DE19735800A1 - Use of known and new triazine derivatives - Google Patents

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)

Description

The invention relates to novel triazine derivatives, processes for their preparation and the Use of triazines as medicaments, in particular as medicaments with adenosine antagonistic action.

Surprisingly, it has been found that triazines of the general formula (I) have an affinity for adenosine receptors and thus a new class of Represent adenosine antagonists.

Adenosine antagonists can have a therapeutically useful effect in cases unfold in which diseases or pathological situations with a Activation of adenosine receptors are linked.

Adenosine is an endogenous neuromodulator with predominantly inhibitory (inhibitory) effects in the CNS, in the heart, in the kidneys and other organs. The effects of adenosine are mediated by at least three receptor subtypes: adenosine A ₁ , A ₂ and A ₃ receptors.

In the CNS, adenosine exerts inhibitory effects predominantly via the activation of A ₁ receptors: presynaptically by inhibiting synaptic transmission (inhibition of the release of neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, glutamate, etc.), postsynaptically by inhibiting neuronal activity.

A ₁ antagonists abolish the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.

A ₁ antagonists are therefore of great interest for the treatment of central nervous degenerative diseases such as senile dementia of the Alzheimer's disease type and age-related disorders of memory and learning performance.

The disease includes beside the forgetfulness in the mild form and the complete one Helplessness and absolute care in the heaviest form a number other concomitant symptoms such as sleep disorders, moto-coordination disorders up Picture of a parkinson's disease, also an increased affect lability as well depressive symptoms. The disease is progressive and can lead to death.  

The previous therapy is unsatisfactory. Specific therapeutics are missing so far Completed. Therapeutic trials with acetylcholinesterase inhibitors only show However, a small proportion of patients have an effect but are at a high level Side effect rate associated.

The pathophysiology of M. Alzheimer's and SDAT is characterized by a severe impairment of the cholinergic system, but there are others Transmitter systems affected. By the loss of presynaptic cholinergic and other neurons and the resulting lack of provision of Neurotransmitters is the neuronal transmission and neuronal activity in the for learning and memory sensitive brain areas are sensitively diminished.

Selective adenosine A ₁ receptor antagonists promote neuronal transmission by increasing the supply of neurotransmitters, increase the excitability of postsynaptic neurons and can thus symptomatically counteract the disease.

The high receptor affinity and selectivity of some of the claimed compounds should allow M. Alzheimer's and SDAT to be treated at low doses so that side effects unlikely to be attributed to blockade of A ₁ receptors.

Another indication for centrally acting adenosine A ₁ antagonists is depression. The therapeutic success of antidepressant substances seems to be associated with an upregulation of A ₁ receptors. A ₁ antagonists can lead to the upregulation of adenosine A ₁ receptors and thus offer a new therapeutic approach for the treatment of depressive patients.

Further fields of application in particular for A ₂ -selective adenosine antagonists are neurodegenerative diseases such as Parkinson's disease and, in addition, migraine. Adenosine inhibits the release of dopamine from central synaptic terminals through interactions with dopamine D ₂ receptors. A ₂ antagonists increase the release and availability of dopamine and thus provide a new therapeutic principle for the treatment of Parkinson's disease.

In migraine, a mediated via A ₂ receptors vasodilation of cerebral vessels seems to be involved. Selective A ₂ antagonists inhibit vasodilation and may thus be useful for the treatment of migraine.

Adenosine antagonists can also be used for the treatment of peripheral indications Find use.

For example, activation of A ₁ receptors in the lung can lead to bronchoconstriction. Selective adenosine A ₁ antagonists relax tracheal smooth muscle, cause bronchodilation, and thereby may be useful as an antiasthmatic agent.

Through the activation of A ₂ receptors, adenosine can cause respiratory depression and respiratory arrest, among other things. A ₂ antagonists cause respiratory stimulation. For example, adenopsine antagonists (theophylline) are used to treat respiratory distress and to prevent "sudden infant death" in premature delivery.

Important therapeutic fields for adenosine antagonists are also cardiovascular Diseases and kidney diseases.

At the heart, adenosine exerts an inhibition of electrical and contractile activity via the activation of A ₁ receptors. Associated with coronary vasodilation mediated by A ₂ receptors, adenosine has a negative effect on chronotropic, inotropic, syndromic, bam- motropic, bradycardia and decreases cardiac output.

Adenosine A ₁ receptor antagonists are able to prevent damage to the heart and lungs due to ischemia and subsequent reperfusion. Therefore, adenosine antagonists for the prevention or early treatment of ischemia-reperfusion-related damage to the heart z. B. after coronary bypass surgery, heart transplantation, angioplasty or thrombolytic therapy of the heart and similar procedures. The same applies to the lungs.

In the kidneys, activation of A ₁ receptors causes vasoconstriction of afferent arterioles, resulting in decreased renal blood flow and glomerular filtration.

A ₁ antagonists act on the kidney like strong potassium-sparing diuretics and can thus be used for kidney protection as well as for the treatment of edema, renal insufficiency and acute renal failure.

Due to the adenosine antagonism at the heart and the diuretic effect A ₁ antagonists can be used therapeutically effective in various cardiovascular diseases such. In heart failure, arrhythmias (bradyarrhythmias) associated with hypoxia or ischemia, conduction disorders, hypertension, ascites in liver failure (hepato-renal syndrome) and as an analgesic in circulatory disorders.

A ₃ antagonists inhibit the A ₃ receptor activation-induced degranulation of mast cells and are therefore therapeutically useful in all diseases and pathological situations associated with mast cell degranulation: e.g. B. as anti-inflammatory substances in hypersensitivity reactions such. As asthma, allergic rhinitis, urticaria, in myocardial reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases, among others

Cystic fibrosis - also known as cystic fibrosis - is a hereditary metabolic disorder caused by a genetic defect of a particular chromosome. Increased production and increased viscosity of the secretions of the mucous glands in the bronchi can lead to severe complications in the respiratory tract. Initial studies have shown that A ₁ antagonists the efflux of chloride ions z. B. Increase CF PAC cells. Based on these findings, it can be expected that in patients suffering from cystic fibrosis (mucovicidosis), the compounds of the present invention will regulate the disturbed electrolyte balance of the cells and alleviate the symptoms of the disease.

The invention relates to the use of triazines of the general formula (I)

as a medicament, in particular as a medicament with adenosinantagonistischer effect, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₅ -alkyl, preferably hydrogen;
R ^{3 is} -COOH, COO-C ₁ -C ₄ -alkyl or CN;
R ^{3 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ³ is C ₆ -C ₁₀ -aryl, which may optionally be substituted by one or more of the groups OH, Halogen ₁ CN, NO _2, CF _3, CF ₃ -SO ₂ -O-, C ₁ -C ₄ alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylcarbonyl, C ₆ -C ₁₀ -arylcarbonyl, C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, HO-C ₁ -C ₄ -alkyl- , C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl bridge, one or more Atoms may be selected from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ alkyl;
R ^{3 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene;
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} C ₆ -C ₁₀ -aryl, which may optionally be substituted by one or more of the radicals OH, halogen, CN, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylcarbonyl, C ₆ -C ₁₀ -arylcarbonyl, C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, HO-C ₁ -C ₄ -alkyl- , C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{4 is} phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group may contain oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen.

Preference according to the invention is given to the use of triazines of the general formula (I)

as a medicament, in particular as a medicament with adenosinantagonistischer effect, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₅ -alkyl, preferably hydrogen;
R ^{3 is} C ₃ -C ₆ -cycloalkyl, which may optionally be substituted by OH, = O, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{3 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{3 is} a 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl;
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group may contain oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen.

Of particular interest is the use of triazines of general formula (I)

as a medicament, in particular as a medicament with adenosinantagonistischer effect, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ -alkyl, preferably hydrogen;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl;
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group may contain oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen.

The invention further pharmaceutical compositions, in particular pharmaceutical compositions having adenosine antagonistic action containing as active ingredient one or more compounds of general formula (I), wherein the radicals R ¹ , R ² , R ³ and R ^{4 have} the abovementioned meaning.

The use of the compounds of the general formula (I) includes the Use of the optionally present enantiomers or diastereomers in optically pure form or as mixtures with one. Furthermore, the Compounds of general formula (I) in their salts, in particular for pharmaceutical application in its physiologically acceptable salts-with a inorganic or organic acid. When acids come For example, hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, Methanesulfonic acid, citric acid, tartaric acid or maleic acid into consideration. Further mixtures of the abovementioned acids can be used.

