Substituted phenoxyacetic acids, their esters and amides containing 2,6-dioxo-2,3,6,7-tetrahydro-1h-pyrin-8-yl fragments - a2a adenosine receptor antagonists and use thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula

, R1, R2 and R3, optionally simultaneously represent hydrogen. C1-C5alkyl, C3-C5alkenyl or C3-C5-alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy; R5 represents hydrogen, C1-C3alkyl, the group -C(O)R6;R6 represents hydroxyl, C1-C5alkyloxy, C3-C5alkenyloxy, C3-C5alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C1-C3alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C1-C3alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C1-C3alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond.

EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A2a adenosine receptor activity.

15 cl, 3 tbl, 7 ex

 

This invention relates to new compounds, substituted phenoxyacetyl acids and their esters and amines, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment showing antagonistic activity against adenosine A2Areceptors, and to their use as medicinal beginning and funds (adjuvant) for pharmaceutical compositions, medicaments and methods of treatment of diseases of the Central nervous system, cancer, viral and bacterial diseases.

And2Areceptors are one of the 4 subtypes (A1, A2A, A2Band a3) adenosine receptors. A1receptor inhibits adenylate cyclase and activates or inhibits (depending on cell type) phosphoinositide metabolism. In addition, with the participation of G-proteins, the receptor activates K-channels and inhibits CA-channels. A2receptor stimulates adenylate cyclase. Both types of receptors have seven transmembrane domains and is homologous to other membrane receptors associated with G-proteins. Adenosine binds with intracellular site on the catalytic subunit of adenylate cyclase, causing its inhibition. Adenosine receptors are localized in different types of tissues and are involved in regulating a number of biological processes. Activation of A1and As 3receptors causes a decrease in the level of camp [Jockers R., M.E. Linder, Hoehnegger M. J. Biol. Chem. 1994,269, 32077. Palmer T.M., T.W. Gettys, Stiles G.L. J. Biol. Chem. 1995, 270, 16895.], and activating A2Aand A2Breceptor leads to its increased level of camp [Kull C., Svenningsson P., Fredholm B.B. Mol. Pharmacol. 2000b58, 771. R.F. Bruns, Lu GH, Pugsley T.A. Mol. Pharmacol. 1986, 29, 331.]. In addition, stimulation of A1receptors causes activation of potassium and decontamination of calcium channels [Iredale P.A., Alexander, S.P.H., Hill S.J. Br. J. Pharmacol. 1994, 111, 1252. Bunemann, M., Pott L.J. Physiol. 1995,482, 81.], and stimulating A2Areceptors leads to inhibition of the functional activity of D2dopamine receptor that is important in the development of neurological and psychiatric diseases [Fuxe K., Ferre s, Zoli m, Agnati L.F. Brain Res. Rev. 1998,26, 258. Franco R., Ferre, S., Agnati L. Torvinen, M., Gines, S., J. Hillion Neuropsychoparmacol, 2000,23, S50.].

The ligands of adenosine receptors are widely used in pharmacology and medicine. A large number of scientific papers and patents devoted to research on the use of antagonists of A2Areceptors as drug candidates for the treatment of diseases of the Central nervous system (CNS), in particular Parkinson's disease [Pinna A. Novel investigational adenosine A2Areceptor antagonists for PA's disease. Expert Opinion on Investigational Drugs, 2009, 18(11), 1619-1631.];

various kinds of depression [E1 Yacoubi M, Costentin J, Vaugeois JM (December 2003). "Adenosine A2A receptors and depression" Neurology 61 (11 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 A1 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 A1 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.2008.01.012. PMID 18289757.],

cognitive disorders [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 Library13(13):2614-32. doi:10.2741/2870. PMID 17981738. http://www.bioscience.org/2008/v13/af2870/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.].

Recently it was shown that adenosine, which accumulates near the tumor tissue [Blay J., White .D., Oskin D.W. The increasing interest among 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 contact with tumor cells and kill them [Hoskin D. W, T. Reynolds, J. Blay 2-Chloroadenosine inhibits the MHC unrestricted cytolytic activity of anti-CD3-activated killer cells: evidence forthe involvement of a non-A 1/A2cell-surface adenosine receptor. Cell Immunol. (1994) 159:85-93. D.W. Hoskin, T. Reynolds, 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 terms of solid tumors, initiates the formation of higher concentrations of adenosine near the tumor tissue. Adenosine binding to adenosine receptors type a2Alocated on the cell membrane of lymphocytes, reports adenosine signal inside cells by activating intracellular accumulation of cyclic adenosine monophosphate (camp), which, in turn, reduces the ability of lymphocytes to attack the tumor tissue [M.V. Sitkovsky, Kjaergaard 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 unlimited company, Ronchese F., D. Lukashev, M. Wong K.K., Huang X., Caldwell, S., Liu K., Patrick Smith P., Chen J.-F., Jackson, E. K, Apasov, S., Abrams, S., Sitkovsky M. A2Aadenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA (2006), 103, 13132-13137. D. Lukashev, Sitkovsky M., Ohta A.. From "Hellstrom Paradox" to anti-adenosinergic cancer immunotherapy. Purinergic Signalling (2007) 3, 129-134] proposed an innovative approach to strengthening the effectiveness protivoradarnyh vaccine with adjuvant, which is an inhibitor of A2Aadenosine receptor [Ohta a, Sitkovsky M. METHODS AND COMPOSITIONS FOR IMPROVING IMMUNE RESPONSES, WO 2008/147482 04.12.2008].

Described and patented a large number of antagonis the s And 2Areceptors, including clinical candidates:

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

- Biogen-34: 5-[4-[[5-chlorol-1-methyl-3-(trifluoromethyl)-1H-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)of 1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine;

- DMPX: 3,7-dimethyl-1-propargylxanthine,

for which have been thoroughly studied pharmacological profiles in rats and compared And2Areceptor activity and selectivity to other adenosine receptors.

The search for effective and selective antagonists And2Areceptor is one of the main directions of development of new pharmacological agents for the treatment of CNS disorders, in particular Parkinson's disease, cancer, and inflammatory processes. In this regard, it is urgent to develop new antagonists A2Areceptors, pharmaceutical compositions and pharmaceutical preparations and methods for their preparation and use.

Below are definitions of terms used in the description of this invention.

"Adjuvant" (adjuvant)- a substance or idea is with substances, used to enhance the immune response or increase the effects of medicines.

"Azaheterocycle"means an aromatic or non-aromatic monocyclic or polycyclic system containing a loop, at least one nitrogen atom. Azaheterocycle can have one or more cyclic substituents" of the system.

"Alkenyl"means aliphatic linear or branched hydrocarbon group containing 2 to 7 carbon atoms and containing at least one carbon-carbon double bond.

Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, arelaxation,

heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", the value of which is determined Yes in the EBM section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate.

Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylmethanol.

"Alkenylacyl"means of alkenyl-O-group in which alkenyl defined in this section. The preferred alkenylamine groups are allyloxy and 3 butenyloxy.

"Alkenylacyl"means of alkenyl-O-accelgroup, in which the alkyl and alkenyl defined in this section.

"Alkyl"means aliphatic hydrocarbon of 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. The alkyl may have one or more identical or different substituents ("alkyl substituents is), including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation,

heteroarylboronic or RkaRk+1aN-, RkaRk+1NC(=O)-, RkaRk+1aNC(=S)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, the CEC shall opentimer, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or RkaRk+1aN-, Rkak+1aNC(=O)-, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Quinil"means aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond.

Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, linelike, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, uralkomsnab the sludge, heteroarylboronic or RkaRk+1aN-, RkaRk+1aNC(=O)-, RkaRk+1aNSO2-, where Rkaand Rk+1aindependently from each other represent "amino substituents", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or Rkaand Rk+1atogether with the N atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl, buta-1,3-Dien and hexa-1,3,5-Triin.

"Alkoxy"means alkyl-O-group in which alkyl is defined in this section. The preferred alkyloxyaryl are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Amino group"means RkaRk+1aN-group, a substituted or unsubstituted what th "Deputy amino group", Rkaand Rk+1awhose value is defined in this section, for example, amino (H2N-), methylamino, diethylamino, pyrrolidino, morpholino, benzylamino or phenethylamine.

"Antagonists"mean the ligands that bind to receptors of a particular type and do not cause active cellular response. Antagonists inhibit the binding of agonists to receptors and thereby block the transmission of specific receptor signal.

"Antidepressant"means a drug intended for the treatment of depression.

"Aryl"means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preimushestvenno from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Halogen"means fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.

"Heterocyclyl"means an aromatic or non-aromatic saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, mainly about the 5 to 6 carbon atoms, in which one or more carbon atoms 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 nitrogen atom, oxygen atom or sulfur atom, respectively. Heterocyclyl may have one or more "cyclic system substituents"which may be the same or different. Atoms of nitrogen and sulfur, in heterocyclyl, can be oxidized to N-oxide, S-oxide or S-dioxide. Representatives heterocyclyl are piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, thiazolidine, 1,4-dioxane, tetrahydrofuran, tetrahydrothiophene, etc.

