DE1470161B - 5- (gamma-alkylaminopropyl) -5, 7-dihydro-6H-dibenzo square brackets on d, square brackets on square brackets on 1,3 square brackets on -diazepin-6-one derivatives - Google Patents

Description

in which R and R _{1 are} methyl or ethyl radicals and their acid addition salts.

2. 5 - (γ- dimethylaminopropyl) -5,7-dihydro-6 H -dibenzo [d, f] [1,3] diazepin-6-one maleate.

The invention relates to 5- (γ-alkylaminopropyl) -5,7-dihydro-6H-dibenzo [d, f] [1,3] diazepin-6-one derivatives the general formula

R ₁

(D

amide and mixtures of these solvents. Preferred solvents are dioxane and xylene. The temperature and duration of the reaction can be varied within a wide range, namely from about 40 ^° C. for a period of about 24 hours, up to 200 ° C. for a period of about 1 to 2 hours. The reaction mixture is preferably heated 2 to 10 hours at the reflux temperature of the solvent

ίο Use quantities of the reactants. Preferably however, the aminoalkyl halide is used in a slight excess. The alkali salt of 5,7-dihydro-6 H-dibenzo [d, f] [1,3] diazepin-6-one is most conveniently prepared in situ by making a mixture des dibenzodiazepinons and an alkali amide, e.g. B. sodium amide, or an alkali hydride, e.g. B. sodium hydride, heated under reflux of the solvent until the end of the salt formation. Possibly the reaction can be carried out in a single step by adding a mixture of the dibenzodiazepinone, of the aminoalkyl halide and the alkali amide or alkali hydride in the chosen solvent heated until the reaction is complete. The reaction products are used directly as free bases or isolated after their conversion into acid addition salts.

The dibenzodiazepinone used as starting material in the above process is produced by heating 2,2'-diaminobiphenyl with urea to a temperature of about 180 to 210 ^° C. until the evolution of ammonia ceases.

The compounds of the invention can also can be prepared by adding a 2-amino-2 '- (aminopropylaminoj-biphenyl compound the general formula

in which R and R _{1 represent} methyl or ethyl radicals, and their acid addition salts.

The compounds of the invention can be prepared by adding an alkali salt of 5,7-dihydro - 6H - dibenzo [d, f] [l, 3] diazepin - 6 - one of the formula ■

(Π)

H-N Ν --Η

with an aminoalkyl halide of the general formula

N- (CH ₂ J ₃ -X

(III)

in which R and R ₁ denote a methyl or ethyl radical and X denotes a halogen atom, brings about the reaction. The reaction can be carried out in suitable non-reactive solvents such as hydrocarbons, e.g. B. benzene, toluene or xylene, ethers, e.g. B. dioxane, tetrahydrofuran, dibutyl ether or glycol ether without free hydroxyl groups, tertiary amides, z. B. Dimethylform

NH

(CH ₂ ) ₃ -N

(IV)

in

the R and R _{1 have} the meaning given above, reacts with a reactive derivative of carbonic acid. Reactive carbonic acid derivatives suitable for this purpose are e.g. B. Compounds of the general formula

O
X-C-Y

wherein X and Y are each a lower alkoxy, aralkoxy or aryloxy radical, an amino radical, a halogen atom, preferably a chlorine atom, or together form a lower alkylimino, aralkylimino or arylimino radical and furthermore other reactive derivatives, e.g. B. carbon dioxide and alkali salts of cyanic acid. Preferred carbonic acid derivatives are urea, phosgene, ammonium carbamate, lower alkyl carbamates (urethanes) and lower alkyl esters of chloroformic acid. At least one equivalent of the reactive carbonic acid derivative is normally used. However, it is preferred to use an excess of this reagent. The reaction is normally carried out at temperatures between about 0 and 25O ⁰ C, depending on the selected reactants,

