DE1161278B - Process for the production of azepine derivatives and their salts. - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY Internat. Class: C07d

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12p-5

Number:
File number:
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G 28521 IVd / 12 ρ December 5, 1959 January 16, 1964

The invention relates to a process for the production of azepine derivatives and their salts with valuable pharmacological properties.

10, ll-dihydro-5H-dibenzo [b, f] azepine monoalkylated or halogenated in an aromatic ring and 5H-dibenzo [b, f] azepines and their N-derivatives and salts have not yet become known. It it has now been found that compounds of the general formula

in which X is the ethylene or vinylene group, R is an alkyl radical having 2 to 4 carbon atoms, a chlorine or Bromine atom, Y is an alkylene radical with 2 to 6 carbon atoms and two to four bridge members, Ri and R2 are lower alkyl radicals or Ri and R2 together with the nitrogen atom and optionally an oxygen atom, an alkylimino, Hydroxyalkylimino or alkanoyloxyalkylimino group is a heterocyclic radical or R2 also mean an alkylene radical which is connected to the alkylene radical Y, as well as the salts thereof, if

a) 3-alkyl- or 3-halo-iminodibenzyls or 3-Alkyl- or 3-Haiogeniminostilbene of the general formula

Process for the production of azepine derivatives and their salts

Applicant:

J. R. Geigy A. G., Basel (Switzerland) Representative:

Dr. F. Zumstein, Dipl.-Chem. Dr. rer. nat. E. Assmann and Dipl.-Chem. Dr. R. Koenigsberger, Patent Attorneys, Munich 2, Bräuhausstr.

Named as inventor:

Dr. Walter Schindler, Riehen, Dr. Henri Dietrich, Basel (Switzerland)

Claimed priority:

Switzerland of December 6, 1958 (No. 67 045, No. 67 046, No. 67 048 and No. 67 049)

Switzerland of January 12, 1959 (No. 68 200 and No. 68 201)

b) compounds of the general formula

oco

Ri

II CO - O - Y - N (

heated to split off carbon dioxide or

c) reactive esters of compounds of the general formula

in the presence of condensing agents with reactive esters of amino alcohols of the alJ ^ " my formula

HO -Y-N

Ri
R ₂ Y-OH with secondary amines of the general formula

III H —N (

R ₂ '

implements or

in which R2 'has the meaning given _{for R 2,}

309 779/253

but cannot be bonded to the alkylene radical Y, converts or
d) compounds of the general formula

VII

in which Rs denotes a hydrogen atom or a lower alkyl group, treated with low molecular weight alkylating agents or

e) compounds of the general formula

VIII

R ₂ "

in the Yi, Ri "and R2" residues corresponding to the mean radicals given for Y, Ri and R2, however, in at least one of the radicals at least one bonded to a nitrogen atom Methylene group is replaced by a carbonyl group, treated with alkali metal-earth metal hydrides and optionally reacting the bases obtained with inorganic or organic acids.

The compounds of general formula I have valuable pharmacological properties, especially antiallergic, sedative, spasmolytic, serotonin antagonistic, antiemetic and adrenolytic Effectiveness; they also inhibit, for example, the secretion of saliva caused by pilocarpine. The substances mentioned are used for oral and, if appropriate, also subcutaneous administration To treat certain forms of mental illness, particularly depression Treatment of allergic rhinitis as well as to potentiate the effects of other drugs, especially of narcotics.

Compared to the German Auslegeschrift 1 038 047 and the Austrian patent specification 200 578 known, disubstituted in 3,7-position Iminodibenzylene and iminostilbenes 5c have the compounds prepared according to the invention in the case of toxicities of the same order of magnitude, a 1.5 to 2-fold higher serotonin antagonist Effectiveness, which is determined by determining the inhibitory effect of the compounds on the formation of edema after injection of an aqueous solution of serotonin creatinine sulfate into the hind paws was found in rats. The compounds obtained according to the invention also show a antiemetic efficacy by reducing the ability to vomit in dogs exposed to a Dose of 0.1 mg / kg body weight apomorphine was administered subcutaneously, can be determined while the known compounds even increase its breaking effect.

For the preparation of the compounds of the general formula I according to the procedure given under a) are used as condensing agents in particular sodium amide, lithium amide. Potassium amide, sodium or potassium, butyllithium, phenyllithium, sodium hydride or lithium hydride are used. The implementation can be in the presence or absence of an inert organic solvent, examples of which Benzene, toluene and xylenes may be mentioned.

