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  • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
  • C07D251/40—Nitrogen atoms
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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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• 2003
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