UA77816C2 - 1,3,5- triazine derivatives as ligands for human adenosine-a3 receptors - Google Patents

Abstract

The invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A3 receptors, as well as to pharmaceutical compositions containing a pharmacologically active amount of at least one of these compounds as an active ingredient. The invention relates to compounds of the genera] formula (1) wherein Y represents a group of the general formula (A), (B) or (C) and all other symbols have the meanings as given in the description.

Description

Description of the invention

This invention relates to a group of novel triazine derivatives which are ligands for human adenosine-AZ 2 receptors. The invention also relates to pharmaceutical compositions containing a pharmaceutically effective dose of at least one of these new triazine derivatives as an active ingredient.

The pharmacological activity of caffeine and theophylline - two known natural compounds - is manifested in the interaction with adenosine receptors. This discovery had a major impact on the study of adenosine receptors. At this time, four types of adenosine receptors have been identified, which are designated A 3, Agod, Aov and Az. All of them belong to the 710 superfamily of seven transmembrane receptors associated with -protein. Adenosine receptors exist and participate in a wide variety of biological processes. Therefore, during the last decades, the therapeutic potential of adenosine receptor ligands has attracted enormous attention of researchers. Among the latest reviews, we will name |5. Nezv,

Kesepi admapsevz ip adepovzipe geseriog apiadopivi gezeagsp, Ekhregi Orip.TNeg. Raiepiv 11, 1547-1562, 2001, and

MA. asorzop, Adepozipe heseriog adopiv, Ekhregi Orip. Tneg. Raiepiz 12 (4), 489-501, 20021. 12 Many applications and patents have been filed for ligands for various adenosine receptors. Only two mention triazines. Application MULO 991163 describes a series of 2,4-bisphenyl-substituted triazines that exhibit nanomolar affinity for human adenosine-A1 receptors.

The second application, which describes triazines, namely OP 11158073, is the closest analogue of the present invention. It refers to a series of substituted 1,3,5-triazines that are ligands for human adenosine-A receptors, with the most potent of them having an affinity of about 15NM.

It has now been unexpectedly established that in a number of triazine derivatives with a new combination of substituents, a certain group of compounds has affinity for human adenosine-Az receptors in the low nanomolecular range.

The invention relates to compounds of the general formula (1)

OP)

In, ke, where: (Se)

Ki. represents halogen, alkyl(1-3C), O-alkyl(1-3C), CE z, MH", M-(di)-alkyl(1-3C), M-(di)-alkenyl(1-3C) , "-

M-(di)-alkynyl(1-3C), M-alkyl(1-3C)alkenyl(1-3C), M-alkyl(1-3C)alkynyl(1-3C), M-alkenyl(1-3C )alkynyl(1-3C) or Co-Cv cycloalkylamino group, possibly substituted, with

Ko", Kz and Ku; independently of each other - H, halogen, alkyl(1-3C), C3, OH, O-alkyl(1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1- 2C), phenyl, M-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OSE3, BECH3, BZOCH», 5O05CH» or K» and Kz together with a phenyl ring, to to which they are attached - represent possibly substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system,

X - MH, M-alkyl (1-3C), CH", O, 5 or a carbon-carbon bond, "

Y is a group of the general formula (A), (B) or (C):

With Ra and

So what if and" C - KD - that's them;

K. Y. I

Y and Vo OH Ka 2 them (FA) (B) (C) and in which: o Kv - OH or SNYON tsu 5 Kv - H, alkyl (1-3C), phenyl, MH", M-(di)- alkyl(1-3C), OH, O-alkyl(i-3C) or hydroalkyl(1-2C), n has a value of 0.1 or 2, 4") KU - alkyl(1-3C), benzyl, hydroxyalkyl( 1-2C) or methoxyalkyl(1-2C),

Ka and Co independently of each other - H, halogen, alkyl(1-3C), C3, OH, O-alkyl(1-3C), M-(di)-alkyl(1-3C), 1-morpholinyl, 1 -piperidinyl, 1-piperazinyl, ОСЕ3, ЗСН3, BOSN» or 505СНу»

K10 - H or alkyl(1-3C),

Ku - H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), iF) 7 - MON, MOalkyl(1-3C), O or 5, ko and their pharmaceutically acceptable salts .

