RU2480469C1 - Substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydropurine-2,6-diones - antagonists of adenosine a2a receptor and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydropurine-2,6-diones of general formula 1, which exhibit antagonist activity on adenosine A_2A receptors. The compounds can be used as an active source of a medicinal agent or adjuvant for pharmaceutical compositions and medicinal agents. The invention also relates to a method of inhibiting and a method of treating diseases of the central nervous system, oncological, viral and bacterial diseases which are mediated by adenosine A_2a receptor activity. In general formula 1

, where: Ar is 2,5-dimethoxyphenyl, 4-isobutoxy-3-methoxyphenyl, 3-phenoxyphenyl substituted with pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, C₁-C₅alkoxy group, amino group, optionally substituted with a mono- or di-C₁-C₅alkyl; 3-methylthiophen-2-yl, pyrazol-4-yl, substituted with C₁-C₅alkyl; 2,3-dihydro-benzo[1,4]dioxin-6-yl, optionally substituted with C₁-C₅alkoxycarbonyl, carbamoyl, which is optionally substituted with mono- or di-C₁-C₅alkyl, or carbonyl-piperazine, optionally substituted with C₁-C₅alkyl.

EFFECT: improved properties.

13 cl

Description

This invention relates to new compounds - substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione, exhibiting antagonistic activity against adenosine A _2A receptors, to their use as a medicinal agent and as an adjuvant for pharmaceutical compositions, drugs and to methods for treating diseases of the central nervous system, oncological, viral and bacterial diseases and inflammatory processes.

A _2A receptors are one of 4 subtypes (A ₁ , A _2A , A _2B and A ₃ ) of adenosine receptors. A ₁ 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 A ₁ and A ₃ receptors causes a decrease in cAMP level [Jockers R., Linder ME, Hoehnegger MJ 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 BB Mol. Pharmacol 20006 58, 771. Bruns RF, Lu GH, Pugsley TA Mol. Pharmacol 1986, 29, 331.]. In addition, stimulation of A ₁ receptors causes potassium activation and calcium channel deactivation [Iredale PA, Alexander SPH, Hill SJ Br. J. Pharmacol. 1994, 111, 1252. Bunemann M., Pott LJ Physiol. 1995, 482, 81.], and stimulation of A _2A 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 works 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 _2A receptor antagonists for Parkinson's disease. Expert Opinion on Investigational Drugs, 2009, 18 (11), 1619-1631).];

various kinds of depression [El Yacoubi M, Costentin J, Vaugeois JM (December 2003). "Adenosine A2A receptors and depression." Neurology 61 (11 Suppi 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.2008.01.01.012. 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/v13/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 (II): 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, adenosine has been shown to accumulate near tumor tissue [BIay 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-A ₁ / 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, by binding to type A _2A 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, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia. din 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. KK, Huang X., Caldwell S., Liu K., Patrick Smith P ., Chen J.-F., Jackson E. K, Apasov S., Abrams S., Sitkovsky M. A _2A adenosine receptor protects tumors from antitumor T cells. Proc Nati 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 has been proposed to enhance the effectiveness of anticancer vaccines using an adjuvant that inhibits the A _2A adenosine receptor [Ohta A., Sitkovsky M. METHODS AND COMPOSITIONS FOR IMPROVING IMMUNE RESPONSES, WO 2008/147482 December 4, 2008].

A large number of A _2A 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] -1-piperazinyl] -2- (2-furanyl) - [1,2,4] triazolo [1,5-α] [1,3,5] 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) -1-propargylxanthine;

- KW-6002: (E) 1,3-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 activity and selectivity 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 _2A receptors is one of the main directions in the creation of 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 active substances - antagonists of A _2A receptors, pharmaceutical compositions and drugs, as well as methods for their preparation and use, is relevant.

,

,

, где

и

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

и

вместе с атомом N, с которым они связаны, образуют через

и

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, метоксикарбонилметил, бензилоксикарбонилметил и пиридилметилоксикарбонилметил. Предпочтительными алкенильными группами являются этенил, пропенил, н-бутенил, изо-бутенил, 3-метилбут-2-енил, н-пентенил и циклогексилбутенил.The following are the 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. The 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 a 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, heterocyclylalkyloxyalkyloxycarboxyloxyloxycarbonyl

,

,

where

and

independently, they are “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or

and

together with the N atom with which they are bonded, form through

and

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, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine. 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.

