Composition for treating pain and/or inflammation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of peptide, which has sequence originating from amino acid sequence of protein SNAP-25, for treatment of pain and/or inflammation.

EFFECT: obtaining novel composition.

9 cl, 1 dwg, 1 tbl, 2 ex

 

The SCOPE of the INVENTION

The present invention relates to compositions for the treatment of pain and/or inflammation, preferably for the treatment of acute pain, chronic pain, inflammatory pain, pain caused by cancer or cancer treatment, visceral pain, neuropathic pain, post herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, migraine and fibromyalgia. This composition contains an effective amount of at least one peptide having the sequence originating from the amino acid sequence of the protein SNAP-25, or its cosmetically or pharmaceutically acceptable salts.

PRIOR art

Pain is a serious social and economic problem. According to estimates, over two million people every day become disabled, suffering from transient or chronic pain [Williams, M., Kowaluk, E.A. and Americ S.P (1999) "Emerging Molecular approaches to pain therapy" J. Med. Chem. 42, 1481-1500]. A clear example is the increased sensitivity to pain experienced by patients suffering from cancer, migraines, arthritis, burns, trauma, and surgical interventions. Pain without effective treatment can be exhausting for people, limiting their opportunities, reducing their mobility, causing sleep disorders and significantly impairing ka is estvo their lives. Despite the seriousness of the problem, the pharmaceutical Arsenal to combat, prevent and/or minimize its symptoms and its development is unexpectedly limited, partly due to the lack of specific therapeutic targets for exposure to and knowledge of the metabolic pathways, mediating the transduction of pain.

The integrity of our body is correctly connected to two highly specialized systems: the immune system and nervous system. In the case of tissue damage caused by harmful stimuli physical or chemical nature, both systems operate in interaction, leading to sensitization of the affected area to stop the spread of damage and ensure quick recovery of damaged areas [Belmonte, C. and Cervero, F. Eds. (1996) "Neurobiology of Nociceptors" Oxford University Press]. This process is called inflammation, and it can be one of two types, either humoral, if it is mediated mainly by the immune system, or neurogenic, if it is caused by the nervous system. In any case, one important aspect is that both types of inflammation reinforce each other, thereby increasing the perception of pain accompanying inflammatory process.

The pain sensation you receive when you activate peripheral endings sensitive groups of neurons, known as the nociceptor the s neurons, or nociceptors, chemical, mechanical or thermal noxious stimuli. Nociceptive neurons transmit information about the tissue damage in the centers of pain in the spinal cord and brain [Belmonte, C. and Cerver6, F. Eds. (1996) "Neurobiology of Nociceptors" Oxford University Press; Baranauskas, G. and Nistri, A. (1998) "Sensltization of pain pathways in the spinal cord: cellular mechanisms" Prog. Neurobiol. 54, 349-365; Richardson, D.J. and Vasko, M.R. (2002) "Cellular mechanisms of neurogenic inflammation" J. Pharmacol. Exp. Ther. 302, 839-845J. An important property of nociceptors is that although they are mainly primary afferent neurons, when activated, they are able to perform efferent function, releasing Pro-pain and anti-inflammatory molecules, such as substance P (SP), a peptide related to calcitonin (CGRP), histamine, adenosine triphosphate (ATP), glutamate and bradykinin (BK). These molecules stimulate autocrine and paracrine activation of neighboring neurons, and cells of other types, such as mast cells, neutrophils and platelets. When you activate surrounding cells, non-neuronal release neurotrophins (nerve growth factor (NGF)), cytokines (tumor necrosis factor α (α-TNF), interleukin-1β (IL1-β), interleukin-6 (IL-6)), prostaglandins, leukotrienes and protons, giving inflammatory exudate acid properties. All of these factors in turn act on nociceptors, strengthening local vospolenie is or neurogenic inflammation changing the sensitivity of nociceptors or peripheral sensitization and the resulting changes in the perception of stimuli acting on the damaged area, such as hyperalgesia, which is defined as abnormally increased response to slightly harmful stimulus, such as low temperature 35-40°C, or allodynia, which is defined as the phenomenon painful perception of innocuous stimuli such as light wind [Belmonte, C. and Cerver6, F. Eds. (1996) "Neurobiology of Nociceptors" Oxford University Press; Baranauskas, G. and Nistri, A. (1998) "Sensitization of pain pathways in the spinal cord: cellular mechanisms" Prog. Neurobiol. 54, 349-365; Richardson, D.J. and Vasko, M.R. (2002) "Cellular mechanisms of neurogenic inflammation" J. Pharmacol. Exp. Ther. 302, 839-845; Brune, K. and Handworker, H.O. Eds. (2004) "Hyperalgesia: molecular mechanisms and clinical implications" Progress in Pain Research and Management, vol 30. IASP Press. Seattle]. Constant excitability of peripheral nociceptors leads to changes in the synapses at the level of the spinal cord that leads to the process of Central sensitization, which in turn enhances the perception of pain in inflamed areas [Richardson, D.J. and Vasko, M.R. (2002) "Cellular mechanisms of neurogenic inflammation" J. Pharmacol. Exp. Ther. 302, 839-845; Brune, K. and Handworker, H.O. Eds. (2004) "Hyperalgesia: molecular mechanisms and clinical implications" Progress in Pain Research and Management, vol 30. IASP Press. Seattle].

Molecular and cellular basis of neurogenic inflammation and its regulation by inflammatory mediators largely unknown, mainly due to weeks is enough information about the molecular identity of many of the involved receptors and ambiguities signaling pathways involved in the operation of nociceptors. However, it is known that the mechanisms by which components of the inflammatory exudate modifying neuronal excitability, can act directly through interaction with ion channels on the surface of nociceptors or indirectly through intracellular cascades [Richardson, D.J. and Vasko, M.R. (2002) "Cellular mechanisms of neurogenic inflammation" J. Pharmacol. Exp. Ther. 302, 839-845; Brune, K. and Handworker, H.O. Eds. (2004) "Hyperalgesia: molecular mechanisms and clinical implications" Progress in Pain Research and Management, vol 30. IASP Press. Seattle]. Thus, BK, NGF and interleukins render action, activating metabolic pathway that activates protein kinase a protein kinase C (CSWs) and protein kinase a (PKA), which can alter membrane receptors engaged in the transduction of external stimuli, and/or modulation of gene expression of neurons (especially in chronic inflammatory processes). Receptors-target intracellular signaling pathways include the potential-dependent ion Na+channels, and vanilloideae the TRPV1 receptor, sensory integrator chemical and thermal noxious stimuli, and mechanochemically channels. Activation of these receptors triggers action potentials, stimulating the afferent and efferent function of nociceptors, leading to increased peripheral and Central sensitization. Thus, all those observing the demonstrate the key role of neurogenic or neurological inflammation in acute and chronic inflammatory processes. Therefore, compounds that reduce the intensity of neurogenic inflammation, will have anti-inflammatory and analgesic activity. For example, the antagonists involved neural receptors such as TRPV1, PA+channels, receptors bradykinin or purinergic (purinegenic) receptors, will act as a powerful anti-inflammatory and/or analgesic agents. Evidence of this are the antagonists of the TRPV1 receptor [Garcia-Martinez, C., Planells-Cases, R., Fernandez, A.M. Royo, M.; Albericio, F., Messeguer, A., Perez-Paya, E., Saggio, C. and Ferrer-Montiel, A. (2003) "Small molecules targeting the TRPV1 complex as new drugs for pain management," Drugs of the Future 28, 15-23].

Despite this knowledge, modern anti-inflammatory and/or analgesic compounds is limited to non-steroidal anti-inflammatory drugs (NSAID)such as aspirin or ibuprofen and narcotic drugs such as morphine. NSAIDs have side effects that limit their use; on the one hand, they have a limit of activity, after which increasing the dose does not reduce pain, on the other hand, they can also cause irritation in the intestinal tract, and for this reason their prolonged use can lead to the development of stomach ulcers. This is certainly important for elderly patients, often receiving NSAID on a daily basis for the treatment of chronic and is kriticheskih pathological conditions. Unfortunately, opioids also have unwanted side effects such as constipation, depression of the respiratory system and psychoactive effects, such as euphoria, sedation and addictive. These side effects occur when using doses similar to doses used in the treatment, so dose that can be entered to the patients is very limited, and this means that their application is often referred to the treatment of patients with incurable diseases.

Thus, there is a significant need to increase the existing pharmacological Arsenal for the treatment of pain.

However, in addition to action at the level of neural receptors, molecular basis of neurogenic inflammation also include additional therapeutic target, such as a blockade or inhibition of release of proinflammatory (or Pro-pain) neurogenic substances, such as CGRP, substance P, L-glutamate, ATP, histamine, and the like, provide stimulation of the immune and nervous systems. The release of Pro-pain neurogenic substances occurs through the mechanism of exocytosis-dependent cation Ca2+and mediated by SNARE proteins [Bennett, M.K. and Scheller, R.H. (1993) "The molecular machinery for secretion is conserved from yeast to neurons" Proc. Natl. Acad. Sci. USA 90, 2559-2563; Sudhof, T.C. (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions", Nature 375, 645-653; Yang, Y., Xia, Z., and Liu, Y. (200) "SNAP25 functional domains in the SNARE core complex assembly and release of glutamate cerebellar granule cells" J. Biol. Chem. 275, 29482-29487; Brunger, A.T. (2001) Structure of proteins involved in synaptic vesicle fusion in neurons" Annu. Rev. Biophys. Biolmof. Struct. 30, 157-171; Chen, Y.A. and Scheller, R.H. (2001) "SNARE-mediated membrane fusion" Nat. Rev. Mol. Cell Biol. 2, 98-106].

