Enantiomers of spiro-oxindole compounds and their uses as therapeutic agents

The present invention is directed to a specific enantiomer of spiro-oxindole compound, in particular an enantiomer for use in human or animal therapy for treating diseases or conditions in a mammal, preferably a human, which are alleviated or reduced by modulation, preferably inhibition, of voltage-gated channels sodium.

BACKGROUND OF THE INVENTION [0002] Published PCT Patent Application No. WO 2006/110917 discloses certain spiro-indole compounds, in particular, 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole7.3'-indolo] -2 '(1'H) -one, i.e., a compound of the following formula (I):

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These compounds are disclosed herein as being useful in the treatment of diseases or conditions, such as pain, in mammals, preferably humans, which are alleviated or reduced by the modulation, preferably inhibition, of voltage-gated sodium channels.

SUMMARY OF THE INVENTION [0003] The present invention is directed to the discovery that the (S) enantiomer and (R) enantiomer of the compound of

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show a difference in potency for inhibiting voltage gated sodium channel activity. The problem of the present invention is solved on the basis of claims 1 to 9.

[0004] Accordingly, in one aspect, the invention provides the (S) 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] enantiomer. benzodioxole-7,3'-indolo] -2 '(1'H) -one, i.e., the (S) enantiomer having the following formula (IS):

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or a pharmaceutically acceptable solvate thereof. Preferably, the (S) enantiomer is substantially free of the (R) enantiomer.

In another aspect, the invention provides a pharmaceutical composition comprising the (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer and one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical composition comprising the (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer, in a pharmaceutically acceptable carrier and in an amount effective to treat diseases or conditions. related to pain when administered to an animal, preferably a mammal, most preferably a human.

In another aspect, the application illustrates a pharmaceutical therapy in combination with the (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer and one or more other existing therapies or as any combination thereof, to increase the effectiveness of existing or future drug therapies or to reduce adverse events associated with existing or future drug therapy. In one embodiment, the present invention relates to a pharmaceutical composition combining the (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer, with recognized or future therapies for the indications mentioned in the invention.

In another aspect, the invention provides a (S) enantiomer as set forth above, or a pharmaceutically acceptable solvate thereof, for use in treating a disease or condition in a mammal, preferably a human, wherein the disease or condition is selected from the group consisting of pain, depression. , cardiovascular diseases, respiratory diseases, mental diseases, neurological diseases and seizures and combinations thereof.

[0009] In another aspect, the invention provides a (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer for use in the treatment of pain in a mammal, preferably a human.

[0010] In another aspect, the present invention provides a (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer for use in treating or reducing the severity of a disease, condition or disease in which activation or hyperactivity. one or more voltage gated sodium channel proteins, including Nav1: 1 Nav1: 2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8 naïve sodium channel or

Nav1.9, is involved in the disease, condition or disorder.

[0011] In another aspect, the invention provides a (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer for use in treating a disease or condition in a mammal, preferably a human, that is associated with channel activity. vodka gated with tension. Accordingly, the invention provides the (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) to 2 enantiomer.

For use in the treatment of a disease or condition in a mammal, preferably a human, which is alleviated or reduced by the modulation, preferably inhibition, of voltage-gated sodium channels. Examples of such diseases and conditions include pain of any kind and origin, HIV-related pain, HIV-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, diabetic neuropathy, regional complex pain syndrome (CRPS), paroxysmal extreme pain disorder (PEPD), eudynamic disease, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with multiple sclerosis (MS), impaired MS motor function, ALS, pruritus, hypercholesterolemia, benign prostatic hyperplasia, peripheral neuropathy, arthritis rheumatoid arthritis,

[0012] In another aspect, the invention provides a (S) enantiomer or a pharmaceutically acceptable solvate thereof as set forth above, preferably substantially free of the (R) enantiomer for use in treating a disease or condition in a mammal, preferably a human, by inhibiting ion flow through the channel. nitrided gaseous in the mammal.

[0013] In another aspect, the invention provides a (S) enantiomer or a pharmaceutically acceptable solvate thereof, as set forth above, preferably substantially free of the (R) enantiomer for use in reducing the flow of ions through the gaseous nitrogen channel gated in a mammalian cell.

[0014] The invention further provides the use of the (S) enantiomer or a pharmaceutically acceptable solvate thereof, as set forth above, preferably substantially free of the (R) enantiomer, for the preparation of a medicament composition for treating diseases or conditions that are associated with voltage gated sodium channel activity. Accordingly, the invention provides the use of an (S) enantiomer or a pharmaceutically acceptable solvate thereof, as set forth above, preferably substantially free of the (R) enantiomer, for the preparation of a medicament composition for treating a disease or condition that is alleviated or reduced by modulation, preferably inhibition of the sodium channel gated voltage.

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present description and are incorporated to further illustrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with a detailed description of the specific embodiments set forth herein.

Figure 1 shows the concentration-response relationships for (S) and (R) enantiomers in the guanidine influx study from Biological Example 1 herein.

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Figure 2 shows a comparison of the efficacy of (S) and (R) enantiomers with oral dosing in a model of inflammatory pain of Biological Example 3 herein.

Figure 3 shows a comparison of the efficacy of (S) and (R) enantiomers for topical administration in the neuropathic pain model of Biological Example 3 herein.

Figure 4 shows the time course of histamine-induced pruritus in untreated mice by the in vivo test described in Biological Example 7. Data are expressed as the mean ± SD of itch seizures. Figure 5 shows anti-histamine-induced pruritus with locally applied ointment containing 8% (w / v) of the (S) enantiomer. Data are expressed as the mean ± SD of itching attacks. Figure 6 shows the efficacy of the (S) enantiomer against histamine-induced pruritus when administered orally instead of topically. Data are expressed as the mean ± SD of itching attacks.

DETAILED DESCRIPTION OF THE INVENTION

Definitions [0016] As used in the specification and appended claims, the following terms have, unless otherwise indicated, the following meanings:

"Analgesia" means no pain in response to a stimulus that would normally be painful.

"Allodynia" means a condition in which normally harmless sensations, such as pressure or light touch, are perceived as extremely painful.

The term "enantiomers" refers to asymmetric molecules that can exist in two isomeric forms that have different configurations in space. Other terms used to designate or refer to enantiomers include "stereoisomers" (due to the different distribution or stereochemistry around the chiral center, although all enantiomers are stereoisomers, not all stereoisomers are enantiomers) or "optical isomers" (due to the optical activity of the pure enantiomers) , i.e. the ability of various pure enantiomers to twist the plane of polarization of polarized light in different directions). Because they do not have a plane of symmetry, the enantiomers are not identical to their mirror reflections; molecules that occur in two enantiomeric forms are chiral, which means that they can be treated as occurring in "left" and "righteous" forms. The most common cause of chirality in organic molecules is the presence of a tetrahedral coal associated with four different substituents or groups. Such carbon is called a center of chirality or a stereogenic center. The method of indicating the three-dimensional arrangement of atoms (or configurations) in the stereogenic center is with respect to the group priority system when the group with the lowest priority is oriented away from the hypothetical observer: If the arrangement of the other three groups from higher to lower priority is clockwise, the center stereogenic has the "R" (or "D") configuration; if the system is left, the stereogenic center has the "S" (or "L") configuration. that they can be treated as occurring in "left" and "righteous" forms. The most common cause of chirality in organic molecules is the presence of a tetrahedral coal associated with four different substituents or groups. Such carbon is called a center of chirality or a stereogenic center. The method of indicating the three-dimensional arrangement of atoms (or configurations) in the stereogenic center is with respect to the group priority system when the group with the lowest priority is oriented away from the hypothetical observer: If the arrangement of the other three groups from higher to lower priority is clockwise, the center stereogenic has the "R" (or "D") configuration; if the system is left, the stereogenic center has the "S" (or "L") configuration. that they can be treated as occurring in "left" and "righteous" forms. The most common cause of chirality in organic molecules is the presence of a tetrahedral coal associated with four different substituents or groups. Such carbon is called a center of chirality or a stereogenic center. The method of indicating the three-dimensional arrangement of atoms (or configurations) in the stereogenic center is with respect to the group priority system when the group with the lowest priority is oriented away from the hypothetical observer: If the arrangement of the other three groups from higher to lower priority is clockwise, the center stereogenic has the "R" (or "D") configuration; if the system is left, the stereogenic center has the "S" (or "L") configuration.

[0017] Enantiomers have the same empirical chemical formula and are generally chemically identical in terms of their reactions, their physical properties and spectroscopic properties. However, the enantiomers show a different chemical reactivity to other asymmetric compounds and react differently to asymmetric physical disturbances. The most common asymmetric disorder is polarized light.

[0018] The enantiomer may twist the plane of polarization of polarized light; in this way, the enantiomer is optically active. Two different enantiomers of the same compound will twist the polarization polarized light plane in the opposite direction; in this way the light can be twisted to the left or in the opposite direction to the hypothetical observer (it's left-handed or "I" or minus, or it can be turned right or in the opposite direction (it's clockwise or "d" or plus "+").

The sign of optical (+) or (-) rotation is not related to the R, S designation. A mixture of equal amounts of two chiral enantiomers is called a racemic mixture or a racemate and is indicated by the symbol (+/-) or the prefix "d, I" indicating the mixture right-handed and left-handed forms. The compound of formula (I) as described herein is a racemate. Racemates or racemic mixtures exhibit no optical rotation because the amounts of these (+) and (-) forms themselves are present. In general, the presence of a single enantiomer twists the polarized light in only one direction; in this way, the single enantiomer is further optically pure.

[0019] The designations "R" and "S" are used to denote the absolute configuration of the molecule around its center of chirality (S). Designations may appear as an additive or as a suffix; they may or may not be separated from the name of the enantiomer by a hyphen; they may or may not be separated by a thinkin; and may or may not be in parentheses.

[0020] The designations or prefixes "(+) and (-)" are used herein to designate the sign of rotation of the polarization plane of the polarized light of the compound, with (-) indicating that the compound is left-handed (turning to the left). The relationship to the (+) prefix is ​​clockwise (rotates to the right).

[0021] "Decomposition" or "separation", when used in reference to a racemic form of a compound or mixture, refers to the resolution of the racemate into its two enantiomeric forms (i.e., the forms (+) and (-), (R) and ( S)).

[0022] "Enantiomeric excess" or "ee" refers to a product in which one enantiomer is in excess relative to the other and is defined as the absolute difference in the molar fraction of each enantiomer. The excess of the enantiomer is usually expressed as a percentage of the enantiomer present in the mixture relative to the other enantiomer. For purposes of the present invention, the (S) enantiomer of the invention is considered "substantially free" from the (R) enantiomer when the (S) -enantiomer is present in an enantiomeric excess of greater than 80%, preferably greater than 90%, more preferably greater than 95%. , most preferably greater than 99%.

[0023] The chemical naming of protocols and the structural schemes used in this document are a modified form of the IUPAC nomenclature system using the software version of ACD / name version 9.07. For example, the compound of formula (I) as set forth above in the summary of the invention is referred to herein as 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3f] [ 1,3] benzodioxole-7,3'-indol] -2 '(1'H) -one. The corresponding (S) enantiomer, i.e. the (S) -enantiomer of formula (IS) as set forth above in the Summary of the Invention, is referred to herein as (S) 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl } spiro [furo [2,3-f] [1,3] benzodioxole-7,3'-indol] -2 '(1'H) -one. Corresponding (R) enantiomer, (R) enantiomer of the following formula (IR):

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or a pharmaceutically acceptable solvate or prodrug thereof is referred to herein as (R) -1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole-7,3'-indol] -2 '(1'H) -one.

[0024] By "prodrugs" is meant compounds that can be transformed under physiological conditions or by solvolysis into a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. The prodrug may be inactive when administered to a patient in need thereof but is converted in vivo into the active compound of the invention. Prodrugs are usually rapidly converted in vivo, e.g. by hydrolysis in the blood, to give the parent compound of the invention. The prodrug often presents benefits in terms of solubility, tissue compatibility or delayed release in the mammalian body (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). The discussion of prodrugs is contained in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14 and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0025] By "prodrug" is also meant any covalently bonded carriers that release the active compound of the invention in vivo when such a prodrug is administered to mammals. Prodrugs of the compounds of the invention may be prepared by modifying functional groups present in a compound of the invention in a manner such that modifications of the compound are cleaved, both routinely and in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention in which a hydroxyl, amino or mercapto group is associated with any group that, when the prodrug of the invention is administered to a mammal, cleaves to form a free hydroxyl group, a free amino group, or a free mercapto group, respectively. Examples of prodrugs include acetate,

[0026] The invention disclosed herein also includes the (S) enantiomers disclosed herein and radiolabelled (R) enantiomers in which one or more atoms are replaced with an atom having a different atomic mass or mass number. Examples of isotopes that can be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, such as, respectively,²H ³H ¹¹C ¹³C ¹⁴C ¹³N ¹⁵N ¹⁶ABOUT, ¹⁷ABOUT,¹⁸O and ¹⁸F. These radiolabelled compounds may be useful in determining or measuring the efficacy of compounds by determining, for example, the site or mode of action on voltage-gated sodium channels or affinity binding to a pharmacologically significant site of action in voltage gated channels. Isotopically-labeled compounds of the invention, e.g. compounds containing a radioactive isotope, are useful in tissue and / or substrate tissue distribution studies.

Radioactive isotopes, tritium, i.e. ³H and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose because of the ease of their introduction and detection. The radioligand (3H) containing tritium is particularly useful in membrane-ligand binding studies that contain voltage-gated sodium channels because

The tritium has a long half-life of disintegration and the emission is of relatively low energy, and the radioisotope is therefore relatively safe. Radioligand is usually prepared by exchanging tritium with hydrogen in an unlabeled relationship. The identification of active and inactive enantiomers of a particular racemate facilitates the development of a ligand binding assay, since an unlabeled active enantiomer may be added to the assay to reduce, eliminate or otherwise control the non-specific binding of the tritiated active enantiomer.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may lead to certain therapeutic advantages resulting from greater metabolic stability, e.g. an increased in vivo half-life or reduced dosage, and may therefore be beneficial in some circumstances.