где

и

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

и

вместе с атомом N, с которым они связаны, образуют через

и

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, метоксикарбонилметил, этоксикарбонилметил, бензилоксикарбонилметил метоксикарбонилметил и пиридилметилоксикарбонилметил. 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. 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, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroaryl heterocyclenyl, annelated heteroaryl heterocyclyl, annelated aero cycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, or geteroaralkiloksikarbonil

Where

and

independently, they are “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or

and

together with the N atom with which they are bonded, form through

and

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, methoxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethoxymethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethoxymethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonylmethyloxycarbonyl . 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.

где

и

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

и

вместе с атомом N, с которым они связаны, образуют через

и

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, метоксикарбонилметил, бензилоксикарбонилметил и пиридилметилоксикарбонилметил. Предпочтительными алкенильными группами являются этенил, пропенил, н-бутенил, изо-бутенил, 3-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, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonylalkyl, a

Where

and

independently, they are “amino substituents”, the meanings of which are defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or

and

together with the N atom with which they are bonded, form through

and

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, methoxycarbonylmethyl, benzyloxycarbonylmethylmethyl and pyridine. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 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, iso-propoxy and n-butoxy.

замещенную или незамещенную «заместителем аминогруппы»,

и

значение которых определено в данном разделе, например, амино (H₂N-), метиламино, диэтиламино, пирролидино, морфолино, бензиламино или фенетиламино.“Amino group” means

substituted or unsubstituted by “amino substituent group”,

and

the meanings of which are defined in this section, for example, amino (H ₂ N-), methylamino, diethylamino, pyrrolidino, morpholino, 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 “cyclic system 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. Representatives of heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, 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 of 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, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, geterotsiklilaminokarbonil, alkylaminothiocarbonyl, arylaminothiocarbonyl, heteroarylaminothiocarbonyl, heterocyclylaminothiocarbonyl, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl annelated heteroaryl heterocyclyl annelirs arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated arylheterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl. The meaning of “amino group substituents” is defined in this section.

или

где

и

представляют собой независимо друг от друга «заместители аминогруппы», значение которых определено в данном разделе, например, водород, необязательно замещенный алкил, необязательно замещенный арил, необязательно замещенный аралкил, или необязательно замещенный гетероаралкил, или заместитель

в котором

может быть ацил или ароил, а значение

определено выше, или «заместителями циклической системы» являются

или

в которых

и

вместе с атомом азота, с которым они связаны, образуют через

и

4-7-членный гетероциклил или гетероцикленил."Substituent cyclic system" means a substituent attached to an aromatic or non-aromatic cyclic system, including hydrogen, alkylalkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro , cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, arylalkyloxyalkyl, heterocyclylalkyloxyalkyl, alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, finil, arylsulfinyl, geterotsiklilsulfinil, alkylthio, arylthio, heterocyclylthio, heterocyclylthio, alkylsulfonylalkyl, arylsulfonylalkyl, geterotsiklilsulfonilalkil, alkylsulfinylalkyl, arylsulfinylalkyl, geterotsiklilsulfinilalkil, alkylthioalkyl, arylthioalkyl geterotsikliltioalkil, arilalkilsulfonilalkil, geterotsiklilalkilsulfonilalkil, arilalkiltioalkil, geterotsiklilalkiltioalkil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, amidino,

 or

 Where

 and

 independently represent “amino substituents”, the meanings of which are defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, or a substituent

 wherein

 maybe acyl or aroyl, and the value

defined above, or “cyclic system substituents” are

 or

 in which

 and

 together with the nitrogen atom with which they are bound, form through

 and

 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, cognitive, executive and creative abilities, orientation in time and space, in particular cognitive Alzheimer's, Parkinson's and Huntington's disease disorders; 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 substance” (drug substance, drug 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, injections, ointments and other formulations, intended to restore, correct or alter the physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.

"Ligands" are chemicals (small molecule, inorganic ion, peptide, protein, etc.) that can interact with receptors that transform this interaction into a specific signal.

“Neurodegenerative disease (ND)” 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 mnestic disorders, mania (hypomania, graphomania, kleptomania, shop-mania, persecution mania, monomania, pornography, erotomania, etc.); Disorder of multiple personality, amentia, delirium tremens, delirium, delusional syndrome, hallucinatory syndrome, hallucinations, hallucination, tomitsidomaniyu, delirium, illusion querulant, clinical lycanthropy, macropsia, Manichean delusions micropsia, drug addiction, anorexia nervosa, oneiroid syndrome, paronoid, paranoia , paraphrenia, pseudo-hallucinations, psychosis, Cotard's syndrome, schizoaffective disorder, schizotypal disorder, schizophrenia, schizophrenia-like disorder, schizophrenomorphic disorder, Schreber syndrome, Daniel Pau la); 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, Asperg's syndrome , Rett syndrome, Fregoli syndrome, attention deficit hyperactivity disorder, obsessive states syndrome, chronic anesthesia effects syndrome, mental automatism syndrome, early childhood syndrome tizma, madness, taphophilia, anxiety, Hikikomori syndrome, erotografiyu, 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” are biological macromolecules located on the cytoplasmic membrane of a cell or intracellularly, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal of this interaction into a specific cellular response.

