DE1470369C - 2 alkyl 4 alkylamino 6 alkoxy s triazines, process for their preparation and their use in pharmaceutical preparations - Google Patents

Description

(I)

N N

NH-R ₇

wherein R ₁ , R ₂ and R ₃ each represent a methyl or ethyl radical.

2. Process for the preparation of the s-triazines according to Claim 1, characterized in that a compound of the general formula II is used in a manner known per se

N-

OR,

(Π)

25th

OR,

30th

in which the radicals R ₁ and R _{3 have} the meaning given above, is reacted with an amine of the general formula H ₂ N - R ₂ , in which R _{2 has} the meaning given above.

3. A pharmaceutical preparation consisting of a compound according to claim 1 and one suitable carrier.

35

40

45

It has been found that the s-triazines of the following general formula I upon treatment of Stimulate the respiration of animals and that, due to their low toxicity observed in animals, they are considered to be new, excellent means of stimulating breathing for the purpose of remedying those caused by operations respiratory paralysis caused by traffic accidents.

The invention therefore relates to 2-alkyl - Alkylamino - 6 - alkoxy - s - triazines of the general formula I

60

N N

(I)

NH-R,

65

in which R ₁ , R ₂ and R ₃ each represent a methyl or ethyl radical, as well as a process for the preparation

OR,

N N

Xx

(ID

10 OR,

in which the radicals R ₁ and R _{3 have} the abovementioned meaning, with an amine of the general formula HN - R ₂ , in which R _{2 has} the abovementioned meaning, is reacted.

The invention relates to the properties of the compounds of the invention in addition to pharmaceutical preparations which contain the compounds according to the invention and a suitable one Contain carrier.

The s-triazines of the formula which are used as starting materials in the process according to the invention II can easily be achieved by reacting the corresponding 2-ethyl-4,6-dihalogeno-s-triazine with the produce appropriate alcohol.

The reaction is carried out with or without a solvent. Suitable solvents are, for example, water, alcohols such as methanol, ethanol or propanol, ethers such as dioxane or tetrahydrofuran, or mixtures of these compounds. The reaction can expediently be carried out under increased pressure if the amine used in the reaction has a lower boiling point. The reaction is usually carried out by heating the reaction mixture to a temperature of about 70 to 100 ^° C. for several hours. The most favorable reaction conditions are of course to be determined on a case-by-case basis.

The free triazines of the formula I can "form acidic salts with acids, for example with mineral acids, like hydrochloric acid, sulfuric acid, nitric acid and carbonic acid, and with organic acids like acetic acid, Citric acid, succinic acid, maleic acid, fumaric acid and tartaric acid. -With the help of these acidic salts it is possible to make the free triazines water soluble or if they are obtained in the form of an oil to convert them into the solid form. The s-triazines according to the invention have as medicaments for example the following effect:

1. Stimulating effect on breathing

In intact cats that are anesthetized with chloralose, or in intact dogs that are anesthetized with amobarbital sodium, s-triazines of the general formula are effective when administered intravenously Dose greater than about 10 mg / kg body weight will accelerate and deepen the Breath. The effect lasts on average for more than about 1 hour. This effect is through bilateral Carotid chemoreceptor vagotonia and / or denervation does not affect and creates one significant increase in the frequency of discharge of the phrenic nerve. Also has an intravertebral injection s-triazines of the general formula I clearly stimulate breathing even in small doses result. It is therefore believed that the mode of action of the s-triazines according to the invention

is due to its direct effect on the respiratory center.

In rabbits that are lightly anesthetized with urethane, the s-triazines increase the general formula I with an intravenous dose of about 5 mg / kg body weight, the respiratory volume per minute 37.5%. The effects last about 27 minutes on average. When administering a dose of about 20 mg / kg body weight increases the respiratory volume by 106%, and the effect lasts on average about 2 hours. The will work in rabbits anesthetized with urethane in the same way s-triazines prepared according to the invention counteract the respiratory depression caused by morphine, dl-3-hydroxy-N-methylmorphinan or pentobarbital sodium is triggered.

2. Effect on the circulatory system

In cats anesthetized with chloralose or in dogs anesthetized with amobarbital sodium cause the s-triazines of general formula I at an intravenous dose of about 40 mg / kg body weight cause a moderate, short-term increase in blood pressure, but change it not the pulse rate. Furthermore, these cause s-triazines in the same animals at this dose no change in blood pressure so great that breath is stimulated.

3. Effects on the autonomic nervous system

s-Triazines of the general formula I increase the effect of epinephrine or serotonin on the Blood pressure of cats or dogs, in the isolated seminal vesicles of guinea pigs or in the isolated Rat up uterus.

4. Effects on the central nervous system

In mice, s-triazines of the general formula I cause more at an intraperitoneal dose sedation and intensification of the narcotic effect of sodium pentobarbital than about 50 mg / kg body weight, while at the same time exerting a slight analgesic effect. You don't have one Influence on trained behavior of rats when the intraperitoneal dose is less than is about 50 mg / kg body weight. In monkeys, they cause sedation at doses greater than about 50 mg / kg body weight and a catatonia-like effect at very large doses.

