MXPA04011948A - 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors. - Google Patents
1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors.Info
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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 general 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
DERIVATIVES OF 1,3,5-TRIAZINE AS LIGANDS FOR HUMAN ADENOSINE RECEPTORS-A3 DESCRIPTIVE MEMORY
The present invention relates to a group of novel triazine derivatives, which are ligands for human adenosine-A3 receptors. The invention also relates to pharmaceutical compositions containing a pharmacologically active amount of at least one of these new triazine derivatives as an active ingredient. Caffeine and theophylline, two well-known natural compounds, exert their pharmacological activities by interacting with adenosine receptors. This discovery has a major impact on adenosine receptor research. At present, four types of adenosine receptors have been identified and designated, Ai, A2A. A2B, and A3, respectively. All four belong to the super family of seven receptors coupled to the G protein of the transmembrane. Adenosine receptors are ubiquitous and are involved in a wide variety of biological processes. Thus, during the past decades, the therapeutic potential of the adenosine receptor ligands has resulted in a substantial research interest. Recent reviews are: S, Hess, Recent advances in adenosine receptor antagonist research, Expert. Opin.
Ther. Patents, 11, 1547-1562, 2001, and M.A. Jacobson, Adenosine receptor agonists, Expert. Opin. Ther. Patents, 12 (4), 489-501, 2002. Ligands for the various adenosine receptors are the subject of a large number of patent applications and patents. Triazines are described in only two of these. WO 991 163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-Ai receptors. The second patent application describing triazines, JP 1 1 158073, is the closest prior art. It describes a series of 1, 3,5-substituted triazines, which are ligands for human adenosine-A3 receptors, the most potent of them having affinities around 15 nM. Surprisingly, it has now been found that in a series of triazine derivatives with new combinations of substituents, a group of compounds showed to have an affinity for human adenosine-A3 receptors in the low nanomolar range. The invention relates to compounds of the general formula (1)
wherein: Ri represents halogen, alkyl (1-3C), 0-alkyl (1-3C), CF3, NH2, N- (di) -alkyl (1 -3C), N- (di) -alkenyl (1- 3C), N- (di) -alkynyl (1 -3C), N-alkyl (1-3C) alkenyl (1-3C), N-alkyl (1-3C) alkynyl (1 -3C), N-alkenyl ( 1-3C) alkynyl (1-3C) or an optionally substituted C2-Cs cycloalkylamino group, R2, R3 and R4 independently represent H, halogen, alkyl (1 -3C), CF3, OH, 0-alkyl (1-3C) ), phenoxy, hydroxyalkyl (1 -3C), alkoxy (1-2C) -alkyl (1-2C), phenyl, N- (di) -alkyl (1-3C), 1-morpholinyl, 1-piperidinyl, 1- piperazinyl, OCF3, SCH3, SOCH3 > S02CH3 or R2 and R3 together with the phenyl ring to which they are attached, represent a ring system benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene, optionally substituted, X represents NH, N-alkyl (1-3C), CH2, O, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):
(B) wherein: R5 is either OH or CH2OH R6 represents H, (1-3C) alkyl, phenyl, NH2, N- (di) -alkyl (1-3C), OH, O-alkyl (1- 3C) or hydroxyalkyl (1-2C); n has the value of 0, 1 or 2;
R7 represents (1 -3C) alkyl, benzyl, hydroxyalkyl (1-2C) or methoxyalkyl (1-2C), R8 and Rg independently represent H, halogen, alkyl (1-3C), CF3, OH, 0 -alkyl (1-3C), N- (di) -alkyl (1 -3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF3, SCH3 > SOCH3, or S02CH3, R10 represents H or alkyl (1-3C), Rn represents H, alkyl (1-3C), benzyl, hydroxyalkyl (1-C) or methoxyalkyl (1-2C), Z represents NOH, NOalkyl (1 -3C), O u S, and pharmacologically acceptable salts thereof. In the description of substituents, the abbreviation "alkyl (1-3C) means" methyl, ethyl, n-propyl or isopropyl. "In this specification," C2-C8 cycloalkylamino "means any cyclic amine containing from 2 to 8 carbons in the ring. The cycloalkylamino ring may contain other atoms and may be optionally substituted Examples of C2-Ce cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl, and the like This