DD228811A1 - PROCESS FOR THE PREPARATION OF NEW TRIAZOLOPYRIMIDINES - Google Patents

Abstract

The invention relates to new, in 5- and 7-position by basic groups substituted s-triazolo (1,5-a) pyrimidines of the general formula, process for their preparation from the corresponding halogen compounds by reaction with substituted amines and the use as medicaments, especially as a coronary therapeutic.

Description

Title of the invention

Novel triazolopyriinidines and process for their preparation

Field of application of the invention

The invention relates to novel triazolopyrimidines which are substituted in the 5- and 7-position by basic groups and methods of their preparation The novel compounds can be used as medicaments.

Explanation of the essence of the invention

Based on the knowledge of the Coronarwirkungen the basic substituted compounds described in DD 61 269 was surprisingly found that hitherto unknown Verbindüngen this class have cardiovascular effects that exceed the effects of the known compounds by a multiple and at the same time of so low toxicity that they are applicable as medicines. The novel compounds correspond to the general formula (I)

(D

where the substituents have the following meanings:

- Rp and Eo is a Η atom, an alkyl group of chain length C. to C ~ or a halogen atom;

- R ^ is a straight- or branched-chain alkyl group of the chain length (L · to Cq, optionally substituted by alkoxy or alkyl groups of chain length C to C, substituted aralkyl groups, 2,5-moxaheptyl or 3-oxahexylreste;

Rc is an H atom, an alkyl group of chain length C. to C.3, a hydroxyethyl or hydroxypropyl group;

- Rg and R ~ Η atoms, a straight or branched-chain alkyl group of chain length C. to C ₁ -, wherein Rc and R ~ may also be components of a cycloaliphatic ring. The substituents in the 5- and 7-position can also be interchanged.

From the large number of possible compounds of the specified substituents according to formula (I), the following compounds have been found to be particularly effective with regard to their cardiovascular activity:

5-piperidino-7- (N- (n-pentyl) -N- (3-hydroxyethyl) amino) -striazolo (1,5-a) pyrimidine

- S -diethylamino-C N -Cn-pentyD-N-Cβ-hydroxyethyl-amino-O-striazolo (1,5-a) pyrimidine

5-Siethylamino-7- (N- (n-hexyl) -N- (β-hydroxyethyl) amino) -striazolo (1,5-a) pyrimidine.

5-piperidino-7- (N- (n-hexyl) -N- (S-hydroxyethyl) amino) -striazolo (1,5-a) pyrimidine

5-morpholino-7- (N- (n-butyl) -N- (S-hydroxyethyl) amino) -striazolod , 5-3.) ΤίγτΐΜ ± ά ± η

5-piperidino-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine

- 5-2iethylamino-7- (N- (ethoxyethyl) -N- (3-hydroxyethyl) -amino) -s-triazolod _r 5- a) pyrimidine

They compounds according to formula (I) can be particularly well in the form of their physiologically well-tolerated

Apply salts. Chlorine, bromine or hydriodic acid, sulfuric and nitric acid are particularly suitable for salt formation. Oxalic, halonic and tartaric acids. The compounds of the formula (I) according to the invention can be prepared analogously to the compounds of DD 61 269 by reacting triazolopyrimidines of the general formula (II)

shark

^R 2 \ i ^ NN

(II)

in which Rp and H- have the stated meanings and, Hai is a chlorine or bromine atom, with amines of the general formula (III)

^R (4 or 6) _(m)

' ^R (5 or 7)

where Leg, ~ have the meanings given. The reactions are in solvents like water. ¥ asser / alcohol mixtures, alcohols, toluene or gasoline performed. The reaction proceeds in two stages

/ "" V with the respectively substituted amines.

At temperatures below 293 K, first the halogen atom in the 7-position is substituted by amines and at temperatures up to the boiling point of the particular solvent used, the halogen atom in the 5-position.