In the modern prior art it is known that subcutaneous injection of botulinum toxin a, a potent inhibitor of neuronal exocytosis, a destructive protein SNAP-25 [Bennett, M.K. and Scheller, R.H. (1993) "The molecular machinery for secretion is conserved from yeast to neurons" Proc. Natl. Acad. Sci. USA 90, 2559-2563; Sudhof, T.C. (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions", Nature 375, 645-653], reduces pain caused vnutripolostny the introduction of a chemical irritant formalin [Cui, M., Khanijou, S., Rubino, J. and Aoki, K.R. (2004) "Subcutaneous administration of botulinum toxin A reduces formalin-induced pain" Pain 107, 125-133]. Development of different serotypes of botulinum toxin for the treatment of various types of pain known in modern technology, such as, without limitation, therapeutic applications, are described, inter alia, in US patents 7381700, US 7374769, US 7361358, US 7294339, US 7255866, US 7211262, US 7172763, US 7091176, US 7067137, US 6887476, US 6869610, US 6838434, US 6776992, US 6641820, US 6623742, US 6565870, US 6500436, US 6464986, US 6458365, US 6423319, US 6372226, US 6333037, US 6235289, US 6113915 and US 5714468.

However, the toxicity inherent in the botulinum toxin, leads to the fact that his introduction to a wide range of doses includes any unwanted side effects, such as immunogenic responses, headaches, nausea, paralysis or muscle weakness, respiratory failure and, in extreme cases, death is the subject, treatment [PDA News, February 8, 2008, "PDA Notifies Public of Adverse Reactions Linked to Botox Use"; Cote, T.R., Mohan, A.K., Polder, J.A., Walton, M.K. and Braun, M.M. (2005) "Botulinum toxin type A injections: Adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases" J. Amer. Acad. Derm. 53 (3), 407-415]. These serious side effects, together with the high cost of treatment, severely limit the use of botulinum toxin for the treatment of pain and/or inflammation, relating to applications for chronic conditions and/or pathological conditions, from which there is no suitable treatment. For this reason, there is a need in finding a safer alternative treatment with compounds that mimic the action of botulinum toxin, but not cause immune reactions, with fewer side effects and less expensive to obtain.

The author of the present invention have found that there are compounds that may exhibit anti-inflammatory and/or analgetic activity, inhibiting the formation of the SNARE complex, required for neuronal exocytosis, and to solve problems caused by treatment with botulinum toxin. In the modern prior art it is known that certain peptides, originating from protein sequences, forming the SNARE complex can inhibit neuronal exocytosis, such as, for example, peptides, originating from the N-terminal and C-terminal domains of the tree of SNAP-25 [Apland, J.P., Biser, J.A., Adier, M., Ferrer-Montiel, A.V., Mental, M., Canaves, J.M., and Filbert, M.G. (1999) "Peptides that mimic the carboxy-terminal domain of SNAP-25 block acetylcholine release at an aplysia synapse" J. Appl. Toxicol. 19, Suppl. 1: S23-S26; Mehta, P.P., Battemger, E., and Wilson, M. (1996) "SNAP-25 and synaptotagmin involvement in the final Ca2+-dependent triggering of neurotransmitter exocytosis" Proc. Natl. Acad. Sci. USA 93: 10471-10476; Ferrer-Montiel, A.V., Gutierrez, L.M., Apland, J.P., Canaves, J.M., Gil, A., Viniegra, S., Biser, J.A., Adier, M., and Montal, M. (1998) "The 26-mer peptide released from cleavage by botulinum neurotoxin E inhibits vesicle docking" FEBS Lett. 435, 84-88; Gutierrez, L.M., Canaves, J.M., Ferrer-Montiel, A.V., Reig, J.A., Montal, M. and Viniegra, S. (1995) "A peptide that mimics the carboxy-terminal domain of SNAP-25 blocks Ca2+-dependent exocytosis in chromaffin cells" FEBS Lett. 372, 39-43; Gutierrez, L.M., Viniegra, S., Rueda, J., Ferrer-Montiel, A.V., Canaves, J.M., and Montal, M. (1997) "A peptide that mimics the C-tenninal sequence of SNAP-25 inhibits secretory vesicle docking in chromaffin cells" J. Biol. Slit, 2634-2639; Blanes-Mira, C, Valera, E., Femandez-Ballester, G., Merino, J.M., Viniegra, S., Gutierrez, L.M., Perez-Paya, E., and Ferrer-Montiel, A. (2004) "Small peptides patterned after the N-terminus domain of SNAP-25 inhibit SNARE complex assembly and regulated exocytosis" J. Neurochem. 88, 124-135], peptides, originating from the amino acid sequence syntaxin [Martin, F., Salinas, E., Vazquez, J., Soria, C., and Reig, J.A. (1996) "Inhibition of insulin release by synthetic peptides show that the H3 region at the C-terminal domain of syntaxin-1 is crucial for Ca2+-but not for guanosine 5'-[gamma-thio]thriphosphate-induced secretion" Biochem. J. 320, 201-205], synaptobrevin [Comille, F., Deloye, F., Foumie-Zaluski, M.C., Roques, B.P. and Poulain, B. (1995) "Inhibition of neurotransmitter release by synthetic proline-rich peptides shows that the N-terminal domain of vesicle-associated membrane protein/synaptobrevin is critical for neuro-exocytosis" J. Biol. Chem. 270, 16826-16830], synaptotagmin [Mehta, P.P., Battemger, E., and Wilon, M. (1996) "SNAP-25 and synaptotagmin involvement in the final Ca2+-dependent triggering of neurotransmitter exocytosis" Proc. Natl. Acad. Sci. USA 93: 10471-104], and protein Snapin (Snapin) [llardi, J.M., Mochida, S., and Sheng, Z.H. (1999) "Snapin: A SNARE associated protein implicated in synaptic transmission" Nat. Neurosci. 2, 119-124]. Similarly, the rational design or by scanning synthetic chemical libraries were also derived synthetic peptides that can inhibit the formation of the SNARE complex by inhibiting neuronal exocytosis [Blanes-Mira, C., Pastor, M.L., Valera, E., Femandez-Ballester, G., Merino, J.M., Gutierrez, L.M., Perez-Paya, £., and Ferrer-Montiel, A. (2003) "Identification of SNARE complex modulators that inhibit exocytosis form an a-helix-constrained combinatorial library" Biochem J. 375, 159-166].

Industrial application of compounds of this type are limited. In the cosmetic industry has been a major effort to develop compounds that mimic the action of botulinum toxin, for exclusive use in the treatment and prevention of facial wrinkles [Blanes-Mira, C., Clemente, J., Joe/as, G., Gil, A., Femandez-Ballester, G., Ponsati, C., Gutierrez, L.M., Perez-Paya, E. and Ferrer-Montiel, A. (2002) "A synthetic hexapeptide (Argireline®) with anti-wrinkle activity" Int. J. Cosmet. Sci. 24, 303-310]. Specifically, in patent applications OR A1 and WO 2008/049945 from Lipotec, S.A., described peptides, originating from the N-terminal fragment of the protein SNAP-25, available or modified at their N - and/or C-terminal regions, with the effect against wrinkles, and in international application WO 97/34620 also described pepti is s, originating from the amino acid sequence of the protein SNAP-25 in particular, it is the end, or synaptobrevin, or syntaxin able to inhibit neuronal exocytosis.

None of the above patents is not to the use of peptides having the origin of the protein SNAP-25, as analgesic and/or anti-inflammatory agent, nor, in particular, to the use of peptides having the origin of the protein SNAP-25, for the treatment of pain and/or inflammation.

According to this invention, the proposed solution needs, including a demonstration that the peptides having the origin of the protein SNAP-25, the blocking neuronal exocytosis, are anti-inflammatory and/or analgesic.

Description of the INVENTION

According to this invention a simple, effective and reliable solution for the treatment of pain and/or inflammation comprising applying a composition containing at least one peptide having the sequence of 3-40 neighboring amino acids included in the amino acid sequence of the protein SNAP-25, a certain SEQ ID NO:1.

Therefore, the first aspect of the present invention relates to compositions for the treatment of pain and/or inflammation, containing an effective amount of at least one peptide of General formula (I);

the th stereoisomers and racemic or narramissic mixtures, and its cosmetically or pharmaceutically acceptable salts, where

AA is a sequence of 3-40 neighboring amino acids included in the amino acid sequence of SEQ ID NO:1;

R1selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-C(O)-; and

R2selected from the group consisting of-NR3R4, -OR3and-SR3where R3and R4independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;

where R5selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group, and substituted or unsubstituted heteroaryl is Lila.

In one particular embodiment of the composition for treating pain and/or inflammation is a cosmetic or pharmaceutical composition.

In another specific embodiment of AA is a sequence of 3-30 neighboring amino acids included in the amino acid sequence of SEQ ID NO:1.

In another specific embodiment of the preferred structure of the peptides represented by the General formula (I)represent patterns, where

R1represents H, substituted or unsubstituted non-cyclic aliphatic group having 2-24 carbon atoms, substituted or unsubstituted alicikoglu group having 2-24 carbon atoms, or R5-C(O)-, where R5represents a substituted or unsubstituted non-cyclic aliphatic group having 1-24 carbon atoms, or substituted or unsubstituted alicikoglu group having 1-24 carbon atoms; and

R2represents-NR3R4or-or SIG3where R3and R4independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group having 1-24 carbon atoms, and substituted or unsubstituted aliciella group having 1-24 carbon atoms.

In another specific embodiment of the preferred patterns are patterns where 1is a polymer of polyethylene glycol. Even more preferred structures are structures where the polymer of the polyethylene glycol is a

,

where n can vary from 1 to 100 and most preferably can vary from 1 to 5.

In another specific embodiment of the preferred patterns are patterns, where R1represents H, acetyl, tert-butanol, hexanol, 2-methylhexanoic, cyclohexanecarbonyl, octanoyl, decanoyl, lauroyl, myristoyl, Palmitoyl, stearoyl, oleoyl and linoleoyl.

In another specific embodiment of the preferred patterns are patterns, where R3and R4independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl.

