HU194880B - Process for preparing 2,4-diamino-6-imidazo/1,2-a/ pyrdyl-1,3,5-triazine derivatives and pharmaceuticals comprising these compounds - Google Patents

Abstract

2,4-diamino-6-imidazo-(1,2-a)- pyridyl-1,2,5-triazine derivs. (I) and their pharmaceutically useful acid addn. cpds. are claimed. - R1 is a hydrogen or halogen atom, R2 a hydrogen atom or alkyl gp. of 1-4C or an alkanoyl-benzyl or 2-phenoxy-ethyl gp. of 2-4C. R3, a hydrogen atom or alkyl gp. of 1-4C; further, -NR2R3 together represent a piperazino-, 4-methyl--piperazino, 4-ethoxy-carbonyl-piperazino or morpholino-gp., R4, a hydrogen atom or 2-4C alkanoyl gp. 'A' represents a valency bond or a -(CH2)n- gp. 'n' being 1 or 2, or a -CH=CH- gp.

Description

The present invention relates to novel 2,4-diamino-6-imidazo [1,2-a] pyridyl-1,3,5-triazine derivatives of the formula (I) and their pharmaceutically acceptable acid addition salts. In the formula (I), R 'is hydrogen or halogen;

R ² is hydrogen, C 1-4 alkyl, C 2-4 alkanoyl, benzyl or 2-phenoxyethyl;

R ³ is hydrogen or C 1-4 alkyl, with the proviso that when R ³ is. C 14 alkyl, then

R ² 's -C 1-4 alkyl means' · - '', more preferably -NR ² R ³ -alkyl may also be piperazino, 4-methylpiperazino, 4-ethoxycarbonylpiperazino or morpholino;

R ⁴ is hydrogen or C 2 -C 4 alkanoyl, provided that when R ⁴ is C 2 -C 4 alkanoyl, then R ² is C 2 -C 4 alkanoyl; and

A is a bond or -CH ₂ - or -CH = CH.

Particularly preferred compounds of formula I are those wherein R ¹ is hydrogen; R ² and R ³ are hydrogen or R ² and R ³ together with the adjacent nitrogen atom form a morpholine or piperazine ring; R ⁴ is hydrogen and A is a bond or -CH ₂ -; and the triazine ring is attached to the 3-carbon of the imidazo [1,2-a] pyridazine ring system.

It is well known that circulatory disorders (such as chronic myocardial insufficiency, myocardial infarction, hypertension) are among the most common causes of death. Among these diseases, the number of cardiac patients suffering from chronic myocardial insufficiency is constantly increasing. Today, the disease is predominantly treated with cardiac glycosides, but it is known that the use of these drugs is not without risk for a number of reasons. On the one hand, adverse side effects (such as bradycardia, i.e., heart rate decrease and arrhythmia) are to be expected and, on the other hand, dose adjustment is difficult because of the narrow therapeutic margin of these agents. In addition, cardiac glycosides should not be used in acute and post-infarction heart failure.

In the last decade, there has been a growing need for therapeutic agents which, even with long-term treatment, can increase the performance of malfunctioning heart muscle without adverse effects (undesirable circulatory and other toxic effects). Novel cardiotonic (positively inotropic) compounds include, for example, adrenergic beta, agonists (specifically, cardiac muscle stimulants) represented by prenalterol [1- (4-hydroxyphenoxy) -3-i-propylamino- 2 propanolj.

This compound is very effective when administered intravenously in acute heart failure, but does not improve cardiac function over a longer period of time [J. Cardiovasc. Pharm. 6, 491 (1984)].

Pyrbuterol [2-t-butylamino-1- (3-hydroxy-2-hydroxymethyl-6-pyridyl) ethanol], which stimulates both beta and beta ₂ -adrenergic receptors, has been shown for several weeks. however, its beneficial effect over a longer period of time is a common practice [New Engl. J. Med. 305, 185 (1981)].

The effect of bipyridine-type cardiotonic agents other than that of adrenergic beta-agonists has not been elucidated. A prominent representative of this class of compounds, amrinone [3 amino-5- (4-pyridyl) -2-pyridone] significantly increases cardiac output (rejection power) and reduces peripheral vascular resistance in patients with chronic heart failure; however, its serious blood side effects are of therapeutic use. substantially limit [Am. J. Med., 72, 113 (1982); Briton. J. Clin. Pharm. 17, 317 (1984)].