[0028] In positron emission tomography (PET) studies, a substitution with positron emitting isotopes may be useful to investigate the saturation of receptors with substrates, such as ¹¹C ¹⁸F ¹⁶O and ¹³N. The radiolabeled enantiomers of the invention can usually be prepared by standard methods known to those skilled in the art or analogously to those described herein using a suitable isotopically-labeled reagent in place of a non-labeled reagent previously used.

[0029] The application also illustrates in vivo metabolic products of the disclosed enantiomers. Such products may be formed as a result of, for example, oxidation, reduction, hydrolysis, amidation, esterification of administered compounds, mainly due to enzymatic processes. Thus, the invention includes metabolic products made by a process comprising administering to the mammal an enantiomer of the present invention for a period sufficient to produce a metabolic product. Such metabolic products can be identified by administering an isotopically labeled enantiomer, at a detectable dose, to an animal such as a rat, mouse, guinea pig, monkey or human, waiting for a sufficient time for metabolic events, and isolating the metabolic product from urine, blood or other biological samples .

[0030] "Selectivity" and "selective" as used herein is a relative measure of the tendency of a compound of the invention to preferential association with one, as opposed to another (or other groups), as well as between or among voltage gated sodium channels. For example, selectivity can be determined by comparative measurements of the kinetics and equilibrium of binding affinity and / or functional measures of ion transport through voltage-gated sodium channels. The tendency of a voltage-gated association compound for a voltage-gated sodium channel can be measured in a number of different ways, and many types of compound are known to those skilled in the art, as described elsewhere herein. Selectivity means that in a particular type of association, measured in a certain way, the compound has a tendency or priority to associate with one voltage-gated sodium channel compared to one or more other voltage-gated sodium channels. This relationship may be different for different types of tests or different measurement methods.

[0031] A "stable enantiomer" and a "stable structure" indicate a compound that is sufficiently stable to survive isolation from the reaction mixture to a usable degree of purity and the process of formulation into an effective therapeutic agent.

[0032] "Mammal" includes humans and both domestic and farm animals, such as laboratory animals and pets (e.g. cats, dogs, pigs, cattle, sheep, goats, horses and rabbits), as well as non-domestic animals, such as wild animals.

[0033] "Pharmaceutically acceptable carrier, diluent" includes any additive, carrier, excipient, lubricant, sweetener, diluent, preservative, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, tonicity agent, diluent or emulsifier that has been approved for use in human or domestic animals and farm animals by, by way of non-limiting example, the US Food and Drug Administration (FDA), Health Canada or the European Medicines Agency .

[0034] A "pharmaceutical composition" refers to a formulation of a compound of the invention and an agent generally acceptable in the art for delivering a biologically active compound to mammals, e.g. humans. Such an agent includes all pharmaceutically acceptable carriers, diluents or excipients.

The pharmaceutical compositions of the invention contain one or more pharmaceutically acceptable excipients which include any solvent, enhancer, support, lubricant, sweetening agents, diluent, preservative, colorant / coloring agent, flavoring agent, surfactant. , a wetting agent, a dispersing agent, suspending agent, stabilizer, isotonic agent, buffer and / or emulsifier approved by, as a non-limiting example, as acceptable for human or veterinary use households. Examples of pharmaceutically acceptable excipients include the following:

benzyl alcohol benzyl benzoate caprylcaproil-macrogolgiglycerides (e.g. Labrasol®) dimethylamine ("DMA") ethanol

2- (2-ethoxyethoxy) ethanol (e.g., Transcutol®) glucose (solution) glycerol caprylate / caprate and PEG-8 (ethylene glycol), caprylate / caprate complex (e.g. Labrasol®) isopropyl alcohol

Lauroyl Macrogol-32 Glycerides (e.g. Gelucire® 44/14) macrogol-15 hydroxystearate (e.g., Solutol® HS15) medium chain triglycerides (e.g. Miglyol® 810, Miglyol® 840 or Miglyol® 812) peanut oil polysorbate 80 (e.g., Tween® 80) polyethylene glycol (PEG) polyethylene glycol 400 (PEG400, e.g. Lutrol® E 400) polyethylene glycol 6000 polyoxyethylene castor oil (e.g., Cremophor® EL) polyoxyl 40 hydrogenated castor oil (e.g., Cremophor® RH 40) propylene glycol (PG) propylene glycol monocaprylate (Capryol® 90) soybean sulphobutylether-e-cyclodextrin oil (e.g. Capitsol®)

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TPGS (α-tocopherol-polyethylene glycol, succinate) water [0036] Additional pharmaceutically acceptable excipients are disclosed herein.

[0037] As a result of the crystallization process, a solvate of a compound of the invention is often obtained. As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of a compound of the invention with one or more solvent molecules. The solvent may be water, in which case the hydrate will be the solvate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may be in the form of a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as suitable solvated forms. The compounds of the invention may be "real" solvates, whereas in other cases,

[0038] The term "therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effectively treat a disease or condition of interest in a mammal, preferably a human. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease condition and its severity, the mode of administration, the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on its knowledge and description.

[0039] The term "treat" or "treatment", as used herein, refers to the treatment of a disease or condition in a mammal, preferably a human, and includes:

(i) preventing a disease or condition in a mammal, in particular when such a mammal is predisposed to a given condition, but has not yet been diagnosed with it;

(ii) inhibiting the disease or condition, i.e. inhibiting its development;

(iii) relieving the disease or condition, i.e. causing regression of the disease or condition; or (iv) relieving symptoms resulting from the disease or condition, i.e., relieving pain without combating the underlying disease or condition.

[0040] As used herein, the terms "alleviate", "alleviate", "decrease" or "decrease" are given in their generally accepted definitions. For example, "alleviate" means generally improve or improve the condition relative to the condition prior to the mitigation event. "Reduce" generally means making the state more tolerable in relation to the state before the reduction event. The term "alleviation" or "alleviate" as used herein may refer to a disease or condition that is improved or improved by administering a compound of the invention. The term "reducing" or "reducing" as used herein may refer to a disease or condition that is rendered bearable by administering a compound of the invention. For example, "reducing"

[0041] As used herein, the terms "disease" and "condition" can be used interchangeably or differently, because the causative agents of particular ailments or conditions may be unknown (and thus their aetiology is still unclear), thus this condition or status is not yet considered

The disease is only an undesirable syndrome or condition in which doctors have identified a more or less specific set of symptoms.

UTILITY AND TESTING OF THE COMPOUNDS OF THE INVENTION [0042] The present invention relates to the (S) 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole enantiomer. -7.3-indole] -2 '(1'H) -one, pharmaceutical composition I (S) -enantiomer of the invention and a pharmaceutical composition for use in the treatment of diseases or conditions that are alleviated or reduced by modulation, preferably inhibition, voltage gated sodium channels, preferably diseases and conditions associated with pain and pruritus; central nervous system conditions such as epilepsy, restless legs syndrome, anxiety disorders, depression and bipolar disorder; cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions, such as muscle paralysis, myotonia or tetanus; neuroprotection against stroke, neural trauma and multiple sclerosis; and channelopathy, such as erythromelalgia and paroxysmal anal pain, by administering to a patient in need of such treatment an effective amount of a modulating voltage-gated sodium channel blocker, especially a suppressor, preferably enantiomers of the invention.

[0043] In general, the present invention provides a (S) enantiomer or a pharmaceutically acceptable solvate or prodrug thereof as set forth above in a summary of the invention for use in treating a mammal, preferably a human, or protecting a mammal, preferably a human, prior to developing a disease or condition that is associated with the activity of voltage-gated sodium channels, in particular pain, wherein the (S) -enantiomer modulates, preferably inhibits, the activity of one or more sodium channels gated with a voltage.

[0044] Extensive studies of the voltage gated protein family of sodium channels have shown that they are involved in a number of vital vital functions. Studies in this area have identified variants of alpha subunits that cause significant changes in channel function and activity that may eventually lead to serious pathophysiological conditions. In addition, excessive sodium intake may occur indirectly through inflammatory agents or agents that cause hyperactivity. This family of proteins, due to their functions, is considered the main goals of therapeutic intervention. Nav1.1 and Nav1.2 gated protein sodium channels are highly expressed in the brain (Raymond, CK, et al., J. Biol. Chem. (2004), 279 (44): 46234-41) and are important for its proper functioning. In humans, mutations in Nav1.1 and Nav1.

Kamiya, K., et al., J. Biol. Chem. (2004), 24 (11): 2690-8; Pereira, S., et al., Neurology (2004), 63 (1): 191-2).

As such, both channels are considered to be important targets in the treatment of epilepsy (see WO Patent Publication

01/38564).

[0045] Nav1.3 is mainly expressed in the central nervous system of newborn animals at low levels throughout the body in adults (Raymond, CK, et al., Op cit.). It has been shown to be activated in rat dorsal neuron sensory neurons after injury to the nervous system (Hains,

BD, et al., J. Neurosci. (2003), 23 (26): 8881-92). Many specialists have also considered Nav1.3 as an appropriate therapeutic target for the treatment of pain, because its expression is induced by nerve injury Lai, J., et al., Curr. Opin. Neurobiol. (2003), (3): 291-72003; Wood, JN, et al., J. Neurobiol. (2004), 61 (1): 5510

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71; Chung, JM, et al., Novartis Found Symp. (2004), 261: 19-27; discussion 27-31, 47-54; Priest, BT, Curr. Opin. Drug Discov. Devel. (2009) 12: 682-693).

[0046] Expression of Nav1.4 is basically limited to muscles (Raymond, CK, et al., Op cit.).

It has been shown that mutations in this gene significantly affect muscle function, including paralysis, (Tamaoka A., Intern. Med. (2003), (9): 769-70). Thus, this channel can be taken as a target for the treatment of abnormal muscle contractility, cramps or paralysis.

[0047] The voltage-gated naïve sodium channel, Nav1.5, is mainly expressed in the heart and atrium (Raymond, CK, et al., Op cit.) And may be located in the atrial sinus node, the ventricular node and probably in Purkinje cells. . The rapid jump of the cardiac action potential and the rapid conduction of the impulse through the cardiac tissue are due to the opening of Nav1.5. As such, Nav1.5 is the key to the genesis of cardiac arrhythmia. Human Nav1.5 mutations cause various arithmetic syndromes, including, for example, long QT type 3 (LQT3), Brugada syndrome (BS), congenital heart conduction disorder, sudden unexpected nocturnal death syndrome (SUNDS) and sudden infant death syndrome (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics (2003), 3 (3): 173-9). In the treatment of cardiac arrhythmias, tension gated DC blocker therapy is widely used. The first anti-arrhythmic drug, the quinidine invented in 1914, is classified as a sodium channel blocker.

[0048] Nav1.6 encodes numerous, widely-occurring, voltage-gated sodium channels located in the central and peripheral nervous system, concentrated in Ranvier axonal constrictions (Caldwell, JH, et al., Proc. Natl. Acad. Sci. USA (2000) ), 97 (10): 5616-20). Loss of mutations in mice resulted in ataxia and convulsions (Papale, LA et al., Human Mol. Genetics (2009) 18, 1633-1641). Although no mutations have been found in humans, Nav1.6 is believed to play a role in the occurrence of symptoms associated with multiple sclerosis and may be taken as a target for the treatment of this disease (Craner, MJ, et al., Proc. Natl. Acad. Sci. USA (2004), 101 (21): 8168-73).

[0049] NaV1.7 is primarily expressed in the peripheral nervous system in both sensory and sympathetic neurons (Raymond, CK, et al., Op. Cit.). Loss of human mutation causes congenital pain indifference (CIP) without compromising cognitive and communication functions (Cox, JJ et al., Nature (2006) 444 (7121), 894-8; Goldberg, YP et al., Clin. Genet (2007) 71 (4), 311-9). People with CIP do not experience inflammatory and neuropathic pain, suggesting that the selective NaV1.7 block will eliminate many forms of chronic and acute pain, without adversely affecting the central or peripheral nervous system or muscles. In addition, the single nucleotide polymorphism (R1150W), which has a very subtle effect on the time-dependent and voltage-dependent gating of NaV1.7, has a large effect on the perception of pain (Reimann, F. et al., Proc. Natl. Acad. Sci. USA (2010), 107 (11), 5148-53): About 10% of patients with various pain conditions are heterozygous for the allele that gives greater sensitivity to pain. The involvement of NaV1.7 in the mediation of pain responses also shows the enhancement of functional mutations that cause erythromelalgia or paroxysmal disorders of extreme pain (Dib-Hajj SD et al.,

Adv. Genet. (2009) 63: 85-110). Although NaV1.7 is primarily expressed in the peripheral nervous system, the point mutation in NaV1.7 causes febrile seizures, which indicates the role of this channel in the CNS. Thus, voltage-gated sodium channel blockers may be useful as anticonvulsants.

[0050] Expression of Nav1.8 occurs essentially in dorsal root ganglion (DRG) (Raymond, CK, et al., Op cit.). The increase of the functional potential in sensory neurons from DRG is mainly carried out by 11

The current flowing through NaV1.8, such that the block of this current may block pain responses (Blair, NT and Bean, BP, J. Neurosci. 22: 10277-90). According to this finding, knock-down NaV1.8 in rats was obtained with antisense DNA or small interfering RNAs, and virtually complete reversal of neuropathic pain was achieved in core nerve ligation models and chronic constriction injuries. The selective blocker NaV1.8 was written and it is effective in blocking both neuropathic pain and inflammatory pain (Jarvis, MF et al., Proc. Natl. Acad. Sci. USA (2007), 104 (20), 8520-5). Published PCT Patent Application No. WO 03 / 037274A2 describes pyrazolamides and sulfonamides for the treatment of central and peripheral nervous system conditions, in particular pain and chronic pain, by blocking sodium channels associated with the onset or relapse of the indicated conditions. Published patent application PCT No. WO 03 / 037890A2 describes piperidines for the treatment of central and peripheral nervous system conditions, in particular pain and chronic pain, by blocking sodium channels associated with the onset or relapse of the indicated conditions. The compounds, compositions and methods of these inventions are particularly useful in the treatment of neuropathic or inflammatory pain by inhibiting ionic flow through a channel that includes the PN3 subunit (Nav1.8). [0051] Tetrodotoxin insensitive, peripheral sodium channel Nav1.9 disclosed by DibHajj, SD, et al. (see Dib-Hajj, SD, et al., Proc. Natl Acad. Sci USA (1998), 95 (15): 8963-8) is expressed in the dorsal root ganglion. Nav1 was shown. 9 is the basis of depolarization and excitation induced by neurotrophin (BDNF). Due to the limited expression pattern, this channel is a potential target for the treatment of pain (Lai, J, et al., Op cit. Wood, JN, et al., Op cit., Chung, JM et al., Op. cit.).