is, "optionally substituted" means that a group may or may not be further , substituted by one or more groups selected from alkyl, alkenyl, alkynyl, aryl, fluoro, chloro, bromo, hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo , nitro, acyl, amido, alkylamido, dialkylamido, carboxyl or two optional substituents can, together with the carbon atoms to which they are attached, form an aromatic or non-aromatic ring of 5 or 6 elements containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur. Optional substituents may themselves carry additional optional substituents. Preferred optional substituents include C 1 -3 alkyl, such as for example methyl, ethyl and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C 1-3 alkyloxy, such as for example methoxy, ethoxy and trifluoromethoxy and amino. All compounds having the formula (1), in which the substituents on the asymmetric carbon atoms are in either the R configuration or the S configuration, belong to the invention. Also prodrugs, ie, compounds which when administered to humans by any known route, are metabolized to compounds having the formula (1), belong to the invention. In particular, this refers to compounds with amino groups or primary or secondary hydroxy groups, a typical example is the compound with formula (9) and its enantiomers (see below). Such compounds can be reacted with organic acids to produce compounds, which can be metabolized to compounds having the formula (1). The invention particularly relates to compounds having the formula (1), wherein Ri represents halogen, alkyl (1-3C), 0-alkyl (1-3C), CF3l NH2, or N- (di) -alkyl (1 -3C), and all other symbols have the meanings as given above.
More particularly, the invention relates to compounds having the formula (1), wherein Ri = Cl, R 2 = H, X = NH, Y is either the group (A), (B) or (C), R 6 = H, n = 1, Z = O, R10 = H and R3, R4, R5, Rr, Re, g and R11 have the meanings as described above, and include all possible stereo-isomers and prodrugs as summarized above , thus as represented by the general formulas (2), (3) and (4):
(4)
Still more particularly, the invention relates to compounds of either formula (2), (3) or (4), wherein R5 = 3-CH2OH; R7 = CH3; R8 = H; R9 = H; R11 = CH3 and R3 and R4 have the meanings as described above, and include all possible stereo-isomers and prodrugs as summarized above, as well as represented by the general formulas (5), (6) and (7) : (6)
Even more preferred is the compound having the formula (8) and enantiomers.
The best mode of the invention is the compound represented by the formula (9):
This compound has an affinity for human adenosine-A3 receptors of pKi 9.0 ± 0.3. The compounds of the invention and their salts can be obtained in accordance with the general routes outlined below. Those with R-? = Cl are synthesized according to reaction scheme 1: Reaction Scheme 1 Experimental details are given for the first step in this general route in: • J. Amer. Chem. Soc. 116, 199 4326 for X = NH; • Chem. Pharm. Bull. 45, 1997, 291 for X = N-alkyl; • Tetrahedron 56, 2000, 9705 for X = CH2; • Pol. J. Chem. 74, 2000, 837 for X = O; • J. Chem. Soc. C 1967, 466 for X = S, and in • Tetrahedron 56, 2000, 9705 for X = carbon-carbon bond. The compounds of the invention with Ri = F or Br, can be obtained completely analogously from the corresponding tri-halo derivatives. Experimental details are given in: • J. Med Chem. 36 (26), 4195-4200, 1993 for RI is F, and in • J. Prakt. Chem. 82, 536, 910 for Ri = Br. The compounds of the invention with Ri = 0-alkyl (1-3C) or any of the amine substituents: NH2, N- (di) -alkyl (1-3C), N- (di) -alkenyl (1-3C), N- (di) -alkynyl (1-3C), N-alkyl (1 -3C) alkenyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-alkenyl (1-3C) alkynyl (1-3C) or an optionally substituted C2-C8 cycloalkylamino group can be obtained by further substitution of the chloro derivatives as outlined below scheme Reaction 2:
Reaction Scheme 2 Experimental details are given in: • Heterocycles 31 (5), 895-909, 1009 for Ri = alkoxy, and in • Tetrahedron, 54 (1998) 4051-4056 for Ri = amine (substituted). The compounds of the invention with Ri = alkyl (1-3C), CF3 or iodine can be obtained by following the sequence of synthetic steps summarized below in reaction scheme 3.
