WO1999011633A1 - Triazines ayant un effet antagoniste vis-a-vis de l'adenosine - Google Patents

Triazines ayant un effet antagoniste vis-a-vis de l'adenosine Download PDF

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WO1999011633A1
WO1999011633A1 PCT/EP1998/005101 EP9805101W WO9911633A1 WO 1999011633 A1 WO1999011633 A1 WO 1999011633A1 EP 9805101 W EP9805101 W EP 9805101W WO 9911633 A1 WO9911633 A1 WO 9911633A1
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phenyl
alkyl
methylphenyl
hydrogen
optionally
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PCT/EP1998/005101
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German (de)
English (en)
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Ulrike Küfner-Mühl
Stefan Wolfgang Scheuplein
Gerald Pohl
Wolfgang Gaida
Erich Lehr
Joachim Mierau
Christopher John Montague Meade
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Boehringer Ingelheim Pharma Kg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to new triazine derivatives, processes for their preparation and the use of triazines as medicaments, in particular as medicaments with an adenosine antagonistic effect.
  • triazines of the general formula (I) have an affinity for adenosine receptors and thus represent a new class of adenosine antagonists.
  • Adenosine antagonists can have a therapeutically useful effect in cases where diseases or pathological situations are associated with the activation of adenosine receptors.
  • Adenosine is an endogenous neuromodulator with predominantly inhibitory (inhibitory) effects in the CNS, heart, kidneys and other organs.
  • the effects of adenosine are mediated via at least three receptor subtypes: adenosine A ⁇
  • Activation of A-j receptors pre-synaptic by inhibiting synaptic transmission (inhibiting the release of neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate etc.), postsynaptically by inhibiting neuronal activity.
  • neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamate etc.
  • a ⁇ antagonists abolish the inhibitory effects of adenosine and promote neuronal transmission and activity.
  • Antagonists are therefore of great interest for the therapy of central nervous degenerative diseases such as senile dementia of the Alzheimer's type and age-related disorders of memory and learning performance.
  • the disease includes a number of other accompanying symptoms such as sleep disorders, moto-coordination disorders up to the picture of Parkinson's disease, an increased affectability and depressive symptoms.
  • the disease is progressive and can lead to death.
  • the previous therapy is unsatisfactory.
  • Specific therapeutic agents have so far been completely lacking.
  • Attempted therapy with acetylcholinesterase inhibitors only shows an effect in a small part of the patients, but is associated with a high rate of side effects.
  • the pathophysiology of Alzheimer's disease and SDAT is characterized by severe impairment of the cholinergic system, but other transmitter systems are also affected. Due to the loss of presynaptic cholinergic and other neurons and the resulting lack of provision of neurotransmitters, neuronal transmission and neuronal activity in the brain areas essential for learning and memory are significantly reduced.
  • -Receptor antagonists promote neuronal transmission by increasing the availability of neurotransmitters, increase the excitability of postsynaptic neurons and can thus counteract the disease symptomatically.
  • A-i antagonists can be used to upregulate adenosine A ⁇
  • Adenosine inhibits the release of dopamine from central synaptic endings through interactions with dopamine D2 receptors.
  • A2 antagonists increase the release and availability of dopamine and thus offer a new therapeutic principle for the treatment of Parkinson's disease.
  • vasodilation of cerebral vessels mediated via A2 receptors appears to be involved.
  • Selective A2 ⁇ antagonists inhibit vasodilation and can therefore be useful for the treatment of migraines.
  • Adenosine antagonists can also be used to treat peripheral indications.
  • adenosine By activating A2 receptors, adenosine can cause respiratory depression and respiratory arrest, among other things.
  • A2 antagonists cause respiratory stimulation.
  • adenosine antagonists (theophylline) are used to treat shortness of breath and to prevent "sudden child death" in premature babies.
  • adenosine antagonists are cardiovascular diseases and kidney diseases.
  • Adenosine unfolds at heart through the activation of A-
  • Receptors inhibit electrical and contractile activity.
  • adenosine has a negative chronotropic, inotropic, dromotropic, bathmotropic, bradycardic effect and lowers the cardiac output.
  • Adenosine A- Receptor antagonists are able to prevent damage to the heart and lungs caused by ischemia and subsequent reperfusion. Therefore adenosine antagonists for the prevention or early treatment of ischemia reperfusion-related damage to the heart could e.g. after coronary bypass surgery, heart transplantation, angioplasty or thrombolytic therapy of the heart and similar interventions. The same applies to the lungs.
  • Antagonists act on the kidney like strong potassium-sparing diuretics and can therefore be used for kidney protection as well as for the treatment of edema, renal insufficiency and acute kidney failure.
