KR880001866B1 - Method for preparing 5(amino-alkyl)-phenyl-5h-dibenzo(b,e)(1,4)diazepines - Google Patents

Abstract

A method for prepg. the title compd. (I) comprises (1) reductively alkylating O-nitrodiphenylamine with 3-(1-phthalimido)-1chloropropane to obtain N-[3-(1-phthalimido)propyl -Oaminodiphenylamine (III), (2) reacting (III) with benzoyl chloride (iv) to N-[3-(phthalimido) propyl -O-benzamidodiphenylamine (V), (3) dehydration-ring closing of (v) to 5-(3-phthalimido-propyl)11-phenyl-5H-dibenzo[b,e [1,4 diazepin (vi), (4) reacting (vi) with hydrazine to 5-(3-aminopropyl)-11- phenyl-5H-dibenzo[b,e [1,4 diazepin (vii) (R1, and R2=H) and (5) opt. reacting (vii) with triethyl oroformate and sodium borohydride to (viii) (R1=H, R2=Me). X=halogen.

Description

5-(Aminoalkyl)-11-Phenyl-5H-Dibenzo [b, e] [1, 4] Preparation of diazepine

The present invention relates to 5- (aminoalkyl) -11-phenyl-5H-dibenzo- [b, e] [1,4] diazepine of the general formula (I) and pharmaceutically acceptable salts thereof which are useful as therapeutic agents for depression. It relates to a manufacturing method.

Wherein R ¹ and R ² are selected from the group consisting of hydrogen and methyl, and X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine.

Compounds in which R ¹ and R ² are both hydrogen or one methyl and the other hydrogen are novel compounds.

Pharmaceutically acceptable acid addition salts are physiologically acceptable salts, such as those formed by strong acids or weak acids.

Representative examples of strong acids are hydrochloric acid, sulfuric acid and phosphoric acid. Representative examples of the weak acid include fumaric acid, maleic acid, succinic acid, oxalic acid, and cyclohexamic acid.

British Patent No. 907,646 (Wander. A.) describes a process for the preparation of certain dibenzodiazepines (such as the active ingredient in the maleate form of Example 1 below) used in the process of the present invention.

British Patent No. 959,994 (Wander. A.) discloses 5- (aminoalkyl) -11-phenyl-10, 11-dihydro-5H- as parasympathetic blockers, antihistamines, antispasmodics, neurostabilizers and psychostimulants. The use of reduced forms such as dibenzo- [b, e] [1,4] diazepines is described.

It is reported in the literature that a kind of dibenzo diazepine compound, in particular 2-chloro-5- (dimethylaminoethyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, in mice shows hypersensitivity [Greig, ME, et al., J. Med. Chem. 14, No. 2 page 153 (1971).

To test the antidepressive action of the compounds of the present invention, the following methods described in the literature, which have been demonstrated in the past for the effectiveness of compounds for treating depression in the human body, are used [Englehardt, EL, et al. , J. Med. Chem. 11 (2): 325 (1968)]: 20 mg / kg of the compound to be tested was sewage-induced amount of tetrabenazine (as methanesulfonate salt) in 32 adult female mice (ICR-DUB species). Intraperitoneally) 30 minutes before administration. After 30 minutes, each animal is examined for complete eyelid closure (sewage). The methods described in the literature can determine the ED ₅₀ (average effective dose) of each test compound that blocks tetrabenazine, which causes depression in mice. See Litchfield et al., J. Pharmacol. Exp Therap. 96: 99-113 (1949).

Preferred dibenzo diazepines useful in the process of the invention include the active material of Example 1, i.e. 5- (3-dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine to be.

The present invention provides a method for treating depression and a pharmaceutical composition thereof.

Other objects and advantages of the present invention are well known to those skilled in the art, and other differences can be appreciated from the following description and claims.

In the method of the present invention, conventional dosage forms of the active substance containing the active ingredient of formula (I) and the appropriate pharmaceutical carrier may be used as solutions, syrups, elixirs, tablets, capsules, suppositories, powders and the like.

Formula (I) compounds in which the 5-position is substituted with 3-dimethylaminopropyl radicals may be prepared by using a dehydration-condensation catalyst such as phosphorus pentoxide or oxyhalogenide of phosphorus (preferably). Prepared by dehydrating ring closure of N- (3-dimethylaminopropyl) -0-benzamino-diphenylamine (see British Patent Application No. 907,646) in 1,2,2, -tetrachloroethane). The scheme is as follows:

Wherein X is as defined in the general formula (I) above.

