DE3149923A1 - 5- (AMINOALKYL) -11-PHENYL-5H-DIBENZO (B, E), (1,4) DIAZEPINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS THAT CONTAIN THESE COMPOUNDS - Google Patents

Description

DR. BE & Q ··. fipJ

DIPL.-ING. SCHWABE · ^: ° Öti. D'RZ

PATENTANWÄLTE PO Box 86 02 45 8000 Munich

Qr. Befß Dlpl.-Ing. Stapf and Partner, F.O.Dos 860245, SOQD Munich 06 '

Your sign
Your ref.

Our sign

ourrer. 31

Mauerkircherstraße 45 8000 MUNICH 80

Lawyer file no .: 31

A. H. ROBINS COMPANY, INC. Richmond, Virginia / USA

5- (Aminoalkyl) -11-phenyl-5H-dibenzo [b, e] [1,4! Diazepine,

Process for their manufacture and pharmaceutical preparations containing them Connections included

X / Si

© (039) 988272 988273 988274 983310

Case 410

Telegrams:

BERGSTAPFPATENT Munich TELEX: 0524560 BERG d Bank accounts: Hypo-Bank Munich 4410122850 (BL / 7 (1020011) Swift Code- HYI ¹ O »Γ MM Bnycc Vercinsbunk Munich 453100 (BLZ 70020270) Postscheck Munich 6SJ43-R08 (BL / 70010080)

3U9

The present invention relates to certain 5- (aminoalkyl) -11-phenyl-5H-dibenzo [b, e] [1,4 ! diazepine, a process for the preparation of the compounds and pharmaceutical preparations, which contain these compounds.

GB-PS 907 646 discloses a process for the preparation of certain dibenzodiazepines, e.g. of the active ingredient of Example 1 below, in the form of the maleate salt.

GB-PS 959 994 discloses the utility of reduced forms such as 5- (aminoalkyl) -11-phenyl-IO, 11-dihydro-5H-dibenzo [b, e] [1,4] diazepines as parasympathologics, antihistamines, spasmolytics ", tranquilizers and psychoenergizers.

By ME Greig, et al., J. Med. Formerly, JM, No. 2 _r page 153 (1971) describes the anaphylactic activity of certain dibenzodiazepine homologues in the mouse, and in particular of 2-chloro-5- (dimethylaminoethyl) -11-phenyl-5H-diben-- · zo [b, e] [1,4] diazepine.

The compounds of the present invention which are useful for treating depression in humans have the general formula I below

(D

(CHa) ₃ NR ¹ R ²

1 7

in which R and R are hydrogen and / or methyl, X is hydrogen, chlorine, bromine or fluorine, and the pharmaceutically acceptable acid addition salts thereof.

1 2 Those compounds in which both radicals R and R Are hydrogen, or in which one radical is methyl and the other radical is hydrogen, are new.

Pharmaceutically acceptable acid addition salts are such Salts that are physiologically harmless, such salts being formed with either strong or weak acids will. Representative examples of strong acids are hydrochloric acid, sulfuric acid and phosphoric acids. Representative Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, cyclohexamic acid, and the like.

In order to show the antidepressant usefulness of the compounds of the general formula I, the method described by EL Englehardt et al., J ₀ . Med. Chem. 1_H2) » ³²⁵ (1968) described processes ; which previously indicated the utility of compounds for treating depression in human medicine, applied as follows; 20 mg / kg of the compound to be investigated were administered intraperitoneally to 5 adult female mice (ICR-DUB strain) 30 minutes before the administration of a ptotic dose (32 mg / kgy ip ») of tetrabenazine (as methanesulfonate salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) was determined for each animal. For each compound tested, blocking tetrabenazine-induced depression in mice can be used by the method of Litchfield et al., J. Pharmacol "Exp. Therap. 96_, 99 to 113 (1949) a (mean effective dose). That

3143323

. AO-

preferred dibenzodiazepine of the present invention the active agent of Example 1, namely 5- (3-dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine.

In the pharmaceutical preparations of the present invention, the usual dosage forms of the active substance are used used, consisting of the active ingredient of general formula I and a suitable pharmaceutical carrier for the production of solutions, syrups, elixirs, tablets, capsules, suppositories, powders, and the like.

