JP2016029033A - Combinations - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improvement method for management of pain.SOLUTION: The invention relates to a method for treatment of pain comprising the separate, sequential or simultaneous use of a compound of formula (I) and gabapentin or pregabalin, or a pharmaceutically acceptable salt thereof. In the formula, Y is -Cl or CF.SELECTED DRAWING: None

Description

  The present invention relates to the treatment of pain using a combination of pharmaceutically active agents. More particularly, the invention relates to the use of combinations of N-thiazolyl-4-phenoxybenzenesulfonamide derivatives with a second pharmaceutically active agent and pharmaceutical compositions containing them.

The first component of the combination of the present invention, N-thiazolyl-4-phenoxybenzenesulfonamide derivative, is a modulator of Na _V 1.7 sodium channel. This compound is disclosed in the international patent application PCT / IB2010 / 050033, which is published as WO2010 / 079443.

  Voltage-gated sodium channels are found in all excitable cells, including muscle myocytes and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating a rapid rise in action potential. Thus, sodium channels are essential for the initiation and propagation of electrical signals in the nervous system. Thus, normal functioning of neurons requires proper and proper functioning of sodium channels. As a result, abnormal sodium channel function is believed to underlie various medical disorders (for a general review of hereditary ion channel disorders, see Hubner CA, Jentsch TJ, Hum. Mol. Genet., 11 (20): 2435-45 (2002)), and its disorders include sputum (Yogeswari et al., Curr. Drug Targets, 5 (7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99 (9): 5755-6 (2002)), myotonia (Cannon, SC, Kidney Int. 57 (3): 772-9. (2000)), and pain (Wood, JN et al., J. Neurobiol., 61 (1): 55. ~ 71 (2004)).

Currently, there are at least nine known members in the family of voltage-gated sodium channel (VGSC) α subunits. The names of this family include SCNx, SCNAx, and Na _V x. x is included. The VGSC family is phylogenetically divided into two subfamily Na _V 1. x (everything except SCN6A) and Na _V x (SCN6A). Na _V The x subfamily is functionally subdivided into two groups: those sensitive to block by tetrodotoxin (TTX sensitive or TTX-S) and those resistant to block by tetrodotoxin (TTX resistant or TTX-R). Can do.

Increasing body of evidence suggests that Na _v 1.7 may play an important role in various pain states, including acute, inflammatory, and / or neuropathic pain. . Deletion of the SCN9A gene in mouse nociceptive neurons resulted in reduced thresholds of mechanical and thermal pain, and reduced or eliminated inflammatory pain responses (Nassar et al., Proc Natl Acad Sci USA, 101 (34): 12706-11 (2004)). In humans, it has been shown that Na _v 1.7 protein accumulates in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144 (8): 803-10 (2002). )). Na _v 1.7 gain-of-function mutations, both familial and sporadic, are characterized by primary lupus erythema, ie, burning pain and extremity inflammation (Yang et al., J. Med. Genet., 41 (3): 171-4 (2004)), and paroxysmal pain disorder (Waxman, SG Neurology. 7; 69 (6): 505-7 (2007)). Consistent with this observation, in cases of familial acromegaly, the non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief (Legroux-Crepel et al., Ann. Dermatol Veneol. 130: 429-433), carbamazepine is effective in reducing the number and severity of seizures in PEPD (Fertleman et al., Neuron .; 52 (5): 767-74 (2006)). Further evidence for the role of Nav1.7 in pain has been found in the loss-of-function mutation phenotype of the SCN9A gene. Cox and coworkers (Nature, 444 (7121): 894-8 (2006)) found that SNC9A loss-of-function mutations and congenital analgesia (CIP), i.e. complete indifference to painful stimuli or We have reported for the first time that there is an association with a rare autosomal recessive disorder characterized by insensitivity. Subsequent studies revealed several different mutations that resulted in loss of function of the SCN9A gene and CIP phenotype (Goldberg et al., Clin Genet .; 71 (4): 311-9 (2007), Ahmad et al., Hum Mol Genet. 1; 16 (17): 2114-21 (2007)).

Thus, Na _V 1.7 inhibitors may be useful for the treatment of a wide range of disorders, particularly pain.

  The second component of the combination of the present invention is a pharmaceutically active agent selected from gabapentin and pregabalin.

Gabapentin (2- [1- (aminomethyl) cyclohexyl] acetic acid) and pregabalin ((S) -3- (aminomethyl) -5-methylhexanoic acid) are ligands for the α ₂ -δ subunit of the calcium channel. It is. These have been reported to be effective in the treatment of neuropathic pain. Gabapentin is marketed under the trade name Neurontin and pregabalin is marketed under the trade name Lyrica.

International Patent Application PCT / IB2010 / 050033 WO2010 / 079443 US Pat. No. 6,106,864 WO00 / 35298 WO91 / 11172 WO94 / 02518 WO98 / 55148 WO2008 / 118758 WO2013 / 114250

Hubner C.I. A. Jentsch T. J. et al. Hum. Mol. Genet. , 11 (20): 2435-45 (2002) Yogeswari et al., Curr. Drug Targets, 5 (7): 589-602 (2004) Noble D. Proc. Natl. Acad. Sci. USA, 99 (9): 5755-6 (2002). Cannon, S.M. C. , Kidney Int. 57 (3): 772-9 (2000) Wood, J. et al. N. Et al. Neurobiol. 61 (1): 55-71 (2004). Nassar et al., Proc Natl Acad Sci USA, 101 (34): 12706-11 (2004). Kretschmer et al., Acta. Neurochir. (Wien), 144 (8): 803-10 (2002) Yang et al. Med. Genet. , 41 (3): 171-4 (2004) Waxman, SG Neurology. 7; 69 (6): 505-7 (2007) Legroux-Crepel et al., Ann. Dermatol Veneleol. 130: 429-433. Fertleman et al., Neuron. 52 (5): 767-74 (2006); Nature 444 (7121): 894-8 (2006) Goldberg et al., Clin Genet. 71 (4): 311-9 (2007) Ahmad et al., Hum Mol Genet. 1; 16 (17): 2114-21 (2007) “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Polymorphism in Pharmaceutical Solids, K.M. R. By Morris (edited by HG Brittain, Marcel Dekker, 1995) "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995) Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001) “Pharmaceutical Dosage Forms: Tables”, Vol. Lieberman and L.L. By Lachman (Marcel Dekker, New York, 1980) “Pharmaceutical Technology On-line”, 25 (2), 1-14, by Verma et al., (2001). J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999) Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 1 Woolf & Salter, 2000, Science, 288, 1765-1768 Classification of Chronic Pain, http: // www. iasp-pain. org McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 3 Lawrence et al., 2008, Arthritis Rheum, 58, 15-35. Bielefeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 48 Aziz et al., 2009, Dig Dis27, Addendum 1, 31-41. Dworkin, 2009, Am J Med, 122, S1-S2 Geber et al., 2009, Am J Med, 122, S3-S12 Haanpaa et al., 2009, Am J Med, 122, S13-S21. Woolf, 2010, J Clin Invest, 120, 3742-3744

