WO2016009303A1

WO2016009303A1 - Pharmaceutical combinations comprising gabapentin or pregabalin with nav1.7 inhibitors

Info

Publication number: WO2016009303A1
Application number: PCT/IB2015/055100
Authority: WO
Inventors: Douglas Scott KRAFTE; Rosemarie ROELOFFS
Original assignee: Pfizer Inc.
Priority date: 2014-07-17
Filing date: 2015-07-06
Publication date: 2016-01-21
Also published as: AR101227A1; CA2897306A1; JP2016029033A; TW201605439A

Abstract

The invention relates to a method of treating pain comprising the separate, sequential or simultaneous administration to an individual in need of such treatment of a therapeutically effective amount of a compound according to formula (I) or pharmaceutically acceptable saltsthereof, wherein Y is –Cl or –CF₃; and of a therapeutically effective amount of gabapentin or pregabalin, or a pharmaceutically acceptable salt thereof.

Description

PHARMACEUTICAL COMBINATIONS COMPRISING GABAPENTIN OR PREGABALIN WITH NAV1 .7 INHIBITORS

Field of the Invention

The invention relates to the treatment of pain using combinations of pharmaceutically active agents. More particularly, this invention relates to the use of combinations of an A/-thiazolyl-4-phenoxybenzenesulfonamide derivative and a second pharmaceutically active agent, and to pharmaceutical compositions containing them.

Background

The A/-thiazolyl-4-phenoxybenzenesulfonamide derivatives that are the first component of the combinations of the present invention are modulators of the Na_v1.7 sodium channel. The compounds are disclosed in International Patent Application PCT/IB2010/050033, published as WO2010/079443.

Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner C.A. , Jentsch T.J., Hum. Mol. Genet, 11 (20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et a/., Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)), myotonia (Cannon, S.C., Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, J. N. et ai, J. NeurobioL, 61 (1 ): 55-71 (2004)).

There are currently at least nine known members of the family of voltage-gated sodium channel (VGSC) alpha subunits. Names for this family include SCNx, SCNAx, and Na_vx.x. The VGSC family has been phylogenetically divided into two subfamilies Na_v1.x (all but SCN6A) and Na_v2.x (SCN6A). The Na_v1.x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX- sensitive or TTX-S) and those which are resistant to blocking by tetrodotoxin (TTX- resistant or TTX-R). An increasing body of evidence suggests that Na_v1.7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. Deletion of the SCN9A gene in nociceptive neurons of mice led to a reduction in mechanical and thermal pain thresholds and reduction or abolition of inflammatory pain responses (Nassar et al., Proc Natl Acad Sci USA, 101(34): 12706-1 1 (2004)). In humans, Na_v1.7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10 (2002)). Gain of function mutations of Na_v1.7, both familial and sporadic, have been linked to primary erythermalgia, a disease characterized by burning pain and inflammation of the extremities (Yang et al., J. Med. Genet., 41(3): 171-4 (2004), and paroxysmal extreme pain disorder (Waxman, SG Neurology. 7;69(6): 505-7 (2007)). Congruent with this observation is the report that the non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief in cases of familial erythermalgia (Legroux- Crepel et al. , Ann. Dermatol Venereol., 130: 429-433) and carbamazepine is effective in reducing the number and severity of attacks in PEPD (Fertleman et al, Neuron. ; 52(5): 767-74 (2006). Further evidence of the role of Nav1.7 in pain is found in the phenotype of loss of function mutations of the SCN9A gene. Cox and colleagues (Nature, 444(7121): 894-8 (2006)) were the first to report an association between loss- of-function mutations of SNC9A and congenital indifference to pain (CIP), a rare autosomal recessive disorder characterized by a complete indifference or insensitivity to painful stimuli. Subsequent studies have revealed a number of different mutations that result in a loss of function of the SCN9A gene and and the CIP phenotype (Goldberg et al, Clin Genef.;71(4): 311-9 (2007), Ahmad et al, Hum Mol Genet. 1 ;16(17): 21 14-21 (2007)).

Nav1.7 inhibitors are therefore potentially useful in the treatment of a wide range of disorders, particularly pain.

The second component of the combinations 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- (aminomethy)-5-methylhexanoic acid) are ligands for the α₂-δ subunit of calcium channels. They have been reported to be effective in the treatment of neuropathic pain. Gabapentin is marketed under the brand name Neurontin and pregabalin is marketed under the brand name Lyrica.

There is an ongoing need to provide improved methods for managing pain. The use as disclosed herein of a combination of a Na_v1.7 modulator and a modulator of activity at the alpha-2 delta subunit of calcium channels may afford a therapeutic regimen that provides: a greater efficacy; and/or the ability to use lower doses of the combination when compared to the individual agents; and/or an improved tolerability to the use of either agent alone.

