AU2003250232B2 - 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 Download PDF

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AU2003250232B2
AU2003250232B2 AU2003250232A AU2003250232A AU2003250232B2 AU 2003250232 B2 AU2003250232 B2 AU 2003250232B2 AU 2003250232 A AU2003250232 A AU 2003250232A AU 2003250232 A AU2003250232 A AU 2003250232A AU 2003250232 B2 AU2003250232 B2 AU 2003250232B2
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disease
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Jacobus A. J. Den Hartog
Gary R. Gustafson
Maria L. Pras-Raves
Jan H. Reinders
Guustaaf J. M. Van Scharrenburg
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Abbott Healthcare Products BV
Arqule Inc
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Solvay Pharmaceuticals BV
Arqule Inc
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Description

00
O
1,3,5-TRIAZINE DERIVATIVES AS LIGANDS FOR HUMAN _ADENOSINE-A3 RECEPTORS The present invention relates to a group of novel triazine derivatives which are ligands for human adenosine-A 3 receptors. The invention also relates to pharmaceutical compositions containing a pharmacologically active amount of at least one of these nO novel triazine derivatives as an active ingredient.
(N
Caffeine and theophylline, two well known natural compounds, exert their Spharmacological activities by interacting with adenosine receptors. This discovery had a major impact on adenosine receptor research. At present, four types of adenosine receptors have been identified and designated A 1 A2A, A2B and A 3 respectively. All four belong to the super-family of seven transmembrane G-protein coupled receptors. Adenosine receptors are ubiquitous and involved in a great variety of biological processes. Thus, during the past decades the therapeutic potential of 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. In only two of those triazines are described. WO 9911633 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A 1 receptors.
The second patent application describing triazines, JP 11158073, is the closest prior art. It describes a series of substituted 1,3,5-triazines which are ligands for human adenosine-A 3 receptors, the most potent of which having affinities around nM.
Surprisingly, it has now been found that in a series of triazine derivatives with novel combinations of substituents, a group of compounds was shown to have an affinity for human adenosine-A 3 receptors in the low nanomolar range.
The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the W:UFO~7284069728469 SPECIE 280708.ado 00
O
O material referred to was published, known or part of the common general knowledge as at the priority date of any of the claims.
Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.
(c The invention relates to compounds of the general formula (1)
R
4
N
wherein: R, represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF3, NH 2 N-(di)-alkyl(1-3C), N- (di)-alkenyl(2-3C), N-(di)-alkynyl(2-3C), N-alkyl(1-3C)alkenyl(2-3C), N-alkyl(1- 3C)alkynyl(2-3C), N-alkenyl(2-3C)alkynyl(2-3C) or an optionally substituted C2-
C
6 cycloalkylamino group,
R
2
R
3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 OH, O-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, OCF 3
SCH
3
SOCH
3 SO2CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system, X represents NH, N-alkyl CH 2 O, S or a carbon-carbon bond, Y represents a group of the general formula or W:UFQ\728469B728469 SPECIE 280708 doc 00 R8I R 8 N-N-lR 7 Ri
NN
R
5
R
6 Rio OH R, 0 z c-1(A)
(C)
in which:
R
5 is either OH or CH 2 0H
R
6 represents H, alkyl(1-3C), phenyl, NH 2 N-(di)-alkyl(1-3C), OH, O-alkyl(1-3C) or hydroxyalkyl(1-2C); n has the value of 0,1 or 2;
R
7 represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
R
8 and R 9 independently represent H, halogen, alkyl(1-3C), OIF 3 OH, O-alkyl(1-3C), N-(di)-alkyl(1 1 -morpholinyl, 1 -piperidinyl, 1 -piperazinyl, OCF 3
SCH
3
SOCH
3 or SO 2
CH
3 Rio represents H or alkyl(1 -3C), Ril represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-20), Z represents NOH, NOalkyl(1-3C), 0 or S, and pharmacologically acceptable salts thereof, and all compounds having formula (1) 1 5 in which the substituents on potentially asymmetrical carbon atoms are in either the Rconfiguration or the S-config uration, as well as prodrugs thereof.
In the description of the substituents the abbreviation 'alkyl(1-3C)' means 'methyl, ethyl, n-propyl or isopropyl'.
In this specification 'C 2 -CISCYCloalkylamino' means any cyclic amine containing from 2 to 6 carbons in the ring. The cycloalkylamino ring may contain other atoms and may be optionally substituted. Examples Of 0 2
-C
6 cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.