There is a continuing need to improve the way pain is managed. The use as disclosed herein of a combination of a Na _V 1.7 modulator and an activity modulator of the α-2δ subunit of the calcium channel has greater efficacy; and / or a lower dose compared to the individual drug. A combination can be used; and / or a treatment regimen can be provided that results in improved tolerability to the use of only one drug.

  In the first aspect A1, the present invention provides a method for treating pain.

  In the first embodiment A1E1, the present invention provides a therapeutically effective amount of formula (I) to an individual in need of treatment for pain.

の化合物または薬学的に許容できるその塩（式中、−Ｙは、−Ｃｌまたは−ＣＦ_３である）を投与することを含む疼痛の治療方法であって、前記方法は、治療有効量の、ギャバペンチンおよびプレガバリンから選択される第２の薬学的に活性な化合物または薬学的に許容できるその塩を別個、逐次的または同時に投与することをさらに含む、治療方法を提供する。

Or a pharmaceutically acceptable salt thereof, wherein -Y is -Cl or -CF ₃ , wherein the method comprises a therapeutically effective amount of There is provided a method of treatment further comprising separately, sequentially or simultaneously administering a second pharmaceutically active compound selected from gabapentin and pregabalin or a pharmaceutically acceptable salt thereof.

  In a further embodiment A1E2, the invention provides a compound of formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both of said compounds The method of Embodiment A1E1 consists essentially of the administration of

In a further embodiment A1E3, the invention relates to a compound of formula (I) wherein 4- [2- (5-amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2- ^A method of Embodiment A1E1 or A1E2 is provided that is fluoro-N- (1,3-thiazol-4-yl) benzenesulfonamide (I ^A ) or a pharmaceutically acceptable salt thereof.

In a further embodiment A1E4, the invention relates to a compound of formula (I) wherein 4- [2- (5-amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5 - chloro -2-fluoro-N-(1,3-thiazol-4-yl) benzenesulfonamide ^{(I B)} or a pharmaceutically acceptable salt thereof, provides a method of embodiment A1E1 or A1E2.

  In a further embodiment A1E5, the invention relates to the method of any one of embodiments A1E1, A1E2, A1E3, and A1E4, wherein the second pharmaceutically active compound is gabapentin or a pharmaceutically acceptable salt thereof. I will provide a.

  In a further embodiment A1E6, the invention relates to the method of any one of embodiments A1E1, A1E2, A1E3, and A1E4, wherein the second pharmaceutically active compound is pregabalin or a pharmaceutically acceptable salt thereof. I will provide a.

  In a further embodiment A1E7, the invention relates to any of embodiments A1E1, A1E2, A1E3, A1E4, A1E5, and A1E6, wherein the compound of formula (I) and the second pharmaceutically active compound are administered simultaneously. One method is provided.

  In a further embodiment A1E8, the invention provides the method of embodiment A1E7, wherein the compound of formula (I) and the second pharmaceutically active compound are administered together as a single pharmaceutical dosage form. .

  In a further aspect A2, the present invention provides a combination of pharmaceutically active agents.

  In the first embodiment A2E1, the invention provides a pharmaceutically active compound of formula (I) and a second pharmaceutically active compound as defined in embodiment A1E1 or A1E2, or one or both of said compounds A combination comprising an acceptable salt is provided.

In a further embodiment A2E2, the present invention provides:
4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with gabapentin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with pregabalin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2-fluoro-N- (1,3-thiazole in combination with gabapentin -4-yl) benzenesulfonamide; and 4- [2- (5-amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2- in combination with pregabalin Fluoro-N- (1,3-thiazol-4-yl) benzenesulfonamide;
Or a combination according to embodiment A2E1 selected from pharmaceutically acceptable salts of one or both of said compounds.

  In a further aspect A3, the present invention provides a pharmaceutical dosage form.

  In the first embodiment A3E1, the invention provides a compound of formula (I) as defined in any one of embodiments A1E1, A1E2, A1E3, A1E4, A1E5, and A1E6 and a second pharmaceutically active Or a pharmaceutically acceptable salt of one or both of said compounds; and one or more pharmaceutically acceptable excipients.

  In a further embodiment A3E2, the present invention provides a pharmaceutical dosage form according to embodiment A3E1 for use as a medicament.

  In a further embodiment A3E3, the present invention provides a pharmaceutical dosage form according to embodiment A3E1 or A3E2 for use in the treatment of pain.

  In a further aspect A4, the present invention is a compound of formula (I) as defined in embodiment A1E1 or a pharmaceutically acceptable salt thereof for use in the treatment of pain, wherein said treatment comprises Providing the compound or a pharmaceutically acceptable salt thereof further comprising separately, sequentially or simultaneously administering a second pharmaceutically active compound or a pharmaceutically acceptable salt thereof as defined in Form A1E1 To do.

  In a further embodiment A4E1, the invention essentially consists in that said treatment further comprises separately, sequentially or simultaneously administering a second compound as defined in embodiment A1E1 or a pharmaceutically acceptable salt thereof. A compound for use in the treatment of pain according to aspect A4 is provided.

  In a further aspect A5, the present invention provides a combination as defined in embodiment A2E1 or A2E2, or a pharmaceutically acceptable salt of one or both of said compounds, for use in the treatment of pain.

  In a further aspect A6, the invention relates to the use of a compound of formula (I) as defined in embodiment A1E1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain, The treatment provides use further comprising separately, sequentially or concurrently administering a second pharmaceutically active compound as defined in embodiment A1E1 or a pharmaceutically acceptable salt thereof.

  In a further embodiment A6E1, the present invention provides the use of a compound according to aspect A6, wherein the treatment further comprises a second compound according to claim 1 or a pharmaceutically acceptable salt thereof. It consists essentially of administering separately, sequentially or simultaneously.

