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules for incorporation into a tablet or capsule. May be.

Pulsed release dosage forms mimic multiple dosage profiles without repeated administration, and typical dosages are conventional (eg, as a conventional solid dosage form, as a solution or rapid drug release). Compared to the drug presented as the dosage form, at least a double reduction in dosage frequency is possible. The pulsatile release profile is characterized by a period of no release (time difference) or reduced release following rapid drug release.

Each dosage form contains a therapeutically effective amount of the active agent. In example dosage forms that mimic a twice daily dosing profile, about 30 to 70 weight percent, ideally 40 to 60 weight percent of the total amount of active agent in the dosage form, Released in the initial pulse, correspondingly, 70 to 30 weight percent, ideally 60 to 40 weight percent of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms that mimic a twice daily dosing profile, the second pulse is released about 3 to less than 14 hours, more ideally about 5 to 12 hours after administration.

Another dosage form includes a compressed tablet or capsule with an immediate release dosage unit, a delayed release dosage unit, and an optional second delayed release dosage unit that the drug has. In this dosage form, the immediate release dosage unit comprises a plurality of beads and granules of particles that release the drug substantially immediately after oral administration to provide the initial dose. The delayed release dosage unit comprises coated beads or granules that release the drug approximately 3 to 14 hours after oral administration to provide a second dose.

For transdermal (eg, topical) administration, other methods similar to the parenteral solution described above include diluted sterile aqueous or partially (usually used at a concentration of about 0.1% to 5%). An aqueous solution can be prepared.

Those skilled in the art will be familiar with, or will be apparent in light of the present disclosure, various pharmaceutical compositions containing certain amounts of one or more compounds of Formula I or other active agents. Let's go. See Remington's Pharmaceutical Sciences 19th Edition (1995, Mack Publishing Company, Easton, PA) for an example of how to prepare a pharmaceutical composition.

Further, in certain embodiments, the composition covered by this application can be lyophilized, or other suitable drying techniques such as spray drying. The subject compositions may be administered in a single dose or divided into several lower doses administered at varying time intervals, depending in part on the rate of release of the composition and the desired dosage. May be.

Formulations useful in the methods provided in this application include those suitable for oral, nasal, topical (including buccal and sublingual), enteral, vaginal, aerosol and / or parenteral administration. The formulation may conveniently be provided 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 can vary depending upon the subject being treated and the particular mode of administration.

Methods for preparing these formulations or compositions include the step of combining the composition of the present invention and a carrier, optionally with one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately combining with a liquid carrier or a finely divided solid carrier or both and, if necessary, by shaping the product which provides the subject composition.

The compounds of formula I described in this application can be administered by inhalation or aerosol formulation. An inhalant or aerosol formulation may include one or more agents, such as adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is for example 0.005-90% w / w, ie 0.005 to 50%, 0.005 to 5% w / w, or 0.01, relative to the total weight of the formulation From 1.0 to 1.0% w / w.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition is admixed with one or more pharmaceutically acceptable carriers and / or any of the following. (1) Fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid (2) Binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, 3) wetting agents such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (5) dissolution retardants such as paraffin, (6 ) Absorption enhancers 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, stearic acid Magnesium, solid Polyethylene glycol, lubricants, such as sodium lauryl sulfate, and mixtures thereof, (10) coloring agents. In the case of capsules, tablets and round tablets, the pharmaceutical composition may also comprise a buffer. In addition, similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules using lactose or lactose, similar to 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 can be, for example, water or other solvents, or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Of butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof Inert diluents commonly used in the art, such as solubilizers and emulsifiers can be included.

Suspensions, for example, in addition to the compositions of the present invention include ethoxyl isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. Such a suspending agent may be included.

Formulations for rectal or vaginal administration are, for example, cocoa butter, polyethylene glycol, suppository wax, salicylate, etc., solid at room temperature but liquid at body temperature, and therefore melted and encapsulated in appropriate body cavities One or more suitable nonirritating carriers capable of releasing the compound and composition (s) may be presented as suppositories that can be prepared by mixing the compositions of the present invention. Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams, spray formulations containing carriers as known in the art to be appropriate, and the like.

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 groups and hydrophilic groups to achieve desirable water solubility and transport properties.

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

Methods of delivering a composition or composition 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: 100 weight units of polyvinyl chloride-polyurethane composite and 2-10 weight units of styrene-ethylene-butylene-styrene copolymer. A composite film formed of a resin composition, a first adhesive layer on one side of the composite film, a polyalkylene terephthalate film attached to one side of the composite film by the first adhesive layer, a polyester containing a saturated polyester resin A base sheet comprising a primer layer formed on the surface of an alkylene terephthalate film, and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a laminated pharmaceutical product on the primer layer. The base sheet is manufactured by molding a resin composition on a composite film by calendering to prepare the resin composition, and then bonding a polyalkylene terephthalate film to one side of the composite film using an adhesive layer. Thus, a base sheet is formed, and a primer layer made of a saturated polyester resin on the outer surface of the polyalkylene terephthalate film is formed.

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

Transdermal patches can 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 ionized material through a membrane by passing an electric current. An example of an iontophoretic membrane is described in US Pat. No. 5,080,646 to Theeuwes. The main mechanisms by which iontophoresis enhances molecular transport across the skin are: (a) a method of repelling charged ions from the same charge electrode; (b) preference for counterions when an electric field is applied. Electroosmosis, which is the convective movement of the solvent through the charging pores in response to a typical passage, or (c) a method of increasing skin permeability by passing an electric current.

In some cases it may be desirable to administer in the form of a kit comprising 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 desirable to administer separate components in different dosage forms (eg, oral and parenteral), when administered at different dosage intervals, or when an infusion of individual components of the combination is desired by the prescribing physician 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 consist of a sheet of relatively hard material covered with a foil of plastic material that can generally be transparent.

Methods and compositions for the treatment of local pain. In particular, methods of treating local pain are provided by administering to a patient in need of a therapeutically effective amount of a compound of formula I in this application.
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof.
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, -OH, -OD, C1-C6-alkyl, -NH2, or -COCH3.
n is independently 1, 2, 3, 4 or 5.
Methods using compounds of formula I:

The present invention treats local pain such as infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia and neuralgia A way to do it is also included.
How to make

Examples of synthetic routes useful for preparing compounds of formula I are described in the following examples and generalized in Scheme 1:

Scheme 1:
Step-1: Synthesis of Compound 3:

Under an argon atmosphere, in a three-necked round bottom flask equipped with a mechanical stirrer, dropping funnel and condenser, 19.4 g 2-picolinic acid hydrochloride, 0.3 ml N, N-dimethylformamide, 225 ml dichloromethane Was added. A solution of 11 ml oxalyl chloride (1.05 eq) in 4 ml dichloromethane was then added to the mixture during 30 minutes at 20-25 ° C. The reaction mixture was held at 20-25 ° C for an additional 4.5 hours with vigorous stirring and then cooled to -5 ° C. A solution of 15 ml 2,6-xylidine (1.0 eq) and 20 ml pyridine (2.0 eq) in 15 ml dichloromethane was added at the same temperature over 1 h. The reaction mixture was stirred at −5 ° C. to 0 ° C. for 1 hour, warmed to 20 ° C. and maintained at that temperature for an additional hour to complete the reaction. 200 ml of water was added to the reaction product, stirred for an additional 15 minutes, and the mixture was transferred to a separatory funnel. The organic layer was separated and washed with 100 ml of water. The aqueous layers were mixed and extracted once with 50 ml of dichloromethane. The two organic layers were combined, dried over MgSO 4, filtered and the solvent was removed on a rotary evaporator. The resulting crude solid product (-32 g) was recrystallized with 75 ml chlorohexane, filtered, and the crystals were washed with 15 ml cyclohexane, dried and then yielded to provide 26.0 grams. A slightly yellowish crystal of pipecolic-2-acid-2′6′-xylidide (Compound 3) with 94%, melting point 104.2-104.5 ° C. was obtained.

Step 2: Synthesis of Compound 4:

To an SS reaction bottle equipped with a mechanical stirrer, 25 g piperic-2-acid-2'6'-xylidide (compound 3), 625 ml methanol, 63 ml acetic acid and 15 g Raney nickel were added. The mixture was then passed through with argon for 5 minutes, sealed and filled with 18 kg / cm (260 psi) of hydrogen. The reaction mixture was heated to 50 ° C. and kept under isothermal isothermal conditions for 28-30 hours until the reaction was complete. The reaction product was filtered to remove the catalyst and the mother liquor was concentrated on a rotary evaporator. The crude reaction product was dissolved in 250 ml of toluene, transferred to a separatory funnel, 250 ml of water was added and made basic with 50 ml of 20% aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted twice with 100 ml of toluene. After extraction, the combined organic layers were dried over MgSO 4 and concentrated on a rotary evaporator. The obtained crude solid product was recrystallized from 70 ml of toluene to obtain 18.5 g of a slightly pink solid (Compound 4) having a melting point of 116% at a yield of 72%.

Step 3: Synthesis of Compound 6:

To potassium carbonate (7.2 mmol), 4 (4.8 mmol) and dry suspension, 3-chloropropan-1-ol 5 (5.3 mmol in DMF) was heated to 90 ° C. for 5 hours. The glass microfiber filter filtered above, the filtrate was concentrated and purified by silica gel column chromatography to provide residue 6.

Step 4: Synthesis of Compound 8:

Dichloromethane (DCM) (200 mL, LR grade), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. In HCl (EDCI.HCl) (527.0 mmol, 1.5 eq) and 4-dimethylaminopyridine (DMAP) (18.0 mmol, 1.0 eq), compound 6 (18.0 mmol, 1.0 eq) And a solution of R − (+) − lipoic acid were stirred at room temperature (RT) for 24 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (200 mL), washed with water (2 × 300 mL) followed by brine solution (300 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. It was. The crude product was purified by column chromatography on 100-200 mesh silica gel using ethyl acetate-petroleum ether to give compound 8. Molecular weight: 478.23. Elemental analysis: C, 62.72; H, 8.00; N, 5.85; O, 10.03; S, 13.40.