The A ₁ receptor binding values determined for the compounds of the formula (I) were determined in analogy to Ensinger et al. in "Cloning and functional characterization of human A ₁ adenosine receptor - Biochemical and Biophysical Communications, Vol. 187, No. 2, 919-926, 1992" and are summarized in Table 6.

The A ₃ receptor binding values summarized in Table 7 were determined in analogy to Salvatore et al. "Molecular cloning and characterization of the human A ₃ aadenosine receptor" (Proc Natl Acad Sci USA 90, 10, 365-10, 369, 1993).

1,3,5-triazine derivatives are known in the art. The connections 2-Amino-4,6-bis (4-methylphenyl) -1,3,5-triazine, 2-amino-4,6-bis (3-methoxyphe nyl) -1,3,5-triazine, 2-amino-4,6-bis (3,4-dimethoxyphenyl) -1,3,5-triazine, 2-amino-4,6-bis (4-di methylaminophenyl) -1,3,5-triazine and 2-amino-4,6-bis (4-methoxyphenyl) -1,3,5-tri Azin be described for example by DE 12 12 547. On Process for the preparation of u. a. 2-Amino-4,6-diphenyl-1,3,5-triazine is by the DE 1135477 known. BE 667044 discloses unsymmetrically substituted Triazines such. For example, the 2-amino-4- (2,4-dihydroxyphenyl) -6-phenyl-1,3,5-triazine, the 2-Amino-4- (2-hydroxy-4-ethoxyphenyl) -6- (4-chlorophenyl) -1,3,5-triazine, the 2-Ami no-4- (2,4-dihydroxyphenyl) -6- (4-chlorophenyl) -1,3,5-triazine or 2-methylamino-4- (2,4-di hydroxyphenyl) -6- (4-chlorophenyl) -1,3,5-triazine. From DE 20 13 424 u. a. the 2-phenyloxy-4-amino-4,6-phenyl-1,3,5-triazine known. DE 22 62 188 describes 2-amino-4,6-bis (4-pyridyl) -1,3,5-triazine. Further, for example  the amino-triazines 2-amino-4,6-bis (2-hydroxyphenyl) -1,3,5-triazine are known (CH 419155) and 2-amino-4,6-bis (2-furyl) -1,3,5-triazine (GB 1094858).

The invention further relates to the novel triazine derivatives of the general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ -alkyl, preferably hydrogen;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl chain, one or more Atoms may be selected from the group oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5- Methyl-2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl,
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Preference is given to compounds of the general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ -alkyl, preferably hydrogen;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} furyl, thienyl, pyridyl or pyrrolyl, which may optionally be mono- or polysubstituted by C ₁ -C ₄ -alkyl;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} pyrimidinyl, pyridyl, which may optionally be substituted by one or more of halogen, C ₁ -C ₄ -alkyl or -SC ₁ -C ₄ -alkyl;
R ^{4 is} pyridyl C ₁ -C ₄ alkyl or pyridyl C ₂ -C ₄ alkenyl;
R ⁴ furyl, which is optionally substituted by one or more of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ -C ₄ alkyl, phenyl, NO ₂ or halogen may be substituted;
R ^{4 is} tetrahydropyranyl or tetrahydrofuranyl;
R ^{4 is} thienyl, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, halogen, oxazolyl or NO ₂ ;
R ^{4 is} dithiolanyl, thiolanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, quinolinyl, benzo [b] furanyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl, which may optionally be substituted by one or more of the radicals C. C ₁ -C ₄ -alkyl, preferably methyl, NO ₂ or halogen, means
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5-methyl 2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Of particular interest are compounds of general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen, methyl or ethyl, preferably hydrogen;
R ^{3 is} cyclopropyl, cyclopentyl or cyclohexyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of the radicals OH, chlorine, fluorine, NO ₂ , methyl, methoxy, hydroxymethyl, methoxymethyl, amino, methylamino, ethylamino, N-acetylamino, dimethylamino, CF ₃ , CF ₃ SO ₂ -O-, acetoxy, ethylcarbonyloxy, phenylcarbonyloxy or phenyloxycarbonyloxy;
R ³ furyl, thienyl, pyridyl or pyrrolyl, which may each be mono-, di- or trisubstituted by methyl;
R ⁴ optionally mono- or polysubstituted by OH, = O, methyl or methoxy substituted cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which is optionally substituted by one or more of OH, fluorine, chlorine, bromine, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, methyl, ethyl, propyl, butyl, methoxy, acetyl, phenylcarbonyl, acetoxy , Ethylcarbonyloxy, phenylcarbonyloxy, hydroxymethyl, hydroxyethyl, methoxymethyl, amino, methylamino, ethylamino, dimethylamino, N-acetylamino, methoxycarbonyloxy, ethoxycarbonyloxy or phenyloxycarbonyloxy;
R ^{4 is} benzyl, phenylethyl, phenylethenyl, phenylethynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} optionally substituted by methyl pyrimidinyl, pyridyl, which may optionally be mono- or polysubstituted by fluorine, chlorine, bromine, methyl or -S-methyl;
R ^{4 is} pyridylmethyl or pyridylethenyl;
R ⁴ furyl, which may optionally be mono- or polysubstituted by methyl, ethyl, propyl, butyl, methoxy, methoxymethyl, phenyl, NO ₂ , fluorine, chlorine or bromine;
R ^{4 is} tetrahydropyranyl or tetrahydrofuranyl;
R ^{4 is} thienyl, which may optionally be mono- or polysubstituted by methyl, fluorine, chlorine, bromine, oxazolyl or NO ₂ ;
R ^{4 is} dithiolanyl, thiolanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, quinolinyl, benzo [b] furanyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl, which may optionally be monosubstituted or polysubstituted by methyl, Ethyl, propyl, NO ₂ , fluorine, chlorine or bromine
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5-methyl 2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Particular preference is given to compounds of the general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or ethyl, preferably hydrogen;
R ^{3 is} cyclohexyl, phenyl, hydroxyphenyl, 3,5-dihydroxyphenyl, methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, 3-chloro-4- methylphenyl, 4-chloro-3-methylphenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3,5-difluorophenyl, 3 Acetoxyphenyl, 3-ethylcarbonyloxyphenyl, 3-phenylcarbonyloxyphenyl, 3-phenoxycarbonyloxyphenyl, 3-trifluoromethanesulfonyloxyphenyl, 3-methoxymethylphenyl, 2-furyl, 2-thienyl, pyridyl or 1,5-dimethyl-2-pyrrolyl;
R ^{4 is} cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxycyclohexyl, methoxycyclohexyl, cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl, hydroxyphenyl, methoxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 3-acetylphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-ethylcarbonyloxyphenyl, 3-phenylcarbonyloxyphenyl, 3-phenoxycarbonyloxyphenyl, 3-trifluoromethanesulfonyloxyphenyl, chlorophenyl, 3,4-dichlorophenyl, methylphenyl, ethylphenyl, propylphenyl, 4-t Butylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-hydroxymethylphenyl, arninophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, acetylaminophenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino 3-methylphenyl, nitrophenyl, 4-nitro-3-methylphenyl, 3-nitro-4-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, fluorophenyl, 3,4-difluorophenyl, trifluoromethylphenyl, 3 Methoxymethylphenyl, benzyl, 2-phenylethyl, phenyl-CH = CH-, phenyl-C~C-, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy, 3,4-methylenedioxophenyl, 2,3-Me thylenedioxophenyl or phenylamino;
R ^{4 is} optionally substituted by methyl pyrimidinyl, pyridyl, pyridylmethyl, pyridyl-CH = CH-, 6-chloro-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-3-pyridyl, 2-thiomethyl-pyridine-3 -yl, 2-benzo [b] furanyl, furyl, 5-methyl-2-furyl, 5-methyl-3-furyl, 2-methyl-3-furyl, 3-methoxymethyl-2-fluoro, 3-methyl 2-furyl, 2,5-dimethyl-3-furyl, 4,5-dimethyl-2-furyl, 5-t-butyl-2-methyl-3-furyl, 5-nitro-2-furyl, 2-methyl 5-phenyl-3-furyl, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, thienyl, 5-methyl-2-thienyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 5-chloro 3-thienyl, 2,5-dichloro-3-thienyl, 5-nitro-3-thienyl, 5-nitro-2-thienyl, 1,3-dithiolan-2-yl, 5- (1,2-oxazole-3 -yl) -3-thienyl, thiolan-2-yl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-imidazol-2-yl, 1-methyl-pyrazol-4-yl, 1,5-dimethyl pyrazol-3-yl, 4,5-dichloro (1,2-thiazol) -3-yl, 2,4-dimethyl- (1,3-thiazol) -5-yl, 4-methyl- (1-thia -2,3-diazole) -5-yl, 1,2-oxazol-5-yl, quinolin-2-yl or quinolin-3-yl,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl or 5-methyl-2-furyl can be;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen,
R ³ and R ⁴ can not be simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl or 2-pyridyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Of particular interest are furthermore compounds of the general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or ethyl, preferably hydrogen;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, 3-chloro-4-methylphenyl, 4- Chloro-3-methylphenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3,4-difluorophenyl, 3-pyridyl, 2- Thienyl or 1,5-dimethyl-2-pyrrolyl;
R ^{4 is} phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-hydroxymethylphenyl, 3-acetylphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-amino-4-methylphenyl, 4-amino-3- methylphenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl;
R ⁴ 1,3-pyrimidin-2-yl, 1,3-pyrimidin-5-yl, 6-chloro-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-3-pyridyl, 2-benzo b] furanyl, furyl, 5-methyl-2-furyl, 5-methyl-3-furyl, 2-methyl-3-furyl, 3-methyl-2-furyl, 2,5-dimethyl-3-furyl, 4, 5-Dimethyl-2-furyl, 5-t-butyl-2-methyl-3-furyl, 5-nitro-2-furyl, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, thienyl, 5-methyl-2- thienyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 5-chloro-3-thienyl, 2,5-dichloro-3-thienyl, 5-nitro-3-thienyl, 5-nitro-2- thienyl, 5- (1,2-oxazol-3-yl) -3-thienyl, 1,3-dithiolan-2-yl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-imidazol-2-yl, 1-methyl-pyrazol-4-yl, 1,5-dimethyl-pyrazol-3-yl, 4,5-dichloro (1,2-thiazol) -3-yl, 2,4-dimethyl- (1,3 -thiazole) -5-yl, 4-methyl- (1-thia-2,3-diazole) -5-yl, 1,2-oxazol-5-yl, 4,5-dichloro-1,2-thiazole 3-yl, quinolin-2-yl or quinolin-3-yl,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ⁴ can not be phenyl, 2-hydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, 2-furyl, 5-nitro-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be 42859 00070 552 001000280000000200012000285914274800040 0002019735800 00004 42740 phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl or 2-furyl;
when R ^{2 is} hydrogen,
R ³ and R ⁴ can not be simultaneously 4-chlorophenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Furthermore, compounds of the general formula (I) are particularly preferred