W.VFOU7284891728460 SPECIE 280708880c 00 SIn this specification '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, CLN alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, alkylamido, dialkylamido, carboxyl, or two optional substituents may together C with the carbon atoms to which they are attached form a 5-or 6-membered aromatic or (N non-aromatic ring containing 0,1 or 2 heteroatoms selected from nitrogen, oxygen 0
(N
W:UFO7284691728469 SPECIE 280708 doc WO 03/101980 PCT/EP03/50203 4 or sulphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include C1-3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C1.3 alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino.
All compounds having formula in which the substituents on asymmetrical carbon atoms are in either the R-configuration or the S-configuration belong to the invention.
Also prodrugs, i.e. compounds which when administered to humans by any known route, are metabolized to compounds having formula belong to the invention. In particular this relates to compounds with primary or secondary amino groups or hydroxy groups, a typical example being the compound with formula and its enantiomers (see below). Such compounds can be reacted with organic acids to yield compounds which can be metabolized to compounds having formula The invention particularly relates to compounds having formula wherein R 1 represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF3, NH 2 or N-(di)-alkyl(1-3C), and all other symbols have the meanings as given above.
More particular the invention relates to compounds having formula wherein R 1 Cl,
R
2 X NH, Y is either group or Rg H, n=1, Z=0, R 0 o=H and R 3
R
4 Rs, RT, R 8 Rgand R 11 have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas and Cl CI
R
3 R Y NN R 7
R
8 RN N N R NR, N H R H H
OH
R
5 (3) WO 03/101980 PCT/EP03/50203 (4) Yet more particular the invention relates to compounds of either formula or in which R5 3-CH 2 0H; R 7
CH
3 Rg H; R 9 H; R 11
CH
3 and R 3 and R 4 have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas and Cl R
C
N N N OH R 4 H R N 4 H H
OH
Even more preferred is the compound having formula and its enantiomers.
ci O T 1 N(8) I II I (8) The best mode of the invention is the compound represented by formula 00 Cl 0 I S" i N SN (9) N N N R.
C H H OH C This compound has an affinity for human adenosine-A 3 receptors of pKi 9.0 0.3.
C,
O The compounds of the invention and their salts can be obtained according to the CN general routes outlined below. Those with R 1 CI are synthesized according to scheme 1: CI R2 Cl R2 k R3
R
3 N- N N I N i I N cI Nc RX N CI X N scheme 1 Experimental details for the first step in this general route are given in: J. Amer. Chem. Soc. 116, 1994, 4326 for X NH; Chem. Pharm. Bull. 45, 1997, 291 for X N-alkyl; Tetrahedron 56, 2000, 9705 for X CH 2 Pol. J. Chem. 74, 2000, 837 for X 0; 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 R 1 F or Br can be obtained fully analogously from the corresponding tri-halo derivatives. Experimental details are given in: J. Med Chem. 36 4195-4200, 1993 for R, is F, and in J. Prakt. Chem. 82, 536, 1910 for R, Br.
The compounds of the invention with R, O-alkyl(1-3C) or any of the amine substituents: NH 2 N-(di)-alkyl(1-3C), N-(di)-alkenyl(2-3C), N-(di)-alkynyl(2-3C), Nalkyl(1-3C)alkenyl(2-3C), N-alkyl(1-3C)alkynyl(2-3C), N-alkenyl(2-3C)alkynyl(2-3C) or an optionally substituted C 2
-C
6 cycloalkylamino group, can be obtained by further substitution of the chloro-derivatives as outlined below in scheme 2: W;UFQ\728469728469 SPECIE 280708.doc WO 03/101980 PCT/EP03/50203 R2 Cl R2 KI SR4 scheme 2 Experimental details are given in: Heterocycles 31 895-909, 1990 for R 1 alkoxy, and in Tetrahedron, 54 (1998) 4051-4065 for R 1 (substituted) amine.
Compounds of the invention with R, alkyl(1-3C), CF 3 or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3.
R R 2 R R R CI4NCI CIN CI X N4 C A N Y Scheme 3 Experimental details are given in: J. Med Chem 42 805-818, 1999 for R 1 alkyl, J. Chem Soc., Chem Comm 1988, (10) 638-639 for R 1
CF
3 and in Eur. J. Org. Chem., 2002, 4181-4184 for R, iodine Pharmaceutically acceptable salts may 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, sulphuric acid, phosphoric acid and nitric acid, or with organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoro acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid.
