SE204792C1 - - Google Patents

Description

Inventors: J R Schindler and II Blattner Priority given from April 17 and December 4, 1962 (Switzerland, 4682, 14214). The present invention relates to a process for the preparation of novel azepine derivatives having valuable pharmacological properties.

Compounds of the general formula Z-Am (I) Y of R represent a lower molecular weight alkyl radical or an aralkyl radical, X and Y independently of one another denote -Me or chlorine atoms, Z represents an alkylene radical having 2 to 6 carbon atoms and straight or branched chain and Am denotes a lig molecule N-arylmethyl-alkylamino- or a lower molecular weight dialkylamino group, the alkyl residues of which may be directly attached to each other or Over a lower molecular weight alkylimino group, is not previously known. It has now been found that these compounds have valuable pharmacological properties, especially reserve antagonist, antiallergic and a central nervous system sedative, e.g. anesthetic potentiating effect. The dr e.g. Suitable for the treatment of certain forms of mental illness, especially chronic depression. Bee can, possibly in combination with other drugs, be used orally or in the form of aqueous solutions of its salts with non-toxic, inorganic or organic acids, also parenterally.

The compounds of general formula 1 are also suitable as intermediates for the preparation of other pharmacologically active substances.

In the compounds of general formula I, R is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl or (β-phenylethyl) residue.

Z consists, for example, of an ethylene, propylene, trimethylene, 2-methyl-trimethylene, 3-methyl-trimethylene, tetramethylene, pentamethylene or hexamethylene residue and Am e.g. of a methylamino-, ethylamino-, n-propylamino-, isopropylamino-, n-butylamino-, dimethylamino-, methylethylamino-, diethylamino-, methyl-n-propylamino-, methyl-isopropylamino-, di-n-butyl-amino-, di -isobutylamino-, N-methyl-benzylamino-, N-ethyl-benzylamino-, 1-pyrrolidinyl-, piperidino-, hexamethyleneimino-, 4-methyl-1-piperazinyl-, 4-isopropyl-1-piperazinyl- or 4-methyl -1-homopiperazinyl group.

For the preparation of the new compounds of general formula I, compounds of general formula II are condensed CO-CH, (II) X1 \ 1 II of R, X and Y have the meaning given above, with reaction-prone esters of compounds of general formula HO — Z — Am (III) - 2 vanes in Am and Z have the meaning given above, with the aid of an alkaline condensing agent. Suitable alkaline condensing agents are especially sodium amide, lithium amide, potassium amide, sodium or potassium, butyllithium, phenyllithium, lithium hydride or sodium hydride. The reaction is preferably carried out in the presence of an inert organic solvent such as benzene, toluene or xylene in heat. As a condensing agent, e.g. also potassium carbonate in a suitable organic solvent such as acetone.

Starting materials of the general formula II are, for example, 5-methyl-, 5-ethyl-, 5-n-propyl-, 5-isopropyl- and 5-benzyl-5H-dibenz [b, flazepin-10- (11H) -one and corresponding to 5-substituted 3,7-dichloro-5H-dibenz [b, f] azepine-10 (11H) -ones. These and other starting materials of general form II are obtained, for example, using 5-acetyl-5H-dibenz [b, f] azepine (iminostilbene) resp. 5-acetyl-3,7-dildor-5H-dibenz [b, f] azepine as starting material by storing bromine in the 10,11-position, converting the obtained dibromo compounds by means of alkali alkoxide to 10-alkoxy5H-dibenz [ b, lazepines, substitution of these in 5- e.g. by condensation with alkyl or aralkyl halides with the aid of sodium amide, and hydrolysis of the obtained 5-substituted 10-alkoxy-5H-dibenz [b, f] azepines e.g. by means of diluted hydrochloric acid.

Using 5-alkanoyl-3-chloro-5H-dibenz [b, flazepines, especially 5-acetyl-3-chloro-5H-dibenz [b, flazepine, as starting material, compounds of the general formula H having a chlorine atom X or Y and a water atom Y resp. X is also prepared by transfer to corresponding dibromo compounds, converting the latter either directly or over mixtures of 3-chloro-10-bromo- and 3-chloro-11-bromo-5H-dibenz [b, f] azepine to mixtures of 3-chloro- 10-alkoxy- and 3-chloro-11-alkoid-5H-dibenz [b, f] azepine and separation thereof, e.g. by fractional crystallization from suitable solvents, such as ethanol.