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl, 2-thienyl or 3-pyridyl;
R ^{4 is} phenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-methylamihophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-hydroxymethylphenyl, 3-aminophenyl, 4-aminophenyl, 3-amino-4-methylphenyl, 3-acetylaminophenyl, 3-acetylamino-4-methylphenyl, 3-nitrophenyl, 3-nitro-4-methylphenyl, 4- Chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 3,4-methylenedioxophenyl, 2,3-methylenedioxophenyl, 6-methyl-3- pyridyl, 2-methyl-3-pyridyl, 2-benzo [b] furanyl, 1,5-dimethyl-2-pyrrolyl, 5-methyl-3-furyl, 3-methyl-2-furyl, 4,5-dimethyl 2-furyl, 5-methyl-2-thienyl, 5-chloro-3-thienyl, 5-nitro-2-thienyl or 4,5-dichloro-1,2-thiazol-3-yl,
with the proviso that
when R ^{3 is} 3-pyridyl, R ⁴ can not be phenyl and
when R ^{3 is} phenyl, R ⁴ can not be phenyl or 4-methylphenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts.

Particular preference is given to compounds of the general formula (I)

wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl or 3-pyridyl;
R ^{4 is} 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-hydroxymethylphenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 3-amino-4-methylphenyl, 3-acetylamino-4-methylphenyl, 3-nitrophenyl, 3-nitro-4-methylphenyl, 3-chloro-4-methylphenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 3-methyl-2-furyl, 1,5-dimethyl-2-pyrrolyl, 4,5-dimethyl-2-furyl or 4,5-dichloro-1,2-thiazol-3-yl,
with the proviso that when R ^{3 is} phenyl, R ⁴ can not be 4-methylphenyl.

Optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, the compounds of general formula (I) in their Salts, in particular for pharmaceutical use, in their physiological compatible salts with an inorganic or organic acid become. As acids for this example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid into consideration. Furthermore, mixtures of the aforementioned acids be used.  

As alkyl groups (even if they are part of other radicals) are branched and unbranched alkyl groups having 1 to 10 carbon atoms, as far as not otherwise described, preferably with 1-4 carbon atoms for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. These terms include the respective possible isomers; provided Propyl, for example, is n-propyl, iso-propyl, and is not described otherwise Butyl is n-butyl, iso-butyl, sec-butyl, tert-butyl, etc.

Substituted alkyl groups, unless otherwise described (even if they are part of other groups), for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy, amino, alkylamino, dialkylamino, cyano, Nitro, = O, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl.

As alkenyl groups (even if they are part of other radicals) branched and unbranched alkenyl groups having 2 to 10 carbon atoms, preferably called 2 to 3 carbon atoms, as far as they are at least one Have double bond, for example, the above-mentioned alkyl groups referred to as far as they have at least one double bond, such as Vinyl (provided that no volatile enamines or enol ethers are formed), Propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.

Substituted alkenyl groups, unless otherwise described (even if they are part of other groups), for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy, amino, alkylamino, dialkylamino, cyano, Nitro, = O, -CHO, -COOH, COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl.

As alkynyl groups (even if they are part of other radicals) Alkynyl groups having 2 to 10 carbon atoms, as far as they are at least have a triple bond, for example, ethynyl, propargyl, butynyl, pentynyl, Hexynyl.

Substituted alkynyl groups, unless otherwise described (even if they are part of other groups), for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, C ₁ -C ₆ alkyloxy, amino, alkylamino, dialkylamino, cyano, Nitro, = O, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl.

Examples of cycloalkyl radicals having 3-6 carbon atoms are cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl, which is also characterized by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and / or halogen or substituted as previously defined.

The halogen is generally fluorine, chlorine, bromine or iodine.

The term aryl stands for an aromatic ring system having 6 to 10 carbon atoms, which, unless otherwise stated, may carry, for example, one or more of the following substituents: C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkyloxy, halogen, Hydroxy, mercapto, amino, alkylamino, dialkylamino, CF ₃ , cyano, nitro, -CHO, -COOH, -COO-C ₁ -C ₆ -alkyl, -SC ₁ -C ₆ -alkyl. Preferred aryl radical is phenyl.

Examples of N-linked cyclic radicals of the general formula NR ⁸ R ⁹ are: pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N- (n-propyl ) -piperazine, N-benzylpiperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, N-benzylpiperazine, piperazine, and piperidine, said heterocycles also being preferred by alkyl of 1 to 4 carbon atoms Methyl, or substituted as indicated in the definitions.

As C-linked 5- or 6-membered heterocyclic rings, called heteroatoms 5 may contain nitrogen, oxygen or sulfur, for example, furan, Tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, Tetrahydrofuranone, γ-butylrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, Dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, Pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, Piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, Thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole Called pyrazolidine, wherein the heterocycle is as indicated in the definitions may be substituted.

"= O" means an oxygen atom linked via a double bond.

The new compounds of the general formula (I) can be administered orally, transdermally, be administered by inhalation or parenterally. The compounds of the invention are present as active ingredients in common dosage forms,  for example, in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as for example, tablets, dragees, capsules, wafers, powders, solutions, Suspensions, emulsions, syrups, suppositories, transdermal systems, etc. effective dose of the compounds of the invention is an oral Application between 1 and 100, preferably between 1 and 50, especially preferably between 5-30 mg / dose, with intravenous or intramuscular Application between 0.001 and 50, preferably between 0.1 and 10 mg / dose.

According to the invention, suitable solutions for inhalation are 0.01 to 1.0, preferably contain 0.1 to 0.5% of active ingredient. For inhalative application is the Use of powders preferred. Likewise, it is possible the Compounds of the invention as an infusion solution, preferably in one physiological saline or saline solution.

The compounds according to the invention can be prepared by the following processes, which are partially known in the art, are manufactured.

The synthesis of triazines of the general formula (I) in which R ³ = R ⁴ = R can be carried out by reacting nitriles (1) with the guanidine derivatives (2) on the basis of methods known from the literature (Scheme 1).

