WO2012136873A2

WO2012136873A2 - Trpv1 antagonists and uses thereof

Info

Publication number: WO2012136873A2
Application number: PCT/ES2012/070234
Authority: WO
Inventors: Antonio Ferrer Montiel; Asia Fernández Carvajal; José Manuel GONZÁLEZ ROS; Carlos BELMONTE MARTÍNEZ; Félix VIANA DE LA IGLESIA; Ana GOMIS GARCÍA; Ángel MESSEGUER PEYPOCH; Jordi BUJONS VILAS; Miquel VIDAL MOSQUERA; Rosa Planells Cases
Original assignee: Universidad Miguel Hernández De Elche; Consejo Superior De Investigaciones Científicas C.S.I.C.; Fundación De La Comunidad Valenciana Centro De Investigación Príncipe Felipe
Priority date: 2011-04-05
Filing date: 2012-04-04
Publication date: 2012-10-11
Also published as: WO2012136873A8; ES2390326A1; WO2012136873A3; ES2390326B1

Abstract

The invention relates to compounds derived from triazine, which can block the activity of TRPV1, and to the therapeutic uses thereof. More specifically, the applicants have synthesised trisubstituted triazines which can specifically inhibit thermoreceptor TRPV1 in the activated state thereof.

Description

TRPVL ANTAGONISTS AND THEIR USES

FIELD OF THE INVENTION

The invention relates to compounds derived from triazine that have the ability to block the activity of TRPV 1 and its therapeutic uses. More specifically, the authors of the invention have synthesized trisubstituted triazines that are capable of specifically inhibiting the TRPV1 thermoreceptor in its activated state.

BACKGROUND OF THE INVENTION

Nociceptive neurons recognize mechanical, thermal and chemical stimuli that can be harmful to the body. Therefore, nociceptors are considered as guardians of tissue integrity and nociception as an essential safety mechanism for life. At the molecular level, nociceptors have in their terminals a set of protein receptors prepared to recognize and transduce harmful physical (mechanical, osmotic, and thermal) and chemical stimuli. In this sense, the human being has receptors capable of recognizing the spectrum of temperatures from very cold (<17 ° C) to very hot (> 50 ° C) (Belmonte et al. Mol. Pain, 2008; 4: 14) .

The channels or receivers TRP (Transient Potential Receptors) are receptors that constitute a large family subdivided into 8 subfamilies: TRPC, TRPM, TRPV, TRP A, TRPP, TRPML, TRPN (present in invertebrates) and TRPY (in yeasts). These receptors play a fundamental role in the transduction of different somatosensory modalities in mammals, including thermosensing, pheromone reception, vascular tone regulation, nociception and pain. It is increasingly clear that TRP channels are very important in sensory physiology and that their functional alteration, either through mutations or by harmful stimuli or pro-inflammatory factors, leads to pathological states in humans.

The TRPV (Transient Potential Receptors activated by Vanilloides) subfamily in mammals is made up of 6 members divided into 2 groups according to the degree of homology, TRPVl-4 and TRPV5-6. The receptors that recognize thermal stimuli are TRPVl-4, and among them the TRPVl receptor stands out as a sensor molecular threshold of harmful temperatures for the organism (Caterina, MJ et al. 2001. Annu. Rev. Neurosci. 24: 487-517).

TRP channels are expressed in a wide variety of multicellular organisms that comprise yeasts, worms, fruit flies, zebrafish, and mammals. All TRP receptors are cationic channels that allow the flow of Ca ²⁺ and Na ⁺ , although, depending on the isoform, the permeability and selectivity for mono or divalent cations varies substantially. Its pattern of tissue distribution is very wide, appearing expressed in virtually all tissues, especially in the central and peripheral nervous systems, in which they play a crucial role in sensory transduction, converting environmental stimuli into changes in neuronal membrane excitability (Venkatachalan et al. Annu. Rev. Biochem. 2007; 76: 387-417). In addition, its permeability to the Ca ²⁺ cation leads to the activation of cellular transduction signals that also contribute to sensory transmission.

Structurally, TRP channels are homo or hetoroligomers formed by the association of four subunits around a central axis of symmetry that coincides with the ionic pore. Each subunit consists of 6 transmembrane segments (SISÓ), a hydrophilic loop between the fifth and sixth transmembrane segments that structure the ionic pore and two intracellular domains at the N- and C-terminal ends. The C-terminal domain contains a region (TRP domain) important for the association of subunits and contains zones of interaction with phosphoinositides and regulatory proteins (Venkatachalan et al. Cited ad supra).

TRPVl was the first identified member of the TRP family of thermosensors. It is a non-selective ionic channel with high calcium ion permeability and activated by cap saicin and various endogenous compounds (endocanabinoids, forage trees), harmful temperatures (> 42 ° C) and acidic pH. Because it is activated by various stimuli, TRPVl is considered a molecular integrator of harmful stimuli in nociceptors. The genetic and pharmacological suppression of TRPVl activity significantly reduces thermal hyperalgesia, a typical characteristic of inflammatory pain (Messeguer, A et al. Curr Neuropharmacol. 2006; 4, 1-15). It should be noted that overexpression of this channel has been observed in chronic pathologies, such as arthritis and chronic pain. In fact, TRPVl plays a crucial role in peripheral sensitization of nociceptors after tissue injury and / or inflammation caused by a trauma, infection, surgery, burns or diseases with an inflammatory component (Szallasi, A et al. Curr. Pharm. Design 2008; 14, 32-41). In addition, the TRPV1 receptor is gaining interest as a therapeutic target for the treatment of neuropathic, postoperative and chronic pain, as well as to treat pain in bone cancer (Kim, H. Y et al. J. Pain 2008; 9, 280- 288). The TRPV1 receptor is involved in both neuropathic and inflammatory pain, specifically it is overexpressed in neuropathic pain. There is evidence that TRPV1 antagonists are able to attenuate hyperalgesia and allodynia associated with inflammatory pain models (March et al, Current Opinion in Neurobiology 2002; 12: 372-379).

The treatment of pain is one of the challenges facing current medicine and for which there are no highly effective compounds. It can be classified as acute or chronic depending on the duration of pain (Foley, Pain, Cecil Textbook of Medicine 100-107 (JC Bennett and F. Plum eds., ^20th ed., Goldman Bennet 1996). Chronic pain can Classify as "nociceptive" or "neuropathic." Nociceptive pain includes pain induced by tissue damage, such as a cut or burn and inflammatory pain, such as arthritis. It is due to the activation of pain-sensitive nerve fibers, both somatic type as I saw sceral Dol or nociceptive has been traditionally treated by the administration of non-opioid analgesics, including acetylsalicylic acid, choline, magnesium trisalicylate, acetaminophen, ibuprofen, phenorofen, diflusinal and naproxen, among others (Foley, Pain, In :... Cecil Textbook of Medicine, pp, 100-107, Bennett and Plum eds, ^20th ed, 1996) neuropathic pain refers to pain induced by damage to the central or peripheral nervous system and is characterized by a process somatose aberrant nsorial (McQuay, Anaesthesiol Act. Scand. 1997; 41 (1 Pt 2): 175-83). In contrast to the immediate pain caused by tissue damage, neuropathic pain may develop days or months after traumatic damage. It is often resistant to available drug therapies. Such therapies include opioids, anti-epileptics, NMDA antagonists, tricyclic anti-depressants. However, none of these treatments is particularly effective, reaching an effectiveness of less than 50%.

The discovery and development of ligands for ion channels belonging to the family of thermo-TRPs has been focused mainly on compounds capable of binding either to known binding sites for agonists, or to the extracellular pore of the canal (Messeguer, A. et al. 2006; Curr. Neuropharmacol. 4: 1-9; Khairatkar-Joshi, N et al. 2009. Trends Mol. Med. 15, 14-22). For example, compounds targeting agonist binding sites already validated for the TRPV1, TRPM8 and TRPA1 receptors have been tested (Messeguer, A. et al. Cited ad supra; Ma, S et al. 2008. Pak. J. Pharm. Sci. 21, 370-78; Viana F et al. 2009. Expert. Opin. Ther. Pat 19, 1787-99). This strategy has been successful in generating a large number of modulating compounds, characterized by a wide variety of efficiencies and potencies. On the contrary, few results have been achieved for channels that do not have well defined such binding sites. In principle, this limitation could be overcome if new drug interaction sites are identified and validated. In this context, the intracellular domains of the channels, involved in their opening, offer a novel opportunity to design new strategies in the design of ionic channel modulators. This unexplored approach so far for ion channels has been successfully tested for GPCRs, where compounds directed against intracellular protein domains consisting of lipid-conjugated peptides (pepducins) have been tested, identifying agonists and antagonists that have shown significant therapeutic activities ( Covic L et al. 2002. Proc. Nati. Acad. Sci. USA 99, 643-48).

The validation as a therapeutic target of TRPV1, and its involvement in a multitude of pathologies, from inflammatory to oncological pain, have led to the development of a large number of activators and receptor inhibitors for use as anti-inflammatory and analgesic agents. The first of the antagonists characterized was capsacepin, a restricted analogue of capsaicin that contains a thiourea group. Capsacepin acts as a competitive antagonist, since it binds to the capsaicin binding site (Messeguer, A. et al. Cited ad supra). Despite behaving as a potent antagonist in vitro, its application in animal models has yielded conflicting results. Thus, the compound has not shown analgesic or anti-inflammatory activity in rats, but it has attenuated thermal hyperalgesia in guinea pigs. Another of the compounds developed and tested has been 5-iodo-resiniferatoxin, a halogenated derivative of the agonist that makes it a very potent antagonist (Messeguer, A. et al. Cited ad supra). This compound shows a more constant and reproducible analgesic activity in vitro, so its clinical development for the treatment of urinary incontinence is being considered. However, like that for resiniferatoxin, its oral bioavailability is zero, and it contains the forbol ester that has a tumorigenic potential. In addition, the chemical synthesis of the compound is remarkably complex, involving more than 45 reaction steps (Messeguer, A. et al. Cited ad supra).

In an attempt to develop competitive antagonists with greater oral bioavailability, pharmaceutical companies have used high-performance assays to track chemical libraries composed of thousands to millions of chemical compounds. As a result, an abundance of molecules with good antagonistic activity in vitro and in animal models have been isolated and characterized. The structural and functional optimization of the best candidates has yielded oral TRPV1 inhibitors with an apparent good therapeutic profile (Messeguer, A. et al. Cited ad supra). These include the SB-705498 (GlaxoSmith-Kline), NGD- 8243 (Merck / Neurogen), AMG-517 (Amgen), and GRC-621 (Glenmark) compounds, which are currently in different stages of development clinical. A second family of TRPV1 inhibitors that has been explored is the non-competitive and competitive antagonists, which bind to the receptor at different binding sites than capsaicin (Messeguer, A. et al. Cited ad supra). These compounds include ruthenium red and peptides rich in arginine residues, which act as potent blockers but have no therapeutic value due to their excessive toxicity. The use of a combinatorial chemistry approach identified the molecules DD161515 and DD191515 as potential non-competitive antagonists with analgesic and anti-inflammatory activity in vivo (Messeguer, A. et al. Cited ad supra). These pharmacological properties were improved by obtaining the DDO 1050 compound, a 10 times more potent analog in vitro and in vivo. However, the good therapeutic profile of DDO 1050 remained in the background due to its still high toxicity, which has slowed its clinical development (Messeguer, A. et al. Cited ad supra). However, these studies have identified the chemical and pharmacological principles required to obtain competitive antagonists with better properties and low toxicity. An example of this new generation of molecules is represented by the identification of methoctramine (Messeguer, A. et al. Cited ad supra). This compound blocks TRPV1 in primary nociceptor cultures with a voltage dependent mechanism, being inhibition greater than negative than positive membrane potentials. However, the anti-inflammatory and analgesic activity of this compound has not yet been described.

Despite the therapeutic potential of these TRPV1 antagonists, only a small number of candidates have reached clinical trials, due to unforeseen side effects, such as hyperthermia. In addition, it seems that the total blockade of TRPV1 in some chronic pain models has increased hypersensitivity (Gavva, N. R et al. Pain 2008, 136, 202-210). These observations are consistent with the wide distribution of the channel in neuronal and non-neuronal tissues and suggest a participation of the channel in other functions of the body in addition to nociception and pain; for example, in the regulation of body temperature. It is clear that the indiscriminate pharmacological blockade of the recipient through the use of competitive antagonists of high affinity, almost irreversible, may be responsible for the observed side effects. That is why these potent antagonists, which act both in the resting state and in the activated state of the canal, show a limited therapeutic index. Together, these data expose the need for a different class of antagonists, which act specifically on activated or hyperactive channels, respecting those at rest.

Non-competitive capsaicin antagonists are a class of activity-dependent inhibitors that specifically bind to the agonist-receptor complex or the open state of the canal (Planells-Cases, R. et al. Drug Future 2003, 28, 787-797) . Due to their interaction with active receptors, these compounds have attracted considerable interest as drugs with a potential improvement in the therapeutic index. This property is considered a solid argument so that its blocking is preferential over highly activated receptors and the interaction is minimal over resting or physiologically active channels. An example of the therapeutic benefit of non-competitive antagonists is memantine, a non-competitive L-glutamate antagonist of the NMDA receptor, approved for the treatment of Alzheimer's dementia (Johnson, JW et al. Curr. Opin. Pharmacol. 2006 , 6, 61-67).

