WO2013058681A2 - Substituted phenoxyacetic acids and esters and amides thereof, comprising a 2,6-dioxo-2,3,6,7-tetrahydro-1н-purine-8-yl fragment and constituting а2a adenosine receptor antagonists, and the use thereof - Google Patents

Abstract

The invention relates to novel compounds of general formula 1, namely substituted phenoxyacetic acids and esters and amides thereof, which comprise a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl fragment and exhibit antagonist activity against A_2A adenosine receptors, and to the use thereof as a therapeutic principle and agent (adjuvant) for pharmaceutical compositions and drugs, as well as to methods for treating diseases of the central nervous system, oncological diseases and viral and bacterial diseases, where R1, R2 and R3, not necessarily simultaneously, are hydrogen, C1-C5 alkyl, C3-C5 alkenyl or C3-C5 alkynyl; R4 is hydrogen, a halogen atom, a hydroxyl, C1-С3 alkyl, C1-С3 alkyloxy; R5 is hydrogen, C1-C3 alkyl, the group -C(O)R6; and R6 is a hydroxyl, C1-С5 alkyloxy, С3-С5 alkenyloxy, С3-С5 alkynyloxy, an optionally substituted amino group where the substitutes, not necessarily identical, are selected from hydrogen, C1-C5 alkyl optionally substituted with a mono- or dialkylamino group or an alkoxy group or a 5-6 membered saturated heterocyclyl comprising 1-2 heteroatoms selected from nitrogen and oxygen; pyridyl or phenyl optionally substituted with 1-3 methoxy groups; or an optionally substituted 6 membered saturated heterocyclyl optionally annulated with a 5 membered unsaturated heterocyclyl and comprising 2 nitrogen atoms, where the substitutes are selected from С1-С5 alkyl optionally substituted with a 5 membered heteroaryl comprising 1-3 heteroatoms selected from nitrogen and oxygen; or a 6 membered optionally saturated heterocyclyl comprising 1-2 nitrogen atoms optionally substituted with C1-C5 alkyl, oxo, optionally substituted with phenyl; and the broken line with an adjacent unbroken line represents a single, double or triple bond.

Description

 Substituted phenoxyacetic acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety - antagonists of adenosine

A ₂ d receptor and their use

 Technical field

This invention relates to new compounds - substituted phenoxyacetic acids and their esters and amines, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment, exhibiting antagonistic activity against adenosine A ₂ d receptors, and their use as a medicinal agent and means (adjuvant) for pharmaceutical compositions, drugs, and to methods of treating diseases of the central nervous system, cancer, viral and bacterial diseases.

 State of the art

A ₂ d receptors are one of 4 subtypes (Ai, A ₂ d, A ₂ B and A ₃ ) of adenosine receptors. A] receptor inhibits adenylate cyclase, and also activates or inhibits (depending on the type of cells) phosphoinositide metabolism. In addition, with the participation of G-proteins, this receptor activates K-channels and inhibits Ca-channels. A ₂ receptor stimulates adenylate cyclase. Both types of receptors have seven transmembrane domains and are homologous to other membrane receptors conjugated to G-proteins. Adenosine also binds to the intracellular region on the catalytic subunit of adenylate cyclase, causing its inhibition. Adenosine receptors are localized in different types of tissues and are involved in the regulation of a number of biological processes. Activation of Ai and A ₃ receptors causes a decrease in cAMP [Jockers R., Linder M.E., Hoehnegger M. J. Biol. Chem. 1994, 269, 32077. PalmerTM, Gettys TW, Stiles GLJ Biol. Chem. 1995, 270, 16895.], and activation of A _2A and A _2B receptors leads to its increase in cAMP level [Kull B., Svenningsson P., Fredholm V.V. Mol. Pharmacol 20006 58, 771. Bruns RF, Lu GH, Pugsley TA Mol. Pharmacol 1986, 29, 331.]. In addition, stimulation of Ai receptors causes potassium activation and calcium channel deactivation [Iredale P.A., Alexander SPH, Hill SJ Br. J. Pharmacol. 1994, 111, 1252. Bunemann M., Pott LJ Physiol. 1995, 482, 81.], and stimulation of A ₂ d receptors leads to inhibition of the functional activity of D ₂ dopamine receptors, which is important in the development of neurological and mental illness [Fuxe K., Ferre S., Zoli M., Agnati LF Brain Res. Rev. 1998, 26, 258. Franco R., Ferre S., Agnati L., Torvinen M., Gines S., Hillion J. Neuropsychoparmacol, 2000, 23, S50.].

Adenosine receptor ligands are widely used in pharmacology and medicine. A large number of scientific papers and patents are devoted to studies on the use of A _2A receptor antagonists as drug candidates for the treatment of diseases of the central nervous system (CNS), in particular Parkinson’s disease [Pinna A. Novel investigational adenosine A ₂ e receptor antagonists for Parkinson's disease. Expert Opinion on Investigational Drugs, 2009, 18 (1 1), 1619-1631).];

various kinds of depression [El Yacoubi M, Costentin J, Vaugeois JM (December 2003). "Adenosine A2A receptors and depression." Neurology 61 (1 1 Suppl 6): S82-7. PMID 14663017. http://www.neurology.org/cgi/pmidlookup?view=long&pmid= 14663017; Kaster MP, Rosa AO, Rosso MM, Goulart EC, Santos AR, Rodrigues AL (January 2004). "Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of Al and A2A receptors." Neuroscience Letters 355 (1-2): 21-4. doi: 10.1016 / j.neulet.2003.10.040. PMID 14729225. http://linkinghub.elsevier.com/retrieve/pii/S0304394003012345; Lobato KR, Binfare RW, Budni J, Rosa AO, Santos AR, Rodrigues AL (May 2008). "Involvement of the adenosine Al and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test." Progress in Neuro-psychopharmacology & Biological Psychiatry 32 (4): 994-9. doi: 10.1016 / j.pnpbp.2008.01.01.01. PMID 18289757.],

cognitive impairment [Takahashi RN, Pamplona FA, Prediger RD (2008). "Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies." Frontiers in Bioscience: a Journal and Virtual Library 13 (13): 2614-32. doi: 10.2741 / 2870. PMID 17981738. http://www.bioscience.org/2008/vl3/af/2870/fulltext.htm.]

and inflammatory processes [Sullivan GW (November 2003). "Adenosine A2A receptor agonists as anti-inflammatory agents." Current Opinion in Investigational Drugs (London, England: 2000) 4 (11): 1313-9. PMID 14758770; Lappas CM, Sullivan GW, Linden J (July 2005). "Adenosine A2A agonists in development for the treatment of inflammation." Expert Opinion on Investigational Drugs 14 (7): 797-806. doi: 10.1517 / 13543784.14.7.797. PMID 16022569.].

More recently, it has been shown that adenosine, which accumulates near the tumor tissue [Blay J., White T. D., Oskin DW The Extracellular Fluid of Solid Carcinomas Contains immunosuppressive Concentrations of Adenosine. Cancer Research, (1997) 57, 2602-2605.], Significantly inhibits the ability of activated T-lymphocytes and natural killer cells to bind to and kill tumor cells [Hoskin D. W, Reynolds T., Blay J. 2-Chloroadenosine inhibits the MHC unrestricted cytolytic activity of anti-CD ₃ -activated killer cells: evidence for the involvement of a non-Ai / A ₂ cell-surface adenosine receptor. Cell Immunol. (1994) 159: 85-93. Hoskin DW, Reynolds T., Blay, J. Adenosine as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumours. Int. J. Cancer, (1994) 59: 854-855.]. It was shown that hypoxia, developing in conditions of solid tumors, initiates the formation of increased concentrations of adenosine near the tumor tissue. Adenosine, binding to type A ₂ adenosine receptors located on the cell membrane of lymphocytes, transmits an adenosine signal into cells by activating intracellular accumulation of cyclic adenosine monophosphate (cAMP), which, in turn, reduces the ability of lymphocytes to attack tumor tissue [Sitkovsky M. V, Kjaerga J, Lukashev D, Ohta A. Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia. Clin Cancer Res (2008) 14 (19), 5947-5952.]. Based on these observations [Ohta A., Gorelik E., Simon J., Prasad S. J, Ronchese F., Lukashev D., Wong M. K. K., Huang X., Caldwell S., Liu K., Patrick Smith P., Chen J.-F., Jackson E., Apasov S., Abrams S., Sitkovsky M. A _2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci, USA (2006), 103, 13132-13137. Lukashev D., Sitkovsky M., Ohta A. .. From "Hellstrom Paradox" to anti-adenosinergic cancer immunotherapy. Purinergic Signalling (2007) 3, 129-134], an innovative approach to enhancing the efficacy of anticancer vaccines using an adjuvant that inhibits the A ₂ d adenosine receptor [Ohta A., Sitkovsky M. METHODS AND COMPOSITIONS FOR IMPROVING IMMUNE RESPONSES, WO 2008 / 147482 12/04/2008].