Particularly suitable reactive esters of amino alcohols of the general formula III are the halides; / Ϊ-dimethylaminoisopropyl chloride, γ-dimethylaminopropyl chloride, o-dimethylaminobutyl chloride, «-Methyl-γ-dimethylamino-n-amyl chloride, / i- (di-n-propylamino) ethyl chloride, / HMethylisopropylamino) ethyl chloride, / ii- ( Di-n-butylamino) ethyl chloride, β - (di - isobutyl - amino) - ethyl chloride, pyrrolidino ethyl chloride, piperidino ethyl chloride, γ-ΡΊ-peridinopropyl chloride, morpholino ethyl chloride, ^ - (N-methyl piperazino) ethyl chloride, / M4-acetoxyethyl - piperazino) ethyl chloride, γ - (4 - acetoxyäthylpiperazino) propyl chloride and / iN-methyl piperidyl (2) ethyl chloride and the corresponding bromides and iodides.

Starting materials of the general formula II are, for example, 3-ethyl-iminodibenzyl, 3-n-propyliminodibenzyl, 3-n-butyl-iminodibenzyl. 3-isobutyliminodibenzyl, 3-ethyl-iminostilbene, 3-chloro- and 3-bromo-iminodibenzyl and -iminostilbene, 3-n-butyliminostilbene. Process for the preparation of the aforementioned iminodibenzyl derivatives are the subject of Patent applications G 28520 IVd / 12p and G 28522 IVd / 12p.

The starting materials of the process given under b), the compounds of the general formula IV, are e.g. B. by reacting 3-alkyl or 3 - halogen - 5 - chlorocarbonyl - iminodibenzylene or -iminostilbenes with amino alcohols of the general formula III.

The reaction according to the process identified under c) can be carried out, for example, at a temperature of 80 to 120 ^: C in an inert solvent such as a low molecular weight alkanol or alkanone, an excess of the amine to be reacted being expediently used 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. The reactive esters of compounds of the general formula V used as starting material are obtained, for example, in a manner known per se by reacting hydroxyalkylimino-dibenzyls or -iminostilbenes with inorganic acid halides, methanesulphonic acid chloride or arylsulphonic acid chlorides, 5-haloalkyl-iminodibenzyls, 5-methanesulphonyloxy-imines , 5-Arylsulfonyloxyalkyl-iminodibenzyle or the corresponding iminostilbene derivatives are obtained. This can be done, for example, with dimethylamine. Methylethylamine, diethylamine, pyrrolidine, piperidine, morpholine, N-methyl-piperazine, N-hydroxyethyl-piperazine or N-acetoxyethyl-piperazine are implemented.

As low molecular weight alkylating agents for the process identified under d), for. B. Dimethyl sulfate. Diethyl sulfate. Methyl iodide, ethyl

iodide, ethyl bromide, N-propyl bromide and methyl p-toluenesulfonate in the presence of acid-binding agents, such as sodium or potassium carbonate, and an inert organic solvent, and furthermore z. B. formaldehyde in the presence of formic acid.

The process identified under e) is particularly suitable for the production of N, N-disubstituted compounds 3-alkyl- or 3-halo-5- (a-aminomethyl-alkyl) -iminodibenzylene or -iminostilbenes of importance because these compounds only together, for example by the process mentioned under a) with the isomeric N, N-disubstituted 3-alkyl- or 3-halo-5 - (/ 3-amino-alkyl) -iminodibenzylene formed by rearrangement or -iminostilbenes can be obtained. Starting materials of the general formula VIII are, for. B. N, N-disubstituted 3-alkyl or 3-halo-5- (a-carbamylalkyl) iminodibenzyls or iminostilbenes, 3-alkyl or 3-halogen-substituted 5- (dialkyl-amino-alkanoyl) -, 5- (piperidino-alkanoyl) -, 5- (N-alkyl-alkanoylaminoalkyl) -, 5- (N, N-dialkanoyl-aminoalkyl) -, 5-succinimidoalkyl- and 5-glutarimidoalkyl-iminodibenzyls and -iminostilbene. The 5-dialkyl-amino-alkanoyl compounds are z. B. in a known manner by reacting 5-haloalkanoyl compounds obtainable with amines of the general formula VI.

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, make up the obtained tertiary base salts, some of which are water-soluble.

