DE2023182C3 - 1 - (beta-acetoxyethyl) -5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2one derivatives - Google Patents

Description

N-C

CH ₂ (I)

in which R _{1 is} a halogen atom and R _{2 is} a hydrogen or chlorine atom, and their salts.

2. I - (/ f-AcetoxyethyO-S-phenyl-T-chloro-1,3-dihydro-2 H-I, ^ benzodiazepin ^ -one.

3. 1 - (β - acetoxyethyl) - 5 - (o - chlorophenyl) -7-chloro-1,3-dihydro-2 H-1, ^ benzodiazepin ^ -one.

4. Medicinal preparations consisting of a compound according to claim 1 and customary pharmaceuticals Carriers.

The invention relates to the subject matter characterized in the claims.

The benzodiazepines of the general formula 1 can be prepared by in itself known way either

(a) a benzodiazepine derivative not substituted in the 1-position of the general formula II

(b) a 2-aminomethylindole of the general formula III

(II)

in which R, and R _{2 have} the above meaning, alkylated with a reactive ester of / f-acetoxyethyl alcohol, or

Uli)

CH ₂ - NH ₂

in which R ₁ and R _{2 have} the meaning given above, or the salt thereof is treated in an acidic medium and in a solvent with chromic acid or ozone in at least a stoichiometric amount and, if appropriate, the obtained

tene compound by reacting with an inorganic or organic acid into a salt convicted.

The compounds of general formula 1 and their pharmacologically acceptable salts are valuable Medicines, especially excellent tranquilizers, sedatives, muscle relaxants, and antispasmodics. The compounds potentiate the effects of hexobarbital.

Examples of the reactive esters of / i-acetoxyethyl alcohol are the hydrohalic acid esters, such as the chlorides, bromides and iodides, as well as the Sulfonic acid ester, ζ. B. the methanesulfonate, p-toluenesulfonate, / ϊ-naphthalene sulfonate and trichloromethanesulfonate. In the alkylation reaction, a compound of the general formula II with the reactive ester of / f-acetoxyethyl alcohol in The presence of a base can be brought to react. You can also first connect the general formula II with a basic metal salt to form the corresponding metal salt bring the compound of general formula II to the reaction and then this with a reactive ester of 0-acetoxyethyl alcohol let react. Examples of bases that can be used are alkali metal hydrides, such as sodium hydride or Lithium hydride, alkali metal hydroxides such as potassium hydroxide, alkali metal amides such as sodium amide, potassium amide or lithium amide, alkali alkyls such as butyllithium, phenylalkali compounds such as phenyllithium. Alkali metal alcoholates, such as sodium methylate, sodium ethylate or potassium tert-butylate.

The alkylation reaction is generally carried out in an organic solvent or mixture of solvents. Examples of suitable solvents are benzene, toluene, xylene, dimethylformamide, dimethylacetamide, diphenyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide, methyl ethyl ketone, N-methylpyrrolidone and mixtures thereof. The reaction can be carried out at temperatures from about room temperature to the boiling point of the solvent used.
According to procedure (b) the 2-amino ·

IO

w- uryiuiui "of the general formula HI or its ffijz treated with chromic acid or ozone. Examples of the salts that can be used in accordance with the process are the hydrochlorides, hydrobromides, sulfates or phosphates. In general, the oxidation reaction proceeds smoothly

f! temperature. The reaction temperature can also be higher or lower, e.g. B. from 0 to 100 ° C or at the boiling point of the solvent used, preferably from 10 to 60 ⁰ C, are. The reaction temperature depends on the type of oxidizing agent used. The type of solvent used also depends on the type of oxidizing agent. Examples of suitable solvents are water, acetone, carbon tetrachloride, formic acid, acetic acid and sulfuric acid. W 'When using chromium trioxide in acetic acid are preferably used Ntfs Oxidatiossmittel E, the 2- to 3-fold stoichiometric amount of Chromfcoxid and * ^{"ηΓΐ the} V ^{IMPLEMENTATION} **' room temperature by the 2-Aminomethylindol or its salt is dissolved in the solvent or suspended and When using ozone as the oxidizing agent, the reaction is preferably carried out at room temperature. The 2-aminomethylindole is dissolved or suspended in a solvent such as formic acid or acetic acid, and ozone-containing oxygen is introduced into the solution or suspension with stirring .

