NO118920B - - Google Patents

Description

Process for the production of pharmacologically active 10, 11-dihydro-5H-dibenz [b,f] azepine derivatives.

The present invention relates to a process for the production of new, pharmacologically active 10,11-dihydro-5H-dibenz[b,f]-azepine derivatives.

Compounds of the general formula I,

where Rt means a lower alkyl group with

1-4 carbon atoms,

R2hydrogen or a lower alkyl group with

1-4 carbon atoms,

R3hydrogen or a lower alkyl group with 1-4 carbon atoms and R4a lower alkyl group with 1-4 carbon atoms,

m is 1 or 2,

n 0, 1 or 2 and (m+n) 1, 2 or 3,

and their acid addition salts are not yet known.

As has now been found, these compounds and their addition salts with inorganic and organic acids possess valuable pharmacological properties. They potentiate, among other things, a. the action of catecholamines and antagonizes the action of reserpine. The pharmacological properties characterize azepine derivatives of the general formula I and their acid addition salts, which due to their mood-elevating and impulse-accelerating effect alone or in combination with other pharmaceuticals are suitable for the treatment of mental depressions.

The compound produced according to the invention, 3-isopropylsulfinyl-5-(3-methylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (I), shows in the tests carried out compared to the previously known compounds, '5-(3-dimethylamino-propyl)-10,11-dihydro-5H-dibenz[b,f]azepine (II) and 3-methyl-sulfinyl-5-[2-(N-methyl-piperidin-2- yl)-ethyl]-phenothiazine (III), a significantly greater reserpine antagonist effect. Thus, of the compound II, an approx. 35 times higher and of compound III an approx. 180 times higher dose necessary to achieve the same effect as with compound I.

The superiority of the compound I produced according to the invention regarding the noradrenaline potentiation over the previously known compounds II and III is significant. The experiments carried out show that compound I has, compared to the previously known compound II, an approx. 3.5 times larger and compared to the previously known compound III even an approx. 200 times greater effect.

In the compounds of the general formula I, R1, R2, Ra and R4 as lower alkyl groups can be the methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group.

The compounds of the general formula I can surprisingly be prepared by a partial oxidation of the corresponding 3-alkylthio compounds. The process according to the invention is characterized by using a compound of the general formula II,

allows an oxygen-releasing agent to act. Periodic acid or a periodate soluble in the reaction medium is particularly suitable as such agent. Appropriately, the aforementioned oxidizing agents are used in equimolar amounts for the compound with the general formula I. However, periodic acid and its salts do not attack it against other oxidizing agents, such as e.g. hydrogen peroxide, mentioned nitrogen atom in the side chain when it is present in excess. Therefore, one can e.g. also drip or allow to flow to a solution of the base to be oxidized or a salt thereof to the submitted solution of the periodic acid or one of its salts. The reaction medium used in the oxidation with periodic acid, i.e. in the acidic pH range, is preferably water. The compound with the general formula II can, however, also be dissolved in an organic solvent that is at least partially miscible with water, such as methanol, dioxane or acetic acid, brought together with an aqueous or aqueous-organic solution of the oxidizing agent and the oxidation carried out also in this case in a slightly acidic or slightly basic pH range. The reaction temperature in an acidic reaction medium is preferably around 0° to

temperature, with decreasing hydrogen ion concentration the temperature must be increased to approx. 50° and/or the reaction time is extended. A simple embodiment of the oxidation with periodic acid consists in dripping or allowing to flow an aqueous solution of a mineral acid or oxalic acid salt of a compound of the general formula II with good stirring into an aqueous solution of sodium or potassium metaperiodate , whose temperature is around 0°.

As further oxidizing agents, e.g. organic peracids, such as peracetic acid, benzoperic acid and phthalmonoperic acid in inert organic solvents, such as e.g. diethyl ether, chloroform, methylene chloride in consideration as well as chromic acid (chromic trioxyd) in acetic acid solution.