Summary of the Invention

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

In a first embodiment A1 E1 , the present invention provides a method of treating pain comprising the administration to an individual in need of such treatment of a therapeutically effe (I)

or a pharmaceutically acceptable salt thereof, wherein -Y is -CI or -CF3;

wherein said method further comprises the separate, sequential or simultaneous administration of a therapeutically effective amount of a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt thereof.

In a further embodiment A1 E2, the present invention provides the method of embodiment A1 E1 which consists essentially of the administration of a compound according to formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both said compounds. In a further embodiment A1 E3, the present invention provides the method of embodiments A1 E1 or A1 E2, wherein the compound according to formula (I) is 4-[2-(5- amino-1 /-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3-thiazol-4- yl)benzenesulfonamide (l^A) or a pharmaceutically acceptable salt thereof.

In a further embodiment A1 E4, the present invention provides the method of embodiments A1 E1 or A1 E2, wherein the compound according to formula (I) is 4-[2-(5- amino-1 /-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/-(1 ,3-thiazol-4- yl)benzenesulfonamide (l^B) or a pharmaceutically acceptable salt thereof.

In a further embodiment A1 E5, the present invention provides the method of any one of embodiments A1 E1, A1 E2, A1 E3 and A1 E4, wherein the second pharmaceutically active compound is gabapentin or a pharmaceutically acceptable salt thereof.

In a further embodiment A1 E6, the present invention provides the method of any one of embodiments A1 E1 , A1 E2, A1 E3 and A1 E4, wherein the second pharmaceutically active compound is pregabalin or a pharmaceutically acceptable salt thereof. In a further embodiment A1 E7, the present invention provides the method of any one of embodiments A1 E1 , A1 E2, A1 E3, A1 E4, A1 E5 and A1 E6 wherein the compound according to formula (I) and the second pharmaceutically active compound are administered simultaneously.

In a further embodiment A1 E8, the present invention provides the method of embodiment A1 E7, wherein the compound according to 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 a first embodiment A2E1 , the present invention provides a combination comprising a compound according to formula (I) and a second pharmaceutically active compound, as defined in embodiments A1 E1 or A1 E2, or a pharmaceutically acceptable salt of one or both said compounds.

In a further embodiment A2E2, the present invention provides the combination according to embodiment A2E1 selected from:

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3-thiazol-4- yl)benzenesulfonamide in combination with gabapentin; 4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3-thiazol-4- yl)benzenesulfonamide in combination with pregabalin;

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with gabapentin; and

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with pregabalin; or a pharmaceutically acceptable salt of one or both said compounds. In a further aspect A3, the present invention provides a pharmaceutical dosage form.

In a first embodiment A3E1 , the present invention provides a pharmaceutical dosage form comprising a compound according to formula (I) and a second pharmaceutically active compound, as defined in any one of embodiments A1 E1 , A1 E2, A1 E3, A1 E4, A1 E5 and A1E6, or a pharmaceutically acceptable salt of one or both said compounds; and one or more pharmaceutically acceptable excipients. In a further embodiment A3E2, the present invention provides the pharmaceutical dosage form according to embodiment A3E1 for use as a medicament.

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

In a further aspect A4, the present invention provides a compound according to formula (I) as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, wherein the treatment further comprises the separate, sequential or simultaneous administration of a second pharmaceutically active compound as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof.

In a further embodiment A4E1 , the present invention provides the compound according to aspect A4 for use in the treatment of pain, wherein the treatment further consists essentially of the separate, sequential or simultaneous administration of a second compound as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof.

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 said compounds, for use in the treatment of pain.

In a further aspect A6, the present invention provides the use of a compound according to formula (I) as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain, wherein the treatment further comprises the separate, sequential or simultaneous administration of of a second pharmaceutically active compound as defined in embodiment A1 E1 , 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 consists essentially of the separate, sequential or simultaneous administration of a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

In a further aspect A7, the present invention provides the use of a combination as defined in embodiment A2E1 or A2E2, or a pharmaceutically acceptable salt of one or both said compounds, for the manufacture of a medicament for the treatment of pain. In a further aspect A8, the present invention provides a kit comprising:

(i) a pharmaceutical dosage form comprising a compound according to formula (I) as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and

(ii) a pharmaceutical dosage form comprising a second pharmaceutically active compound as defined in embodiment A1 E1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; for use in the the treatment of pain.

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

Fig 1 is a graphical representation of the degree of flinching over time for the high dose of pregabalin (Group 5).