The compounds of general formula I in which the 5-position is substituted by the 3-dimethylaminopropyl radical, the N- (3-dimethylaminopropyl) -obenzamido-diphenylamines are obtained by cyclodehydrogenation according to GB-PS 907 646 using a dehydration-condensation catalyst manufactured; for example phosphorus pentoxide or oxyhalides of phosphorus, preferably the latter, in a suitable solvent, e.g. in 1,1,2,2-tetrachloroethane. The reaction equation is as follows:

HW

POCl.

(CH ₂ ) ₃ N (CH ₃ ) 2

In this equation, the radical X has the meaning given above for the general formula I.

The new compounds of the general formula I in which the 5-position is substituted by the 3-aminopropyl radical, are obtained by cyclodehydration of new N- [3- (1-phthalimido) propyl] -obenzamido-dipheny! amines Hb and subsequent conversion of the phthalimido group into an amino group with hydrazine and acid. The reaction equation is following

I) NH ₂ NH ₂ 2) acid

(III)

(Ib)

In the compounds of the above reaction _{equation, the radical X has the same meaning s} as it was given for the general formula I »The compounds of the general formula III are also new.

The new compounds of general formula I in which the 5-position is substituted by 3-monomethylpropylamine, by further reaction of the 3-aminopropyl compound with triethyl orthoformate and subsequent reaction with sodium borohydride (method by Crocket & Blanton), 1974 (1): 55-6 Synthesis). The reaction equation is as follows:

• - / 6 -

-At

1) (EtO) ₃ CH

2) NaBH ₄

(Ib)

(Ic)

NHCH ₃

The benzamido starting compounds II (Ha and lib) are prepared by a modified process according to GB-PS 907 646
manufactured. First, o-nitrodiphenylamine is used with a
Solution of ß-chloropropyldimethylamine or 3- (1-phthalimido) 1-chloropropane reductively alkylated and then reduced the nitro group with hydrogen in the presence of a palladium on carbon catalyst to the corresponding o-amino compound. The amino radical in the ortho position is then unified in Bonzoy halogen or oinom substituted benzoyl halide. The course of the reaction is given by the following equations:

OO 6 β

O η «β β

3145923

O ₂ N

(VI)

2) Cl- (CHa) ₃ Q

O ₂ N

(IV)

Pyridine |

(II)

or 1-phthalimides

Manufacturing process 1 N- (3-dimethylaminopropyl) -o-aminodiphenylamine

A mixture of 32.0 g (0.107 mol) of N- (3-dimethylaminopropyl) -onitrodiphenylamine (Boiling point 155 ° / O, 4 to 174 ° C / O, 33 mm),

-A-

100 ml of "200 proof" ethyl alcohol and 1.5 g of 10% palladium on carbon catalyst was added under a hydrogen atmosphere Shaken room temperature for 1 hour. After approximately the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off through a celite filter cake and the solvent removed under reduced pressure. The residue was distilled under high vacuum as follows:

_, .. boiling point amount

Fraction _(O g _} *

18O-130 ° / O, 2mm 4.0

2 130-137 ° / O, 2mm 7.0

3 137-142 ° / O, 2mm 15.5

Thin-layer chromatography using 20% methyl alcohol / 80 % Benzene on silica gel indicated fraction 3 was perfectly pure.

Preparation process 2 N- (3-Dimethylaminopropyl) -obenzamidodiphenylamine

To one cooled to about 5 ° C under a nitrogen atmosphere Solution of 15.5 g (0.0575 mol) of N- (3-dimethylaminopropyl) -oaminodiphenylamine in 100 ml of pyridine were 17.8 g (0.063 mol) Benzoyl chloride added. A small amount of benzene was used to flush the remaining benzoyl chloride into the reaction vessel used. The mixture was stirred for 1 hour, the reaction vessel sealed and in the refrigerator over the weekend switched off. The solvent was then reduced under reduced pressure

(ϊ α β

ο 6 <$

Pressure evaporated, the remaining oil dissolved in 100 ml of methylene chloride and the solution once with 150 ml of 3N sodium hydroxide and washed three times with 250 ml of water. The methylene chloride layer was dried over magnesium sulfate and under reduced pressure Evaporated pressure. The remaining pyridine was then removed under high vacuum (0.2 mm Hg) overnight. The weight of the residual oil, the free base, was 24.9 g.

Oxalate salt

To a hot solution of 4.0 g of the free base in isopropyl alcohol 1.35 g (0.0107 mol) of oxalic acid dihydrate was added. The precipitated oxalate salt of the title compound weighed 3.5 g and had a melting point of 16 2 ° to 165 ° C. After 1 hour Drying at 97 ° to 98 ° C (propylene alcohol under reflux) and The following analytical values were obtained overnight at room temperature, in each case at 0.1 mm Hg.

