HU187394B - Process for preparing 5-/aminoalkyl/-11-phenyl-5h-dibenzo/b,a//1,4/diazepines and pharmaceutical compositions containing such compounds as active substanes - Google Patents

Abstract

5-(Aminoalkyl)-11-phenyl-5H-dibenzo [b,e][1,4]diazepines having the formula: <IMAGE> (wherein R<1> and R<2> each represent a hydrogen atom or a methyl group and X represents a hydrogen, chlorine, bromine or fluorine atom) and their salts are antidepressants.

Description

The present invention relates to novel 5-aminoalkyl-11-phenyl-5H-dibenzo [b, e] [1,4] diazepines of the formula I and their pharmaceutically acceptable acid addition salts. In the formula

X is hydrogen, chlorine, bromine or fluorine atom, R ¹ and R ² are both hydrogen or ^R1 is hydrogen and ^R2 is methyl.

The present invention also relates to a process for the preparation of a medicament having an antidepressant effect comprising the compounds of the formula I and their acid addition salts.

British Patent No. 907,646 describes a process for the preparation of a dibenzodiazepine derivative, 5- (3-dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine. The compound was prepared as maleate.

Also, Wander, A., in British Patent No. 959,994, discloses reduced forms of these compounds, such as 5- (aminoalkyl) 11-phenyl-10,11-dihydro-5H-dibenzo [b, e] [1,4]. Diazepines have parasympathological, antihistamine, spasmolytic, tranquillising, and psychoactive effects.

Greig Μ. E. et al. Report the anaphylactic effect of some dibenzodiazepine homologs, namely 2-chloro-5- (dimethylamino-ethyl, ethyl) -1-phenyl-5H-dibenzo [b, e] [1,4] diazepine, in mice. [J. Chem. 14, 2, 153 (1971)].

It has now been found that compounds of formula I as defined above and pharmaceutically acceptable acid addition salts thereof are useful in the treatment of depression.

The pharmaceutically acceptable acid addition salts are the physiologically acceptable salts of the compounds of formula I. For example, salts with strong acids such as hydrochloric acid, sulfuric acid or phosphoric acid or weak acids such as fumaric acid, maleic acid, succinic acid or cyclohexamic acid.

The antidepressant activity of the compounds of the formula I according to the method of JSnglehardt et al. Chem. 77 (2), 325 (1968)]. This method, which has long been used to demonstrate the suitability of human therapy for depression, has been used as follows.

Five adult female mice of the ICR-DUB strain were intraperitoneally injected with 20 mg / kg of the test compound and, after 30 minutes, a ptotic dose of tetrabenazine methanesulfonate (32 mg / kg) was also administered intraperitoneally. After another 30 minutes, the animals were observed to have ²⁰ eyes completely closed (ptosis) or not. - We evaluated the effect of the drug accordingly. For each test compound, the ED ₅₀ dose required to inhibit tetrabenazine-induced depression in mice was determined. Evaluation by the method of Litchfield et al. Pharmacol. Exp. Therap. 96, 99-113 (1994)].

On the basis of these results, the compounds of formula I and their pharmaceutically acceptable acid addition salts, which are obtainable by the process of the present invention, have been found to be useful in the treatment of depression.

For this purpose, the compounds of formula I or their pharmaceutically acceptable acid addition salts are formulated with pharmaceutical excipients in the form of solutions, syrups, efixirs, tablets, capsules, suppositories, powders, or the like, containing the desired dosage.

Compounds of formula I are prepared according to the invention by reductively alkylating a) o-nitrodiphenylamine with a solution of 3- (1-phthalimido) -1-chloropropane to give N- [3- (1-phthalimido) -propyl] -o-nitro-diphenylamine to give N- [3- (1445-phthalimido) -propyl] -o-aminodiphenylamine of Formula IV with an optionally substituted benzoyl chloride of Formula VII wherein X is as defined above reacting the resulting N- (3-phthalimidopropyl) -o-benzamidodiphenylamine of formula II, wherein X is as defined above, by ring closure to give 5- (3-phthalimidopropyl) -11- of formula III. phenyl-5H-dibenzo [b, e] [1,4] diazepine, wherein X is as defined above, is reacted with hydrazine and an acid, and the resulting compound of formula I, wherein R ¹ and R ² are each substituted with hydrogen, optionally ortho-formic acid; triethyl ester followed by sodium borohydride. A compound of formula I wherein ^R1 is hydrogen and ^R2 is methyl, and, if desired, into an acid addition salt of the compound of formula I in known manner, or ₂₎ a N- (3-ftalimidopropil formula II) -o- benzamido-diphenylamine, where X is as defined above, is dehydrated by ring closure to give 5- (3-phthalimidopropyl) -1-phenyl-2,187,394 of formula III.