As reaction-prone esters of compounds of the general formula III, the halides in particular and in addition e.g. p-toluenesulfonic acid esters, 2,4-dinitro-benzenesulfonic acid esters and methanesulfonic acid esters. Examples which may be mentioned are: 13-dimethylamino-ethyl chloride, β-methylethylaminoethyl chloride, β-diethylamino-ethyl chloride, butylamino) -ethyl chloride, 13-dimethylamino-propyl chloride, γ-dimethylamino-propyl chloride, γ- (N-methyl-isopropylamino) -propyl chloride, γ-diethylaminopropyl chloride, γ-dimethylamino-butyl chloride-γ-dimethylamino-16-methylpropyl chloride, γ-dimethylamino-butyl chloride, γ- (N-methyl-benzylamino) -propyl chloride -ethyl-benzylamino) -propyl chloride, γ (N-methylbenzylamino) - [3-methyl-propyl chloride, p (1-pyrrolidinyl) -ethyl chloride, fl-piperidino-ethyl chloride, 7- (1-pyrrolidinyl) -propyl chloride, γ-piperidino propyl liloride, γ-hexamethyleneimino-propyl chloride, γ-piperidino-1-methyl-propyl chloride, 18- (4-methylpiperazinyl-ethyl chloride, γ- (4-methyl-1-piperazinyl) -propyl chloride, γ- ( 4-Isopropyl-1-piperazinylpropyl chloride and γ- (4-methyl-1-homopiperazinylpropyl chloride saint corresponding to bromides and ptoluenesulfonic acid esters.

With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 13-hydroxyethanesulfonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid and mandelic acid the all-manna formula I salts, which are partially water-soluble.

The invention is further illustrated in the following examples. The temperatures are given in Celsius degrees.

Example 1. 22.3 g of 5-methyl-5H-dibenz [b, flazepin40 (11H) -one are dissolved in 250 ml of absolute benzene and continued with a suspension of 4.0 g of sodium amide in toluene. The mixture is boiled for 3 hours under reflux, then cooled to 50 °, continued with 13.5 g of freshly distilled γ-dimethylaminopropyl chloride and then refluxed for 20 hours. The reaction mixture is cooled and continued with water. The benzene phase is filtered off and shaken out three times with 1N hydrochloric acid. The combined acidic extracts are made alkaline and shaken out with ether. The ether solution is dried and evaporated. 16 g of the residual oil are heated with 48 ml of 2-n hydrochloric acid for 5-10 minutes to 80 ° and the hydrochloric acid solution is then cooled with ice. The precipitated crystals of the 5-methyl-dibenz [b, f] azepine-10 (11H) -one liberated by-base basic enol ether are filtered off and the hydrochloric acid filtrate is made alkaline and extracted with ether. The ether solution is dried and continued with ethanolic hydrochloric acid, whereby the hydrochloride of 5-methyl-11- (γ-dimethylaminopropyl) -5H-dibenz [b, lazepin-10 (11H) -one] crystallizes out. Melting point 236-238 °. 13a analogue sad is obtained e.g. The following compounds: 5-methyl-11-11- (13-dimethylamino-ethyl-5H-dibenz [b, f] -azepin-10 (11H) -one, m.p. 116-117 '; 5-methyl-11- (γ-dimethylamino - [3-methyl-propyl) -5H-dibenz [b, f] azepin-10 (11H) -one, b.p. 160 ° at 0.005 mm Hg; 5-methyl-11- [3- (1,1-pyrrolidinyl) -ethyl] - 5H-dibenz [b, flazepin-10 (11H) -one; hydrochloride m.p. 182 '; 5-methyl-11- (γ-piperidinopropyl) -5H-dibens [b, f] - azepine-10 (11H) -one, boiling point 215 ° at 0.02 mm Hg; 5-methyl-1114γ- (4`-methyl-r-piperazinyl) -propyl] -5H-dibenz [b, flazepin-10 (11H) -one, m.p. 104-105 '; 3 5-ethyl-11- (16-dimethylamino-propyl) -5H-dibenz [b, f] azepin-10 (11H) -one, m.p. 64-65'; 5-ethyl-11- { γ-4'-methyl-r-piperazinyl) -propyl] -5H-dibenz [b, f] azepin-10 (11H) -one, m.p. 107-108 '; 5-isopropyl-11- (γ-dimethylamino-propyl) -5H-dibenz [b, flazepin-10 (11H) -one, m.p. 76 '; 5-Benzyl-11- (3-dimethylamino-ethyl) -5H-dibens [b, flazepin-10 (11H) -one, m.p. 117-118 '; 5-Benzyl-11- [γ- (4'-methyl-r-piperazinyl) -propyl] 5H-dibenz [b, f] azepin-10 (11H) -one; hydrochloride melting point 241 '; 3,7-dichloro-5-methyl-11- (γ-dimethylamino-propyl) -5H-dibenz [b, f] azepin-10 (11H) -one; 5-methyl-11 + - (N-benzyl-methylamino) -propyl] -5H-dibenz [b, f] azepin-10 (11H) -one; 5-methyl-1114 / 3- (N-benzyl-methylamino) -ethyl] -5H-dibenz [b, f] azepin-10 (11H) -one and 5-methyl-11- (19-diethylamino-ethyl) -5H- dib ens [b, f 1- azepin-10 (11H) -on.