Scheme 1

For this purpose, a nitrile with a guanidine derivative in an inert solvent, preferably dimethyl sulfoxide, dissolved and treated with base, preferably sodium hydride. After stirring at room temperature, the reaction is at 50 to 100 ° C, preferably 70 heated to 90 ° C, particularly preferably 80 ° C. The reaction is after 2 to 24 hours, preferably 4 to 12 hours completely.

Triazine derivatives of the general formula (I) in which R ³ ≠ R ⁴ are obtainable by a different route. For this purpose, first the nitriles (1) are transferred to the imidoester (3). (Scheme 2).

Scheme 2

For the representation of the Imidoester (3) are the commercially available or after nitrile (1) accessible in the literature methods in an inert solvent, preferably in an ethereal solvent, more preferably in diethyl ether dissolved and mixed with the corresponding alcohol, preferably methanol. Then, dry hydrogen chloride gas is introduced and the approach below Cooling or at room temperature between 8 and 24 hours, preferably between Stirred for 12 and 20 hours, more preferably 18 hours. The hydrochlorides of Imidoester (3) are obtained by crystallization. The imidates (3) can be then from the hydrochlorides thus obtained by treatment with base release.

An alternative procedure for the synthesis of imidates (3) comprises Reaction of the nitriles (1) with alkali or alkaline earth alcoholates. Suitable alkali and Alkaline earth metals are, for example, lithium, sodium, potassium, magnesium, Calcium, preferably sodium. Preferred as the base is sodium methoxide. These Implementation is z. B. based on J. Org. Chem. 26 (1961) 417 feasible.

The imidoesters (3) are then converted by reaction with carbonyl chlorides (4) into the acylimidates (5) (Scheme 3).

Scheme 3

For this purpose, the imino ether (3) in an inert solvent, preferably in a weakly polar solvent, particularly preferably in toluene, and dissolved with a organic base, preferably a tertiary amine, more preferably Triethylamine added. With cooling to -10 to + 10 ° C, particularly preferably 0-5 ° C, is the suitably substituted acid chloride, which is either commercially available or after literature method is slowly added and until complete conversion at constant temperature or room temperature touched. For working up, it is filtered and the filtrate is freed from the solvent. A Further purification of the crude products (5) thus obtained is in general not mandatory.  

By treating the crude acylimidates (5) with the guanidine derivatives (2) the unsymmetrically substituted triazines of the formula (I) accessible (Scheme 4).

Scheme 4

For this purpose, the acylimidates (5) in an inert solvent, preferably in an alcoholic solvent, more preferably in tert-butanol with the Guanidine derivatives (2) reacted with stirring. The reaction can be elevated at Temperature, but preferably at room temperature and is after 0.5 to 24 hours ended. The free guanidine is preferred directly before Reaction from an acid addition salt, preferably from guanidine hydrochloride generated by the action of base. For this purpose, alkali metal alkoxides in alcoholic Solution particularly suitable, preferred is the use of sodium or Potassium methoxide or sodium or potassium ethoxide, is particularly preferred Ethoxide.

Following the reaction described above in Scheme 4, the triazines (I) depending on solubility by crystallization or chromatography on silica gel cleaned.

Depending on the substitution pattern, the triazines (I) in which the radicals R ¹ , R ² and R ^{4 can have} the abovementioned meanings can be further functionalized by methods known from the literature. These functionalizations include the processes of oxidation, reduction, ether cleavage, acylations, alkylations, etc. which are familiar to the person skilled in the art.

The present invention will be described below by way of example Synthesis instructions explained in more detail. These examples are for illustration, without to limit the invention to its scope.  

I. Preparation of triazines of the general formula (I) where R ³ = R ⁴ and R ¹ = R ² = H General working instructions

To 0.1 mol of nitrile (1) and 0.025 mol of guanidine carbonate in 100 ml of DMSO be at Room temperature 0.1 mol of sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 2 h, stirring is continued at 80 ° C. for a further 4 to 12 h. After complete reaction, the batch is mixed with 120 ml of water. The obtained crystals are filtered off with suction and washed with water. The cleaning the crude triazines (I), depending on their solubility by crystallization or Chromatography on silica gel.

After this procedure, u. a. received the following compounds.

Table 1

II. Preparation of triazines of the general formula (I) with R ³ = R ⁴ and R ² ≠ H General working instructions

On the basis of methods known from the literature (eg J. Heterocycl Chem 13, (1976) 917) are added to 0105 mol of nitrile (1) and 0.025 mol of the corresponding substituted Guanidine hydrochloride (or 0.0125 mol guanidine carbonate or sulfate) in 50 ml  DMSO 0.05 mol sodium hydride (60% dispersion in mineral oil). After 2 h Stirring at room temperature is stirred at 75 ° C for a further 20 to 24 h. To complete reaction, the batch is added to 50 ml of ice water. The precipitated solid is filtered off with suction, washed with water and dried. The Purification of the crude triazines (I) is carried out by recrystallization from an alcohol.

After this procedure, u. a. the following compounds were prepared.

Table 2

III. Preparation of triazines of the general formula (I) with R ³ ≠ R ⁴ A) General working instructions for the preparation of imidoesters (3) version 1

1.2 mol of methanol are added to 0.6 mol of nitrile (1) in 550 ml of ether. HCl gas is then introduced at 10-15 ° C until the solution is saturated and stirred for a further 16 h at room temperature. The resulting Imidoesterhydrochlorid is crystallized, filtered off, washed with ether and then added at 10 ° C in a mixture of 1.4 mol KOH in 700 ml of water and 1.7 l of dichloromethane. After 10 to 15 minutes of stirring, the organic phase is separated, dried over MgSO ₄ and the solvent distilled off in vacuo. The remaining residue is reacted without further purification.

Variant B

In 5 ml of anhydrous methanol, 52 mmol of sodium are dissolved. At 10-15 ° C, 52 mmol of nitrile (1), optionally dissolved in methanol, added dropwise. The mixture is then stirred at room temperature until complete conversion. For workup, 100 ml of dichloromethane are added. The organic phase is washed with water and dried over MgSO ₄ . After distilling off the solvent in vacuo, the Imidoester (3) remain as an oil or solid. The crude products are used without further purification in the next stage.

B) General working instructions for the preparation of acylimidates (5)

21.5 mmol of triethylamine are added to 19.5 mol of imidoester (3) in 60 ml of toluene. After cooling to 0-2 ° C, 21.5 mmol of the acid chloride (4) become slow added dropwise and then stirred at room temperature until the Implementation is complete. For workup is filtered and the filtrate in vacuo Solvent freed. The crude products obtained are without further Cleaning used in the next stage.

C) General working instructions for the preparation of the triazines (I)

Guanidine hydrochloride (90.9 mmol) is used to prepare the free base to a Solution of sodium ethanolate (90.9 mmol) in 75 ml of anhydrous ethanol and stirred at room temperature for 20 min. After filtration, the solvent is in Vacuum distilled off, the guanidine thus obtained in 30 ml of anhydrous tert-butanol taken up at room temperature with stirring with a solution of acylimidate (5) (43.6 mmol) in 150 ml of tert-butanol and until complete conversion (1-17 h) stirred at the same temperature. The pure triazines (I) are obtained by crystallization or chromatography on silica gel.

In accordance with this regulation, u. a. the following connections receive.

Table 3

IV. Derivatization of suitably substituted triazines of the formula (I) A) Ether cleavage of methoxyaryl-substituted triazines

The methoxyaryl-substituted triazine is added at a 10-fold excess Pyridinium bromide well mixed and stirred at 180-190 ° C oil bath temperature for 1-2 h. The melt is then cooled to room temperature, with 4N HCl triturated, filtered off with suction, washed with water and then by means of Purified column chromatography.

After this procedure, u. a. the following compounds were prepared.

Table 4a

B) Cleavage of methoxyalkyl ethers

7.0 mmol of triazine and 30.0 mmol of tetrabutylammonium iodide are suspended in 20 ml of chloroform. At room temperature, then 50.0 mmol BF ₃ -Ethe rat added and the resulting brown solution for 16 h at reflux temperature. For workup, the mixture is cooled to room temperature, diluted with 200 ml of dichloromethane and washed successively with 100 ml of 5% NaHCO ₃ solution (aq.), 5% sodium thiosulfate solution (aq.) And water. The organic phase is dried over MgSO ₄ and the solvent is distilled off in vacuo. The residue which remains is taken up in 300 ml of ether, stirred vigorously for 6 hours, filtered off with suction and the filtrate is concentrated. The purification is carried out by column chromatography.

After this procedure, u. a. the following compounds were prepared.