Scheme-2:
Step-1: Synthesis of Compound 10:

To a stirred solution of compound 9 (10.0 g, 43.10 mol) in DMF (50.0 mL) was added K ₂ CO ₃ (11.3 g, 81.89 mmol) at room temperature, followed by 3-bromopropanol ( 4.69 ml, 51.72 mmol) was added at 0 ° C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water and extracted with DCM (50 mL × 3). The combined organic solvent was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by flash silica gel column chromatography eluting with 4% methanol in dichloromethane to give 10 g (79% yield) of compound 10 as a colorless oil. Mass: 291.2 (M ⁺ + H).

Step-2: (5Z, 8Z, 11Z, 14Z, 17Z) -icosa-5,8,11,14,17-pentaenoic acid 3- [2- (2,6-dimethyl-phenylcarbamoyl) -piperidine-1- Yl] -propyl ester synthesis:

A solution of compound 1 (1.0 g, 0.00331 mol) and compound 10 (0.96 g, 0.00331 mol) in DCM (5 mL) was stirred at 0 ° C. for 30 minutes. Thereafter, EDC. HCl (0.949 g, 0.00496 mol) and DMAP (0.283 g, 0.00232 mol) were added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. After completion, water (20 mL) was added and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified on flash silica gel and eluted with DCM to give 1.05 g (55.16% yield) of CLX-SYN-G16-C02 as a pale yellow oil. Mass: 575.0 [M + H];

Pharmacokinetic assessment of bupivacaine (BU) and Formula I (1-1) in Sprague-Dawley rats free of case pathogens:

300-350 g male Sprague-Dawley rats without specific pathogens were obtained from the laboratory. Animals had free access to food and water. Rats were anesthetized with 1.0 g / mL urethane and 0.1 g / mL (1 mL / kg, ip) chloralose prior to surgery. The femoral vein was cannulated for drug administration, and the body temperature of the rats was maintained with a heating pad during the experiment. All rats remained anesthetized for the duration of the experiment where concentrations of Formula I (1-1) and BU in blood, brain and bile were monitored and an excess amount of CO ₂ under anesthesia after the experimental endpoint. Euthanized by.

Bupivacaine (3 mg / mL) was prepared in 0.9% (w / v) sodium chloride. Formula I (1-1) is equivalent to 3 mg / mL BU. Rats were divided into groups (n = 5 for each group) and administered drugs intravenously. : Group 1 was administered (20 mg / kg) 10 minutes before the administration of BU (3 mg / kg), and Group 2 was administered chemical formula I (1-1) (3 mg / kg).

The chromatographic system is a PM-80 chromatographic pump (BAS, West Lafayette, Indiana, USA), an offline injector (CMA / 140, Stockholm, Sweden) equipped with a 20 L sample loop injector (Rheodynemodel 7125), room temperature (25 ± 2 ° C. ) -Operated UV-Vis detector (Soma, Tokyo, Japan). Separation was accomplished with a LiChrosphere 60RP-select B column (4.6 mm x 250 mm, 5 m, Merck). The mobile phase for plasma, brain homogenate, hemodialysate and brain dialysis consists of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (67: 33: 0.01) adjusted to pH 4.3 with H ₃ PO _4. It was. The mobile phase for bile dialysis consisted of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (60: 40: 0.01) adjusted to pH 6.0 with H ₃ PO ₄ . The flow rate was set at 1.0 mL / min for both mobile phases.

Results: Pharmacokinetic BU parameters and formula I (1-1), both blood and brain as follows:
blood
brain

The term “sample” refers to a sample of body fluid, a sample of isolated cells, or a sample from a tissue or organ. Body fluid samples can be obtained by well-known techniques and ideally include blood, plasma, serum or urine samples, more ideally blood, plasma or serum samples. Tissue or organ samples can be obtained from any tissue or organ, for example, by biopsy. Separated cells can be obtained from body fluids, tissues, or organs by separation techniques such as centrifugation or cell sorting. Ideally, a sample of cells, tissues or organs should be obtained from cells, tissues or organs that express or produce the peptides described herein.
Equivalent

The present disclosure provides, among other things, methods and compositions for treating local pain and its complications. While specific embodiments of the present disclosure have been discussed, the application is illustrative and not restrictive. Many variations of the system and method will be apparent to those in the field upon reviewing this application. The full scope of claimed systems and methods should be determined by application with such variations, and by reference to the claims along with their full equivalents.
Replenishment by quotation

All publications or patents referred to herein, including those listed above, are incorporated herein in their entirety as if all publications and patents were specifically and individually indicated to be incorporated by reference. Incorporated in the book as a reference. In case of conflict, this application, including any definitions in this application, will be determined.

This application is based on International Application No. PCT / IB2013 / 051268 (Title of Invention “Composition and Treatment for Local Pain”, International Publication No. WO / 2013/168006) filed on Feb. 16, 2013. Domestic transition application. This international application further claims the priority of Indian patent application number 1843 / CHE / 2012 filed on May 10, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

  This announcement is widely related to compounds and compositions for the treatment of local pain. More specifically, the invention relates to pharmaceutically acceptable dosages of compounds, crystals, polymorphs, esters, salts, stereoisomers, enantiomers, hydrates, prodrugs, and mixtures thereof. Related to treating the subject.

  Pain is a subjective experience that is influenced by physical, psychological, social, and mental factors. The concept of holistic pain recognizes the importance of all these aspects and recognizes that excellent pain relief would not be possible without paying attention to each aspect. Diseases such as pain and cancer are not synonymous. This is because at least two-thirds of patients experience pain at some point in their illness, and most require powerful analgesics.

  Severe pain, such as pain, depression, fibromyalgia, rheumatoid arthritis, restless leg syndrome, and bipolar disorder, are heterogeneous diseases that have a very different etiology of the nervous system, including the brain, spinal cord, and peripheral nerves It is a gathering of. Many are hereditary and some occur following toxic or metabolic processes. Free radicals are very reactive molecules or species that can exist independently. The generation of highly reactive oxygen species (ROS) is an essential feature of normal cellular functions such as mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. Oxygen free radical release is also delivered during the recovery phase from many pathologically harmful stimuli to the brain tissue. The neurological disorders associated with pain include injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia, diabetic nerves Disability, cancer pain, fibromyalgia, back pain, etc. may be included.

  Managing acute pathology often relies on identifying the underlying pathology and disease symptoms. There is currently a need in the art for new compositions for treating local pain.

  The present invention provides compounds, compositions containing compounds, and methods for using the same to treat, prevent, ameliorate, or all of the effects of conditions such as local pain .

  The present invention provides herein a composition composed of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof. The present invention also provides a pharmaceutical composition composed of one or more compounds consisting of Formula I, its intermediate products, and one or more pharmaceutically acceptable carriers, media or diluents. Offer things. These compositions may be used to treat local pain and related complications.

In certain embodiments, the present invention relates to Formula I and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomeric compounds and compositions thereof. .
Formula I
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, —OH, —OD, C ₁ -C ₆ -alkyl, —NH ₂ , or —COCH ₃ .
n is independently 1, 2, 3, 4 or 5.

As a specific example, an example of a compound of formula I is as follows.
(1-1)
(1-2)

  The application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit may also include instructions for use in the treatment of local pain or its associated complications.

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

  The present application further provides kits comprising the pharmaceutical compositions described herein. The kit may further include instructions for use in the treatment of local pain or related complications.

The compositions described herein have several uses. The present application provides methods for treating patients suffering from, for example, local pain, related complications manifested by metabolic status, and severe diseases and disorders. These include complications such as hepatology, cancer, blood, orthopedics, circulatory organs, kidneys, skin, neurology, and eyes.

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 in the art as one universal technique.

  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 invention may also be solvated, for example hydrated. Solvation may be affected during the manufacturing process or may be made as a hygroscopic result (hydration) of inherently anhydrous compounds of formula I.

  Compounds that have the same molecular formula but differ in their nature, arrangement of atomic bonds, or spatial arrangement of atoms are termed “isomers”. Among them, isomers having different atomic arrangements are called “stereoisomers”. Diastereomers are stereoisomers that have the opposite configuration with respect to one or more chiral centers and that are not enantiomers. Among stereoisomers, stereoisomers with one or more chiral centers that are non-superimposable mirror images of each other are termed “enantiomers”. If the compound has a chiral center, for example when the carbon atom is bonded to 4 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of one or more chiral centers and are represented by the Cahn, Ingold and Prelog R- and S-sequencing rules, or by how the molecule rotates the plane of polarized light. , Dextrorotatory or levorotatory (ie (+) or (−)-isomer in order). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

  As used herein, the term “metabolic state” refers to an inborn error of metabolism (or genetic metabolic condition), a genetic disorder resulting from a defect in one or more metabolic pathways. Specifically, the function of the enzyme is affected and is deficient or completely absent.

  In some examples, the molecular conjugate is R lipoic acid (CAS number 1200-22-2), salsalate (CAS number 552-94-3), acetylcysteine (CAS number 616-91-1), It consists of a compound selected from icosapentaenoic acid (CAS number 10417-94-4) and docosahexaenoic acid (CAS number 6217-54-5).

  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”, as used herein, refer to dosage forms other than enteral and topical administration, and without limitation, intravenous, intramuscular, intrathoracic, Intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal Including injections and infusions.

  “Patient”, “subject”, “host” to be treated by the subject methods will mean either humans or non-human animals such as primates, mammals and vertebrates.

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

  The phrase “pharmaceutically acceptable carrier” is pharmaceutically recognized in the art, eg, a pharmaceutically acceptable substance, composition, or medium, liquid or solid filler, diluent, solvent or An encapsulating material carries the composition of interest from one organ or body part to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is harmful to the patient, does not compete with other components of the subject composition, and is not invasive to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can serve are: (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, 3) Cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) 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, (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol, (12) olein Ethyl acid Esters such as 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) ethanol, (20) phosphate buffer solution, (21) other non-toxic non-competitive substances used in pharmaceutical formulations.

  The term “prodrug” is intended to include compounds that are converted under physiological conditions to an active agent for treatment according to the present invention. A common method for producing prodrugs is to include selected moieties that have been hydrolyzed under physiological conditions to reveal the desired molecule. In another embodiment, the prodrug is converted by the activity of the host animal enzyme.

  The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to a host having one or more of the subject compositions. If it is administered before clinical signs of an undesired situation (eg, host animal disease or other unwanted condition), the treatment is a preventive measure, that is, it progresses to an undesirable condition Protect your host from doing. On the other hand, if it is administered after an indication of an undesirable situation, it is a therapeutic measure. (Example: It is intended to suppress, improve, and stabilize existing unwanted conditions and their side effects.)