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

"Depression"means great depression; episodic, chronic and recurrent forms of major depression; delimitable disorder (dysthymia); cyclothymia; affective disorders; syndrome of seasonal affective disorder; bipolar disorders including bipolar disorder type I and II; and other depressive disorders and conditions. The term depression refers also depression that accompany Alzheimer's disease, vascular dementia; mood disorders induced by alcohol is the substance; schizoaffective disorder depressive type; adjustment disorders. In addition, the depression includes depression in cancer patients; Parkinson's disease; depression after myocardial infarction; depression of infertile women, pediatric depression; postpartum depression; and other depressive conditions accompanying somatic, neurological and other diseases.

"Deputy"means a chemical moiety that is attached to scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "Deputy carbamoyl", "Deputy cyclic system, the values of which are defined in this section.

"Deputy amino group"means the Deputy attached to the amino group. Deputy amino group represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, acyl, aroyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, alkylaminocarbonyl, allumination, heteroarylboronic, heterocyclization, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, Anne is profiled arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonylmethyl, alcoxycarboxylates, heteroarylboronic. The value of the substituents of the amino group" is defined in this section.

"Deputy cyclic systemmeans the Deputy attached to aromatic or non-aromatic cyclic system, including hydrogen, alkylaryl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkoxy, aryloxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arelaxation, alkyloxyalkyl, aryloxyalkyl, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskikh, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylsulfonyl, arylsulfonyl, heterocyclization, alkylthio, aaltio, heterocyclic, heterocyclic, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylsulfonates, arylsulfonyl, geterotsiklicheskikh, alkylthiomethyl, alltoall, geterotsiklicheskikh, arylalkylamines, geterotsiklicheskie, arylalkylamines, geterotsiklicheskikh, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, amidino,

RkaRk+1the aN-, RkaN=, RkaRk+1aN-alkyl-, RkaRk+1aNC(=O)- or RkaRk+1aNSO2-, where Rkaand Rk+1arepresent independently from each other "Vice-amino group", which is defined in this section, for example, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroalkyl, or the substituent RkaRk+1aN-, in which Rkacan be acyl or aroyl, and a value of Rk+1adefined above, or a "cyclic system substituents" are RkaRk+1aNC(=O)- or RkaRk+1aNSO2-, in which Rkaand Rk+1atogether with the nitrogen atom to which they are bound, form a through Rkaand Rk+1a4-7-membered heterocyclyl or heterocyclyl.

"Cognitive disorder or cognitive impairment (cognitive disorder)"violate the (weakening) of mental abilities, including attention, memory, thinking, cognition, learning, speech, cognitive, Executive and creative abilities, orientation in time and space, in particular cognitive resstr Ista, associated with diseases such as Alzheimer, Parkinson and Hantington; senile dementia; age-related memory disorders (age-associated memory his or her, AAMI); dysmetabolic encephalopathy; psychogenic disturbances of memory; amnesia; amnestic disorder; transient global amnesia; dissociative amnesia; vascular dementia; light (or moderate) cognitive impairment (mild cognitive his or her, MCI); syndrome of disturbance of attention with hyperactivity (attention deficit hyperactivity disorder, AD/HD); cognitive impairment accompanying psychotic diseases, epilepsy, delirium, autism, psychosis, down syndrome, bipolar disorder and depression; AIDS-associated dementia; dementia with hypothyroidism; dementia induced by alcohol, substances, addictive, and neurotoxins; dementia accompanying neurodegenerative diseases such as cerebellar degeneration and amyotrophic lateral sclerosis; cognitive disorders, developing stroke, infectious diseases and cancer of the brain, as well as with traumatic brain injury; cognitive impairment associated with autoimmune and endocrine diseases; and other cognitive disorders.

"Medicinal beginning"(drug substance, drug substance, drug-substance) means fiziologicheskii substance is synthetic or of other origin (biotechnology, plant, animal, microbial or other things)with pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"Medicinal product (drug)"- a substance (or mixture of substances in the form of pharmaceutical compositions, in the form of tablets, capsules, injections, ointments and other ready-made forms, designed to restore, correct or modify physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Ligands"(from the Latin ligo - link) is a chemical (small molecule, an inorganic ion, a peptide, a protein, etc.) capable of interacting with receptors that transform this interaction in specific signal.

"Neurodegenerative disease (NC)"the meaning of the specific condition and a disease characterized by damage to the primary and death of populations of nerve cells in certain regions of the Central nervous system. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease and Parkinson's disease; disease (horay) Huntington's, multiple sclerosis, cerebellar degeneration; amyotrophic lateral the actual sclerosis; dementia with calves Levi; spinal muscular atrophy; peripheral neuropathy; spongiform encephalitis ("mad cow disease", Creutzfeld-Jakob Disease); AIDS-associated dementia; multi-infarct dementia; frontotemporal dementia; leucoencephalopathy (illness vanishing white matter); chronic neurodegenerative disease; stroke; ischemic and reperfusion of 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 developing during hypoxia, substance abuse, addictive, when exposed to neurotoxins, infectious and oncological diseases of the brain and 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"nootropic"they also neurometabolic stimulants - substances taken to improve mental abilities.

"Mental disorder"(mental illness) is a disease or morbid status is I, associated with the violation and/or mental disorder. Mental disorders include affective disorders (bipolar disorder, major depression, gipomania, shallow depression, manic syndrome, Kotar, cyclothymia, schizoaffective disorder, and others); intellectual-mnestic disorders, mania (hypomania, graphomania, kleptomania, magazineline, persecution mania, monomania, pornografiya, erotomania and others); disorder of multiple personality, Amancio, white fever, delirium, delusional syndrome, hallucinatory syndrome, hallucination, hallucinosis, gemicitabine, delirium, delusion, querulant, clinical lycanthropy, macropsia, Manichaean delirium, micropsia, drug addiction, nervous anorexia, oneyroidno syndrome, paranoid, paranoia, paraphrenia, pseudohallucinations, psychosis syndrome Kotar, schizoaffective disorder, schizotypical disorder, schizophrenia, schizophrenia-like psychosis disorder, isoprenaline disorder, syndrome Schreber, Daniel Paul; phobias (agoraphobia, arachnophobia, autophobia, verminophobia, hydrocodobe, the hydrophobicity, demophobia, zoophobia, cancerophobia, claustrophobic, climacophobia, xenophobia, misophobia, primarily, photophobia, scoleciphobia, scotophobia, social phobia, tetraphobia, triskaidekaphobia, erotophobia); alcoholic psychosis, alcohol is the first palimpsest, allotriophagy, aphasia, graphomania, dissociative Fugue, dissociative disorders, dysphoria, Internet addiction, hypochondria, hysteria, koprofilia, persecution mania, melancholy, misanthropy, obsession, panic attacks, Asperger's syndrome, Capgras syndrome, Munchausen syndrome, rett syndrome, the syndrome Fregoli, the syndrome of attention deficit and hyperactivity syndrome obsessive-compulsive disorder, syndrome effects of chronic anesthesia, a syndrome of psychic automatism, the syndrome of early infantile autism, delirium, taphophilia, anxiety syndrome Hikikomori, erotographomania and other

"Psychotic illness"are all types of schizophrenia; schizophrenia-like psychosis disease; shizotimichesky disorders; schizoaffective disorders, including bipolar and depressive type; delusional disorders, including delirium relations, persecution, grandeur, jealousy, erotomania, and hypochondriac, somatic, mixed and dedifferentiate delirium; brief psychotic disorder; induced psychotic disorder; induced psychotic substances disorder, and other psychotic disorders.

"Receptors"(from Latin recipere to receive, to learn) are biological macromolecules that are located on the cytoplasmic membranes of the cells or intracellular, able to interact specifically with a limited set of physiologically active substances (ligands) and transform the signal about this interaction in a specific cellular response.