A large number of A ₂ d receptor antagonists have been described and patented, including clinical candidates:

 • SCH58261: 2- (2-furanyl) -7- (2-phenylethyl) -7H-pyrazolo [4,3-e] [1,2,4] triazolo [1, 5-c] pyrimidin-5-amine;

 • Biogen-34: 5- [4 - [[5-chlorol-l-methyl-3- (trifluoromethyl) -lH-pyrazol-4-yl] methyl] -l-piperazinyl] -2- (2-furanyl) - [l, 2,4] triazolo [l, 5-a] [l, 3,5] triazin-7-amine;

• Ver-6623: 2-isopropyl-4- (thiazol-2-yl) thieno [3,2-d] pyrimidine; • MSX-2: 3- (3-hydroxypropyl) -7-methyl-8- (m-methoxystyryl) -l - propargylxanthine;

 • KW-6002: (E) l, 3-diethyl-8- (3,4-dimethoxystyryl) -7-methylxanthine;

• DMPX: 3,7-dimethyl-l-propargylxanthine,

for which the pharmacological profiles in rats were studied in detail and A _2A receptor activities and selectivities to other adenosine receptors were compared.

 SCH58261 Biogen-34

Ver-6623 DMPX

 KW-6002 DMPX

The search for highly effective and selective antagonists of A ₂ d receptors is one of the main directions of creating new pharmacological agents for the treatment of central nervous system diseases, in particular, Parkinson's disease, oncological diseases and inflammatory processes. In this regard, the development of new antagonists of A ₂ d receptors, pharmaceutical compositions and drugs, as well as methods for their preparation and use, is relevant.

 Disclosure of invention

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

 "Adjuvant" (adjuvant) - a substance or complex of substances used to enhance the immune response or enhancing the effect of drugs.

 “Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring. Preferred optionally substituted and saturated bis-membered diazinyls: piperazinyl, pyridazinyl, pyrimidinyl; tetrahydropurinyl, oxadiazolyl, pyridinyl, morpholinyl. An azaheterocycle may have one or more “cyclic” substituents.

 “Alkenyl” means an aliphatic linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including at least one carbon-carbon double bond.

 Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkenyl chain.

An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyl, aralkoxycarbonyl, getroaralkiloksikarbonil or _{R ^ R k + i ^ -} , R k a R k + i a NC (= ^{_{0) -, R k a R k}} + i a NS0 ₂ -, where R _k ^a and R _{k +} i ^{a are} independently “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or _k ^a and R _{k +} i ^a together with the N atom to which they are bonded form through R _k ^a and R _{k +} i ^a 4 - 7 membered heterocyclyl or maple. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbnylmethyl, benzyloxycarbonylmethylmethyl and pyridinyl.

 Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl.

 “Alkenyloxy” means an alkenyl-O— group in which alkenyl is defined in this section. Preferred alkenyloxy groups are allyloxy and 3-butenyloxy.

 “Alkenyloxyalkyl” means an alkenyl-O-alkyl group in which alkyl and alkenyl are defined in this section.

R_k ^aR_k+i^aNS0₂-, где R_k ^a и R_k+i^a независимо друг от друга представляют собой «заместители амино группы», значение которых определено в данном разделе, например, атом водорода, алкил, арил, аралкил, гетероаралкил, гетероциклил или гетероарил, или R_k ^a и R_k+i^a вместе с атомом N, с которым они связаны, образуют через R_k ^a и _k+i^a 4 - 7 членный гетероциклил или гетеоцикленил. Предпочтительными алкильными группами являются метил, трифторметил, циклопропилметил, циклопентилметил, этил, н-пропил, изо-пропил, н-бутил, трет-бутил, н- пентил, 3-пентил, метоксиэтил, карбоксиметил, метоксикарбонилметил, этоксикарбонилметил, бензилоксикарбонилметил метоксикарбонилметил и пиридилметилоксикарбнилметил. Предпочтительными «алкильными заместителями» являются циклоалкил, арил, гетероарил, гетероциклил, гидрокси, алкокси, алкоксикарбонил, аралкокси, арилокси, алкилтио, гетероарилтио, аралкилтио, алкилсульфонил, арилсульфонил, алкоксикарбонил, аралкоксикарбонил, гетероаралкилоксикарбонил или

аннелированный арилгетероцикленил, аннелированный арилгетероциклил. "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" substituents. Preferably C ₁ -C 5 alkyls, including branched, for example, isopropyl, isobutyl radicals. Alkyl may have one or more identical or different substituents (“alkyl substituents”) including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbnyl, alkylthio, heteroaryo , aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcyclic alkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or k'k ₊ i'N-, Rk'RiH-i'NCCO) -,

R _k ^a R _k + i ^a NS0 ₂ -, where R _k ^a and R _{k +} i ^{a are} independently “amino substituents”, the meaning of which is defined in in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k +} i ^a together with the N atom to which they are bonded, form through R _k ^a and _{k +} i ^a 4 - 7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethylmethyloxycarbonylmethyloxycarbonylmethyloxycarbylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonymethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethylene . Preferred “alkyl substituents” are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl or

annelated arylheterocyclenyl, annelated arylheterocyclyl.

 “Alkynyl” means an aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond.

R_k ^aR_k+! ^aNS0₂-, где R_k ^a и R_k+i^a независимо друг от друга представляют собой «заместители амино группы», значение которых определено в данном разделе, например, атом водорода, алкил, арил, аралкил, гетероаралкил, гетероциклил или гетероарил, или R_k ^a и R_k+i^a вместе с атомом N, с которым они связаны, образуют через R_k ^a и R_k+i^a 4 - 7 членный гетероциклил или гетероцикленил. Предпочтительными алкильными группами являются метил, трифторметил, циклопропилметил, циклопентилметил, этил, н- пропил, изо-пропил, н-бутил, трет-бутил, н-пентил, 3-пентил, метоксиэтил, карбоксиметил, метоксикарбнилметил, бензилоксикарбонилметил и пиридилметилоксикарбнилметил. Предпочтительными алкенильными группами являются этенил, пропенил, н-бутенил, изо- бутенил, З-метилбут-2-енил, н-пентенил, бута-1,3-диин и гекса-1,3,5-триин. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkynyl chain. An alkyl group may have one or more substituents, for example, such as halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, quinilyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclyloxycarbonyl, aryloxycarbonyl, a _k + i ⁸ ! ^ -,

R _k ^a R _{k +!} ^a NS0 ₂ -, where R _k ^a and R _{k +} i ^a independently represent “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k +} i ^a together with the N atom to which they are bonded form through R _k ^a and R _{k +} i ^a 4 to 7 membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbnylmethyl, benzyloxycarbonylmethylmethyl and pyridinyl. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, buta-1,3-diine and hexa-1,3,5-triine.

 “Alkoxy” means an alkyl-O— group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

замещенную или незамещенную «заместителем аминогруппы», R^³ и R_k+A значение которых определено в данном разделе, предпочтительно амино (H₂N-), необязательно замещенные метиламино, диметиламино, этиламино, метилэтиамино, диэтиламино, пирролидино, морфолино, пиперазино, бензиламино или фенэтиламино. “Amino group” means

substituted or unsubstituted with “amino substituent group”, R ^ ³ and R _k + A are defined in this section, preferably amino (H ₂ N-), optionally substituted methylamino, dimethylamino, ethylamino, methylethamino, diethylamino, pyrrolidino, morpholino, piperazino, benzylamino or phenethylamino.

 “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.

 "Antidepressant" means a medication intended to treat depression.

 “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. Representative aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be annelated with a non-aromatic ring system or heterocycle.

 “Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

“Heterocyclyl” means an aromatic or non-aromatic saturated monocyclic or polycyclic system comprising from 3 to 10 carbon atoms, preferably from 5 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. 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 of the cyclic system", which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to Ν-oxide, S-oxide or S-dioxide. Preferred heterocyclyls are piperidine, pyrrolidine, piperazine, priridine, tetrahydropurin, oxadiazole, morpholine, pyridazine, pyrimidine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

 "Hydrate" means a stoichiometric or non-stoichiometric composition of a substance (compound) or its salt with water.

 “Depression” means major depression; episodic, chronic and recurrent forms of major depression; dysthymic disorder (dysthymia); cyclotymia; affective disorders; seasonal affective disorder syndrome; bipolar disorders, including type I and type II bipolar disorders; as well as other depressive disorders and conditions. The term depression also means the depressive conditions accompanying Alzheimer's disease, vascular dementia; mood disorders induced by alcohol and substances; schizoaffective disorder of the depressive type; adaptation disorders. In addition, depression includes depressive states of cancer patients; with Parkinson's disease; depression after myocardial infarction; depression of infertile women; pediatric depression; postpartum depression; as well as other depressive conditions accompanying somatic, neuralogical and other diseases.

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

“Substituent amino group” means a substituent attached to an amino group. Amino group substituent represents hydrogen, alkyl (optionally branched C ₁ -S5), alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl. The meaning of “amino group substituents” is defined in this section.

или R_k ^aR_k+i^aNS0₂-, где R_k ^a и R_k+i^a представляют собой независимо друг от друга «заместители аминогруппы», значение которых определено в данном разделе, например, водород, необязательно замещенный Ci-C₅ алкил, необязательно замещенный арил, необязательно замещенный аралкил, или необязательно замещенный гетероаралкил, или заместитель R_k ^aR_k+i^aN-, в котором R_k ^a может быть ацил или ароил, а значение R_k+i^a определено выше, или «заместителями циклической системы» являются

"Substituent cyclic system" means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, C1-C5 alkyl, Ci-C alkenyl, C] -C ₅ alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, amino, amino C1-C5 alkyl, C1-C5 alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano, carboxy, C1-C5 alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, Ci- C5 alkyloxy C] -C ₅ alkyl, aryloxyalkyl, heterocyclyl , heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfon yl, heterocyclylsulfonyl, alkylsulfinyl, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonyl al keel, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl 4-7chlenny , 4-7 membered cycloalkenyl, heterocyclyl, heterocyclenyl, amidino, R _k ^a R _{k +} i ^a N-, R _k ^a N =, k ^ k ₊ ^ -alkyl-,

or R _k ^a R _{k +} i ^a NS0 ₂ -, where R _k ^a and R _{k +} i ^a are independently “amino substituents”, the meanings of which are defined in this section, for example, hydrogen, optionally substituted Ci-C ₅ alkyl optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or a substituent R _k ^a R _{k +} i ^a N-, in which R _k ^a may be acyl or aroyl, and the value R _{k +} i ^{a is as} defined above, or “cyclic substituents systems "are

or R _k ^a R _{k +} i ^a NS0 ₂ -, in which R _k ^a and R _{k +} i together with the nitrogen atom to which they are bonded form through R _k ^a and R _{k +} i ^a 4-7 membered heterocyclyl or heterocyclenyl.

