FR2513249A1 - (AMINOALKYL) -5 PHENYL-11 5H-DIBENZO (B, E) (1,4) DIAZEPINES USEFUL AS ANTIDEPRESSANT MEDICINES AND INTERMEDIATES FOR THEIR PREPARATION - Google Patents

Abstract

THE INVENTION RELATES TO (AMINOALKYL) -5 PHENYL-11 5H-DIBENZOB, E 1,4DIAZEPINES USEFUL AS ANTIDEPRESSANT MEDICINAL PRODUCTS AND INTERMEDIARIES FOR THEIR PREPARATION; THE MEDICINAL PRODUCTS OF THE INVENTION COMPLY WITH THE FORMULA: (CF DRAWING IN BOPI) OR R AND R REPRESENT AN ATOM OF HYDROGEN OR A RADICAL METHYL AND X REPRESENTS AN ATOM OF HYDROGEN, CHLORINE, BROMINE OR FLUORINE, AND THEIR SALTS OF ADDITIONAL ACIDS ACCEPTABLE IN PHARMACY; SOME OF THESE COMPOUNDS ARE NEW.

Description

The present invention relates to (aminoalkyl) -5-phenyl-1,5-H

  dibenzofb, ell 1,4 ldiazdpines useful antidepressants and intermediates for their

of these compounds are new.

  British Patent No. 907,646 to some of the dibenzodiazepines useful as the invention; for example the active ingredient of

hereinafter as maldate.

  British Patent No. 959,994 reduced forms, for example (aminoalkyl) -5 as drug preparation Some describes the drug preparation according to the compound of Example 1 describes the utility of

phenyl-11 dihydro-

  , 11 5 H-dibenzolb, and 1,4 ldiazdpines as parasympatholytics,

  antihistamines, spasmolytics, tranquillizers and psychostimulants.

  Greig, M E, et al In J Med Chem 14, No. 2

  page 153 (1971) describe the anaphylactic activity of certain homo-

  dibenzodiazdine regimens in mice, particularly

  chloro-2 (dimethylaminoethyl) -5-methyl-11,5 H -dibenzolb, 1,14 l -diazole

  pine. The compounds useful as antidepressant drugs of the invention have the formula

X

11 C 1 formula I

(CH 2) 3 NR 1 R 2

  R 1 and R represent a hydrogen atom or a methyl radical, and X represents a hydrogen, chlorine, bromine or fluorine atom,

  and their pharmaceutically acceptable acid addition salts.

  The compounds o R and R both represent a hydrogen atom or one represents a methyl radical and the other a

hydrogen atom are new.

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

  strong acids, hydrochloric, sulfuric and phosphoric acids.

  Examples of weak acids are fumaric acids,

  maleic, succinic, oxalic, cyclohexamic and the like.

  To demonstrate the antidepressant activity of the compounds of formula I, the method described by Englehardt, E L et al, J; Med Chem 11 (2): 325 (1968), which has already been used to indicate the utility of compounds for the treatment of depression in humans; mg / kg of the test compound was administered to five adult female mice (strain ICR-DUB) intraperitoneally 30 minutes prior to administration of a dose causing ptosis (32 mg / kg, ip) of tetrabenazine (in the form of methanesulfonate) 30 minutes after, the presence or

  the absence of complete closure of the eyelids (ptosis) was deter-

  on each animal For each compound studied, it is possible to establish

  the ED 50 (median effective dose) for the inhibition of depression

  induced by tetrabenazine in mice, according to the technique reported by Litchfield et al, J. Pharmacol Exp Therap 96:

  99-113 (1949) The dibenzodiazepine which is preferred according to the invention

  tion is the active agent of Example 1, ie (dimethylamino).

  3 propyl) -5 phenyl-11,5 H -dibenzolb, 1,4 1,4-diazepine.

  The invention also relates to a method for treating depression and pharmaceutical compositions useful for this purpose. Other features and advantages of the invention

  from the following description and claims

  cations. The usual dosage forms consist of an active ingredient of formula I and a pharmaceutical carrier

  suitable for obtaining solutions, syrups, elixirs,

  premiums, capsules, suppositories, powders and the like.

