CA2484981C - 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors - Google Patents
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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
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; -research. At present, four types of adenosine receptors have been identified and designated A,, 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, 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 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A, 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 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; -research. At present, four types of adenosine receptors have been identified and designated A,, 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, 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 991163 describes a series of 2,4-bisphenyl substituted triazines showing nanomolar affinity for human adenosine-A, 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) wherein:
R, 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-Ca 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-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, 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):
~N n R R11 N N
R10 Rio z (A) (B) (C) in which:
R5 is either OH or CH2OH
R, 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-Ca 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-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, 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):
~N n R R11 N N
R10 Rio z (A) (B) (C) 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, Rio 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), 0 or S, and pharmacologically acceptable salts thereof.
According to one aspect of the present invention, there is provided a compound of the general formula (1) R2 ~R1 R3 N \ N (1) \ X~N" 'Y
wherein:
R, 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(I-3C)alkynyl(1-3C) or an optionally substituted C2-C6 cycloalkylamino group, 3a 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-K), 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, 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):
N R7 Rq R11 Rq N N
(A) (B) (C) 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, 3b 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), 0 or S;
a pharmacologically acceptable salt thereof, a compound having formula (1) in which substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, or a pharmaceutically acceptable ester thereof.
According to another aspect of the present invention, there is provided a use of a compound as described herein for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
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, alkylamido, dialkylamido, carboxyl, or two optional 3c 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 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 (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 R1 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 R1 =
Cl, 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, R9and R11 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):
CI CI
R3 N/ \ N R3 / NN N R7 \ NJ`N 9 R4 N~N~ N R4 R
H H H
OH
(2) R5 (3) CI
R3 i N R1~ /
NN~N \
O
(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; R11 = CH3 and R3 and R4 have the meanings as described above, and including all possible stereo-isomers and 5 prodrugs as outlined above, thus as represented by the general formulas (5), (6) and (7):
CI
R3 \ CI
N N /
R4 \
R
(5) OH
(6) CI
a R H N H
O
(7) Even more preferred is the compound having formula (8) and its enantiomers.
CI
O / N" \ N /
O N N N
H H
OH
The best mode of the invention is the compound represented by formula (9):
~CI
0 / N'O`N /
OH
This compound has an affinity for human adenosine-A3 receptors of pK; 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, = Cl are synthesized according to scheme 1:
NN R3 N" N 3 / N N
CI Ra XN~CI R4 X~N~Y
CI 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 = CH2;
= 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 R1 = 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 R1 = Br.
The compounds of the invention with R, = 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 chioro-derivatives as outlined below in scheme 2:
R2 CI R2 Ri R3 NI \-N N ' N
R4 R X~N" 'Y
scheme 2 Experimental details are given in:
= Heterocycles 31 (5), 895-909, 1990 for R1 = alkoxy, and in = Tetrahedron, 54 (1998) 4051-4065 for R, = (substituted) amine.
Compounds of the invention with R, = alkyl(1-3C), CF3 or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3.
CI RI R2 Ri R2 R1 N N N'-~N R3 i -N R3 N" \N
CIN'5~CI CI"'N~CI Rq XN~CI I x~N~Y
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 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 (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 C.A. 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 ['251]-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. 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 pKi 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:
pKi= -log (IC50 / (1 + S/Kd) ) in which the IC50 is as described above, S is the concentration [I251]-AB-MECA
used in the assay expressed in mol/I (typically 0.1 nM), and Kd is the equilibrium dissociation constant of [125I]-AB-MEGA 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:
5 R4 \ X~ N Y
wherein Y represents a group of the general formula (A), (B) or (C):
RS Ra n R7 R9 R11 /
Rg \N I / \N
Rio 0H Rio Z
(A) (B) (C) 10 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.
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, Rio 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), 0 or S, and pharmacologically acceptable salts thereof.
According to one aspect of the present invention, there is provided a compound of the general formula (1) R2 ~R1 R3 N \ N (1) \ X~N" 'Y
wherein:
R, 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(I-3C)alkynyl(1-3C) or an optionally substituted C2-C6 cycloalkylamino group, 3a 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-K), 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, 0, S or a carbon-carbon bond, Y represents a group of the general formula (A), (B) or (C):
N R7 Rq R11 Rq N N
(A) (B) (C) 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, 3b 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), 0 or S;
a pharmacologically acceptable salt thereof, a compound having formula (1) in which substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, or a pharmaceutically acceptable ester thereof.