  • -Antagonists are used therapeutically effective in various cardiovascular diseases such as cardiac insufficiency, arrhythmias (bradyarrhythmias) associated with hypoxia or ischemia, conduction disorders, hypertension, ascites in liver failure (hepato-renal syndrome) and as an analgesic for circulatory disorders.
  • Aß antagonists inhibit degranulation of mast cells caused by A3 receptor activation and are therefore therapeutically useful in all diseases and pathological situations associated with mast cell degranulation: e.g. as anti-inflammatory substances, in hypersensitivity reactions such as Asthma, allergic rhinitis, urticaria, myocardial reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases, etc.
  • the cystic fibrosis - also known as cystic fibrosis - is an inherited metabolic disorder caused by a genetic defect in a particular chromosome. Increased production and increased viscosity of the secretions of the mucous glands in the bronchi can lead to serious complications in the area of the respiratory tract.
  • the invention relates to the use of triazines of the general formula (I)
  • R 1 is hydrogen
  • R 2 is hydrogen or C-
  • R 3 C6-C ⁇ o-aryl, which may optionally be substituted by one or more of the radicals OH, halogen, CN, NO2, CF3, CF3-SO2-O-, C -] - C4-alkyl, C-
  • R 3 is via a single bond or via a C 1 -C 6 -alkyl
  • C2-Cß-alkenyl or C2-C6-alkynyl bridge linked 5, 6 or 7-membered heterocycle which may contain one or more atoms from the group, oxygen, nitrogen or sulfur and optionally by one or more of the benzyl or radicals C 1-4 alkyl may be substituted;
  • R 3 one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or
  • R 4 C3-C7-cycloalkyl, which may optionally be substituted by
  • OH O, -C -C 4 alkyl or -C -C4 alkyloxy
  • R 4 cyciopentenyl or cyclohexenyl
  • R 4 Cß-C-io-aryl, which may optionally be substituted by one or more of the radicals OH, halogen, CN, NO2, CF3, CF3-SO2-O-, -C-C-4-alkyl, C- ⁇ - C4-alkyloxy, Ci ⁇ alkylcarbonyl, Cß-Ci o-arylcarbonyl, C ⁇ -C4-alkylcarbonyloxy, c 6 _c 1 o-arylcarbonyloxy, HO-C-
  • R 4 one via a single bond or via a C-
  • 7-membered heterocycle which can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and can optionally be substituted by one or more of the radicals C ⁇
  • R 4 is one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1, 2-methylenedioxobenzene, which can optionally be substituted by one or more of the radicals C-
  • R "1 is hydrogen
  • R 2 is hydrogen or Cj-Cs-alkyl, preferably hydrogen;
  • R 3 is phenyl, which can optionally be substituted by one or more of the radicals OH, halogen, NO2, CF3, CF3-SO2-O-,
  • R 3 is a 5, 6 or 7-membered heterocycle which can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and optionally by one or more of the benzyl or radicals
  • C -] - C4 alkyl may be substituted
  • R 4 C1 -C4 alkyl, -COOH, -COO-C-) -C alkyl, NH 2 or CN;
  • R 4 C3-C7-cycloalkyl, which may optionally be substituted by
  • OH, O, C-j-C4-alkyl or C-
  • R 4 cyclopentenyl or cyclohexenyl
  • R 4 phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO2, CF3, CF3-SO2-O-, C «
  • R 4 benzyl, phenyl-Ci-C ⁇ alkyl, phenyl-C2-C4-alkenyl, phenyl-C2-C4-alkynyl, biphenyl, 4-N-pyrrolyl-phenyl, naphthyl,
  • R 4 is a 5, 6 or linked via a single bond or via a C -] - Cg-alkyl, C2-C6-alkenyl or C2-Cs-alkynyl chain 7-membered heterocycle, which can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and can optionally be substituted by one or more of the residues C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, Ci -C ⁇ alkyloxy-Ci -C ⁇ alkyl, phenyl, NO2, oxazolyl, halogen or -SC-
  • R 4 one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or 1, 2-methylenedioxobenzene, which can optionally be substituted by one or more of the radicals C- ⁇ -C4 -Alkyl, NO2 or halogen can mean.
  • R 2 is hydrogen or Cj-Cs-alkyl, preferably hydrogen
  • R 3 C3-C6 cycloalkyl
  • R 3 phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO2, C-
  • R 3 is a 5, 6 or 7-membered heterocycle which can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and can optionally be substituted by one or more of the benzyl or C-
  • R 4 Ci -C-4-alkyl, -COOH, -COO-C ⁇
  • R 4 cyclopentenyl or cyclohexenyl
  • R 4 is phenyl, which can optionally be substituted by one or more of the radicals OH, halogen, NO2, CF3, CF3-SO2-O-, C-
  • CQ-CI o-arylcarbonyl C-
  • R 4 benzyl, phenyl -CC-4-alkyl, phenyl-C2-C4-alkenyl,
  • Phenyl-C2-C4-alkynyl biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
  • R 4 one via a single bond or via a C-
  • R 4 is one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole,
  • the invention furthermore relates to pharmaceutical compositions, in particular pharmaceutical compositions having an adenosine-antagonistic action, comprising as active ingredient one or more compounds of the general formula (I) in which the radicals R1, 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. Furthermore, the compounds of the general formula (I) can be converted into their salts, in particular for pharmaceutical use into their physiologically compatible salts with an inorganic or organic acid.