Fig 2 is a graphical representation of the degree of flinching over time for the high dose of the compound of formula (l^B) (Group 3). Fig 3 is a graphical representation of the degree of flinching over time for the high dose combination of the compound of formula (l^B) and pregabalin (Group 7). Fig 4 is a graphical representation of the degree of flinching over time for the low dose of pregabalin (Group 4).

Fig 5 is a graphical representation of the degree of flinching over time for the high dose of the compound of formula (l^B) (Group 2).

Fig 6 is a graphical representation of the degree of flinching over time for the low dose combination of the compound of formula (l^B) and pregabalin (Group 6). Fig 7.1 is a visualisation using posterior distribution plots on the log scale of the high dose combination during phase 2.

Fig 7.2 is a visualisation using posterior distribution plots on the log scale of the high dose combination during phase 2a.

Detailed description of the Invention

As used herein, the term "combinations of the invention" refers to a combination of a compound of formula (I) and a second pharmaceutically active compound, including:

4-[2-(5-amino-1 /-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3-thiazol-4- yl)benzenesulfonamide in combination with gabapentin;

4-[2-(5-amino-1 /-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3-thiazol-4- yl)benzenesulfonamide in combination with pregabalin; 4-[2-(5-amino-1 /-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with gabapentin; and

4-[2-(5-amino-1 /-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with pregabalin.

The terms "treatment", "treating" and the like refer to palliative, curative and prophylactic treatment. In the context of the treatment of pain resulting from an injury or pathological condition, it will be understood that it is the pain that is being treated rather than the underlying cause of the pain. "Separate" administration refers to a therapeutic regimen in which the two agents are administered according to independent schedules. It includes the possibility that, where multiple doses of each agent are administered, then some of the doses may be taken together.

"Sequential" administration refers to a therapeutic regimen in which the two agents are administered according to the same schedule. "Simultaneous" administration refers to a therapeutic regimen in which the two agents are administered together in a single action.

A method of treatment "which consists essentially of the administration of a compound according to formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both said compounds" refers to a method consisting of the administration of two, and only two, pharmaceutically active agents.

The term "consists essentially of" when used in connection with:

a combination of a compound according to formula (I) and a second pharmaceutically active compound;

a compound according to formula (I) for use in the treatment of pain wherein the treatment involves a second pharmaceutically active compound;

use of a compound according to formula (I) in the manufacture of a medicament for the treatment of pain wherein the treatment involves a second pharmaceutically active compound; and

a kit of pharmaceutical dosage forms of a compound according to formula (I) and a second pharmaceutically active compound;

has the same meaning as that described just above in connection with a method of treatment.

The compounds of formula (I) may exist in tautomeric forms. Specifically, the aminopyrazole moiety may exist 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 specific compounds should be understood to refer to the compound and/or its tautomer.

The compounds of formula (I) are capable of forming pharmaceutically acceptable addition salts with acids, and these salts may be used in the invention. Suitable acid addition salts are formed from acids which form non-toxic salts. .Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate salts.

Gabapentin and pregabalin have been reported to form salts with both acids and bases. The skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.

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

Pharmaceutically acceptable salts of compounds of formula (I), gabapentin and pregabalin may be prepared by one or more of three methods: i) by reacting the compound of formula (I), gabapentin or pregabalin with the desired acid or base;

ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I), gabapentin or pregabalin using the desired acid or base; or

iii) by converting one salt of the compound of formula (I), gabapentin or pregabalin to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically 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 ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of formula (I), gabapentin and pregabalin, or pharmaceutically acceptable salts thereof, may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of formula (I), gabapentin or pregabalin, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molcules, for example ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂0, d₆-acetone and d₆-DMSO.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molcules are isolated from direct contact with each other by intervening organic molcules. In channel hydrates, the water molcules lie in lattice channels where they are next to other water molcules. In metal-ion coordinated hydrates, the water molcules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The compounds of formula (I), gabapentin and pregabalin may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molcular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molcular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

The 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 by any other method known in the art for the preparation of compounds of analogous structure. Compound (l^A) is Example 788 of WO2010/079443 and compound (l^B) is Example 1029 thereof. Gabapentin and pregabalin are well known compounds and may be prepared by methods disclosed in the literature.

The compounds of formula (I), gabapentin and pregabalin may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

The compounds of formula (I), gabapentin and pregabalin may be administered separately or in combination. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compounds of formula (I), gabapentin and pregabalin. The choice of excipient will to a large extent 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 the delivery of combinations of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration. When the compounds of formula (I), gabapentin and pregabalin are administered separately they may be administered by different routes.

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

The compounds of formula (I), gabapentin and pregabalin, or combinations thereof, may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches..