To intercept the hydrogen halides formed in the reaction, the amines of the general formula (III) or triethylamine, alkali metal carbonates or caustic alkalis used in excess are used. The workup of the crude products is carried out in the usual way. The end products are separated from the by-products by extraction, distillation or recrystallization and purified.

Disturbing discolorations can be removed by adding adsorbents, such as activated carbon, alumina or bleaching earth.

The compounds obtained can be converted into their salts with acids. If stereoisoinere compounds are obtained, they can be broken down into their constituents by known methods.

The compounds according to the invention, in particular the individual compounds mentioned, have highly effective and therapeutically interesting properties in animal experiments. Central to this is an inhibition, the platelet aggregation in vitro and in vivo, the corresponding effects of known drugs such as acetylsalicylic acid or trapidil exceed the multiple. On isolated cardiac and YORK preparations they develop coronary dilatation and a positive inotropic efficacy. The blood pressure is preferably lowered at a hypertensive starting position. They prevent a deformation loss of the erythrocytes induced by hyperosmolar conditions and their tendency to aggregation and thus improve the flow conditions in the microcirculation area. By influencing the arachidonic acid metabolism, they reduce the formation of thromboxane Ap or promote the synthesis of aggregation-inhibiting prostaglandins, especially of prostacyclins their versatile pharmacological spectrum of activity and their acute toxicity days allow the use of the compounds of the invention as therapeutics for ischemic heart and circulatory diseases and distinguish them from previously known compounds. The application is carried out as Ingektionslösung in the form of a 5% aqueous solution or in the form of coated by known methods granules of the composition 58 % active ingredient, 20 % lactose, 19 % water and 3 % magnesium stearate

 The invention is illustrated by the following examples:

C _

example 1

18.9 g of 5,7-dichloro-s-triazolo (1,5-a) pyrimidine are dissolved or suspended in 50 ml of ethanol and dissolved at 278 to 283 K with the solution of 26.1 g of n-amyl ethanolamine Slowly add 25 ml of ethanol. The mixture is stirred and kept at 283 to 288 K for 1 hour after completion of the addition. Then added to the resulting suspension, the solution of 17.0 g of piperidine in 20 ml of ethanol at 293 to 298 K and 3 hours at 313 to 323 K and concentrated the approach. Thereafter, taken up in 100 ml of methylene chloride, washed 3 times with 75 ml of water, the water was separated. The methylene chloride is concentrated, the residue is crystallized. Recrystallized from petrol, 26.5 g of piperidino-7- (N- (n-pentyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1, 5-a) -pyrimidine (80 % d .Th.) Melting point 390 to 391 K.

Example 2

18.9 g of 5-7-dichloro-s-triazolo (1,5-a) pyrimidine are dissolved or suspended in 50 ml of ethanol and dissolved at 278 to 283 K with the solution of 26.1 gn-Amy! Ethanolamine in 25 ml of ethanol slowly added. The batch is stirred and left for a further 1 hr. At 283 to 288 K after completion of the addition. The resulting suspension is filtered off, suspended in 50 ml of ethanol and mixed at 293 to 298 K with the solution of 1A-, 6 g of diethylamine.

The reaction is then refluxed for 3 hours and then concentrated under vacuum. The residue is taken up in 100 ml of methylene chloride, the methylene chloride phase washed with 50 ml of water and separated. The methylene chloride is concentrated, the residue is crystallized and recrystallized from ether. The resulting 5-diethylamino-7- (N- (n-pentyI) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine of melting point 352 to 353 K is recovered in a yield of 225 g (70 % of theory).

Example 3

18.9 g of 5.7-bichloro-s-triazolo (1,5-a) pyrimidine are suspended in 50 ml of ethanol. 29.4 g of n-hexylaminoethanol are added dropwise with stirring at 5 to 10 ° C., the temperature of the mixture is allowed to reach 293 K and stirred for 1 hour at this temperature. Then the resulting compound is filtered off, re-suspended in 150 ml of ethanol. At room temperature, 15 g of diethylamine are added, then the mixture is heated to boiling for 3 hours. The mixture is concentrated under vacuum, the residue taken up in 75 ml of chloroform and washed with water. After washing, the organic phase is concentrated, the resulting 5-diethylaraino-7- (N- (n-hexyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine recrystallized from petroleum ether. The melting point is 335 to 336 K and the yield 162 g (50 * of theory).