  • suitable acids for this purpose are 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. Mixtures of the aforementioned acids can also be used.
  • determined for the compounds of formula (I) Receptor binding values were determined in analogy to Ensinger et al. in "Cloning and functional characterization of human A ⁇ adenosine Receptor - Biochemical and Biophysical Communications, Vol 187, No. 2, 919-926, 1992" and are summarized in Table 6.
  • the A3 receptor binding values summarized in Table 7 were analogous to Salvatore et al. "Molecular cloning and characterization of the human A3 adenosine receptor” (Proc. Natl. Acad. Sci. USA 90, 10365-10369, 1993).
  • 1,3,5-triazine derivatives are known from the prior art.
  • the compounds 2-amino-4,6-bis (4-methylphenyl) -1,3,5-triazine, 2-amino-4,6-bis (3-methoxyphenyl) -1,3,5-triazine, 2- Amino-4,6-bis (3,4-dimethoxyphenyl) -1, 3,5-triazine, 2-amino-4,6- bis (4-dimethylaminophenyl) -1, 3,5-triazine and 2-amino- 4,6-bis (4-methoxyphenyl) -1,3,5-triazine are described for example by DE 1212547.
  • BE 667044 discloses asymmetrically substituted triazines such as 2-amino-4- (2,4-dihydroxyphenyl) -6-phenyl-1, 3,5-triazine, 2-amino-4- (2-hydroxy-4- ethoxyphenyl) -6- (4-chlorophenyl) -1, 3,5-triazine, the 2-amino- 4- (2,4-dihydroxyphenyl) -6- (4-chlorophenyl) -1, 3,5-triazine or the 2-methylamino-4- (2,4-dihydroxyphenyl) -6- (4-chlorophenyl) -1,3,5-triazine.
  • DE 2013424 discloses 2-phenyloxy-4-amino-6- ⁇ henyl-1, 3,5-triazine, among others.
  • DE 2262188 describes the 2-amino-4,6-bis (4-pyridyl) -1,3,5-triazine.
  • amino-thazines 2-amino-4,6-bis (2-hydroxyphenyl) -1, 3,5-triazine (CH 419155) and 2-amino-4,6-bis (2-furyl) -1, 3 , 5-triazine (GB 1094858).
  • the invention further relates to the new triazine derivatives of the general formula (I)
  • R 2 is hydrogen or C-
  • R 3 C3-C6 cycloalkyl
  • R 3 phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO2, C-
  • R 3 is a 5, 6 or 7-membered heterocycle which can contain one or more atoms from the group consisting of oxygen, nitrogen or sulfur and can optionally be substituted by one or more of the radicals benzyl or C- ] -C4-alkyl;
  • R 4 cyclopentenyl or cyclohexenyl
  • R 4 phenyl which can optionally be substituted by one or more of the radicals OH, halogen, NO2, CF3, CF3-SO2-O-, -C -C4-alkyl, -C -C4-alkyloxy, C-
  • R 4 benzyl, phenyl-C ⁇
  • Phenyl-C2-C4-alkynyl biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
  • R 4 is via a single bond or via a Ci-Cß-alkyl, C2-Cß-
  • R 4 one of the bicyclic heterocycles quinoline, isoquinoline, benzo [b] furan, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole, benzodiazine or
  • R 4 is not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl,
  • R 4 cannot be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl; when R 2 is hydrogen and R 3 is 2-methoxyphenyl,
  • R 4 cannot be 2-hydroxyphenyl; when R 2 is hydrogen and R 3 is 4-methylphenyl, R 4 cannot be phenyl or 4-methylphenyl; when R 2 is hydrogen and R 3 is 4-chlorophenyl,
  • R 4 cannot be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl; when R 2 is hydrogen and R 3 is 4-nitrophenyl, R 4 cannot be phenyl or 3-nitrophenyl; when R 2 is hydrogen and R 3 is 3-nitrophenyl,
  • R 4 cannot be 4-nitrophenyl; when R 2 is hydrogen and R 3 is 2-hydroxy-4-ethoxyphenyl,
  • R 4 cannot be 4-chlorophenyl; when R 2 is hydrogen and R 3 is 3-pyridyl, R 4 cannot be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 4-pyridyl,
  • R 4 cannot be phenyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 2-furyl,
  • R 4 cannot be phenyl, 2-furyl or 3-pyridyl; when R 2 is hydrogen and R 3 is 5-methyl-2-furyl,
  • R 4 cannot be phenyl