“Cognitive disorders or cognitive disorders (cognitive disorder))) means a violation (weakening) of mental capabilities, including attention, memory, thinking, cognition, learning, speech, thought, executive and creative abilities, orientation in time and space, in particular cognitive impairment associated with Alzheimer's, Parkinson's and Huntington; senile dementia; age-related memory impairment (AAMI); dysmetabolic encephalopathies; psychogenic memory impairment; amnesia; amnestic disorders; transient global amnesia; dissociative amnesia; vascular dementia; mild (or moderate) cognitive impairment (mild cognitive impairment, MCI); attention deficit hyperactivity disorder (AD / HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, Down syndrome, bipolar disorder and depression; AIDS-related dementia; dementia with hypothyroidism; dementia induced by alcohol, addictive substances, and neurotoxins; dementia accompanying neurodegenerative diseases, for example, cerebellar degeneration and amyotrophic lateral sclerosis; cognitive disorders that develop with stroke, infectious and oncological diseases of the brain, as well as with traumatic brain injuries; cognitive impairment associated with autoimmune and endocrine diseases; and other cognitive disorders.

 “Medicinal principle” (drug substance, medicinal substance, drug-substance) means a physiologically active substance of synthetic or other origin (biotechnological, plant, animal, microbial and other), which has pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

 “Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition), in the form of tablets, capsules of injections, ointments, and other finished forms designed to restore, correct, or alter physiological functions in humans and animals, as well as for the treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Ligands" (from Latin ligo - bind) are chemicals (small molecule, inorganic ion, peptide, protein, etc.) that can interact with receptors that transform this interaction into a specific signal. "Neurodegenerative disease (H3)" means a specific condition and disease characterized by damage and primary death of populations of nerve cells in certain areas of the central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's and Parkinson's disease; Huntington's disease (chorea); multiple sclerosis; cerebellar degeneration; amyotrophic lateral sclerosis; dementia with Levy bodies; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-related dementia; multi-infarct dementia; frontotemporal dementia; leukoencephalopathy (a disease of endangered white matter); chronic neurodegenerative diseases; stroke; ischemic, reperfusion, and hypoxic brain damage; epilepsy; cerebral ischemia; glaucoma; traumatic brain injury; Down syndrome; encephalomyelitis; meningitis; encephalitis; neuroblastoma; schizophrenia; depression. In addition, neurodegenerative diseases include pathological conditions and disorders that develop with hypoxia, abuse of addictive substances when exposed to neurotoxins, infectious and oncological diseases of the brain, as well as neuronal damage associated with autoimmune and endocrine diseases; and other neurodegenerative processes.

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

 "Nootropics" or "nootropics", they are neurometabolic stimulants - substances taken to improve mental abilities.

“Mental disorders” (mental illness) are illnesses or illnesses associated with a mental disorder and / or disorder. Mental disorders include affective disorders (bipolar affective disorders, major depression, hypomania, minor depression, manic syndrome, Cotard syndrome, cyclothymia, schizoaffective disorder, etc.); intellectual and mnemonic disorders, mania (hypomania, graphomania, kleptomania, shop-mania, persecution mania, monomania, pornography, erotomania, etc.); multiple personality disorder, amentia, delirium tremens, delirium, delusional syndrome, hallucinatory syndrome, hallucinations, hallucinosis, homicidomania, delirium, illusion, cerulence, clinical lycanthropy, macropsy, Manichean delirium, micropsy, drug addiction, anorexia nervosa, oneiric syndrome, paronoid, paranoia, paraphrenia, pseudo-hallucination, psychosis, Cotard's syndrome, schizophrenic disorder, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia, schizophrenia Schreber, Daniel Paul); phobias (agarophobia, arachnophobia, autophobia, verminophobia, hydrosophobia, hydrophobia, demophobia, zoophobia, carcinophobia, claustrophobia, climacophobia, xenophobia, pseudophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, celophobia, trichobia) alcoholic psychoses, alcoholic palimpsest, allotriophagy, aphasia, graphomania, dissociative fugues, dissociative disorders, dysphoria, Internet addiction, hypochondria, hysteria, coprofemia, persecution mania, melancholy, misanthropy, obsession, panic attacks, Kapusgra syndrome, Aspergus syndrome , Rett syndrome, Fregoli syndrome, attention deficit hyperactivity disorder, obsessive states syndrome, chronic anesthesia effects syndrome, mental automatism syndrome, early childhood syndrome tism, madness, taphophilia, anxiety, Hikikomori syndrome, erotomomaniyu, etc.

 “Psychotic diseases” are all types of schizophrenia; schizophrenic diseases; schizotypal disorders; schizoaffective disorders, including bipolar and depressive types; delusional disorders, including delusions of attitude, persecution, greatness, jealousy, erotomania, as well as hypochondriacal, somatic, mixed and undifferentiated delusions; short-term psychotic disorders; induced psychotic disorders; substance-induced psychotic disorders; as well as other psychotic disorders.

 “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.

"Pharmaceutical composition" means a composition comprising a compound of 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 perceptive means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration 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 achieved using 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, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“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 specifically based on 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. The subject of this invention is substituted phenoxyacetic acids, their esters and amides, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety, of the general formula 1, as well as their pharmaceutically acceptable salts,

wherein Rl, R2 and R3, optionally simultaneously represent hydrogen, C _\ - C ₅ alkyl, Cs-C ₅ alkenyl, or _Cz-C5 alkynyl;

R4 represents hydrogen, a halogen atom, hydroxyl, CpCalkyl, C _\ -Czalkyloxy;

 R5 represents hydrogen, d-C 1-6 alkyl, the group-C (0) R 6;

R6 represents hydroxyl, C] -C ₅ alkyloxy, Cs-C ₅ alkenyloxy, C ₅ Sz- alkynyloxy, optionally substituted amino, wherein the substituents, optionally identical, are selected from hydrogen, C1-C ₅ alkyl, optionally substituted mono- or dialkylamino , alkoxy, 5-6 membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen; pyridyl, or phenyl optionally substituted with 1-3 methoxy groups; or an optionally substituted 6- membered, optionally annelated with a 5-membered unsaturated heterocycle, saturated heterocycle having 2 nitrogen atoms, wherein the substituents are selected from C _\ - C ₅ alkyl, optionally substituted 5-membered heteroaryl containing 1-3 heteroatoms selected from nitrogen and oxygen; or a 6-membered optionally saturated heterocyclyl containing 1 to 2 nitrogen atoms, optionally substituted with Q-Cs alkyl, oxo, optionally substituted phenyl;

 the dashed line with the solid line accompanying it () is a single, double or triple bond;

excluding {4- [2- (1, 3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) - vinyl] phenoxy} acetic acid and {4- [2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy} acetic acid ethyl ester. According to this invention, preferred substituted phenoxyacetic acids with their esters and amides of general formula 1 are compounds of general formula 1.1 and 1.2,

 in which Rl, R2, R3, R4, R5, R6 and the dashed line with the accompanying solid line () have the meaning indicated for compounds of General formula 1.

More preferred substituted phenoxyacetic acids with their esters and amides of general formula 1 are also compounds of general formula 1.3 and 1.4, in which R6 is as defined above, and R4 is hydrogen or a methoxy group.

More preferred compounds of the invention are: {5 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine methyl ester -8-yl) vinyl] -2-methoxy-phenoxy} acetic acid 1.1.1,

 {4 - [(E) -2- (1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2-methoxyphenoxy} acetic acid 1.2.0 (1),

{4 - [(E) -2- (1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy} acetic acid 1.2.0 (2) 2- (4- (2- (1, Zdiethyl-7methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) ethyl) phenoxy) acetic acid methyl ester 1.2.0 (3)

 2- (4- (2- (1, Zdiethyl-7methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) ethyl) phenoxy) acetic acid 1.2.0 (4 ),

 {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy methyl ester } acetic acid 1.3.2,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy } acetamide 1.3.3,

2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2 _> 3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - ^" S,> 1-di- (2-methoxyethyl) acetamide 1.3.4,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - H- (2-dimethylaminoethyl) -M-methyl acetamide 1.3.5,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -Y- (3-morpholin-4-ylpropyl) acetamide 1.3.6,

 1,3-diethyl-8 - ((E) -2- {4- [2- (4-isopropylpiperazin-1-yl) -2-oxo-ethoxy] phenyl} vinyl) - 7-methyl-3,7- dihydropurin-2,6-dione 1.3.7,

 1,3-diethyl-7-methyl-8 - [(E) -2- (4- {2-oxo-2- [4- (1,3,6-trimethyl-2,4-dioxo-1,2 , 3,4-tetrahydro-pyrimidin-5-yl) piperazin-1-yl] ethoxy} phenyl) vinyl] -3,7-dihydropurin-2,6-dione 1.3.9,

 1,3-diethyl-8 - {(E) -2- [4- (2- {4- [6- (2-methoxy-5-fluorophenyl) pyrimidin-4-yl] piperazin-

1-yl} -2-oxoethoxy) phenyl] vinyl} -7-methyl-3,7-dihydropurin-2,6-dione 1.3.10,

 1,3-diethyl-7-methyl-8 - [(E) -2- (4- {2-oxo-2- [4- (6-phenylpyrimidin-3-yl) piperazin-1-yl] ethoxy} phenyl) vinyl] -3,7-dihydropurin-2,6-dione 1.3.11,

 8 - {(E) -2- [4- (2- {4- [3- (3,4-dimethoxyphenyl) - [1,2,4] oxadiazol-5-ylmethyl] piperazin-1-yl} -2 -oxyethoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione 1.3.12.

