DE1445665C - Derivatives of 2 (2 Morpholinoathylmer capto) pyridine compounds - Google Patents

Description

The invention relates to compounds of the general formula I.

The compounds of general formula I according to the invention are prepared by a compound of the general formula II

X-CH ₂ -CH ₂ -NHO

S-CH, -CH ₇ -N

O II

wherein R is a hydrogen or halogen atom and X is the group

S -

O O

\ f ■

- S -

means, and their salts as well as a process to their manufacture. .

in which R has the meaning given above, or ίο their salts, in a manner known per se with hydrogen peroxide or with potassium permanganate or peracetic acid or nitric acid is oxidized and, if desired, a base obtained is mixed with an acid . Salt transferred.

The compounds according to the invention are analytically effective.

The following table shows the analgesic effect and toxicity of the products of the process various applications, with the known commercial preparation N-methyl-1-phenyl-2,3-dimethyl-5-oxo-pyrazoline- (3) -yl- (4) -aminomethanesulfonic acid-sodium compared.

Mouse tail test 11; substance Lh H u ED ₅₀ Th *) mg / kg 1.1 opener ¹ ) tan Th mg / kg 5.1 intraperitoneally Th 1.8 LD ₅ ; ² ) mouse mg / kg intra orally 3000 4.6 subcu 1000 7.5 ED ₅₀ mg / kg ■ 4.9 orally subculan peritoneal N-methyl-1-phenyl-2,3-dimethyl-
5-oxo-pyrazoline- (3) -yl- (4) -ami-
sodium nomethanesulfonate - 750 - ED ₅₀ 181 5.8 1700 - (2-morpholino-ethyl) - [3-chloro-
pyridyl (2)] sulfoxide HCl 507 6.3 156 5.1 226 11.7 2200 (2-morpholino-ethyl) - [5-chloro-
pyridyI- (2)] sulfoxide-HCl 371 5.9 21 Γ. 12.6 133 9.4 4050 5200 1140 (2-morpholino ^: ethyl) - [6-chloro-
pyridyl (2)] suIfoxyd-HCl 710 4.9 250 12.0 111 8.5 3460 1310 - (2-morpholino-ethyl) -pyridyI-
(2) sulfoxide HCl '490 2.6 147 - 235 -. - 900 .1300 (2-morpholino-ethyl) - [3-chloro-
pyridyl (2)] sulfone HCl 535 6.8 - 8.6; 148 7.4 2320 980 2210 (2-morpholino-ethyl) - [5-chloro-
pyridyl (2)] sulfone HCl 339 6.1 153 9.9 - 9.5 4150 3130 1260 (2-morpholino-ethyl) - [6-chloro-
pyridyl (2)] sulfone HCl 1016 273 109 2430 1770 - (2-morpholino-ethyl) -pyridyl-
(2) sulfone HCl 218 1400 - 730 2100 1220 1985 4650 2390

*) Th = therapeutic range ¹ )

From the table it is apparent that the process products orally 3 to Ί-, parenterally even 4 to 19 times more analgesically potent than the comparative product Video- same applies door the therapeutic index (LD ₅₀ ZDE ₅₀₎ for oral and intraperitoneal administration at least Twice and a maximum of even six times the value of the reference substance. '

methodology
') Analgesic effect

The analgesic effect was tested in the mouse tail test according to Haffner (Deutsche Medizinische Wochenschrift, 55, [1929], p. 731). The dose was determined in mg / kg which produced an analgesic effect in 50% of the animals used (ED ₅₀ ). The substances were administered orally, subcutaneously and intraperitoneally.

² ) Toxicological test

The toxicity test was carried out on the mouse in several forms of administration (oral, subcutaneous, intraperitoneal) by determining the acute toxicity (LD ₅₀ in mg / kg) according to Miller and Tainter (Proc.Soc.Exper.Biol. And Med., 57, [1944 ], P. 261). Observation time: 24 hours.

