RU2603770C2 - Substituted pyrazine pyrimidinones as trpa1 channel blockers, pharmaceutical composition, methods of production and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrazine pyrimidinones of general formula I or racemic mixtures, individual optical isomers and pharmaceutically acceptable salts thereof, which possess properties of TRPA1 channel blockers. In formula I, R1=H, (C₁-C₅) alkyl; R2=H, (C₁-C₅) alkyl; R3=H, (C₁-C₅) alkyl; R4=H, (C₁-C₇) alkyl, (C₁-C₇) alkyl, substituted with (C₃-C₇) cycloalkyl, (C₃-C₇) cycloalkyl; R5=H, (C₁-C₅) alkyl, heterocyclyl, where heterocyclyl denotes a saturated monocyclic system including 4 to 6 carbon atoms, in which one carbon atom is substituted by a heteroatom, such as nitrogen.

EFFECT: invention also relates to a method of producing compounds of general formula I, an active component, a pharmaceutical composition and a method of anaesthesia using said compounds.

6 cl, 3 tbl, 1 dwg, 3 ex

Description

The invention relates to new physiologically active substances, new TRPA1 channel blockers, active components for pharmaceutical compositions, to pharmaceutical compositions and drugs containing substituted pyrazinopyrimidinones as TRPA1 channel blockers that block pain signal transmission; a method for the treatment of painful conditions accompanied by acute and chronic pain of various etiologies.

There are various proteins called ion channels, which are responsible for penetration through cell membranes. Proper expression and functionality of ion channels is important for maintaining cell function, intercellular communication, and transmission of nerve impulses. Numerous diseases and painful conditions can be caused by a violation or malfunction of the regulation of membrane potential. Due to the critical importance of ion channels for modulating the membrane potential, the identification of various agents that can accelerate or inhibit specific ion channels is very important from the point of view of creating new therapeutic agents.

One such channel is the Transient Receptor Potential A1 (TRPA1) channel. The TRPA1 channel is a calcium channel and specifically a non-selective calcium cation channel. In addition to calcium cations, the TRPA1 channel can be used to penetrate through membranes and other cations, in particular sodium. Thus, TRPA1 channels modulate the membrane potential through modulating the penetration of calcium and sodium ions through the membranes. Despite the fact that TRPA1 channels modulate the penetration of calcium ions into the cell, mechanistically they are different from voltage-gated channels.

In recent years, a number of patents have appeared, as well as evidence of clinical trials of new drugs for pain relief of various etiologies based on TRPA1 channel blockers. So, in 2012, American companies Cubist Pharmaceuticals and Hydra Biosciences announced the first phase of clinical trials of CB-189,625 as a new TRPA1 modulator as a potential analgesic. Glenmark Pharmaceuticals in August 2014 announced the positive results of the second phase A clinical trial of compound GRC 17536, the new TRPA1 channel blocker, as an analgesic for diabetic neuropathy. Studies were conducted on 138 patients in Europe and in India.

Thus, the search for effective channel blockers TRPA1 seems to be an extremely important, relevant and promising task.

As an analogue of this invention, you can specify a substance blocker channels TRPA1 AR-18 [1]:

The substance AP-18 has antagonistic activity against TRPA1 channels at the level of IC ₅₀ 3.1 mM and exhibits some analgesic activity in experiments on rats.

The disadvantages of the analogue are a number of parameters of the AP-18 molecule, which together make its potential use as a medicine impossible: low in-vitro activity involves the introduction into the body in high doses, while the presence of a double bond in the molecule makes it potentially dangerous from the point of view toxicology vision even with minimal dosages.

[1] Petrus, M .; Peier, A.M .; Bandell, M .; Hwang, S.W .; Huynh, T .; Olney, N .; Jegla, T .; Patapoutian, A. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain, 2007, 3, 40.

The generally accepted approach to the development of new oral bioavailable drugs is to follow the so-called "rule of five" Lipinski. So, in order to obtain the “drug like” properties of the molecule, it is recommended that a sufficient number of heteroatoms be introduced, in particular in the form of heterocyclic structures.

Following the above, the substance HC-030031 (McNamara, CR; Mandel-Brehm, J .; Bautista, DM; Siemens, J .; Deranian, KL; Zhao, M .; Hayward, NJ; Chong has a much greater prospect of becoming a potential drug , JA; Julius, D .; Moran, MM; Fanger, CM TRPA1 mediates formalin-induced pain. Proc. Natl. Acad. Sci. USA, 2007, 104 (33), 13525-13530), which can be considered the prototype of the present invention

The substance NS-030031 has antagonistic activity against TRPA1 channels at the level of IC ₅₀ 1.0 mM and exhibits analgesic activity in experiments on rats.