The compounds with the general formula II required as starting materials can be prepared completely analogously to the further methods described below for the preparation of compounds with the general formula I, whereby instead of 3-alkylsulfinyl-10,11-dihydro-5H-dibenz- [b,f]azepines with the following general formula III are used correspondingly to 3-alkylthio compounds.

Exclusively for those compounds of the general formula II, where R3 is hydrogen, which are necessary as starting materials, a second method is used, in which a compound of the general formula IIa,

where R1, R2, R4, m as well as n have the meaning given under formula I and R- means the cyano group or the acyl residue of a carboxylic acid or a monofunctional derivative of the carboxylic acid,

hydrolyzed.

In the compounds of general formula IIa, the residue is R5f. e.g. the cyano group, a lower alkanoyl or alkoxycarbonyl group, the phenoxycarbonyl group, the chlorocarbonyl group or the benzoyl group. Cyano-. The alkanoyl, chlorocarbonyl, phenoxycarbonyl and alkoxycarbonyl groups can e.g. is split off by acid or alkaline hydrolysis. The acid hydrolysis preferably takes place by treatment with an inorganic acid, such as e.g. hydrochloric or sulfuric acid, the alkaline by means of an alkali hydroxide, such as e.g. potassium hydroxide, at elevated temperature in a hydroxyl-containing solvent. Such solvents are e.g. lower alkanols, such as methanol, ethanol, further ethylene glycol, diethylene glycol or diethylene glycol monoethyl ether.

The starting substances with the general formula Ila are, for example, obtainable by reacting sodium derivatives of 3-alkylthio-10,11-dihydro-5H-dibenz[b,f]azepines with reactive esters of compounds of the general formula Hb

where R 2 , R 4 , R 5 , m and n have the meanings given under formula I and formula IIa respectively.

A further manufacturing possibility for starting substances with the general formula IIa lies in the reaction of compounds with the general formula II, where R3 and R4 are lower alkyl groups, with a molar equivalent of an organic acid halide or anhydride, especially with a carboxylic acid ester chloride (chloroformic acid ester), acetic anhydride, acetyl bromide, benzoyl chloride or phosgene.

Examples of starting substances with the general formula IIa are the 3-methylthio-, 3-ethylthio- and 3-isopropylthio derivatives of N-[3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl )-propyl]-N-methyl-carbamic acid ethyl ester, N- [3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-N-methyl-cyanamide and N-[3-(10,11-dihydro-5H-dibenz [b,f]azepin-5-yl)-propyl]-N-methyl-acetamide,

-N-ethyl-acetamide, -N-propyl-acetamide and -N-propyl-acetamide and -N-butyl-acetamide. According to a second method for preparing compounds of the general formula I and their acid addition salts, a compound of the general formula III is reacted,

where Rt has the meaning given under formula I, in the presence of a basic condensing agent with a reactive ester of an amino alcohol of the general formula IV,

where R3' has the meaning given under formula I for R3 with the exception of hydrogen and

R1, R4, m and n have the meaning given under formula I,

and, if desired, converts the obtained compound of the general formula I into a salt with an inorganic or organic acid. Particularly suitable condensation agents are sodium amide, lithium amide, potassium amide, sodium, potassium, lithium, butyllithium, phenyllithium, sodium tert. butylate, sodium hydride or lithium hydride. The turnover, at which a reaction temperature of approx. 75-150° is maintained, can be carried out in the presence or absence of an inert organic

solvent, such as benzene, toluene, xylene, cumene, tetralin or dimethylformamide.

For starting substances with the general formula III, when e.g. by diazotizing a 3-amino-5-acyl-10,11-dihydro-5H-dibenz[b,f]azepine and transferring the resulting diazonium salt with the help of copper II chloride and sulfur dioxide to a 3-chloro-sulfonyl- 5-acyl-10,11-dihydro-5H-dibenz[b,f]azepine, which is reduced with hydroiodic acid to a bis-(5-acyl-10,11-dihydro-5H-dibenz[b,f]azepine- 3-yl)-disulfide. The disulfide obtained is further reduced with glucose to a 5-acyl-10,11-dihydro-5H-dibenz[b,f]azepin-3-thiol, the latter in the same procedure being alkylated with an alkyl halide to a 3-alkylthio-5- acyl-10,11-dihydro-5H-dibenz[b,f]azepine, this is oxidized with periodic acid or a soluble periodate, analogously to the first-mentioned method for the preparation of compounds of the general formula I, and the obtained 3-alkylsulfinyl- compound is avacylated with potassium hydroxide.

