DE2310338C3 - 1,3-bis (beta-ethylhexyl) -5-amino-5-methy! -RiexahydropyTimidine-pyr (din-3-carboxylate - Google Patents

Description

C ₂ H ₅

H ₉ C ₄ -CH-CH ₂ -Nv /] r-CH,

NH ₃ (hexetidine nicotinate)

V-coo

2. Process for the preparation of the compound according to claim 1, characterized in that a solution of hexetidine or its acid addition salts is reacted by conventional methods in an organic solvent with nicotinic acid or a salt of this acid in a molar ratio of about 1: 1, the reaction mixture is cooled and the precipitated nicotinate is isolated.

3. Medicinal preparations consisting of the compound according to claim 1 as an active ingredient and usual Thinners and / or carriers.

From the work of Witold S aski and SG S hah ("J. of Pharmaceutical Science", 54, 277 to 280, 1965) it is known that the compound 1,3 - bis - ψ - ethylhexyl) - 5 - methyl - 5 - amino - hexahydropyrimidine, hereinafter referred to as "hexetidine", has a remarkable antibacterial effect. Furthermore, FA Barkley, FJ Turner, RS Pianotti, PL Cartage and BS Schwa rt ζ report ("Antimicrobial Agents Annu.", 1960, 507 to 519, 1961). that salt formation of hexetidine with organic acids sometimes increases the effectiveness.

Surprisingly, it has now been found that a Hitherto unknown salt of hexitidine, namely l, 3-bis (/ i-ethyl) -5-amino-5-methyl-hexahydropyrimidine - pyridine - 3 - carboxylate, hereinafter referred to as "hexetidine nicotinate", with the following general formula I.

C ₂ H

₂ H ₅

C ₂ H ₅ H ₉ C ₄ -CH-CH ₂ -

CH ₂ -CH-C ₄ H ₉ CH ₃

NH ₃

COO

has a particularly advantageous increase in activity and is therefore excellent as an active ingredient for Medicinal preparations are suitable.

The compound according to the invention has the following chemical and physical characteristics:
Elemental analysis for C ₂₇ H ₅₀ N ₄ O ₂ :

Calculated ... C 70.08. H 11.15. N 12.10. O 6.92; found .... C 69.31. H 10.78, N 11.92. O 7.87.

Molecular Weight: 462.73.

IR spectrum: 3250 cm " ¹ (NH), 1630 _{cm" (amide I). 6j}

The process according to the invention for the preparation of the compound of the formula I given above is characterized in that a solution of hexetidine or its acid addition salts after usual methods in an organic solvent with nicotinic acid or a salt of this acid in a molar ratio of about 1: 1, the reaction mixture cools and the precipitated nicotinate isolated.

Aliphatic, alicyclic and aromatic hydrocarbons that are liquid at room temperature are used as solvents, lower aliphatic alcohols or their mixtures with water and ketones with up to 6 carbon atoms, aliphatic and alicyclic ethers with up to 8 carbon atoms. Acid amides and sulfoxides are suitable. Petroleum ethers are preferably 40-80. Methanol, η-hexane. Dimethylformamide. Isopropanol, benzene and ethyl alcohol are used.

The reaction with nicotinic acid or its salt at temperatures up to Boiling point of the solvent, preferably at temperatures between 40 and 60 C, carried out. The following examples explain the invention:

example 1

1 mol of hexetidine is dissolved in 1000 ml of petroleum ether 40/80 dissolved and with stirring at 25'C in portions Nicotinic acid (1 mol) added. It is then refluxed for! Hours, then under Cooled stirring to room temperature. The crystal pulp is filtered off with suction and dried at 50 to 80.degree.

Yield of hexetidine nicotinate: 60% (melting point: 108 to 111T).

Example 2

1 mole of hexetidine is eingeiragen in 1000 ml of methanol and Warming to 50 ⁰ C !. Nicotinic acid (1 mol) is then added in portions. After I ¹ ₂ hours of stirring at 50 "C half of the solvent is removed in vacuo at 40 ° C. After crystallization at room temperature, the K.ristaübrei is filtered off and recrystallized from Essigsäureälhylester., To yield the hexetidine-nicotinate in white crystalline form.

Yield: 70%.

Example 3

0.1 mol of hexetidine is introduced into 40.0 ml of η-hexane and heated to 55 ° C. Nicotinic acid is then added (0.1 mol) added and while stirring while cooling to room temperature the Hexetidine nicotinate precipitated.

Yield: 70%.

Example 4

0.1 mole of hexetidine is dissolved at 40 ⁰ C in dimethylformamide, then 0.1 moles of nicotinic acid is added and stirred for half an hour at 40 ° C. After cooling, the excreted hexetidine nicotinate is isolated.

Yield: 80%.