The following examples are intended to describe the process for the preparation of the new azepine derivatives and their Explain salts in more detail. Parts therein mean parts by weight.

example 1

10 parts of 3-ethyl-iminodibenzyl are dissolved in 50 parts by volume of anhydrous benzene and the solution of the base released from 9 parts of ß-pyrrolidinoethyl chloride hydrochloride in 150 parts by volume of anhydrous benzene is added. For this purpose, letting under stirring at 50 ⁰ C, a suspension of 2.2 parts of sodium amide in toluene is added dropwise and the reaction mixture is then boiled for 16 hours under reflux. It is then cooled and water is added. The benzene phase is separated off and extracted with 2η hydrochloric acid; the hydrochloric acid extract is made alkaline with dilute sodium hydroxide solution and extracted with ether. The ether solution is evaporated and the residue is distilled in a high vacuum, the 3-ethyl-5 - (/? - pyrrolidinoethyl) -iminodibenzyl passing over at 164 ° C. under 0.005 mm pressure. Treatment with ethereal hydrogen chloride solution gives the hydrochloride of the base mentioned, which melts ^{at 156 to 158 ° C. after recrystallization from acetone-ether.} Yield 80%.

The same compound is obtained if the 3-ethyl-iminodibenzyl instead of ß-pyrrolidinoethyl chloride in the presence of sodium amide with / i-pyrrolidinoethyl bromide is reacted in the presence of lithium amide.

In an analogous manner, using the ß-dimethylaminoethyl chloride hydrochloride obtained from 8 parts released base the 3-ethyl-5- (ß-dimethylamino-ethyl) -iminodibenzyl of boiling point 0.005 145 to 147 ° C (yield 80%), and using 9 parts of y- (N-methyl-piperazino) -propyl chloride 3-ethyl-5- [y- (N'-methyl-piperazino) -propyl] -iminodibenzyl from bp 0.004 183 to 184 ° C, its dihydrochloride at 236 to 140 ° C with decomposition melts (yield 65%).

Similarly, starting from 10.7 parts of 3-n-propyl-iminodibenzyl and the base liberated from 8.5 parts of γ-dimethylamino-propyl chloride hydrochloride, 3-n-propyl-5- (γ-dimethylamino) is obtained -propyl) -iminodibenzyl of boiling point 0.001 142 to 144 ° C (yield 65%), and starting from 9.9 parts of 3-ethyl-iminostilbene and the base released from 8.5 parts of y-dimethylamino-propyl chloride hydrochloride, the 3 -Ethyl-5- (γ-dimethylamino-propyl) -iminostilbene of boiling point 004 152 ⁰ C (yield 82%).

Example 2

22.9 parts of 3-chloro-iminodibenzyl dissolved in 300 parts by volume of xylene are mixed with 4 parts of sodium amide suspended in toluene in a nitrogen atmosphere while stirring. The xylene solution immediately turns dark, but brightens again when the sodium salt crystallizes out. The reaction mixture is stirred for 2 hours at 8O ⁰ C, until the evolution of ammonia stopped. A solution of γ-dimethylaminopropyl chloride, which has been obtained by treating 17.4 parts of the corresponding hydrochloride with sodium hydroxide solution, adding toluene and drying over anhydrous sodium sulfate, is added to the sodium salt, and the reaction mixture is stirred under reflux for 15 hours. The precipitated sodium chloride is filtered off and the filtrate is concentrated. The residue is diluted with ether and the hydrochloride of 5- (γ-dimethylaminopropyl) -3-chloro-iminodibenzyl is precipitated by passing in dry hydrogen chloride. It is purified by repeated recrystallization from acetone, whereupon it melts at 191.5 to 192 ⁰ C. Yield 80%.

In an analogous manner, y-N-methyl-N-ethylamino-propyl chloride is obtained from 16.0 parts - Hydrochloride released base the S-iy-N-methyl-N-ethylaminopropyO-S-chloro-iminodibenzyl-hydrochloride, Mp. 178 to 180 ° C (yield 80%), and starting from 27.4 parts of 3-bromoiminodibenzyl and γ-dimethylaminopropyl chloride the 5- (y-dimethylamino-propyl) -3-bromiminodibenzyl hydrochloride is obtained, Mp. 173 to 175 ° C (yield 75%).

Example 3

4.3 parts of sodium amide are added to 23 parts of 3-chloro-iminodibenzyl dissolved in 190 parts by volume of xylene (powdered and suspended in toluene) and added for 3 hours at 80 ° C in a nitrogen atmosphere touched. The solution turns dark at first, but brightens as soon as the sodium salt begins to crystallize. A ß-morpholino ethyl chloride solution, by adding 20.5 parts of the corresponding hydrochloride with dilute Obtain caustic soda and take up in benzene

is added to the sodium salt. The reaction mixture is then refluxed for 16 hours with constant stirring. After concentration and cooling, the precipitated sodium chloride is filtered off and washed with absolute ether. In the cold, dry hydrogen chloride is passed into the solution. The hydrochloride of 3-chloro-5 - (/ I-morpholinoethyl) -iminodibenzyl is recrystallized as alcohol. It melts at 242 ^; C. Yield 82%.