Sulmazol] 2- (4-methylsulfinyl-2-methoxyphenyl) -1H-imidazo [4,5-b] pyridine, which belongs to the group of imidazopyridines, has a vasodilatory effect in addition to its cardiotonic effect, but adverse side effects [Annal Cardiol. Anghiol. 33, 219 (1984)].

The properties of the major agents with cardiotonic (positive inotropic) activity other than cardiac glycosides indicate that there is still a need for new, chronically usable, drug-free drugs.

In our studies we have found that the compounds of the formula I significantly increase the myocardial contractility, that is, they have a cardiotonic (positive inotropic) effect, while being favorable in terms of both toxicity and side effects [LD ₅₀ po> 200 mg / kg].

The positive inotropic effect was anesthetized in an open-foot cat, Walton-Brodie [J. Pharmacol. Exp. Ther. 90, 26 (1947)] with a modified version of strain gauge arc measurement. A strain gauge was sewn to the heart and a pressure gauge was attached. The deflection is measured as the change in ohmic resistance caused by the distortion of the disk.

Ventricular animals (cats, dogs) underwent ventricular cannulation, and changes in the first derivative of ventricular pressure wave were measured as changes in contractile strength of the myocardium.

The positive ino-2194880 tropical activity of the compounds of formula (I) prepared according to the invention is summarized in Table I below. Isoproterenol was used as a control substance at 0.2 micrograms / kg i.v. bolus injection. A strong effect (+ + +) was considered when the given compound was 5 mg / kg i.v. administration, it was considered to have a stronger effect than the control, with a moderate effect (+ +), a weak effect than the control (- (-)), but a noticeable effect.

Table 1

Positive inotropic activity of the compounds of formula (I)

The number of the example Positive inotropic effect 1. +++ Second + Third + 4th + 5th ++ 8th + 14th + 15th ++ 16th ++ 17th ++ 18th +

+++ strong effect ++ medium effect + weak effect

Table 1 shows that the compound of Example 1, i.e. 2,4-diamino-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine, is more potent than the control. cardiotonic.

The compounds of formula (I) are prepared according to the process of the invention by:

a) for the preparation of compounds of formula I wherein R ¹ is as defined above, R ² , R ³ and R ⁴ are hydrogen and A is a compound of formula II as defined above except vinyl R ¹ and A are as defined above - reacted with dicyandiamide; obsession

b) for the preparation of compounds of formula I wherein R ¹ is as defined above, R ² is hydrogen, C 1-4 alkyl, benzyl or 2-phenoxyethyl, R ³ and -NR ² R ³ is as defined above, R ⁴ is hydrogen and A is a vinyl group, except for a compound of formula III as defined above wherein R ¹ and A are as defined above and R ⁵ is C 1-4 alkyl, a compound of general formula IV biguanidszármazékkal - wherein R ² and R ³ and -NR ² R ³ is as defined above and m is 1 or 2, (m - l reaction) ^m shed base - (; or

c) for the preparation of compounds of formula I wherein R ¹ is as defined above, R ² is hydrogen, C 1-4 alkyl, benzyl or 2-phenoxyethyl, R ³ and -NR ² R ³ are as defined above, R ⁴ is hydrogen and A is -CH = CH-, an aldehyde of formula (V) wherein R ¹ is as defined above is a 6-methyl-3,5-triazine of formula (VI) a derivative wherein R ² , R ³ , -NR ² R ³ and R ⁴ are as defined above; and, if desired, for the preparation of compounds of formula I wherein R 1, R ³ and A are as defined above, and R ² and / or R ⁴ are C 2 -C 4 alkanoyl, by any of the processes (-c) above. The resulting compound of formula (I) wherein R ² and R ⁴ are hydrogen is acylated with a C 2 -C 4 alkanoic acid or a reactive derivative thereof and optionally converted to the acid addition salt of a base of formula (I) with a pharmaceutically acceptable acid.

In a preferred embodiment of the process a) a solution of the compound of the formula II in a suitable solvent such as isopropanol, benzene, dioxane or acetonitrile with dicyandiamide is used in the presence of a basic catalyst, preferably potassium hydroxide or potassium carbonate. Boil for 20 hours.

In a preferred embodiment of process b), a solution of a compound of formula III in a suitable solvent such as methanol or ethanol is mixed with a compound of formula IV in the presence of an organic base, preferably 2 or 3 moles of sodium methylate. The reaction is conveniently carried out for 2 days at room temperature and then refluxed for 1-12 hours.

In a preferred embodiment of process c), an acetic acid solution of the aldehyde V and 2,4-diamino-6-methyl-1,3,5-triazine is prepared in the presence of a base, preferably piperidine, in an amount of boil for an hour.

