Enantiomers of spiro-oxindole compounds and using them as therapeutic agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound, namely to (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxol-7,3'-indole]-2'(1'H)-one of formula (I), and a method for preparing it which is effective for treating diseases and conditions, such as pain, an intensity of which can be reduced or relieved by modulating potential-dependent sodium channel gatings.

EFFECT: invention refers to the pharmaceutical composition of the above compound, methods of treating and a method of relieving an ion flux through the potassium channel gating in a cell.

10 cl, 5 tbl, 6 dwg, 11 ex

 

The SCOPE of the INVENTION

The present invention is directed to a specific enantiomer Spiro-oxindoles connection, in particular, on the use of the enantiomer in therapeutic treatment of a human or in veterinary medicine, for the treatment of diseases or conditions in mammals, preferably humans, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate sodium channels.

BACKGROUND of the INVENTION

Published patent application PCT No. WO 2006/110917, the disclosure of which is included in full in the present application by reference, discloses certain Spiro-oxindole connection, in particular, 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he, that is, the compound of the following formula (I):

These compounds are disclosed in this application as useful for treatment of diseases or conditions, such as pain, in mammals, preferably in humans, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate sodium channels.

BRIEF description of the INVENTION

The present invention is directed to establish what (S)-enantiomer and (R)-enant the Omer, the following compounds of formula (I):

demonstrate the difference in degree of inhibition activity potential-dependent gate of the sodium channel.

Accordingly, in one aspect the invention provides (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-she, that is, (S)-enantiomer having the following formula (I-S):

or its pharmaceutically acceptable MES or prodrug. Preferably, (S)-enantiomer does not contain (R)-enantiomer.

In another aspect, the invention provides a pharmaceutical composition comprising (S)-enantiomer or its pharmaceutically acceptable MES or prodrug, as described above, preferably containing no (R)-enantiomer, and one or more pharmaceutically acceptable excipients.

In one variant embodiment, the present invention relates to a pharmaceutical composition comprising (S)-enantiomer or its pharmaceutically acceptable MES or prodrug, as described above, preferably containing no (R)-enantiomer, pharmaceutically acceptable carrier and in an amount effective for the treatment of diseases or conditions associated with pain, with the introduction of an animal, preferably a mammal, most preferably a human.

In another aspect, the invention provides pharmaceutical therapy in combination with (S)-enantiomer, or its pharmaceutically acceptable MES or prodrug, as described above, preferably containing no (R)-enantiomer, and one or more other existing therapies, or any combination thereof, to improve the effectiveness of existing or prospective drug therapy or to reduce the side effects associated with existing or potential drug therapy. In one variant embodiment of the present invention relates to pharmaceutical compositions which combine (S)-enantiomer or its pharmaceutically acceptable MES or prodrug, as described above, preferably containing no (R)-enantiomer, with existing or prospective therapeutic treatments for indications listed in the present invention.

In another aspect the invention provides a method of treatment of a disease or condition in a mammal, preferably a human, which disease or condition selected from the group comprising pain, depression, cardiovascular disease, respiratory disease, mental illness, neurological disorders and convulsions, and combinations thereof, where the method comprises the administration to a mammal requiring the of Eudemus, a therapeutically effective amount of (S)-enantiomer, as specified above, or its pharmaceutically acceptable MES or prodrugs.

In another aspect, the invention provides a method of treating pain in a mammal, preferably a human, where the method comprises the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer, or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer.

In another aspect the present invention provides a method of treating or reducing the severity of the disease, condition or disorder where activation or hyperactivity of one or more protein voltage-dependent gate sodium channels, including, but not limited to, NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9 potential-dependent gate sodium channel, is directly related to the disease, condition or disorder, where the method comprises the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer.

In another aspect of Britanie provides a method of treating diseases or conditions in mammals, preferably in humans that are associated with the activity of voltage-dependent gate sodium channels. Thus, the invention provides a method of treating diseases or conditions in mammals, preferably in humans, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate sodium channels. Examples of such diseases or conditions include,but not limited to, pain of any nature and origin, the pain associated with HIV treatment of HIV-induced neuropathy, trigeminal neuralgia, post herpetic neuralgia, diabetic neuropathy, complex regional pain syndrome (CRPS), paroxysmal extreme pain disorder (PEPD), Evgeniy, sensitivity to heat, sarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with multiple sclerosis (MS); motor disorders associated with multiple sclerosis; amyotrophic lateral sclerosis (ALS), itching, hypercholesterolemia, benign prostatic hyperplasia, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, paroxysmal dystonia, periodic paralysis, myasthenic syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, acute necrosociety muscles, bipolar depression, anxiety, schizophrenia; disease caused by exposure to insecticides or other means, which cause increased excitability of neurons or muscles; hereditary erythermalgia, secondary erythermalgia, hereditary rectal pain, hereditary facial pain, migraine, headache, neuralgic headache, hereditary hemiplegic migraine; conditions associated with headache; sinus headache, tensional headache, phantom pain in amputated limbs, peripheral nerve injury, cancer, epilepsy, partial and General tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection in ischemic conditions, caused by stroke; glaucoma or neural trauma, tachyarrhythmias, atrial fibrillation and ventricular fibrillation, where the method comprises the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer.

In another aspect the invention provides a method of treatment of a disease or condition in a mammal, preferably human, by inhibiting the flow of ions through a potential-dependent gate sodium channel in MLEKO is melting, where the method comprises the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer.

In another aspect the invention provides a method of decreasing ion flux through potential-dependent gate sodium channel in a cell of a mammal, where the method comprises contacting the cells with (S)-enantiomer or its pharmaceutically acceptable MES or prodrug indicated above, preferably containing no (R)-enantiomer.

The present invention also provides the use of (S)-enantiomer or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer to obtain pharmaceutical compositions for the treatment of a disease or condition which is associated with the activity of the potential-dependent gate of the sodium channel. Thus, the invention provides the use of (S)-enantiomer or its pharmaceutically acceptable MES or prodrugs, as specified above, preferably containing no (R)-enantiomer to obtain pharmaceutical compositions for the treatment of diseases or conditions, improvement or relief which the CSO is achieved through modulation, preferably inhibiting, the potential-dependent gate of the sodium channel.

BRIEF DESCRIPTION of DRAWINGS

The following drawings form part of the description of the present invention and are included to demonstrate some of the aspects of the present invention. The invention may be better understood with reference to one or more of these drawings in combination with the detailed description of specific variants of the embodiments presented in this application.

Fig. 1 shows the dependence of the concentration-response for (S)- and (R)-enantiomers in the analysis of guanidine influx of Biological example 1 in this application.

Fig. 2 shows a comparison of the effectiveness of (S)- and (R)-enantiomers by oral administration in a model of inflammatory pain from Biological example 3 in this application.

Fig. 3 shows a comparison of the effectiveness of (S)- and (R)-enantiomers with the local introduction in the model of neuropathic pain from Biological example 3 in this application.

Fig. 4 shows the time dependence of histamine-induced itch in untreated mice in the analysis ofin vivodescribed in Biological example 7. Data are presented as the number of reactions itching, average value ± standard deviation.

Fig. 5 shows the effectiveness of the ointment against induced histamine itching, used by local, steriade is 8%(mass/about) (S)-enantiomer. Data are presented as mean value ± standard deviation reactions itching.

Fig. 6 shows the effectiveness of (S)-enantiomer against itch induced by histamine, and ingestion, and not locally. Data are presented as the number of reactions itching, average value ± standard deviation.

DETAILED description of the INVENTION

Definition

When used in the description and the claims, unless otherwise specified, the following terms have the following meanings:

"Analgesia" refers to the absence of pain in response to a stimulus that is normally painful.

"Allodynia" refers to the condition in which usually innocuous sensations such as pressure or light touch, are perceived as painful.

"Enantiomers" refers to asymmetric molecules, which can exist in two different isomeric forms, which have different configurations in space. Other terms used to refer to or related to the enantiomers are stereoisomers" (because of the different location or stereochemistry around the chiral centre; although all enantiomers are stereoisomers that are not all stereoisomers are enantiomers or optical isomers" (due to the optical activity of the pure enantiomers, which represents the ability of the various pure enantiomers rotate plane-polarized light in different directions). Because they have no plane of symmetry, the enantiomers are not identical to their mirror reflections; molecules that exist in two enantiomeric forms, are chiral, which means that they can be considered as present in the "left" and "right-handed" forms. The most frequent cause of chirality in organic molecules is the presence of tetrahedral carbon associated with four different substituents or groups. This carbon is called a chiral center or stereogenic center. The method of specifying the three-dimensional arrangement of atoms (or configuration) at the stereogenic center is correlated with the order of priority groups, when the group with the lowest priority is oriented away from the hypothetical observer: at the location of the other three groups with priority from higher to lower clockwise stereogenic center is "R" (or "D") configuration; at their location counterclockwise stereogenic center has a "S" or "L" configuration.

Enantiomers have the same empirical chemical formula and, as a rule, are chemically identical to their reactions, their physical properties and their spectroscopic properties. However, the enantiomers exhibit different reactivity in relation to other asymmetric connections and once the WMD react to asymmetric physical abnormalities. The most common asymmetric deviation is the polarized light.

Enantiomer can rotate plane-polarized light; thus, the enantiomer is optically active. Two different enantiomers of the same compound will rotate plane-polarized light in the opposite direction; thus, the light can be rotated to the left or counterclockwise for a hypothetical observer (this levogyrate or "l" or a minus sign or "-") or it can rotate to the right or clockwise (this programalso or "d", or plus or "+"). The sign of the optical rotation (+) or (-) is not associated with the designation R,S. a Mixture of equal amounts of two chiral enantiomers is called a racemic mixture or a racemate, and is denoted either by the symbol (+/-), or by using the prefix "d,l" to denote a mixture programada and levogyrate forms. The compound of formula (I), as described in this application, is a racemate. The racemates or racemic mixtures show zero optical rotation, because there are equal amounts of (+) and (-) forms. As a rule, the presence of only one enantiomer rotates polarized light in one direction only; thus, a single enantiomer is called optically pure.

The designations "R" and "S" are used to seat the s absolute configuration of the molecule about its chiral center (centers). Signs may be in the form of a prefix or a suffix; they can be separated by a hyphen, or is not separated from the name enantiomer; they can be specified with a hyphen or without the use of a hyphen; and they can be enclosed in parentheses or specified without brackets.

Signs or prefixes(+) and ( - ) are used in this application to designate the sign of rotation of plane-polarized light by the compound, with (-) sign means that the connection is levogyrate (rotates to the left). The connection to the prefix (+) is Pervouralsk (rotates to the right side).

"Division" or "separating", when used in respect of racemic compounds or mixtures, refers to the separation of the racemate in two enantiomeric forms (i.e. the (+) and (-); (R) and (S) forms).

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

The Protocol chemical names and structural schema used in this application represent a modified form of the system of item I. U. P. A. C. (international Union of pure and applied chemistry), using the software ACD/Name version 9.07 for Example, the compound of formula (I) as described above in the section “Brief description of the invention”, is referred to in this application as 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he. The corresponding (S)-enantiomer, that is, (S)-enantiomer of formula (I-S), as described above in the section “Brief description of the invention”, is named in this application as (S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'h)-he. The corresponding (R)-enantiomer, (R)-enantiomer of the following formula (I-R):

or its pharmaceutically acceptable MES or prodrug are defined in this application as (R)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he.

"Prodrug" means a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the present invention. Thus, the term "prodrug" the relative is raised to a metabolic precursor compounds of the present invention, which is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need this, but converted toin vivothe active compound according to the present invention. Prodrugs, as a rule, quickly convertsin vivowith the provision of the initial compounds of the present invention, for example, by hydrolysis in blood. Proletarienne connection often has the advantages of solubility, tissue compatibility or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems", A. C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both publications are included in full in the present application by reference.

The term "prodrug" also includes any covalently associated media, which releasein vivothe active compound according to the present invention with the introduction of such prodrug to the mammal subject. Prodrugs of the compounds of the present invention can be obtained by modifying functional groups present in the compound of the present invention, so that such modification was cut, either by the usual manipulation orin vivoproviding the source is Obedinenie of the present invention. Prodrugs include compounds of the present invention, in which hydroxy, amino or mercaptopropyl associated with any group so that with the introduction of the prodrug compounds of the present invention to a mammal it was useplease education free hydroxy, free amino or free mercaptopropyl, respectively. Examples of prodrugs include, but are not limited to, acetate, formiate and benzoate alcohol derivatives or amide derivatives of amine functional groups in the compounds of the present invention, etc.

The invention disclosed in this application also covers the (S)-enantiomer and (R)-enantiomer disclosed in the present application, which is the isotope-labeled, where one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, such as2H,3H,11C,13C,14C,13N15N15O,17Oh,18O and18F, respectively. These radioactively labeled compounds may be useful in helping to determine or measure the effectiveness of the connection, describing, for example, the location or mechanism of action potential-dependent gate sodium channels Il is binding capacity with pharmacologically important site of action potential-dependent gate sodium channels. Isotope-labeled compounds are useful in studies of the distribution of drugs and/or fabric substrate. Radioactive isotopes, such as tritium, that is,3N, and carbon-14, that is,14With, especially useful for this purpose, in view of the simplicity of their inclusion and the existing means of detection. Radioligand, including tritium (3N), is particularly useful for stages binding of ligand to the membranes that contain the potential-dependent gate sodium channels, because lithium has a long half-life and radiation with relatively low energy, and for this reason, the radioisotope is relatively safe. Radioligand usually get through an exchange of tritium with hydrogen in unlabeled connection. Identification of active and inactive enantiomers of a particular racemate useful for analysis of ligand binding, because its inactive enantiomer can be used in the analysis for the reduction, removal, or, in other cases, control of nonspecific binding processed tritium active enantiomer.

The substitution of heavier isotopes such as deuterium, i.e2H, can provide some therapeutic benefits due to higher metabolic stability, for example, increasingin vivohalf-life, or red eye reduction is the desired dosage and therefore, it may be preferable under certain circumstances.

Substitution of positron-emitting isotopes, such as11C,18F,15O and13N, may be useful in studies of positron-emission tomography (PET) to study the level of employment of the receptor substrate. Isotope-labeled enantiomers of the present invention, as a rule, can be obtained by conventional methods known to experts in the field, or by methods similar to those described in this application, using an appropriate isotopically-labeled reagent instead of its reagent used previously.

The invention disclosed in this application also covers thein vivometabolic products of disclosed enantiomers. Such products may result, for example, oxidation, recovery, hydrolysis, amidation, esterification, etc., input connections, primarily due to enzymatic processes. Thus, the invention includes metabolic products formed by the process comprising contacting enantiomer of the present invention with a mammal for a time sufficient for the formation of a product of metabolism. Such products of metabolism can be defined by introducing a radioactively labeled enantiomers of the present invention found in urivaeva dose animal such as rat, mouse, Guinea pig, monkey, or to man, allowing sufficient time for the implementation of metabolism, with the release of metabolic product from the urine, blood and other biological samples.

"Selectivity" and "selective" as used in this application, is a relative measure of the tendency of compounds of the present invention to communicate mainly with the same substance as opposed to another (or group), for example, or from among the voltage-dependent gate sodium channels. For example, the selectivity can be determined by comparative measurements of the kinetics and affinity of equilibrium binding and/or functional measurements of ion transport through potential-dependent gate sodium channels. The tendency of the compound to contact potential-dependent gate sodium channel can be measured in various ways, and many types of binding known to specialists in this field, as described later in this application. Selectivity means that in a certain type of binding measured in a certain way, the connection shows a tendency or preference to bind with one potential-dependent gate sodium channel in contrast to one or more other voltage-dependent gate sodium channels. This tie is of(Association) may be different for different types of analyses or different methods of measurement.

"Stable enantiomer" and "stable structure" refer to a compound that is sufficiently robust to keep the selection to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic tool.