B e i s ρ i e 1 5

0.1 mole of hexetidine is dissolved in 30.0 ml lospropanol and heated to 6O ⁰ C. After adding 0.1 mol nicotinic acid, the mixture is cooled to room temperature with stirring and the crystal slurry is filtered off with suction.

Yield 60 to 70%.

Example 6

0.1 mol of hexetidine is introduced ^{into benzene at 40 °} C. and nicotinic acid is added in portions. After a reaction time of 2 hours, the mixture is cooled while stirring. The KristaMisat is suctioned off and dried.

Yield: 60%.

Example 7

0.1 mol of nicotinic acid is mixed with 45.0 ml of ethanol. At 50 ^° C., 0.1 mol of hexetidine, dissolved in 10 ml of ethanol, is added dropwise with stirring. After 2 _^1/2 hours of stirring at this temperature, cooled to room temperature and the precipitated hexetidine nicotinate aspirated.

Yield: 65 to 70%.

60

65 By comparative toxicological and microbiological studies of hexetidine, hexetidine oxalate, hexetidine cinnamate and hexetidine nicotinate it was found that hexelidine nicotinate has particularly beneficial properties.

The invention therefore also relates to medicinal preparations made from hexetidine nicotinate and customary diluents and / or nutrients exist.

Toxicology and Bacteriostatic Effectiveness

The toxicity of hexetidine is significantly reduced by salt formation with nicotinic acid. Female mice with a body weight of 20 to 30 g of the strain NMR1 were used for the experiments used. The observation time was 10 days. The hexetidine salts were made in a commercially available manner Carboxymethyl cellulose suspended, 10 ml kg of the suspension were injected. The results were using the method of L itch field and Wilcoxon calculated (Litchfield, G. T .. and W i 1 c ο χ ο η, F. G., Pharmacol, exp. Therap. 96 [1949], 99).

The following LD ₅₀ values were determined:

p.o. i.p. kgl (mg / kg) (mg Hexetidine 960 33 55) (519-1776) (20 Hexetidine oxalate 970 23 29) (561 - 1678) (19th Hexetidine cinnamate 1740 54 83) (1543-1963) (35 Hexet idin-nicotinat 1830 63 -86) (1331-2516) (46

To determine the bacteriostatic effectiveness, solutions of hexetidine, hexetidine oxalate are used and hexetidine nicotinate compared. The solutions have the following composition:

Hexetidine solution

Hexetidin-oxalat-Lösuim

Hexet idin nicotinate solution

100 mg hexetidine
100 ml

113.2 mg hexelidine oxalate (equivalent to 100 mn
Hxetidine) / 10 () ml
136.2 mg hexetidine nicotinate (equivalent to 100 mg
Hexetidine) 100 ml

The vaccine suspension is prepared by a sterile Slandard 1 nutrient agar petri dish with a Test germ stock culture (Escherichia coli, Proteus vulgaris. Pseudomonas acruginosa). Incubated for 24 hours at 30 C and / to use or test the test stored at 4-4 C.

The germs of this Petri dish are washed away with 5 ml of physiological saline solution and diluted to 50 ml with the same saline solution (1: 101.

Inoculating the nutrient solution

250 ml of double strength thioglycolate solution (60 g / l) are mixed with 100 drops (~ 5 ml) of the above Bacterial culture of the test germ stock culture diluted 1:10 offset and evenly distributed by shaking.

A dilution series is made in 10 test tubes each (Content 100 ml) from each de: three solutions described above, the following concentrations contain:

; -Hexetidine / ml: 1000; 500; 250; 125; 62.5; -31; - 16; -8th; ~ 4 and —2.

5 ml of double-strength thioglycolate nutrient solution previously inoculated with Teslor organisms are placed in each test tube pipetted in, so that the end concentrations are halved for the individual test tubes results.

The evaluation takes place after 24 to 72 hours of incubation of the test series at 3 (YC.

The concentration of that test tube in which after 72 hours no cloudiness (growth) can be observed.

The following table shows the bacteriostatic sanitation depending on the concentration.

solution 100 ml Bacteriostalic Effectiveness after > 125; · solution contain 1 2 3 4 5 6 1 th ..j > 62.5 witch tidin (mg) Hexetidine 100 Hxetidine 100 --500; · oxalate Hxetidine 100 nicotinal

All samples are incubated for 6 days at 30 (.

Hexetidine in a concentration of! 25 still shows sufficient effect after 6 days.

Hydroxetidine oxalate shows no significant values even at 500- Effect more while hexctidine-ciiinamat because of its extreme insolubility can be.

Hcxetidine nicotinate is still effective at a concentration of 62.5 - ·.

Claims (1)

Patent claims: , ι u u, ^^ r.vrimiHin-Dvridin-3-carboxylate of the following 1. 1,3-bis (/ i-ethylhexyl) -5-amino-5-methyl-hexahydropynmidm pyna π formula 1 C ₂ H ₅ CH ₁ -CH-C ₄ H ₉