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -

2-methoxyphenoxy} - - (3,4,5-trimethoxyphenyl) acetamide 1.3.13,

 {4 - [(E) -2- (1, 3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-yl) vinyl] -2 - chlorphenoxy} acetic acid 1.3.14,

{4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2 -methoxyphenoxy} -acetic acid 1.3.15, methyl ester {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1.3.16,

 isopropyl ether {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1.3.17,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetamide 1.3.18,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -Y-methyl acetamide 1.3.19,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -Y-ethyl acetamide 1.3.20,

 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -M, dimethyl acetamide 1.3.21,

 [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] acetic acid ethyl ester 1.4 .one,

 [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] acetamide 1.4.2,

 [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] -M-methyl acetamide 1.4.3

 1,3-diethyl-8- [3-methoxy-4- (2-oxo-2-piperazin-1-yl-ethoxy) phenylethinyl] -7-methyl-3,7-dihydropurin-2,6-dione 1.4 .four,

 [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] -Y-pyridine- 3-yl acetamide 1.4.5.

The subject of this invention is a method for producing substituted phenoxyacetic acids, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety, of general formula 1a, by acylation of 5,6-diamino-1H-pyrimidine -2,4-diones of general formula 3 acids of the general formula 4 in the presence of suitable reagents, e.g., (- (benzotriazol-1-yl) ^{_^:,} / V -tetragidrouroniya tetrafluoroborate or 1- hydroxybenzotriazole ^ (3- (dimethylamino) propyl) -L ^ -ethylcarbodiimide, by cyclization of the resulting compounds of general formula 5 into phenoxyacetic acids of general formula 1a,

где: Rl, R2, R4, R5 и пунктирная линия с сопровождающей ее сплошной линией

where: Rl, R2, R4, R5 and the dashed line with the solid line accompanying it

() have the meaning indicated for the compounds of general formula 1; R7 represents optionally substituted _C1-C5 alkyloxy optionally substituted Cs-C ₅ alkenyloxy, optionally substituted Cs-C ₅ alkynyloxy or amino, R8 is an optionally substituted and optionally saturated C] -Szalkil.

 According to the present invention, a preferred method for the preparation of optionally substituted amides of substituted phenoxyacetic acids, including a 2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl moiety of the general formula Id, involves reacting methyl esters of the general formula lbb with ammonia, primary or secondary amines of the general formula 6,

где: Rl, R2, R4 R5 и пунктирная линия с сопровождающей ее сплошной линией ) имеют значение указанное для соединений общей формулы 1; R9 и R10 необязательно одинаковые и представляют собой необязательно замещенный СрСзалкил, необязательно замещенный С₃-С₅алкенил, необязательно замещенный С₃-С₅алкинил.

where: Rl, R2, R4 R5 and the dashed line with the accompanying solid line) have the meaning indicated for compounds of General formula 1; R9 and R10 optionally the same and are optionally substituted CpCalkyl, optionally substituted C ₃ -C ₅ alkenyl, optionally substituted C ₃ -C ₅ alkynyl.

 According to the present invention, a preferred method for producing optionally substituted amides of substituted phenoxyacetic acids, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety of the general formula Id, involves reacting the acids of the general formula 1c with ammonia, primary or secondary amines of the general formula 6 in the presence of 1-hydroxybenzotriazole, N- (3-dimethylaminopropyl) -K'-ethylcarbodiimide hydrochloride and diisopropylethylamine,

 where: Rl, R2, R4 R5 and the dashed line, with its accompanying solid line

() have the meaning indicated for the compounds of general formula 1; R9 and R10 optionally identical and represent hydrogen, an optionally substituted C _\ - C ₅ alkyl, optionally substituted C ₃ -C ₅ alkenyl, optionally substituted C ₃ - Szalkinil or optionally substituted heterocyclyl comprising one or two nitrogen atoms.

The subject of this invention is new antagonists of the adenosine A ₂ A receptor, which are substituted phenoxyacetic acids, their esters and amides, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment, total formula 1, their pharmaceutically acceptable salts.

The antagonistic activity of the new compounds of general formula 1 and their pharmaceutically acceptable salts with respect to the adenosine A ₂ d receptor was carried out ex vitro in a functional test on cells. In the experiment, cells of the ValiScreen cell line line (PerkinElmer, USA) expressing the recombinant human type A ₂ adenosine receptor were used.

Table 1 presents data on the activity of K; for some of the compounds of general formula 1, confirming their high antagonistic activity for relative to the adenosine A ₂ d receptor: + corresponds to K]> 50 pM, ++ corresponds to K] from 20 to 50 pM, +++ corresponds to K] from 10 to 20 pM and ++++ corresponds to K] <10 pM.

Table 1. Antagonistic activity of some of the compounds of general formula 1 with respect to the adenosine A ₂ d receptor in a functional test on cells.

The subject of this invention are compounds of the general formula 1, which are a drug substance (substance) for the preparation of pharmaceutical compositions and finished dosage forms for the prevention and treatment of diseases of the central nervous system, cancer, viral and bacterial diseases in warm-blooded animals and humans. According to this invention, the new compounds of General formula 1 are an agent (adjuvant) for enhancing the immune response or action of drugs in the combinatorial treatment of cancer, viral and bacterial diseases.

The subject of this invention is a pharmaceutical composition having antagonistic activity against an adenosine A ₂ d receptor, comprising, as a drug principle (substance) or agent (adjuvant), compounds of general formula 1 or their pharmaceutically acceptable salts and / or hydrates in a therapeutically effective amount.

 Pharmaceutical compositions 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 compound of general formula 1 or a pharmaceutically acceptable salt thereof, of the present invention, may include other active substances, including those having anti-influenza activity, provided that they do not cause undesirable effects.

 If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with traditional pharmaceutical carriers.

 The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical industry 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.

The subject of this invention is a method for preparing a pharmaceutical composition by mixing with an inert excipient and / or solvent of at least one drug principle (substance) of general formula 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount. To determine the selectivity of the interaction with the adenosine A _2A receptor, a radioligand analysis of the interaction of compounds of the general formula 1 with adenosine A _1} A ₂ d, A ₂ B AND A ₃ receptors was performed.

Radioligand interaction analysis of compounds of general formula 1 with adenosine A [, A ₂ g, A ₂ and A ₃ receptors demonstrated their high selectivity towards the adenosine A _2A receptor.

So, for example, under conditions of competitive radioligand binding, the methyl ester activity {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1Н -purin-8-yl) -vinyl] -2-methoxy-phenoxy} -acetic acid 1.3.16 with respect to the adenosine A ₂ d receptor is 131 times higher than its activity with respect to the adenosine Ai receptor, 148 times higher than its activity in relation to adenosine A ₂ in the receptor and 1159 times higher than its activity in relation to adenosine A ₃ receptor. For comparison, the data on the activity and selectivity of compound 1.3.16 and the known ligand KW-6002, which was used as a reference preparation under radioligand analysis conditions, are presented below.

As can be seen from these data, the ligand 1.3.16 with respect to the adenosine A _2A receptor surpasses the known ligand KW-6002 both in activity and selectivity.

Table 2. The activity and selectivity of ligands 1.3.16 and KW-6002 under the conditions of radioligand analysis in relation to adenosine Ai, A ₂ d, A ₂ B and A ₃ receptors.

The subject of this invention is a method for selectively inhibiting the activity of an adenosine A ₂ d receptor, which comprises contacting a sample containing an adenosine A ₂ d receptor with a composition comprising an antagonist adenosine A ₂ d receptor, which is a substituted phenoxyacetic acid, its ester or amide, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment of the general formula 1, its pharmaceutically acceptable salt .

The subject of this invention is a medicament having antagonistic activity with respect to the adenosine A _2A receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package intended for the prevention and treatment of diseases of the central nervous system, cancer, viral and bacterial diseases in humans and warm-blooded animals, which includes in its composition a new drug source (substance) of the general formula 1 or a pharmaceutical composition in a therapeutic effective amount, as well as for preventing and treating Parkinson's disease, cognitive disorders, depression and inflammatory processes.

 In accordance with this invention, a method for the prophylaxis and treatment of diseases of the central nervous system, cancer, infectious diseases and sepsis in animals and humans consists in introducing to the patient a new drug or a new pharmaceutical composition in a therapeutically effective amount.

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or locally. The clinical dosage of the general formula 1 in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion, as well as depending on the age, sex and stage of the patient’s disease, the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg, therefore, during preparation If the dosage form from the pharmaceutical composition of the drug of the present invention is in the form of dosage units, the above effective dosage should be taken into account, with each dosage unit of the preparation containing 10 ~ 500 mg of the agent of general formula 1, preferably 50 ~ 300 mg. drugs can be taken several times during certain periods of time (preferably from one to six times). The best embodiment of the invention

 The invention is illustrated, but not limited to the following examples.