Example 2. a) 235 g of 3-chloro-5-acetyl-5H-dibenz [b, f] azepine are dissolved in 800 ml of chloroform. After cooling to -10 DEG, 44 ml of bromine solution in 200 ml of chloroform are added dropwise over a period of 3 hours over a period of 3 hours, the reaction temperature being between - and 0 DEG. The reaction solution is then stirred for a further 3 hours and then evaporated in a rotary evaporator at a bath temperature of 30-40 °. The residue is dissolved in 200 ml of ethanol and the solution is continued with 150 ml of ether, whereby 3-chloro-5-acetyl-10,11-dibromo-10,11-dihydro-5H-dibenz [b, f] azepine crystallizes. After the whole part has been left to stand for a long time in ice, the crystals are sucked off and washed with ethanol and ether. After crystallization from ethanol, the substance narrows at 122-124 °. 100 g of the dibrona compound obtained according to a) are dissolved with gentle heating in 500 ml of dioxane. A vigorous addition of 15 g of potassium hydroxide in 60 ml of absolute ethanol is then added dropwise at 25 DEG C. over the course of 1 hour. The reaction solution is metered in for a further 24 hours at room temperature, the precipitated potassium bromide is filtered off and the filtrate is evaporated on a rotary evaporator. The residue is pre-mites with 200 ml of ether, after which crystallization takes place. After the whole part has been left to stand in the ice for 24 hours, the crystals are sucked off.

By fractional crystallization from ethanol, the more volatile 3-chloro-5-acetyl-11-bromo-5H-dibenz [b, the flazepine with the melting point 198-200 ° is separated from the more readily soluble acetyl-10-bromo-5H-dibene [b , f] azepine with a narrowing point of 148-149 °. 27 g of 3-chloro-5-acetyl-11-bromo-51-I-dibenz [b, f] azepine are boiled under mewing and reflux for 24 hours in a solution of 26 g of sodium methylate in 200 ml of absolute methanol. Then about 110 ml of methanol are distilled off and the residue is boiled again for 24 hours under reflux. After cooling to room temperature, 100 ml of water were added dropwise, the precipitated crystals were filtered off with suction, washed neutral and dried in vacuo. After recrystallization twice from ethanol, the resulting 3-chloro-11-methoid-5H-dibenz [b, f] azepine narrows at 143-144 °.

IR spectrum shows the following bands in methylene chloride: 2.99, a, 6.11, a; I nujol: 11.8 u, 12.11, a, 13.55, a.

UV spectrum shows a maximum at 261 ma (log e = 4.56) and an approach at 290 mu (loge = 3.53).

With 8.5 g of sodium methylate in 70 ml of absolute methanol, 9 g of 3-chloro-10-bromo-5H-dibenz [b, f] azepine are obtained in an analogous manner as starting material 3-chloro-10-methoxy-5H-dibenz [b, f] azepine, m.p. 128-129 ° (from methanol).

IR spectrum shows the following bands in methylene chloride: 2.99 h, 11.1 h, 12.23 kt; and nujol: 13.21 tt.

UV spectrum shows the following bands in methanol: 216 my (log € = 4.28), 244 ma (log = 4.51), 274 rnp (log r = 4.04), 368 mu (log = 3.74) .