"Pharmaceutical composition"refers to a composition that includes a compound of formula I and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorine is ethanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, aginova acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active beginning can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form introduced what I include oral forms, such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt"means relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like (for a Detailed description of the properties of such salts are described in Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids also could the t to be specially obtained by the reaction of purified acid with a suitable base, this can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts. Suitable inorganic bases which can be obtained metal salts are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a 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, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The subject of this invention are substituted F. natsukashii acid, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1 and their pharmaceutically acceptable salt,

where R1, R2 and R3, optionally simultaneously represent hydrogen, C1-C5alkyl, C3-C5alkenyl or3-C5quinil;

R4 represents hydrogen, halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy;

R5 represents hydrogen, C1-C3alkyl, a group-C(O)R6;

R6 represents hydroxyl,1-C3alkyloxy,3-C5alkenylacyl,3-C5alkyloxy, optionally substituted by an amino group, where the substituents do not necessarily identical, are selected from hydrogen, C1-C5the alkyl, optionally substituted mono - or dialkylamino, alkoxygroup, 5-6-membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen; pyridyl, or phenyl, optionally substituted by 1-3 methoxypropane; or optionally substituted 6-membered, optionally annelirovannymi with a 5-membered unsaturated heterocycle, saturated heterocyclyl containing 2 nitrogen atom, where the substituents are selected from C1-C5the alkyl, optionally substituted 5-membered heteroaryl containing 1-3 heteroatoms selected the s from nitrogen and oxygen; or 6-membered optionally saturated heterocyclyl containing 1-2 nitrogen atom, optionally substituted C1-C5the alkyl, oxo, optionally substituted by phenyl;

the dotted line with its accompanying solid lineis (single, double, or triple bond;

excluding {4-[2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid ethyl ester {4-[2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid.

According to this invention, the preferred substituted proxyusername acids and their esters and inorganic salts of General formula 1 are compounds of General formula 1.1 and 1.2,

in which R1, R2, R3, R4, R5, R6 and the dotted line with its accompanying solid linehave the meanings specified for compounds of General formula 1.

Preferred substituted proxyusername acids and their esters and inorganic salts of General formula 1 are compounds of General formula 1.3 and 1.4, in which R6 has the meaning indicated above, and R4 represents hydrogen or a methoxy group.

According to this invention the preferred compounds are the Xia

methyl ester{5-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-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-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.2.0(1),

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

methyl ester of 2-(4-(2-(1,diethyl-7 methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-ethyl)phenoxy)-acetic acid 1.2.0(3),

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

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

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

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-di-(2-methoxyethyl)-ndimethylacetamide 1.3.4,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(2-dimethylaminoethyl)-N-methyl-ndimethylacetamide 1.3.5,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(3-morpholine-4-ylpropyl)-ndimethylacetamide 1.3.6,

1,3-diethyl-8-((E)-2-{4-[2-(4-isopropyl-piperazine-1-yl)-2-oxo-ethoxy]-phenyl}-vinyl)-7-methyl-3,7-dihydro-purine-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-tet is ahydro-pyrimidine-5-yl)-piperazine-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1.3.9,

1,3-diethyl-8-{(E)-2-[4-(2-{4-[6-(2-methoxy-5-fluoro-phenyl)-pyrimidine-4-yl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-7-methyl-3,7-dihydro-purine-2,6-dione 1.3.10,

1,3-diethyl-7-methyl-8-[(E)-2-(4-{2-oxo-2-[4-(6-phenyl-pyrimidine-3-yl)-piperazine-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1.3.11,

8-{(E)-2-[4-(2-{4-[3-(3,4-dimethoxy-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione 1.3.12.

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(3,4,5-trimethoxyphenyl)-ndimethylacetamide 1.3.13,

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

{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.15,

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

ISO-propyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.17,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-ndimethylacetamide 1.3.18,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-methyl-ndimethylacetamide 1.3.19,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-f is noxy}-N-ethyl-ndimethylacetamide 1.3.20,

2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-dimethyl-ndimethylacetamide 1.3.21,

ethyl ester [4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-acetic acid 1.4.1,

[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-ndimethylacetamide 1.4.2,

[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-N-methyl-ndimethylacetamide 1.4.3,

1,3-diethyl-8-[3-methoxy-4-(2-oxo-2-piperazine-1-yl-ethoxy)-phenylethynyl]-7-methyl-3,7-dihydro-purine-2,6-dione 1.4.4,

[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-N-pyridin-3-yl-ndimethylacetamide 1.4.5.

The subject of this invention is a method of obtaining substituted PHENOXYACETIC acids, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1A, acylation 5,6-diamino-1H-pyrimidine-2,4-diones of General formula 3 acids of General formula 4 in the presence of appropriate reagents, for example, O-(benzotriazol-1-yl)-N,N,N',N'-tetrahydrofurane of tetrafluoroborate or 1-hydroxybenzotriazole N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide, the cyclization of the resulting compounds of General formula 5 in ferociously acid of General formula 1A,

where R1, R2, R4, R5 and the dotted line with its accompanying solid line have the meanings specified for compounds of General formula 1; R7 represents an optionally substituted C1-C5alkyloxy, optionally substituted C3-C5alkenylacyl, optionally substituted C3-C5alkyloxy or amino group, R8 represents an optionally substituted and optionally saturated With1-C5alkyl.

According to this invention the preferred method of obtaining optionally substituted amides of substituted PHENOXYACETIC acids, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1d, lies in the interaction of the methyl esters of the General formula 1bb with ammonia, primary or secondary amines of General formula 6,

where R1, R2, R4, R5 and the dotted line with its accompanying solid linehave the meanings specified for compounds of General formula 1; R9 and R10 are not necessarily identical and represent an optionally substituted C1-C5alkyl, optionally substituted C3-C5alkenyl, optionally substituted C3-C5quinil.

According to this invention the preferred method of obtaining optionally substituted amides of substituted PHENOXYACETIC acids, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1d, lies in the interaction of the acids of General formula 1c with ammonia, primary or secondary amines of General formula 6 in the presence of 1-hydroxybenzotriazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and diisopropylethylamine,

where R1, R2, R4, R5 and the dotted line with its accompanying solid linehave the meanings specified for compounds of General formula 1; R9 and R10 are not necessarily identical and represent hydrogen, optionally substituted C1-C5alkyl, optionally substituted C3-C5alkenyl, optionally substituted C3-C5quinil or optionally substituted heterocyclyl comprising one or two nitrogen atom.

The subject of this invention are the new antagonists of adenosine A2Areceptor, represents a substituted ferociously acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1, and their pharmaceutically acceptable salts.

Antagonistic activity of the new compounds of General formula 1 and their pharmaceutically acceptable salts relative to the adenosine A2Athe receptor was performed ex vitro functional test cells. The experiment used a cell line ValiScreen cell line (PerkinElmer, USA)expressing recombin ntny human adenosine receptor type A 2A.

Table 1 presents data on the activity; for some of the compounds of General formula 1, confirming their high antagonistic activity against adenosine A2Areceptor: + corresponds to K1>50 nM, ++ corresponds to K1from 20 to 50 nM, +++ corresponds to K1from 10 to 20 nM and ++++ corresponds to K1<10 nM.

The subject of this invention are compounds of General formula 1, which represents the drug beginning (substance) for the preparation of pharmaceutical compositions and 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 the means (adjuvant to enhance the immune response or action of medicines in the combinatorial treatment of cancer, viral and bacterial diseases.

The subject of this invention is a pharmaceutical composition having antagonistic activity of the Yu in relation to adenosine A 2Areceptor, including as a medicinal beginning (substance) or means (adjuvant) compounds of General formula 1 or their pharmaceutically acceptable salts and/or hydrates in therapeutically effective amounts.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. Pharmaceutical composition, along with the compound of General formula 1 or its pharmaceutically acceptable salt according to the present invention may include other active substances, including with anti-influenza activity, provided that they do not cause unwanted effects.

If you want to use the pharmaceutical compositions of the present invention in clinical practice it can be mixed with conventional pharmaceutical carriers.

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, escutia agents, the korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The subject of this invention is a method of obtaining a pharmaceutical composition by mixing with an inert filler and/or solvent, at least one medicinal beginning (substance) of General formula 1 or its pharmaceutically acceptable salt in a therapeutically effective amount.

To determine the selectivity of the interaction to the adenosine A2Athe receptor was performed radioligand analysis of the interaction of compounds of General formula 1 with adenosine A1, A2A, A2Band a3the receptors.

Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A1, A2A, A2Band a3receptors showed high selectivity for adenosine A2Athe receptor.

For example, in a competitive radioligand binding activity of the methyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.16 relative to the adenosine A2Areceptor 131 times higher than its activity against adenosine A1receptor, 148 times to enter the activity against adenosine A 2Breceptor and in 1159 times higher activity against adenosine A3the receptor. For comparison below presents data on the activity and selectivity of the compounds 1.3.16 and known ligand KW-6002, which was used as the comparison drug, in terms of radioligand analysis.

As can be seen from these data, the ligand 1.3.16 relative to the adenosine A2Athe receptor than the known ligand KW-6002 as activity and selectivity.

Table 2
The activity and selectivity of ligands 1.3.16 and KW-6002 in terms of radioligand analysis in relation to adenosine A1, A2A, A2Band a3receptors
The ligandActivity (KinM) to adenosine receptorsSelectivity for adenosine hell receptor
A1And2AA2BAnd3A1/A2AA2B/A2AAnd3/A2A
KW-6002248056.4192092504434164
1.3.16395030.14450349001311481159

The subject of this invention is a method of selective inhibition of the activity of the adenosine A2Areceptor, which consists in contacting the sample containing the adenosine A2Areceptor with a composition comprising the antagonist of adenosine A2Areceptor, represents a substituted Phenoxyethanol acid, its ester or amide comprising 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1, its pharmaceutically acceptable salt and/or hydrate.