 Example 1. The synthesis of compounds of General formula 1A. To a solution of 1 mmol (198 mg) of 1,3-diethyl-5,6-diaminouracil 3 and 15 mmol of acid 4 in 8 ml of dimethyl ida was added 1.5 mmol (372 mg) of o- (benzotriazol-1-yl) - , L ^, LH-tetrahydruronium tetrafluoroborate. The mixture was stirred overnight at room temperature, poured into water, extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was chromatographed on silica gel with a mixture of dichloromethane and methanol. A yield of 26-92% amide 6 was obtained, which (0.1 mmol) was suspended in 8 ml of methanol, 8 ml of 4N aqueous sodium hydroxide solution was added. The mixture was stirred for 1.5 hours at 80-90 ° C. Cooled, neutralized with an 18% aqueous hydrochloric acid solution to pH = 7-8. The precipitate of phenoxyacetic acid, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety, of the general formula 1a, was filtered (yield 42-92%).

 {4 - [(E) -2- (1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2-methoxyphenoxy} acetic acid 1a.1 = (1.2.0 (1)) - LC MS: found 415 (M + 1), calculated 415 (M + 1). {4 - [(E) -2- (1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl) vinyl] phenoxy} acetic acid 1a.2 = (1.2.0 (2)) - LC MS: found 385 (M + 1), calculated 385 (M + 1).

 Example 2. The synthesis of compounds of General formula lb. A mixture of acid 1a (0.44 mmol), 4 ml of dimethyl ida 132 g (1 mmol) of calcined potassium carbonate and 2.2 mmol of alkyl iodide was stirred for 2 hours at 70 ° C, another 1.1 mmol of alkyl iodide was added, and 2 more were mixed hours 70 ° C. It was cooled, water was added, the precipitate formed was filtered off, which was dissolved in a suitable solvent, the resulting solution was filtered through a layer of silica gel, and the obtained filtrate was evaporated in vacuo. Received with a yield of 31-54% phenoxyacetic acid ester, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment, of General formula lb.

{4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) -vinyl] methyl ester] -2-methoxy-phenoxy} -acetic acid lb.l = (1.3.16). LC MS: Found 443 (M + 1); Calculated 443 (M + 1). Ή NM? (DMSO-D6, 400 MHz) δ: 7.61 (d, J = 16.4 Hz, 1H), 7.45 (s, 1H), 7.24 (m, 2H), 6.90 (d, J = 8 Hz, 1H), 4.83 (s, 2H), 4.05 ( m, 5H), 3.89 (m, 5H), 1.25 (t, J = 6.4 Hz, ZN), 1.12 (t, J = 6.8 Hz, ZN).

 {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy methyl ester } acetic acid 1b.2 = (1.3.2). LC MS: found 412 (M + 1); calculated 412 (M + 1). 1 H NMR (DMSO-D6, 400 MHz) δ: 7.73 (d, J = 8 Hz, 1H), 7.62 (d, J = 15.6 Hz, 1H), 7.19 (d, J = 16 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 4.86 (s, 2H), 4.06 (q, J = 6.4 Hz, 2H), 4.01 (s, ZN), 3.91 (q, J = 6.8 Hz, 2H), 3.71 (s, ZN), 1.25 (t, J = 6.8 Hz, ZN), 1.12 (t, J = 6.8 Hz, ZN).

 Methyl ester {5 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6, 7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1b. 3 = (1.1.1). LC MS: Found 443 (M + 1); Calculated 443 (M + 1). Ή NMR (DMSO-D6, 400 MHz) b: 7.58 (d, J = 15.2 Hz, 1H), 7.37 (m, 2H), 7.18 (d, J = 15.6 Hz, 1H), 7.03 (d, J = 8 Hz, 1H), 4.87 (s, 2H), 4.06 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H) 3.91 (q, J = 7.2 Hz, 2H), 3.82 (s, ZN), 3.72 (s, ZN), 1.25 (t, J = 7.2 Hz, ZN) 1.13 (t, J = 6.8 Hz, 3P).

Ethyl [4 - [(1,3-diethyl-2,3,6, 7-twtrahydro-7-methyl-2, 6-dioxo-Ш-purin-8-yl) ethynyl] -2-methoxyphenoxy] acetic acid (1.4.1). LCMS (M + 1) 455 Ή NMR (DMSO-D6, 400 MHz) 5 1.22 (t, Ji = 7.00, J ₂ = 2.88, 9Н), 3.84 (t, J, = 9.40, J ₂ = 0.25, ЗН) , 3.95 (d, J = 13.35, ЗН), 4.05 (d, J = 7.06, 4Н), 4.23 (d, J - 4.15, 2Н), 4.69 (t, Jj = 16.30, J ₂ = 0.17, 2Н), 6.84 (t, J, = 2.00, = 0.72, 1H), 6.97 (m, 2H).

Ethyl ester [2-chloro-4 - [(E) -2- (1,3-diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purin-8-yl ) ethenyl] phenoxy] acetic acid (1.3.14). LCMS (M + 1) 461 Ή NMR (DMSO-D6, 400 MHz) 5 1.22 (br, J, = 7.00, J ₂ = 2.88, 9H), 4.00 (d, J = 13.35, ZN), 4.07 ( d, J = 7.06, 4H), 4.25 (d, J = 4.15, 2H), 4.61 (t, Ji = 16.30, J ₂ = 0.17, 2H), 6.97 (d, J = 0.87, 1H), 7.01 (t , J, = 15.60, = 0.60, 1H), 7.31 (m, 1H), 7.44 (m, 1H), 7.45 (t, J, = 8.60, J ₂ = 2.20, 1H).

 Example 3. The synthesis of compounds of General formula 1C. 0.4 ml of a 1N lithium hydroxide solution was added to a solution of 0.34 mmol of lb ether in 2 ml of methanol. The mixture was stirred for 16 hours at room temperature. Evaporated to dryness, the residue was dissolved in water, washed with ether. A 6N hydrochloric acid solution was carefully added to pH = 7-8, and the precipitate formed was filtered off. Receive acid 1c with a yield of 41-71%.

{4 - [(E) -2- (1,3-Diethyl-7-methyl-2, 6-dioxo-2,3, 6, 7-tetrahydro-1H-purin-8-yl) vinyl] -2- methoxyphenoxy} acetic acid (1.3.15). LC MS: Found 429 (M + 1), calculated 429 (M + l). Ή NMR (DMSO-D6, 400 MHz) δ: 7.63 (d, J = 15.6 Hz, 1H), 7.44 (s, 1H), 7.26 (d, J = 8 Hz, 1H) 7.22 (d, J = 16 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.72 (s, 2H), 4.06 (q, J = 7, 2 Hz, 2H), 4.02 (s, 3H), 3.91 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.25 (t, J = 6, 8 Hz, ZN), 1.12 (t, J = 6.4 Hz, ZN).

 Example 4. General method for producing amides Id. In a test tube containing a suspension of 0.226 mmol of methyl ester of general formula lbb in 2 ml of methanol or ethanol, an appropriate amount of amine was saturated or added. The tube was closed, heated for 10 hours at a temperature of 50 ° C, then cooled, the precipitate was filtered off. Amide Id was obtained with a yield of 29-58%.

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy } acetamide ld.l = (1.3.3). LC MS: Found 398 (M + 1), calculated 398 (M + 1).

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetamide ld.2 = (1.3.18). LC MS: Found 428 (M + 1); Calculated 428 (M + 1). Ή NMR (DMSO-D6, 400 MHz) 6: 7.62 (d, J = 15.6 Hz, W), 7.33 (m, 5H), 6.93 (d, J = 8.8 Hz, W), 4.48 (s, 2H), 4.05 (m, 5H), 3.91 (m, 5H), 1.26 (t, J = 6.4 Hz, ЗН), 1.13 ( t, J = 6.4 Hz, ZN).

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -M-meth1 acetamide ld.3 = (1.3.19). LC MS: Found 442 (M + 1); Calculated 442 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 7.62 (d, J - 15.6 Hz, 1H), 7.33 (m, 5H), 6.93 (d, J = 8.8 Hz, 1H), 4.48 (s, 2H), 4.05 (m, 5H), 3.91 (m, 5H), 1.26 (t, J = 6.4 Hz, 3H), 1, 13 ( t, J = 6.4 Hz, ZN).

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -T ^ -ethyl acetamide ld.4 = (1.3.20). LC MS: Found 456 (M + 1); Calculated 456 (M + 1). 1 H NMR (DMSO-D6, 400 MHz) δ: 7.92 (m, 1H), 7.62 (d, J = 15.6 Hz, W), 7.44 (s, 1H), 7.24 ( m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 4.48 (s, 2H), 4.04 (m, 5H), 3.90 (m, 5H), 3, 16 (t, J = 5.6 Hz, 2H), 1.26 (t, J = 6 Hz, ZN), 1.12 (t, J = 6 Hz, ZN), 1.04 (t, J = 6.4 Hz, ZN).