  As used herein, the term “predict” refers to abnormalities, complications, and / or terminal platelet aggregation, disability and / or death (ie, mortality) within a future set period (predicted period). To assess the probability associated with a disease that a patient will suffer. This mortality may be caused by the central nervous system or complications. This prediction period is a period during which one or more of the aforementioned complications are progressing according to the predicted probability of the subject. In the analysis by the method of the present invention, the prediction period may be the entire remaining life of the target.

  The term “treating” is art-recognized. Preventing a disease, disorder, or condition that occurs in an animal that may have a predisposition to the disease, disorder, and / or symptom but has not yet been diagnosed with it, for example, slowing its progression, disease, disorder, or condition And causing regression of the disease, disorder, and / or condition, eg, alleviating the disease, disorder, or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected. Specifically, anesthesia, nerve block, epidural anesthesia, intrathecal anesthesia, pain, severe pain, chronic pain, including local infiltration of the subject, even though such drugs do not treat the cause of the condition , Chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia, administration of drugs for neuralgia, and the like. As used herein, the terms “treating”, “treat” or “treatment” include curative treatment, prophylactic treatment (eg, prophylactic treatment), preventive adjuvant treatment and palliative treatment. Yes.

  The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount by which a salt or composition shown herein 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. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 to reach a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of composition administered to a patient depends on absorption, inactivation and excretion rates of the drug, as well as the rate of transfer of salt and composition from the subject composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

  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 containing material. For example, the maximum plasma concentration (Cmax) or the area under the plasma concentration-time curve from time 0 to infinity may be used.

  When used with respect to pharmaceutical compositions or other substances, the term “sustained release” is art-recognized. In contrast to a bolus-type administration in which the entire amount of the substance is made bioavailable at one time, for example, a subject composition that releases the substance over time can exhibit a sustained release characteristic. For example, in one embodiment, one or more pharmaceutically acceptable excipients may be associated with any substance, such as therapeutic, when contacted with a bodily fluid such as blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc. And / or slow release (eg compared to release from a bolus) of sustained or prolonged (eg hydrolysis) by concomitant release of and / or biologically active salts and / or compositions ). This release can result in sustained delivery of a therapeutically effective amount to any therapeutic agent disclosed herein.

  The phrases “systemic administration”, “administered systemically”, “peripheral administration”, “administered peripherally” are recognized in the art, and the subject composition, therapeutic agent or other substance can be administered to the treatment site. Administration to a site away from the body. Administration of a drug for the disease to be treated is not directly into the central nervous system, even if the drug has subsequently diffused systemically, for example, entering a system in the patient's body, where metabolism and other similar processes Depending on the subject's subcutaneous administration, etc., it may be referred to as “local” administration.

  The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount by which a salt or composition shown herein 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. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 and prodrugs.

  The present application also discloses that a pharmaceutical composition comprising a composition of a pharmaceutically acceptable carrier and a compound of formula I can be formulated for systemic administration, topical administration and 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, the pharmaceutical compositions described herein are delivered in an amount sufficient to deliver a therapeutically effective amount of a compound of formula I to a patient as part of a prophylactic or therapeutic treatment. Incorporates the disclosed compounds and compositions (Formula I). The desired concentration of Formula I or a pharmaceutically acceptable salt thereof depends on the absorption, inactivation, excretion rate of the drug, the salt from the composition of interest and the rate of transmission of the composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

  Concentration and / or amount of any compound of Formula I is facilitated by routine screening of animals such as rats by screening the concentration and / or amount range of the substance of interest using an appropriate assay. Can be identified. Also, well-known methods are 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. One such method is described in T.W. E. Microdialysis reviewed in Techniques, Chapter 7, Chapter 1 in Robinson et al., “Microdialysis in the neurosciences” (1991). Briefly, the method reviewed by Robinson can be adapted as follows. The microdialysis loop is placed in situ in the test animal. Dialysate is forced through the loop. When a compound having Formula I as disclosed herein is injected along the loop, the released drug is recovered in the dialysate in proportion to their local tissue concentration. The progress of diffusion of the salt or composition can be determined by following appropriate adjustment procedures using known concentrations of the salt or composition.

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

  In general, when 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 about 100 mg / kg / day in single or divided doses. For example, from 0.01 mg / kg / day to about 50 mg / kg / day, a single dose or divided doses are used. The compound of formula I is, for example, less than 0.2 mg / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day. , 30 / kg / day, or 40 mg / kg / day. Formula I is for human patients, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0 mg per day, 9.0 mg, 12.0 mg, 20.0 mg, 50.0 mg 75.0 mg, 100 mg, 300 mg, 400 mg, 500 mg, 800 mg, 1000 mg, 2000 mg, 5000 mg. In certain examples, the present compositions require less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% of the compound of Formula I, respectively. The amount to be administered for the same therapeutic effect.

  An effective amount of a compound of formula I as described herein indicates the amount of a salt or composition described above that can inhibit or prevent disease.

  Effective doses prevent the severity of complications resulting from nerve damage or demyelination and / or high temperature reactive oxidative nitrosated species and / or abnormal physiological homeostasis in patients at risk of such complications May be sufficient to treat, reduce, improve, stop, suppress, slow or reverse progression or alleviate. Thus, these methods include both medical therapeutic (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 variability between patients, the above dosage is merely a guideline, and the doctor can determine the dosage of the drug to achieve the treatment that the doctor considers appropriate for the patient. Considering the degree of treatment desired, the physician must balance various factors such as the age of the patient, the presence of pre-existing conditions, and the presence of other diseases.

  The compositions provided herein can be administered to a subject in need of treatment through a variety of conventional routes of administration, including, for example, oral, topical, and parenteral, such as intravenous, subcutaneous or intramedullary. Further, the composition may be administered intranasally, as a rectal suppository, or as a “flash” formulation, ie, an agent that dissolves in the mouth without the need for water. In addition, the composition may be administered by controlled release drugs, site-specific drug delivery, transdermal drug delivery patches (active / passive), mediated drug delivery, stereotactic injection, or to subjects in need of treatment with nanoparticles. Can do.

  The composition can be administered either alone 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. The pharmaceutical composition formed by combining the composition, pharmaceutically acceptable carrier, vehicle or diluent can then be in various dosage forms such as tablets, powders, troches, syrups, injectable solutions, etc. Easy to administer. 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, such as starch, alginic acid and certain complex silicates, etc. It can be used with various disintegrants and with 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 or 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 may be combined with various sweetening or flavoring agents, coloring materials or dyes, optionally with emulsifiers or suspensions, Can be combined with diluents such as ethanol, propylene glycol, glycerin and combinations thereof. As is well known in the pharmaceutical arts, the compound of Formula I can also include various excipients coated enterically.

  For parenteral administration, a solution of the composition can be prepared (for example) in sesame or peanut oil, aqueous propylene glycol, or used in a sterile aqueous solution. Such aqueous solutions should be appropriately buffered as needed, 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 in the art.

  Formulations such as tablets are, for example, 10-100 mg, 50-250 mg, 150-500 mg, or 350-800 mg, such as 10 mg, 50 mg, 100 mg, 300 mg, 500 mg, 700 mg, 800 mg of a compound of formula I or a compound of formula I Compounds of Formula I disclosed herein can be included, such as pharmaceutically acceptable salts.

  In general, the compositions described herein can be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be suggested, for example, when the patient suffers from a gastrointestinal disorder and cannot be administered orally, or when the physician determines that the drug is most effective at the surface of the tissue or organ. Local administration may be indicated if high dose administration is desired for the target tissue or organ. Compositions active for buccal administration can take the form of tablets or troches formed in a conventional manner.

  The dosage depends on the identity of the metabolic disease, ie the type of host involved, including age, health, weight, etc., the type of simultaneous treatment, if any, the frequency of treatment and the rate of treatment.

  Illustratively, the dosage levels of the active ingredient to be administered are as follows. 0.1 to about 200 mg / kg for intravenous, 1 to about 500 mg / kg for intramuscular, 5 to about 1000 mg / kg for oral, relative to host body weight (kg), intranasal 5 to about 1000 mg / kg for instillation and 5 to about 1000 mg / kg for aerosol.

  Expressed in concentration, the active ingredient in the composition of the present invention is about 0 to the composition in concentration for topical use in the dermis, intranasal, throat, larynx, bronchus, vagina, rectum, or eye. 0.01 to about 50% w / w, preferably about 1 to about 20% w / w, and for parenteral use at a concentration of about 0.05 to about 50% w / v to the composition, preferably It can be present at about 5 to about 20% w / v.

  The compositions of the present invention are preferably presented in unit dosage form for administration to humans and animals, eg tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions Or it contains an appropriate amount of the active ingredient, such as a suspension, a sterile parenteral solution, an oral solution or suspension of the suspension. For oral administration, solid or liquid unit dosage forms can be prepared.

  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 the like A mixture of Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxy Examples include phenyl cellulose, hydroxyethyl cellulose (HEC), hydroxy pentacellulose, hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose, and hydroxypropyl ethyl cellulose, 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, but are not limited to, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, such as those commercially available from Noveon Chemicals under the trade name CARBOPOL®. High molecular weight crosslinked acrylic acid homopolymers and copolymers are mentioned. Examples of suitable hydrocolloids include, but are not limited to, alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galacto Mannan, pustulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, wilan, 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. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

  The carrier may contain one or more suitable excipients for tablet formulation. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, controlled release excipients, super disintegrants, antioxidants, And mixtures thereof.

  Suitable binders include, but are not limited to, dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, or acacia, alginate, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, cod, gum arabic, Water-soluble polymers containing hydrocolloids such as tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, inulin, weelan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan, Wet binders such as polyvinylpyrrolidone, cellulose, sucrose, and starch, and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch 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 such as magnesium stearate and stearic acid and salts thereof, 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.

  Suitable insoluble edible materials for use as modified release excipients include, but are not limited to, water insoluble polymers and low melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and Of the mixture. 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 vegetable oils such as hydrogenated soybean oil, free fatty acids and their salts, And mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, monoglycerides, diglycerides, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glycerin tris. Laurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl selenium, phosphatidylinositol, phosphatidic 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, paraffin wax, fat-containing mixtures such as chocolate, and mixtures thereof. It is done. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In some embodiments, the tablet core contains super disintegrant up to about 5% of its weight.