"Mammal" includes humans and as domestic animals such as laboratory animals and domestic animals (e.g. cats, dogs, pigs, cattle, sheep, goats, horses and rabbits), and non-domestic animals, such as wild animals and the like.

"Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, control flowability, sweetener, diluent, preservative, dye/dye amplifier taste and fragrance, surfactant, wetting agent, dispersant, suspendisse substance, stabilizer, isotonic agent, solvent, or emulsifier which has been approved as a non-limiting example, the control for food and pharmaceuticals USA, health Canada or the European Agency for the control of medicines, as acceptable for application to humans or animals.

"Pharmaceutical composition" refers to a composition that includes Obedinenie of the present invention and the environment, common in this area for the delivery of biologically active compounds mammals, for example humans. Thus, this environment includes all pharmaceutically acceptable carriers, diluents or excipients.

The pharmaceutical compositions of the present invention include one or more pharmaceutically acceptable excipients, which include, but are not limited to, any solvent, adjuvant, power bioavailability, media control flowability, sweetener, diluent, preservative, dye/dye, flavor enhancer, surfactant, wetting agent, dispersant, suspendisse substance, stabilizer, isotonic agent, buffer and/or emulsifier approved as a non-limiting example, control food and drugs U.S. The Ministry of health Canada or the European Agency for control over the trafficking of drugs as acceptable for use in humans or domestic animals. Examples of pharmaceutically acceptable fillers include, but are not limited to, the following:

benzyl alcohol

the benzyl benzoate

caprolactamate (e.g., Labrasol®)

dimethylamine ("DMA")

ethanol

2-(2-ethoxyethoxy)ethanol (e.g., Transcutol®)

glucose (solution)

complex glycerolipids/capret and PEG-8 (polyethylene glycol) kaprilat/capret (e.g., Labrasol®)

isopropyl alcohol

Lauroyl Macrogol-32 Glycerides (for example, Gelucire® 44/14)

macrogol-15 hydroxystearate (e.g., Solutol® HS15)

triglyceride medium chain length (e.g., Miglyol® 810, Miglyol® 840 or Miglyol® 812)

peanut butter

Polysorbate 80 (e.g., Tween® 80)

polyethylene glycol (PEG)

polyethylene glycol 400 (PEG400, for example, Lutrol® E 400)

polyethylene glycol 6000

polyoxyl 35 castor oil (e.g., Cremophor® EL)

polyoxyl 40 hydrogensource castor oil (e.g., Cremophor® RH 40)

propylene glycol (PG)

propilenglikolmonostearata (Capryol® 90)

soybean oil

sulphobutylether-β-cyclodextrin (for example, Capitsol®)

TPGS (α-tocopherolacetate)

water

Additional pharmaceutically acceptable excipients disclosed in this application.

Often, when crystallization is formed MES compounds of the present invention. As used in this application, the term "MES" refers to the unit that includes one or more molecules of the compound of the present invention with one or more solvent molecules. The solvent may be water, in this case, the MES may be a hydrate. Alternatively, the solvent which may be an organic solvent. Thus, the compounds of the present invention can exist as a hydrate, including the monohydrate, dihydrate, hemihydrate, Politologija, trihydrate, tetrahydrate and the like, and in the corresponding solvated forms. The compound of the present invention may be true MES, while in other cases, the connection of the present invention can only hold a concomitant water, or a mixture of water plus a number of associated solvent.

"Therapeutically effective amount" refers to that amount of the compound of the present invention that, when administered to a mammal, preferably a human, is sufficient to effect the treatment, as defined below, of interest disease or condition in a mammal, preferably human. The number of compounds according to the present invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the route of administration and age of the mammal being treated, but it can determine the routine by a person skilled in the art on the basis of their own knowledge and to this disclosure.

"Treat" or "treatment" as that term is used in this request is e, refers to the treatment of interest disease or condition in a mammal, preferably a human, having a disease or condition of interest, and includes:

(i) preventing a disease or condition in a mammal, in particular, when such mammal is predisposed to the condition but it is not diagnosed in him;

(ii) inhibiting the disease or condition that is stopping its development;

(iii) facilitation of the disease or condition, i.e. causing regression of the disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition, i.e., the lessening of pain, impact or not on the underlying disease or condition.

As used in this application, the terms "the improvement", "superior", "relief" or "light" should be considered as having their commonly accepted definitions. For example, "improve" mainly means to make better or to correct the condition regarding the state that preceded the adoption of measures for its improvement. "To facilitate" mainly means to make the condition easier portable relative to the state that preceded the adoption of measures for its relief. As used in this application, "improved" or "improved" may about what to wear to the disease or condition, which was better or normalized with the introduction of the compounds of the present invention. As used in this application, a "relief" or "Lite" may refer to a disease or condition, which has become portable with the introduction of the compounds of the present invention. For example, "relief" pain involves reducing the severity or amount of pain.

As used in this application, the terms "disease", "disorder" and "condition" may be used interchangeably or may differ from each other by the fact that the disease or condition may not have known pathogen (so that etiology has not yet determined), and therefore not yet recognized as a disease but only as an undesirable condition or syndrome, where the doctor found more or less specific set of symptoms.

APPLICATION AND testing of the COMPOUNDS of the PRESENT INVENTION

The present invention relates to (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-she, to pharmaceutical compositions and methods of use (S)-enantiomer of the present invention and pharmaceutical compositions for treatment of diseases or conditions, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate is sodium channels, preferably the diseases and conditions related to pain and itch; the conditions of the Central nervous system such as epilepsy, restless legs syndrome, anxiety, depression and bipolar disease; cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as paralysis of the muscles, myotonia or tetanus; neuroprotection against stroke, neural trauma and multiple sclerosis; and kanaapali, such as erythromelalgia and the syndrome of hereditary rectal pain, by introducing a patient in need of such treatment, an effective amount of the antagonist, modulating, in particular, inhibitory potential-dependent gate sodium channel, preferably enantiomers of the present invention.

In General, the present invention provides a method of treating a mammal, preferably human, or protecting a mammal, preferably human, from the development of the disease or condition that is associated with the activity of voltage-dependent gate sodium channels, especially pain, where the method comprises the administration to a mammal a therapeutically effective amount of (S)-enantiomer or its pharmaceutically acceptable MES or prodrug, as described above in the section “Brief description of the invention, where (S)-enantiomer which modulates, preferably inhibits, the activity of one or more voltage-dependent gate sodium channels.

A family of proteins voltage-dependent gate sodium channels has been carefully investigated, and it was shown that they are involved in a number of vital body functions. Research in this area revealed variants of alpha-subunits, which lead to significant changes in the function and activity of channels that can ultimately lead to serious pathophysiological States. In addition, excessive influx of sodium may occur indirectly via stimulating agents or factors that lead to increased excitability. As related to function, this family of proteins is considered to be the main points for therapeutic intervention. Protein voltage-dependent gate sodium channels NaV1.1 and NaV1.2 in large quantities expressed in the brain (Raymond, C. K., et al., J. Biol. Chem. (2004), 279(44):46234-41) and are vital for normal brain function.

In humans, mutations in NaV1.1 and NaV1.2 lead to epileptic States and, in some cases, decrease in mental abilities and migraines (Rhodes, T. H., et al., Proc. Natl. Acad. Sci. USA(2004), 101 (30): 11147-52; Kamiya, K., et al., J. Biol. Chem. (2004), 24(11):2690-8; Pereira, S., et al., Neurology(2004), 63(1):191-2; Meisler, M. H. et al., J. Physiol. (Lond.) (in press). In this regard,both channels are confirmed targets for the treatment of epilepsy (see patent PCT publication no WO 01/38564).

NaV1.3 is expressed predominantly in the Central nervous system of newborn animals and at low levels in the adult body (Raymond, C. K., et al., op. cit). It was demonstrated that its expression is activated in sensory neurons of the dorsal horn of rats after damage to the nervous system (Hains, B. D., et al., J. Neurosci. (2003), 23(26): 8881-92). Many experts in this field believe NaV1.3 a suitable therapeutic target for the treatment of pain, since its expression is induced by nerve damage (Lai, J., et al., Curr. Opin. Neurobiol. (2003), (3):291 -72003; Wood, J. N., et al., J. Neurobiol. (2004), 61(1):55-71; Chung, J. M., 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).

Expression Of Nav1.4, essentially limited to the muscles (Raymond, C. K., et al., op. cit). Mutations in this gene have been shown to have a strong effect on muscle function, including paralysis (Tamaoka A., Intern. Med. (2003), (9):769-70). Thus, this channel is a target for treatment of periodic paralysis, myotonia, abnormal contractility of muscle spasm or paralysis.

Cardiac potential-dependent gate sodium channel NaV1.5 is expressed predominantly in cardiac myocytes (Raymond, C. K., et al., op. cit), and can be detected in the Atria, the ventricles, the sinus-atrial node, the atrioventricular node and the Purkinje cells. Quick jump up potential is La heart action and rapid impulse conduction through the cardiac tissue occurs as a result of the opening of Na V1.5. Thus, NaV1.5 involved in cardiac arrhythmia. Mutations in the human NaV1.5 lead to multiple arrhythmic syndromes, including, for example, long QT3 (LQT3), Brugada syndrome (BS), a hereditary defect in cardiac conduction, the syndrome of sudden unexpected death during sleep (SUNDS) syndrome and sudden infant death (SIDS) (Liu, H. et al., Am. J. Pharmacogenomics(2003), 3(3): 173-9; Ruan, Y et al., Nat. Rev. Cardiol. (2009) 6: 337-48). Therapy with the use of blockers of voltage-dependent gate sodium channels are widely used for the treatment of cardiac arrhythmias. The first drug against arrhythmia, quinidine, opened in 1914, is regarded as a blocker of sodium channels.

NaV1.6 codes present in abundance, widespread potential-dependent gate sodium channel, common in the Central and peripheral nervous systems, the accumulation of which is found in the nodes of Ranvier of nerve axons (Caldwell, J. H., et al., Proc. Natl. Acad. Sci USA(2000), 97(10): 5616-20). Mutations with loss of function in mice leads to ataxia and seizures (Papale, L. A. et al., Human Mol. Genetics (2009) 18, 1633-1641). Although no mutations in humans was not detected, it is believed that NaV1.6 plays a role in the manifestation of symptoms associated with multiple sclerosis, and it is considered a target for treatment of this disease (Craner, M. J., et al., Proc. Natl. Acad. Sci USA(2004), 101(21):8168-73).

NaV1.7 is expressed predominantly in the peripheral nervous system both touch and sinteticheskih neurons (Raymond, C. K., et al., op. cit). Mutations with loss of function in humans cause congenital indifference to pain (CIP) without disturbance of cognitive or motor function (Cox, J. J. et al., Nature(2006) 444 (7121), 894-8; Goldberg, YP. et al., Clin. Genet. (2007) 71 (4), 311-9). Subjects with CIP does not have inflammatory or neuropathic pain, and this suggests that selective blocking of NaV1.7 can eliminate various forms of chronic and acute pain, with no adverse effect on the Central or peripheral nervous system or muscles. In addition, polymorphism, single nucleotide (R1150W), which has subtle effects on time - and potential-dependence of the gate mechanism of NaV1.7, has strong effects on the perception of pain (Reimann, F. et al., Proc. Natl. Acad. Sci USA( 2010), 107 (11), 5148-53). About 10% of patients with different pain States are heterozygous for the allele, indicating greater sensitivity to pain. The participation of NaV1.7 in mediating pain responses also confirmed mutations purchasing functions, which lead to erythromelalgia or paroxysmal extreme pain disorder (Dib-Hajj, S. D. et al., Adv. Genet. (2009) 63: 85-110). Although NaV1.7 is expressed predominantly in peripheral not the main system, point mutation in NaV1.7 causes seizures with high fever, indicating the role of this channel in the CNS. Thus, blockers of voltage-dependent gate sodium channels can be useful as anticonvulsants.

Expression of NaV1.8 occurs predominantly in the dorsal radicular ganglia (DRG) (Raymond, C. K., et al., op. cit). Jump up the action potential in sensory neurons of the DRG mainly occurs due to the current through NaV1.8, thus, blocking this current must block pain responses (Blair, NT and Bean BP, J. Neurosci. 22: 10277-90). In accordance with this discovery, "knock-down" NaV1.8 in rats is achieved using antisense DNA or small interfering RNA, and the almost complete inversion of neuropathic pain was achieved in models of ligation of spinal nerve and chronic constrictional defeat. Selective blocker of NaV1.8 has been described in the literature, and it is effective in blocking both neuropathic and inflammatory pain (Jarvis, M. F. et al., Proc. Natl. Acad. Sci USA(2007), 704 (20), 8520-5). Published patent application PCT No. WO03/037274A2 describes pyrazole-amides and sulfonamides for the treatment of conditions of the Central or peripheral nervous system, in particular, pain and chronic pain by blocking sodium channels associated with the beginning of the development or recurrence of these conditions. Published patent application PCT No. WO03/037890A2 describes piperidine for the treatment of conditions of the Central or peripheral nervous system, in particular, pain and chronic pain by blocking sodium channels associated with the development or recurrence of these conditions. Compounds, compositions and methods in accordance with this invention are particularly useful for treating neuropathic or inflammatory pain through inhibition of ion flux through a channel that includes PN3 (NaV1.8) subunit.

It was shown that the potential-dependent gate sodium channel Nav1.9 the peripheral nervous system, unveiled Dib-Hajj, S. D., et al. (see Dib-Hajj, S. D., et al., Proc. Natl. Acad. Sci USA(1998), 95(15):8963-8), is expressed in the dorsal radicular ganglia. It was shown that NaV1.9 underlies neurotrophin (BDNF)-induced depolarization and excitation. Limited pattern of expression of this channel have made it a candidate as a target for treatment of pain (Lai J, et al., op. cit; Wood, J. N., et al., op. cit.; Chung, J. M. et al., op. cit).

NaX is a prospective sodium channel, which has not been confirmed as being potential-dependent. In addition to expression in lung, heart, dorsal radicular nerve cells and Swanna peripheral nervous system, NaX detected in neurons and ependymal cells in limited areas the parts of the CNS, in particular, in oculovestibular bodies, which are involved in the homeostasis of body fluids (Watanabe, E., et al., J. Neurosci. (2000), 20(20):7743-51). Mice with deficiency of NaX showed anomalous absorption of hypertonic saline in the States of water and solitudine. These findings suggest that NaX plays an important role in the Central sense of the level of sodium in the body fluids and the regulation of behavior in the consumption of salt. Picture of its expression and function suggests that he might be a target for the treatment of cystic fibrosis and other related regulation salts diseases.

Studies using blocker of voltage-dependent gate sodium channels tetrodotoxin (TTX) to reduce neural activity in certain areas of the brain indicates its potential application in the treatment of addiction. Combined with drug stimuli cause an irresistible desire for the drug and relapse behavior associated with addiction and search the drug in rats. The functional integrity basolateral amygdala (BLA) is required for recovery of cocaine-seeking behavior induced by cocaine-related stimuli, but not cocaine itself. BLA plays a similar role in the recovery of heroin-seeking behavior. TTX-induced inactivation of BLA on conditioned and heroin-primed reinstatement of extinguished heroin-seeking behaviorin a rat model (Fuchs, R. A. and See, R. E., Psychopharmacology(2002) 160(4):425-33).

Subgroup C fiber mediates responses to causing itching agents, especially for itching caused by histamine, activators of PAR-2 receptors, cholestasis and viral infections (Steinhoff, M. et al., J. Neurosci. 23:6176-80; frameworks of Twycross, R. et al., Q. J. Med. 96: 7-26). Potential-dependent gate sodium channels expressed in and mediate C-fiber nerve impulses.

Overall assessment (S)-enantiomer of the present invention, modulation, especially inhibition, ion flow in a voltage-dependent gate sodium channels can be determined using the assays described below in the section “Biological assays”. Alternatively, a General evaluation of (S)-enantiomer of the present invention in the treatment of conditions and diseases can be defined in used industrial standard animal models for demonstrating the efficacy of compounds in treating pain. Were developed animal models of neuropathic pain States in humans that lead to reproducible sensory deficits (allodynia, hyperalgesia, and spontaneous pain) over an extended period of time, which can be evaluated by sensory testing. By establishing the extent present mechanically, chemically and thermally-induced allodynia and hyperalgesia can be modeled some psychopathologies the state, observed in humans, allowing to assess pharmacotherapy.