According to another aspect of the present invention, there is provided a use of a compound as described herein for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
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, alkylamido, dialkylamido, carboxyl, or two optional 3c 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 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 (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 R1 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 R1 =
Cl, 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, R9and R11 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):
CI CI
R3 N/ \ N R3 / NN N R7 \ NJ`N 9 R4 N~N~ N R4 R
H H H
OH
(2) R5 (3) CI
R3 i N R1~ /
NN~N \
O
(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; R11 = CH3 and R3 and R4 have the meanings as described above, and including all possible stereo-isomers and 5 prodrugs as outlined above, thus as represented by the general formulas (5), (6) and (7):
CI
R3 \ CI
N N /
R4 \
R
(5) OH
(6) CI
a R H N H
O
(7) Even more preferred is the compound having formula (8) and its enantiomers.
CI
O / N" \ N /
O N N N
H H
OH
The best mode of the invention is the compound represented by formula (9):
~CI
0 / N'O`N /
OH
This compound has an affinity for human adenosine-A3 receptors of pK; 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, = Cl are synthesized according to scheme 1:
NN R3 N" N 3 / N N
CI Ra XN~CI R4 X~N~Y
CI 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 = CH2;
= 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 R1 = 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 R1 = Br.
The compounds of the invention with R, = 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 chioro-derivatives as outlined below in scheme 2:
R2 CI R2 Ri R3 NI \-N N ' N
R4 R X~N" 'Y
scheme 2 Experimental details are given in:
= Heterocycles 31 (5), 895-909, 1990 for R1 = alkoxy, and in = Tetrahedron, 54 (1998) 4051-4065 for R, = (substituted) amine.
Compounds of the invention with R, = alkyl(1-3C), CF3 or iodine can be obtained by following the sequence of synthetic steps outlined below in Scheme 3.
CI RI R2 Ri R2 R1 N N N'-~N R3 i -N R3 N" \N
CIN'5~CI CI"'N~CI Rq XN~CI I x~N~Y
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 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 (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 C.A. 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 ['251]-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. 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 pKi 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:
pKi= -log (IC50 / (1 + S/Kd) ) in which the IC50 is as described above, S is the concentration [I251]-AB-MECA
used in the assay expressed in mol/I (typically 0.1 nM), and Kd is the equilibrium dissociation constant of [125I]-AB-MEGA 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:
5 R4 \ X~ N Y
wherein Y represents a group of the general formula (A), (B) or (C):
RS Ra n R7 R9 R11 /
Rg \N I / \N
Rio 0H Rio Z
(A) (B) (C) 10 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.
cli M E M = ~+
3: 3: 4 U U = = = = = = = 2 = 2 2 2 2 2 = _ = 2 2 2 2 2 = _ _ d _ _ 0000000000000000000===========
La N TN N N N N TN N N N N N N N N N N N N O O O O O O O O O O O
1 1 1 1 1 1 . 1 . 1 1 UUUUUUUUUUUUUUUUUUUMe! d d ~et~t d d d ~!
M M M M M M M M M M M M M M M M M M M
= r r r r r r r r r r r r r r f r T r r r r T r r T r r r 77 >- aaaaaaaaaaaaaaaaaaaaaaaaaaaaaa _ V I U I I = = I U I U N
0 O o v V 0 O O=
E =000 N N N
r G1I=I
99 d 6 6 M M M M M U_ (M M M 'I
=UUUUUI UUI = LL U- `rQ I=UU=U
00000 0 = U 00 0 0 U
= I = _ Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z
~ U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U
N M T U) O ti M Q) O r N M d O O N. CO 0) O r N M 'd' to CD N. CO C) O
~. r r r r r r r r r r N N N N N N N N N N M
= aaaaaaaaaaaaaaaaaaaaaaaaaaaaaa __== 2 2 2 2=__= 2 2 2 2 2 2=_= 2 2 2 2 2 2 2 2 _ 2 = _ =========00000000000000000000==
Ill N N N N N N N N N N N N N N N N N N N N
000000Q00==================== O O
1 1 1 1 1 I 1 1 1 ..