  To prepare compounds of formula I, whose posi-

  5 is substituted by the 3-dimethylaminopropyl radical, a N- (3-dimethylamino-3-propyl) benzamidodiphenylamine cyclodehydration is carried out as in the aforementioned British Patent No. 907,646 with a dehydration-condensation catalyst, for example phosphorus or preferably oxyhalides of

  phosphorus in a suitable solvent, for example tetrachloro-

  1,1,2,2 ethane The equation is: x X X

C O POC 13

  c -NH I Ia 1 (CH) (CH) IIa (f H J, 23 la

2 3 N (CH)

N (CH 32

  oh X has the meaning indicated for formula I above.

  The new compounds of formula I, the

  position 5 is substituted by the 3-amino-propyl radical by cyclopentyl

  dehydration of new N-1-phthalimido-1) -3 propyll o-benzamido

  diphénylamines (11 b) then transformation of the phthalimido radical into amino radical (N Hl 2) with hydrazine and an acid, the equation is as follows: 1) NKNH O x 3 2) acid 2 t 2 i b

(1 2) 3 (CH 2) 3

(2) 3% N O III 2 Ib

WE

  o X has the meanings indicated for the formula I The compounds

  of formula III are also new.

  The novel compounds of formula I, the 5-position of which is substituted by the monomethylamino-3-propyl radical, are prepared by complementary reaction of the 3-aminopropyl compound with triethylorthoformate followed by reaction with sodium borohydride (Crocket et al. Blanton, 1974 (1): 55-6 Synthesis) The equation is:

X X

  9 1) (and O) CH 2)) N a BH 4

NOT

(CH 'c, 23

(CH 2) 3 (, H 2 3

  NH 2 lb NHCH 3 The starting composites of benzamido type II (I Ia and I Ib) are prepared according to a modification of the process of the British patent

  No. 907,646 mentioned above. First of all, alkylation is carried out by reduction.

  o-nitro-diphenylamine with a solution of P-chloropropyl-

  dimethylamine or (phthalimido-1) -3 chloro-1 propane then the nitro radical is reduced with hydrogen on palladium on charcoal to obtain the corresponding o-amino compound is then reacted with the amino radical ortho position with a halide benzoyl or a substituted benzoyl halide The equation is: ON NN OH 1) Na H

2) C 1-

Q

I H 2 / Pd-

VI

(CH 2) 3 Q

V C a.I CH pyridine 'Ji

(CH 2) 3

Q N (oe 3) 2 or phthalimido-1.

Preparation i

  N (3-dimethylaminopropyl) o-aminodiphenylamine.

  The mixture is stirred under azeotope atmosphere at room temperature.

  During 32 hours, a mixture of 32.0 g (0.107 mol) of N- (dimethyl)

  3-amino-propyl) o-n-tri-diphenylamine (E 155 ° C / 0.53 mbar at 1740 ° C / 0.44 mbar), 100 ml of 1001% by volume ethyl alcohol and 1.5 g of palladium charcoal catalyst When the theoretical amount of hydrogen had been substantially absorbed, the catalyst was filtered off through a filter bed of celite and the solvent was removed under reduced pressure. The residue was distilled under high vacuum in the following manner. ,, OC Quantié, fraction 1 8 O-130 O Ci 0.26 mbar 4.0 2 130-137 * C / 0.26 obar 7.0 3 137-1420 C / 0.26 mxbar 15.5 Chromatography thin layer with a 20% alcohol mixture

  methyl and 80% X of benzene on silica salt shows that the fraction

3 is completely pure.

-6 Preparation 2

  N- (3-dimethylaminopropyl) o-benzamidodiphenylamine.

