AT217045B - Process for the preparation of new monoalkylated or monohalogenated N-derivatives of 10,11-dihydro-5H-dibenzo [b, f] azepines and 5H-dibenzo [b, f] azepines - Google Patents

Description

  

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  Process for the preparation of new monoalkylated or monohalogenated N-derivatives of 10, 11-dihydro-5H-dibenzo [b, f] azepines and 5H-dibenzo [b, f] azepines
The present invention relates to a process for the preparation of new, in an aromatic ring monoalkylated or monohalogenated N-derivatives of 1O, 1l-dihydro-5H-dibenzo [b, f] azepines and 5H-dibenzo- [b, f] azepines, which have valuable pharmacological properties, in particular antiallergic, sedative, spasmolytic, serotonin-antagonistic, antiemetic and adrenolytic activity, and the general formula I:

   
 EMI1.1
 where X is the ethylene or vinylene group -CH2-CH2- or -CH = CH-, Y is an alkylene radical with 2-6 carbon atoms, of which 2-4 are in the direct chain between N and Am, Am is a low molecular weight dialkylamino group and R is an alkyl radical with 2-4 carbon atoms, a chlorine or bromine atom, where one of the two alkyl radicals of Am directly (1) with the alkylene radical of Y or both alkyl radicals directly (2) or via an oxygen atom (3), an alkylimino (4), hydroxyalkylimino (5 ) or alkanoyloxyalkylimino group (6) may be linked. These compounds of formula I inhibit z. B. also the saliva secretion caused by pilocarpine.

   The substances mentioned come u. a. in the case of peroral and optionally also subcutaneous administration for the treatment of certain forms of mental illnesses, in particular mood depressions, for the treatment of allergic rhinitis and for potentiating the action of other medicinal substances, in particular narcotics.



   The following formulas are specific examples to explain the above-mentioned 6 bonding possibilities in the group Y-Am:
 EMI1.2
 
Quaternary ammonium salts derived from the tertiary bases defined above act as ganglioplegics.

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To prepare the new compounds, a reactive ester of a compound of the general formula II is used:
 EMI2.1
 
 EMI2.2
 the amine of the general formula III:

     Am-H (111) um, where R, X, Y and Am have the meanings given above, but naturally there cannot be a connection between an alkyl radical of Am and Y, and converts the base obtained in this way into its salts with inorganic or organic Acids or by addition of a reactive ester of an aliphatic or araliphatic alcohol into a quaternary ammonium compound.



  The reaction can, for example, at a moderately high temperature of, for. B. 80 to 120 C in an inert solvent, such as. B. a low molecular weight alkanol, or alkanone, it is expedient to use an excess of the amine to be reacted as the acid-binding agent. Depending on the boiling point of the amine and the solvent used and the required reaction temperature, the reaction may have to be carried out in a closed vessel.

   Reactive esters of compounds of general formula II are obtained, for example, by reacting alkali metal compounds of iminodibenzyl or iminostilbene compounds of general formula IV:
 EMI2.3
 with alkylene oxides and reaction of the hydroxyalkyl derivatives obtained with inorganic acid halides, methanesulfonic acid chloride or arylsulfonic acid chlorides, 5-haloalkyl-iminodibenzyls, 5-methanesulfonyloxy-iminodibenzyls, 5-arylsulfonyloxyalkyliminodibenzyls or the corresponding iminostilbene derivatives being obtained. These can be reacted, for example, with dimethylamine, methylethylamine, diethylamine, pyrrolidine, piperidine, morpholine, N-methylpiperazine, N-hydroxyethyl piperazine or N-acetoxyethyl piperazine.



   By addition of reactive esters, especially halides or sulfates of aliphatic or araliphatic alcohols, e.g. B. of methyl iodide, dimethyl sulfate, ethyl bromide, ethyl iodide or benzyl chloride arise from the tertiary amines of the general formula I in the usual way monoquaternary ammonium compounds, the group Am reacting.