d ~! d d et d d U U U U U U U U U U U U U U U U U U U U M M
N N N N N N M M M M M M M M
r r r r r r r r r r r T r r r r r r r r r r r r r r r r r O O
aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa ~/ M M
>1 =
N
/y o O M 1,7 M = O M M
m 3: 04 M
U U U =_ = U U Q U=
O E -.0 E 0000000000000 r N r N N N N N N N N N N N N N
U U U U U U U U U U U U U U
_ 1 1 1 1 I 1 1 1 1 I I I I 1 M M M M M M M
t=_= LL LL U U U=__= LL U =
O
M
~' X z z Z Z z z z Z z z z z Z z Z Z z z z z z Z Z Z O O_v 20 z z z -n: ~UUUr N M d' tf) Cfl I` co O O r N M t7 lf! CO I- co O O r cm M O ti d' d-T LC) LO L() Uf) ~4t4 aaaaaaaaa 2 Z = = 2 = _ _ _ _ 2 2 2= 2 2 2== O
000000000c"
=
i ch %~ i 1 ch 1 %~ c~ U
~ aaaaaaaaaa M M
Z: 3: O o v U 0 E O
L
T" = N
t U
O
U U=_= U LL LL
O
x = _ z z Z Z Z Z z Z Z z D U U U U U U U U U U
N M 'd' tC) CO 1` CO O O r i O CO CO t0 CO CO C0 CO I.- N-aaaaaaaaaa GU) ueõ N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N
f A ~ f n f n f n ui U n d vi d d C t6 C6 C6 C6 0 tC f n 0 f n 0 C6 0 cui c co fn fn r r r r r r r r r !" r r r T r r T r r r r r r r r r T !" T
p M M M co M co N Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z T
= i Z Z Z Z
Z = = Z Z Z = _ = Z Z Z = Z Z Z Z Z = _ _ _ _ _ _ _ = i = i __= Z= Z '2 == Z Z= 2 Z Z Z= Z Z= Z= Z Z=_= i i i c') M = _ M M M M M M M M M M = 0 Q) M M M M M M M M M M M M M M M
Z= Z Z= Z 2== U ~-~ T== 2 Z 2 Z Z= Z== 2 Z= 2 U U U U U U U U O U U = T i U U U U O O O O O V U U O U
U U = U
~- mmmmmca co co co ca co mmca ca mca ca mmco mmED mmmmmm Q 2 2 2 2 = _ _ _ _ _ = = 2 2 2 2 = _ _ _ _ = 2 2 2 = _ _ _ _ M M M= Q
cq 3: 3: N L~.
0 0 0 0 o O
M M
co co = _ M M M M co M M 2 2 U U
ZZZZZZZ=====__= N=--== a) N
Ii U U U U U U U U U .~
0000000000 0 0 az 9->E z co _ _ 3: _ _ _ _ _ 3: 3: _ 3: _ _ z z Z 0 U 2 Z Z Z Z Z Z Z Z Z Z Z z Z Z Z Z Z Z z Z Z Z Z
UC)C~t~t~UUUUC~t)UC~UUUUC~C~C)C)U V V 000000 y. r J NM et Ltd LO I~ 00 07 O T- N M d LA M 1*- 00 01 O r N M d' LO ~p I~ 00 Cn O
r r r r r r r r r r N N N N N N N N N N M
m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m a0i w w W W W W U W W W W W N W W W W W W w w w w w 2 N N w zõ N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N
.8.= f6 f6 00f6 U00NC60 fu uiuid(of60 00 /U N(f6C60 fC 0 C/) N r r r r r r r r r r r r r r r r r r r r r- r r r r r r r r r M co T T M M M T T T M M M M
cl) v 1 w _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ = 000 UO
N
TM TM TM TM TM 3:n m TM X: 3:m M M TM TM TM TM TM TM TM TM TM TM TM TM M M TM
TM TM TM TM
3: 3: 3: m m //./~ /~~ co . //~ M M M M~ M~ .- . . M~
co W W co W W W W W W W W co W W W W W W W W W W W W W W W W W m a c 0 M M M M M
M G> 0 N
U Q M"0 000 0 A 1 1 1 1 1 1 1 1 1 '14 IN i 'IN IN 111 11 1 1 TN N N N TN TN TN TN N TN TN TN TN TN N TN TN TN
.C 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 M M M
U- U. U. U. U U U
_ _ 3: :c _ =c =
ZZZZZZZZZZZZZZZZZZZZO~v22ZZZZZZZ
>, N C
LL U V U U U U U U U U U U V U V U V V U U U V U U U V U V Z U =~
Z Q
M d Lo W M O r N M Ct W N M z' Lo tG 00 m O M d eF ed er L() 10 Z 1 1 1 1 1 1 mmmmmmmm mmmmmmmmmmmmmmmmmmmmmm O
4) N N N N N N
V)toV)COf/)U
V) r r r r r r 0 2 Z = Z
__= N 0 0 0 0 0 0 0 0 0 0 0 zZZZz cy) U U U U U U U
= 2 2 Z Z 2= 2 2 2 2 M M M M M M
N 2 = = 2 = _ 1.1U U U U U U
n Z Z Z 2 2 Z 2 Z 2 2 Z
~- co mco co ca m co 2 2 2 2 2 2 2= 2 2 2 2 2= 2 2 2 >- U U U U U U U U U U U
= 2 2 2= 2 2 2= 2 2 N N N N N N
= 2 2 2 2 =
U U U U U U U
M M
X= 2 2 2 1 2 U= U=
>i 0 X = 2 2 2 2= 2 2 2 2 2 Z Z Z Z Z Z z z Z z z O 'a a- M
w a a o 2-L) Q O
E/ 2 U U = U U U U U
U U U
r r Z Q
IN M L V7 c~ C?