Table 4b

C) Hydrogenations of nitro compounds

In 30 ml of tetrahydrofuran are added 10 mmol of triazine and with about 1 g Raney nickel (MeOH wet) hydrogenated at 24-30 ° C and 5.0 bar for 5-7 h. After separation of the Raney nickel, the mixture is filtered off with suction through kieselguhr and the filtrate is freed from the solvent in vacuo. The remaining residue will be purified by crystallization or chromatography on silica gel.

After this procedure, u. a. the following compounds are shown.

Table 4c

D) O- and N-acylations

5.3 mmol of triazine are suspended in 30-50 ml of dichloromethane and admixed with 26.5 mmol of pyridine. At 5-7 ° C, 7.5 mmol of acid chloride or anhydride are added slowly. The mixture is then warmed to room temperature and stirred for a further 1-5 h. If a suspension is present, the product is filtered off with suction, washed with dichloromethane and optionally an alcoholic solvent is added. If there is a solution, wash with water and 1N HCl (aq.). The organic phase is dried over MgSO ₄ and the solvent is distilled off in vacuo. The remaining residue is purified by chromatography on silica gel.

After this procedure, u. a. the following compounds are shown.

Table 4d

E) Oxidations

1.9 mmol of triazine are suspended in 25 ml of dichloromethane. Then, 1.7 equivalents of pyridinium chlorochromate are added and stirred overnight at room temperature. The resulting suspension is diluted with 50 ml of dichloromethane and washed twice with water. The organic phase is dried over MgSO ₄ , concentrated by evaporation and the remaining residue is purified by chromatography on silica gel.

After this procedure, u. a. the following compounds were prepared.

Table 4e

Table 5 summarizes the compounds of general formula (I) prepared in analogy to the methods described above.

The structures of the previously synthesized examples of the compounds (I) were described below confirmed by NMR spectroscopy. The following will be NMR spectroscopic data of selected compounds are listed.

Example (2)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.54-7.45 (10H, m, aryl-H); 7.65 (2H, s, broad, NH ₂ ).

Example (4)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.57-7.50 (10H, m, aryl-H); 8.14 (1H, t, J = 5.5 Hz, NH); 3.55 (2H, m, N -CH ₂ ); 1.25 (3H, t, J = 6.5 Hz, CH ₃ ).

Example (11)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.50 (2H, s, broad, OH); 7.89-6.99 (8H, m, aryl-H); 7.57 (2H, s, broad, NH ₂ ).

Example (13)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.48 (4H, s, broad, OH); 7.44 (2H, s, broad, NH ₂ ); 7.34 (4H, d, J = 2.0 Hz, aryl-H); 6.40 (2H, t, J = 2.0 Hz, aryl-H).

Example (20)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 7.71-6.69 (8H, m, aryl-H); 7.47 (2H, s, broad, NH ₂ ); 5.87 (2H, q, J = 5.5 Hz, NH); 2.75 (6H, d, J = 5.5 Hz, CH ₃ ).

Example (36)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 13.60, 9.78, 9.00 (3H, 3s, broad, OH); 8.04, 7.91 (2H, 2s, broad, NH ₂ ); 7.88-6.72 (7H, m, aryl-H).

Example (37)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 7.93-6.94 (4H, m, aryl-H); 7.34 (2H, d, J = 2.0 Hz, aryl-H); 6.45 (1H, t, J = 2.0Hz, aryl-H); 7.62 (2H, s, broad, NH ₂ ); 5.47 (3H, s, broad, OH).

Example (39)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.70 (1 H, s, broad, OH); 8.45-6.94 (8H, m, aryl-H); 7.71 (2H, s, broad, NH ₂ ).

Example (40)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.69 (1 H, s, broad, OH); 8.46, 7.64 (4H, 2m, aryl-H); 7.95-6.94 (4H, m, aryl-H); 7.68 (2H, s, broad, NH ₂ ).

Example (42)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.70 (1 H, s, broad, OH); 8.62-6.94 (8H, m, aryl-H); 7.59 (2H, s, broad, NH ₂ ); 2:44 (3H, s, CH _3).

Example (43)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.62 (1H, s, broad, OH); 8.37, 7.38 (4H, 2m, aryl-H); 7.96-6.93 (4H, m, aryl-H); 7.57 (2H, s, broad, NH ₂ ); 2:40 (3H, s, CH _3).

Example (48)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.69 (1H, s, broad, OH); 8.46-6.99 (9H, m, aryl-H); 7.59 (2H, s, broad, NH ₂ ).

Example (49)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.50-7.33 (9H, m, aryl-H); 7.71 (2H, s, broad, NH ₂ ); 2.33 (3H, s, CH ₃ ).

Example (51)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.55 (2H, s, broad, OH); 8.46-7.45 (5H, m, aryl-H); 7.56 (2H, s, broad, NH ₂ ); 7.38 (2H, d, J = 2.0 Hz, aryl-H); 6.41 (1H, t, J = 2.0 Hz, aryl-H).

Example (58)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.52-7.50 (9H, m, aryl-H); 7.69 (2H, s, broad, NH ₂ ); 4.53 (2H, s, CH ₂ -O); 3:33 (3H, s, CH _3).

Example (59)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.52-7.43 (9H, m, aryl-H); 7.66 (2H, s, broad, NH ₂ ); 5.34 (1H, t, J = 5.0 Hz, OH); 4.62 (3H, s, CH _3).

Example (60)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.52-7.40 (9H, m, aryl-H); 7.66 (2H, s, broad, NH ₂ ); 5.31 (1H, d, J = 3.5 Hz, OH); 4.84 (1H, m, CH); 1.39 (3H, d, J = 6.5 Hz, CH ₃ ).

Example (61)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.10-7.50 (9H, m, aryl-H); 7.80 (2H, s, broad, NH ₂ ); 2.68 (3H, s, CH _3).

Example (65)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.50-6.71 (9H, m, aryl-H); 7.52 (2H, s, broad, NH ₂ ); 528 (2H, s, broad, NH ₂ ).

Example (66)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.19, 6.64 (4H, 2m, aryl-H); 8.47-7.47 (5H, m, aryl-H); 7.31 (2H, s, broad, NH ₂ ); 5.83 (2H, s, broad NH ₂ ).

Example (67)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 10.54 (1H, s, NHCO); 8.97-7.57 (9H, m, aryl-H); 7.90 (2H, s, broad, NH ₂ ); 2:06 (3H, s, CH _3).

Example (69)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.46-6.69 (8H, m, aryl-H); 7.31 (2H, s, broad, NH ₂ ); 5.61 (2H, s, broad, NH ₂ ); 2.14 (3H, s, CH _3).

Example (70)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.45-6.68 (8H, m, aryl-H); 7.32 (2H, s, broad, NH ₂ ); 5.61 (2H, s, broad, NH ₂ ); 2.14 (3H, s, CH _3).

Example (71)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.60 (1H, s, NH); 8.51-7.33 (8H, m, aryl-H); 7.60 (2H, s, broad, NH ₂ ); 2.29 2:08 (6H, 2s, CH _3).

Example (77)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.20-7.51 (9H, m, aryl-H); 7.84 (2H, s, broad, NH ₂ ).

Example (82)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.59, 8.76, 8.72, 7.57 (4H, 4m, pyridyl); 8.47-7.50 (5H, m, aryl-H); 7.53 (2H, s, broad, NH ₂ ).

Example (85)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.47, 8.63, 7.45 (3H, 3m, pyridyl-H); 8.52-7.50 (5H, m, aryl-H); 7.75 (2H, s, broad, NH ₂ ); 2:58 (3H, s, CH _3).

Example (102)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 8.50-7.47 (5H, m, aryl-H); 8.12, 7.91, 7.09 (3H, 3m, piperonyl-H); 7.57 (2H, s, broad, NH ₂ ); 6.18 (2H, s, CH ₂ ).

Example (121)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.59, 8.78, 8.72, 7.59 (4H, 4m, pyridyl); 8.39-7.37 (4H, 2m, aryl-H); 7.75 (2H, s, broad, NH ₂ ); 2.42 (3H, s, CH ₃ ).

Example (127)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.56, 8.78, 8.72, 7.59 (4H, 4m, pyridyl-H); 8.43, 8.33, 7.55 (3H, 3m, aryl-H); 7.83 (2H, s, broad, NH ₂ ); 2.43 (3H, s, CH ₃ ).

Example (128)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.60, 8.78, 8.74, 7.58 (4H, 4m, pyridyl-H); 8.44, 8.29, 7.59 (3H, 3m, aryl-H); 7.82 (2H, s, broad, NH ₂ ); 2.46 (3H, s, CH ₃ ).