5. Hypothermic and anti-inflammatory effects

In rats, the s-triazines according to the invention show the same hypothermic effect as aminophenazone. They show a moderate inhibition of edema caused by dextran. .

6. Toxicity

The mean lethal dose of the s-triazines of the general formula I in mice is about 380 mg / kg Body weight when injected intraperitoneally. The administration of the lethal dose occurs sequentially Salivation, diarrhea, and cardiac arrest, but no cramp.

7. Comparative tests

Compared to the active ingredients lobeline and nicotinic acid diethylamide known from the prior art, the compounds according to the invention show a significantly increased range of activity, as can be seen from the comparison tests described below.
The mean effective dose (DE ₅₀ ), determined in mg / kg, is determined in animal experiments on cats that had been anesthetized with pentobarbital. The effectiveness is determined according to the respiratory volume method. If this DE _{50 is} related to the mean lethal dose (LD ₅₀ ) of the respective compound - also determined in mg / kg, specifically by intraperitoneal injection into mice - one obtains the ranges of activity of the respective compound according to the following table.

15th
connection DE ₅₀
(rag / kg) LD ₅₀
(mg / kg) Effect
broad Lobeline
20 Nicotinic acid diethylamide
2-ethylamino-4-ethyl-
6-methoxy-s-triazine ..
2-methylamino-4-ethyl
6-ethoxy-s-triazine ....
²⁵ 2-ethylamino-4-ethyl
6-ethoxy-s-triazine .... 0.2
5.0
10
10
10 0.8
100
450
410
420 4th
20th
45
41
42

In the following examples the temperatures are uncorrected. The quantities given relate to the weight.

example 1

A mixture of 5 g of 2-ethyl-4,6-dimethoxy-s-triazine, 2 cm ³ of a 70% aqueous Äthylaminlösung and 20 cm ³ of water is sealed in a test tube and heated for 3 hours at 70 ⁰ C. The reaction mixture is extracted with chloroform. The extract is dried with sodium sulfate and concentrated. The residue is recrystallized from petroleum ether, 2 -ethyl-4-äthy lamino - 6 - methoxys-triazine being obtained. The triazine compound (2 g) is dissolved in a mixture of oxalic acid (0.5 g) and a small amount of methanol by heating. After cooling, the crystals separated out are separated off and recrystallized from methanol to give the oxalate of 2-ethyl-4-ethylamino-6-methoxy-s-triazine is obtained of melting point 84-85 ⁰ C.

B e i s ρ i e 1 2

A mixture of 15.5 g of 2-methyl-4,6-dimethoxys-triazine, 10.5 cm ^{3 of} a 30% strength aqueous methylamine solution and 100 cm ^{3 of} water is sealed in a tube and heated to 70 ° C. for 3 hours. The reaction mixture is extracted with chloroform. The extract is dried with sodium sulfate and concentrated. After recrystallization of the residue from petroleum ether, 2-methyl-4-methylamino-6-methoxys-triazine with a melting point of 155 to 157 ° C. is obtained.

Example 3

A mixture of 15.5 g of 2-methyl-4,6-dimethoxys-triazine, 6.5 cm ^{3 of} a 70% strength aqueous ethylamine solution and 100 cm ^{3 of} water is sealed in a tube and heated to 70 ° C. for 2.5 hours heated. The reaction mixture is concentrated and the residue is eliminated

η - hexane recrystallized, with 2 - methyl - 4 - ethylamino - 6 - methoxy - s - triazine of melting point 83 to 87 ° C is obtained.

Example 4

A mixture of 18.3 g of 2-methyl-4,6-diethoxys-triazine, 10.5 cm ^{3 of} a 30% strength aqueous methylamine solution and 100 cm ^{3 of} water is sealed in a tube and ^{heated to 70 °} C. for 3 hours. The reaction mixture is extracted with chloroform. The extract is dried with sodium sulfate and concentrated. After recrystallization of the residue from petroleum ether, 2-methyl-4-methylamino-6-ethoxy-s-triazine with a melting point of 92 to 95.degree. C. is obtained.

At s ρ i e I 5

A mixture of 18.3 g of 2-methyl-4,6-diäthoxys-triazine, 6,5 cm ³ of a 70% aqueous Äthylaminolösung and 50 cm ³ of water is sealed in a tube and kept for 3 hours at 70 to 80 ⁰ C. . The reaction mixture is concentrated and the residue is recrystallized from ligroin, 2-methyl-4-ethylamino-6-ethoxy-s-triazine having a melting point of 97 ° to 99 ° C. being obtained.

Claims (1)

Patent claims: 1. 2-Alkyl-4-alkylamino-6-alkoxy-s-triazines of the general formula of these compounds, which is characterized in that a compound is established in a manner known per se of the general formula II