accomplished. With phosgene or a lower Alkylesler of chloroformate the reaction is usually carried out below 50 "C while applied with the use of urea, ammonium carbamate and urethanes temperatures of about 100 to 25O ^r C. The reaction may be carried out with or without a solvent. Suitable Solvents are ethers, e.g. diethyl ether, tetrahydrofuran and glycol ether without a free hydroxyl group, and also hydrocarbons, e.g. benzene or toluene, halogenated hydrocarbons and similar non-reactive solvents.When urea is used, the reaction is preferably carried out in the absence of a solvent. Sometimes the yield is improved if the reaction is carried out in the presence of an acidic or static reagent or catalyst. If carbon dioxide is used as the reactant, then the reaction is preferably carried out under high pressure. Depending on the choice of reagents and the isolation method, can d The products are obtained as free bases or in the form of their acid addition salts. The ^ -amino-Z'-iaminopropylaminoJ-biphenyl compounds of the general formula IV used as starting materials in the above process can be obtained by catalytic or chemical reduction of biphenyl compounds of the general formula

NO ₂ NH - (CH ₂ ) ₃ - N

(V)

getting produced. These can be obtained by alkylating 2-nitro-2'-aminobiphenyl or the N-formyl derivative the same with a γ-aminopropyl halide the general formula

N - (CH ₂ J ₃ -X

(VI)

in which X is a halogen atom. If the N-formyl derivative is used, then the N-formyl group removed by hydrolysis prior to reduction of the nitro group. The 2-nitro-2'-aminobiphenyl becomes by selective, catalytic or chemical reduction of one of the nitro groups of 2,2'-dinitrobiphenyl manufactured.

The compounds according to the invention can be in the form of the free bases of the general formula 1 or in the form of one of their acid addition salts with an inorganic or organic acid. Examples more representative, non-toxic, pharmaceutically acceptable acid addition salts are the hydrochlorides, Hydrobromides, sulfates, hydroiodides, nitrates, phosphates, acetates, propionates, benzoates, citrates, maleates, Tartrates, succinates, sulfamates, p-toluenesulfonates and benzenesulfonates. If a compound according to the invention is to be used in the form of an acid addition salt are, then one prepares the salt expediently so that the base with the chosen Reacts acid in an inert solvent.

The acid addition salts can be prepared by reaction with a base, e.g. B. sodium hydroxide or potassium hydroxide, converted into the free bases.

The compounds according to the invention are valuable pharmacological active ingredients. They are stimulants for the central nervous system and diuretics. As central nervous system stimulants, they can suppress the depression caused by reserpine and tetrabenazine. As a result of this effectiveness They can be used as mental lifters or antidepressant agents. she are preferably administered orally, but are also effective when administered parenterally.

The compound 5- (γ-dimethylaminopropyl) -5,7-dihydro - 6 H - dibenzo [d, f] [1,3] diazepin - 6 - one - maleate was with two commercial products, namely 5- (3-dimethylaminopropyl) - 10.11 - dihydro - 5 H - dibenzo- [b, f] azepine hydrochloride (imipramine) and 5- (3-dimethylaminopropylidene) - dibenzo [a, d] [l, 4] cycloheptadiene hydrochloride (amitriptyline hydrochloride) with regard to the energization or the effect of suppressing depression, as demonstrated by tetrabenazine methanesulfonate (2 - oxo - 3 - isobutyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - 11 bH - benzo [a] quinolizine) is caused, compared. This connection according to the invention has proven to be more advantageous here shown as the two known drugs. The lethal dose of the new compound is also greater than that of amitriptyline hydrochloride and is of the same order of magnitude as that of Imipramine.

