DE1445677C - Acylaminopyndine - Google Patents

Description

N - CO - R ³

The invention relates to acylaminopyridines of the general formula I.

in which R ^{1 is} either a chlorine atom or a methyl group, R ^{2 is} either a hydrogen atom or a methyl group and R ^{3 is} either an ethoxy or methylamino group, as well as their acid addition salts.

2. Process for the preparation of acylaminopyridines according to claim 1, characterized in that that in a known manner either

a) a compound of the general formula II

NH

C ₂ H ₄ -N (C ₂ Hs) ₂

with ethyl chloroformate in the presence of an organic solvent and, if necessary, in the presence of an acid-binding agent, or
b) a compound of the general formula III

N - COR ³

(III)

N-COR ³ -

CH ₂ - CH ₂ - OH

60

₆₅

converts, in this the hydroxyl group through

in which R ^{1 is} either a chlorine atom or a methyl group, R ^{2 is} either a hydrogen atom or a methyl group and R ^{3 is} either an ethoxy or methylamino group, their acid addition salts and a process for their preparation.

These new compounds show a strong anti-inflammatory effect with therapeutic indices, which are higher than those of the well-known 3,5-dioxo-1,2 - diphenyl - 4 - η - butyl - pyrazolidine. This mode of action was surprising because the previously known similarly built connections, for example 2- (2-diethylamino-ethylamino) -pyridine acylated by substituted benzoic acid, picolinic acid and nicotinic acid Antihistamine effect or the 2- (2-diethylamino-ethylamino) -pyridines acylated by phenylacetic acid show a hypnotic and analgesic effect.

The following table shows the pharmacological action of the compounds according to the invention:

40
example LD ₅₀
mouse
intra-
peritoneal mg / kg
rat
. per os. edema-
inhibiting
in % 45 1. 200
275 325
235 52
51
36 2: Phenylbutazone ..

50

condensed with an ester of / 3-diethylamino-ethanol in the presence of a condensing agent and a solvent or
c) a compound of the general formula III with a / S-haloethyl alcohol to form a compound of the general formula IV

methodology

The test for anti-inflammatory effects was carried out on the protein edema of the rat paw at a dose of 300 mg / kg orally according to the method of Domenjoz and coworkers, compare Arch. Exp. Pharm. Path., 230 (1957), p. 325. The anti-inflammatory effect is as edema inhibition in percent compared to the untreated Control group indicated.

toxicity

The oral mean acute toxicity in the white mouse was determined according to the international test arrangement (cf. Miller and Tainter, Proc. Soc. Exper. Biol. A. Med., 57 [1944], p. 261) with an observation time of 24 Hours. The toxicity is given as LD ₅₀ in mg / kg. The LD ₅₀ is that dose which leads to death in 50% of the animals used.

The preparation of the new compounds takes place in a manner known per se by either

a) a compound of the general formula II R ²

(Π)

IO

in which R ¹ and R ^{2 have} the above meaning, with ethyl chloroformate in the presence of an organic solvent and optionally in the presence of an acid-binding agent or
b) a compound of the general formula III

N - COR ³

(III)

in which R ¹ , R ² and R ^{3 have} the above meaning, condensed with an ester of / J-diethylaminoethanol in the presence of a condensing agent and a solvent or c) a compound of the general formula III with a / 5-halogenoethyl alcohol to form a compound of general formula IV

N - COR ³

CH ₂ - CH ₂ - OH

(IV) The used starting substances of the general Formula II can, for example, according to F. C. W h i tm o r e and coworkers (cf. Am. Chem. Soc, 67 [1945], p. 393), by reacting an aminopyridine with an aminoalkyl halide in the presence from sodium in an inert solvent.

The starting materials of the general formula III are obtained by reacting a corresponding aminopyridine obtained with an acid halide in a solvent in the presence of acid-binding substances. In the event that the acyl radical is a carbamoyl group, the starting compound can also can be obtained by reacting the aminopyridine with an isocyanate.

The compounds according to the invention prepared in this way can be in the form of the free base or as Acid addition salts, for example as fumarates, maleates, salicylates and hydrochlorides, can be isolated.