IO

Example 4

23 parts of 3-chloro-iminodibenzyl are in 190 parts by volume Dissolved xylene, added 4.3 parts of sodium amide to the solution, pulverized and suspended in toluene, added, and the reaction mixture is stirred in a nitrogen atmosphere at 80 ° C. for 3 hours. Then a dimethylamino-isopropyl chloride solution, which is obtained by adding 18 parts of the Hydrochloride of dimethylamino-isopropyl chloride with dilute sodium hydroxide solution, taken up in Benzene and drying the benzene solution with anhydrous sodium sulfate is added and the reaction mixture was refluxed for 16 hours. The excreted sodium chloride is filtered off, washed with absolute ether and removed from the filtrate by passing in dry hydrogen chloride, the hydrochloride of the resulting 3-chloro-5-0? -dimethylamino- <5-methylethyl) iminodibenzyl pleases. It is recrystallized from acetone and melts at 247 ° C. Yield 83%.

Example 5

A solution of 15 parts of 3-ethyl-5 - (/? - chloroethyl) -iminodibenzyl in 100 parts by volume of absolute 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 absolute alcoholic hydrochloric acid is added to the residue, the hydrochloride of 3-ethyl-5 - (/ 3-pyrrolidinoethyl) -iminodibenzyl crystallizing out. As indicated in Example 1, it can be recrystallized and then melts at 156 to 158 ^° C. Yield 70%.

Example 6

10 parts of 3-n-propyl-5- (γ-methylamino-propyl) -iminodibenzyl are dissolved in 7.0 parts by volume of 85% formic acid, and the solution is mixed with 4.5 parts by volume of 30% aqueous formaldehyde offset. The mixture is left to stand for 3 hours at room temperature and then heated for 12 hours the steam bath. After cooling, the reaction mixture is concentrated in vacuo, the The residue was made alkaline with 30% sodium hydroxide solution and extracted with ether. After washing and Drying is concentrated and the residue is distilled, the 3-n-propyl-5- (γ-dimethylamino-propyl) -iminodibenzyl from bp 0.001 142 to 144 ° C. Yield 70%.

Example 7

23 parts of S-chloro-S-iy-chlorpropyO-iminodibenzyl are dissolved in 150 parts by volume of methyl ethyl ketone, and after the addition of 10 parts of sodium iodide and 13 parts of N-methyl-piperazine, the mixture is 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 acidic extracts are made alkaline, and the precipitated base is taken up in ether. After drying and evaporation of the solution, the 3-chloro-5 - [- / - (N'-methyl-piperazino) -propylj-iminodibenzyl is obtained as an 01. Yield 50%. M.p. of base 83 ^: C; Melting point of the hydrochloride 228 to 230 ^: C. This compound is prepared according to the procedure described in Example 2. a yield of 73% is obtained.

The same is done using N-hydroxyethyl piperazine instead of N-methyl-piperazine, 3-chloro-5 - [- / - (N'-hydroxyethyl-piperazino) propyl] -iminodibenzyl obtain. Yield 30%. Monofumarate m.p. 168 to 170 C; Difumarate m.p. 177 to 179C: dioxalate m.p. 215 to 216C.

Example 8

23 parts of 3-chloro-iminodibenzyl in 150 parts by volume of absolute xylene are mixed with a suspension of 4.3 parts of sodium amide powdered in toluene. The mixture is stirred and heated to 9O ⁰ C with ammonia escapes and forms the sodium salt. The resulting suspension of the same is then treated with a / i- [N-methylpiperidyl- (2)] - ethyl chloride solution, which has been obtained by adding 22 parts of the corresponding hydrochloride with dilute sodium hydroxide solution and taking up in toluene, and refluxed for 16 hours . After cooling, the precipitated sodium chloride is separated off, the solution is concentrated and the oil is distilled at 0.1 mm pressure. The 3-chloro-5 - [/ i-N'-methyl-piperidyl- (2 ') - ethyl] -iminodibenzyl passes over at 195.degree. Yield 76%.