The acylation is conveniently carried out by reacting the corresponding compound of formula (I) wherein R ² and / or R ⁴ is hydrogen with a chloride or anhydride, preferably anhydride, optionally in the presence of zinc chloride, of a C 2 -C 4 alkanoic acid. Reaction temperature. Acylation in the presence of zinc chloride gives a monoacyl derivative, while acylation in the absence of zinc chloride gives the diacyl derivative.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are conveniently prepared by treating the base of formula I with a suitable solvent, preferably methanol, ethanol, or iso

A solution of the saturated acid in a suitable solvent, such as lower alkanol, acetone or ether, is added to a solution of -3194880 in propanol and the resulting salt is isolated and, if desired, purified by recrystallization. Pharmaceutically acceptable organic or inorganic acids may be used in the salt formation. Preferred acids include hydrochloric, maleic and fumaric acids.

Most of the compounds of formula 11 used as starting materials for the process of the invention are known. Examples include imidazo [1,2-a] pyridine-2-carbonitrile [J. Chem. 15 '982 (1972)], imidazo [1,2-a] pyridine-3-carbonitrile [Boll. Chim. Farm. 105, 32 (1966); C.A.65,699 h (1968)], imidazo [1,2-a] pyridin-2-yl-acetonitrile [Farm. Ed. Sci. 30, 815 (1975)] and imidazo [1,2-a] pyridyl-3-yl-acetonitrile [J. Chem. 12, 122 (1969)].

For example, compounds of formula (II) which are not known in the literature can be prepared by reacting the acid amide derivatives of formula (VII) wherein R ¹ is as defined above and A is vinyl as above with the aid of phosphoryl chloride, thionyl chloride or acetic anhydride. , in a manner known per se.

Most of the compounds of formula (III) are known in the literature. These include methyl (imidazo [1,2-a] pyridine-3-carboxylate) [Compt. Order. 257, 3434 (1963); C.A. 60, 14496b (1964)], ethyl (imidazo [1,2-a] pyridine-2-acetate (Farm. Ed. Sci. 23, 1141 (1968)).

Compounds of general formula (III) which are not known in the literature can be prepared by methods known in the art or similar methods. For example, ethyl (imidazo [1,2-a] pyridine-3-carboxylate) may conveniently be prepared or imidazo [1,2-a] pyridine-3-carbonitrile may be prepared so that its ethanolic solution is hydrogen chloride. in the presence of imidazo [1,2-a] pyridine-3-carboxylic acid chloride hydrochloride [Farm. Ed. Sci. 27, 101 (1972)] was heated to reflux for 5 hours.

Compounds of formula IV are known in the art. See, e.g., U.S. Patent No. 776,176. British Patent No. 6,901,981; Japanese Patent, Indian J.Chem. 3, 573 (1965), J. Am. Chem. Soc. 81, 3728 (1959) J. Org. Chem., 24, 1809 (1959), Helv. Chim. Acta 48, 1940 (1965), 3,057,780. U.S. Pat.

Compounds of formula (V) are known, for example, imidazo [1,2-a] pyridine-3-carbaldehyde [Boll. Chim. Farm. 105, 32 (1966)] and 7-chloroimidazo [1,2-a] pyridine-3-carbaldehyde [J. Med. Chem. 13, 1048 (1970)].

Compounds of formula VI are known, for example, 2,4-diamino-6-methyl-1,3,5-triazine [Chem. Wage. 7, 776 (1874)].

Most of the compounds of formula VII are known. For example, 7-chloroimidazo [1,2-a] pyridine-3-carboxylic acid amide [Farm. Ed. Sci. 23, 1141 (1968)].

Compounds of formula (VII) not known in the literature can be prepared by analogous procedures, for example, by reacting the corresponding ester of formula (III) with ammonia in a known manner.

The process of the present invention is described in detail in the following non-limiting Examples.

Example 1

2,4-Diamino-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine 1.44 g (0.01 mol) of imidazo [1,2-a] To a mixture of pyridine-3-carbonitrile, 0.84 g (0.01 mol) of dicyandiamide and 50 ml of isopropanol at room temperature, a solution of 0.14 g (2.6 mmol) of potassium hydroxide in 10 ml of isopropanol is added dropwise and the reaction mixture is stirred for 16 hours. boil for a long time. After cooling, the precipitated crystals are filtered off, washed with water and dried, and then recrystallized from ethanol. Yield: 1.90 g (84%); m.p.> 260 ° C.