Z Z
m U U U U m m m m EXAMPLES OF PRODRUGS
To illustrate the concept 'prod rugs' the following compounds with the general formula (10) have been prepared:
CI
lO N 'N \ (10) O N H H =
OR
example R- group Pro-1 propionyl Pro-2 pivaloyl Pro-3 nicotinoyl Pro-4 N-acetyl-isonipecot l Pro-5 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 (9) (see above) which is highly active.
3: 3: 4 U U = = = = = = = 2 = 2 2 2 2 2 = _ = 2 2 2 2 2 = _ _ d _ _ 0000000000000000000===========
La N TN N N N N TN N N N N N N N N N N N N O O O O O O O O O O O
1 1 1 1 1 1 . 1 . 1 1 UUUUUUUUUUUUUUUUUUUMe! d d ~et~t d d d ~!
M M M M M M M M M M M M M M M M M M M
= r r r r r r r r r r r r r r f r T r r r r T r r T r r r 77 >- aaaaaaaaaaaaaaaaaaaaaaaaaaaaaa _ V I U I I = = I U I U N
0 O o v V 0 O O=
E =000 N N N
r G1I=I
99 d 6 6 M M M M M U_ (M M M 'I
=UUUUUI UUI = LL U- `rQ I=UU=U
00000 0 = U 00 0 0 U
= I = _ Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z
~ U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U
N M T U) O ti M Q) O r N M d O O N. CO 0) O r N M 'd' to CD N. CO C) O
~. r r r r r r r r r r N N N N N N N N N N M
= aaaaaaaaaaaaaaaaaaaaaaaaaaaaaa __== 2 2 2 2=__= 2 2 2 2 2 2=_= 2 2 2 2 2 2 2 2 _ 2 = _ =========00000000000000000000==
Ill N N N N N N N N N N N N N N N N N N N N
000000Q00==================== O O
1 1 1 1 1 I 1 1 1 ..
d ~! d d et d d U U U U U U U U U U U U U U U U U U U U M M
N N N N N N M M M M M M M M
r r r r r r r r r r r T r r r r r r r r r r r r r r r r r O O
aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa ~/ M M
>1 =
N
/y o O M 1,7 M = O M M
m 3: 04 M
U U U =_ = U U Q U=
O E -.0 E 0000000000000 r N r N N N N N N N N N N N N N
U U U U U U U U U U U U U U
_ 1 1 1 1 I 1 1 1 1 I I I I 1 M M M M M M M
t=_= LL LL U U U=__= LL U =
O
M
~' X z z Z Z z z z Z z z z z Z z Z Z z z z z z Z Z Z O O_v 20 z z z -n: ~UUUr N M d' tf) Cfl I` co O O r N M t7 lf! CO I- co O O r cm M O ti d' d-T LC) LO L() Uf) ~4t4 aaaaaaaaa 2 Z = = 2 = _ _ _ _ 2 2 2= 2 2 2== O
000000000c"
=
i ch %~ i 1 ch 1 %~ c~ U
~ aaaaaaaaaa M M
Z: 3: O o v U 0 E O
L
T" = N
t U
O
U U=_= U LL LL
O
x = _ z z Z Z Z Z z Z Z z D U U U U U U U U U U
N M 'd' tC) CO 1` CO O O r i O CO CO t0 CO CO C0 CO I.- N-aaaaaaaaaa GU) ueõ N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N
f A ~ f n f n f n ui U n d vi d d C t6 C6 C6 C6 0 tC f n 0 f n 0 C6 0 cui c co fn fn r r r r r r r r r !" r r r T r r T r r r r r r r r r T !" T
p M M M co M co N Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z T
= i Z Z Z Z
Z = = Z Z Z = _ = Z Z Z = Z Z Z Z Z = _ _ _ _ _ _ _ = i = i __= Z= Z '2 == Z Z= 2 Z Z Z= Z Z= Z= Z Z=_= i i i c') M = _ M M M M M M M M M M = 0 Q) M M M M M M M M M M M M M M M
Z= Z Z= Z 2== U ~-~ T== 2 Z 2 Z Z= Z== 2 Z= 2 U U U U U U U U O U U = T i U U U U O O O O O V U U O U
U U = U
~- mmmmmca co co co ca co mmca ca mca ca mmco mmED mmmmmm Q 2 2 2 2 = _ _ _ _ _ = = 2 2 2 2 = _ _ _ _ = 2 2 2 = _ _ _ _ M M M= Q
cq 3: 3: N L~.