  In a further aspect A7, the present invention relates to the use of a combination as defined in embodiment A2E1 or A2E2 or a pharmaceutically acceptable salt of one or both of said compounds for the manufacture of a medicament for the treatment of pain I will provide a.

In a further aspect A8, the present invention provides:
(I) a pharmaceutical dosage form comprising a compound of formula (I) as defined in embodiment A1E1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and (ii) defined in embodiment A1E1. A kit for use in the treatment of pain, comprising a pharmaceutical dosage form comprising a second pharmaceutically active compound as described or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

  In a further embodiment A8E1, the present invention provides a kit for use in the pain of aspect A8, consisting essentially of pharmaceutical dosage forms (i) and (ii).

FIG. 5 is a graph showing the degree of flinching over time for high dose pregabalin (Group 5). FIG. 3 is a graph showing the degree of flinching over time for high dose compounds of formula (I ^B ) (Group 3). FIG. 7 is a graph showing the degree of flinching over time for a high dose combination of a compound of formula (I ^B ) and pregabalin (Group 7). FIG. 4 is a graph showing the degree of flinching over time for low dose pregabalin (Group 4). FIG. 2 is a graph showing the degree of flinching over time for a high dose of the compound of formula (I ^B ) (Group 2). FIG. 6 is a graph showing the degree of flinching over time for a low dose combination of a compound of formula (I ^B ) and pregabalin (Group 6). FIG. 6 is a visualization using a posterior distribution plot on a log scale of a high dose combination during Phase 2. FIG. 3 is a visualization using a posterior distribution plot on a log scale of a high dose combination during phase 2a.

As used herein, the term “a combination of the invention” refers to a combination of a compound of formula (I) and a second pharmaceutically active compound,
4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with gabapentin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with pregabalin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2-fluoro-N- (1,3-thiazole in combination with gabapentin -4-yl) benzenesulfonamide; and 4- [2- (5-amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2- in combination with pregabalin Fluoro-N- (1,3-thiazol-4-yl) benzenesulfonamide is mentioned.

  The terms “treatment”, “treating”, and the like refer to palliative, curative, and prophylactic treatment. It will be appreciated that in the context of the treatment of pain resulting from an injury or pathological condition, it is pain being treated rather than the underlying cause of pain.

  “Separate” administration refers to a treatment regimen in which the two agents are administered according to an independent schedule. This includes the possibility that if each agent is administered multiple times, it may be administered several times together.

  “Sequential” administration refers to a treatment regimen in which two drugs are administered according to the same schedule.

  “Simultaneous” administration refers to a treatment regimen in which two agents are administered together in a single motion.

  Treatment method "consisting essentially of administration of a compound of formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both of said compounds" Refers to a method consisting of administration of only two pharmaceutically active agents.

The term “consisting essentially of”
A combination of a compound of formula (I) and a second pharmaceutically active compound;
A compound of formula (I) for use in the treatment of pain comprising a second pharmaceutically active compound;
Use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain comprising a second pharmaceutically active compound; and a pharmaceutical agent of a compound of formula (I) and a second pharmaceutically active compound When used in conjunction with a shaped kit, it has the same meaning as just described for the method of treatment.

  Compounds of formula (I) may exist in tautomeric forms. In particular, the aminopyrazole moiety may be present in one or more of the following forms.

  All such tautomers and mixtures of tautomers are included within the scope of the present invention. References herein to a particular compound should be understood to refer to that compound and / or its tautomers.

  The compounds of formula (I) can be combined with acids to form pharmaceutically acceptable addition salts, and these salts can be used in the present invention. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamic acid Salt, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / Bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotine Acid salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharinate, stearate, succinic acid Salt, tannate Tartrate, tosylate, trifluoroacetate, and xinafoate salt (xinofoate) and the like.

  Acid and base hemi-salts, such as hemisulfate, can also be formed.

  Gabapentin and pregabalin have been reported to form salts with both acids and bases. One skilled in the art will appreciate that the foregoing salts include salts in which the counterion is optically active, such as d-lactic acid or l-lysine, or a racemate, such as dl-tartaric acid or dl-arginine.

  For a review of suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of the compound of formula (I), gabapentin, and pregabalin can be prepared by one or more of the following three methods:
i) a method by reacting a compound of formula (I), gabapentin, or pregabalin with the desired acid or base;
ii) a method by removing the acid or base labile protecting group from the appropriate precursor of the compound of formula (I), gabapentin, or pregabalin using the desired acid or base, or iii) the appropriate acid or A method of converting a salt of a compound of formula (I), gabapentin or pregabalin into another salt by reaction with a base or using a suitable ion exchange column.

  All three reactions are generally carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from complete ionization to almost non-ionization.

The compounds of formula (I), gabapentin, and pregabalin, or pharmaceutically acceptable salts thereof can exist in both unsolvated and solvated forms. The term “solvate” as used herein refers to a compound of formula (I), gabapentin, or pregabalin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, such as ethanol. Is used to describe a molecular complex comprising The term “hydrate” is used when the solvent is water. Pharmaceutically acceptable solvates in accordance with the present invention, those wherein the solvent of crystallization may be isotopically substituted and the like, for _example, D 2 _O, d 6 _- acetone, and d _6-DMSO.

  Currently accepted classification systems for organic hydrates are those that define isolated sites, channels, or metal ion coordination hydrates, which are incorporated herein by reference in Polymorphism in Pharmaceutical Solids, K. et al. R. See Morris (edited by HG Brittain, Marcel Dekker, 1995). Isolated site hydrates are hydrates in which water molecules are isolated from each other's direct contact by intervening organic molecules. In channel hydrates, water molecules are located in lattice channels where they are adjacent to other water molecules. In metal ion coordination hydrate, water molecules are bound to metal ions.

  If the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of moisture. However, if the solvent or water is weakly bound, the water / solvent content will depend on moisture and dry conditions, as well as channel solvates and hygroscopic compounds. In such cases, non-stoichiometry would be common.

  The compounds of formula (I), gabapentin, and pregabalin can exist in a continuous solid state ranging from fully amorphous to fully crystalline. The term “amorphous” refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials do not exhibit a characteristic X-ray diffraction pattern and are described more formally as liquids while exhibiting solid properties. Upon heating, a change from solid to liquid properties occurs, which is typically characterized by a secondary state change (“glass transition”). The term “crystalline” refers to a solid phase in which the material has a characteristic X-ray diffraction pattern with an internal structure regularly arranged at the molecular level and having a defined peak. Although such materials also exhibit liquid properties when fully heated, the change from solid to liquid is typically characterized by a first order phase change ("melting point").