Reaction Scheme 3 Experimental details are given in: • J. Med Chem 42 (5), 805-818, 1999 for Ri = alkyl, • J. Cem. Soc, Chem Comm 1988, (10) 638-639 for R1 = CF3, and in · Eur. J. Org. Chem., 2002, 4181-4184 for Ri = iodo Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by mixing a compound of the present invention with a suitable acid.
Suitable acid addition salts can be formed with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, or with organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid and naphthalenesulfonic acid. The compounds of the invention of the general formula (1), as well as the salts thereof, have (ant) agonistic activity of adenosine-A3. They are useful in the treatment of disorders in which adenosine-A3 receptors are involved, or which can be treated via manipulation of these receptors. For example in: chronic and acute pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastro-intestinal disorders such as ulcers, inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic responses such as eczema, dermatitis and atopic rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anemia, arteriosclerosis, angina pectoris, skin diseases such as urticaria, lupus erythematosus and pruritus; ophthalmological disorders such as glaucoma; respiratory disorders that include chronic obstructive pulmonary diseases, bronchitis and cystic fibrosis; disorders of the central nervous system that include various forms of epilepsy, stroke, depression, sleep apnea; disorders characterized by cognitive and memory impairment such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain injuries); acute injury of the spinal cord or brain; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. The (ant) agonistic properties of the adenosine-A3 receptor of the compounds of the invention are determined using the method summarized below.
Linkage of the receptor to the human adenosine-A¾ receptors The affinity of the compounds for the adenosine-A3 receptors was determined, using the receptor binding assay described by C.A. Salvatore et al .: Molecular cloning and characterization of the human A3 adenosine receptor, Proc. Nati Acad. Sci. USA, 90, 10365-10369, 1993. Briefly, membrane preparations were obtained from recombinant human cells (HEK 293), in which the human adenosine-A3 receptor was stably expressed. The membranes were incubated at 22 ° C for 90 minutes with [125 I] -AB-MECA in the absence or presence of test compounds in a concentration range of 10 μ? below 0.1 nM, diluted in a suitable pH regulator. The separation between bound radioactivity and free radioactivity was done by filtration through GF / B Packard fiberglass filters, with several washes with ice-cooled pH regulator using a Packard cell harvester. The bound radioactivity was measured with a scintillation counter (Topcount, Packard), using a liquid scintillation cocktail (Microscint 0, Packard). The radioactivity measured was plotted against the concentration of the test compound that was displaand the displacement curves were calculated by four logistic regression parameters, resulting in IC50 values, that is, the concentration of the moving compound through which the 50% of the radioligand. The affinity pKi values were calculated by correcting the IC50 values for the radioligand concentration and its affinity for the human adenosine-A3 receptor, according to the Cheng-Prusoff equation pK, = -log (IC50 / (1 + S / Kd )) in which the IC50 is as described above, S is the concentration [25I] -AB-MECA used in the test expressed in mol / l (typically 0.1 nM), and Kd is the equilibrium dissociation constant of [ 25I] -AB-MECA for human adenosine-A3 receptors (0.22 nM). The compounds of the invention have a high affinity for the adenosine-A3 receptors in the binding assay described above. This property makes them useful in the treatment of disorders in which adenosine-A3 receptors are involved, or that can be treated via manipulation of these receptors.