  • 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 Can be -2-furyl or 3,4,5- trimethoxyphenyl,
  • R 4 when R 2 is methyl and R 3 is phenyl, R 4 cannot be phenyl or 2-hydroxyphenyl; when R 2 is methyl and R 3 is 2-hydroxyphenyl,
  • R 4 cannot be 2,4-dihydroxyphenyl
  • R 4 cannot be 2-hydroxy-4-methoxyphenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4-methoxyphenyl,
  • R 4 cannot be phenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4,6-dimethylphenyl, R 4 cannot be 2-hydroxy-5-chlorophenyl; when R 2 is ethyl and R 3 is 2-hydroxy-5-chlorophenyl,
  • R 4 cannot be 2-hydroxy-4,6-dimethylphenyl
  • R 2 is hydrogen or C-
  • R 3 C3-C6 cycloalkyl
  • R 3 phenyl which may optionally be substituted by one or more of the radicals OH, halogen, NO2, C-
  • R 3 furyl, thienyl, pyridyl or pyrrolyl, which may optionally be substituted one or more times by C 1-4 alkyl;
  • R 4 C3-C7-cycloalkyl, which may optionally be substituted by
  • OH, O, -C4-alkyl or C-
  • R 4 is phenyl, which can optionally be substituted by one or more of the radicals OH, halogen, NO2, CF3, CF3-SO2-O-,
  • R 4 benzyl, phenyl -CC4-alkyl, phenyl-C2-C4-alkenyl,
  • Phenyl-C2-C4-alkynyl biphenyl, 4-N-pyrrolyl-phenyl, naphthyl, phenyloxy or phenylamino;
  • R 4 pyrimidinyl, pyridyl, which can optionally be substituted by one or more of the radicals halogen, C 1 -C 4 -alkyl or -S-C 1 -C 4 -alkyl;
  • R 4 pyridyl -CC-C4-alkyl or pyridyl-C2-C4-alkenyl
  • R 4 furyl which may optionally be substituted by one or more of the C 1 -C 4 alkyl, C 4 -C 4 alkyloxy, C 1 -C 4 alkyloxy C 1 -C 4 alkyi, phenyl, NO2 or halogen;
  • R 4 thienyl which is optionally replaced by one or more of the radicals C-
  • R 4 dithiolanyl, thiolanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, quinolinyl, benzo [b] furanyl, 3,4-methylenedioxophenyl or 2,3-methylenedioxophenyl, which can optionally be substituted by one or more of the
  • 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,
  • R 4 cannot be 2-hydroxyphenyl; when R 2 is hydrogen and R 3 is 2,4-dihydroxyphenyl,
  • R 4 cannot be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl; when R 2 is hydrogen and R 3 is 2-methoxyphenyl,
  • R 4 cannot be 2-hydroxyphenyl; when R 2 is hydrogen and R 3 is 4-methylphenyl,
  • R 4 cannot be phenyl or 4-methylphenyl; when R 2 is hydrogen and R 3 is 4-chlorophenyl, R 4 cannot be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl; when R 2 is hydrogen and R 3 is 4-nitrophenyl,
  • R 4 cannot be phenyl or 3-nitrophenyl; when R 2 is hydrogen and R 3 is 3-nitrophenyl, R 4 cannot be 4-nitrophenyl; when R 2 is hydrogen and R 3 is 2-hydroxy-4-ethoxyphenyl,
  • R 4 cannot be 4-chlorophenyl; when R 2 is hydrogen and R 3 is 3-pyridyl,
  • R 4 cannot be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 4-pyridyl,
  • R 4 cannot be phenyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 2-furyl,
  • R 4 cannot be phenyl, 2-furyl or 3-pyridyl; when R 2 is hydrogen and R 3 is 5-methyl-2-furyl, R 4 cannot 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- Can be methyl-2-furyl or 3,4,5-trimethoxyphenyl,
  • R 4 cannot be 4-chlorophenyl; when R 2 is methyl and R 3 is 4-chlorophenyl, R 4 cannot be 2,4-dihydroxyphenyl;
  • R 4 cannot be 2-hydroxy-4-methoxyphenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4-methoxyphenyl, R 4 cannot be phenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4,6-dimethylphenyl,
  • R 4 cannot be 2-hydroxy-5-chlorophenyl; when R 2 is ethyl and R 3 is 2-hydroxy-5-chlorophenyl, R 4 cannot be 2-hydroxy-4,6-dimethylphenyl;
  • Diastereomers and their mixtures, and optionally in the form of their pharmacologically acceptable acid addition salts are included.