[0052] NaX is a putative sodium channel that has not been shown to be voltage-gated. In addition to the expression of NaX in the lungs, heart, dorsal root ganglion and Schwann cells of the peripheral nervous system, its presence was also found in neurons and lining cells in the limited areas of the central nervous system, in particular in periventricular organs involved in maintaining homeostasis of body fluids (Watanabe, E., et al., J. Neurosci.

(2000), 20 (20): 7743-51). It has been demonstrated that mice with the NaX zero mutation, under conditions of both water and salt restriction, have taken incorrect doses of hypertonic saline solution. These findings suggest that NaX plays an important role in the central reception of sodium in body fluids and regulation of salt intake. His pattern of expression and function suggest that he may be the target in the therapy of cystic fibrosis and other related disorders related to regulation of salt levels.

[0053] Studies using the voltage-lost sodium channel blocker, tetrodotoxin (TTX) used to lower the activity of neurons in certain areas of the brain, indicate its potential use in the treatment of addiction. The stimulus associated with the drug induces drug craving and relapse of addicts and the search for drug in rats. The functional integrity of the basolateral amygdala (BLA) is essential for the recurrence of the cocaine-seeking reaction induced by cocaine-associated stimulus, but not by cocaine itself. BLA plays a similar role in the reversal of the heroin search. In the rat model, the effect of TTX inactivation of BLA on conditioned and heroin-conditioned recurrence of the suppressed heroin search reaction was examined (Fuchs, RA, and See, RE,

[0054] Responses through the subset of C fibers to pruritic factors, in particular itchiness induced by histamine, PAR-2 ​​receptor activators, cholestasis and viral infections (Steinhoff, M. et al., J. Neurosci. 23: 6176-80; Twycross , R. et al., QJ Med. 96: 7-26). Voltage-gated sodium channels are expressed in and mediate in nerve impulses of C fibers.

[0055] The general utility of the (S) -enantiomers of the invention in the modulation, and in particular inhibition, of the voltage-gated sodium channeling can be determined using the tests described below under Biological Studies. Alternatively, the general utility of the (S) enantiomer of the invention in the treatment of conditions and diseases can be determined using standard animal models to demonstrate the efficacy of compounds in the treatment of pain. Animal models of neuropathic pain in humans have been developed, which leads, over a prolonged period of time, to repetitive sensory deficits (allodynia, hyperalgesia and spontaneous pain), which can be assessed in a sensory study. By determining the degree of mechanically, chemically and thermally induced allodynia and hyperalgesia,

[0056] In rat models of peripheral nerve injury, ectopic activity in the damaged nerve correlates with behavioral signs of pain. In these models, the intravenous administration of the (S) enantiomer of the invention and the local anesthetic, lidocaine, can inhibit the ecotopic activity and compensate for mechanical allodynia (pain when touched) at concentrations not affecting overall behavior and motor functions (Mao, J. and Chen , LL, Pain (2000), 87: 7-17). As a result of allometric grading, effective doses are transferred in these rat models to dose-related doses that have been shown to be effective for humans (Tanelian, DL and Brose, WG, Anesthesiology (1991), 74 (5): 949-951). In addition, the use of Lidoderm®, lidocaine in the form of skin patches, is now approved by the FDA,

[0057] Voltage-gated sodium channel blockers have additional clinical applications relative to pain management. Epilepsy and cardiac arrhythmias are often targeted by sodium channel blockers.

Recent data from animal models indicate that sodium channel blockers may also be useful in neuroprotection in ischemic states caused by stroke or neural trauma and in patients with multiple sclerosis (MS) (Clare, JJ et al., Op cit. And Anger, T. et al., Op cit.).

[0058] The (S) -enantiomer of the invention modulates, preferably inhibits, the flow of ions through voltage-gated sodium-gated sodium channels in, in particular in humans. Any kind of modulating effect, whether it is partial or complete inhibition or disruption of ion flow, is sometimes referred to herein as "blocking" and the corresponding compounds as "blockers" or "inhibitors". In general, the compound of the invention modulates the downstream activity of voltage gated sodium channels, inhibits the voltage-dependent voltage-dependent sodium channeling activity and / or reduces or prevents the passage of sodium ions across the cell membrane, preventing the activity of voltage-gated sodium channels, such as ion permeation.

[0059] The (S) -enantiomer of the invention is a sodium channel blocker and is therefore useful in treating diseases and conditions in mammals, preferably humans, and other organisms, including all those diseases and conditions in humans that are caused by abnormal biological activity of the canals. Voltage-gated sodium or that can be ameliorated by modulation, preferably inhibition, of the voltage-gated sodium channel's biological activities.

[0060] As used herein, a disease or condition that is alleviated or reduced by modulation, preferably inhibition, of voltage-gated sodium channels refers to a disease or condition that can be alleviated or reduced by modulation, preferably inhibition, of a voltage-gated sodium channel and includes, but is not limited to, pain and pruritus, central nervous system conditions such as

Epilepsy, anxiety disorders, depression (Morinville et al., J. Comp. Neurol., 504: 680-689 (2007)) and bipolar disorder (Ettinger and Argoff, Neurotherapeutics, 4: 75-83 ( 2007)); cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular disorders such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neural trauma and multiple sclerosis; and canalopathies, such as erythromelalgia and paroxysmal anal pain.

[0061] Additional diseases and conditions include HIV-related pain, HIV-induced neuropathy, trigeminal neuralgia, laryngopharyngeal neuralgia, metastatic secondary neuropathy, Dercum disease, thalamic changes, hypertension, autoimmune disease, asthma, dependence on drugs (e.g. from opiates, benzodiazepine, amphetamine, cocaine, alcohol, inhalation of butane), Alzheimer's disease (Kim DY, Carey et al., Nat. Cell Biol. 9 (7): 755-764 (2007)), dementia, age-related memory disorders, Korsakoff syndrome, restenosis, urinary tract dysfunction, urinary incontinence, Parkinson's disease (Do and Bean, Neuron 39: 109-120 (2003); Puopolo et al., J.

Neurosci. 27: 645-656 (2007)), cerebrovascular ischaemia, neurosis, gastrointestinal disease, sickle cell disease, sickle cell disease, transplant rejection, cardiac failure, myocardial infarction, post-reperfusion syndrome, intermittent claudication, angina, epileptic seizures, respiratory disorders , myocardial ischemia or cerebral ischemia, long QT syndrome, catecholamine-dependent multiform tachycardia, eye disease, spasticity, spastic paraplegia, myopathy, myasthenia gravis, congenital parathyroidism, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, alopecia, anxiety disorders, psychotic, mania, delusional disorders, seasonal affective disorder, panic disorder, obsessive-compulsive disorder (OCD), phobias, autism, Asperger syndrome, Rett syndrome,

EP 2 448 943 B1

Chamberland C, Dumaine R, J. Mol. Cell Cardiol. 42 (3): 469-477 (2007)), multi-drug resistant seizures, seizure prevention (anti-epileptic effect), familial Mediterranean fever, gout, restless legs syndrome, arrhythmias, fibromyalgia, neuroprotection in ischemic states caused by stroke or neural trauma, tachyarrhythmias, atrial fibrillation and ventricular fibrillation as well as general or local anesthetics.

[0062] As used herein, the term "pain" refers to all types of pain, regardless of its nature and origin, and includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgia, or oral pain. facial pain, post-burn pain, chronic bone pain, lower back pain, neck pain, lower abdominal pain, mouth burning syndrome, somatic pain, visceral pain (including lower abdomen), myofascial pain, toothache, cancer pain, pain associated with with chemotherapy, myofascial pain syndrome, algodystrophic syndrome (CRPS), temporal joint pain, post-traumatic pain, paroxysmal extreme pain disorder, operative pain, postoperative pain, pain associated with delivery, pain associated with uterine contractions during delivery, reflex sympathetic dystrophy, removal of the brachial plexus, neurogenic bladder dysfunction,acute pain (for example, musculo-muscular and post-operative pain), chronic pain, persistent pain, pain transmitted through the peripheral nervous system, pain transmitted by the central nervous system, chronic headache, stress headache, cluster headache, migraine headache, familial migraine headache, conditions associated with headache, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain following stroke, changes in the thalamus, radiculopathy, pain associated with HIV, pain in the post-herpetic pain, non-chest pain in the chest , irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia and combinations thereof.chronic headache, stress headache, cluster headache, migraine headache, familial half-life migraine, conditions associated with headache, sinus headache, tension headache, phantom pain in limbs, peripheral nerve injury, pain following a stroke, changes in of the thalamus, radiculopathy, HIV-related pain, post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia, and combinations thereof.chronic headache, stress headache, cluster headache, migraine headache, familial half-life migraine, conditions associated with headache, sinus headache, tension headache, phantom pain in limbs, peripheral nerve injury, pain following a stroke, changes in of the thalamus, radiculopathy, HIV-related pain, post-herpetic pain, non-cardiac chest pain, irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia, and combinations thereof.irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia and their combinations.irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia and their combinations.

[0063] The present invention also relates to compounds, pharmaceutical compositions and compounds and pharmaceutical compositions for use in the treatment or prevention of diseases or conditions, such as benign prostatic hyperplasia (BPH), hypercholesterolemia, cancer and pruritus (itching).

[0064] Benign prostatic hyperplasia (BPH), also known as benign prostatic hypertrophy, is one of the most common diseases affecting aging men. BPH is a progressive condition characterized by nodular enlargement of the prostate tissue causing constipation of the urethra. The effects of BPH may include hypertrophy of bladder smooth muscle, bladder decompensation, acute urinary retention and more frequent urinary tract infection.

[0065] BPH has a major impact on public health and is one of the most common causes of surgical intervention among older men. Attempts have been made to explain its aetiology and pathogenesis, and experimental models have been developed for this purpose. Spontaneous animal models are limited to the chimpanzee and canine model. BPH in humans and dogs have many common features. In both species, the development of BPH occurs spontaneously with an advanced age and can be prevented by early / prepubescent castration. In order to treat health and safety and its consequences, a medical alternative to surgery is very welcome.

[0066] Hyperplasia of the prostatic epithelium in both humans and dogs is sensitive to androgens; Epithelial hyperplasia undergoes involution with androgen deprivation and resumption when androgens are replenished. It has been found that cells derived from the prostate gland express high amounts of voltage-gated sodium channels. By immunostaining, clear evidence of the presence of voltage gated sodium channels in prostate tissues was obtained (Prostate Cancer Prosatic Dis. 2005; 8 (3): 266-73). Inhibition of the tetrodotoxin-gated sodium channel function,

As a selective blocker, it inhibits the migration of cells derived from prostate and breast cancers (Brackenbury, WJ and Djamgoz, MBA, J. Physiol. (Lond) (2006) 573: 343-56; Chioni, AM. Et al., Int. J.

Biochem. Cell Biol. (2009) 41: 1216-1227).

[0067] Hypercholesterolemia, i.e. elevated blood cholesterol, is a recognized risk factor for the development of, e.g., atherosclerosis, coronary heart disease, hyperlipidemia, stroke, hyperinsulinemia, hypertension, obesity, diabetes, cardiovascular disease (CVD), myocardial ischemia. and heart attack. And so, it has been found that lowering plasma total cholesterol levels in individuals with high cholesterol levels reduces the risk of these diseases. In particular, lowering cholesterol levels associated with low-density lipoproteins is an important step in the prevention of CVD. Despite the existence of a number of hypercholesterolemia therapies, there is a continuing need and constant search for alternative therapies in this field of technology.

[0068] The invention provides compounds that are useful as anti-hypercholesterolemic and related agents. The present compounds can operate in a number of ways. Without being restricted to any particular mechanism of action, the compounds may be direct or indirect inhibitors of the acyl-CoA: cholesterol acyltransferase enzyme (ACAT), resulting in the inhibition of cholesterol esterification and transport across the intestinal wall. Another possibility may be that the compounds of the invention may be direct or indirect inhibitors of cholesterol biosynthesis in the liver. It is possible that certain compounds of the invention may act as either direct or indirect ACAT inhibitors as well as cholesterol biosynthesis.

[0069] Itching, commonly referred to as itching, is a common dermatological condition. There are two main categories of pruritus based on inflammatory etiology: itchy skin and neuropathic itching (Binder et al., Nature Clinical Practice, 4: 329-337, 2008). In the first case, inflammatory mediators activate skin prureceptory, a subset of afferent skin nerve fibers, mainly unmanned C fibers. Treatment of this type of pruritus involves blocking receptors for inflammatory agents (e.g. anti-inflammatory drugs, antihistamines) or blocking the associated electrical activity. Voltage-gated sodium channels play a fundamental role in the transmission of electrical activity in neurons, and modulation of voltage-gated sodium channels is a well-established method of modulating this signaling. Although the exact causes of pruritus are complex and poorly understood, there are well-established evidence of central sensitization and hypersensitivity of entry from the sensory neuron of C fibers in the dermis. Regarding inflammatory itching, sodium channels are probably necessary for the propagation of electrical signals from the skin to the CNS. Moving the itching pulses causes an unpleasant sensation that evokes the need or scratching reflex.

[0070] Both inflammatory and neuropathic itching can be blocked by known voltage-gated sodium channel blockers, most commonly lidocaine (Villamil et al., American Journal of Medicine 118: 1160-1163, 2005; Inan et al., Euorpean Journal of Pharmacology 616 : 141-146, 2009; Fishman et al., American Journal of Medicine 102: 584-585, 1997; Ross et al., Neuron 65: 886-898, 2010). Lidocaine doses needed to relieve itching are comparable to those effective in treating pain. Both sensory circuits share common mediators and associated neuronal pathways (Ikoma et al., Nature Reviews Neuroscience, 7: 535-547, 2006). However, other treatments for pain are ineffective for itching and may increase itching rather than soothe it. For example, opiates are particularly effective in combating pain, but they can generate severe pruritus. Therefore,

[0071] The compounds of the present invention were found to exhibit analgesic activity in a range of animal models at oral doses ranging from 1 mg / kg to 100 mg / kg. The compounds of the invention may also be useful for treating pruritus.