EXAMPLES
(1 S.2R) -2- (r4-chloro-6- (3,4-methylenedioxy-phenylamino) -f1, 3,5-ltriazin-2-in-amino) -1-phenyl-propan-1-ol A solution of cyanuric chloride (1.84 g) in acetonitrile (20 ml), maintained at a temperature of -20 ° C under stirring, subsequently added dropwise solutions of 3,4-methylenedioxyaniline (1.3 g) in acetonitrile (20 ml) and diisopropylethylamine (DIPEA) (1.2 g) in acetonitrile (20 ml). After stirring at -20 ° C for 1 hour, trickle solutions of DIPEA (1.29 g) in acetonitrile (20 ml) and (1 S, 2R) - (+) - norephedrine (1.51 g) were subsequently added again in acetonitrile (20 ml). The mixture was allowed to warm to room temperature and stirred for another 2 hours. The resulting reaction mixture was concentrated in vacuo. After the addition of ethylacetate (250 ml), the organic layer was subsequently washed with a solution of HCl in water (1 M, 100 ml), a solution of NaOH in water (1 M, 100 ml) and brine (50 ml). ). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography using silica gel and a mixture of heptane: ethyl acetate (3: 1) as the eluent. The resulting pure product (formula (9), see above, example B-44, see table), was obtained as a white solid in 80% yield.
The invention is further illustrated by means of the following specific examples listed in the following tables and represented by the general formula:
wherein Y represents a group of the general formula (A), (B) O (C):
These examples are only proposed to further illustrate the invention in more detail, and therefore are not considered to restrict the scope of the invention in any way.
nr Ri X R2 Ra and R7 Re R9 R10 stereo
B-1 Cl NH H H H (B) CH 3 H H H 1 S 2 R
B-2 Cl NH H H H (B) CH 3 H H H 1 R, ZS
B-3 Cl NCH3 H | H H (B) CH3 H H H 1S.2R
B-4 Cl O H H H (B) CH 3 H H H 1 S 2 R
B-5 Cl CH2 H H H < B > CH3 H H H 1S.2R
B-6 Cl S H H H (B) CH 3 H H H 1 S 2 R
B-7 Cl bond H H H (B) CH 3 H H H 1 S 2 R
B-8 Cl NH H H H (B) CH 3 H H CH 3 1R 2 R
B-9 Cl NH OCHj H H (B) CH 3 H H H 1 S.2R
B-10 Cl H OCHj H H (B) CH 3 H H H 1R.2S
B-11 Cl NH OCHj H H (B) CH 3 H H CH 3 1R.2R
B-12 C H NH OCH 3 H H (B) CH 2 CH 3 H H H 1 S 2 R
B-13 Cl NH OCH 3 H H (B) (CH 2) _CH 3 H H H 1 S 2 R
B-14 Cl NH OCHj H H (B) CH 2. Phenyl H H H 1 S.2R
B-15 Cl NH OCH 3 H H (B) CH 2 OH H H H 1 S 2 R
B-16 Cl NH OCH2CH3 H H (B) CH3 H H H 1S.2R
B-17 Cl NH OCH2CH3 H H (B) CH3 H H CHj 1R.2R
B-18 Cl NH CH 3 H H (B) CH 3 H H H 1 S, 2R