5H-dibenzo [b, e] [1,4] diazepine, wherein X is as defined above, is reacted with hydrazine and an acid to give the compound of formula I wherein R ¹ and R ² are both hydrogen, optionally with ethyl ortho-acetic acid. and then with sodium borohydride to form a compound of formula I wherein R ^{1 is} hydrogen and R ^{2 is} methyl, and if desired, converting a compound of formula I into an acid addition salt in a known manner.

The cyclization dehydration of the compounds of formula II and the conversion of the resulting compounds of formula III to the phthalimido group of the naphtha to the amino group, i.e. the reaction of the latter compounds with hydrazine and an acid, is illustrated in Scheme A. It is noted that the compounds of formula III are also novel compounds.

Compounds of formula I containing a 3-monomethylpropyl group at the 5-position are prepared by

3-Aminopropyl Compound is reacted with ethyl ortho-formic acid followed by sodium borohydride. (Crocket and Blanton Method, 1974 (1) 55-6 Synthesis). The reaction is illustrated in Scheme B.

Benzamido compounds of formula II may be prepared by the following modification of the process described in British Patent No. 907,646.

The o-nitrodiphenylamine of Formula VI is reductively alkylated with a solution of 3- (1-phthalimido) -1-chloropropane. The nitro-powder of the resulting compound of formula V is then reduced with hydrogen on a palladium on carbon catalyst. This gives the corresponding o-amino compound of formula IV. The ortho-amino group is then reacted with a benzoyl halide or a substituted benzoyl halide. This gives the compound of formula II. This reaction sequence is illustrated in Scheme C. In the formulas V ', IV' and IP (corresponding to formulas V, IV and II), respectively, Q represents a phthalimido group.

The invention will now be illustrated by the following non-limiting examples; it is noted that the invention is illustrated in Figs. 1-3. example.

Production Method 1

N- (3-dimethylaminopropyl) -O-nitrodiphenylamine 'hydrochloride x'

30.0 g (0.140 mole) of 2-phytodiphenylamine, 84.0 g (1.05 mole) of 50% sodium hydroxide, 33.0 g (0.210 mole) of 3-dimethylaminopropyl- chloride hydrochloride,

A stirred mixture of 4.5 g (0.014 mol) of tetrabutylammonium bromide and 60 ml of toluene was heated at reflux for 4 hours. The reaction mixture was cooled and diluted with water (100 mL) and toluene (100 mL). The layers were separated and the organic phase was extracted three times with 100 ml of 3N hydrochloric acid solution and once with 50 ml of water. The combined aqueous extracts were basified with 50% sodium hydroxide solution and extracted with twice 100 ml of methylene chloride. The combined methylene chloride extracts were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate and concentrated in vacuo. This gave 34 g (81%) of the title compound as the free base. The solid was converted to the hydrochloride by reaction with hydrochloric acid and recrystallized twice from a mixture of isopropyl ether-isopropyl alcohol. The resulting golden yellow material had a melting point of 147.5-149 ° C.

Analysis for C ₁₇ H ₂₂ N ₃ O ₂ C1 O:

Calculated: C, 60.80; H, 6.60; N, 12.51%;

Found: C, 60.76; H, 6.64; N, 12.38%.

Production Method 2

N- (3-dimethylaminopropyl) -o-aminodiphenylamine

32.0 g (0.107 mol) of N- (3-dimethylaminopropyl) -onitrodiphenylamine (b.p. 155 ° C / 53.33 Pa-174 ° C / 43.99 Pa), 100 ml of ethyl alcohol ( 200 ', according to a proof system) and 1.5 g of 10% palladium on carbon was shaken under a hydrogen atmosphere at room temperature for 1 hour. After approximately a theoretical amount of hydrogen has been absorbed, the catalyst is filtered through a Celite filter and the solvent is removed under reduced pressure. The residue is distilled under high vacuum as follows:

faction Boiling point 'C quantity g 1 80-130 / 26.7 Pa 4.0 2 130-137 / 26.7 Pa 7.0 3 137-142 / 26.7 Pa 15.5

According to TLC on a silica gel mixture of 20% methyl alcohol and 80% benzene, fraction 3 contained the completely pure final product.

3, Production Process

N- (3-dimethylaminopropyl) -o-aminodiphenylamine dihydrochloride

A solution of 35.5 g (0.118 mol) of N- (3-dimethylaminopropyl) -onitrodiphenylamine (free base) in 175 ml of 95% ethyl alcohol and 4.0 g of palladium hydroxide (20%) was added. Carbon) was shaken in a Parr flask for two hours at room temperature under a hydrogen pressure of 282.69 MPa. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The remaining free base is reacted with hydrochloric acid in isopropyl alcohol-water to give the dihydrochloride salt. Recrystallization gave a beige solid, m.p. 224-230 ° C (dec.).

Analysis for C ₁₇ H ₂₅ N ₃ Cl ₂ :

Calculated: C, 59.65; H, 7.36; N, 12.28%;

Found: C, 59.61; H, 7.41; N, 12.27%.