When describing substituents, the abbreviation "(1-3C)alkyl" means methyl, ethyl, n-propyl or isopropyl. In this specification, "C0-C0 cycloamine" means any cyclic amine containing from 2 to 8 carbon atoms in the ring. The cycloamine ring may contain other atoms and may be substituted. Examples of Co-Cv cycloamines are pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.

As used herein, "optionally substituted" means that the group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxy, alkyloxy, alkynyloxy , aryloxy, acyloxy, amine, alkylamine, dialkylamine, arylamine, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amide, alkylamide, dialkylamide, carboxyl, or two possible substituents may together with the carbon atoms to which they are attached , form a 5- or 66-membered aromatic or non-aromatic ring containing 0.1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur. Possible substitutes may themselves have additional substitutes. Such additional substituents preferably include C. 3 alkyls, such as, for example, methyl, ethyl, and trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, C..3 alkoxy, such as, for example, methoxy, ethoxy, and trifluoromethoxy, as well as amines.

All compounds of the formula (1), in which the substituents on the asymmetric carbon atoms are in both the K- and the 5-configuration, are covered by the scope of the invention.

Also, prodrugs, i.e., compounds that, entering the human body by any means, are metabolized into 7/0 U compounds of formula (1), belong to the scope of the invention. In particular, this applies to compounds with primary or secondary amino groups or hydroxy groups, typical examples of which are compounds of formula (9), and their enantiomers (see below). Such compounds are capable of reacting with organic acids, forming compounds that can be metabolized into compounds of formula (1).

The invention, in particular, relates to compounds of formula (1), where K; represents halogen, alkyl(1-3C), O-alkyl(1-3C), CEz, 75. МН", M-(di)-alkyl(1-3C) and all other symbols, the values of which are given above.

In particular, the invention relates to compounds of the formula (1), where Ku is SI, Co» is H, X is MH, XU is one of the groups (A), (B) or (C), Kv

EN, p 1.250, Ko U H, and Kz, Ku, Kv, K7, Ka, Ko and K./4 have the values given above, including all possible stereoisomers and prodrugs, as indicated above, represented by the general formulas (2), (3) and (4): in -e already ze: ik Y

Tsatchi yav at I, . y 7 y ee still In Ko Y rshchy ve M 1 y-y (hi y what.

BO io) ze g she she: SHO o Ge)

S DE Ts ssh in the action of Yang I - the front of Yashinya is not there:

B o and h-

More specifically, the invention relates to compounds of one of the formulas (2), (3) or (4), where K5 is ЗСНООН; KU - SNuz; Ka. - m

N; Ko - N; Ku/4 is SNU, and Kz and K have the values given above, including all possible stereoisomers and prodrugs, as indicated above, represented by general formulas (5), (6) and (7):

And Sh Koch "

KI, she shshcha. 2)". and sh sho sh in -y her sh o ra Her | S shu 20 so

F y

More preferred is the compound of formula (8) and its enantiomers. and There are St. NN and I s

А Z з: ше ши во The compound of formula (9) is optimal for the invention:

SI o v : what v o bo N NOT he

This compound has affinity for human adenosine-AZ pK receptors. 9.0-0.3.

The compounds of the invention and their salts can be prepared by the general routes shown below. Compounds with K4 t SI are synthesized according to scheme 1: in, t

A, with "AH, t U

Ah, HA HA

Y E,. n SI I-th M

Scheme 1 70 The details of the experiment for the first stage of this general path are given in: - U. Ateg.Spet.5os. 116, 1994, 4326 for X - MH; - Spet.RNapt.VIII. 45, 1997, 291 for X - M-alkyl; - Teganeadgop 56, 2000, 9705 for X - SNO - RoI.).Spet. 74, 2000, 837 for X - 0; - U. Snet. Zos. C 1967, 466 for X - 8; - Temggapedgop 56, 2000, 9705 for X - carbon-carbon bond.