Examples of starting substances with the general formula III should be mentioned 3-methylsulfinyl-, 3-ethylsulfinyl-, 3-propylsulfinyl- and 3-iso-propylsulfinyl-10,11-dihydro-5H-dibenz [b,f ] the azepine.

As reactive esters of amino alcohols with the general formula IV, the halides in particular come into consideration, individual mention should be made of: 2-dimethylamino-ethyl chloride, 2-diethyl-imino-ethyl chloride, 2-methylethylamino-ethyl chloride, 2-dimethylamino-propyl chloride, 3- dimethylamino-propyl chloride, 3-dimethylamino-butyl chloride, 4-dimethylamino-butyl chloride, 3-dimethylamino-2-methyl-propyl chloride, 2-dipropylamino-ethyl chloride and 2-methyl-isopropylamino-ethyl chloride, as well as the corresponding bromides, iodides and p-toluenesulfonic acid esters.

The azepine derivatives of the general formula I obtained according to one of the methods according to the invention are then transferred, if desired, in the usual way to their addition salts with inorganic and organic acids. For example a solution of an azepine derivative of the general formula I is added in an organic solvent with the desired acid as salt component or with a solution of the same. Preferably, organic solvents are chosen for the reaction, in which the formed salt is poorly soluble, so that it can be separated by filtration, similar solvents are e.g. methanol, methanol-ether or ethanol-ether.

For use as active substances in pharmaceuticals, non-toxic acid addition salts can be used instead of free bases, i.e. salts with such acids, whose anions at the dosage in question are pharmaceutically acceptable. Furthermore, it is advantageous when the salts which can be used as active substances are easily crystallizable and not or slightly hygroscopic. For salt formation with azepine derivatives of the general formula I, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, 1,2-ethanedisulfonic acid, 2-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 is used.

The following examples explain the preparation of the new compounds of the general formula I and of previously undescribed intermediates in more detail. The temperatures are indicated in degrees Celsius.

Example 1.

3-methylsulfinyl-5-(3-dimethylamino-propyl)-10,11-dihydro-5H-dibenz[b,f]azepine oxalate and hydrochloride.

0.59 g of sodium metaperiodate is dissolved in 90 ml of water and introduced into a stirring flask with ice-water cooling. 1 g of 3-methylthio-5-(3-dimethylamino-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine hydrochloride (see below) is dissolved in 20 ml of water and the solution is added dropwise during of 15 minutes to the aqueous sodium periodate solution. The reaction mixture is then stirred for 24 hours at room temperature. The reaction solution is made alkaline with ammonia and extracted with ether. After drying the ether extract over sodium sulphate, the ether is distilled off. 3-methylsulfinyl-5-(3-dimethylamino-propyl)-10,11-

The dihydro-5H-dibenz[b,f]azepine remains as a yellow oil. It is transferred by adding 0.3 g of anhydrous oxalic acid to the oxalate. After two crystallizations of the latter from ethanol-ether, it melts at 166°.

If desired, the hydrochloride is prepared by shaking the oxalate with dilute caustic soda and ether, evaporation of the ethereal solution of the base, addition of ethanolic hydrochloric acid, renewed evaporation and crystallization of the residue from ethanol-ether.

In an analogous manner, 3-ethylsulfinyl-5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz[b,f]azepine oxalate is obtained, m.p. 128— 130° from ethanol-ether, from the corresponding 3-ethylthio compound (see below).