0 0 0 0 o O
M M
co co = _ M M M M co M M 2 2 U U
ZZZZZZZ=====__= N=--== a) N
Ii U U U U U U U U U .~
0000000000 0 0 az 9->E z co _ _ 3: _ _ _ _ _ 3: 3: _ 3: _ _ z z Z 0 U 2 Z Z Z Z Z Z Z Z Z Z Z z Z Z Z Z Z Z z Z Z Z Z
UC)C~t~t~UUUUC~t)UC~UUUUC~C~C)C)U V V 000000 y. r J NM et Ltd LO I~ 00 07 O T- N M d LA M 1*- 00 01 O r N M d' LO ~p I~ 00 Cn O
r r r r r r r r r r N N N N N N N N N N M
m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m a0i w w W W W W U W W W W W N W W W W W W w w w w w 2 N N w zõ N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N
.8.= f6 f6 00f6 U00NC60 fu uiuid(of60 00 /U N(f6C60 fC 0 C/) N r r r r r r r r r r r r r r r r r r r r r- r r r r r r r r r M co T T M M M T T T M M M M
cl) v 1 w _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ = 000 UO
N
TM TM TM TM TM 3:n m TM X: 3:m M M TM TM TM TM TM TM TM TM TM TM TM TM M M TM
TM TM TM TM
3: 3: 3: m m //./~ /~~ co . //~ M M M M~ M~ .- . . M~
co W W co W W W W W W W W co W W W W W W W W W W W W W W W W W m a c 0 M M M M M
M G> 0 N
U Q M"0 000 0 A 1 1 1 1 1 1 1 1 1 '14 IN i 'IN IN 111 11 1 1 TN N N N TN TN TN TN N TN TN TN TN TN N TN TN TN
.C 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 M M M
U- U. U. U. U U U
_ _ 3: :c _ =c =
ZZZZZZZZZZZZZZZZZZZZO~v22ZZZZZZZ
>, N C
LL U V U U U U U U U U U U V U V U V V U U U V U U U V U V Z U =~
Z Q
M d Lo W M O r N M Ct W N M z' Lo tG 00 m O M d eF ed er L() 10 Z 1 1 1 1 1 1 mmmmmmmm mmmmmmmmmmmmmmmmmmmmmm O
4) N N N N N N
V)toV)COf/)U
V) r r r r r r 0 2 Z = Z
__= N 0 0 0 0 0 0 0 0 0 0 0 zZZZz cy) U U U U U U U
= 2 2 Z Z 2= 2 2 2 2 M M M M M M
N 2 = = 2 = _ 1.1U U U U U U
n Z Z Z 2 2 Z 2 Z 2 2 Z
~- co mco co ca m co 2 2 2 2 2 2 2= 2 2 2 2 2= 2 2 2 >- U U U U U U U U U U U
= 2 2 2= 2 2 2= 2 2 N N N N N N
= 2 2 2 2 =
U U U U U U U
M M
X= 2 2 2 1 2 U= U=
>i 0 X = 2 2 2 2= 2 2 2 2 2 Z Z Z Z Z Z z z Z z z O 'a a- M
w a a o 2-L) Q O
E/ 2 U U = U U U U U
U U U
r r Z Q
IN M L V7 c~ C?
Z Z
m U U U U m m m m EXAMPLES OF PRODRUGS
To illustrate the concept 'prod rugs' the following compounds with the general formula (10) have been prepared:
CI
lO N 'N \ (10) O N H H =
OR
example R- group Pro-1 propionyl Pro-2 pivaloyl Pro-3 nicotinoyl Pro-4 N-acetyl-isonipecot l Pro-5 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 (9) (see above) which is highly active.
Claims (57)
1. A compound of the general formula (1) (1) wherein:
R1 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-C6 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-piperidinyl, 1-piperazinyl, OCF3, SCH3, SOCH3, S02CH3 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):
(A) (B) (C) in which:
R5 is either OH or CH2OH;
R6represents 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;
R7represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), R8and 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, NO alkyl(1-3C), O or S;
a pharmacologically acceptable salt thereof, a compound having formula (1) in which substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, or a pharmaceutically acceptable ester thereof.