Compounds according to the invention, where Ki is E or Bg, can be obtained in a completely analogous way from the corresponding trihalo derivatives. Details of the experiment are given in: - U.Med.Spet. 36 (26), 4195-4200, 1993 for CC. - E - ).RgakiSsNo. 82, 536, 1910 for V. - Vg

Compounds according to the invention, where Ki is O-alkyl(1-3C) or any amine substituents: МН 5», M-(di)-alkyl(1-3C),

M-(di)-alkenyl(1-3C), M-(di)-alkynyl(1-3C), M-alkyl(1-3C)alkenyl(1-3C), M-alkyl(1-3C)alkynyl (1-3C),

M-alkenyl(1-3C)alkynyl(1-3C) or a possibly substituted Co-Ca cycloalkylamino group can be obtained by further substitution of chlorine derivatives, as described below, according to scheme 2: c

Kk, si t. v, (o) work ovo -----

V, va v ke, i-th 4 "-

Scheme of 2 so

The details of the experiment are given in: i- - Neuroscience 31 (5), 895-909, 1990 for Ku - alkoxy, 3o - Tegapeidgop, 54 (1998) 4051 -4065 for B. - (substituted) amine. in

Compounds according to the invention, where KK. - alkyl(1-3C), CEz or iodine can be obtained by performing the sequence of synthesis stages according to scheme 3: si and y c. I, in ch er -- r ve r -- re ke 7 u» forging B, aa k he -I 35 Scheme 3

Details of the experiment are given in: - and - ). Med. Snet 42 (5), 805-818, 1999 for Ku :- alkyl, o - ). Spet. 5Bos, Spet. Sotit. 1988, (10) 638-639 for Ku - SEz, - Etsg.9U.Oga.Spet., 2002, 4181-4184 for Ku - iodine. Pharmaceutically acceptable salts can be obtained by known methods, for example, by mixing the compound according to

F of the invention with the corresponding acid.

Suitable adduct salts can be prepared with inorganic acids such as hydrochloric, sulfuric, phosphoric and nitric or with organic acids such as citric, fumaric, maleic, tartaric, acetic, trifluoroacetic, benzoic, p-toluenesulfonic, methanesulfonic and naphthalenesulfonic.

Compounds according to the invention of the general formula (1), as well as their salts, possess (ant)agonistic activity against (F) adenosine-Az. They may be useful in the treatment of disorders associated with adenosine-Az receptors, or those that can be treated by acting on these receptors. For example, these are: acute and chronic pain, inflammatory diseases (arthritis, multiple sclerosis, asthma and psoriasis); gastrointestinal diseases (ulcer, inflammatory bowel disease, or Crohn's disease, ulcerative colitis); allergic reactions (eczema, atopic dermatitis, rhinitis); cardiovascular diseases (myocardial infarction, arrhythmia, hypertension, thrombosis, anemia, atherosclerosis, breast frog), skin diseases (pruritus, lupus, urticaria); ophthalmic disorders (glaucoma); respiratory disorders (chronic obstructive pulmonary diseases, bronchitis, cystofibros); disorders of the central nervous system, including various forms of epilepsy, stroke, depression, insomnia); disorders associated with impairment of cognitive ability and memory, such as Alzheimer's disease, Creutzfeldt-Jakob disease,

Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain damage); acute injuries of the brain or spine; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. The (ant)agonistic properties of the compounds according to the invention in relation to adenosine-Az were determined by the following method.

Human adenosine-Az receptor binding assay

The affinity of compounds to human adenosine-Az receptors is determined using the receptor binding test described in the work (S.A. Zaimaige ei aiI.: Moiesciag siopipud apa spagasiegigayop oi (pe putap Az adepovzipe geseriog, Rgos. Mai. Asai. Zsi . OBA, 90, 10365-10369, 1993). Briefly, preparations of membranes of human recombinant cells (NEK 293) in which the human adenosine-A3 receptor is stably expressed are obtained. 70 The membranes are incubated at 222C for 90 minutes with I"29C- AB-MESA in the presence or absence of test compounds in the concentration range from 1μM to 0.1n8M when diluted with the appropriate buffer.Bound and free radioactivity are separated on a Packard CP/B glass fiber filter with several washes with ice buffer using a Packard cell harvester . The bound radioactivity is measured with a scintillation counter (Packard Torsocpi) using a liquid scintillation cocktail (Packard Misgossipi O). 75 The measured values of radioactivity are deposited on the figure relative to the concentration of the reconstitution test compound, and the reconstitution curves are calculated using four-parameter logistic regression, obtaining the values

ISvo, that is, concentrations of the remodeling compound at which 5075 radioligands are remodeled. Values of pK ) are calculated by correcting the value of IS so taking into account the concentration of the radioligand and its affinity to human adenosine-Az receptors according to the Cheng-Prusov equation:

RKALOD(Syok1 Z/Ka)) where ISvo is indicated above, 5 - concentration | 129C-AB-MESA used in the test is in moles/L (typically 0.1nM), and Ku is the equilibrium dissociation constant of I22-AB-MESA for human adenosine-A receptors with (0.22nM).