  To a solution of 15.5 g (0.0575 mol) of N- (dimethyl)

  3-amino-propyl) o-aminodiphenylamine in 100 ml of pyridine

  At about 5 ° C. under a nitrogen atmosphere, 17.8 g (0.063 mol) of benzoyl chloride are added. A small amount of benzene is used to drive the remainder of the benzoyl chloride into the reactor. The mixture is stirred for one hour. and the container is sealed and placed in the refrigerator during the weekend. The solvent is then evaporated off under reduced pressure. The residual oil is dissolved in ml of methylene chloride and the solution is washed once with ml of sodium hydroxide. 3 N and three times with 250 ml of water The methylene chloride layer is dried over magnesium sulfate and evaporated under reduced pressure The residual pyridine is then removed under high vacuum (0.26 mbar) overnight.

  residual oil, in the form of the free base, is 24.9 g.

  Oxalate Has a hot solution of 4.0 g of the free base in

  isopropyl cool, add 1.35 g (0.0107 mol) of oxalic acid dihydrate The precipitated oxalate of the desired compound weighs 3.5 g and melts

  a 162-165 ° C. Salt after one hour of drying & 97 ° -98 ° C.

  refluxed) and overnight at room temperature, both under 0.13 mbar at the following analysis: Analysis: theoretical for C 26 H 29 N 305: C = 67.37; H, 6.31; N, 9.06

  found: C = -67.42; H, 6.35; N = 9.01.

Preparation 3

  According to the procedure of Preparation 2, in

  placing the benzoyl chloride by the following chlorides: 2-chlorobenzoyl chloride 3-chlorobenzoyl chloride 2-fluoro benzoyl chloride 3-fluoro benzoyl chloride 2-bromo-benzoyl chloride 3-bromo benzoyl chloride and chloro chloride -4 benzoyl, we obtain:

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  N- (3-dimethylaminopropyl) -O- (2-chlorobenzainido) diohenylamine, N (3-dimethyl-3-propyl) - (3-chloro) -benzamido) -diphenylamine, N (dimethylamino-3-propyl) - ( 2-fluorobenzamido) diphenylamine, N (3-dimethylaminopropyl) o- (3-fluoro-benzazido) diphenylnomin, N (3-dimethylaminopropyl) o (bromo-2-benzamido) -diphenylamine, N (3-dimethylaminopropyl) ) o- (3-bromo-benzamido) diphenylamine and

  N- (3-dimethylaminopropyl) o- (4-chlorobenzamido) diphenylamine.

Preparation 4

  N-f (1-phthalimido) -propyl-aminodiphenylamine.

  O-nitrodiphenylamine is reacted with sodium hydride and (1-phthalimido-1-chloro-propane to give N- (3-phthalimido) -propyl-nitrodiphenylamine which is then reduced by hydrogen on palladium charcoal in ethanol to get

the desired compound.

  Preparation 5 When, according to the procedure of Preparation 2, N- (1-phthalimido) -3-propyl-aminodiphenylamine is reacted with each of the following acyl chlorides in excess of 2-chlorobenzoyl chloride, chloro chloride 3-benzoyl, 2-fluoro-benzoyl chloride, 3-fluoro-benzoyl chloride, 2-bromo-benzoyl chloride, 3-bromo-benzoyl chloride and 4-chlorobenzoyl chloride, N- (phthalimido-1) is obtained. 3-propyl- (2-chloro-2-chlorophenyl) -diphenylamine, N (3-phthalimido) -propyl-3- (3-chlorobenzamido) -diphenylamine, N- (3-phthalimido) -propyl o- (fluoro-2) benzamido) diphenylamine, N- (1-phthalimido-1-propyl) -3-fluoro-benzamido-diphenylamine, N- (1-phthalimido) -propyl (bromo-2-benzamido) -diphenylamine, N- (phthalimido-1) 3-propyl o- (3-bromobenzamido) diphenylamine and

  N- (3-phthalimido) -propyl-4- (4-chlorobenzamido) -iphenylamide.

  The following nonlimiting examples illustrate

  the compounds of the invention are useful as medicaments.

Example 1

  (5-Dimethylamino-3-propyl) phenyl-5H-dibenzolb fumarate, el

11.4 jdiazepine, 1/1 l.