The compounds of the invention of the general formula as well as the salts thereof, have adenosine-As (ant)agonistic activity. They are useful in the treatment of WO 03/101980 PCT/EP03/50203 8 disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of those receptors. For instance in: acute and chronic 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, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections.
The adenosine-As receptor (ant)agonistic properties of the compounds of the invention were determined using the method outlined below.
Receptor Binding to human adenosine-A 3 receptors Affinity of the compounds for human adenosine-A 3 receptors was determined using the receptor binding assay described by C.A. Salvatore et al.: Molecular cloning and characterization of the human A 3 adenosine receptor, Proc. Natl. Acad. Sci. USA, 10365-10369, 1993. Briefly, membrane preparations were obtained from human recombinant (HEK 293) cells in which the human adenosine-A 3 receptor was stably expressed. Membranes were incubated at 220C for 90 minutes with [251]-AB-MECA in the absence or presence of testcompounds in a concentration range from 10 pM down to 0.1 nM, diluted in a suitable buffer. Separation of bound radioactivity from free was done by filtration through Packard GF/B glass fiber filters with several washings with ice-cold buffer using a Packard cell harvester. Bound radioactivity was measured with a scintillation counter (Topcount, Packard) using a liquid scintillation cocktail (Microscint 0, Packard). Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC5s values, i.e. that WO 03/101980 PCT/EP03/50203 9 concentration of displacing compound by which 50% of the radioligand is displaced.
Affinity pKI values were calculated by correcting the IC50 values for radioligand concentration and its affinity for the human adenosine-A 3 receptor according to the Cheng-Prusoff equation: pKi= -log (IC 5 o S/Kd)) in which the IC50 is as described above, S is the concentration 125 ]-AB-MECA used in the assay expressed in mol/l (typically 0.1 nM), and Kd is the equilibrium dissociation constant of [1251]-AB-MECA for human adenosine-A 3 receptors (0.22 nM).
The compounds of the invention have a high affinity for adenosine-A 3 receptors in the binding assay described above. This property makes them useful in the treatment of disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of these receptors.
EXAMPLES
(1 S,2R)-2-{[4-chloro-6-(3,4-methylenedioxy-phenylamino)-[1,3,5]triazin-2yl]-amino}-1-phenyl-propan-1-ol To a solution of cyanuric chloride (1.84 gr) in acetonitrile (20 ml), kept at a temperature of- 200C under stirring, dropwise were subsequently added solutions of 3,4-methylenedioxy-aniline (1.37 gr) in acetonitrile (20 ml) and diisopropylethylamine (DIPEA) (1.29 gr) in acetonitrile (20 ml). After stirring at 20°C for 1 hour, again dropwise were subsequently added solutions of DIPEA (1.29 gr) in acetonitrile ml) and (1S,2R)-(+)-norephedrine (1.51 gr) in acetonitrile (20 ml). The mixture was allowed to warm to room temperature and was stirred for another 2 hours. The resulting reaction mixture was concentrated in vacuo. After addition of ethylacetate (250 ml) the organic layer was subsequently washed with a solution of HCI in water (1M, 100ml) a solution of NaOH in water (1M, 100 ml) and brine (50 ml). The organic layer was dried over sodiumsulphate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography using silicagel and a mixture of heptane: ethylacetate as the eluent. The resulting pure product (formula see above, example B-44, see table) was obtained as a white solid in yield.
WO 03/101980 PCT/EP03/50203 The invention is further illustrated by means of the following specific examples listed in the tables below and represented by the general formula:
R
2
RI
R4 Y wherein Y represents a group of the general formula or NR R9 N R9 N 1
R
5
R
6 RI OH Ro Z
(C)
These examples are only intended to further illustrate the invention in more detail, and therefore are not deemed to restrict the scope of the invention in any way.