[0072] Types of itchy or irritated skin include, but are not limited to:

a) psoriatic itch, itch due to hemodialysis, itching, and itching caused by skin diseases (e.g., contact dermatitis), systemic disorders, neuropathy, psychogenic agents or a mixture thereof;

b) itching caused by allergic reactions, insect bites, hypersensitivity (eg dry skin, acne, eczema, psoriasis), inflammation or injuries;

c) itching associated with vaginal vestibular syndrome; and

d) skin irritation or inflammation caused by the administration of other therapeutic agents, such as, for example, antibiotics, antivirals and antihistamines.

e) itching caused by the activation of PAR-2 ​​receptor coupled proteins.

[0073] The (S) -enantiomer of the invention modulates, preferably inhibits, ion flux through the voltage-gated sodium channel. Preferably, the (S) -enantiomer of the invention is dependent on the state or frequency of the low-affinity sodium channel modifier which is doped with a low affinity to a dormant / closed state and high affinity to the inactivated state. Without wishing to be bound by any particular mechanism of action, the (S) -enantiomer of the invention may interact with overlapping sites located in the inner cavity of the sodium-conducting pore in a channel similar to that described for other state-dependent sodium channel blockers (Cestćle, S., et al. ., op cit.). The (S) -enantiomer of the invention may also interact with sites outside of the inner cavity and will exhibit allosteric effects on the conduction of ions through the channel pore.

[0074] In a preferred embodiment of the invention, the (S) -enantiomer of the invention modulates, preferably inhibits, Nav1.7 activity. In another preferred embodiment of the invention, the (S) -enantiomer of the invention selectively modulates and preferably inhibits the activity of Nav1.7 relative to the modulation or inhibition of other voltage-gated sodium channels (i.e. Nav1.1 to Nav1.6 and Nav1.8 to Nav1 .9).

Because most other sodium channels play a role in other important physiological processes such as cardiac contraction and rhythm (Nav1.5), skeletal muscle spasm (Nav1.4) and conduction of electrical activity in the CNS and motor neurons (Nav1.1, Nav1.2 and Nav1.6), it is desirable that the (S) enantiomer of the invention avoids significant modulation of other sodium channels.

[0075] Any of the consequences of these activities can be ultimately responsible for the overall therapeutic benefit provided by the (S) enantiomer of the invention.

[0076] Typically, an effective therapeutic agent of the invention will meet some or all of the following criteria. The availability for oral administration should be at least 20%. The efficacy in the animal model is less than about 0.1 μg to about 100 mg / kg body weight, and the target dose for humans is in the range of 0.1 μg to about 100 mg / kg body weight, although doses outside this range may be allowed (the term "mg / kg" means milligrams of compound per kilogram of body weight of the subject to which it is administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 100. The potency (expressed by the IC50 value) should be

The temperature is lower than 10 μΜ, preferably below 1 μΜ, and most preferably below 50 μM. IC 50 ("inhibitory concentration" - 50% ") is a measure of the amount of the (S) -enantiomer of the invention required for 50% inhibition of ion flux through the sodium channel, at a given time, in the study of the invention. [0077] Another aspect of the invention relates to a method of inhibiting the activity of Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8 or Nav1.9 in biological samples or in a mammal, preferably a human, which comprises administering to the mammal an (S) -enantiomer of the invention or a composition comprising (S) -enantiomer of the invention or contacting said biological samples with a compound of formula I or a composition comprising the (S) -enantiomer of the invention. The term "biological sample," as used herein, includes, but is not limited to, cell cultures and their extracts; biopsy material from a mammal or extracts thereof; and blood, saliva, urine, faeces, semen, or other body fluids or extracts thereof.

[0078] In addition to the above uses of the (S) -enantiomer of the invention, this compound may also be useful in modulating, preferably inhibiting, voltage-gated sodium channel activities in biological samples for various purposes known to those skilled in the art. Examples of such targets include, but are not limited to, sodium testing of voltage-gated ion channels in biological and pathological phenomena; and a comparative assessment of new or other sodium modulators of voltage-gated ion channels.

The (S) -enantiomer of the invention can also be used for the treatment of non-human mammals (i.e. veterinary methods of treatment) for diseases or conditions that are alleviated or reduced by modulation, preferably inhibition, of voltage-gated sodium channels, in particular for the treatment of inflammation and pain. Such treatment is considered particularly interesting for companion animals, such as dogs and cats.

PHARMACEUTICAL COMPOSITIONS FOR THE INVENTION AND METHODS OF ADMINISTRATION [0080] The present invention also relates to pharmaceutical compositions comprising the enantiomer of the invention. In one embodiment, the present invention relates to a composition comprising an enantiomer of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate, preferably inhibit, the flow of ions through voltage-gated sodium channels for treating diseases such as pain when administered to animals, preferably mammals, and most preferably to people. [0081] The administration of the (S) -enantiomer of the invention in its pure form or in a suitable pharmaceutical composition can be carried out by any accepted means of administering agents for similar uses. The pharmaceutical compositions of the invention may be prepared by combining a compound of the invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and may be formulated in solid, semi-solid, liquid or gas form, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injectables, inhalants, gels, microspheres and aerosols. Typical routes of administration for such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and nasal routes. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques. The pharmaceutical compositions of the invention are formulated such that to allow the bioavailability of the active ingredients contained therein after administration of the composition to the patient. Compositions to be administered to a subject or patient, preferably a mammal, more preferably a human, take the form of one or more

For example, the tablet may be a single dosage unit, and a pack of a compound of the invention in the form of an aerosol may contain multiple dosage units. Specific methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see The Science and Practice of Pharmacy, ed. 20 (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof for the treatment of a given disease or condition, according to the information disclosed in the present invention.

[0082] Pharmaceutical compositions useful herein also include a pharmaceutically acceptable carrier, including any suitable diluent or excipient, that includes any pharmaceutical agent that itself does not produce antibodies harmful to the subject receiving the composition and that can be administered without causing undue toxicity. Pharmaceutically acceptable carriers include liquids such as water, saline, glycerol and ethanol. A thorough discussion of pharmaceutically acceptable carriers, diluents and other excipients is provided in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ, current edition).

[0083] The pharmaceutical composition of the invention may be in the form of a solid or liquid substance.

In one aspect, the carrier or carriers are solid particles, thus the compositions are in the form of, for example, tablets or a powder. The carrier or carriers can be liquid, and the compositions are, for example, oral syrup, liquid for injection, or an aerosol that is useful, for example, for administration by inhalation.

[0084] In the case where the pharmaceutical composition is intended for oral administration, it is preferably in solid or liquid form, with the forms considered herein as solid or liquid including semi-solid, semi-liquid, suspensions and gels.

[0085] As a solid composition for oral administration, the pharmaceutical composition can be formulated as a powder, granules, compressed tablets, pills, capsules, chewing gum, wafers or the like. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders, such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch, lactose or dextrins, disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants, such as magnesium stearate or Sterotex; lubricants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate or orange flavoring; and dyes.

[0086] When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, it may contain, in addition to substances of the above type, a liquid carrier such as polyethylene glycol or oil.

[0087] The pharmaceutical composition may be in the form of a liquid, for example, an elixir, a syrup, a solution, an emulsion or a suspension. Two examples of the purpose of this liquid are oral administration or delivery by injection. When intended for oral administration, the preferred compositions contain, in addition to the (S) enantiomer of the invention, one or more sweetening agents, preservatives, colorants and flavor enhancers. One or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and tonicity agents may be included in the composition intended for administration by injection.

[0088] Liquid pharmaceutical compositions according to the invention, whether in the form of solutions, suspensions or other similar forms, may contain one or more of the following additional substances: sterile diluents, such as water for injections, saline, preferably saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic mono- or diglycerides, which may act as a solvent or suspending medium, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates and agents for the regulation of tonicity, such as sodium chloride or dextrose. Preparations for parenteral administration may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The preferred additive is physiological saline. The pharmaceutical composition for injection is preferably sterile.

The liquid pharmaceutical composition according to the invention intended for parenteral or oral administration should contain an amount of the (S) -enantiomer of the invention in order to obtain a suitable dosage. Typically, such an amount is at least 0.01% of the (S) enantiomer of the invention in the composition. When the composition is intended for oral administration, the amount may vary from 0.1 to about 70% by weight. of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% of the (S) -enantiomer of the invention. Preferred pharmaceutical compositions and formulations of the present invention are prepared so that the parenteral dosage unit contains from 0.01 to 10 wt%. (S) of the (S) -enantiomer of the invention before dilution.

[0090] The pharmaceutical composition of the invention may be intended for topical administration; in this case, the carrier may suitably be a base in the form of a solution, emulsion, ointment or gel. The base may include, for example, one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical administration. Where the composition is intended for transdermal administration, it may include a transdermal patch or iontophoretic device. Formulations for topical administration may contain a compound of the invention at a concentration of about 0.1 to about 10% w / v. (by weight per unit of volume). [0091] In topical applications, it is preferred to administer an effective amount of a pharmaceutical composition according to the invention to a target site, e.g., the surface of the skin, mucous membranes and the like, which are adjacent to the peripheral nerves to be treated. This amount will generally be in the range from about 0.0001 mg to about 1 g of the (S) -enantiomer of the invention for one use and will depend on the area being treated, the nature of the application (diagnostic, profiling or therapeutic), the severity of symptoms and the type of carrier used. topical application. A preferred topical formulation is an ointment in which about 0.001 to about 50 mg of active ingredient per 1 cm is used which are adjacent to the peripheral nerves to be treated. This amount will generally be in the range from about 0.0001 mg to about 1 g of the (S) -enantiomer of the invention for one use and will depend on the area being treated, the nature of the application (diagnostic, profiling or therapeutic), the severity of symptoms and the type of carrier used. topical application. A preferred topical formulation is an ointment in which about 0.001 to about 50 mg of active ingredient per 1 cm is used which are adjacent to the peripheral nerves to be treated. This amount will generally be in the range from about 0.0001 mg to about 1 g of the (S) -enantiomer of the invention for one use and will depend on the area being treated, the nature of the application (diagnostic, profiling or therapeutic), the severity of symptoms and the type of carrier used. topical application. A preferred topical formulation is an ointment in which about 0.001 to about 50 mg of active ingredient per 1 cm is used³ ointment bases. The pharmaceutical composition may be formulated as a transdermal composition or transdermal delivery device ("slices"). Such compositions include, for example, a primer layer, a reservoir of active compound, a control membrane, a protective layer, and an adhesive layer. Such transdermal patches can be used to provide the compounds of the present invention in the desired manner: continuous, pulsed or on request.

[0092] The pharmaceutical composition of the invention may be intended for rectal administration, for example in the form of suppositories that will melt in the rectum and release the drug. The composition for rectal administration may contain an oily base as a suitable non-irritating excipient. Such substrates include, but are not limited to, lanolin, cocoa butter and polyethylene glycol.

[0093] A typical formulation for intramuscular or intrathecal administration includes a suspension or solution of the active ingredient in oil or a solution of the active ingredient in an oil, for example peanut oil or sesame oil. A typical formulation for intravenous or intrathecal administration includes a sterile aqueous isotonic solution containing, on the fly, an active ingredient and dextrose or sodium chloride or a mixture of dextrose and sodium chloride.

[0094] The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient, e.g. the (S) -enantiomer of the invention, after administration to the patient using procedures known in the art. Drug controlled release systems include osmotic pumps and soluble systems containing polymer coated reservoirs or polymeric drug delivery formulations. Examples of controlled drug release systems are provided in US 3845770 and 4326525 and in PJ Kuzma et al., Regional Anesthesia 22 (6): 543-551 (1997).

[0095] The compositions of the invention may also be delivered using intranasal delivery systems for local, systemic and therapeutic therapy in which the drug is delivered through the nose to the brain (nose-to-brain). It is known to those skilled in the art that Controlled Particle Dispersion (CPD) ™ technology, traditional nasal spray bottles, inhalers or nebulizers provide effective local and systemic delivery of drugs by acting on the nasal mucosa and paranasal sinuses.

[0096] The invention also relates to an apparatus for the vaginal delivery of a drug contained in a sheath or core suitable for administering to an animal or a female animal. The device may consist of an active pharmaceutical ingredient in a polymer matrix, encapsulated and capable of daily release of the (S) -enantiomer of the invention, substantially zero order kinetics, similar to the testosterone delivery devices described in published PCT Patent Application No. WO 98 / 50016.

[0097] Current methods of ocular administration include topical administration (eye drops), subconjunctival injection, periocular injection, intravitreal injection, surgical implants, and iontophoresis (a method that uses small electrical currents to carry ionized medicaments to and through the body's tissues). Those skilled in the art will know how to combine the most suitable excipients with the (S) enantiomer of the invention, providing safe and effective ocular administration.

[0098] The most appropriate route of administration will depend on the nature and severity of the condition being treated. Those skilled in the art are able to determine methods of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other matters relevant to delivering the (S) -enantiomer of the invention to a subject in need thereof.

[0099] The pharmaceutical composition of the invention may contain various substances that modify the physical form of the solid or liquid dosage unit. For example, the composition may contain substances that form a coating layer around the active ingredients. The substances that form the coating layer are usually inert and may be selected from, for example, sugar, shellac and other enteric coating agents. Alternatively, the active ingredients may be enclosed in a gelatin capsule.

[0100] The pharmaceutical composition of the invention in solid or liquid form may contain an agent that binds to the (S) enantiomer of the invention and thus helps in providing the compound.

Suitable agents that may function in this capacity include monoclonal or polyclonal antibodies, proteins or liposomes.

[0101] The pharmaceutical composition of the invention may consist of dosage units that can be administered in the form of an aerosol. The term aerosol is used to describe various systems, from those of a colloidal nature to systems consisting of pressurized containers. The delivery can be effected by means of liquefied or compressed gas, or by means of a suitable pump system that dispenses the active ingredients. In order to provide an active ingredient or components, the aerosols of the (S) enantiomers of the invention may be provided in single-phase, two-phase or three-phase systems. The delivery of the aerosol includes the necessary container, activators, valves, reservoirs and the like, which together can form a set. One skilled in the art can determine preferred aerosols without unnecessary experimentation.