  A stirred mixture of 18.9 g (0.05 mol) of N- (3-dimethylaminopropyl) obenzamidodiphenylamine and 32.19 g (0.2 mol Dd) is heated at 150 ° C. under a nitrogen atmosphere for 1.5 hours. Phosphorus oxychloride in 50 ml of 1,1,2,2-tetrachloroethane The mixture is cooled slightly and poured onto about 1,000 ml of crushed ice and then diluted with sufficient water to obtain a final volume of 1000 ml The aqueous suspension is extracted twice with methylene chloride and the methylene chloride layer is discarded. The aqueous layer is made alkaline with 3N sodium hydroxide and extracted with three 250 ml portions of sodium chloride. These three portions of methylene chloride are combined, dried over magnesium sulphate and evaporated under reduced pressure to give a residual oil weighing 13.8 g of the desired compound in the form of the free base. isopropyl alcohol and is reacted with c 4.5 g (0.039 mol) of fumaric acid The fumarate is collected by filtration; yield 13 g

after drying; F 168-170 C.

  Theoretical analysis for C 28 H 29 N 304: C = 71.32; H, 6.20; N = 8.91

  found: C, 71.19; H, 6.19; N = 8.89.

Example 2

  According to the procedure of Example 1 and replacing

  N- (3-Dimethylamino) equimolar amounts N- (3-dimethylaminopropyl) N- (3-dimethylaminopropyl) N- (3-dimethylamino) propyl) N (3-dimethylaminopropyl) N- (3-dimethylaminopropyl) N - (3-Dimethylaminopropyl) N- (3-dimethylaminopropyl) is obtained: propyl) obenzamidodiphenylamine by the following compounds: o- (2-chlorobenzamido) diphenylamine, o- (3-chlorobenzamido) diphenylamine, o- ( 2-fluorobenzamido) diphenylamine, o- (3-fluorobenzamido) diphenylamine, o- (2-bromo-benzamido) -diphenylamine, o- (3-bromo-benzamido) -diphenylamine, and o- (chlorobenzamido) diphenylamine, fumarate ( 2-chloro-phenyl) -ll- (3-dimethylaminopropyl) -5H-dibenzolb, 11α-diazepine,

2 5 132 4 9

  (3-chloro-phenyl) -11 (3-dimethylamino-propyl) -5-dibenzofbell-1,4-diazepine fumarate, (2-fluoro-phenyl) -11 (3-dimethyl-3-propyl) -5H-dibenzolbell fumarate ldiazepine, (3-fluoro-phenyl) -11 (3-dimethylamino-propyl) -5H-dibenzofbell-1,4-diazepine fumarate, (2-bromo-2-phenyl) -3- (3-dimethyl-3-propyl) fumarate fumarate dibenzolbell 1,4 ldiazepine, fumarate (3-bromo-phenyl) -ll (3-dimethylamino-propyl) -5 H-dibenzolbell 1,4 ldiazepine, and fumarate (4-chloro-phenyl) -Il (3-dimethylamino) propyl) -5 H-dibenzolbell 1,4 ldiazepine

Example 3

  When in the procedure of Example 1, before the addition of fumaric acid, N- (3-dimethylaminopropyl) obenzamidodiphenylamine is replaced by the following compounds N- (phthalimido-1) -3-propylbenzamidodiphenylamine N- (3-phthalimido) -propyl-2- (2-chloro-L-benzo) -diphenylamine, N- (3-phthalimido) -propyl-3- (3-chloro-lenzamido) -diphenylamine, N- (phthalimido-1) -3 propyl (3-fluoro-1H) -epzamido) phenylmethyl, N- (phthalimido-1) -3-propyl-3- (3-fluorobenzamido) -phenylamine, N- (phthalimido-1) -3-propylb- (bromine) 2-Benzamido) diphenylamine, N- (Phthalimido-1) -3-propyl-3- (bromo-3-benzamido) -dipilenylamine, and N- (3-phthalimido) -propyl-4- (4-chlorobenzamido) -diphenylamine, 23 are obtained. E (phthalimido-1) -3 (1-phimimido-1) -3,1,4-diazepine, 1-phthalimido-1,3,11-diazepine, 1-phthalimidol) 1.41 diazepine, l (1-plitalimido) -1.141 diazepine, 1 (phthalimido-1) -1.141 diazepine, 5-propyll-5-propyll-phenyl-1 (chloro2H-dibenzolbell 1 , 4 ldiazepine,