The subject of this invention is a medicinal product, which has antagonistic activity against adenosine A2Athe receptor, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing intended for the prevention and treatment of diseases of the Central nervous system, Oncology, in the originate and bacterial diseases in humans and warm-blooded animals, includes the beginning of a new medication (substance) of General formula 1 or a pharmaceutical composition in a therapeutically effective amount, as well as for prevention and treatment of Parkinson's disease, cognitive disorders, depression, and inflammatory processes.

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

Drugs can be administered orally or parenterally (e.g. intravenously, subcutaneously, intraperitoneally or topically). Clinical dosage means the General formula 1 in patients may be adjusted depending on therapeutic efficacy and bioavailability of the active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the daily dose in adults is usually 10~500 mg, preferably 50~300 mg. Therefore, during the preparation of the pharmaceutical composition of the medicinal product according to the present invention in the form of dosage units it is necessary to consider wycena is EN effective dosage, in addition, each unit dosage of the drug should contain 10~500 mg funds General formula 1, preferably 50~300 mg. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a certain period of time (preferably, one to six times).

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

Example 1. The synthesis of compounds of General formula 1A. To a solution of 1 mmol (198 mg), 1,3-diethyl-5,6-diaminoanisole 3 and 15 mmol acid 4 in 8 ml of dimethylformamide was added 1.5 mmol (372 mg) o-(benzotriazol-1-yl)-N,N,N',N'-tetrahydrofurane of tetrafluoroborate.

The mixture was stirred overnight at room temperature, poured into ice water, extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, was evaporated to dryness. The residue was chromatographically on silica gel with a mixture of dichloromethane with methanol. Was obtained with the yield 26-92% amide 6 (0.1 mmol) suspended in 8 ml of methanol was added 8 ml of 4N aqueous sodium hydroxide solution. The mixture was stirred 1.5 hours at 80-90°C. Cooled, neutralized 18% aqueous hydrochloric acid solution to pH 7-8. The precipitation phenoxyalkanoic acid include 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1A, filtered (output 42-92%).

{4-[(E)-2-(1,3-Diethyl-2,6-dioxo-2,3,6,7-Tetra the DRO-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid a=(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-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid a=(1.2.0(2)) - LC MS: found 385 (M+1), calculated 385 (M+1).

Example 2. The synthesis of compounds of General formula 1b. The mixture of acid 1A (0.44 mmol), 4 ml of dimethylformamide 132 g (1 mmol) of calcined potassium carbonate and 2.2 mmol alkyl iodide was stirred 2 hours at 70°C, was added 1.1 mmol of iodine alkyl, another was stirred 2 hours at 70°C. was Cooled, added to water, the precipitation was filtered, dissolved in a suitable solvent, the resulting solution was filtered through a layer of silica gel and the filtrate was evaporated in vacume. Was obtained with the yield 31-54% ether phenoxyalkanoic acid include 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1b.

Methyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1b.1=(1.3.16). LC-MS: found 443 (M+1), calculated 443 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: to 7.61 (d, J=16.4 Hz, 1H), 7,45 (s, 1H), 7,24 (m, 2H), make 6.90 (d, J=8 Hz, 1H), a 4.83 (s, 2H), of 4.05 (m, 5H), to 3.89 (m, 5H), 1,25 (t, J=6.4 Hz, 3H), of 1.12 (t, J=6.8 Hz, 3H).

Methyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid 1b.2=(1.3.2). LC-MS: found 412 (M+1), computed 412 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 7,73 (d, J=8 Hz, 1H), 7.62mm (d, J=15.6 Hz, 1H), 7,19 (d, J=16 Hz, 1H), 6,98 (d, J=8,8 Hz, 2H),a 4.86 (s, 2H), 4,06 (K, J=6,4 Hz, 2H), 4,01 (s, 3H), 3,91 (K, J=6,8 Hz, 2H), 3,71 (s, 3H), 1,25 (t, J=6.8 Hz, 3H), of 1.12 (t, J=6.8 Hz, 3H).

Methyl ester {5-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1b.3=(1.1.1). LC-MS: found 443 (M+1), calculated 443 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 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), to 4.87 (s, 2H), 4,06 (K, J=7.2 Hz, 2H), 4,01 (s, 3H), 3,91 (K, J=7.2 Hz, 2H), 3,82 (s, 3H), and 3.72 (s, 3H), 1,25 (t, J=7.2 Hz, 3H), of 1.13 (t, J=6.8 Hz, 3H).

Ethyl ester [4-[(1,3-diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethinyl]-2-methoxyphenoxy]-acetic acid (1.4.1). LCMS (M+1) 4551H NMR (DMSO-D6, 400 MHz) δ 1.22 (t, J1=7.00, J2=2.88, 9H), 3.84 (t, J1=9.40, J2=0.25, 3H), 3.95 (d, J=13.35, 3H), 4.05 (d, J=7.06, 4H), 4.23 (d, J=4.15, 2H), 4.69 (t, J1=16.30, J2=0.17, 2H), 6.84 (t, J1=2.00, J2=0.72, 1H), 6.97 (m, 2H).

Ethyl ester of [2-chloro-4-[(E)-2-(1,3-diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethynyl]phenoxy]-acetic acid (1.3.14). LCMS (M+1) 4611H NMR (DMSO-D6, 400 MHz) δ 1.22 (OST, J1=7.00, J2=2.88, 9H), 4.00 (d, J=13.35, 3H), 4.07 (d, J=7.06, 4H), 4.25 (d, J=4.15, 2H), 4.61 (t, J1=16.30, J2=0.17, 2H), 6.97 (d, J=0.87, 1H), 7.01 (t, J1=15.60, J2=0.60, 1H), 7.31 (m, 1H), 7.44 (m, 1H), 7.45 (t, J1=8.60, J2=2.20, 1H).

Example 3. The synthesis of compounds of General formula 1C. To a solution of 0.34 mmol of ester 1b in 2 ml of methanol was added 0.4 ml of 1N solution of lithium hydroxide. The mixture was stirred 16 hours at room temperature is. Was evaporated to dryness, the residue was dissolved in water, washed with ether. Caution was added 6N hydrochloric acid to pH 7-8, the precipitation was filtered. Get acid 1C with access 41-71%.

{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid (1.3.15). LC-MS: found 429 (M+1), calculated 429 (M+1).1H 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 in (d, J=8,4 Hz, 1H), 4.72 in (s, 2H), 4.06 (K, J=7.2 Hz, 2H), was 4.02 (s, 3H), 3,91 (K, J=7,2 Hz, 2H), 3,86 (s, 3H), 1,25 (t, J=6.8 Hz, 3H), of 1.12 (t, J=6.4 Hz, 3H).

Example 4. A common way to obtain amides 1d. In a test tube containing a suspension 0,226 mmol methyl ester of General formula 1bb in 2 ml of methanol or ethanol saturated or added appropriate amount of amine. The tube was closed and heated for 10 hours at a temperature of 50°C, then cooled, filtered, precipitated sludge. Received amide Id with the release of 29-58%.

2-{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-ndimethylacetamide 1d.1=(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-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-ndimethylacetamide 1d.2=(1.3.18). LC-MS: found 428 (M+1), calculated 428 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: a 7.62 (d, J=15.6 Hz, 1H), 7,33 (m, 5H), 6,93 (d, J=8,8 Hz, 1H), 4,48 (s, 2H), of 4.05 (m, 5H), 3,91 (m, 5H), of 1.26 (t, J=6.4 Hz, 3H), of 1.13 (t, J=6.4 Hz, 3H).

2-{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 is-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-methyl-ndimethylacetamide 1d.3=(1.3.19). LC-MS: found 442 (M+1), calculated 442 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: a 7.62 (d, J=15.6 Hz, 1H), 7,33 (m, 5H), 6,93 (d, J=8,8 Hz, 1H), 4,48 (s, 2H), of 4.05 (m, 5H), 3,91 (m, 5H), of 1.26 (t, J=6.4 Hz, 3H), of 1.13 (t, J=6.4 Hz, 3H).

2-{4-[(E)-2-(1,3-Diethyl-7-methyl--2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-ethyl-ndimethylacetamide 1d.4=(1.3.20). LC-MS: found 456 (M+1), calculated 456 (M+1).1H NMR (DMSO-D6,400 MHz) δ: a 7.92 (m, 1H), 7.62mm (d, J=15.6 Hz, 1H), 7,44 (s, 1H), 7,24 (m, 2H), 6,92 (d, J=7,6 Hz, 1H), 4,48 (s, 2H), Android 4.04 (m, 5H), 3,90 (m, 5H), and 3.16 (t, J=5.6 Hz, 2H), 1.26 in (t, J=6 Hz, 3H), of 1.12 (t, J=6 Hz, 3H), was 1.04 (t, J=6.4 Hz, 3H).

