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WO2003101980A1 - 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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Publication number
WO2003101980A1
WO2003101980A1 PCT/EP2003/050203 EP0350203W WO03101980A1 WO 2003101980 A1 WO2003101980 A1 WO 2003101980A1 EP 0350203 W EP0350203 W EP 0350203W WO 03101980 A1 WO03101980 A1 WO 03101980A1
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Prior art keywords
alkyl
general formula
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PCT/EP2003/050203
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French (fr)
Inventor
Jacobus A.J. Den Hartog
Jan H. Reinders
Guustaaf J.M. Van Scharrenburg
Maria L. Pras-Raves
Gary R. Gustafson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Healthcare Products BV
Arqule Inc
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Solvay Pharmaceuticals BV
Arqule Inc
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Priority to HK05107314.9A priority Critical patent/HK1075045B/en
Priority to UA20041210642A priority patent/UA77816C2/en
Priority to EP03755982A priority patent/EP1513827A1/en
Priority to JP2004509671A priority patent/JP4590260B2/en
Priority to BR0304925-6A priority patent/BR0304925A/en
Priority to HR20040970A priority patent/HRP20040970A2/en
Priority to AU2003250232A priority patent/AU2003250232B2/en
Priority to MXPA04011948A priority patent/MXPA04011948A/en
Application filed by Solvay Pharmaceuticals BV, Arqule Inc filed Critical Solvay Pharmaceuticals BV
Priority to CA2484981A priority patent/CA2484981C/en
Publication of WO2003101980A1 publication Critical patent/WO2003101980A1/en
Priority to NO20040397A priority patent/NO326697B1/en
Priority to IL164240A priority patent/IL164240A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • 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 novel triazine derivatives as an active ingredient.
  • 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 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A-i receptors.
  • JP 11158073 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 15 nM.
  • Ri represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 , 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 C 2 -C 8 cycloalkylamino group,
  • R 2 , R 3 and R 4 independently represent H, halogen, alkyl(1-3C), CF 3 , OH, O-alkyl(1-
  • 1-morpholinyl, 1-piperidinyI, 1-piperazinyl, OCF 3 , SCH 3 , SOCH 3 , SO 2 CH 3 or R 2 and R 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-aIkyl(1-3C), CH 2 , O, S or a carbon-carbon bond
  • Y represents a group of the general formula (A), (B) or (C):
  • R 5 is either OH or CH 2 OH
  • 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), CF 3 , OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyI, OCF 3 , SCH 3 , SOCHs, or SO 2 CH 3 ,
  • R-io represents H or alkyl(1-3C),
  • R 11 represents H, alkyI(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
  • Z represents NOH, NOalkyl(1-3C), O or S,
  • 'alkyl(1-3C)' means 'methyl, ethyl, n-propyl or isopropyl'.
  • C 2 -C 8 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 C 2 -C 8 cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.
  • 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, aikylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur.
  • Optional substituents may themselves bear additional optional substituents.
  • Preferred optional substituents include
  • C ⁇ _ 3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C- ⁇ - 3 alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino.
  • prodrugs i.e. compounds which when administered to humans by any known route, are metabolized to compounds having formula (1), belong to the invention.
  • this relates to compounds with primary or secondary amino groups or hydroxy groups, a typical example being the compound with formula (9) and its enantiomers (see below).
  • Such compounds can be reacted with organic acids to yield compounds which can be metabolized to compounds having formula (1).
  • the invention particularly relates to compounds having formula (1) wherein R-i represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF 3 , NH 2 or N-(di)-alkyl(1-3C), and all other symbols have the meanings as given above.
  • This compound has an affinity for human adenosine-A 3 receptors of pKj 9.0 + 0.3.
  • R-i O-alkyl(1-3C) or any of the amine substituents: NH 2, 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 C 2 -C 8 cycloalkylamino group, can be obtained by further substitution of the chloro-derivatives as outlined below in scheme 2:
  • compositions 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.
  • inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid and nitric acid
  • 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 (1), as well as the salts thereof, have adenosine-A 3 (ant)agonistic activity. They are useful in the treatment of disorders in which adenosine-A 3 receptors are involved, or that can be treated via manipulation of those receptors.
  • 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'
  • adenosine-A 3 receptor (ant)agonistic properties of the compounds of the invention were determined using the method outlined below.
  • Affinity of the compounds for human adenosine-A 3 receptors was determined using the receptor binding assay described by CA. Salvatore et al.: Molecular cloning and characterization of the human A 3 adenosine receptor, Proc. Natl. Acad. Sci. USA, 90, 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 22°C for 90 minutes with [ 125 I]-AB-MECA in the absence or presence of testcompounds in a concentration range from 10 ⁇ M down to 0.1 nM, diluted in a suitable buffer.
  • S is the concentration r [125r IJ-AB-MECA used in the assay expressed in mol/l (typically 0.1 nM)
  • K d is the equilibrium dissociation constant of [ 125 1]-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.
  • Y represents a group of the general formula (A), (B) or (C):
  • Prodrugs having formula (10) have no affinity for human adenosine-A3 receptors, but after hydrolysis they generate the compound with formula (9) (see above) which is highly active.