phenyl) -11 H-dibenzolbel-

  propyll-5 (3-chlorophenyl) -11 H-dibenzelbel-

  propyl-5 (eluoro-phenyl) -11,511-dibenzolbel-

  propyll-5 (3-fluoro-phenyl) -11 H-dibenzolbel-

  propyll-5 (bromo-2-phenyl) -11 H-dibenzolbel-

  (1-Phthalimido-1-propyl-5-bromo-3-phenyl) -11 H -dibenzolb, el

l 1,4 ldiazepine, and

  1-phthalimido-3-propyl-5 (3-bromo-phenyl) -11 H -dibenzofb, el

Example 4

  (3-Amino-propyl) -5-phenyl-5H-dibenzolb hydrochloride,

  diazepine. refluxed for 2.5 hours a mixture of

  0.035 moles of 1-phthalimido-3-propyl-5-phenyl-511-dibenzolb, el

  1,4-ldiazepine, 0.039 mol hydrazine hydrate and 175 ml 95% ethyl alcohol by volume and allowed to stand for several

  A solution of 10 ml of hydrochloric acid is added to the mixture.

  concentrated in 50 ml of water and stirred for several hours. The mixture is filtered and the filtrate is evaporated under pressure.

  The hydrochloride is isolated by recrystallization from

  suitable and dried under reduced pressure.

Example 5

  According to the procedure of Example 4 and replacing

  1-Phthalimido-3-propyl-5-phenyl-5H-benzbenzolbate,

  diazdine with equimolar amounts of the following compounds

  (2-chlorophenyl) -1,1-phthalimido-3-propyl-5H-dibenzolb, 1, 4 J-

diazé pine,

  (3-chlorophenyl) -1H (1-phthalimido) propyl-5H-dibenzofb, ell 1, 41-

diazepine

  (1-fluoro-phenyl) -1 (1-phthalimido) -propyl-5H-dibenzolb, 1,4-i

diazé pine,

  (3-fluoro-phenyl) -1H-1-phthalimido-3-propyl-5H-dibenzofb, el (1,41-

diazepine

  (1-bromo-2-phenyl) -1 (1-phthalimido) -propyl-5H-dibenzolb, 1,41-

diazdpine,

  (1-bromo-3-phenyl) -1- (1-phthalimido) -propyl-5H-1-dibenzolb, 1,4-i

  diazepine, and (4-chlorophenyl) -1 (phthalimido-1) -3-propyll-5H-dibenzolb, elf 1, 4 1 diazepine, we obtain

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  (3-Amino-3H, 4-diazapine hydrochloride, (3-amino-1-amino) -1,4-diazdine hydrochloride, (3-aminobenzyl) -1,4-diazdine hydrochloride, hydrochloride. (3-amino-1-amine, 1, 4-diazine, (3-amino-1H) hydrochloride, 1,4-diazepine hydrochloride, (3-amino-1-amino, 1,4-diazepine hydrochloride, and (amino) hydrochloride. -3

lb, ell 1,4 ldiaz pine.

Example 6

  propyl) -5 (2-chlorophenyl) -1H-dibenzo-

  propyl) -5 (chloro-3-phenyl) -115-dibenzo-

  propyl) -5 (2-fluorophenyl) -111H-dibenzo-

  propyl) -5 (fluoro-3-pdnyl) -ll 5 U-dibenzo-

  propyl) -5 (2-bromo-phenyl) -115-dibeuzo

  propyl) -5 (3-bromo-phenyl) -11 H-dibenzo-

  propyl) -5 (4-chlorophenyl) -115 H-dibenzo-

  N-methyl-phenyl-11H-dibenzolb hydrochloride, 1,4-l-diazepine hydrochloride

  propanamine. The hydrochloride of (3-aminopropyl) -phenyl-5H-dibenzolb and 1,4-diazdine is converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating. After drying the methylene chloride layer, adding anhydrous benzene and then concentrating again to remove the benzene. The resulting free base is dissolved in a large excess of freshly distilled tryleyl orthoformate with reflux for several hours. The mixture is concentrated under vacuum. , ethanol is added and the mixture is concentrated again. The imidate is dissolved.