  Examples of antioxidants include, but are not limited to, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylhydroxyanisole, 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 certain embodiments, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns, such as, for example, from about 250 microns to about 1000 microns. In an embodiment, the immediate release coating is typically compressed to a density of about 0.9 grams / cc or greater as measured by the weight and volume of that particular layer.

  In certain embodiments, 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, each portion contacts each other on the central axis of the tablet. In certain embodiments, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent.

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

  In certain embodiments, 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 could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multi-layer tablets, capsules, etc. comprising 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, for example, in gelatin capsules. Many methods are known in the art for preparing drugs by coating, covering, or incorporating them.

  As a dosage unit, ie as an outer layer of a tablet, multiple drug-containing beads, granules or particles, or a coated core dosage form, an immediate release agent, together with conventional pharmaceutical excipients, is therapeutically effective. Contains an amount of active ingredient. The immediate release dosage unit may or may not be coated (as in an encapsulated mixture of granules, particles or beads containing immediate release drug and granules or beads containing delayed release drug. ) May or may not be mixed with delayed release dosage units.

  Sustained release formulations are generally available as diffusion or osmotic systems, for example, Lippincott Williams & Wilkins “Remington-The Science and Practice of Pharmacy” 20th edition (2001, Baltimore, Mary (Land)). A diffusion system is typically composed of one of two types of devices, a reservoir and a matrix, as is well known and described in the art. Matrix devices are generally prepared by compression into a tablet form with a polymeric carrier that slowly dissolves the drug.

  Immediate release parts apply multiple release systems such as applying an immediate release layer over a sustained release core, utilizing a coating or compression process, or encapsulating sustained release and immediate release beads Or can be added to the sustained release system using any method.

  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 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. A drug-containing composition is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules for incorporation into a tablet or capsule. May be.

  Pulsed release dosage forms mimic multiple dosage profiles without repeated administration, and typical dosages are conventional (eg, as a conventional solid dosage form, as a solution or rapid drug release). Compared to the drug presented as the dosage form, at least a double reduction in dosage frequency is possible. The pulsatile release profile is characterized by the period of no release (time difference) or reduced release following rapid drug release.

  Each dosage form contains a therapeutically effective amount of the active agent. In example dosage forms that mimic a twice daily dosing profile, about 30 to 70 weight percent, ideally 40 to 60 weight percent of the total amount of active agent in the dosage form, Released in the initial pulse, correspondingly, 70 to 30 weight percent, ideally 60 to 40 weight percent of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms that mimic a twice daily dosing profile, the second pulse is released about 3 to less than 14 hours, more ideally about 5 to 12 hours after administration.

  Another dosage form includes a compressed tablet or capsule with an immediate release dosage unit with the drug, 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 and granules of particles that release the drug substantially immediately after oral administration to provide the initial dose. The delayed release dosage unit comprises coated beads or granules that release the drug approximately 3 to 14 hours after oral administration to provide a second dose.

  For transdermal (eg, topical) administration, other methods similar to the parenteral solution described above include diluted sterile aqueous or partially (usually used at a concentration of about 0.1% to 5%). An aqueous solution can be prepared.

  Those skilled in the art are familiar with, or will be apparent in light of the present disclosure, various pharmaceutical compositions containing certain amounts of one or more compounds of Formula I or other active agents. Let's go. See Remington's Pharmaceutical Sciences 19th Edition (1995, Mack Publishing Company, Easton, PA) for an example of how to prepare a pharmaceutical composition.

  Further, in certain embodiments, the composition covered by the present application can be lyophilized or other suitable drying techniques such as spray drying. The subject compositions may be administered in a single dose or divided into several lower doses administered at varying time intervals, depending in part on the rate of release of the composition and the desired dosage. May be.

  Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), enteral, vaginal, aerosol and / or parenteral administration. The formulation may conveniently be provided 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 can vary depending upon the subject being treated and the particular mode of administration.

  Methods for preparing these formulations or compositions include the step of combining the composition of the present invention and a carrier, optionally with one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimate combination with a liquid carrier or a finely divided solid carrier, or both, and if necessary, by shaping the product which provides the subject composition.

  The compounds of formula I described herein can be administered by inhalation or aerosol formulation. An inhalant or aerosol formulation may include one or more agents, such as adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is for example 0.005-90% w / w, ie 0.005 to 50%, 0.005 to 5% w / w, or 0.01, based on the total weight of the formulation From 1.0 to 1.0% w / w.

  For solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition is mixed with one or more pharmaceutically acceptable carriers and / or any of the following. (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid, (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, (3) wetting agents such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retardants such as paraffin, ( 6) Absorption enhancers 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, stearin Magnesium acid, Body polyethylene glycol, lubricants, such as sodium lauryl sulfate, and mixtures thereof, (10) coloring agents. In the case of capsules, tablets and round tablets, the pharmaceutical composition may also comprise a buffer. In addition, similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules using lactose or lactose, similar to 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 can be, for example, water or other solvents, or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Of butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof Inert diluents commonly used in the art, such as solubilizers and emulsifiers can be included.

  Suspensions, for example, in addition to the compositions of the present invention include ethoxyl isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. Such a suspending agent may be included.

  Formulations for rectal or vaginal administration are, for example, cocoa butter, polyethylene glycol, suppository wax, salicylate, etc., solid at room temperature but liquid at body temperature, and therefore melted and encapsulated in appropriate body cavities One or more suitable nonirritating carriers capable of releasing the compound and composition (s) may be presented as suppositories that can be prepared by mixing the compositions of the present invention. Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams, spray formulations containing carriers as known in the art to be appropriate, and the like.

  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 groups and hydrophilic groups to achieve desirable water solubility and transport properties.

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

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

  In another embodiment, the transdermal patch may comprise: 100 weight units of polyvinyl chloride-polyurethane composite and 2-10 weight units of styrene-ethylene-butylene-styrene copolymer. A composite film formed of a resin composition, a first adhesive layer on one side of the composite film, a polyalkylene terephthalate film attached to one side of the composite film by the first adhesive layer, a polyester containing a saturated polyester resin A second adhesive layer comprising a base sheet comprising a primer layer formed on the surface of an alkylene terephthalate film, and a styrene-diene-styrene block copolymer comprising a laminated pharmaceutical on the primer layer. The base sheet is manufactured by molding a resin composition on a composite film by calendering to prepare the resin composition, and then bonding a polyalkylene terephthalate film to one side of the composite film using an adhesive layer. Thus, a base sheet is formed, and a primer layer made of a saturated polyester resin on the outer surface of the polyalkylene terephthalate film is formed.

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

  Transdermal patches can 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 ionized material through a membrane by passing an electric current. An example of an iontophoretic membrane is described in US Pat. No. 5,080,646 to Theeuwes. The main mechanisms by which iontophoresis enhances molecular transport across the skin are: (a) a method of repelling charged ions from the same charge electrode; (b) preference for counterions when an electric field is applied. Electroosmosis, which is the convective movement of the solvent through the charging pores in response to a typical passage, or (c) a method of increasing skin permeability by passing an electric current.

  In some cases it may be desirable to administer in the form of a kit comprising 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 desirable to administer separate components in different dosage forms (eg, oral and parenteral), when administered at different dosage intervals, or when an infusion of individual components of the combination is desired by the prescribing physician 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 consist of a sheet of relatively hard material covered with a foil of plastic material that can generally be transparent.

Methods and compositions for the treatment of local pain. In particular, methods of treating local pain are provided by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, —OH, —OD, C ₁ -C ₆ -alkyl, —NH ₂ , or —COCH ₃ .
n is independently 1, 2, 3, 4 or 5.

  Methods using compounds of formula I: The present invention includes infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, post-herpes Also included are methods for treating local pain such as neuralgia and neuralgia.

Preparation Methods: Examples of synthetic routes useful for preparing compounds of formula I are described in the following examples and generalized in Scheme 1:

Scheme 1:
Step-1: Synthesis of Compound 3:

  Under an argon atmosphere, in a three-necked round bottom flask equipped with a mechanical stirrer, dropping funnel and condenser, 19.4 g 2-picolinic acid hydrochloride, 0.3 ml N, N-dimethylformamide, 225 ml dichloromethane Was added. A solution of 11 ml oxalyl chloride (1.05 eq) in 4 ml dichloromethane was then added to the mixture during 30 minutes at 20-25 ° C. The reaction mixture was held at 20-25 ° C for an additional 4.5 hours with vigorous stirring and then cooled to -5 ° C. A solution of 15 ml 2,6-xylidine (1.0 eq) and 20 ml pyridine (2.0 eq) in 15 ml dichloromethane was added at the same temperature over 1 h. The reaction mixture was stirred at −5 ° C. to 0 ° C. for 1 hour, warmed to 20 ° C. and maintained at that temperature for an additional hour to complete the reaction. 200 ml of water was added to the reaction product, stirred for an additional 15 minutes, and the mixture was transferred to a separatory funnel. The organic layer was separated and washed with 100 ml of water. The aqueous layers were mixed and extracted once with 50 ml of dichloromethane. The two organic layers were combined, dried over MgSO4, filtered and the solvent was removed on a rotary evaporator. The resulting crude solid product (-32 g) was recrystallized with 75 ml chlorohexane, filtered and the crystals washed with 15 ml cyclohexane and dried, then 26.0 grams yield -94%, mp 104. A slightly yellowish crystal of pipecolic-2-acid-2′6′-xylidide (Compound 3) at 2-104.5 ° C. was obtained.

Step 2: Synthesis of Compound 4:

  To an SS reaction bottle equipped with a mechanical stirrer was added 25 g pipecolic-2-acid-2'6'-xylidide (compound 3), 625 ml methanol, 63 ml acetic acid and 15 g Raney nickel. The mixture was then passed through with argon for 5 minutes, sealed and charged with 18 kg / cm (260 psi) of hydrogen. The reaction mixture was heated to 50 ° C. and kept under isothermal isothermal conditions for 28-30 hours until the reaction was complete. The reaction product was filtered to remove the catalyst and the mother liquor was concentrated on a rotary evaporator. The crude reaction product was dissolved in 250 ml of toluene, transferred to a separatory funnel, 250 ml of water was added and made basic with 50 ml of 20% aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted twice with 100 ml of toluene. After extraction, the combined organic layers were dried over MgSO4 and concentrated on a rotary evaporator. The resulting crude solid product was recrystallized from 70 ml of toluene to give 18.5 g of a slightly pink solid (Compound 4) with a yield of 72% melting point 116 ° C.