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Production Method 4

N- (3-Dimethylaminopropyl) -o-benzamido-diphenylamine

15.5 g (0.0575 mole) of N- (3-dimethylaminopropyl) o-aminodiphenylamine in 100 ml of pyridine were prepared in ca. To the solution cooled to 5 ° C was added 17.8 g (0.063 mol) of benzoyl chloride under a nitrogen atmosphere. Wash the remaining benzoyl chloride with a small amount of benzene. The reaction mixture was stirred for one hour, then the flask was plugged and placed in a refrigerator for one weekend. The solvent was removed under reduced pressure. The residual oil was dissolved in methylene chloride (100 mL) and washed with 3N sodium hydroxide (150 mL) and water (3 x 250 mL). The methylene chloride layer was dried over magnesium sulfate and concentrated under reduced pressure. The remaining pyridine was then removed under high vacuum (26.66 Pa) overnight. The residual oil (free base) weighed 24.9 g.

The oxalate salt was prepared by adding 1.35 g (0.0107 mol) of oxalic acid dihydrate to a hot solution of 4.0 g of the free base in isopropyl alcohol. The precipitated oxalate salt is the oxalate of the title product, weighing 3.5 g, m.p. 162-165 ° C. The salt was dried for one hour at 97-98 ° C (reflux in propyl alcohol) and overnight at room temperature and 0.1 mm Hg.

Analysis for the formula C _2e H ₂₉ N ₃ O _s :

Calculated: C, 67.37; H, 6.31; N, 9.06%;

Found: C, 67.42; H, 6.35; N, 9.01%.

Production Method 5

N- (3-dimethylaminopropyl) -o- (2-fluorobenzamido) diphenylamine

12.0 g (0.0444 mol) of N- (3-dimethylaminopropyl) o-aminodiphenylamine were added dropwise to a mixture of 4.7 g (0.0466 mol) of triethylamine and 150 µl of anhydrous methylene chloride 15-20 ° C

7.4 g (0.0466 mol) of 2-fluorobenzoyl chloride are added. The reaction mixture was stirred at room temperature for 4 hours and then filtered. The filtrate was washed with 25 mL of water, twice with 25 mL of 5% sodium hydroxide solution, once with more than 25 mL of water, then with 25 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether

12.5 g (72.5%) of product are obtained. Recrystallization from isopropyl alcohol / isopropyl ether gave a white solid, m.p. 64-65 ° C.

Analysis for the formula C ₂₄ H ₂₆ N ₃ OF: '

Calculated: C, 73.63; H, 6.69; N, 10.73%;

Found: C, 73.49; H, 6.70; N, 10.61%.

Production Method 6

Following Production Method 5, however, instead of 2-fluorobenzoyl chloride

2-chlorobenzoyl chloride,

3-chlorobenzoyl chloride,

3-fluorobenzoyl chloride,

2-bromobenzoyl chloride,

3-bromobenzoyl chloride and

Using 4-chlorobenzoyl chloride, the following products are obtained:

N- (3-dimethylamino-propyl) -o- (2-chlorobenzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (3-chlorobenzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (3-fluoro-benzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (2-bromo-benzamido) diphenylamine,

N- (3-dimethylaminopropyl) -o- (3-bromobenzamido) diphenylamine and

N- (3-dimethylamino-propyl) -o- (4-chlorobenzamido) diphenylamine.

Production Method 7

N- [3- (1-phthalimido) propyl] -o-nitrodiphenylamine

Under nitrogen atmosphere, a solution of 53.6 g (0.25 mol) of 2-nitrodiphenylamine in 100 ml of anhydrous dimethylformamide was added dropwise at 30-35 ° C over 30 minutes to 18 g (0.375 mol) of sodium hydride (50%). (in oil) to a stirred suspension of 100 ml of anhydrous dimethylformamide. The reaction mixture was stirred for 3 hours at room temperature. A solution of N- (3-bromopropyl) phthalimide (80.4 g, 0.30 mol) in dimethylformamide (100 mL) was added dropwise over 45 min. The reaction mixture was stirred at room temperature for 34 hours. The excess sodium hydride was quenched by careful dropwise addition of 50 mL of water and the solution concentrated in vacuo at 90 ° C. The residue was partitioned between ethyl acetate (300 mL) and dilute aqueous sodium hydroxide (400 mL). The organic phase is washed once with 100 ml of 10% sodium hydroxide solution and then three times with 100 ml of water each time. The organic phase is then dried over sodium sulfate and the residue is concentrated to give 50 g. Recrystallization twice from ethyl acetate-isopropyl ether gave a light red solid, m.p. 116-117 ° C.

Analysis for the formula C ₂₃ Hi ₉ N ₃ O ₄ :

Calculated: C, 68.82; H, 4.77; N, 10.47%;

Found: C, 68.64; H, 4.76; N, 10.37%.