B ice ρ iel 1

6-methyl-2- (N-carbethoxy-2-diethylamino-ethylamino) pyridine hydrochloride

30th

35

40

reacts, in this the hydroxyl group is replaced by a halogen atom and then with diethylamine lets react

and optionally converting the free bases obtained in this way into their acid addition salts.

In process route a) can be used as acid-binding agents such. B. Sodium hydroxide, potash, soda, pyridine, Triethylamine, diethylaniline or tributylamine and as a solvent z. B. ether, tetrahydrofuran, Chloroform, benzene or dioxane can be used.

Among the condensing agents that are suitable for route b) are, for. B. pyridine, sodium alcoholate, Sodium amide, potassium hydroxide or potash should be mentioned.

To carry out route c), the corresponding esters of / 3-diethylaminoethanol are used Halides, especially the chlorides, are preferred. The replacement of the hydroxyl group with a chlorine atom can be done, for example, with thionyl chloride.

CO ₂ C ₂ H ₅

N-CH ₂ - CH ₂ - N (C ₂ Hj) ₂ • HCl

10 g of 6 - methyl - 2 - (2 - diethylamino - äthylamino) pyridine are dissolved in 150 ml of absolute ether and a solution of 6 g of ethyl chloroformate in 150 ml of absolute ether is added. After 2 hours is filtered off and recrystallized from dioxane. The substance melts at 142 to 143 ° C. Yield 80% the theory.

Example 2

5-chloro-2- (N-methylcarbamoyl-2-diethylaminoethylamino) pyridine hydrochloride

45

CO -NH-CH ₃

N - CH ₂ - CH ₂ - N (C ₂ Hs) ₂ • HCl

50gN- [5-chloro-pyridyl- (2)] - N'-methyl-urea (prepared by reacting 5-chloro-2-aminopyridine with ethyl chloroformate and heating the reaction product with methylamine solution) are dissolved in 1.5 l of hot toluene , 21 g of 50% sodium amide suspension were added dropwise, the mixture was boiled for 1 hour, then an ethereal solution prepared from 50 g of diethylaminoethyl chloride hydrochloride was added and the mixture was refluxed for a further 5 to 6 hours. After cooling, a precipitate (starting material) is filtered off with suction, the filtrate is extracted by shaking with 7% hydrochloric acid, neutralized with ammonia and this solution is extracted with chloroform. After the chloroform has been distilled off, the hydrochloride is prepared from the residue with alcoholic hydrochloric acid and recrystallized first from isopropanol / acetone and then from dioxane. The substance melts at 160 ^° C. Yield 25 g.

Example 3

N- [4,6-Dimethyl-pyridyl- (2)] - N- (2-diethylaminoethyl) carbonic acid ethyl ester amide hydrochloride

CH

CH ₂ - N (C ₂ Hs) ₂ • HCl

To a solution of 22.1 g of 2- (2-Diäthylaminoäthylamino) 4,6-dimethyl-pyridine in 300 cm ³ of absolute ether, the solution of 9.5 cm ³ of ethyl chloroformate in 300 cm ³ of absolute ether is added. After standing for 24 hours, it is filtered off with suction and recrystallized first from dioxane, then from benzene / gasoline and finally from butyl acetate. Mp 115-116 ° C. Yield 50%.

Example 4

N- [6-chloro-pyridyl- (2)] - N- (2-diethylamino-ethyl) carbonic acid ethyl ester amide hydrochloride

.QO ₂ C ₂ H ₅ ! ., ·.

N-CH ₂ - CH ₂ - N (C ₂ Hs) ₂ • HCl

To a solution of 22.7 g of 6-chloro-2- (2-diethylamino-ethylamino) -pyridine (prepared from 6-chloro-2 - amino - pyridine and 2 - diethylamino - ethyl chloride in the presence of NaNH ₂ ) in 300 m ³ ethers, the solution of 9.5 cm ^{3 of} ethyl chloroformate in 300 cm ^{3 of} ether is added. After standing for 24 hours, it is filtered off with suction and recrystallized from dioxane. Mp 146-147 ° C. Yield 70%.

Claims (1)

i 445 Patent claims:
1. Acylaminopyridines of the general formula I replaced a halogen atom and then allowed to react with diethylamine and optionally converting the free bases obtained in this way into their acid addition salts.