  • R 2 is hydrogen, methyl or ethyl, preferably hydrogen
  • R 3 cyclopropyl, cyclopentyl or cyciohexyl
  • R 3 is phenyl, which can optionally be substituted by one or more of the radicals OH, chlorine, fluorine, NO2, methyl, methoxy, hydroxymethyl, methoxymethyl, amino, methylamino, ethylamino,
  • R 3 furyl, thienyl, pyridyl or pyrrolyl, each of which can be substituted once, twice or three times by methyl;
  • R 4 cyclopentenyl or cyclohexenyl
  • R 4 is phenyl, which is optionally substituted by one or more of OH, fluorine, chlorine, bromine, NO2, CF3, CF3-SO2-O-, methyl, ethyl, propyl, butyl, methoxy, acetyl, phenylcarbonyl, acetoxy,
  • Ethylcarbonyloxy, phenylcarbonyloxy, hydroxymethyl, hydroxyethyl, methoxymethyl, amino, methylamino, ethylamino, dimethylamino, N-acetylamino, methoxycarbonyloxy, ethoxycarbonyloxy or phenyloxycarbonyloxy may be substituted;
  • R 4 benzyl, phenylethyl, phenylethenyl, phenylethinyl, biphenyl, 4-N-pyrrolylphenyl, naphthyl, phenyloxy or phenylamino;
  • R 4 optionally substituted by methyl pyrimidinyl, pyridyl, which may optionally be substituted one or more times by fluorine, chlorine, bromine, methyl or -S-methyl;
  • R 4 pyridylmethyl or pyridylethenyl
  • R 4 furyl which can optionally be mono- or polysubstituted by methyl, ethyl, propyl, butyl, methoxy, methoxymethyl, phenyl, NO2, fluorine, chlorine or bromine;
  • R 4 thienyl which may optionally be mono- or polysubstituted by methyl, fluorine, chlorine, bromine, oxazolyl or NO2;
  • Methylenedioxophenyl or 2,3-methylenedioxophenyl which may be substituted one or more times by methyl, ethyl, propyl, NO2, fluorine, chlorine or bromine,
  • R 4 is not phenyl, phenylamino, phenyloxy, 2-hydroxyphenyl,
  • R 4 cannot be phenyl, 2,4-dihydroxyphenyl or 4-chlorophenyl; when R 2 is hydrogen and R 3 is 2-methoxyphenyl,
  • R 4 cannot be 2-hydroxyphenyl; when R 2 is hydrogen and R 3 is 4-methylphenyl, R 4 cannot be phenyl or 4-methylphenyl; when R 2 is hydrogen and R 3 is 4-chlorophenyl,
  • R 4 cannot be 4-chlorophenyl, 2,4-dihydroxyphenyl or 2-hydroxy-4-ethoxyphenyl; when R 2 is hydrogen and R 3 is 4-nitrophenyl, R 4 cannot be phenyl or 3-nitrophenyl; when R 2 is hydrogen and R 3 is 3-nitrophenyl,
  • R 4 cannot be 4-nitrophenyl; when R 2 is hydrogen and R 3 is 2-hydroxy-4-ethoxyphenyl,
  • R 4 cannot be 4-chlorophenyl; when R 2 is hydrogen and R 3 is 3-pyridyl, R 4 cannot be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 4-pyridyl,
  • R 4 cannot be phenyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 2-furyl,
  • R 4 cannot be phenyl, 2-furyl or 3-pyridyl; when R 2 is hydrogen and R 3 is 5-methyl-2-furyl,
  • R 4 cannot be phenyl
  • R 3 and R 4 are not simultaneously 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-diethylaminophenyl, 2-pyridyl,
  • R 4 when R 2 is methyl and R 3 is phenyl, R 4 cannot be phenyl or 2-hydroxyphenyl; when R 2 is methyl and R 3 is 2-hydroxyphenyl,
  • R 4 cannot be 2,4-dihydroxyphenyl
  • R 4 cannot be 2-hydroxy-4-methoxyphenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4-methoxyphenyl,
  • R 4 cannot be phenyl; when R 2 is ethyl and R 3 is 2-hydroxy-4,6-dimethylphenyl, R 4 cannot be 2-hydroxy-5-chlorophenyl; when R 2 is ethyl and R 3 is 2-hydroxy-5-chlorophenyl,
  • R 4 cannot be 2-hydroxy-4,6-dimethylphenyl
  • R 2 is hydrogen or ethyl, preferably hydrogen
  • R 3 cyciohexyl, phenyl, hydroxyphenyl, 3,5-dihydroxyphenyl, methoxyphenyl, 3,5-dimethoxyphenyl, 3-methylphenyl, 4-methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-aminophenyl,
  • R 4 is cyclopropyl, cyclopentyl, cyciohexyl, cycloheptyl, hydroxycyclohexyl, methoxycyclohexyl, cyclopentenyl or cyclohexenyl;
  • R 4 phenyl, hydroxyphenyl, methoxyphenyl, 2,3-dihydroxyphenyl,
  • 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 cannot be phenyl or 4-methylphenyl; when R 2 is hydrogen and R 3 is 2-methoxyphenyl,
  • R 4 cannot be 2-hydroxyphenyl; when R 2 is hydrogen and R 3 is 4-nitrophenyl, R 4 cannot be phenyl or 3-nitrophenyl; when R 2 is hydrogen and R 3 is 3-nitrophenyl,