Production Method 8

Nf 3- (1-phthalimido) -propyl] -o-aminodiphenylamine g (0.050 mol) N- [3- (1-phthalimido) -propyl] -onitrodiphenylamine 225 ml ethyl acetate anhydrous A mixture of ethyl alcohol in a 9: 1 solvent mixture and 4.9 g of palladium hydroxide (20% on carbon) was shaken in a Parr flask for 2% at room temperature under a hydrogen pressure of 253.7 MPa. The reaction mixture was filtered and the filtrate concentrated in vacuo to give 18.0 g of residue. 2.0 g of the residue is recrystallized from a mixture of isopropyl alcohol-water. Recrystallization of the solid-4187 394 solid from ethyl alcohol gives 1.5 g of a deep yellow solid, m.p. 103.5-105 ° C.

Analysis for C ₂₃ H ₂₁ N ₃ O ₂ :

Calculated: C, 74.38; H, 5.70; N, 11.31%;

Found: C, 74.01; H, 5.67; N, 11.21%.

Production Method 9

N- [3- (1-Phthalimido) -propyl] -o- (benzamido) -diphenylamine g (0.108 mol) N- [3- (1-phthalimido) -propyl] -amino-diphenylamine and 11.4 g To a solution of anhydrous triethylamine (0.113 mol) in 200 ml of anhydrous methylene chloride was added dropwise at 15-20 ° C 15.8 g (0.113 mol) of benzoyl chloride. The reaction mixture was stirred at room temperature for 4 hours and then filtered. The filtrate was washed successively with water (50 mL), 5% aqueous sodium hydroxide (2 x 50 mL), water (50 mL), and brine (30 mL), and concentrated. Residual mass spectroscopy showed the title product to weigh 5 g ·

Production Method 10

N- {3- (1-Phthalimido [-propyl] -o- (2-fluorobenzamido) diphenylamine)

36.6 g (0.099 mol) of N- [3- (1-phthalimido) propyl] -amino-diphenylamine, 10.5 g (0.104 mol) of triethylamine, 2 g of powdered molecular sieve and 200 ml of methylene chloride to the stirred mixture was added 16.3 g (0.103 mol) of 2-fluorobenzoyl chloride. The reaction mixture was stirred for 3 hours at room temperature and then filtered. The filtrate was washed successively with water (100 mL), once with 100 mL of 10% sodium hydroxide and once with 50 mL of water, then dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (35.4 g, 62.5%). Recrystallization from ethyl acetate / isopropyl ether gave a white fluffy solid, m.p. 116-117 ° C.

Analysis for C _3O H ₂₄ N ₃ O ₃ F Calcd:

Calculated: C, 73.01; H, 4.90; N, 8.51%;

Found: C, 73.14; H, 4.88; N, 8.49%.

Production Method 11

When in process 10, N-3- (1-phthalimido) -propyl-o-aminodiphenylamine is reacted with one of the following acid chlorides:

2-chlorobenzoyl chloride,

3-chlorobenzoyl chloride,

3-fluorobenzoyl chloride,

2-bromobenzoyl chloride,

3-bromobenzoyl chloride,

The following compounds were obtained as the 4-chlorobenzoyl chloride product: N- [3- (1-phthalimido) propyl] -o- (2-chlorobenzamido) diphenylamine,

N- [3- (1-phthalimido) propyl] -o- (3-chlorobenzamido) diphenylamine,

N- [3- (l-phthalimido) propyl] -o- (3-fluoro-benzamido) diphenylamine,

N- [3- (1-phthalimido) propyl] -o- (2-bromobenzamido) diphenylamine,

N- [3- (l-phthalimido) propyl] -o- (3-bromo-benzamido) diphenylamine,

N- [3- (l-phthalimido) propyl] -o- (4-chloro-in / .amido) diphenylamine.

Example 1

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

18.9 g (0.05 mol) of N- (3-dimethylaminopropyl) -benzamidodiphenylamine and 32.19 g (0.2 mol) of phosphorus oxychloride in 50 ml of 1,1,2,2 A stirred mixture of tetrachloroethane was heated at 150 ° C under nitrogen for 1.5 hours. The reaction mixture was cooled slightly and ca. Pour into 1000 ml of crushed ice and then dilute with water to a final volume of 1000 ml. The aqueous suspension was extracted twice with methylene chloride and the methylene chloride phase was discarded. The aqueous layer was basified with 3N sodium hydroxide and extracted with methylene chloride (3 x 250 mL). The three methylene chloride solutions were combined, dried over magnesium sulfate and evaporated under reduced pressure. 13.8 g of an oily residue are obtained, which is the free base of the title compound. The oil was dissolved in hot isopropyl alcohol and treated with fumaric acid (4.5 g, 0.039 mol). The fumarate was collected by filtration and dried. 13.0 g of product are obtained, m.p. 168-170 C. Analysis for C ₂₈ H ₂₃ N ₃ O ₄ :

Calculated: C, 71.32; H, 6.20; N, 8.91%;

Found: C, 71.19; H, 6.19; N, 8.89%.