The disadvantages of the prototype include the fact that in the molecule there is an amide bond, usually rapidly metabolized in the human body. A potential drug with an amide bond may have a very short “life time” and require repeated administration throughout the day. Also, in-vitro activity at the level of IC ₅₀ 1.0 mM seems insufficient (entails the introduction of significant amounts of the substance into the body to achieve a therapeutic effect, which can have a toxic effect).

Thus, the task is to create new analgesic drugs based on TRPA1 channel blockers.

To solve the problem of developing new highly effective TRPA1 channel blockers, the authors of this invention performed extensive in-vitro screening studies of low molecular weight compounds of various classes, hit compounds and leader compounds belonging to several families of heterocyclic compounds were detected, then directed modifications of many positions of the detected structures and their testing, the “structure-activity” relationship was established, and the most promising series were selected. As a result, a series of new derivatives is synthesized that are original and highly effective TRPA1 channel blockers. The resulting physiologically active heterocyclic compounds include novel derivatives of substituted pyrazinopyrimidinones that have not previously been described in the literature. To date, the ability of these compounds to exhibit the properties of TRPA1 channel blockers has also not been known.

The following are definitions of terms that are used in the description of this invention.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" (C ₁ -C ₆ ) alkyl substituents. Preferred alkyl groups are lower (C ₁ -C ₆ ) alkyl or methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n- pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl. Alkyl may have substituents.

“Aliphatic” radical means a radical obtained by removing a hydrogen atom from a non-aromatic CH bond. An aliphatic radical may additionally contain substituents — aliphatic or aromatic radicals defined in this section. aliphatic radicals Representatives include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkiloksialkil, aralkiloksikarbonilalkil, aralkyl, aralkynyl, aralkiloksialkenil, heteroaralkenyl, heteroaralkyl, geteroaralkiloksialkenil, geteroaralkiloksialkil, anelirovanny arylcycloalkyl, anelirovanny heteroarylcycloalkyl, anelirovanny arylcycloalkenyl, anelirovanny heteroarylcycloalkenyl, anelated arylheterocyclyl, anelated heteroarylheterocyclyl, anelated ari heterocyclenyl, anelirovanny heteroarylheterocyclenyl.

"Alkenyl" means an aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including a carbon-carbon double bond. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. One or more aromatic, cyclic or heterocyclic systems may be attached to an alkenyl group.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

“Antagonists” means ligands that bind to receptors of a particular type and do not elicit an active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of a specific receptor signal.

“Alkyloxy” or “Alkoxy” means an Alkyl O group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.

“Amino group” means an R′R ″ N group, substituted or unsubstituted, optionally with the same substituents R ′ and R ″. An amino group may have substituents.

“Alkylthio” means an alkyl-S group in which an alkyl group is defined in this section.

“Aminocarbonyl” means a C (= O) NR _k ^a R _{k + 1} ^a group substituted or unsubstituted with optionally identical carbamoyl substituents R _k ^a and R _{k + 1} ^a , including hydrogen, methyl, cycloalkyl, which forms a pyrrolidine atom with a nitrogen atom cycle.

“Annelated cycle” (condensed ring) means a bi- or polycyclic system in which the annelated cycle and the cycle or polycycle with which it is “annelated” have at least two atoms in common. Aromatic, non-aromatic systems and heterocyclic systems can be annelated.

“Aralkyl” means an alkyl group substituted with one or more aryl groups, in which the meanings of aryl and alkyl are defined in this section. Examples of aralkyl groups are optionally substituted benzyl, phenethyl, phenpropyl.

“Aryl” means an aromatic monocyclic or polycyclic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more “cyclic system substituents”, which may be the same or different.

“Aromatic cycle” (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system, which, according to the Hückel rule, includes (4n + 2) p-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic cycles”, the p-electrons and p-electrons of the heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. An aromatic ring may have one or more “ring system substituents” and may be anelated with a non-aromatic ring, heteroaromatic or heterocyclic ring.

“Acyl group” (Acyl) means HC (= O) -, optionally substituted C ₁ -C ₅ alkyl-C (= O) -, C ₁ -C ₅ alkenyl-C (= O) -, C ₁ -C ₅ cycloalkyl-C (= O) - (preferably cyclopropyl-C (= O) -, cyclobutyl-C (= O) -); heterocyclyl-C (= O) - (preferably 2-methylfuran), aryl-C (= O) - (aroyl), aralkyl-C (= O) - (preferably 3-phenylpentane-C (= O) -), heteroaryl -C (= O) - (heteroaroyl), heteroarylalkyl-C (= O) - groups in which C ₁ -C ₅ alkyl-, C ₁ -C ₅ alkenyl-, C ₁ -C ₅ cycloalkyl-, heterocyclyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, methoxy group, these groups may have substituents, see "cyclic system substituents", "substituted alkyl", "substituted alkenyl", "heterocyclic system substituents" defined in this section.