The novel compounds of general formula (I) in which the 5-position is substituted with 3-aminopropyl radicals are prepared using the novel N- [3- (1-phthalimido) propyl] -0-benzamido-diphenylamine (II b). The phthalimido moiety is converted to amino (NH ₂ ) with hydrazine and acid after dehydration ring closure.

In the above formula, X is as defined in general formula (I).

A novel compound of formula (I) in which the 5-position is substituted with 3-monomethyl propylamine is prepared by reacting a 3-aminopropyl compound with triethylorthoformate followed by sodium borohydride. (Method of Crocket & Blanton, 1974 (1): 55-6 Synthesis).

The scheme is as follows:

Benzamido compounds, starting compounds of formula II (II a and II b), are prepared by modifying the method of British Patent Application No. 907,646. Ortho-nitro-diphenylamine is first alkylated with β-chloropropyl dimethylamine or 3- (1-phthalimido) -1-chloropropane and then the nitro moiety is reduced to hydrogen over Pd / c to give the corresponding orthoamino Obtain the compound. The amino radical in the ortho position is reacted with benzoyl halide or substituted benzoyl halide. The reaction scheme is as follows.

Q = -N (CH ₃ ) ₂ or 1-phthalimido

Preparation Example 1

N- (3-dimethylaminopropyl) -0-aminodiphenylamine

32.0 g (0.107 mol) N- (3-dimethylaminopropyl) -0-nitrodiphenylamine (boiling point 155 ° / 0.4-174 ° C./0.33 mm), 100 ml of 200 standard strength ethyl alcohol and 1.5 g of 10% The mixture of palladium on carbon catalyst is shaken under hydrogen atmosphere at room temperature for 1 hour.

After absorbing approximately the theoretical amount of hydrogen, the catalyst is filtered off through a celite filter cake and the solvent is removed under reduced pressure.

The residue is distilled under high vacuum as follows:

Thin layer chromatography using 20% methyl alcohol-80% benzene on silica gel showed that Fraction 3 was very pure.

Production Example 2

N- (3-dimethylaminopropyl) -0-benz amido diphenylamine

17.8 g (0.063 mol) of benzoyl chloride is added to 15.5 g (0.0575 mol) of N- (3-dimethyl-aminopropyl) -0-aminophenylamine in 100 ml of pyridine cooled to about 5 ° C. under nitrogen atmosphere. . A small amount of benzene is placed in the reaction vessel to wash out remaining benzoyl chloride. The mixture is stirred for 1 hour, the container is sealed and stored in the refrigerator for the weekend. The solvent is then evaporated under reduced pressure and the remaining oil is dissolved in 100 ml of methylene chloride and the solution is washed once with 150 ml 3N sodium hydroxide and three times with 250 ml of water. The methylene chloride layer is dried over magnesium sulfate and evaporated under reduced pressure. The remaining pyridine is then removed under high vacuum overnight. The residual free oil base weight is 24.9 g.

[Oxalate salt]

1.35 g (0.0107 mol) of oxalic acid dihydrate is added to a 4.0 g free base thermal solution in isopropyl alcohol.

The weight of the oxalate salt of the precipitated title compound is 3.5 g and the melting point is 162 to 165 ℃. The salt is dried at 97-98 ° C. for 1 hour and dried overnight at room temperature at 0.1 mmHg (with reflux of propyl alcohol) and analyzed as follows.

Elemental Analysis: C ₂₆ H ₂₉ N ₃ O ₅

Preparation Example 3

According to the method of Preparation Example 2, the following compound (i) was used instead of benzoyl chloride to obtain the following compound (ii):

(i) 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride and 4 -Chloro-benzoyl chloride:

(ii) N- (3-dimethylaminopropyl) -0- (2-chlorobenzamido) diphenylamine, N- (3-dimethylaminopropyl) -0- (3-chlorobenzamido) diphenylamine , N- (3-dimethylaminopropyl) -0- (2-fluorobenzamido) diphenylamine, N- (3-dimethylaminopropyl) -0- (3-fluorobenzamido) diphenylamine , N- (3-dimethylaminopropyl) -0- (2-bromobenzamido) diphenylamine, N- (3-dimethylaminepropyl) -0- (3-bromobenzamido) diphenylamine And N- (3-dimethylaminepropyl) -0- (4-chlorobenzamido) diphenylamine.