2-{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-dimethyl-ndimethylacetamide 1d.5=(1.3.21). LC-MS: found 456 (M+1), calculated 456 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: a 7.62 (d, J=15.6 Hz, 1H), 7,43 (s, 1H), 7,22 (m, 2H), 6,86 (d, J=8 Hz, 1H), a 4.83 (s, 2H), 4,06 (K, J=5.6 Hz, 2H), was 4.02 (s, 3H), 3,91 (K, J=6,8 Hz, 2H), a 3.87 (s, 3H), 3,01 (s, 3H)), 2,85 (s, 3H), of 1.26 (t, J=6.4 Hz, 3H), of 1.13 (t, J=6.8 Hz, 3H).

Example 5. A common way to obtain amides 1d. To a mixture of 30.5 mg (0,226 mmol, 2 EQ.) 1-hydroxybenzotriazole, to 43.3 mg (0,226 mmol, 2 EQ.) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 45 mg (0,113 mmol, 1 EQ.) the original acid N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride 1C was added 1.8 ml of DMF. The resulting mixture was stirred at room temperature for 1 hour. Then added sequentially 0,170 mmol (1.5 EQ.) Amin 6 and the required number of diisopropylethylamine. The reaction mass was kept for 12 h at anatoy temperature, then mixed it with 50 ml of 10% Na2CO3. If the product is precipitated in the form of a precipitate, the precipitate was filtered, washed 2 times with water on the filter, dried in the air. In the case of fine sediment, separation was performed by centrifugation. If the product was in the form of oil, carried out the extraction with dichloromethane, the organic phase was washed 1 time with water, dried anhydrous Na2SO4and evaporated on a rotary evaporator. Further purification was performed either by recrystallization from ethanol or column chromatography using the solvent system chloroform - methanol in ratios from 40:1 to 10:1. Received amides 1d with access 26-89%.

2-{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-di-(2-methoxyethyl)-ndimethylacetamide 1d.6=(1.3.4). LC-MS: found 514 (M+1), computed 514 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 7,71 (d, J=8,4 Hz, 2H), to 7.61 (d, J=15.6 Hz, 1H), 7,18 (d, J=16 Hz, 1H), 6,92 (d, J=8,8 Hz, 2H), is 4.93 (s, 2H), 4,06 (K, J=7.2 Hz, 2H), 4.00 points (s, 3H), 3,91 (K, J=6,8 Hz, 2H), 3,53 (m, 4H), 3.46 in (m, 2H), 3,42 (m, 2H), 3.33 and (s, 3H), 3,24 (s, 3H), 1,25 (t, J=7.2 Hz, 3H), of 1.12 (t, J=6.4 Hz, 3H).

2-{4-[(E)-2-(1,3-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(2-dimethylaminoethyl)-N-methyl-ndimethylacetamide 1d.7=(1.3.5). LC-MS: found 483 (M+1), calculated 483 (M+1). LCMS (M+1) 4831H NMR (DMSO-D6, 400 MHz) δ 1.22 (OST, J1=7.00, J2=2.88, 6H), 2.17 (t, J1=13.35, J2=0.98, 6H), 2.43 (t, J1=13.29, J2=6.21, 2 is), 3.00 (d, J=14.23, 3H), 3.62 (d, J=8.79, 2H), 4.00 (d, J=13.35, 3H), 4.07 (d, J=7.06, 4H), 4.63 (t, J1=14.95, J2=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-Diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(3-morpholine-4-ylpropyl)-ndimethylacetamide 1d.8=(1.3.6). LC-MS: found 525 (M+1), calculated 525 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 8,11 (t, J=6,4 Hz, 1H), of 7.75 (d, J=8,4 Hz, 2H), to 7.61 (d, J=15.6 Hz, 1H), 7,21 (d, J=15.6 Hz, 1H), 7,00 (d, J=8,4 Hz, 2H), to 4.52 (s, 2H), 4,05 (K, J=6,4 Hz, 2H), 4,01 (s, 3H), 3,92 (K, J=6,8 Hz, 2H), 3,54 (m, 4H), 3,17 (K, 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, 3H), of 1.12 (t, J=6.8 Hz, 3H).

1,3-Diethyl-8-((E)-2-{4-[2-(4-isopropyl-piperazine-1-yl)-2-oxo-ethoxy]-phenyl}-vinyl)7-methyl-3,7-dihydro-purine-2,6-dione 1d.9=(1.3.7). LC-MS: found 509 (M+1), calculated 509 (M+1). LCMS (M+1) 5091H NMR (DMSO-D6, 400 MHz) δ 1.10 (t, J1=6.28, J2=1.13, 6N), 1.22 (OST, J1=7.00, J2=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, J1=13.35, J2=0.25, 3H), 4.05 (d, J=7.06, 4H), 4.63 (t, J1=14.00, J2=0.23, 2H), 6.90 (t, J1=2.20, J2=0.50, 2H), 6.94 (t, J1=15.60, J2=0.70, 1H), 7.29 (d, J=0.25, 1H), 7.45 (t, J1=8.60, J2=0.50, 2H).

8-((E)-2-{4-[2-(1,6-dimethyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)-2-oxo-ethoxy]-Neil}-vinyl)-1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione 1d.10=(1.3.8). LC-MS: found 531 (M+1), calculated 531 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 7,73 (d, J=8,4 Hz, 2H), to 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 (2 m, 1H), 4,99 (m, 2H), 456, 4,34 (2 m, 1H), 3,42 (m, 1H), 4,06 (m, 2H), 4.00 points (m, 3H), 3,90 (m, 2H), 3,76 (m, 1H), only 3.57 (m, 1H), 2,12 (s, 3H), 1,48, 1,32 (2 m, 3H), 1,25 (t, J=7.2 Hz, 3H), 1.14 in (t, J=6 Hz, 3H).

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-pyrimidine-5-yl)-piperazine-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1d.11=(1.3.9). LC-MS: found 619 (M+1), calculated 619 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 8,61 (s, 1H), 7,73 (d, J=8,4 Hz, 2H), 7.62mm (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 (K, J=7.2 Hz, 2H), 4.00 points (s, 3H), 3,91 (, J=6,4 Hz, 2H), 3,85 (s, 3H), of 3.77 (m, 2H), 3,69 (m, 2H), 3,61 (m, 4H), 1,2 (t, J=7.2 Hz, 3H), of 1.12 (t, J=6.4 Hz, 3H).

1,3-Diethyl-8-{(E)-2-[4-(2-{4-[6-(2-methoxy-5-fluoro-phenyl)-pyrimidine-4-yl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-7-methyl-3,7-dihydro-purine-2,6-dione 1d.12=(1.3.10). LC-MS: found 669 (M+1), calculated 669 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 8,61 (s, 1H), 7,73 (d, J=8,4 Hz, 2H), 7.62mm (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 (K, J=7.2 Hz, 2H), 4.00 points (s, 3H), 3,91 (, J=6,4 Hz, 2H), 3,85 (s, 3H), of 3.77 (m, 2H), 3,69 (m, 2H), 3,61 (m, 4H), 1,2 (t, J=7.2 Hz, 3H), of 1.12 (t, J=6.4 Hz, 3H).

1,3-Diethyl-7-methyl-8-[(E)-2-(4-{2-oxo-2-[4-(6-phenyl-pyrimidine-3-yl)-piperazine-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1d.13=(1.3.11). LC-MS: found 621 (M+1), calculated 621 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: 8,03 (d, J=7.2 Hz, 2H), 7,98 (d, J=10 Hz, 1H), 7,73 (d, J=7.2 Hz, 2H), 7.62mm (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), to 4.98 (s, 2H), 4,06 (m, 2H), 4.00 points (s, 3H), 3,91 (m, 2H), 3,78 (m, 2H), 3,65 (m, 6N), 1,25 (m, 3H), of 1.18 (m, 3H).

8-{(E)-2-[4-(2-{4-[3-(3,4-Dimatix is-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione 1d.14=(1.3.12). LC-MS: found 685 (M+1), calculated 685 (M+1).1H NMR (DMSO-D6, 400 MHz) δ: of 7.70 (d, J=8,4 Hz, 2H), 7,60 (d, J=12,4 Hz, 2H), of 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), was 4.02 (m, 7H), 3,91 (m, 2H), 3,82 (m, 6N), to 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-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(3,4,5-trimethoxyphenyl)-ndimethylacetamide 1d.15=(1.3.13). LC-MS: found 564 (M+1), calculated 564 (M+1).1H NMR (DMSO-D6, 400 MHz) δ:. 9,98 (ush, 1H), 7,68 (m, 3H), 7,11 (m, 5H), 4,71 (s, 2H), 3,99 (m, 6N), 3,71 (m, 10H), of 1.23 (m, 3H), 1,10 (m, 3H).