Compounds according to the invention have a high affinity for adenosine-Az receptors in the above-described CM binding test. This property makes them useful in the treatment of disorders associated with adenosine-Az receptors, or those that can be treated by acting on these receptors.

Examples (15,2K)-2-C4-chloro-6-(3,4-methylenedioxy-phenylamine)-(1,3,5)griazin-2-yl|-amine)-1-phenyl-propan-1- ol

To a solution of 1.84 g of cyanuric chloride in 20 ml of acetonitrile, which is maintained at a temperature of -202C with stirring, sequentially add dropwise solutions of 1.37 g of 3,4-methylenedioxyaniline in 20 ml of acetonitrile and "- 1.20 g of diisopropylethylamine (DIPEA) in 20 ml of acetonitrile . After stirring at -20 °C for 1 hour, solutions of 1.29 g of DIPEA in 20 ml of acetonitrile and 1.51 g of (15.2K)-(-)-norephedrine so in 20 ml of acetonitrile are successively added dropwise. The mixtures are allowed to warm to room temperature and stirred for another 2 hours. The resulting reaction mixture is concentrated under vacuum. After adding 250 ml of ethyl acetate, the organic phase is successively washed with a solution of 1 M NOI in 100 ml of water, a solution of 1 M Mahon in 10 ml of water and 5 ml of brine. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The obtained product is purified by column chromatography with silica gel and a mixture of 3:1 heptane-ethyl acetate as an eluent. A pure white solid is obtained (formula (9), see above, Example B-44, see Table) with a yield of 8095.

Further, the invention is illustrated by the following specific examples, which are listed in the following tables and represented by the general formula: З с 1» Кк, Кк, ий | (1) - | t, ke

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Examples of prodrugs - To illustrate the concept of "prodrugs", the following compounds of the general formula (10) are prepared: 42)

F) name) 60 b5 yu VE o VVA r prov /Oolpriai 00001 vai S.

G77lyrei 111010101000oikotinoiy 110101 t Iposchei o... Metoksvtsemia,

She shreu | 0 is fighting in

Prodrugs of formula (10) do not have affinity for human Az receptors, but after hydrolysis form a compound of formula (9) (see above), which is very active.

Claims (13)