B-19 Cl NH Cl H H (B) CH 3 H H H 1 S 2 R
B-20 Cl NH Cl H H (B) CH 3 H H CH 3 1R 2
B-21 Cl NH CH (OH) CH 3 H H (B) CH 3 H H H 1 S 2 R
B-22 Cl NH CH (OH) CH 3 H H (B) CH 3 H H CH 3 1R 2 R
B-23 CI NH O-phenyl H H (B) CH 3 H H H 1 S, 2 R
B-24 Cl NH O-phenyl H H (B) CH 3 H H CH 3 1 .2 R
B-25 Cl NH H OCH 3 H (B) CH 3 H H H 1 S 2 R
B-26 Cl NH H OCH 3 H (B) CH 3 H H H 1 R, 2 S
B-27 Cl NH H OCH 3 H (B) CH 3 H H CH 3 1R, 2R
B-28 Cl NH H OCH 2 CH 3 H (B) CH 3 H H H 1 S 2 R
B-29 Cl NH H 1 -morpholino H (B) CH 3 H H H 1 S 2 R
B-30 Cl NH H CH 3 H (B) CH 3 H H H 1 S, 2R
Nr Ri X R3 R4 and Rr R «Ra R.1B stereo
B-31 Cl NH H CF3 H (B) CH 3 H H H 1 S 2 R
B-3Z Cl NH H O-phenyl H (B) CH 3 H H H 1 S 2
B-33 Cl NH H O-phenyl H (B) CH 3 H H CH 3 1R 2
B-34 Cl NH H (CH 2) 2 OH H (B) CH 3 H H CH 3 1R 2 R
B-35 Cl NH H CH 3 H (B) CH 3 H H H 1 S 2 R
B-36 Cl NH F OCH 3 H (B) CH 3 H H H 1 S 2 R
B-37 C! NH F OCH3 H (B) CHj H H CH3 1R.2R
B-38 Cl NH F OCH3 H (B) CH3 H H CH3 1R.2S
B-39 Cl NH OCH, H CF3 < B) CH3 H H H 1S, 2R
B-40 Cl NH OCH 3 H OCH 3 (B) CH 3 H H H 1 S 2 R
B-41 Cl NH OCH3 H OCH3 (B) CH3 H H CH3 1R.2R
B-42 Cl NH CH 3 CH 3 H < B) CH3 H H H 1S.2R
B-43 Cl NH-phenyl- H (B) CH3 H H H 1S.2R
B-44 Cl NH -O-CH 2 -O- H (B) CH 3 H H H Í S.2R
B-45 Cl NH -0-CH2-0- H (B) CH3 H H H 1R, 2S
B-46 Cl NH -0-CHs-O- H (B) CH3 H H CH3 1S.2R
B-47 Cl NH -0-CH2-O- H (B) CH3 H H CH3 1S.2S
B-48 Cl NH -0-CH2-0- H (B) CH3 H H CH3 1R.2S
B-49 Cl NH -0-CH2-0- H (B) CH3 H H CH3 1R.2R
B-50 Cl NCH3 -0-CH2-0- H < B) CH3 H H H 1S.2R
B-51 Cl 0 -0-CH2-0- H < B) CH3 H H H 1S.2R
B-52 Cl S -O-CHj-O- H < B) CH3 H H H 1S.2R
B-53 Cl CH2 -O-CH2-0- H (B) CH3 H H H 1S.2R
B-54 Cl bond -0-CH2-0- H (B) CH3 H H H 15.2R
B-55 Cl NH -O-CHj-O- H (B) CH 3 3 -OH H H 1R.2S
B-56 Cl H -0-CH2-0- H (B) CH3 4-OH H H 1S.2R
B-57 Cl H -0-CH2-0- H (B) CH3 3-OH 4-OH H 1R.2S
B-58 CJ H -0-CH2-0- H (B) CH3 2-OCH3 5-OCH3 H racemic
B-59 NH2 NH -0-CH2-0- H (B) CH3 H H H 1R.2S
B-60 N (CH3) 2 NH -O-CH2-O- H (B) CH3 H H H 1R.2S
B-61 1-pyrrolidinyl NH -O-CH2-O- H (B) CH3 H H H 1S.2R
Nr X Rj Rs R4 Y; R., stereo R10
B-62 1 -morpholinyl NH -O-CH2-O-H < B) CH3 H H H 1S.2R
B-63 1-piperidinyl NH -O-CHa-O-H (B) CH3 H H H 1S.2R
B-64 NH-propargyl NH -O-CH2-O- H (B) CH3 H H H 1S.2R
B-65 N (CH3) propargyl NH -0-CH2-0- H (B) CH3 H H H 1S.2R
B-66 CH3 NH -O-CH2-O- H (B) CH3 H H H 1S.2R
B-67 OCH3 NH -0-CHz-O-H < B) CH3 H H H 1S.2R
