NO120268B - - Google Patents

Description

Analogy methods for the production of hitherto unknown, pharmacologically active 10-base substituted 5H-dibenz

[b, f] azepine derivatives.

The invention relates to analogous methods for the production of hitherto unknown, pharmacologically active 5H-dibenz[b,f]azepine derivatives with the general formula I,

where R, means a lower alkyl residue,

1*2 hydrogen or methyl residue,

and R^ hydrogen or lower alkyl residues,

and their addition salts with inorganic or organic acids.

As has now been found, such compounds possess valuable central and peripheral pharmacological properties. When administered orally, rectally or parenterally, they act as sedatives, anti-convulsants, anesthetic potentiators; they inhibit monosynaptic and polysynaptic reflexes and antagonize drugs, such as e.g. tetrabenazine, which has a depressant effect on the central nervous system. Furthermore, they exhibit spasmolytic, histamineolytic and noradrenaline potentiating activity. These pharmacological properties characterize the new compounds as suitable for the treatment of tension and irritation conditions, such as e.g. is conditioned through neuroses or depressions.

In the French patent document No. 1,355,948, 10-(dialkylamino-alkyl)-10,11-dihydro-5H-dibenz [b,f]azepines are already known, which in the 5-position can be substituted with hydrocarbon residues. Furthermore, French patent document No. 1,377,680 describes 10-(mono-or di-alkylamino-alkyl)-5H-dibenz[b,f Jazepine derivatives, which in the 5-position can be substituted with lower alkanoyl residues. Both groups of compounds are structurally similar to the compounds according to the invention and also have a comparable spectrum of pharmacological action. Their effect is substantially inferior to the compounds according to the invention, as can be seen from the following table.

In the above table A, the Roman numerals denote the following compounds: I 5-methyl-10-methylaminomethyl-5H-dibenz[b,f]azepine- hydrochloride (according to the present application)

II 5-methyl-10-dimethylaminomethyl-5H-dibenz[b,f]azepine hydrochloride (according to the present application)

IV 10-((3-methylamino-ethyl)-10,11-dihydro-5H-dibenz [b,f]

azepine hydrochloride (according to French patent document

No. 1,355,948)

VI 10-Methylaminomethyl-5H-dibenz[b,fJazepine Hydrochloride

(according to French patent document no. 1,277,680)

VII 10-dimethylaminomethyl-5H-dibenz[b,f]azepine hydrochloride

(according to French patent document no. 1,277,680)

VIII 5-Acetyl-10~dimethylaminomethyl-5H-dibenz[b,fJazepine hydrochloride (according to French patent document no. 1,277,680)

In the compounds with the general formula I, e.g. R^, R^ and R^ methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec. the butyl or tert.butyl group.

For the preparation according to the invention of compounds of the general formula I, a reactive ester of a hydroxyl compound of the general formula II is reacted,

where R 1 and R 2 have the meaning given under formula I, with a compound of the general formula III,

where R^ and R^ have the under formula I indicated

importance,

or with a metal compound of an N-acyl derivative of a lower alkylamine, subjecting, if necessary, the reaction product to a hydrolysis to remove an acyl residue attached to a nitrogen atom in the side chain and transferring, if desired, a compound of the general formula I with an inorganic or organic acid to an addition salt.

As reactive esters of hydroxyl compounds of the general formula II, the halides, in particular the bromides, come into consideration. Further such derivatives are present in the sulphonic acid esters, which e.g. the tosyl esters or the mesyl esters.

Reactions of reactive esters of compounds of the general formula II with amines of the general formula III are carried out, e.g. in inert solvents, whereby an excess of amine can serve as an acid-binding agent and possibly also as the sole reaction medium. Suitable inert solvents are e.g. hydrocarbons, such as benzene or toluene, lower alkanols such as methanol or ethanol, lower alkanones, such as acetone or methyl ethyl ketone as well as water. Depending on the meaning of R^, R2, R-j 0<3R4, the reaction is more or less exothermic, if necessary, it is completed by heating the reaction mixture. The reactive esters of compounds with the general formula II can e.g. reacted with dimethylamine, methylethylamine, diethylamine, dipropylamine, dibutylamine, methylamine, ethylamine, propylamine, isopropylamine, sec.butylamine or ammonia.

The reaction of a reactive ester of a compound of the general formula II with a metal compound of *an N-acyl derivative of a lower alkylamine, such as e.g. the sodium compound of a lower N-formyl-, N-alkoxycarbonyl-, N-phenoxycarbonyl-, N-alkoxythiocarbonyl- or an N-phenoxythiocarbonyl-alkylamine, find e.g. place in an inert organic solvent under anhydrous conditions. Suitable solvents for these turnovers are e.g. hydrocarbons, such as benzene or toluene. The acyl residue in the reaction product obtained, which is bound to a nitrogen atom in the side chain, can then be cleaved off by heating the reaction product with an alkali metal hydroxide, such as potassium hydroxide in an organic solvent. Suitable reagents are e.g. solvents containing hydroxyl groups, such as ethylene glycol or diethylene glycol, their lower alkyl ethers or lower alkanols, such as ethanol. The lower alkanols are preferably used in a closed vessel. Furthermore, the hydrolysis can take place e.g. also by boiling with alkanol hydrochloric acid.