2-[4-[(1,3-Diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethinyl]-2-methoxyphenoxy]-ndimethylacetamide, (1.4.2). LCMS (M+1) 4261H NMR (DMSO-D6, 400 MHz) δ 1.22 (t, J1=7.00, J2=2.88, 6N), 3.84 (t, J1=9.40, J2=0.25, 3H), 3.95 (d, J=13.35, 3H), 4.02 (d, J=7.06, 4H), 4.55 (t, J1=15.10, J2=0.17, 2H), 6.96 (m, 1H), 7.03 (t, J1=2.00, J2=0.72, 1H), 7.15 (d, J=8.00, 1H), 7.42 (t, J1=2.60, J2=1.33, 2H).

2-[4-[(1,3-Diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethinyl]-2-methoxyphenoxy]-N-methyl-ndimethylacetamide (1.4.3). LCMS (M+1) 4401H NMR (DMSO-D6, 400 MHz) δ 1.23 (t, J1=7.00, J2=2.88, 6N), 2.68 (d, J=14.23, 3H), 3.84 (t, J1=9.40, J2=0.25, 3H), 3.95 (d, J=13.35, 3H), 4.05 (d, J=7.06, 4H), 4.45 (t, J1=14.00, J2=0.23, 2H), 6.97 (m, 1H), 7.03 (t, J1=2.00, J2=0.72, 1H), 7.13 (d, J=8.00, 1H), 7.85 (m, 1H).

1-[[4-[(1,3-Diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethinyl]-2-methoxyphenoxy]acetyl]-piperazine (1.4.4). LCMS (M+1) 495+1=7.00, J2=2.88, 6N), 2.82 (m, 2H), 2.98 (m, 2H), 3.27 (m, 2H), 3.35 (m, 2H), 3.68 (m, 1H), 3.84 (t, J1=9.40, J2=0.25, 3H), 3.95 (d, J=13.35, 3H), 4.04 (d, J=7.06, 4H), 4.73 (t, J1=14.00, J2=0.23, 2H), 6.96 (m, 1H), 7.03 (t, J1=2.00, J2=0.72, 1H), 7.13 (d, J=8.00, 1H).

2-[4-[(1,3-diethyl-2,3,6,7-tetrahydro-7-methyl-2,6-dioxo-1H-purine-8-yl)ethinyl]-2-methoxyphenoxy]-N-3-pyridinyl-ndimethylacetamide (1.4.5). LCMS (M+1) 5031H NMR (DMSO-D6, 400 MHz) δ 1.22 (t, J1=7.00, J2=2.88, 6N), 3.84 (t, J1=9.40, J2=0.25, 3H), 3.95 (d, J=13.35, 3H), 4.06 (d, J=7.06, 4H), 4.58 (m, 2H), 6.97 (m, 2H), 7.03 (t, J1=2.00, J2=0.72, 1H), 7.13 (d, J=8.00, 1H), 7.32 (m, 1H), 8.32 (t, J1=7.70, J2=1.30, 1H), 8.39 (d, J=4.60, 1H), 8.60 (m, 1H).

Example 6. The study of the antagonistic activity of the compounds of General formula 1 and their pharmaceutically acceptable salts relative to the adenosine A2Athe receptor. Antagonistic activity of the new compounds of General formula 1 and their pharmaceutically acceptable salts relative to the adenosine A2Athe receptor was performed ex vitro functional test cells. The experiment used a cell line ValiScreen cell line (PerkinElmer, USA)expressing recombinant human adenosine receptor type A2A. Stimulation of receptors in these cells agonist CGS 21680 (Tocris) activates adenylate cyclase, which, in turn, leads to increased synthesis of intracellular cyclic monophosphate is (camp). The amount of camp was determined using technologies LANCE (LANCE Ultra cAMP kit, PerkinElmer). The ability of test compounds to reduce the number of camp synthesized in the presence of CGS 21680, were evaluated for their antagonistic activity. As standard (connection comparison) used are described in the literature antagonist KW-6002 (Axon Medchem, Netherlands).

Cells were maintained in DMEM (Paneco, Russia) with the addition of 10% FBS (Biological Industries), a mixture of penicillin/streptomycin (Paneco) and G418 (Sigma) at 37°C in an atmosphere of 5% CO2. Before the experiment the cells were removed from the culture bottle with a solution of Versene (Paneco) and suspended in buffer SB2 (Wednesday Hanks+5 mm HEPES (pH 7.4)+0.1% of BSA+200 uM Ro-20-1734+2U/mL ADA (adenosine deaminase)) to a density of 0.2 million cells per milliliter. To the cell suspension were added to 1:150 (by volume) ULightTM-anti-cAMP Antibody (PerkinElmer) and the mixture is poured into white 384-well plates (PerkinElmer) 5 µl (1000 cells) in each well.

Test compounds were dissolved in DMSO to a concentration of 6.32 mm and prepared 3.16-fold serial dilution in DMSO. Prepared serial dilution was diluted 50-fold with buffer SB1 (Wednesday Hanks+5 mm HEPES (pH 7.4)+0.1% of BSA). The obtained solutions of the compounds in SB1 buffer were mixed in a 1:1 ratio with a solution of CGS 21680 (12.64 nm), pre-cooked in the buffer SB3 (SB1+0.1% Pluronic F127). The mixture of the subjects of the response to agonist was added (5 μl in duplicate into the wells of the plate, containing 5 µl of cells (as described above) and the plates incubated for 30 minutes at room temperature. Each plate also contained 16 holes for each control (MAX and MIN). MAX - cells with 3.16 nm CGS 21680 (concentration of agonist, the corresponding EU90, i.e. the concentration that causes 90% of the activity of the cells); the signal from these holes were 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 (the concentration of the antagonist, the corresponding IC100i.e. concentration causing 100% inhibition of the activity of cells); the signal from these holes were used in the calculations as 0% activity (100% inhibition). In addition, each plate contained wells (4 repeats), where cells were treated with agonist (CGS 21680) at different concentrations. The final concentration of DMSO in all wells was equal to 1%.

Formed in the cells of camp was determined quantitatively using a set of LANCE Ultra cAMP kit (PerkinElmer, USA) in accordance with the methodology recommended by the manufacturer. Fluorescent signal was measured on the device Victor3V (PerkinElmer)with an integrated program for measuring LANCE High Count.

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

Ki=IC50/(1+L/KD),

where IC50the concentration of antagonist, in which the activity of adenylate cyclase accounts for 50% of the maximum, L - concentration of CGS 21680, in which measurements are made (3.16 nM) and Co - apparent affinity constant CGS 21680, quantitatively corresponds to the value of EC50(concentration premaxillae stimulation of cells) for CGS 21680 and some curves to stimulate accumulation of camp in the cells at various concentrations of agonist.

Table 1 presents data on the activity Toisome representatives of the compounds of General formula 1.

Example 7. Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A1, A2A, A2Band a3the receptors. Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A1, A2A, A2Band a3receptors were performed to determine the selectivity of the interaction of compounds of General formula 1 with adenosine A2Athe receptor. When determining the interaction of these compounds with adenosine A2Athe receptor used membrane preparations derived from embryonic human kidney cells expressing recombinant human And2Athe receptor. The receptor expression was 7 pmol/mg protein. As radioligand used [3H]CGS 21680 at a concentration of 0.05 μm. Solutions of test compounds were prepared as described in the procedure for the functional test with the times is iciam, instead of environment SB1, used a buffer of the following composition: 50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 1 mM EDTA, 2 U/mL Adenosine Deaminase. Membrane preparations were incubated in the presence of a mixture of test compounds and [3H]CGS 21680 for 90 min at 25°C and the mixture was filtered on steklofibrobetonnykh filters GF (Millipor, USA). Radioactivity on the filters was determined using gidrostimulyatsionnye MicroBeta counter (PerkinElmer, USA). Nonspecific binding was measured in the presence of 50 μm NECA, which amounted to no more than 15% of the total binding. The affinity of the test compounds was determined by the formula

Ki=IC50/(1+L/KD),

where IC50the concentration of antagonist, in which the binding of [3H]CGS 21680 is reduced to 50% of the maximum, L is the concentration of [3H]CGS 21680, in which measurements are made (50 nM), and KD- constant affinity of [3H]CGS 21680, quantitatively relevant EC50(concentration premaxillae binding) [3H]CGS 21680, and some curves radioactive binding at different concentrations of [3H]CGS 21680 (KD=64 nm).