The peptides included in the composition according to this invention can exist in the form of stereoisomers or mixtures of stereoisomers; for example, the constituent amino acids may be L-, D-configuration, or to be racemic independently from each other. Thus, it is possible to obtain mixtures of isomers as well as racemates or mixtures of diastereomers or pure diastereomers or enantiomers, depending on the number of asymmetric carbon atoms and which isomers or mixtures of isomers are present. Prefer the performance communications patterns of peptides, included in the composition according to the invention are pure isomers, i.e. enantiomers or diastereomers.

In the context of this invention the term "non-cyclic aliphatic group" used in this invention to include, for example, without limitation, alkyl, alkenyl and etkinlik groups, linear or branched.

The term "alkyl group" refers in this invention to a linear or branched saturated group having 1 to 24, preferably 1 to 16, even more preferably 1 to 14, still more preferably 1-12, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms, and linked with the rest of the molecule by a simple bond, including, for example, without limitation, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl A 5-methylhexan and the like.

The term "Alchemilla group" refers in this invention to the group having 2-24, preferably 2 to 16, even more preferably 2-14, even more preferably 2 to 12, even more preferably 2, 3, 4, 5 or 6 carbon atoms, with one or more than one double carbon-carbon bond, preferably 1, 2 or 3 double carbon-carbon bonds, paired or unpaired, associated with the rest of the molecule by a simple bond, including, n is the sample, without limitation, a vinyl group, oleyl, linoleyl and the like.

The term "Alchemilla group" refers in this invention to the group having 2-24, preferably 2 to 16, even more preferably 2-14, even more preferably 2 to 12, even more preferably 2, 3, 4, 5 or 6 carbon atoms, with one or more than one triple carbon-carbon bond, preferably 1, 2 or 3 triple carbon-carbon bonds, paired or unpaired, associated with the rest of the molecule by a simple bond, including, for example, without limitation, group ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, for example, 1-pentenyl, and the like.

The term "aliciella group" used in this invention to include, for example, without limitation, cycloalkyl, or cycloalkenyl, or cycloalkenyl groups.

The term "cycloalkyl" refers in this invention to mono - or polycyclic saturated aliphatic group having 3 to 24, preferably 3 to 16, more preferably 3 to 14, more preferably 3 to 12 and more preferably 3, 4, 5 or 6 carbon atoms, and linked with the rest of the molecule by a simple bond, including, for example, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, dimethylcyclohexyl, octahedrons, damaged naftalin, dodecahedronal and the like.

The term "cycloalkenyl" refers in this invention to mono - or polycyclic non-aromatic aliphatic group having 5-24, preferably 5 to 16, even more preferably 5 to 14, more preferably 5 to 12 and even more preferably 5 or 6 carbon atoms, with one or more than one double carbon-carbon bond, preferably 1, 2 or 3 double carbon-carbon bonds, paired or unpaired, and linked with the rest of the molecule by a simple bond, including, for example, without limitation, group cyclopent-1-EN-1-yl and the like.

The term "cycloalkenyl" refers in this invention to mono - or polycyclic non-aromatic aliphatic group having 5-24, preferably 5 to 16, even more preferably 5 to 14, more preferably 5 to 12 and even more preferably 5 or 6 carbon atoms, with one or more than one double carbon-carbon bond, preferably 1, 2 or 3 triple carbon-carbon bonds, paired or unpaired, and linked with the rest of the molecule by a simple bond, including, for example, without limitation, group cyclohex-1-Jn-1-yl and the like.

The term "aryl group" refers in this invention to an aromatic group having 6-30, preferably 6 to 18, more preferably 6-10 is more preferably 6 or 10 carbon atoms, consisting of 1, 2, 3 or 4 aromatic rings linked by carbon-carbon bond or condensed, including, for example, without limitation, inter alia, phenyl, naphthyl, diphenyl, indenyl, phenanthrol or anthranol, or aranceles group.

The term "kalkilya group" refers in this invention to the alkyl group, substituted aromatic group having 7-24 carbon atoms and including, for example, without limitation, -(CH2)1-6-phenyl, -(CH2)1-6-(1-naphthyl), -(CH2)1-6-(2-naphthyl), -(CH2)1-6-CH(phenyl)2and the like.

The term "heterocyclyl group" refers in this invention to 3-10-membered hydrocarbon ring in which one or more than one atom in the ring, preferably 1, 2 or 3 atom of the ring is an element other than carbon, such as nitrogen, oxygen or sulphur, and which may be saturated or unsaturated. For the purposes of this invention, the heterocycle may be a cyclic, monocyclic, bicyclic or tricyclic system, which may include a condensed ring system, and the atoms of nitrogen, carbon or sulfur in heterocyclyl radical may be oxidized; the nitrogen atom may possibly be Quaternary, and the heterocyclic radical may be partially or fully nassen the m or to be aromatic. More preferably, the term "heterocyclic" refers to 5 - or 6-membered ring.

The term "heteroallyl group" refers in this invention to an alkyl group substituted by a substituted or unsubstituted aromatic heterocyclyl group, where the alkyl group has 1-3 carbon atoms, and aromatic heterocyclyl group has 2-24 carbon atoms and 1 to 3 atoms other than carbon, including, for example, without limitation, -(CH2)1-6-imidazolyl, -(CH2)1-6-triazolyl, -(CH2)1-6-thienyl, -(CH2)1-6-furyl, -(CH2)1-6-pyrrolidinyl and the like.

As understood in the art, the radicals defined above, can be to some extent replaced. Thus, any group in this invention can be substituted. In this application references to substituted groups in groups of this invention means that the organic radical can be substituted by one or more than one available position by one or more than one Deputy, preferably 1, 2 or 3-positions, more preferably 1 or 2 terms and even more preferably 1 position. Such substituents include, for example, without limitation, With1-C4alkyl; hydroxyl; C1-C4alkoxyl; amino; C1-C4aminoalkyl; the 1-C4carbonyloxy; C1-C4oxycarbonyl; halogen, such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido,1-C4alkylsulfonyl; thiol; C1-C4alkylthio; aryloxy, such as phenoxy, -NRb(C=NRb)NRbRcwhere Rband Rcindependently selected from the group consisting of H, C1-C4of alkyl, C2-C4alkenyl,2-C4the quinil,3-C10cycloalkyl,6-C18aryl, C7-C17aralkyl, 3-10-membered heterocyclic group or amino-protective group.

In the context of this invention, "amino acid sequence, with the origin of the amino acid sequence of the protein SNAP-25" refers to any amino acid sequence or fragments of the amino acid sequence of the protein SNAP-25, a certain SEQ ID NO:1, or any amino acid sequence that differs from the sequence SEQ ID NO:1 by mutation, insertion, deletion or substitution of at least one amino acid, or degeneracy of the genetic code, provided that it meets the peptide having the activity of a protein SNAP-25. Mutation, insertion or replacement can be carried out by the amino acids encoded by the genetic code, or non-coding amino acids, natural or artificial, for example, b is C restrictions among other things, citrulline, ornithine, sarcosine, desmosine, Norvaline, 4-aminobutyric acid, 2-aminobutyric acid, 2-aminoethanol acid, 6-aminohexanoic acid, 1-naphtylamine, 2-naphtylamine, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminoalkanes acid, cycloserine, carnitine, cysteine, penitsillaminom, pyroglutamic acid, titillandus, hydroxiproline, alliteration, allocreadium, isonipecotic acid (isonipecotic acid), azaserine, phenylglycinol, statin, beta-alanine, norleucine, N-methyliminodiacetic, beta - or gamma-amino acids and their derivatives. List of artificial amino acids can be found in the article "Unusual amino acids in peptide synthesis" D.C. Roberts and Vellaccio F., in "The Peptides", Vol 5 (1983), Chapter VI, Gross, E. and Meienhofer, J., Eds., Academic Press, New York, USA, or commercial directory of companies specializing in this sector, such as, among others, NeoMPS, Bachem, Novabiochem, Sigma-Aldrich, Peptides International, Advanced ChemTech, Chem-lmpex, Maybridge Chemical, Chirotech Technology, Peninsula Laboratories or RSP Amino Acid Analogues.

Among the peptides originating from the amino acid sequence of SNAP-25, a certain SEQ ID NO:1, is included in compositions according to the invention, preferred sequences are sequences that have a sequence of neighboring amino the slot, included in the sequence of aminobenzoic region of the protein SNAP-25, a certain SEQ ID NO:2, or carboxykinase region of the protein SNAP-25, a certain SEQ ID NO:3, more preferably in the region from 10 to 22 balance, certain SEQ ID NO:4, or a member of the region from 25 to 40 residue certain SEQ ID NO:5, or a member of the region from 65 to 81 the rest, a certain SEQ ID NO:6, or a member of the region with 181 206 on balance, a certain SEQ ID NO:7, more specifically, included in the region from 12 to 19 balance, certain SEQ ID NO:8, or a member of the region from 26 to 38 balance, certain SEQ ID NO:9, or a member of region 68 through 79 balance, certain SEQ ID NO:10, and especially included in the region from 12 to 17 balance, certain SEQ ID NO:11.

In particular, the preferred amino acid sequence preferably represent a sequence having a sequence of adjacent amino acids included in any of the sequences selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32.

In addition, the invention also includes compositions containing the peptides, essentially homologous peptides, originating from the amino acid sequence of the protein SNAP-25,passed irreversible chemical modification. "Essentially homologous peptides of this invention indicated amino acid sequence at least 60%, preferably 80% and more preferably 95%identical to any of the preceding sequences. "Percent identity" refers to the percentage of amino acids that are identical in the two compared amino acid sequences after optimal alignment of these sequences, where this percentage is purely statistical and the differences between the two amino acid sequences are randomly distributed along the sequence. The term "optimal alignment" refers to the alignment of amino acid sequences leading to a greater percentage of identity. The percentage identity is calculated by determining the number of identical positions where the amino acid is identical among the two compared sequences, dividing the number of identical positions by the number of compared positions and multiplying the result by 100 to obtain the percent identity of two sequences. Comparison of the sequence of two amino acid sequences can be carried out manually or using software such as the BLAST algorithm (Basic Local Alignment Search Tool), available online on the website http://www.ncbi.nlm.nih.gov/BLAST/.