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of formula (I), gabapentin and pregabalin, or combinations thereof, may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11. (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

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

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents. Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to 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, may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I), gabapentin and pregabalin used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified 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, may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may 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 delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

The compounds of formula (I), gabapentin and pregabalin, or combinations thereof, can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound of formula (I), gabapentin or pregabalin, or a combination thereof, comprising, for example: ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active; a propellant(s) as solvent; and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the 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 atomiser using electrohydrodynamics to produce a fine mist may contain from ^g to 20mg of the compounds of formula (I), gabapentin or pregabalin per actuation and the actuation volume may vary from 1 μΙ to 100μΙ. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from ^g to 100mg of the compounds of formula (I), gabapentin or pregabalin. The overall daily dose will typically be in the range ^g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

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

The compounds of formula (I), gabapentin and pregabalin, or combinations thereof, may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. The compounds of formula (I), gabapentin and pregabalin may be combined with soluble macromolcular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. W091/11 172, WO94/02518 and W098/55148. For administration to human patients, the total daily dose of the compounds of formula (I) is typically in the range 10mg to 5g, such as 100mg to 3g, for example 250mg to 2g depending, of course, on the mode of administration and efficacy. The total daily dose of gabapentin is typically in the range 200mg to 3g, such as 500mg to 2.5g, for example 900mg to 1.8g. The total daily dose of pregabalin is typically in the range 50mg to 1 g, such as 150mg to 750mg, for example 300mg to 600mg. For example, oral administration may require a total daily dose of from 300mg to 2g of a compound of formula (I) and from 750mg to 2g of gabapentin, or from 150mg to 600mg of pregabalin.

The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. Disorders for which the combinations of the invention are indicated include pain. Pain may be either acute or chronic and additionally may be of central and/or peripheral origin. Pain may be of a neuropathic and/or nociceptive and/or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 Ed), Chapter"!). These sensory fibres are known as nociceptors, and are characteristically small diameter axons with slow conduction velocities, of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury or alteration which can be associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768). As such, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain, but may include any chronic painful condition affecting any system, such as those described by the International Association for the Study of Pain (Classification of Chronic Pain, a publication freely available for download at http://www.iasp-pain.org). The clinical manifestation of pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms can include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5^th Ed), Chapterl). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Apart from acute or chronic, pain can also be broadly categorized into: nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells); or neuropathic pain.

Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5^th Ed), Chapterl). Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy). Back pain may be due to herniated or ruptured intervertabral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating. Nociceptive pain can also be related to inflammatory states. The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5^th Ed), Chapter3). A common inflammatory condition assoiciated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Rheumatoid arthritis is an immune-mediated, chronic, inflammatory polyarthritis disease, mainly affecting peripheral synovial joints. It is one of the commonest chronic inflammatory conditions in developed countries and is a major cause of pain. In regard to nociceptive pain of visceral origin, visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal organs (Bielefeldt and Gebhart, 2006, Wall and Melzack's Textbook of Pain (5^th Ed), Chapter48). This includes the reproductive organs, spleen, liver, gastrointestinal and urinary tracts, airway structures, cardiovascular system and other organs contained within the abdominal cavity. As such visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowl syndrome, endometriosis and dysmenorrhea! (Classification of Chronic Pain, available at http://www.iasp-pain.org). Currently the potential for a neuropathic contribution (either through central changes or nerve injury/damage) to visceral pain states is poorly understood but may play a role in certain conditions (Aziz et al., 2009, Dig Dis 27, Suppl 1 , 31-41)

Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post- stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a 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). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (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). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain, cancer pain and even migaine headaches may include both nociceptive and neuropathic components.

Similarly other types of chronic pain, perhaps less well understood, are not easily defined by the simplistic definitions of nociceptive or neuropathic. Such conditions include in particular fibromyalgia and chronic regional pain syndrome, which are often described as dysfunctional pain states e.g. fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http://www.iasp-pain.org). The combinations of the invention may optionally be used in combination with one or more further pharmacologically active compounds. Such combinations offer the possibility of further significant advantages, including patient compliance, ease of dosing and synergistic activity. In the combinations that follow the combination of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents. Useful further pharmacologically active agents include one or more agents selected from:

• a selective Nav1.3 channel modulator, such as a compound disclosed in WO2008/118758;

· a selective Nav1.8 channel modulator, such as a compound disclosed in WO2013/1 14250;

• a selective Nav1.9 channel modulator;

• a compound which modulates activity at more than one Nav channel, including a non-selective modulator such as bupivacaine, carbamazepine, lamotrigine, lidocaine, mexiletine or phenytoin;