Compounds of formula (I) may be prepared by the methods disclosed in International Patent Application PCT / IB2010 / 050033 published as WO2010 / 079443, the disclosure of which is incorporated herein by reference, or for preparing compounds of similar structure Can be prepared by any other method known in the art. Compound (I ^A ) is Example 788 of WO2010 / 079443, and Compound (I ^B ) is Example 1029 thereof.

  Gabapentin and pregabalin are known compounds and can be prepared by methods disclosed in the literature.

  Compounds of formula (I), gabapentin, and pregabalin can be obtained by methods such as precipitation, crystallization, lyophilization, spray drying, or evaporation drying, for example, as a solid plug, powder, or film. Microwave or radio frequency drying can be used for this purpose.

  The compound of formula (I), gabapentin, and pregabalin can be administered separately or in combination. Generally, these are administered as a formulation in combination with one or more pharmaceutically acceptable excipients. As used herein, the term “excipient” is used to describe any ingredient other than the compound of formula (I), gabapentin, and pregabalin. The choice of excipient will often depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

  Pharmaceutical compositions suitable for delivery of the combinations of the invention and methods for their preparation are expected to be readily understood by those skilled in the art. Such compositions and methods for their preparation can be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).

  Suitable modes of administration include oral, parenteral, topical, inhalation / intranasal, rectal / vaginal, and ocular / ear administration. When the compound of formula (I), gabapentin, and pregabalin are administered separately, they can be administered by various routes.

  Formulations suitable for the aforementioned modes of administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and planned release.

  The compound of formula (I), gabapentin, and pregabalin, or combinations thereof can be administered orally. Oral administration can be swallowed so that the compound enters the gastrointestinal tract, or buccal or sublingual administration where the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include tablets, microparticles, liquids or capsules containing powders, lozenges (including liquids), chews, multiparticulates and nanoparticles, gels, Examples include solid preparations such as solid solution, liposome, film, oval, spray, liquid preparation, and buccal / mucoadhesive patch.

  Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillers in soft or hard capsules and are generally carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more Contains emulsifiers and / or suspending agents. Liquid formulations can also be prepared, for example, by reconstitution of a solid from a sachet.

  Compounds of formula (I), gabapentin, and pregabalin, or combinations thereof are also described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, Liang and Chen (2001), etc. Can be used in fast-dissolving, fast-disintegrating dosage forms.

  For tablet dosage forms, depending on dose, the drug may be made from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to this drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate. Generally, the disintegrant will comprise 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets also include lactose (monohydrate, spray dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dicalcium phosphate dihydrate, etc. Can be included.

  Tablets may also contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant can comprise 0.2% to 5% by weight of the tablet and the glidant can comprise 0.2% to 1% by weight of the tablet.

  Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10%, preferably 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and flavor masking agents.

  Exemplary tablets have up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, and about 2% to about 10% disintegrant. %, About 0.25 wt.% To about 10 wt.% Lubricant. Tablet blends can be compressed directly or by roller to make tablets. Alternatively, a tablet blend or portion of a blend can be tableted after being wet, dry, or melt granulated, melt frozen, or extruded. The final formulation can be composed of one or more layers and may be coated or uncoated and further encapsulated. The formulation of tablets is described in “Pharmaceutical Dosage Forms: Tables”, Vol. Lieberman and L.L. Discussed in Lachman (Marcel Dekker, New York, 1980).

  Suitable modified release formulations for the purposes of the invention are described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersants and osmotic and coated particles can be found in “Pharmaceutical Technology On-line”, 25 (2), 1-14, by Verma et al. (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of formula (I), gabapentin, and pregabalin, or combinations thereof can also be administered directly into the bloodstream, muscle, or internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needled (including microneedle) syringes, needleless syringes, and infusion techniques.

  Parenteral formulations are generally aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably pH 3-9), but for some applications these are more suitably Can be formulated as a sterile non-aqueous solution or in dry form and used with a suitable vehicle such as sterile pyrogen-free water.

  Preparation of parenteral formulations under sterile conditions, such as lyophilization, can be readily performed using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of the compounds of formula (I), gabapentin, and pregabalin used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as incorporating a dissolution enhancer. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and planned release. Thus, the compounds of the invention can be formulated as solids, semisolids, or thixotropic liquids for administration as implanted depots that provide controlled release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-coglycolic acid) (PGLA) microspheres.

  The compounds of formula (I), gabapentin, and pregabalin, or combinations thereof can also be administered topically to the skin or mucosa, ie dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, bandages, foams, films, skin patches, cachets, implants , Sponges, fibers, bandages, and microemulsions. Liposome agents can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated, see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).

  Other means of topical administration include electroporation, iontophoresis, sonophoresis, ultrasound introduction, and delivery by microneedle or needle-free (eg, Powderject ™, Bioject ™, etc.) injection. Can be mentioned.

  The compounds of formula (I), gabapentin, and pregabalin, or combinations thereof are also generally dry powders from dry powder inhalers (alone, eg, as a mixture in a dry blend with lactose, or, for example, , As mixed component particles mixed with phospholipids such as phosphatidylcholine), or 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, etc. As an aerosol spray from pressurized containers, pumps, sprays, atomizers (preferably atomizers using electrohydrodynamics that generate fine mists) or nebulizers with or without the use of appropriate propellants, or in the nasal cavity Can be administered by inhalation. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or alternative agents suitable for dispersion, solubilization, or extended release of actives, propellants as solvents, and sorbitan trioleate A solution or suspension of a compound of formula (I), gabapentin, or pregabalin, or combinations thereof, including any surfactant, such as oleic acid, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (generally less than 5 microns). This can be achieved by any suitable comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid process for forming nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters, and cartridges used in inhalers or infusers are composed of a compound of the invention and a suitable powder base such as lactose or starch, It can be formulated to contain a powder mixture with a performance modifier such as leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A suitable solution formulation for use in an atomizer that produces a fine mist using electrohydrodynamic methods can contain 1 μg to 20 mg of a compound of formula (I), gabapentin, or pregabalin per operation, The manipulated volume may vary in the range of 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Appropriate flavors such as menthol and levomenthol, or sweeteners such as saccharin or saccharin sodium can be added to these formulations of the present invention intended for inhalation / intranasal administration.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units according to the invention are generally arranged to administer a metered dose or “puff” containing 1 μg to 100 mg of a compound of formula (I), gabapentin or pregabalin. The total daily dose is typically in the range of 1 μg to 200 mg, which can be administered in a single dose or, more generally, as divided doses throughout the day.