Antagonists that block TRPV1 with micromolar efficacy have been described when interacting with the outer vestibule of the ionic canal (García-Martínez, C. et al. Proc. Nati. Acad. Sci. US A 2002, 99, 2374-2379). Although these compounds showed activity in vivo in animal pain models, their development was interrupted due to unforeseen side effects, derived from the release of α-CGRP from nociceptive neurons when using antagonists in submicromolar concentrations. Specifically, the N-alkylglycine trimers (peptoids) were the first family of compounds that interacted with the receptor, in what appears to be a seemingly located junction outside the membrane electric field, at the entrance of the pore (Garcia- Martínez, C. et al. Cited ad supra). However, it was possible that the junction site located at the entrance of the pore was also accessible in the closed channel state, which would explain the unwanted effects observed.

It is very remarkable that, even after the enormous scientific and economic effort made in recent years in the search and development of TRPV1 modulators, only seven compounds have progressed to clinical trials in humans. There is, therefore, the need for identification and validation of non-competitive antagonists blocking TRPV1 channels, for the development of drugs with potential activity as analgesics. These new antagonists will be more selective since they recognize a cavity in the pore of the ionic channel, accessible only if the channel is open. In addition, the access time to said cavity is directly proportional to the time in which the channel is in the open conformation. Therefore, drug-target binding will occur to a greater extent in those channels that are overactivated, compared to those at rest or that open briefly in response to a nociceptive signal. It is necessary that said antagonists do not activate the receptor at a low concentration, that their bioavailability is high, of zero toxicity and that their synthesis be simple. SUMMARY OF THE INVENTION

In one aspect, the invention relates to a compound that inhibits the activity of TRPV1 of formula (I):

where both Ri are equal and Ri is selected from the group consisting of:

, wherein the phenyl group may be substituted in any position by a group selected from: O-C1-C3 alkyl, nitro, halogen, COOR and COR (where R is C1-C3 linear alkyl or H), or it may comprise two adjacent substituents that together form a dioxolane;

wherein R3 is a halogen, n is selected between 1, 2 and 3 and m between 1, 2, 3, 4 and 5; and where Ri is not:

and where R ₂ is selected from the group consisting of:

| _ |

( ^a ) ^N ( ^CH2 ) n R _{4j is} selected from the group consisting of:

(a. l) R5R5, wherein R ₅ and 5 are independent and are selected from the group consisting of: a C1-C3 linear alkyl, hydrogen and formamidine group; (a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(b) O (CH ₂ ) _n

^R io;

(c) NH H R-i -,

(d) ½; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

going

where n is selected from 1, 2, 3, 4, 5, 6 and 7, m between 1, 2 and 3 and where R ₇ , R ₈ , R9, Rio, R11 and R15 are independent and are selected from hydrogen and C1-C3 linear alkyl;

or any pharmaceutically acceptable salts, solvates and prodrugs of said compound.

In another aspect, the invention relates to a process for the preparation of the compound of the invention of formula (I), which comprises:

(a) reacting a compound of formula (III)

where X is a halogen or -OS0 ₂ R, where R is selected from the group: methyl, CF3 and paratolyl,

with a RiH compound, where Ri has the previously indicated meaning, to form a compound of formula (II); Y

(b) reacting the compound of formula (II) with a compound R ₂ H, where R ₂ has the previously indicated meaning.

In another aspect, the invention relates to a pharmaceutical or cosmetic composition comprising a cosmetic or pharmaceutically effective amount of the compound of the invention and a cosmetic or pharmaceutically acceptable carrier. In another aspect, the invention will be a compound of formula I:

where both Ri are equal and Ri is selected from the group formed

wherein the phenyl group may be substituted in any position by a group selected from: OC ₁ -C3 alkyl, nitro, halogen, COOR and COR (where R is C ₁ -C3 linear alkyl or H), or it may comprise two adjacent substituents that together form a dioxolane;

wherein R3 is a halogen, n is selected between 1, 2 and 3 and m between 1, 2, 3, 4 and 5; and where R ₂ is selected from the group consisting of:

H

(a) N- - (CH ₂₎ _{4 N ^} _ecc i i _{is is} _one does the group consisting of:

(a. l) NR ₅ R ₅ , wherein R ₅ and 5 are independent and are selected from the group consisting of: a C 1 -C 3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ^ R ₁₂ ; where R ₁₂ is selected from the group consisting of:

(d. l) N- C ₁ -C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

or any pharmaceutically acceptable salts, solvates and prodrugs of said compound,

in the manufacture of a medicament for the treatment and / or prevention of pain, inflammation, pruritus, diseases of the respiratory tract, diseases of the skin, mucosa and / or nails and disorders associated with calcium imbalances.

In a final aspect, the invention relates to a cosmetic method for the care of the skin, mucous membranes and / or nails comprising the administration of at least one compound of formula I or any cosmetically acceptable salts, solvates and prodrugs thereof. formula I is:

where both Ri are equal and Ri is selected from the group formed

, wherein the phenyl group may be substituted in any position by a group selected from: 0-Ci-C ₃ alkyl, nitro, halogen, COOR and COR (where R is Ci-C ₃ linear alkyl or H), or may comprise two adjacent substituents that together they form a dioxolane;

wherein R ₃ is a halogen, n is selected between 1, 2 and 3 and m between 1, 2, 3, 4 and 5; and where R ₂ is selected from the group consisting of:

H

(a) -N- - ^(C H ₂ ⁾ _n R _{4 ^ is} referred to from the group consisting of:

(a. l) NR ₅ R ₅ , wherein R ₅ and 5 are independent and are selected from the group consisting of: a C1-C3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ^ R ₁₂ ; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

or any cosmetically acceptable salts, solvates and prodrugs of said compound.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 describes the overall synthetic route for obtaining the symmetric trisubstituted triazines of the invention.

Figure 2 shows the structural diversity with which the different triazine derivatives have been synthesized. Ri corresponds to constituent groups with aromatic functionality. R ₂ corresponds to constituent groups with protonable functionality.

Figure 3 describes the representative ionic currents showing the blockade of responses evoked by capsaicin by compounds 1-13, Il l, 1-10, respectively (ac), and the triazine-induced activity of compounds 1-13, Il l, 1-10, respectively (df) at different concentrations. Ionic currents were measured in Mg ²⁺ Ringer buffer. Horizontal bars indicate the protocol used for stimulation and blockage.

Figure 4 shows the blocking and activation of TRPV1 caused by triazines. (a) Triazine-induced capsaicin response block at a concentration of 10 μΜ; (b) ionic currents activated by the application of 10 μΜ of the triazines in TRPV1 expressed heterologously in oocytes, the triazines are represented by a number in the order of ordinates and correspond to 11-135; (C) example of three representative dose-response curves, 1-10, I-11 and 1-33. The solid lines illustrate the adjustment of the experimental data to the Michaelis-Menten equation and (d) IC ₅₀ values for all the triazines tested, the triazines are represented by a number on the ordinate axis and correspond to 11-135. These values are obtained from the adjustment of the data of the dose-response curves. The responses were recorded at -60 mV and normalized with respect to the current produced by the application of 10 μΜ of capsaicin. Data are shown as the mean ± SEM with n> 6.

Figure 5 shows in (a) representative ionic currents produced by the application of 10 μΜ of capsaicin, using a linear ramp protocol from -60 mV to +60 mV in absence (Cap) and in presence (Cap / I-10) of compound 1-10 at 10 μΜ. (b) Fraction of the TRPV1 block by triazine 1-10 as a function of voltage. The solid line represents the adjustment to the Woodhull model that gives a distance (δ) of 0.34A within the membrane electric field of the junction site of 1-10 within the membrane electric field.

Figure 6 shows the inhibition of neuronal activity of the nociceptor fibers of the knee joint by triazine 1-10. (ad) Instantaneous frequency of nerve impulse discharge created by intra-arterial injections of 100 μΐ of capsaicin, 10 μΜ (arrows) before (a) and 15 minutes (b), 35 minutes (d) and 55 minutes (d) after of the administration of 100 μΜ of triazine 1-10. (e) and (f) They show respectively the pulse discharge caused by a rotation of the joint for 10 s (starting on the arrow), applied before the injection of capsaicin and triazine and 35 minutes after the administration of triazine ( immediately before c). The example of recording the activity produced by capsaicin (a) and by mechanical stimulation (e).

Figure 7 shows the quantification of nerve activity blockade of afferent fibers by triazine 1-10, both for the activity stimulated by capsaicin (a), and by a mechanical stimulus (b). The values represent the mean ± sem, with n (number of animals)> 5. * * p <0.01, * p <0.05 (Anova test, followed by the Bonferroni test).

Figure 8 shows that triazine 1-10 does not alter the electrical properties of nociceptor membranes. (a and b) Measures representative of the potential of resting membrane of neurons in the absence (vehicle, 0.001% DMSO) and presence of triazine 1-10 at 10 μΜ. The numbers on the left side show the resting membrane potential of the neuron membrane, (c and d) Effect of the vehicle and 10 μΜ triazine on the evoked neuronal action potentials. The resting potential and the action potential were measured in the current setting configuration using the "patch-clamp" technique in primary cultures of rat nociceptors from DRGs. The records are representative of 4 cells for each condition.

DETAILED DESCRIPTION OF THE INVENTION

The authors of the present invention have identified a family of compounds derived from a triazine skeleton that act as TRPV1 receptor blockers when the channel is in the open state. Thus, as illustrated in Example 2 and Figure 4, most of the identified compounds are capable of blocking the TRPV1 receptor with micromolar efficacy and also have high selectivity for said receptor in the activated state. The antagonists found are effective, since they do not activate the receptor at low concentration, their bioavailability is high, they are of zero toxicity and their synthesis is quite simple. Also, the inventors have verified the effectiveness of said compounds in vivo, as shown in Example 3

TRPVl activity inhibitor compounds

Therefore, in a first aspect, the invention relates to a compound that inhibits the activity of TRPV1, hereinafter the compound of the invention, of general formula I:

where both Ri are equal and Ri is selected from the group consisting of:

(to)

and where R ₂ is selected from the group consisting of:

| _ |

( ^a ) ^N ( ^CH2 ) n R _{4j is} selected from the group consisting of:

(a. l) R5R5, wherein R ₅ and 5 are independent and are selected from the group consisting of: a C1-C3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen (a.4) Heterocycle

(d) ^ R ₁₂ ; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

going

In a particular embodiment, the compound has the general formula I and three substituents, where two of them are the same and are called Ri and the third substituent is R ₂ . The general formula I is as follows:

and Ri and R ₂ are selected from the group consisting of:

In a particular embodiment, the compound of the invention is selected from the group of compounds described in Table 1 and named as II to 135. Said compounds have the general formula I and three substituents, wherein two of them they are the same and are called Ri and the third substituent is R ₂ . The general formula I is as follows

and wherein the substituents Ri and R ₂ of each of the compounds of the invention II to 135 is:

In a particular embodiment, Ri is not

In a preferred embodiment, the compound of the invention is 1-10, whose general formula corresponds to formula I and wherein Ri and R ₂ correspond to:

The term "alkyl" refers to a linear or branched hydrocarbon chain consisting of carbon and hydrogen atoms, which does not contain any unsaturation, it has one to eight carbon atoms, unless the number of carbons is specifically indicated and which is linked to the rest of the molecule by a single bond, for example methyl, ethyl, n-propyl, i-propyl, n -butyl, t-butyl, n-pentyl, etc.

The term "halogen" refers to a substituent of chlorine, bromine, fluorine or iodine. The term "heterocycle" refers to a stable ring radical of 3 to 15 members consisting of carbon atoms and one to three heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur, preferably a ring of 4 to 8 members with one or more heteroatoms, more preferably a 5 or 6 member ring with one or more heteroatoms. More preferably the ring has two heteroatoms. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tri-cyclic ring system that may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom could be optionally quaternized; and the heterocyclyl radical could be partially or totally saturated or aromatic. Examples of such heterocycles include, but are not limited to, acepinyl, benzimidazolyl, benzothiazolyl, f ranyl, isothiazolyl, imidazolyl, indolyl, piperidinyl, piperazinyl, purinyl, quinolinyl, thiadiazolyl and tetrahydrof ranyl.

The term "pharmaceutically acceptable salts or solvates" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound that, in its administration, is capable of providing (directly or indirectly) a compound such as those described herein. document. However, it will be noted that pharmaceutically unacceptable salts also fall within the scope of the invention, since these may be useful for the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the state of the art.

For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the compound of the invention, by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. In general, media are preferred non-aqueous such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of acid addition salts include addition salts of mineral acids such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkaline addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and organic alkaline salts such as, for example, et al. amine, ethanol amine, N, N-dialkylene ethanolamine, glucamine and basic amino acid salts.

Especially preferred derivatives or prodrugs are those that increase the bioavailability of the compounds of the invention when these compounds are administered to the subject (for example, allowing an orally administered compound to be absorbed more rapidly into the blood) or that improve the supply of the compound to a biological compartment (for example, the brain or lymphatic system) with respect to the initial compound.

The compounds of the invention may be in a crystalline form as free compounds or solvates and both forms are intended to be within the scope of the present invention. Solvation methods are generally known in the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.

The compounds of the invention or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form. As a pharmaceutically acceptable form, inter alia, what is meant in a pharmaceutically acceptable purity, excluding normal pharmaceutical additives such as diluents and excipients, and not including any material considered toxic at normal dosage levels. The purity levels for the compound of the invention are preferably above 50%, more preferably above 70%), and even more preferably above 90%. In a preferred embodiment it is above 95% of the compound of the invention, or of its salts, solvates or prodrugs.

The compounds of the present invention may include enantiomers depending on the presence of chiral centers or isomers depending on the presence. multi-link (for example, Z, E). The individual isomers, enantiomers or diastereomers and mixtures thereof are within the scope of the present invention. When a compound is drawn with explicit stereochemistry, it is intended to represent the racemic structure with relative stereochemistry, as well as enantiomers in different degrees of purity. In any case, the enantiomers and the shallow diastereoi of the compounds represented with a particular stereochemistry also form part of the compounds of the invention.

