NO138089B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BENZODIAZEPIN DERIVATIVES - Google Patents

Description

This invention relates to the preparation of new 1-aryl-3H-1,4-benzodiazepine-2,5'-(1H,4H)-diones with the general formula

In this formula means:

R, a phenyl residue, which is optionally substituted in o-, m- or p-

position with a fluorine, chlorine or bromine atom or with a trifluoromethyl or nitro group, and

1*2 a fluorine, chlorine or bromine atom or a trifluoro

methyl, nitro, amino, cyano or hydroxy group.

The new compounds are produced according to the invention

a) by cyclization of a compound with the general formula

where

and R has the above meaning, and

R means a hydroxy, O-tosyl or lower acyloxy group or

a halogen atom, preferably a lower alkoxy group;

b) by oxidation of a compound with the general formula

where

R^ and R^ have the meaning indicated above.

The cyclization according to reaction a) is carried out using common inert solvents, e.g. a lower alcohol, ethyl acetate, tetrahydrofuran, dimethylacetamide, optionally with the addition of a condensing agent such as sodium methylate, sodium bicarbonate or triethylamine, and optionally with heating.

One can then either proceed from an isolated connection with

the general formula II, or the amino compound of formula II

which is formed according to the equation

can be subjected to ring closure without prior insulation.

In this equation, X generally stands for a nucleophobic group which can easily be replaced by the N1^ group, e.g. a chlorine, bromine or iodine atom, an O-tosyl or lower acyloxy group.

In the latter case, one introduces a compound of formula IV either in liquid ammonia or reacts it, dissolved in an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide or methanol, with an ammonia-releasing compound, e.g. an ammonium salt or urotropin.

For the preparation of compounds of the general formula I with a substituent in the o-position of the 5-phenyl ring, it has proved advantageous to carry out the reaction in an autoclave. It takes place within a short time at room temperature.

Compounds of formula IV have not previously been described.

One prepares the compounds e.g. where R = OCH3 and X = Cl

according to the following form:

During the reaction, the phenylarylamine derivative V is dissolved in an inert organic solvent, e.g. benzene, toluene, xylene or dimethylformamide, and heated with chloroacetic anhydride under reflux. The compound 11a obtained in this way is dissolved in a dilute lower alcohol and a small excess of diazomethane is added. A compound Ub is obtained, which, as described above, reacts with ammonia xesp. an ammonia-releasing compound to form the starting product II.

Method b) is carried out using suitable oxidizing agents such as chromic acid/sulfuric acid, potassium permanganate or activated manganese dioxide.

For the oxidation with chromic acid/sulphuric acid and potassium permanganate, it has proven particularly advantageous to use water-miscible solvents which cannot themselves be oxidized under the specified reaction conditions, e.g. acetone, methyl ethyl ketone, glacial acetic acid, dioxane, tetrahydrofuran or mixtures of these solvents.

The oxidation with activated manganese oxide can also be carried out using ethyl acetate, diethyl ether, methylene chloride or chloroform.

The reaction temperature to be used depends

of the starting material used and usually varies between 20°C and the boiling temperature of the chosen solvent.

The synthesis of the 1-aryl-3,4-dihydro-(2H,5H)-1,4-benzodiazepine-5-one of the general formula III used as starting material in method b) can be carried out by cyclization of the correspondingly substituted, ring-opening connection with the formula

This is described in German patent application P 21 65 310.

The above-described final products obtained with the general formula I are new. They possess strong psycho-sedative and anti-convulsant properties with very low toxicity, and can be used as sedatives or as anti-convulsants.

In particular, such connections where are are to be emphasized here

a phenyl radical optionally substituted with a halogen atom, and R 2 is a chlorine atom or a trifluoromethyl group.

While e.g. 8-chloro-1-phenyl-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione has a pronounced sedative effect, is for 1-phenyl-8-trifluoromethyl-3H-1,4- benzodiazepine-2,5-(1H,4H)-dione anticonvulsant effect prominently. The toxicity for all the new compounds is above 2,000 mg/kg p.o. (mouse). In most cases it could not be determined accurately, as it was not technically possible to administer to the animals the amount of compound necessary to determine LD,-q.

As a dose for use of the new compounds of the general formula I, 1-50 mg, preferably 5-25 mg as a single dose and 10-150 mg as a daily dose is suggested.

The new compounds can be used alone or in combination with other active substances produced according to the invention, possibly also in combination with further pharmacologically active substances such as spasmolytics or psychopharmaceuticals. Suitable application forms are e.g. tablets, capsules or dispersible powders.

The following examples shall serve to further illustrate the invention.

Example 1

8-nitro-1-phenyl-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione

a) Dissolve 9 g of N-chloroacetyl-N-phenyl-4-nitro-anthranilic acid methyl ester in 150 ml of acetone and add 8 g of potassium iodide. After 20 hours

stirring at room temperature, the solution is evaporated in vacuo, the residue is added to water, shaken out with ethyl acetate, the organic phase is dried with magnesium sulfate and the solvent is evaporated in vacuo. An oil remains which is dissolved in 20 ml of methanol. 200 ml of liquid ammonia is added to this solution and left to stand

1 hour, and the reaction mixture is then poured onto ice. After neutralization with glacial acetic acid, extract several times with ethyl acetate. Activated charcoal is added to the solution, dried and suctioned off. After evaporation of the solvent in vacuo, the residue is recrystallized from acetonitrile. 8-nitro-1-phenyl-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione is obtained in a yield of 4.9 g (64% of the theoretical)

with sm.p. 222-223°C.