“Heteroaryl” (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to an N-oxide. Heteroaryl may have one or more “ring system substituents”, which may be the same or different. Preferably, pyrrolyl, furanyl, thienyl, pyridinyl, pyrrolidine, imidazolyl, oxazolyl, benzothiadiazole, benzothiazolyl, quinolinyl, imidazolyl, thienopyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinyl-pyridinopyridinyl , thienopyrrolyl, furopyrrolyl, etc.

“Heterocyclyl” means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclyls are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc.

"Substituted alkenyl" may also have one or more identical or different substituents, including halogen, alkenyloxy, aroyl, heteroaroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, aryls heteroaralkyloxy, etc. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl and n-hexenyl.

"Substituted alkyl" may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, , aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy R _k ^a R _{k + 1} ^a N-, where R _k ^a and R _{k + 1} ^{a are} independently “amino substituents”, the meaning of which is defined in this section, for example, atom hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k + 1} ^a, together with the N atom to which they are bonded, form ^a 4-7 membered heterocyclyl or heterocyclenyl through R _k ^a and R _{k + 1} ^a . The preferred "alkyl substituents" are aryl, heteroaryl, heterocyclyl, hydroxy, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or R _k geteroaralkiloksikarbonil ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= О) -, anelated arylheterocyclenyl, anelated arylheterocyclyl. Namely, the hydroxy group substituted by fluorophenyl oxy group, mono- and diC ₁ -C ₅ alkylamino group (dimethylamino group, methylamino group), C ₁ -C ₅ alkyloxycarbonyl group (ethyloxycarbonyl), phenyl, chlorophenyl, fluorophenyl, C ₁ -C ₅ alkyl (methyl) substituted phenyl, C ₁ -C ₅ cycloalkyl (cyclopentyl) substituted phenyl, C ₁ -C ₅ alkoxy substituted phenyl (methoxyphenyl), thiophenyl, furanyl, pyrrolidine.

"Substituents of the cyclic system" may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferred cyclic system moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy-group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “aminocarbonyl”), phenyl annelated with 5-7 saturated membered ring containing 1–3 heteroatoms (nitrogen, oxygen, and sulfur atoms ochtitelno).

“Heterocyclyl substituents” may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be anelated with a non-aromatic ring system or heterocycle. Preferred cyclic system moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cycloC ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy-group, C ₁ -C ₅ alkyloxy group ( methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see aminocarbonyl), phenyl anelated with 5-7 - membered saturated ring containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms pre preferably).

“Substituent” means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.

“Substituted amidine group” means R′R ″ N- (C = NR ′ ″) - a group in which the substituents R ′, R ″ and R ′ ″ may be optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. The R′R ″ N fragment of the amidine group may be a non-aromatic azaheterocycle, preferably azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, homopiperidine, homopiperazine.

“Substituted aminocarbonyl group” (aminocarbonyl) means R′R ″ N — C (= O) - a group in which the substituents R ′ and R ″ may be optionally substituted by alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. Preferred aminocarbonyl groups are optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see cyclic substituent), optionally substituted hetaryl (see cyclic substituent), optional substituted heterocyclyl (see heterocyclyl substituent) or an amino group R'R ”N.

“Substituted aminothiocarbonyl group” (aminothiocarbonyl) means R′R ″ N — C (= S) is a group in which the substituents R ′ and R ″ may be optionally substituted with alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetaryl and heterocyclyl, the meaning of which is defined in this section. Preferred aminocarbonyl groups are alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, hetarylaminothiocarbonyl and benzylaminothiocarbonyl.

“Substituted oxy group” means a hydroxy group in which hydrogen can be substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, aryl, hetaryl and heterocyclyl, forming ethers, or acyl, forming esters or an aminocarbonyl group to form carbamates, or an oxycarbonyl group to form carbonates.

“Substituted oxycarbonyl group” (oxycarbonyl) means R — O — C (= O) - a group in which the substituent R may be optionally substituted by alkyl, alkenyl, cycloalkyl, aryl, hetaryl and heterocyclyl, as defined in this section. Preferred hydroxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

“Carbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclylenyl, annelated arylheterocyclylenyl. Preferred “carbamoyl substituents” are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl annelated arylheterocyclenyl; annelated arylheterocyclyl.