  obtained in ethanol and sodium borohydride is added with stirring.

  at 15-20 ° C. until thin layer chromatography indicates practically no starting material. The mixture is cooled, water is added gradually and then extracted with ethyl acetate. Wash the ethyl acetate layer until neutral, add salt, filter and evaporate. The crude free base is isolated by column chromatography, reacted with hydrochloric acid in ether and we recrystallize for

obtain the desired compound.

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Example 7

  According to the procedure of Example 6 and replacing

  (5-Amino-propyl) -5-phenyl-5H-dibenzofb, el-1,4-diazepine by equimolar amounts of (3-aminopropyl) hydrochloride, and 1,4 1,4-diazepine hydrochloride. (3-Aminopropyl) -5 Ib, 1, 4, 1diazepine, 5-Amino-propyl) hydrochloride, 1: 1, 1,4-diazepine, (3-aminopropyl) -5 Ib hydrochloride, el 1.41 diazepine, 5 (amino-3-propyl) -hydrochloride, 1,4-1,4-diazepine, 5-amino-propyl-5-lb, 1,4-diazepine hydrochloride, and (3-amino-propyl) hydrochloride 5-chloro-2-phenyl-5-diazepinpropanamine hydrochloride is obtained. (3-chlorophenyl) diazepin-5-propanamine hydrochloride, (2-fluoro-phenyl) diazepin-5-propanamine hydrochloride, (fluoro) phenyl diazepine hydrochloride. -5 propanamine, following compounds

(2-chlorophenyl) -11 H-dibenzo-

(3-chlorophenyl) -11 H-dibenzo-

(2-fluoro-phenyl) -11 H-dibenzo-

(3-fluoro-phenyl) -11 H-dibenzo-

(bromo-2 phenyl) -11 Ri-dibenzo-

(3-bromo-phenyl) -11,511-dibenzo-

(4-chlorophenyl) -11 Hi-dibenzo-

  ) -11 N-methyl 5 H-dibenzolbell 1.4 J-

  ) -ll N-methyl 511-dibenzolb, ell 1,41-

  ) -ll N-methyl 5 H-dibenzolbelf 1.41-

  (2-bromo-2-phenyl) -N-methyl-5H-dibenzolb, 1-yl chloride

diazep pine 5 propanamine,

  (3-bromo-phenyl) -N-methyl-5H-dibenzolbell hydrochloride

diaz Epine-5-propanamine, and

  (4-chlorophenyl) -N-methyl-5H-dibenzolb hydrochloride, 1,43-

diazepine-5 propanamine.

  Therapeutically effective amounts of the pharmacologically active compounds of formula I can be administered to humans according to the usual modes of administration and in

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  usually, for example orally, in the form of solutions, emulsions, suspensions, pills, tablets and capsules, in vehicles suitable for use in pharmacies and parenterally in the form of

sterile solutions.

  Examples of solid vehicles

  suitable for oral administration, lactose, magnesium stearate

  sium, gypsum, sucrose, talc, stearic acid, gelatin

  agar, pectin or gum arabic.

  Examples of liquid vehicles

  for oral administration, vegetable oils and water.

  For intramuscular administration, the vehicle or

  excipient may be a sterile liquid suitable for

  such as water or an oil suitable for parenteral

  such as peanut oil contained in ampoules.

  Although very small amounts of the active products of the invention are effective in the case of a minor treatment or in the case of administration to subjects with a relatively low body weight, the unit doses are generally 5 mg or more and preferably 10, 25, 50 or 100 mg or more and is preferably administered three or four times daily, depending, of course, on the urgency of the situation, the compound used and the particular desired result. The optimal unit dose seems to be 25 to 200 mg and a wider range seems to be 10 to 500 m Z. Generally the daily dosage should be between about 0.5 and about 20 mg / kg and preferably between 0.5 and 10 mg / kg The active ingredients of the invention can be combined with other pharmacological agents as previously indicated. It is sufficient if the active ingredient is present in an effective amount, i.e.

  to obtain an effective dosage in accordance with the form of adminis-

  Of course, several unit doses can be administered at about the same time The precise individual dosage and the daily doses should be established according to the principles

  medical care under the direction of a doctor or veterinarian.

