DE2001128C3 - - Google Patents

Description

Substituted glycidamides have been known for many years, but only a few 2-phenylglycidamides have emerged described in the literature, and so far only the 3-methyl-2-phenylglycidamide and the 2,3-Diphenylglycidamide (Murray et al. J. Am. Chem. Soc. 56, page 2749 (1934) ^

It has now been found, surprisingly, that the / Msomer of 3-chloro-2- (2,4-dichlorophenyI) -glycidamide Has a depressant effect on the nervous system, which is why this substance is an advantageous active ingredient for pharmaceuticals with a hypnotic, sedative or antispasmodic effect.

According to the invention, the new 2-phenylglycidamide derivative can be obtained by dehydrochlorinating 2,4-dichloro-2- (dichloromelhyl) mandelic acid amide by reacting this compound with sodium hydroxide, sodium methoxide or sodium hydride. This 2,4-dichloro-2- (dichloromethyl) mandelic acid amide can easily be prepared by hydrolysis of the corresponding 2,4-dichloro (dichloromethyl) -mandelonitrile with 80 to 95% strength sulfuric acid at temperatures of about 80 to 110 ⁰ C, preferably about 95 ° C. The nitrile can in turn be prepared in a known manner by reacting 2,2,2 ', 4'-tetrachloroacetophenone with hydrogen cyanide in the presence of a small amount of potassium cyanide as a catalyst, while the 2,2,2', 4'-tetrachloroacetophenone after various processes can be obtained in a conventional manner, e.g. B. by the well-known Friedel-Crafts acylation of m-dichlorobenzene with dichloroacetyl chloride.

The 2-phenylglycidamide derivative which can be prepared in the manner indicated is obtained in two geometrically isomeric forms. For the purposes of the invention this isomeric pair has to be separated. The jS isomer makes up the largest part of the Mixture of isomers. It melts lower and has longer chromatographic retention times on silica gel G as the «isomer.

The invention is further illustrated by the following example explained. In the preparation example, parts are by weight unless otherwise stated. the Elemental analyzes are also based on weight.

example

(a) 2,4-dichloro-α- (dichloromethyl) mandelonitrile

There were 202 parts of 2,2,2 ', 4'-tetrachloroacetophenone,

obtained from m-dichlorobenzene and dichloroacetyl chloride according to Friedel-Crafts, in 80 Parts by volume of liquid hydrogen cyanide dissolved at 15 ° C

Cl

Calculated for C ₉ II ₅ Cl ₄ NO 4.9 49.8%

Rounding 5.2 50.0%

(b) 300 parts of the nitrile obtained from step (a) in 1000 parts by volume of 80% strength sulfuric acid were used for 16 hours Heated on a water bath, cooled and poured over ice. The gummy precipitate obtained was dissolved in methylene chloride, dried and cooled. There were 258 parts of 2,4-dichloro- <x- (dichloromethylmandic acid amide from 1 ". 155 to 137" C. The compound was identified by infrared spectroscopy.

(c) To a stirred suspension of 2.4 parts of 50% sodium hydride washed with hexane in Mineral oil in 50 parts by volume of anhydrous tetrahydrofuran was at once a solution of 15 parts of the Amide from step (b) was added in 100 parts by volume of anhydrous tetrahydrofuran. An exotherm occurred Reaction with evolution of hydrogen and formation of a lingering precipitate. The reaction mixture was stirred for 6 h, poured into water and extracted with ether. The ether extracts were made with water washed, dried over anhydrous magnesium sulfate and freed from the solvent. there has been a yellow viscous liquid obtained. Recrystallization from methylene chloride / hexane turned 6 parts white Crystals with a melting point of 115 to 121 ° C were obtained. The connection contained a mixture of two isomers in the ratio 6: 1. The chromatographic separation of the mixture with subsequent recrystallization gave 3.1 parts of the ^ -isomer (melting point 122 to 123 ° C.) and 0.4 parts of the α-isomer (mp 170 to 171.5 ° C) of 3-chloro-2- (2,4-dichlorophenyl) glycidamide. The compounds were determined by elemental analysis and infrared spectroscopy identified.