The 3-alkylthio compounds used as starting materials are prepared as follows: a) 40 g of 5-acetyl-10,11-dihydro-5H-dibenz [b,f]azepine-3-sulfonyl chloride are dissolved in 520 ml of glacial acetic acid and added in small portions 180 ml 57% hydroiodic acid. The reaction mixture is allowed to stand for 70 hours at 20°, whereupon it half solidifies. It is then poured into 2.5 1 of a 5% sodium thiosulphate solution and the precipitate is scraped off. The brown filter residue is dissolved in 1.5 1 chloroform and shaken with 300 ml of 10% sodium thiosulphate solution. Thereby the solution decolourises. The chloroform phase is washed with water and dried over sodium sulphate. After distilling off the chloroform in vacuum, bis-(5-acetyl-10,11-dihydro-5H-dibenz[b,f]

azepin-3-yl)-disulfide back.

For further purification, the product is dissolved in acetic acid ethyl ester and the solution is filtered through a column of aluminum oxide (Woelm, activity I, neutral). By concentrating the filtrate in vacuum, the pure disulphide is obtained as an amorphous powder, which decomposes at 110°.

b) To 32 g of the not further purified disulphide and 23 g of glucose in 700 ml of ethanol, 12 g of sodium hydroxide in 250 ml of metha-

nil The reaction mixture is then stirred for 1 hour at 60° and cooled to 20°. Then drip

man 40 g of methyl iodide in 150 ml of ethanol during

30 minutes. After the end of dripping, stir

the reaction mixture first for 2 hours at 20 g and then for 2 hours at 60°. It is then evaporated under reduced pressure and the remaining residue is taken up in chloroform and water. The chloroform phase is washed neutrally with water and dried

over sodium sulfate. After evaporation of the chloroform in vacuo, the 3-methylthio-5-acetyl-10,1 l-dihydro-5H-dibenz[b,f]azepine is returned,

which is purified by distillation in high vacuum, bp. 160°/0.003 Torr.

c) 99 g of the above-mentioned acetyl compound are heated with 95 g of potassium hydroxide and 500 ml of diethylene glycol monoethyl ether for 8 hours under reflux. The reaction mixture is poured into 5 1 water and extracted with diethyl ether. The ether extract is washed well with water, dried over sodium sulphate and evaporated in

vacuum. The obtained 3-methylthio-10,11-dihydro-5H-dibenz[b,f]azepine crystallizes from diethyl ether-petroleum ether, m.p. 64°. d) 30 g of the thioether obtained according to lc is introduced into a stirring flask with 750 ml.

abs. toluene at 70° under a nitrogen atmosphere. To this solution is added a suspension of 5.6 g sodium amide in 30 ml abs. toluene and the mixture is refluxed for 90 minutes. 19 g of 3-dimethylaminopropyl chloride are then added dropwise in 250 ml of abs. toluene and boil the reaction mixture for 17 hours below

backflow. It is then cooled to 20° and washed with water. It is extracted from the toluene phase by extraction with 2N hydrochloric acid in basic parts. The acidic extract is then made alkaline with concentrated caustic soda and extracted

free bases with diethyl ether. The ether solution

washed with water, dried over sodium sulfate and

evaporated in vacuum. The residue is dissolved in acetone and ethereal hydrochloric acid is added to the solution. The 3-methylthio-5-(dimethyl-aminopropyl)-10,11-dihydro-5H-dibenz [b,f] azepine hydrochloride obtained melts after recrystallization from acetone-diethyl ether at 170°.

e) If you use b) instead of methyl iodide, the corresponding amount of ethyl iodide is obtained

man 3-ethylthio-5-acetyl-10,11-dihydro-5H-dibenz [b,f]azepine with m.p. 102° from diethyl ether. Analogous to c), the 3-ethylthio-10,11-dihydro-5H-dibenz [b,f]azepine with b.p. 150°/0.001 Torr. If this is reacted with 3-dimethylamino-2-methyl-propyl chloride analogously to d), then 3-ethylthio-5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz is obtained [b,f] the azepine and hence its hydrochloride with m.p. 164° (from chloroform-acetone).