In rat models of peripheral nerve injury ectopic activity in the damaged nerve correlates with behavioral signs of pain. In these models, intravenous use (S)-enantiomer of the present invention and the local anesthetic lidocaine can suppress ectopic activity and backward development of the tactile allodynia at concentrations that do not affect the overall behavior and motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17). Allometrically define the scope of the doses effective in these rat models, translated in doses similar to those that have been identified as effective for the individual (Tanelian, D. L. and Brose, W. G., Anesthesiology(1991), 74(5):949-951). In addition, Lidoderm®, lidocaine used in the form of a skin patch, is an FDA approved treatment of post herpetic neuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain(2000), 16(3):205-8).

Blockers of voltage-dependent gate sodium channels have clinical application in addition to the pain. Epilepsy and cardiac arrhythmias are often targets for blockers of sodium channels. Recently received confirmation from animal models suggests that blockers of voltage-dependent gate sodium channels can also be useful for neuroprotection in ischemic conditions, the calling is the R stroke or neurological injury in patients with multiple sclerosis (MS) (Clare, JJ. et al., op. cit. and Anger, T. et al., op. cit.).

(S)-enantiomer of the present invention modulates, preferably inhibits, the ion flux through the potential-dependent gate sodium channel in a mammal, in particular humans. Any such modulation, which can be a partial or complete inhibition or prevention of ion flow, sometimes indicated in this application as "blocking", and the corresponding connection as "blockers" or "inhibitors". Typically, the compound of the present invention modulates the activity of the potential-dependent gate sodium channel downward, inhibits dependent voltage activity potential-dependent gate of the sodium channel and/or reduces or prevents the flow of sodium ions through the cell membrane by preventing the activity of the potential-dependent gate of the sodium channel, such as ion stream.

(S)-enantiomer of the present invention is a blocker of sodium channels and is therefore useful for the treatment of diseases and conditions in mammals, preferably in humans, and other organisms, including all those human diseases and conditions that are the result of aberrant biological activity of voltage-dependent gate sodium channels or which can be used to treat the or be facilitated by modulation, preferably inhibiting, the biological activity of voltage-dependent gate sodium channels.

As defined in this application, the disease or condition, the intensity of which can be reduced or which can be alleviated by the modulation, preferably inhibition, potential-dependent gate sodium channel, refers to the disease or condition, the intensity of which decreases or which is easier when the modulation, preferably inhibition, potential-dependent gate of the sodium channel, and includes, but is not limited to, pain, and itching; state of the Central nervous system such as epilepsy, anxiety, depression (Morinville et al., J. Comp. Neurol., 504:680-689 (2007)) and bipolar disorder (Ettinger and Argoff, of neurotherapeutics, 4:75-83 (2007)); cardiovascular conditions such as arrhythmias, atrial fibrillation and ventricular fibrillation; neuromuscular conditions such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neural trauma and multiple sclerosis; and kalapati, such as erythromelalgia and hereditary rectal pain syndrome.

Additional diseases and conditions include pain associated with HIV-induced treatment of HIV neuropathy, trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy WTO the ranks to metastatic infiltration, morbid obesity, thalamic damage, hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate, 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 impairment, Korsakov's syndrome, restenosis disorder urination, incontinence, Parkinson's disease (Do and Bean, Neuron 39:109-120 (2003); Puopolo et al., J. Neurosci. 27:645-656 (2007)), cardiovascular ischemia, neurosis, gastrointestinal disease, sickle cell anemia, sickle cell disease, graft rejection, cardiac failure, myocardial infarction, reperfusion lesion, alternating lameness, angina, seizures, respiratory disorders, ischemic brain disease or infarction, syndrome, long-QT catecholaminergic polymorphic ventricular tachycardia, eye diseases, muscle spasticity, the spastic paraplegia, myopathy, malignant gravis, paramythia congentia, gipercalziemiceski periodic paralysis, gipokaliemichesky periodic paralysis, alopecia, anxiety disorder, psychotic disorders, manic syndrome, paranoia, seasonal affective disorder, panic disorder, obsessive-compulsive disorder (OCD), phobias, autism, syndrome Aspergers, Ingram of RETA, disintegrative disorder, attention deficit disorder, aggression, disorders of impulse control, thrombosis, preeclampsia, congestive heart failure, cardiac arrest, Friedrich's ataxia, spinal and cerebellar ataxia, tremor, muscle weakness, myelopathy, radiculopathy, systemic lupus erythematosus, granulomatoses disease, Olivo-Ponto-cerebellar atrophy, spinal and cerebellar ataxia, episodic ataxia, myokymia, progressive palledorous atrophy, progressive supranuclear paralysis and muscle spasticity, traumatic brain damage, brain edema, hydrocephalus, spinal injuries, nervous anorexia, bulimia, the Prader-Willi syndrome, obesity, optic neuritis, cataracts, retinal hemorrhage, ischemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, occlusion of the retinal artery, horey, Huntington's disease, horey's disease, brain edema, proctitis, post herpetic neuralgia, Evgeniy, sensitivity to heat, sarcoidosis, irritable bowel syndrome, syndrome Tourette, Lesch-Nyhan syndrome, the syndrome Brugada syndrome Liddle, Crohn's disease, multiple sclerosis and pain associated with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), dissemi the new sclerosis, diabetic neuropathy, peripheral neuropathy, syndrome Charcot-Marie-Toot, arthritis, rheumatoid arthritis, osteoarthritis, chondrocalcinosis, paroxysmal dystonia, myasthenic syndromes, myotonia, myotonias dystrophy, muscular dystrophy, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, acute necrosis of skeletal muscles, mental handicap, bipolar depression, anxiety, schizophrenia, a disease associated with the toxin sodium channel family erythromelalgia, primary erythromelalgia, rectal pain, cancer, epilepsy, partial and General tonic seizures, convulsions, high fever, small epileptic seizures (petit mal), myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut, West Syndome (baby cramps, weakness syndrome sinus node (Haufe V, Chamberland C, Dumaine R, J. Mol. Cell Cardiol. 42(3):469-477 (2007)), multidrug-resistant seizures, prevention of convulsions (antiepileptic), family syndrome Mediterranean fever, gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection in ischaemic conditions caused by stroke or neurological injury, tachyarrhythmia, atrial fibrillation and ventricular fibrillation, and as a General or local anesthetic.

As used in this application, the term "pain" refers to all categories of pain, independent which from its nature or origin, and this term includes, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain, Orofacial pain, burn pain, chronic bone pain, back pain, neck pain, abdominal pain, syndrome burning mouth, somatic pain, visceral pain (including abdominal), myofascial pain, dental pain, cancer pain, pain caused by chemotherapy, myofascial pain syndrome, complex regional pain syndrome (CRPS), temporomandibular joint pain, traumatic pain, paroxysmal extreme pain disorder surgical pain, post-surgical pain, pain in childbirth, reflex simpaticheskuyu dystrophy, pain due to the rupture of the brachial plexus, neurogenic bladder, acute pain, musculoskeletal pain, postoperative pain, chronic pain, persistent pain, perifericheskie - mediated pain, centrally mediated pain, chronic headache, headache with pressure, cluster headache, migrainebuy headache, hereditary hemiplegic migraine, conditions associated with headache, sinus headache, headache with pressure, phantom pain in amputated limbs, injured peripheral nerve pain after a stroke, calamites the e damage the syndrome caused by HIV pain, post-herpetic pain, non-cardiac pain in the chest, irritable bowel syndrome and pain associated with intestinal disorders and dyspepsia, and combinations thereof.

The present invention also relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment or prevention of diseases or conditions such as benign prostatic hyperplasia (BPH), hypercholesterolemia, cancer, and itching (itch).

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 that is characterized nodosum increase in prostate gland tissue, leading to obstruction of the urethra. The consequences of BPH may include hypertrophy of the smooth muscle of the bladder, the bladder decompensation, acute urinary retention and the likelihood of urinary tract infections.

BPH is of great importance for health and is one of the most common reasons for surgical intervention among older men. Attempts were made to clarify the etiology and pathogenesis and, in achiev is Tate, were developed experimental models. Spontaneous animal models are limited to chimpanzees and dogs. BPH in men and dogs have common characteristics. In both species the development of BPH occurs spontaneously with achievement of the elderly, and it can be prevented by early/prepubertal castration. Medical alternative to surgery is highly desirable for the treatment of BHP and consequences.

Epithelial hyperplasia of the prostate of a man, and the dog is androgen-sensitive undergoing involution with androgen deprivation and renewal of epithelial hyperplasia with the substitution of androgen. Cells derived from prostate cancer have been shown to Express high levels of voltage-dependent sodium channels, studies using immune labels gave clear evidence for the presence of voltage-dependent sodium channels in tissues of the prostate (Prostate Cancer Prostatic Dis. 2005; 8(3):266-73). Inhibition of the function of voltage-dependent gate sodium channels by tetrodotoxin, which is a selective blocker, inhibits the migration of cells derived from prostate cancer and breast cancer (Brackenbury, W. J. and Djamgoz, M. B. A., J. Physiol. (Lond) (2006) 573: 343-56; Chioni, A-M. et al., Int. J. Biochem. Cell Biol. (2009) 41: 1216-1227).

Hypercholestero the Accademia, that is, the level of cholesterol in the blood, is an established risk factor in the development of, for example, atherosclerosis, coronary artery disease, hyperlipidemia, stroke, hyperinsulinemia, hypertension, obesity, diabetes, cardiovascular disease (CVD), coronary heart disease, heart failure and heart attack. Thus, reduced levels of total serum cholesterol in subjects with high cholesterol levels is known as reducing the risk of these diseases. The cholesterol-lowering low-density lipoprotein, in particular, is an essential step in preventing CVD. Although there are various methods of therapeutic treatment of hypercholesterolemia, in this area there is still a need for alternative therapies and continued their search.

The invention provides compounds that are useful as anti-hypercholesterolemia and related conditions. Compounds of the present invention can operate in various ways. Not wanting to tie it to any particular mechanism of action, the connection may be direct or indirect inhibitors of the enzyme acyl CoA: cholesterylester (ACAT), which leads to inhibition of esterification and transport of cholesterol through the intestinal wall. Another possibility which may be the compounds of the present invention can be direct or indirect inhibitors of the biosynthesis of cholesterol in the liver. It is possible that some compounds of the present invention can act both direct and indirect inhibitors of ACAT and the biosynthesis of cholesterol.

Itching, commonly known as scabies, is a widespread dermatological condition. There are two broad categories of scabies, based on etiology: inflammatory skin itch and neuropathic itch (Binder et al., Nature Clinical Practice, 4:329-337, 2008). In the first case of inflammatory mediators activate skin receptors itching, representing a subset of cutaneous afferent nerve fibers, mainly demyelinizing C fibers. Treatment of this type of scabies is either blocking the receptors for inflammatory agents (such as antihistamines), or blocking the resultant electrical activity. Potential-dependent gate sodium channels play a Central role in the transmission of electrical activity in neurons and modulation of voltage-dependent gate sodium channels is a common means to modulate this signaling activity. While the causes of neuropathic itch are complex and less studied, there is accepted evidence is Central sensitization and hypersensitivity input from sensory neurons C fibers in the skin. With regard to inflammatory scabies, sodium channels apparently are essential for the propagation of electrical signals from the skin to the Central nervous system. The transmission of impulses itching leads to unpleasant sensation that causes the desire or reflex to scratch.

As inflammatory and neuropathic itch can be blocked by means of known blockers of the voltage-dependent gate sodium channels, of which the most widely used is 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). Dose of lidocaine needed to relieve itching, comparable to the doses that are effective for the treatment of pain. Both sensory schemes are common mediators and related neural pathways (Ikoma et al., Nature Reviews Neuroscience, 7:535-547, 2006). However, other pain treatment is not effective against itching and can increase itching and not to facilitate it. For example, opioids, in particular, are effective for relief of pain, but can cause severe itching. Thus, blocking the voltage-dependent gate sodium channels represents a particularly promising therapy for the treatment of pain and itching.

Compounds of the present invention, as has been shown to have analgesic effects in various animal models of the ri oral doses ranging from 1 mg/kg to 100 mg/kg Compounds of the present invention may also be useful for the treatment of itching.

Types of itching or skin irritation include, but are not limited to:

a) psoriatic itching, itching due to hemodialysis, aquagenic itching and itching caused by skin disorders (e.g. contact dermatitis), systemic disorders, neuropathy, spokojnymi factors, or a combination thereof;

b) itching caused by allergic reactions, insect bites, hypersensitivity (e.g., dry skin, acne, eczema, psoriasis), inflammatory conditions, or trauma;

c) itching associated with vulvar vestibulitis;

d) skin irritation or inflammatory effect of another therapeutic agent, such as, for example, antibiotics, antiviral agents, and antihistamines; and

e) itching due to activation associated with PAR-2 and G-protein receptors.

(S)-enantiomer of the present invention modulates, preferably inhibits, the ion flux through the potential-dependent sodium channel. Preferably, (S)-enantiomer according to the present invention is dependent on a condition or frequency modifier of voltage-dependent gate sodium channels having a low affinity for dormant/closed state and a high affinity to inaktivirovannaja state. Not wanting coupling is the substance of it to any particular mechanism of action, (S)-enantiomer of the present invention is likely interact with overlapping sites located in the internal cavity of the sodium-conducting pore of the channel, just as described for the other dependent status blockers of sodium channels (Cestele, S., et al., op. cit). (S)-enantiomer of the present invention also likely interacts with sites outside of the internal cavity and has an allosteric effect on the conductivity of sodium ions through the pore of the channel.

In a preferred variant embodiment of the present invention, (S)-enantiomer of the present invention modulates, preferably inhibits, the activity of Nav1.7. In another preferred variant of embodiment of the present invention, (S)-enantiomer of the present invention selectively modulates, preferably inhibits, the activity of Nav1.7 in comparison with the modulation or inhibition of other voltage-dependent gate sodium channels (i.e Nav1.1-Nav1.6 and Nav1.8-Nav1.9). Because most of the other sodium channels involved in other important physiological processes, such as rate and rhythm of heart contractions (Nav1.5), the reduction in skeletal muscle (Nav1.4) and the conduction of electrical activity in the CNS and motor neurons (Nav1.1, Nav1.2 and Nav1.6), preferably (S)-enantiomer of the present invention has avoided significant modulation of the above other sodium channels.

Any of these consequences, ultimately, may be responsible for the overall therapeutic benefit provided (S)-enantiomer of the present invention.

Usually, a successful therapeutic agent of the present invention must meet some or all of the following criteria. Oral availability must be at or above 20%. Efficacy in animal models must be from less than about 0.1 μg to about 100 mg/kg of body weight, and target dose for humans must remain in the range from 0.1 μg to about 100 mg/kg of body weight, although a dose outside this range may be acceptable ("mg/kg" means milligrams of compound per kilogram of body weight of the subject, which is administered dose). therapeutic index (or ratio of toxic dose to therapeutic dose) must be greater than 100. Activity (expressed as the value IR50) must be less than 10 μm, preferably below 1 μm, and most preferably below 50 nm. Value IR50("Inhibitory Concentration 50%) is a measure of the number (S)-enantiomer of the present invention required to achieve 50% inhibition of ion flux through sodium channel during a certain period of time in the analysis of the present invention.