Analysis for ^C 26 ^H 29 ^N 3 ° 5 ^:

Calculated: C 67.37%, H 6.31%, N 9.06%; Found s C 67.42%, H 6.35%, N 9.01%.

Manufacturing process 3

Following the procedure of Preparation Process 2 and using the following compounds in place of benzoyl chloride, namely

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-benzoy! Chloride

- / 10 -

contained the following compounds:

N- (3-Dimethylaminopropyl) -o- (2-chlorobenzamido) -diphenylamine, N- (3-Dimethylaminopropyl) -o- (3-chlorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (2-fluorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (3-fluorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (2-bromobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (3-bromobenzamido) -diphenylamine, and N- (3-dimethylaminopropyl) -o- (4-chlorobenzamido) -diphenylamine.

Preparation process 4 N- [3- (1-Phthalimido) propyl] -o-aminodiphenylamine

o-Nitrodiphenylamine is combined with sodium hydride and 3- (1-phthalimido) -1-chloropropane with formation of N-3- (1-phthalimido) propyl -o-nitrodiphenylamine reacted, which is then hydrogenated with hydrogen over palladium-on-carbon in ethanol to form will.

Manufacturing process 5

If in the procedure of the preparation process 2 N-3- (1-phthalimido) propyl-o-aminodiphenylamine with each one of the following acrylic chlorides 2-chloro-benzoyl chloride,

S-chloro-benzoyl chloride,

2-fluoro-benzoyl chloride,

3-fluoro-benzoyl chloride,

2-bromo-benzoyl chloride,

3-bromo-benzoyl chloride, and 4-chloro-benzoyl chloride

in excess according to the operation of the manufacturing process 2, the following compounds are obtained:

- / 11 -

-A - . / IJ-

N-3- (1-Phthalimido) -propyl-o- (2-chlorobenzamido) -diphenylamine, N-3- (1-Phthalimido) -propyl-o- (3-chlorobenzamido) -diphenylamine, N-3- (1 -Phthalimide) -propyl-o- (2-fluorobenzamido) -diphenylamine, N-3- (1-phthalimido) -propyl-o- (3-fluorobenzamido) -diphenylamine, N-3- (1-phthalimide) -propyl- o- (2-bromobenzainido) -diplionylamine, N-3- (1-phthalimido) -propyl-o- (3-bromobenzamido) -diphenylamine, and
N-3- (1-phthalimido) propyl-o- (4-chlorobenzamido) diphenylamine.

The following examples, however, do not support the invention intended to limit, serve to further explain the invention.

example 1

5- (3-Dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] L1,4 jdiazepine fumarate [1: 1]

A stirred mixture of 18.9 g (0.05 mol) of N- (3-dimethylaminopropyl) -obenzamidodiphenylamine and 32.19 g (0.2 mol) of phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane heated to 150 ° C under nitrogen for 1.5 hours. The mixture was cooled somewhat, about 1000 ml pushed Poured ice and then diluted with sufficient water to a final volume of 1000 ml. The aqueous suspension was extracted twice with methylene chloride and the methylene chloride layer discarded. The aqueous layer was made with 3N sodium hydroxide made alkaline and made three times with 250 ml portions Extracted methylene chloride. These three methylene chloride washes were combined over magnesium sulfate dried and evaporated under reduced pressure. An oil weighing 13.8 g was obtained, namely the free base the title compound. The oil was dissolved in hot isopropyl alcohol and reacted with 4.5 g (0.039 mol) of fumaric acid. That

- / 12 -

Fumarate salt was collected by filtration to obtain after drying 13g with a melting point of 168 ° to

Analysis for Cj ^ H ^ N ^ O,:

Calculated: C 71.32%, H 6.20%, N 8.91 I; Found: C 71.19%, H 6.19%, N 8.89%.

example

According to the operation of Example 1, if one obtains instead of N- (3-dimethylaminopropyl) -obenzamidodiphenylamine equal molar amounts of the following compounds, namely N- (3-dimethylaminopropyl) -o- (2-chlorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (3-chlorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (2-fluorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (3-fluorobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (2-bromobenzamido) -diphenylamine, N- (3-dimethylaminopropyl) -o- (3-bromobenzamido) -diphenylamine,