2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} ^^ - dimethyl acetamide ld.5 = (1.3.21). LC MS: Found 456 (M + 1); Calculated 456 (M + 1). Ή NMR (DMSO-D6, 400 MHz) 8: 7.62 (d, J = 15.6 Hz, 1H), 7.43 (s, 1H), 7.22 (m, 2H), 6.86 ( d, J = 8 Hz, 1H), 4.83 (s, 2H), 4.06 (q, J = 5.6 Hz, 2H), 4.02 (s, ZN), 3.91 (q, J = 6.8 Hz, 2H), 3.87 (s, ZN), 3.01 (s, ZN), 2.85 (s, ZN), 1.26 ( t, J = 6.4 Hz, ZN), 1, 13 (t, J = 6.8 Hz, ZN).

Example 5. General method for producing amides Id. To a mixture of 30.5 mg (0.226 mmol, 2 equiv.) Of 1-hydroxybenzotriazole, 43.3 mg (0.226 mmol, 2 equiv.) Of 1CH- (3-dimethylaminopropyl) -H'-ethylcarbodiimide hydrochloride and 45 mg (0.113 mmol, 1 eq.) Of the starting acid N- (3-dimethylaminopropyl) -Y'-ethylcarbodiimide hydrochloride 1c was added in 1.8 ml of DMF. The resulting mixture was stirred at room temperature for 1 hour. Then, 0.170 mmol (1.5 equiv.) Of amine 6 and the required amount of diisopropylethylamine were added sequentially. The reaction mass was kept for 12 hours at room temperature, then mixed with 50 ml of 10% Na ₂ C0 ₃ . If the product precipitated as a precipitate, the precipitate was filtered off, washed 2 times with water on a filter, and dried in air. In the case of a fine precipitate, separation was carried out by centrifugation. If the product was obtained in the form of an oil, extraction was carried out with dichloromethane, the organic phase was washed 1 time with water, dried with anhydrous Na ₂ SC> 4 and evaporated on a rotary evaporator.

 Further purification was carried out either by recrystallization from ethanol or column chromatography using chloroform – methanol solvent systems in ratios from 40: 1 to 10: 1. Amides of Id were obtained with a yield of 26-89%.

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-Sh1) vinsh1] - 2-methoxyphenoxy} ^, -di- (2-methoxyethyl) acetamide ld.6 = (1.3.4). LC MS: Found 514 (M + 1), Calculated 514 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 7.71 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 15.6 Hz, 1H), 7.18 (d, J = 16 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H),

4.06 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.91 (q, J = 6.8 Hz, 2H), 3.53 (m, 4H), 3, 46 (m, 2H), 3.42 (m, 2H), 3.33 (s, 3H), 3.24 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 6.4 Hz, 3P).

2- {4 - [(E) -2- (1,3-Diet -7-me yl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2-methoxyphenoxy} - N- (2-dmethyl aminoet ιν-Ν -methylamide id Id.7 = (1.3.5). LC MS: found 483 (M + 1), calculated 483 (M + 1). LCMS (M + 1) 483 Ή NMR (DMSO-D6, 400 MHz) δ 1.22 (br t, J, = 7.00, J ₂ = 2.88, 6H), 2.17 (t, Ji = 13.35 , J ₂ = 0.98, 6H), 2.43 (t, J, = 13.29, = 6.21, 2H), 3.00 (d, J = 14.23, ZN), 3.62 (d, J = 8.79, 2H), 4.00 (d, J = 13.35, ZN),

4.07 (d, J = 7.06, 4H), 4.63 (t, J _t = 14.95, J ₂ = 0.23, 2H), 6.91 (m, 2H), 6.94 (m, 1H), 7.33 (d, J = 0.25, 1H), 7.46 (d, J = 8.60, 2H). 2- {4 - [(E) -2- (1,3-Dutyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - - (3-morpholin-4-ylpropsh1) acetamide ld.8 = (1.3.6). LC

MS: found 525 (M + 1); calculated 525 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 8.1 1 (t, J = 6.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.61 (d , J = 15.6 Hz, 1H), 7.21 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 4.52 (s, 2H ), 4.05 (q, J = 6.4 Hz, 2H), 4.01 (s, 3H), 3.92 (q, J = 6.8 Hz, 2H), 3.54 (m, 4H) ), 3.17 (q, J = 6.4 Hz, 2H), 2.28 (m, 4H), 2.24 (t, J = 6.8 Hz, 2H), 1.58 (p, J = 6.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, ZN), 1.12 (t, J = 6.8 Hz, ZN).

1,3-Diethyl-8 - ((E) -2- {4- [2- (4-isopropylpiperazin-1-yl) -2-oxoethoxy] phenyl} vinyl) -7-methyl-3,7-dihydropurin- 2,6-dione ld.9 = (1.3.7). LC MS: Found 509 (M + 1); Calculated 509 (M + 1). LCMS (M + 1) 509 Ή NMR (DMSO-D6, 400 MHz) 8 1.10 (t, J, = 6.28, = 1.13, 6H), 1.22 (br.t, J] = 7.00, J ₂ = 2.88, 6H ), 2.40 (m, 2H), 2.48 (m, 2H), 2.70 (m, 1H), 3.38 (m, 2H), 3.45 (m, 2H), 4.00 (t, Ji = 13.35, J ₂ = 0.25, ЗН), 4.05 (d, J - 7.06, 4Н), 4.63 (t, J, = 14.00, = 0.23, 2Н), 6.90 (t, J, = 2.20, J ₂ = 0.50, 2Н), 6.94 (t, J, = 15.60, J ₂ = 0.70, 1H), 7.29 (d, J = 0.25, 1H), 7.45 (t, J, = 8.60, J ₂ = 0.50, 2H).

 8 - ((E) -2- {4- [2- (1,6-dimethyl-3,4-dihydro-III-pyrrolo [1,2-a] pyrazin-2-yl) -2-oxoethoxy] phenyl } vinyl) -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione ld.10 = (1.3.8). LC MS: Found 531 (M + 1); Calculated 531 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 7.73 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 16 Hz, 1H), 7.19 (d, J = 15.6 Hz, 1H), 6.99 (m, 2H), 5.73 (s, 2H), 5.44, 5.24 (2m, 1H), 4.99 (m, 2H), 4, 56, 4.34 (2m, W), 3.42 (m, 1H), 4.06 (m, 2H), 4.00 (m, ZN), 3.90 (m, 2H), 3.76 (m, 1H), 3.57 (m, 1H), 2.12 (s, 3H), 1.48, 1.32 (2m, 3H), 1.25 (t, J = 7.2 Hz, ZN), 1.14 (t, J = 6 Hz, ZN).

 1,3-Diethyl-7-Metsch1-8 - [(E) -2- (4- {2-oxo-2- [4- (1,3,6-tr1shvtsh1-2,4-dioxo-1,2 , 3,4-tetrahydropyrimidin-5-ш1) -piperazin-1-1ш] ethoxy} fensch1) vinyl] -3,7-dihydropurin-2,6-dione ld.ll = (1.3.9). LC MS: found 619 (M + 1); calculated 619 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 8.61 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.62 (m, 2H), 7.34 ( s, 1H), 7.28 (s, W), 7.19 (m, 2H), 6.99 (d, J = 8.4 Hz, 2H), 4.96 (s, 2H), 4, 05 (q, J = 7.2 Hz, 2H), 4.00 (s, ZN), 3.91 (k, J = 6.4 Hz, 2H), 3.85 (s, ZN), 3, 77 (m, 2H), 3.69 (m, 2H), 3.61 (m, 4H), 1.2 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 6 , 4 Hz, ZN).

1,3-Diethyl-8 - {(E) -2- [4- (2- {4- [6- (2-methoxy-5-fluorofensch1) pyrimidin-4-] piperazin-1-sh1} -2- oxoethoxy) fensch1] vinyl} -7-methyl-3,7-dihydropurin-2,6-dione ld.12 = (1.3.10). LC MS: found 669 (M + 1); calculated 669 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: 8.61 (s, 1Η), 7.73 (d, J = 8.4 Hz, 2H), 7.62 (m, 2H), 7.34 (s, 1H), 7.28 (s, 1H), 7.19 (m, 2H), 6.99 (d, J - 8.4 Hz, 2H), 4.96 (s, 2H), 4.05 (q, J = 7, 2 Hz, 2H), 4.00 (s, 3H), 3.91 (q, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.77 (m, 2H), 3 69 (m, 2H), 3.61 (m, 4H), 1.2 (t, J = 7.2 Hz, ZN), 1.12 (t, J = 6.4 Hz, ZN).

 1,3-Diethyl-7-methyl-8 - [(E) -2- (4- {2-oxo-2- [4- (6-phenylpyrimidin-3-yl) piperazine-

1-yl] ethoxy} phenyl) vinyl] -3,7-dihydropurin-2,6-dione ld.13 = (1.3.11). LC MS: found 621 (M + 1); calculated 621 (M + 1). Ή NMR (DMSO-D6, 400 MHz) 5: 8.03 (d, J = 7.2 Hz, 2H), 7.98 (d, J = 10 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 15.2 Hz, 1H), 7.49 (m, 3H), 7.41 (m, 1H), 7, 19 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 2H), 4.98 (s, 2H), 4.06 (m, 2H), 4.00 (s, 3H) 3.91 (m, 2H); 3.78 (m, 2H); 3.65 (m, 6H); 1.25 (m, 3H); 1.18 (m, 3H).