Preparation of the hydrochloride salt:

The base thus obtained (2.27 g, 0.01 mol) is suspended in hot methanol (100 ml) and the suspension is acidified to pH 2-3 with 3N hydrochloric acid in methanol. After cooling, the precipitated crystals are filtered off, washed with isopropanol and dried. Yield: 2.24 g (85%), m.p.> 260 ° C.

By the procedure described in Example 1, the following compounds were prepared:

Example 2

2,4-diamino-6- (imidazo [1,2-a] pyridin-2-yl) 1,3,5-triazine.

All proceed as in Example 1 except starting from imidazo [1,2-a] pyridine-2-carbonitrile. Yield: 87%, m.p.> 260 ° C.

Preparation of the hydrochloride salt:

The base (2.27 g, 0.01 mol) was dissolved in 100 ml of 6N hydrochloric acid under reflux, the solution was clarified with hot charcoal, filtered and cooled. The precipitated crystals are filtered off, washed with acetone and dried. Yield: 1.71 g (65%), m.p. > 260 ° C.

Example 3

2,4-diamino-6- (7-chloro- (imidazo [1,2-a] ^{pyridin-3-yl;))} - 1,3,5-triazine

All proceed as in Example 1 except starting from 7-chloroimidazo [1,2-a] pyridine-3-carbonitrile. Yield: 88%, m.p.> 260 ° C.

The starting 7-chloro-imidazo [1,2-a] pyridine-3-carbonitrile can be prepared as follows:

To a solution of 7-chloroimidazo [1,2-a] pyridine-3-carboxylic acid amide (1.95 g, 0.01 mol) in dimethylform-4194880 (30 ml) was stirred at 0-5 ° C with 2 ml of thionyl chloride solution in dimethylformamide (3 ml) was added dropwise. The reaction mixture was stirred at room temperature throughout the day, allowed to stand overnight, poured into ice-water (150 mL) and neutralized with solid potassium carbonate. The crystals were filtered off, washed with water, desalted, dried and then recrystallized from methanol. Yield: 0.80 g (45%), m.p. 186 ° C.

Example 4

2,4-Diamino-6- (imidazo [1,2-a] pyridin-2-ylmethyl) -1,3,5-triazine.

All were carried out as in Example 1, except that imidazo [1,2-a] pyridine-2-yl-1-acetonitrile was used. Yield: 70%, m.p. 262 ° C.

Hydrochloride salt: 82%, m.p.> 260 ° C (isopropanol).

Example 5

2,4-Diamino-6- (imidazo [1,2-a] pyridin-3-ylmethyl) -1,3,5-triazine

All proceed as in Example 1 except starting from imidazo [1,2-a] pyridin-3-yl-acetonitrile.

Yield: 75%, m.p.> 260 ° C.

Hydrochloride salt: 80% yield, mp 260 ° C (isopropanol).

Example 2 Amino-2-butylamino-6- (imidazo [1,2-a] 10 pyridin-2-yl) -1,3,5-triazine

To a solution of 1-butyl biguanidine hydrochloride (0.96 g, 5 mmol) in methanol (40 mL) at room temperature was added a solution of sodium (0.23 g, 10 mmol) in methanol (10 mL) followed by ethyl imidazo (0.95 g, 5 mmol). [1,2-a] Pyridine 2-carboxylate) is added to the reaction mixture. The mixture was stirred at room temperature for 1 day, then refluxed for 5 hours and finally evaporated to dryness in vacuo.

The residue was treated with water (5 ml), the crystals were filtered off, washed with water, desalted, dried and recrystallized from ethanol. Yield: 0.61 g (43%), m.p. 220 ° C.

By following the procedure described in Example 6, the compounds described in Table 2 were prepared at various reaction times:

Table 2 Compounds of Formula I wherein R ¹ and R ⁴ are H, R ² , R ³ or -NR ² R ³ and A are as defined in the Table

'Elda 5 would close R ² or -NR ² R ³ R ³ THE Sheaf- gap time /Sun/ Boiling time / hour / Yield 7 op. / c / 7 imidazo [l, 2-a ^) pyridin-2- ch ₃ ch ₃ valency Tek binding 1 5 36 > 260 8th imidazo [1,2-a] pyridine-2- 4-morpholinyl lino 11 1 5 30 > 260 9th imidazo [1,2-a] pyridin-2- C ₄ H ₉ H -ch ₂ - 1 1 42 158 10th imidazo [1,2-a 'pyridine-2- ch ₃ ch ₃ -ch ₂ - 1 1 32 97 1 1 imidazo-1,2-a pyridin-3- CUHg H valency Tek binding 2 10 22 152 12th - imidazo [1,2-a] pyridin-3- ch ₃ ch ₃ t r 2 10 25 247