The method according to the invention is explained in more detail using the following examples.

example 1

A mixture of 7 g of 5,7-dihydro-6H-dibenzo [d, f] - [l, 3] diazepin-6-one and 1.04 g of sodium amide in 200 ml of dry dioxane was stirred for one hour until the cessation of the Ammonia development heated to refluxing boiling. The mixture, which now contained diazepin-6-on the sodium salt of 5,7-dihydro-6H-dibenzo [d, f] [l, 3] was cooled to 6O ⁰ C, a solution of 3.06 g Ν , Ν-Dimelhyl-y-chloropropylamine in 40 ml of dry dioxane was added over the course of 30 minutes with stirring and heated to refluxing for 4 hours with continued stirring. After cooling, unreacted sodium amide was destroyed by adding 10 ml of methanol, filtering the mixture, evaporating the solvent from the filtrate, extracting the residue with cold, dilute hydrochloric acid and filtering the acidic extract. The filtrate was made alkaline with aqueous ammonia, the alkaline mixture was extracted with ether and the ether solution was dried and evaporated to dryness, 5- (γ-dimethylaminopropyI) -5,7-dihydro-6H-dibenzo [d, f] [ l, 3] diazepin-6-one obtained, which, after recrystallization from ether-ethyl acetate, at 116

melted to 119 ° C.
60

B e i s ρ i e 1 2

A mixture of 10.5 g of 5,7-dihydro-6H-dibenzo- [d, f] [l, 3] diazepin-6-one, 1.95 g of sodium amide and 6.7 g of N-N-dimethyl-y-chloropropylamine in 400 ml of xylene was heated to refluxing for 7 hours with stirring. After cooling, 10 ml

35

Methanol was added and the mixture was extracted with aqueous 2N hydrochloric acid solution. The acidic aqueous Layer was separated and filtered and the filtral made basic with aqueous ammonia. The basic mixture was extracted with allyl acetate, which Ethyl acetate solution dried and evaporated to dryness, giving 5 - () '- dimethylaminopropyl) -5,7-dihydro-6H-dibenzo [d, f] [l, 3] diazepin-6-one obtained, which, after crystallization from a mixture of ethyl acetal and pelrolether, at 116 to 119 ° C melted.

A solution of 3 g of the free base in 25 ml of ethyl acetate was treated with 1.2 g of maleic acid, the mixture concentrated and the precipitated maleic acid salt of 5 - () < - Dimethylaminopropyl) - 5,7 - dihydro-6H-dibenzo [d, f] [1,3] diazepin-6-one filtered off and from a mixture of ethyl acetate, ethanol and ether recrystallized, whereupon it melted at 122-124 ° C.

Replaced Ν, Ν-Dimelhyly-chloropropylamine in the above process by an equivalent amount of Ν, Ν-diethyl-y-chloropropylamine, then one obtained 5 - (y - diethylaminopropyl) - 5,7 - dihydro - 6 H - dibenzo [d, f] [l, 3] -diazepin-6-one, which melted at 77/78 "C.

Example 3

A solution of 1.5 g of 2 - () '- dimethylaminopiopylamino) -2'-nitrobiphynyl, in 100 ml of ethanol, which contained a 10 ⁿ / _o strength palladium-activated carbon catalyst. was hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered off and the solvent was evaporated from the filtrate. The crude 2-amino-2 '- ()> - dimethylaminopropylamino) -biphenyl thus obtained was intimately mixed with 0.6 g of urea and the mixture was heated to 180 to 185 ° C. in an oil bath for 30 minutes. The solid was extracted with an aqueous 2N hydrochloric acid solution, the acidic solution was made alkaline with aqueous ammonia, and the basic mixture was extracted with ethyl acetal. The organic solution was dried and evaporated to dryness, giving 5- (9'-dimethylaminopropyl) -5,7-dihydro-6H-dibenzo [d, f] [1.3] diazepin-6-one, which

after recrystallization from ethyl acetate n-hexane at 116 to 118 "C melted.

If 0.8 g of ammonium carbamate was used instead of 0.6 g of urea in the above process, then the result was one the same product.

Claims (1)

Patent claims: 1. 5- (γ-Alkylaminopropyl) -5,7-dihydro-6H-dibenzo [d, f] - [l, 3] diazepin-6-one derivatives of all common formula H-N. (CH ₂ ) ₃ -N