Another aspect of the present invention relates to ingibirovannojj Na v1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.8, or Nav1.9 in a biological sample or in the body of a mammal, preferably a human, the method comprises administration to a mammal or contacting these biological sample, (S)-enantiomer of the present invention or compositions comprising (S)-enantiomer of the present invention. The term "biological sample", as used in this application includes, without limitation, cell cultures or extracts; taken from a mammal by biopsy substance or its extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

In addition to the above applications of (S)-enantiomer of the present invention, the connection may also be useful for modulating, preferably inhibiting, the activity of the potential-dependent gate sodium channel in a biological sample for a variety of purposes that are known to specialists in this field. Examples of such purposes include, but are not limited to, research on voltage-dependent sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new or other modulators of voltage-dependent sodium ion channels.

(S)-enantiomer for this is the overarching invention can also be used for treating non-human mammals (i.e. in the veterinary treatment) of diseases or conditions, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate sodium channels, in particular, for the treatment of inflammation and pain. It is believed that such treatment is of particular interest for Pets, such as dogs and cats.

The PHARMACEUTICAL COMPOSITIONS of the PRESENT INVENTION AND INTRODUCTION

The present invention also relates to pharmaceutical compositions containing (S)-enantiomer of the present invention. In one variant embodiment of the present invention relates to compositions comprising (S)-enantiomer of the present invention in a pharmaceutically acceptable carrier and in an amount effective for modulating, preferably inhibiting, the ion flow through potential-dependent gate sodium channels for the treatment of diseases such as pain, when administered to a patient animal, preferably a mammal, most preferably a human.

Introduction (S)-enantiomer of the present invention, in pure form or in an appropriate pharmaceutical composition, can be accomplished in any acceptable way of introducing funds for such purposes. The pharmaceutical compositions of the present invention can be obtained by combining the compounds of the present invention with a suitable pharmaceutical is Ki acceptable carrier, the diluent or excipient, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injectable preparations, preparations for inhalation, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, without limitation, oral, local, percutaneous, through inhalation, parenteral, sublingually, rectal, vaginal, and intranasal. The term “parenteral” as used in this application, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion. The pharmaceutical compositions according to the present invention is formulated so that the active ingredients contained in them, were bioavailable when introducing the composition to the patient. Compositions intended for administration to a subject or patient, preferably a mammal, more preferably human, take the form of one or more dosage units, for example, a tablet may be a single unit dosing, and the container comprising a compound of the present invention in aerosol form may contain a variety of dosage units. Practical methods for such dosage forms are known, or will be about eveny specialists in this field; for example, see The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science, 2000). The composition is intended for administration in any case must contain a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salts for the treatment of a disease or condition of interest, in accordance with the methods of the present invention.

Pharmaceutical compositions useful in the present invention, also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any use of pharmaceutical substance, which itself does not cause the production of antibodies harmful to the subject receiving the composition, and which can be entered without unwanted toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol and the like. A detailed discussion of pharmaceutically acceptable carriers, diluents and other excipients are presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N. J., current edition).

The pharmaceutical composition of the present invention may be in the form of solids or liquids. In one aspect, the carrier(s) is in the form of particles, thus, the compositions take the form, for example, tablets is whether powder. The carrier(s) may be liquid, while the compositions are, for example, oral syrup, liquid for injection or aerosol, which is useful, for example, for administration by inhalation.

When it is intended for oral administration, the pharmaceutical composition preferably is either in solid or in liquid form, while semi-solid, semi-liquid form, suspensions and gels included in the forms considered in this invention as a solid or a liquid.

As solid compositions for oral administration, the pharmaceutical composition may be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers or similar forms. Such a solid composition typically contains one or more inert diluents or food carriers. In addition, you may attend one or more of the following ingredients: a binder such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragakant or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; regulators flowability, such as colloidal dioxide cream is s; sweeteners such as sucrose or saccharin; flavoring, such as peppermint, methyl salicylate or orange flavoring; and dye.

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

The pharmaceutical composition may be in the form of a liquid, for example, elixir, syrup, solution, emulsion or suspension. The fluid may be intended for oral administration or for delivery by injection, as two examples. In the case of oral administration, preferred compositions contain, in addition to (S)-enantiomer of the present invention, one or more substances selected from a sweetener, preservatives, dye/coloring substance and flavor enhancer. In a composition intended for administration by injection may be included one or more substances such as a surfactant, a preservative, a moisturizer, a dispersing agent, suspendisse agent, buffer, stabilizer and an isotonic agent.

Liquid pharmaceutical compositions of the present invention, whether they are in the form of solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile is thinner, such as water for injection, saline solution, preferably physiological solution, ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as a solvent or medium for suspension, polyethylene glycols, glycerine, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; hepatoblastoma agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for regulating toychest, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or mnogorazovye vials made of glass or plastic. Saline is the preferred adjuvant. Pharmaceutical composition for injection is preferably sterile.

Liquid pharmaceutical composition of the present invention, intended for parenteral or oral administration should contain such number (S)-enantiomer of the present invention, which will provide the appropriate dose. Typically, this amount is at least 0.01% of (S)-enantiomer by nastasemarian in the composition. When the composition is intended for oral administration, this number can vary in the range from 0.1 to about 70% by weight of the composition. Preferred oral pharmaceutical compositions contain from about 4% to about 50% (S)-enantiomer of the present invention. Preferred pharmaceutical compositions and preparations in accordance with the present invention receive so that parenteral unit dosage contains from 0.01 to 10 wt%. (S)-enantiomer of the present invention to dilution.

The pharmaceutical composition of the present invention may be intended for topical administration, in this case, the carrier may suitably include a solution, an emulsion, a basis for ointments or gel. The basis of, for example, may include one or more of the following ingredients: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. The thickener may be present in pharmaceutical compositions for local administration. If the composition is intended for percutaneous introduction, it may include percutaneous patch or device for iontophoresis. Compositions for local injection can contain (S)-enantiomer of the present invention in a concentration of from about 0.1 to about 10% of the mass/R (weight on what dinicu volume).

For topical application, preferably the introduction of an effective amount of the pharmaceutical composition in accordance with the invention at the target site, e.g., skin, mucous membranes, etc., that are in close proximity to the peripheral neurons subject to treatment. This number typically ranges from about of 0.0001 mg to about 1 g (S)-enantiomer of the present invention per application, depending on the area being treated, regardless of whether the application of diagnostic, prophylactic or therapeutic, the severity of symptoms and the nature of the used local media. Preferred local preparation is an ointment, where to use from about 0.001 to about 50 mg of the active ingredient in cm3the basis for ointments. The pharmaceutical composition may be formulated as transdermal compositions or devices for percutaneous delivery ("patches"). Such compositions include, for example, a substrate, a reservoir with an active connection, the controlling diaphragm, gasket and contact adhesive. Such transdermal patches may be used to provide continuous pulsating delivery or delivery on demand of the compounds of the present invention, as is desirable.

The pharmaceutical composition is really the invention can be intended for rectal administration, for example, in the form of a suppository, which melts in the rectum and release the drug. Composition for rectal injection may contain oil-based as a suitable non-irritating to excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

A typical composition for intramuscular or intrathecal injection consists of a suspension or solution of the active substance in the oil or solution of the active ingredient in the oil, such as peanut oil or sesame oil. A typical composition for intravenous or intrathecal injection is a sterile isotonic aqueous solution containing, for example, the active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride.

The compositions of the present invention can be formulated in such a way as to ensure rapid, prolonged or delayed release of the active ingredient, i.e., (S)-enantiomer of the present invention, after administration to the patient, using procedures known from the prior art. Delivery system with controlled release of drugs include osmotic pump and dissolving system containing tanks with a polymer coating or a pharmaceutical composition cf the rotary-polymer matrix. Examples of controlled release systems are presented in U.S. Patent No. 3845770 and 4326525, and P. J. Kuzma et al., Regional Anesthesia 22 (6): 543-551 (1997), which are all included in the present application by reference.

The compositions of the present invention can also be delivered via intranasal delivery system medicinal products for local, systemic treatment and delivery through the nose to the brain. Method of controlled dispersion of particles (CPD)™, traditional bottles of nasal spray, inhalers or nebulizers known to specialists in this area as providing effective local and systemic delivery of drugs by targeting the olfactory region and paranasal sinuses.

The invention also relates to intravaginal device for the delivery of the drug in the form of a shell or kernel, suitable for administration to a human or animal female. Such a device may consist of active pharmaceutical ingredient in a polymer matrix, surrounded by a shell, and is capable of releasing (S)-enantiomer of the present invention, essentially, in the zero order every day, like the devices used to apply testosterone, as described in published patent PCT application no WO 98/50016.

Existing methods for ocular delivery include drugs is s for local injection (eye drops), subconjunctival injection, periocular injection, intravitreal injections, surgical implants and drugs for iontophoresis (using a weak electric current for the transport of ionized drugs into and through the tissues of the body). Specialists in this field will be able to combine the most suitable excipients with (S)-enantiomer of the present invention for safe and effective intraocular injection.

The most suitable route of administration will depend on the nature and severity of the condition to be treated. The experts also know how to determine the route of administration (e.g., orally, intravenously, by inhalation, subcutaneous, rectal, etc.,), dosage form, suitable pharmaceutical excipients and other substances, are suitable for delivery (S)-enantiomer of the present invention to a subject in need of it.

The pharmaceutical composition of the present invention may include various substances, which modify the physical form of a solid or liquid unit dosage. For example, the composition may include substances which form the coating or shell around the active ingredients. Substances which form the coating or shell, are typically inert and can be selected from, for example, sugar, Shallaki other intersolubility substances to cover. Alternatively, the active ingredients can be enclosed in a gelatin capsule.

The pharmaceutical composition of the present invention in solid or liquid form may include a substance that is associated with (S)-enantiomer of the present invention and, thus, contributes to the delivery connection. Suitable substances which can act in this way include monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may consist of dosage units that can be entered in the form of an aerosol. The term “aerosol” is used to refer to different systems from those that are colloidal in nature, to systems containing pressurized packaging. Delivery can be done by using liquefied or compressed gas or by using a suitable system pump that dispenses the active ingredients. Aerosols (S)-enantiomer of the present invention can be delivered in single phase, bi-phase or three-phase systems designed for delivery of the active ingredient(ingredient). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, etc. which can be set. The person skilled in the art, without undue experimentation, can determine the preferred aerosols.

The pharmaceutical compositions of the present invention can be obtained by methods well known in the pharmaceutical field. For example, a pharmaceutical composition intended for administration by injection, can be obtained by combination of (S)-enantiomer of the present invention with sterile distilled water so as to obtain a solution. You can add a surfactant to facilitate the formation of homogeneous solution or suspension. Surfactants are compounds that ecovalence interact with (S)-enantiomer of the present invention in such a way as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.

(S)-enantiomer of the present invention should be entered in therapeutically effective amount, which varies depending on various factors, including the activity of the specific compound; the metabolic stability and length of action (S)-enantiomer of the present invention; the age, body weight, General health, sex and diet of the patient; the method and time of administration; rate of excretion; the combination of medicines; the severity of a particular disorder or condition; and the subject of taking Leche is tion. Typically, a therapeutically effective daily dose of (S)-enantiomer of the present invention is for a mammal with a body weight of 70 kg) from about 0.001 mg/kg (i.e 0.07 mg) to about 100 mg/kg (i.e. 7.0 g); preferably therapeutically effective dose is (for a mammal with a body weight of 70 kg) from about 0.01 mg/kg (i.e 0,70 mg) to about 50 mg/kg (i.e. 3.5 g); and more preferably a therapeutically effective dose is (for a mammal with a body weight of 70 kg) from about 1 mg/kg (that is, 70 mg) to about 25 mg/kg (i.e. about 1.75 g).

Limits of effective doses specified in this application should not be considered as limiting, and they are the preferred dose ranges. However, the most preferred dose can be selected for a specific subject, as should be clear and it is possible for the person skilled in the art (see, for example, Berkowef al., eds., The Merck Manual, 16th edition, Merck and Co., Rahway, NJ., 1992; Goodmanetna., eds., Goodman and Cilman''s The Pharmacological Basis of Therapeutics, 10th edition, Pergamon Press, Inc., Elmsford, N. Y., (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., eds., Remington''s Pharmaceutical Sciences, 18thedition, Mack Publishing Co., Easton, PA (1990); Katzung, Basic and Clinical Pharmacology, Appleton and Lange, Norwalk, CT (1992)).

The total dose required for each treatment can be administered using neskolkochasovyh doses or as a single dose during the day, as it is desirable. Typically, the treatment should be started with lower doses that are less than the optimum dose of the compound. Then increase the dose by small increments until the optimum effect under the circumstances. Diagnostic pharmaceutical compound or composition can be entered separately or in combination with other diagnostic tools and/or pharmaceutical substances, aimed at pathology or directed to other symptoms of the disease. An effective amount of (S)-enantiomer of the present invention or compositions of the present invention comprise from about 0.1 μg to about 100 mg/kg body mass, which is injected at intervals of 4-72 hours, over a period of time from 2 hours to 1 year, and/or using any range or value within the limits specified, for example, 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 50-100 mg/kg, at intervals of 1-4, 4-10, 10-16, 16-24, 24-36, 24-36, 36-48, 48-72 hours, over a period of time 1-14, 14-28 or 30-44 days, or 1-24 weeks, or any range or value within the limits specified.

Recipients of introduction (S)-enantiomer of the present invention and/or compositions of the present invention can be any animal, such as mammals. Of mammals are the preferred recipients are mammals detachment ol the mats (including humans and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), rodents (including mice, rats, rabbits and hamsters) and predators (including cats and dogs). The birds preferred recipients are turkeys, chickens and other members of this group. The most preferred recipients are people.

COMBINATION THERAPY

(S)-enantiomer of the present invention is useful together with one or more other therapeutic means, or any combination thereof, for the treatment of diseases and conditions in mammals, preferably in humans, improvement or relief which is achieved through the modulation, preferably inhibition, voltage-dependent gate sodium channels. For example, (S)-enantiomer of the present invention can be administered simultaneously, sequentially or separately in combination with other therapies including, but not limited to:

• opiate analgesics, e.g. morphine, heroin, cocaine, oxymorphine, Levorphanol, levallorphan, oxycodone, codeine, Dihydrocodeine, propoksifen, nalmefene, fentanyl, hydrocodone, hydromorphone, maripily, methadone, nalorfin, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine;

• non-opioid analgesics, for example, acetomeniphen, salicylates (eg, aspirin);

• Nester is ednie anti-inflammatory drugs (NCPLS), for example, ibuprofen, naproxen, fenoprofen, Ketoprofen, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, meclofenamic acid, mefenamovaya acid, meloxicam, nabumetone, naproxen, nimesulide, nitroprussiate, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazin, sulindac, tolmetin, zomepirac;

• anticonvulsants, such as carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin, pregabalin;

• antidepressants, such as tricyclic antidepressants, such as amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline;,

• selective COX-2 inhibitors, e.g. celecoxib, rofecoksib, parecoxib, valdecoxib, deracoxib, etoricoxib and lumiracoxib;

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

• sedatives on the basis of barbiturates, for example, amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, SEAMILL and thiopental;

• antagonist tachykinin (NK), in particular, the antagonist of NK-3, NK-2 Il the NK-1, for example, (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4 - were)-7H-[1,4]thiazocine[2,1-g][1,7]-naphthiridine-6-13-dione (TAK-637), 5-[[2R3S)-2-[(1R)-1-[3,5-bis(triptoreline]ethoxy-3-(4-forfinal)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (MK-869), either aprepitant, lapitan, dapitan or 3-[[2-methoxy-5-(triptoreline)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

• coal analgesics, in particular, paracetamol;

• inhibitors of reuptake of serotonin, for example, paroxetine, sertraline, noruoxetine, the metabolite of fluoxetine desmethyl), a metabolite of desmethylsertraline, '3 fluvoxamine, paroxetine, citalopram, citalopramsee metabolite to demethylcitalopram, ESCITALOPRAM, d,l-fenfluramine, femoxetine, ifoxetine, cyanidation, litoxetine, priligy generic, nefazodone, cericlamine, trazodone and fluoxetine;

• inhibitors of reuptake of noradrenaline (norepinephrine), for example, maprotiline, lofepramine, mitrazapine, oxaprotiline, Ptolemy, tomoxetin, mianserin, buproprion, bupropionbuy metabolite of hydroxybupropion, nomifensine and viloxazine (Vivalan®)), especially selective inhibitor of the reuptake of norepinephrine, such as reboxetine, in particular, (S,S)-reboxetine, and neuroleptic sedative/anxiolytic drug venlafaxine DULOXETINE;

• with dual action inhibitors repeat the re-absorption of serotonin, norepinephrine, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, DULOXETINE, milnacipran and imipramine;

• acetylcholinesterase inhibitors such as donepezil;

• antagonists 5-HT3, such as ondansetron;

• antagonists of metabotropic glutamate receptor (mGluR) or agonists or allosteric activators of glutamate on mGluR receptors;

• local anesthetic, such as meksiletin and lidocaine;

• corticosteroid, such as dexamethasone;

• anti-arrhythmia, for example, meksiletin and phenytoin;

• muscarinic antagonists, for example, tolterodine, propiverine, tropium t chloride, darifenacin, solifenacin, temiverine and ipratropium;

• muscarinic agonists or allosteric activators of acetylcholine at muscarinic receptors;

• cannabinoids or allosteric activators of endorphins on cannabinoid receptors;

• agonists ballisodare receptor (e.g., resiniferatoxin) or antagonists (e.g., capsazepine);

• sedatives, for example, glutethimide, meprobamate, methaqualone, and dichloralphenazone;

• anxiolytic agents such as benzodiazepines,

• antidepressants, such as mirtazapine,

• local funds (e.g., lidocaine, capsaicin and resiniferatoxin);

• we are Ichnya ward, such as benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, Methocarbamol and Harpenden;

• antihistamines or H1 antagonists;

• antagonists NDA receptor;

• agonists/antagonists of 5-HT receptor;

• PDEV inhibitors;

• Tramadol®;

• cholinergic (nicotinic) analgesics;

• alpha-2-Delta ligands;

• antagonists of prostaglandin E2 subtype;

• antagonists of leukotriene B4;

• inhibitors of 5-lipoxygenase; and

• antagonists 5-HT3.