  • R 4 cannot be 4-nitrophenyl; when R 2 is hydrogen and R 3 is 3-pyridyl,
  • R 4 cannot be phenyl, 2-furyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 4-pyridyl,
  • R 4 cannot be phenyl, 3-pyridyl or 4-pyridyl; when R 2 is hydrogen and R 3 is 2-furyl,
  • R 4 cannot be phenyl, 2-furyl or 3-pyridyl
  • R 3 and R 4 cannot simultaneously be 3-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl or 2-pyridyl,
  • R 2 is hydrogen or ethyl, preferably hydrogen
  • R 3 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,
  • R 4 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,
  • R 4 cannot 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 cannot be phenyl or 4-methylphenyl; when R 2 is hydrogen and R 3 is 4-nitrophenyl,
  • R 4 cannot be phenyl or 3-nitrophenyl; when R 2 is hydrogen and R 3 is 3-nitrophenyl, R 4 cannot be 4-nitrophenyl; when R 2 is hydrogen and R 3 is 3-pyridyl, R 4 cannot be phenyl or 2-furyl;
  • R 3 and R 4 cannot simultaneously be 4-chlorophenyl
  • R 2 is hydrogen
  • R 3 is phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl, 2-thienyl or 3-pyridyl;
  • R 4 phenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-acetoxyphenyl, 3- (1'-hydroxyethyl) phenyl, 3-methylaminophenyl,
  • R 4 when R 3 is 3-pyridyl, R 4 cannot be phenyl and when R 3 is phenyl, R 4 cannot be phenyl or 4-methylphenyl,
  • R 2 is hydrogen
  • R 3 is phenyl, 3-hydroxyphenyl, 3-methylaminophenyl, 3,5-dihydroxyphenyl or 3-pyridyl;
  • R 4 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3-methylaminophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl,
  • R 4 cannot be 4-methylphenyl.
  • the compounds of the general formula (I) can be converted into their salts, in particular for pharmaceutical use, into their physiologically tolerable salts with an inorganic or organic acid.
  • acids for this are 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. Mixtures of the aforementioned acids can also be used.
  • alkyl groups also insofar as they are part of other radicals
  • branched and unbranched alkyl groups having 1 to 10 carbon atoms are preferably considered to have 1-4 carbon atoms, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, Heptyl and octyl.
  • Alkenyl groups are branched and unbranched alkenyl groups with 2 to 10 carbon atoms, preferably 2 to 3 carbon atoms, insofar as they have at least one double bond, for example also alkyl groups mentioned above, insofar as they have at least one double bond, such as vinyl (provided that no volatile enamines or enol ethers are formed), propenyl, isopropenyl, butenyl, pentenyl, hexenyl.
  • Alkynyl groups are alkynyl groups with 2 to 10 carbon atoms if they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl.
  • Cycloalkyl radicals with 3 to 6 carbon atoms are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyciohexyl, which can also be substituted by branched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy, and / or halogen or as previously defined.
  • Halogen is generally referred to as fluorine, chlorine, bromine or iodine.
  • aryl stands for an aromatic ring system with 6 to 10 carbon atoms which, unless otherwise described, can carry, for example, one or more of the substituents mentioned below: C-
  • the preferred aryl radical is phenyl.
  • N-linked cyclic radicals of the general formula NR 8 R9 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, the heterocycles mentioned also being alkyl with 1 to 4 carbon atoms, preferably methyl , or as specified in the definitions may be substituted.
  • the C-linked 5- or 6-membered heterocyclic rings which may contain nitrogen, oxygen or sulfur as heteroatoms are, for example, furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, tetrahydrofuranone, ⁇ -butylrolactone, ⁇ -pyran, ⁇ - pyran, dioxolane, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, Triazol.Tetrazol, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, Tetrazine, morpholine, thiomorpholine, oxazole, isoxazole, o
  • the new compounds of the general formula (I) can be administered orally, transdermally, by inhalation or parenterally.