Example 2

- (2-Fluorophenyl) -5-dimethylaminopropyl) -5H-dibenzo [b]] [1] diazepine fumarate hemihydrate

Under nitrogen, a solution of 7.56 g (0.0193 mol) of N- (3-dimethylaminopropyl) -o- (2-fluorobenzamido) diphenylamine and 24.7 g (0.161 mol) of phosphorus oxychloride was added for 16 hours. using a reflux condenser. The reaction mixture was cooled and carefully poured into portions of 50 g of ice and stirred for 15 minutes. The solution was made basic with concentrated ammonium hydroxide and extracted three times with 50 ml of methylene chloride each time. The combined methylene chloride extracts were washed with water (50 mL) followed by brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue is converted to the fumarate salt and the salt is recrystallized three times from isopropyl alcohol / isopropyl ether. Recrystallization from two additional methyl cyanide / water mixtures gave 2 g of a yellow solid, m.p. 155-159 ° C (145-150 ° C phase change).

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Analysis for C _S6 H ₅₈ N ₆ O ₈ F O:

Calculated: C, 67.46; H, 5.86; N, 8.43%;

Found: C, 67.88; H, 5.68; N, 8.44%.

Example 3

The procedure of Example 2 is followed, but using the same molar amount of one of the following compounds instead of N- (3-diphenylaminopropyl) -o- (2-fluorobenzamido) diphenylamine: aminopropyl) -o- (2-chlorobenzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (3-chlorobenzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (3vfluor benzamide) diphenylamine,

N- (3-dimethylamino-propyl) -o- (2-bromo-benzamido) diphenylamine,

N- (3-dimethylamino-propyl) -o- (3-bromo-benzamido) diphenylamine

N- (3-dimethylamino-propyl) -o- (4-chlorobenzamido) diphenylamine.

The following compounds were obtained as final product:

- (2-chlorophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine fumarate,

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

- (3-fluoro-phenyl) -5- (3-dimethylamino-propyl) -5H-dibenzo [b, e] [l, 4] diazepin-fumarate,

- (2-bromophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, e] [1,4] diazepine fumarate,

- (3-Bromophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo [b, ej [1,4] diazepine fumarate and 11- (4-chlorophenyl) -5- (3- dimethylaminopropyl) -5H-dibenzo [b, e] (1,4-diazepine fumarate.

Example 4

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

Under nitrogen, 49.0 g (0.11 mol) of N- [3- (1-phthalimido) propyl-o- (benzamido) diphenylamine and 152 g (0.99 mol) of phosphorus oxychloride in 100 ml of 14.2 2-tetrachloroethane was heated at 110 ° C for 64 hours. The reaction mixture was cooled to 10 ° C and carefully poured into 600 ml of ice in portions. The mixture was stirred for 20 minutes, then made basic with ammonium hydroxide (concentrated) and extracted three times with 100 ml of methylene chloride each. The combined methylene chloride extracts were washed with water, dried over sodium sulfate and concentrated in vacuo at 99 ° C. The residue was triturated with methyl alcohol to give 38.5 g (82%) of product. Recrystallization from acetone followed by acetone-methylene chloride gave a mustard-yellow solid, m.p. 192-194 ° C.

Analysis for C ₃₀ H ₂₃ N ₃ O ₂ :

Calculated: C, 78.76; H, 5.07; % N9,18;

Found: C, 78.44; H, 5.02; * N, 9.10%.

Example 5

5- [3- (1-Phthalimido) -propyl] -11- (2-fluorophenyl) -5H-dibenzo [b, ej [1,4] diazepine

Under N2, 28.4 g (0.0576 mol) of N- [3- (1-phthalimido) propyl] -o- (2-fluorobenzamido) diphenylamine and 117 g (0.765 mol) of phosphorus oxychloride in 57 ml of 1, A solution of 1,2,2-tetrachloroethane was heated at 110 ° C for 30 hours. The reaction mixture was cooled and carefully poured onto 300 g of ice and stirred for 20 minutes. The reaction mixture was made basic with concentrated ammonium hydroxide and ice was added, stirred for 1 hour and extracted twice with 75 ml of methylene chloride. The combined methylene chloride extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo at 100 ° C. The residue was recrystallized from ethyl alcohol to give 26 g (95%) of product. Recrystallization from ethyl alcohol / ethyl acetate gave a yellow solid, m.p. 178-179 ° C. Analysis for C ₃₀ H ₂₂ N ₃ O ₂ F:

Calculated: C, 75.78; H, 4.66; N, 8.84%;

Found: C, 75.62; H, 4.72; N, 8.67%.