Example 9

23 parts of 3-chloro-iminostilbene in 250 parts by volume of absolute xylene are refluxed with 4.3 parts of sodium amide suspended in toluene for 3 hours. A γ-dimethylaminopropyl chloride solution, which has been obtained by adding 18 parts of the corresponding hydrochloride with dilute sodium hydroxide solution and taking up in xylene, is then added and the mixture is heated to boiling for a further 20 hours while stirring. The reaction mixture obtained is evaporated to dryness, and the basic components are extracted from the residue mixed with ether with dilute hydrochloric acid. The acidic extracts are made alkaline and the free base is taken up in ether. After drying and concentration of the ether solution gives the 3-chloro-5- (y-dimethylamino-propyl) iminostilbene, which, recrystallized from petroleum ether, melts at 53 ⁰ C. Yield 90%.

Example 10

S-chloro-iminodibenzyl-S-carboxylic acid-iy-dimethylamino-propyl ester), which has been obtained from 29.2 parts of 5-chlorocarbonyl-3-chloro-iminodibenzyl (melting point 142 ° C.) and 10.3 parts of γ-dimethylaminopropanol ^{, is heated to 160 °} C. in a water jet vacuum, the temperature gradually increases to 210 ^° C. until the elimination of carbon dioxide has ended

increased. The residue is distilled in a high vacuum, the 3-chloro-5- (γ-dimethylaminopropyl) -iminodibenzyl at the bp 0.04, m.p. 152 to 160 ° C, passes. From this base one obtains when mixed with dilute hydrochloric acid, the hydrochloride has a melting point of 191 to 192 ° C. Yield 65%.

Example 11

34.3 parts of S-chloro-S-ty-N-methyl-N-acetylaminopropyl) iminodibenzyl with a melting point of 82 to 84 ° C. are dissolved in 900 parts by volume of absolute ether, and the solution is added to 4 parts of lithium aluminum hydride in 50 parts by volume, while stirring dripped into absolute ether. The mixture is boiled for 4 hours under reflux ^ ^1, cautiously, then then decomposed with 4 parts of water with 4 parts by volume of 15% sodium hydroxide solution and 12 parts of water. The precipitate is filtered off with suction and washed thoroughly with ether. After evaporation of the ether, an almost colorless oil remains, which can either be converted directly into a salt or, if necessary, purified by distillation or chromatography. The oil is z. B. absorbed in petroleum ether on neutral aluminum oxide and the 3-chloro-5- (yN-methyl-N-ethylaminopropyl) -iminodibenzyl eluted with petroleum ether-benzene in a ratio of 3: 2. Its refractive index nf is 1.5780. The hydrochloride melts at 179 to 182 ° C. Yield 74 ° / _0th

Claims (1)

Claim: Process for the preparation of azepine derivatives of the general formula 40 45 in which X is the ethylene or vinylene group, R is an alkyl radical with 2 to 4 carbon atoms, a chlorine or bromine atom, Y an alkylene radical having 2 to 6 carbon atoms and two to four Bridge members, Ri and R2 lower alkyl radicals or Ri and R2 together with the nitrogen atom and optionally an oxygen atom, an alkylimino, hydroxyalkylimino or alkanoyloxyalkylimino group is a heterocyclic group Radical or R2 also denote an alkylene radical which is bonded to the alkylene radical Y, as well as their salts, characterized that he a) 3-alkyl- or 3-halo-iminodibenzyls or 3-alkyl or 3-haloiminostilbenes of the go general formula reactive esters of amino alcohols of the general formula HO - Y - N Ri
R ₂ implements or
b) compounds of the general formula CO —Ο —Υ —Nv Ri
'R ₂ heated to split off carbon dioxide or c) reactive esters of compounds of the general formula Y-OH
with secondary amines of the general formula H-N Ri
R ₂ ' in which R ₂ 'has the _{meaning given for R 2} , but cannot be bonded to the alkylene radical Y, reacts or
d) compounds of the general formula in which R3 denotes a hydrogen atom or a lower alkyl group, treated with low molecular weight alkylating agents or
e) compounds of the general formula in the presence of condensing agents in which Yi, Ri "and R ₂ " are radicals corresponding to the radicals _{indicated for Y, Ri and R 2} , but at least one of the radicals having at least one bonded to a nitrogen atom 309 779/253 Methylene group is replaced by a carbonyl group, with alkali metal-earth metal hydrides treated and the bases obtained, optionally with inorganic or organic acids implements. Considered publications: German Patent No. 829 167; German interpretative document No. 1 038 047; Austrian patent specification No. 200 578. When the registration was announced, four pages of the test report were laid out. 309 779/253 1.64 © Bundesdruckerei Berlin