 8 - {(E) -2- [4- (2- {4- [3- (3,4-Dimethoxyphenyl) - [1,2,4] oxadiazol-5-ylmethyl] piperazin-1-yl} -2 -oxoethoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione ld.14 = (1.3.12). LC MS: Found 685 (M + 1); Calculated 685 (M + 1). Ή NMR (DMSO-D6, 400 MHz) 5: 7.70 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 12.4 Hz, 2H), 7.48 (s, 1H), 7.17 (d, J = 15.6 Hz, 1H), 7.12 (d, J - 9.2 Hz, 1H), 6.95 (d, J = 8 Hz, 2H), 4 88 (s, 2H), 4.02 (m, 7H), 3.91 (m, 2H), 3.82 (m, 6H), 3.50 (m, 4H), 2.61 (m, 2H), 2.53 (m, 2H), 1.25 (m, 3H), 1.10 (m, 3H).

 2- {4 - [(E) -2- (1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl) vinyl] - 2-methoxyphenoxy} -T - (3,4,5-trimethoxyphenyl) acetamide ld.15 = (1.3.13). LC

MS: found 564 (M + 1), calculated 564 (M + 1). Ή NMR (DMSO-D6, 400 MHz) δ: D9.98 (br, 1H), 7.68 (m, 3H), 7.1 1 (m, 5H), 4.71 (s, 2H), 3 99 (m, 6H), 3.71 (m, UN), 1.23 (m, ZN), 1.10 (m, ZN).

 2- [4 - [(1,3-Diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purin-8-yl) ethynyl] -

2-methoxyphenoxy] acetamide, (1.4.2). LCMS (M + 1) 426 Ή NMR (DMSO-D6, 400 MHz) 5 1.22 (t, Ji = 7.00, J ₂ = 2.88, 6Н), 3.84 (t, Ji = 9.40, J ₂ = 0.25, ЗН), 3.95 (d, J = 13.35, ЗН), 4.02 (d, J = 7.06, 4Н), 4.55 (t, J, = 15.10, J ₂ = 0.17, 2Н), 6.96 (m, 1Н), 7.03 (t, J, = 2.00, J ₂ = 0.72, W), 7.15 (d, J = 8.00, 1H), 7.42 (t, J, = 2.60, J ₂ = 1.33, 2H).

2- [4 - [(1,3-Dieth1-2,3,6 ^ -tetrahydro-7-meths1-2,6-dioxo-1Н-purine-8-1) ethyn11-2-methoxyphenoxy] - methyl acetamide (1.4.3). LCMS (M + 1) 440 Ή NMR (DMSO-D6, 400 MHz) 5 1.23 (t, Ji = 7.00, J ₂ = 2.88, 6Н), 2.68 (d, J = 14.23, ЗН), 3.84 (t, J ] = 9.40, J ₂ = 0.25, ZN), 3.95 (d, J = 13.35, ЗН), 4.05 (d, J = 7.06, 4Н), 4.45 (t, J, = 14.00, J ₂ = 0.23, 2Н), 6.97 (m, 1Н), 7.03 (t, = 2.00, J ₂ = 0.72, 1H), 7.13 (d, J = 8.00, 1H), 7.85 (m, 1H).

1- [[4 - [(1,3-Dietes1-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purin-8-yl) ethynyl] -2-methoxyphenoxy] acetyl ] piperazine (1.4.4). LCMS (M + 1) 495 Ή NMR (DMSO-D6, 400 MHz) 5 1.23 (t, J, = 7.00, J ₂ = 2.88, 6H), 2.82 (m, 2H), 2.98 (m, 2H), 3.27 (m, 2H), 3.35 (m, 2H), 3.68 (m, 1H), 3.84 (t, J, = 9.40, J ₂ = 0.25, ЗН), 3.95 (d, J = 13.35, ЗН), 4.04 ( d, J = 7.06, 4H), 4.73 (t, J] = 14.00, J ₂ = 0.23, 2H), 6.96 (m, 1H), 7.03 (t, J, = 2.00, J ₂ = 0.72, 1H), 7.13 (d, 1 = 8.00, 1H).

2- [4 - [(1,3-diethyl-2,3, 6, 7-tetrahydro-7-methyl-2, 6-dioxo-Ш-purin-8-yl) ethynyl] - 2-methoxyphenoxy] -M -3-pyridinyl acetamide (1.4.5). LCMS (M + 1) 503 Ή NMR (DMSO-D6, 400 MHz) 5 1.22 (t, J, = 7.00, J ₂ = 2.88, 6Н), 3.84 (t, = 9.40, J ₂ = 0.25, ЗН), 3.95 (d, J = 13.35, ЗН), 4.06 (d, J = 7.06, 4Н), 4.58 (m, 2Н), 6.97 (m, 2Н), 7.03 (t, J, = 2.00, J ₂ = 0.72, W), 7.13 (d, J = 8.00, 1H), 7.32 (m, 1H), 8.32 (t, J, = 7.70, J ₂ = 1.30, 1H), 8.39 (d, J = 4.60, W), 8.60 (m, 1H).

Example 6. The study of the antagonistic activity of compounds of General formula 1 and their pharmaceutically acceptable salts with respect to the adenosine A ₂ d receptor. The antagonistic activity of the new compounds of general formula 1 and their pharmaceutically acceptable salts with respect to the adenosine A _2A receptor was carried out ex vitro in a functional test on cells. In the experiment, cells of the ValiScreen cell line line (PerkinElmer, USA) expressing the recombinant human Adenosine receptor type A ₂ d were used. When the receptors are stimulated in these cells with a CGS 21680 agonist (Tocris), adenylate cyclase is activated, which, in turn, leads to an increase in synthesis intracellular cyclic adenosine monophosphate (cAMP). The amount of cAMP was determined using LANCE technology (LANCE Ultra cAMP kit, PerkinElmer). By the ability of the test compounds to reduce the amount of cAMP synthesized in the presence of CGS 21680, their antagonistic activity was evaluated. The KW 6002 antagonist (Axon Medchem, Netherlands) described in the literature was used as a standard (comparison compound).

Cells were cultured in DMEM (PanEco, Russia) supplemented with 10% FBS (Biological Industries), a mixture of penicillin / streptomycin (PanEco) and G418 (Sigma) at a temperature of 37 ° С in an atmosphere of 5% С0 ₂ . Before the experiment, the cells were removed from the culture vial with Versen's solution (PanEco) and suspended in SB2 buffer (Hanks medium + 5 mM HEPES (pH 7.4) + 0.1% BSA + 200 uM Ro-20-1734 + 2U / mL ADA (adenosine deaminase)) until a density of 0.2 million cells per milliliter. ULight ™ -anti-cAMP Antibody (PerkinElmer) was added 1: 150 (v / v) to the cell suspension and this mixture was poured into white 384-well plates (PerkinElmer), 5 μl (1000 cells) per well.

 Test compounds were dissolved in DMSO to a concentration of 6.32 mM and 3.16-fold serial dilutions in DMSO were prepared. The prepared serial dilutions were diluted 50 times with SB 1 buffer solution (Hanks medium + 5 mM HEPES (pH 7.4) + 0.1% BSA). The resulting solutions of the compounds in SB1 buffer were mixed in a 1: 1 ratio with a solution of CGS 21680 (12.64 nM), previously prepared in SB3 buffer (SB 1 + 0.1% Pluronic F127). The resulting mixtures of test compounds with an agonist were added (5 μl in duplicates) to plate wells containing 5 μl of cells (as described above) and the plates were incubated for 30 minutes at room temperature. Each plate also contained 16 wells for each control (MAX and MIN). MAX - cells with 3.16 nM CGS 21680 (agonist concentration corresponding to ECad, that is, a concentration that causes 90% cell activity); the signal from these wells was used in the calculations as 100% activity (0% inhibition). MIN - cells with a mixture of 3.16 nM CGS 21680 and 2 μM KW 6002 (antagonist concentration corresponding to 1Cuo, that is, a concentration that causes 100% inhibition of cell activity); the signal from these wells was used in the calculations as 0% activity (100% inhibition). In addition, each plate contained wells (in 4 repetitions), where the cells were treated with an agonist (CGS 21680) at different concentrations. The final concentration of DMSO in all wells was 1%.

 The cAMP formed in the cells was quantified using the LANCE Ultra cAMP kit (PerkinElmer, USA), in accordance with the methodology recommended by the manufacturer. The fluorescent signal was measured on a Victor3V instrument (PerkinElmer) equipped with a built-in LANCE High Count software.

 The apparent affinity of the test compounds was determined by the formula:

K _{ = 1C ₅₀ 1 (\ + b1Ko),

where ICso is the concentration of the antagonist at which the activity of adenylate cyclase is 50% of the maximum, L is the concentration of CGS 21680, at which measurements (3.16 nM) and ^ is the apparent affinity constant of CGS 21680, quantitatively corresponding to the value of £ C ₅₀ (concentration of half-maximal cell stimulation) for CGS 21680 and determined from the stimulation curves of cAMP accumulation in cells at different agonist concentrations.

 Table 1 presents data on the activity of K; some representatives of the compounds of general formula 1.

