DE1493782B1 - Basically substituted dibenzo [b, f] -oxepines and their non-toxic salts - Google Patents

Description

The invention relates to basic substituted dibenzo- [b, f] -oxepines of the general formula I.

CH-N

(D

in which X is a hydrogen atom, a chlorine atom or the methoxy radical, R _{1 is} a hydrogen atom or the methyl radical and R ₂ and R _{3 are} a hydrogen atom or lower alkyl radicals which, together with the nitrogen atom, can form the pyrrolidine or piperidine ring or where the radicals R ₂ and R ₃ with the nitrogen atom represent the 4-methyl-piperazine ring, and their non-toxic salts.

It has been found that these compounds have valuable pharmacological properties, in particular Have adrenolytic and central depressant, as well as sedative and narcosis-potentiating effectiveness.

The free bases of the general formula I and their acid addition salts are therapeutic in their own right Effect to be described as equivalent. When administering both forms in the blood turns out independently on the form and method of application between ionized, non-ionized and bound form the same state of equilibrium which is necessary for the therapeutic effect to occur is.

In comparative tests, the anesthesia-potentiating effect of some of the above compounds tested taking into account the toxicities of known compounds.

Here, the compounds to be examined were male and female mice with a weight of 17 to 25 g 30 minutes prior to intraperitoneal administration of 40 mg / kg des narcotically active 2-methoxy-4-allylphenoxyacetic acid-N, N-diethylamide injected subcutaneously. the The duration of the lateral position of the animals treated in this way was measured and the duration of the lateral position of Compared control animals that had only received the narcotic mentioned, but not the test substance. The change in the length of the lateral position compared to the controls was given as a percentage.

The toxicity (DL ₅₀ ) of the compounds was tested in white mice when administered intravenously.

The experiments were carried out with the following compounds in the form of their hydrochlorides:

ί 10 - (2 '- dimethylamine - ethyl) - dibenzo - [b, fj oxepin (known from U.S. Patent 3,100,207);

JI 11 - (3-Dimethylaminopropylidene) -6, l 1 -dihydro-dibenzo- [b, e] -oxepine (known from Belgian patent specification 623 259);

III 10-dimethylarnino-methyl-dibenzo- [b, f] -oxepine (Example 1, a);

IV 10-MethyIamino-methyl-dibenzo- [b, f] -oxepine (Example Ib ¹ );

V 10- (Γ - dimethylamine - ethyl) - dibenzo - [b, f] oxepin (Example 2, a ¹ );

VI 10- (l'-methylamino-ethyl) -dibenzo- [b, fJ-oxe-

pin (example 2, a ² ); VII 8-methoxy-10-dimethyIamino-methyl-dibenzo

[b, fj-oxepin (Example 3, a); VIII 8-methoxy-10-methylamino-methyl-dibenzo-

[b, f] -oxepin (Example 3, a ¹ ); IX 8 - chlorine -10 - dimethylamino - methyl - dibenzo-

[b, f] -oxepin (Example 4, a '); X 10 - pyrrolidino - methyl - dibenzo - [b, f] - oxepine

(Example l, b ² );
XI 10- (4'-methyl-l'-piperazinyl-methyl) -dibenzo-

[b, f] -oxepin (Example 1, b ³ ); XII 8-Methoxy-10- (4'-methyl-1'-piperazinyl-methyl) -dibenzo- [b, f] -oxepine (Example 3, a ² ).

The results obtained are summarized in the following table:

link

II

ill

IV

VI

VII
VIII

IX

XI

XII

Anesthesia potentiation (side lying time)

dose

50 mg kg sc
20 mg kg sc
50 mg / kg sc
50 mg / kg sc
20 mg / kg sc
20 mg / kg sc
50 mg / kg sc
20 mg / kg sc
50 mg / kg sc
50 mg / kg sc
20 mg / kg sc
50 mg / kg sc
50 mg / kg sc
50 mg / kg sc
50 mg / kg sc
50 mg / kg sc

Change in ° / ₍

+ 57 + 38 + 1 (X) + 314 + 157 + 380 + 720 + 200 + 560 +> 829 + 220 + 940 + 160 + 160 + 160 + 140

Toxicity DL ₅₀ mouse iv

38 29

39

45

48

39 18

35

62

25 52 48

The values found show that the compounds III to XII are the two known compounds I and II with the same direction of action are very clearly superior. The toxicity of the tested Connections are of the same order of magnitude. The results show that the new compounds have a clear central damping effect. They are therefore suitable for the treatment of at Symptoms of anxiety and tension appearing in depression.