nr RX R2R 3 R4 Y n RsR6 A-1 CI NH H H H 1 3-CH 2 0H H A-2 CI NH OCH 3 H H 1 3-CH 2 0H H A-3 CI NH OCH 3 H H 1 3-CH 2 0H 4-CH 3 A-4 CI NH OCH 3 H H I 3-CH 2 0H 4-phenyl CI NH OCH 3 H H (A)L 1 3-CH 2 0H _4-N(CH 3 2 A-6 CI NH OCH 3 H H I 3-CH 2 0H 5-CH 2 0H A-7 CI NH H OCH 3 H I _3-CH 2 OH H A-8 CI NH CH 3 H H I 3-CHOH H A-9 CI NH CI H H I 3-CH 2 0H H cI NH 0C 2
H
5 H H 1 3-CH 2 0H H A-I1 CI NH H 0C 2 H, H I 3-CH OH H A-12 CI NH CH(OH)CH 3 I H H 1 3-CH 2 0H H A-13 CI NH H 1-morpholinyl H (A 1 3-CH 2 0H H A-14 CI NH CH 3
CH
3 H 1 3-CH 2 0H H CI NH F CH 3 H I 3-CH 2 0H H A-16 CI NH F OCH 3 H I 3-CH 2 0H H A-17 CI NH OCH 3 H CF 3 I 3-CH 2 0H H A-18 CI NH OCH 3 H OCH 3 I 3-CH 2 0H H A-19 CI NH -phenyl- H )A 1 3-CH 2 0H H cI NH -O-CH 2 H I 3-OH H A-21 cI NH -O-CH 2 H A~ I 4-OH H A-22 CI NH -O-CH 2 H (A 1 4-OH 4-phenyl A-23 CI NH H H H I 4-OH H A-24 CI NH H CH, H 1 4-OH H CI NH CI H H I 4-OH H A-26 CI NH OCH 3 H H I 4-OH H A-27 CI NH H OCH 3 H I 4-OH H A-28 CI NH 0C 2
H
5 H H (A 1 4-OH H A-29 CI NH H 0C 2
H
5 H I 4-OH H CI NH H (CH 2 H H 1 4-OH H nr R 1 X R2 R 3 R4 Y n R 5 R6 A-31 CI NH _-phenyl H H 1 4-OH H A-32 CI NH H 0-phenyl H 1 4-OH H A-33 CI NH H 1-morpholinyl H 1 4-OH H A-34 CI NH CH 3
CH
3 H I 4-OH H CI NH F CH 3 H I 4-OH H A-36 CI NH F OCH 3 H A I 4-OH H A-37 CI NH OCH 3 H CF 3 1 4-OH H A-38 CI NH OCH 3 H OCH, 1 4-OH H A-39 CI NH -phenyl- H 1 4-OH H CI NH -O-CH 2 H (A I 2-CH 2 0H H A-41 CI NH OCH 3 H H 1 2-CH 2 0H H A-42 CI NH H OC- 3 H 1 2-CH 2 0H H A-43 CI NH H 0C 2
H
5 H 1 2-CH 2 OH H A-44 CI NH H 1-morpholinyl H 1 2-CH 2 0H H CI NH CH 3
CH
3 H I 2-CH 2 0H H A-46 CI NH F OCH 3 H 1 2-CH 2 0H H A-47 CI NH OCH 3 H OCH 3 1 2-CH 2 0H H A-48 CI NH -O-CH 2 H 1 3-CH 2 0H H A-49 CH 3 NH -O-CH 2 H 1 3-CH 2 OH H
OCH
3 NH -O-CH 2 H 1 3-CH 2 OH H A-51 1-morpholinyl NH -O-CH 2 H 1 3-CH 2 0H H A-52 1-pyrrolidinyl NH -O-CH 2 H 1 3-CH 2 0H H A-53 NH-propargyl NH -O-CH 2 H 1 3-CH 2 0H H A-54 CI NCH 3
-O-CH
2 H I 3-CH 2 0H H CI 0 -O-CH 2 H 1 3-CH 2 0H H A-56 CI S -O-CH 2 H (A I 3-CH 2 0H H A-57 CI CH 2
-O-CH
2 H A I 3-CH 2 0H H A-58 CI bond -O-CH 2 H (A 1 3-CH 2 0H H A-59 CI NH -O-CH 2 H 1 4-CH 2 0H H CI NH -O-CH 2 H 0 3-OH H A-61 CI NH CH, H H 0 3-OH H nr R, X R 2 R3R 4 Y I n R 5
R
6 A-62 cI NH CI H H 0 3-OH H A-63 CI NH OCH 3 H H- 0 3-OH H A-64 Cl NH H OCH 3 H 0 3-OH H CI NH H 0C 2
H
5 H 0 3-OH H A-66 CI NH H 1-morpholinyl H 0 3-OH H A-67 CI NH CH 3
CH