A “therapeutic cocktail” is a simultaneously administered combination of two or more drugs with a different mechanism of pharmacological action and aimed at different biological targets involved in the pathogenesis of the disease.

"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 perceiving agents, agents deliveries 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, such as 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.

“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.

The subject of this invention is substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-diones of the general formula 1, as well as their pharmaceutically acceptable salts

where Ar is 2,5-dimethoxyphenyl; 4-isobutoxy-3-methoxyphenyl; 3-phenoxyphenyl substituted with pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, C ₁ -C ₅ alkoxy, an amino group optionally substituted with mono- or di-C ₁ -C ₅ alkyl; 3-methylthiophen-2-yl; pyrazol-4-yl substituted with C ₁ -C ₅ alkyl; 2,3-dihydro-benzo [1,4] dioxin-6-yl optionally substituted with C ₁ -C ₅ alkoxycarbonyl, carbamoyl optionally substituted with mono- or di-C ₁ -C ₅ alkyl, or carbonyl piperazine, optional substituted C ₁ -C ₅ alkyl.

According to this invention, more preferred compounds are:

8 - [(E) -2- (2,5-dimethoxyphenyl) vinyl] -1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.1,

8 - [(E) -2- (4-isobutoxy-3-methoxyphenyl) vinyl] -1.3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.2,

8 - [(E) -2- (3-methylthiophen-2-yl) vinyl] -1.3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.4,

8 - [(E) -2- (1,3-dimethylpyrazol-4-yl) vinyl] -1.3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.5,

6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl) -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid methyl ester of formula 1.6,

6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl) -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid methylamide of the formula 1.7,

6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl) -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid dimethylamide of the formula 1.8,

6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl) -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid diethylamide of the formula 1.9,

1,3-diethyl-7-methyl-8 - {(E) -2- [2- (piperazin-1-carbonyl) -2,3-dihydro-benzo [1,4] dioxin-6-yl vinyl} -3,7-dihydro-purin-2,6-dione of the formula 1.10,

1,3-diethyl-7-methyl-8 - {(E) -2- [2- (4-methylpiperazin-1-carbonyl) -2,3-dihydro-benzo [1,4] dioxin-6-yl- vinyl} -3,7-dihydro-purine-2,6-dione of the formula 1.11,

8 - {(E) -2- [3- (4-dimethylaminophenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.12,

8 - {(E) -2- [3- (4-dimethylaminophenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.13,

8 - {(E) -2- [3- (4-pyrrolidin-1-ylphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.14 ,

8 - {(E) -2- [3- (4-piperidin-1-ylphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.15 ,

8 - {(E) -2- [3- (4-morpholin-4-ylphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.16 ,

8 - {(E) -2- [3- (4-piperazin-1-ylphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.17 ,

8 - {(E) -2- [3- (4-methoxyphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.18,

8 - {(E) -2- [4-methoxy-3-phenoxyphenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydro-purin-2,6-dione of the formula 1.19,

8 - {(E) -2- [6-methoxy-3-phenoxyphenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione of the formula 1.20,

8 - {(E) -2- [6-methoxy-3- (4-methoxyphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.21 ,

8 - {(E) -2- [4-methoxy-3- (4-methoxyphenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.22 ,

8 - {(E) -2- [6-methoxy-3- (4-dimethylaminophenoxy) phenyl] vinyl} -1.3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione of the formula 1.23 ,

The subject of this invention is a method for producing substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione of general formula 1 by acylation of 5,6-diamino-1H-pyrimidin-2, 4-diones of general formula 2 with acids of general formula 3 in the presence of appropriate reagents, for example, O- (benzotriazol-1-yl) -N, N, N`, N`-tetrahydruronium tetrafluoroborate or 1-hydroxybenzotriazole N- (3- (dimethylamino ) propyl) -N`-ethylcarbodiimide, cyclization of the resulting compounds of general formula 4 into purines of general formula 5 and methylation of the latter into target products of general formula 1

where Ar has the above meaning.

The subject of this invention is new antagonists of the adenosine A _2A receptor, which are the preparation of substituted 1.3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-dione of general formula 1 and 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 _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 a recombinant human adenosine aza type receptor were used.