Example 13

4-Amino-2-benzylamino-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine

To a solution of 1-benzyl-biguanidine hydrochloride (1.14 g, 5 mmol) in methanol (40 mL) was added a solution of sodium (0.23 g, 10 mmol) in methanol (10 mL) at room temperature, followed by ethyl imidazo (0.95 g, 5 mmol). [1,2-a] Pyridine-3-carboxylate) is added to the reaction mixture. The mixture was stirred at room temperature for 2 days, then refluxed for 12 hours and finally evaporated to dryness in vacuo. The residue was dissolved in water (20 ml), extracted with chloroform, the combined chloroform solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ether and then recrystallized from ethanol. Yield: 0.35 g (26%), m.p. 198 ° C. The starting ethyl (imidazo [1,2-a] pyridin-3-ylcarboxylate) can be prepared by the following methods:

"Method A:

A mixture of imidazo [1,2-a] pyridine-3-carboxylic acid hydrochloride (2.06 g, 9.5 mmol) in ethanol (20 mL) was heated to reflux for 5 hours and then evaporated to dryness in vacuo. The residue is dissolved in 10 ml of water, _θ5 is neutralized with concentrated aqueous ammonium hydroxide solution and

Extract with -5194880 farm. The combined chloroform solution was washed twice with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ether. Yield: 1.46 g (82%), m.p. 62 ° C.

Method B:

Hydrogen chloride gas was bubbled through a solution of imidazo [1,2-a] prridine-3-carbonitrile (0.68 g, 4.8 mmol) in ethanol (35 mL) for 14 hours and the reaction mixture was concentrated to dryness in vacuo.

The residue was treated with water (5 ml) and the mixture was neutralized with concentrated aqueous ammonium hydroxide, the crystals were filtered, washed with water, desalted, dried and then recrystallized from ethanol. Yield: 0.56 g (62%), identical to product A.

Following the procedure of Example 13, the following compounds of formula (I) were prepared (Table 3). The amount of sodium and the reaction time are also shown for each example.

Table 3 Compounds of Formula I wherein R ² , R ³ and -NR ² R ³ are as defined in the Table, R ¹ and R ¹ * are hydrogen, and A is a bond

Example number R ² or -mr ² r ³ R ³ sodium heaven. / Mmol / mixing here /Sun/ boil, time e / hour / Yield % op. / ° C / SALT op. / ° C / 14th imidazo 1,2-a] pyridin-3- 2-phenoxyethyl H 13 2 12 55 167 - - 15th imidazo 1,2-a Pyridine-3- 4-morpholino 10 2 12 32 228 - - 16th imidazo 1,2-3- a1piridin 4 etoxikarbon.il- morpholino 1-PI 10 2 12 20 260 17th imidazo 1,2-a] pyridin-2- 4-methyl-1-piperazino 1.3 1 5 40 248 2HC1 245 18th imidazo 1,2a] pxridin-3- 4-methyl-1-piperazino 15 2 5 25 202 2HC1 240

Example 19

2.4-Diamino-6- (1- (imidazo [1,2-a] pyridin-3-yl) -2-vinyl) -1,3,5-triazine

1.50 g (0.1 mol) of imidazo [1,2-a] pyridine-3-carbaldehyde, 1.30 g (0.01 mol) of 2,4-diamino-6-methyl-1,3,5- A mixture of triazine, 5 mL of piperidine and 10 mL of acetic acid was refluxed for 10 hours. The reaction mixture was cooled, diluted with water (10 mL) and neutralized with concentrated aqueous ammonium hydroxide. The crystals were filtered off, washed with water, desalted, dried and recrystallized from methanol. Yield: 1.06 g (42%), m.p.> 260 ° C.

Example 20

2-Acetamido-4-amino-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine

0.80 g (3.5 mmol) of 2,4-diamino-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine (compound of Example 1), A mixture of 50 g of zinc chloride and 5 ml of acetic anhydride was heated to reflux for 6 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was stirred with water (15 mL) and neutralized with potassium carbonate. The crystals were filtered off, washed with water, desalted, dried and then recrystallized from methanol. Yield: 0.63 g (67%), m.p.> 260 ° C, [mass spectrum: M + = 269 (100%)].