  The compounds of formula (I), gabapentin, and pregabalin, or combinations thereof can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, bactericidal agent, intravaginal ring, or enema. Cocoa butter is a conventional suppository base, but various alternatives can be used as appropriate.

  The compounds of formula (I), gabapentin, and pregabalin, or combinations thereof, are also typically in the form of micronized suspensions or solution droplets in isotonic pH adjusted sterile saline. Can be administered directly to the eye or ear. Other formulations suitable for ocular and otic administration include ointments, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, cachets, lenses, As well as particulate or vesicular systems such as niosomes or liposomes. Incorporate polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum together with preservatives such as benzalkonium chloride May be. Such formulations can also be delivered by iontophoresis.

  The compounds of formula (I), gabapentin, and pregabalin, when used in any of the aforementioned modes of administration, to improve their solubility, dissolution rate, flavor masking, bioavailability, and / or stability, It can be combined with soluble macromolecules such as cyclodextrins and their appropriate derivatives or polyethylene glycol-containing polymers.

  Drug-cyclodextrin complexes have been found to be generally useful, for example, for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent, or solubilizer. For these purposes, α, β, and γ-cyclodextrins are most commonly used, examples of which can be found in international patent applications WO 91/11172, WO 94/02518, and WO 98/55148. .

  For administration to human patients, the total daily dose of the compound of formula (I) is typically in the range of 10 mg to 5 g, such as 100 mg to 3 g, eg 250 mg to 2 g, although of course depending on the mode of administration and effect. Dependent. The total daily dose of gabapentin is typically in the range of 200 mg to 3 g, such as 500 mg to 2.5 g, such as 900 mg to 1.8 g. The total daily dose of pregabalin is typically in the range of 50 mg to 1 g, such as 300 mg to 600 mg, such as 150 mg to 750 mg. For example, oral administration may require a total daily dose of 300 mg to 2 g of the compound of formula (I) and 750 mg to 2 g of gabapentin or 150 mg to 600 mg of pregabalin.

  The total daily dose can be administered in single or divided doses and may deviate from the typical ranges set forth herein at the physician's discretion. These dosages are based on an average human subject having a weight of about 60kg to 70kg. For subjects whose weight does not fall within this range, such as infants and the elderly, the dose can be easily determined by a physician.

  The disorder to which the combination of the present invention is applied includes pain. Pain can be either acute or chronic, and in addition can be central and / or peripheral pain. Pain can be neuropathic and / or nociceptive and / or inflammatory, such as pain affecting the body system or visceral system, and dysfunctional pain affecting multiple systems.

  Physiological pain is an important defense mechanism designed to warn of danger from stimuli that can be harmful from the outside environment. This system functions by a specific set of primary sensory neurons and is activated through peripheral transmission mechanisms by noxious stimuli (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th edition), (See Chapter 1). These sensory nerve fibers are known as nociceptors and are characteristically small-diameter axons with slow transmission rates, which include A delta fibers (myelinated) and C There are two main types of fibers (non-myelinated). Nociceptors encode the intensity, duration, and nature of the noxious stimulus and the location of the stimulus (by its projection onto the tissue-distributed spinal cord). The activity produced by the nociceptor input is transmitted to the cortex, following the basal ventral thalamus, either directly or via the brainstem relay nucleus after complex processing in the dorsal horn, where pain sensation is transmitted. Occur.

  Pain can generally be classified as acute or chronic. Acute pain begins suddenly and is brief (usually 12 weeks or less). This is usually, but not always, associated with a specific cause, such as a clear injury, often sensitive and severe, and from a number of causes such as surgery, dental treatment, muscular contusion, or sprain May occur. Acute pain generally does not produce a sustained psychological response. When substantial damage occurs in body tissue due to disease or trauma, the properties of nociceptor activation change and sensitization occurs in the periphery (locally near the injury) and in the center where the nociceptors terminate It becomes like this. These effects lead to an increase in pain sensation. In acute pain, these mechanisms may be useful to promote defensive behavior that may make it possible for the repair process to occur. The normal expectation would be that sensitivity returns to normal as soon as the injury heals. However, in many chronic pain states, this hypersensitivity continues long after the healing process, often due to nervous system damage or changes associated with maladaptation and abnormal activity (Woolf & Salter, 2000, Science, 288, 1765). ~ 1768). Chronic pain is therefore long-term pain, typically lasting longer than 3 months, resulting in significant mental and emotional problems. Common examples of chronic pain are neuropathic pain (eg, painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, joint pain, and chronic postoperative Any chronic pain condition that is pain but affects any system, such as those described by the International Association for the Study of Pain, etc. (Classification of Chronic Pain, http : / Publications freely downloadable from www.iasp-pain.org).

  Clinical symptoms of pain exist when unpleasant and abnormal sensitivity is predominant among the patient's symptoms. Patients tend to be very heterogeneous and may exhibit various pain symptoms. Such symptoms include: 1) spontaneous pain, which can be dull pain, burning pain, or stinging; 2) excessive pain response to noxious stimuli (hyperalgesia); and 3) pain produced by normally harmless stimuli (Allodynia) may be included (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 1). Patients suffering from various forms of acute and chronic pain may have similar symptoms, but the underlying mechanisms may be different and therefore require different treatment strategies There is. Apart from acute or chronic, pain can also be broadly categorized into: a violation that affects the body or visceral system and can be inflammatory (related to tissue damage and immune cell infiltration) Receptive pain; or neuropathic pain.