Diseases and conditions that can be treated and/or prevented with the use of such combinations include, but are not limited to, pain, Central and perifericheskie mediated, acute, chronic, neuropathic diseases, and other diseases with accompanying pain and other disorders of the Central nervous system such as epilepsy, anxiety, depression and bipolar disease; and cardiovascular disorders such as arrhythmia, atrial fibrillation and ventricular fibrillation; neuromuscular disorders, such as restless leg syndrome and muscle paralysis or tetanus (Hamann M, Meisler MH, Richter, Exp. Neurol. 184(2):830-838 (2003)); neuroprotection against stroke, neural trauma and multiple sclerosis; and kalapati, such as erythromelalgia and the syndrome of hereditary rectal pain.

p> The term "combination" as used in this application, refers to any mixture or permanence (S)-enantiomer of the present invention with one or more additional therapeutic agents. Unless the context clearly requires otherwise, "combination" may include simultaneous or sequential delivery of (S)-enantiomer of the present invention with one or more therapeutic agents. Unless the context clearly requires otherwise, "combination" may include pharmaceutical form (S)-enantiomer of the present invention with another therapeutic agent. Unless the context clearly requires otherwise, "combination" may include route of administration (S)-enantiomer of the present invention with another therapeutic agent. Unless the context clearly requires otherwise, "combination" may include song (S)-enantiomer of the present invention with another therapeutic agent. Dosage form, route of administration and pharmaceutical compositions include, but are not limited to, those described in this application.

One combination therapy of the present invention includes a local application (S)-enantiomer of the present invention with an oral remedy. Local application (S)-enantiomer of the present invention has a very low systemic exposure and today the activity, which is additive with a number of oral analgesic funds. Another possible combination therapy includes oral dose of (S)-enantiomer of the present invention with an oral remedy. Another combination therapy of the present invention includes a local application (S)-enantiomer of the present invention with a means for local use.

(S)-enantiomer of the present invention can be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular implants, stents and catheters. Thus, the present invention, in another aspect, includes a composition for coating an implantable device comprising the compound of the present invention, described above, and a carrier suitable for coating implantable devices. In the following aspect, the present invention includes an implantable device coated with a composition comprising (S)-enantiomer of the present invention and a carrier suitable for coating implantable devices. Suitable coatings and the General methods of obtaining implantable devices with coatings described in U.S. Patent No. 6099562; 5886026; and 5304121.

SETS

The present invention also provides kits that contain the pharmaceutical composition is Yu of the present invention. The set also includes instructions for using the pharmaceutical composition for modulating the activity of ion channels for the treatment of pain, in other applications disclosed in this application. Preferably, commercial packaging contains one or more standard doses of the pharmaceutical composition. For example, such a standard dose can be an amount sufficient for the preparation of intravenous injection. Professionals should be obvious that such compositions that are sensitive to light and/or air, require special packaging and/or formulation. For example, you can use the packaging that does not transmit light and/or hermetically protected from contact with the surrounding atmosphere, and/or a drug formulated with suitable coatings or excipients.

OBTAIN (S)-ENANTIOMER of the PRESENT INVENTION

(S)-enantiomer of the present invention and the corresponding (R)-enantiomer is obtained by selection of the compounds of formula (I) as described above in the section “Brief description of the invention, using either of the methods of chiral high-performance liquid chromatography, or ways chromatography with pseudoviruses layer, as described below in the following reaction scheme, where chiral HPLC" refers to chiral high-performance liquid is Oh chromatography and "SMB" refers to chromatography with pseudoviruses layer:

The SCHEME of REACTIONS

The compound of formula (I) can be obtained by the methods disclosed in the published patent PCT application no WO 2006/110917, by methods disclosed in this application, or by methods known to experts in this field.

Professionals in this field should be clear changes in the above reaction Scheme, which are suitable for separation of individual enantiomers.

Alternatively, (S)-enantiomer of formula (I-S) and (R)-enantiomer of formula (I-R) can be synthesized from starting substances are known or can be easily obtained using methods similar to those known.

Preferably, (S)-enantiomer of the present invention, obtained using the methods of isolation, disclosed in this application does not contain (R)-enantiomer or contains only trace amounts of (R)-enantiomer.

The following Examples of synthesis are used to illustrate how the selection, disclosed in the above reaction Scheme, and are not intended to limit the scope of the present invention.

EXAMPLE of SYNTHESIS 1

Synthesis of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-she (the Compound of formula (I))

It is Uspenie Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-she (1.0 g, 3.6 mmol), which can be obtained in accordance with methods disclosed in the published patent PCT application no WO 2006/110917, and cesium carbonate (3,52 g, 11 mmol) in acetone (50 ml) was added 2-methyl bromide-5-triptorelin (1.13 g, 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, elwira a mixture of ethyl acetate/hexane (1/9-1/1), to obtain 1'-{[5- (trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-it, i.e. the compounds of formula (I), (1,17 g, 76%) as a white solid: so pl. 139-141°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 (1H), 5,90-5,88 (m, 2H), of 5.05, a 4.86 (ABq, JAB=16.1 Hz, 2H), 4,91 (d, J=9,0 Hz; 1H), 4,66 (d, J=9.0 Hz, 1H);13With NMR (75 MHz, CDCl3) δ 176,9, 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);

Calculated for C22H14F3NO5: C, 61,54%; H, 3,29%; N, 3,26%; Found: C, 61,51%; H, 3,29%; N, 3,26%.

EXAMPLE of SYNTHESIS 2

The selection of the compounds of formula (I) using chiral HPLC

The compound of formula (I) divided by (S)-enantiomer of the present invention and the corresponding (R)-enantiomer by chiral method is ASH using the following conditions:

Column: Chiralcel ® OJ-RH; 20 mm C. D. ×250 mm, 5 μm; Lot: OJRH CJ-EH001 (Daicel Chemical Industries, Ltd.)

Eluent: Acetonitrile/Water (60/40, V/V, Socrat.)

Flow rate: 10 ml/min

The time of the experiment: 60 min

Load: 100 mg of the compounds of formula (I) in 1 ml of acetonitrile

Temperature: ambient

In the above-mentioned conditions of chiral HPLC, (R)-enantiomer of compounds of formula (I), that is (R)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]-benzodioxole-7,3'-indol]-2'(1 N)-he was isolated as the first fraction in the form of a white solid; ei (enantiomeric excess) >99% (analytical OJ-RH, 55% acetonitrile in water); so pl. 103-105°C;

1H NMR (300 MHz, DMSO-d6) δ 7,32-6,99 (m, 5H), of 6.71 (d, J=3,4 Hz, 1H), to 6.67 (s, 1H), equal to 6.05 (s, 1H), 5,98 (d, J=6.2 Hz, 2H), 5,13, 5,02 (AB kV, JAB=16.4 Hz, 2H), 4,82 4,72 (AB kV, JAB=9.4 Hz; 2H),13With 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-17,46° (C 0.99, and DMSO).

(S)-enantiomer of compounds of formula (I), that is, (S)- 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]-benzodioxole-7,3'-indol]-2'(1 N)-he was identified as the second fraction in the form of a white solid; ei >99% (analytical OJ-RH, 55% acetonitrile in water); so pl. 100-102°C; MS (ES+)

1H NMR (300 MHz, DMSO-d6) δ 7,32-6,99 (m, 5H), of 6.71 (d, J=3,4 Hz, 1H), to 6.67 (s, 1H), equal to 6.05 (s, 1H), of 5.89 (d, J=6.3 Hz, 2H), 5,12, 5,02 (AB kV, JThe in =16.4 Hz, 2H), 4,82, 4,72 (AB kV, JAB=9.4 Hz, 2H);13With NMR (75 MHz, CDCl3) δ 177,2, 155,9, 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, and DMSO).

EXAMPLE of SYNTHESIS 3

The selection of the compounds of formula (I) using SMB chromatography

The compound of formula (I) divided by (S)-enantiomer of the present invention and the corresponding (R)-enantiomer method SMB chromatography using the following conditions:

Extract: 147,05 ml/min

The raffinate: 76,13 ml/min

Eluent: 183,18 ml/min

Flow: 40 ml/min

Recycling: 407,88 ml/min

The time of the experiment: 0,57 min

Temperature: 25°C

Pressure: 46 bar

The feed solution (25 g of compound of formula (I) in 1.0 l of mobile phase (25:75:0.1 to about:about:about) mixture of acetonitrile/methanol/triperoxonane acid)) was injectively continuously in the SMB system (Novasep Licosep Lab Unit), which was equipped with eight identical columns in 2-2-2-2 configuration containing 110 g (per column, 9.6 cm, 4.8 cm C. D.) ChiralPAK-AD as a stationary phase. The first eluting enantiomer ((R)-enantiomer of compounds of formula (I) contained in the stream of the raffinate, and the second eluting enantiomer ((S)-enantiomer of compounds of formula (I) contained in the extract stream. Characteristics of (S)-enantiomer and (R)-enantiomer obtained by the method of the SMB separation, were identical to those polucheniya using chiral HPLC.

The compound of formula (I) was separated into its constituent enantiomers on an automatic cleaning system Waters preparative LCMS. The first eluting enantiomer of the chiral column was Bremerhaven (on the site, easily removed from the stereogenic center) to obtain the corresponding 5'-bromo derivative, which then led to obtain a single crystal suitable for x-ray crystallography. Determined the crystal structure of this brominated derivative of the first eluting enantiomer, and it was found that the absolute configuration was the same as the (R)-enantiomer of the present invention. Therefore, the second eluting enantiomer of the chiral column consisted of (S)-enantiomer of the present invention. In addition, a substance obtained from the extract stream in the SMB division, had a specific optical rotation of the same sign (positive, i.e., programalso) as the substances obtained by the above-described LC separation.

BIOLOGICAL ASSAYS

Various methods are known in the art for testing the activity of the compounds of the present invention or the determination of their solubility in the well-known pharmaceutically acceptable excipients. In order for the invention described in this application was clearer, the following describes the following biological EN is Lisa. It should be clear that these examples are intended for illustrative purposes only, and should not be construed as limiting in any way the present invention.

BIOLOGICAL EXAMPLE 1

Analysis of the inflow of guanidine (in vitroanalysis)

This example describesin vitroanalysis testing and profiling of the test substances against voltage-dependent gate sodium channels in human or rat, stably expressed in cells of either endogenous or heterologous origin. The analysis is also useful for determining the values IR50for compounds modulating (preferably locking) potential-dependent gate sodium channel. The analysis is based on the analysis of the inflow of guanidine, which is described Reddy, N. L., et al., J. Med. Chem. (1998), 41(17):3298-302.

Analysis of guanidine influx presents an analysis of the inflow of radioactive indicator used for determining the activity of ion flow potential-dependent gate sodium channels in high throughput format using a microplate. In the analysis of use14C-guanidine hydrochloride in combination with various known modulators of voltage-dependent gate sodium channels, which provide supported inflow, to analyze the activity of the test substance. Activity is ü determined by calculating the values IR 50. Selectivity was determined by comparing the activity of the connection in relation to interest potential-dependent gate of the sodium channel with its activity against other voltage-dependent gate sodium channels (also referred to as 'the determination of the selectivity profile').

Each of the test substances were analyzed against cells that Express interest in a potential-dependent gate sodium channels. Potential-dependent gate sodium channels are characterized as TTX sensitive or insensitive. This property is useful in determining the activity of interest potential-dependent gate sodium channel, when present in mixed populations with other potential-dependent gate sodium channels. In the following Table 1 shows the cell lines that are useful for testing some activity on voltage-dependent gate sodium channels in the presence or in the absence of TTX.

TABLE 1
Cell lineExpression of mRNAFunctional specifications
CHO-K1 cells Chinese hamster ovary; recom is dovanna cell line-host)
ATTS access number CCL-61
•expression of Nav1.4 was shown using RT-PCR
•found no expression other Nav
•18-20-fold increase in the inflow of [14C]guanidine was completely blocked using TTX. (Nav1.4 is TTX-sensitive channel)
L6 (rat cultured myoblasts) ATTS number CRL-1458• expression of Nav1.4 and 1.5•10-15-fold increase in the inflow of [14C]guanidine was only partially blocked using TTX at a concentration of 100 nm (Nav1.5 is TTX resistant)
SH-SY5Y (human neuroblastoma) ATTS number CRL-2266• expression of Nav1.9 and Nav1.7 is described in the published document (Blum et al.)•10-16-fold increase in the inflow of [14C]guanidine above background values was partially blocked with the use of TTX (Nav1.9 is TTX resistant)
SK-N-BE2C (cell line human neuroblastoma ATTS number CRL-2268)• expression of Nav1.8•stimulation WAS cells pyrethroids leads to a 6-fold increase in the inflow of [14C]guanidine above background C is achene •TTX partially blocks the influx of Na v1.8 is TTX resistant)
RS (rat pheochromocytoma) ATTS number CRL-1721• expression of Nav1.2 and Nav1.7•8-12-fold increase in the inflow of [14C]guanidine was completely blocked using TTX. (Nav1.2 and Nav1.7 are TTX-sensitive channels)
NEC (human embryo kidney) ATTS number CRL-1573• expression of Nav1.7Nav1.7 is TTX-sensitive channel. Specifications IR50functional analysis using guanidine is 8 nm.

You can also use an immortalized cell line that is heterologous way Express the potential-dependent gate sodium channels. Cloning, stable transfection and reproduction of such cell lines known to specialists in this field (see, for example, Klugbauer N, et al., EMBO J.(1995), 14(6): 1084-90; and Lossin, C1 et al., Neuron (2002), 34, pp. 877 - 884).