• any inhibitor of nerve growth factor (NGF) signaling, such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist, or an agent that inhibits downstream signaling in regard to NGF stimulated TrkA or P75 signalling;

• an inhibitor of neurotrophic pathways, where such inhibition is achieved by: (a) an agent that binds to nerve growth factor (NGF) (e.g. tanezumab, fasinumab or fulranumab), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or neurotrophin-4 (NT-4), or to more than one of the aforementioned neurotrophins (e.g. soluble P75); or (b) an agent that inhibits receptor function at one or more of TrKA, TrKB, TrKC or P75, either at the orthosteric site, an allosteric site or by inhibition of the catalytic activity of the receptor(s);

• a compound which increases the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase inhibitory (FAAH) or monoacylglycerol lipase (MAGL) activity;

• an analgesic, in particular paracetamol;

• an opioid analgesic, such as: buprenorphine, butorphanol, cocaine, codeine, dihydrocodeine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan levorphanol, meperidine, methadone, morphine, nalmefene, nalorphine, naloxone, naltrexone, nalbuphine, oxycodone, oxymorphone, propoxyphene or pentazocine;

• an opioid analgesic which preferentially stimulates a specific intracellular pathway, for example G-protein as opposed to beta arrestin recruitment, such as TRV130;an opioid analgesic with additional pharmacology, such as: noradrenaline (norepinephrine) reuptake inhibitory (NRI) activity, e.g. tapentadol; serotonin and norepinephrine reuptake inhibitory (SNRI) activity, e.g. tramadol; or nociceptin receptor (NOP) agonist activity, such as GRT6005;

a nonsteroidal antiinflammatory drug (NSAID), such as a non-selective cyclooxygenase (COX) inhibitor, e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac; or a COX-2 selective inhibitor, e.g. celecoxib, deracoxib, etoricoxib, mavacoxib or parecoxib;

a prostaglandin E2 subtype 4 (EP4) antagonist;

a microsomal prostaglandin E synthase type 1 (mPGES-1) inhibitor;

a sedative, such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

a GABAA modulator with broad subtype modulatory effects mediated via the benzodiazepine binding site, such as chlordiazepoxide, alprazolam, diazepam, lorazepam, oxazepam, temazepam, triazolam, clonazepam or clobazam;

a GABAA modulator with subtype-selective modulatory effects mediated via the benzodiazepine binding site with reduced adverse effects, for example sedation, such as TPA023, TPA023B, L-838,417, CTP354 or NSD72;

a GABAA modulator acting via alternative binding sites on the receptor, such as barbiturates, e.g. amobarbital, aprobarbital, butabital, mephobarbital, methohexital, pentobarbital, phenobartital, secobarbital, or thiopental; neurosteroids such as alphaxalone, alphadolone or ganaxolone; β-subunit ligands, such as etifoxine; or δ- preferring ligands, such as gaboxadol;

a GlyR3 agonist or positive allosteric modulator;

a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxolone, methocarbamol or orphrenadine;

a glutamate receptor antagonist or negative allosteric modulator, such as an NMDA receptor antagonist, e.g. dextromethorphan, dextrorphan, ketamine or, memantine; or an mGluR antagonist or modulator;

an alpha-adrenergic, such as clonidine, guanfacine or dexmetatomidine;

a beta-adrenergic such as propranolol; • a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

• a tachykinin (NK) antagonist, such as aprepitant or maropitant;

• a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

· a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), varenicline or nicotine;

• a Transient Receptor Potential V1 (TRPV1) receptor agonist (e.g. resinferatoxin or capsaicin) or antagonist (e.g. capsazepine or mavatrap);

• a Transient Receptor Potential A1 (TRPA1) receptor agonist (e.g. cinnamaldehyde or mustard oil) or antagonist (e.g. GRC17536 or CB-625);

• a Transient Receptor Potential M8 (TRPM8) receptor agonist (e.g. menthol or icilin) or antagonist;

• a Transient Receptor Potential V3 (TRPV3) receptor agonist or antagonist (e.g.

GRC- 15300);

· a corticosteroid such as dexamethasone;

• a 5-HT receptor agonist or antagonist, particularly a 5-HTIB/ID agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

• a 5-HT_2A receptor antagonist;

• a PDEV inhibitor, such sildenafil, tadalafil or vardenafil;

· an alpha-2-delta ligand such as gabapentin, gabapentin enacarbil or pregabalin, ;

• a serotonin reuptake inhibitor (SRI) such as sertraline, demethylsertraline, fluoxetine, norfluoxetine, fluvoxamine, paroxetine, citalopram, desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

· anNRI , such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine, especially a selective noradrenaline reuptake inhibitor such as reboxetine;