3 H 0 3-OH H A-68 CI NH F CH 3 H 0 3-OH H A-69 CI NH F OCH 3 H 0 3-OH H CI NH -phenyl- H 0 3-OH H A-71 CI NH -0-CH 2 H 0 3-CH 2 0H H rir RXR23 R 4 y R R3 R, Rio stereo B-I cI NH H H H CH 3 H H H 1IS,2R B-2 CI NH H H H CH- 3 H H H 1IR,2S B-3 CI NCH 3 H H H CH 3 H H H IS,2R B-4 CI 0 H H H CH 3 H H H IS,2R CI CH 2 H H H CH 3 H H H 18,2R B-6 CI S H H H CH 3 H H H IS,2R B-7 CI bond H H H CH 3 H H H 1S,2R B-8 CI NH H H H CH 3 H H CH 3 1R,2R B-9 CI NH OCH 3 H H CH 3 H H H IS,2R CI NH OCH 3 H H CH 3 H H H I R,2S B-11 CI NH OCH 3 H H CH 3 H H CH 3 I R,2R B-12 CI NH OCH 3 H H CH 2 CH2 H H H IS,2R B-13 CI NH OCH 3 H H (CH 2 2
CH
3 H H H IS,2R B-14 CI NH OCH 3 H H C H 2 .phenyl H H H IS,2R B-1 5 cI N H OCH 3 H H CH 2 0H H H H IS,2R B-16 CI N H OCH 2
CH
3 H H C H 3 H H H IS,2R B-17 CI N H OCH 2
CH
3 H H CH 3 H H CH 3 1R,2R B-18 CI N H CH 3 H H CH 3 H H H IS,2R B-19 CI N H CI H H CH 3 H H H 1IS,2R CI NH CI H H CH, H H CH 3 1IR,2R B-21 CI NH CH(OH)CH 3 H H CH 3 H IH H 1IS,2R B-22 CI NH CH(OH)CH 3 H H CH 3 H H CH 3 1R,2R B-23 CI NH 0-phenyl H H CH 3 H H H IS,2R B-24 CI NH 0-phonyl H H CH, H H CH 3 1IR,2R CI NH H OCH 3 H (B CH 3 H H H I S,2R B-26 CI NH H OCH 3 H CH 3 H H H 1IR,2S B-27 CI NH H OCH 3 H (B3) CH 3 -H H CH 3 1IR,2R B-28 CI NH H QCH 2
CH
3 H CH 3 IH H H IS,2R B-29 CI NH H 1-morpholinyl H CH, H H H IS,2R CI NH H CH 3 H CH 3 H H H IS,2R Nr R, XR23 R 4 Y R R 8
R
9 Rio stereo B-31 CI NH H CFs H CH 3 H H H IS,2R B-32 CI NH H 0-phenyl H CH 3 H H H IS,2R B-33 CI NH H 0-phenyl H CH 3 H H CH 3 IR,2R B-34 CI NH H (CH- 2 2 0H H CH 3 H H CH 3 IR,2R CI NH FCH 3 H CH 3 H H H IS,2R B-36 CI NH F OCH 3 H CH 3 H H H IS,2R B-37 CI NH F OCH 3 H CH 3 H H CH 3 I R,2R B-38 CI NH F OCH 3 H CH 3 H H CH 3 1IR,2S B-39 CI NH OCH, H CF 3
CH
3 H H H IS,2R CI NH OCH 3 H OCH 3
CH
3 H H H IS,2R B-41 CI NH OCH 3 H OCH 3
CH
3 H H CH 3 1IR,2R B-42 CI NH CH 3
CH
3 H CH 3 H H H IS,2R B-43 CI NH -phenyl- H CH 3 H H H IS,2R B-44 CI NH -O-CH 2 H CH 3 H H H I S,2R CI N H -O-CH 2 H CH3 H H H I R,2S B-46 CI NH -O-CH 2 H CH 3 H H CH 3 IS,2R B-47 CI NH -O-CH 2 H CH 3 H H CH 3 IS,2S B-48 CI NH -O-CH 2 H CH 3 H H CH 3 I R,2S B-49 CI NH -O-CH 2 H CH 3 H H CH 3 1IR,2R CI NCH, -O-CH 2 H CH, H H H IS,2R B-51 CI 0 -O-CH 2 H CH 3 H H H IS,2R B-52 CI S -0-CH 2 H CH 3 H H H IS,2R B-53 CI CH 2
-O-CH
2 H CH 3 H H H IS,2R B-54 CI bond -O-CH 2 H CH 3 H H H 1S,2R CI NH .O-CH 2 H CH 3 3-OH H H 1IR,2S B-56 CI NH -O-CH 2 H CH 3 4-OH H H IS,2R B-57 CI NH -O-CH 2 H CH 3 3-OH 4-OH H 1IR,2S B-58 CI NH -O-CH 2 H I CH, 2-OCH3 5-QOCH 3 H racemic B-59 NH 2 NH -O-CH 2 H CH 3 H H H 1IR,2S
N(CH