Example 21

2.4-Diacetamido-6- (imidazo [1,2-a] pyridin-3-yl) -1,3,5-triazine 0.40 g (1.75 mmol) 2,4-diamino-6- (imidazo [ A mixture of 1,2-a] pyridin-3-yl) -1,3,5-triazine (the compound of Example 1) and 5 ml of acetic anhydride was heated to reflux for 10 hours. The reaction mixture was cooled and the crystals were filtered off, first with 10% aqueous sodium 6

washed with bicarbonate and then with water, then desalted, dried and recrystallized from methanol. Yield: 0.40 g (72%), m.p.

> 260 ° C, [mass spectrum: M ⁺ = 311 (100%)].

Claims (6)

A process for preparing a compound of formula (I) 40 R ¹ is hydrogen or halogen, R ² is hydrogen, C 1-4 alkyl, C 2-4 alkanoyl, benzyl or 2-phenoxyethyl 45, R ³ is hydrogen or C 1-4 alkyl, with the proviso that when R ³ is C 1-4 alkyl, then R ² 50 is C 1 -C 4 alkyl; and -NR ² R ^{3 taken} together are also piperazino, 4-methylpiperazino, 4-ethoxycarbonylpiperazinyl or morpholino; R ⁴ is hydrogen or C 2 -C 4 alkanoyl, provided that when R ⁴ is C 2 -C 4 alkanoyl, 60 then R ² is C 2-4 alkanoyl; and A is a bond or a -CH ₂ or -CH = CH group, θ5 new 2,4-diamino-6-imidazo [1,2-a] pyridyl-1,3,5-triazine derivatives, and pharmaceutical-6194880 lags. can be used to prepare their acid addition salts, characterized in that: a) for the preparation of compounds of formula I wherein R ¹ is as defined in the foregoing, R ² , R ⁵ and R ⁴ are hydrogen and A is for the preparation of a compound of the formula II as defined in the above except for vinyl - wherein R ¹ and A are as defined above - with dicyano diamide; obsession b) for the preparation of compounds of the formula I in which R * is as defined in the preceding paragraph, R ² is hydrogen, C 1-4 alkyl, benzyl or 2-phenoxyethyl, R ³ and -NR ² R ³ is as defined herein, R ⁴ is hydrogen and A is vinyl except for a compound of Formula III wherein R ¹ and A are as defined above and R ⁵ is C 1-4 alkyl as defined above. A biguanide derivative of formula IV wherein R ² and R ³ and -NR ² R ³ are as defined above and m is 1 or 2 - (m + 1) moles in the presence of a base; obsession c) for the preparation of compounds of the formula I in which R ¹ is as defined herein, R ² is hydrogen, C 1-4 alkyl, benzyl or 2-phenoxyethyl, R ³ and -NR ² R ³ R ⁴ is hydrogen and A is -CH = CH; an aldehyde of formula (V) wherein R 'is as defined above is a 6-methyl-1,3,5 of formula (VI) a triazine derivative wherein R ² , R ³ , -NR ² R ³ and R ⁴ are as defined above; and, if desired d) for the preparation of compounds of formula I wherein R ¹ , R ³ and A are as defined herein and R ² and / or R ⁴ is C 2 -C 4 alkanoyl obtained by any of the above processes a) -c). The compound of formula (I) wherein R ² and R ⁴ are hydrogen is acylated with a C 2 -C 4 alkanoic acid or a reactive derivative thereof and optionally converted to the pharmaceutically acceptable acid addition salt of the resulting base of formula (I). Process (a) according to Claim 1, characterized in that the compound of the formula (II) is basic with dicyandiamide In the presence of 15 catalysts, it is reacted at the boiling point of the reaction mixture. Process b) according to claim 1, characterized in that the reaction of the compounds of the formulas III and IV is carried out in the presence of an excess of lower alcohol in lower alcohol. C) 4 A method according to claim 1, characterized in that the reaction solvent is acetic acid, and optionally a base, preferably piperidine ^25. The process of claim 1, wherein the acylation is carried out with a C 2 -C 4 alkanoic anhydride, optionally in the presence of zinc chloride. 6. A method in particular pharmaceutical compositions inotropic preparation, characterized in that one or more of (1) a compound of formula or a pharmaceutically top ³⁵ usable acid addition salt thereof prepared according to the method of claim 1 - wherein R ^1, R ^2, R ^3, -NR ² R ³ , R ⁴ and A are as defined in claim 1 - mixed with the solvent, carrier, excipient and excipient used in the preparation of a medicament for constitution with a medicament.