• an SNRI, such as venlafaxine, O-desmethylvenlafaxine, clomipramine, desmethylclomipramine, duloxetine, milnacipran and imipramine;

• an inducible nitric oxide synthase (iNOS) inhibitor;

• a leukotriene B4 antagonist;

• a 5-lipoxygenase inhibitor, such as zileuton; • a potassium channel opener or positive modulator, such as an opener or positive modulator of KCNQ/Kv7 (e.g. retigabine or flupirtine), a G protein-coupled inwardly- rectifying potassium channel (GIRK), a calcium-activated potassium channel (Kca) or a potassium voltage-gated channel such as a member of subfamily A (e.g. Kv1.1), subfamily B (e.g. Kv2.2) or subfamily K (e.g. TASK, TREK or TRESK);

• a P2X₃ receptor antagonist (e.g. AF219) or an antagonist of a receptor which contains as one of its subunits the P2X₃ subunit, such as a P2X₂/3 heteromeric receptor;

• a Ca_v2.2 calcium channel blocker (N-type), such as ziconotide; and

· a Cav3.2 calcium channel blocker (T-type), such as ethosuximide.

There is also included within the scope the present invention combinations of the combinations of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus, among the agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. The isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may 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)-1 H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide. It is within the scope of the invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula (I) and one of which contains gabapentin or pregabalin, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) and one of which contains gabapentin or pregabalin, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

Experimental

In vivo evaluation in mice

Animals: Male CD-1 mice (Charles River, Raleigh, NC) weighing 27-36 grams on the day of dosing were housed five per cage. Animals had free access to food and water and were maintained on a 12: 12 hour light/dark schedule.

Compounds and dosing solutions: The Compound of formula (l^B) and pregabalin were formulated as solutions in 0.5% methyl cellulose. The high and low dose combinations were formulated together in 0.5% methyl cellulose into a single suspension for oral dosing. Compounds were dosed via oral gavage at 10mL/kg.

Experimental procedure. Animals were tested for paw movement responses to an injection of a 2.5% formalin solution (20 μΙ in saline) using the Automated Nociception Analyzer (Yaksh et al., 2001). This device uses a magnetic detection system to measure paw movements defined as flinches. Small metal bands were attached to the left hind paw of mice just before placement into individual circular test chambers (4 mice per session) 60 minutes prior to formalin injection. Mice were orally administered test compounds 2 hours prior to formalin injection. To initiate the experiment mice were injected with 20 μΙ of 2.5% formalin subcutaneously on the dorsal surface of the left hind paw and placed in the test chambers. The instrument then recorded rapid foot movements counted in one minute bins continuously for 60 minutes. Treatment groups were assigned to balance treatments across days and across test chambers.

Immediately following the 60 minute flinching observation, the mice were euthanized and blood and brain tissue were removed for bioanalysis of the compound of formula (l^B) and pregabalin levels.

Experimental grou s: Table 1 summarizes the groups tested in the study.

Group 6 low dose combination

Group 7 high dose combination

Excluded animals: One mouse was excluded from both the vehicle group and from the compound of formula (l^B) 30 mg/kg group because of an incomplete formalin injection. One mouse was excluded from the compound of formula (l^B) 100 mg/kg group because the metal paw band fell off during the course of the flinching study. One mouse was excluded from the pregabalin 30mg/kg group because it only received a partial dose of test compound. Data analysis: The total flinches were counted over particular time intervals or phases. The phases summarized in this study were:

Phase 1 : 0-9 minutes

Phase 2: 10-60 minutes

Phase 2a: 10-40 minutes

Flinching events were automatically recorded by the Automated Nociception Analyzer (Yaksh et al., 2001) and the total number of flinches for each phase was calculated automatically. The results for each experimental group are set out in tables 2.1 to 2.7 below.

Table 2.1 : Vehicle (Group 1)

Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

1 178 121 97 97 218 195 210 203 102 61 163 93

2 266 149 77 150 213 71 15 61 11 0 0 0

3 302 187 240 267 229 256 32 16 14 97 52 5

4 317 204 210 220 273 275 247 226 227 132 80 96

5 283 105 71 234 240 175 27 30 48 7 18 0

6 290 196 208 293 293 215 68 15 3 0 0 30

7 310 241 198 288 230 188 86 31 26 78 124 206

8 270 217 180 233 228 173 137 79 125 106 103 93

9 225 157 172 190 189 154 149 49 76 2 1 3

10 263 138 1 16 96 313 210 283 29 15 14 9 136

1 1 195 51 92 197 149 163 145 137 16 2 4 123

12 201 140 139 178 153 123 6 34 10 33 202 103

13 268 168 238 208 210 235 69 44 96 4 0 0

14 279 237 160 183 273 66 5 4 129 31 7 18 mean 261 165 157 202 229 179 106 68 64 41 55 65

