Patent DE-19735800-A1 (DE)
Title: Use of known and new triazine derivatives
Inventor: KUEFNER-MUEHL ULRIKE DR
IPC: C07D409/14
Filed: 1997-08-18
Abstract: Known and new 2,4,6-trisubstituted-triazine derivatives (I) are used for the production of medicaments.- DETAILED DESCRIPTION - Medicaments are produced using 2-amino-4,6-disubstituted-triazine derivatives (I) or their racemates, enantiomers, diastereomers, mixtures of  diastereomers or addition salts.- R1  = H; - R2  = H or 1-5C alkyl; - R3  = COOH; COO-1-4C alkyl; CN; 3-7C cycloalkyl optionally substituted with OH, oxo, 1-4C alkyl or 1-4C alkoxy; 6-10C aryl optionally substituted with 1 or more Q; 5-7 membered heterocyclyl linked via a single bond or 1-6C alkylene, 2-6C alkenylene or 2-6C alkynylene, containing 1 or more O, N and/or S atoms and optionally substituted with 1 or more benzyl or 1-4C alkyl; quinolinyl; isoquinolinyl; benzo(b)furanyl; isobenzofuranyl; benzothiophenyl; benzoxazolyl; benzothiazolyl; benzimidazolyl; benzodiazinyl; or 1,2-methylenedioxyphenyl; - R4  = 1-4C alkyl; COOH; COO-1-4C alkyl; NH2; CN; 3-7C cycloalkyl optionally substituted with OH, oxo, 1-4C alkyl or 1-4C alkoxy; cyclopentenyl; cyclohexenyl; 6-10C aryl optionally substituted with 1 or more Q ; phenyl-1-4C alkyl; phenyl-2-4C alkenyl; phenyl-2-4C alkynyl; biphenylyl; N-4-pyrrolyl-phenyl; naphthyl; phenoxy; phenylamino; 5-7 membered heterocyclyl linked via a single bond or 1-6C alkylene, 2-6C alkenylene or 2-6C alkynylene, containing 1 or more O, N and/or S atoms and optionally substituted with 1 or more 1-4C alkyl, 1-4C alkoxy, 1-4C alkoxy-1-4C alkyl, phenyl, NO2, oxazolyl, halo or 1-4C alkylthio; or quinolinyl, isoquinolinyl, benzo(b)furanyl, isobenzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodiazinyl or 1,2-methylenedioxyphenyl optionally substituted with 1 or more 1-4C alkyl, NO2 or halo; - Q  = OH; halo; CN; NO2; CF3; CF3SO2O; 1-4C alkyl; 1-4C alkoxy; 1-4C alkylcarbonyl; 6-10C arylcarbonyl; 1-4C alkylcarbonyloxy; 6-10C arylcarbonyloxy; HO-1-4C alkyl; 1-4C alkoxy-1-4C alkyl; NH2; NH(1-4C alkyl); N(1-4C alkyl)2; 1-4C alkylcarbonylamino; 1-4C alkoxycarbonyloxy; or 6-10C aryloxycarbonyloxy.- An INDEPENDENT CLAIM is also included for compounds (I) where: - R1  = H; - R2  = H or 1-3C alkyl; - R3  = 3-6C cycloalkyl; phenyl optionally substituted with 1 or more OH, halo, NO2, 1-4C alkyl, 1-4C alkoxy, HO-1-4C alkyl, 1-4C alkoxy-1-4C alkyl, NH2, NH(1-4C alkyl), N(1-4C alkyl)2, 1-4C alkylcarbonylamino, CF3, CF3SO2O, 1-4C alkylcarbonyloxy, 6-10C arylcarbonyloxy, 1-4C alkoxycarbonyloxy or 6-10C aryloxycarbonyloxy; or 5-7 membered heterocyclyl containing 1 or more O, N and/or S atoms and optionally substituted with 1 or more benzyl or 1-4C alkyl; - R4  = 3-7C cycloalkyl optionally substituted with OH, oxo, 1-4C alkyl or 1-4C alkoxy; cyclopentenyl; cyclohexenyl; phenyl optionally substituted with 1 or more OH, halo, NO2, CF3, CF3SO2O, 1-4C alkyl, 1-4C alkoxy, 1-4C alkylcarbonyl, 6-10C arylcarbonyl, 1-4C alkylcarbonyloxy, 6-10C arylcarbonyloxy, HO-1-4C alkyl, 1-4C alkoxy-1-4C alkyl, NH2, NH(1-4C alkyl), N(1-4C alkyl)2, 1-4C alkylcarbonylamino, 1-4C alkoxycarbonylamino o r 6-10C aryloxycarbonyloxy; benzyl; phenyl-1-4C alkyl; phenyl-2-4C alkenyl; phenyl-2-4C alkynyl; biphenylyl; 4-N-pyrrolyl-phenyl; naphthyl; phenoxy; or phenylamino; 5-7 membered heterocyclyl linked via a single bond or 1-6C alkylene, 2-6C alkenylene or 2-6C alkynylene, containing 1 or more O, N and/or S atoms and optionally