The compounds of the invention have the function of blocking the activity of TRPV1, that is, they have the ability to inhibit the TRPV1 receptor. The TRPV1 protein, as used herein, refers to a protein derived from mammals, such as human, monkey, rat, mouse, dog, bovine species, rabbit and the like, from birds, fish or other animals. . The amino acid sequence of TRPV1 is registered in the GenBank database under or accession number CAB89866 (human).

Suitable methods for determining the ability of the compound to inhibit TRPV1 activity, include, but are not limited to, the method described in Figure 4 of the present invention, based on monitoring intracellular Ca ²⁺ signals in amphibian oocytes expressing TRPV1 of rat. Specifically, to determine the ability of a compound of the invention to block the activity of the TRPV1 receptor, the function of TRPV1 is used as a calcium channel. The activation of the TRPV1 receptor by treatment with capsaicin entails the opening of the ionic channel of the receptor expressed in said cells and the consequent increase in the concentration of intracellular calcium. However, when a TRPV1 receptor inhibitor compound is added, the intracellular calcium concentration decreases with respect to the cells untreated with the compound of the invention. Another suitable method to determine if the compound of the invention is capable of inhibiting the activity of TRPV1, includes the method described in Example 2, based on the monitoring of the total current in the cells using the voltage clamp technique or "voltage -clamp ". Specifically, in said method the channels are activated by adding capsaicin and the inhibitor compound is added (as control cells are maintained without adding the inhibitor compound), using a potential of -60 mV and measuring the ionic currents in said cells. A compound of the invention is considered to inhibit the activity of TRPV1, if it inhibits its function, that is if the activity of TRPV1 is decreased by at least 15%, at least 20%, at least 30%>, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, with respect to the cells expressing the receptor TRP untreated with the inhibitor compound.

Process for preparing the compound of the invention

In one aspect, the invention relates to a process for the preparation of a compound of the invention, comprising:

(a) reacting a compound of formula (III)

with a compound RiH, where Ri has the previously indicated meaning, to form the formula (II); Y

(b) reacting the compound of formula (II) with a compound R ₂ H, wherein R ₂ has the previously indicated meaning, to give rise to a compound of formula (I) defined in any one of claims 1 to 3.

The person skilled in the art knows the suitable conditions to carry out both stages, in particular, he will define the temperature, the equivalents to react of each compound and the time that the reaction will be maintained. In a particular embodiment, steps (a) and (b) are performed by heating. In a preferred embodiment, in step (a) a temperature between 40 and 100 ° C is used, more preferably said temperature is 70 ° C. In a preferred embodiment, in step (b) a temperature between 50 and 120 ° C is used, more preferably said temperature is 100 ° C. In one embodiment In particular, stage (a) is carried out in a microwave oven and stage (b) in a microwave oven or in a pressure vessel. In a particular embodiment, in step (a) the compound of formula (III) is reacted with RiH in a ratio between 0.5: 3 to 1.5: 5. Preferably, 1 equivalent of compound III is reacted with 4 equivalents of RiH. In a particular embodiment, in step (b) the compound of formula (II) is reacted with R ₂ H in a ratio between 0.5: 3 to 1.5: 5 equivalents. Preferably, 1 equivalent of compound II is reacted with 4 equivalents of R ₂ H. As for the reaction time, in a particular embodiment, step (a) is carried out for 7-15 minutes. Preferably, for 10 minutes. Step (b) is carried out, in a particular embodiment, for 10-25 minutes. Preferably, for 20 minutes.

In a particular embodiment, the solvent for both stages is an organic solvent. In a preferred embodiment, said solvent is an ether, preferably tetrahydrofuran (THF).

A person skilled in the art will know the steps to follow to carry out the process of the invention. In a preferred embodiment, the specific steps of the process of the invention are those described below.

The starting material is a solution of 2,4,6-trichlorotriazine in THF, which is reacted with the corresponding amine (RiH compounds of Figure 2), heating in a microwave oven. Then, the reaction crude is poured into water, heated and filtered. The precipitate is subjected to the same treatment, the insoluble material is washed with cold absolute ethanol and dried to obtain the intermediate disubstituted triazine (Formula II). Next, a suspension of the triazine disubstituted in THF is reacted with the corresponding amine (R ₂ H compounds of Figure 2) under microwave activation. The reaction crude is diluted in ethyl acetate and washed with water and brine and dried over MgSC. If it is necessary to obtain a higher purity than that obtained by the described procedure, the resulting residue after solvent removal is removed. Purify by semi-preparative HPLC using mixtures of CH ₃ CN and water, containing 0.1% trifluoroacetic acid. The collected fractions are evaporated in vacuo, redissolved in ethyl acetate and washed with a saturated solution of NaHC0 ₃ and brine, and dried over MgSC. Solvent removal results in pure trisubstituted triazine (formula I) which is part of the compound of the invention. In a preferred embodiment, the steps are those described in Example 1 of the present invention.

Pharmaceutical or cosmetic compositions of the invention

In another aspect, the invention relates to a pharmaceutical or cosmetic composition, hereinafter pharmaceutical or cosmetic composition of the invention, comprising a therapeutically or cosmetically effective amount of the compound of the invention and a pharmaceutically or cosmetically acceptable carrier.

In the context of the present invention, "therapeutically or cosmetically effective amount" means the amount of compound of the invention necessary to achieve the desired effect which, in this particular case, is the inhibition of TRPV1. In general, the therapeutically or cosmetically effective amount of the compound according to the present invention to be administered will depend, among other factors, on the individual to be treated, on the severity of the disease suffered by said individual, on the chosen form of administration, etc. . For this reason, the doses to be administered will be adjusted by a person skilled in the art, depending on the circumstances and as directed the composition to be treated or for cosmetic use.

The term "pharmaceutically or cosmetically acceptable vehicle" refers to a vehicle that must be approved by a federal government regulatory agency or a state government or listed in the United States Pharmacopoeia or European Pharmacopoeia, or other pharmacopoeia generally recognized for use in animals , and more specifically in humans. The term "vehicle" refers to a diluent, adjuvant, excipient or carrier with which the compounds of the invention should be administered; obviously, said vehicle must be compatible with said compounds.

Such pharmaceutical or cosmetic vehicles can be liquids, such as water, solvents, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as, for example, and without limitation, peanut oil, soybean oil, mineral oil , sesame oil, castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, digitonine and the like. "Remington's Pharmaceutical Sciences" by EW Martin describes diluents, adjuvants or excipients as suitable carriers. The composition of the invention can be administered together with a sustained release vehicle. The term "sustained release" is used in the conventional sense referring to a system of vehiculization of a compound that provides for the gradual release of said compound over a period of time and preferably, but not necessarily, with relatively constant levels of compound release at over a period of time.

Illustrative examples of sustained release vehicles or systems include, but are not limited to, liposomes, mixed liposomes, oleosomes, niosomes, etosomes, milicocapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles, phospholipid mixed micelles - surfactant, microspheres, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, miniparticles, miliparticles, microparticles, nanoparticles, solid lipid nanoparticles and nanostructured lipid supports.

In a particular embodiment, the composition of the invention can be presented in the form of a formulation selected from the group consisting of creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels, solutions hydroalcoholics, hydro-glycol solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serums, ointments, mousses, ointments, powders, bars, pencils, vaporizers, aerosols, capsules, gelatin capsules, soft capsules, hard capsules, tablets, tablets Coated with sugar, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, polysaccharide films, jellies and gelatin.

In a particular embodiment, the pharmaceutical or cosmetic composition of the invention is incorporated into a tissue, a non-woven fabric or a medical device. Illustrative examples of such fabric, non-woven fabric or medical device include, but are not limited to, bandages, gauze, t-shirts, socks, socks, underwear, girdles, gloves, diapers, compresses, bedding, bedspreads, wipes, patches adhesives, non-adhesive patches, occlusive patches, microelectric patches and facial masks.

The pharmaceutical or cosmetic composition of the invention may comprise a combination of more than one compound of the invention, so that the desired effect is obtained more efficiently. In a particular embodiment, the pharmaceutical composition of the invention is administered topically, transdermally, orally, nasally, intramuscularly, intravenously, intraperitoneally, subcutaneously, enterally or parenterally. Illustrative examples of topical or transdermal administration include, but are not limited to, iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, needleless injections by pressure, microelectric patches and any combination thereof. Examples illustrative of oral administration pharmaceutical forms include tablets, capsules, granules, solutions, suspensions, etc., and may contain conventional excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and may be prepared by conventional methods. The pharmaceutical compositions can also be adapted for parenteral administration, in the form of, for example, sterile lyophilized solutions, suspensions or products, in the appropriate dosage form; in this case, said pharmaceutical compositions will include suitable excipients, such as buffers, surfactants, etc. In any case, the excipients will be chosen based on the pharmaceutical form of administration selected. A review of the different pharmaceutical forms of drug administration and their preparation can be found in the book "Galenica Pharmacy Treaty", by C. Faulí i Trillo, 10 Edition, 1993, Luzán 5, SA de Ediciones.

In a particular embodiment, the composition of the invention further comprises an adjuvant. Eg adjuvant empires that can be used accompanying the composition of the invention include, but are not limited to, anti-inflammatory and / or analgesic agents, anti-pruritus agents, soothing agents, anesthetic agents, inhibitors of aggregation of acetylcholine receptors, inhibitors of muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloprotease inhibitors, melanin synthesis stimulating or inhibiting agents, bleaching or depigmenting agents, propigmentation agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors , 5α-reductase inhibitors, lysyl- and / or prolyl hydroxylase inhibitors, antioxidant agents, free radical capture and / or anti-air pollution agents, carbonyl reactive species capture agents, anti-glycation agents, agents antihistamines, antivir agents ales, antiparasitic agents, emulsifying agents, emollients, organic solvents, liquid propellants, skin conditioners, humectants, moisture-retaining substances, alpha hydroxy acids, betahydroxy acids, moisturizers, hydrolytic epidermal enzymes, vitamins, amino acids, proteins, pigments or dyes, dyes, biopolymers , gelling polymers, thickening agents, surfactants, softening agents, emulsifiers, binding agents, preservatives, anti-wrinkle agents, agents capable of reducing or treating the bags under the eyes, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, Bacteriostatic agents, stimulatory agents of the synthesis if they are of dermal or epidermal macro molecules and / or capable of inhibiting or preventing their degradation, collagen synthesis stimulating agents, elastin synthesis stimulating agents, synthesis stimulating agents of of Chorina, laminin synthesis stimulating agents, defensin synthesis stimulating agents, aquaporin synthesis stimulating agents, hyaluronic acid synthesis stimulating agents, fibronectin synthesis stimulating agents, sirtuin synthesis stimulating agents , agents that stimulate the synthesis of heat shock proteins, agents that stimulate the synthesis of lipids and components of the stratum corneum, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit elastin degradation, agents that inhibit serine proteases such as cathepsin G, fibroblast proliferation stimulating agents, keratinocyte proliferation stimulating agents, adipocyte proliferation stimulating agents, melanocyte proliferation stimulating agents, keratinocyte differentiation stimulating agents, agents adipocyte differentiation stimulants, acetylcholinesterase inhibiting agents, dermorelative agents before, agent can be found in the same way if it is aminogly and canine, antihyperkeratosis agent, comedolytic agents, antipsoriasis agents, agents DNA repairers, DNA protective agents, stabilizers, agents for the treatment and / or care of sensitive skin, firming agents, anti-stretch agents, astringent agents, sebum production regulating agents, lipolytic agents or lipolysis stimulants, anti-cellulite agents , antiperspirant agents, healing agents, healing agents, agents reepithelialization stimulators, reepithelializing adjuvant agents, cytokine growth factors, agents acting on capillary circulation and / or microcirculation, angiogenesis stimulating agents, vascular permeability inhibiting agents, venotonic agents, agents acting on the metabolism of cells, agents intended to improve the dermis-epidermis junction, hair growth inducing agents, hair growth inhibitors or retardants, hair loss retardants, preservatives, perfumes, chelating agents, plant extracts , essential oils, marine extracts, agents from a biofermentation process, mineral salts, cell extracts, sunscreens and photoprotective agents of an organic or mineral nature active against ultraviolet A and / or B rays and mixtures thereof.

Illustrative examples of anti-wrinkle agents and / or anti-aging agents include, but are not limited to, Vitis vinifera extract, Rosa canina extract, Turmeric longa extract, Iris pallida extract, Theobroma cacao extract, Ginkgo biloba extract, extract Leontopodium alpinum, Dunaliella salina extract, pentapeptide-1 8, acetyl hexapeptide do-8, acetyl heptapeptide-4, acetyl octapeptide-3, acetyl tetrapeptide-5, tripeptide-10 citrulline, acetyl tripeptide-30 citrulline, diaminopropionoyl-tripeptide-33 acetyl tetrapeptide-22, dimethylmethoxy chromanol, dimethylmethoxy chromanyl palmitate, the mixture of hydrolyzed wheat protein, soy protein to hydrolyzed and tripeptide-1, the mixture of ferment extract from Pseudoalteromonas, hydrolyzed wheat protein, soy protein to hydrolyzed , tripeptide-10 citrulline and tripeptide-1, ferment extract of Pseudoalteromonas, the mixture of Lysine-HCl, lecithin and tripeptide-10 citrulline, acetyl h exapeptide-30, acetylaginyltriptofil diphenylglycine, acetyl tetrapeptide-22, other calcium channel antagonists, alverin, manganese or magnesium salts, magnesium gluconate, secondary or tertiary amines, retinol and its derivatives, idebenone and its derivatives, Coenzyme Q10 and its derivatives, boswellic acid and its derivatives, GHK and its derivatives, carnosine and its derivatives, DNA repair enzymes, photoliase, T4 endonuclease type V and chloride channel agonists.