SEM 12 14 16 16 13 16 25 19 17 12 18 18 Table 2.2: Compound (l^B) 30 mg/kg (Group 2)

Table 2.3: Compound (l^B) 100 mg/kg (Group 3)

Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

1 318 191 56 32 16 14 1 17 145 133 225 161 1 16

2 280 106 219 41 74 76 28 20 7 30 7 9

3 210 63 1 0 36 75 62 56 66 37 42 11

4 296 147 137 215 265 154 199 189 68 67 155 239

5 285 203 138 181 169 130 127 82 60 26 23 6

6 178 91 22 96 144 68 46 17 15 33 12 24

7 289 1 11 63 123 189 173 72 45 42 39 1 1 5

8 214 314 335 84 35 1 12 13 14 0 0 0

9 208 128 175 61 44 1 14 138 9 0 0 0 74 Total number of flinches counted at 5 minute intervals

Table 2.4: Pregabalin 10 mg/kg (Group 4)

Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

1 322 65 5 186 182 202 34 28 56 152 12 8

2 258 109 170 313 318 173 75 328 226 186 107 96

3 291 106 144 197 217 157 163 33 5 6 6 3

4 198 95 7 61 172 1 10 144 88 29 60 2 0

5 321 217 209 224 210 1 12 73 170 10 1 4 0

6 239 43 28 283 235 235 158 87 32 5 2 4

7 294 149 163 281 244 198 191 51 8 76 127 34

8 154 49 6 0 32 123 67 96 61 22 13 5

9 259 186 2 74 11 165 144 22 109 1 14 140 159

10 280 105 71 286 258 24 12 5 8 6 0 0

1 1 223 63 8 134 177 134 42 12 9 2 12 0

12 192 62 36 154 166 139 54 5 0 2 0 1

13 249 1 12 84 148 248 154 122 98 12 13 10 10

14 287 209 159 219 285 260 198 293 219 229 35 11

15 202 52 83 21 1 181 129 168 35 78 7 2 40

16 176 91 83 21 78 103 1 14 58 7 2 0 0 mean 247 107 79 175 188 151 110 88 54 55 30 23

SEM 13 14 18 24 21 14 15 24 18 19 12 1 1 Table 2.5: Pregabalin 30 mg/kg (Group 5)

Table 2.6: Low Dose Combination (Group 6)

Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

1 295 100 48 143 234 156 59 130 18 17 20 11

2 288 75 122 250 198 122 14 44 18 11 5 40

3 199 56 16 88 86 86 84 30 28 64 1 1 7

4 239 106 69 131 192 56 6 28 6 5 0 0

5 270 1 19 126 231 181 73 287 134 17 10 6 8

6 258 93 205 322 337 284 168 66 31 0 0 208

7 119 71 165 140 52 224 95 68 66 42 41 1 14

8 193 23 71 146 264 167 65 53 10 6 1 0

9 281 51 28 32 233 263 1 11 23 152 91 3 12 Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

10 245 158 161 89 233 223 107 127 51 75 22 14

1 1 242 108 49 203 180 199 1 15 12 6 10 5 158

12 135 1 1 1 1 23 42 49 22 18 10 0 1

13 273 121 27 175 188 191 43 16 11 11 3 43

14 230 142 109 256 178 99 86 5 3 1 3 100

15 184 56 8 132 171 1 13 80 27 31 1 0 0

16 133 45 35 86 29 58 25 0 0 0 0 22 mean 224 83 78 152 174 147 87 49 29 22 8 46

SEM 14 10 16 21 22 19 17 11 9 7 3 16

Table 2.7: High Dose Combination (Group 7)