3 2 N H -O-CH 2 H CH 3 H H H I R,2S B-61 1-pyrroildinyl NH -O-CH 2 H CH 3 H -H H 1S,2R Nr R, XR2 I R 4 Y R R 8
R
9 RID stereo B-62 1-morpholinyl NH -O-CH 2 H CH 3 H H H IS,2R B-63 1-piperidinyl NH -O-CH 2 H CH 3 H H H IS,2R B-64 NH-propargyl NH -O-CH 2 H OH 3 H H H IS,2R
N(CH
3 )propargyl NH -O-CH 2 H OH 3 H H H IS,2R B-66 OH 3 NH -O-CH 2 H CH 3 H H H IS,2R B-67 OCH 3 NH_ -O-CH 2 H OH 3 H H H IS,2R Nr R, X R 2 R3R 4 Y Rs Rg RD Rl Z C-1 cI NH -O-CH 2 O- H H H H H 0 C-2 CI NH -O-CH 2 O- H H H H CH 3 0 C-3 CHa NH -O-CH 2 O- H H H H CH 3 0 C-4 OCH 3 NH -O-CH 2 O- H H H H CH 3 0 CI NH OCH 3 H H H H H CH 3 0 0-6 CI NH H OCH 3 H H H H CH 3 0 C-7 cI NH -O-CH 2 O- H H H H CH 3
N-OH
0-8 CI NH -O-CH 2 O- H H H H CH 3
N-OCH
3 C-9 cI NH -O-CH 2 0- H H H H H N-OH C-1 0 CI N H OCH 3 H H H H H H N-OH C-1I cI NH H OCH 3 H H H H H N-OH WO 03/101980 PCT/EP03/50203 17 EXAMPLES OF PRODRUGS To illustrate the concept 'prodrugs' the following compounds with the general formula have been prepared:
CI
N NN H H
OR
example R-group Pro-I propionyl Pro-2 pivaloyl Pro-3 nicotinoyl Pro-4 N-acetyl-isonipecotyl methoxyacetyl Pro-6 acethoxyacetyl Pro-7 nonaoyl Prodrugs having formula (10) have no affinity for human adenosine-A3 receptors, but after hydrolysis they generate the compound with formula (see above) which is highly active.

Claims (15)

1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 SCH 3 SOCH 3 50 2 CH 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent an 1 5 optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system, X represents NH, N-alkyl(1-3C), OH 2 0, S or a carbon-carbon bond, Y represents a group of the general formula or in which: R 5 R6 (A) R 7 R R 0 OH (B) R 1 1 R9 (C) in which: W.UFQ\728469\728469 SPECIE 280708 doc WO 03/101980 PCT/EP03/50203 19 R 5 is either OH or CH 2 0H R 6 represents H, alkyl(1-3C), phenyl, NH 2 N-(di)-alkyl(1-3C), OH, O-alkyl(1 or hydroxyalkyl(1-2C); n has the value of 0, 1 or 2; R 7 represents alkyl( benzyl, hydroxyalkyl( 1-20) or methoxyalkyll R 8 and R 9 independently represent H, halogen, alkyl(1-3C), CF 3 OH, O-alkyl(1-3C), N-(di)-alkyl(1 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 00F 3 SCH 3 SOCH 3 or SO 2 CH 3 R10 represents H or alkyl(1 -3C), R 11 represents H, alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), Z represents NOH, NOalkyl(1-3C), 0 or S, pharmacologically acceptable salts thereof, and all compounds having formula in which the substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, as well as prodrugs thereof.