Illustrative examples of anti-inflammatory and / or analgesic agents include, but are not limited to, madecasoside, equinacin, amaranth seed oil, sandalwood oil, peach leaf extract, Aloe vera extracts, Arnica montana, Artemisia vulgaris, Asarum máximum, Calendula officinalis, Capsicum, Centipeda cunninghamii, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens, Hypericum perforatum, Lilium candidum, Malva sylvestris, Melaleumumumus, Melaleunus Origusanumusus, Lalausumus Origusanumusus, Origlaneus Origusanumusus, Origlaeus Origusanumusus, Melaleunus Origusanus, Originaeusus Originaeusus, Originalausus Origusausus, Originalausus Originaeus, Originaeusus Originaeusus, Originalausus Origusanumus, Origins officialis, Salix alba, Silybum marianum, Tanacetum parthenium, Thymus vulgaris, Uncaria guianensis or Vaccinum myrtillus, mometasone furoate and prednisolone, anti-infl non-spheroidal amatoriums, cyclooxygenase or lipoxygenase inhibitors, benzidamine acid, rosalylic acid, rossamic acid, rossamic acid, rossamic acid, rossamic acid, rossamic acid, rossamic acid derivatives of glycyrrhizinate, α-bisabolol, azulene and the like, sericoside, ruscogenin, escina, scoline, rutin and the like, hydrocortisone, clobetasol, dexamethasone, prednisone, paracetamol, amoxiprin, benorylate, choline salicylate, diflunisal, phathylamine, detocyl, methylamine magnesium salicylate, salsalate, diclofenac, acecl ofenaco, acemetacin, bromfenac, etodolac, indomethacin, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, dexibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, loxoprofen, naproxen, miroprofen, oxaprozin, pranoprofen, tiaprofenic acid, suprofen , mefenamic acid, meclofenamate, meclofenamic acid, flufenamic acid, tolfenamic acid, nabumetone, phenylbutazone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib , rofecoxib, valdecoxib, nimesulide, naproxcinod, fluprocuazone or licofelone; morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, brupenorfina, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, tricyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalin, panthenol, biotin, lauriminodipropionato tocopheryl phosphate disodium, ciclopirox olamine , ethical dihydroguarial acid and alkyl glycerin ethers.

Therapeutic uses of TRPV1 activity inhibitor compounds

The compounds of the invention are capable of blocking or inhibiting the activity of the TRPV 1 receptor channel. The TRPV1 inhibitor compounds probably act by binding to a relatively deep place in the aqueous pore of the channel and by a non-type channel blocking mechanism. competitive as is It can be extrapolated from Figure 5. Therefore, the compounds of the invention are capable of blocking the channel in the open state.

Thus, the TRPV1 inhibitor compounds of the invention can be used for the treatment and / or prevention of pathologies in which it is necessary to keep the blocked TRPV1 channel in the open state. In another aspect, the invention relates to the use of a compound in the manufacture of a medicament for the treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, skin diseases, mucosa and / or nails. and disorders associated with calcium imbalances, wherein the compound has the general formula I:

where both Ri are equal and Ri is selected from the group consisting of:

wherein the phenyl group may be substituted in any position by a group selected from: OC ₁ -C ₃ alkyl, nitro, halogen, COOR and COR (where R is C ₁ -C ₃ linear alkyl or H), or it may comprise two adjacent substituents that together form a dioxolane;

(C)

H

( ^a ) ^N ( ^CH 2) n R _{4j is} selected from the group consisting of:

(a. l) NR5R6, wherein R ₅ and Re are independent and are selected from the group consisting of: a Ci-C ₃ linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) N½; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m -NR ₁₃ Ri4,

where n is selected between 1, 2, 3, 4, 5, 6 and 7, m between 1, 2 and 3 and where R ₇ , R ₈ , R9, Rio, Ri and R15 are independent and are selected from hydrogen and C1-C3 linear alkyl;

In a particular embodiment, a combination of the compounds of the invention can be used for the manufacture of a medicament for the treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, skin diseases, mucosa and / or nails and disorders associated with calcium imbalances. Also, the compounds of the invention can be combined with other compounds that are conventionally used for the same purpose, that is, for the treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, diseases of the skin, mucosa and / or nails and disorders associated with calcium imbalances.

Alternatively, the invention relates to a compound for use in the treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, skin diseases, mucous membranes and / or nails and disorders associated with calcium imbalances. , wherein the compound has the general formula I:

where Ri is selected from the group consisting of:

(b), and the phenyl group may be substituted in any position by a group selected from: O-C1-C3 alkyl, nitro, halogen, COOR and COR (where R is C1-C3 linear alkyl or H), or it can comprise two adjacent substituents that together form a dioxolane;

where R3 is a halogen, n is selected between 1, 2 and 3 and m between 1, 2, 3, 4 and and where R ₂ is selected from the group consisting of:

H

(a) ^N ( ^CH 2) n R _{4j is} selected from the group consisting of:

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

R ₁₂ is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

Alternatively, the invention relates to a method of treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, skin, mucous and / or nail diseases and disorders associated with calcium imbalances, which comprises administration. of a compound presenting the general formula:

where both Ri are equal and Ri is selected from the group consisting of:

| _ |

( ^a ) ^N ( ^CH2 ) n R _{4j is} selected from the group consisting of:

(a.2) hydroxyl group (a.3) Hydrogen

(a.4) Heterocycle

(d) ½; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

In a particular embodiment, the invention relates to the use of a compound having the general formula I and three substituents, wherein two of them are the same and are called Ri and the third substituent is R _2, in the manufacture of a medicament for the treatment and / or prevention of pain, inflammation, itching, respiratory tract diseases, skin diseases, mucous membranes and / or nails and disorders associated with calcium imbalances, wherein the compound has the general formula I:

and Ri and R ₂ are selected from the group consisting of:

Table 1

The term "treatment" as used in the context of this specification means administration of a compound according to the invention to alleviate or eliminate one of the diseases mentioned above or reduce or eliminate one or more symptoms associated with said disease. The term "treatment" also encompasses alleviating or eliminating the physiological sequelae of the disease. The term "prevention", as used in the present invention, refers to the ability of a compound of the invention to prevent, minimize or hinder the onset or development of a disease or condition before its onset. The compounds of the invention are used for the treatment and / or prevention of pain, inflammation, pruritus, respiratory tract diseases, skin, mucous and / or nail diseases and disorders associated with calcium imbalances.

In a particular embodiment, at least one compound of the invention is used for the treatment and / or prevention of pain. The term "pain", as used in the present invention, refers to a sensory (objive) and emotional (subjective) experience, generally unpleasant, that all living beings that have a nervous system can experience. It is an experience associated with a tissue injury and can refer either to acute or chronic pain. The pain is selected, without limitation, from the group consisting of neuropathic pain, inflammatory pain, visceral pain, abdominal pain, digestive system pain, respiratory system pain, urogenital system pain, endocrine system pain, heart pain, pain pancreatic, intestinal pain, stomach pain, spleen pain, blood vessel pain, irritable bowel syndrome, tension headache, sinusitis headache, migraine, eye pain, dry eye syndrome, post-operative pain , post-operative pain due to surgical incisions, post-operative pain due to the insertion of bone implants, post-operative pain due to bone replacement, post-operative pain due to infections, pain due to cancer, pain due to bone cancer, pain associated with benign bone tumors, pain associated with osteoid osteomas, pain associated with osteoblastomas, pain due to cancer treatment r, musculoskeletal pain, spastic muscle pain, fibromyalgia, neuralgic pain, neck pain associated with cervical dystonia, back pain, low back pain, sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, post-herpetic neuralgia, peripheral neuropathies, phantom pain, allodynia, pain due to carpal tumel syndrome, burning pain, paraesthesia, facial pain, trigeminal neuralgia, neuropathic pain due to diabetes, associated pain of tattoo processes or tattoo removal, pain due to bunions, testicular pain, myofascial pain, urinary bladder pain, urinary tract pain, vulvar pain, vaginal pain, scrotal pain, perineal pain, pelvic pain, skin irritation or irritation after surgery, after treatment with pulsed light therapy (IPL, Intense Pulse Lig ht), after treatment with monochromatic pulsed light therapy (laser), after a treatment with chemical descaling agents or after overexposure to aggressive external agents. In a preferred embodiment, the compounds of the invention are used for the treatment and / or prevention of neuropathic pain and inflammatory pain.

The compounds of the invention can also be used for the treatment and / or prevention of inflammatory pain, which is generally the result of an inflammatory response to tissue damage, such as nerve clamping, surgical methods, cancer or arthritis (Brower, Nature Biotechnology 2000; 18 : 387-391). Most patients with inflammatory pain do not experience pain continuously, but experience more pain when they move the inflamed site.

In a particular embodiment, at least one compound of the invention is used for the treatment and / or prevention of inflammation resulting from disorders or pathologies selected from the group formed by neurogenic inflammation, related to joint inflammation, sepsis, vascular inflammation, inflammation. respiratory, asthma, intestinal inflammation, conditions related to chronic inflammation, with acute inflammation, nephritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, glomerulonephritis, vasculitis and sarcoidosis, among others.

In a particular embodiment, the compounds of the invention are used for the prevention and / or treatment of pruritus. As used in the present invention, pruritus is a peculiar tingling or uncomfortable irritation of the skin that entails a desire to scratch the part in question. The pruritus may present well disseminated in various areas of the body (generalized pruritus) or in a specific area (localized pruritus). In a preferred embodiment, pruritus is associated with diseases and / or epithelial disorders selected from the group consisting of dermatitis, atopic dermatitis, photodermatosis, eczema, sensitive skin, psoriasis, dandruff, seborrhea, athlete's foot, sunburn, xerosis and dry skin , or pruritus associated with dialysis, pregnancy, menopause, infection of acquired immunodeficiency virus, chicken pox, herpes, malignant neoplasms, Hodgkin's disease, leukemia, myeloma, lymphoma, solid tumors, lung cancer, liver diseases , jaundice, cholestasis, liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome, essential thrombocythemia, myelodysplastic syndrome, iron deficiency anemia, systemic lupus erythematosus, endocrine diseases, thyroid diseases, parathyroid diseases, diabetes mellitus, kidney diseases, uremia, parasitic infections, scabies, lice, intestinal worms, allergic reactions, drug allergies, food allergies, chemical allergies, exposure to Poisonous plants, exposure to insect bites, chemotherapy, stress and anxiety.

In another particular embodiment, the compounds of the invention are used for the treatment and / or prevention of pain and / or inflammation associated with epithelial disorders, gastrointestinal diseases, diseases of the cardiovascular system, urinary tract diseases, diseases of the endocrine system, brain diseases , diseases of the reproductive system and cancer.

In another particular embodiment, the compounds of the invention can be used for the treatment and / or prevention of pain and inflammation associated with brain diseases, such as cerebral infarction, cerebral ischemia, cognitive disorders, memory problems, schizophrenia and bipolar disorder, among others.

In another particular embodiment, the compounds of the invention can be used for the treatment and / or prevention of pain and inflammation associated with pathologies of the reproductive system, such as vulvodynia.

In another particular embodiment, the compounds of the invention can be used for the treatment and / or prevention of pain and inflammation associated with different types of cancer, such as breast cancer, among others.

In another particular embodiment, the compounds of the invention can be used for the treatment and / or prevention of pain and inflammation associated with gastrointestinal diseases. Gastrointestinal diseases include, without limitation, inflammatory bowel disease, Crohn's disease, pancreatitis, gastroesophageal reflux disease and ulcerative colitis, among others.

In a particular embodiment, the compounds of the invention can be used in respiratory diseases. Examples of such diseases or disorders include, but are not limited to, obstructive diseases, such as chronic obstructive pulmonary disease, emphysema, chronic bronchitis, asthma, asthma caused by industrial irritants, cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, or tuberculosis; Lung diseases restrictive such as asbestosis, radiation-caused fibrosis, extrinsic allergic alveolitis or insensitivity pneumonitis, childhood respiratory distress syndrome, idiopathic pulmonary fibrosis, sarcoidosis, idiopathic interstitial pneumonia, eosinophilic pneumonia, lymphangioleiomyomatosis, Langerhave pulmonary cell histiocytosis; respiratory tract infections including common cold, sinusitis, tonsillitis, pharyngitis, laryngitis or pneumonia; Respiratory malignant tumors such as small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, carcinoid, mesothelioma, metastatic lung cancer, germ cell metastatic cancer, benign tumors respiratory such as pulmonary hamartoma; congenital malformations such as bronchopulmonary sequestration and cystic adenomatoid congenital malformation; diseases of the pleural cavity such as empyema and mesothelioma; pulmonary vascular diseases such as embolism, pulmonary thromboembolism, gaseous or iatrogenic embolism, pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation and damage to the capillaries in the lungs resulting in blood dripping into the alveoli; disorders that affect the mechanics of breathing such as obstructive sleep apnea, central sleep apnea, amyotrophic lateral sclerosis, Guillain-Barré syndrome and myasthenia gravis; shortness of breath or breathlessness, cough, coughing up blood or hemoptysis, chest pain such as pleuritic chest pain, noisy breathing, wheezing and cyanosis.

In another particular embodiment, the compounds of the invention are used for the prevention and / or treatment of epithelial disorders or disorders, as well as disorders or diseases of the mucosa and / or nails. Examples of epithelial disorders include, but are not limited to, touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-depilation skin irritation, post-shaved skin irritation, dermatitis, atopic dermatitis, allergic contact dermatitis, diaper dermatitis , photodermatosis, psoriasis, eczema, burns, sunburn, sensitive skin, xerosis and dry skin.