The N-chloroacetyl-N-phenyl-4-nitro-anthranilic acid methyl ester used as starting material can be prepared as follows: b) 26 g of 4-nitro-(N-phenyl)-anthranilic acid are heated in 500 ml of absolute benzene with 26 g of chloroacetic anhydride in 1 hour under reflux cooling. The mixture is then shaken several times with water, the organic phase is dried with magnesium sulphate and suction is applied. Evaporate in vacuo and recrystallize the residue from isopropyl ether/cyclohexane.

Yield: 30 g (98% of the theoretical) with m.p. 172-173°C.

c) Preparation of N-chloroacetyl-N-phenyl-4-nitroanthranilic acid methyl ester

10 g of N-chloroacetyl-N-phenyl-4-nitro-anthranilic acid are dissolved

in 1 liter of methanol and 100 ml of water. A small excess of ethereal diazomethane solution is introduced into the solution while stirring for 10 minutes. It is then evaporated to dryness in

vacuum. The residue is crystallized from methanol.

Yield: 10 g (97% of the theoretical) with m.p. 126-127°C.

Example 2

8- trifluoromethyl- 1- phenyl- 3H- 1, 4- benzodiazepine- 2, 5-( 1H, 4H)-dione

25 g of N-chloroacetyl-N-phenyl-4-trifluoromethyl-anthranilic acid (prepared analogously to example 1 b) is dissolved in 250 ml of dimethylacetamide and 40 g of methyl iodide and 30 g of potassium acetate are added. You let it all react while stirring for 30 minutes and then dilute with 1 liter of water. It is extracted several times with methylene chloride, dried and evaporated in a vacuum. A little acetonitrile is added to the oily residue and the crystalline by-product is filtered off. The acetonitrile solution is evaporated in a vacuum, the residue is dissolved in 300 ml of acetone and 10 g of sodium iodide is added to

the acetone solution. The mixture is stirred for 20 hours at room temperature, the solvent is evaporated in vacuo and water is added to the residue. The mixture is shaken with ethyl acetate, the organic phase is dried with magnesium sulphate and the solvent is evaporated again in vacuo. It will be

return an oil which is dissolved in 30 ml of methanol, 250 ml of liquid ammonia is added to the solution, allowed to stand for 1 hour, and the reaction mixture is then poured onto ice. After neutralization with glacial acetic acid, extract again with ethyl acetate. Activated charcoal is then added to the solution, dried, and the charcoal is sucked off. After evaporation of the solvent in vacuo, the residue is recrystallized from methylene chloride/isopropyl ether.

Yield: 9.3 g (41% of theoretical) with m.p. 249-251 C.

IN

Example 3

8- chloro- l- phenyl- 3H- l, 4- benzodiazepine- 2, 5-( 1H, 4H)-dione

2.5 g of 8-chloro-1-phenyl-3,4-dihydro-(2H,5H)-1,4-benzodiazepine-5-one are dissolved in 250 ml of acetone. At room temperature, add 5 ml of a solution of 2.7 g of chromium (VI) oxide, 2.3 ml

concentrated sulfuric acid, diluted with distilled water to 10 ml of solution. The whole is left to react for 1 hour with stirring at room temperature, filtered off over diatomaceous earth and washed with acetone. Evaporate in vacuo and crystallize the residue from acetonitrile.

Yield: 2.4 g = 88% of the theoretical with m.p. 244-245°C.

As described above - the following end products are further produced:

Claims (4)

1. Analogy method for the production of new, therapeutically active l-aryl-3H-1,4-benzodiazepine-2,5-(1H,4H)- diones with the general formula where means a phenyl residue which is optionally substituted in o-, m- or p-position with a fluorine, chlorine or bromine atom or with a trifluoromethyl or nitro group, and R2 is a fluorine, chlorine or bromine atom or a trifluoromethyl, nitro, amino, cyano or hydroxy group, characterized in that a) a connection with. the general formula where R 1 and R 2 have the meaning indicated above, and R means a hydroxy, O-tosyl or lower acyloxy group or a halogen atom, preferably a lower alkoxy group, is submitted ring closure, or b) a compound of the general formula where and R2.has the above meaning, is oxidized with strong oxidizing agents. 2. Process as stated in claim 1 for the production of 8-chloro-1-phenyl-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione, characterized in that starting materials are used where R^ is phenyl and R 2 is chlorine. 3. Process as stated in claim 1 for the production of 8-chloro-1-(o-chlorophenyl)-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione, characterized in that starting materials where R 1 is o-chlorophenyl and R 2 is chlorine. 4. Process as stated in claim 1 for the production of 8-chloro-1-(o-fluorophenyl)-3H-1,4-benzodiazepine-2,5-(1H,4H)-dione, characterized in that starting materials where R 1 is o-fluorophenyl and R 2 is chlorine.