Example (130)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.67, 8.79, 8.74, 7.62 (4H, 4m, pyridyl); 8.47-7.52 (4H, m, aryl-H); 7.89 (2H, s, broad, NH ₂ ).

Example (131)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.59, 8.78, 8.71, 7.64 (4H, 4m, pyridyl-H); 8.49, 7.63 (4H, 2m, aryl-H); 7.83 (2H, s, broad, NH ₂ ).

Example (133)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.50, 8.78, 8.66, 7.58 (4H, 4m, pyridyl); 8.19-7.26 (4H, 2m, aryl-H); 7.87 (2H, s, broad, NH ₂ ).

Example (134)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.60, 8.79, 8.76, 7.62 (4H, 4m, pyridyl); 8.38-7.41 (4H, 2m, aryl-H); 7.89 (2H, s, broad, NH ₂ ).

Example (136)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.60, 8.78, 8.74, 7.60 (4H, 4m, pyridyl-H); 8.47-7.55 (3H, m, aryl-H); 7.88 (2H, s, broad, NH ₂ ).

Example (140)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.70 (1 H, s, broad, OH); 9.57, 8.72, 8.70, 7.60 (4H, 4m, pyridyl); 7.74 (2H, s, broad, NH ₂ ); 7.95-6.94 (4H, m, aryl-H).

Example (161)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.56, 8.78, 8.70, 7.60 (4H, 4m, pyridyl-H); 8.00 (1H, s, furyl-H); 8.01, 7.90 (2H, 2s, broad, NH ₂ ); 7.85-7.28 (4H, m, benzofuranyl-H).

Example (163)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.57, 8.77, 8.72, 7.57 (4H, 4m, pyridyl); 8.13, 7.93, 7.08 (3H, 3m, aryl-H); 7.69 (2H, s, broad, NH ₂ ); 6.15 (2H, s, CH ₂ ).

Example (167)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.50, 8.76, 8.62, 7.58 (4H, 4m, pyridyl); 7.83, 6.62 (2H, 2d, J = 2.0 Hz, furyl-H); 7.70 (2H, s, broad, NH ₂ ); 2:59 (3H, s, CH _3).

Example (177)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.52, 8.76, 8.65, 7.57 (4H, 4m, pyridyl-H); 8.38, 6.68 (2H, 2d, J = 1.0 Hz, furyl-H); 7.64 (2H, s, broad, NH ₂ ); 2:35 (3H, s, CH _3).

Example (181)

¹ H-NMR (250 MHz; DMSO-d6): δ [ppm] = 9.50, 8.77, 8.64, 7.52 (4H, 4m, pyridyl); 7.71 (2H, s, broad, NH ₂ ); 7.94, 6.99 (2H, 2d, J = 3.5Hz, thienyl-H); 2:54 (3H, s, CH _3).

Example (186)

¹ H-NMR (250 MHz, DMSO-d6): δ [ppm] = 9.51, 8.78, 8.66, 7.59 (4H, 4m, pyridyl-H); 8.17, 8.07 (2H, 2d, J = 4.0Hz, thienyl-H); 8.07 (2H, s, broad, NH ₂ ).

The following table contains KiA ₁ (human) receptor binding values.

Table 6

The following table contains KiA ₃ (human) receptor binding values.

Table 7

The compounds of general formula (I) may be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active agents, are used. suitable Examples of applications are tablets, capsules, suppositories, solutions, Juices, emulsions or dispersible powders. Appropriate tablets can for example, by mixing the active substance (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as  Starch or gelatin, lubricants, such as magnesium stearate or talc, and / or Means for achieving the depot effect, such as carboxyethylcellulose, Cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can be coated analogously to the tablets manufactured cores with commonly used in dragee coatings, For example Kollidon or shellac, gum arabic, talc, titanium dioxide or Sugar, to be produced. To achieve a depot effect or to avoid of incompatibilities, the core can also consist of several layers. Similarly, the dragee cover to achieve a depot effect from several layers are those mentioned above in the tablets Excipients can be used.

Juices of erfindungsgeinäßen active ingredients or drug combinations may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent, e.g. B. flavorings, such as vanillin or orange extract. You can also use suspension aids or Thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example Condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are in the usual manner, for. B. with the addition of Preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid and in injection bottles or ampoules bottled.

The one or more active substances or combinations of active substances containing capsules can be prepared, for example, by the Ingredients with inert carriers, such as lactose or sorbitol, and mixes in Encapsulating gelatin capsules.

Suitable suppositories can be, for example, by mixing with it provided carriers, such as neutral fats or polyethylene glycol or its derivatives.

A therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.  

However, the following examples illustrate the present invention without them to limit its scope:

Pharmaceutical Formulation Examples A)

tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg           500 mg         

The finely ground active ingredient, lactose and part of the corn starch will be mixed together. The mixture is sifted, followed by a solution of polyvinylpyrrolidone in water moistened, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture becomes tablets of suitable form and Size pressed.

B)

tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg magnesium stearate 2 mg           400 mg         

The finely ground active ingredient, part of the corn starch, lactose, microcrystalline Cellulose and polyvinyl pyrrolidone are mixed together, the mixture sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. Add the sodium car boxymethyl starch and the magnesium stearate, mixed and compressed Mixture to tablets of appropriate size.  

C)

dragees per dragée active substance 5 mg corn starch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 mg           80 mg         

The active ingredient, corn starch, lactose and polyvinylpyrrolidone will be good mixed and moistened with water. The moist mass is pressed through a sieve with 1 mm mesh, dries at about 45 ° C and hits the granules then through the same sieve. After admixing magnesium stearate On a tableting machine, curved dragée kernels are combined with one Diameter of 6 mm pressed. The dragé kernels produced in this way are opened up known manner coated with a layer consisting essentially of sugar and Talc exists. The finished dragees are polished with wax.

D)

capsules per capsule active substance 50 mg corn starch 268.5 mg magnesium stearate 1.5 mg           320 mg         

Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is in Hard gelatine capsules size 1 bottled.

e)

ampoule solution active substance 50 mg sodium chloride 50 mg Aqua pro inj. 5 mg

The active ingredient is at intrinsic pH or optionally at pH 5.5 to 6.5 in water dissolved and treated with sodium chloride as isotonic. The resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules  bottled, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg active substance.

F)

suppositories active substance 50 mg Adeps solidus 1650 mg           1700 mg         

The hard fat is melted. At 40 ° C, the ground active substance homogeneously dispersed. It is cooled to 38 ° C and slightly pre-cooled Suppository forms poured out.

G)

oral suspension active substance 50 mg hydroxyethyl 50 mg sorbic acid 5 mg Sorbitol (70%) 600 mg glycerin 200 mg Aroma 15 mg Water ad 5 ml

Distilled water is heated to 70 ° C. Herein is stirring Hydroxyethyl cellulose dissolved. After adding sorbitol solution and glycerin is added Room temperature cooled. At room temperature, sorbic acid, flavor and substance added. To vent the suspension is stirred evacuated.

Claims (14)