Example 6

In the same manner as in Example 5, one of the following compounds was used instead of N- [3- (1-phthalimido) propyl] -O- (2-fluorobenzamido) diphenylamine:

N-3- (1-phthalimido) propyl-o- (2-chlorobenzamido) diphenylamine,

N-3- (l-phthalimido) propyl-o- (3-chlorobenzamido) diphenylamine,

N-3- (1-phthalimido) -propyl-o- (3-fluorobenzamido) diphenylamine,

N-3- (1-phthalimido) propyl-o- (2-bromobenzamido) diphenylamine,

N-3- (1-phthalimido) -propyl-o- (3-bromobenzamido) diphenylamine,

N-3- (l-phthalimido) propyl-o- (4-chlorobenzamido) diphenylamine. . > 'to get the following products:

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- (3-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine,

5- (3- (1-phthalimido) propyl] -11 _r (2-bromo-feoil) -5H-dibenzo {b, e] (1,4] benzodiazepine, 5- (3- (l-phthalimido) propyl ] -1- (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 7

5- (3-Amino-propyl) -II-phenyl-5H-dibenzo [b, ej [1,4] diazepine hydrochloride

0.035 mol of 5- [3- (1-phthalimido) -propyl-11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, 0.039 mol of hydrazine-61

A mixture of 187,394 hydrates and 175 ml of ethyl alcohol (190 ', according to the proof system) was heated at reflux for 2.5 hours and then the reaction was allowed to stand for several hours. A solution of concentrated hydrochloric acid (10 mL) in water (50 mL) was added and the mixture was stirred again for several hours. After filtration, the filtrate was concentrated under reduced pressure. The hydrochloride salt is isolated by recrystallization from isopropyl alcohol and dried under reduced pressure.

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

5- (3-aminopropyl) -1- (3-fluorophenyl) -5H-dibenzo [b] [1,4] diazepine,

5- (3-aminopropyl) -11- (2-bromophenyl) -5H-dibenzo [b, e] [1,4] diazepine,

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

5- (3-Aminopropyl) -11- (4-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine.

Example 8

5- (3-Amino-propyl) -11- (2-fluoro-phenyl) -5H-dibenzo [b, e] [1,4] -diazepine

24.0 g (0.050 mol) of 5- [3- (1-phthalimido) * propyl] -1-1 (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine, 2.8 A stirred suspension of g (0.060 mol) of hydrazine hydrate (85%) and 250 ml of 95% ethyl alcohol was heated at reflux for 16 hours. The solution was cooled to 30 ° C, 25 mL. concentrated hydrochloric acid and 125 ml of water were added and the reaction mixture was stirred at 60-70 ° C for two hours. The reaction mixture was cooled, filtered, and the ethanol removed from the filtrate by evaporation. The remaining aqueous mixture was drained again, and this filtrate was made basic by addition of 30 g of sodium hydroxide granulate and ice, and extracted three times with 50 ml of methylene chloride each. The combined methylene chloride extracts were washed with 50 mL water and 30 mL saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The resulting crystalline residue (18 g) was recrystallized from a solvent mixture of isopropyl alcohol-isopropyl ether (charcoal-treated) to give 9.5 g. The filtrate gave 3.5 g of a yellow solid, m.p. 143.5-145 ° C. The total yield is 75%. Analysis for C ₂₂ H ₂₀ N ₃ F:

Calculated: C, 76.50; H, 5.84; N, 12.16%;

Found: C, 76.36; H, 5.98; N, 11.86%.

Example 9

The procedure of Example 8 is followed, however

Instead of 5- (3- (1-phthalimido) propyl] -11- (2-fluorophenyl-5H-dibenzo [b, e] [1,4] diazepine) use one of the following in equal amounts of one of the following:

- (2-chlorophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo [b, e] [1,4] diazepine,

- (3-chlorophenyl) -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, 1- (2-bromophenyl) -5- (3- (1-phthalimido) -propyl] -5H-dibenzo [b , e] [1,4] Diazepine, 1- (3-bromophenyl-5- [3- (1-phthalimido) propyl-5H-dibenzo [b, e] [1,4] diazepine, 11- (4-) chlorophenyl) -5- [3- (l-phthalimido) propyl] -5H-dibenzo [b, e] [l, 4] dziazepin.