"Carboxyl" means a group -CO ₂ H.

“Combined medicinal product (preparation)” - a combination of several medicinal substances for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other finished forms, designed to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things. Medicinal substances in one set can be presented in the form of various ready-made forms intended for administration into an animal or human body in various ways, for example, orally and rectally.

"Metabolic diseases" - a group of diseases associated with metabolic disorders. These diseases can be caused by a hereditary predisposition, disruptions in the endocrine and nervous systems, as well as disturbances in the functioning of metabolically active organs. Currently, there are a large number of metabolic disorders, however, this invention mainly addresses diseases associated with the signaling cascade of GPR119 receptors, in particular, such as diabetes, obesity, diabetes, metabolic syndrome, hypercholesterolemia, dyslipidemia, etc.

"Lower alkyl" means a linear or branched alkyl with 1-5 carbon atoms (C ₁ -C ₅ alkyl).

"Receptors" (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal about this interaction into a specific cellular response.

"Sulfonyl" means R-SO ₂ - a group in which the substituent R can be represented by optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ alkenyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see the Deputy of the cyclic system ), optionally substituted hetaryl (see cyclic substituent), optionally substituted heterocyclyl (see cyclic substituent), or R′R ″ N amino group, the meanings of which are defined in this section.

“Thioacyl group” (Thioacyl) means optionally substituted alkyl-C (= S) -, alkenyl-C (= S) -, cycloalkyl-C (= S) -, heterocyclyl-C (= S) -, aryl-C ( = S) - aralkyl-C (= S) -, heteroaryl-C (= S) -, heteroarylalkyl-C (= S) - groups.

“Cycloalkyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms. Cycloalkyl may have one or more “ring system substituents”, which may be the same or different. Representative cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalin, norbornyl, adamant-1-yl and the like. Preferred “cyclic system substituents” are alkyl, alkoxy, hydroxy or amino group, the meaning of which is defined in this section.

“Cycloalkenyl” means a non-aromatic mono- or polycyclic system containing from 3 to 10 carbon atoms and containing one or more carbon-carbon double bonds. Representatives of cycloalkenyl groups are cyclopentenyl and cyclohexenyl.

"Pharmaceutical composition" means a composition comprising a compound of general formula I and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials flax agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and purpose of the method and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier. For the manufacture of suppositories, in addition to the active components, cocoa butter, its alloys with paraffin and hydrogenated fats, vegetable and animal hydrogenated fats, solid fat, lanol, alloys of hydrogenated fats with wax, hard paraffin and other bases approved for medical use are also used.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

"Pharmaceutically acceptable excipients" by pharmaceutically acceptable excipients refers to pharmaceutical diluents, excipients and / or carriers.

An object of the present invention is to provide new TRPA1 channel blockers as potential painkillers.

The problem is achieved by substituted pyrazinopyrimidinones of the general formula I in the form of free bases, as well as in the form of their pharmaceutically acceptable salts and / or hydrates and solvates.

The subject of the present invention is new TRPA1 channel blockers, which are derivatives of substituted pyrazinopyrimidinones of the general formula I in the form of free bases, as well as their pharmaceutically acceptable salts and / or hydrates, solvates

Where

R1 = H, (C ₁ -C ₅ ) alkyl,

R2 = H, (C ₁ -C ₅ ) alkyl,

R3 = H, (C ₁ -C ₅ ) alkyl,

R4 = H, (C ₁ -C ₇ ) alkyl, substituted (C ₁ -C ₇ ) alkyl, (C ₃ -C ₇ ) cycloalkyl,

R5 = H, (C ₁ -C ₅ ) alkyl, heterocyclyl, where heterocyclyl means a saturated monocyclic system containing from 4 to 6 carbon atoms, in which one carbon atom is replaced by a heteroatom such as nitrogen.

The subject of this invention is the pharmaceutically acceptable salts of the compounds of general formula I. The compounds of general formula I contain ionic groups (primary, secondary amines) and can form salts that have been prepared by methods known in the art.

The subject of this invention is racemic mixtures and individual optical isomers of compounds of general formula I, since a number of compounds of general formula I have an asymmetric center, and substances can exist in the form of racemic mixtures and isomeric forms.

The subject of this invention is a method for producing derivatives of substituted pyrazinopyrimidinones of the general formula I according to the following stepwise sequence, which is shown in Scheme 1.

Scheme 1

where R ₁ , R ₂ , R ₃ , R ₄ , R ₅

have the above meanings.