In this volume izaberete the Oia also included cosmetically or pharmaceutically acceptable salts of the peptides, included in compositions according to the invention. The term "cosmetically or pharmaceutically acceptable salts" in this invention refers to salt, recognized for use in animals and, more specifically, in humans, including salt used to obtain the salts of the accession of the bases, or inorganic, such as, for example, without limitation, inter alia, salts of lithium, sodium, potassium, calcium, magnesium or aluminum, or organic, such as, for example, without limitation, inter alia, salt, ethylamine, diethylamine, Ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine, or a salt accession acids or organic, such as, for example, without limitation, among other things, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, triptorelin, oxalate, pamoate or gluconate, or inorganic, such as, for example, without limitation, among other things, chloride, sulfate, borate or carbonate. The nature of the salt is not critical, provided that it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the peptides included in the composition according to the invention can be obtained by conventional means, well known in the art [Berge, S.M., Bighley, L.D., and Monkhouse, D.C. (1977) "Pharmaceutical Salts" J. Pharm. Sci66:1-19].

In d is acceptable, possible reversible chemical modification of the peptides according to the invention for improving their bioavailability and facilitate their passage through the blood-brain barrier or epithelial tissue.

The peptides included in the compositions according to the invention, it is possible to enter in any way, leading to contact of peptides to place their actions in the body of a mammal, preferably humans. These compositions can be manufactured by conventional methods known to experts in the art ["Harry's Cosmeticology", Eight [sic] edition (2000) M.M. Rieger, ed., New York Chemical Pub., NY, US; "Remington: The Science and Practice of Pharmacy, Twentieth edition (2003) Genaro A.R., ed., Lippincott Williams & Wilkins, Philadelphia, US].

The peptides included in the compositions of this invention have different solubility in water, depending on the nature of their sequence or possible modifications of their amino and/or carboxy-late that they have. Therefore, the peptides of this invention can be included in the composition using an aqueous solution, and peptides, insoluble in water, can be solubilisation in a cosmetically or pharmaceutically acceptable conventional solvents, such as, for example, without limitation, ethanol, propanol, isopropanol, propylene glycol, glycerin, butyleneglycol or glycol, or any combination thereof.

An effective amount of the peptides included in to the position according to the invention, their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts, which must be entered for the treatment of pain and/or inflammation, as well as their dosage will depend on several factors, including age, condition of the patient, the cause of the pain and/or inflammation, the severity of pain and/or inflammation, the method and frequency of administration and the specific nature of the used peptides.

"Effective amount" means non-toxic but sufficient amount of at least one peptide to provide the desired effect. The peptides used in the compositions of this invention in concentrations effective to achieve the desired effect; preferably, relative to the total weight of the composition, from 0,00000001% (by weight) to 20% (by weight), preferably from 0.000001% (by weight) to 20% (by weight), more preferably from 0.0001% by mass to 10% by weight and more particularly from 0.0001% (by weight) to 5% (by weight).

In another specific embodiment, the peptides included in the composition according to the invention can also be incorporated into the delivery system and/or systems with a long release.

The term "delivery system" refers to a diluent, adjuvant, excipient or carrier with which the injected peptide derivative according to the invention. These media may be a liquid, such as water, oil and surfactant, the key such which are the origin of petroleum, animal, plant, or synthetic, such as, for example, without limitation, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, Polysorbate, esters sorbitan, ethersulfate, sulfates, betaines, glucosides, maltoside, fatty alcohols, nonoxynol, poloxamer, polyoxyethylene, polyethylene glycol, dextrose, glycerol and the like. Diluents, adjuvants or excipients suitable carriers are described in "Remington''s Pharmaceutical Sciences", E.W. Martin.

The term "extended release" is used in the usual sense in relation to the delivery system connections that provide a gradual release of the connection specified period of time and preferably, though not necessarily, with constant levels of release of the compound over a period of time.

Examples of delivery systems or systems with long release are liposomes, milecastle, microparticles, nanoparticles, sponges, vesicles, micelles, military, microspheres and nanospheres, liposphere, millicapsules, microcapsules, nanocapsules, micro-emulsions and nano-emulsion, which can be added to achieve greater penetration of the active ingredient and/or to improve its pharmacokinetic and pharmacodynamic properties.

In another specific embodiment is oppozitsii with prolonged release can be manufactured by methods known in the art, and compositions containing them can be introduced, for example, local introduction, including sticky bandages and non-sticky plasters, or system introduction, such as, for example, without limitation, enteral or parenteral route of administration, and they preferably should release a relatively constant number of peptides included in the compositions according to the invention. The number of peptide included in the composition with a long release, will depend, for example, from the place of introduction, the kinetics and duration of release of the peptide included in the compositions according to the invention, as well as the cause and severity of pain and/or inflammation, the method of administration, frequency of administration and the specific nature of the peptides.

In the context of this invention, the term "enteral or parenteral" includes oral, nasal, inhalation, rectal routes of administration, sticky or non-sticky patches, subcutaneous, intradermal, intravascular injection, such as intravenous, intramuscular, intraarterial injection, injection into the vitreous body, spinal, intracranial, intra-articular, intrathecal and intraperitoneal injection, as well as any similar methods of injection or infusion.

In another particular embodiment the composition according to the invention optionally in the cancel acceptable carriers and/or auxiliary agents, necessary for the introduction of the composition in the desired manner. Carriers and/or auxiliary agents include excipients, thickeners, thinners, solvents, dispersing agents, agents for improving freeze drying or adjuvants that are appropriate for each route of administration and well-known specialist in this field of technology. Thickeners include, without limitation, water soluble polymers, such as polymers selected from the group consisting of modified cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethyl cellulose, dextrans, gelatino, collagen, hyaluronic acid, polyethylene glycol or polyvinylpyrrolidone. Thinners and solvents include, without limitation, diluents and solvents selected from the group consisting of ethanol, polyethylene glycol, glycoluril, N-methyl-2-pyrrolidone, glycerol, propane diol, polypropylenglycol, benzyl alcohol or dimethyl sulfoxide. Dispersing agents include, without limitation, surfactants, selected from the group consisting of monoamino fatty acids and polyoxyethylenesorbitan (Tween®, Emalex, Nikkol®, Hodag, Dacol or Liposorb®), monoamino fatty acids and sorbitan (Span®), 15-hydroxystearate floor is ethylene glycol (Solutol ®HS15), esters of fatty acids and of polyethylene glycol (Crodet, Cithrol, Kessco®, Nikkol®, Mapeg®, Myrj, Tagat®, Aldo®, Capmul®, Glycerox, Lactomul®or Emerest®), esters of polyoxyethyleneglycol (Emulphor®), polyethoxylated castor oil (Cremophor®, Emalex, Eumulgin®, Nikkol®or Simusol®), esters of fatty acids and polyglycerol (Nikkol Decaglyn, Polymuls, Caprol®), ethers of polyethylene glycol (Volpo or Brij®), poloxamer (Lutrol®or Pluronic®), phenyl esters of polyoxyethylene (Triton®or Igepal®or mixtures thereof. Agents to improve freeze-drying include, without limitation, sugars such as sugar selected from the group consisting of mannitol, sucrose, glucose, fructose, lactose, trehalose, sucrose, dextrose, sorbitol, glycine, gelatin, polyvinylpyrrolidone or mixtures thereof. Preferably, the composition for treating pain and/or inflammation also includes one or more than one acceptable excipient, such as moisturizers, pH buffering agents, preservatives, antibacterial and antifungal agents, agents that slow down the absorption, agents, accelerating the absorption, or any other excipient known to the person skilled in the technical field.

In another specific embodiment, the peptides included in the compositions of this invention may also be also borovany solid organic polymers or solid mineral media, such as, without limitation, among other things, talc, bentonite, silica, starch or maltodextrin.

In another specific embodiment of the compositions according to the invention can also be incorporated into fabrics, non-woven fabrics and medical devices in direct contact with the skin, mucous membranes and/or scalp, so that they release the peptides either by biodegradation locking system cloth, non-woven fabric or medical device, or in the force of friction fabric, non-woven fabric or medical device on the body, sweating, skin pH or body temperature. Similarly, fabrics and non-woven materials can be used for making clothes directly in contact with the body.

Examples of fabrics, non-woven materials, clothing, medical devices and means of fixation of peptides, including delivery systems and/or systems with a long release, described above, is described and can be found in the literature and known in the art [Schaab C.K. (1986) "Impregnating Fabrics With Microcapsules", HAPPI May 1986; Nelson G. (2002) "Application of microencapsulation in textiles" Int. J. Pharm. 242:55-62; "Bio-functional Textiles and the Skin" (2006) Curr. Probl. Dermatol. v.33, Hipfer U.C. and ElsnerP., eds. S. KargerAG, Basel, Switzerland; Malcom R.K., McCullagh S.D., Wool f son A.D., German S.P., Jones D.S. and Cuddy J. (2004) "Controlled release of a model antibacterial drug from a novel self-lubricating silicone bioaterial" J. Cont. Release 97:313-320]. Preferred fabrics, non-woven materials, clothing, and medical devices are bandages, gauze, t-shirts, socks, stockings, underwear, girdles, gloves, diapers, wraps, bandages, bed covers, napkins, hydrogels, adhesive patches, non-sticky plasters, Mikroelektronika patches (micro-electric patches) and/or face masks.

In another specific embodiment of the compositions containing the peptides according to this invention, their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts can be used in various types of compositions for local or dermal application, which will probably contain acceptable excipients necessary for the manufacture of the desired dosage form [Fault I Trillo C. (1993) in "Tratado de Farmacia Galenica" [Treatise on Galenic Pharmacy], Luzan 5, S.A. Ediciones, Madrid].