N- (3-Dimethylaminopropyl) -o- (4-chlorobenzamido) -diphenylamine uses the compounds listed below:

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

11- (3-chlorophenyl) -5- (3-dimethylaminopropyl) -5H-dibenzo- [b, e] C1,4] 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- (2-bromophenyl) -5- (3-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. - / 13 -

Example 3

If you follow the procedure of Example 1 before adding of fumaric acid instead of N- (3-dimethylaminopropyl) -obenzamidodiphenylamine the following compounds, namely N-3- (1-phthalimido) propyl-o-benzamidodphenylamine, N-3 -, '(1-phthalimido) propyl-o- (2-chlorobenzamido) diphenylamine, N-3- (1-Phthalimido) -propyl-o- (3-chlorobenzamido) -diphenylamine, N-3- (1-Phthalimido) -propyl-o- (2-fluorobenzamido) -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, and

N-3- (1-phthalimido) -propyl-o- (4-chlorobenzamido) -diphenylamine, is used, the compounds listed below are obtained:

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 J-11 - (3-chlorophynyl) -511-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-fluorophenyl) -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-Phthalimido) propyl] -11- (3-bromophenyl) -5H-dibenzotb, e] [1,4] diazepine,

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

- / 14 -

Example 4

5- (3-aminopropyl) -11-phenyl-5H-dibenzo [b, e3 [1,4] diazepine.hydrochloride

A mixture of 0.035 moles of 5- [3- (1-phthalimido) propyl} -11-phenyl-5H-dibenzo [b, e] [1 _r 4] diazepine, 0.039 moles of hydrazine hydrate and 175 ml of "190 proof" ethyl alcohol is refluxed for 2.5 hours and left to stand for several hours. A solution of 10 ml of concentrated hydrochloric acid 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 isolated by recrystallization from a suitable solvent and dried under reduced pressure.

Example 5

If the procedure of Example 4 is followed and instead of 5- [3- (1-phthalimido) propyl] -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine equal molar amounts of the following compounds, namely

11- (2-chlorophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo- [b, e] L1,4] diazepine,

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

11- (2-Fluorophenyl) -5- [3- (1-phthalimide) ^ 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] -r5H-dibenzo- [b, e] [1,4] diazepine,

11- (3-bromophenyl) -5- [3- (1-phthalimido) propyl] -5H-dibenzo- [b, e] [1,4] diazepine, and

- / 15 -

11- (4-Chlorophenyl) -5- [3- (1-phthalimido) propyl] -SH-dibenzo- [b, e] [1,4] diazepine is used, the compounds listed below are obtained:

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-dibonzoIb, e3 L1,4J-diazepine hydrochloride, 5- (3-aminopropyl) -11 - (2-bromophenyl) -5H-dibenzol.b, c j L1, 4] -diazepine hydrochloride, 5- (3-aminopropyl) -11 - (3-bromophenyl) -5H-dibenzo [b, e] [1,4] -diazepine hydrochloride, 5- (3-aminopropyl) -11 - (4-chlorophenyl) -5H-dibenzo [b, e] [1,4] -diazepine hydrochloride.

' Example

N-Methy 1-11 -phenyl-5H-dibenzo [.b, cJ [1,4 JdiazcpJn- 5- propanamine.hydrochloride

The hydrochloride salt of 5- (3-aminopropyl) -11-phenyl-SH-dibenzo [b, e] [1,4] diazepine is converted into the free base by partitioning between dilute sodium hydroxide and methylene chloride, dried, the methylene chloride layer concentrated to dryness, dry benzene added and again to drive off of the benzene concentrated. The free base obtained is in a large excess of freshly distilled triethyl orthoformate dissolved under reflux over a period of several hours. The mixture is concentrated in vacuo, and ethanol is added and the mixture concentrated again. The imidate obtained

- / 16 -

3Η9923

is dissolved in ethanol and sodium borohydride was added with stirring at 15 ° to 20 ⁰ C until thin layer chromatography indicates the absence of substantial amounts of starting material ·. The mixture is cooled and water is gradually added and then extracted with ethyl acetate. The ethyl acetate layer is washed until neutral and salted out, filtered and evaporated. The free crude base is isolated by column chromatography, reacted with ethereal hydrogen chloride and, after recrystallization, yields the title compound.