The resulting benzodiazepine can from ocm The reaction mixture can be separated off by extraction, if appropriate after prior neutralization. The extract is then evaporated to dryness. The product can be obtained by recrystallization from a solvent such as ethanol or isopropanol, further purified in the usual way.

The free bases of the general formula I form with pharmacologically acceptable inorganic ones and organic acids salts. Examples of these acids are; Hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, nitric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, Succinic acid, citric acid, camphor sulfonic acid, ethanesulfonic acid, ascorbic acid and lactic acid.

In order to demonstrate the superior effect of the compounds of the invention, the following compounds were used examined:

a) Compounds according to the invention

Connection A:

l - (/ i-Acetoxyethyl) -5- (o-chlorophenyl) -7-chloro-1,3-dih ydro-2 H -1,4-benzodiazepin-2-one.

Connection B:

30th

35 Test methodology a) Antipentamethylene tetrazole ester

This test was found to be a very sensitive measure of the depressant effects of 1,4-benzodiazepines uses the central nervous system.

The suppression of convulsions produced by pentametnylenetetrazole was performed on groups of ten male albino mice weighing 20 ± 2 g in seven different doses by the method of EA Swinyard, J. Amer. Pharm. Assoc. (Sci. Ed.), Vol. 38 (1949), pp. 201-204. Thirty minutes after the oral administration of the compound to be examined, the mice were given 65 mg / kg of pentamethylenetetrazole intravenously. The ED ₅₀ was calculated using probit analysis, taking into account both convulsive suppression and deaths.

b) Maximum electric shock test (MES test)

This test was used as a measure of the anticonvulsant activity of a compound.

Maximum electric shock shocks were generated by electrical discharges (25 mA, 0.15 seconds) through the corneal electrodes according to the method of Swinyard and coworkers (J. Pharmacol. Exp. Ther., Vol. 106 [1952], pp. 319 to 330) induced. Each group of test animals consisted of ten male albino mice with a body weight of 20 ± 2 g. The compound to be tested was administered orally in seven different doses. The number of mice which lost the tonic phase of convulsions with maximum electric shock was determined. The ED ₅₀ , ie that dose which suppresses the beat in 50% of the animals, was calculated by probitanaiysis.

45

c) torsion bar test

This test was used as a measure of muscle relaxant effect and coordination activity.

The device used had a horizontal rod 3 cm in diameter rotating at a speed of 7 rpm. Each test group consisted of ten male albino mice with a body weight of 20 ± 2 g. For the experiments, those animals were selected that could hold on to the torsion bar. The ED ₅₀ , that is the dose at which 50% of the animals could not hold on to the torsion bar, was calculated by probit analysis.

1 - (ß - acetoxyethyl) - 5 - phenyl - 7 - chlorine -1,3 - dihydro -2 H-1 ^ -benzodiazepin ^ -one.

b) Known connection

Chlordiazepoxide:

2-methylamino-5-phenyl-7-chloro-3H-1,4-benzodiazepine-4-oxide.

60 d) Acute toxicity

The acute toxicity was determined in groups of ten mice with a body weight of 20 ± 2 g in three different doses. The LD ₅₀ 65 is that dose of a compound which kills 50% of the animals to be examined 10 days after oral administration.

The results are shown in Table I.

Table I.

Test ver Anti-penta MES test Torsion bar test Acute LD ₅₀ / X LD ₅₀ / Y LD ₅ binding methylene ED ₅₀ (p. Ο.) ED ₅₀ (po) Toxicity, LD ₅₁ , tetrazole test Ip- ο.) ED ₅₀ (po) mgÄg mg / kg mgAg mg / kg PC) (Y) (Z) A. 0.5 10 5.0 2000 4000 200 400 B. 0.8 8th 4.5 1800 2250 225 400 Diazepara 1.0 12th 2.7 680 680 57 252 Oxazepam 2.4 21 9.0 1700 708 81 189

From TabeJJe, it can be seen that the compounds of the invention have more favorable therapeutic ratio than the known compounds.