Compositions for local or percutaneous application can be submitted in any solid, liquid or semi-solid dosage form, such as, for example, without limitation, creams, heterogeneous emulsion, such as, for example, without limitation, emulsions of oil and/or silicon in water, emulsion water in oil and/or silicon, the emulsion of the type water/oil/water or water/silicon/water emulsion type oil/water/oil or silicon/water/silicon", anhydrous compositions, aqueous dispersions, oil, milk, Bal is the AMA, foams, lotions, gels, hydroalcoholic solutions, liquid, ointments, serums, Soaps, shampoos, ointments, mousses, lipstick, powders, chalks, pencils and spray or aerosol ("spray"), including songs leave after application ("leav-on"composition), and compositions, rinse-off after application ("rinse-off compositions). These compositions for local or percutaneous application can be enabled by techniques known to a person skilled in the technical field in different types of solid accessories, such as, for example, without limitation, tissues, hydrogels, adhesive patches, non-sticky patches or face masks, or can be incorporated into various cosmetic products.

In another specific embodiment of the compositions according to the invention may additionally include agents that enhance percutaneous absorption of peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts, such as, for example, without limitation, among others, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylsulfate-2-one), alcohol, acetone, propylene glycol or polyethylene glycol. Similarly, the compositions of this invention can be applied to limited areas for the introduction of local or percutaneous method of injection intradermally through the injection iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or injection under pressure without the use of needles, such as injection pressure of oxygen, Mikroelektronika patches, or any combination thereof, to achieve greater penetration of the peptide according to the invention. The scope of application will be determined by the nature of pain and/or inflammation to be treated.

The composition of the invention can also be entered, in addition to the local or percutaneous method of administration, any other suitable method, for example, enteral or parenteral method of administration, with the inclusion of acceptable excipients necessary for the manufacture of the desired dosage form. An overview of the different dosage forms of active ingredients and excipients required for their production can be found, for example, in the "Tratado de Farmacia Galenica", C. Fauli i Trillo, 1993, Luzan 5, S.A. Ediciones, Madrid.

In another particular embodiment the composition according to the invention additionally comprises an effective amount of at least one active ingredient selected from the group consisting of an antioxidant, an inhibitor of NO-synthase, agent, soothing the skin, anti-inflammatory agent, analgesic agent, antimicrobial agent, antifungal agent or with the Yessei.

In another specific embodiment the present invention relates to compositions containing an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts and an effective amount of at least one analgesic compound and/or anti-inflammatory compounds to enhance analgesic and/or anti-inflammatory effect of the compositions according to the invention. These compounds include synthetic compounds such as hydrocortisone, clobetasol, dexamethasone, prednisone, paracetamol, acetylsalicylic acid, aloxiprin, benorilate, choline salicylate, diflunisal, filamin, methyl salicylate, magnesium salicylate, salsalate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacin, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, Ketoprofen, Ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, suprofen, mefenamovaya acid, meclofenamate, meclofenamic acid, nabumetone, phenylbutazone, azapropazone, Metamizole, oxyphenbutazone, sulfinpirazon, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoksib, valdecoxib, nimesulide, licofelone, omega-3 fatty acids and their biometabolic, Mor is in, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, bupenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, three cyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalin, bisabolol, panthenol, Biotin, disodium-lauramidopropyl-tocopherylacetate, ciclopiroxolamine, nordihydroguaiaretic acid, coenzyme Q10 or alkylglycerol esters or natural extracts or essential oils with their own pain and/or anti-inflammatory activity, such as, for example, without limitation, among other things, madecassoside, ehinatsin, oil seeds, amaranth, sandalwood oil, placenta extract, leaf extract peach, Aloe vera, Arnica montana, Artemis/a vulgaris, Asarum maximum, Calendula officinalis, Capsicum, Centipede cunninghamii, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens, Hypericum perforatum extract, Lilium candidum, Malva sylvestris, Melaleuca altemifolia, Origanum majorana, Salix alba, Silybum marianum, Tanacetum parthenium or Uncana guianensis.

The biological activity of the compositions according to this invention was determined in models of pain and inflammation in animals. The composition of the invention can reduce the inflammation caused vnutripolostnoe injection of carrageenan, as well as to inhibit thermal hyperalgesia caused vnutripolostnoe injection complete adjuvant's adjuvant (CFA).

In another specific embodiment of the compositions of this invention are podhodjashaja treatment of pain and/or inflammation occur in response to various noxious stimuli (mechanical, chemical and temperature), causing acute and chronic inflammatory pain, and is caused by lesions of the nervous system, causing neuropathic pain, and pain and/or inflammation in pathological conditions, including visceral pain. Pain and inflammation include, for example, without limitation, neuropathic pain, inflammatory pain, visceral pain, including abdominal pain, pain in the digestive system, pain in the respiratory system, pain in the urogenital system, pain in the endocrine system, heart pain, pain in the pancreas, pain in the bowels, pain in the stomach, pain in the spleen, pain in the blood vessels, irritable bowel syndrome, headache, tension, headache associated with sinusitis, migraine, eye pain, dry keratitis, post-operative pain, including postoperative pain due to surgical incision, postoperative pain, due to the introduction of the implant into the bone, postoperative pain, caused by substitution or infection bone pain caused by cancer, including pain caused by bone cancer, pain associated with benign tumors of the bone, including the pain associated with osteoid-osteoma, osteoblastoma, pain caused by cancer treatment, skeletal-mysec the th pain fibromyalgia, neuralgia, neck pain associated with cervical dystonia, back pain, including back pain and/or sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, post herpetic neuralgia, peripheral neuropathy, phantom pain, allodynia, pain caused by carpal tunnel syndrome, burning pain, paresthesia, facial pain, trigeminal neuralgia, neuropathic pain caused by diabetes, the pain associated with the application or removal of tattoos, the pain caused by the great buritama toe, testicular pain, myofascial pain, spastic muscle pain, pain in the bladder, pain in the urinary tract, pain in the female external genitalia, vaginal pain, pain in the scrotum, pain in the perineum, pelvic pain, pain or skin irritation after surgery, after treatment with therapy pulsed light (intense pulsed light (IPL)), after treatment with therapy pulsed monochromatic light (laser), after treatment, chemical exfoliation agents, or after excessive exposure to aggressive external agents, such as excessive exposure to sunlight or excessive cold or heat.

In cha is in the surrounding area, treatment of postoperative pain exercise by introducing the composition according to the invention before, during or immediately after surgery. Preferably, the surgical procedure is selected from the group consisting of tumors, bone implantation, remove the bones, cosmetic surgical procedures, diagnostic surgical procedures and skin incisions.

The second aspect of the present invention relates to a peptide of General formula (I)

its stereoisomers and racemic or deracemization mixtures or its cosmetically or pharmaceutically acceptable salts, where

AA is a sequence of 3-40 neighboring amino acids included in the amino acid sequence of SEQ ID NO:1;

R1selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-C(O)-; and

R2selected from the group consisting of-NR3R4, -Or SIG3and-SR3where R3and R4independently selected from the group consisting of H, substituted or unsubstituted netsecl the political aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaromatic, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl; and

R5selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroaromatic,

for treatment of pain and/or inflammation.

In another specific embodiment of AA is a sequence of 3-30 neighboring amino acids included in the amino acid sequence of SEQ ID NO:1.

In another specific embodiment of the preferred structure of the peptides represented by the General formula (I)represent patterns, where

R1represents H, substituted or unsubstituted non-cyclic aliphatic group having 2-24 carbon atoms, substituted or unsubstituted alicikoglu group having 2-24 carbon atoms, or R5-C(O)-, where R5represents a substituted or unsubstituted non-cyclic aliphatic group having 1-24 carbon atoms, or substituted or unsubstituted alicikoglu group, having the Yu 1-24 carbon atoms; and

R2represents-NR3R4or-or SIG3where R3and R4independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group having 1-24 carbon atoms, and substituted or unsubstituted aliciella group having 1-24 carbon atoms.

In another specific embodiment of the preferred patterns are patterns, where R1is a polymer of polyethylene glycol. Even more preferred structures are structures where the polymer of the polyethylene glycol is a

where n can vary from 1 to 100 and most preferably can vary from 1 to 5.

In another specific embodiment of the preferred patterns are patterns, where R1represents H, acetyl, tert-butanol, hexanol, 2-methylhexanoic, cyclohexanecarbonyl, octanoyl, decanoyl, lauroyl, myristoyl, Palmitoyl, stearoyl, oleoyl and linoleoyl.

In another specific embodiment of the preferred patterns are patterns, where R3and R4independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl.

The peptides used for the treatment of pain and/or inflammation may exist in the form of art is reisopera or mixtures of stereoisomers; for example, the constituent amino acids may be L - or D-configuration or may be racemic independently from each other. Thus, it is possible to obtain mixtures of isomers as well as racemates or mixtures of diastereomers or pure diastereomers or enantiomers, depending on the number of asymmetric carbon atoms and which isomers or mixtures of isomers are present. The preferred structure of peptides represent pure isomers, i.e. enantiomers or diastereomers.

Among the peptides originating from the amino acid sequence of SNAP-25, a certain SEQ ID NO:1, used to treat pain and/or inflammation, the preferred sequences are sequences that have a sequence of adjacent amino acids provided in the sequence of aminobenzoic region of the protein SNAP-25, a certain SEQ ID NO:2, or carboxykinase region of the protein SNAP-25, a certain SEQ ID NO:3, more preferably included in the region from 10 to 22 balance, certain SEQ ID NO:4, or a member of the region from 25 to 40 residue certain SEQ ID NO:5, or a member of the region from 65 to 81 the rest, a certain SEQ ID NO:6, or a member of the region with 181 206 on balance, a certain SEQ ID NO:7, or rather, included in the region from 12 to 19 balance, certain SEQ ID NO:8, or a member of the region from 26 to 38 balance, certain SEQ ID NO:9, or when the Yu in region 68 through 79 residue, certain SEQ ID NO:10, and especially included in the region from 12 to 17 balance, certain SEQ ID NO:11.

In particular, the preferred amino acid sequences are sequences that have a sequence of adjacent amino acids included in any of the sequences selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32.

In addition, the invention also includes peptides, essentially homologous peptides, originating from the amino acid sequence of the protein SNAP-25, passed irreversible chemical modification, for the treatment of pain and/or inflammation.