Example 7

If one works according to the procedure of Example 6 and there is 5- (3-Aitiinopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] -diazepine the following compounds, namely 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- ^ uOrphenyl) -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-bromphenyi) -5H-dibenzo [b, e] [1,4] diazepine hydrochloride, and

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

the compounds listed below are obtained:

- / 17 -

• ο «« t

• ·. a

3H9923

- / rf - - 53.

11- (2-chlorophenyl) -N-methyl-SH-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride,

■ 11- (3-chlorophenyl) -N-methyl-SH-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride,

11- (2-fluorophenyl) -N-methyl-5H-dibenzo [b, e] [1,4] diazepine-5-propanamine hydrochloride ,

H-O-FluorophenyD-N-methyl-SH-dibenzoCb ^ eJCI ^ ldiazepine-S-propanamine.hydrochloride,

11- (2-bromophenyl) -N-methyl-SH-dibenzo [b, eJL1,4jdiazopin-5-propanaitiin. hydrochloride,

11 - (3-bromophenyl) -N-methyl-SH-dibenzo [b, e] [1,4] diazepine-5-propanamine.hydrochloride, and

11 - (4-Chlorophenyl) -N-methyl-511-dibenzo [b, e] L1,4] diazepine-5-propanamine, hydrochloride.

Formulation and administration

There can be pharmacologically effective amounts of the foregoing active compounds of general formula I to patients for therapeutic purposes by the usual route of administration and the usual forms such as oral in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutical compatible carriers and administered parenterally in the form of sterile solutions.

Examples of solid carriers for oral administration are such as lactose, magnesium stearate, terra alba. Cane sugar, Talc, stearic acid, gelatin, agar, pectin or gum arabic.

Examples of liquid carriers for oral administration are Vegetable oils and water.

- / 18

.At-

For intramuscular administration, the carrier or excipient can be a sterile, parenterally acceptable liquid e.g. water or a parenterally acceptable oil, e.g. peanut oil in ampoules.

Although very small amounts of the active materials of the present Invention are effective when a smaller scope therapy is sought or in cases of administration For relatively low body weight patients, unit doses are usually 5 mg or more, and preferably at 10, 25, 50 or 100 mg or even higher, and are preferably administered three or four times per day, of course, depending on the respective illness situation, the compound used and the particular one desired result. 25 to 200 mg seems optimal for a unit dose, or the usual wider ranges appear To be 10 to 500 mg per unit dose. Ordinarily required daily doses should range from about 0.5 to about 20 mg / kg / day, preferably in the range from 0.5 to 10 mg / kg. The active ingredients of the invention can with other pharmacologically active agents as indicated above can be combined. It is only necessary that the active ingredient is an effective amount, i.e. such an amount that a suitable effective dose is obtained, die.mit the dosage form used is compatible. Apparently multiple unit dosage forms can be administered at about the same time. The exact individual Dosages, as well as the daily doses, are of course according to the usual medical principles under the Under the supervision of a doctor or veterinarian.

The following formulations are representative of the pharmacologically active compounds of the present invention.

- / 19 -

Formulations
1. Capsules

There were capsules with 10 mg and 50 mg of active ingredient each Capsule made. With the higher amounts of active ingredient, the amount of lactose can be reduced.

Typical mix for encapsulation

Active ingredient, as the salt, lactose

strength

Magnesium stearate

Total:

10 mg
Per capsule 50 mg
Per capsule 10 50 259 219 126 126 4th 4th 399 399

Further capsule formulations preferably contain a higher one Dose of active ingredient as follows:

Ingredients · " ¹⁰ ° ^{mg 25} ° ^{mg 50} ° ^mg

aesranarexxe _{prQ capsule per capsule} ei per capsule

Active ingredient, _25Q

as salt

Lactose
strength
Magnesium stearate Total: 208
87
4th 163
81
6th - 95
47
8th 399 500 650

- / 20

- 2O -

In either case, the selected active ingredient is mixed evenly with lactose, starch and magnesia stearate and encapsulated the mixture.

2. Tablets

A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet follows. The formulation can be used for other levels of active ingredient by adjusting the weight of dicalcium phosphate.

Per tablet, mg

1. Active component 10.0

2. Corn starch .- .. «..- -15.0

3. Corn starch (paste) 12.0

4th Lactose 35.0

5. Dicalcium phosphate 132.0

6th Calcium stcarate 2.0

Total: 206.0

The ingredients 1, 2, 4 and 5 are mixed evenly and produces component 3 as a 10% paste in water. That The mixture is granulated with the starch paste and the moist mass is pressed through an 8 mesh sieve (sieve with a mesh size of 2.4 mm). The moist granules will dried and classified through a 12 mesh sieve (sieve with a mesh size of 1.4 mm). The dried granules is mixed with the calcium stearate and pressed.