Cells expressing interest in the potential-dependent gate sodium channel, was grown in accordance with the instructions of the supplier or, in the case of recombinant cells in the presence of selective medium, such as G418 (Gibco/Invitrogen). Cells were separated from cups to stump the financing with the use of enzyme solution (1X) Trypsin/EDTA (Gibco/Invitrogen) and analyzed to determine the density and viability using hemocytometer (Neubauer). The separated cells were washed and resuspendable in their culture medium and then were sown in coated with Poly-D-Lysine tablets Scintiplates (Perkin Elmer) (approximately 100,000 cells/well) and incubated at 37°C/5% CO2for 20-24 hours. After thorough washing HEPES-buffered salt solution with low sodium (LNHBSS) (150 mm Choline Chloride, 20 nm HEPES (Sigma), 1 mm Calcium Chloride, 5 mm Potassium Chloride, 1 mm Magnesium Chloride, 10 mm Glucose) test substance was diluted using LNHBSS and then added to each well at a desired concentration. (You can use varying concentrations of the test substance). Activating/containing radioactive label mixture contained alkaloid, such as veratridine or Amanitin (Sigma), or a PYRETHROID, such as deltamethrin, Scorpion venomLeiurus quinquestriatus hebraeus(Sigma) and14C-guanidine hydrochloride (ARC) for measuring flow through the potential-dependent gate sodium channels.

After load cells test substance and an activating/containing radioactive label mixture, covered with Poly-D-Lysine tablets Scintiplates incubated at ambient temperature. After incubation coated with Poly-D-Lysine tablets Scintplates thoroughly washed using LNHBSS, supplemented by Guanidine (Sigma). Coated with Poly-D-Lysine tablets Scintiplates dried and then read using a Wallac MicroBet TriLux (Perkin-Elmer Life Sciences). The ability of test substances to block the activity of voltage-dependent gate sodium channels was determined by comparing the number of14C-guanidine that is present inside the cells expressing the different potential-dependent gate sodium channels. Based on these data, various calculations specified in this description can be used to determine whether or not the test substance is selective with respect to a particular potential-dependent gate of the sodium channel.

Value IR50for test substances with respect to a particular potential-dependent gate of the sodium channel can be determined using the above General method. Value IR50you can define using 3, 8, 10, 12 or 16-point curve in two or three iterations, using the initial concentration of 1, 5 or 10 μm for serial dilution to obtain the final concentration reaching the sub-nanomolar, nanomolar and low micromolar range. Typically sredneetazhnye concentration of the test substance is set at 1 μm, and used consistently received greater or smaller concentration of ½ dilutions (for example, 0.5 μm; 5 μm and 0.25 μm; 10 μm and 0.125 μm; 20 μm and so on). IR50the curve was calculated using logistic m is Delhi with 4 parameters or formula sigmoidal model dose-response (fit=(A+((B-A)/(1+((C/x) ΛD)))).

Fold selectivity, the selectivity factor or fold selectivity was calculated by dividing values IR50to test the potential-dependent gate of the sodium channel on the standard(reference) potential-dependent gate sodium channel, for example, Nav1.5.

Thus, the compound of formula (I), (S)-enantiomer of compounds of formula (I), that is (S)-enantiomer of the present invention, and (R)-enantiomer of compounds of formula (I) when tested in this assay showed an activity of blocking the potential-dependent gate sodium channel against hNav1.7, as shown below in Table 2:

TABLE 2
ConnectionChemical nameIR50(µm)
(I)1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he0,007
(I-R)(R)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he4,200
(I-S)(S)-1'-{[5-(trifluoromethyl)furan-2-yl]methylspiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he 0,003

The relationship of the concentration-response for (S)-enantiomer of the present invention and (R)-enantiomer is shown in Fig. 1. Solid curves indicate the best selection of the method of least squares to 1:1 binding isotherm; values IR50that describe these curves, are presented in Table 2. (S)-enantiomer of the present invention demonstrated significantly higher (i.e., >1000-fold) the activity of inhibition against Nav1.7 in this model compared to the activity of inhibition of the corresponding (R)-enantiomer.

These results speak in favor of the use of (S)-enantiomer of the present invention in contrast to (R)-enantiomer or the compounds of formula (I) (racemate) for the purposes described in this application, because a higher pharmacological activity is achieved at lower dose levels with the possibility of fewer side effects. In addition, (R)-enantiomer is a very important tool for security studies, because it separates based on the mechanism effects (those that are mediated by blocking sodium channels) and activity outside of the target, which can be eliminated in counterparts, without sacrificing efficiency. If an adverse effect is based on the mechanism of action, then (S)-enantiomer Bud the t is much more active than (R)-enantiomer as secondary areas of action are unlikely to have identical stereoselectivity, and the two enantiomers are unlikely to have the same effects, including activity in peripheral sites of action.

BIOLOGICAL EXAMPLE 2

Electrophysiological analysis (In vitroanalysis)

HEK293 cells expressing hNav1.7, cultivated in a nutrient medium DMEM (Gibco) with 0.5 mg/ml G418, +/-1% PSG and 10% thermoinactivation fetal bovine serum at 37°C and 5% CO2. For electrophysiological registrations cells were sown on 10 mm Cup.

Registration in the configuration of the "whole cell" explored a common method of fixation potential in configuration "a cage" (Bean et al., op. cit.) using Axopatch 200B amplifier and Clampex program (Axon Instruments, Union City, CA). All experiments were performed at ambient temperature. The electrodes were polished flame to the resistances of 2-4 Mω. The error voltage and the electric capacitance was minimized by series compensation resistance and the compensation capacitance, respectively. Data were obtained at 40 kHz and filtered at 5 kHz. The external solution (in the tub) consisted of: NaCl (140 mm), KCl (5 mm), CaCl2(2 mm), MgCl2(1 mm), HEPES (10 mm) at a pH of 7.4. The internal solution (pipette) consisted of (in mm): NaCl (5), CaCl2(0,1), MgCl2(2), CsCl (10), CsF (120),HEPES (10), EGTA (10), at a pH of 7.2.

To assess the steady-state affinity of compounds in relation to the state of rest and inactivated state of the channel (Krand Ki, respectively), 12.5 msec test pulses for depolarization voltages from -60 to +90 mV from an initial potential of -120 mV was used to build the dependency of the current-voltage (I-V curves). The voltage near the peak I-V-curve (-30 to 0 mV) was used as the test pulse in the rest of the experiment. Curves inactivation in a stable state (availability) is then constructed by measuring the current that is activated during 8,75-msec test pulse after a 1-sec converts pulses to voltages between -120 to -10 mV.

Stationary potential-dependence of binding of compounds with potential-dependent gate sodium channel was determined by measuring the blockade of ionic current when the two input voltages. Linking with the rest of the channels was determined using the source potential of -120 mV, thus, ensured maximum availability. Linking with inaktivirovannoj state channels was evaluated at the source potential, so about 10% of the channels available for opening. The membrane potential was maintained at this voltage for at least 10 seconds for uranous the cation binding drug.

The apparent dissociation constant at each voltage was calculated using the equation:

% inhibition=[Drug]×100

([Drug]+Kd)

where Kdrepresents the dissociation constant (or Kror Kiand [the Drug] is the concentration of the test compound.

Thus, the compound of formula (I), (S)-enantiomer of compounds of formula (I), that is (S)-enantiomer of the present invention, and (R)-enantiomer of compounds of formula (I) when tested in this model showed affinity in relation to the state of rest/closed state and an inactivated state hNav1.7, as shown below in Table 3:

TABLE 3
ConnectionChemical nameKi(µm)Kr(µm)
(I)1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he0,142>10 microns
(I-R)(R)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]2'(1'H)-he 0,869>10 microns
(I-S)(S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-he0,161>10 microns

As shown by these results, (S)-enantiomer according to the present invention is dependent on a condition or voltage modifier hNav1.7 having a low affinity in relation to the state of rest/closed state and a high affinity in relation to the inactivated state. The results showed that (S)-enantiomer was approximately 5 times more active in linking with inaktivirovannoj state hNav1.7 compared with (R)-enantiomer. In addition, the results showed that (S)-enantiomer is predominantly responsible for the activity of the racemate, i.e. the compounds of formula (I).

BIOLOGICAL EXAMPLE 3

In vivoTests

Acute pain (formalin test)

Formalin test is used as an animal model of acute pain. In the formalin test animals quickly accustomed to the camera for testing of Plexiglas on the day preceding the experiment, for 20 minutes. On the day of the test animals randomly injected substances by injection. After 30 mi the ut after the introduction of the drug was injected 50 μl of 10% formalin solution by subcutaneous injection into the plantar surface of the left hind paw of the rat. The collection of video data is started immediately after injection of formalin and carried out within 90 minutes.

Images were obtained using the program Actimetrix Limelight, which stores files in *IIii expansion and then converts by MPEG-4 encoding. Video data is then analyzed using the analyze program behavior, "The Observer 5,1", (Version 5.0, Notdus Information Technology, Wageningen, The Netherlands). Video analysis was carried out by observing the behavior of animals and evaluate each according to its type, to determine the duration of this behavior (Dubuisson and Dennis, 1977). Behavior assessment include: (1) normal, (2) does not rely on a paw, (3) raising the legs, (4) licking/biting or scratching paws. Strengthening loyalty to this or excessive licking, biting and scratching paws, which was administered an injection point to the pain response. On analgesic response or protection through connections indicated this behavior when both feet safely touch the ground in the absence of manifest behavior, excessive licking, biting or scratching paws, which was administered an injection.

Data analysis formalin test was carried out according to two factors: (1) the Percentage of Maximum Potential Inhibitory Effect (%MPIE) and (2) assessment of pain. %MPIE expected Paladino, where the first step b is lo summation of the length of non-normal behavior (behavior 1,2,3) each animal. A single value for a group introduction media was obtained by averaging all scores in the group handling the media. The following calculation gives the value of the MPIE for each animal:

MPIE (%)=100-[(sum of processing/average value for processing by the media)×100%]

Assessment of pain was calculated by the scale weight as described above. The duration of the behavior was multiplied by the mass (the assessment of the severity of the response) and divide by the total duration of the observations to determine pain scores for each animal. The calculation represented by the following formula:

Assessment of pain=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)

CFA-induced chronic inflammatory pain

In this test, tactile allodynia was assessed using calibrated fibers von Frey. After acclimatization during the week in vivarium, 150 ál of "Complete Adjuvant-blockers" (CFA) emulsion (emulsion CFA, suspended in the oil/saline (1:1) at a concentration of 0.5 mg/ml) was administered by subcutaneous injection into the plantar surface of the left hind paws of rats under light anesthesia with isoflurane. The animals were allowed to recover from anesthesia, and basic thermal and mechanical nociceptive thresholds of all animals was assessed one week after the injection of CFA. All animals were habituated to the experimental equipment for 20 minutes a day prior to the experiment. Animals were injected with the test and control substances and nociceptive thresholds were measured at specific time points after administration of the medicinal product to determine the analgesic responses to each of the six treatments. Used the time points were determined in advance to demonstrate higher analgesic effect for each test compound.

(S)-enantiomer of the present invention and the corresponding (R)-enantiomer compared using both oral and local administration. Fig. 2 shows a comparison of the effectiveness of (S)-enantiomer of the present invention and (R)-enantiomer by oral administration. Each enantiomer was administered at the dose of 10, 30, 100, or 200 mg/kg Also determined the plasma concentration achieved at each dose, and the inversion of the pain response (as % increase from the baseline threshold) was applied on a graph as a function of plasma concentration.

(S)-enantiomer had a higher maximum effect at the dose of 200 mg/kg of (R)-enantiomer was reached significantly higher plasma concentrations at equivalent doses. It was unexpected and unusual opening. As a consequence, the use of a racemate, i.e. the compounds of formula (I), will give about 10-fold excess of the inactive enantiomer, that is (R)-enantiomer. Thus, using (S)-enantiomer of the present invention significantly improve the it the likelihood of achieving efficiency while minimizing the likelihood is not aimed at the target activities, which are not stereoselective.

(S)-enantiomer of the present invention also introduced by local animals in different doses (1%, 2%, 4% and 8% (mass/R)), and nociceptive thresholds were measured at specific time points after administration of the medicinal product to determine the analgesic responses to each of the treatments. Used the time points were determined in advance to demonstrate higher analgesic effect for each test compound.

Thresholds of responses of animals to tactile stimuli was measured using anesthesiometer Model 2290 Electrovonfrey (HTC Life Science, Woodland Hills, CA) after testing by the method of Hargreaves. Animals were placed in a high fence made of plexiglass, mounted on the surface of the wire mesh. After a 15-minute habituation to these conditions, pre-calibrated balance von Frey made perpendicular to the soles of the ipsilateral hind paw with sufficient force, measured in grams, to cause a pronounced response paws. The answer was expressed in OTDELENIE from painful stimulus and was the endpoint of efficacy. The test continued until, not yet determined the lowest power at which the hair caused rapid licking paws, or has not yet reached the power cutoff of about 20, This force cutoff used is Ali, because it represents approximately 10% of the body mass of animals and serves to prevent lifting of the entire limb from the use of more rigid hairs, which can change the nature of the stimulus. Data were expressed as the percentage increase from the baseline threshold, measured in grams.

(S)-enantiomer of the present invention when tested in this model demonstrated analgesic effect, as indicated below in Table 4.

TABLE 4
% increase from baseline (CFB)
Connection1% locally2% topically4% locally8% locally
(I-S)0,6216,7128,7945,06

(S)-enantiomer of the present invention, with 2%, 4% and 8% (mass/about) showed increased mechanical thresholds otdergivanija paws in the test according to the method of von Frey expressed as a percentage increase from the baseline (IFB), which indicates that the analgesic effect. Analgesic effect for (S)-enantiomer increased with increasing doses up to n is andá tertiary tested doses of 8% (mass/about), which showed the maximum percentage IFB +45,1%. However, the introduction of 1% (mass/mass) dose showed no discernible increase in mechanical threshold otdergivanija paws in the test according to the method of von Frey. The results show that (S)-enantiomer has analgesic effects in a model of CFA-induced inflammatory pain within 2%-8% (mass/about).

Postoperative models of nociception

In this model, the hyperalgesia caused intraplanar incision in the leg, measured by application of the reinforced tactile stimuli to the foot up until your pet from pulling back his paw on the applied stimulus. While the animals were under anesthesia 3,5% isofluorane, which was administered through a nasal passageway, making a 1-cm longitudinal incision using scalpeling blade No. 10 in the plantar region of the left hind paws through the skin and fascia, starting at a distance of 0.5 cm from the proximal end of the heel and further towards the toes. After cutting the skin connected overlay 2, 3-0 sterilized silk sutures. The damaged area was covered with polysporin and Betadine. Animals were returned to their cages for recovery during the night.

Thresholds otdergivanija paws animal in response to tactile stimuli as for the operated (ipsilateral) and unoperated (contralateral) paw from the Erith using anesthesiometer Model 2290 Electrovonfrey (IITC Life Science, Woodland Hills, CA).

Animals were placed in a high fence made of plexiglass, mounted on the surface of the wire mesh. After a 10-minute habituation to these conditions, pre-calibrated balance von Frey was applied perpendicularly to the plantar surface of both feet of the animals in increasing order, starting with 10 g of hair, with sufficient force to cause slight bending of the hairs attached to the foot. The test continued until, not yet determined the lowest power at which the hair caused rapid licking paws, or has not yet reached the power cutoff of about 20, This force cutoff was used because it represents approximately 10% of the body mass of animals and serves to prevent lifting of the entire limb from the use of more rigid hairs, which can change the nature of the stimulus.

Model of neuropathic pain; chronic constructionno defeat

In this model did about 3-cm incision through the skin and fascia at the level of the mid thigh of the left hind paws of the animals using scalpeling blade No. 10. The left sciatic nerve was exposed by dissection through the biceps femoral muscle, gently, so that the bleeding was minimal. Put four loose ligatures along the sciatic nerve using 4-0 indestructible with realizowany silk sutures at a distance of 1-2 mm from each other. Tension free ligatures was sufficient to cause a weak constrictio sciatic nerve, when observed through preparevalue magnifier with a 4-fold increase. The falsely operated animal left sciatic nerve was exposed without further manipulation. Antibiotic ointment was applied directly to the wound and muscle covered using sterilized suture material. The Betadine was applied to the muscle and its surroundings, followed by retraction of the skin with surgical clips.

