DE1470428C - 5- (beta-dimethylaminoethyl) -5,6dihydro-6-oxomorphanthridines - Google Patents

Description

where R is an alkyl group with at most 5 carbon atoms, and acid addition salts thereof.

2. · 5 - (ß - Dimethylaminoethyl) - 11 - methyl-5,6 - dihydro - 6 - oxomorphanthridine and its acid addition salts.

3. Process for the preparation of 5 - (ß- dimethylaminoethyl) -5,6-dihydro-6-oxomorphanthridines of the general formula I and their acid addition salts, characterized in that either in a manner known per se

a) 5,6 - dihydro-III-R-6- oxomorphanthridines with reactive esters of / S-dimethylaminoethanol or reactive esters of 5 - (ß - hydroxyethyl) - 5,6 - dihydro -11 - R - 6-oxomorphanthridine with Dimethylamine, optionally using a condensing agent, or

30th

b) compounds of the general formula
CH ₂ - CH ₂ - N (CH ₃ ) ;, OR ₂
NR ₁ CO

in which R is an alkyl group with at most 5 carbon atoms, R _{1 is} a hydrogen atom or a berizoyl or acetyl group and R _{2 is} a hydrogen atom or a lower alkyl group, optionally in the presence of a solvent, heated or
c) compounds of the general formula

CH ₂ -CH ₂ -NH-R '
N-CO

(III)

in which R 'denotes a hydrogen atom or a methyl group, methylated to the tertiary amine and the compounds obtained according to a) to c) are optionally converted into the salts with acids.

The invention relates to 5 - (/? - Dimethylaminoäthyi) -5,6-dihydro-6-oxomorphanthridines the general formula -

CH ₂ -CH ₂ -N (CH ₃ ) ₂

(I)

in which R denotes an alkyl radical having at most 5 carbon atoms, and their acid addition salts.

The compounds are pharmacologically active substances that can be used as antidepressants.

The following table shows a comparison of the effects of the 5 - (/? - dimethylaminoethyl) - 11 - methyl - 5.6 - dihydro - 6 - oxomorphanthridine and 5 - (ß - dimethylaminoethyl) -11 - ethyl - 5.6 - dihydro - 6 - oxomorphanthridine on the one hand and the well-known antidepressants dibenzepine hydrochloride, nortriptylinum and imipramine on the other.

on the one hand with regard to the anti-Tet'rabenazine effect and the peripheral parasympathicolytic effect. As a measure of the anti-tetrabenazine effect, that dose of active ingredient is given which reduces the rigidity (catalepsy) caused by tetrabenazine (10 mg / kg ip) in 50% of the treated rats to less than 30 seconds (ED ₅₀ ). The peripheral parasympatholytic effect is assessed on the basis of the pupil dilation. The dose, which doubles the pupil size in the test mice compared to the initial value (ED ₂₀₀ ), serves as a measure of the pupil dilation. The table also gives the oral LD ₅₀ on the mouse as a measure of the acute toxicity.

table Peripheral
parasympatholytic
effect
ED ₂₀₀ in mg / kg P- o.
(Mouse)
Pupil size toxicity
LD ₅₀ in mg / kg po
(Mouse) , Active ingredient anti-tetrabenazine
effect
ED ₅₀ in mg / kg ip
(Rat)
catalepsy > 70
> 100
49
19th
39 235 ■
360
225
370 '
385 a) Compounds according to the invention
5 - (/ 9-dimethylaminoethyl) -ll-methyl-
S ^ -dihydro-o-oxomorphanthridine-hydro-
chloride 17th
. "23 -
25th
25 ■
12.5. 5-09-dimethylaminoethyl) -l 1-ethyl-
5,6-dihydro-6-oxomorphanthridine
b) Known antidepressants
Dibenzepine Hydrochloride .:
Nortriptylinum
Imipramine

The compounds of general formula I are obtained by being known per se Way either

a) 5,6 - Dihydro -ll-R-6- oxomorphanthridines with reactive esters of ^ -dimethylaminoethanol or reactive esters of 5- (ß-Hy droxyäthyl) - 5,6 - dihydro -ll-R-6- oxomorphanthridins with Dimethylamine, optionally using a condensing agent,