Production Example 4

N- [3- (1-phthalimido) propyl] -0-aminodiphenylamine

Reacting 0-nitrodiphenylamine with sodium hydride and 3- (1-phthalimido) -1-chloropropane to give N-3- (1-phthalimido) propyl-0-nitrodiphenylamine It is reduced with hydrogen on Pd / c in ethanol to afford the title compound.

Production Example 5

The method of Preparation Example 2 was reacted with N-3- (1-phthalimido) propyl-0-aminodiphenylamine with each of the following acylchlorides (i) excess to yield the following compound (ii):

(i) 2-chloro-benzoyl chloride, 3-chloro-benzoyl chloride, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride and 4 -Chloro-benzoyl chloride:

(ii) N-3 (1-phthalimido) propyl-0- (2-chlorobenzamido) diphenylamine, N-3 (1-phthalimido) propyl-0- (3-chlorobenzamido ) Diphenylamine, N-3 (1-phthalimido) propyl-0- (2-fluorobenzamido) diphenylamine, N-3 (1-phthalimido) propyl-0- (3-fluoro Low benzamido) diphenylamine, N-3 (1-phthalimido) propyl-0- (2-bromo benzamido) diphenylamine, N-3 (1-phthalimido) propyl-0- (3-bromo benzamido) diphenylamine, and N-3 (1-phthalimido) propyl) -0- (4-chloro benzamido) diphenylamine.

The present invention is not limited to the following examples, which is useful for practicing the method of the present invention.

Example 1

5- (3-dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, fumarate [1: 1]

18.9 g (0.05 mole) N- (3-dimethylaminopropyl-0-benzamidodiphenylamine and 32.19 g (0.2 mole) phosphorus pentachloride in 50 ml of 1,1,2,2, -tetrachloroethane The stirred mixture of is heated under nitrogen atmosphere for 1.5 hours at 150 ° C. The mixture is cooled slightly and poured onto about 1000 ml of ice and diluted with water to a final volume of 1000 ml. The aqueous suspension is extracted twice with methylene chloride and methylene The chloride layer is decanted The aqueous layer is basified with 3N sodium hydroxide solution and extracted each time with 250 ml of methylene chloride Three times methylene chloride washes are mixed, dried over magnesium sulfate and evaporated under reduced pressure to give the title compound as an oil. 13.8 g of free base are obtained The oil is dissolved in hot isopropyl alcohol and reacted with 4.5 g (0.039 moles) of fumaric acid The fumarate salt is collected by filtration and dried to 13 g. The title product is obtained (melting point 168 to 170 ℃).

Elemental Analysis: C ₂₈ H ₂₉ N ₃ O ₄

Example 2

According to the method of Example 1, the following compound (ii) is obtained using an equimolar amount of the following compound (i) instead of N- (3-dimethylamino-propyl) -0-benzamido diphenylamine:

(i) N- (3-dimethylaminopropyl) -0- (2-chlorobenzamido) diphenylamine, N- (3-dimethylaminopropyl) -0- (3-chlorobenzamido) diphenylamine , N- (3-dimethylaminopropyl) -0- (2-fluorobenzamido) diphenylamine, N- (3-dimethylaminopropyl) -0- (3-fluorobenzamido) diphenylamine , N- (3-dimethylaminopropyl) -0- (2-bromobenzamido) diphenylamine, N- (3-dimethylaminopropyl) -0- (3-bromobenzamido) diphenylamine And N- (3-dimethylaminopropyl) -0- (4-chlorobenzamido) diphenylamine:

(ii) 11- (2-chlorophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, 11- (3-chlorophenyl) -5- (2-Dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, 11- (2-fluorophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, 11- (3-fluorophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, 11- (3-fluorophenyl) -5- (3-dimethylamizopropyl) -5H-dibenzo [b, e] [1,4] diazepine, puma Late, 11- (2-bromophenyl) -5- (2-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, 11- (3-bromophenyl ) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine, fumarate, and 11- (4-chlorophenyl) -5- (3-dimethylaminopropyl ) -5H-dibenzo [b, e] [1,4] diazepine, fumarate.