  Nociceptive pain can be defined as a process in which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers called nociceptors, either by tissue damage or by damage Can be triggered by intense stimuli that can cause. Pain afferents are activated by the transmission of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at their terminal level. This then travels up the spinal tract and is relayed to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 1). Myelinated A delta fibers propagate quickly and cause a sharp tingling sensation, while unmyelinated C fibers propagate at a slower rate and convey blunt or aching pain. Moderate to severe acute nociceptive pain includes pain from muscle contusions / sprains, burns, myocardial infarction, and acute pancreatitis, postoperative pain (pain following all types of surgical procedures), posttraumatic pain, It is a prominent feature of pain associated with gout, cancer pain, and back pain. Cancer pain is pain associated with a tumor (eg, bone pain, headache, facial pain, or visceral pain) or pain associated with cancer treatment (eg, in response to chemotherapy, immunotherapy, hormone therapy, or radiation therapy). Can be chronic pain. Back pain may be due to a herniated or broken disc, or an abnormality in the lumbar intervertebral joint, sacroiliac joint, paraspinal muscle group, or posterior longitudinal ligament. Back pain may resolve spontaneously, but in some patients, it lasts over 12 weeks and becomes a chronic condition that can be significantly debilitating.

  Nociceptive pain may also be associated with an inflammatory condition. The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue injury or the presence of xenobiotics resulting in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook). of Pain (5th edition), Chapter 3). A common inflammatory condition with pain is arthritis. It is estimated that nearly 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most degenerative joints Patients with symptoms seek medical attention because of the associated pain. Arthritis is known to have a significant impact on psychosocial and physical functions and is a major cause of disability in later years. Rheumatoid arthritis is an immune-mediated chronic inflammatory polyarthritic disease that primarily affects peripheral synovial joints. This is one of the most common chronic inflammatory conditions in developed countries and is a major cause of pain.

  With reference to nociceptive pain from the viscera, visceral pain results from activation of nociceptors in the chest, pelvis, or abdominal organs (Bielfeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5th edition), Chapter 48). This includes the reproductive organs, spleen, liver, gastrointestinal tract, ureter, airway structure, cardiovascular system, and other organs contained within the abdominal cavity. Thus visceral pain is pain associated with such organ conditions, such as bladder pain syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowel syndrome, uterus Refers to endometriosis, dysmenorrhea and the like (available from Classification of Chronic Pain, http://www.iasp-pain.org). Currently, the possible contribution of neuropathy to visceral pain conditions (either through central changes or nerve injury / injury) is not well understood but may affect certain conditions (Aziz) 2009, Dig Dis27, Addendum 1, 31-41).

  Neuropathic pain is currently defined as pain that results directly from a lesion or disease that affects the somatosensory system. Since nerve injury can be caused by trauma and disease, the term “neuropathic pain” includes many disorders of various causes. These include peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancerous neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and chronic alcoholism Related pain, including but not limited to hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiencies. Neuropathic pain is pathological because it has no protective role. It often exists well after the disappearance of the original cause, usually lasting several years, significantly reducing the patient's quality of life (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al. 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21). Symptoms of neuropathic pain are often heterogeneous among patients with the same disease and are difficult to treat (Dworkin, 2009, Am J Med, 122, S1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21). These include spontaneous pain that can be continuous, and paroxysmal or abnormal evoked pain such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally harmless stimuli) It is.

  Because some types of pain have multiple etiologies, they can be classified in multiple areas, such as nociceptive and neuropathic factors for back pain, cancer pain, and even migraine Note that either of these can be included.

  Similarly, other types of chronic pain are probably not well understood, but cannot be easily defined with a nociceptive or neuropathic simplified definition. Such conditions include in particular fibromyalgia and chronic local pain syndrome, most often described as dysfunctional pain conditions, such as fibromyalgia or complex local pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744) and included in the classification of chronic pain states (available from Classification of Chronic Pain, http://www.iasp-pain.org).

  The combinations of the present invention may optionally be used in combination with one or more additional pharmacologically active compounds. Such combinations can result in further significant benefits including patient compliance, ease of administration, and synergistic activity.

  In the combinations described below, the combination of the invention can be administered simultaneously, sequentially or separately in combination with another therapeutic agent or agent.