Example 2

3-isopropylsulfinyl-5-(3-methylamino-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine oxalate and hydrochloride.

Analogous to example 1, 3-isopropyl-thio-5-(3-methylamino-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine oxalate or the corresponding hydrochloride is oxidized to 3-isopropyl-sulfinyl-5- (3-methylamino-propyl)-10,11-dihydro-5H-dibenz [b,f]azepines. Likewise, analogous to example 1, oxalate with m.p. is prepared from this base. 168°

(from ethanol) and the hydrochloride.

The 3-isopropylthio compound required as a starting material is obtained, e.g. in the following way: a) Analogous example lb) is prepared from bis-(5-acetyl-10,H-dihydro-5H-dibenz [b,f]azepin-3-yl)-disulfide with glucose, sodium hydroxide and isopropyl bromide 3-isopropylthio -5-acetyl-10,11-dihydro-5H-dibenz [b,f]azepine, m.p. 89° from diethyl ether and b) from this analogous example lc) with potassium hydroxide in diethylene glycol monoethyl ether 3-isopropylthio-10,11-dihydro-5H-dibenz [b,f]azepine, m.p. 79° from diethyl ether-petroleum ether. c) Analogous example ld) is obtained from 3-iso-propylthio-10,11-dihydro-5H-dibenz [b,f] azepine with 3-dimethylamino-propyl chloride 3-isopropyl-thio-5-(3-dimethylamino-propyl) -10,11-dihydro-5H-dibenz [b,f]azepine, oxalate m.p. 169° from ethanol. d) 16 g of 5-(3-dimethylamino-propyl)-3-isopropylthio-10,11-dihydro-5H-dibenz [b,f] azepine in 480 ml abs are introduced into a stirring flask. benzene at 65°. 5.5 g of ethyl chloroformic acid is then added dropwise over the course of 20 minutes in 80 ml of abs. benzene and heat the reaction mixture for 3 hours under reflux. The benzene solution is extracted to separate basic parts which have remained unchanged, with 2N hydrochloric acid, then washed with water and evaporated in vacuo. e) it is heated from crude 5[3-(N-ethox3'-carbonyl-methylamino)-propyl]-3-isopropylthio-10,11-dihydro-5H-dibenz [b,f] azepine consisting residue with 7.5 g of potassium hydroxide in 100 ml of diethylene. glycol monoethyl ether for 6 hours under reflux and then adds 1 liter of water. Thereby, the reaction product precipitates out. It is extracted with diethyl ether. The basic parts are extracted from the ether extract with 2N hydrochloric acid. The hydrochloric acid phase is made alkaline with concentrated sodium hydroxide solution and the free bases are taken up in diethyl ether. The ether phase is washed with water, dried over sodium sulphate and evaporated in vacuo. The resulting 3-isopropylthio-5-(3-methylamino-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine is dissolved in ethanol and transferred with ethanolic oxalic acid solution. solution to the oxalate. This melts after recrystallization from ethanol at 185°.

Example 3.

3-Ethylsulfinyl-5-(3-dimethylamino-2-methyl-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine oxalate.

To a solution of 1.3 g of 3-ethylsulfinyl-10,11-dihydro-5H-dibenz [b,f]azepine in 100 ml of abs. toluene is added at 70° under a nitrogen atmosphere and stirring to a suspension of 0.15 g of sodium amide in 5 ml of abs. toluene and the mixture is boiled for 30 minutes under reflux. Then 0.75 g of 2-methyl-3-dimethylamino-propyl chloride is added dropwise in 10 ml of abs. toluene and reflux the reaction mixture for 15 hours. It is then cooled to 20° and extracted with

2n hydrochloric acid. The hydrochloric acid extract is made alkaline with concentrated caustic soda and the liberated basic part is extracted with ether. The ether solution is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in acetone and 0.3 g of anhydrous oxalic acid in 5 ml of ethanol is added. The 3-ethylsulfinyl-5-(2-methyl-3-dimethylamino-propyl)-10,11-dihydro-5H-dibenz [b,f] azepine oxalate precipitates out crystalline: it melts after recrystallization from acetone-ether at 128— 130° total e.g. 1.