  Characteristic compositions of the compounds to

  pharmacological activity of the invention are given below.

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i 4

Compositions

1 sasules.

  Capsules containing 10 active ingredient are prepared. For larger quantities, the amount of lactose must be reduced. Typical mixture for capsules 10 mg per capsule active ingredient in the form of a lactose salt 259 starch 126

mg or 50 mg of

  Ingredient mg per capsule magnesium stearate 4 4 total 399 399 Other capsule compositions contain a larger amount of active ingredient and are as follows: ingredients 100 mg per 250 mg per 500 m per capsule capsule capsule active ingredient in the form of 100 250 500 of a lactose salt 214 163 95 starch 87 81 47 magnesium stearate 4 6 8 total 399 500 650 In all cases, the selected active ingredient is uniformly mixed with lactose, starch and stearate magndsium

  and the mixture is introduced into capsules.

  2 tablets A typical composition for a tablet containing

  mg of active ingredient is shown below.

  with other amounts of active ingredient by adjusting the

weight of dicalcium phosphate.

  1 active ingredient 2 maize starch 3 March starch (starch) 4 lactose dicalcium phosphate 6 total calcium stearate per tablet, mg, O, 0 12.0, 0 132.0 202.0 202.0 l

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  Mix evenly 1, 2, 4 and 5 Prepare 3 as a 101% A poison in water Granulate the mixture with the starch paste and pass the wet mass through a sieve of 2.38 mm dia. The wet granules are dried and sieved through a 1.41 mm sieve of mesh size.

  dry granules with calcium stearate and compress.

  3 Sterile injectable solution at 27 per cm active ingredient 20 mg preservative, eg chlorobutanol,% w / v 0.5

injectable water q s.

  Prepare the solution, clarify by filtration, condition

  bottle, stop and autoclave.

  Of course various modifications may be made by those skilled in the art to devices or methods which

  have been described only as non-limitative examples

  without departing from the scope of the invention.

16 2 5513249

Claims (6)

  1 New compounds characterized in that they correspond to the formula: X N o> (CH 2) 3 NR R 2   X represents a hydrogen, chlorine, bromine or fluorine atom and R 1 and R 2 each represent a hydrogen atom or R 1 represents a hydrogen atom and R represents a methyl radical, and their acid addition salts.   2 New drugs useful especially as antidepressants   characterized in that they contain as active product at least one compound corresponding to the formula: (C 1 2) 3 sl R 2 1 2 o R and R represent a hydrogen atom or a methyl radical and X represents an atom of hydrogen, chlorine, bromine or fluorine,   and their pharmaceutically acceptable acid addition salts.   3 New drugs according to claim 2, characterized   in that the active product is (3-dimethylaminopropyl) -5   phenyl-5 H-dibeuzolb, 1,4-ldiazdpine and / or dimethyl fumarate   3-amino-propyl) -5-phenyl-5H-dibenzolb, 1,4-diazepine, 1/11. 13249   Medicaments according to one of claims 2 or 3,   characterized in that they are packaged for the purpose of   corresponding amounts of approximately 5 mg to 500 mg of the product   active orally or parenterally.   New intermediate compounds, necessary for the preparation of the compounds of claim 1, characterized in that they correspond to the formula O v <X HN RN (CH 2) 3   N oX represents a hydrogen, chlorine, bromine or fluorine atom.   6- (3-Phthalimidopropyl) -ll-phenyl-51-dibenzolbell 1,4   diazepines useful as intermediates in the preparation of   poses of formula I according to claim 1 wherein R and R are hydrogen, characterized in that they correspond to the general formula   wherein X is as defined in claim 1.