Useful additional pharmacologically effective agents include one or more agents selected from the following:
A selective Nav1.3 channel modulator, such as the compounds disclosed in WO2008 / 118758;
A selective Nav1.8 channel modulator, such as the compounds disclosed in WO2013 / 114250;
A selective Nav1.9 channel modulator;
• non-selective modulators such as bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine, or phenytoin that modulate activity at multiple Nav channels;
Any inhibitor of nerve growth factor (NGF) signaling, eg, an agent that binds to NGF and inhibits NGF biological activity and / or downstream pathways mediated by NGF signaling (eg, tanezumab), A TrkA antagonist or a p75 antagonist, or an agent that inhibits downstream signaling related to TrkA or P75 signaling by NGF stimulation;
• inhibitors of the neurotrophic pathway, such inhibition is realized by: (a) Nerve growth factor (NGF) (eg, tanezumab, facinumab, or fluranumumab), brain-derived neurotrophic factor (BDNF), neuron An agent that binds to trophin-3 (NT-3) or neurotrophin-4 (NT-4) or to two or more of the aforementioned neurotrophins (eg, soluble P75); or (b) TrKA, TrKB, In one or more of TrKC or P75, an agent that inhibits the receptor function at the orthosteric site, allosteric site, or inhibits the catalytic activity of the receptor;
Compounds that increase the level of endocannabinoids, such as compounds having fatty acid amide hydrolase (FAAH) inhibitory or monoacylglycerol lipase (MAGL) activity;
Painkillers, especially paracetamol;
Opioid analgesics such as buprenorphine, butorphanol, cocaine, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levalorphan, levorphanol, meperidine, methadone, morphine, nalmefene, nalolphine, naltrexone, nalbumorphone, codon , Propoxyphene, or pentazocine;
G proteins as opposed to β-arrestin recruitment, such as opioid analgesics that preferentially stimulate specific intracellular pathways, eg TRV130; opioid analgesics with further pharmacological action, eg noradrenaline (norepinephrine (norepinephrine) ) Having reuptake inhibition (NRI) activity, such as tapentadol; serotonin and norepinephrine reuptake inhibition (SNRI) activity, such as tramadol; or having nociceptin receptor (NOP) agonist activity, such as GRT6005;
Non-steroidal anti-inflammatory drugs (NSAIDs), such as non-selective cyclooxygenase (COX) inhibitors such as aspirin, diclofenac, diflucinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, Indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmethine, or zomepilac; or COX-2 selection Inhibitors, such as celecoxib, deracoxib, etoroxib, mabacoxib, or parecoxib;
A prostaglandin E ₂ subtype 4 (EP4) antagonist;
A microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor;
Sedatives such as glutethimide, meprobamate, methacarone, or dichlorfenazone;
GABA _A modulators with a broad subtype of regulatory effects mediated via the benzodiazepine binding site, such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam, or clobazam;
A subtype-selective regulatory effect mediated via a benzodiazepine binding site with reduced adverse effects, such as GABA _A modulators with sedation, such as TPA023, TPA023B, L-838,417, CTP354, or NSD72;
GABA _A modulators acting through alternative binding sites on the receptor, such as barbiturates, such as amobarbital, aprobarbital, butarbital, mefobarbital, methhexital, pentobarbital, phenobarbital, secco Barbital, or thiopental; neurosteroids such as alphaxalone, alphadrone, or ganaxolone; β-subunit ligands such as etifoxin; or δ-preferred ligands such as gaboxadol;
GlyR3 agonist or positive allosteric modulator;
Skeletal muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methaxone, metcarbamol, or orphrenadine;
A glutamate receptor antagonist or negative allosteric modulator, such as an NMDA receptor antagonist, such as dextromethorphan, dextrorphan, ketamine, or memantine; or an mGluR antagonist or modulator;
Α-adrenergic agonists such as clonidine, guanfacine, or dexmetomidine, etc .;
Β-adrenergic agonists such as propranolol;
• Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;
A tachykinin (NK) antagonist, such as aprepitant or malopitant;
Muscarinic antagonists, such as oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine, and ipratropium;
Cholinergic (nicotinic) analgesics such as ispronicrin (TC-1734), varenicline, or nicotine;
A transient receptor potential V1 (TRPV1) receptor agonist (eg, resiniferatoxin or capsaicin) or antagonist (eg, capsazepine or mavatrap);
A transient receptor potential A1 (TRPA1) receptor agonist (eg cinnamaldehyde or mustard oil) or antagonist (eg GRC17536 or CB-625);
A transient receptor potential M8 (TRPM8) receptor agonist (eg menthol or icilin) or antagonist;
A transient receptor potential V3 (TRPV3) receptor agonist or antagonist (eg GRC-15300);
Corticosteroids such as dexamethasone;
-5-HT receptor agonists or antagonists, especially 5-HT _{1B / 1D} agonists such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;
A 5-HT _2A receptor antagonist;
A PDEV inhibitor, such as sildenafil, tadalafil, or vardenafil;
An α-2-δ ligand, such as gabapentin, gabapentin enacarbyl, or pregabalin;
Serotonin reuptake inhibitors (SRI) such as sertraline, dimethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, ecitalopram, d, l-fenfluramine, femoxetine, femoxetine Such as cyanodothiepine, ritoxetine, dapoxetine, nefazodone, cericlamin, and trazodone;
NRIs such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolites hydroxybuproprion, nomifensine, and viloxazine, especially selective noradrenaline reuptake inhibitors such as reboxetine ;
SNRI, such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran, and imipramine;
An inducible nitric oxide synthase (iNOS) inhibitor;
A leukotriene B4 antagonist;
-5-lipoxygenase inhibitors, such as zileuton;
• Potassium channel openers or positive modulators such as KCNQ / Kv7 openers or positive modulators (eg retigabine or flupirtine), G protein-coupled inward rectifier potassium channels (GIRK), calcium activated potassium channels (Kca ) Or a potassium voltage-gated channel such as a member of subfamily A (eg, Kv1.1), subfamily B (eg, Kv2.2), or subfamily K (eg, TASK, TREK, or TRESK);
· P2X ₃ receptor antagonists (e.g., AF219), or _{P2X 2/3,} such as atypical receptor antagonists of the receptor containing the P2X ₃ subunit as one of the receptor subunits;
• Ca _V 2.2 calcium channel blockers (N-type), such as ziconotide; and • Ca _V 3.2 calcium channel blockers (T-type) such as ethosuximide.

  Also included within the scope of the invention are combinations of the invention together with one or more other therapeutic agents that reduce the metabolic rate of the compounds of the invention and increase patient exposure. Increasing exposure in this way is known as boosting. This has the advantage of increasing the efficacy of the compounds of the present invention or reducing the dose required to achieve the same efficacy as the unboosted dose. Metabolism of the compounds of the present invention involves the oxidation process performed by the P450 (CYP450) enzyme, particularly CYP 3A4, and conjugation by UDP glucuronosyltransferase and sulfate enzymes. Accordingly, agents that can be used to increase exposure of a patient to a compound of the present invention include those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzyme. Isoforms of CYP450 that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Suitable agents that can be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N- (3,4-difluorobenzyl) -N-methyl-2-{[(4-methoxypyridin-3-yl ) Amino] sulfonyl} benzamide, and N- (1- (2- (5- (4-fluorobenzyl) -3- (pyridin-4-yl) -1H-pyrazol-1-yl) acetyl) piperidine-4- Yl) methanesulfonamide.

  Two or more pharmaceutical compositions wherein at least one pharmaceutical composition contains a compound of formula (I) and at least one pharmaceutical composition contains gabapentin or pregabalin are suitable for co-administration of this composition It is within the scope of the present invention that they can be conveniently combined in the form of a kit. Accordingly, the kit of the present invention comprises at least one pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutical composition comprising two or more separate pharmaceutical compositions comprising gabapentin or pregabalin. A means for holding the composition separately, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is the well-known blister pack used for packaging tablets, capsules and the like. The kit of the present invention is to administer different dosage forms, such as oral and parenteral dosage forms, to administer separate compositions at different dosing intervals, or to dose-adjust separate compositions to each other. Especially suitable. To assist compliance, the kit generally includes instructions for administration and may be provided with a so-called memory aid.

In vivo assessment in mice Animals: Five male CD-1 mice (Charles River, Raleigh, NC) weighing 27-36 g on the day of administration were housed per cage. The animals were freely accessible to food and water and maintained on a 12:12 hour light / dark schedule.

The compounds and dosing solutions: Compound of formula (I ^B) and pregabalin were formulated as solutions in 0.5% methylcellulose. The high dose combination and the low dose combination were formulated together in 0.5% methylcellulose into a single suspension for oral administration. The compound was administered by oral ingestion at 10 mL / kg.