In an analogous way, they can further in e.g. 1

and 2 said compounds are prepared.

The starting material for the above-mentioned example is produced, e.g. in the following way: a) To an ice-cooled solution of 3.8 g of sodium metaperiodate in 56 ml of water and 28 ml of ethanol, a solution of 5.0 g of 3-ethylthio-5-acetyl-10,11 -dihydro-5H dibenz [b,f]azepine (comp. ex. le) in 56 ml of ethanol with stirring, whereby the temperature of the reaction mixture is kept between 0 and 5°. After the infusion is finished, stir for 3 hours under ice cooling and then for 12 hours at room temperature. The ethanol is mostly distilled off under reduced pressure, the remaining reaction mixture is added to 200 ml of water and extracted 3 times with ether. The combined ether solutions are evaporated and the remaining 3-ethyl-sulfinyl-5-acetyl-10,11-dihydro-5H-dibenz [b,f] azepine is recrystallized from benzol ether, m.p. 135°. b) 3.5 g of 3-ethylsulfinyl-5-acetyl-10,11-dihydro-5H-dibenz [b,f] azepine, 3.2 potassium hydroxide and 100 ml of ethanol are boiled for 10 hours under reflux. The ethanol is then evaporated under a water jet vacuum, the residue is added to 100 ml of water and extracted with chloroform. The chloroform solution is washed with water and evaporated. From the oily residue, the pure 3-ethyl-sulfinyl-10,11-dihydro-5H-dibenz [b,f]azepine is obtained by crystallization from benzol ether, m.p. 128°.

Example 4.

3-Ethylsulfinyl-5-(3-dimethylamino-2-methyl-propyl)-10,11-dihydro-5H-dibenz [b,f]azepine oxalate.

Dissolve 3.1 g of 3-ethylthio-5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz [b,f]azepine (comp. ex. le) in 50 ml of ethanol and is added dropwise over the course of 30 minutes with stirring to the 0° cooled solution of 1.9 g of sodium metaperiodate in 42 ml of water and 22 ml of ethanol. The solution is then stirred for a further 2 hours at 0° and 48 hours at room temperature. The ethanol is distilled from under a water jet vacuum and the remaining emulsion is extracted with ether. After washing the ether extract with water, drying over sodium sulfate and evaporation, the 3-ethylsulfinyl-5-(3-dimethylamino-2-methylpropyl)-10,11-dihydro-5H-dibenz [b,f]azepine is returned. It is dissolved in 10 ml of ethanol and 10 ml of 10% ethanolic oxalic acid solution is added. The precipitated oxalate is recrystallized twice from ethanol-ether. After drying at 100° high vacuum, it melts at 128-130°, sm. e.g. 1 and 4.

Claims (1)

Process for the preparation of new, pharmacologically active 10,11-dihydr6-5H-dibenz [b,f] azepine derivatives of the general formula I, where Rj means a lower alkyl group with 1-4 carbon atoms, R2 hydrogen or a lower alkyl group with 1-4 carbon atoms, R3 hydrogen or a lower alkyl group with 1-4 carbon atoms and R4 a lower alkyl group with 1-4 carbon atoms, m is 1 or 2, n 0, 1 or 2 and (m+n) 1, 2 or 3, and their addition salts with inorganic and organic acids, characterized in that on a compound of the general formula II, where Rj, R2, R3, R4, m and n have the meaning given under formula I, allows an oxygen indicating agent to act, or that one reacts a compound with the general formula III, where Rj has the meaning given under formula I, in the presence of a basic condensing agent with a reactive ester of an amino alcohol of the general formula IV, where R3' corresponds to the meaning given in claim 1 for R3 with the exception of hydrogen and R2, R4, m and n have the meaning given in claim 1, and, if desired, transfers the obtained compound of the general formula I to an addition salt with an inorganic or organic acid.