In the scope of the present invention also includes cosmetically or pharmaceutically acceptable salts of the peptides of General formula (I). The nature of the salt is not critical, provided that it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the peptides can be obtained by conventional means, well known in the art [Berge, S.M., Bighley, L.D., and Monkhouse, D.C. (1977) "Pharmaceutical Salts" J. Pharm. Sci 66:1-19].

In addition, the possible reversible chemical modification of peptides for invites is their bioavailability and facilitate their passage through the blood-brain barrier or epithelial tissue.

The peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for the treatment of pain and/or inflammation may be included in the composition, and may be entered in any way, leading to contact of peptides to place their actions in the body of a mammal, preferably humans. These compositions can be manufactured by conventional methods known to experts in the art ["Harry's Cosmeticology", Eight [sic] edition (2000) M.M. Rieger, ed., New York Chemical Pub., NY, US; "Remington: The Science and Practice of Pharmacy, Twentieth edition (2003) Genaro A.R., ed., Lippincott Williams & Wilkins, Philadelphia, US].

The peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for the treatment of pain and/or inflammation have different solubility in water, depending on the nature of their sequence or possible modifications of their amino - and/or carboxy-end that they have. Therefore, these peptides can be included in the composition using an aqueous solution, and peptides, insoluble in water, can be solubilisation in a cosmetically or pharmaceutically acceptable conventional solvents, such as, for example, without limitation, ethanol, propanol, isopropanol, propylene glycol, glycerin, butyleneglycol or glycol, or any combination thereof.

An effective amount of the peptides of General fo the formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts, which must be entered for the treatment of pain and/or inflammation, as well as their dosage will depend on several factors, including age, condition of the patient, the cause of the pain and/or inflammation, the severity of pain and/or inflammation, the method and frequency of administration and the specific nature of the used peptides.

The peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salt included in the composition in concentrations effective to achieve the desired effect for treatment of pain and/or inflammation; preferably, relative to the total weight of the composition, from 0,00000001% (by weight) to 20% (by weight), more preferably from 0.000001% (by weight) to 20% (by weight), more preferably from 0.0001% by mass to 10% by weight and more particularly from 0.0001% (by weight) to 5% (by weight).

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for the treatment of pain and/or inflammation included in delivery systems and/or systems with a long release.

These media may be a liquid, such as water, oils or surfactants, including those that are the origin of petroleum, animal, plant, or synthetic, t is the cue as, for example, without limitation, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, Polysorbate, esters sorbitan, ethersulfate, sulfates, betaines, glucosides, maltoside, fatty alcohols, nonoxynol, poloxamer, polyoxyethylene, polyethylene glycol, dextrose, glycerol and the like. Diluents, adjuvants or excipients suitable carriers are described in "Remington''s Pharmaceutical Sciences", E.W.Martin.

Examples of delivery systems or systems with long release are liposomes, milecastle, microparticles, nanoparticles, sponges, vesicles, micelles, military, microspheres and nanospheres, liposphere, millicapsules, microcapsules, nanocapsules, micro-emulsions and nano-emulsion, which can be added to achieve greater penetration of the active ingredient and/or to improve its pharmacokinetic and pharmacodynamic properties.

In another specific embodiment of the compositions with prolonged release can be manufactured by methods known in the art, and compositions containing them can be introduced, for example, local introduction, including sticky bandages and non-sticky plasters, or system introduction, such as, for example, without limitation, enteral or parenteral route of administration, and they preferably should release regarding the post of the permanent number of peptides, included in compositions according to the invention. The number of peptide included in the composition with a long release, will depend, for example, from the place of introduction, the kinetics and duration of release of the peptide included in the compositions according to the invention, as well as the cause and severity of pain and/or inflammation, the method of administration, frequency of administration and the specific nature of the peptides.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for the treatment of pain and/or inflammation is included in the composition, optionally including acceptable carriers and/or auxiliary agents necessary for the introduction of the composition in the desired manner. Carriers and/or auxiliary agents include excipients, thickeners, thinners, solvents, dispersing agents, agents for improving freeze drying or adjuvants that are appropriate for each route of administration and well-known specialist in this field of technology. Thickeners include, without limitation, water soluble polymers, such as polymers selected from the group consisting of modified cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose, the code the runs, gelatino, collagen, hyaluronic acid, polyethylene glycol or polyvinylpyrrolidone. Thinners and solvents include, without limitation, diluents and solvents selected from the group consisting of ethanol, polyethylene glycol, glycoluril, N-methyl-2-pyrrolidone, glycerol, propane diol, polypropylenglycol, benzyl alcohol or dimethyl sulfoxide. Dispersing agents include, without limitation, surfactants, selected from the group consisting of monoamino fatty acids and polyoxyethylenesorbitan (Tween®, Emalex, Nikkol®, Hodag, Dacol or Liposorb®), monoamino fatty acids and sorbitan (Span®), 15-hydroxystearate of polyethylene glycol (Solutol®HS15), esters of fatty acids and of polyethylene glycol (Crodet, Cithrol, Kessco®, Nikkol®, Mapeg®, Myrj, Tagat®, Aldo®, Capmul®, Glycerox, Lactomul®or Emerest®), esters of polyoxyethyleneglycol (Emulphor®), polyethoxylated castor oil (Cremophor®, Emalex, Eumulgin®, Nikkol®or Simusol®), esters of fatty acids and polyglycerol (Nikkol Decaglyn, Polymuls, Caprol®), ethers of polyethylene glycol (Volpo or Brij®), poloxamer (Lutrol®or Pluronic®), phenyl esters of polyoxyethylene (Triton®or Igepal®or mixtures thereof. Agents to improve freeze-drying include, but are not limited to the texts, sugar, such as sugar selected from the group consisting of mannitol, sucrose, glucose, fructose, lactose, trehalose, sucrose, dextrose, sorbitol, glycine, gelatin, polyvinylpyrrolidone or mixtures thereof. Preferably, the composition that contains the peptide includes one or more than one acceptable excipient, such as moisturizers, pH buffering agents, preservatives, antibacterial and antifungal agents, agents that slow down the absorption, agents, accelerating the absorption, or any other excipient known to the person skilled in the technical field.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts for the treatment of pain and/or inflammation may also be adsorbed on solid organic polymers or solid mineral medium, such as, without limitation, among other things, talc, bentonite, silica, starch or maltodextrin.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salt included in the composition that can be incorporated into fabrics, non-woven fabrics and medical devices in direct contact with the skin, mucous membranes and/or scalp, so that he shall release the peptides either by biodegradation of the retention system tissue, non-woven fabric or medical device, or in the force of friction fabric, non-woven fabric or medical device on the body, sweating, skin pH or body temperature. Similarly, fabrics and non-woven materials can be used for making clothes directly in contact with the body.

Examples of fabrics, non-woven materials, clothing, medical devices and means of fixation of peptides, including delivery systems and/or systems with a long release, described above, is described and can be found in the literature and known in the art [Schaab S. Kaliev (1986) "Impregnating Fabrics With Microcapsules", HAPPI May 1986; Nelson G. (2002) "Application of microencapsulation in textiles" Int. J. Pharm. 242:55-62; "Bio-functional Textiles and the Skin" (2006) Curr. Probl. Dermatol. v.33, Hipler U.C. and ElsnerP., eds. S. KargerAG, Basel, Switzerland; Malcom R.K., McCullagh S.D., Woolfson A.D., German S.P., Jones D.S. and Cuddy J. (2004) "Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial" J. Cont. Release 97:313-320]. Preferred fabrics, non-woven materials, clothing, and medical devices are bandages, gauze, t-shirts, socks, stockings, underwear, girdles, gloves, diapers, wraps, bandages, bed covers, napkins, hydrogels, adhesive patches, non-sticky plasters, Mikroelektronika patches (micro-electric patches) and/or face masks.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, their mixtures or incosmetics or pharmaceutically acceptable salts contained in the compositions, which can be used in various types of compositions for local or dermal application, which will probably contain acceptable excipients necessary for the manufacture of the desired dosage form [Fault i Trillo C. (1993) in "Tratado de Farmacia Galenica", Luzan 5, S.A. Ediciones, Madrid].

Compositions for local or percutaneous application can be submitted in any solid, liquid or semi-solid dosage form, such as, for example, without limitation, creams, heterogeneous emulsion, such as, for example, without limitation, emulsions of oil and/or silicon in water, emulsion water in oil and/or silicon, the emulsion of the type water/oil/water or water/silicon/water emulsion type oil/water/oil or silicon/water/silicon", anhydrous compositions, aqueous dispersions, oils, lotions, balsams, foams, lotions, gels, hydroalcoholic solutions, liquid, ointments, serums, Soaps, shampoos, ointments, mousses, lipstick, powders, chalks, pencils and sprays or aerosols (sprays"), including songs leave after application ("lv-on"composition), and compositions, rinse-off after application ("rinse-off"song). These compositions for local or percutaneous application can be enabled by techniques known to a person skilled in the technical field in different types of solid accessories, such as, for example, without limitation, napkins, guide ogeli, adhesive tapes, non-sticky patches or face masks, or can be incorporated into various cosmetic products.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salt included in the composition, which may include additional agents that enhance percutaneous absorption of peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts, such as, for example, without limitation, among others, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylsulfate-2-one), alcohol, acetone, propylene glycol or polyethylene glycol. In addition, these compositions can be applied to limited areas for the introduction of local or percutaneous method of administration by intradermal injection, iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or injection under pressure without the use of needles, such as injection pressure of oxygen, Mikroelektronika patches, or any combination thereof, to achieve greater penetration of the peptide according to the invention. The scope of application will be determined by the nature of pain and/or inflammation of the subject treatment is s.