[0102] The pharmaceutical compositions of the invention may be made by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection may be prepared by combining a compound of the invention with sterile, distilled water to form a solution. To facilitate the preparation of a homogeneous solution or suspension, a surfactant can be added. Surfactants are compounds that interact non-covalently with the (S) -enantiomer of the invention to facilitate dissolution of a homogeneous suspension of a compound in an aqueous delivery system.

[0103] The (S) -enantiomer of the invention, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount that will vary depending on many factors, including the activity of the particular compound employed; metabolic stability and duration of action of the (S) -enantiomer of the invention; the age, weight, general health, sex and diet of the patient; the manner and time of administration; speed of excretion; combinations of drugs; the severity of a particular disorder or condition; and the subject being treated. In general, the therapeutically effective daily dosage of the (S) enantiomer of the invention is (for 70 kg mammalian) from about 0.001 mg / kg (i.e., 0.07 mg) to about 100 mg / kg (i.e., 7.0

g); preferably, the therapeutically effective dose is (for 70 kg mammal) from about 0.01 mg / kg (i.e., 0.7 mg) to about 50 mg / kg (i.e., 3.5 g); more preferably, the therapeutically effective dose is (for 70 kg mammal) from about 1 mg / kg (i.e., 70 mg) to about 25 mg / kg (i.e., 1.75 g).

[0104] The ranges of effective doses provided herein are not intended to be limiting and mean preferred dosage ranges. However, the most preferred dose will be determined and adapted to a given subject by a specialist in the relevant field (see, e.g., Berkowet al., Ed., The

Merck Manual, 16th edition, Merck and Co., Rahway, NJ, 1992; Goodmanetna., Wyd., Goodman and

Cilman's The Pharmacological Basis of Therapeutics, 10th edition, Pergamon Press, Inc., Elmsford, NY, (2001); Avery's Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins, Baltimore, MD. (1987), Ebadi, Pharmacology, Little, Brown and Co., Boston, (1985); Osolci al., Ed., Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA (1990); Katzung, Basic and Clinical-Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

[0105] The total dose required in each therapy can be administered daily in multiple dose or single-dose form, if desired. In general, treatment starts with lower doses, 22

These are lower than the optimal dose of the compound. The dose is then increased slowly until the optimal dose is reached under the given conditions. The diagnostic pharmaceutical compound or composition may be administered alone or in combination with other diagnostic and / or pharmaceutical agents directed to pathology or directed to other symptoms of pathology. The effective amount of the (S) enantiomer of the present invention or composition of the invention is from about 0.1 μg to about 100 mg / kg of body weight, administered at 4-72 hours intervals, for a period of 2 hours to 1 year and / or each range or values ​​within this framework, such as 0.0001-0.001, 0.001-0.01, 0.01-0.1, 0.1-1.0, 1.0-10, 5-10, 10-20, 20 -50 and 50100 mg / kg, in increments of 1-4, 4-10, 10-16, 16-24, 24-36, 24-36, 36-48, 48-72 hours, for 1-14,

[0106] The recipients of administering the (S) -enantiomer of the invention and / or the composition of the present invention may be any animals, such as mammals. Among mammals, non-human primate mammals (including humans, gorillas and monkeys), ungulates (including horses, goats, cows, sheep, pigs), rodents (including mice, rats, rabbits and hamsters) and predators (in cats and dogs). Of the birds, turkeys, chickens and other representatives of this order are preferred. People are the most beneficial users.

COMBINATION THERAPY [0107] The (S) -enantiomer of the invention may be useful in combination with one or more therapeutic agents or as any combination thereof in the treatment of diseases and conditions in mammals, preferably humans, which are alleviated or reduced by modulation, preferably inhibition voltage-gated sodium channels. For example, the (S) enantiomer of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to:

• opioid analgesics, for example, morphine, heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

• non-opioid analgesics, e.g. acetomeniphenes, salicylates (e.g., aspirin);

• NSAIDs, for example ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprosine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac;

Anti-convulsive agents, e.g. carbamazepine, oxcarbazepine, lamotrigine, valproat, topiramate, gabapentin and pregabalin;

Antidepressants such as tricyclic antidepressants, e.g. amitriptyline, clomipramine, desipramine, imipramine and nortriptyline;

Selective COX-2 inhibitors, for example celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib and lumiracoxib;

• alpha-adrenergic drugs, for example doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4- tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;

• barbiturate sedatives, for example, amobarbital, aprobarbital, butabarbital, butabital, mefobarbital, metarbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, thiamylal and thiopental;

• tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, for example (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl)] - 8,9,10 , 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H [1,4] diazocino [2,1-g] [1,7] naphthyridine-6-13-dione (TAK-637), 5 - [[2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethylphenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro -3H-1,2,4-triazol-3-one (MK869), aprepitant, lanepitant, dapitant or 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] -methylamino] -2-phenylpiperidine (2S, 3S);

• painkillers containing coal tar, in particular paracetamol;

• serotonin reuptake inhibitors, for example, paroxetine, sertraline, norfluoxetine (desmethyl metabolite fluoxetine), metabolite demetylserraline, '3 fluvoxamine, paroxetine, citalopram, desitylcitalopram citalopram metabolite, escitalopram, d, l-fenfluramine, femoxetine, ifoxetine, cyanodotiepine, lixoxetine, dapoxetine, nefazodone, crylamine, trazodone and fluoxetine;

• norepinephrine reuptake inhibitors (norepinephrine), for example maprotiline, lofepramine, mirtazepine, oxaprillin, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifenzynic and voxoxazine (Vivalan®), and in particular selective norepinephrine reuptake inhibitor such as reboxetine , in particular (S, S) -reboxetine, and venlafaxine, duloxetine - neuroleptics, sedatives / anxiolytics;

• dual serotonin-noradrenaline reuptake inhibitors such as venlafaxine, the metabolite venlafaxine O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;

• acetylcholinesterase inhibitors such as donepezil;

• 5-HT3 receptor antagonists such as ondansetron;

Antagonists or agonists or allosteric enhancers of glutamate on (mGluR) metabotropic glutamate receptors;

• local anesthetics, such as mexiletine and lidocaine;

• corticosteroids, such as dexamethasone;

• anti-arrhythmic drugs, for example mexiletine and phenytoin;

Muscarinic receptor antagonists, e.g. tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverin and ipratropium;

• muscarinic agonists or allosteric acetylcholine enhancers at muscarinic receptors;

• cannabinoids or allosteric endorphin enhancers at cannabinoid receptors;

Vanilloid receptor agonists (e.g. resiniferatoxin) or antagonists (e.g. capsazepine);

• sedatives, for example glutethymide, meprobamate, methalevone and dichloralfenazone;

Anti-depressants, such as benzodiazepines, anti-depressants, such as mirtazapine, topical agents (e.g., lidocaine, capsacine, and resiniferatoxin);

Muscle relaxants, e.g. benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprin, metcarbamol and orfrenadine;

• antihistaminic or H1 agonists;

• NMDA receptor antagonists;

• 5-HT receptor agonists / antagonists;

• PDEV inhibitors;

• Tramadol®;

• cholinergic (nicotine) painkillers;

• alpha-2-delta ligands;

• E2 prostaglandin antagonists;

• Leukotriene B4 receptor antagonists;

• 5-lipoxygenase inhibitors; and;

• 5-HT3 receptor antagonists.

[0108] Diseases and conditions that can be treated and / or prevented using such combinations include, but are not limited to, acute and chronic neuropathic diseases transmitted through the central and peripheral nervous systems, as well as other pain-related diseases and other disorders of the central system neural disorders such as epilepsy, anxiety disorders, depression and bipolar disorder; or cardiovascular disorders such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular disorders such as restless leg syndrome and muscle paralysis or tetanus (Hamann M, Meisler MH, Richter, A Exp. Neurol. 184 (2): 830-838 (2003)); neuroprotection against stroke, neural trauma and multiple sclerosis; and canalopathies such as erythromelalgia and paroxysmal anal pain.

[0109] As used herein, the term "combination" refers to any mixture or permutation of the (S) enantiomer of the invention with one or more additional therapeutic agents. Unless the context otherwise requires, the "combination" may comprise the simultaneous or sequential delivery of the (S) -enantiomer of the invention with one or more therapeutic agents. Unless the context indicates otherwise, the "combination" may include the use forms of the (S) enantiomer of the invention with other therapeutic agents. Unless the context otherwise requires, a "combination" may include methods of administering the (S) -enantiomer of the invention with another therapeutic agent. Unless the context indicates otherwise, the "combination" may include formulations of the (S) enantiomer of the invention with another therapeutic agent. Application forms,

[0110] One combination therapy according to the invention comprises the topical administration of the (S) -enantiomer of the invention with an oral agent. The topical use of the (S) enantiomer of the invention has very low systemic exposure and has activity that is additive with the amount of oral analgesic. Another possible combination therapy includes the oral dose of the (S) -enantiomer according to

In the present invention, an oral agent is used. Further combination therapy according to the invention comprises topical administration of the (S) -enantiomer of the invention with a topical agent.

[0111] The (S) -enantiomer of the invention may be incorporated into a coating composition of an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present inventive other aspect comprises a composition for coating an implantable device, comprising a compound of the present invention as described above, and a carrier suitable for coating an implantable device. In yet another aspect, the present invention includes an implantable device coated with a composition comprising the (S) enantiomer of the invention and a carrier suitable for coating an implantable device. Suitable coatings and the general preparation of coated implantation devices are described in US Patent Nos. 6,099,562; 5886026; and 5,304,112.

KITS [0112] The present invention also provides kits that comprise a pharmaceutical composition of the invention. The kit also includes instructions for using a pharmaceutical composition for modulating the activity of ion channels, for treating pain as well as for other uses as disclosed herein. Preferably, the commercial package will contain one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be in an amount suitable for the preparation of an intravenous injection. It will be obvious to those skilled in the art that compounds that are sensitive to light and / or air may require special packaging and / or formulation. For example, light-impermeable and / or sealed packages that prevent contact with ambient air may be used,

MANUFACTURE OF THE ENANCJOMER (S) FOR THE INVENTION [0113] The (S) -enantiomer of the invention and the corresponding (R) -enantiomer is prepared by separating the compound of formula (I) as set out above in the Summary of the invention using either high-pressure liquid chromatography chiral or by simulated moving bed chromatography as described in the following reaction scheme, wherein "chiral HPLC" refers to chiral high performance liquid chromatography, and "MSP" refers to a simulated moving bed chromatography:

REACTION SCHEME

[0114] EP 2 448 943 B1

<img file="PL2448943T3_D0005.tif" />

<img file="PL2448943T3_D0006.tif" />

[0115] The compound of formula (I) can be prepared by the methods disclosed in PCT Patent Application Publication No. WO 2006/110917, by methods described herein or by methods known to those skilled in the art.

[0116] One of ordinary skill in the art would recognize differences in the above reaction scheme that are suitable for the separation of the individual enantiomers.

[0117] Alternatively, the (S) -enantiomer of formula (IS) and the (R) -enantiomer of formula (IR) can be synthesized from starting materials that are known or can be easily prepared using a process analogous to those known.

Preferably, the (S) enantiomer of the invention obtained by the separation methods disclosed herein is substantially free of the (R) enantiomer or contains only traces of the (R) -enantiomer.

[0119] The following synthetic examples serve to illustrate the separation methods disclosed in the above reaction schemes.

SYNTHETIC EXAMPLE 1

Synthesis of 1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole-7,3'-indolo] 2' (1'H) -one (Compound of formula (I))

<img file="PL2448943T3_D0007.tif" />

[0121] To a suspension of spiro [furo [2,3-f] [1,3] benzodioxole-7,3'-indol] -2 '(1'H) -one (1.0 g, 3.6 mmol) which can be prepared according to the methods disclosed in the PCT patent application publication of patent application No. WO 2006/110917, and cesium carbonate (3.52 g, 11 mmol) in acetone (50 ml), 2-bromomethyl-5-trifluoromethylfuran (1.13 g) is added. , 3.9 mmol) in one portion and the reaction mixture was stirred at 55-60 ° C for 16 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography, eluting with ethyl acetate (1/9 - 1/1) to give 1,1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3f] [1,3] benzodioxole -7, 3'-indolo] -2 '(1'H) -one, i.e. a compound of formula (I) (1.17 g, 76%) as a white solid:

MP 139-141 &amp; lt; 0 &amp; gt; C; ¹H NMR (300 MHz, CDCl3) δ 7.32-6.97 (m, 5H), 6.72 (d, J = 3.3 Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.05, 4.86 (ABq, JAB = 16.1 Hz, 2H), 4.91 (d, J = 9.0 Hz; 1H), 4.66 (d, J = 9.0 Hz, 1H); ¹³C NMR (75 MHz, CDCl3) δ 176.9, 155.7, 153.5, 148.8, 142.2, 141.9, 140.8, 140.2, 139.7, 139.1,

132.1, 129.2, 124.7, 124.1, 123.7, 121.1, 120.1, 117.6, 114.5, 114.4, 110: 3, 109.7, 103.0, 101.9, 93.8, 80.0, 57.8, 36.9; MS (ES +) m / z 430.2 (M + 1), 452.2 (M + 23); Cal'd for C22H14F3NO6: C, 61.54%; H, 3.29%; N, 3.26%; Found: C, 61.51%; H, 3.29%; N, 3.26%.