The following compounds are obtained as product:

5- (3-aminopropyl) -11- (2-chlorophenyl) -5H-dibenzo [b, e] (1,4) diazepine,

Example 10

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

The hydrochloride of 5- (3-aminopropyl) -1-phenyl-5H-dibenzo [b, ejfl, 4] diazepine is converted to the free base by partitioning between dilute sodium hydroxide solution and methylene chloride. The methylene chloride phase was dried and evaporated, to the residue was added anhydrous benzene and concentrated again by removing the benzene. The resulting free base was dissolved in a large excess of freshly distilled ortho-formic acid triethyl ester and heated under reflux for several hours. The reaction mixture was concentrated in vacuo, ethanol was added and then concentrated again. The resulting imidate is dissolved in ethanol and sodium borohydride is added at 15-20 ° C with stirring until only a negligible amount of starting material can be detected by thin layer chromatography. The reaction mixture was cooled and water was gradually added thereto, followed by extraction with ethyl acetate. The ethyl acetate layer was washed neutral, saturated with salt, filtered and evaporated. The crude free base was separated by column chromatography and reacted with ethereal hydrochloric acid. The title product is obtained, which is purified by recrystallization.

Example 11

N-Methyl-II- (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate [1: 1]

A solution of 10.0 g (0.029 mol) of 5- (3-aminopropyl) -1- (2-fluorophenyl) -5H-dibenzo [b, e] (1,4) diazepine in 150 ml of freshly distilled ortho-formic acid ethyl ester. The cooled solution was concentrated in vacuo, the residue was dissolved in 100 ml of anhydrous ethanol and the solution was concentrated in vacuo, the residue was dissolved in 200 ml of anhydrous ethanol and the solution was cooled to 27 ° C. Sodium borohydride (8 g) was added and the reaction mixture was stirred at room temperature for 80 hours, then another 3 g of sodium borohydride was added and the mixture was stirred at 35 ° C for 1.25 hours and then heated under reflux for 1 hour. After cooling, 70 ml of water was added in portions, the mixture was diluted with 600 ml of water and extracted three times with 75 ml of ether each. wash until the pH of the wash water is neutral after washing

187,394 remains. The ethereal solution was dried over sodium sulfate and concentrated in vacuo. The resulting residue (12.5 g) was purified on a 4.5 x 45 cm alumina (neutral) column using methyl alcohol-methylene chloride as the eluent in the following manner:

factions volume liter Solvent composition melilalkohol: methylene chloride 1-12 6.5 1.25: 98.75 13-20 4.5 2.5: 97.5 21-22 1.0 3.75: 96.25 23-24 1.0 5.95: 94.05 25-26 1.0 7.5: 92.5 27 0.5 10: 90

14-27. fractions were combined and concentrated in vacuo to give 3.2 g of residue. This is converted to the oxalate salt and recrystallized twice from isopropyl alcohol in isopropyl ether solvent. Light yellow solid (2 g), m.p. 190-192 ° C (dec.). Analysis for the formula C _{2 J} H ₂₄ N ₃ O ₄ F:

Calculated: C, 66.80; H, 5.38; N, 9.35%;

Found: C, 66.77; H, 5.35; N, 9.32%.

Example 12

All. However, by the same procedure as in Example 1, the same compounds were used in place of 5- (3-amino-propyl) -1- (2-fluorophenyl) -5H-dibenzo [b, e] [1,4] diazepine as one of the following:

5- (3-aminopropyl) -11- (2-chlorophenyl) -5H-dibenzo [b, e] (1,4-diazepine,

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

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

5- (3-aminopropyl) -11- (2-bromophenyl) -5H-dibenzo [b, e] (1,4) diazepine,

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

5- (3-Aminopropyl) -11- (4-chlorophenyl) -5H-dibenzo [b, e] [1,4] diazepine.

The following compounds were obtained:

- (2-chlorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate,

- (3-chlorophenyl) -N-methyl-5H-dibenzo [b, e] | 1,4] diazepine-5-propanamine oxalate, 1- (3-fluorophenyl) -N-methyl-5 H -dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate .

II- (2-bromophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate, II- (3-bromophenyl) -N- methyl 5 H -dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate and

II - (4-Chlorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine oxalate.

In human therapy, the compounds of Formula I may be administered in the amounts and to the extent necessary to exert their therapeutic effect, such as oral solutions, emulsions, suspensions, pills, tablets or capsules, and the appropriate pharmaceutical carriers. in the form of a solution.

For oral administration, solid carriers such as lactose, magnesium stearate, magnesium, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia are prepared from the compounds of Formula I.

Vegetable oils or water may be used as a liquid carrier for oral administration.

For intramuscular administration, the vehicle is formulated into a vial with a sterile, parenteral-acceptable liquid such as water or an oil for parenteral use, such as peanut oil.

The active compounds are already effective in small amounts, for example, in the case of lesser intervention (minor therapy) or in the treatment of patients with light weight, but their unit dosage is generally at least 5 mg, preferably 10.25, 50 or 100 mg, but may be higher. The formulation is administered three or four times daily. The dose and frequency of administration will depend on the severity of the event and the nature of the active ingredient and the therapeutic result sought. Unit doses may contain from 10 to 500 mg of active ingredient, but preferably from 25 to 200 mg. The generally required daily dose is from about 0.5 mg to about 20 mg, preferably from 0.5 mg to 10 mg per kilogram of body weight. The active ingredient of the present invention may also be combined with other active ingredients. Of course, the active ingredient must always be administered in the amount necessary to produce the desired effect, so that a unit dosage form of a particular form is effective. Various unit dosage formulations may be used simultaneously. The exact individual dose or daily dose will, of course, be determined by the physician or veterinarian, for medical reasons.