Thresholds of responses of animals to tactile stimuli was measured using anesthesiometer Model 2290 Electrovonfrey (IITC Life Science, Woodland Hills, CA). Animals were placed in a high fence made of plexiglass, mounted on the surface of the wire mesh. After a 10-minute habituation to these conditions, pre-calibrated balance von Frey was applied perpendicularly to the plantar surface of both feet of the animals in increasing order, starting with 0.1 g of hair, with sufficient force to cause slight bending of the hairs attached to the foot. The test continued until, not yet determined the lowest power at which the hair caused rapid licking paws, or has not yet reached the power cutoff of about 20, This force cutoff was used because it represents approximately 10% of body weight of animals and the service is t to prevent lifting of the entire limb from the use of more rigid hairs, that may change the nature of the stimulus.

Thermal nociceptive thresholds of the animals were evaluated in the test according to the method of Hargreaves. After measuring tactile thresholds animals were placed in a fence made of plexiglass, mounted on an elevated glass platform with heating elements. Glass platform thermostatically controlled at a temperature of about 24-26°C for all tests. The animals were allowed to acclimate to these conditions for 10 minutes after putting them into the fence until the termination of their exploratory behavior. Device for measuring analgesia by stimulating the soles/tail model 226 (IITC, Woodland Hills, CA) was used for application of radiation heat from the bottom of the glass platform to the plantar surfaces of hind feet. During all tests the idle intensity and active the intensity of the heat source was set at 1 and 55, respectively, and the time of the cutoff of 20 seconds was used to prevent tissue damage.

(S)-enantiomer compared with the corresponding (R)-enantiomer and the racemate (compound of formula (I)) in this CCI model using local drug application, as described for the CFA model (see Fig. 3). Each test compound was administered in the form of an ointment containing 2% (mass/about). In accordance with the fact that these two Enan is imera have different activity as inhibitors of voltage-dependent gate sodium channels, only (S)-enantiomer of the present invention provided a reverse development of pain responses, whereas (R)-enantiomer did not show any significant increase from the baseline. (S)-enantiomer and the racemate both showed the same percentage increase from the baseline, and this suggests that (S)-enantiomer is responsible for the analgesic effect.

BIOLOGICAL EXAMPLE 4

Analysis aconitine-induced arrhythmia

Antiarrhythmic activity of the compounds of the present invention was demonstrated in the following test. Arrhythmia provoked by intravenous aconitine (2.0 µg/kg) dissolved in physiological saline. The test compounds of the present invention was intravenously injected 5 minutes after the introduction of aconitine. Evaluation of anti-arrhythmic activity was carried out by measuring the time from the introduction of aconitine to the occurrence of extrasystoles (ES) and the time from the introduction of aconitine to the occurrence of ventricular tachycardia (VT).

In rats under anesthesia with isoflurane (1/4-1/3 2%), performed tracheotomy, making a first incision in the neck area, then isolating the trachea and making a 2-mm incision for insertion of the tracheal tube 2 cm into the trachea so that the tube is positioned to the top of the mouth. The tube was secured with the help of open the seams and connected with a fan at the time of the experiment.

Sections (2.5 cm) then made in the femoral regions and used a blunt probe for dissection, the femoral vessels were isolated. Both femoral veins were Coulibaly, one for the maintenance of anaesthesia by pentobarbital (0,02-0,05 ml), and one for infusion and injection drug and carrier. The femoral artery was Coulibaly using gel catheter and pressure sensor.

ECG electrodes were attached to the thoracic muscle in the position of the electrodes II (upper right/above heart - white electrode, and the lower left/lower heart - red electrode). The electrodes were secured by suturing.

All surgical sites were covered with gauze moistened with 0.9% saline solution. Saline solution (1-1,5 ml of 0.9% solution) was applied to wet areas after surgery. ECG animals and ventilation balanced, at least for 30 minutes.

Fibrillation was induced by infusion of 2 mcg/kg/min aconitine within 5 minutes. At this time, was carried out by recording ECG and continuous control.

BIOLOGICAL EXAMPLE 5

Analysis of induced ischemia arrhythmia

Model of ventricular fibrillation in rodents, as in acute cardioversion and prevention paradigms used to test potential therapeutic agents for atriale and ventricular arrhythmias in humans. Heart is ischemia, leading to myocardial infarction is a common cause of morbidity and mortality. The ability of compounds to prevent ischemia-induced ventricular tachycardia and fibrillation is a common model to determine the efficacy of compounds in clinical conditions as regards atriale, and ventricular tachycardia and fibrillation.

Anesthesia is first induced by pentobarbital (intraperitoneally) and maintained with intravenous bolus infusion. In male SD rats trachea was kemuliaan for artificial ventilation of room air when the systolic volume of 10 ml/kg, 60 beats/min. The right femoral artery and vein were Coulibaly tube of PE50 for registration mean arterial pressure (MAP) and intravenous administration of the compounds, respectively.

The chest was opened between the 4th and 5th ribs with the formation of a 1.5-cm holes to see heart. Each rat was placed on a platform with hollows(cog) and metal restraints were hooked by the hooks on the edges surrounding the open cavity of the chest. The surgical needle is used to enter the ventricle directly under the raised atrium and exit the ventricle in a downward direction diagonally to get the >30%-<50% of the area of occlusion (OZ). State the output is ~0.5 cm below where the aorta connects to the left ventricle. The seam was delayed so to get the free loop (obturator) around the branch artery. The chest was then closed end of the obturator is available outside of the thorax.

The electrodes were placed in the position of the electrodes II (right atrium to the apex) for ECG measurements as follows: one electrode was inserted in the right front leg, and the other electrode was inserted into the left hind paw.

Body temperature, mean arterial pressure (MAP), ECG and heart rate were continuously recorded throughout the experiment. Once the critical parameters stabilized, carried out 1-2 minute registration to establish baseline values. Infusion of the compounds of the present invention or a control substance began immediately after the establishment of baseline values. After 5 minutes of infusion connection or control the seam tight delayed for ligating the LCA and the creation of ischemia in the left ventricle. Critical parameters are continuously recorded during 20 minutes after ligation, unless the MAP has not reached a critical level 20-30 mm RT.article for at least 3 minutes, in this case, registration was stopped, as they felt sick, and then squashed. The ability of compounds according to the present izobreteny is to prevent arrhythmia and maintain MAP and HR about the standards were evaluated and compared with the control.

BIOLOGICAL EXAMPLE 6

In comparison with the racemate, i.e. a compound of formula (I), (S)-enantiomer, almost not containing (R)-enantiomer has the best profile of solubility in various pharmaceutically acceptable excipients. Thus, it is possible to carry out the formulation (S)-enantiomer with getting a smaller number of dosage units in comparison with the racemate. This property facilitates the introduction patients at higher level, if necessary, to achieve efficiency. Examples of differences in solubility are shown in Table 5 below:

TABLE 5
ExcipientThe compound of formula (I) (racemate)(S)-enantiomer
Labrasol®72,5 mg/ml231 mg/ml
Propylene glycol2.7 mg/mlof 9.8 mg/ml
PEG 400<50 mg/ml>55 mg/ml
Capriol® 9018,1 mg/ml96 mg/ml
Tween® 8064 mg/ml >123 mg/ml
Ethanol10.0 mg/mlof 36.4 mg/ml
Labrasol®/PEG 400 60/40of 70.4 mg/ml182 mg/ml
Labrasol®/Capriol®90 60/40for 44.4 mg/ml191 mg/ml
Labrasol®/Transcutol® 60/40to 74.2 mg/ml186 mg/ml

BIOLOGICAL EXAMPLE 7

In VivoThe analysis for the treatment of itching

Histamine induced itch (scabies) in humans. Thus, this analysis assesses the effectiveness of local and oral administration of (S)-enantiomer of the present invention on histamine-induced itch in male ICR mice.

Animals were randomly divided into groups of tests, including the untreated group, group treatment a pharmaceutical composition for topical application with 8% (mass/about) (S)-enantiomer and the processing group oral pharmaceutical composition comprising 50 mg/kg (S)-enantiomer. The day before the test scapularies the area of the body of animals shaved the hair clipper. On the day of testing, animals were trained within 60 minutes to the condition of the camera for testing, which was a transparent plastikowe the tube, located vertically on a flat surface. After a period of habituation, animals were removed from the plastic tube, was placed in a clamping device and injected by the injection of histamine on shaved scapulare area. The injection was administered by intradermal skin in small volumes (10 μl) using a Hamilton syringe. Solutions for injection consisted of histamine dissolved in saline at a concentration of 100 μg/10 μl (10 mg/ml). 10 μg of the solution was administered by injection to each mouse. Immediately after injection, animals were returned to the chamber for testing and observed using a camera located above the chambers for testing, just 50 minutes. The camera was connected to the computer, which is created, maintained and analyzed digital video files.

The number of bouts of itching was calculated for 40 minutes. "Attack itch" was determined by raising the hind legs, using it for scratching scapulary area and then putting her back on the floor. Alternatively, if instead of being placed back paws back on the floor, it was observed that the mouse licks a paw, then these two actions considered by the attack of itching.

As for the untreated group of animals (n=7) were trained within 60 minutes to the cell environment for testing before injection of histamine. To assess local application (S)-enant the Omer during histamine-induced itch, animals (n=16/group) were habituated to the test chamber environment for testing within 30 minutes, followed by local application of 50 mg 8% (mass/about) (S)-enantiomer or media on a shaved area on the back. Animals were returned to the chamber of trials to habituation for 30 minutes before injection of histamine. To assess oral (S)-enantiomer, the animals (n=8/group) was administered via a stomach tube 50 mg/kg (S)-enantiomer or media with a subsequent period of habituation to the chamber for testing within 60 minutes before injection of histamine.

Data were analyzed using statistical analysis GraphPad Prism 5, and an unpaired student test was used for univariate analysis. The results were expressed as mean ±SEM(mean standard error). Values that reached p<0.05 level of significance was considered statistically significant.

Results

Injection of histamine in the skin caused scabies in animals with sporadic bouts of itching that lasted 1-2 seconds. In the untreated group, bouts of itching started immediately after the injection and lasted after about 40 minutes (see Fig. 4). Processing group 8% (mass/about) (S)-enantiomer for local use showed a significant reduction in itching (see Fig. 5). Animals that were treated with only the media had, in General, 134,3±13,31 (n=16) pristupa the itching, then as the mouse, which was treated with (S)-enantiomer for local use, had 89,00±10,51 (n=16) bouts of itching. The difference between these groups was statistically significant, at p=0,0122. The group that was treated with 50 mg/kg oral (S)-enantiomer, also showed a significant reduction in itching (see Fig. 6). Animals that were treated with only the media had, in General, 42,88±6,667 (n=8) bouts of itching, whereas mouse, which was treated with (S)-enantiomer had to 17.25±6,310 (n=8) bouts of itching. The difference between oral-treated groups was also statistically significant when p value=0,0144. The results showed that oral input and the local path (S)-enantiomer reduces itching. Moreover, it is clear that the two generally accepted ways of drug delivery, oral and local, can be used for delivery (S)-enantiomer to achieve therapeutic effect.

BIOLOGICAL EXAMPLE 8

A clinical trial of the treatment of primary/inherited erythromelalgia (IEM) in humans

Primary/hereditary erythromelalgia (IEM) is a rare hereditary painful condition. The reasons underlying the IEM may include one or more mutations purchasing functions in Nav1.7 voltage-dependent gate sodium channels, which has been shown to be inhibited ()-enantiomer of the present invention.

People who are patients with IEM, have recurrent episodes of strong burning pain associated with redness and a burning sensation of the palms and soles, but eventually, the pain becomes constant. The pain eases when cooled, but is largely resistant to pharmacological intervention. However, there are reports that blockers of voltage-dependent gate sodium channels demonstrate pain relief in degree from mild to strong in this state.

A clinical trial to determine the effectiveness of (S)-enantiomer of the present invention in reducing the intensity or relief IEM can be designed as a three-period, double-blind, mnogomodovoi and cross-testing to minimize the number of participants who drop out of the test, and it should be noted that patients who agreed to participate in the test will be available only during the 10-day test. Each patient participating in the trial, will serve as its own control, taking as placebo and 400 mg (S)-enantiomer of the present invention twice a day alternately.

BIOLOGICAL EXAMPLE 9

A clinical trial of treatment of dental pain in humans

The purpose of this clinical trial was to compare the safety and efficacy and (start, the duration of the period of relief and overall efficiency) of a single 500 mg dose (S)-enantiomer of the present invention against the introduction of placebo for pain relief after extraction of impacted third of a molar tooth.

The number of test participants was 61. The average age of participants was 20.4 years, and all subjects were male. The majority of the subjects belonged to evropeoidnoi race (95,1%).

Heaviness and pain relief was measured using 11-point scale digital assessment of pain intensity (0 = no pain, 10 = strongest imaginable pain) (PINRS) and the 5-point scale categories of pain relief (REL). The subjects filled PINRS after surgery, but before the introduction of (S)-enantiomer of the present invention. The performance indicators were obtained from REL PINRS and assessments, and they included a total pain relief (TOTPAR), the difference in pain intensity (PID) and the total difference in pain intensity (SPID), and evaluation was carried out at time points 4, 6, 8 and 12 hours after administration of (S)-enantiomer of the present invention.

However, the primary and all secondary endpoints showed a consistent analgesic trend with a clear distinction (S)-enantiomer from placebo. These results suggest that (S)-enantiomer possesses analgesic properties, but statistical mn is cimoli from placebo was not achieved for two main reasons: (1) a relatively high rate of response to placebo, and (2) slow onset of action (S)-enantiomer. Used dental model is designed and best suited for the evaluation of drugs with rapid onset of action, such as NSAID class of anti-inflammatory drugs. It was evident from this test that (S)-enantiomer of the present invention does not have such quick start steps as NSAID. However, pain relief, demonstrated by those entities that have adopted (S)-enantiomer, was higher compared to those subjects who received only placebo, enough for the General population efficiency showed consistent analgesic signal for all measured endpoints.

BIOLOGICAL EXAMPLE 10

Clinical safety test (S)-enantiomer of the present invention for a person

This clinical trial was a Phase 1, randomized, double-blind, placebo-controlled trial in healthy subjects to assess the safety and pharmacokinetic properties of ointments for topical application, containing (S)-enantiomer of the present invention.

Contains (S)-enantiomer ointment was applied daily for 21 consecutive days to determine local toxic/irritating the skin of the action (S)-enantiomer. Systemic pharmacokinetic properties and local level the drug in the skin was also evaluated. Estimated systemic exposure (S)-enantiomer after local application and local skin irritation after a few doses ointments containing (S)-enantiomer. Each subject received 5 treatments for 21 consecutive days: (S)-enantiomer in the form of ointments with 4% and 8% (mass/mass) (1×100 μl; processing a and B, respectively), and placebo in the form of ointment (treatment C), saline (0.9%) solution (1×100 μl; negative control; treatment D) and sodium lauryl sulfate (SLS) 0.1% solution (1×100 μl; positive control; process E). Processing was done on different areas of the upper back of each subject occluded image (five treatments) and partially occluded image (the first three processing). Place for each treatment at each site (treatment A, B, C, D and E on the occluded area, and processing A, B and C on partially occluded area) were selected randomly. Subjects were under constant surveillance for clinical research, starting in about 18 hours before the first dose on Day 1 up to about 8 hours after administration of the 2nd dose (Day 2). The subjects came every day for 19 consecutive days (Days 3 through 21) for introducing doses and procedures of the study.

Not reported no serious adverse effects (SAE) or deaths. Adverse effects (AE) were all weak or CPE is it severity, the majority of AE treat local skin reactions from surgical adhesive used for adhesion of the occlusal bandages. All subjects responded to the positive control. The positive control was stopped in all subjects at Day 4 after complaints of subjects to excessive discomfort. Evaluation of skin irritation were low for all treatments (maximum score of 3 on a scale from 0 to 7), indicating that (S)-enantiomer in the form of ointment was well tolerated locally. No difference was observed between cumulative estimates of irritation for (S)-enantiomer of 4% (mass/mass), (S)-enantiomer of 8% (mass/mass), placebo in the form of ointments and negative control (0.9% of saline). Signs of irritation had completely disappeared by Day 28 (7 days after the final dose) in most subjects.