In another particular embodiment, the compounds of the invention are used for the prevention and / or treatment of pain and inflammation associated with cardiovascular diseases. The disease of the cardiovascular system is selected, although it is not It limits angina, ischemia, reperfusion, hypertension, chronic heart disease and cardiac fibrosis, among others.

In a particular embodiment, the compounds of the invention are used in the treatment and / or prevention of a disease or condition that benefits from the inhibition of an ion channel, that is, a canalopathy (Kass RS. (2005) J Clin Invest 115: 1986-1989). In a preferred embodiment, said ion channel is a calcium channel. In an even more preferred embodiment, said calcium channel receptor is the TRPV1 receptor. Therefore, in a particular embodiment, the compounds of the invention can be used in disorders associated with calcium imbalances. Examples of such disorders include, without limitation, vitamin D deficiency, rickets, osteomalacia, growth retardation, post-menopausal osteoporosis, hypercalciuria and parathyroid hormone-related disorders, among others.

Cosmetic method of the invention

In another aspect, the invention relates to a cosmetic method for the care of the skin, mucous membranes and / or nails comprising the administration of at least one compound of formula I or any cosmetically acceptable salts, solvates and prodrugs of said compound, in where formula I is:

where both Ri are equal and Ri is selected from the group consisting of:

, wherein the phenyl group may be substituted in any position by a group selected from: OC ₁ -C ₃ alkyl, nitro, halogen, COOR and COR (where R is C ₁ -C ₃ linear alkyl or H), or it can comprise two adjacent substituents that together form a dioxolane;

H

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ^ R ₁₂ ; where R ₁₂ is selected from the group consisting of:

(d. l) N- C ₁ -C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

or any cosmetically acceptable salts, solvates and prodrugs of said compound,

In a particular embodiment, the compound used in the cosmetic method is selected from the group consisting of II to 135, wherein said compounds have the following substituents:

In a preferred embodiment, said compound used in the cosmetic method

presents as substitutes

The following examples serve to illustrate the invention and should not be considered as limiting the scope thereof.

EXAMPLE 1

Synthesis of the compounds

All solvents, including those of HPLC purity, were obtained from VWR

(Barcelona, Spain). HPLC (high pressure liquid chromatography) analyzes of the synthesized compounds were performed with a Hewlett Packard 1 100 (UV 1315 A) device, using a MS Xterra RP18 4.6 x 150 mm column (Waters) and using mixtures CH ₃ CN-H ₂ 0 containing 0.1% TFA at 1 ml / min as mobile phase, with 220 nm recording. When necessary, the products were purified by HPLC at semi-preparatory scale. For this, an X-terra RP18 15-20 m column, 47 x 300 mm (Waters) was used. Mixtures of CH ₃ CN-H ₂ 0 containing 0.1% trifluoroacetic acid were used as the mobile phase at a flow rate of 10 ml / min. Subsequently, nuclear magnetic resonance (NMR) spectra were recorded. Unless otherwise indicated, NMR spectra were recorded in CDC1 ₃ at 48 ° C with a Varian Inova 400 apparatus (1 H NMR, 400 MHz, ¹³ C NMR, 100 MHz). Chemical shifts are expressed in ppm (δ) relative to CDC1 ₃ (7.24 ppm for 1 H NMR and 77.23 ppm for ¹³ C NMR), and coupling constants (J) are expressed in Hertz (Hz). The high resolution mass spectra (HRMS) were registered in the Mass Spectrometry Service of the IQAC-CSIC (Barcelona, Spain).

The triazines of the invention were synthesized following the steps indicated in Figure 1, the starting material being trichlorotriazine (left), which was improved in aspects of treatment of the reaction crude, taking into account the chemical diversity that was introduced into positions 2,4,6 of trichlorotriazine (Figure 2). Specifically, a solution of 2,4,6-trichlorotriazine (0.05 mmol, 1 eq) in THF (4 mL) was reacted with the corresponding amine (20 mmol, 4 eq) (Figure 2, left panel), in a microwave oven for 10 minutes at 70 ° C (90 W closed system).

Then, the reaction crude was poured into water (20 ml), heated for 10 minutes at 60 ° C and filtered. The precipitate was subjected to the same treatment, the insoluble material was washed with cold absolute ethanol and dried to obtain the intermediate disubstituted triazine. Then, a suspension of the disubstituted triazine (0.05 mmol, 1 eq) in THF (5 ml) was reacted with the corresponding amine (0.2 mmol, 4 eq) (Figure 2, right panel) for 20 min at 100 ° C below or microwave activation (1 10 W, closed system). The reaction crude was diluted in ethyl acetate (20 ml) and washed with water (20 ml) and brine (20 ml) and dried over MgSO ₄ . When it was necessary to obtain a higher purity than that obtained, the resulting residue after removal of the solvent was purified by semi-preparative HPLC using mixtures of CH ₃ CN and water, containing 0.1% trifluoroacetic acid. The collected fractions were evaporated in vacuo, redissolved in ethyl acetate and washed with a saturated solution of NaHC0 ₃ (20 ml) and brine (20 ml), and dried over MgSO ₄ . Removal of the solvent yielded pure trisubstituted triazine, with different substituents Ri and _R2. The amount obtained in the triazine synthesis process, the process performance, the NMR parameters, the coupling constants (J) and the molecular weights of the triazines obtained by mass spectrometry, for each of the triazines 11- 135 are shown below:

1-1: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6- (3'-hydroxypropylamino) -l, 3,5-triazine.

100 mg, 91% yield as a colorless oil.

1 H NMR: 7, 14 (dd, J = 8, 6, 4H); 6.96 (t, J = 9.4H); 3.70-3.35 (m, 8H); 2.82 (t, J = 7, 4H); 1.68 (s, 2H).

1 ³ C NMR: 166.67; 166.00; 161.87 (d, J = 244.3); 135.05 (d, J = 3.0); 130.33 (d, J = 7.8); 115.51 (d, J = 21.2); 58.63; 42.25; 36.87; 35.47; 33.34.

HRMS calculated for C22H26N6OF2 (M + H): 429.2214; Found: 429.2207.

1-2: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6 - ((' 5-dimethylamino) pentylamino) -l, 3,5-triazine.

48 mg, 23% yield as yellowish oil.

1 H NMR: 7, 14-6.96 (m, 8H); 3.80-3.70 (m, 4H); 3.53-3.43 (m, 2H); 3, 16-3.07 (m, 2H); 2.93-2.89 (m, 10H); 1.80-1.64 (m, 4H); 1.47-1.37 (m, 2H).

1 ³ C NMR: 160.67 (d, J = 244); 155.78; 132.60; 130.06 (d, J = 18); 115.91.

HRMS calculated for C26H35N7F2 (M + H): 484.3000; Found: 484.2992.

1-3: 2,4-Bis- (2 '- (4 "-fluorophenyl) ethylamino) -6-propylamino-l, 3,5-triazine.

84 mg, 53% yield as a colorless oil.

1 H NMR: 7, 15-6.97 (m, 8H), 3.74 (bb, 4H), 3.48-3.40 (m, 2H), 2.91 (t, J = 7), 1 , 66 (m, 2H), 1.00-0.95 (m, 3H).

¹³ C NMR: 162.21 (d, J = 254), 154.47, 152.45, 152, 11, 133.08, 130.261, 115.85 (d, J = 21), 44.31, 43, 55, 34,29, 22, 14, 11, 15.

HRMS calculated for C22H26N6F2 (M + H): 413.2265; Found: 413.2279.

1-4: 2,4-Bis- (2 '- (4 "-fluorophenyl) ethylamino) -6-hexylamino-l, 3,5-triazine.

85 mg, 73% yield as a colorless oil. 1 H NMR: 7, 15-6.97 (m, 8H), 3.76-3.62 (m, 4H), 3.47-3.39 (m, 2H), 2.91-2.88 ( m, 4H), 2.91-2.88 (m, 4H), 1.64-1.58 (m, 2H), 1.33-1.28 (m, 6H), 0.90 (bb, 3H).

1 ³ C NMR: 161.97 (d, J = 244), 154.96, 153.96, 153.46, 153.070, 133.212, 130.07 (d, J = 8), 115.70 (d, J = 21), 42,969, 42, 15, 34.34, 31.30, 28.51, 26.40, 22.45, 13.84.

HRMS calculated for C25H32N6F2 (M + H): 455.2734; Found: 455.2739.

1-5: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6- (3'-dimethylamino) propyloxy-l, 3,5-triazine.

90 mg, 32% yield as a colorless oil.

1 H NMR: 7, 17-7.09 (m, 4H), 7.00-6.92 (m, 4H), 4.37-4.25 (bb, 2H), 3.67-3.55 ( bb, 4H), 2.88-2.76 (bb, 4H), 2.52-2.60 (bb, 2H), 2.34 s (6H), 1.92-2.25 (bb, 2H ); ¹³ C NMR: 167.38, 161.87 (d, J = 245), 134.81, 138.34 (d, J = 8), 115.56 (d, J = 21), 60.52, 56 , 46, 45, 11, 42.28, 35.33, 25.43. HRMS calculated for C24H30N6F2O (M + H): 457.2527; Found: 457.2515.

1-6: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6- (5'-dimethylaminoethyloxyethylamino-l, 3,5-triazine.

50 mg, 23% yield as yellowish oil.

1 H NMR: 7, 15-7, 11 (m, 4H), 7.00-6.96 (m, 4H), 3.80-3.61 (m, 10H), 3.41 (m, 2H) , 3.00-284 (m, 10H).

¹³ C NMR: 161.95 (d, 7 = 243), 155, 18, 153.89, 133.32, 130.08 (d, 7 = 8), 115.65 (d, 7

= 21), 68.82, 63.80, 58, 11, 43.88, 43.88, 42.99, 40.99, 34.33.

HRMS calculated for C25H33N7F2O (M + H): 486.2793; Found: 486.2796. 1-7: 2,4-Bis- (2 '- (4 "-fluorophenyl) ethylamino) -6- (4'-guanidyl) butylamino-l, 3,5-triazine.

60 mg, 23% yield as a colorless oil.

1 H NMR: 7, 17-7.09 (m, 4H, 7.03-6.95 (m, 4H), 3.74-3.60 (m, 4H), 3.54-2.83 (m , 4H), 2.94-2.83 (m, 4H), 1.76-1.59 (m, 4H).

¹³ C NMR: 162.84 (d, J = 240), 158.30, 156.54, 136.23, 131.75 (d, J = 8), 116.20 (d, J = 21), 43 , 30, 42.47, 41.27, 35.376, 30, 16, 26.83, 26.79.

HRMS calculated for C24H31N9F2 (M + H): 484.2749; Found: 484.2722. 1-8: 2,4-Bis- (2 '- (4''- fluorophenyl) ethylamino) -6- (4' - (l '' - methylpiperidin-4-yl) piperazm ^ l-il-l, 3 , 5-triazine 250 mg, 95% yield as yellowish oil.

1 H NMR: 7.52-7.50 (m, 4H), 7.37-7.24 (m, 4H), 5, 11 (bb, 2H), 4.03 (bb, 4H), 3.49 -3.84 (m, 4H), 3, 17-3.04 (m, 6H), 2.80-2-66 (m, 6H).

1 ³ C NMR: 166.50, 165.34, 138, 17, 132.37, 130.31, 128.84, 61, 14, 53.44, 43.35, 42, 12, 38.94, 35 , 78, 30.61.

HRMS calculated for C29H38N8F2 (M + H): 537.3265; Found: 537.3209.

1-9: 2,4-Bis- (2 '- (4 "-fluorophenyl) ethylamino) -6- (4'-dimethylaminoethyl) piperazin-l-yl-1,3,5-triazine. 192 mg, 73% yield as yellowish oil.

1 H NMR: 7, 18-7, 10 (m, 4H), 6.95 (t, J = 8.6, 4H), 4.74 (s, 2H), 3.76 (s, 4H), 3 , 57 (d, J = 6.5, 4H), 2.82 (t, J = 7.0, 4H), 2.54-2.41 (m, 8H), 2.27 (s, 6H)

1 ³ C NMR: 165.42, 164.27, 160.90 (d, J = 244), 134.42, 129.53 (d, J = 7), 114, 16 (d, J = 21), 56, 17, 56, 11, 52.96, 45.26, 42.25, 41.48, 34.67.

HRMS calculated for C27H36N8F2 (M + H): 511.3109; Found: 511,3092.

1-10: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6 - ((3'-dimethylamino) propylamino) -1,3,5-triazine. 2.28 g, 73% yield as a colorless oil.

1 H NMR: 7, 11 (dd, J = 8, 5, 4H), 7.00 - 6.83 (m, 4H), 3.54 (d, J = 6, 4H), 3.37 (bb, 2H), 2.79 (t, j = 7, 4H), 2.32 (t, j = 7, 2H), 2.25-2, 10 (s, 6H), 1.79-1.60 ( m, 2H).

¹³ C NMR: 166.39, 161.75 (d, J = 244), 135.30 (d, J = 3), 130.28 (d, J = 8,), 1 15.37 (d, J = 21.2), 57.91, 45.60, 42.24, 39.64, 35.53, 27.71.

HRMS calculated for C24H31N7F2 (M + H): 456.2687; Found: 456.2668. 1-11: 2,4-Bis- (2 '- (4' '- chlorophenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine. 64 mg, 71% yield as a white solid.

1 H NMR: 7.33-7.20 (m, 8H), 3.65-3.52 (m, 4H), 3.45-3.38 (m, 2H), 3.08 (qn, J = 7, 2H), 2.89-2.83 (m, 4H), 2.76-2.79 (m, 6H), 1.98-1.90 (m, 2H).