R1 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-C6 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-piperidinyl, 1-piperazinyl, OCF3, SCH3, SOCH3, S02CH3 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):
(A) (B) (C) in which:
R5 is either OH or CH2OH;
R6represents 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;
R7represents alkyl(1-3C), benzyl, hydroxyalkyl(1-2C) or methoxyalkyl(1-2C), R8and 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, NO alkyl(1-3C), O or S;
a pharmacologically acceptable salt thereof, a compound having formula (1) in which substituents on potentially asymmetrical carbon atoms are in either the R-configuration or the S-configuration, or a pharmaceutically acceptable ester thereof.
2. A compound as claimed in claim 1, wherein R1 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 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), 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; R7represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R8and 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.
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; R7represents alkyl(1-3C), benzyl or hydroxyalkyl(1-2C); R8and 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.
3. A compound as claimed in claim 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. A compound as claimed in claim 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 2.
5. A compound as claimed in claim 1, wherein Y is a group of the general formula (B) and R1, R2, R3, R4, R7, R8, R9, R10 and X have the meanings as in claim 1.
6. A compound as claimed in claim 1, wherein Y is a group of the general formula (B) and R1, R2, R3, R4, R7, R8, R9, R10 and X have the meanings as in claim 2.
7. A compound as claimed in claim 1, wherein Y is a group of the general formula (C) and R1, R2, R3, R4, R8, R9, R10, R11, X and Z have the meanings as in claim 1.
8. A compound as claimed in claim 1, wherein R1 = Cl, R2 = H, X = NH, Y
is either group (A), (B) or (C), R6 = H, n = 1, Z = 0, R10 = H and R3, R4, R5, R7, R8, R9 and R11 have the meanings as in claim 1.
is either group (A), (B) or (C), R6 = H, n = 1, Z = 0, R10 = H and R3, R4, R5, R7, R8, R9 and R11 have the meanings as in claim 1.
9. A compound as claimed in claim 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, R8 =
H; R9 = H, Z = O, R10 = H, R11 = CH3 and R3 and R4, have the meanings as in claim 1.
is either group (A), (B) or (C), R5 = 3-CH2OH, R6 = H, n = 1, R7 = CH3, R8 =
H; R9 = H, Z = O, R10 = H, R11 = CH3 and R3 and R4, have the meanings as in claim 1.
10. A compound as claimed in claim 1 having formula (8) or an enantiomer thereof:
(8)
(8)
11. A compound as claimed in claim 1 having formula (9):
(9)
(9)
12. A compound as claimed in claim 1, wherein the compound is the ester, the ester having formula (10):
(10) wherein R is propionyl, pivaloyl, nicotinoyl, N-acetyl-isonipecotyl, methoxyacetyl, acethoxyacetyl or nonaoyl.
(10) wherein R is propionyl, pivaloyl, nicotinoyl, N-acetyl-isonipecotyl, methoxyacetyl, acethoxyacetyl or nonaoyl.
13. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 12 and a pharmaceutically acceptable carrier or diluent.
14. A use of a compound as defined in any one of claims 1 to 12 in preparation of a pharmaceutical composition for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
15. A use according to claim 14, wherein the inflammatory disease is arthritis, multiple sclerosis, asthma or psoriasis.
16. A use according to claim 14, wherein the gastro-intestinal disorder is an ulcer, inflammatory bowel disease or ulcerative colitis.
17. A use according to claim 16, wherein the inflammatory bowel disease is Crohn's disease.
18. A use according to claim 14, wherein the allergic response is eczema, atopic dermatitis or rhinitis.
19. A use according to claim 14, wherein the cardio vascular disorder is myocardial infarction, arrhythmia, hypertension, thrombosis, anaemia, arteriosclerosis or angina pectoris.
20. A use according to claim 14, wherein the cutaneous disease is urticaria, lupus erythematosus or pruritus.
21. A use according to claim 14, wherein the ophthalmological disorder is glaucoma.
22. A use according to claim 14, wherein the central nervous system disorder is epilepsy, stroke, depression or sleep apnoea.
23. A use according to claim 14, wherein the disorder characterized by impairment of cognition and memory is Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease or neurorehabilitation.
24. A use according to claim 23, wherein the neurorehabilitation involves post-traumatic brain lesions.
25. A use of a compound as defined in any one of claims 1 to 12 for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
26. A use according to claim 25, wherein the inflammatory disease is arthritis, multiple sclerosis, asthma or psoriasis.
27. A use according to claim 25, wherein the gastro-intestinal disorder is an ulcer, inflammatory bowel disease or ulcerative colitis.