The formula of the invention p 1. Compounds of the general formula (1) o ve v, no R. ovo M prysh F zo v, KS U - where: co Ki. represents halogen, alkyl(1-3C), O-alkyl(1-3C), CE z, MH", M-(di)-alkyl(1-3C), M-(di)-alkenyl(1-3C) , M-(di)-alkynyl(1-3C), M-alkyl(1-3C)alkenyl(1-3C), M-alkyl(1-3C)alkynyl(1-3C), M-alkenyl(1- 3C)alkynyl(1-3C) or C»-C8 - a cycloalkylamino group, possibly substituted, Co, Kz and K. independently of each other - H, halogen, alkyl(1-3C), CEz, m OH, O-alkyl( 1-3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, /M-(di)-alkyl(1-3C), 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, OSEz, CH, BOSNZ, 5O0oCHz, or Co and Kz, together with the phenyl ring to which they are attached, represent possibly substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or the naphthalene ring system, " X - MH, M- alkyl (1-3C), CH», О, 5 or a carbon-carbon bond, what is U - a group of the general formula (A), (B) or (C): c c) Be (B) BE OO ) » še o Ky tre MAZH ve RE M : M : - - Y Rid ON KA in which: so VEB - OH or СНоОН, -oUu 70 Kv - H, alkyl(1-3C), phenyl, MH», M- (di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroalkyl(1-2C), n has a value of 0, 1 or 2, 4» KU - alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), Ka and Ke independently of each other - H, halogen, alkyl(1-3C), CEz, OH, O-alkyl(1-3C), M-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, ОСЕ3, ЗСН3, BOSN» or 505СН», Co - H or alkyl(1-3C), o Ku4 - H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), 7 - MON, MOalkyl(1-3C), О or 5, ю and their pharmacologically acceptable salts and all compounds of formula (1), where the substituents on potentially asymmetric carbon atoms are either in the K-configuration or in the 5-configuration, as well as their prodrugs. 60 2. Compounds according to claim 1 of the general formula (1), where Ku; represents halogen, alkyl(1-3C), O-alkyl(1-3C), CEz, MNo or M-(di)-alkyl-(1-3C)3; Ko, Kz and K/; independently of each other represent H, halogen, alkyl(1-3C), C3, OH, O-alkyl(1-3C), phenyl, M-(di)-alkyl(1-3C), 1-morpholinyl, 1- piperidinyl, 1-piperazinyl, OSEz, ZCHz, ZOCH», 5O»CH», or Co and Kz, together with the phenyl ring to which they are attached, represent the ring system of benzofuran, benzodioxane or benzodioxolane, X represents MH, M-alkyl (1 -3C), CH 5", 0, 5 or carbon-carbon bond, U represents a group of the general formula (A) or (B), in which K 5 is OH or SNOH; Ko represents H, alkyl(1-3C), phenyl, MH», M-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C); n has a value of 0, 1 or 2; K 7 represents alkyl(1-3C), benzyl or hydroxylalkyl(1-2C); K 8 and Co independently represent H, halogen, alkyl(1-3C), CE 3, OH, O-alkyl(1-3C), M-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, ОСЕ3, BСН3, BOСН», 5О2СН», and K /0-N. Z. Compounds according to claim 1 of the general formula (1), where U is a group of the general formula (A), and Ku, Ko, Kz, Ku, Kb, Kv, X tap have the values given in claim 1. 4. Compounds according to claim 1 of the general formula (1), where U is a group of the general formula (A), and Ku, Ko, Kz, Ku, Kv, Kv, X tap have the values given in claim 2. 5. Compounds according to claim 1 of the general formula (1), where U is a group of the general formula (B), and Ku, Ko, Kz, Ku, Kb, Kv, X tap 7/0 have the values given in claim 1. 6. Compounds according to claim 1 of the general formula (1), where U is a group of the general formula (B), and Ku, Ko, Kz, Ku, Kb, Kv, X tap have the values given in claim 2. 7. Compounds according to claim 1 of the general formula (1), where U is a group of the general formula (C), and Ki, K", Kz, Ku, Kv, Kv, X tap have the values given in claim 1. 8. Compounds according to claim 1 of the general formula (1), where К/-СИ, К»-Н, ХАМН, М is one of the groups (A), (B) or (C), Ke-Н, n-1, 250, ZO-H, and Ku, Ku, Kv, Ku, Ka, Ko and K./4 have the values given in claim 1. 9. Compounds according to claim 1 of the general formula (1), where К.-СИ, К»-Н, ХАМН, У - one of the groups (А), (В) or (С), К5-3-СНоОН, Ev- H, n-1, K/-CH3, Kv-H, Keo-H, 2-0, K/0-H, K34-CH», and K»z and K.; have the values given in claim 1. 10. Compounds according to claim 1 of formula (8) and their enantiomers: 2 si (8). a: re, g tn. de i y-- - shi sia se sch Nn N o an 11. Compounds according to claim 1 of formula (9) 12. A pharmaceutical composition containing a pharmacologically acceptable amount of at least one of the compounds specified in claims 1-11. 13. Use of the compound specified in any of claims 1-11 for the preparation of a pharmaceutical composition "for the treatment of disorders associated with adenosine-A z receptors, or those that can be treated by acting on these receptors." - c 14. Application according to claim 13, which differs in that the specified disorders are acute and chronic pain, inflammatory diseases (arthritis, multiple sclerosis, asthma and psoriasis); gastrointestinal diseases (ulcer, )» inflammatory bowel disease or Crohn's disease, ulcerative colitis); allergic reactions (eczema, atopic dermatitis, rhinitis); cardiovascular diseases (myocardial infarction, arrhythmia, hypertension, thrombosis, anemia, atherosclerosis, breast frog), skin diseases (pruritus, lupus, urticaria); ophthalmological disorders -i (glaucoma); respiratory disorders (chronic obstructive pulmonary diseases, bronchitis, cystofibros); disorders of the central nervous system, including various forms of epilepsy, stroke, depression, insomnia; disorders associated with impairment of cognitive ability and memory, such as Alzheimer's disease, Creutzfeldt-Jakob disease, (ee) Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain damage); acute injuries in 20 brain or spine; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. 42) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 1, 15.01.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. F) name) 60 b5