SYNTHETIC EXAMPLE 2

Resolution of the compound of formula (I) by chiral HPLC [0122] The compound of formula (I) is separated into the (S) -enantiomer of the invention and the corresponding (R) enantiomer by means of chiral HPLC under the following conditions:

Column:

Chiralcel ® OJ-RH; 20 mm ID χ 250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical Industries,

Ltd)

eluent:

Acetonitrile / water (60/40, v / v, isocratic)

Flow speed:

10ml / min

Time:

min. Cargo:

100 mg of the compound of formula (I) in 1 ml of acetonitrile

Temperature: Ambient [0123] In the above conditions, the chiral HPLC (R) enantiomer of the compound of formula (I), i.e., (R) -1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo] 2,3-f] [1,3] -benzodioxole-7,3'-indolo] -2 '(1'H) -one, was isolated as the first fraction as a white solid; ee (enantiomeric excess)&gt; 99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105 ° C;¹H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J = 3.4 Hz, 1 H), 6.67 (s, 1H); 6.05 (s, 1H), 5.89 (d, J = 6.2 Hz, 2H), 5.13, 5.02 (ABq, JAB = 16.4 Hz, 2H), 4.82, 4 72 (ABq, JAB = 9.4 Hz, 2H);¹³C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0,

129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES +) m / z 430.2 (M + 1), [α] ν-17 ° (c 0.99, DMSO). The (S) -enantiomer of the compound of formula (I), i.e., (S) -1 '- {[5- (trifluoromethyl) furan-2-yl] methyl) spiro [furo [2,3-f] [1,3 ] benzodioxole-7,3'-indolo] -2 '(1'H) -one was isolated as a second fraction in the form of a white solid; ee&gt; 99% (analytical OJ-RH, 55% acetonitrile in water); mp 100-102 ° C;¹H NMR (300 MHz, DMSO-d6) δ 7.32-6.99 (m, 5H), 6.71 (d, J = 3.4 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J = 6.3 Hz, 2H), 5.12, 5.02 (ABq, JAB = 16.4 Hz, 2H), 4.82, 4 72 (ABq, JAB = 9.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9,

120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES +) m / z 430.2 (M + 1), [α] D + 14.04 ° (c 0.99, DMSO).

EP 2 448 943 B1

SYNTHETIC EXAMPLE 3

Separation of the compound of formula (I) by SMB chromatography [0124] The compound of formula (I) is separated into the (S) -enantiomer of the invention and the corresponding (R) -enantiomer by SMB chromatography under the following conditions:

Extract:

147.05 ml / min

The raffinate:

76.13 ml / min

eluent:

183.18 ml / min

Power supply:

ml / min

recovery:

407.88 ml / min

Time:

0.57 minutes

Temperature:

° C Pressure:

bars [0125] A feed solution (25 g of the compound of formula (I) in 1.0 L mobile phase (25: 75: 0.1 (v: v: v) acetonitrile / methanol / trifluoroacetic acid)) was fed continuously to the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in a 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm ID) ChiralPak-AD as a stationary phase. The first eluting enantiomer (the (R) enantiomer of the compound of formula (I)) was included in the raffinate stream and the second eluting enantiomer (S (enantiomer of the compound of formula (I)) was included in the extract stream. Data characterizing the (S) enantiomer and the (R) enantiomer obtained SMBs were identical to those obtained above using chiral HPLC.

The compound of formula (I) was separated into its constituent enantiomers by a Waters LCMS apparatus of a preparative auto-purification system. The first enantiomer eluted from the chiral column was brominated (in place, well removed from the stereogenic center) to give the corresponding 5'-bromo derivative, which then crystallized to generate a single crystal suitable for X-ray crystallography. The crystal structure of this brominated derivative of the first eluted enantiomer was obtained and the absolute configuration was found to be the same as in the (R) -enantiomer of the invention. Hence the second enantiomer eluted from the chiral column (S) -enantiomer of the invention. In addition, the material obtained from the SMB extract stream extract had

Optical rotation with the same sign (positive, i.e. dextrorotatory), like that of the material obtained from said LC separation.

BIOLOGICAL STUDIES [0127] Various techniques are known in the art to test the activity of a compound of the invention or to determine their solubility in known pharmaceutically acceptable excipients. To enable a more complete understanding of the invention described herein, the following biological studies are provided below. It should be understood that these examples are illustrative only.

BIOLOGICAL EXAMPLE 1

Guanidine influx study (in vitro study) [0128] This example describes an in vitro test for testing and profiling test agents for human or rat voltage gated sodium channels stably expressed in cells of endogenous origin or from heterologous expression. The test is also useful for determining the IC 50 value of a voltage modulating gated, preferably blocking, sodium channel. The assay is based on the guanidine flow assay described by Reddy, NL, et al., J

Med Chem (1998), 41 (17): 3298-302.

[0129] The guanidine influx study is a radiotracer flow study used to determine the ionic activity of voltage-gated sodium channels in a high-performance microplate based format. The study uses hydrochloride¹⁴C-guanidines in combination with various known voltage-gated sodium channel modulators that generate sustained flow to determine the potency of the agents being tested. The potency is determined by calculating the IC50 value. Selectivity is determined by comparing the potency of a voltage-blocking compound of a given sodium channel with its potency against other voltage-gated sodium channels (so-called "selectivity profiling").

[0130] Each of the test agents is tested on the cells in which the voltage gated channel is expressed. Voltage-gated sodium channels are characterized as sensitive or insensitive to TTX. This property is useful in assessing the activity of a given voltage-gated sodium channel when it is in a mixed population with other voltage gated sodium channels. The following Table 1 lists cell lines useful in screening for the activity of a specific voltage-gated sodium channel in the presence or absence of TTX.

TABLE 1

<td>CELL LINE</td><td>Expression of mRNA</td><td>Functional characteristics</td>

<td></td><td>• Nav1.4 expression was demonstrated by the RTPCR method</td><td>• 18- to 20-fold increase in inflow [¹⁴C] guanidine was completely blocked by TTX (Nav1.4 is sensitive to TTX)</td>

EP 2 448 943 B1

<td rowspan="2">CHO-K1 (Hamster ovary cells Chinese; recommended host cell line) ATTC number: CCL-61 L6 (rat mioblast) number ATTC: CRL-1458</td><td>• No expression was found Nav</td><td rowspan="2">• 10- to -15-fold increase in inflow [¹⁴C] guanidine was only partially blocked via TTX at 100 nM (Nav1.5 is a channel resistant to TTX)</td>

<td>• Expression of Nav1,4 and 1.5</td>

<td>SH-SY5Y (human neuroma) number ATTC: CRL-2266</td><td>• Published expressing Nav1.9 and Nav1.7 (Blum et al.)</td><td>• 10- to 16-fold increase in inflow [¹⁴C] guanidine above the background has been partially blocked by TTX (Nav1.9 is a channel resistant to TTX)</td>

<td>SK-N-BE2C (human neuroma cell line, ATTC number: CRL2268)</td><td>• Expression NaV1.8</td><td>• Stimulation of BE2C cells with pyrethroid causes a 6-fold increase in inflow [¹⁴C] guanidines over background. • TTX partially blocked the inflow (Nav1.8 is a TTX-resistant channel)</td>

<td rowspan="2">PC12 (rat stump) number ATTC: CRL-1721 CHO-K1 (Hamster ovary cells Chinese; recommended host cell line) ATTC number: CCL-61</td><td>• Expression of Nav1.2</td><td>• 8 - up to -12-fold increase in inflow [¹⁴C] guanidine was completely blocked via TTX (Nav1.2 is a sensitive channel on TTX)</td>

<td>• Nav1.4 expression was demonstrated by the RTPCR method • No expression was found Nav</td><td>• 18- to 20-fold increase in inflow [¹⁴C] guanidine was completely blocked via TTX (Nav1.4 is sensitive to TTX)</td>

<td>L6 (rat mioblast) number ATTC: CRL-1458</td><td>• Expression of Nav1,4 and 1.5</td><td>• 10- to -15-fold increase in inflow [¹⁴C] guanidine was only partially blocked via TTX at 100 nM (Nav1.5 is a channel resistant to TTX)</td>

<td>HEK293 (human cells embryonic kidneys) ATTC Number CRL-1573</td><td>• Expressing hNaV1.7</td><td>• Nav1.7 is a TTX-resistant channel. TTX IC50 in a functional guanidine study is 8 nM.</td>

[0131] It is also possible to use immortalized cell lines expressing voltage-gated sodium channels. Methods for cloning, stable transfection and propagation of such cells are known to those skilled in the art (see, for example, Klugbauer, N, et al., EMBO J. (1995), 14 (6): 1084-90; and Lossin, C., et al., Neuron (2002), 34, pp. 877-884).

[0132] Cells expressing a voltage-gated sodium channel are grown according to the supplier's instructions or, in the case of a recombinant cell, in the presence of G418 selective growth carrier

EP 2 448 943 B1 (Gibco / Invitrogen). The cells are separated from the cell culture plates with the enzyme solution (1X) Trypsin / EDTA (Gibco / Invitrogen) and analyzed for density and viability using a hemocytometer (Neubauer). The cells are washed and resuspended in media and then plated on Poly-D-lysine-coated Scintiplates (Perkin Elmer) plates (approximately 100,000 cells / well) and incubated at 37 ° C / 5% CO 2. for 20-24 hours. After extensive washing with low-salt HEPES buffered saline (LNHBSS) (150 mM choline chloride, 20 nM HEPES (Sigma), 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose), the well is added to each well. test agents diluted with LNHBSS (different concentrations of the test agent may be used) at the appropriate concentration.¹⁴C-guanidines (ARC) to measure the flow through voltage-gated sodium channels.

[2158] After introducing the test agent and the activation / radiolabelled mixture into the cells, the Scintiplates-coated Poly-D-lysine plates are incubated at ambient temperature. After incubation, the Scintiplates-coated Poly-D-lysine plaques are thoroughly washed with LNHBSS supplemented with guanidine (Sigma). The Scintiplates are dried and counted using a Wallac MicroBeta TriLux (PerkinElmer Life Sciences). The ability of the test agent to block voltage-gated sodium channel activity is determined by comparing the amount¹⁴C-guanidine present in cells expressing different voltage-gated sodium channels. Based on this data, various calculations may be used as given elsewhere in this specification to determine if the test agent is selective for a specific voltage-gated sodium channel.

[0134] Using the general method described above, the IC 50 value of the test agent for a specific voltage-gated sodium channel can be determined. The IC 50 can be determined using 3, 8, 10, 12 or 16 point (two or three repeats) curve at an initial concentration of 1.5 or 10 μM, serial dilution and final concentrations up to sub-nanomolar, nanomolar and low micromolar ranges. Typically, the middle concentration of the test agent is set to 1 μM, and subsequent concentrations are used with half the dilution of greater or less (e.g., 0.5 μM, 5 μM and 0.25 μM, 10 μM and 0.125 μM, 20 μM etc.). The IC50 value is calculated using the four-parameter logistic model or sigmoidal dose-response model (fit = (A + ((BA) / (1 + ((C / x)^ANDD)))).

[0135] The selectivity ratio (fold selectivity, factor of selectivity or multiple of selectivity) is calculated by dividing the IC 50 value of the voltage gated sodium channel tested by the voltage gated reference voltage sodium channel, for example Nav1.5.

In this connection, the compound of formula (I), the (S) enantiomer of the compound of formula (I), i.e. the (S) enantiomer of the invention and the (R) -enantiomer of the compound of formula (I), tested in this test have demonstrated the blocking activity of the voltage-gated sodium channel on hNaV1.7, as shown in the Table below

2:

TABLE 2

<td>Relationship</td><td>Chemical name</td><td>IC50 (ΜΜ)</td>

<td>(AND)</td><td>1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole-7,3'indolo] -2' (1'H) - he</td><td>0,007</td>

EP 2 448 943 B1

<td>(IR)</td><td>(R) -1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole-7,3'indolo] -2' (1 H) -one</td><td>4,200</td>

<td>(IS)</td><td>1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioxole-7,3'indolo] -2' (1'H) - he</td><td>0.003</td>

[0137] The concentration-response relationship for the (S) -enantiomer of the invention and the (R) -enantiomer is shown in Figure 1. The solid curves indicate the smallest best alignment of the squares with a 1: 1 binding isotherm; The IC50s that describe these curves are shown in Table 2. The (S) -enantiomer of the invention showed a significantly higher (e.g., 1000-fold) inhibitory potency for hNaV1.7 in this model compared to the inhibitory potency with the corresponding (R) -enantiomer.

[0138] These results favor the use of the (S) enantiomer of the invention with respect to the (R) enantiomer or compound of formula (I) (racemate) for the uses described herein, because a higher pharmacological activity can be achieved at lower dosage levels with as few effects as possible. side. In addition, the (R) enantiomer is a very important tool for safety research because it allows to distinguish between mechanism-based effects (those mediated by a sodium channel block) and activities beyond the purpose of the invention that can be removed without impairing the efficacy of analogs. If the adverse effect is based on the mechanism, the (S) enantiomer will be much stronger than the (R) enantiomer,

BIOLOGICAL EXAMPLE 2

Electrophysiological study (in vitro study) [0139] HEK293 cells expressing Nav1.7 are cultured in DMEM culture medium (Gibco) with 0.5 mg / ml G418, +/- 1% PSG and 10% heat inactivated fetal bovine serum in 37C ° and 5% CO2. For electrophysiological readings, the cells are placed on 10 mm plates.

[0140] The registration is carried out in whole-cell configuration with the whole cell voltage clamp technique (Bean et al., Op cit.), Using an Axopatch 200B amplifier and Clampex software (Axon Instruments, Union City, CA). All experiments are carried out at room temperature. The electrodes are polished in fire to a resistance of 2-4 MΩ. Voltage and capacitance errors are minimized by, respectively, serial resistance compensation and capacitance compensation. Data is downloaded at 40 kHz and filtered at 5 kHz. Composition of external solution (bath): NaCl (140 mM), KCI (5 mM), CaCl2 (2 mM), MgCl2 (1 mM), HEPES (10 mM) at pH 7.4. The composition of the internal solution (pipette) (in mM): NaCl (5), CaCl2 (0,1) MgCl2 (2), CsCl (10), CsF (120), HEPES (10), EGTA (10), pH 7, 2.

[0141] In order to assess the affinity at steady-state of the compounds for the dormant channel in the inactive state (Kr and Ki respectively), 12.5 ms test impulses from the holding potential of -120 mV are used for depolarization voltages ranging from -60 mV to +90 mV, in order to construct current-voltage relationships (curves IV). Voltage close to the peak value

The curve IV (from -30 to 0 mV) is used as the test pulse voltage during the remainder of the experiment. Next, inactivity curves are constructed in the steady state (availability), measuring the current excited during the 8.75 ms test pulse and the next 1 s of the boost pulses to the potentials in the range from -120 to -10 mV.

[0142] The dependence on the binding voltage of the compound to the steady state sodium channel is determined by measuring the ionic current blocking for the two holding potentials. Binding to dormant channels is determined using a holding potential of -120 mV, in order to achieve maximum availability. Binding to channels in the inactivated state was evaluated at the holding potential such that only 10% of the channels were available for opening. The membrane potential is maintained at this voltage for at least 10 seconds, so that the binding of the drug can be established.