Step 3: Synthesis of Compound 6:

  To potassium carbonate (7.2 mmol), 4 (4.8 mmol) and dry suspension, 3-chloropropan-1-ol 5 (5.3 mmol in DMF) was heated to 90 ° C. for 5 hours. The glass microfiber filter filtered above, the filtrate was concentrated and purified by silica gel column chromatography to provide residue 6.

Step 4: Synthesis of Compound 8:

Dichloromethane (DCM) (200 mL, LR grade), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. In HCl (EDCI.HCl) (527.0 mmol, 1.5 eq) and 4-dimethylaminopyridine (DMAP) (18.0 mmol, 1.0 eq), compound 6 (18.0 mmol, 1.0 eq) And a solution of R-(+)-lipoic acid were stirred at room temperature (RT) for 24 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (200 mL), washed with water (2 × 300 mL) followed by brine solution (300 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. . The crude product was purified by column chromatography on 100-200 mesh silica gel using ethyl acetate-petroleum ether to give compound 8. Molecular weight: 478.23. Elemental analysis: C, 62.72; H, 8.00; N, 5.85; O, 10.03; S, 13.40.

  Example: Pharmacokinetic assessment of bupivacaine (BU) and Formula I (1-1) in Sprague-Dawley rats free of pathogens:

300-350 g male Sprague-Dawley rats without specific pathogens were obtained from the laboratory. Rats had free access to food and water. Rats were anesthetized with 1.0 g / mL urethane and 0.1 g / mL (1 mL / kg, ip) chloralose prior to surgery. The femoral vein was cannulated for drug administration, and the body temperature of the rats was maintained with a heating pad during the experiment. All rats remained anesthetized for the duration of the experiment where concentrations of Formula I (1-1) and BU in blood, brain and bile were monitored and an excess amount of CO ₂ under anesthesia after the experimental endpoint. Euthanized by.

  Bupivacaine (3 mg / mL) was prepared in 0.9% (w / v) sodium chloride. Chemical formula I (1-1) is equivalent to 3 mg / mL BU. Rats were divided into groups (n = 5 per group) and administered drugs intravenously. Group 1 was administered (20 mg / kg) 10 minutes before the administration of BU (3 mg / kg), and Group 2 was administered Chemical Formula I (1-1) (3 mg / kg).

The chromatographic system is a PM-80 chromatographic pump (BAS, West Lafayette, Indiana, USA), an offline injector (CMA / 140, Stockholm, Sweden) equipped with a 20 L sample loop injector (Rheodynemodel 7125), room temperature (25 ± 2 ° C. ) -Operated UV-Vis detector (Soma, Tokyo, Japan). Separation was accomplished with a LiChrosphere 60RP-select B column (4.6 mm x 250 mm, 5 m, Merck). The mobile phase for plasma, brain homogenate, hemodialysate and brain dialysis consists of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (67: 33: 0.01) adjusted to pH 4.3 with H ₃ PO _4. It was. The mobile phase for bile dialysis consisted of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (60: 40: 0.01) adjusted to pH 6.0 with H ₃ PO ₄ . The flow rate was set at 1.0 mL / min for both mobile phases.

Results: Blood and brain pharmacokinetic parameters of BU and Formula I (1-1) were as follows.
blood
brain

    The term “sample” refers to a sample of body fluid, a sample of isolated cells, or a sample from a tissue or organ. Body fluid samples can be obtained by well-known techniques and ideally include blood, plasma, serum or urine samples, more ideally blood, plasma or serum samples. Tissue or organ samples can be obtained from any tissue or organ, for example, by biopsy. Separated cells can be obtained from body fluids, tissues, or organs by separation techniques such as centrifugation or cell sorting. Ideally, a sample of cells, tissues or organs should be obtained from cells, tissues or organs that express or produce the peptides described herein.

  Equivalents: The present disclosure provides methods and compositions specifically for treating local pain and its complications. While specific embodiments of the present disclosure have been discussed, the application is illustrative and not restrictive. Many variations of the system and method will become apparent to those skilled in the art upon review of this application. The full scope of the claimed systems and methods should be determined by this application along with such variations and by reference to the claims along with their full equivalents.

  Supplementation by citation: All publications or patents referred to herein are those listed above, and all publications and patents are specifically and individually indicated to be incorporated by reference as if Incorporated herein by reference in its entirety. In case of conflict, the present application, including any definitions in the present application, will prevail.

This application is based on International Application No. PCT / IB2013 / 051268 (Title of Invention “Composition and Treatment for Local Pain”, International Publication No. WO / 2013/168006) filed on Feb. 16, 2013. Domestic transition application. This international application further claims the priority of Indian patent application number 1843 / CHE / 2012 filed on May 10, 2012. The entire disclosure of the priority application is relied upon for all purposes and is incorporated herein by reference.

  This announcement is widely related to compounds and compositions for the treatment of local pain. More specifically, the invention relates to pharmaceutically acceptable dosages of compounds, crystals, polymorphs, esters, salts, stereoisomers, enantiomers, hydrates, prodrugs, and mixtures thereof. Related to treating the subject.

  Pain is a subjective experience that is influenced by physical, psychological, social, and mental factors. The concept of holistic pain recognizes the importance of all these aspects and recognizes that excellent pain relief would not be possible without paying attention to each aspect. Diseases such as pain and cancer are not synonymous. This is because at least two-thirds of patients experience pain at some point in their illness, and most require powerful analgesics.

  Severe pain, such as pain, depression, fibromyalgia, rheumatoid arthritis, restless leg syndrome, and bipolar disorder, are heterogeneous diseases that have a very different etiology of the nervous system, including the brain, spinal cord, and peripheral nerves It is a gathering of. Many are hereditary and some occur following toxic or metabolic processes. Free radicals are very reactive molecules or species that can exist independently. The generation of highly reactive oxygen species (ROS) is an essential feature of normal cellular functions such as mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. Oxygen free radical release is also delivered during the recovery phase from many pathologically harmful stimuli to the brain tissue. The neurological disorders associated with pain include injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, postherpetic neuralgia, diabetic nerves Disability, cancer pain, fibromyalgia, back pain, etc. may be included.

  Managing acute pathology often relies on identifying the underlying pathology and disease symptoms. There is currently a need in the art for new compositions for treating local pain.

  The present invention provides compounds, compositions containing compounds, and methods for using the same to treat, prevent, ameliorate, or all of the effects of conditions such as local pain .

  The present invention provides herein a composition composed of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, or stereoisomer thereof. The present invention also provides a pharmaceutical composition composed of one or more compounds consisting of Formula I, its intermediate products, and one or more pharmaceutically acceptable carriers, media or diluents. Offer things. These compositions may be used to treat local pain and related complications.

In certain embodiments, the present invention relates to Formula I and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, or stereoisomeric compounds and compositions thereof. .
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof.
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, —OH, —OD, C ₁ -C ₆ -alkyl, —NH ₂ , or —COCH ₃ .
n is independently 1, 2, 3, 4 or 5.

As a specific example, an example of a compound of formula I is as follows.
(1-1)
(1-2)

  The application also provides kits comprised of any of the pharmaceutical compositions disclosed herein. The kit may also include instructions for use in the treatment of local pain or its associated complications.

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

  The present application further provides kits comprising the pharmaceutical compositions described herein. The kit may further include instructions for use in the treatment of local pain or related complications.

The compositions described herein have several uses. The present application provides methods for treating patients suffering from, for example, local pain, related complications manifested by metabolic status, and severe diseases and disorders. These include complications such as hepatology, cancer, blood, orthopedics, circulatory organs, kidneys, skin, neurology, and eyes.

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 in the art as one universal technique.

  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 invention may also be solvated, for example hydrated. Solvation may be affected during the manufacturing process or may be made as a hygroscopic result (hydration) of inherently anhydrous compounds of formula I.

  Compounds that have the same molecular formula but differ in their nature, arrangement of atomic bonds, or spatial arrangement of atoms are termed “isomers”. Among them, isomers having different atomic arrangements are called “stereoisomers”. Diastereomers are stereoisomers that have the opposite configuration with respect to one or more chiral centers and that are not enantiomers. Among stereoisomers, stereoisomers with one or more chiral centers that are non-superimposable mirror images of each other are termed “enantiomers”. If the compound has a chiral center, for example when the carbon atom is bonded to 4 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of one or more chiral centers and are represented by the Cahn, Ingold and Prelog R- and S-sequencing rules, or by how the molecule rotates the plane of polarized light. , Dextrorotatory or levorotatory (ie (+) or (−)-isomer in order). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

  As used herein, the term “metabolic state” refers to an inborn error of metabolism (or genetic metabolic condition), a genetic disorder resulting from a defect in one or more metabolic pathways. Specifically, the function of the enzyme is affected and is deficient or completely absent.

  In some examples, the molecular conjugate is R lipoic acid (CAS number 1200-22-2), salsalate (CAS number 552-94-3), acetylcysteine (CAS number 616-91-1), It consists of a compound selected from icosapentaenoic acid (CAS number 10417-94-4) and docosahexaenoic acid (CAS number 6217-54-5).

  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”, as used herein, refer to dosage forms other than enteral and topical administration, and without limitation, intravenous, intramuscular, intrathoracic, Intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal Including injections and infusions.

  “Patient”, “subject”, “host” to be treated by the subject methods will mean either humans or non-human animals such as primates, mammals and vertebrates.

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

  The phrase “pharmaceutically acceptable carrier” is pharmaceutically recognized in the art, eg, a pharmaceutically acceptable substance, composition, or medium, liquid or solid filler, diluent, solvent or An encapsulating material carries the composition of interest from one organ or body part to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is harmful to the patient, does not compete with other components of the subject composition, and is not invasive to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can serve are: (1) sugars such as lactose, glucose and sucrose, (2) starches such as corn starch and potato starch, 3) Cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) 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, (10) glycols such as propylene glycol, (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol, (12) olein Ethyl acid Esters such as 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) ethanol, (20) phosphate buffer solution, (21) other non-toxic non-competitive substances used in pharmaceutical formulations.