Electrocardiographic recordings showed no clinically significant changes in pulse rate, latent state of rest, or QTwithintervals from the subjects, and observed no clinically significant changes from baseline in subjects regarding the main indicators of the condition of the body, physical examination or laboratory assessments. Systemic exposure (S)-enantiomer was negligible, because the concentration of (S)-enantiomer in plasma were below the lower limit of detection (LLOQ) (0.1 ng/ml or 100 PG/ml) in b is the most samples (489 of 546=~90%). The highest level (S)-enantiomer, which was observed in one subject in the period of introduction dose (Day 22), was 994 PG/ml On the basis of minimal local irritation and favorable safety profile, with low systemic exposure (S)-enantiomer, a conclusion was made that (S)-enantiomer of the present invention is portable and safe as a local analgesic.

BIOLOGICAL EXAMPLE 11

Clinical trial for the treatment of post herpetic neuralgia in humans

Post-herpetic neuralgia (PHN) is an established and generally accepted model for the study of neuropathic pain. In addition, PHN demonstrates reliable evidence of efficacy in blocking sodium channels. The next trial is a randomized, double-blind, placebo-controlled, including two treatment, two period cross-over study to assess the safety, tolerability, preliminary efficacy and systemic exposure (S)-enantiomer of the present invention, administered topically to patients with PHN. The main objectives were: (a) comparison of the safety and efficacy of an ointment containing (S)-enantiomer, with placebo for pain relief in patients with PHN, and (b) to assess the extent of systemic exposure (S)-enantiomer after topical application (S)-enantiomer the and in patients with PHN. Processing include (S)-enantiomer of 8% (mass/mass) in the form of ointments and used to compare the placebo ointment.

The test includes the following four periods:

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

2. Period one-sided blind test, the introduction of placebo (1 week);

3. The period of cross-processing, which consists of 2 periods of treatment, each of which lasts for 3 weeks, in between which 2-week washout period/one-way-blind trials with the introduction of the placebo (8 weeks); and

4. The final period of the safety assessment (2 weeks).

All U.S. patents, published patent applications U.S. patent application U.S., foreign patents, foreign patent applications and non-patent publications referenced in this description are incorporated in this application by reference in their entirety.

Although the above invention has been described in some detail in order to facilitate its understanding, it should be clear that almost you can use some changes and modifications in the scope of the attached claims. Thus, the options described embodiment should be considered as illustrative and not restrictive, and the invention is not limited to the details described in this application, but can be fashion is adopted within the scope and equivalents of the appended claims.

1. (S)-enantiomer of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1 N)-she, having the following formula (I-S):

2. The pharmaceutical composition intended for the treatment of a disease or condition selected from the group comprising pain, depression, cardiovascular disease, respiratory disease, mental illness, neurological disorders and convulsions, and combinations thereof, including pharmaceutically acceptable excipient and (S)-enantiomer under item 1.

3. The method of treatment of a disease or condition in a mammal selected from the group comprising pain, depression, cardiovascular disease, respiratory disease, mental illness, neurological disorders and convulsions, and combinations thereof, where the method includes the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer under item 1.

4. The method according to p. 3, where the disease or condition selected from the group including neuropathic pain, inflammatory pain, visceral pain, cancer pain, toothache, pain caused by chemotherapy, pain caused by injury, pain caused by surgical intervention, the pain of childbirth, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, prefer the Cesky-mediated pain, centrally mediated pain, chronic headache, migrainebuy headache, sinus headache, tensional headache, phantom pain in amputated limbs, peripheral nerve injury, and combinations thereof.

5. The method according to p. 3, where the disease or condition selected from the group including the pain associated with HIV, HIV treatment induced neuropathy, trigeminal neuralgia, post herpetic neuralgia, Evgeniy, sensitivity to heat, sarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with multiple sclerosis, Lou Gehrig's disease, pruritus, hypercholesterolemia, benign prostatic hyperplasia, diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, paroxysmal dystonia, myasthenic syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, acute necrosis of skeletal muscles, bipolar depression, anxiety, schizophrenia, and disease-related toxin sodium channels, hereditary erythermalgia, primary erythromelalgia, hereditary rectal pain, episodic paroxysmal pain disorder, cancer, epilepsy, partial and General tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuropath is the Ktsia in ischemic conditions, caused by stroke or neurological injury, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

6. The method of treatment of a disease or condition in a mammal by the inhibition of ion flux through potential-dependent gate sodium channel in the mammal, where the method includes the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer under item 1.

7. Method of decreasing ion flux through potential-dependent gate sodium channel in a cell in a mammal, comprising contacting the cells with (S)-enantiomer under item 1.

8. Application (S)-enantiomer under item 1 to obtain drugs for the treatment of diseases or conditions that can be improved or facilitated by inhibiting the potential-dependent gate of the sodium channel in the mammal.

9. A method of treating pruritus in a mammal, where the method includes the administration to a mammal in need, a therapeutically effective amount of (S)-enantiomer under item 1.

10. The method of obtaining (S)-enantiomers of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1 N)-she, having the following formula (I-S):

including:
(a) treating compound of the following formula:

2-romethyl-5-triptoreline in terms provides the formation of compounds of formula (I):
;
(b) the allotment (S)-enantiomers of 1'-{[5-(trifluoromethyl)furan-2-yl]methyl}Spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1 N)-it method chiral high-performance liquid chromatography or by chromatography with pseudoviruses layer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I where A is such as given in the invention formula, R is selected from the group consisting of H and C1-6 alkyl, n and p each is independently selected from 0, 1 and 2, on condition that n + p = 2; Y represents -O- or -S-; R1, R2, R3, R4 in each position are independently selected from H and C1-6 alkyl; R5 is selected from the group consisting of -C(O)-CH2-indol-3-yl, -C(O)-(CH2)2-indol-3-yl, -C(O)-(CH2)3-indol-3-yl, trans -C(O)-(CH=CH)-indol-3-yl, -SO2-4-fluorophenyl, -C(O)-CH(n-propyl)2, -C(O)-(4-hydroxy-3,5-di-tert-butylphenyl), -C(O)-CH(NH2)-CH2-indol-3-yl and -C(O)-CH2CH3; and R6 represents H. Invention also relates to pharmaceutical composition for modulation of muscarinic receptor M1, containing formula I compounds, and methods of treating disease or state, curable by modulator of muscarinic receptor M1.

EFFECT: formula I compounds as modulators of muscarinic receptor M1.

33 cl, 1 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula

, where X1, X2, Y, R1a, R1b, R2a, R2b, A1, A2, A3 and A4 have the values specified in the description, which are vanilloid receptor subtype 1 (VR1) antagonists.

EFFECT: preparing a pharmaceutical composition on the basis of the compounds of formula 1 and developing methods of managing pain, neurotic pain, allodynia, inflammation or inflammatory disease associated pain, inflammatory hyperalgesia, bladder hyperactivity and urine incontinence.

22 cl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): or to their pharmaceutically acceptable derivatives selected from a group consisting of pharmaceutically acceptable salts and esters; in which: R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c and R8d are such as presented in the patent claim 1. The invention also refers to compounds of formula (I), to a compounds selected from a group, to a pharmaceutical composition, to methods of treating, to a method of decreasing the plasma cholesterol level in a patient, to a method of modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, to a method of modulating farnesoid X receptor activity, to a compound representing 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b]indole-5-isopropylcarboxamide, to a composition, to a method of reducing the risk of an onset or a recurrence, to a method of modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal, and also to a method of modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal.

EFFECT: preparation of the new biologically active compounds showing possessing nuclear receptor activity.

73 cl, 76 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

The invention relates to compounds of formula (I)

where NRR1attached a 5 - or 6-position of the ring properidine; R is hydrogen, C1-C4-alkyl, or COR2; R1represents (CH2)nAr, CH2CH=CHAr, or CH2With?CAr; n is 0-3; a is N or NO; Ar represents a 5 - or 6-membered aromatic or heteroaromatic ring which contains 0 to 4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom; or an 8-, 9 - or 10-membered condensed aromatic or heteroaromatic cyclic system containing 0-4 nitrogen atom, 0-1 oxygen atoms and 0-1 sulfur atom, any of which may be optionally substituted by 1-2 substituents independently selected from halogen, trifloromethyl or1-C4-alkyl; R2represents hydrogen; C1-C4-alkyl; C1-C4-alkoxy or phenyl ring, optionally substituted by 1-3 of the following substituents: halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, CO2R5, -CN, -NO2, -NR3R4or-CF3; R3, R4and R5can be hydrogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, HE OS1-C4-alkyl, -CN, -NO2or-CF3; to their enantiomers and pharmaceutically acceptable salts

The invention relates to new biologically active compounds, namely spiroheterocyclic heterocyclic compounds of the formula I

< / BR>
where n is 0 or 1;

m is 0 or 1;

p is 0;

X represents oxygen or sulfur;

Y represents CH, N or NO;

W represents oxygen or H2;

And represents N or C(R2);

G represents N or C(R3);

D represents N or C(R4)

provided that not more than one of A, G and D represents nitrogen, but at least one of Y, a, G, and D represents nitrogen or NO;

R1represents hydrogen or C1-C4-alkyl;

R2, R3and R4are independently hydrogen, halogen, C1-C4-alkyl, C2-C4alkenyl,2-C4-quinil, aryl, heteroaryl, including five - or six-membered aromatic ring with 1 or 2 nitrogen atoms, as well as furyl or morpholyl, HE OS1-C4-alkyl, CO2R1, -CN, -NO2, -NR5R6or R2and R3or R3and R4accordingly, together with part a and G or G and D southwest a hydrogen, WITH1-C4-alkyl, C(O)R7C(O)OTHER8WITH(O)OR9, SO2R10, -NR5R6, (CH3)3Si and phenyl, or may together represent (CH2)jQ(CH2)kwhere Q represents a bond; j is 2 and k is 0 to 2;

R7, R8, R9, R10and R11are independently C1-C4-alkyl, NH2, aryl or its enantiomer,

and their pharmaceutically acceptable salts, and methods for their preparation, intermediate compounds and pharmaceutical compositions, which has an activating effect against nicotine7-acetylcholine receptors and can be used for the treatment and prevention of psychotic disorders and disorders of the type of lower intellectual

The invention relates to a method for producing derivatives 4A,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, in the case neobmennoe alkyl group; at least one lower, if necessary, the branched alkinoos group; at least one lower, if necessary branched alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, the nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, halides

FIELD: medicine.

SUBSTANCE: agent possessing the anti-inflammatory, antipyretic and antimicrobial action representing a dry extract of drug hedge hyssop leaves and blossom by grinding them, extracting in 96% alcohol on a water bath to a boil, and boiling, evaporating, diluting the evaporated residue by distilled water first, adding chloroform then, cooling to a room temperature and centrifuging, separating a water fraction and drying it in the certain environment.

EFFECT: agent possesses the pronounced anti-inflammatory, antipyretic and antimicrobial action.

5 dwg, 5 tbl, 2 ex

FIELD: biotechnology.

SUBSTANCE: invention is a composition having antibacterial, immunostimulating, anti-allergic and anti-inflammatory action, containing bacterial waste products useful for human body, in the form of exometabolites and fermentolysis products, characterised in that it is a culture medium of lactic acid bacteria, containing laxarane in an amount of 5-10 g/ml, caseicyne, isracydine or their mixture and lectins in an amount of 0.05-2.5 mol/l, histamine in an amount of 0.8-2.0 mmol/l and monocarboxylic fatty acid with an unbranched chain, namely, acetic acid, propionic acid, butyric acid and valeric acid - in an amount of 10-20 mg/ml.

EFFECT: expanding the range of agents having complementary antibacterial, immunomodulating, anti-allergic and anti-inflammatory action.

4 cl, 5 ex

FIELD: medicine.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a method of treating visceral pain and/or one or more symptoms of visceral pain, involving administering a therapeutically effective amount of an antagonist antibody against calcitonin gene-related peptide (CGRP) into an individual suffering visceral pain, or an individual suffering a risk of visceral pain, wherein the CGRP agonist antibody is applicable for peripheral administration. What is also presented is a pharmaceutical composition containing the CGRP agonist antibody and a pharmaceutically acceptable carrier, applicable for peripheral administration.

EFFECT: presented group of inventions provides the effective treatment of visceral pain with using no opiates.

18 cl, 3 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to lambertianic acid amides of formula (Ia, b), which have expressed analgesic activity and stimulating action, manifested in increase of motor and investigation activity of animals, absence of anxiety, etc. In formula I ; (Ib).

EFFECT: improvement of compound properties.

6 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: in general formula

A represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C1-C5alkyl, possibly substituted with C1-C3alkoxy, C3-C6cycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C1-C5alkyl, C1-C5alkoxy, halogen, C1-C5acylamino group, or naphthyl; or amino group is selected from C3-C7heterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C1-C3alkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C1-C6alkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C1-C5alkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C1-C5alkyl, C1-C5alkoxy, C1-C5alkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C1-C5alkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C1-C3alkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C2-C6alkenyl; aryl, selected from phenyl, substituted with C1-C5alkyl, C1-C5alkoxy, ethylenedioxy, methylenedioxy, halogen, C1-C3alkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C4-C6cycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.

EFFECT: increased efficiency of application of compounds.

12 cl, 8 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new crystalline forms of acid addition salts of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, wherein the acid is specified in methanesulphonic, maleic, fumaric, citric, orotic, 10-camphor sulphonic acids and fencifose. The salts possess the agonist properties of neuronal nicotine receptor (NNR) and can be used for managing or preventing pain, an inflammation or a CNS disorder. Each of the crystalline salts is characterised by an X-ray powder diffraction diagram. The invention also involves an amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate and polymorphic forms of the above crystalline salts.

EFFECT: invention refers to a pharmaceutical composition containing an effective amount of the presented salts.

19 cl, 8 dwg, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: biotechnology.

SUBSTANCE: humanised antibody against human IFN-α is proposed, obtained based on the murine antibodies ASO-1. Also the therapeutic composition and method of prevention, treatment or diminution of intensity of the symptoms of an autoimmune or inflammatory disease or disorder is considered.

EFFECT: invention may find further application in treatment of IFN-α-related diseases.

13 cl, 13 dwg, 18 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: in formula (I) each of A1, A2 and A3 is independently selected from the group, consisting of O and S, R1 represents an alkyl chain with the length of 2-28 carbon atoms, R2 is selected from the group, consisting of (3-carboxy)propyl and (20carboxy)ethyl, and R3 is selected from the group, consisting of H, C1-20acyl, phosphate, phosphocholine, phosphoethanolamine, phosphoethanolamine-N-glutaric acid and phosphoserine. The invention also relates to a pharmaceutical composition, containing the said compounds, and to the application of the compounds for manufacturing a medication, intended for treatment or prevention of diseases or disorders, associated with inflammation, or for the reduction of the level of cytokine, selected from the group, consisting of interleukin-12 and interleukin-23.

EFFECT: increase of the treatment efficiency.

60 cl, 39 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: biotechnology.

SUBSTANCE: aqueous composition for anaesthesia is proposed, which comprises propofol as an active agent, the PEG-660-12-hydroxystearate as a solubiliser, benzyl alcohol, or chloroethanol or parabens as preservative, the tocopherol and arginine or glycine at a specific content of components wt %. The GABA agonists can be additionally added to the composition, e.g. aminophenyl-butyric acid, local anesthetics such as lidocaine, alpha-2-adrenoceptor agonists such as xylazine. The method is proposed for implementing anaesthesia comprising administering to a patient of an effective amount of the claimed composition.

EFFECT: invention provides low toxicity of dosage form and high efficiency.

5 cl, 3 tbl, 1 ex

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