28. A use according to claim 27, wherein the inflammatory bowel disease is Crohn's disease.
29. A use according to claim 25, wherein the allergic response is eczema, atopic dermatitis or rhinitis.
30. A use according to claim 25, wherein the cardio vascular disorder is myocardial infarction, arrhythmia, hypertension, thrombosis, anaemia, arteriosclerosis or angina pectoris.
31. A use according to claim 25, wherein the cutaneous disease is urticaria, lupus erythematosus or pruritus.
32. A use according to claim 25, wherein the ophthalmological disorder is glaucoma.
33. A use according to claim 25, wherein the central nervous system disorder is epilepsy, stroke, depression or sleep apnoea.
34. A use according to claim 25, wherein the disorder characterized by impairment of cognition and memory is Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease or neurorehabilitation.
35. A use according to claim 34, wherein the neurorehabilitation involves post-traumatic brain lesions.
36. A compound as defined in any one of claims 1 to 12 for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
37. A compound according to claim 36, wherein the inflammatory disease is arthritis, multiple sclerosis, asthma or psoriasis.
38. A compound according to claim 36, wherein the gastro-intestinal disorder is an ulcer, inflammatory bowel disease or ulcerative colitis.
39. A compound according to claim 38, wherein the inflammatory bowel disease is Crohn's disease.
40. A compound according to claim 36, wherein the allergic response is eczema, atopic dermatitis or rhinitis.
41. A compound according to claim 36, wherein the cardio vascular disorder is myocardial infarction, arrhythmia, hypertension, thrombosis, anaemia, arteriosclerosis or angina pectoris.
42. A compound according to claim 36, wherein the cutaneous disease is urticaria, lupus erythematosus or pruritus.
43. A compound according to claim 36, wherein the ophthalmological disorder is glaucoma.
44. A compound according to claim 36, wherein the central nervous system disorder is epilepsy, stroke, depression or sleep apnoea.
45. A compound according to claim 36, wherein the disorder characterized by impairment of cognition and memory is Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease or neurorehabilitation.
46. A compound according to claim 45, wherein the neurorehabilitation involves post-traumatic brain lesions.
47. A pharmaceutical composition according to claim 13 for treatment of a disorder in which adenosine-A3 receptors are involved, wherein the disorder is acute pain, chronic pain, an inflammatory disease, a gastro-intestinal disorder, an allergic response, a cardio-vascular disorder, a cutaneous disease, an ophthalmological disorder, a respiratory disorder, a central nervous system disorder, a disorder characterized by impairment of cognition and memory, acute brain injury, acute spinal cord injury, diabetes, osteoporosis, an immune system disease, a carcinoma, leukemia, a bacterial infection or a viral infection.
48. A pharmaceutical composition according to claim 47, wherein the inflammatory disease is arthritis, multiple sclerosis, asthma or psoriasis.
49. A pharmaceutical composition according to claim 47, wherein the gastro-intestinal disorder is an ulcer, inflammatory bowel disease or ulcerative colitis.
50. A pharmaceutical composition according to claim 49, wherein the inflammatory bowel disease is Crohn's disease.
51. A pharmaceutical composition according to claim 47, wherein the allergic response is eczema, atopic dermatitis or rhinitis.
52. A pharmaceutical composition according to claim 47, wherein the cardio vascular disorder is myocardial infarction, arrhythmia, hypertension, thrombosis, anaemia, arteriosclerosis or angina pectoris.
53. A pharmaceutical composition according to claim 47, wherein the cutaneous disease is urticaria, lupus erythematosus or pruritus.
54. A pharmaceutical composition according to claim 47, wherein the ophthalmological disorder is glaucoma.
55. A pharmaceutical composition according to claim 47, wherein the central nervous system disorder is epilepsy, stroke, depression or sleep apnoea.
56. A pharmaceutical composition according to claim 47, wherein the disorder characterized by impairment of cognition and memory is Alzheimer's disease, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease or neurorehabilitation.