[0143] The apparent dissociation constant at each voltage is calculated using the equation:

<img file="PL2448943T3_D0008.tif" />

where K d is the dissociation constant (Kr or Ki), and [drug] is the concentration of the test compound.

In this connection, the compound of formula (I), the (S) enantiomer of the compound of formula (I), i.e., the (S) enantiomer of the invention and the (R) enantiomer of the compound of formula (I), tested in this model, showed affinity for resting / closed and inactivated state of hNaV1.7, as shown below in Table 3:

TABLE 3

<td>Relationship</td><td>Chemical name</td><td>Ki (ΜΜ)</td><td>Cr (ΜΜ)</td>

<td>(AND)</td><td>1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioksolo7,3'-indol] -2' (1'H) -one</td><td>0.142</td><td>&gt; 10um</td>

<td>(IR)</td><td>(R) -1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3f] [1,3] benzodioxole-7,3'-indol] -2' (1 ' H) -one</td><td>0.869</td><td>&gt; 10um</td>

<td>(IS)</td><td>1 '- {[5- (trifluoromethyl) furan-2-yl] methyl} spiro [furo [2,3-f] [1,3] benzodioksolo7,3'-indol] -2' (1'H) -one</td><td>0.161</td><td>&gt; 10um</td>

[0145] As shown by these results, the (S) -enantiomer of the invention is a hNaV1.7-dependent-voltage-dependent modifier with low affinity for resting / closed status and high affinity for the inactivated state. The results showed that the (S) -enantiomer is approximately 5-fold more strongly bound to hNaV1.7 in the inactivated state than the (R) enantiomer. In addition, the results show that the (S) enantiomer is primarily responsible for the strength of the racemate i.e. the compound of the formula (I).

BIOLOGICAL EXAMPLE 3

In vivo studies

EP 2 448 943 B1

Acute Pain (Formalin Test) [0146] The fomalin test is used as an animal model of acute pain. In the formalin test, on the day before the experiment day, the animals are briefly acclimated to the plexiglass test chambers for 20 minutes. On the day of the test, the animals are randomly injected with the test substances. 30 minutes after drug administration, 50 μΐ of 10% formalin is injected subcutaneously in the plantar region of the left hind paw of rats. The collection of video data starts immediately after the administration of formalin and lasts 90 minutes.

[0147] Images are recorded using the Actimetrix Limelight program, which stores files with the extension * .Ilii, and then converts them to the MPEG-4 format. Then video recordings are analyzed using the "The Observer 5.1" behavioral analysis program, (version 5.0, Noldus Information Technology, Wageningen, the Netherlands). The video analysis is carried out by observing the behavior of the animals and awarding points for each behavior depending on its type, as well as determining the duration of the behavior (Dubuisson and Dennis, 1977). Targeted types of behavior include: (1) normal behavior, (2) paw removal, (3) paw lift, (4) licking / biting or scratching the paw. Lifting, relieving or excessive licking, biting and scratching the injected paw indicates a painful reaction. An analgesic response or protective action of the compounds indicates that both paws are in contact with the substrate without significant unloading, excessive licking, biting or scratching of the injected paw.

[0148] Analysis of data from the formalin test is performed with respect to two factors: (1) the percentage of the maximum possible inhibition effect (Percent Maximal Potential Effect Inhibitors,% MPIE) and (2) the score on the pain scale. The% MPIE values ​​are calculated in several stages, the first of which is to sum up the duration of abnormal behaviors (behavior 1, 2, 3) of each animal. A single value for the therapeutic group with vehicle is obtained by averaging all results within this therapeutic group. The following calculation gives the MPIE value for each animal:

MPIE (%) = 100 - [(sum for treatment groups / mean value for a vehicle group) X 100%] [0149] The score on the pain scale is counted using a weighted scale as described above. In order to determine the result on the pain scale for each animal, the duration of the behavior by the weight is multiplied (the severity of the reaction) and divided by the total duration of the observation. The calculations are represented by the following formula:

Pain rating = [0 (To) + 1 (T1) + 2 (T2) + 3 (T3) J / (To + T1 + T2 + T3)

CFA-induced chronic inflammatory pain [0150] In this study, mechanical allodynia is assessed using calibrated von Frey filaments. After a full week of acclimation to the vivarium room, the plantar region of the left hind paw of rats was injected subcutaneously, under light general anesthesia, isoflurane, 150 μl of Freund's Complete Adjuvant emulsion (CFA) (CFA suspended in an oil-in-saline emulsion (1: 1 ), at a concentration of 0.5 mg / ml). Animals were allowed to recover from anesthesia and reference values ​​were established for mechanical and thermal nociceptive pain thresholds for all animals, one week after CFA administration.

On the day before the experiment started, all animals were habituated to the test devices for 20 minutes. Test and control products were administered to the animals and the threshold values ​​measured

In order to determine analgesic responses to each of six available therapies, nociceptive at fixed time points after drug administration. Selected time points were determined earlier in order to show the highest analgesic effect for each of the tested compounds.

[0151] The (S) -enantiomer of the invention and the corresponding (R) enantiomer were compared using both orally and externally dispensed dosages. Figure 2 shows a comparison of the efficacy of the (S) -enantiomer of the invention and the (R) enantiomer with oral dosing. Each enantiomer was dosed at 10, 30, 100 or 200 mg / kg. The plasma concentration at each dose was also determined, and the reversal of the pain response (as a% increase from the reference threshold) was plotted as a function of plasma concentration.

[0152] The (S) enantiomer had a larger maximum effect when it was dosed at 200 mg / kg. The (R) enantiomer has significantly higher plasma concentrations at the equivalent dose level. It was an unexpected and unusual discovery. Consequently, the use of a racemate, i.e. a compound of formula (I), would result in a 10-fold excess of the non-active enantiomer, i.e. the (R) enantiomer. Accordingly, the use of the (S) -enantiomer of the invention significantly improves the likelihood of efficacy with minimal probability of encountering off-target activities that are not stereoselective. [0153] The (S) -enantiomer of the invention was also administered topically to animals at various doses (1%, 2%, 4% and 8% (w / v)) and nociceptive thresholds were measured at predetermined time points after drug administration, to determine the analgesic responses to each of the six available therapies. Selected time points are defined earlier in order to show the highest analgesic effect for each tested compound.

[0154] After the Hargreaves test, the threshold values ​​of the animals' response to tactile stimuli were determined using an Electrovonfray estimate, model 2290 (IITC Life Science, Woodland Hills, CA). The animals were placed in suspended plexiglass chambers based on a wire mesh surface. After 15 minutes of acclimatization, previously calibrated von Frey filaments were applied perpendicular to the plantar space of the hind paws of the animals on the same side with sufficient force, measured in grams to induce a violent paw response. The answer indicated the withdrawal of the painful stimulus and set the end point of effectiveness. The test was continued until the filament was indicated, which, at the lowest applied force, caused a rapid withdrawal of the paw or until the limit of applied force was reached, amounting to about 20 g. This limit of force is applied because it is equal to about 10% of the body weight of the animals; this is to prevent lifting the whole limb due to the use of stiffer filaments, which would change the nature of the stimulus. Data were expressed as a percentage increase compared to the initial threshold value measured in grams.

[0155] The (S) -enantiomer of the invention tested in this model showed analgesia as shown below in Table 4.

TABLE 4

<td></td><td colspan="4">% increase from baseline (CFB)</td>

<td>Relationship</td><td>1% locally</td><td>2% locally</td><td>4% locally</td><td>8% locally</td>

<td>(IS)</td><td>0.62</td><td>16.71</td><td>28.79</td><td>45,06</td>

[0156] The (S) -enantiomer of the invention at 2%, 4% and 8% (w / v) showed an increase in von Frey's mechanical withdrawal thresholds expressed as a percentage increase from baseline (IFB) in order to

EP 2 448 943 discloses analgesia. The analgesic effect of the (S) enantiomer increased with increasing doses up to the highest 8% dose tested (w / v), which showed that the maximum percentage of IFB at + 45.1%. A 1% (w / v) dosing group, however, did not show an appreciable increase in von Frey's mechanical withdrawal thresholds. The results show that the (S) enantiomer has an analgesic effect in the CFA-induced inflammatory pain model in the range of 2% to 8% (w / v).

Nociception Model in the Postoperative Period [0157] In this model, cutaneous hyperalgesia is determined in the plantar leg of the paw by subjecting the paw to the developing tactile stimulus until the paw withdraws from the stimulus applied. While the animals are under general anesthesia induced by 3,5% isoflurane administered intranasally, in the plantar area of ​​the left hind paw, using a blades number 10, a 1 cm long incision is made, crossing the skin and fascia, starting 0.5 cm from the proximal heel edge up to the fingers. After making the incision, the skin is sutured using a sterile silk suture 2, 30. The damaged area is covered with polysporin and betadine. The animals are allowed to regenerate in cages overnight.

[0158] The retraction threshold under the influence of the tactile touch on animals, the treated (ipsilateral) paw and the untreated (contra-lateral) paw are determined using the Electrovonfray estimate, model 2290 (IITC, Life Science, Woodland Hills, CA). The animals are placed in suspended plexiglass chambers based on a wire mesh surface. After at least 10 minutes of acclimatization, the previously calibrated von Frey filaments are applied perpendicular to the plantar space of both paws of animals in ascending order, starting with a 10 g filament, with a force sufficient to cause a slight deflection of the filament. The test was continued until the filament was indicated, which, at the lowest applied force, causes the paw to be rapidly withdrawn or until in which a strength limit of about 20 g is reached. This force limit is applied because it is about 10% of the body weight of the animals; this is to prevent lifting the whole limb due to the use of stiffer filaments, which would change the nature of the stimulus.

Model of neuropathic pain: injury due to constant pressure [0159] In this model, at the height of half the left thigh of the animal, using a blades number 10, a 3 cm incision was made, crossing the skin and fascia. The left sciatic nerve was exposed by dividing the tissues bluntly through the biceps femoris, trying to minimize bleeding. Four ligatures were loosely placed around the sciatic nerve using a sterile non-absorbable 4-0 silk suture at a distance of 1 to 2 mm. The stress of loosely ligated ligatures is to be sufficient to cause slight sciatic nerve compression observed by a dissecting microscope in a 4-fold magnification. In the sham-operated animal, the left sciatic nerve was exposed without further manipulation. Antibacterial ointment was applied directly to the wound and the muscle was sutured using sterile sutures.

[0160] The animal response thresholds for tactile stimuli were determined using an Electrovonfray estimate, Model 2290 (IITC Life Science, Woodland Hills, CA). The animals are placed in

EP 2 448 943 B1 suspended plexiglass chambers based on a wire mesh surface. After 10 minutes of acclimatization, previously calibrated von Frey filaments were applied perpendicular to the plantar space of both paws of the animals in ascending order, starting with a 0.1 g filament, with a force sufficient to cause a slight deflection of the filament. The test shall be continued until the filament is indicated which, at the lowest applied force, causes the paw to back violently or to a point where a force limit of approximately 20 g is reached. This limit of force is applied because it is about 10% of body weight animals; this is to prevent lifting the whole limb due to the use of stiffer filaments, which would change the nature of the stimulus.

[0161] The nociceptive thermal pain thresholds for the animals were determined using the Hargreaves test. After measuring the threshold of touch sensitivity, the animals were placed in suspended plexiglass chambers, the base of which is a glass platform with heating units. In all test samples, the temperature of the thermostated glass platform is set at approximately 24-26 ° C. After being placed in the chambers, the animals were allowed to adapt for 10 minutes in order to stop any exploratory behavior. A beam of infrared radiation was applied to the underside of the glass platform towards the plantar zone of the hind paws, using the Plantar / Tail Stimulator analgetic model 226 (IITC, Woodland Hills, CA). During all trials to prevent tissue damage,

[0162] The (S) enantiomer was compared to the corresponding (R) -enantiomer and racemate (compound of formula (I)) in this CCI model using topical drug use as described for the CFA model (see Figure 3). Each test compound was administered as an ointment containing 2% (w / v). According to the various activities of these two enantiomers as voltage-gated sodium channel inhibitors, only the (S) enantiomer of the invention reversed the pain responses, while the (R) -enantiomer had a significant increase from the initial value. Both the (S) enantiomer and the racemate show a similar percentage increase from the beginning of the study, which seems to suggest that the (S) -enantiomer is responsible for analgesia.

BIOLOGICAL EXAMPLE 4

Study of aconitine-induced arrhythmia [0163] The anti-arrhythmic effect of the compounds of the invention is demonstrated in the following study. Arrhythmia is provoked by intravenous administration of aconitine (2.0 μg / kg) dissolved in physiological saline. Test compounds of the invention were administered intravenously 5 minutes after aconitine administration. The assessment of antiarrhythmic activity is performed by measuring the time from aconitine to extrasystole (ES) and the time from aconitine to ventricular tachycardia (VT).

[0164] In isoflurane anesthesis rats (1/4 to 1/3 of 2%), a tracheotomy is performed, first making an incision in the neck area, and then isolating the trachea and making a 2 mm incision to insert the 2 cm tracheal tube into the trachea, so that the opening of the cannula is placed just above the muzzle. The cannula is secured with sutures and connected to the respirator for the duration of the experiment.

[0165] In the thigh area, an incision is made (2.5 cm) and using a probe with a blunt end, the thyroid blood vessels are extracted. Both femoral veins are cannulated, one to maintain anesthesia with pentobarbital (0.02-0.05 ml), and the other for infusion and injection of drug and vehicle. The femoral artery is cannulated using a gel catheter to monitor blood pressure with the transmitter.

[0166] ECG electrodes connect to the pectoral muscle in the Lead II position (the upper right side above the heart - the white electrode and the lower one on the left below the heart - the red electrode). The electrodes are secured with seams.

[0167] All areas in which surgical procedures have been performed are coated with gauze soaked in 0.9% saline. Saline (1-1.5 ml 0.9% solution) is used to moisten areas after surgery. Animals were allowed to equilibrate the heart and breath for at least 30 minutes.

[0168] Arrhythmia is induced by infusion of 2 μg / kg / min aconitine for 5 minutes. During this time, the ECG is recorded and continuously monitored.