Starting materials which are reactive esters of the compound with the general formula II are e.g. 10-bromomethyl- or 10-(c-bromo-ethyl)-5-alkyl-5H-dibenz [b, f Jazepines. These compounds can surprisingly be prepared, e.g. by bromination of 10-methyl henh. 10-Ethyl-5-alkyl-dibenz[b,fJazepines with bromosuccinimide.

According to another method according to the invention, compounds of the general formula I are prepared, by alkylating compounds of the general formula IV,

where 1*2, R., °<3 R. has the above meaning, preferably in the presence of solvents and basic condensing agents by means of reactive esters of alkanols of the general formula V,

where R has the meaning given under formula I,

and optionally transfer the obtained compounds with inorganic or organic acids to their addition salts.

Starting substances with the general formula IV are described in the literature. Further compounds of this type are produced analogously. As a second reaction component, reactive esters of alkanols with the general formula V, whose residue R corresponds to the groups then explicitly mentioned in the general formula I, are used. As reactive esters, e.g. halides, such as chlorides, bromides or iodides, sulfonic acid esters, such as methanesulfonic acid, benzenesulfonic acid, o- and p-toluenesulfonic acid or 2,4-dinitro-benzenesulfonic acid esters as well as sulfuric acid esters, such as dimethyl or diethyl sulfate, are used.

The reaction can be carried out in the presence or absence of an inert organic solvent. Suitable inert solvents are e.g. hydrocarbons, such as benzene, tbluene, xylene, cumol or tetralin, ether-like liquids, such as dioxane, alkanones, such as acetone or methyl ethyl ketone, carboxylic acid amides, such as dimethylformamide, or sulfoxides, such as dimethyl or diethyl sulfoxide. As basic condensation agents, e.g. alkali metals, such as sodium, potassium or lithium, alkali hydroxides, such as sodium or potassium hydroxide, alkali carbonates, such as potassium carbonate, alkali amides, such as sodium, potassium or lithium amide, alkali hydrides, such as sodium or lithium hydride, alkali alcoholates, such as sodium methylate , sodium ethylate; or sodium tert.butylate or alkyl-dg aryllithium compounds, such as butyl or phenyllithium.

The compounds of the general formula I obtained by the process according to the invention are then transferred, if desired, in the usual way to their addition salts with inorganic and organic acids. E.g. one adds one solution of a compound of the general formula I in an organic solvent with the desired acid as salt component or a solution of the same. Organic solvents are preferably chosen for the reaction, in which the formed salt is poorly soluble, so it can be separated by filtration. Such solvents are, for example, methanol, ethanol, methanol-diethyl ether or ethanol-diethyl ether.

For use as medicinal substances, acid addition salts can be used instead of free bases, i.e. salts with such acids, whose anions are pharmaceutically acceptable at the dosages in question. Furthermore, it is advantageous when the salts used as medicinal substances are easily crystallisable and not or slightly hygroscopic. For the preparation of pharmaceutically acceptable salts of compounds with the general formula I can e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid are used.

The following examples give a more detailed account of the preparation of the new compounds of the general formula I and of previously undescribed intermediates. The temperatures are indicated in degrees Celsius.

EXAMPLE 1

a) Dissolve 15 g of 5-methyl-10-bromomethyl-5H-dibenz[b,f]azepine in 50 ml of absolute benzene and add at a temperature of 0 - 5°

to a solution of 10 g of dimethylamine in 100 ml of absolute benzene. The reaction mixture is then stirred for 1 hour at 40 - 50°. The organic phase is then washed well with sodium chloride and extracted with 2-N hydrochloric acid. The acidic extracts are made phenol-phthalein alkaline with concentrated aqueous ammonia and shaken out with diethyl ether. The ethereal solution is washed with water, dried over potassium carbonate and evaporated in a vacuum. The residue, which is distilled in a high vacuum, boils at 140 - 144°/ 0.01 Torr. The free base obtained, 5-methyl-10-dimethylamino-methyl-5H-dibenz[b,f]azepine, is transferred with absolute ethanolic hydrochloric acid to the hydrochloride, m.p. 225 - 228° from absolute ethanol.

The starting material, 5-methyl-10-bromomethyl-5H-dibenz[b, f Jazepinet,. is prepared in the following way: b) 37.5 g of 5,10-dimethyl-5H-dibenz[b,fJazepine is dissolved in 375 ml of carbon tetrachloride and 30.5 g of bromosuccinimide are added once. The reaction mixture is heated with stirring to 70° and illuminated with two 200 watt lamps. The temperature is maintained by gentle cooling for 3-5 minutes at 70°'. The reaction mixture is then cooled to 20°, the succinimide is sucked off and washed with carbon tetrachloride. The filtrate is extracted with water, the organic phase is dried over sodium sulphate and evaporated in vacuo at 40°. The residue is recrystallized from cyclohexane, whereupon the compound obtained melts at 109 - 111°.