Table 1 presents data on the activity of K _i for some of the compounds of General formula 1, confirming their high antagonistic activity against the adenosine A _2A receptor. It was unexpectedly discovered that the activity of new compounds is 1.3-10 times higher than the activity of the known analogue KW-6002.

Table 1 Antagonistic activity (K _i ) of compounds of the general formula 1 with respect to the adenosine A _2A receptor in a functional test on cells Connection No. K _i , nM 1.1 0.4 1.2 1.4 1.4 1.7 1.5 3.2 1.6 0.9 1.7 2,8 1.13 2.3 1.18 1.1 1.23 0.7 KW-6002 4.0

The subject of this invention is the compounds of 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, bacterial diseases and inflammatory processes 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 diseases mediated by the action of an A _2A receptor antagonist, including cancer.

The subject of this invention is a pharmaceutical composition having antagonistic activity with respect to the adenosine A _2A receptor, comprising, as a drug principle (substance) or agent (adjuvant), compounds of the general formula 1 or their pharmaceutically acceptable salts 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 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.

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 source (substance) or agent (adjuvant) 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 the compounds of general formula 1 with adenosine A ₁ , A _2A , A _2B and A ₃ receptors was performed.

The radioligand analysis of the interaction of compounds of general formula 1 with adenosine A ₁ , A _2A , A _2B and A ₃ receptors showed their higher activity and selectivity with respect to the adenosine A _2A receptor than the known prototype KW-6002 (Table 2).

table 2 The activity and selectivity of certain ligands of the general formula 1 and prototype KW-6002 under conditions of radioligand analysis with respect to adenosine A ₁ , A _2A , A _2B and A ₃ receptors Ligand Adenosine receptor activity (K _i , nM) Selectivity for adenosine A _2A receptor A ₁ A _2A A _2B A ₃ A ₁ / A _2A A _2B / A _2A A ₃ / A _2A KW-6002 2,48E-06 5.64E-08 1.92E-06 9.25E-06 44 34 164 1.1 1.30E-06 2.58E-08 4.42E-06 8.53E-06 53 99 543 1.6 1.95E-06 9.38E-09 7.69E-06 7.52E-06 216 474 1323 1.7 3.39E-06 5.02E-08 1.52E-05 1.66E-05 70 174 546

The subject of this invention is a method for selectively inhibiting the activity of an adenosine A _2A receptor, comprising contacting a sample containing an adenosine A _2A receptor with a composition comprising an adenosine A _2A receptor antagonist, which is a compound of general formula 1, or a pharmaceutically acceptable salt thereof.

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, including Parkinson's disease, cognitive disorders , depressions, oncological, viral, bacterial diseases and inflammatory processes in humans and warm-blooded animals, which includes a new drug an essential principle (substance) of the general formula 1 or a pharmaceutical composition in a therapeutically effective amount.

In accordance with this invention, a method for the prevention and treatment of diseases mediated by the action of an A _2A receptor antagonist, including diseases of the central nervous system, oncological diseases, inflammatory processes and sepsis in animals and humans, consists in administering 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 agent of 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 must be taken into account, with each dosage unit containing 10 ~ 500 mg of an agent of general formula 1, preferably 50 ~ 300 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 invention is illustrated, but not limited to the following examples.

Example 1. Synthesis of compounds of general formula 1. To a solution of 1 mmol (198 mg) of 1,3-diethyl-5,6-diaminouracil 2 and 15 mmol of acid 3 in 8 ml of dimethylformamide was added 1.5 mmol (372 mg) of o- ( benzotriazol-1-yl) -N, N, N`, N`-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. Received with a yield of 26-92% amide 4, which (0.1 mmol) was suspended in 8 ml of methanol, 8 ml of a 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 was filtered off and purine 5 was obtained with a yield of 40-90%. The resulting purine 5 (0.44 mmol), 4 ml of dimethylformamide, 132 g (1 mmol) of calcined potassium carbonate and 2.2 mmol of methyl iodide were stirred for 2 hours at 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 silica gel layer, and the obtained filtrate was evaporated in vacuo. Received with the release of 30-70% purine of General formula 1. The results of the analysis of some purines of General formula 1 are presented in table 3.

