NO128154B - - Google Patents

Description

Analogy method for the production of

therapeutically active 1,4-benzodiazepines.

The invention relates to an analogue method for the production of hitherto unknown compounds belonging to the well-known group of 1,4-benzodiazepines with sedative, muscle relaxing, anticonvulsant and calming effects.

The compounds referred to here have the general formula

where R denotes hydrogen, halogen or a nitro group, and R denotes an alkyl group with up to 6 carbon atoms: The compounds of formula I are to be used as pharmaceuticals, as they have similar sedative and calming properties as e.g. the well-known 7-chloro-1,3-dihydro-1-methyl-5-phenyl-3H-1,4-benzodiazepine-2-one (diazepam), but differs from this by not to have a hypotensive effect or to have synergism with hypotensive drugs. The compounds referred to here are prepared according to the invention by splitting off water from the corresponding compounds of the general formula II 12 in which R and R have the meaning indicated above. The water separation is particularly smooth and easy when according to the invention, phenyl isocyanate is used as a release agent. The compounds with the general formula II-' are prepared.. ••• according to the following reaction scheme

12

wherein R and R have the previously stated meanings..-.

The compounds with formula III are known compounds, the preparation of which is described in French patent no. 1,482,641.

The following examples serve to illuminate the preparation of the new 1,4-benzodiazepines and intermediate products. in

Example.

7- chloro- 2- methoxy- 5- phenyl- 5H- 1, 4- benzodiazepine.

7-chloro-2-methoxy-4-hydroxy-5-phenyl-4, 5-dihydro-3H-1,4-benzodiazepine (6.2 g, 0.0205 mol) is dissolved in a mixture of isobutyl ester of acetic acid (60 ml ) and 1,4-dimethylpiperazine (6 mL)

at 20°C, and the solution is stirred for 5 minutes at 25°C. Phenyl isocyanate (4.85 ml, 0.0456 mol) is added and the solution is heated to reflux for a period of 15 min. A development of CC^ begins at about 40°C and stops when reflux begins. The resulting yellow suspension is cooled to 25°C and methylene chloride (100 ml) is added with stirring. The secreted white crystals are filtered off, washed with methylene chloride (30 + 30 ml) and dried (60°C), whereby 4.0 g of carbanilide (92%) with melting point 243°C are obtained. Filtrate and washing liquid are combined and evaporated under reduced pressure to dryness on a water bath (70°C). Boiling cyclohexane (100 ml) is added to the yellow-brown evaporation residue and dissolves most of it. The mixture is left at 5°C until the next day, after which the solution is decanted from the undissolved, oil-like material. The cyclohexane solution is evaporated to dryness under reduced pressure in a water bath (90°C). The pale yellow, highly viscous evaporation residue (6.45 g) is distilled on an oil bath (178-182°C) and gives 5.29 g (91%) of the desired product with bp 162-165°C.

Calculated for Cl6H13ClN26 (284.7): C 67.5 H 4.6 Cl 12.5 N 9.9

OCH^ 10.8%

Found: C 67.3 H 4.7 Cl 12.1 N 9.8

OCH^ 10.7%.

In a similar manner, 7~nitro-2-methoxy-5-phenyl-5H-1,4-benzodiazepine is prepared with bp , 165-175°C.

The starting compound is prepared in the following way: 7-chloro-2-methoxy-5H-1,4-benzodiazepine-4-oxide (IV).

7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide (14.7 g, 0.0700 mol) is suspended in a mixture of methanol (150 ml)

and ether (150 mL). A 0.5 molar ethereal solution of diazomethane (225 ml, 0.113 mol) is added at 10°C with stirring to the suspension in portions of 25 ml at 15 minute intervals. The yellow suspension is left with stirring until the next day, and the suspension is then colourless. A further amount of diazomethane solution (150 ml,

0.075 mol) is added at 10°C in 25 ml portions at 60 minute intervals. After the last addition, bleaching does not occur

the yellow diazomethane color, and the methylation appears to be complete.

The undissolved material is filtered off and washed with two 10 ml portions of ether, and the filtrate and washing liquids are evaporated to dryness in a vacuum (20 mm Hg) on a water bath (50°C). The crystalline evaporation residue (12.5 g) is dissolved in acetone (100 ml) at 50°C. The hot solution is filtered, and the filtrate is cooled to 10°C and set aside until the next day. The crystals thus separated are filtered off, washed with cold acetone (10 + 10 ml) and dried in vacuum (0.1 mm Hg) at 50°C. The yield of voluminous white crystal needles of the above compound is 3.14 g (20%) with melting point 205-207°C. Recrystallization from acetone gives an analytically pure product with a melting point of 209-210°C during cleavage.

Calculated for C1()H9C1N202 (224.6): C 53.5 H 4.0 Cl 15.8 N 12.5% Found: C 53.4 H 4.1 Cl 15.7 N 12.4% 7- chloro-2-methoxy-4-hydroxy-5-phenyl-4,5-dihydro-3H-1,4-benzodiazepine ( II).

The compound prepared according to example 1 (1.68 g, 0.00750 mol) is suspended in a mixture of dry ether (60 ml) and dry tetrahydrofuran (25 ml), and the suspension is heated to 35°C with stirring. A solution of phenylmagnesium bromide, prepared from 0.300 g of magnesium (0.0124 mol) and 1.88 g of bromobenzene (0.0120 mol)

in ether (30 ml), is added dropwise at about 35°C over 50 minutes. The resulting orange colored solution is kept at 40°C for 35 minutes, cooled to 0°C and worked up in the usual way. Crystallization of the reaction product from benzene and then from cyclohexane gives 1.57 g (70%) of the desired product as white crystals melting at 146-147°C.

Calculated for Cl6H15ClN202 (302.8): C 63.5 H 5.0 Cl 11.7 N 9.3

0CH3 10.2%

Found: C 63.2 H 5.1 Cl 12.1 N 9.3

OCHj 10.3%.

Claims (1)

Analogy method for the preparation of therapeutic active 1,4-benzodiazepines with the general formula in which R 1 denotes hydrogen, halogen or a nitro group, and R<2> denotes an alkyl group with up to 6 carbon atoms, characterized in that water is split off from a corresponding compound with the general formula where R 1 and R 2 have the stated meaning, preferably by means of phenyl isocyanate.