The following are some examples of pharmaceutical compositions containing the compounds of the present invention as active ingredients.

I. Capsule Preparation Capsules containing mg or 50 mg of active ingredient are prepared according to the table below. The higher active ingredient formulation contains less lactose according to the excess active ingredient.

Blend ingredients 10 mg capsules 50 mg capsules Active ingredient in salt form 10 mg 50 mg lactose 259 mg 219 mg starch 126 mg 126 mg magnesium stearate 4 mg 4 mg 399 mg 399 mg

. 187,394

Other, higher dose capsule compositions may be formulated, for example, with the following composition.

Blend Component-100 mg 250 mg 500 mg section capsule capsule capsule Active ingredient, salt 100 mg 250 mg 500 mg the form lactose 209 mg 163 mg , 95 mg starch 87 mg 81 mg 47 mg magnesium steroid 4 mg 6 mg 8 mg reap 400 mg 500 mg 650 mg

For each formulation, the active ingredient selected is mixed with lactose, starch and magnesium stearate, the mixture is homogenized and filled into a capsule.

II. Preparation of tablets

A tablet formulation containing 5.0 mg of the active ingredient is prepared in the following table. Similarly, a composition with a higher halide content can be prepared except that the amount of dicalcium phosphate is reduced proportionately.

agent 10 mg corn 15 mg Corn starch (paste) 12 mg Lactose 35 mg Dik calcium phosphate 132 mg Calcium stearate 2 mg

202 mg

The active ingredient, corn starch, lactose ⁴⁰ and dicalcium phosphate are mixed and homogenized. A 10% solution of the corn starch paste is prepared with water. The former mixture is granulated with starch paste and the wet mass is then passed through a 2.38 mm mesh sieve. The wet granulate was dried and passed through a 1.41 mm mesh sieve. The dried granulate is then mixed with calcium stearate.

III. Preparation of injection solution

A sterile solution for injection containing 2% of the active ingredient is prepared with the following composition: 55 active ingredients 20 mg chlorobutanol preservative 0.5 w / v. % sterile viz q. s.

A solution of the above ingredients is prepared, then filtered sharp, filled into an ampoule, sealed and autoclaved.

Many other variations and embodiments of the present invention will be apparent to one of ordinary skill in the art, both with respect to the compounds, compositions, and methods of the process. This, however, is within the scope of the claims.

Claims (2)

Patent claims A process for the preparation of 5- (aminoalkyl) 11-phenyl-5 H -dibenzo [b, e] [1,4] diazepines of the formula I and their pharmaceutically acceptable acid addition salts comprising: X is hydrogen, chlorine, bromine or fluorine atom, R ¹ and R ² are both hydrogen or ^R1 is hydrogen and ^R2 is methyl, characterized in that a) Reductive alkylation of o-nitrodiphenylamine with a solution of 3- (1-phthalimido) -1-chloropropane, the resulting N- [3- (1-phthalimido) propyl] -o-nitrodiphenylamine of formula V is reduced, N- [3- (phthalimido) -propyl] -o-aminodiphenylamine of formula IIa is reacted with an optionally substituted benzoyl chloride of formula VII, wherein X is as defined above, to give the N- (3-phthalimido-) propyl) -o-benzamido-diphenylamine, where X is as defined above, is dehydrated by ring closure to give 5- (3-phthalimidopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine, * X is reacted with hydrazine and an acid as described above, and the resulting compound of formula I, wherein R ¹ and R ² are each substituted with hydrogen, is optionally converted to triethyl ortho formic acid, followed by sodium borohydride, to give R ¹ and hydrogen. R ^{2 is} methyl, and is not optionally converting the resulting compound of formula I into an acid addition salt, or b) dehydrating an N- (3-phthalimidopropyl) -o-benzamidodiphenylamine of formula II, wherein X is as defined above, to give 5- (3-phthalimidopropyl) -11-phenyl-5H- dibenzo [b, e] [1,4] diazepine, wherein X is as defined above, is reacted with hydrazine and an acid to give a compound of formula I wherein R 1 and R ² are both hydrogen, optionally with ethyl ortho-acetic acid; with sodium borohydride to form a compound of formula I wherein R * is hydrogen and R ^{2 is} methyl and, if desired, converting the resulting compound of formula I into an acid addition salt. A process for the preparation of a pharmaceutical composition having an antidepressant effect, characterized in that a compound of the formula I according to claim 1, wherein R ¹ , R ² and X are as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof. it is formulated into a medicament mixed with customary excipients, diluents and, if desired, other excipients. 4 pieces of figure