¹³ C NMR: 163.32, 155.57, 155.25, 154.78, 136.50, 132.71, 129.97, 128.852, 55.93, 43.57, 42.34, 37.39, 34.63, 24.33.

HRMS calculated for C24H31N7CI2 (M + H): 488,2096; Found: 488.2103. 1-12: 2,4-Bis- (2 '- (4''- chlorophenyl) ethylamino) -6- (2' - (l ^^

1,3,5-triazine. 70 mg, 64% yield as a colorless oil.

1 H NMR: 7.30-7, 10 (m, 8H), 3.91-3.08 (m, 8H), 2.97-2.70 (8H), 2.36-1.76 (m, 6H). ¹³ C NMR: 162.35, 155.43, 154.80, 136.30, 132.86, 129.94, 128.93, 68.23, 56.78, 42.50, 40.66, 38, 00, 34.59, 29.60, 29.32, 21.55.

HRMS calculated for C26H33N7CI2 (M + H): 514.2253; Found: 514.2230.

1-13: 2,4-Bis- (2 '- (4' '- chlorophenyl) ethylamino ^

triazine

102 mg, 75% yield as white powder.

1 H NMR: 7.27-7.25 (m, 4H), 7, 10-7.8 (m, 4H), 3.95-3.83 (m, 2H), 3.70-3.57 ( m, 4H), 3.45-3.37 (m, 2H), 3.00-2.99 (m, 6H), 2.88-2.85 (m, 2H).

¹³ C NMR: 154.86, 153.64, 135.96, 132.80, 129.89, 128.90, 57.02, 44, 15, 42.59, 35.88, 34.42.

HRMS calculated for C23H29N7CI2 (M + H): 474.194; Found: 474, 1942.

1-14: 2,4-Bis- (2 '- (4' '- chlorophenyl) ethylamino) -6- (4'-methyl) piperazin-l-yl) -l, 3,5-triazine.

52 mg, 36%) yield as white powder.

1 H NMR: 7.26-7.24 (m, 4H), 7, 10-7.08 (m, 4H), 4.74 (d, J = 15, 2H), 3.82 (d, J = 6, 2H), 3.64 (q, 7 = 6, 4H), 3.37 (t, 7 = 13, 2H), 3.02 (d, 7 = 3.5, 3H), 2.88- 2.76 (d, 7 = 3.5, 6H). 1 ³ C NMR: 162.01, 155.28, 136.56, 132.70, 130, 10, 128.84, 53.99, 44.08, 42.51, 40.73, 34.94.

HRMS calculated for C24H29N7CI2 (M + H): 486.194; Found: 486, 1986. 1-15: 2,4-Bis- (2 '- (4' '- chlorophenyl) ethylamino) -6 - ((4'-methyl) piperazin-l-yl-amino) -l, 3,5-triazine. 81 mg, 55% yield as white solid.

1 H NMR: 7.29-7.04 (m, 8H), 3.77-3.43 (m, 10H), 3, 16-3.01 (m, 2H), 2.93-2.82 ( m, 7H). ¹³ C NMR: 157.54, 154.29, 135.50, 133.43, 129.87, 129.20, 53.50, 51.60, 43.61, 43.24, 34.26.

HRMS calculated for C24H30N8CI2 (M + H): 501.2049; Found: 501.2058. 1-16: 2,4-Bis- (2 '- (4''- chlorophenyl) ethylamino) -6 (-2' (piperazin-l '' - yl) ethylamino) -l, 3,5-triazine. 116 mg, 64% yield as white solid.

1 H NMR; ¹³ C NMR: 155.30, 136.51, 132.75, 130.08, 128.86, 53.20, 52, 10, 42, 19, 35.27, 34.64, 29.60.

HRMS calculated for C25H32N8CI2 (M + H): 515.2205; Found: 515,2204.

1-17: 2,4-Bis- (2'-phenylethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

105 mg, 74% yield as a colorless oil.

1 H NMR: 7.28-7.252 (m, 4), 7.20-7, 17 (m, 6H), 3.61 (dd, J = 13, 6, 4H), 3.41 (bb, 2H) , 2.86 (t, J = 7, 4H), 2.41 (t, J = 7, 2H), 2.27 (s, 6H), 1.74 (qn, J = 7, 2H).

¹³ C NMR: 166.20, 139.65, 129.00, 128.74, 126.50, 57.86, 45.43, 42.28, 39.61, 36.40, 27.51.

HRMS calculated for C24H34N7 (M + H): 432, 1703; Found: 432, 1703. 1-18: 2,4-Bis- (2 '- (4' '- methoxyphenyl) ethylamino) -6- (3'-dimethylamino) propylamino) - 1,3,5-triazine.

87 mg, 57% yield as a colorless oil.

1 H NMR: 7, 11-6.84 (m, 8H), 3.84 (m, 6H), 3.67-3.48 (m, 6H), 3.20 (m, 2H), 2.89 -2.84 (m, 10H), 2.08 (m, 2H).

1 ³ C NMR: 162.07, 158.35, 155.55, 154.55, 130.07, 129.66, 114.44, 55.94, 43.59, 42.94, 37.64, 34 , 25, 24, 18.

HRMS calculated for C26H37N7O2 (M + H): 480.3087; Found: 480,309.

1-19: 2,4-Bis- (2 '- (2'% 4 '' - dichlorophenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -1,3,5-triazine. 100 mg, 88% yield as yellowish oil.

1 H NMR: 7.39-7.36 (m, 2H), 7.20-7, 12 (m, 4H), 3.73-3.60 (m, 4H), 3.57-3.48 ( m, 2H),

3.22-3, 14 (m, 2H), 3.02-2.96 (m, 4H), 2.9 (m, 6H), 2, 11-2.05 (m, 2H).

¹³ C NMR: 162.78, 155.60, 154.74, 134.77, 134.30, 133.50, 131.62, 129.43, 127.36,

55.73, 43.24, 40.39, 37.36, 32.64, 24.03.

HRMS calculated for C24H29N7CI4 (M + H): 556.1317; Found: 556, 1320.

1-20: 2,4-Bis- (2 '- (4''- nitrophenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine. 224 mg, 97% yield as brown oil.

1 H NMR: 8, 10 (d, J = 8.7, 4H), 7.34 (d, J = 8.7, 4H), 3.62 (m, 4H), 3.41 (bb, 2H) , 2.96 (t, J = 7, 4H), 2.47 (t, J = 7, 2H), 2.31 (d, J = 12, 6H), 1.77 (qn, J = 7, 2H); ¹³ C NMR: 166.26, 147.53, 147.03, 129.82, 123.85, 57.59, 45.23, 41.65, 39.41, 36.31, 27.20. HRMS calculated for C24H31N9O4 (M + H): 510.2577; Found: 510.2594.

1-21: 2,4-Bis- (2 '- (2' '- fluorophenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

143 mg, 57% yield as white solid.

1 H NMR: 7.25-7, 15 (m, 4H), 7, 11-6.99 (m, 4H), 3.76-3.65 (m, 4H), 3.63-3.50 ( m, 2H), 3.28-3, 18 (2H), 2.97-2.92 (m, 10H), 2, 16-2.07 (m, 2H).

¹³ C NMR: 163.87, 161.26 (d, 7 = 243), 155.89, 155.06, 153.91, 131.05, 128.85, 124.54, 124.33, 115.38 (d, 7 = 22), 56.00, 43.58, 41.48, 37.76, 28.51, 24, 11.

HRMS calculated for C24H31N7F2 (M + H): 456.2687; Found: 456.2701.

1-22: 2,4-Bis- (2 '- (4' '- fluorophenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

133 mg, 53% yield as white solid.

1 H NMR 7.27-7.23 (m, 2H), 6.97-6.88 (m, 6H), 3.70-3.61 (m, 4H), 3.57-3.49 (m , 2H), 3.23-3, 12 (m, 2H), 2.92-2.86 (m, 10H), 2, 14-2.03 (m, 2H).

¹³ C NMR: 163.88, 161.28 (d, 7 = 236), 155.88, 155.60, 131.00 (d, 7 = 5), 128.52, 125.00, 124, 16, 115.27 (d, 7 = 22), 55.60, 43.26, 41, 18, 37, 11, 28.97, 24.32.

HRMS calculated for C24H31N7F2 (M + H): 456.2687; Found: 456.2705. 1-23: 2,4-Bis- (2 '- (3' '- indolyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

20 mg, 34% yield as a brown solid.

1 H NMR (CD ₃ CN, 48 ° C): 9.03 (s, 2H), 7.62 (d, J = 7.9, 2H), 7.38 (d, J = 8.2, 2H) , 7, 12 (t, J = 7.6, 2H), 7.06 (s, 2H), 7.02 (t, J = 7.4, 2H), 5.49 (s, 1H), 5 , 25 (s, 2H), 3.62 (m, 4H), 3.35 (s, 2H), 2.99 (t, J = 7.2, 4H), 2.30 (t, J = 6 , 9, 2H), 2, 16 (s, 6H), 1.68 (qn, J = 6.6, 2H). ^La NMR (CD ₃ CN, 48 ° C): 167.86 Cq, 138.03 Cq, 129.04 Cq, 123.77 Ct, 122.71 Ct, 120.05 Ct, 119.88 Ct, 114, 38 Cq, 112.55 Ct, 58.76 Cs, 45.95 Cs, 42.38 Cp, 40.45 Cs, 28.76 Cs, 26.82 Cs.

HRMS calculated for C28H35N9 (M + H): 498,3094; Found: 498,3084.

1-24: 2,4-Bis- (2 '- (l''cyclohexenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

220 mg, 95% yield as clear oil.

1H NMR: 5.46 (s, 2H), 3.35-3.47 (m, 6H), 2.34 (t, J = 7.0, 3H), 2.21 (s, 6H), 2 , 14 (t, J = 8, 2H), 2.00 - 1.86 (m, 8H), 1.70 (qn, J = 8.5), 1.62 - 1.50 (m, 8H) .

¹³ C NMR: 166.24, 135.08, 123.50, 57.95, 45.65, 39.66, 38.84, 38.26, 28.29, 27.79, 25.48, 23, 13, 22.64.

HRMS calculated for C24H41N7 (M + H): 428.3502; Found: 428.3505. 1-25: 2,4-Bis- (2 '- (4' '- chlorophenyl) methylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

110 mg, 68% yield as a colorless oil.

1 H NMR: 7.31-7, 10 m (8H), 8 H, 4.56-458 m (m, 4H), 3.56-3.53 (m, 2H) „2.93-2.86 (m, 6H), 2.24-2.01 (2H).

1 ³ C NMR: 162.50, 155, 10, 134.26, 129, 17, 56.012, 44.89, 43.74, 38, 15, 24.09.

HRMS calculated for C22H27N7CI2 (M + H): 460.1783; Found: 460, 1779.

1-26: 2,4-Bis- (2 '- (4 "-fluorophenyl) methylamino) -6- (3'-dimethylamino) propylamino) -1,3,5-triazine.

105 mg, 72% yield as white solid.

1 H NMR: 7.24-6.98 (m, 8H), 4.61 (bb, 4.61), 3.57-3.53 (m, 2H), 3.25-3, 15 (m, 2H), 2.93-2.89 (m, 6H), 2, 16-2.03 (m, 2H).

¹³ C NMR: 162.80 (d, 7 = 251), 160.05, 154.73, 153.80, 131.49, 129.49, 1 15.93 (d, J = 22), 56.01 , 45.05, 43.82, 38.29, 24, 10.

HRMS calculated for C22H27N7F2 (M + H): 428.2374; Found: 428.2394. 1-27: 2,4-Bis- (2 '- (2'% 4 '' - dichlorophenyl) methylamino) -6- (3'-dimethylamino) propylamino) -1,3,5-triazine.

38 mg, 20% white solid yield.

1 H NMR: 7.41-7.05 (m, 6H Ar), 4.67-4.61 (m, 4), 3.55-3.46 (m, 2H), 3, 17-3, 10 (m, 2H), 2.90-2.86 (m, 6H), 2, 12-2.05 (m, 2H).

¹³ C NMR: 163.64, 155.95, 155.39, 134.40, 133.88, 132.59, 129.85, 129.48, 127.28, 55.92, 43.54, 42, 18, 37.95, 24.23.

HRMS calculated for C22H25N7CI4 (M + H): 528,1004; found 528.0992. 1-28: 2,4-Bis- (2 '- (2'% 4 '' - difluorophenyl) methylamino) -6- (3'-dimethylamino) propylamino) -1,3,5-triazine.

52 mg, 40% yield as white solid.

1 H NMR: 7.29-7, 18 (m, 2H), 6.88-6.79 (m, 4H), 4.67-4.59 (m, 4H), 3.65-3.47 ( m, 2H), 3.22-3, 17 (m, 2H), 2.91 (m, 6H), 2, 14-2.05 (m, 2H).

1 ³ C NMR: 163 (dd, J¡ = 197, J ₂ = 12), 163.02, 160.88 (dd, J¡ = 197, J ₂ = 12), 155.39, 154.79, 131 , 08-130.66 +, 112.09 - 111-60, 104.56 (t, J = 25), 56, 17, 43.80, 39, 11, 37.94, 24.26.

HRMS calculated for C22H25N7F4 (M + H): 464.2186; found 464.2199. 1-29: 2,4-Bis- (2 '- (4 "-trifluoromethylphenyl) methylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

220 mg, 96% yield as a colorless oil.

1H-NMR: 7.54-7.39 (m, 8H), 4.58 (bb, 4H), 3.37 (dd, J = 12 j = 6, 2H), 2.39-2, 122 ( m, 8J), 1.68 (bb, 2H).