Example 7. Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A A _2A , A ₂ B And AZ receptors. Radioligand interaction analysis of compounds of general formula 1 with adenosine Ai, d A _2, A ₂ and As receptors was performed to determine the selectivity of the reaction of compounds of general formula 1 to the adenosine A ₂ receptor d. When determining the interaction of the studied compounds with the adenosine A ₂ d receptor, membrane preparations were used, obtained from human kidney embryonic cells expressing the recombinant human A _2A receptor. Receptor expression was 7 pmol / mg protein. As the radioligand, [ ³ H] CGS 21680 was used at a concentration of 0.05 μM. Solutions of the test compounds were prepared as described in the functional test procedure, with the difference that instead of SB 1, a buffer of the following composition was used: 50 mM Tris-HCl, pH 7.4, 10 tM MgCl ₂ , 1 tM EDTA, 2 U / mL Adenosine Deaminase. Membrane preparations were incubated in the presence of a mixture of test compounds and [H] CGS 21680 for 90 min at 25 ° C and the mixtures were filtered on GF glass fiber filters (Millipor, USA). The radioactivity on the filters was determined using a MicroBeta liquid-oscillation counter (PerkinElmer, USA). Nonspecific binding was measured in the presence of 50 μM NECA, which was not more than 15% of the total binding. The affinity of the tested compounds was determined by the formula:

where 1С ₅ о is the concentration of the antagonist at which the binding of [ ³ H] CGS 21680 is reduced to 50% of the maximum, L is the concentration of [ ³ H] CGS 21680, at which measurements are taken (50 pM) and K _D is the affinity constant [ ³ H] CGS 21680, quantitatively corresponding to the EC50 value (half-maximum binding concentration) for [ ³ H] CGS 21680, and determined from the curves of radioactive binding at different concentrations of [ ³ H] CGS 21680 Ko = 64 nM). Interactions were similarly studied. new compounds of General formula 1 with adenosine A A ₂ b and A ₃ receptors, under the conditions described below.

 Table 3.

 Table 4.

Receptor 200510 Adenosine A _2B 200610 Adenosine A ₃

 Human recombinant cells HEK-293 cells Human recombinant cells CHO- 1 cells

Ligand 1.6 nM [.H] MRS 1754 0.5 nM [... I] AB-MECA

 Medium l% DMSO l% DMSO

 Hatching 90 minutes @ 25. C 60 minutes @ 25. C

time / temperature

 inhibition inhibition criterion

Radioligand interaction analysis of compounds of general formula 1 with adenosine Ai, d A _2, A ₂ and A ₃ receptors demonstrated their high selectivity towards the adenosine A _2A receptor (Table 2).

 Industrial applicability

 The invention can be used in medicine, biochemistry and veterinary medicine.

Claims

Claim 1. Substituted phenoxyacetic acids, their esters and amides, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl moiety, of the general formula 1, as well as their pharmaceutically acceptable salts,

wherein Rl, R2 and R3, optionally simultaneously represent hydrogen, C \ - C ₅ alkyl, C ₃ -C ₅ alkenyl, or C ₃ -C ₅ alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, Ci-Szalkyl,

C ₃ alkyloxy; R5 represents hydrogen, C] -C ₃ alkyl, the group —C (0) R6; R6 is hydroxyl, GHS ₅ alkyloxy, C ₃ -C alkenyloxy, C ₃ - C _b alkynyloxy, optionally substituted amino, wherein the substituents, optionally identical, are selected from hydrogen, C1-C ₅ alkyl, optionally substituted mono- or dialkylamino, alkoxy , 5-6 membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen; pyridyl, phenyl optionally substituted with 1-3 methoxy groups; or optionally substituted 6-membered, optionally annelated with a 5-membered unsaturated heterocycle, saturated heterocyclyl containing 2 nitrogen atoms, where the substituents are selected from C] -C ₅ alkyl optionally substituted with a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from nitrogen and oxygen; or a 6-membered optionally saturated heterocyclyl containing 1 to 2 nitrogen atoms, optionally substituted with C1-C5 alkyl, oxo, optionally substituted phenyl;  the dashed line with the solid line accompanying it () represents a single, double or triple bond; SUBSTITUTE SHEET (RULE 26) excluding {4- [2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy} acetic acid and ethyl {4- [2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy} ester ester. 2. The compounds according to claim 1, which are phenoxyacetic acids, their esters and amides, including a 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment, the general form

where Rl, R2, R3, R4, R5, R6 and the dashed line with the solid line accompanying it  () have the meanings indicated for the compounds of general formula 1.  3. The compounds according to claim 1, which are phenoxyacetic acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl fragment, General form

where R6 has the meaning indicated for the compounds of general formula 1, and R4 represents hydrogen or a methoxy group.  4. The compounds of claim 1, which are: methyl ester {5 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1.1.1, {4 - [(E) -2- (1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2-methoxyphenoxy} acetic acid 1.2.0 (1),  {4 - [(E) -2- (1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy} acetic acid 1.2.0 (2)  2- (4- (2- (1, Zdiethyl-7methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) ethyl) phenoxy) acetic acid methyl ester 1.2.0 (3)  2- (4- (2- (1, 3 diethyl-7methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-yl) ethyl) phenoxy) acetic acid 1.2.0 (four),  {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy methyl ester } acetic acid 1.3.2,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] phenoxy } acetamide 1.3.3,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -Y, Y-di- (2-methoxyethyl) acetamide 1.3.4,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - K- (2-dimethylaminoethyl) -Y-methyl acetamide 1.3.5,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - - (3-morpholin-4-ylpropyl) acetamide 1.3.6,  1,3-diethyl-8 - ((E) -2- {4- [2- (4-isopropylpiperazin-1-yl) -2-oxoethoxy] phenyl} vinyl) - 7-methyl-3,7-dihydropurin- 2,6-dione 1.3.7,  1, 3-diethyl-7-methyl-8 - [(E) -2- (4- {2-oxo-2- [4- (1, 3, 6-trimethyl-2,4-dioxo-1, 2 3,4-tetrahydro-pyrimidin-5-yl) piperazin-1-yl] ethoxy} phenyl) vinyl] -3,7-dihydropurin-2,6-dione 1.3.9,  1,3-diethyl-8 - {(E) -2- [4- (2- {4- [6- (2-methoxy-5-fluorophenyl) pyrimidin-4-yl] piperazin-1-yl} -2 -oxyethoxy) phenyl] vinyl} -7-methyl-3,7-dihydropurin-2,6-dione 1.3.10,  1,3-diethyl-7-methyl-8 - [(E) -2- (4- {2-oxo-2- [4- (6-phenylpyrimidin-3-yl) piperazin-1-yl] ethoxy} phenyl ) vinyl] -3,7-dihydropurin-2,6-dione 1.3.11,  8 - {(E) -2- [4- (2- {4- [3- (3,4-dimethoxyphenyl) - [1,2,4] oxadiazol-5-ylmethyl] piperazin-1-yl} -2 -oxyethoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione 1.3.12. 2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} - - (3,4,5-trimethoxyphenyl) acetamide 1.3.13, {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2- chlorophenoxy} acetic acid 1.3.14,  {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2- methoxyphenoxy} acetic acid 1.3.15,  methyl ester {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1.3.16,  isopropyl ether {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetic acid 1.3.17,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} acetamide 1.3.18,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -M-methylacetamide 1.3.19,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] - 2-methoxyphenoxy} -M-ethylacetamide 1.3.20,  2- {4 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) - vinyl] -2-methoxy-phenoxy} -K, 1hG-dimethylacetamide 1.3.21,  [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] acetic acid ethyl ester 1.4 .one,  [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] acetamide 1.4.2,  [4- (1, 3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8-yl-ethynyl) -2-methoxyphenoxy] -M-methylacetamide 1.4.3  1,3-diethyl-8- [3-methoxy-4- (2-oxo-2-piperazin-1-yl-ethoxy) phenylethynyl] -7-methyl-3,7-dihydropurin-2,6-dione 1.4. four,  [4- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-ethynyl) -2-methoxyphenoxy] - pyridin-3 -yl acetamide 1.4.5. 5. Antagonists of the adenosine A ₂ d receptor, which are substituted phenoxyacetic acids, their esters and amides, including a 2,6-dioxo-2,3,6,7-tetrahydro-S-purin-8-yl fragment, of General formula 1, or their pharmaceutically acceptable salts according to any one of paragraphs 1 to 4. 6. The drug source for the preparation of pharmaceutical compositions and medicines having the properties of an A ₂ d receptor antagonist for the prevention and treatment of diseases of the central nervous system, such as cognitive disorders, Parkinson's disease, depression, tumor diseases and inflammatory processes, which is an antagonist according to claim 5. 7. A tool (adjuvant) for enhancing the immune response or the action of drugs in the combinatorial treatment of diseases mediated by the action of the antagonist A ₂ d receptor, including oncological, which is an antagonist according to claim 5. 8. A pharmaceutical composition having antagonistic activity to the adenosine A _2A receptor, comprising the drug principle of claim 6 or the agent (adjuvant) of claim 7 in a therapeutically effective amount. 9. A method for selectively inhibiting the activity of an adenosine A ₂ d receptor, which comprises contacting a sample containing an adenosine A _2A receptor with an antagonist of the adenosine A ₂ d receptor according to claim 5. 10. A drug with antagonistic activity against the adenosine A ₂ d receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package intended for the prevention and treatment of diseases of the central nervous system, such as cognitive disorders, Parkinson's disease, or depression, neoplastic diseases, inflammatory processes, which includes the drug substance according to claim 6 or the agent (adjuvant) according to claim 7, or the pharmaceutical composition according to claim 8, to a therapist nical effective amount.  1 1. The drug of claim 10 for the prevention and treatment of Parkinson's disease.  12. The drug of claim 10 for the prevention and treatment of cognitive disorders.  13. The drug of claim 10 for the prevention and treatment of depression.  14. The drug of claim 10 for the treatment of inflammatory processes. 15. A method for the prevention and treatment of diseases mediated by the action of the antagonist A ₂ d receptor, which consists in the introduction of a pharmaceutical patient a composition according to claim 8 or a drug according to any one of claims 10-14, in a therapeutically effective amount.