Nr Ri X R2 R3 4 Y Re R9 R10 R11 Z C-1 Cl NH -O-CH20- H (C) HHHHO C-2 Cl NH -O-CH20- H (C) HHH CH3 0 C-3 CH3 NH- O-CH.0- H < C) HHH CH3 0 C-4 OCHj NH -0-CH20- H (C) HHH CH3 0 C-5 Cl NH OCH3 HH (c) HHH CH3 0 C-6 Cl NH H OCH3 H (C) HHH CH3 0 C -7 Cl NH -O-CH20- H (C) HHH CH3 N-OH
C-8 Cl NH -0-CH20- H (C) H H H CH3 N-OCH3
C-9 Cl NH -0-CH20- H (C) H H H H N-OH
C-10 Cl NH OCHj H H (C) H H H H N-OH
C-11 Cl NH H OCH 3 H (c) H H H H N-OH
EXAMPLES OF PROFARMACOS
To illustrate the concept "prodrugs", the following compounds have been prepared with the general formula (10):
The prodrugs having the formula (10), have no affinity for the human adenosine-A3 receptors, but after the hydrolysis generate the compound with the formula (9) (see above), which is highly active.
Claims (14)
1. Compounds of the general formula (1) wherein: Ri represents halogen, alkyl (1-3C), 0-alkyl (1-3C), CF3, NH2, N- (di) -alkyl (1-3C), N- (di) -alkenyl (1 - 3C), N- (di) -alkynyl (1-3C), N-alkyl (1 -3C) alkenyl (1-3C), N-alkyl (1-3C) alkynyl (1-3C), N-alkenyl ( 1-3C) alkynyl (1 -3C) or an optionally substituted C2-C8 cycloalkylamino group, R2, R3 and R independently represent H, halogen, alkyl (1 -3C), CF3, OH, O-alkyl (1-3C) ), phenoxy, hydroxyalkyl (1 -3C), alkoxy (1-2C) -alkyl (1-C), phenyl, N- (di) -alkyl (1-3C), 1-morpholinyl, 1-piperidinyl, 1- piperazinyl, OCF3, SCH3l SOCH3, SO2CH3 or R2 and R3 together with the phenyl ring to which they are attached, represent a ring system benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene, optionally substituted, X represents NH, N-alkyl (1- 3C), CH2, O, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C): wherein: R5 is either OH or CH2OH; R6 represents H, (1-3C) alkyl, phenyl, NH2, N- (di) -alkyl (1 -3C), OH, O-alkyl (1 -3C) or hydroxyalkyl (1-2C); n has the value of 0, 1 or 2; R7 represents (1-3C) alkyl, benzyl, hydroxyalkyl (1-2C) O methoxyalkyl (1-2C), R8 and Rg independently represent H, halogen, alkyl (1-3C), CF3, OH, O-alkyl (1 -3C), N- (di) -alkyl (1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF3, SCH3, SOCH3, or SO2CH3, Rio represents H or alkyl (1-3C), Rn represents H, (1 -3C) alkyl, benzyl, hydroxyalkyl (1-2C) or methoxyalkyl (1-2C), Z represents NOH, NOalkyl (1-3C), O or S, pharmacologically acceptable salts thereof, and all compounds having the formula (1) in which the substituents on the potentially asymmetric carbon atoms are in either the R configuration or the S configuration, as well as prodrugs thereof.