  • the compounds according to the invention are present here as active constituents in customary dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems, etc.
  • An effective dose of Compounds according to the invention are between 1 and 100, preferably between 1 and 50, particularly preferably between 5-30 mg / dose in the case of oral use, and between 0.001 and 50, preferably between 0.1 and 10 mg / dose in the case of intravenous or intramuscular use.
  • Solutions which contain 0.01 to 1.0, preferably 0.1 to 0.5% active ingredient are suitable for inhalation.
  • the use of powders is preferred for inhalation application.
  • the compounds according to the invention as an infusion solution, preferably in a physiological saline or nutrient solution.
  • the compounds according to the invention can be prepared by the following processes, some of which are known from the prior art.
  • a nitrile is dissolved with a guanidine derivative in an inert solvent, preferably dimethyl sulfoxide, and base, preferably sodium hydride, is added.
  • an inert solvent preferably dimethyl sulfoxide
  • base preferably sodium hydride
  • Triazine derivatives of the general formula (I), in which R 3 ⁇ R 4 , can be obtained in another way.
  • the nitriles (1) are first converted into the imido esters (3). (Scheme 2).
  • An alternative procedure for the synthesis of the imidates (3) comprises the 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.
  • Sodium methoxide is preferred as the base.
  • This implementation is e.g. B. on the basis of J. Org. Chem. 26 (1961) 417 feasible.
  • the imidoesters (3) are then converted into the acylimidates (5) by reaction with carboxylic acid chlorides (4) (Scheme 3).
  • the imino ethers (3) are dissolved in an inert solvent, preferably in a weakly polar solvent, particularly preferably in toluene, and an organic base, preferably a tertiary amine, particularly preferably triethylamine, is added.
  • an organic base preferably a tertiary amine, particularly preferably triethylamine
  • the suitably substituted acid chloride which can be obtained either commercially or by methods known from the literature, is slowly added and stirred until conversion is complete at constant temperature or room temperature.
  • the mixture is filtered and the filtrate is freed from the solvent.
  • a further purification of the crude products (5) thus obtained is generally not necessary.
  • the acylimidates (5) are reacted in an inert solvent, preferably in an alcoholic solvent, particularly preferably in partial butanol with the guanidine derivatives (2) with stirring.
  • the reaction can and is carried out at elevated temperature, but preferably at room temperature terminated after 0.5 to 24 hours.
  • the free guanide is preferably generated directly before the reaction from an acid addition salt, preferably from guanidine hydrochloride, by the action of base.
  • Alkaline alcoholates in an alcoholic solution are particularly suitable for this purpose; preference is given to using sodium or potassium methoxide or sodium - or potassium ethanolate, sodium methoxide is particularly preferred
  • the triazines (I), in which the radicals RR 2 , R 3 and R 4 may have the meanings mentioned above, can be further functionalized by methods known from the literature. These functionalizations include the processes of oxidation, reduction and ether cleavage familiar to the person skilled in the art , Accy erieux, Alky erungen, etc
  • 0.1 mol of sodium hydride (60% dispersion in mineral oil) is added to 0.1 mol of nitrile (1) and 0.025 mol of guanidine carbonate in 100 ml of DMSO at room temperature. After stirring for 2 hours at room temperature, the mixture is stirred at 80 ° C. for a further 4 to 12 hours. After the reaction is complete, 120 ml of water are added to the mixture. The crystals obtained are suction filtered and washed with water. Depending on the solubility, the crude triazines (I) are purified by crystallization or chromatography on silica gel.
  • the methoxyaryl-substituted triazine is mixed well with a 10-fold excess of pyhdinium bromide and stirred at an oil bath temperature of 180-190 ° C. for 1-2 hours.
  • the melt is then cooled to room temperature, triturated with 4N HCl, suction filtered, washed with water and then purified by means of column chromatography.
  • Table 5 summarizes the compounds of the general formula (I) prepared analogously to the processes described above.
  • the following table contains KiA 3 (human) receptor binding values.
  • the compounds of the general formula (I) can be used alone or in combination with other active compounds according to the invention, optionally also in combination with other pharmacologically active compounds. Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can, for example, by mixing the active ingredient (s) with known auxiliaries, 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 agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • auxiliaries 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 agents for achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate can be obtained.
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities.
  • the coated tablet to achieve a depot effect can consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g.
  • Flavorings such as vanillin or orange extract
  • suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection solutions are made in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be produced, for example, by mixing them with 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.
  • the following examples illustrate the present invention without, however, restricting its scope.
  • Active ingredient 100 mg milk sugar 140 mg corn starch 240 mg
  • the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
  • the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of a suitable shape and size.
  • the active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • domed dragee cores with a diameter of 6 mm are pressed on a tablet machine.
  • the dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch 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 filled into size 1 hard gelatin capsules.