Similarly investigated the interaction of the new compounds of General formula 1 with adenosine A1, A2Band a3receptors in the conditions below.

table 3
Receptor200510 Adenosine A 1200610 Adenosine A2A
CellHuman recombinant CHO cellsHuman recombinant HEK-293 cells
Radioligand1 nM of [3H] DPCPX0.05 µm [.H] CGS-21680
Wednesday1% DMSO1% DMSO
Incubation time/temperature90 minutes @ 25.C90 minutes @ 25.C
The incubation buffer20 mM HEPES, pH 7.4, 10 mM MgCl., 100 mM NaCl50 mM Tris-HCl, pH 7.4, 10 mM MgCl., 1 mM EDTA, 2 U/mL Adenosine Deaminase

Non-specific ligand:100 μm R(-)-PIA50 μm NECA
KD+1.4 nM*0.064 ÙM*
BMAX2.7 pmole/mg Protein*7 pmole/mg Protein*
Specific binding85%* 85%*
Quantitative methodRadioligand BindingRadioligand Binding
The significance of the criterion>50% of max stimulation or inhibition> 50% of max stimulation or inhibition

Table 4
Receptor200510 Adenosine A2B200610 Adenosine A3
CellHuman recombinant HEK-293 cellsHuman recombinant CHO-K1 cells
The ligand1.6 nM [.H]MRS17540.5 nM [...I] AB-MECA
Wednesday1% DMSO1% DMSO
Incubation time/temperature90 minutes @ 25.C60 minutes @ 25.C
The incubation buffer50 mM Tris-HCl, pH 6.5, 5 mM MgCl., 1 mM EDTA, 0.01% Bacitracin25 mM HEPES, pH 7.4, 5 mM MgCl, 1 mM CaCl., .1% BSA
Non-specific ligand:100 ÙM NECA1 ÙM IB-MECA
KD+0.77 nM*5.9 nM*
BMAX6.2 pmole/mg Protein*1.8 pmole/mg Protein*
Specific binding77%*83%*
Quantitative methodRadioligand BindingRadioligand Binding
The significance of the criterion>50% of max stimulation or inhibition> 50% of max stimulation or inhibition

Radioligand analysis of the interaction of compounds of General formula 1 with adenosine A1, A2A, A2Band a3receptors showed high selectivity for adenosine A2Athe receptor (table 2).

1. Substituted ferociously acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1 and their pharmaceutically acceptable salts

where R1, R2 and R3 are not necessarily simultaneously represent hydrogen, C1-C5alkyl, C3-C5alkenyl or3-C5quinil;
R4 represents hydrogen, halogen atom, hydroxyl, C1-C3lcil, C1-C3alkyloxy;
R5 represents hydrogen, C1-C3alkyl, a group-C(O)R6;
R6 represents hydroxyl,1-C5alkyloxy,3-C5alkenylacyl,3-C5alkyloxy, optionally substituted by an amino group, where the optional substituents are the same are selected from hydrogen, C1-C5the alkyl, optionally substituted mono - or dialkylamino, alkoxygroup, 5-6-membered saturated heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen; pyridyl, phenyl, optionally substituted by 1-3 methoxypropane; or optionally substituted 6-membered, optionally annelirovannymi with a 5-membered unsaturated heterocycle, saturated heterocyclyl containing 2 nitrogen atom, where the substituents are selected from C1-C5the alkyl, optionally substituted 5-membered heteroaryl containing 1-3 heteroatom selected from nitrogen and oxygen; or 6-membered optionally saturated heterocyclyl containing 1-2 nitrogen atom, optionally substituted C1-C5the alkyl, oxo, optionally substituted by phenyl;
the dotted line with its accompanying solid line (represents a single, double or triple bond;
excluding {4-[2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-VI is Il]-phenoxy}-acetic acid ethyl ester {4-[2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid.

2. Compounds according to claim 1, which represents ferociously acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1.1 and 1.2

where R1, R2, R3, R4, R5, R6 and the dotted line with its accompanying solid line () have the meanings specified for compounds of General formula 1.

3. Compounds according to claim 1, which represents ferociously acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1.3 and 1.4

where R6 has the meaning indicated for the compounds of General formula 1, and R4 represents hydrogen or a methoxy group.

4. Compounds according to claim 1, including:
methyl ester{5-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-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-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.2.0(1),
{4-[(E)-2-(1,3-diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid 1.2.0(2),
methyl ester of 2-(4-(2-(1,diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-ethyl)phenoxy)-acetic acid 1.2.0(3),
2-(4-(2-(1,diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-of puree-8-yl)-ethyl)phenoxy)-acetic acid 1.2.0(4),br/> methyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-phenoxy}-acetic acid 1.3.2,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-VL)-vinyl]-phenoxy}-ndimethylacetamide 1.3.3,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-di-(2-methoxyethyl)-ndimethylacetamide 1.3.4,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(2-dimethylaminoethyl)-N-methyl-ndimethylacetamide 1.3.5,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-(3-morpholine-4-ylpropyl)-ndimethylacetamide 1.3.6,
1,3-diethyl-8-((E)-2-{4-[2-(4-isopropyl-piperazine-1-yl)-2-oxo-ethoxy]-phenyl}-vinyl)-7-methyl-3,7-dihydro-purine-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-pyrimidine-5-yl)-piperazin-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1.3.9,
1,3-diethyl-8-{(E)-2-[4-(2-{4-[6-(2-methoxy-5-fluoro-phenyl)-pyrimidine-4-yl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-7-methyl-3,7-dihydro-purine-2,6-dione 1.3.10,
1,3-diethyl-7-methyl-8-[(E)-2-(4-{2-oxo-2-[4-(6-phenyl-pyrimidine-3-yl)-piperazine-1-yl]-ethoxy}-phenyl)-vinyl]was 3.7-dihydro-purine-2,6-dione 1.3.11,
8-{(E)-2-[4-(2-{4-[3-(3,4-dimethoxy-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-piperazine-1-yl}-2-oxo-ethoxy)-phenyl]-vinyl}-1,3-diethyl-7-methyl-3,7-dihydro-purine-2,6-dione 1.3.12.
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)vinyl]-2-methoxy-phenoxy}-N-(3,4,5-trimethoxyphenyl)-ndimethylacetamide 1.3.13,
{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-chloro-phenoxy}-acetic acid 1.3.14,
{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.15,
methyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.16,
isopropyl ester {4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-acetic acid 1.3.17,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-ndimethylacetamide 1.3.18,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-methyl-ndimethylacetamide 1.3.19,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N-ethyl-ndimethylacetamide 1.3.20,
2-{4-[(E)-2-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-yl)-vinyl]-2-methoxy-phenoxy}-N,N-dimethyl-ndimethylacetamide 1.3.21,
ethyl ester [4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-acetic acid 1.4.1,
[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-ndimethylacetamide 1.4.2,
[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-N-methyl-ndimethylacetamide 1.4.3,
1,3-diethyl-8-[3-methoxy-4-(2-oxo-2-piperazine-1-yl-ethoxy)-phenylethynyl]-7-methyl-3,7-dihydro-Puri is -2,6-Dion 1.4.4,
[4-(1,3-diethyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-ylethynyl)-2-methoxy-phenoxy]-N-pyridin-3-yl-ndimethylacetamide 1.4.5.

5. Antagonists of adenosine A2Areceptor, represents a substituted ferociously acids, their esters and amides, including 2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-silt fragment of General formula 1, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

6. Medicinal beginning for the preparation of pharmaceutical compositions and medicines with the antagonist properties of A2Areceptor for the prevention and treatment of CNS disorders such as cognitive disorders, Parkinson's disease, depression, neoplastic diseases and inflammatory processes, representing the antagonist according to claim 5.

7. Agent (adjuvant to enhance the immune response or action of medicines in the combinatorial treatment of diseases mediated by the action of the antagonist A2Areceptor, including cancer, representing an antagonist according to claim 5.

8. Pharmaceutical composition having antagonistic activity to adenosine A2Areceptor, including medicinal beginning according to claim 6 or agent (adjuvant) according to claim 7 in therapeutically effective amounts.

9. The method of selective inhibition of the activity of the adenosine A2Areceptor bookmark is different in the contacting of the sample, contains adenosine A2Athe receptor with the antagonist of adenosine A2Areceptor according to claim 5.

10. The drug, which has antagonistic activity against adenosine A2Athe receptor, in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing 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, incorporating medicinal beginning according to claim 6 or agent (adjuvant) according to claim 7, or pharmaceutical composition of claim 8, in therapeutically effective amounts.

11. The drug of claim 10 for the treatment and prevention 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. Method of prevention and treatment of diseases mediated by the action of the antagonist A2Areceptor, which consists in the introduction to the patient the pharmaceutical composition of claim 8 or drugs on any of PP-14 in therapeutically effective amounts.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula in which R1 and R2 independently denote C1-6alkyl; R4 denotes phenyl, substituted with trifluoromethyl if necessary; X denotes hydrogen or methyl; and Y denotes -C(O)R, where R denotes C1-6alkyl; or Y denotes -P(O)(OR5)2, where R5 denotes hydrogen or C1-6alkyl; or pharmaceutically acceptable salts thereof. Said compounds are prodrugs of adenosine A2B receptor. The invention also relates to a pharmaceutical composition which is an adenosine A2B receptor antagonist based on the compound of formula I.