2. The compounds according to claim 1, further characterized by the general formula (1), wherein Ri represents halogen, alkyl (1-3C), O-alkyl (1-3C), CF3, NH2 or N- ( di) -alkyl (1-3C); R2, R3 and R4 independently represent H, halogen, alkyl (1-3C), CF3, OH, O-alkyl (1-3C), phenyl, N- (di) -alkyl (1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF3, SCH3, SOCH3, SO2CH3, or R2 and R3 together with the phenyl ring to which they are attached, represent a ring system of benzofuran, benzodioxane or benzodioxolane, X represents NH, N-alkyl ( 1-3C), CH2, O, S or a carbon-carbon bond, Y represents a group of the general formula (A) or (B), wherein R5 is either OH or CH2OH; R6 represents H, alkyl (1 -3C), phenyl, NH2, N- (d1) -alkyl (1-3C), OH, 0-alkyl (1-3C) or hydroxyalkyl (1-2C); n has the value of 0, 1, or 2; R7 represents (1 -3C) alkyl, benzyl or hydroxyalkyl (1-2C); R8 and R9 independently represent H, halogen, alkyl (1-3C), CF3, OH, 0-alkyl (1 -3C), N- (di) -alkyl (1 -3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF3, SCH3, SOCH3, or S02CH3; and R10 = H.
3. The compounds according to claim 1, further characterized by the general formula (1), wherein Y is a group of the general formula (A) and R1, R2, R3, R4, R5, R6, X and n have the meanings as in claim 1.
4. The compounds according to claim 1, further characterized by the general formula (1), wherein Y is a group of the general formula (A) and Ri, R2, R3, R4, R5, R6, X and n have the meanings as in claim 2.
5. The compounds according to claim 1, further characterized by the general formula (1), wherein Y is a group of the general formula (B) and R- ?, R2, R3, R4, R7, Re, R9, R10 and have the meanings as in claim 1.
6. The compounds according to claim 1, further characterized by the general formula (1), where Y is a group of the general formula (B) and Ri, R2, R3, R4, R7, Re, R9, R10 and X have the meanings as in claim 2.
7. The compounds according to claim 1, further characterized by the general formula (1), wherein Y is a group of the general formula (C) and Ri, R2, R3, R4, Rs. 9, R10, Rn, X and Z have the meanings as in claim 1.
8. The compounds according to claim 1, further characterized in that they have the formula (1), wherein R1 = Cl, R2 = H, X = NH, Y is either group (A), (B) or (C), R6 = H, n = 1, Z = O, R 0 = H and R3, R4, R5, R7, Re, R9 and R11 have the meanings as in claim 1.
9. The compounds according to claim 1, further characterized by having the formula (1), wherein R1 = Cl, R2 = H, X = NH, Y is either group (A), (B) or (C), R5 = 3-CH2OH, R6 = H, n = 1, R7 = CH3; Ra = H; R9 = H, Z = 0, R10 = H, R = CH3 and R3 and R4, have the meanings as in claim 1.
10. The compounds according to claim 1, further characterized by having the formula (8), and enantiomers thereof:
1 1. The compounds according to claim 1 further characterized in that they have the formula (9)
12. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in one of claims 1-1 1 as an active ingredient.
13. The use of a compound as claimed in one of claims 1-11 for the preparation of a pharmaceutical composition for the treatment of disorders, in which adenosine-A3 receptors are involved, or which can be treated via manipulation of these receptors. The use as claimed in claim 13, wherein said disorders are chronic and acute pain, inflammatory diseases including, arthritis, multiple sclerosis, asthma and psoriasis; gastrointestinal disorders such as ulcers, inflammatory bowel disease (Crohn's disease) and ulcerative colitis; allergic responses such as eczema, dermatitis and atopic rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; ophthalmological disorders such as glaucoma; respiratory disorders that include chronic obstructive pulmonary diseases, bronchitis and cystic fibrosis; disorders of the central nervous system that include various forms of epilepsy, stroke, depression, sleep apnea; disorders characterized by cognitive and memory impairment such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntlngton's disease, Parkinson's disease, neurorehabitation (post-traumatic brain injuries); acute injury of the spinal cord or brain; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections.
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