  The term “prodrug” is intended to include compounds that are converted under physiological conditions to an active agent for treatment according to the present invention. A common method for producing prodrugs is to include selected moieties that have been hydrolyzed under physiological conditions to reveal the desired molecule. In another embodiment, the prodrug is converted by the activity of the host animal enzyme.

  The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to a host having one or more of the subject compositions. If it is administered before clinical signs of an undesired situation (eg, host animal disease or other unwanted condition), the treatment is a preventive measure, that is, it progresses to an undesirable condition Protect your host from doing. On the other hand, if it is administered after an indication of an undesirable situation, it is a therapeutic measure. (Example: It is intended to suppress, improve, and stabilize existing unwanted conditions and their side effects.)

  As used herein, the term “predict” refers to abnormalities, complications, and / or terminal platelet aggregation, disability and / or death (ie, mortality) within a future set period (predicted period). To assess the probability associated with a disease that a patient will suffer. This mortality may be caused by the central nervous system or complications. This prediction period is a period during which one or more of the aforementioned complications are progressing according to the predicted probability of the subject. In the analysis by the method of the present invention, the prediction period may be the entire remaining life of the target.

  The term “treating” is art-recognized. Preventing a disease, disorder, or condition that occurs in an animal that may have a predisposition to the disease, disorder, and / or symptom but has not yet been diagnosed with it, for example, slowing its progression, disease, disorder, or condition And causing regression of the disease, disorder, and / or condition, eg, alleviating the disease, disorder, or condition. Treating a disease or condition includes ameliorating at least one symptom of a particular disease or condition, even if the underlying pathophysiology is not affected. Specifically, anesthesia, nerve block, epidural anesthesia, intrathecal anesthesia, pain, severe pain, chronic pain, including local infiltration of the subject, even though such drugs do not treat the cause of the condition , Chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia, administration of drugs for neuralgia, and the like. As used herein, the terms “treating”, “treat” or “treatment” include curative treatment, prophylactic treatment (eg, prophylactic treatment), preventive adjuvant treatment and palliative treatment. Yes.

  The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount by which a salt or composition shown herein 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. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 to reach a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of composition administered to a patient depends on absorption, inactivation and excretion rates of the drug, as well as the rate of transfer of salt and composition from the subject composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

  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 containing material. For example, the maximum plasma concentration (Cmax) or the area under the plasma concentration-time curve from time 0 to infinity may be used.

  When used with respect to pharmaceutical compositions or other substances, the term “sustained release” is art-recognized. In contrast to a bolus-type administration in which the entire amount of the substance is made bioavailable at one time, for example, a subject composition that releases the substance over time can exhibit a sustained release characteristic. For example, in one embodiment, one or more pharmaceutically acceptable excipients may be associated with any substance, such as therapeutic, when contacted with a bodily fluid such as blood, cerebrospinal fluid, mucus secretions, lymph fluid, etc. And / or slow release (eg compared to release from a bolus) of sustained or prolonged (eg hydrolysis) by concomitant release of and / or biologically active salts and / or compositions ). This release can result in sustained delivery of a therapeutically effective amount to any therapeutic agent disclosed herein.

  The phrases “systemic administration”, “administered systemically”, “peripheral administration”, “administered peripherally” are recognized in the art, and the subject composition, therapeutic agent or other substance can be administered to the treatment site. Administration to a site away from the body. Administration of a drug for the disease to be treated is not directly into the central nervous system, even if the drug has subsequently diffused systemically, for example, entering a system in the patient's body, where metabolism and other similar processes Depending on the subject's subcutaneous administration, etc., it may be referred to as “local” administration.

  The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount by which a salt or composition shown herein 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. Effective amounts can vary greatly depending on factors such as the disease or condition being treated, the particular subject construct being administered, the size of the subject being administered, the severity of the disease or condition. Those having ordinary skill 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 and prodrugs.

  The present application also discloses that a pharmaceutical composition comprising a composition of a pharmaceutically acceptable carrier and a compound of formula I can be formulated for systemic administration, topical administration and 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, the pharmaceutical compositions described herein are delivered in an amount sufficient to deliver a therapeutically effective amount of a compound of formula I to a patient as part of a prophylactic or therapeutic treatment. Incorporates the disclosed compounds and compositions (Formula I). The desired concentration of Formula I or a pharmaceutically acceptable salt thereof depends on the absorption, inactivation, excretion rate of the drug, the salt from the composition of interest and the rate of transmission of the composition. It should be noted that dosage values can also be varied to reduce the severity of the condition. Further, for any particular subject, it should be understood that the particular dosing regimen should be adjusted accordingly according to the individual's needs and the professional judgment of the person or person who supervises the administration of the composition. I want to be. Typically, dosing is determined using techniques known in the art.

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

  Concentration and / or amount of any compound of Formula I is facilitated by routine screening of animals such as rats by screening the concentration and / or amount range of the substance of interest using an appropriate assay. Can be identified. Also, well-known methods are 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. One such method is described in T.W. E. Microdialysis reviewed in TechnIques, Volume 7, Chapter 1 in Robinson et al., “MIcrodIallysIs in the neurosciences” (1991). Briefly, the method reviewed by Robinson can be adapted as follows. The microdialysis loop is placed in sItu in the test animals. Dialysate is forced through the loop. When a compound having Formula I as disclosed herein is injected along the loop, the released drug is recovered in the dialysate in proportion to their local tissue concentration. The progress of diffusion of the salt or composition can be determined by following appropriate adjustment procedures using known concentrations of the salt or composition.

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

  In general, when 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 about 100 mg / kg / day in single or divided doses. For example, from 0.01 mg / kg / day to about 50 mg / kg / day, a single dose or divided doses are used. The compound of formula I is, for example, less than 0.2 mg / kg / day, 0.5 mg / kg / day, 1.0 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day. , 30 / kg / day, or 40 mg / kg / day. Formula I is for human patients, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0 mg per day, 9.0 mg, 12.0 mg, 20.0 mg, 50.0 mg 75.0 mg, 100 mg, 300 mg, 400 mg, 500 mg, 800 mg, 1000 mg, 2000 mg, 5000 mg. In certain examples, the present compositions require less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% of the compound of Formula I, respectively. The amount to be administered for the same therapeutic effect.

  An effective amount of a compound of formula I as described herein indicates the amount of a salt or composition described above that can inhibit or prevent disease.

  Effective doses prevent the severity of complications resulting from nerve damage or demyelination and / or high temperature reactive oxidative nitrosated species and / or abnormal physiological homeostasis in patients at risk of such complications May be sufficient to treat, reduce, improve, stop, suppress, slow or reverse progression or alleviate. Thus, these methods include both medical therapeutic (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 variability between patients, the above dosage is merely a guideline, and the doctor can determine the dosage of the drug to achieve the treatment that the doctor considers appropriate for the patient. Considering the degree of treatment desired, the physician must balance various factors such as the age of the patient, the presence of pre-existing conditions, and the presence of other diseases.

  The compositions provided herein can be administered to a subject in need of treatment through a variety of conventional routes of administration, including, for example, oral, topical, and parenteral, such as intravenous, subcutaneous or intramedullary. Further, the composition may be administered intranasally, as a rectal suppository, or as a “flash” formulation, ie, an agent that dissolves in the mouth without the need for water. In addition, the composition may be administered by controlled release drugs, site-specific drug delivery, transdermal drug delivery patches (active / passive), mediated drug delivery, stereotactic injection, or to subjects in need of treatment with nanoparticles. Can do.

  The composition can be administered either alone 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. The pharmaceutical composition formed by combining the composition, pharmaceutically acceptable carrier, vehicle or diluent can then be in various dosage forms such as tablets, powders, troches, syrups, injectable solutions, etc. Easy to administer. 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, such as starch, alginic acid and certain complex silicates, etc. It can be used with various disintegrants and with 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 or 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 may be combined with various sweetening or flavoring agents, coloring materials or dyes, optionally with emulsifiers or suspensions, Can be combined with diluents such as ethanol, propylene glycol, glycerin and combinations thereof. As is well known in the pharmaceutical arts, the compound of Formula I can also include various excipients coated enterically.

  For parenteral administration, a solution of the composition can be prepared (for example) in sesame or peanut oil, aqueous propylene glycol, or used in a sterile aqueous solution. Such aqueous solutions should be appropriately buffered as needed, 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 in the art.

  Formulations such as tablets are, for example, 10-100 mg, 50-250 mg, 150-500 mg, or 350-800 mg, such as 10 mg, 50 mg, 100 mg, 300 mg, 500 mg, 700 mg, 800 mg of a compound of formula I or a compound of formula I Compounds of Formula I disclosed herein can be included, such as pharmaceutically acceptable salts.

  In general, the compositions described herein can be administered orally or parenterally (eg, intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be suggested, for example, when the patient suffers from a gastrointestinal disorder and cannot be administered orally, or when the physician determines that the drug is most effective at the surface of the tissue or organ. Local administration may be indicated if high dose administration is desired for the target tissue or organ. Compositions active for buccal administration can take the form of tablets or troches formed in a conventional manner.

  The dosage depends on the identity of the metabolic disease, ie the type of host involved, including age, health, weight, etc., the type of simultaneous treatment, if any, the frequency of treatment and the rate of treatment.

  Illustratively, the dosage levels of the active ingredient to be administered are as follows. 0.1 to about 200 mg / kg for intravenous, 1 to about 500 mg / kg for intramuscular, 5 to about 1000 mg / kg for oral, relative to host body weight (kg), intranasal 5 to about 1000 mg / kg for instillation and 5 to about 1000 mg / kg for aerosol.

  Expressed in concentration, the active ingredient in the composition of the present invention is about 0 to the composition in concentration for topical use in the dermis, intranasal, pharynx, bronchial, vagina, rectum, or eye. 0.01 to about 50% w / w, preferably about 1 to about 20% w / w, and for parenteral use at a concentration of about 0.05 to about 50% w / v to the composition, preferably It can be present at about 5 to about 20% w / v.

  The compositions of the present invention are preferably presented in unit dosage form for administration to humans and animals, eg tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions Or it contains an appropriate amount of the active ingredient, such as a suspension, a sterile parenteral solution, an oral solution or suspension of the suspension. For oral administration, solid or liquid unit dosage forms can be prepared.