EFFECT: formula I compounds and the pharmaceutical composition can be used in treating different diseases in mammals, such as gastrointestinal disorders, immunological disorders, allergic disorders, neurological disorders, cardiovascular disorders and diseases associated with cell hyperproliferation.

13 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-methyl-8-piperazino-7-(thiethanyl-3)-1-ethylxanthine hydrochloride of formula .

EFFECT: novel compound which can be used in medicine as an antiaggregation and disaggregation agent is obtained and described.

3 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing compounds of formula I, which are antagonists of adenosine receptors A2B, and useful in treating different conditions, including asthma and diarrhoea, as well as intermediate compounds for their production. In formula (I) R1 and R2 are independently optionally substituted alkyl; X is pyrazol-4-yl; Y is a covalent bond or a lower alkylene; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl. The method involves ring closure of the compounds of formula (3): , in which R1, R2, X, Y and Z are as described above, in the presence of a base. In the method new intermediate compounds are obtained, which makes the method of producing compounds of formula I more cost effective since the primary products used are obtained using simple technology.

EFFECT: design of a simple method of obtaining said compounds.

47 cl, 6 dwg, 30 ex

FIELD: chemistry.

SUBSTANCE: method involves alkylation of 7-potassium salt of 3-methylxanthine with 1,4-dibromobutane, with subsequent reaction of the formed 7-(4-bromobutyl)-3-methylxanthane with 1-benzhydrylpiperazine and neutralisation of the obtained base 7-/4-(4-benzhydrylpiperazinyl-1)butyl/-3-methylxanthane with organic or inorganic acid.

EFFECT: obtained compounds have better pharmacotherapeutic properties than current antihistaminic drugs.

2 cl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compound of the formula (I): or (II): wherein R1 and R2 are chosen independently from hydrogen, optionally substituted alkyl or the group: -D-E wherein R represents a covalent bond or alkylene; E represents optionally substituted alkoxy-group, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl under condition that if D represents a covalent bond then E can't represents alkoxy-group; R3 represents hydrogen atom, optionally substituted alkyl or optionally substituted cycloalkyl; X represents optionally substituted arylene or heteroarylene; Y represents a covalent bond or alkylene wherein one carbon atom can be substituted optionally for -O-, -S- or -NH-, and optionally substituted hydroxy-, alkoxy-, optionally substituted amino-group or -COR wherein R represents hydroxy-, alkoxy- or amino-group under condition that if an optional substitute represents hydroxy- or amino-group then it can't be adjacent with a heteroatom; Z represents hydrogen atom, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl under condition that Z represents hydrogen atom only under condition that Y represents a covalent bond, and X represents optionally substituted 1,4-pyrazolene, and under condition that if X represents optionally substituted arylene then Z represents optionally substituted monocyclic heteroaryl. Also, invention describes a method for treatment of the morbid state by inhibition of adenosine receptors describes as A2B based on compounds of the formula (I) or the formula (II). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

32 cl, 35 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly oncology and surgery, and may be used in treating rectal cancer. That is ensured by teleirradiation, oral administration of capecitabine, intrarectal administration of metronidazole, local SHF hyperthermia followed by a surgical intervention. Capecitabine is administered 2000 mg/m2 from the 1st to 14th days. Metronidazole 10 g/m2 is intrarectally administered on the 3rd and 5th therapeutic days as a part of a composite mixture having the following proportions, wt %: metronidazole 12-22, sodium alginate 4-6, dimethylsulphoxide 2, distilled water up to 100. The 5-hour exposure of metronidazole is followed by a session of teletherapy. The local SHF hyperthermia at temperature 41-45° for one hour follows a session of teletherapy on 3rd, 4th and 5th therapeutic days. The surgical intervention is conducted 4 weeks after the completion of the preoperative therapy.

EFFECT: method provides ensuring complete therapeutic pathomorphism of the tumour in 25% of patients, reducing toxic and post-therapeutic complications, as well as enables conducting sphincter-preserving surgical interventions.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to production of sterol derivatives, and can be used in producing 4-hydroxy-17R-methylincisterol from ergosterol by photoisomeration. When carrying out the method, a weighed portion of ergosterol is dissolved in a weakly polar solvent while illuminating the solution with optical radiation in the near UV range. The obtained solution is chromatographically separated. The fraction which is cytotoxic for HeLa line of cancer cells and human myeloid leukaemia cells is sorbed. The pH is raised to neutral value and the solution is evaporated until a milky appearance is achieved. The weakly polar solvent is added and extracted, and the organic layer is separated on separating funnel. The organic layer is evaporated and dissolved. The obtained solution is separated by analytical HPLC with subsequent purification and separation of incisterol.

EFFECT: invention enables to obtain a 4-hydroxy-17R-methylincisterol preparation by chemical synthesis.

10 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely 12-imidazolyl-1-dodecantole or its pharmaceutically acceptable salts.

EFFECT: what is prepared is a new imidazole derivative effective in treating, including malignant pathological conditions.

4 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and represents a method of treating new growths involving using ozone, differing by the fact that ozone is artificially prepared by an electrode of a medical ozone generator in the concentration of 20 mcg/ml to 500 mcg/ml; a glass electrode probe is applied on skin in a projection of a tumour and with a contact of the glass probe and an earth with a body surface for 10 to 180 min, 1-4 times a day in the presence of a conductor 1-3% hydrogen peroxide or water by formation of atomic oxygen in body fluids having a selective effect on the tumours.

EFFECT: invention provides a wide range of the methods of treating the new growths, creating the method alternative to the commonly accepted in oncology, enables eliminating injuries and disability of the patients and has a selective effect on the new growth cells causing their elimination or degeneration without the use of operative, chemotherapeutic, radiological methods of treating.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to immunology. There are presented versions of antibodies specifically bound with amino acid residues of murine 1446-1725 Notch1 or human 1446-1735 Notch1. What is disclosed is a coding polynucleotide, an expression vector based on the polynucleotide, a host cell for antibody expression. What is described is a method for producing the antibody with the use of the vector, as well as using the antibodies as a therapeutic agent or in a method of treating the disorders associated with higher signal transmission or higher Notch1 expression.

EFFECT: use of the invention provides the antibodies which reduces the Notch1 signal transmission that can find application in medicine for treating the disorders associated with higher Notch1 expression.

42 cl, 17 dwg, 5 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to antibody crystallisation. What is presented is a method for series crystallisation of hIL-12 specific antibody ABT-874. It enables producing an aqueous crystallisation mixture of the antibody of the concentration of approximately 0.5 to approximately 280 mcg/ml and polyalkylene glycol of average molecular weight approximately 400-10000 and of the concentration of 5% to 30% (wt/vol.). The prepared mixture is incubated at pH approximately 4 to approximately 6.5 and at temperature approximately 4 °C to 37 °C for form the crystals 2-500 mcm long. There are described versions of the hIL-12 crystals prepared by said method. There are disclosed versions of the pharmaceutical composition, an injected liquid composition, a crystalline suspension composition, versions of a method of treating the hIL-12 mediated disorders, based on using the antibody crystals. What is presented is using the crystals for preparing the pharmaceutical composition for treating IL-12 associated disorder.

EFFECT: using the invention enables producing the antibody crystals on a commercial scale that can find application for industrial production of the antibody crystals for treating the hIL-12 mediated disorders.

40 cl, 13 dwg, 3 tbl, 47 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention discloses CD19-binding agents representing an antibody or an antigen-binding fragment containing an amino acid sequence of a variable region of a heavy chain, and an amino acid sequence of a variable region of a light chain which are bound with human CD 19 with a dissociation constant equal or less 1x10 -7M. The amino acid sequences are presented in the description. There are disclosed nucleic acid coding the heavy and/or light chain of the antibody or the antigen-binding fragment and a ligand conjugate - a therapeutic agent, or its pharmaceutically acceptable salt or solvate for treating a CD19-associated disorder in a mammal specified in a group involving CD19-expressing cancer, chronic leukaemia, B-cell lymphoma, multiple myeloma and a number of the other oncological diseases. The conjugate for treating the disorder in the mammal is used in an effective amount.

EFFECT: use of the presented antibodies or conjugate enables higher survival rate of the patients with oncological diseases expressing CD19, as well as in treating immunopathological diseases.

18 cl, 26 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide, to a based composition, the use of said crystalline form 1, methods for preparing it.

EFFECT: what is prepared is the new crystalline form 1 of 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide effective for treating cancer.

10 cl, 9 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are 3-hydroximino derivatives of 2,3-secolupane type of general formula: , where R=H or CH3, demonstrating inhibiting activity with respect to influenza A virus. Compound with R=H combines antiviral activity with respect to influenza A virus with anti-HIV activity.

EFFECT: compounds are promising for elaboration of antiviral preparations and as key intermediates for obtaining new biologically active compounds.

3 cl, 2 tbl, 4 ex

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