1 ³ C NMR: 166.47, 166.38, 144.07, 129.57 (q, j = 32), 127.67, 125.54 (q, j = 4), 124.39 (q, J = 270), 57.71, 45.41, 44.32, 38.57, 27.29.

HRMS calculated for C ₂ 4H27N ₇ F ₆ M + H), 528.2310; Found: 528.2292.

1-30: 2,4-Bis- (2'-5 "-methylenedioxyphenyl) methylamino) (3'-dimethylamino) propylamino) -l, 3,5-triazine.

226 mg, 94% yield as a colorless oil. 1 H NMR: 6.84-6.70 (m, 6 H), 5.93 (s, 4H), 4.46 (bb, 4H), 3.45 (bb, 2H), 2.9-2, 36 (m, 8 H), 1.82 (qn, J = 7 Hz).

¹³ C NMR: 165.24, 148.06, 147.00, 133.41, 120.98, 108.48, 101, 18, 77.55, 77.23, 76.91, 57.52, 44, 89, 44.73, 39.40, 26.72.

HRMS calculated for C24H29N7O4 (M + H): 480.2359; Found: 480.2365.

1-31: 2,4-Bis- (2 '- (4 "-methoxycarbonylphenyl) methylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

97 mg, 42% yield as a colorless oil.

1 H NMR: 7.93 (d, J = 7.7, 4H), 7.31 (d, J = 5.7, 4H), 4.57 (d, J = 5.3, 4H), 3, 88 (s, 6H), 3.35 (dd, J = 11.8, 6.4, 2H), 2.31 (t, J = 6.7, 2H), 2, 19 (s, 6H), 1.66 (qn, J = 6.7, 2H). ¹³ C NMR: 167, 11 C l, 166.58, 166.53, 145.20, 130.01, 129.24, 127.40, 57.96, 52.20, 45.61, 44.62, 39.81, 27.51.

HRMS calculated for C28H37N7O4 (M + H): 508.263; Found: 508.2633.

1-32: 2,4-Bis (4- (bis (4-fluorophenyl) methyl) piperazin-l-yl) -6- (3'-dimethylamino) propylamino-l, 3,5-triazine.

120 mg, 80% yield as white solid.

1 H NMR: 7.33 (dd, J¡ = 8.7, J ₂ = 5.4, 8H), 6.96 (dd, J¡ = 1 1.3, J ₂ = 6, 1, 8H), 4.23 (s, 2H), 3.71 (s, 8H), 3.41 (dd, J = 13, 2H), 2.69 (t, J = 9, 2H), 2.48 (s, 6H), 2.39-2.24 (m, 8H), l, 88 (qn J = 9, 2H).

¹³ C NMR: 162.09 (d, J = 247), 138, 11 (d, J = 3.0), 129.51 (d, J = 7.8), 115.60 (d, J = 21 ), 74.66, 56.87, 51.85, 44.21, 43.51, 38.60, 26.39.

HRMS calculated for C42H47N9F4 (M + H): 754.3969; Found: 754.3958.

1-33: 2,4-Bis (3,4-dihydro-lH-pyrido [3,4-b] indole-2 (9H) -yl) -6- (3'-dimethylamino) propylamino-l, 3, 5-triazine

80 mg, 63% yield as brown oil.

1 H NMR (CD ₃ CN, 48 ° C): 9.00 (s, 2H), 7.38 (dt, J = 22.7, 7.4, 4H), 7.06 (ddd, J = 14, 9, 14.0, 7.0, 4H), 4.98 (bb, 4H), 4, 15 (bb, 4H), 3.52-3.31 (m, 2H), 2.79 (bb, 4H), 2.33 (t, j = 7, 2H), 2, 19 (s, 6H), 1.71 (qn, j = 7.2, 2H). ^La NMR (CD ₃ CN, 48 ° C): 167.70 Cq, 167.00 Cq, 137.60 Cq, 133.27 Cq, 128.38 Cq, 122, 18 Ct, 120.07 Ct, 118, 71 Ct, 112.06 Ct, 109.45 Cq, 58.68 Cs, 45.90 Cp, 42.48 Cs, 42.35 Cs, 40.36 Cs, 28.64 Cs, 21.97 Cs.

HRMS calculated for C ₃₀ H ₃₅ N ₉ F ₄ (M + H): 522,3094; Found: 522,3079.

1-34: 2,4-Bis- (2 '- (4 "-hydroxycarbonylphenyl) ethylamino) -6- (3'-dimethylamino) propylamino) -l, 3,5-triazine.

49 mg, 47% yield as a colorless oil.

1 H NMR (C ₅ D ₅ N, 70 ° C): 8.38 (d, J = 8.0, 4H), 7.63 (d, J = 7.7, 4H), 4.87 (s, 4H), 3.61 (t, J = 6.3, 2H), 3.09 (t, J = 7.5, 2H), 2.70 (s, 6H), 2, 15 - 2.05 ( m, 2H).

¹³ C NMR (C5D5N, 48 ° C): 169.28 Cq, 164.91 Cq, 145.54 Cq, 13 1.85 Cq, 13 1, 12 Ct, 130.49 Ct, 128.38 Ct, 128, 05 Ct, 56.31 Cs, 45, 15 Cs, 43, 19 Cp, 38.74 Cs, 25.81 Cs. HRMS calculated for C ₂₆ H ₃₃ N ₇ O ₄ (M + H): 480.2395; Found: 480.2354. 1-35: 2,4-Bis- (2 '- (4 "-hydroxycarbonylphenyl) ethylamino) -6- (butylamino) -l, 3,5-triazine.

1 H NMR: 25 mg, 16% yield as a colorless oil. 1 H NMR (C ₅ D ₅ N, 70 ° C): 8.37 (d, J = 8.0, 4H), 7.62 (d, J = 7.8, 4H), 4.88 (s, 4H), 3.56 (t, J = 7.0, 2H), 1.63 (qn, J = 7, 1, 2H), 1.44-1.35 (m, 2H), 0.90 ( t, J = 7.4, 3H).

¹³ C NMR (C5D5N, 48 ° C): 169.32 Cq, 166.61 Cq, 146.20 Cq, 131.73 Cq, 131, 12 Cq, 130.47 Cq, 128.40 Cq, 128.05 Cq , 45.21 Cq, 41.30 Cq, 32.76 Cq, 20.83 Cq, 14.21 Cq. HRMS calculated for C ₂₅ H ₃₀ N ₆ O ₄ (M + H): 451,2094; Found: 451.2087.

EXAMPLE 2

Heterologous expression of rat TRPV1 channels and channel blockage

The triazine inhibitory activity was evaluated in rat TRPV1 channels expressed heterologously in amphibian oocytes. All procedures were described in detail above (García-Martínez, C. et al. J. Pain 2006, 7, 735-746; Valente, P. et al. FASEB J. 2008, 22, 3298-3309). Total current was recorded in oocytes injected with rat TRPV1 in a Mg ²⁺ -Ringer solution (10 mM Hepes pH 7.4, 1 15 mM NaCl, 2.8 mM KCl, 0.1 mM BaCl _2, 2 mM MgCl ₂ ), using the voltage clamp technique (voltage-clamp) with two microelectrodes, at 20 ° C. TRPV1 channels were activated by applying 10 μΜ capsaicin in the absence or presence of individual compounds at a potential (V _h ) of -60 mV. The dose-response curves obtained for the compounds were adjusted to the Hill equation:

[blocker] '

1 +

where IC ₅₀ indicates the concentration of channel blocker that inhibits half of the response, Imax is the current obtained in the absence of blocker and n _H indicates the Hill coefficient, which is an estimate of the number of binding sites. The IV curves were recorded using a ramp protocol. The oocytes were depolarized from -80 mV to 20 mV in 5 s (20 mV / s). Leakage currents were measured in the absence of agonist and subtracted from the ionic current recorded in the presence of the ligand. The dependence on the voltage block was studied as described in Ferrer-Montiel et al. (Neuropharmacology 1998, 37, 139-147). The experimental data were adjusted to the Hill or Woodhull equations with a nonlinear least squares regression algorithm using GraphPad Prism 5 software.

RESULTS

As illustrated in Figure 3 (ac), the application of capsaicin in the oocytes that express the TRPV1 channel, maintaining the membrane potential at -60 mV, causes the current to be blocked dose-dependently when applying triazines I - 13, I-11 and 1-10, respectively. It is worth highlighting the blocking efficacy of three of the triazines 1-10, 1-11, 1-13, 1-10 being the most potent. Triazine 1-10 completely blocks the response evoked by capsaicin at 10 μΜ. Triazine blockade is reversible, as shown after the recovery of capsaicin currents by removing the compounds by washing the cell. Since the identified triazines I are protonable compounds at physiological pH and that previously described blocking agents had shown agonist activity, it has been evaluated whether said triazines are capable of activating the TRPV1 channel. It is observed that some of the triazines (1-13 and 1-11) have activity as agonists, while others, such as triazine I-10, do not show this activity (Figure 3 (df)). As for the overall blocking activity, Figure 4a shows that of the triazines tested, it can be seen that 15 of them produced a blockage greater than 80% of the channel activity. Complete screening of the triazine set revealed that only a few act as pure blockers, that is, they do not activate the channel (Figure 4b). The most potent triazine (1-10) showed no significant agonist activity. Of the dose-response relationships of the triazines tested (Figure 4c), triazine 1-10 is the most effective, with an IC ₅₀ of 50 ± 10 nM and an nH of 0.9 ± 0, 1. Most of the Triazines tested showed inhibitory efficiencies in the my molar environment (Figure 4d).

To investigate the mechanism of blocking triazine 1-10, the current-voltage ratio was evaluated. It is known that open channel blockers are sensitive to the membrane electric field, so that they exert their activity in a defined voltage range. For positively charged molecules, blocking efficiency is more potent at negative membrane potentials than at positive (V> 0 mV). As Figure 5a shows, the blocking activity of triazine 1-10 is presented to negative membrane potentials and is absent from voltaj is depolarized membrane, which suggests a strong voltage-dependent blockage. In fact, a representation of the percentage of blockage as a function of voltage shows a curve that could approximate a Woodhull model (Figure 5b), giving an electrical distance from the binding site of the blocker within the membrane electric field (δ) of 0 , 36 (Figure 5b). This result is consistent with a place of relatively deep interaction in the aqueous pore of the canal and with a non-competitive channel blocking mechanism. The fact that the EC ₅₀ of capsaicin is not altered by the presence of 1-10 (data not shown) indicates that this compound does not act as a competitive antagonist.

EXAMPLE 3

Measures of membrane potential of rat nociceptors in culture.

Primary cultures of neonatal dorsal root ganglia were prepared from newborn rats, as described in Camprubí et al. (FASEB J. 2009, 23, 3722-3733). In summary, Wi-star rats 3-6 days old were anesthetized and decapitated. The spinal cord was removed and the DRG neurons were separated, which were dissected with the help of a microscope and transferred to 2 ml of Eagle medium (Dulbecco) modified (DMEM) supplemented with collagenase IA. After collagenase digestion at 37 ° C for 60 minutes, the cells were centrifuged for 5 min and resuspended in DMEM containing 10% fetal bovine serum (FBS). The cells were dispersed through 0.9 mm syringes and then 0.43 mm syringes and filtered through a 40 μιη filter. After centrifugation (1000 rpm for 10 min), the cells were resuspended in DMEM containing 10% SFB, 1% penicillin / streptomycin, 1% L-Glutamine, 100 ng / ml NGF, 10 µΜ arabinose cytosine and placed on plates covered with polylysine-laminin. Neural cells were maintained in a humidified incubator with 5% C0 ₂ . All experiments were carried out on the third-fourth day of cultivation.

The experiments of electrophysiological measurements with DRG neurons were carried out using the pipette solution (internal solution) with the following salt concentration: 144 mM KCl, 2 mM MgCl ₂ , 5 mM EGTA and 10 mM HEPES, adjusted pH 7.2 with KOH; while the external solution contained: 140 mM NaCl, 4 mM KCl, 2 mM CaCl ₂ , 2 mM MgCl ₂ , 10 mM HEPES, 5 mM glucose, pH 7.4 adjusted with NaOH and the osmolarity maintained around 315 mosm / kg with mannitol A gravity based local microperfusion system was applied at a flow of 200 μΐ / min placed in -100 μιη of the registered cells to apply the different saline solutions. The membrane voltage was recorded by "patch-clamp" using the whole cell configuration described in García-Sanz et al. (J. Neurosci. 2004, 24, 5307-5314). The log pipettes were prepared from thin-walled glass capillaries of borosilicate (World Precision Instruments, Sarasota, FL), stretched with a horizontal stretcher (P-97, Sutter Ins. Co., Novato, CA) to have a resistance of 2-4 ΜΏ and filled with the internal solution. Data were collected using a 10 kHz filter (EPC10 with "pulse" software, HEKA electronics, Lambrecht, Germany) and using a 3 kHz filter for analysis (PulseFit 8.54, HEKA; Origin 7.5, OriginLab Corp. Southampton MA ). The series resistance was normally less than 10 Ω and was compensated at 60-80%) to minimize voltage errors. The cells were visualized using an inverted microscope (Axiovert 200 HAL 100, Zeiss) equipped with 40X, 20X and 10X objectives. All measurements were made at room temperature (18-21 ° C). Data are expressed as mean ± standard error (SE) of several cells (n) under different conditions. Preparation of rat knee nociceptor fibers

Adult male rats of the Wistar variety (300-350 g) were anesthetized with thiopental (100 mg / kg intraperitoneally (ip)). The trachea, the left femoral vein and the femoral artery were cannulated. Blood pressure was monitored continuously. An additional catheter was inserted into the right saphenous artery to perform local injections of the triazines in the joint area. The right femur was fixed with a specially designed screw and a cavity was formed separating the skin. The cavity was filled with hot paraffin oil. The proximal end of the saphenous nerve was dissected to obtain fine filaments. The nerve fibers that innervate the knee joint were identified by the location of the recipient field, which was determined by the discharges of action potentials of the knee tissue and adjacent tissues in response to the pressure produced with a glass tip. The records were made in filaments containing between 2 and 5 identifiable units. The mechanical stimuli consisted of rotations in and out of the knee joint in the ranges of harmful and normal movement with a duration of 10 seconds. To verify that the solutions that were injected reached the sensory endings of the joint, the activation of the joint sensory fibers was examined by injecting intracellularly KC1 (0.1 mM, 0.1 ml). All results are expressed as the mean ± SEM, with N (number of animals)> 7. The data were analyzed statistically with the ANOVA tests of one or two variables, setting the parameter p <0.05.