Table 3 Connection No ¹ H NMR Spectra LC MS (M + 1) 1.1 ¹ H NMR DMSO-D6, 400 MHz) δ 7.90 (d, J = 15.6 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 16 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.93 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 4, 05 (q, J = 7.2 Hz, 2H), 4.02 (s, 3H), 3.90 (k, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3, 78 (s, 3H), 1.25 (t, J = 6.8 Hz, 3H), 1.12 (s, 3H). 385 1.2 ¹ H NMR DMSO-D6, 400 MHz) δ 7.60 (d, J = 15.6 Hz, 1H), 7.41 (s, 1H), 7.27 (d, J = 7.2 Hz, 1H ), 7.20 (d, J = 16 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.05 (q, J = 6.8 Hz, 2H), 4, 02 (s, 3H), 3.92 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.76 (d, J = 6.8 Hz, 2H), 2.03 ( sep, J = 6.4 Hz, 1H), 1.25 (t, J = 6.8 Hz, 3H), 1.12 (t, J = 6.4 Hz, 3H), 0.98 (d, J = 6.8 Hz, 6H). 427 1.4 ¹ H NMR DMSO-D6, 400 MHz) δ 7.77 (d, J = 16 Hz, 1H), 7.54 (m, 1H), 6.98 (m, 1H), 6.81 (d, J = 17.2 Hz, 1H), 4.05 (m, 2H), 3.99 (s, 3H), 3.90 (m, 2H), 2.34 (s, 3H), 1.25 (m , 3H), 1.12 (m, 3H) 345 1.5 ¹ H NMR DMSO-D6, 400 MHz) δ 8.11 (s, 1H), 7.46 (d, J = 15.6 Hz, 1H), 6.79 (d, J = 15.6 Hz, 1H ), 4.05 (q, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.90 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H ), 2.29 (s, 3H), 1.24 (t, J = 6.8 Hz, 3H), 1.12 (t, J = 6.8 Hz, 3H). 343 1.6 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.69 (d, J = 15.6 Hz, 1H); 7.15 (dd, J ₁ = 8.3 Hz, J ₂ = 1.8 Hz, 1H); 7.13 (d, J = 1.9 Hz, 1H); 7.05 (d, J = 8.3 Hz, 1H); 6.76 (d, J = 15.6 Hz, 1H); 4.91 (m, 1H); 4.45 (m, 2H); 441 4.23 (q, J = 7.0 Hz, 2H); 4.09 (q, J = 7.0 Hz, 2H); 4.04 (s, 3H); 3.85 (s, 3H); 1.39 (t, J = 7.0 Hz, 3H); 1.27 (t, J = 7.0 Hz, 3H) 1.7 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.68 (d, J = 16.0 Hz, 1H); 7.17 (s, 1H); 7.13 (d, J = 8.8 Hz, 1H); 6.97 (d, J = 7.8 Hz, 1H); 6.77 (d, J = 15.6 Hz, 1H); 6.59 (d, J = 2.4 Hz, 1H); 4.74 (d, J = 5.9 Hz, 1H); 4.59 (d, J = 11.5 Hz, 1H); 4.22 (q, J = 6.7 Hz, 2H); 4.09 (q, J = 6.9 Hz, 2H); 4.04 (s, 3H); 2.92 (d, J = 4.6 Hz 3H); 1.39 (t, J = 7.0 Hz, 3H); 1.25 (t, J = 7.0 Hz, 3H). 440 1.8 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.17 (s, 1H); 7.13 (d, J = 8.8 Hz, 1H); 6.97 (d, J = 7.8 Hz, 1H); 6.77 (d, J = 15.6 Hz, 1H); 6.59 (d, J = 2.4 Hz, 1H); 4.74 (d, J = 5.9 Hz, 1H); 4.59 (d, J = 11.5 Hz, 1H); 4.22 (q, J = 6.7 Hz, 2H); 4.09 (q, J = 6.9 Hz, 2H); 4.04 (s, 3H); 3.18 (s, 3H); 2.99 (s, 3H); 1.39 (t, J = 7.0 Hz, 3H); 1.25 (t, J = 7.0 Hz, 3H). 454 1.9 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.33 (d, J = 1.6 Hz, 1H); 7.32 (s, 1H); 7.10 (d, J ₁ = 8.3 Hz, 1H); 6.95 (d, J = 1.9 Hz, 1H); 6.92 (d, J = 8.3 Hz, 1H); 5.13 (d, J = 1.9 Hz, 1H); 4.15 (d, J = 1.9 Hz, 2H); 4.03 (d, J = 1.9 Hz, 2H); 4.01 (d, J = 1.9 Hz, 2H); 4.0 (s, 3H) 3.51 (d, J = 5.4 Hz, 2H); 3.53 (d, J = 4.7 Hz, 2H); 1.20 (d, J = 7.4 Hz, 3H); 1.22 (d, J = 7.7 Hz, 3H); 1.13 (d, J = 7.4 Hz, 3H); 1.16 (d, J = 7.7 Hz, 3H). 