DE1795858C2 - Benzylaminopyridines - Google Patents

Description

O ₇ N

Y \

H ₂ N NH CH

R, (H)

R,

in which Ri and R _{2 have} the above meaning, the nitro group is reduced to the amino group and the C ₂ HsOCO-ReSt is introduced into the amino group thus obtained and the compound thus obtained is optionally converted into an acid addition salt.

O ₂ N

H ₂ N

(Ul

40

The invention relates to the subject matter characterized in more detail in claims 1 and 2.

The compounds according to the invention are therapeutically valuable substances, in particular have good anti-inflammatory and analgesic activity.

The compounds according to the invention are prepared by using a method known per se Way in a compound of the general formula II

■ Ti

example 1

2-Am! No-3-carbethoxyammo-6- (p-f! Uorbenzylamino) pyridine

NH-COOC ₂ H ₅

CH ₂ -NH

NH ₂

26.2 g (0.1 mol) of 2-amino-3-nitro-6- (p-fIuorbenzy! Amino) pyridine are treated with 15 g Raney nickel in 250 ml of dioxane at 50 ⁰ C. and from 30 atm of the 10.8 ml (0.13 mol) of ethyl chloroformate are added with stirring, the hydrochloride crystallizing out after about 15 minutes. This is filtered off with suction and recrystallized _{from H 2 O.}
Yield: 19 g;
Hydrochloride temperature 214-215 ° C.

Example 2

d-2-Amino-3-carbethoxyamino-6- (1,2-diphenylethylamino) pyridine

JO X-CH,

NH-COOC ₂ H ₅

<ζ / -CH NH NH,

29 g of d-2-amino-3-nitro-6- (1,2-diphenylethylamino) pyridine are hydrogenated with 15 g of Raney nickel and 40 g of magnesium sulfate in 450 ml of dioxane in an autoclave at 50 ^° C. and 40 atm. The hydrogenation solution is freed from the catalyst and drying agent and reacted with 10 g of ethyl chloroformate. After 30 minutes, 1.5 liters of an ether / gasoline mixture (1: 1) are added to the solution. The syrupy precipitate which separates out is dissolved in 200 ml of methanol, neutralized with ammonium hydroxide solution and the base is shaken out with 500 ml of ether. A solution of 12 g of 1-mandelic acid in isopropanol is added to the ethereal solution of the base. The salt crystallizes when rubbing and adding petrol.
Yield: 30 g;
F. of the i-mandelic acid salt 134 ° C. [Α]; * + 3.5 °.

Example 3

2-Amino-3-csrbethoxyamino-6- (1-p-fluorophenyl-2-phenylethylamino) pyridine

NH CH

CH ₂

CH NH

Nil COOC ₂ H,

NH,

47 g of 2-amino-3 ^ nitn> 6- (1 * p-fluorophenyl-2 "phenyl

in which Ri and R _{2 have} the above meaning, the äthylamino) -pyndin are reduced to the amino group with 15 g of Raney nickel and nitro group and in the so 65 40 g of magnesium sulfate in 450 ml of dioxane in the autoclave with the amino group obtained the C ₂ HsOCO- ReSt introduces 50 ⁰ C and 40 atm hydrogenated. The hydrogenation solution is freed from and, if appropriate, the compound thus obtained in a catalyst and desiccant and transferred with 15 ml of acid addition salt. Ethyl chloroformate added while stirring

After 30 minutes, the solution is mixed with 1.51 ether / gasoline mixture (1: 1). The solution is decanted off from the syrupy precipitate which separates out. The syrupy precipitate is dissolved in 200 ml of methanol, neutralized with ammonium hydroxide solution and the base extracted with 500 ml of ether. The organic phase is washed three times with water; the desired product separates out in crystalline form. It is filtered off with suction and recrystallized from n-propanol / dioxane.
Yield: 10 g;
F. 88 -89 ° C.

Example 4

2-Amino-3-carbethoxyamino-6- (o-methoxybenzylamino) pyridine

NH-COOC ₂ H ₅

Il

CH, NH

NH ₁

OCH,

NH COOCH,

Il

CH ₂ NH

NII,

41 g of 2-amino-3-nitro-6- (o-methoxybenzyIamino) pyridine are hydrogenated in 300 ml of dioxane with Raney nickel as in Example 3 and the Raney nickel solution is treated with 16 g of ethyl chloroformate while stirring. After 30 minutes, ether and gasoline (1: 1) are added to the solution until it becomes cloudy. The hydrochloride of the desired compound gradually crystallizes out. After 2 hours, it is filtered off with suction and recrystallized from methanol.
Yield: 24 g;
F. of the Hydrochloride 153-155 ° C.