substituted with 1 or more benzyl, 1-4C alkyl, 1-4C alkoxy, 1-4C alkoxy-1-4C alkyl, phenyl, NO2, oxazolyl, halo or 1-4C alkylthio; or quinolinyl, isoquinolinyl, benzo(b)furanyl, isobenzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodiazinyl or 1,2-methylenedioxyphenyl optionally substituted with 1 or more 1-4C alkyl, NO2 or halo; - compounds are excluded when R2 = H, R3 = phenyl and R4 = phenyl, phenylamino, phenoxy, 2-OH-phenyl, 2,4-di(OH)-phenyl, 4-Me-phenyl, 4-NO2-phenyl, benzyl, 3- or 4-pyridyl, 2-furyl or 5-(NO2, Br or Me)-furyl; R2 = H, R3 = 2-OH-phenyl and R4 = phenyl, 2-(OH or OMe)-phenyl or phenyl-CH=CH-; R2 = H, R3 = 4-OH-phenyl and R4 = 2-OH-phenyl; R2 = H, R3 = 2,4-di(OH)-phenyl and R4 = phenyl, 2,4-di(OH)-phenyl or 4-Cl-phenyl; R2 = H, R3 = 2-OMe-phenyl and R4 = 2-OH-phenyl; R2 = H; R4 = p-tolyl and R4 = phenyl or p-tolyl; R2 = H, R3 = 4-Cl-phenyl and R4 = 4-Cl-phenyl, 2,4-di(OH)-phenyl or 2-OH-4-OEt-phenyl; R2 = H, R3 = 4-NO2-phenyl and R4 = phenyl or 3-NO2-phenyl; R2 = H, R3 = 3-NO2-phenyl and R4 = 4-NO2-phenyl; R2 = H, R3 = 2-OH-4-OEt-phenyl and R4 = 4-Cl-phenyl; R2 = H, R3 = 3-pyridyl and R4 = phenyl, 2-furyl or 3- or 4-pyridyl; R2 = H, R3 = 4-pyridyl and R4 = phenyl or 3- or 4-pyridyl; R2 = H, R3 = 2-furyl and R4 = phenyl, 2-furyl or 3-pyridyl; R2 = H, R3 = 5-Me-2-furyl and R4 = phenyl; R2 = H and R3 = R4 = 3- or 4-OMe-phenyl, 3,4-di(OMe)-phenyl, 4-(NEt2)-phenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-Cl-phenyl, 2,4-di(Cl)-phenyl, 5-Me-2-furyl or 3,4,5-tri(OMe)-phenyl; R2 = Me, R3 = phenyl and R4 = phenyl or 2-OH-phenyl; R2 = Me, R3 = 2-O H-phenyl and R4 = phenyl, phenyl-CH=CH- or 2-OH-phenyl; R2 = Me, R3 = 2,4-di(OH)-phenyl and R4 = 4-Cl-phenyl; R2 = Me, R3 = 4-Cl-phenyl and R4 = 2,4-di(OH)-phenyl; R2 = Et, R3 = phenyl and R4 = 2-OH-4-OMe-phenyl; R2 = Et, R3 = 2-OH-4-OMe-phenyl and R4 = phenyl; R2 = Et, R3 = 2-OH-4,6-di(Me)-phenyl and R4 = 2-OH-5-Cl-phenyl; and R2 = Et, R3 = 2-OH-5-Cl-phenyl and R4 = 2-OH-4,6-di(Me)-phenyl.- ACTIVITY - Vasodilator, antidepressant, bronchodilator, diuretic, - MECHANISM OF ACTION - Adenosine antagonist. 2-Amino-4-(2,3-dihydroxyp henyl)-6-(3-hydroxyphenyl)-1,3,5-triazine (I) has an adenosine A1 (human) receptor binding value (KiA1) of 1.7 nM.- USE - (I) are useful for the treatment of CNS degenerative disorders, e.g. senile dementia, Alzheimer's disease and learning and memory problems, sleep disorders, motor-coordination disorders, Parkinson's disease, depression, migraine and peripheral neurological disorders.(I) can also be used for the treatment of respiratory disorders, e.g.asthma, and dyspnea, and for the prevention of sudden death in neonates. Further, (I) are useful in the treatment of cardiovascular disorders, e.g. cardiac and pulmonary damage caused by ischemia and subsequent reperfusion, cardiac insufficiency, arrythmias, circulatory problems and hypertension, and renal disorders, e.g. oedema, kidney insufficiency and acute kidney failure. Other conditions which can be treated with (I) are ascites associated with liver failure, inflammation, allergic rhinitis, urticaria, scleroderma, arthritis, autoimmune diseases, inflammatory bowel disease, cystic fibrosis and pain associated with perfusion problems.TF  - TECHNOLOGY FOCUS - ORGANIC CHEMISTRY - Preparation: Compounds (I) are prepared by: (A) reacting a nitrile (II) with a guanidine derivative (III); or (B) reacting an acylimidate (IV) with a guanidine derivative (III). (A) - R  =   R3 = R4.- (B)