EXAMPLE 2

Analogous to example la), the following end products are prepared from 5-methyl-10-bromomethyl-5H-dibenz[b,f]azepine: a) with methylamine: 5-methyl-10-methylaminomethyl-5H-dibenz[b,f]-azepine, kp. 147 - 149°/0.05 Dry, hydrochloride, m.p. 175 -

177° (from absolute ethanol-diethyl ether);

b) with diethylamine: 5-methyl-10-diethylaminomethyl-5H-dibenz[b,f]-azepine, b.p. 147 - 150°/0.04 Dry, fumarate, m.p. 148 - 149°

(from absolute ethanol).

EXAMPLE 3

a) Analogous to example la) the following end product is prepared from 5-ethyl-10-bromomethyl-5H-dibenz[b,fJazepine: a"<*>") with dimethylamine: 5-ethyl-10-(dimethylaminomethyl)-5H- dibenz-[b,fJazepinet, kp. 150 - 15 2°/0.04 Dry, hydrochloride, m.p.

247 - 249° (from absolute ethanol).

b) The necessary 5-ethyl-10-bromomethyl-5H-dibenz[b,fJazepine (raw product) is prepared analogously to that described in example lb)

5-methyl-10-bromomethyl-5H-dibenz[b,fJazepine from 5-ethyl-10-methyl-5H-dibenz[b,fJazepine, m.p. 143 - 145° (from ethanol). This out-

starting material is obtained analogously to the 5,10-dimethyl-5H-dibenz[b,fJazepine described in the literature by starting from 10-methoxy-5H-dibenz[b,fJazepine, m.p. 124°, over the following intermediates: 5-ethyl-10-methoxy-5H-dibenz[b,fJazepine, m.p. 186 - 188° (from ethanol),

5-ethyl-5H-dibenz[b,fJazepin-10(11H)-one, m.p. 126 - 128° (from ethanol),

5-Ethyl-10-methyl-10,11-dihydro-5H-dibenz[b,fJazepin-10-ol (crude product).

EXAMPLE 4

To 72 g of 10-dimethylaminomethyl-5H-dibenz[b,fJazepine in 720 ml of absolute toluene, a suspension of 13.8 g of sodium amide in 30 ml of absolute toluene is added dropwise while stirring over the course of 15 minutes and the reaction mixture is then refluxed for 1 hour . It is cooled to 50° and 45 g of methyl iodide is added dropwise over the course of 90 minutes, maintaining a temperature of 50 - 52°. The reaction mixture is then stirred for 16 hours between 50 and 52° and then for 1 hour between 85 and 95° and cooled to 20°. One adds 100 ml of water, separates from the organic phase and extracts it with 2-N hydrochloric acid. From the hydrochloric acid extract, the free base is precipitated with concentrated caustic soda and extracted with diethyl ether. The ethereal solution is washed with water, dried over potassium carbonate and evaporated in vacuo. The distillation of the residue in high vacuum gives 5-methyl-10-dimethylaminomethyl-5H-dibenz[b,fJazepinet with b.p. 140 - 144°/0,Ol Dry. The free base is transferred with ethanolic hydrochloric acid to the hydrochloride, which once crystallized from absolute ethanol melts at 225 - 228°.

EXAMPLE 5

Analogous to example 4, the following is obtained:

from 10-(a-dimethylamino-ethyl)-5H-dibenz[b,f Jazepine with methyl iodide: 5-methyl-10-(a-dimethylamino-ethyl)-5H-dibenz[b,f Jazepine, bp. 145 - 149°/0.04 Dry, hydrochloride, m.p. 156 - 160° (from absolute ethanol-diethyl ether).

Claims (1)

Analogous methods for the production of hitherto unknown, pharmacologically active 10-base substituted 5H-dibenz [b,fJazepine derivatives with the general formula I, where R^ means a lower alkyl residue, 1*2 hydrogen or the methyl residue, R., and R4 hydrogen or lower alkyl residues, as well as their addition salts with inorganic or organic acids, characterized by) reacting a reactive ester of a compound with the general formula II, where R 1 and R 2 have the meaning given under formula I, with a compound of the general formula III, where R, and R. have the meaning given under formula I, or with a metal compound of an N-acyl derivative of a lower alkylamine, subjecting, if necessary, the reaction product to a hydrolysis to remove an acyl residue bound to a nitrogen atom in the side chain, or b) that one alkylates compounds with the general formula IV, where R£, R^°9R4^are the meaning indicated above, preferably in the presence of solvents and basic condensation agents by means of reactive esters of alkanols of the general formula V, where R^ has the above meaning, and optionally transfer the obtained compounds with inorganic or organic acids to their addition salts.