1. triazine derivatives of the general formula (I)
wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ alkyl;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle ₁ which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl chain, one or more Atoms may be selected from the group oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5-methyl 2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl,
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 2. Compounds of general formula (I) according to claim 1 wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ alkyl;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} furyl, thienyl, pyridyl or pyrrolyl, which may optionally be mono- or polysubstituted by C ₁ -C ₄ -alkyl;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} pyrimidinyl, pyridyl, which may optionally be substituted by one or more of halogen, C ₁ -C ₄ -alkyl or -SC ₁ -C ₄ -alkyl;
R ^{4 is} pyridyl C ₁ -C ₄ alkyl or pyridyl C ₂ -C ₄ alkenyl;
R ⁴ furyl, which is optionally substituted by one or more of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ -C ₄ alkyl, phenyl, NO ₂ or halogen may be substituted;
R ^{4 is} tetrahydropyranyl or tetrahydrofuranyl;
R ^{4 is} thienyl, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, halogen, oxazolyl or NO ₂ ;
R ^{4 is} dithiolanyl, thiolanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, quinolinyl, benzo [b] furanyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl, which may optionally be substituted by one or more of the radicals C. C ₁ -C ₄ -alkyl, NO ₂ or halogen,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl,
3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5-methyl-2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl,
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 3. Compounds of general formula (I) according to claim 1 or 2 wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen, methyl or ethyl;
R ^{3 is} cyclopropyl, cyclopentyl or cyclohexyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of the radicals OH, chlorine, fluorine, NO ₂ , methyl, methoxy, hydroxymethyl, methoxymethyl, amino, methylamino, ethylamino, N-acetylamino, dimethylamino, CF ₃ , CF ₃ SO ₂ -O-, acetoxy, ethylcarbonyloxy, phenylcarbonyloxy or phenyloxycarbonyloxy;
R ³ furyl, thienyl, pyridyl or pyrrolyl, which may each be mono-, di- or trisubstituted by methyl;
R ⁴ optionally mono- or polysubstituted by OH, = O, methyl or methoxy substituted cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which is optionally substituted by one or more of OH, fluorine, chlorine, bromine, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, methyl, ethyl, propyl, butyl, methoxy, acetyl, phenylcarbonyl, acetoxy , Ethylcarbonyloxy, phenylcarbonyloxy, hydroxymethyl, hydroxyethyl, methoxymethyl, amino, methylamino, ethylamino, dimethylamino, N-acetylamino, methoxycarbonyloxy, ethoxycarbonyloxy or phenyloxycarbonyloxy;
R ^{4 is} benzyl, phenylethyl, phenylethenyl, phenylethynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} optionally substituted by methyl pyrimidinyl, pyridyl, which may optionally be mono- or polysubstituted by fluorine, chlorine, bromine, methyl or -S-methyl;
R ^{4 is} pyridylmethyl or pyridylethenyl;
R ⁴ furyl, which may optionally be mono- or polysubstituted by methyl, ethyl, propyl, butyl, methoxy, methoxymethyl, phenyl, NO ₂ , fluorine, chlorine or bromine;
R ^{4 is} tetrahydropyranyl or tetrahydrofuranyl;
R ^{4 is} thienyl, which may optionally be mono- or polysubstituted by methyl, fluorine, chlorine, bromine, oxazolyl or NO ₂ ;
R ⁴ dithiolanyl, thiolanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, quinolinyl, benzo [b] furanyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl, which may optionally be mono- or polysubstituted by methyl , Ethyl, propyl, NO ₂ , fluorine, chlorine or bromine,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl, 5 May be bromo-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ^{4 is} not phenyl 2-methoxyphenyl, 2-hydroxyphenyl,
4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxy-4-ethoxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 5-methyl-2-furyl,
R ⁴ can not be phenyl;
when R ^{2 is} hydrogen,
R ³ and R ^{4 are} not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl, 4-ethyl-2-pyridyl, 2-chlorophenyl, 2,4-dichlorophenyl, 5-methyl 2-furyl or 3,4,5-trimethoxyphenyl,
when R ^{2 is} methyl and R ^{3 is} phenyl,
R ⁴ can not be phenyl or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, phenyl-CH = CH- or 2-hydroxyphenyl;
when R ^{2 is} methyl and R ^{3 is} 2,4-dihydroxyphenyl,
R ⁴ can not be 4-chlorophenyl;
when R ^{2 is} methyl and R ^{3 is} 4-chlorophenyl,
R ⁴ can not be 2,4-dihydroxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} phenyl,
R ⁴ can not be 2-hydroxy-4-methoxyphenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4-methoxyphenyl,
R ⁴ can not be phenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-4,6-dimethylphenyl,
R ⁴ can not be 2-hydroxy-5-chlorophenyl;
when R ^{2 is} ethyl and R ^{3 is} 2-hydroxy-5-chlorophenyl,
R ⁴ can not be 2-hydroxy-4,6-dimethylphenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 4. Compounds of general formula (I) according to any one of claims 1, 2 or 3 wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or ethyl;
R ^{3 is} cyclohexyl, phenyl, hydroxyphenyl, 3,5-dihydroxyphenyl, methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-methyl, aminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, 3-chloro-4-methylphenyl , 4-chloro-3-methylphenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3,5-difluorophenyl, 3-acetoxyphenyl , 3-ethylcarbonyloxyphenyl, 3-phenylcarbonyloxyphenyl, 3-phenoxycarbonyloxyphenyl, 3-trifluoromethanesulfonyloxyphenyl, 3-methoxymethylphenyl, 2-furyl, 2-thienyl, pyridyl or 1,5-dimethyl-2-pyrrolyl;
R ^{4 is} cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, hydroxycyclohexyl, methoxycyclohexyl, cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl, hydroxyphenyl, methoxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 3-acetylphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-ethylcarbonyloxyphenyl, 3-phenylcarbonyloxyphenyl, 3-phenoxycarbonyloxyphenyl, 3-trifluoromethanesulfonyloxyphenyl, chlorophenyl, 3,4-dichlorophenyl, methylphenyl, ethylphenyl, propylphenyl, 4-t Butylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-hydroxymethylphenyl, aminophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, acetylaminophenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino 3-methylphenyl, nitrophenyl, 4-nitro-3-methylphenyl, 3-nitro-4-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, fluorophenyl, 3,4-difluorophenyl, trifluoromethylphenyl, 3 Methoxymethylphenyl, benzyl, 2-phenylethyl, phenyl-CH = CH-, phenyl-C~C-biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy, 3,4-methylenedioxophenyl, 2,3-meth ylendioxophenyl or phenylamino;
R ^{4 is} optionally substituted by methyl pyrimidinyl, pyridyl, pyridylmethyl, pyridyl-CH = CH-, 6-chloro-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-3-pyridyl, 2-thiomethyl-pyridine-3 -yl, 2-benzo [b] furanyl, furyl, 5-methyl-2-furyl, 5-methyl-3-furyl, 2-methyl-3-furyl, 3-methoxy-methyl-2-furyl, 3-methyl 2-furyl, 2,5-dimethyl-3-furyl, 4,5-dimethyl-2-furyl, 5-t-butyl-2-methyl-3-furyl, 5-nitro-2-furyl, 2-methyl 5-phenyl-3-furyl, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, thienyl, 5-methyl-2-thienyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 5-chloro 3-thienyl, 2,5-dichloro-3-thienyl, 5-nitro-3-thienyl, 5-nitro-2-thienyl, 1,3-dithiolan-2-yl, 5- (1,2-oxazole-3 -yl) -3-thienyl, thiolan-2-yl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-imidazol-2-yl, 1-methyl-pyrazol-4-yl, 1,5-dimethyl 2-pyrazol-3-yl, 4,5-dichloro (1,2-thiazol) -3-yl, 2,4-dimethyl- (1,3-thiazol) -5-yl, 4-methyl- (1 -thia-2,3-diazole) -5-yl, 1,2-oxazol-5-yl, quinolin-2-yl or quinolin-3-yl,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ^{4 is} not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-nitro-2-furyl or 5-methyl-2-furyl can be;
when R ^{2 is} hydrogen and R ^{3 is} 2-hydroxyphenyl,
R ⁴ can not be phenyl, 2-methoxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl or phenyl-CH = CH-;
when R ^{2 is} hydrogen and R ^{3 is} 4-hydroxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-methoxyphenyl,
R ⁴ can not be 2-hydroxyphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl,
R ⁴ can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-pyridyl,
R ⁴ can not be phenyl, 3-pyridyl or 4-pyridyl;
when R ^{2 is} hydrogen and R ^{3 is} 2-furyl,
R ⁴ can not be phenyl, 2-furyl or 3-pyridyl;
when R ^{2 is} hydrogen,