The subject of the present invention is an active component having the property of a channel blocker TRPA1, which is a derivative of substituted pyrazinopyrimidinones of the general formula I.

The subject of this invention is a pharmaceutical composition for relieving pain, containing in an effective amount an active component having the property of a channel blocker TRPA1.

The subject of this invention is the aforementioned pharmaceutical composition in the form of tablets, capsules, ointments, gels, injections and other formulations, placed in a pharmaceutically acceptable package.

The pharmaceutical composition may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active component of the present invention may include other active ingredients, provided that they do not cause undesirable effects, such as allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

A new pharmaceutical composition can be obtained by mixing with an inert excipient and / or solvent of the active component, which is at least one of the compounds of general formula I, as well as their free bases, racemic mixtures or individual optical isomers, as well as their pharmaceutically acceptable salts and / or hydrates.

The subject of this invention is a drug.

Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient’s disease, the daily dose in adults is usually 10-300 mg, preferably 30-90 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units, the aforementioned effective dosage must be taken into account, with each dosage unit of the preparation containing 5-100 mg, preferably 10-20 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The following examples illustrate but do not limit the invention.

The structures of the compounds obtained were confirmed by chemical, chromatographic and spectral analysis.

Example 1 Synthesis of Compound 18.1

General procedure for the synthesis of compound 18.1. shown in Figure 2

Scheme 2

i - t-BuONa, Pd (OAc) ₂ , BINAP, toluene, boiling

ii - thionyl chloride, EtOH, boiling

iii - trifluoroacetic anhydride, TEA, methylene chloride, 0 ° C

iv - LiHMDS, valeric acid chloride, tetrahydrofuran, -78 ° C

v - Eaton Reagent, 40 ° C

vi - NH ₃ / MeOH, HCl / dioxane

Stage 1:

In a 2 L conical flask was placed p-bromophenylacetic acid 1 (25.0 g, 0.116 mol), N-side-3-aminopyrrolidine 2 (26.0 g, 0.139 mol), sodium tert-butylate 3 (27.9 g, 0.290 mol) and BINAP 5 (3.6 g, 0.006 mol) in 700 ml of toluene. With stirring, the reaction mass is purged with argon, then palladium acetate (1.3 g, 0.006 mol) is added and heated to boiling. The mixture is boiled for 12 hours, cooled to room temperature and the sodium salt of (4 - {[(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} phenyl) acetic acid 6 is extracted with water 2 × 150 ml. The organic phase is discarded, and the combined aqueous is acidified to pH = 7 with 2M hydrochloric acid and extracted with 3 × 150 ml of chloroform. The chloroform extract was dried over sodium sulfate, the solvent was removed on a rotary film evaporator and (4 - {[(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} phenyl) acetic acid 6 22.5 g was obtained in 60 %

Stage 2:

In a 1 L conical flask, (4 - {[(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} phenyl) acetic acid 6 (22.5 g, 0.070 mol) in 500 ml abs. ethanol and upon cooling in a water-ice bath, thionyl chloride 7 (25.0 g, 0.210 mol) is added dropwise at 0-5 ° C. Cooling is removed and the mixture is refluxed for 3 hours. Then the reaction mass is cooled to room temperature, ethanol is evaporated on EPI, and the residue is triturated with 300 ml of diethyl ether. The resulting precipitate was filtered and dried in a desiccator under reduced pressure. Ethyl dihydrochloride (4 - {[(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} phenyl) acetic acid 9 21.5 g is obtained in 95% yield.

Stage 3:

Ethyl dihydrochloride (4 - {[(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] amino} phenyl) acetic acid 9 (21.5 g, 0.067 mol) in 300 ml of chloride is suspended in a 500 ml three-neck round-bottom flask. methylene and, while cooling in a water-ice bath, triethylamine (37.2 ml, 0.302 mol) is added dropwise at 0-5 ° C, then trifluoroacetic anhydride (27.5 g, 0.147 mol). Cooling is removed, and after the temperature of the reaction mixture rises to room temperature, washed with 3 × 100 ml of water. The organic phase is dried over sodium sulfate, the solvent is removed on a rotary film evaporator and ethyl (4 - {(trifluoroacetyl) [(3R) -1- (trifluoroacetyl) pyrrolidin-3-yl] amino} phenyl) acetate 12 24.0 g is obtained 81%

Stage 4:

In a 500 ml three-necked round-bottom flask was placed a 1M solution of LiHMDS 13 in THF (93 ml, 0.065 mol), cooled to -78 ° C and ethyl (4 - {(trifluoroacetyl) [(3R) -1- (trifluoroacetyl) pyrrolidine solution was added in portions -3-yl] amino} phenyl) acetate 12 (24.0 g, 0.055 mol) in 100 ml THF. Stirred for 15 minutes, then a solution of valeroyl chloride 14 (7.2 g, 0.060 mol) in 50 ml of THF was added dropwise at the same temperature. The cooling was removed and the reaction mass was stirred at room temperature for 12 hours, after which 250 ml of a saturated solution of ammonium chloride were added and left for 30 minutes with vigorous stirring. Stirring is turned off, while the reaction mass is divided into two layers. The upper layer was separated and the solvent was evaporated on EPI. The residue was dissolved in 300 ml of hexane, dried over sodium sulfate and the solvent was evaporated on EPI. The residue was purified by column chromatography on a column (d = 8 cm, h = 30 cm) with a diethyl ether - hexane 1: 2 system. Ethyl 3-oxo-2- (4 - {(trifluoroacetyl) [(3R) -1- (trifluoroacetyl) pyrrolidin-3-yl] amino} phenyl) heptanoate 15 21.3 g is obtained in 75% yield.

Stage 5:

Preparation 17: Ethyl 3-oxo-2- (4 - {(trifluoroacetyl) [(3R) -1- (trifluoroacetyl) pyrrolidin-3-yl] amino} phenyl) heptanoate 15 (1.0 g, 1.9 mmol), 3-aminopyridazine (272 mg, 2.9 mmol) and 2.5 ml of Eaton's reagent (solution of 10 wt.% P ₂ O ₅ in methanesulfonic acid). The mixture was stirred at 50 ° C. for 24 hours, cooled to room temperature, 20 ml of chloroform was added and poured onto a mixture of NaOH (2.4 g, 57 mmol) and 30 g of ice. The chloroform layer was separated, dried over sodium sulfate and evaporated on EPI. The residue was purified by column column chromatography (d = 1 cm, h = 20 cm) with a chloroform – methanol 100: 1 system to obtain 850 mg of N- [4- (2-butyl-4-oxo-4H-pyrimido [1,2- b] pyridazin-3-yl) phenyl] -2,2,2-trifluoro-N - [(3R) -1- (trifluoroacetyl) pyrrole din-3-yl] acetamide 17.1. with a yield of 80%.

Stage 6:

Preparation 18.1 .: 850 mg of N- [4- (2-butyl-4-oxo-4H-pyrimido [1,2-b] pyridazin-3-yl) phenyl] -2,2 is dissolved in a 20 ml conical flask, 2-trifluoro-N - [(3R) -1- (trifluoroacetyl) pyrrole din-3-yl] acetamide 17.1. in 10 ml of methanol and add 3 ml of aqueous concentrated ammonia solution. The mixture was allowed to stir at room temperature for 12 hours, then the solvents were evaporated on EPI. The residue was purified by column chromatography on a column (d = 1 cm, h = 20 cm) with a system of chloroform - methanol - aqueous ammonia 100: 10: 1. After evaporation of the eluent, 10 ml of ether are added, followed by 1 ml of 5M dioxane hydrochloride. The precipitate was filtered, dried in air. 60 mg of 2-butyl-3- {4 - [(3R) -pyrrolidin-3-ylamino] phenyl} -4H-pyrimido [1,2-b] pyridazin-4-one dihydrochloride are obtained. 18.1. with a yield of 9%.

1H NMR (400 MHz, DMSO-D6) ppm 0.78 (t, 7.3Hz, 3H), 1.16-1.21 (m, 2H), 1.56-1.67 (m, 2H), 1.88-1.99 (m, 1H), 2.17- 2.29 (m, 1H), 2.56 (t, 7.7Hz, 3H), 3.05-3.15 (m, 1H), 3.20-3.49 (m, 3H), 4.12-4.20 (m, 1H), 6.72 (d, 8.2Hz , 2H), 7.09 (d, 8.2Hz, 2H), 7.73-7.80 (m, 1H), 8.06-8.14 (m, 1H), 8.83 (br.s, 1H), 9.34 (br.s, 2H)

According to a similar scheme, using other reagents - aminopyrazines 16, as well as other acid chlorides 14 and other amines 2, compounds 18.2-18.8 were obtained, which are presented in table 1

Table 1 No. Structure Like weight M + 1 18.2.

393.49 394.5 18.3.

377.49 378.5 18.4.

388.48 389.5 18.5.

377.49 378.5 18.6.

377.49 378.5 18.7.

336.44 337.4 18.8

361.45 362.4

Example 2. General method for the synthesis of salts of compounds of General formula I.