To 62 g of 3-chloro-10-methoxy-5H-dibenz [b, f] azepine and 51.5 g of methyl iodide in 500 ml of thiophene-free benzene were added during metering at 50-55 ° over the course of about 30 minutes a suspension of 12.5 g of sodium amide in absolute toluene and the mixture ° mitres darpa 1 hour at 60 ° and 5 hours at boiling temperature under reflux. Then the reaction mixture is cooled, continued with water, the organic phase is separated, washed with water, dried over sodium sulfate and evaporated in a evaporator, the residue being 3-chloro-5-methyl-10-methoxy-5H-dibens [b, f lazepine . After recrystallization from absolute ethanol, it narrows at 140-142 °.

In analogous salt, 3-chloro-5-methyl-11-methoxy-5H-dibenz [b, f] azepine is obtained in crude form, which cannot be read to crystallize. g of the 3-chloro-5-methyl-10-methoxy-5H-dibenz [b] obtained in d), the flazepine is boiled with stirring and refluxed for half an hour in 1200 ml of 2-n hydrochloric acid. After cooling, the 3-chloro-5-methyl-5H-dibenz [b, f] azepine-10- (111-1) -one is filtered off, washed with water and dripped with a small amount of ice-cold ether and dried at 70 °. It can be used further directly. After recrystallization from ethanol, it melts at 130-132 °.

In analogous salt, 7-chloro-methyl-5H-dibenz [b, f] azepin-10 (11H) -one is obtained in red form. Its crystals are triturated for purification with a small amount of ethanol, filtered off with suction and dried. After recrystallization from ethanol, the substance melts at 160-161 °. 37 g of 3-chloro-5-methyl-5H-dibenz [b, f] azepin10 (11H) -one are dissolved in 400 ml of absolute toluene and continued at 80-90 ° for 15 minutes with stirring with a suspension of 6 g sodium amide in absolute toluene (volume 18 ml), warp the mixture is boiled for one hour under reflux. The mixture is again added dropwise with stirring at 80 DEG-90 DEG C. over the course of 15 minutes. 20 g of freshly distilled dimethylaminopropyl chloride and the reaction mixture is boiled for 16 hours under reflux. After cooling, water was added, the organic phase was separated and extracted 5 times with 50 ml of 2-n acetic acid each time and once with 50 ml of 1-n hydrochloric acid. The combined acidic extracts were continued after removal of the remaining solvent with 40 ml of conc. hydrochloric acid and heated 5 rainuter to 80 °. The enol ether formed as a by-product (3-chloro-5-methyl-10- (γ-dimethylaminopropoxy)) - 5H-dibenz [13, phasezine) is decomposed and the liberated starting material crystallizes out. It is filtered off, the filtrate is made alkaline with conc. baking soda and extracted twice with ether. The ether extracts are washed with water, dried over potassium carbonate and evaporated. The residue is dissolved under heating in 500 ml of petroleum ether, the solution is cooled, filtered off with dark colored resin and evaporated. The remaining viscous oil is distilled in a hogya vacuum. 3-Chloro-5-methyl-11- (γ-dimethylamino-propyl) -5H-dibenz [b, f] azepin10 (11H) -one exceeds at 205-207 ° and 0.01 mm Hg. Continuing the base with an estimated amount of absolute ethanolic chloroethyl solution and added absolute ether gives the crystallized hydrochloride, which narrows at 207-210 ° after recrystallization from absolute ethanol / absolute ether.

By analogy, 7-chloro-5-methyl-11- (3-dimethylamino-propyl) -5H-dibenz [b, f] azepin10 (11H) -one with a boiling point of 208-212 ° at 0.05 mm Hg is obtained. Upon evaporation of the petroleum ether solution, the product partially crystallizes and narrows after recrystallization from petroleum ether at 838 °. The hydrochloride melts after recrystallization from isopropanol / absolute ether at 222-225 °.

Claims (1)

Patent claim: Process for the preparation of novel azepine derivatives of the general formula Z-Am 2 CO-CH 2 (I) which R represents a low molecular weight alkyl radical or an aralkyl radical, X and Y independently represents hydrogen or chlorine atoms, Z represents an alkylene radical having 2 to 6 carbon atoms and straight or branched chain and Ain represents a lower molecular weight N-arylmethylalkylamino group or a lower molecular weight dialkylamino group, the alkyl radicals of which are directly linked or a lower molecular weight alkylimino group, characterized in that a compound of the general formula "/ CO-CH 2, in which R HO-Z-Am in which Z and Am have the meaning given above, with the aid of an alkaline condensing agent and the obtained compound of the general formula I are optionally transferred to a salt with an inorganic or organic acid. tion: Patents in France 1,030,599.