. implements or

b) compounds of the general formula

CH ₂ -CH ₂ -N (CH ₃ ) ₂ OR ₂
NR ₁ CO

40

in which R is an alkyl group with at most 5 carbon atoms, R _{1 is} a hydrogen atom or a benzoyl or acetyl group and R _{2 is} a hydrogen atom or a lower alkyl group, optionally in the presence of a solvent, heated or
c) compounds of the general formula,

CH ₂ -CH ₂ -NH-R '

N-CO

in which R 'denotes a hydrogen atom or a methyl group, methylated to the tertiary amine and the compounds obtained according to a) .bis c) are optionally converted into the salts with acids. In variant a), particularly suitable reactive esters of the alcohols are those of carbonic acid, of hydrohalic acids or of sulfonic acids, such as p-toluenesulfonic acid. As a condensation agent alkali metals, their hydrides and amides or other alkali metal compounds are suitable, ζ. B. sodium amide, sodium hydride, sodium ethylate, phenyl potassium, phenyllithium and potassium tert-butoxide.

■ The 11-lower alkyl which can be used as starting materials - 5,6 - dihydro - 6 - oxomorphanthridines are more appropriate in excellent yield due to ring closure ο - isocyanato - 1,1 - diphenylalkanes, e.g. B. accessible with the help of aluminum chloride, which in turn from the corresponding o-amino-l, l-diphenylalkanes can be obtained. ·.

In variant b), the starting compound does not need to be used in isolated form. Rather, the process can also be used together with the introduction, which is normally the preliminary stage the basic group -

- CH ₂ - CH ₂ - N (CH ₃ );

can be carried out in a single process step without the compound II being isolated. Here an o-acylamino-o'-carboxy-1,1-diphenylalkane in the presence of a reactive ester of / i-dimethylaminoethanol, z. B. a hydrohalic acid, sulfonic acid or carbonic acid ester, up to Entrance of the ring closure heated, if necessary using a condensing agent, of which those specified are particularly suitable. The 5- (ß-dimethylaminoethyl) - 5,6 - dihydro - 6 - oxomorphanthridines of the general formula I. As a solvent for the (TJ]) Ring closure are xylene or dioxane.

The methylation according to variant c) takes place, for example, by reacting the amine with a methanol ester, in particular a hydrohalic acid ester, or by reacting the amine with formaldehyde either using hydrogen in the presence of a catalyst or using a reducing agent such as formic acid (reductive alkylation).

The compounds I obtained by one of these processes can be used both as free bases and

45

in the form of their addition salts with suitable acids such as hydrohalic acids, sulfuric acid, nitric acid, Phosphoric acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, Tartaric acid or toluenesulfonic acid.

B e i s ρ i e 1 1

A mixture of 6.6 g of II-methyl-5,6-dihydro-6-oxomorphanthridine, 1.5 g of powdered sodium amide and 60 ml of absolute dioxane is refluxed for 2.5 hours. 7.8 ml of a 5 η solution of / S-dimethylaminoethyl chloride in toluene are then added, ^{the mixture is heated under reflux 1} × for 4 hours, the solvent is distilled off from the reaction mixture under vacuum, the residue is mixed with water and, after the addition of concentrated sodium hydroxide solution, with Ether extracted. The ethereal solution is washed with water and extracted with dilute hydrochloric acid. The hydrochloric acid extract is washed with ether and made alkaline with concentrated sodium hydroxide solution. Here an oil separates out, which is extracted with ether. The ethereal solution is washed with water and saturated sodium chloride solution, treated with activated charcoal, filtered through clay and evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and ethanol. The solution is made weakly acidic with ethanolic hydrochloric acid and then concentrated. The addition of ether gives 7.2 g (73% of theory) 5 - (ß - dimethylaminoethyl) - 11 - methyl - 5,6 - dihydro - 6 - oxomorphanthridine - Hydrochloric !, which, recrystallized from ethanol / ether, the Shows melting point 239 to 241 ° C.