A portion of the compounds of the present invention contains ionic groups (primary and secondary amines) and can form salts which are prepared by methods known in the art. For this, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate), a solution of an equivalent amount (sometimes an excess) of an organic or inorganic acid in an inert solvent was added and precipitation of the desired salt was achieved. The inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid. The organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, lactic acid gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, n o not limited to them.

Another option for the synthesis of salts of compounds I is the removal of the protective group in an acidic environment (for example, the removal of the tert-butyloxycarbonyl group) with the simultaneous formation of an amine salt.

Determination of antagonistic activity of compounds with respect to the TRPA1 ion channel.

Compounds were tested using human kidney embryonic epithelial cells exogenously expressing the IPTG-induced ion channel TRPA-1. Antagonistic activity of the compounds was evaluated by suppressing the release of intracellular calcium. FLIPR (Molecular Devices) was chosen as an experimental platform. The release of intracellular calcium was stimulated by Allyl isothiocyanate (AITC), Ruthenium Red (RR) was used as a known TRPA1 antagonist. For all compounds, the dependence of the antagonistic activity of the substance on the concentration of the substance was analyzed. From the obtained dependence plots, IC50 values were determined (the concentration of the substance in micromoles, which causes 50% of the maximum effect).

Cell line: HEK293 line stably expressing TRPA1 upon induction of IPTG. The cell culture medium was a mixture of DMEM (Hyclone, USA), 10% FBS (Hyclone, USA), 1% NEAA, pyruvate Na, 2 mM L-glutamine, 0.3 μg / ml G418 (Sigma, USA), 20 μg / ml hygromycin (Invitrogen, USA).

Preparing cells for the experiment. Cells were suspended in a culture medium with 1 mM IPTG so as to obtain a concentration of 8 × 10 ⁵ cells / ml, which would give 20,000 cells per well. The resulting cell suspension was placed in 384-well experimental culture plates with an optical bottom using automated robotic stations Biomek FX or Biomek NX, 25 μg of suspension in each well. 384-well plates were centrifuged 200xg for 5 minutes. Next, the experimental plates with cell suspension were transferred to an incubator of 37 ° C, 5% CO ₂ .

On the day of the experiment, the cells were loaded with Ca ²⁺ , a sensitive paint prepared according to the manufacturer's instructions. Briefly, the contents of one FLIPR ^R Calcium 4 ampoule test system (Molecular Devices, USA) was dissolved in 20 ml of Hanks / 20mM HEPES buffer and used as a 25-fold runoff. 25 ml of a working solution of Ca ²⁺ - sensitive paint was added to each well of the 384-well experimental plate. The experimental plates loaded with Ca ²⁺ - sensitive paint were incubated for 1 hour at room temperature in a dark place. Next, we started reading on the FLIPR.

Formatting substances.

- The substances were dissolved in DMSO to a concentration of 10 mm.

- Serial dilutions of substances were prepared in DMSO in steps 3.16 using Biomek 2000. When diluting a series of each substance 166.6 times in Hanks / 20mM HEPES / 0.6% Pluronic F-127 / 0.6% DMSO buffer, a 6-fold stock solution of a series of substance was obtained. The final maximum tested concentration is 30 μM.

(Fig. 1). Scheme of the 384-hole plate.

Calcium channel stimulation.

To stimulate the ion TRPA-1 channel, we used an EC ₈₀ agonist concentration of 30 μM. A 6-fold stock of an agonist of 180 μM AITC was prepared on Essay buffer, Hanks / 20mM HEPES / 0.6% Pluronic-127 / 0.6% DMSO.

Control antagonist.

To inhibit the stimulated calcium response, a maximum inhibitory concentration of the control antagonist IC ₁₀₀ of 6 μM was used. A 6-fold runoff of the control antagonist of 36 μM RR was prepared on Essay buffer, Hanks / 20mM HEPES / 0.6% Pluronic-127 / 0.6% DMSO.

Addition of test substances and control antagonist

To detect the agonistic activity of the test substances, 12.5 μl of the substance was added to each well of the 384-well plate according to the plate design. Next, the experimental plate was read on FLIPR.

After an incubation of 667 seconds (11 minutes), 12.5 μl of the TRPA-1 ion channel agonist, AITC allyl isothiocyanate, was added to each well of the 384-well experimental plate and a second read on FLIPR was started immediately to determine antagonists.