482 1.10 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.33 (d, J = 1.6 Hz, 1H); 7.32 (s, 1H); 7.10 (d, J, = 8.3 Hz, 1H); 6.95 (d, J = 1.9 Hz, 1H); 6.92 (d, J = 8.3 Hz, 1H); 5.13 (d, J = 1.9 Hz, 1H); 4.15 (d, J = 1.9 Hz, 2H); 4.03 (d, J = 1.9 Hz, 2H); 4.01 (d, J = 1.9 Hz, 2H); 4.0 (s, 3H) 3.68 (m, 1H); 3.34 (m, 2H); 3.35 (m, 2H); 2.88 (m, 2H); 2.90 (m, 2H); 1.20 (d, J = 7.4 Hz, 3H); 1.22 (d, J = 7.7 Hz, 3H) 495 1.11 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.33 (d, J = 1.6 Hz, 1H); 7.32 (s, 1H); 7.10 (d, J ₁ = 8.3 Hz, 1H); 6.95 (d, J = 1.9 Hz, 1H); 6.92 (d, J = 8.3 Hz, 1H); 5.13 (d, J = 1.9 Hz, 1H); 4.15 (d, J = 1.9 Hz, 2H); 4.03 (d, J = 1.9 Hz, 2H); 4.01 (d, J = 1.9 Hz, 2H); 4.0 (s, 3H); 3.34 (m, 2H); 3.35 (m, 2H); 2.88 (m, 2H); 2.90 (m, 2H); 2.25 (s, 1H); 1.20 (d, J = 7.4 Hz, 3H); 1.22 (d, J = 7.7 Hz, 3H). 509 1.12 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 2.98 (m, 3H); 2.96 (m, 3H); 1.25 (d, J = 7.45 Hz, 3H); 1.22 (d, J = 7.36 Hz, 3H). 460 1.13 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.36 (m, 4H); 1.25 (d, J = 7.45 Hz, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 488 1.14 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.22 (m, 4H); 2.03 (m, 4H); 1.25 (d, J = 7.45 Hz, 3H); 1.22 (d, J = 7.36 Hz, 3H). 486 1.15 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.08 (m, 4H); 1.52 (m, 4H); 1.46 (m, 1H); 1.25 (d, J = 7.45 Hz, 3P); 1.22 (d, J = 7.36 Hz, 3H). 500 1.16 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.66 (d, J = 3.64 Hz, 2H); 3.59 (d, J = 3.87 Hz, 2H); 3.26 (d, J = 4.64 Hz, 2H); 3.24 (d, J = 4.87 Hz, 2H); 1.25 (d, J = 7.45 Hz, 3H); 1.22 (d, J = 7.36 Hz, 3H). 502 1.17 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz. 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.36 (m, 4H); 3.13 (m, 4H); 2.66 (m, 1H); 1.25 (d, J = 7.45 Hz, 3H); 1.22 (d, J = 7.36 Hz, 3H). 501 1.18 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.65 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 447 1.19 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.93 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 447 1.20 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.70 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 447 1.21 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.70 (s, 3H); 3.60 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 477 1.22 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.95 (s, 3H); 3.70 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 477 1.23 ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (m, 1H); 7.33 (d, J = 1.6 Hz, 1H); 7.28 (m, 1H); 7.20 (m, 1H); 7.14 (s, 1H); 6.85 (d, J = 1.2 Hz, 1H); 6.83 (d, J = 0.6 Hz, 1H); 6.81 (d, J = 1.2 Hz, 1H); 6.17 (d, J = 0.3 Hz, 1H); 6.03 (s, 1H); 4.04 (d, J = 3.64 Hz, 2H); 4.02 (d, J = 3.71 Hz, 2H); 4.00 (s, 3H); 3.70 (s, 3H); 2.75 (s, 3H); 2.82 (s, 3H); 1.22 (d, J = 7.36 Hz, 3H); 1.16 (m, 6H). 490