   With inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, citric acid, malic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and phthalic acid, the tertiary bases form salts, some of which are water-soluble.



   The following examples are intended to explain the preparation of the new compounds in more detail. Parts mean parts by weight; these relate to parts by volume as g to cm3. The temperatures are given in degrees Celsius.



   Example 1: A solution of 15 parts of 3-ethyl-5- (ss-chloro-ethyl) -iminodibenzyl in 100 parts by volume of abs. Benzene is mixed with 8 parts of pyrrolidine and refluxed for 12 hours. After cooling, the benzene solution is washed thoroughly with water, dried and evaporated. The calculated amount of abs is added to the residue. alcoholic hydrochloric acid, the hydrochloride of 3-ethyl-5- (ss-pyrrolidino-ethyl) -iminodibenzyl crystallizes out. It can be recrystallized as indicated in Example 1 and then melts at 156-158 o.



     Example 2: 23 parts of 3-chloro-iminodibenzyl and 15 parts of l-chloro-3-bromopropane are dissolved in 200 parts by volume of abs. Benzene dissolved. 4.3 parts of sodium amide are pulverized in toluene and the suspension obtained is slowly added dropwise at 500 ° with stirring, whereupon stirring is continued for 15 hours at 50-600. The reaction mixture obtained is poured into water, the benzene layer is separated off and dried with sodium sulfate. After concentration, the 3-chloro-5- (Y-chloropropyl) -iminodibenzyl is obtained as a dark oil, which can be further processed directly.



   23 parts of the product obtained above are dissolved in 150 parts by volume of methyl ethyl ketone and after
Addition of 10 parts of sodium iodide and 13 parts of N-methylpiperazine, stirred under reflux for 16 hours. The reaction mixture is concentrated, the residue is taken up in ether and the basic components are extracted from the ethereal solution with dilute hydrochloric acid. The sour extracts will be

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 made alkaline and the precipitated base is taken up in ether. After drying and evaporation of the solution, the desired 3-chloro-5- [γ-N'-methyl-piperazino) propyl] -imino-dibenzyl is obtained as an oil.



   Analog is z. B. using N-hydroxyethyl-piperazine instead of N-methyl-piperazine to obtain 3-chloro-5- [Y-N'-hydroxyethyl-piperazino) propyl] -iminodibenzyl.



    PATENT CLAIMS:
1. Process for the preparation of new, in an aromatic ring monoalkylated or monohalogenated N-derivatives of 1O, 1l-dihydro-5H-dibenzo [b, f] azepines and 5H-dibenzo- [b, f] azepines of the general formula I :

   
 EMI3.1
 where X is the ethylene or vinylene group -CH2-CH2- or -CH = CH-, Y is an alkylene radical with 2-6 carbon atoms, of which 2-4 are in the direct chain between N and Am, Am is a low molecular weight dialkylamino group and R is one Alkyl radical with 2-4 carbon atoms, a chlorine or bromine atom, where one of the two alkyl radicals of Am directly with the alkylene radical Y, or both alkyl radicals directly or via an oxygen atom, an alkylimino, hydroxyalkylimino or alkanoyl oxyalkylimino group can as well as their salts or quaternary ammonium compounds, characterized in that a reactive ester of a compound of the general formula II:
 EMI3.2
 with a secondary amine of the general formula III:

     Am-H (111), where R, X, Y and Am have the meanings given above, but naturally no connection between an alkyl radical of Am and Y can be present, and the base thus obtained, if appropriate, into its salts with inorganic or organic acids , or converted into a quaternary ammonium compound by addition of a reactive ester of an aliphatic or araliphatic alcohol.

 

Claims (1)

2. The method according to claim l, characterized in that the starting materials used are compounds of the general formula II in which R is an alkyl radical having 2-4 carbon atoms. 3. The method according to claim 1, characterized in that the starting materials used are compounds of the general formula II in which R is a chlorine or bromine atom.