- / 21 -

β »β ·» β

η β η «. ο

3ο Injectable 2% sterile solution

Per ml

Active ingredient 20 mg

Preservatives, e.g. chlorobutanol,

Weight / volume Percent 0.5

Water for injection q.s.

Prepare the solution, clarify it by filtration, fill it up put them in ampoules, seal them and treat them in an autoclave.

Claims (1)

DR. BER <5 ": f DIPL.-ING. SCHWABE '* "* £> * &. DK. SXNDMAIR PATENTANWÄLTE PO Box 860245 8000 Munich 86 * Dr. Berg Dipl.-Ing. Stapf and Partner, POBox 860245,8000 Munich 8 «* Your sign Your raf. Our sign Ourref. 31 MauerkircherslreDc 45 WXW MÜNCIIKN 80 Attorney File #: 31 AH Robins Company, Inc. Claims 1. Compound of the general formula I in which X is hydrogen., chlorine, bromine or fluorine and the 1 2
R and R radicals are either both hydrogen or one is hydrogen and the other is a methyl group, and the pharmaceutically acceptable acid addition salts of these compounds. X / Si - 12 - «■ (IDS3S9S8272 988273 988274 983310 AHR Gasp " Telegrams: BERGSTAPF PATENT Munich TELEX: 0524560 BERG d Bank accounts: Hypo-Bank Munich 4410I2285O (BLZ 70O20011) Swift Code: HYPO DE MM Boyec Vereinsbank Munich 453 lOO (BL7 70020270) Posischeck Munich 65343-808 (BLZ 'MlOOKO) • · · β 2. Compound of the general formula in which X is hydrogen, chlorine, bromine or fluorine. 3. A method for producing a compound according to claim 1, characterized in that that he (a) o-Nitrodiphenylamine with a solution of 3- (1-phthalimido) -1-chloropropane with formation of N- [3- (1-phthalimido) ■ propylj-o-nitrodiphenylamine of the following formula O ₂ N reducing alkylated, (b) the compound obtained in step (a) with formation of N- [3- (1-phthalimido) propyl] -o-ainodiphenylamine der below formula H ₂ N reduced, (c) the compound prepared in step (b) with a benzoyl chloride the following general formula : —Cl in which X has the same meaning as in claim 1 to form an N- [3- (phthalimide)) propyl] -obenzamidodiphenylamine the following general formula -A- in which X has the same meaning as above, implements, (d) the compound prepared in step (c) to form a 5- (3-phthalimidopropyl) -11-phenyl-SH-dibenzo- [b, e] [1,4] diazepine the following general formula in which X has the same meaning as above, cyclodehydratxsiert, (e) the compound prepared in step (d) with hydrazine and an acid to form a 5- (3-aminopropyl) -1-phenyl-5H-dibenzo [b, e] [1 _r 4] diazepine of the general formula below NR ¹ R ² _{| M} F " _1-L 3H9923 wherein X has the same meaning as above and R and R are both hydrogen, converts, and possibly (f) the connection established in step (e) with (1) triethyl orthoformate, and (2) NaBH ₄ with formation of an N-methyl-11-phenyl-5H-dibenzo- [b, e] [1 ,, 4] diazepine-5-propanamine of the following general formula (afc). NR ¹ R ² in which X has the same meaning as above and 1 2 R is hydrogen and R is methyl. ο pharmaceutical preparation for the treatment of depression, characterized in that it contains an effective amount of a compound of the general formula 1 2 in which R and R are selected from the group consisting of hydrogen and methyl are selected and X is hydrogen, chlorine, bromine or fluorine, or a pharmaceutically acceptable one Acid addition salts thereof, and optionally pharmaceutical Contains carrier and auxiliary materials. 5. Pharmaceutical preparation according to claim 4, characterized in that the compound 5- (3-Dimethylaminopropyl ·) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine is. 6. Pharmaceutical preparation according to claim 4, characterized in that the compound 5- (3-Dimethylaminopropyl) -11-phenyl-5H-dibenzo [b, e] [1,4] diazepine fumarate [1: 1] is. 7. Pharmaceutical preparation according to one of claims 4 to 6, characterized in that it is in the form of a unit dose.