The peptides of General formula (I), their stereoisomers, mixtures thereof or the cosmetically or pharmaceutically acceptable salt included in the composition, can be introduced, in addition to the local or percutaneous method of administration, any other suitable method, for example, enteral or parenteral method of administration, with the inclusion of acceptable excipients necessary for the manufacture of the desired dosage form. An overview of the different dosage forms of active ingredients and excipients required for their production can be found, for example, in the "Tratado de Farmacia Galenica", C. Fauli i Trillo, 1993, Luzan 5, S.A.Ediciones, Madrid.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salt included in the composition, optionally comprising an effective amount of at least one active ingredient selected from the group consisting of an antioxidant, an inhibitor of NO-synthase, agent, soothing the skin, anti-inflammatory agent, analgesic agent, antimicrobial agent, antifungal agent, or mixtures thereof.

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salt included in the composition also includes an effective amount of at least od the CSOs analgesic compounds and/or anti-inflammatory compounds to enhance analgesic and/or anti-inflammatory effect of the composition. Among these compounds can be distinguished synthetic compounds such as hydrocortisone, clobetasol, dexamethasone, prednisone, paracetamol, acetylsalicylic acid, aloxiprin, benorilate, choline salicylate, diflunisal, filamin, methyl salicylate, magnesium salicylate, salsalate, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacin, sulindac, tolmetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, Ketoprofen, Ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, suprofen, mefenamovaya acid, meclofenamate, meclofenamic acid, nabumetone, phenylbutazone, azapropazone, Metamizole, oxyphenbutazone, sulfinpirazon, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoksib, valdecoxib, nimesulide, licofelone, omega-3 fatty acids and their biometabolic, morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, bupenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, tricyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalin, bisabolol, panthenol, Biotin, disodium-lauramidopropyl-tocopherylacetate, ciclopiroxolamine, nordihydroguaiaretic acid, coenzyme Q10 or alkylglycerol esters or natural extracts or essential oil with its own anaesthetic is it and/or anti-inflammatory activity, such as, for example, without limitation, among other things, madecassoside, ehinatsin, oil seeds, amaranth, sandalwood oil, placenta extract, leaf extract of peach, Aloe vera, Arnica montana, Artemisia vulgaris, Asarum maximum, Calendula officinalis, Capsicum, Centipede cunninghamii, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens, Hypencum perforatum extract, Lilium candidum, Malva sylvestris, Melaleuca altemifolia, Origanum majorana, Salix alba, Silybum marianum, Tanacetum parthenium or Uncana guianensis.

The biological activity of the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts was determined in models of pain and inflammation in animals. These peptides can reduce the inflammation caused vnutripolostnoe injection of carrageenan, as well as to inhibit thermal hyperalgesia caused vnutripolostnoe injection complete adjuvant's adjuvant (CFA).

In another specific embodiment, the peptides of General formula (I), their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts are suitable for the treatment of pain and/or inflammation that occurs in response to various noxious stimuli (mechanical, chemical and temperature), causing acute and chronic inflammatory pain, and is caused by lesions of the nervous system, causing neuropathic pain, and pain and/or inflammation in pathological conditions, including visceral pain. The pain and opalanie include, for example, without limitation, neuropathic pain, inflammatory pain, visceral pain, including abdominal pain, pain in the digestive system, pain in the respiratory system, pain in the urogenital system, pain in the endocrine system, heart pain, pain in the pancreas, pain in the bowels, pain in the stomach, pain in the spleen, pain in the blood vessels, irritable bowel syndrome, headache, tension, headache associated with sinusitis, migraine, eye pain, dry keratitis, post-operative pain, including postoperative pain due to surgical incisions, postoperative pain, due to the introduction of the implant into the bone, postoperative pain, caused by substitution or infection bone pain caused by cancer, including pain caused by bone cancer, pain associated with benign tumors of the bone, including the pain associated with osteoid-osteoma, osteoblastoma, pain caused by cancer treatment, musculoskeletal pain, fibromyalgia, neuralgia, neck pain associated with cervical dystonia, back pain, including back pain and/or sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, post herpetic neuralgia, peripheral neuro is atii, phantom pain, allodynia, pain caused by carpal tunnel syndrome, burning pain, paresthesia, facial pain, trigeminal neuralgia, neuropathic pain caused by diabetes, the pain associated with the application or removal of tattoos, the pain caused by buritama big toe, testicular pain, myofascial pain, spastic muscle pain, pain in the bladder, pain in the urinary tract, pain in the female external genitalia, vaginal pain, pain in the scrotum, pain in the perineum, pelvic pain, pain or skin irritation after surgery, after treatment with therapy pulsed light (intense pulsed light (IPL)), after treatment with therapy pulsed monochromatic light (laser), after treatment, chemical exfoliation agents, or after excessive exposure to aggressive external agents, such as excessive exposure to sunlight or excessive cold or heat.

In particular, the treatment of postoperative pain exercise by introducing an effective amount of the peptide contained in the composition according to the invention before, during or immediately after surgery. Preferably, the surgical procedure is selected from the group consisting of tumors, bone implantation, UD is of bones, cosmetic surgical procedures, diagnostic surgical procedures and skin incisions.

In another aspect this invention relates to the treatment of pain and/or inflammation, the method comprising introducing an effective amount of at least one peptide of General formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts, preferably in the form containing cosmetic or pharmaceutical compositions. According to this invention is also a method for treatment of pain and/or inflammation comprising applying to the skin, mucous membranes and/or scalp, or enteral or parenteral administration of a composition containing at least one peptide of General formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts.

According to this invention is also a method of treatment and/or prevention of postoperative pain in a patient, past surgical intervention, including the introduction of the indicated patient a therapeutically effective amount of at least one peptide of formula (I), its stereoisomers, mixtures thereof or the cosmetically or pharmaceutically acceptable salts, preferably in the form containing the pharmaceutical composition before, during or directly to the public after surgery. Preferably, the surgical procedure is selected from the group consisting of tumors, bone implantation, remove the bones, cosmetic surgical procedures, diagnostic surgical procedures and skin incisions.

EXAMPLES

The following specific examples provided here are intended to illustrate the essence of this invention. These examples are only for illustrative purposes and should not be construed as limiting the claimed invention here.

General methodology

Abbreviations

Abbreviations used for amino acids, consistent with the rules of the Commission on biochemical nomenclature (Commission on Biochemical Nomenclature) of the International Union of pure and applied chemistry and International Union of biochemistry (IUPAC-IUB)specified in Eur. J. Biochem. (1984) 138, 9-37 and J. Biol Chem (1989) 264, 633-673.

NSAID, non-steroidal anti-inflammatory drugs; ATP, adenosine triphosphate; BK, bradykinin; BoNT, botulinum toxin serotype A; CFA, complete beta-blockers; CGRP, a peptide related to calcitonin; IL, interleukin; NGF, nerve growth factor; Palm, Palmitoyl; PEG, polyethylene glycol; PEGn, -[NH-CH2-(CH2CH2O)3-(CH2)3-NH-CO-CH2CH2-CO-]n; PKA, protein kinase a; RKS, protein kinase C; SNAP-25, a protein associated with uptake (25 kDa; SP, substance P; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.

EXAMPLE 1. Peptides reduce inflammation caused vnutripolostnoe injection of carrageenan.

To demonstrate that peptides having the origin of the protein SNAP-25, have anti-inflammatory activity in vivo, used the test with carrageenan. Carrageenan is an irritant, the introduction of which causes severe inflammation through four hours after injection. The inflammatory process can be easily recognized as the increase in paw, which was injected carrageenan, measured plethysmometer. Table 1 shows the values of the anti-inflammatory activity of peptides, administered at a dose of 5 mg/kg intramuscularly), with the use of diclofenac (10 mg/kg) as positive control and normalization relative values reduce inflammation, obtained for the positive control. Thus, the peptides of this invention have anti-inflammatory activity in vivo.

Table 1
TRACKAnti-INFLAMMATORY ACTIVITY
Diclofenac100%
AcLESTRRMLQLVEE-NH 298%
Palm-EEMQRR-NH281%
Palm-LESTRRMLQLVEE-NH277%
AC-ELEEMQRRADQLA-NH265%
Palm-ELEEMQRRADQLA-NH258%
Ac-PEG5-EEMQRR-NH253%
Ac-EEMQRR-NH249%
AC-PEG3-EEMQRR-NH242%
AC-PEG2-EEMQRR-NH229%
Ac-PEG4-EEMQRR-NH223%
Ac-PEG1-EEMQRR-NH221%
AC-EEMQRRA-NH214%

EXAMPLE 2. Peptides inhibit thermal hyperalgesia caused vnutripolostnoe injection complete adjuvant's adjuvant (CFA).

For evaluation of analgesic activity of peptides in a model of chronic pain, the inventors used vnutripolostnoe the introduction of CFA (1%), leading to an inflammatory process with thermal hyperalgesia 24 hours after the introduction of irritating the th substance. Thermal hyperalgesia is easily evaluated using research equipment for the soles of focusing the radiation source on the paw of an animal, with an estimate of the delay time from exposure to otdergivanija paws. In this model, the inventors compared the anesthetic efficacy of the peptides (1 mg/kg, intramuscularly) with ibuprofen (1 mg/kg, intramuscularly) 24 hours after injection of CFA. The inventors have also monitored the temperature sensitivity of the opposite legs (which were injected filler CFA) after 1 hour, 2 hours, 4 hours and 6 hours after the injection of CFA. Figure 1 shows that the peptides were reduced thermal hyperalgesia after 2 hours after injection. Thus, the peptides according to the invention have analgesic/anti-inflammatory activity in a model of chronic pain (Figure 1).

1. The use of the peptide of General formula (I)

its stereoisomers, their mixtures and its cosmetically and pharmaceutically acceptable salts, where
AA is a sequence of 6-40 neighboring amino acids included in the amino acid sequence of SEQ ID NO:2 selected from the group consisting of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26;
R1the stand is made by a N, acetyl, tert-butanol, hexanol, 2-methylhexanoic, cyclohexanecarbonyl, octanoyl, decanoyl, lauroyl, myristoyl, Palmitoyl, stearoyl, oleoyl, linoleoyl and the polymer of polyethylene glycol; and
R2represents-NR3R4where R3and R4independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl,
for treatment of pain and/or inflammation.