57. A pharmaceutical composition according to claim 56, wherein the neurorehabilitation involves post-traumatic brain lesions.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02077310.7 | 2002-05-30 | ||
EP02077310 | 2002-05-30 | ||
PCT/EP2003/050203 WO2003101980A1 (en) | 2002-05-30 | 2003-05-28 | 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2484981A1 CA2484981A1 (en) | 2003-12-11 |
CA2484981C true CA2484981C (en) | 2011-07-26 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2484981A Expired - Fee Related CA2484981C (en) | 2002-05-30 | 2003-05-28 | 1,3,5-triazine derivatives as ligands for human adenosine-a3 receptors |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP1513827A1 (en) |
JP (1) | JP4590260B2 (en) |
CN (1) | CN1329388C (en) |
AR (1) | AR040231A1 (en) |
AU (1) | AU2003250232B2 (en) |
BR (1) | BR0304925A (en) |
CA (1) | CA2484981C (en) |
HK (1) | HK1075045A1 (en) |
HR (1) | HRP20040970A2 (en) |
IL (1) | IL164240A (en) |
MX (1) | MXPA04011948A (en) |
PL (1) | PL372418A1 (en) |
RU (1) | RU2312859C2 (en) |
UA (1) | UA77816C2 (en) |
WO (1) | WO2003101980A1 (en) |
ZA (1) | ZA200408029B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005009980A1 (en) * | 2003-07-22 | 2005-02-03 | Neurogen Corporation | Substituted pyridin-2-ylamine analogues |
WO2005028467A1 (en) | 2003-09-15 | 2005-03-31 | Anadys Pharmaceuticals, Inc. | Antibacterial 3,5-diaminopiperidine-substitute aromatic and heteroaromatic compounds |
GB2465405A (en) * | 2008-11-10 | 2010-05-19 | Univ Basel | Triazine, pyrimidine and pyridine analogues and their use in therapy |
BR112014032873B1 (en) | 2012-07-04 | 2019-02-12 | Agro-Kanesho Co., Ltd. | 2-AMINONICOTINIC ACID ESTER DERIVATIVE, AND, BACTERICIDE |
GB201810668D0 (en) | 2018-06-28 | 2018-08-15 | Stiftelsen Alzecure | New compounds |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9226735D0 (en) * | 1992-12-22 | 1993-02-17 | Ici Plc | Azole derivatives |
DE19735800A1 (en) * | 1997-08-18 | 1999-02-25 | Boehringer Ingelheim Pharma | Use of known and new triazine derivatives |
JPH11158073A (en) * | 1997-09-26 | 1999-06-15 | Takeda Chem Ind Ltd | Adenosine a3 antagonist |
-
2003
- 2003-05-28 RU RU2004138803/04A patent/RU2312859C2/en not_active IP Right Cessation
- 2003-05-28 PL PL03372418A patent/PL372418A1/en not_active Application Discontinuation
- 2003-05-28 EP EP03755982A patent/EP1513827A1/en not_active Withdrawn
- 2003-05-28 MX MXPA04011948A patent/MXPA04011948A/en active IP Right Grant
- 2003-05-28 UA UA20041210642A patent/UA77816C2/en unknown
- 2003-05-28 AU AU2003250232A patent/AU2003250232B2/en not_active Ceased
- 2003-05-28 JP JP2004509671A patent/JP4590260B2/en not_active Expired - Fee Related
- 2003-05-28 BR BR0304925-6A patent/BR0304925A/en not_active IP Right Cessation
- 2003-05-28 CN CNB038090937A patent/CN1329388C/en not_active Expired - Fee Related
- 2003-05-28 WO PCT/EP2003/050203 patent/WO2003101980A1/en active Application Filing
- 2003-05-28 CA CA2484981A patent/CA2484981C/en not_active Expired - Fee Related
- 2003-05-30 AR ARP030101920A patent/AR040231A1/en unknown
-
2004
- 2004-09-23 IL IL164240A patent/IL164240A/en not_active IP Right Cessation
- 2004-10-05 ZA ZA200408029A patent/ZA200408029B/en unknown
- 2004-10-15 HR HR20040970A patent/HRP20040970A2/en not_active Application Discontinuation
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2005
- 2005-08-22 HK HK05107314A patent/HK1075045A1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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JP4590260B2 (en) | 2010-12-01 |
CN1329388C (en) | 2007-08-01 |
AU2003250232B2 (en) | 2008-09-11 |
IL164240A0 (en) | 2005-12-18 |
RU2004138803A (en) | 2005-06-10 |
IL164240A (en) | 2010-12-30 |
JP2005531600A (en) | 2005-10-20 |
RU2312859C2 (en) | 2007-12-20 |
HRP20040970A2 (en) | 2005-06-30 |
AR040231A1 (en) | 2005-03-23 |
AU2003250232A1 (en) | 2003-12-19 |
UA77816C2 (en) | 2007-01-15 |
WO2003101980A1 (en) | 2003-12-11 |
PL372418A1 (en) | 2005-07-25 |
CN1646520A (en) | 2005-07-27 |
EP1513827A1 (en) | 2005-03-16 |
ZA200408029B (en) | 2005-10-06 |
CA2484981A1 (en) | 2003-12-11 |
BR0304925A (en) | 2004-09-28 |
MXPA04011948A (en) | 2005-03-31 |
HK1075045A1 (en) | 2005-12-02 |
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