The compounds of the general formula I given above are produced in that a reactive ester of a hydroxyl compound of the general formula

(H)

with an amino compound of the general formula

Η —Ν

(HI)

where R ₁ , R ₂ , R ₃ and X are as defined above, are reacted and the bases obtained are optionally converted into non-toxic salts.

As reactive esters of the hydroxyl compounds in question The halides, in particular the bromides, come into consideration, and also the corresponding ones Sulphonic acid esters, such as toluenesulphonic acid esters or methanesulphonic acid esters.

The implementation of the corresponding reactive ester with a corresponding amine is for example in inert solvents such as benzene, lower alkanols or alkanones or in Water carried out, with an excess of amine ^ as acid-binding agent and optionally also P can serve as the sole reaction medium.

Among non-toxic salts of the compounds of the general formula given above are those to understand with such acids, their anions at the dosages in question pharmacologically are acceptable, d. H. have no toxic effects. It is also advantageous if the The salts to be used are readily crystallizable and have little or no hygroscopic properties. As non-toxic Salts come /. B. the salts with hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, ethane disulphonic acid, // - Hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, Malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid in Consideration.

example 1

a) 151.5 g of 10-bromomethyl-dibenzo- [b.f] -oxepine are dissolved in 380 ecm of absolute benzene and in

, registered a solution of 45 g of dimethylamine in 450 ecm of absolute benzene. The reaction mixture is then ^{heated to 50 to 60 °} C. for 1 hour, then cooled to 20 ° C., washed well with water, dried over potassium carbonate and the solvent is evaporated off in vacuo. The resulting residue is distilled under high vacuum to give the 10-dimethylaminomethyl-dibenzo [b, f] oxepin Kpo.oo4 at 128 to 13O ⁰ C passes. The yield is 86%. The base is converted into the hydrochloride with ethanolic hydrochloric acid, which, after recrystallization from ethanol, melts at 234 to 236 ° C.

b) In an analogous manner, by process a) from 10-bromomethyl] -dibenzo- [b, f] -oxepine, the following are obtained:

b ¹ ) with methylamine 10-MethyIaminomethyl-dibenzo- [b, f] -oxepine with a boiling point of _OO o4 145 ° C and the hydrochloride with a melting point of 185 to 188 ° C (from absolute ethanol);

b ²⁾ with pyrrolidine, the 10-pyrrolidinomethyl-dibenzo [b, f] oxepin from Kp. _OO i 150 to 155 ° C and the hydrochloride, melting at 193-196 ° C (from absolute ethanol) and

b ³ ) with 1-methyl-piperazine the 10- (4'-methyl-l'-piperaz1nylmethyl) -dibenzo- [b, f] -oxepine from the MP 82 to 83 ° C (from pentane) and the dihydrochloride from the F 210 to 215 C (from absolute ethanol).

The 10-bromomethyldibenzo- [b, fj-oxepin used as starting material has been prepared as follows: 100 g of 10-methyl-dibenzo- [b, fj-oxepin are in Dissolved 100 ecm of carbon tetrachloride and added 86.5 g of N-bromosuccinimide. With stirring it becomes The reaction mixture is heated under reflux for 3 hours and with two 200 watt lamps or a UV lamp exposed until all of the succinimide floats on the solution. Then the mixture is cooled to 20 C, the succinimide is sucked off and rewashed with carbon tetrachloride. The obtained filtrate is then washed with water, dried over sodium sulfate and evaporated in vacuo, the 10-bromomethyl-dibenzo- [b, f] -oxepine crystallized out. The compound melts after recrystallization from diethyl ether pentane at 88 to 90 C.