Example 4

The reaction is carried out as in Example 3 Besehrieben. For diethylamine 17.1 piperidine are used. The resulting 5-piperidino-7- (N- (n-hexyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine is recrystallized from benzene. The yield is 28 g and the melting point is 354 K.

Example 5

18.9 g of 5.7-di-chloro-s-triazolo (1.5-a) pyrimidine are suspended in semis of 50 ml of ethanol / 50 ml of water. At a temperature of 278 to 283 K is added slowly 23.6 g of n-butylaminoethanol and the mixture is stirred for 3 hours at room temperature. The precipitated compound is then filtered off with suction, suspended again in 150 ml of methanol, 17.4 g of morpholine are added slowly and the mixture is refluxed for two hours. The methanol is concentrated, the residue is taken up in 75 ml of methylene chloride and washed twice with 50 ml of water. After concentration, this remains

5-morpholino-7- (N- (n-butyl) -N- (β-hydroxyethyl) amino) -s-triazolo (1,5-a) pyrimidine of melting point 375 K with a yield of 16 g (50 %) d. Th.).

Example 6

In 200 ml of methanol, 18.9 g of 5.7-dichloro-s-triazolo (1,5-a) pyrimidine are suspended. At 5 to 283 K, 26.6 g of N- (ethoxyethyl) -N- (.beta.-hydroxyethyl) -amine are added and the mixture is stirred for 2 hours at 288 to 293 K. The reaction product is then filtered off with suction, again in 75 ml Suspended methanol, mixed with 17 g of piperidine and kept at boiling temperature for 3 hours. The suspension is concentrated, the residue crystallized out. The 5-piperidino-7- (N- (ethoxyethyl) -N- (β-hydroxyethyl) amino) -s-triazolo- (1,5-a) pyrimidine, recrystallized from ethyl acetate, has a melting point of 393 to 394 K. at an Au yield of 22 g (65%).

Example 7

The experiment is carried out as indicated in Example 6, for 17 g of piperidine 14.6 g of diethylamine are used. Recrystallized from petrol to give 17.4 g (54 % of theory) of 5-diethyiamino-7- (N- (ethoxyethyl) -N- (ß-hydroxyethyl) amino) -s-triazolo (1, 5-a) pyrimidine of melting point 342 to 343 K.

Claims (1)

invention claim Process for the preparation of 5-substituted and 7-substituted by basic groups new s-Triazolc (l, 5-a) pyrimidines according to formula in which the substituents have the following meanings: - R "and Ro is a Η-atom, an alkyl group of chain length CL to C ₃ or, a halogen atom; --R _{4 is} a straight or branched chain alkyl group of chain length C ₄ to C _{g /} optionally substituted by alkoxy or alkyl groups of chain length G ₁ to C ₃ aralkyl groups, 2,5-Dioxaheptyl- or 3-OxahexyIreste; R _{5 is} an Η-atom, an alkyl group of chain length C. to C ₃ , a hydroxyethyl or hydroxypropyl group; R g and R ₇ Η atoms, a straight- or branched-chain alkyl group of chain length C to C ₅ , where R _g and R _{7 can} also be constituents of a cycloaliphatic ring, characterized in that in the 5- and 7-position halogen-substituted s-triazolo (l _/ 5-a) pyrimidines of the formula shark in which R ₂ and R _{3 have} the meanings mentioned and for Hai is a chlorine or bromine atom, with amines of the formula ^ C MH cäer in which R ₄ to R _{7 have} the meanings mentioned, are reacted in two stages in the presence of solvents, wherein the substitution in the first stage at temperatures up to 293 K in the 7-position and at temperatures of 294 K to the boiling point of the particular used Solvent in the 5-position takes place. Lj 204Ü