BIOLOGICAL EXAMPLE 5

Investigation of induced arrhythmia ischemia [0169] To study potential therapeutic agents for the treatment of atrial and ventricular arrhythmias in humans, rat models of ventricular arrhythmias in the paradigms of acute cardioversion and prophylaxis were used. Myocardial ischemia leading to myocardial infarction is a common cause of disease states and mortality. The ability of a compound to prevent ischemia-induced ventricular tachycardia and ventricular fibrillation is an accepted model for determining the efficacy of a compound in the clinical setting of atrial and ventricular tachycardia and atrial fibrillation and ventricles.

[0170] General anesthesia is first induced with pentobarbital (administered intraperitoneally) and is maintained by intravenous bolus. The trachea of ​​male SD rats are cannulated for mechanical ventilation with room air, with a stroke volume of 10 ml / kg, 60 strokes / minute. The right thigh artery and vein can be cannulated using a PE50 cannula to measure mean arterial blood pressure (MAP) and intravenous administration, respectively.

[0171] The chest opens at an elevation between the fourth and fifth ribs, forming a 1.5 cm opening revealing the heart. Each rat is placed on a corrugated platform and fastens the chest skeleton with metal handles, opening the thoracic cavity. A surgical needle is used to enter the ventricle just under the raised vestibule and diagonal (after pointing down) the exit from the ventricle, resulting in&gt; 30% and &lt;50% occlusion area (OZ). The starting place is ~ 0.5 cm below the point where the aorta connects to the left ventricle. The suture is clamped so as to form a loose loop (occluder) around the artery branch. Then, the chest is closed using the end of the occluder accessible from outside the chest.

[0172] The electrodes are placed in the Lead II position (from the right atrium to the apex of the heart) to measure the ECG as follows: one electrode is placed on the right right paw and the other electrode is placed on the back left paw.

[0173] During the experiment, the body temperature, mean MAP arterial pressure, ECG and heart rate are continuously measured. After these important parameters have stabilized, a 1-2 minute measurement is made to establish a reference value. After determining the reference value, an infusion of the compound of the invention or control begins. After a 5-minute compound or control infusion, the suture is clamped to ligate the left coronary artery and cause ischemia in the left ventricle. For 20 minutes after ligation, important parameters are continuously recorded unless the MAP achieves a critical level of 20-30 mmHg for at least 3 minutes, in which case the record shall stop because the animal is considered to have died, after which the animal is killed.

BIOLOGICAL EXAMPLE 6 [0174] Compared to the racemate, i.e. the compound of formula (I), the (S) enantiomer, substantially free of the (R) -enantiomer, has a better solubility profile in a wide variety of pharmaceutically acceptable excipients. Thus, the (S) enantiomer may be formulated in a smaller number of dosage units than the racemate. This property facilitates dosing to patients at a higher level if efficacy is to be achieved. Examples of the difference in solubility are shown in Table 5 below:

TABLE 5

<td>Additional substance</td><td>Compound of formula (I) (racemate)</td><td>Enantiomer (S)</td>

<td>Labrasol</td><td>72.5 mg / ml</td><td>231 mg / ml</td>

<td>Propylene glycol</td><td>2.7 mg / ml</td><td>9.8 mg / ml</td>

<td>PEG 400</td><td>&lt;50 mg / ml</td><td>&gt; 55 mg / ml</td>

<td>Capryol® 90</td><td>18.1 mg / ml</td><td>96 mg / ml</td>

<td>Tween® 80</td><td>64 mg / ml</td><td>&gt; 123 mg / ml</td>

<td>Ethanol</td><td>10.0 mg / ml</td><td>36.4 mg / ml</td>

<td>Labrasol® / PEG 400 60/40</td><td>70.4 mg / ml</td><td>182 mg / ml</td>

<td>Labrasol® / Capryol®90 60/40</td><td>44.4 mg / ml</td><td>191 mg / ml</td>

<td>Labrasol® / Transcutol® 60/40</td><td>74.2 mg / ml</td><td>186 mg / ml</td>

BIOLOGICAL EXAMPLE 7

In vivo study for the treatment of pruritis [0175] Histamine induces pruritus (itching) in humans. Accordingly, this test evaluates the efficacy of the orally administered and topical (S) -enantiomer of the invention for histamine-induced pruritus in male ICR mice.

[0176] The animals were randomly divided into test groups including the untreated group, the group treated with the local pharmaceutical composition with 8% (w / v) of the (S) enantiomer and the group treated with the oral composition of 50 mg / kg of the enantiomer (S ). One day before the test, the scapular regions on animals were shaved with a hair clipper. On the day of testing, the animals were habituated for 60 minutes in a test chamber containing a transparent plastic ridge placed in a vertical position on a flat surface. After the habituation period, the animals were removed from the plastic tube, placed in a cage and injected with histamine in the shaved paddle region. Injections were made intradermally in small injection quantities (10 μΐ) using a Hamilton syringe. The solutions for injection consisted of histamine dissolved in physiological saline at a concentration of 100 μg / 10 ml (or 10 mg / ml). 10 μg of this solution was injected into each mouse. Immediately after the injection, the animals were returned to the test chambers and observed by cameras placed above the test chambers for a total of 50 minutes. The cameras were connected to a computer where digital video files were created, saved and analyzed.

[0177] The number of pruritus fits was assessed within 40 minutes. The "itching attack" was defined as lifting the hind leg, using it to scratch the scapular region and then placing it back on the ground. Alternatively, if instead of placing the back leg back on the ground licking of the mouse paw was observed, it was also counted as an itching attack.

[0178] In the untreated group, animals (n = 7) were habituated to the test chamber for 60 minutes prior to histamine injection. To assess the (S) -enantial enantiomer in histamine induced it, animals (n = 16 / group) were habituated to the test chamber for 30 minutes, followed by 50 mg, 8% (w / v), topical (S) enantiomer or carrier for the shaved region on the back. The animals return to the test chamber for a further 30 minutes of habituation before injecting histamine. To assess the oral (S) enantiomer, the animals (n = 8 / group) were orally administered by gavage at a dose of 50 mg / kg (S) enantiomer or vehicle and were then habituated in the test chamber for 60 minutes prior to the injection of histamine.

[0179] Data were analyzed using GraphPad Prism 5 software for statistical analysis and unpaired t-test was used for one-dimensional analysis. The results are expressed as mean ± SEM. Values ​​that reached p &lt;0.05 significance level were considered statistically significant.

Results [0180] The injection of histamine into the skin caused the animals to feel sporadic itching in attacks that lasted 1-2 seconds. In the untreated group, itching attacks started immediately after the injection and lasted about 40 minutes after its completion (see Figure 4). A group treated with 8% (w / v) of the topical (S) enantiomer showed a significant decrease in pruritus (see Figure 5). Animals treated with the intake only had a total of 134.3 ± 13.31 (n = 16) of itching, whereas in mice treated with the (S) -enantiomer having 89.00 ± 10.51 (n = 16) itching attacks. The difference between these groups was statistically significant at the p-value of 0.0122. In the 50 mg / kg group, the (S) -enantiomer orally showed a significant decrease in pruritus (see Figure 6). Animals treated with only vehicle, had a total of 42.88 ± 6.667 (n = 8) itching seizures, whereas mice treated with the (S) enantiomer had 17.25 ± 6.310 (n = 8) itching seizures. The difference between the orally treated group was statistically significant at a p-value of 0.0144. The results showed that it was administered

The oral and topical (S) enantiomer reduced pruritus. Furthermore, it is evident that two common methods of drug delivery, oral and topical, can be used to deliver the (S) -enantiomer to achieve this therapeutic effect.

BIOLOGICAL EXAMPLE 8

Clinical trial in humans for primary / inherited erythromelegaly (IEM) treatment [0181] Primary / inherited erythromelalia (IEM) is a rare pain inherited condition. The cause of IEM may be one or more of the potentiation of the mutation function in the NaV1.7 voltage-gated sodium channel, which has been shown to be inhibited by the (S) enantiomer of the invention.

[0182] Human patients with IEM have recurrent episodes of intense burning pain associated with redness and warmth in the hands and feet, but eventually the pain becomes constant. The pain is replaced by cooling, but is largely immune to pharmacological intervention. However, there are reports of voltage-gated sodium channel blockers showing moderate to outstanding pain relief for this condition.

[0183] Clinical trials to determine the efficacy of the (S) -enantiomer of the invention in ameliorating or reducing IEM may be designed for three-period, double-blind, multi-dose and cross-over studies to minimize the rate of dropout of participants and will take into account that patients saved will be available only for a 10-day study. Each of the patients participating in the study will serve as their own control, receiving both placebo and 400 mg of the (S) -enantiomer of the invention twice a day in a cross-over fashion.

BIOLOGICAL EXAMPLE 9

Clinical study in humans in the treatment of toothache [0184] The aim of this clinical trial was to compare the safety and efficacy (start time, relief duration and overall efficacy) of a single 500 mg dose of the (S) -enantiomer of the invention relative to the placebo dose for pain relief after extraction of the third molar.

[0185] Sixty-one patients participated in the study. The average age of patients was 20.4 years and all patients were men. Most of the patients were Caucasian (95.1%).

[0186] Austerity and relief of pain were measured using an 11-point numeric scale of pain intensity assessment (on a scale of 0 = no pain at all 10 = worst pain imaginable), (PINRS) and a 5-point categorical pain relief scale ( REL). Patients completed the PINRS after surgery and prior to administration of the (S) enantiomer of the invention. The efficacy variables were from the REL and PINRS scores and included total pain relief (TOTPAR), pain intensity difference (PID) and peaked pain intensity difference (SPID) and evaluated in time points 4, 6, 8 and 12 hours after administration of the enantiomer (S ) according to the invention.

[0187] However, all primary and secondary endpoints showed a consistent analgesic tendency with pronounced separation of (S) -enantiomer compared to placebo. These results suggest that the (S) enantiomer has analgesic properties, but statistical significance with placebo has not been achieved due to two main reasons: (1) a relatively high response rate to placebo and (2) a slow response rate;

The beginning of the (S) enantiomer's action. The used dental model is designed and is best suited for the evaluation of fast-start medicines, such as the anti-inflammatory agents of the NSAID group. It is evident from this study that the (S) -enantiomer of the invention does not have such a NSAID-like rapid onset of action. However, the pain reduction shown by those patients who received the (S) enantiomer was higher compared to those who received only placebo, sufficiently that the total population showed a signal of analgesic effectiveness for all assessed endpoints.

BIOLOGICAL EXAMPLE 10

Human S enantiomer (S) safety study in accordance with the invention [0188] This clinical trial was Phase 1, a randomized, double-blind, placebo-controlled study in healthy volunteers to evaluate the safety and pharmacokinetics of a topical ointment containing (S) -enantiomer by invention.

[0189] The ointment with the (S) enantiomer was applied daily for 21 days to determine the local toxicity / skin irritation of the (S) enantiomer. Systemic pharmacokinetics and local levels of the drug in the skin were also evaluated. Systemic exposure to the (S) enantiomer after topical administration and local skin irritation after multiple doses of the ointment with the (S) enantiomer were assessed. Each subject received 5 treatments over 21 consecutive days of (S) enantiomer in ointment from 4% to 8% (w / w) (1 x 100 μι; treatment A and B, respectively), with placebo as an ointment (treatment C ), physiological saline (0.9%) (1 x 100 μL, negative control, Treatment D) and sodium lauryl sulfate (SLS) 0.1% solution (1 x 100 μC positive control, treatment E). Treatments were applied in two different places on the upper back of each individual in a covered manner (five treatments) and partly covered (the first three treatments). Location for each treatment on each page (Treatments A, B, C, D and E on a covered site and treatment A,

B and C on a partially covered site) was randomized. Patients were limited to a clinical research center from about 18 hours before the first dosing on day 1 to about 8 hours after the second dose (Day 2). Patients returned each day for 19 consecutive days (from 3 to 21) as part of the dosing and testing procedures.

[0190] There were no serious adverse events (SAEs) or deaths. All adverse events (AEs) were mild or moderate in severity, with most adverse events associated with local skin reactions from the surgical patch to adhere to an occlusive dressing. All patients responded to a positive control. Positive control was stopped for all patients on day 4 after complaints of excessive discomfort of the subjects. Skin irritation scores were low for all treatments administered (maximum score 3 measured on a scale of 0-7), indicating that the (S) enantiomer in the ointment is locally well tolerated. No differences were observed between cumulative irritation results for (S) enantiomer 4% (w / w), enantiomer (S) 8% (w / w) ointment, placebo and negative control (0.9% saline).

[0191] Records of electrocardiography did not show clinically significant changes in the frequency of resting heart rate, quiescent state or QTc intervals in patients, and there were no clinically significant changes from the baseline in the studied vital signs, physical tests or laboratory assessments.

EP 2 448 943 B1

Systemic exposure to the (S) enantiomer was negligible because plasma concentrations of the (S) enantiomer were below the lower limit of quantification (LLOQ) (0.1 ng / ml or 100 pg / ml) in most samples (489 at 546 = ~ 90% ). The highest level of (S) enantiomer observed in one patient in the dosing period (day 22) was 994 pg / ml. Based on the minimal local irritation and favorable safety profile, together with the low systemic exposure of the (S) enantiomer, it has been found that the (S) enantiomer of the invention is well tolerated and safe as a local painkiller.

BIOLOGICAL EXAMPLE 11

Clinical trial in humans for the treatment of neuralgia [0192] Post-herpetic pain (PHN) is a well-established and recognized model for the study of neuropathic pain. In addition, PHN demonstrates strong evidence of the efficacy of the sodium channel blocker. The following study represents randomized, double-blind, placebo-controlled, two-way, cross-over studies to assess the safety, tolerability, pre-efficacy, and systemic exposure of the (S) enantiomer of the invention administered locally to patients with herpes zoster. The main goals are (a) to compare the efficacy and safety of an ointment containing (S) -enantiomer to those of placebo in relieving pain in patients with PHN, and (b) to assess the systemic exposure of (S) -enantiomer after topical application of the (S) -enantiomer in patients with PHN . Treatments consist of an ointment with an (S) enantiomer of 8% (w / w) and a corresponding placebo ointment. [0193] The study will include the following four periods:

1. Initial screening and leaching period (up to 3 weeks);

2. Single-blind study, placebo treatment period (1 week);

3. A period of cross-treatment, which will consist of 2 treatment periods, each lasting 3 weeks, separated by 2 weeks of leaching / single blank test, duration of placebo (a total of 8 weeks); and

4. The following safety period (2 weeks).