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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

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-A3 receptors. The invention also relates to pharmaceutical compositions containing a pharmacologically active amount of at least one of these novel 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 had a major impact on adenosine receptc. l esearch. At present, four types of adenosine receptors have been identified and designated A-i, A2A, A2B and A3 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, 1 1 , 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 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A-i 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-A3 receptors, the most potent of which having affinities around 15 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-A3 receptors in the low nanomolar range. The invention relates to compounds of the general formula (1)
Figure imgf000003_0001
wherein:
Ri represents halogen, alkyl(1-3C), O-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 R4 independently represent H, halogen, alkyl(1-3C), CF3, OH, O-alkyl(1-
3C), phenoxy, hydroxyalkyl(1-3C), alkoxy(1-2C)-alkyl(1-2C), phenyl, N-(di)-alkyl(1-
3C),
1-morpholinyl, 1-piperidinyI, 1-piperazinyl, OCF3, SCH3, SOCH3, SO2CH3 or R2 and R 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-aIkyl(1-3C), CH2, O, S or a carbon-carbon bond,
Y represents a group of the general formula (A), (B) or (C):
Figure imgf000003_0002
in which:
R5 is either OH or CH2OH R6 represents H, alkyl(1-3C), 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 alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
R8 and R9 independently represent H, halogen, alkyl(1-3C), CF3, OH, O-alkyl(1-3C), N-(di)-alkyl(1-3C), 1-morpholinyl, 1-piperidinyl, 1-piperazinyI, OCF3, SCH3, SOCHs, or SO2CH3,
R-io represents H or alkyl(1-3C),
R11 represents H, alkyI(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
Z represents NOH, NOalkyl(1-3C), O or S,
and pharmacologically acceptable salts thereof.
In the description of the 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-C8 cycloalkylamino include pyrrolidinyl, piperidinyl, morpholinyl, aziridinyl, pyrrolinyl and the like.
In 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, alkylamino, dialkylamino, arylamino, thio, alkylthio, arylthio, cyano, oxo, nitro, acyl, amido, aikylamido, dialkylamido, carboxyl, or two optional substituents may together with the carbon atoms to which they are attached form a 5- or 6-membered aromatic or non-aromatic ring containing 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur. Optional substituents may themselves bear additional optional substituents. Preferred optional substituents include
Cι_3 alkyl such as for example methyl, ethyl, and trifluoromethyl, fluoro, chloro, bromo, hydroxyl, C-ι-3 alkyloxy such as for example methoxy, ethoxy and trifluoromethoxy, and amino.
All compounds having formula (1) 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 (1), 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 (9) and its enantiomers (see below). Such compounds can be reacted with organic acids to yield compounds which can be metabolized to compounds having formula (1).
The invention particularly relates to compounds having formula (1) wherein R-i represents halogen, alkyl(1-3C), O-alkyl(1-3C), CF3, NH2 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 (1) wherein Ri =
CI,
R2 =H, X = NH, Y is either group (A), (B) or (C), R6 = H, n=1 , Z=O, R10=H and R3, R4, 5, R7, Rs, Rgand R-π have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas (2), (3) and (4):
Figure imgf000005_0001
(2) ^5 (3)
(4) Yet more particular the invention relates to compounds of either formula (2), (3) or (4) in which R5= 3-CH2OH; R7 = CH3; R8 = H; R9 = H; Rn = CH3 and R3 and R4 have the meanings as described above, and including all possible stereo-isomers and prodrugs as outlined above, thus as represented by the general formulas (5), (6) and (7):
Figure imgf000006_0002
(6)
Figure imgf000006_0003
(7)
Even more preferred is the compound having formula (8) and its enantiomers.
Figure imgf000006_0004
The best mode of the invention is the compound represented by formula (9):
Figure imgf000007_0001
This compound has an affinity for human adenosine-A3 receptors of pKj 9.0 + 0.3.
The compounds of the invention and their salts can be obtained according to the general routes outlined below. Those with R-, = CI are synthesized according to scheme 1 :
Figure imgf000007_0002
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 = 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 R^ = F or Br can be obtained fully analogously from the corresponding tri-halo derivatives. Experimental details are given in:
• J. Med Chem. 36 (26), 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-i = O-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 in scheme 2:
Figure imgf000008_0001
scheme 2 Experimental details are given in:
• Heterocycles 31 (5), 895-909, 1990 for R^ = alkoxy, and in • Tetrahedron, 54 (1998) 4051-4065 for R, = (substituted) amine.
Compounds of the invention with Ri = alkyl(1-3C), CF3 or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3.
Figure imgf000008_0002
Scheme 3
Experimental details are given in: • J. Med Chem 42 (5), 805-818, 1999 for R-, = alkyl,
• J. Chem Soc, Chem Comm 1988, (10) 638-639 for R-, = CF3, and in
• Eur. J. Org. Chem., 2002, 4181-4184 for R1 = 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 (1), as well as the salts thereof, have adenosine-A3 (ant)agonistic activity. They are useful in the treatment of disorders in which adenosine-A3 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-A3 receptor (ant)agonistic properties of the compounds of the invention were determined using the method outlined below.
Receptor Binding to human adenosine-A3 receptors
Affinity of the compounds for human adenosine-A3 receptors was determined using the receptor binding assay described by CA. Salvatore et al.: Molecular cloning and characterization of the human A3 adenosine receptor, Proc. Natl. Acad. Sci. USA, 90, 10365-10369, 1993. Briefly, membrane preparations were obtained from human recombinant (HEK 293) cells in which the human adenosine-A3 receptor was stably expressed. Membranes were incubated at 22°C for 90 minutes with [125I]-AB-MECA in the absence or presence of testcompounds in a concentration range from 10 μM 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 IC50 values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pK| values were calculated by correcting the IC50 values for 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 r [125r IJ-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-A3 receptors (0.22 nM).
The compounds of the invention have a high affinity for 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-{[4-chloro-6-(3,4-methylenedioxy-phenylamino)-[1 ,3,5]triazin-2- yl]-amino}-1 -phenyl-propan-1 -ol
To a solution of cyanuric chloride (1.84 gr) in acetonitrile (20 ml), kept at a temperature of - 20°C 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 (20 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 (1 M, 100ml) , a solution of NaOH in water (1 M, 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 (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 tables below and represented by the general formula:
Figure imgf000011_0001
wherein Y represents a group of the general formula (A), (B) or (C):
Figure imgf000011_0002
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.
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000017_0002
EXAMPLES OF PRODRUGS
To illustrate the concept 'prodrugs' the following compounds with the general formula (10) have been prepared:
Figure imgf000018_0001
Figure imgf000018_0002
Prodrugs having formula (10) have no affinity for human adenosine-A3 receptors, but after hydrolysis they generate the compound with formula (9) (see above) which is highly active.