Example 3. The study of the antagonistic activity of compounds of General formula 1 and their pharmaceutically acceptable salts in relation to the adenosine A _2A 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 type A _2A human adenosine receptor were used. When receptors are stimulated in these cells, a CGS 21680 agonist (Tocris) activates adenylate cyclase, which, in turn, leads to an increase in the synthesis of 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 37 ° C in an atmosphere of 5% CO ₂ . Before the experiment, the cells were removed from the culture vial with Versen's solution (PanEco) and suspended in SB2 buffer (Hanks + 5 mM HEPES (pH 7.4) + 0.1% BSA + 200 uM Ro-20-1734 + 2U / mL ADA ( adenosine deaminase)) to 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 the 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 SB1 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 (SB1 + 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 EC ₉₀ , 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 IC ₁₀₀ , 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:

,

,

where IC ₅₀ is the concentration of the antagonist at which adenylate cyclase activity is 50% of the maximum, L is the concentration of CGS 21680, at which measurements (3.16 nM) are carried out, and K _D is the apparent affinity constant of CGS 21680, quantitatively corresponding to the EC ₅₀ value (concentration of half-maximal stimulation cells) for CGS 21680 and determined from the curves of stimulation of cAMP accumulation in cells at different agonist concentrations. Table 1 presents data on the activity of K _i some representatives of the compounds of General formula 1.

Example 4. Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A ₁ , A _2A , A _2B and A ₃ receptors. A radioligand analysis of the interaction of compounds of general formula 1 with adenosine A ₁ , A _2A , A _2B and A ₃ receptors was performed to determine the selectivity of the interaction of compounds of general formula 1 with an adenosine A _2A receptor. When determining the interaction of the studied compounds with the adenosine A _2A receptor, membrane preparations were used that were 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 SB1, a buffer of the following composition was used: 50 mM Tris-HCl, pH 7.4, 10 mM MgCl ₂ , 1 mM EDTA, 2 U / mL Adenosine Deaminase. Membrane preparations were incubated in the presence of a mixture of the test compounds and [ ³ 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 test compounds was determined by the formula

where IC ₅₀ 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 EC ₅₀ value (half-maximum binding concentration) for [ ³ H] CGS 21680, and determined from the radioactive binding curves at different concentrations of [ ³ H] CGS 21680 (K _D = 64 nM).

Similarly investigated the interaction of new compounds of General formula 1 with adenosine A ₁ , A _2B and A ₃ receptors under the conditions described below.

Table 4 Receptor 200510 Adenosine A ₁ 200610 Adenosine A _2A Cells Human recombinant CHO cells Human recombinant HEK-293 cells Radioligand 1 nM [ ³ H] DPCPX 0.05 μM [.H] CGS-21680 Wednesday 1% DMSO 1% DMSO Incubation time / temperature 90 minutes @ 25.S 90 minutes @ 25.C Incubation buffer 20 mM HEPES, pH 7.4, 10 mM MgCl., 100 mM NaCl 50 mM Tris-HCl, pH 7.4, 10 mM MgCl, 1 mM EDTA, 2 U / mL Adenosine Deaminase Nonspecific Ligand: 100 µM R (-) - PIA 50 µM NECA

1.4 nM * 0.064 ÙM * IN _MAX 2.7 pmole / mg Protein * 7 pmole / mg Protein * Specific binding 85% * 85% * Quantitative method Radioligand binding Radioligand binding The significance of the criterion > 50% of max stimulation or inhibition > 50% of max stimulation or inhibition

Table 5 Receptor 200510 Adenosine A _2B 200610 Adenosine A ₃ Cells Human recombinant HEK-293 cells Human recombinant CHO-K1 cells Ligand 1.6 nM [.H] MRS1754 0.5 nM [... I] AB-MECA Wednesday 1% DMSO 1% DMSO Incubation time / temperature 90 minutes @ 25.S 60 minutes @ 25.S Incubation buffer 50 mM Tris-HCl, pH 6.5, 5 tM MgCl., 1 mM EDTA, 0.01% Bacitracin 25 mM HEPES, pH 7.4, 5 mM MgCl., 1 mM CaCl., 0.1% BSA Nonspecific Ligand: 100 ÙM NECA 1 ÙM IB-MECA

0.77 nM * 5.9 nM * IN _MAX 6.2 pmole / mg Protein * 1.8 pmole / mg Protein * Specific binding 77% * 83% * Quantitative method Radioligand binding Radioligand binding The significance of the criterion > 50% of max stimulation or inhibition > 50% of max stimulation or inhibition

The radioligand analysis of the interaction of the compounds of general formula 1 with adenosine A ₁ , A _2A , A _2B and A ₃ receptors showed their high selectivity with respect to the adenosine A _2A receptor (Table 2).