  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 the like A mixture of Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxy Examples include phenyl cellulose, hydroxyethyl cellulose (HEC), hydroxy pentacellulose, hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose, and hydroxypropyl ethyl cellulose, 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, but are not limited to, potassium methacrylate divinylbenzene copolymer, polymethyl methacrylate, such as those commercially available from Noveon ChemIcals under the trade name CARBOPOL®. High molecular weight crosslinked acrylic acid homopolymers and copolymers are mentioned. Examples of suitable hydrocolloids include, but are not limited to, alginate, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galacto Mannan, pustulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, wilan, 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. Examples of suitable swellable cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, cross-linked sodium carboxymethyl cellulose, and mixtures thereof.

  The carrier may contain one or more suitable excipients for tablet formulation. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, controlled release excipients, super disintegrants, antioxidants, And mixtures thereof.

  Suitable binders include, but are not limited to, dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, or acacia, alginate, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, cod, gum arabic, Water-soluble polymers including hydrocolloids such as tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, inulin, weelan, ramsan, zoolan, methylan, chitin, cyclodextrin, chitosan, Wet binders such as polyvinylpyrrolidone, cellulose, sucrose, and starch, and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch 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 such as magnesium stearate and stearic acid and salts thereof, 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.

  Suitable insoluble edible materials for use as modified release excipients include, but are not limited to, water insoluble polymers and low melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose acetate and derivatives thereof, acrylates, methacrylates, acrylic acid copolymers, copolymers thereof, and Of the mixture. 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 vegetable oils such as hydrogenated soybean oil, free fatty acids and their salts, And mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, monoglycerides, diglycerides, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glycerin tris. Laurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, and mixtures thereof. Examples of suitable phospholipids include phosphatidylcholine, phosphatidyl selenium, phosphatidylinositol, phosphatidic 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, paraffin wax, fat-containing mixtures such as chocolate, and mixtures thereof. It is done. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and crospovidone (crospovidone). In some embodiments, the tablet core contains super disintegrant up to about 5% of its weight.

  Examples of antioxidants include, but are not limited to, tocopherol, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylhydroxyanisole, 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 certain embodiments, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns, such as, for example, from about 250 microns to about 1000 microns. In an embodiment, the immediate release coating is typically compressed to a density of about 0.9 grams / cc or greater as measured by the weight and volume of that particular layer.

  In certain embodiments, 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, each portion contacts each other on the central axis of the tablet. In certain embodiments, the first portion includes a first pharmaceutically active agent and the second portion includes a second pharmaceutically active agent.

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

  In certain embodiments, 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 could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multi-layer tablets, capsules, etc. comprising 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, for example, in gelatin capsules. Many methods are known in the art for preparing drugs by coating, covering, or incorporating them.

  As a dosage unit, ie as an outer layer of a tablet, multiple drug-containing beads, granules or particles, or a coated core dosage form, an immediate release agent, together with conventional pharmaceutical excipients, is therapeutically effective. Contains an amount of active ingredient. The immediate release dosage unit may or may not be coated (as in an encapsulated mixture of granules, particles or beads containing immediate release drug and granules or beads containing delayed release drug. ) May or may not be mixed with delayed release dosage units.

  Sustained release formulations are generally available as diffusion or osmotic systems, for example, Lippincott Williams & Wilkins "RemInton-The ScIence and Practice of Pharmacy" 20th edition (2001, Baltimore, Mary (Land)). A diffusion system is typically composed of one of two types of devices, a reservoir and a matrix, as is well known and described in the art. Matrix devices are generally prepared by compression into a tablet form with a polymeric carrier that slowly dissolves the drug.

  Immediate release parts apply multiple release systems such as applying an immediate release layer over a sustained release core, utilizing a coating or compression process, or encapsulating sustained release and immediate release beads Or can be added to the sustained release system using any method.

  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 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. A drug-containing composition is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated core” dosage form, or a plurality of drug-containing beads, particles or granules for incorporation into a tablet or capsule. May be.

  Pulsed release dosage forms mimic multiple dosage profiles without repeated administration, and typical dosages are conventional (eg, as a conventional solid dosage form, as a solution or rapid drug release). Compared to the drug presented as the dosage form, at least a double reduction in dosage frequency is possible. The pulsatile release profile is characterized by the period of no release (time difference) or reduced release following rapid drug release.

  Each dosage form contains a therapeutically effective amount of the active agent. In example dosage forms that mimic a twice daily dosing profile, about 30 to 70 weight percent, ideally 40 to 60 weight percent of the total amount of active agent in the dosage form, Released in the initial pulse, correspondingly, 70 to 30 weight percent, ideally 60 to 40 weight percent of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms that mimic a twice daily dosing profile, the second pulse is released about 3 to less than 14 hours, more ideally about 5 to 12 hours after administration.

  Another dosage form includes a compressed tablet or capsule with an immediate release dosage unit with the drug, 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 and granules of particles that release the drug substantially immediately after oral administration to provide the initial dose. The delayed release dosage unit comprises coated beads or granules that release the drug approximately 3 to 14 hours after oral administration to provide a second dose.

  For transdermal (eg, topical) administration, other methods similar to the parenteral solution described above include diluted sterile aqueous or partially (usually used at a concentration of about 0.1% to 5%). An aqueous solution can be prepared.

  Those skilled in the art are familiar with, or will be apparent in light of the present disclosure, various pharmaceutical compositions containing certain amounts of one or more compounds of Formula I or other active agents. Let's go. See Remington's Pharmaceutical ScIences 19th Edition (1995, Mack PublShIng Company, Easton, PA) for an example of how to prepare a pharmaceutical composition.

  Further, in certain embodiments, the composition covered by the present application can be lyophilized or other suitable drying techniques such as spray drying. The subject compositions may be administered in a single dose or divided into several lower doses administered at varying time intervals, depending in part on the rate of release of the composition and the desired dosage. May be.

  Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), enteral, vaginal, aerosol and / or parenteral administration. The formulation may conveniently be provided 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 can vary depending upon the subject being treated and the particular mode of administration.

  Methods for preparing these formulations or compositions include the step of combining the composition of the present invention and a carrier, optionally with one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimate combination with a liquid carrier or a finely divided solid carrier, or both, and if necessary, by shaping the product which provides the subject composition.

  The compounds of formula I described herein can be administered by inhalation or aerosol formulation. An inhalant or aerosol formulation may include one or more agents, such as adjuvants, diagnostic agents, contrast agents, or therapeutic agents useful for inhalation therapy. The final aerosol formulation is for example 0.005-90% w / w, ie 0.005 to 50%, 0.005 to 5% w / w, or 0.01, based on the total weight of the formulation From 1.0 to 1.0% w / w.

  For solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the composition is mixed with one or more pharmaceutically acceptable carriers and / or any of the following. (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid, (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, (3) wetting agents such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retardants such as paraffin, ( 6) Absorption enhancers 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, stearin Magnesium acid, Body polyethylene glycol, lubricants, such as sodium lauryl sulfate, and mixtures thereof, (10) coloring agents. In the case of capsules, tablets and round tablets, the pharmaceutical composition may also comprise a buffer. In addition, similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules using lactose or lactose, similar to 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 can be, for example, water or other solvents, or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Of butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof Inert diluents commonly used in the art, such as solubilizers and emulsifiers can be included.

  Suspensions, for example, in addition to the compositions of the present invention include ethoxyl isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. Such a suspending agent may be included.

  Formulations for rectal or vaginal administration are, for example, cocoa butter, polyethylene glycol, suppository wax, salicylate, etc., solid at room temperature but liquid at body temperature, and therefore melted and encapsulated in appropriate body cavities One or more suitable nonirritating carriers capable of releasing the compound and composition (s) may be presented as suppositories that can be prepared by mixing the compositions of the present invention. Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams, spray formulations containing carriers as known in the art to be appropriate, and the like.

  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 groups and hydrophilic groups to achieve desirable water solubility and transport properties.

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

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

  In another embodiment, the transdermal patch may comprise: 100 weight units of polyvinyl chloride-polyurethane composite and 2-10 weight units of styrene-ethylene-butylene-styrene copolymer. A composite film formed of a resin composition, a first adhesive layer on one side of the composite film, a polyalkylene terephthalate film attached to one side of the composite film by the first adhesive layer, a polyester containing a saturated polyester resin A second adhesive layer comprising a base sheet comprising a primer layer formed on the surface of an alkylene terephthalate film, and a styrene-diene-styrene block copolymer comprising a laminated pharmaceutical on the primer layer. The base sheet is manufactured by molding a resin composition on a composite film by calendering to prepare the resin composition, and then bonding a polyalkylene terephthalate film to one side of the composite film using an adhesive layer. Thus, a base sheet is formed, and a primer layer made of a saturated polyester resin on the outer surface of the polyalkylene terephthalate film is formed.

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

  Transdermal patches can 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 ionized material through a membrane by passing an electric current. An example of an iontophoretic membrane is described in US Pat. No. 5,080,646 to Theeuwes. The main mechanisms by which iontophoresis enhances molecular transport across the skin are: (a) a method of repelling charged ions from the same charge electrode; (b) preference for counterions when an electric field is applied. Electroosmosis, which is the convective movement of the solvent through the charging pores in response to a typical passage, or (c) a method of increasing skin permeability by passing an electric current.

  In some cases it may be desirable to administer in the form of a kit comprising 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 desirable to administer separate components in different dosage forms (eg, oral and parenteral), when administered at different dosage intervals, or when an infusion of individual components of the combination is desired by the prescribing physician 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 consist of a sheet of relatively hard material covered with a foil of plastic material that can generally be transparent.

Methods and compositions for the treatment of local pain. In particular, methods of treating local pain are provided by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I herein.
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof.
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
Or
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, —OH, —OD, C ₁ -C ₆ -alkyl, —NH ₂ , or —COCH ₃ .
n is independently 1, 2, 3, 4 or 5.

  Methods using compounds of formula I: The present invention includes infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, post-herpes Also included are methods for treating local pain such as neuralgia and neuralgia.