2. Compounds as claimed in claim 1 of the general formula wherein R, represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 NH 2 or N-(di)-alkyl(1- R 2 R 3 and R 4 independently represent H, halogen, alkyl(1-3C), OF 3 OH, O-alkyl(1-3C), phenyl, N-(di)-alkyl(1-30), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, OCF 3 SCH 3 SOCH 3 S0 2 0H 3 or R 2 and R 3 together with the phenyl ring to which they are attached, represent a benzofuran, benzodioxane, or benzodioxolane ring system, X repre-sents NH, N-alkyl(1-3C), OH 2 0, S or a carbon-carbon bond, Y represents a group of the general formula or in which R 5 is either OH or OH 2 OH; R 6 represents H, alkyl(1-30), phenyl, NH 2 N-(di)-alkyl(1-30), OH, O-alkyl(1-3C) or hydroxyalkyl WO 03/101980 PCT/EP03/50203 n has the value of 0, 1 or 2; R 7 represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R8 and R 9 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, SCH 3 SOCH 3 or SO 2 CH 3 and Rio =H
3. Compounds as claimed in claim 1 of the general formula wherein Y is a group of the general formula and R 1 R 2 R 3 R 4 Rs, R 6 X and n have the meanings as in claim 1.
4. Compounds as claimed in claim 1 of the general formula wherein Y is a group of the general formula and Ri, R2, R 3 R 4 Rs, R 6 X and n have the meanings as in claim 2.
5. Compounds as claimed in claim 1 of the general formula wherein Y is a group of the general formula and R 1 R 2 R 3 R 4 R 7 R 8 R 9 Rio and X have the meanings as in claim 1.
6. Compounds as claimed in claim 1 of the general formula wherein Y is a group of the general formula and R 1 R 2 R 3 R 4 R 7 R 8 R 9 Rio and X have the meanings as in claim 2.
7. Compounds as claimed in claim 1 of the general formula wherein Y is a group of the general formula and R 1 R 2 R 3 R 4 Rs, R 9 Ri 0 R 11 X and Z have the meanings as in claim 1.
8. Compounds as claimed in claim 1 having formula wherein R 1 CI, R 2 =H, X=NH, Y is either group or Re H, n=1, Z=0, Rio=H and R 3 R 4 Rs, R 7 Rs, R9 and R 11 have the meanings as in claim 1
9. Compounds as claimed in claim 1 having formula wherein R 1 CI, R 2 =H, X=NH, Y is either group or R 3-CH 2 0H, R 6 H, n=1, R7 CH 3 R 8 H; R 9 H, Z=0, Rio=H, R 1 1 CH 3 and R 3 and R 4 have the meanings as in claim 1 WO 03/101980 PCT/EP03/50203 21 Compound as claimed in claim 1 having formula and enantiomers thereof: CI (8) O NI N N H H OH
11. Compound as claimed in claim 1 having formula (9) cI (K E I (9) H H O OH
12. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in one of the claims 1-11 as an active ingredient,
13. Use of a compound as claimed in one of the claims 1-11 for the preparation of a pharmaceutical composition for the treatment of disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of those receptors,
14. Use as claimed in claim 13 characterized in that said disorders are acute and chronic 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, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's 00 O disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections. A method for the treatment of a disorder in which adenosine-A 3 receptors are 5 involved, or that can be treated via manipulation of those receptors, said method comprising administering to a subject in need thereof a therapeutically effective Samount of a compound as claimed in any one of claims 1 to 11. (N
16. A method according to claim 15, wherein said disorder is selected from the Sgroup consisting of acute and chronic 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, atopic dermatitis and rhinitis; cardio-vascular disorders such as myocardial infarction, arrhythmias, hypertension, thrombosis, anaemia, arteriosclerosis, angina pectoris, cutaneous diseases such as urticaria, lupus erythematosus and pruritus; opthalmological disorders like glaucoma; respiratory disorders including chronic obstructive pulmonary disease, bronchitis and cystic fibrosis; central nervous system disorders including various forms of epilepsy, stroke, depression, sleep apnoea; disorders characterized by impairment of cognition and memory such as Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease, neurorehabilitation (post-traumatic brain lesions); acute brain or spinal cord injury; diabetes, osteoporosis, diseases of the immune system, various carcinomas and leukemia, bacterial and viral infections.
17. A compound according to claim 1, substantially as hereinbefore described with reference to any of the Examples. W UFO\7284891728469 SPECIE 280708.doc
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