Example 5

2-Amino-3-carbethoxyamino-6- (m-methoxybenzyl-amino) -pyridine

OCH,

38 g of 2-amino-3-nitro-6- (m-methoxybenzylamino) pyridine are hydrogenated in 300 ml of dioxane with Raney nickel as in Example 3 and the Raney nickel solution is reacted with 16 ml of ethyl chloroformate while stirring. The precipitated hydrochloride is recrystallized from ethanol.
Yield: 40 g;
F. of the hydrochloride 180 - 18Γ C.

Example 6

2-Amino-3-carbethoxyamino-6- (2,4-dimethoxybenzylamino) pyridine

NH-COOCH,

/ sy

OCH.,

CH ₁ O

NH ₂

45 g of 2-amino-3-nitro-6- (2,4-dimethoxybenzyIamino) -pyridine are hydrogenated in 300 ml of dioxane with Raney nickel as in Example 3 and the Raney nickel solution with stirring with 16.5 ml of ethyl chloroformate The reaction solution is mixed with 1 liter of ether / gasoline mixture (1: 1), the syrupy precipitate is dissolved in 150 ml of HiO and acidified with 2 ml of concentrated HCl. The hydrochloride. the desired compound crystallizes out in pure form and is filtered off with suction and dried.
Yield: 22 g;
F. 89-90 ° C.

Test report

methodology
a) Antiphlousic effect

The compounds according to the invention were tested on the carrageenin edema of the rat paw by the method von Domenjoz and co-workers, see Arch. exp. Pharm. Path., 230, p. 325 (1957) to anti-inflammatory Checked effect. The anti-inflammatory effect is given as ED50. It was in all attempts applied orally.

b) Analgesic effect

The analgesic effect was determined in the Haffner mouse tail test, see German Medical Wochenschrift, 55, J. 731 (1929). The dose was determined in mg / kg for 50% of the animals used produced a clear analgesic effect (ED ™). The substances were administered orally.

c) toxicity

The oral toxicity on the white mouse was determined in the international test arrangement according to Miller and Tainter, see Proc. Soc. Exper. Biol. A. Med. 57. p. 261 (1944), with an observation time of 2+ hours. The toxicity is called LD ™ given in mg / kg. The LD ™ is the dose which leads to death in 50% of the animals used.

The well-known commercial preparation Phenacelin was used as a comparison substance with the same direction of action chosen. The results are given in the following table:

link OhifTre Anliphlo Anal- To \ i / ital Therapy after gislischc gelische LDs ₁ , lische Brcilc Hot example effect effect mouse Door anal ED50 per os HafTncr-Tcst pel 'os gctische ED50 per os effect LDjo / EDs « I. D 9 998 54 25th 870 35 2 D 10591 US " 13th 312 24

5 17th 95 858 Toxicity Fil 6th Therapeu LD ₅₁₁ table width continuation ChilTre mouse for annl- link Anliphlo ΛπηΙ- per os table well gistic getjsche effect example effect effect LD _{ä ()} / ED _sll EP ₅₀ per os HafTner test 760 30th ED5 (| per os 910 9.3 D 10 527 490 5.2 3 D 10 081 8.4 25th 790 7.9 4th D 10 082 40 98 1740 2.5 5 D 10 250 32 94 6th 42 100 Phenacetin 170 700

Claims (2)

Patent claims:
1, Benzylaminopyridines of the general formula I. C ₁ H ₅ OCO-HN R, (I) H ₂ N NH-CH in in which either Ri is a hydrogen atom and R _{2 is} a 4-fluorophenyl radical or Ri is a hydrogen atom and R _{2 is} a 2-methoxyphenyl radical or Ri is a hydrogen atom and R _{2 is} a 3-methoxyphenyl radical or Ri is a hydrogen atom and R _{2 is} a 2,4- Dimethoxyphenyl radical or Ri a phenyl radical and R ₂ a benzyl radical or Ri a 4-fluorophenyl _{radical in and R 2} a benzyl radical and their acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se in a compound r> of the general formula II