  • the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as the isotonic agent, the solution obtained is filtered free of pyrogen and the filtrate in ampoules under aseptic conditions filled, which are then sterilized and melted.
  • the ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
  • the hard fat is melted.
  • the milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.
  • Distilled water is heated to 70 ° C. Hydroxyethyl cellulose is dissolved therein with stirring. After adding sorbitol solution and glycerin, the mixture is cooled to room temperature. Sorbic acid, aroma and substance are added at room temperature. To vent the suspension, evacuate with stirring.

Abstract

L'invention concerne de nouveaux dérivés de triazine, leur procédé de production, ainsi que l'utilisation de triazines comme médicaments, en particulier comme médicaments ayant un effet antagoniste vis-à-vis de l'adénosine.
PCT/EP1998/005101 1997-08-18 1998-08-12 Triazines ayant un effet antagoniste vis-a-vis de l'adenosine WO1999011633A1 (fr)

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DE1997135800 DE19735800A1 (de) 1997-08-18 1997-08-18 Triazine mit adenosinantagonistischer Wirkung

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WO2003101980A1 (fr) * 2002-05-30 2003-12-11 Solvay Pharmaceuticals B.V. Derives de 1,3,5-triazine comme ligands pour des recepteurs humains de l'adenosine a3
EP1479397A1 (fr) * 2002-02-05 2004-11-24 Yamanouchi Pharmaceutical Co. Ltd. Derives de 2,4,6-triamino-1,3,5-triazine
JP2006505514A (ja) * 2002-07-31 2006-02-16 チバ　スペシャルティ　ケミカルズ　ホールディング　インコーポレーテッド 殺微生物活性物質としてのピリジルトリアジン誘導体
US7015227B2 (en) 2002-06-21 2006-03-21 Cgi Pharmaceuticals, Inc. Certain amino-substituted monocycles as kinase modulators
US7307079B2 (en) 2002-05-30 2007-12-11 Solvay Pharmaceuticals, B.V. 1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors
EP1878733A1 (fr) * 2006-07-14 2008-01-16 Novartis AG Dérivés de pyrimidine comme inhibiteurs de ALK-5
JP2017521489A (ja) * 2014-06-13 2017-08-03 ユマ セラピューティクス，インコーポレーテッド ピリミジン化合物およびその使用方法

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EP2529623A3 (fr) * 2007-04-03 2013-03-13 E. I. du Pont de Nemours and Company Fongicides de benzène substitués
JP7145802B2 (ja) * 2019-03-27 2022-10-03 大阪ガスケミカル株式会社 ２－アミノ－１，３，５－トリアジン化合物の製造方法
CA3153096A1 (fr) 2019-09-13 2021-03-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du recepteur de la tyrosine kinase pour le traitement de maladie ou de trouble sensible a la modulation de la proteine kinase

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EP1479397A1 (fr) * 2002-02-05 2004-11-24 Yamanouchi Pharmaceutical Co. Ltd. Derives de 2,4,6-triamino-1,3,5-triazine
EP1479397A4 (fr) * 2002-02-05 2009-01-07 Astellas Pharma Inc Derives de 2,4,6-triamino-1,3,5-triazine
WO2003101980A1 (fr) * 2002-05-30 2003-12-11 Solvay Pharmaceuticals B.V. Derives de 1,3,5-triazine comme ligands pour des recepteurs humains de l'adenosine a3
US7307079B2 (en) 2002-05-30 2007-12-11 Solvay Pharmaceuticals, B.V. 1,3,5-Triazine derivatives as ligands for human adenosine-A3 receptors
US7015227B2 (en) 2002-06-21 2006-03-21 Cgi Pharmaceuticals, Inc. Certain amino-substituted monocycles as kinase modulators
JP2006505514A (ja) * 2002-07-31 2006-02-16 チバ　スペシャルティ　ケミカルズ　ホールディング　インコーポレーテッド 殺微生物活性物質としてのピリジルトリアジン誘導体
EP1878733A1 (fr) * 2006-07-14 2008-01-16 Novartis AG Dérivés de pyrimidine comme inhibiteurs de ALK-5
JP2017521489A (ja) * 2014-06-13 2017-08-03 ユマ セラピューティクス，インコーポレーテッド ピリミジン化合物およびその使用方法
US10336768B2 (en) * 2014-06-13 2019-07-02 Yuma Therapeutics, Inc. Pyrimidine compounds and methods using the same
AU2015274285B2 (en) * 2014-06-13 2020-12-10 The Brigham And Women's Hospital, Inc. Pyrimidine compounds and methods using the same
US10961254B2 (en) 2014-06-13 2021-03-30 Yuma Therapeutics, Inc. Pyrimidine compounds and methods using the same
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