RESULTS

The in vivo activity of triazine 1-10 has been studied to assess its potential as an analgesic. Thus, the blockade of TRPV1 located in the nociceptive polymodal terminal nerve fibers by 1-10 was investigated. In these experiments, the effect of 1-10 on the sensory discharges evoked by capsaicin and by harmful mechanical stimulation was measured (Figure 6). As shown in Figure 7a, the application of 10 μΜ capsaicin causes an increase in nerve activity that gradually attenuates up to 50% of the initial activity, after repeated applications of capsaicin, reflecting the known process of induced tachyphylaxis by capsaicin. In presence of 10 μΜ of triazine, the decrease in nerve activity evoked by capsaicin was significantly greater (up to 75%) than that induced by receptor tachyphylaxis, indicating an inhibitory activity of compound 1-10 in vivo. In contrast, the compound does not affect the discharge evoked by mechanical stimulation (Figure 7b), indicating a specific blocking activity of triazine I-10.

This observation was confirmed by the absence of a blocker effect on the resting potential of the neuron and the spontaneous action potentials in primary cultures of rat sensory neurons (Figure 8). It should be taken into account that the apparently greater activity of the neuron exposed to the vehicle (0.001% DMSO instead of triazine) is mainly due to its more depolarized resting potential (- 41 mV), compared to that recorded in the neuron in the presence of triazine (-53 mV) (Figure 8 c) and d)).

Together, these results indicate that triazine 1-10 is an open channel blocker and together with its selectivity provide the basis for considering triazine 1-10 as a candidate for the development of drugs for the treatment and / or prevention of pain. , inflammation, pruritus and disorders associated with calcium imbalances.

Claims

1. TRPV1 activity inhibitor compound of formula (I):

where both Ri are equal and Ri is selected from the group consisting of:

, wherein the phenyl group may be substituted in any position by a group selected from: OC ₁ -C3 alkyl, nitro, halogen, COOR and COR (where R is C ₁ -C3 linear alkyl or H), or it may comprise two adjacent substituents that together form a dioxolane;

wherein R ₃ is a halogen, n is selected between 1, 2 and 3 and m between 1, 2, 3, 4 and 5; where Ri is not: ^{NH CH} 2. _/ ) ⁰ - CH. and where R ₂ is selected from the group consisting of

(CH ₂ ) _N R _{4j in} d _onc i _e R4 _is selected from the group formed (a)

by:

(a. l) R ₅ R ₅ , wherein R ₅ and 5 are independent and are selected from the group consisting of: a C1-C3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ½; where R12 is selected from the group consisting of:

(d. l) N-Ci-C ₃ linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

and in

where n is selected from 1, 2, 3, 4, 5, 6 and 7, m between 1, 2 and 3 and where R ₇ , R ₈ , R9, Rio, R11 and R15 are independent and are selected from hydrogen and Ci-C ₃ linear alkyl;

2. A compound according to claim 1 wherein Ri and R ₂ in formula I are selected from the group consisting of:

3. Compound according to claim 1 or 2 selected from the group consisting of II to 135:

4. Process for the preparation of a compound of formula (I) as defined in any of claims 1 to 3, comprising:

(a) reacting a compound of formula (III)

I)

(Π) (b) reacting the compound of formula (II) with a compound R ₂ H, where R ₂ has the previously indicated meaning.

5. Pharmaceutical or cosmetic composition comprising a cosmetic or pharmaceutically effective amount of the compound according to any one of claims 1 to 4 and a cosmetic or pharmaceutically acceptable carrier.

6. Composition according to claim 5, which is administered topically, transdermally, orally, nasally, intramuscularly, intravenously, intraperitoneally, subcutaneously, enterally or parenterally.

7. Composition according to claim 6, wherein the topical or transdermal administration is performed by iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, needleless injections by pressure, microelectric patches or any combination thereof. .

8. Composition according to any one of claims 5 to 7, wherein the vehicle is selected from the group consisting of liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milicapsules, microcapsules, nanocapsules, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed phospholipid-surfactant micelles, microspheres, microspheres, nanospheres, lipospheres, microemulsions, nanoemulsions, miniparticles, miliparticles, microparticles, nanoparticles, solid lipid nanoparticles and nanostructured lipid supports.

9. Composition according to any one of claims 5 to 8, wherein said composition is presented in the form of a formulation selected from the group consisting of creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels , cream gels, hydroalcoholic solutions, hydro-glycol solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serums, ointments, mousses, ointments, powders, bars, pencils, vaporizers, aerosols, capsules, gelatin capsules, soft capsules, capsules hard, tablets, sugar-coated tablets, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, polysaccharide films, jellies and gelatin.

10. Composition according to any of claims 5 to 9, wherein said composition is incorporated into a product selected from the group formed for dark circles, makeup funds, make-up lotions, cleansing milks, eyeshadows, lipsticks, lip gloss, lip balms and powders.

11. Composition according to any of claims 5 to 10, wherein the compound is incorporated into a fabric, a non-woven fabric or a medical device.

12. Composition according to claim 11, wherein said fabric, non-woven fabric or medical device is selected from the group consisting of bandages, gauze, shirts, socks, socks, underwear, girdles, gloves, diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches and facial masks.

13. Composition according to any of claims 5 to 12, wherein said composition further comprises a pharmaceutically effective amount of at least one adjuvant.

14. Composition according to any of claims 12 or 13, wherein said adjuvant is of synthetic origin, is a plant extract, comes from a biotechnological process or comes from a combination of a synthetic procedure and a biotechnological process.

15. Use of a compound of formula:

where both Ri are equal and Ri is selected from the group consisting of:

H

(a) -N- - ^(C H ₂ ⁾ _n R _{4 ^ is} selected from the group consisting of:

(a. l) R ₅ R ₆ , wherein R ₅ and Rs are independent and are selected from the group consisting of: a C ₁ -C 3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ½; where R ₁₂ is selected from the group consisting of:

(d. l) N- C ₁ -C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

16. Use according to claim 15, wherein the compound selects from the group consisting of:

17. Use according to claim 16, in gift

18. Use according to any of claims 15 to 17 wherein the treatment and / or prevention of pain and / or inflammation are associated with a disorder selected from the group consisting of epithelial disorders, gastrointestinal diseases, diseases of the stema cardi ovascul ar, urinary tract diseases, diseases of the endocrine system, brain diseases, diseases of the reproductive system and cancer.

19. Use according to claim 18, wherein the gastrointestinal diseases are selected from the group consisting of inflammatory bowel disease, Crohn's disease, pancreatitis, gastroesophageal reflux disease and ulcerative colitis.

20. Use according to any of claims 15 to 17, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, abdominal pain, digestive system pain, respiratory system pain, urogenital system pain, pain of the endocrine system, heart pain, pancreatic pain, intestinal pain, stomach pain, spleen pain, liver pain, blood vessel pain, irritable bowel syndrome, tension headache, sinusitis-associated headache, migraine , eye pain, dry eye syndrome, post-operative pain, post-operative pain due to surgical incisions, post-operative pain due to the insertion of bone implants, post-operative pain due to bone replacement, pain post-operative due to infections, pain due to cancer, pain due to bone cancer, pain associated with benign bone tumors, pain associated with osteoid osteomas, associated pain associated with osteoblastomas, pain due to cancer treatment, musculoskeletal pain, spastic muscle pain, fibromyalgia, nerve pain, neck pain associated with cervical dystonia, back pain, low back pain, sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, post-herpetic neuralgia, peripheral neuropathies, phantom pain, allodynia, pain due to carpal tunnel syndrome, burning pain, paraesthesia, facial pain, neuralgia Trigeminal pain, neuropathic pain due to diabetes, pain associated with tattooing or tattoo removal, pain due to bunions, testicular pain, myofascial pain, urinary bladder pain, urinary tract pain, vulvar pain, vaginal pain, scrotal pain , perineal pain, pelvic pain and skin pain or irritation after surgery, after treatment with pulsed light therapy (IPL, Intense Pulse Light), after treatment with monochromatic pulsed light therapy (laser), after treatment with chemical descaling agents or after overexposure to aggressive external agents.

21. Use according to any of claims 15 to 17, wherein the inflammation is a consequence of disorders or pathologies selected from the group consisting of disorders related to neurogenic inflammation, disorders related to joint inflammation, sepsis, vascular inflammation, respiratory inflammation, asthma, liver inflammation, intestinal inflammation, conditions related to chronic inflammation, with acute inflammation, nephritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, glomerulonephritis, vasculitis and sarcoidosis.

22. Use according to any of claims 15 to 17, wherein the pruritus is a pruritus associated with diseases and / or epithelial disorders selected from the group consisting of dermatitis, atopic dermatitis, photodermatosis, eczema, sensitive skin, psoriasis, dandruff, seborrhea, athlete's foot, sunburn, xerosis and dry skin, or pruritus associated with dialysis, associated with pregnancy, associated with menopause, infection of acquired immunodeficiency virus, chicken pox, herpes, malignancies, Hodgkin's disease, leukemia, myeloma, lymphoma, solid tumors, lung cancer, liver diseases, jaundice, cholestasis, liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome, essential thrombocythemia, myelodysplastic syndrome, iron deficiency anemia, systemic lupus erythematosus, endocrine diseases, Thyroid diseases, parathyroid diseases, diabetes mellitus, kidney diseases, uremia, parasi infections tarias, scabies, lice, intestinal worms, allergic reactions, drug allergies, food allergies, chemical allergies, exposure to poisonous plants, exposure to insect bites, chemotherapy, stress and anxiety.

23. Use according to any of claims 15 to 17, wherein the disorders and / or diseases of the respiratory tract are selected from the group consisting of obstructive diseases such as chronic obstructive pulmonary disease, emphysema, chronic bronchitis, asthma, asthma caused by industrial irritants , cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, or tuberculosis; Restrictive pulmonary diseases such as asbestosis, radiation-caused fibrosis, extrinsic allergic alveolitis or insensitivity pneumonitis, childhood respiratory distress syndrome, idiopathic pulmonary fibrosis, sarcoidosis, idiopathic interstitial pneumonia, eosinophilic pneumonia, lymphangioleiomyomatosis, Langerhave alveolar and pulmonary cell histiocytosis pulmonary; respiratory tract infections including common cold, sinusitis, tonsillitis, pharyngitis, laryngitis or pneumonia; malignant respiratory tumors such as small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, carcinoid, mesothelioma, metastatic lung cancer, metastatic germ cell cancer, benign respiratory tumors such as pulmonary hamartoma; congenital malformations such as bronchopulmonary sequestration and cystic adenomatoid congenital malformation; diseases of the pleural cavity such as empyema and mesothelioma; pulmonary vascular diseases such as embolism, pulmonary thromboembolism, gaseous or iatrogenic embolism, pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation and damage to the capillaries in the lungs resulting in blood dripping into the alveoli; disorders that affect the mechanics of breathing such as obstructive sleep apnea, central sleep apnea, amyotrophic lateral sclerosis, Guillain-Barré syndrome and myasthenia gravis; shortness of breath or breathlessness, cough, coughing up blood or hemoptysis, chest pain such as pleuritic chest pain, noisy breathing, wheezing and cyanosis.

24. Use according to any of claims 15 to 17, wherein the skin disorders are selected from the group consisting of touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-hair removal skin irritation, post-skin irritation shaving, dermatitis, atopic dermatitis, allergic contact dermatitis, diaper dermatitis, photodermatosis, psoriasis, eczema, burns, sunburn, sensitive skin, xerosis and dry skin.

25. Use according to any of claims 15 to 17, wherein the disorders associated with calcium imbalance are selected from the group consisting of vitamin D deficiency, rickets, osteomalacia, growth retardation, post-menopausal osteoporosis, hypercalciuria and related disorders with parathyroid hormone.

26. A cosmetic method for the care of the skin, mucous membranes and / or nails comprising the administration of at least one compound of formula I or any cosmetically acceptable salts, solvates and prodrugs of said compound, wherein formula I is:

where both Ri are equal and Ri is selected from the group consisting of:

(a) - (CH ₂₎ _N R _{4 is} i _^ _ecc _is iona the group consisting of: (a. l) R ₅ R ₆ , wherein R ₅ and 5 are independent and are selected from the group consisting of: a C1-C3 linear alkyl, hydrogen and formamidine group;

(a.2) hydroxyl group

(a.3) Hydrogen

(a.4) Heterocycle

(d) ½; where R12 is selected from the group consisting of:

(d. l) N-C1-C3 linear alkyl,

- (CH ₂ ) _m - Ri ₃ Ri4,

or any cosmetically acceptable salts, solvates and prodrugs of said compound.

27. Method according to claim 26, wherein the compound is selected from the group consisting of:

and claim 27, wherein Ri is