³ ) Therapeutic breadth

The therapeutic index is the ratio of toxic to effective dose and is expressed by the factor LD ₅₀ ZED ₅₀ . The greater this factor, the greater the distance between the effective dose and the toxic dose, ie the better the tolerance of the compound.

The starting materials used according to claim 2 can according to the German Offenlegungsschrift 1 445 649 can be obtained.

example 1

48 parts 2- (2-morpholinoethylmercapto) pyridine (melting point of the hydrochloride 125 to 128 ° C) are dissolved in 250 parts of methanol and acidified to pH 4 with methanolic hydrochloric acid. so is heated to 50 ° C, and 23 parts of 35% hydrogen peroxide solution are added with stirring. It is then refluxed for 5 hours, then evaporated in vacuo and extracted from ethanol recrystallized. There are 42 parts of the monohydrochloride of (2-morpholinoethyl) pyridyl (2) sulfoxide receive. The melting point is 186 ° C.

Example 2

20 parts of 2- (2-morpholinoethylmercapto) -3-chloropyridine (melting point of the hydrochloride 181 ^° C.) are dissolved in 200 parts of methanol, acidified to pH 4 with hydrochloric acid and heated ^{to 50 ° C.} Then 8 parts of 35% strength hydrogen peroxide are added and the mixture is refluxed for 5 hours. After evaporation in vacuo, it is recrystallized from methanol. 19.5 parts of the hydrochloride of (2 - morpholinoethyl) - [3 - chloropyridyl (2)] sulfoxide are obtained. The melting point is 202 ^° C. (decomposition).

Example 3

50 parts of 2- (2-morpholinoethylmercapto) -3-chloropyridine are dissolved in 450 parts of glacial acetic acid and dissolved 40 ° C heated. Then 55 parts of potassium permanganate, dissolved in 500 parts of water, added in portions. The temperature rises in the process 65 ° C. The mixture is stirred for 1 hour and then suctioned off from the manganese dioxide formed Use of kieselguhr as a filter aid. The filtrate is destroyed with a little formic acid any permanganate that may still be present is added, made alkaline and extracted with benzene. The evaporated benzene solution gives 35 parts of crystalline base of ^ -Morpholinoäthyrj-P-chlorpyridyl- (2)] - sulfone, from which the hydrochloride precipitates in methanol with a melting point of 219 ° C will.

Example 4

Proceed as in Example 2 using 2- (2-morpholinoethylmercapto) -6-chloropyridine (Melting point of the hydrochloride 173 to 175 ° C), the hydrochloride of the corresponding sulfoxide is obtained which melts at 193 ° C.

Example 5

Is made using 2- (2-Morpholinoäthylmercapto) -6-chloropyridine Proceed as in Example 3, the corresponding sulfone, the hydrochloride of which melts at 211 ° C., is obtained.

B e i s ρ i e 1 6

By proceeding as indicated in Example 2, with 2 - (2 - Morpholinoäthylmercapto) - 5 - chloropyridine (melting point of dihydrochloride 223-225 ⁰ C), we obtain the corresponding sulfoxide, the hydrochloride melts at 216-218 ° C.

B e i s ρ i e 1 7

If you proceed as indicated in Example 3, with - (2 - Morpholinoäthylmercapto) - 5 - chloropyridine, this gives the corresponding sulfone, the hydrochloride of which melts at 237 to 240.degree.

Example 8

If the procedure is as in Example 3 using 2 - (2 - Morpholinoäthylmercapto) - pyridine, so the corresponding sulfone is obtained, the hydrochloride of which melts at 222 to 225 ° C.

Claims (2)

Patent claims: 1. Derivatives of 2- (2-morpholinoethylmercapto) pyridine compounds the general form 30th 35 mel I X-CH, -CH, -N in which R is a hydrogen or halogen atom and X is the group O or S - means and their salts. 2. Process for the preparation of compounds of general formula I and their salts, thereby characterized in that compounds of the general formula II S-CH, -CH, -N O II in which R has the meaning given above, or its salts, in a manner known per se with hydrogen peroxide or oxidized with potassium permanganate or peracetic acid or nitric acid and if desired converting an obtained base into a salt with an acid.