Example 2

Analogous to example 1 is

a ^l ) from 10-bromoethyl-dibenzo- [b, fJ-oxepine with dimethylamine the 10-0'-dimethylamino-ethyl) -dibenzo- [b, fj-oxepine of bp. _o0O5 135 to 140 C and the hydrochloride of F. 130 b \, 132 C, furthermore

a ² ) from 10-bromoethyl-dibenzo- [b, f] -oxepine with methylamine the 10- (l'-methylamino-ethyl) -dibenzo- [b, f] -oxepine of bp ₄ . _m , _s 140 to 145 C and the hydrochloride with a melting point of 235 to 237 C.

Example 3

a) According to Example 1, a) 154.9 g of 8-methoxy-10-bromomethyl-dibenzo- [b, fJ-oxepin in 4 (X) ecm of absolute benzene are reacted with 47 g of dimethylamine in 470 ecm of benzene and worked up. 8-Methoxy-10-dimethylamino-methyl-dibenzo- [b, f) -oxepine is obtained in a yield of 84 to 87 °; Kp. _OOO5 147 to 150 C. This compound is dissolved in isopropanol and the solution obtained is treated with ethanolic hydrochloric acid, the hydrochloride having a melting point of 204 to 208.5 C.

In an analogous manner, 8-methoxy-10-bromomethyl-dibenzo- [b, f] -oxepine are converted

a ¹ ) with methylamine das8-methoxy-10-methylaminomethyldibenzo - [b, fj-oxepin (bp. Oül 163 to 164 C) or its hydrochloride with a _{melting point of 151.5 to 154 C and}

a ² ) with the 1-methyl-piperazine the 8-methoxy-10 - (4 '- methyl -Y- piperazinyl - methyl) - dibenzo- [b, f] -oxepine with a temperature of 92 to 94.5 ° C and its dihydrochloride of m.p. 232.3 to 236 ° C. was obtained.

The 8-methoxy-10-bromomethyl-dibenzo- [bj] -oxepine used as starting material has been prepared as follows:
b) 24.4 g of 2-phenoxy-5-methoxy-benzoic acid are refluxed for 20 hours with 100 ecm of absolute benzene, 12.5 ecm of absolute ethanol and 2.4 ecm of concentrated sulfuric acid by removing the water that forms. The reaction mixture is cooled to 10 ° C., water, ice and under

⁶ S stirring 2N sodium carbonate solution until an alkaline reaction. The organic phase is then separated off, washed with water, dried over calcium chloride and evaporated in vacuo.

The 2-phenoxy-5-methoxybenzoic acid ethyl ester of bp-O _- U ₀₇ 126 to 129 ° C. is obtained by distilling the residue in a high vacuum.

c) 27.2 g of the ester obtained according to b) are dissolved in 100 ecm of absolute diethyl ether and the solution is added dropwise within half an hour to 2.4 g of lithium aluminum hydride in 100 ecm of absolute diethyl ether. The reaction mixture is refluxed for 5 hours, cooled to 15 ° C. and slowly mixed with 10 ecm of water. The precipitate which has separated out is then filtered off with suction and washed with diethyl ether. The filtrate is washed with water, dried over sodium sulfate and evaporated in vacuo. By distilling the residue in a high vacuum, 2-phenoxy-5-methoxy-benzyl alcohol with a boiling point of ₀₀₀₁ 137 to 139.degree. C. which solidifies and melts at 53 to 55.4.degree.

d) 23 g of the 2-phenoxy-5-methoxy-benzyl alcohol obtained in c) are dissolved in 70 ecm of absolute benzene, drips into the solution within an hour 0 to 10 C 12 g of phosphorus tribromide and heated the mixture for 1 hour to 50 to 55 C. Then is cooled to 15 ° C., the mixture is decomposed with ice and water and the organic phase is separated off. These is washed neutral with 2N sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated in vacuo. The residue, the 2-phenoxy-5-methoxy-benzyl bromide. crystallized and melts at 92 ° C.