Calculation of IC ₅₀ for antagonists

For substances, the dependence of antagonistic activity on concentration was analyzed. The value of IC ₅₀ was determined from the obtained dependence. The experimental data were analyzed using GraphPad Prizm (GraphPad Software, Inc., San Diego, CA). To build the concentration dependence, the equation was chosen

Y = Lower plateau of the curve + (Upper plateau - Lower plateau) / (1 + 10 ^∧ ((LogIC50-X) * Curve slope))

EC _{50 was} determined based on the constructed schedule, as the concentration of a substance that causes 50% of the maximum effect. The ranges of agonistic activity with respect to GPR119 of some synthesized compounds are shown in Table 2.

Table 2. Compounds of General Formula I — TRPA1 Channel Lock. Connection No. Maximum tested concentration, uM % inhibition at max. concentration IC ₅₀ I8.1. thirty 98 A I8.2. thirty 68 C I8.3. thirty 101 A I8.4. thirty 79 C I8.5. thirty 96 A I8.6. thirty one hundred A I8.7. thirty 33 - I8.8. thirty 87 B

Where A - 5 nM <IC ₅₀ <250 nM

B - 250 nM <IC ₅₀ <1 uM

C - 1 uM <IC ₅₀ <10 uM

Pharmacological properties of the claimed compounds

Example 3. The study of the pharmacological (analgesic) action of compounds 18.1, 18.3. and 18.6. using a tail pain temperature test.

Methodology Experiments to study the analgesic effects of compounds 18.1, 18.3. and 18.6. carried out using a test of temperature pain sensitivity on the tail with the help of a hardware-software complex of Panlab, Harvard Apparatus, Analgesy-meter LE 7106, including a pencil case for fixing the animal with the possibility of placing the tail over the sensor with photocells that fix tail flicking due to pain irritation caused by pain by heating with a focused lamp (focus in the range of 10-90, in the experiment the focus value was 20 units in all experimental series), and the SeDaCom program.

Inhibitors of the cell channel TRPA1 18.1, 18.3. and 18.6. was administered intragastrically at a dose of 3 mg / kg. As a control, we used data obtained by intragastric administration of an equivalent volume of 1% starch solution.

In this test, the time from the start of heating the tail with a focused lamp to its pulling off the surface above the photocell was recorded.

Results.

When conducting a series of experiments to study the analgesic activity of the presented TRPA1 cell channel inhibitors, it was found that, in the outcome, there were no differences in the experimental groups from the indices of intact animals (Table 3).

In the analysis of the absolute indicators of activity (time before tail tailing), significantly different from the tail tailing time in the group of intact animals, compounds 18.1, 18.3. and 18.6. (tab. 3).

Table 3 The effect of TRPA1 cell channel inhibitors on tail withdrawal during a test with focused temperature pain. Indicator / Group Intact 18.1 18.3. 18.6 Before drug administration, sec 7.02 ± 0.66 7.12 ± 1.22 7.23 ± 0.78 6.91 ± 1.17 30 minutes after drug administration, sec 6.61 ± 0.44 12.63 ± 1.41 * ′ ** 4.45 ± 1.21 * ′ ** 11.27 ± 0.89 * ′ ** Note: * - p <0.05 compared with intact; ** - p <0.05 compared with baseline.

The test compound with the laboratory code 18.3 had the most pronounced activity in this test.

Claims (6)

1. Substituted pyrazinopyrimidinones as TRPA1 blockers of channels of general formula I or their racemic mixtures, or individual optical isomers, or pharmaceutically acceptable salts

,
Where
R1 = H, (C ₁ -C ₅ ) alkyl,
R2 = H, (C ₁ -C ₅ ) alkyl,
R3 = H, (C ₁ -C ₅ ) alkyl,
R4 = H, (C ₁ -C ₇ ) alkyl, (C ₁ -C ₇ ) alkyl substituted with (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl,
R5 = H, (C ₁ -C ₅ ) alkyl, heterocyclyl, where heterocyclyl means a saturated monocyclic system containing from 4 to 6 carbon atoms, in which one carbon atom is replaced by a heteroatom such as nitrogen. 2. A method of obtaining compounds of General formula I according to claim 1, comprising the following stages:

,
where R1, R2, R3, R4, R5 have the above meanings. 3. The active component having the property of a channel blocker TRPA1, which is a compound of General formula I according to claim 1. 4. A pharmaceutical composition having analgesic properties, containing in an effective amount the active ingredient according to claim 3. 5. The pharmaceutical composition according to claim 4 in the form of tablets, capsules, injections, ointments, rectal suspensions and gels, placed in a pharmaceutically acceptable package. 6. The method of analgesia by the introduction in an effective amount of a new active component according to claim 3 or the pharmaceutical composition according to claims 4, 5.

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