DD250931A1 - NEW S-TRIAZOLO (1,5-A) PYRIMIDINE AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

The invention relates to processes for the preparation of novel substituted s-triazolo (1,5-a) pyrimidines of general formula I by reacting compounds of general formula I in which R7 represents a halogen atom, with amines of general formula III at temperatures from 0 to 100C and exclusive isolation by crystallization. Compounds of the type mentioned can be used as potential drugs for drugs. Formulas I, II and III

Description

in which R ₁ , R ₂ , R ₃ , R ₄ and η have the abovementioned meaning and R _{7 represents} a halogen atom, with amines of the general formula

in which R ₅ and R ₆ also have the meanings given above, in the presence of acid-binding agents at temperatures between 0 and 100 ⁰ C, optionally under pressure, are reacted.

Field of application of the invention

The present invention relates to a process for the preparation of novel substituted 2-aminoalkyl-s-triazolo (1,5-a) pyrimidines. The compounds of the invention are potential agents.

Characteristic of the known solutions

The compounds of the invention are new. According to DD-PS 78885 similar compounds are known.

Object of the invention

The aim of the invention is a process for the preparation of the new active substances with specific cardiovascular effects.

Explanation of the essence of the invention

The object of the invention was achieved by finding novel substituted 2-aminoalkyl-s-triazolo (1,5-a) pyrimidines and a process for the preparation of these compounds which are characterized by arachidonic acid, collagen or ADP in vitro induced aggregation of platelets (US Pat. Rat, rabbit, human) by drug concentrations of 1 to 5 x 10 " ⁴ mol / l.These effects are also detectable under in vivo conditions as inhibition of arachidonic in rabbits triggered thrombocytopenia and are 10 times more effective compared to the Trapidil spontaneously hypertensive rats lower the arterial mean pressure and lead to an increase in the coronary blood flow in the heart muscle.

The compounds are characterized by calcium antagonist effects by inhibiting the Ca ^{2+ -mediated} smooth muscle contractions (vessels, intestine). The proposed substituted s-Triazoio (1,5-a) pyrimidines and their physiologically acceptable salts correspond to this objective, when compounds of the general formula

be prepared in which the substituents have the following meanings:

- RI and R2 Η-atoms, alkyl radicals of chain length Ci to C ₄ , in the core optionally substituted aryl or aralkyl groups;

- R _{3 is} a Η-atom, alkyl radicals of chain length C ₁ to C ₄ , which are optionally substituted by hydroxyl groups;

R _{4 is} alkyl of chain length C ₄ to C ₉ , alkoxyalkyl, aralkyl or substituted aryl groups;

R _{5 and} R ₆ Η atoms, alkyl radicals of chain length C ₁ to C ₄ , aralkyl radicals;

R ₆ and R ₆ can also be part of an optionally further heteroatom-containing acyclic ring, η can assume values of 1 to 4, R ₃ and R ₄ can be exchanged with R ₆ and R ₆ .

Hydrochloric acid, sulfuric acid, phosphoric acid, malonic acid, malic acid and maleic acid are mentioned as salt-forming acids. ,

The preparation of these compounds is carried out by reacting substituted 2-haloalkyl-7-dialkylamino or 7-alkylamino-s-triazolo (1,5-a) pyrimidines of the general formula

"5f. (21

in which R ₁ , R ₂ , R ₃ and R _{4 have} the meanings given above, R _{7 represents} a halogen atom, with amines of the general formula

in which R ₅ and R ₆ also have the abovementioned meanings. The reaction is carried out without or in the presence of solvents or suspending agents at room temperature to the boiling point of the solvent or suspending agent, optionally under pressure. To bind the liberated during the reaction of hydrogen halide used in excess amines or other acid-binding agents such. As tertiary amines or sodium hydroxide or potassium hydroxide used. The by-products are separated by distillation, extraction, crystallization or chromatographic purification. The compounds of the formula (2) can also be used without prior isolation for the further reaction with amines of the general formula (3)

 The process according to the invention is illustrated by the following examples, which lead to new compounds:

example 1

9.8 g of 2-chloromethyl-5-methyl-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine are dissolved in 50 ml of ethanol with 4.8 g Piperidine held under reflux for 2 hours. It is then concentrated and the residue taken up in 25 ml of methylene chloride. The solution is washed with water and dried. Recrystallized from ethyl acetate to give 4.5 g of 2-piperidinomethyl-5-methyl-7- (N- (ethoxyethyl) -N - (/ 3hydroxyethyl)) - amino-s-triazolo (1,5-a) pyrimidine of melting point 121 bis 123 ° C.

Example 2

9.8 g of 2-chloromethyl-5-methyl-7- (N - (/ 3-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine are refluxed in 75 ml of ethanol with 44 g of diethylamine for 5 hours. The ethanol is distilled off under reduced pressure, the residue is dissolved in chloroform and washed with water until chloride-free. After distilling off the chloroform, the residue is extracted with the mixture ether / petroleum ether. The yield is 4.3 g of 2-diethylaminomethyl-5-methyl-7- (N-hexyl) -N ((3-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine of melting point 70 to 72 ° C.

Example 3

9.8 g of 2-chloromethyl-5-methyl-7- (N- (n-hexyl) -N - (/ 3-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrirnidine are dissolved in 50 ml of Propanol with 9.1 g of piperidine for 3 hours under reflux. After concentration, the residue is taken up in methylene chloride and shaken out with water. The neutral washed methylene chloride solution is separated and concentrated. After crystallization, it is recrystallized from ether. The yield is 4.1 g of 2-piperidinomethyl-5-methyl-7- (N- (n-hexyl) -N - (/ 3-hydroxyethyl) -amino) -s-triazolo (1,5-a) pyrimidine of Melting point 108 to 11O ⁰ C.

Example 4

9.8 g of 2-chloromethyl-5-methyl-7- (N- (n-hexyl) -N- (j8-hydroxyethyl) amino) -s-triazolo (1,5-) pyrimidine and 6.3 g of diethanolamine in 75 ml Methanol is refluxed for 2 hours. The methanol is concentrated, the residue taken up in methylene chloride and washed with water methylene chloride-free. After drying, the methylene chloride is concentrated and the residue is crystallized. Recrystallized from ethyl acetate, to give 76 g of 2-diethanolamino-5-methyl-7- (N-n-hexyl) -N-l / S-hydroxyethyl-aminoJ-s-triazolod ^ -pyrimidine of melting point 72 to 73 ° C.

Claims (2)

· Claim invention. A process for the preparation of novel, as cardiovascular means triazolo (1,5-a) pyrimidines of the general formula in which the substituents - R ₁ and R ₂ Η-atoms, alkyl radicals of chain length C ₁ to C ₄ , optionally substituted aryl or aralkyl groups; - R _{3 is} a Η-atom, alkyl radicals of chain length C ₁ to C ₄ , which are optionally substituted by hydroxyl groups; - R ₄ alkyl radicals of the chains length C ₄ to C ₉ , Al koxyalkylreste, aralkyl or substituted aryl groups; - R ₅ and R ₆ Η-atoms, alkyl radicals of chain length C ₁ to C ₄ , aralkyl radicals, but also part of a ring interrupted by heteroatoms, in particular piperidine or morpholine his skills; and - η can assume the values from .1 to 4, mean, in particular 2-Piperidinomethyl-5-methyl-7- (N- (n-hexyl) -N - (/ 3-hydroxyethyl)) - amino-striazolo (1,5-a) pyrimidine and its salts with physiologically tolerated acids, characterized in that compounds of the general formula