e) 29.3 g of the crude 2-phenoxy-5-methoxy-benzyl bromide obtained according to d) are added within one hour to a refluxing mixture of 15 g of powdered potassium cyanide in 130 ecm of ethanol and then refluxed for a further 3 hours. The reaction mixture is cooled to 15 ° C., concentrated in vacuo, poured into water and extracted with diethyl ether. The ethereal solution is then washed with water, dried over sodium sulfate and evaporated in vacuo. Distillation of the residue in a high vacuum at 134 to 138 ° C. under a pressure of 0.005 Torr gives 2-phenoxy-5-methoxyphenylacetonitrile. which, recrystallized from methylcyclohexane, melts ^{at 47 to 49 C.}

Π 23.9 g of the raw material obtained according to e) are boiled 2-phenoxy-5-methoxy-phenylacetonitrile with 24 ecm 50 "(, potassium hydroxide solution and 100 ecm ethanol for 21 hours under reflux. The reaction mixture is then concentrated in vacuo and the residue is dissolved in water. The aqueous solution is extracted with diethyl ether and acidified with concentrated hydrochloric acid to the Congo acid reaction. A precipitate separates out. the washed with water and in vacuum is dried at 7ff C. By recrystallization the same from cyclohexane becomes 2-phenoxy-5-methoxyphenylacetic acid obtained from m.p. 92 to 95.5 C.

g) 25.8 g of the 2-phenoxy-5-methoxy-phenylacetic acid obtained above are dissolved at 60 ° C. in 235 g of polyphosphoric acid. increases the temperature to 90 to 95 C, maintains this for 20 minutes and then cools it down The reaction mixture drops to 70 ° C. Then the mixture is poured into water and treated with diethyl ether extracted. The ether solution is washed neutral with saturated sodium bicarbonate solution and water, dried over sodium sulfate and concentrated in vacuo. From the remaining essential solution the 8-methoxydibenzo- [b, f] -oxepin-H (IOH) -one crystallizes on cooling to 0 C from 75.8 to 78.5 "C.

h) A suspension of 4 g of sodium amide in 12 ecm of absolute toluene is added dropwise with stirring within 15 minutes to a solution of 24 g of the above 8-methoxy-dibenzo- [b, f] -oxepin-l l (10H) -one in 140 ecm of absolute benzene and refluxed for 2 hours. The reaction mixture is heated to 45.degree cooled and 18 g of methyl iodide were added dropwise at this temperature over the course of one hour and stirred for a further 72 hours. Then the whole thing is refluxed for 4 hours at 15 ° C chilled and poured onto water and ice. The organic phase is separated off and washed with water.

dried over calcium chloride and evaporated in vacuo. Distillation of the residue in a high vacuum, the 8-methoxy-l0-methyl-dibenzo [b, f] oxepin-l l (10H) -one was obtained, bp. _OO i _5163-165 C.

i) A solution of 184 g of the above 8-methoxy-10 - methyl - dibenz - [b, f] - oxepin - H (IOH) - ons in 500 ecm of absolute diethyl ether is used within a Hour to a suspension of 22 g of lithium aluminum hydride in 400 ecm of absolute diethyl ether

.κ dropped in. Then the reaction mixture is 5 hours boiled under reflux, then cooled and carefully mixed with 40 ecm of water. The one here The resulting precipitate is filtered off with suction and washed with diethyl ether. One unites the FiI councils and works up the precipitate and the filtrate.

Ice and concentrated hydrochloric acid are added to the precipitate while stirring, and the precipitate does not Dissolving organic content is suctioned off and washed with water. By recrystallization

.15 Ethanol becomes S-methoxy-10-methyl-10.ll-dihydro-dibenzo- [b, f] -oxepin-1 l-ol, presumably the ice-cream form that melts at 132 to 135.5 ° C.