Example 3

Before adding fumaric acid in Example 1, the following compound (i) was obtained using the following compound (i) instead of N- (3-dimethylaminopropyl) -0-benzamido diphenylamine:

(i) N- (3- (1-phthalimido) propyl-benzamido diphenylamine, N- (3- (1-phthalimido) propyl-0- (2-chloro benzamido) diphenyl Amine, N- (3- (1-phthalimido) propyl-0- (3-chlorobenzamido) diphenylamine, N- (3- (1-phthalimido) propyl-0- (2-fluoro Robenzamido) diphenylamine, N- (3- (1-phthalimido) propyl-0- (3-fluorobenzamido) diphenylamine, N- (3- (1-phthalimido) Propyl-0- (2-bromobenzamido) diphenylamine, N- (3- (1-phthalimido) propyl-0- (3-bromobenzamido) diphenylamine, and N- ( 3- (1-phthalimido) propyl-0- (4-chlorobenzamido) diphenylamine:

(ii) 5- [3- (1-phthalimido) propyl] -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) ) Propyl] -11- (2-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) propyl] -11- (3- Chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) propyl] -11- (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) propyl] -11- (2-fluorophenyl) -5H-dibenzo [b, e] [1, 4] diazepine, 5- [3- (1-phthalimido) propyl] -11- (3-fluorofluoro) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) propyl] -11- (2-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimide Propyl] -11- (3-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 5- [3- (1-phthalimido) propyl] -11- ( 4-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine.

Example 4

5- (3-aminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine hydrochloride

0.035 moles of 5- [3- (1-phthalimido) propyl-11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, 0.039 moles of hydrazine hydrate and 175 ml of 190 standard strength ethyl The mixture of alcohols is refluxed for 2.5 hours and left for several hours.

10 ml concentrated hydrochloric acid solution in 50 ml of water is added to the mixture and the mixture is stirred for several hours. The mixture is filtered and the filtrate is evaporated under reduced pressure. The hydrochloride salt is recrystallized from a suitable solvent and dried under reduced pressure.

Example 5

According to the method of Example 4, an equimolar amount of the following compound instead of 5- [3- (1-phthalimido) propyl-11-phenyl-5H-dibenzo [b, e] [1,4] diazepine i) is used to obtain the following compound (ii):

(i) 11- (2-chlorophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] diazepine, 11- (3-chloro Phenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] diazepine, 11- (2-fluorophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] diazepine, 11- (3-fluorophenyl) -5- [3- (1-phthalimido) propyl ] -5H-dibenzo [b, e] [1,4] diazepine, 11- (2-bromophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b , e] [1,4] diazepine, 11- (3-bromophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] Diazepine, and 11- (4-chlorophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] diazepine:

(ii) 5- (3-aminopropyl) -11- (2-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11 -(3-Chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11- (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11- (3-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine Hydrochloride, 5- (3-aminopropyl) -11- (2-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl)- 11- (3-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11- (4-chlorophenyl) -5H-di Benzo [b, e] [1,4] diazepine hydrochloride.

Example 6

N-methyl-11-phenyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine, hydrochloride

Hydrochloride salt of 5- (3-aminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine is partitioned between ashed sodium hydroxide and methylene chloride, dried and methylene chloride layer Concentrated to dryness, anhydrous benzene was added and concentrated again to remove benzene to convert to free base. The resulting free base is dissolved in excess freshly distilled triethyl orthoformate with reflux for several hours. The mixture is concentrated in vacuo and the mixture is concentrated again by adding ethanol. The resulting imidate is dissolved in ethanol and sodium borohydride is added by stirring at 15 to 20 ° C. until thin layer chromatography shows no starting material.

The mixture is cooled, washed with water and extracted with ethyl acetate. The ethyl acetate layer is washed to neutrality, chlorided, filtered and evaporated. The crude free base is separated by column chromatography, reacted with ethereal hydrogen chloride and recrystallized to give the title compound.

Example 7

According to the method of Example 6, using an equimolar amount of the following compound (i) in place of 5- (3-aminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine The following compound (ii) is obtained:

(i) 5- (3-aminopropyl) -11- (2-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11 -(3-Chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11- (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, 5- (3-aminopropyl) -11- (3-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine Hydrochloride, 5- (3-aminopropyl) -11- (2-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, and 5- (3-aminopropyl) -11- (3-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, and 5- (3-aminopropyl) -11- (4-chlorophenyl) -5H -Dibenzo [b, e] [1,4] diazepine hydrochloride:

(ii) 11- (2-chlorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride, 11- (3-chlorophenyl) -N -Methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride, 11- (2-fluorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride, 11- (3-fluorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine Hydrochloride, 11- (2-bromophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride, 11- (3-bromophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride, and 11- (4-chlorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride.