Claims

Claims
1. Compounds of the general formula (1)
, ,
Figure imgf000019_0001
wherein:
RT represents halogen, alkyl(1-3C), O-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(1-2C), 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 an optionally substituted benzofuran, dihydrobenzofuran, benzodioxane, benzodioxolane or naphthalene ring system,
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):
Figure imgf000019_0002
in which: R5 is either OH or CH2OH
R6 represents H, alkyl(1-3C), 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 alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C),
R8 and R9 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,
R10 represents H or alkyl(1-3C),
R11 represents H, alkyl(1-3C), 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 formula (1) 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 (1) wherein R-i 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 benzofuran, benzodioxane, or benzodioxolane ring system, X repre-sents NH, N-alkyl(1-3C), CH2, O, S or a carbon-carbon bond, Y represents a group of the general formula (A) or (B), in which R5 is either OH or CH2OH; R6 represents H, alkyl(1-3C), 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 alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R8 and R9 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; and R10 =H
Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (A) and R-i, R2, R3, R4, R5, R6, X and n have the meanings as in claim 1.
Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (A) and R-i, R2, R3, R4( R5, R6, X and n have the meanings as in claim 2.
5. Compounds as claimed in claim 1 of the general formula (1 ) wherein Y is a group of the general formula (B) and R-i, R2, R3, R4, R7, Rs, Rg, Rio and X have the meanings as in claim 1.
6. Compounds as claimed in claim 1 of the general formula (1) wherein Y is a group of the general formula (B) and R-i, R2, R3, R4, R7, R8, Rg, Rι0 and X have the meanings as in claim 2.
7. Compounds as claimed in claim 1 of the general formula (1 ) wherein Y is a group of the general formula (C) and R1 ( R2, R3, R4, Rs, Rg, Rio, Rn, X and Z have the meanings as in claim 1.
8. Compounds as claimed in claim 1 having formula (1 ) wherein R-i = CI, R2 =H, X=NH, Y is either group (A), (B) or (C), R6 = H, n=1 , Z=O, R10=H and R3, R4, R5, R7, R8, R9 and R-I-I have the meanings as in claim 1
9. Compounds as claimed in claim 1 having formula (1) wherein R-, = CI, R2 =H, X=NH, Y is either group (A), (B) or (C), R5 = 3-CH2OH, R6 = H, n=1 , R7 = CH3;
R8 = H; R9 = H, Z=O, R10=H, Rn = CH3 and R3 and R^ have the meanings as in claim 1
10. Compound as claimed in claim 1 having formula (8) and enantiomers thereof:
11. Compound as claimed in claim 1 having formula (9)
Figure imgf000022_0002
12. Pharmaceutical compositions containing a pharmacologically active amount of at least one of the compounds as claimed in one of the claims 1-1 1 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-A3 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 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.
PCT/EP2003/050203 2002-05-30 2003-05-28 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors Ceased WO2003101980A1 (en)

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MXPA04011948A (en) 2005-03-31
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CN1646520A (en) 2005-07-27
HK1075045A1 (en) 2005-12-02
AU2003250232A1 (en) 2003-12-19
CA2484981A1 (en) 2003-12-11
EP1513827A1 (en) 2005-03-16
CA2484981C (en) 2011-07-26
RU2004138803A (en) 2005-06-10
HRP20040970A2 (en) 2005-06-30
JP4590260B2 (en) 2010-12-01
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