R ³ and R ⁴ can not be simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl or 2-pyridyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 5. Compounds of general formula (I) according to any one of claims 1, 2, 3 or 4, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or ethyl;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-amino-4-methylphenyl, 4-amino-3-methylphenyl, 3-chloro-4-methylphenyl, 4- Chloro-3-methylphenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3,4-difluorophenyl, 3-pyridyl, 2- Thienyl or 1,5-dimethyl-2-pyrrolyl;
R ^{4 is} phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-hydroxymethylphenyl, 3-acetylphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylaminophenyl, 4-methylaminophenyl, 3-ethylaminophenyl, 4-ethylaminophenyl, 3-amino-4-methylphenyl, 4-amino-3- methylphenyl, 3-acetylaminophenyl, 4-acetylaminophenyl, 3-acetylamino-4-methylphenyl, 4-acetylamino-3-methylphenyl, 3-nitrophenyl, 4-nitrophenyl, 3-nitro-4-methylphenyl, 4-nitro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl;
R ⁴ 1,3-pyrimidin-2-yl, 1,3-pyrimidin-5-yl, 6-chloro-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-3-pyridyl, 2-benzo b] furanyl, furyl, 5-methyl-2-furyl, 5-methyl-3-furyl, 2-methyl-3-furyl, 3-methyl-2-furyl, 2,5-dimethyl-3-furyl, 4, 5-dimethyl-2-furyl, 5-t-butyl-2-methyl-3-furyl, 5-nitro-2-furyl, tetrahydropyrnyl-4-yl, tetrahydrofuran-2-yl, thienyl, 5-methyl-2-thienyl, 3-methyl-2-thienyl, 2-methyl-3-thienyl, 5-chloro-3-thienyl, 2,5-dichloro-3-thienyl, 5-nitro-3-thienyl, 5-nitro-2-thienyl, 5- (1,2-oxazol-3-yl) -3-thienyl, 1,3-dithiolan-2-yl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-imidazol-2-yl, 1 Methyl pyrazol-4-yl, 1,5-dimethyl-pyrazol-3-yl, 4,5-dichloro (1,2-thiazol) -3-yl, 2,4-dimethyl- (1,3-thiazole ) -5-yl, 4-methyl- (1-thia-2,3-diazole) -5-yl, 1,2-oxazol-5-yl, 4,5-dichloro-1,2-thiazole-3 yl, quinolin-2-yl or quinolin-3-yl,
with the proviso that
when R ^{2 is} hydrogen and R ^{3 is} phenyl,
R ⁴ can not be phenyl, 2-hydroxyphenyl, 4-methylphenyl, 4-nitrophenyl, 2-furyl, 5-nitro-2-furyl or 5-methyl-2-furyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-methylphenyl,
R ⁴ can not be phenyl or 4-methylphenyl;
when R ^{2 is} hydrogen and R ^{3 is} 4-nitrophenyl, R can not be phenyl or 3-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-nitrophenyl,
R ⁴ can not be 4-nitrophenyl;
when R ^{2 is} hydrogen and R ^{3 is} 3-pyridyl,
R ⁴ can not be phenyl or 2-furyl;
when R ^{2 is} hydrogen,
R ³ and R ⁴ can not be simultaneously 4-chlorophenyl;
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 6. Compounds of general formula (I) according to any one of claims 1, 2, 3, 4 or 5, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl, 2-thienyl or 3-pyridyl;
R ^{4 is} phenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl, 3-hydroxymethylphenyl, 3-aminophenyl, 4-aminophenyl, 3-amino-4-methylphenyl, 3-acetylaminophenyl, 3-acetylamino-4-methylphenyl, 3-nitrophenyl, 3-nitro-4-methylphenyl, 4- Chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 3,4-methylenedioxophenyl, 2,3-methylenedioxophenyl, 6-methyl-3- pyridyl, 2-methyl-3-pyridyl, 2-benzo [b] furanyl, 1,5-dimethyl-2-pyrrolyl, 5-methyl-3-furyl, 3-methyl-2-furyl, 4,5-dimethyl 2-furyl, 5-methyl-2-thienyl, 5-chloro-3-thienyl, 5-nitro-2-thienyl or 4,5-dichloro-1,2-thiazol-3-yl,
with the proviso that
when R ^{3 is} 3-pyridyl, R ⁴ can not be phenyl and
when R ^{3 is} phenyl, R ⁴ can not be phenyl or 4-methylphenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 7. Compounds of general formula (I) according to any one of claims 1, 2, 3, 4, 5 or 6, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen;
R ^{3 is} phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl or 3-pyridyl;
R ^{4 is} 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphehyl, 3-hydroxymethylphenyl, 3-aminophenyl, 4-aminophenyl, 3-acetylaminophenyl, 3-amino-4-methylphenyl, 3-acetylamino-4-methylphenyl, 3-nitrophenyl, 3-nitro-4-methylphenyl, 3-chloro-4-methylphenyl, 3,4-difluorophenyl, 3-methoxymethylphenyl, 1,5-dimethyl-2-pyrrolyl, 3-methyl-2-furyl, 4,5-dimethyl-2-furyl or 4,5-dichloro-1,2-thiazol-3-yl,
with the proviso that when R ^{3 is} phenyl, R ⁴ can not be 4-methylphenyl,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 8. Use of triazines of the general formula (I)
as a drug in which
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₅ -alkyl;
R ^{3 is} -COOH, -COO-C ₁ -C ₄ -alkyl or CN;
R ^{3 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{3 is} C ₆ -C ₁₀ -aryl, which may optionally be substituted by one or more of the radicals OH, halogen, CN, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylcarbonyl, C ₆ -C ₁₀ -arylcarbonyl, C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, HO-C ₁ -C ₄ -alkyl- , C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or C ₂ -C ₆ -alkynyl bridge, one or more Atoms may be selected from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ alkyl;
R ^{3 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene;
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} C ₆ -C ₁₀ -aryl, which may optionally be substituted by one or more of the radicals OH, halogen, CN, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ -alkylcarbonyl, C ₆ -C ₁₀ -arylcarbonyl, C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, HO-C ₁ -C ₄ -alkyl- , C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{4 is} phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₄ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group may contain oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 9. Use of triazines of the general formula (I) according to claim 8 as a medicament, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₅ -alkyl;
R ^{3 is} C ₃ -C ₆ -cycloalkyl, which may optionally be substituted by OH, = O, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{3 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{3 is} a 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl,
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by OH, OO, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group may contain oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 is} one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ Alkyl, NO ₂ or halogen,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 10. Use of triazines of the general formula (I) according to one of claims 8 or 9 as medicaments, wherein
R ^{1 is} hydrogen;
R ^{2 is} hydrogen or C ₁ -C ₃ alkyl;
R ^{3 is} C ₃ -C ₆ cycloalkyl;
R ^{3 is} phenyl which may optionally be substituted by one or more of OH, halogen, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, HO-C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkyloxy-C ₁ -C ₄ -alkyl, amino, C ₁ -C ₄ -alkylamino, C ₁ -C ₄ -dialkylamino, C ₁ -C ₄ -alkylcarbonylamino, CF ₃ , CF ₃ SO ₂ -O C ₁ -C ₄ -alkylcarbonyloxy, C ₆ -C ₁₀ -arylcarbonyloxy, C ₁ -C ₄ -alkyloxycarbonyloxy or C ₆ -C ₁₀ -aryloxycarbonyloxy;
R ^{3 is} a 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and may optionally be substituted by one or more of the radicals benzyl or C ₁ -C ₄ -alkyl;
R ^{4 is} C ₁ -C ₄ -alkyl, -COOH, -COO-C ₁ -C ₄ -alkyl, NH ₂ or CN;
R ^{4 is} C ₃ -C ₇ -cycloalkyl, which may optionally be substituted by CH, = O, C ₁ -C ₄ -alkyl or C ₁ -C ₄ -alkyloxy;
R ^{4 is} cyclopentenyl or cyclohexenyl;
R ^{4 is} phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO ₂ , CF ₃ , CF ₃ -SO ₂ -O-, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkyloxy, C ₁ -C ₄ alkylcarbonyl, C ₆ -C ₁₀ arylcarbonyl, C ₁ -C ₄ alkylcarbonyloxy, C ₆ -C ₁₀ arylcarbonyloxy, HO-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy C ₁ -C ₄ alkyl, amino, C ₁ -C ₄ alkylamino, C ₁ -C ₄ dialkylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkyloxycarbonyloxy or C ₆ -C ₁₀ aryloxycarbonyloxy ;
R ^{4 is} benzyl, phenyl-C ₁ -C ₄ -alkyl, phenyl-C ₂ -C ₄ -alkenyl, phenyl-C ₂ -C ₄ -alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
R ^{4 is} a 5, 6 or 7-membered heterocycle linked via a single bond or via a C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl chain or more atoms from the group oxygen, nitrogen or sulfur and optionally substituted may include the can by one or more of the radicals C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ -alkyloxy-C ₁ C ₄ alkyl, phenyl, NO ₂ , oxazolyl, halogen or -SC ₁ -C ₄ alkyl;
R ^{4 of} a bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1,2-methylenedioxobenzene, which may optionally be substituted by one or more of the radicals C ₁ -C ₄ - Alkyl, NO ₂ or halogen,
optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts. 11. Use of triazines according to one of claims 1 to 7 as Drug. 12. Use of triazines according to one of claims 1 to 10 as Medicinal products with adenosine antagonist effect. 13. Use of triazines according to one of claims 1 to 10 for Preparation of a medicament with adenosine antagonistic action.   14. Pharmaceutical preparations containing as active ingredient one or more Compounds according to any one of claims 1 to 10 or physiologically thereof compatible acid addition salts in combination with conventional auxiliary and / or Excipients.