Claims (13)

1. Substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-dione of general formula 1, as well as their pharmaceutically acceptable salts,

where Ar is 2,5-dimethoxyphenyl, 4-isobutoxy-3-methoxyphenyl, 3-phenoxyphenyl substituted with pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, C ₁ -C ₅ alkoxy, an amino group optionally substituted with mono- or di-C ₁ - With ₅ alkyl; 3-methylthiophen-2-yl, pyrazol-4-yl substituted with C ₁ -C ₅ alkyl; 2,3-dihydro-benzo [1,4] dioxin-6-yl optionally substituted with C ₁ -C ₅ alkoxycarbonyl, carbamoyl optionally substituted with mono- or di-C ₁ -C ₅ alkyl, or carbonyl piperazine, optional substituted C ₁ -C ₅ alkyl. 2. The compound according to claim 1, selected from the group consisting of 8 - [(E) -2- (2,5-dimethoxyphenyl) vinyl] -1,3-diethyl-8-vinyl-7-methyl-3,7 dihydro-purine-2,6-dione; 8 - [(E) -2- (4-isobutoxy-3-methoxyphenyl) vinyl] -1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione; 8 - [(E) -2- (3-methylthiophen-2-yl) vinyl] -1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6-dione; 8 - [(E) -2- (1,3-dimethylpyrazol-4-yl) vinyl] -1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purine-2,6- dion; 6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid methyl ester; 6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid methylamide; 6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid dimethylamide; 6 - [(E) -2- (1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) vinyl] -2, 3-dihydro-benzo [1,4] dioxin-2-carboxylic acid diethylamide; 1,3-diethyl-7-methyl-8 - {(E) -2- [2- (piperazin-1-carbonyl) -2,3-dihydro-benzo [1,4] dioxin-6-yl vinyl} -3,7-dihydro-purin-2,6-dione; 1,3-diethyl-7-methyl-8 - {(E) -2- [2- (4-methylpiperazin-1-carbonyl) -2,3-dihydro-benzo [1,4] dioxin-6-yl- vinyl} -3,7-dihydro-purin-2,6-dione; 8 - {(E) -2- [3- (4-dimethylaminophenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione; 8 - {(E) -2- [3- (4-dimethylaminophenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione; 8 - {(E) -2- [3- (4-pyrrolidin-1-ylphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione ; 8 - {(E) -2- [3- (4-piperidin-1-ylphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione ; 8 - {(E) -2- [3- (4-morpholin-4-ylphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione ; 8 - {(E) -2- [3- (4-piperazin-1-ylphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione 8 - {(E) -2- [3- (4-methoxyphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione; 8 - {(E) -2- [4-methoxy-3-phenoxyphenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione; 8 - {(E) -2- [6-methoxy-3-phenoxyphenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purin-2,6-dione; 8 - {(E) -2- [6-methoxy-3- (4-methoxyphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione ; 8 - {(E) -2- [4-methoxy-3- (4-methoxyphenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydropurin-2,6-dione ; 8 - {(E) -2- [6-methoxy-3- (4-dimethylaminophenoxy) phenyl] vinyl} -1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione . 3. Antagonists of the adenosine A _2A receptor, which are substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-diones of the general formula 1 and their pharmaceutically acceptable salts according to .1 or 2. 4. Antagonists of the adenosine A _2A receptor, which are substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-dione of the general formula 1 and their pharmaceutically acceptable salts according to claims 1 or 2 as a drug source, for the preparation of a pharmaceutical composition and a medicine, for the prevention and treatment of diseases of the central nervous system, oncological and inflammatory diseases. 5. Antagonists of the adenosine A _2A receptor, which are substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydro-purin-2,6-dione of the general formula 1 and their pharmaceutically acceptable salts according to claim 1 or 2 as an adjuvant to enhance the immune response or action of drugs in the combinatorial treatment of cancer, viral and bacterial diseases. 6. A pharmaceutical composition having antagonistic activity to the adenosine A _2A receptor, comprising a drug onset according to claim 4 or an adjuvant according to claim 5 in a therapeutically effective amount. 7. A method for selectively inhibiting receptor activity, which comprises contacting a sample containing an adenosine A _2A receptor with an adenosine A _2A receptor antagonist according to claim 3. 8. A drug with antagonistic activity against 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, treatment of cancer and inflammatory processes, including the drug composition according to claim 4 or the adjuvant according to claim 5, or the pharmaceutical composition according to claim 6, in a therapeutically effective amount. 9. The drug of claim 8 for the prevention and treatment of Parkinson's disease. 10. The drug of claim 8 for the prevention and treatment of cognitive disorders. 11. The drug of claim 8 for the prevention and treatment of depression. 12. The drug of claim 8 for the treatment of inflammatory processes. 13. A method for the prevention and treatment of diseases mediated by the action of an A _2A receptor antagonist, comprising administering to a patient a pharmaceutical composition according to claim 6 or a medicine according to any one of claims 8-12, in a therapeutically effective amount.