Total number of flinches counted at 5 minute intervals

Animal # 5 10 15 20 25 30 35 40 45 50 55 60

1 130 10 11 25 0 61 20 12 1 0 0 0

2 179 2 2 1 2 40 101 101 63 53 20 11

3 247 44 1 2 4 0 1 25 58 15 10 4

4 274 22 4 99 168 105 44 17 7 0 0 2

5 162 14 8 9 0 5 109 23 10 1 0 0

6 257 106 11 14 6 6 98 58 38 52 25 38

7 265 69 24 17 153 73 274 275 236 140 24 13

8 120 5 14 0 0 20 4 42 34 50 31 21

9 75 76 12 69 18 19 0 2 51 46 33 20

10 292 56 2 8 94 147 174 245 76 25 23 28

1 1 264 58 96 32 35 53 148 100 38 2 7 5

12 239 15 0 38 119 154 35 5 4 2 1 8

13 259 84 14 63 145 180 99 11 20 8 0 0

14 225 19 42 0 53 90 106 165 19 233 17 2

15 243 135 64 136 126 142 1 1 2 1 2 3 10

16 201 1 1 2 1 13 6 37 91 29 0 1 10 mean 215 45 19 32 59 69 79 73 43 39 12 1 1

SEM 16 10 7 10 16 15 19 22 14 16 3 3 Graphical representation of the time course of flinching for both the high dose and low dose combinations are shown in, respectively Figs 1 to 3 and 4 to 6. The total numbers of flinches within each phase were analyzed separately on the log scale using a linear model accounting for experimental day. Individual treatment comparisons were performed and summarized using means, differences, 95% confidence intervals and p-values. Results for the high dose Phase 2 and Phase 2a total flinches, where a statistically significant additive effect was seen, are visualized in Figs 7.1 and 7.2 using posterior distribution plots of the treatment means on the log scale.

Results:

The high dose combination resulted in a significant additive effect in Phase 2 and Phase 2a (p<0.01). In Phase 2 flinching was decreased by 30%, 40% and 69% by the compound of formula (l^B) 100 mg/kg, pregabalin 30 mg/kg and the combination dose, respectively. In Phase 2a flinching was decreased by 36%, 38% and 74% by the compound of formula (l^B) 100 mg/kg, pregabalin 30 mg/kg and the combination dose, respectively.

In vivo evaluation in a man

The combined effects of pregabalin and Nav 1.7 blockade may also be examined in clinical pain studies. Clinical studies can examine single or multiple doses of either or both agents in exploratory pain endpoints in healthy volunteers or patients. Clinical studies can also be carried out in pain patient populations employing, for example, parallel group, cross-over or randomised withdrawal study designs.

Claims

s

A method of treating pain comprising the administration to an individual in need of such treatment of a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein -Y is -CI or -CF3; wherein said method further comprises the separate, sequential or simultaneous administration of a therapeutically effective amount of a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt thereof.

The method according to claim 1 which consists essentially of the administration of a compound according to formula (I) and a second pharmaceutically active compound selected from gabapentin and pregabalin, or a pharmaceutically acceptable salt of one or both said compounds.

The method according to either claim 1 or claim 2 wherein the compound according to formula (I) is 4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-chlorophenoxy]-5- chloro-2-fluoro-/V-(1 ,3-thiazol-4-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

The method according to either claim 1 or claim 2 wherein the compound according to formula (I) is 4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-(trifluoromethyl)- phenoxy]-5-chloro-2-fluoro-/V-(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.

6. 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 according to formula (I) and the second compound are administered simultaneously.

8. The method according to claim 7 wherein the compound according to formula (I) and the second compound are administered together as a single pharmaceutical dosage form.

9. A combination comprising a compound according to formula (I) and a second pharmaceutically active compound, as defined in claim 1 or claim 2, or a pharmaceutically acceptable salt of one or both said compounds.

10. The combination according to claim 9 selected from:

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with gabapentin;

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-/V-(1 ,3- thiazol-4-yl)benzenesulfonamide in combination with pregabalin;

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/- (1 ,3-thiazol-4-yl)benzenesulfonamide in combination with gabapentin; and

4-[2-(5-amino-1/-/-pyrazol-4-yl)-4-(trifluoromethyl)-phenoxy]-5-chloro-2-fluoro-/\/- (1 ,3-thiazol-4-yl)benzenesulfonamide in combination with pregabalin; or a pharmaceutically acceptable salt of one or both said compounds.

1 1. A pharmaceutical dosage form comprising a compound according to formula (I) and a second pharmaceutically active compound, as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt of one or both said compounds, and one or more pharmaceutically acceptable excipients.

12. The pharmaceutical dosage form according to claim 1 1 for use as a medicament.

13. The pharmaceutical dosage form according to either claim 1 1 or 12 for use in the treatment of pain.

14. A compound according to formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, wherein the treatment further comprises the separate, sequential or simultaneous administration of a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 for use in the treatment of pain, wherein the treatment further consists essentially of the separate, sequential or simultaneous administration of a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

16. The use of a compound according to formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain, wherein the treatment further comprises the separate, sequential or simultaneous administration of a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

17. The use of a compound according to claim 16, wherein the treatment further consists essentially of the separate, sequential or simultaneous administration of a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof.

18. A kit comprising:

(i) a pharmaceutical dosage form comprising a compound according to formula (I) as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and

(ii) a pharmaceutical dosage form comprising a second compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; for use in the the treatment of pain.

19. The kit of claim 18 for use in pain which consists essentially of pharmaceutical dosage forms (i) and (ii).