(d) To a stirred solution of 60.6 parts of the amide from step (b) in 175 parts by volume of anhydrous Methanol was added dropwise to a solution of 10.8 parts of sodium methoxide in 100 parts by volume of anhydrous Methanol added. The resulting solution was stirred at room temperature for 6 hours and overnight ditched. The reaction mixture was in water

N Cl ί Calculated for C ₉ H ₆ CI ₁ NO ₂ 5.3 39.9% I.
I. Found for isomer (ß)
M.p. 122-123 C 5.3 39.7% Found for isomer (a)
^Wl F. 170-171.5 C 5.3 39.7%

poured and extracted with methylene chloride. The extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent evaporated. A crude mixture of the two isomers from step (f) was obtained, which was chromatographed and recrystallized. There were 343 parts 0-lsomeres obtained, mp 122 to 124 "C and 1.7 parts α-isomer, mp 1694-170 C ^0, and the identification was performed by nuclear magnetic resonance spectroscopy and by infrared spectroscopy.

Calming effect on the nervous system

The soporific effect of the glycidamide according to the invention was initially determined as follows were 500 mg of the test compound per kg of body weight of the test animals on mice by means of a Tube administered orally. The animals were observed after 15 min, 1 h, 2 h, 4 h, and 24 h Toxicological Signs, particularly the onset and cessation of loss of direction, were observed in recorded in the animals. For comparison, the substance was then injected intraperitoneally, two known hypnotics being used as comparison substances, namely

Table I.

Glutethimide and sodium pentobarbital were used. The results of the tests are shown in Table I. specified.

In addition to the hypnotic effect, the new ·> 2 / Msomeres also have other calming effects on the nervous system. This includes a lower one Sedative effect, as can be seen from the experiment according to Wilfon, J.G. et al. in Fed. Proa, 19, p. 20 (1960) about the damage to the cleaning instinct

κι In addition, the compound shows a relaxation effect on the skeletal muscles, as is evident from the antagonistic effect against a fatal intravenous injection of strychnine sulfate and also from the Antagonism against an overdosed electrical

i "j shock according to the experiment by Swinyard, E.A. in J. Am. Pharm. Assoc 38. page 20! (1949) gives Die Results of these tests are listed in Table II, with the two comparison compounds at the same time Gluiethimide and sodium pentobarbital are also different

.'o give are. The data show that the 2 / msomer is more effective and also has a greater safety factor, i.e. a higher value for the therapeutic index LDs ₀ : EDw than the two comparison compounds.

Trial connection Oral administration Dose, Lcthalc dose, hypnotic mg / kg (approx.) 62 mg / kg (approx.) 180 2j8 isomer 500 125 Glutethimide 560 Pentobarbital Na 500

Hypnotic effect with intraperitoneal application with 180 mg / kg ¹ )

') In test groups of lO mice, hypnosis showed:

+ = 1-2 mice, + f = 3-6 mice, + + + = 7-9 mice and + · (- ++ = 10 mice. ² ) At 100 mg / kg instead of 180 mg / kg and based on the mean response of 11 groups of

ever plumb. ') All mice died in this test series.

Table Il Smaller ones
effect
EI) ₅₀
(mg / kg) Calming
Lp.
LD ₅₀ /
ED ₅₀ Antistrychnine
effect i.p. mg / kg
IiD ₅₀ LD ₅₀ /
(mg / kg) ^EI) 50 21
7.5
3.3 Maximum
i.p. mg / kg
ED ₅₀
(mg / kg) Electric shock
LD ₅₀ / Ip LD ₅₀
^EI) 50 mg / kg 510
560
130 Trial connection 36.5
> 100
> 56 14th
<5.6
<2.3 24.7
75
39 24.7
39 21
}, 3 2 / Msomeres
Glutethimide
Pentobarbital Na

Claims (3)

Patent claims: 1. / Msomer of 3-chloro-2- (2,4-dichlorophenyl glycidamide. 2. Process for producing the glycidamide compound according to claim 1, characterized in that the 2,4-dichloro-2- (dichloromethyl) -mandelic acid zmide dehydrochlorinated in a known manner 3. Use of the glycidamide compound according to claim 1 together with pharmacologically acceptable Carrier material as an active ingredient for pharmaceuticals. and with 15 drops of freshly made potassium cyanide solution treated A violent exothermic reaction occurred, with the hydrogen cyanide boiling under reflux. After 15 minutes under reflux, 100 parts by volume of ether and 4 parts by volume of concentrated sulfuric acid were added added ether and excess hydrogen cyanide were removed by distillation. The solid obtained The substance was recrystallized from hexane: benzene (19.1). 187 parts of 2,4-dichloro-oc- (dichloromethyl) mandelonitrile were obtained obtain. The compound was a white substance, mp 93 to 95 ° C. It became identified by elemental analysis