The used in this Example as the starting material 11 - methyl - 5,6 - dihydro - 6 - oxomorphanthridin is obtained as follows: To a 120 ml at - 10 ⁰ C cooled 20% solution of phosgene in toluene is added with stirring a solution of 22 , 2 g of l- (o-aminophenyl) -l-phenylethane in 200 ml of absolute toluene are added dropwise, the temperature not being allowed to rise above -5 ° C. The reaction mixture is then brought to reflux temperature in 20 minutes while passing in phosgene and kept at this temperature for 15 minutes. After introducing dry nitrogen to displace excess phosgene, the solvent is evaporated and the residue is distilled in a high vacuum. At 100 ° to 105 ° C. and 0.07 torr, 24.8 g (99% of theory) of 1- (o-isocyanatophenyl) -1-phenylethane are obtained.

A solution of 24.5 g of this compound in 150 ml of o-dichlorobenzene is introduced dropwise with stirring into a mixture of 15.4 g of anhydrous aluminum chloride and 150 ml of o-dichlorobenzene heated ^{to 80 ° C.} The temperature is then increased to 140 ° C., the mixture is stirred at this temperature for 1.5 hours, then poured onto ice water and the o-dichlorobenzene is removed from the emulsion formed by steam distillation. The residue is isolated by filtration, washed with water, dried in vacuo and dissolved in hot acetone. The hot solution is treated with activated charcoal, filtered through clay, concentrated until crystals form and cooled. By filtering and washing the resulting crystals with ether, 20.5 g (84% of theory) of 11-methyl-5,6-dihydro-6-oxomorphanthridine with a melting point of 202 to 205 ° C. are obtained.

Example 2

6.5 g of 5 - {β - aminoethyl) - 11 - methyl - 5,6 - dihydro - 6 - oxomorphanthridine are boiled under gentle reflux for 15 hours with 10 ml of 90% formic acid and 8 ml of 38% formaldehyde. After adding 15 ml of 2η hydrochloric acid, the reaction mixture is concentrated to dryness in vacuo. By recrystallizing the residue from ethanol / ether using activated charcoal

• 6.2 g (77.5% of theory) 5 - (/ S-dimethylaminoethyl) -11 - methyl - 5,6 - dihydro - 6 - oxomorphanthridine hydrochloride with a melting point of 239 to 24 ° C.

Example 3

8.92 go-acetylamino-o'-carboxylic acid methyl ester - 1,1 - Diphenylethane (0.03 mol) are in 50 ml of absolute dioxane with 1.29 g of powdered sodium amide (0.033 mol) refluxed for 1 hour. After adding 3.88 g / 3-dimethylaminoethyl chloride (0.036 mol) is heated to boiling for 16 hours.

After evaporation in vacuo, the residue is partitioned between ether and water. The strongly basic components are isolated in the usual way by extraction with dilute acetic acid. A resin is obtained by distillation which, by crystallization from ether / petroleum ether and acetone / petroleum ether, gives 5.97 g of 5 - {ß - dimethylaminoethyl) - 11 - methyl-5,6 - dihydro - 6 - oxomorphanthridine, corresponding to 67.7% the theory. The hydrochloride produced in the usual way has a melting point of 239 to 241 ° C. (from ethanol / ether) and is identical to the product obtained according to Example 1 or 2.

Example4

Using the same procedure as in Example 1, but using an equivalent amount of 11-ethyl5,6 - dihydro - 6 - oxomorphanthridine instead of 11 - methyl - 5,6 - dihydro - 6 - oxomorphanthridine, 5- (ß- Dimethylaminoethyl) -11-ethyl-5,6-dihydro-6-oxomorphanthridine with a melting point of 85 to 88 ° C. (from ether / petroleum ether).

Claims (1)

Patent claims: 1. 5 - (β - dimethylaminoethyl) - 5,6 - dihydro-6-oxomorphanthridines of the general formula CH ₂ - CH ₂ - N (CH ₃ ); N-CO (I)