Preparation Methods: Examples of synthetic routes useful for preparing compounds of formula I are described in the following examples and generalized in Scheme 1:

Scheme 1:
Step-1: Synthesis of Compound 3:

  Under an argon atmosphere, in a three-necked round bottom flask equipped with a mechanical stirrer, dropping funnel and condenser, 19.4 g 2-picolinic acid hydrochloride, 0.3 ml N, N-dimethylformamide, 225 ml dichloromethane Was added. A solution of 11 ml oxalyl chloride (1.05 eq) in 4 ml dichloromethane was then added to the mixture during 30 minutes at 20-25 ° C. The reaction mixture was held at 20-25 ° C for an additional 4.5 hours with vigorous stirring and then cooled to -5 ° C. A solution of 15 ml 2,6-xylidine (1.0 eq) and 20 ml pyridine (2.0 eq) in 15 ml dichloromethane was added at the same temperature over 1 h. The reaction mixture was stirred at −5 ° C. to 0 ° C. for 1 hour, warmed to 20 ° C. and maintained at that temperature for an additional hour to complete the reaction. 200 ml of water was added to the reaction product, stirred for an additional 15 minutes, and the mixture was transferred to a separatory funnel. The organic layer was separated and washed with 100 ml of water. The aqueous layers were mixed and extracted once with 50 ml of dichloromethane. The two organic layers were combined, dried over MgSO4, filtered and the solvent was removed on a rotary evaporator. The resulting crude solid product (-32 g) was recrystallized with 75 ml chlorohexane, filtered and the crystals washed with 15 ml cyclohexane and dried, then 26.0 grams yield -94%, mp 104. A slightly yellowish crystal of pipecolic-2-acid-2′6′-xylidide (Compound 3) at 2-104.5 ° C. was obtained.

Step 2: Synthesis of Compound 4:

  To an SS reaction bottle equipped with a mechanical stirrer was added 25 g pipecolic-2-acid-2'6'-xylidide (compound 3), 625 ml methanol, 63 ml acetic acid and 15 g Raney nickel. The mixture was then passed through with argon for 5 minutes, sealed, and charged with 18 kg / cm (260 psi) of hydrogen. The reaction mixture was heated to 50 ° C. and kept under isothermal isothermal conditions for 28-30 hours until the reaction was complete. The reaction product was filtered to remove the catalyst and the mother liquor was concentrated on a rotary evaporator. The crude reaction product was dissolved in 250 ml of toluene, transferred to a separatory funnel, 250 ml of water was added and made basic with 50 ml of 20% aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted twice with 100 ml of toluene. After extraction, the combined organic layers were dried over MgSO4 and concentrated on a rotary evaporator. The resulting crude solid product was recrystallized from 70 ml of toluene to give 18.5 g of a slightly pink solid (Compound 4) with a yield of 72% melting point 116 ° C.

Step 3: Synthesis of Compound 6:

  To potassium carbonate (7.2 mmol), 4 (4.8 mmol) and dry suspension, 3-chloropropan-1-ol 5 (5.3 mmol in DMF) was heated to 90 ° C. for 5 hours. The glass microfiber filter filtered above, the filtrate was concentrated and purified by silica gel column chromatography to provide residue 6.

Step 4: Synthesis of Compound 8:

Dichloromethane (DCM) (200 mL, LR grade), 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide. In HCl (EDCI.HCl) (527.0 mmol, 1.5 eq) and 4-dimethylaminopyridine (DMAP) (18.0 mmol, 1.0 eq), compound 6 (18.0 mmol, 1.0 eq) And a solution of R-(+)-lipoic acid were stirred at room temperature (RT) for 24 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (200 mL), washed with water (2 × 300 mL) followed by brine solution (300 mL), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. . The crude product was purified by column chromatography on 100-200 mesh silica gel using ethyl acetate-petroleum ether to give compound 8. Molecular weight: 478.23. Elemental analysis: C, 62.72; H, 8.00; N, 5.85; O, 10.03; S, 13.40.

Scheme-2:
Step-1: Synthesis of Compound 10:

To a stirred solution of compound 9 (10.0 g, 43.10 mol) in DMF (50.0 mL) was added K ₂ CO ₃ (11.3 g, 81.89 mmol) at room temperature, followed by 3-bromopropanol (4 .69 ml, 51.72 mmol) was added at 0 ° C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water and extracted with DCM (50 mL × 3). The combined organic solvent was washed with water (50 mL × 3), dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by flash silica gel column chromatography eluting with 4% methanol in dichloromethane to give 10 g (79% yield) of compound 10 as a colorless oil. Mass: 291.2 (M ⁺ + H).

  Step-2: (5Z, 8Z, 11Z, 14Z, 17Z) -icosa-5,8,11,14,17-pentaenoic acid 3- [2- (2,6-dimethyl-phenylcarbamoyl) -piperidine-1- Synthesis of [Ill] -propyl ester:

A solution of compound 1 (1.0 g, 0.00331 mol) and compound 10 (0.96 g, 0.00331 mol) in DCM (5 mL) was stirred at 0 ° C. for 30 minutes. Thereafter, EDC. HCl (0.949 g, 0.00496 mol) and DMAP (0.283 g, 0.00232 mol) were added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. After completion, water (20 mL) was added and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified on flash silica gel and eluted with DCM to give 1.05 g (55.16% yield) of CLX-SYN-G16-C02 as a pale yellow oil. Mass: 575.0 [M + H];

  Example: Pharmacokinetic assessment of bupivacaine (BU) and Formula I (1-1) in Sprague-Dawley rats free of pathogens:

300-350 g male Sprague-Dawley rats without specific pathogens were obtained from the laboratory. Rats had free access to food and water. Rats were anesthetized with 1.0 g / mL urethane and 0.1 g / mL (1 mL / kg, ip) chloralose prior to surgery. The femoral vein was cannulated for drug administration, and the body temperature of the rats was maintained with a heating pad during the experiment. All rats remained anesthetized for the duration of the experiment where concentrations of Formula I (1-1) and BU in blood, brain and bile were monitored and an excess amount of CO ₂ under anesthesia after the experimental endpoint. Euthanized by.

  Bupivacaine (3 mg / mL) was prepared in 0.9% (w / v) sodium chloride. Chemical formula I (1-1) is equivalent to 3 mg / mL BU. Rats were divided into groups (n = 5 per group) and administered drugs intravenously. Group 1 was administered (20 mg / kg) 10 minutes before the administration of BU (3 mg / kg), and Group 2 was administered Chemical Formula I (1-1) (3 mg / kg).

The chromatographic system is a PM-80 chromatographic pump (BAS, West Lafayette, Indiana, USA), an offline injector (CMA / 140, Stockholm, Sweden) equipped with a 20 L sample loop injector (Rheodynemodel 7125), room temperature (25 ± 2 ° C. ) -Driven UV-VIs detector (Soma, Tokyo, Japan). Separation was accomplished with a LICChlosphere 60RP-select B column (4.6 mm x 250 mm, 5 m, Merck). The mobile phase for plasma, brain homogenate, hemodialysate and brain dialysis consists of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (67: 33: 0.01) adjusted to pH 4.3 with H ₃ PO _4. It was. The mobile phase for bile dialysis consisted of 10 mM potassium dihydrogen phosphate-acetonitrile-triethylamine (60: 40: 0.01) adjusted to pH 6.0 with H ₃ PO ₄ . The flow rate was set at 1.0 mL / min for both mobile phases.

Results: Blood and brain pharmacokinetic parameters of BU and Formula I (1-1) were as follows.
blood
brain

    The term “sample” refers to a sample of body fluid, a sample of isolated cells, or a sample from a tissue or organ. Body fluid samples can be obtained by well-known techniques and ideally include blood, plasma, serum or urine samples, more ideally blood, plasma or serum samples. Tissue or organ samples can be obtained from any tissue or organ, for example, by biopsy. Separated cells can be obtained from body fluids, tissues, or organs by separation techniques such as centrifugation or cell sorting. Ideally, a sample of cells, tissues or organs should be obtained from cells, tissues or organs that express or produce the peptides described herein.

  Equivalents: The present disclosure provides methods and compositions specifically for treating local pain and its complications. While specific embodiments of the present disclosure have been discussed, the application is illustrative and not restrictive. Many variations of the system and method will become apparent to those skilled in the art upon review of this application. The full scope of the claimed systems and methods should be determined by this application along with such variations and by reference to the claims along with their full equivalents.

  Supplementation by citation: All publications or patents referred to herein are those listed above, and all publications and patents are specifically and individually indicated to be incorporated by reference as if Incorporated herein by reference in its entirety. In case of conflict, the present application, including any definitions in the present application, will prevail.

Claims (13)

Compound of formula I:
Formula I
Or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer or stereoisomer thereof.
here,
R ¹ independently represents D, —CH ₃ , —OCH ₃ , H, or the following group.
Or
R ² independently represents the following group.
a is independently 2, 3, or 7.
b is independently 3, 5, or 6.
e is independently 1, 2 or 6;
c and d each independently represent H, D, -OH, -OD, C1-C6-alkyl, -NH2, or -COCH3.
n is independently 1, 2, 3, 4 or 5. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. Administered to patients in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subcutaneous, oral solution, rectal administration, buccal administration or transdermal administration The pharmaceutical composition according to claim 2, which is formulated by an effective amount to treat the etiology. A method for treating a disease associated with local pain as an underlying etiology, comprising administering an effective amount according to claim 3 to a patient in need thereof.   Underlying etiology is invasion, nerve block, epidural anesthesia, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, postherpetic neuralgia, neuralgia, motor neuron disease, Selected from diabetic neuropathy, postherpetic neuralgia, trauma, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV, neuropathic pain, cancer pain, low back pain 5. The method of claim 4, wherein such local pain is included. The pharmaceutical composition according to claim 2, further comprising a molecular complex composed of bupivacaine and a carboxylic acid compound selected from the group consisting of R lipoic acid, eicosapentaenoic acid, docosahexaenoic acid, salsalate, acetylsalicylic acid and pantothenic acid. The molecular complex according to claim 6, wherein the carboxylic acid compound is R lipoic acid. The molecular complex according to claim 6, wherein the carboxylic acid compound is eicosapentaenoic acid. The molecular complex according to claim 6, wherein the carboxylic acid compound is docosahexaenoic acid. The molecular complex according to claim 6, wherein the carboxylic acid compound is salsalate. The molecular complex according to claim 6, wherein the carboxylic acid compound is acetylsalicylic acid. The molecular complex according to claim 6, wherein the carboxylic acid compound is pantothenic acid. The molecular complex of claim 6, wherein the carboxylic acid compound is pyridoxamine.