In the same way, the following compound known from US Pat. No. 3,391,138 was more analogous Structure examined and compared to the compounds of the invention:

Connection C:

1 - (fi - ethoxyethyl) - 5 - phenyl - 7 - chlorine -1,3 - dihydro-2H-1,4-benzodiazepin-2-one (LD ₅₀ , mouse, po 1200 mg / kg).

The results are summarized in Table II: Table II

Test connection Anti-penta MES Tesl Torsion bar test methylene ED ₅₀ ED ₅₀ tetrazole (P-o.) (P-O.) Test ED ₅₀ (P- o.) (mg / kg) (mg / kg) (mg / kg) Connection A 0.5 10 5.0 Connection B 0.8 8th 4.5 Compound C 5.5 47 35 (Comparison)

From the table it can be seen that the compounds of the invention correspond to the known compounds are superior to analogous constitution.

The benzodiazepines or their salts can be administered parenterally or orally in the usual therapeutic forms, z. B. in the form of tablets, coated tablets, capsules, suspensions, solutions or elixirs, administered.

The examples illustrate the invention.

example 1

A solution of 2.2 g of 5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 60 ml of dimethylformamide is added dropwise to a suspension of Ig sodium methylate in 15 ml of dimethylformamide given with cooling and stirring. The mixture is stirred for 1 hour at 50 to 60 ° C and then cooled. Thereafter, the mixture is below 10 ° C dropwise with a solution of

2 ml / y-acetoxyethyl bromide in 10 ml of anhydrous toluene are added. After 30 minutes of stirring, the mixture is heated for 15 hours 70 to 80 ⁰ C and stirred. The reaction mixture is then cooled, poured into ice water and extracted with ether. The combined ether extracts are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent is then distilled off under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel and eluted with chloroform. A syrup is obtained which crystallizes after the addition of ethanol. After recrystallization from ethanol, 1- (ß-acetoxyethyl) -5-phenyl-7-chloro-1,3-dihydro-2 H-1,4-benzodiazepine is obtained -2-one in the form of colorless prisms, melting at 102-103 ⁰ C. The hydrochloride is obtained in the usual manner with an ether solution of hydrogen chloride. After recrystallization from a mixture of methanol and acetone, the colorless prisms melt at 193 to 195 ° C with decomposition.

Example 2

According to Example 1, but using 5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 1 - (/ ϊ-acetoxyethyl) -5- (o-chlorophenyl is obtained ) -7-chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one from 120 to 523 ° C.

B e i s ρ i e 1 3

According to Example 1. but using

Sodium hydride instead of nitrium methylate, one obtains the H / if-AcetoxyäthylVS-phenyl ^ -chlor-l ^ -dihydro-2H-1,4-benzodiazepin-2-one with a temperature of 102 to 103 ^° C.

Example 4

A solution of 1 g of chromium trioxide in 1 ml of water is added to a mixture of 1 g of l - (/? - Acetoxyethyl) -2-aminomethyl-3-phenyl-5-chloroindole hydrochloride and 20 ml of acetic acid. The mixture is stirred for 15 hours at room temperature, then diluted with water, made alkaline with aqueous ammonia solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and evaporated. The residue is taken up in chloroform at siUVurroi ^ u ™ ~ "t ~

graphed and eluted in chloroform. The 1 - (/ f-acetoxyethyl) -5-phenyl-7-chloro-1,3-di- • hydro-2H-1,4-benzodiazepin-2-one with a melting point of 102 to 103 ^° C. is obtained Hydrochloride is produced in the usual way with an ethereal solution of hydrogen chloride and from a mixture of methanol and acetone

recrystallized. The colorless prisms melt at 193 to 195 ° C with decomposition.

The following compound is prepared in a similar manner: 1 - (ji - acetoxyethyl) - 5 - (o - chlorophenyl) -7 - chi or -1,3 - dihydro - 2 H -1,4 - benzodiazepin - 2 - one, F. 120 to 123 ⁰ C.

Claims (1)

Patent claims: 1. 1 - (/ i-AcetoxyethyO-S-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula I. CH, IO