Formulation and Administration

For therapeutic purposes, an effective amount of the above-mentioned pharmacologically acceptable compound of general formula (I) may be prepared in a conventional formulation and administered to a human body, for example, prepared as a solution, an emulsion, a suspension, a pill, a tablet, and a capsule. It is prepared by sterilizing solution and parenteral administration.

Solid carriers that can be administered orally include lactose, magnesium stearate, white clay, sucrose, talc, stearic acid, gelatin, agar, pectin or gum arabic.

Liquid carriers that can be orally administered include vegetable oils and water.

Intramuscularly administrable carriers or excipients are sterile parenterally administrable liquids (e.g. water) or parenterally administrable oils (e.g. arachis oil in ampoules).

Small doses of the active ingredient of the present invention may be used for mild therapy or in people with relatively low weight, but the unit dose may be 5 mg or more, preferably 10, 25, 50 or 100 mg or more. It is preferred to administer three to four divided doses per day, which of course depends on the urgency of the condition, the compound used and the desired result. A suitable dosage of 25 to 200 mg per unit dose and within a wider range is about 10 to 500 mg per unit dose. The daily dose is about 0.5 to about 20 mg / kg, preferably 0.5 to 10 mg / kg. The active ingredient of the present invention can be mixed with other pharmacologically active compounds as described above. The active ingredient should be contained in an effective amount, ie, in the dosage form employed, with the appropriate effective amount. Obviously, multiple unit dosage forms may be administered simultaneously. The exact dose and the daily dose can be determined according to the physician's or vet's basic guidelines.

The following formulations are representative of the pharmacologically active ingredients of the invention.

[Suggestions]

1.Capsule

Preparations containing 10 mg and 50 mg of active ingredient per calcel are prepared. The use of higher amounts of active ingredient can reduce the amount of lactose.

Other capsule formulations preferably contain large amounts of active ingredients and are as follows:

In each case, the active ingredient is uniformly mixed with lactose, starch, magnesium stearate and the mixture is filled into capsules.

2. Tablet

Representative formulations of tablets containing 5.0 mg of active ingredient per tablet are as follows. This formulation can also be used for other active ingredients by controlling the weight of dicalcium phosphate.

Mix 1,2,4 and 5 uniformly. 3 is prepared as a 10% paste in water. The mixture is granulated with starch paste and the wetted material is passed through 8 mesh sieves. The wet granules are dried and passed through a 12 mesh sieve. The dried granules are mixed with calcium stearate and pressed.

3. Injection (2% sterile solution)

The solution is prepared, filtered and clarified, filled into vials, sealed and autoclaved.

Those skilled in the art will be familiar with the various modifications and may apply them to the compounds, compositions and methods of the invention as long as they do not violate the scope and object of the invention. Therefore, it can be seen that the present invention is limited only to the scope of the claims.

Claims (3)

Reductive alkylation of 0-nitrodiphenylamine with 3- (1-phthalimido) -1-chloropropane solution to yield N-3- (1-phthalimido) propyl-0-nit of Formula (II) To obtain rodiphenylamine; The compound of formula (II) obtained above was reduced to yield N- [3- (1-phthalimido) propyl] -0-aminodiphenylamine of formula (III); The compound of formula (III) obtained above is reacted with benzoyl chloride of formula (IV) to form N- [3- (phthalimido) propyl] -0-benzamido diphenylamine of formula (V). To obtain; The compound of formula (V) obtained above was dehydrated and closed to yield 5- (3-phthalimido-propyl) -11-phenyl-5H-dibenzo [b, e] [1,4] Obtaining diazepine; 5- (3-aminopropyl) -1-phenyl-5H-dibenzo [b] of the general formula (VII) wherein R ¹ and R ² are both hydrogen by reacting the compound of (VI) of the compound obtained above with hydrazine. , e] [1,4] diazepine is obtained; Optionally reacting a compound of formula (VII) obtained above with (a) triethyloroformate (b) NaBH _{4 where} R ¹ is hydrogen and R ² is methyl N-methyl- 11-phenyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamide, characterized in that it provides a compound of formula (I) and a pharmaceutically acceptable acid addition salt thereof How to manufacture.

Wherein X is hydrogen, chlorine, bromine or fluorine; R ¹ and R ² are both hydrogen or if one is methyl the other is hydrogen. The following general formula compounds and pharmaceutically acceptable acid addition salts thereof.

Wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine, and R ¹ and R ² are both hydrogen or R ¹ is hydrogen when R ³ is methyl. Compound of the following general formula

Wherein X is selected from the group consisting of hydrogen, chlorine, bromine or fluorine.