To work up the ethereal solution, it is washed with water, dried over sodium sulfate and evaporated. The oily residue contains an isomer mixture of 8-methoxy-10-methyl-10.11-dihydro-dibenzo- [bf] -oxepin-n-ols, which is processed further as a crude product.
j) To a solution of 40.7 g of 8-methoxy-l0-methyl-

-i> 10.1 l-dihydro-dibenzo- [b, f] -oxepin-l l-ol in 400 ecm of absolute benzene and 48 g of absolute pyridine becomes a solution of 22 g within half an hour Thionyl chloride in 200 ecm of absolute benzene was added dropwise at 10 to 20 C with thorough stirring. On that The reaction mixture is stirred for a further 4 hours at a temperature of 40 to 50 ° C. and then cooled. the reaction solution is poured into water and the organic phase is separated off. This is done with 2N hydrochloric acid and water, dried over sodium sulfate and evaporated in vacuo at 50 C, the crude 8-methoxy-10-methyl-1 l-chloro-10,11-dihydrodibenzo [b.f] oxepine remains behind.

k) A solution of 40 g of the above crude 8-methoxy-10-methyI-l l-chloro-10.1 l-dihydro-dibenzo- [b.f] -

f »oxepins and 21 g of potassium tertiary butoxide in 250 ecm absolute toluene is refluxed for 16 hours. The reaction mixture is then cooled to 20 ° C. poured onto water, the organic phase separated, washed well with water,

<> 5 dried over sodium sulfate and evaporated in vacuo. The residue obtained is distilled in a high vacuum. The 8-methoxy-IO-methyl-dibenzo- [b.f] -oxepine is obtained from Kp. "," "144 to 146.5 C.

1) 10 g of 8-methoxy-10-methyl-dibenzo- [b, fJ-oxepin are dissolved in 80 ecm of carbon tetrachloride, and 8.0 g of powdered N-bromosuccinimide are added. The reaction mixture is refluxed with stirring for 1 hour and exposed to two 200 watt lamps until all of the succinimide floats on the solution. The mixture is then ^{cooled to 20 °} C., the succinimide is filtered off with suction and washed with carbon tetrachloride. The filtrate is washed with water, dried over sodium sulfate and evaporated in vacuo, the 8-methoxy-10-bromomethyl-dibenzo- [b, f] -oxepine crystallizing out. The compound melts after recrystallization from benzene at 115 to 117 ° C.

More crude 8-methoxy-10-bromomethyl-dibenzo- [b, fj-oxepin is obtained if the mixture of isomers of 8-methoxy-10-methyl-10, ll-dihydro-dibenzo- [b, fJ-oxepin-ll-ols obtained according to i) is obtained analogously to j) in crude 8-methoxy-l 1-chloro-10-methyl-10.1 l-dihydrodibenzo- [b, f] -oxepine converts this analogously to k) into crude 8 - methoxy -10 - methyl - dibenzo - [b, fj - oxepin and the latter is implemented analogously to 1).

Example4

Analogously to Example 3, 8-chloro-10-bromomethyl-dibenzo- [b, f] -oxepine is obtained

a ¹ ) with dimethylamine the 8-chloro-10-dimethylamino-methyl-dibenzo- [b, f] -oxepine from F. 68 to

69 ⁰ C and its hydrochloride with a temperature of 242 to 244 ° C and

a ² ) 8-chloro-10-diethylaminomethyl-dibenzo- [b, fj-oxepin of bp ₀₄ 155 to 157 ° C and its hydrochloride from 182 to 184 ° C with diethylamine obtained.

Claims (1)

Claim: Basically substituted dibenzo- [b, f] -oxepines and their non-toxic salts of the general formula , R ₂ CH-N in which X is a hydrogen atom, a chlorine atom or the methoxy radical, R _{1 is} a hydrogen atom or the methyl radical and R ₂ and R _{3 are} a hydrogen atom or lower alkyl radicals which, together with the nitrogen atom, can form the pyrrolidine or piperidine ring or where the radicals R ₂ and R ₃ with the nitrogen atom represent the 4-methylpiperazine ring. 909 550/97