2. The use according to claim 1, where the polymer of the polyethylene glycol is a

where n may be equal to 1-100.

3. The use according to claim 1, where the peptide of General formula (I), its stereoisomers, mixtures thereof or its cosmetically or pharmaceutically acceptable salts included in the delivery system or a system with a long release, selected from the group consisting of liposomes, millicapsules, microcapsules, nanocapsules, sponges, vesicles, micelles, mallister, microspheres, nanospheres, lipofen, microemulsions, nanoemulsions, milicast, microparticles and nanoparticles.

4. The use according to claim 1, where the peptide adsorbed on organic polymer or solid mineral carrier selected from the group consisting of talc, bentonite, silica, starch or maltodextrin.

5. The use according to claim 1, where the peptide is included in the composition is selected from the group consisting of creams, heterogeneous emulsions, anhydrous compositions, aqueous, disperse is, oils, milk, balsams, foams, lotions, gels, hydroalcoholic solutions, liquid, ointments, serums, Soaps, shampoos, ointments, mousses, ointments, powders, chalks, pencils, sprays and aerosols.

6. The use according to claim 1, where the peptide is included in the fabric, non-woven fabric or medical device.

7. The use according to claim 1, where the peptide is included in the composition comprising an effective amount of at least one active ingredient selected from the group consisting of an antioxidant, an inhibitor of NO-synthase, agent, soothing the skin, anti-inflammatory agent, analgesic agent, antimicrobial agent, antifungal agent, or mixtures thereof.

8. The use according to any one of claims 1 to 7, where the peptide is administered by local, enteral or parenteral means.

9. The use according to claim 1, where pain and/or inflammation selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, abdominal pain, pain in the digestive system, pain in the respiratory system, pain in the urogenital system, pain in the endocrine system, heart pain, pain in the pancreas, pain in the bowels, stomach pain, pain in the spleen, pain in the blood vessels, irritable bowel syndrome, headaches, tension, headache associated with sinusitis, migraine, eye pain, dry keratitis, postoperative Bo and, postoperative pain caused by surgical incision, postoperative pain, due to the introduction of the implant into the bone, postoperative pain, caused by substitution of bone, postoperative pain caused by infections, pain caused by cancer, pain caused by bone cancer, pain associated with benign tumors of bone pain associated with osteoid-osteoma, pain associated with osteoblastoma, pain caused by cancer treatment, musculoskeletal pain, fibromyalgia, neuralgia, neck pain associated with cervical dystonia, back pain, lumbago, sciatica, neurogenic inflammation, irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, post herpetic neuralgia, peripheral neuropathies, phantom pain, allodynia, pain caused by carpal tunnel syndrome, burning pain, paresthesia, facial pain, trigeminal neuralgia, neuropathic pain caused by diabetes, pain associated with the application or removal of tattoos, pain caused by buritama big toe, pain in the testicle, myofascial pain, pain in the bladder, pain in the urinary tract, pain in the female external genitalia, vaginal pain, pain in the scrotum, pain in the perineum, pelvis the howl of pain, pain or irritation of the skin after surgery, after treatment with therapy pulsed light (intense pulsed light (IPL)), after treatment with therapy pulsed monochromatic light (laser), after treatment, chemical exfoliation agents, or after excessive exposure to aggressive external agents.



 

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14 cl, 5 dwg, 2 tbl, 1 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a biotechnology industry, and namely to synthetic peptides having a non-narcotic type of analgetic action of a general formula: 1 H - XDL - L-Leu - D-His - L-Lys - L-Leu - L-Gln - L-Thr - R2 (I), where: H - hydrogen, XDL - absence of amino acid or L-Tyr, R2 - OMe or NH2, as well as peptides - retroinversions of formula (I), which have reverse sequence of amino acids with replacement of L-shape of amino acids with D-shape and D-shape of amino acids with L-shape, with the following general formula: 2 H - D-Thr - D-Gln - D-Leu - D-Lys - L-His - D-Leu - XDL1 - R2 (II), where: H - hydrogen, XDL1 - absence of amino acid or D-Tyr, R2 - OMe or NH2.

EFFECT: invention allows producing safe analgetic medical preparations with a non-narcotic type of analgetic action.

5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a chromatographic method of purifying an insulin analogue selected from aspartate, lispro and glargine, atosiban or eptifibatide, from a mixture containing at least one parent admixture.

EFFECT: method employs agents for forming ionic pairs in OF-preparative linear chromatography, which enables to achieve high degree of purity of the end product.

7 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to molecular pharmacology and particularly to a peptide which is an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound. The invention shows that when bound with an alpha subunit of the receptor (IL-15Rα) the peptide inhibits T cell proliferation induced by IL-15, tumour necrosis factor α (TNFα) induction caused by IL-15, and expression of IL-8 and IL-6 caused by IL-15Rα. The invention also relates to use of the peptide in treating pathologies where anomalous expression of IL-15 or IL-15Rα is associated with the course of a disease such as rheumatoid arthritis (AR) and prostate cancer.

EFFECT: obtaining an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound.

18 cl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: disclosed is use of a heptapeptide of general formula Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2, where X is D-Pro or Dh-Pro, or Dh-D-Pro, where Dh-Pro is 3,4-dehydroproline, as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

EFFECT: obtaining an agent used as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

3 cl, 8 tbl, 26 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to peptides or peptide-like molecules of the following formula: CCLLCCLLC (I) (SEQ ID NO: 1) or CLLCCLLCC (III) (SEQ ID NO:3), where C is cationic aminoacid and L is aminoacid with lipophile group R, in which one of the aminoacids, which has lipophile group R, represents genetically uncoded aminoacid. This compound is probably in the form of pharmaceutically acceptable salt, ester or amide, and refers to their use in therapy, and namely as antitumour agents.

EFFECT: improvement of compound properties.

20 cl, 7 dwg, 12 tbl, 9 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to application of oligopeptide chosen from a group consisting of tripeptide of general formula X-Pro-Tyr (X-P-Y), in which X can be chosen from a group consisting of Ile (I), Val (V), Ala (A), Trp (W), Leu (L), Phe (F), Gly (G), Glu (E) and Asn (N), or peptides including the above tripeptide, in medicine for immunomodulation. Besides, application of the above oligopeptide for production of remedy to be used as an immunomodulator is disclosed. Immunomodulating pharmaceutical composition containing an effective amount of the above oligopeptide, as well as a vaccine containing it are disclosed. Besides, a method for reinforcement of mammal immune system, as well as a method for improvement of immunogenic activity of vaccine composition using the above immunomodulating composition are disclosed. A method providing immunoreactivity to peptide or improvement of peptide immunoreactivity with a peptide compound with the above oligopeptide is disclosed.

EFFECT: use of oligopeptides in medicine for immunomodulation.

19 cl, 2 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: isolated peptide having cytotoxic T lymphocyte (CTL) inducing capacity in the presence of an antigen-presenting cell bearing HLA-A*2402, is used to obtain antigen-presenting cells and therefore CTL. The obtained CTL are used for targeted action against CDCA1-expressing cancer cells.

EFFECT: invention provides an effective vaccine for inducing anti-tumour immunity in a subject.

16 cl, 4 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to peptide derivatives and peptidomimetics as transglutaminase inhibitors, methods for their preparation, pharmaceutical compositions containing said compounds as well as use of said transglutaminase inhibitors in particular for treatmenting coeliac disease and transglutaminase dependent diseases.

EFFECT: high efficiency of using said compounds.

12 cl, 20 dwg, 2 tbl, 7 ex

FIELD: biotechnologies.

SUBSTANCE: proposed peptides represent T-cell epitopes of an endothelial marker of a tumour (TEM8), which are able to induce cytotoxic T-lymphocytes (CTL) in presence of antigen-presenting cells or exosome, which carry or contain HLA-A*0201. A pharmaceutical composition is proposed for elimination of cells expressing TEM8, extracted exosome and antigen-presenting cell, which carry a complex containing a peptide as per invention with HLA-A*0201 molecule. Methods for induction of an antigen-presenting cell, which can induce CTL that destroy the cells expressing TEM8, as well as cytotoxic cells induction methods have been considered.

EFFECT: invention can be further used for cancer therapy.

10 cl, 5 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to field of organic chemistry, namely to novel compound of formula (I), where Y and Z, each independently, are selected from group, consisting of: a) phenyl, if necessary substituted with 1 or 2 R6; b) pyridine, imidazole, thiazole, furan, triazole, quinoline or imidazopyridine, if necessary substituted with 1 R6; and c) substituent, independently selected from group, consisting of hydrogen, C1-C6alkyl or pyperidine; R1, R2 and R3, each independently selected from group, consisting of hydrogen and halogen; A and B is each independently selected from hydrogen, OH and C1-C6alkyl; RA and RB are independently selected from group, consisting of hydrogen, C1-C6alkyl and C3-C8cycloalkyl; or RA and RB together with atom, to which they are attached, form 4-6-membered heterocycle, if necessary having additionally one heteroatom or functional heterogrpoup, selected from group, consisting of -O-, -NH, -N(C1-C6-alkyl)- and -NCO(C1-C6-alkyl)-, and 6-membered heterocycle can be additionally substituted with one or two C1-C6-alkyl groups; R4 and R5, each stands for hydrogen; and each R6 is selected from Br, Cl, F, I, C1-C6-alkyl, pyrrolidine, if necessary substituted with one C1-C6-alkyl, C1-C6alkoxy, halogen-C1-C6alkyl, hydroxyl-C1-C6alkylene, -(NRARB)C1-C6alkylene and (NRARB)carbonyl; or to its individual isomer, stereoisomer or enantiomer, or their mixture, if necessary pharmaceutically acceptable salt. Invention also relates to compound of formula (II), particular compounds of formula (I) and (II), pharmaceutical composition and industrial product based on compound of formula (I) and (II), method of treating said pathological conditions, method of obtaining formula (I) compound and to intermediate compound of formula 3.

EFFECT: novel compounds, useful as inhibitors of poly(ADP-ribose)polymerase, are obtained.

50 cl, 1 tbl, 159 ex

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