  Experimental Procedure: Animals were tested for paw motor response to 2.5% formalin solution (20 μl in saline) injection using an Automated Nociception Analyzer (Yaksh et al., 2001). This device uses a magnetic detection system to measure foot movement, defined as flinch. Sixty minutes prior to formalin injection, a small metal band was placed on the left hind paw of the mouse and immediately thereafter placed in an individual round test room (four mice per session). Two hours before formalin injection, mice were orally administered test compounds. To begin the experiment, 20 μl of 2.5% formalin was injected subcutaneously into the back of the left hind paw of the mouse and placed in the test room. The instrument then recorded fast foot movements that were counted every minute for 60 minutes.

  Treatment groups were assigned to balance treatment across all days and laboratories.

Immediately after 60 minutes of observation of flinch, mice were euthanized and blood and brain tissue were removed for bioanalysis of compound of formula (I ^B ) and pregabalin levels.

Exclusion Animals: For formalin injection was incomplete, excluding one mouse from both compounds 30 mg / kg group vehicle group and the formula (I ^B). One mouse was excluded from the 100 mg / kg group of compounds of formula (I ^B ) because the metal paw band fell during the flinch study. One mouse was excluded from the pregabalin 30 mg / kg group because only a partial dose of test compound was administered.

Data analysis: The total number of flinches was counted for a particular time interval or phase. The phases summarized in this study were as follows:
Phase 1: 0-9 minutes Phase 2: 10-60 minutes Phase 2a: 10-40 minutes

  Flinch events were automatically recorded with an automatic pain analyzer (Yaksh et al., 2001) and the total number of flinches for each phase was automatically calculated. The results of each experimental group are shown in Tables 2.1 to 2.7 below.

  Graphs showing the time course of both high and low dose combination flinch are shown in FIGS. 1-3 and 4-6, respectively.

  The total number of flinches within each phase was analyzed separately on a log scale using a linear model, taking into account the experimental date. Individual treatments were compared and tabulated using means, differences, 95% confidence intervals, and p-values. The results for the sum of the high-dose phase 2 and phase 2a flinch counts are found to have a statistically significant additive effect, using the posterior distribution plot of treatment on a logarithmic scale, and Visualized in 7.2.

result:
The high dose combination produced a significant additive effect in phase 2 and phase 2a (p <0.01). In Phase 2, 100 mg / kg of the compound of formula (I ^B ), 30 mg / kg pregabalin, and combination administration reduced flinch by 30%, 40%, and 69%, respectively. In Phase 2a, 100 mg / kg of the compound of formula (I ^B ), 30 mg / kg pregabalin, and combination administration reduced flinch by 36%, 38%, and 74%, respectively.

In vivo assessment in humans The combined effects of pregabalin and Nav1.7 blockade can also be investigated in clinical pain studies. In clinical studies, single or multiple doses of one or both drugs at an exploratory pain endpoint in healthy volunteers or patients can be investigated. Clinical studies can also be conducted in pain patient populations using, for example, a parallel group crossover or randomized treatment discontinuation study design.

Claims (19)

In an individual in need of treatment for pain, a therapeutically effective amount of formula (I)

Or a pharmaceutically acceptable salt thereof, wherein -Y is -Cl or -CF ₃ , wherein the method comprises a therapeutically effective amount of A method of treatment further comprising separately, sequentially or simultaneously administering a second pharmaceutically active compound selected from gabapentin and pregabalin or a pharmaceutically acceptable salt thereof.   2. Consisting essentially of administration of a compound of formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both of said compounds. The method described in 1.   The compound of formula (I) is 4- [2- (5-amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazole- The method according to claim 1 or 2, which is 4-yl) benzenesulfonamide or a pharmaceutically acceptable salt thereof.   The compound of formula (I) is 4- [2- (5-amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2-fluoro-N- (1 , 3-thiazol-4-yl) benzenesulfonamide or a pharmaceutically acceptable salt thereof.   5. The method according to any one of claims 1 to 4, wherein the second compound is gabapentin or a pharmaceutically acceptable salt thereof.   5. The method according to any one of claims 1 to 4, wherein the second compound is pregabalin or a pharmaceutically acceptable salt thereof.   7. The method according to any one of claims 1 to 6, wherein the compound of formula (I) and the second compound are administered simultaneously.   8. The method of claim 7, wherein the compound of formula (I) and the second compound are administered together as a single pharmaceutical dosage form.   A combination comprising a compound of formula (I) according to claim 1 or 2 and a second pharmaceutically active compound, or a pharmaceutically acceptable salt of one or both of said compounds. 4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with gabapentin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4-chlorophenoxy] -5-chloro-2-fluoro-N- (1,3-thiazol-4-yl) in combination with pregabalin Benzenesulfonamide;
4- [2- (5-Amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2-fluoro-N- (1,3-thiazole in combination with gabapentin -4-yl) benzenesulfonamide; and 4- [2- (5-amino-1H-pyrazol-4-yl) -4- (trifluoromethyl) -phenoxy] -5-chloro-2- in combination with pregabalin Fluoro-N- (1,3-thiazol-4-yl) benzenesulfonamide;
Or a combination according to claim 9 selected from pharmaceutically acceptable salts of one or both of said compounds.   7. A compound of formula (I) according to any one of claims 1 to 6 and a second pharmaceutically active compound, or a pharmaceutically acceptable salt of one or both of said compounds, and one or more A pharmaceutical dosage form comprising a pharmaceutically acceptable excipient of:   12. A pharmaceutical dosage form according to claim 11 for use as a medicament.   13. A pharmaceutical dosage form according to claim 11 or 12 for use in the treatment of pain.   A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of pain, wherein said treatment is a second compound or pharmaceutical according to claim 1. Or a pharmaceutically acceptable salt thereof. The method further comprises separately, sequentially or simultaneously administering the salts thereof.   15. In the treatment of pain according to claim 14, wherein the treatment further consists of administering the second compound of claim 1 or a pharmaceutically acceptable salt thereof separately, sequentially or simultaneously. Compound for use.   Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain, said treatment further comprising a second according to claim 1. Or a pharmaceutically acceptable salt thereof, comprising separate, sequential or simultaneous administration.   17. Use of a compound according to claim 16, wherein the treatment further consists essentially of separate, sequential or simultaneous administration of the second compound according to claim 1 or a pharmaceutically acceptable salt thereof. (I) a pharmaceutical dosage form comprising the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and (ii) the first of claim 1 A kit for use in the treatment of pain comprising a pharmaceutical dosage form comprising two compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.   19. A kit for use in pain according to claim 18, consisting essentially of pharmaceutical dosage forms (i) and (ii).

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