FR2531428A1 - 2-Anilino-5-phenyl-1,3-benzodiazepines; preparation process and medicament containing them - Google Patents

Abstract

The invention relates to 2-anilino-5-phenyl-1,3-benzodiazepines represented by the formula: in which R1 and R2 are hydrogen, a halogen atom or a lower alkyl or alkoxy radical; R3, R4 and R5 are hydrogen, a halogen or a lower alkyl or alkoxy, trifluoromethyl, carboxyl or alkoxycarbonyl radical; R6 is hydrogen or a lower alkyl radical. Use of these compounds as diuretic medicaments.

Description

The present invention relates to novel 2-anilino-5-phenyl-4,5-dihydro-1,3-benzodiazepines, a process for their preparation and their application in the therapeutic field.
A few 2-anilino-4,5-dihydro-1,3-benzodiazepines not substituted at the 5-position have already been described in US Pat. No. 3,849,400, as antihypertensive products and central nervous system depressants.

dans laquelle
R1 et R2 sont l'hydrogènes, un atome d'hyalogène, undical alcoyle ou alcoxy inférieur , R2 pouvant etre en position ortho ou para du cycle benzodiazépine-1,3.The compounds of the present invention are represented by the general formula I

in which
R1 and R2 are hydrogen, a hyalogen, alkyl or lower alkoxy, R2 may be in the ortho or para position of the benzodiazepine-1,3 ring.

R3, R4, R5 may be the same or different and are hydrogen, halogen, alkyl or lower alkoxy trifluoroxymethyl carboxy, alkoxycarbonyl. Ras R4S R5 substituents may occupy any of the available positions on the anilino ring.

R6 is hydrogen or a lower alkyl radical
The lower term applied to an alkyl or alkoxy group means that it may be linear or branched and may comprise from 1 to 4 carbon atoms
The compounds of formula I for which R 1 is hydrogen or chlorine and R 6 is hydrogen constitute a particularly valuable class of compounds when R 3 and R 4 are halogen, lower alkyl or lower alkoxy, R 5 being hydrogen.

 The pharmaceutically acceptable salts form an integral part of the invention. These may be salts prepared either from mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or from organic acids such as tartaric acid, citric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid.

 The 2-anilino-5-phenyl-4,5-dihydro-1,3-benzodiazepines are obtained according to the sequence of reactions below in which R1, R2, R3, R4, R5, R6 have the meanings given above.

est traitée par l'oxychlorure de phosphore à reflux pour conduire à une chloro-2 phényl-5 dihydro-4,5-3H-benzodiazépine-1,3 de formule III

a) In a first step, a 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one-2 of the general formula II described in the patent application No. 82 10.466

is treated with refluxing phosphorus oxychloride to give a 2-chloro-5-phenyl-4,5-dihydro-1,3-benzodiazepine-1,3-benzodiazepine of formula III

lesquels réagissent dans la suite comme les composés III.Compounds of formula III are used crude in the next step. They are contaminated with varying amounts of IV compounds

which react in the following as compounds III.

b) The compounds of formula III or the mixtures of III and IV are then treated with an aniline of general formula V.

The reaction is carried out at temperatures between 1000C and the boiling point of the aniline used. The reaction time can vary from 90 minutes to 3 hours.

The compounds of formula I for which at least one of the substituents R 3, R 4, R 5 is the carboxy group are preferably obtained by saponification of the corresponding I derivatives for which one of the substituents R 3, R 4, R5 is an alkoxycarbonyl group.

 The compounds of the invention possess remarkable diuretic and natriuretic properties. They result in a sharp increase in sodium excretion while potassium excretion is not significantly affected. They can be advantageously associated with powerful diuretics such as thiazides in order to greatly reduce potassium losses. These properties make them useful in human medicine for the treatment of arterial hypertension and certain edematous conditions.

 These diuretic properties are demonstrated particularly in rats according to the following methodology: a batch of 6 Sprague-Dawley rats is set to fast for 16 hours. Each animal is then administered orally with the product in gummy suspension, at the rate of 100 mg / kg. The rats are in individual cages and the urine of each collected 6 hours after administration of the product. The dosage of urinary sodium and potassium ions is carried out by flame spectrophotometry with lithium as a reference.

 Table I summarizes the results obtained for some products of the invention. The results are expressed as a percentage increase in the excretion of sodium and potassium compared to a control group. The statistical comparison is made by Student-Fiacher t-tests and Mann-Whitney U with the following meanings: * 1% <p <5% ** 0.1% <p <1% * * * p < 0.1% NS (not significant): p> 5%.

TABLE I]

<tb><SEP> Products <SEP> Na + <SEP> K +
<tb><SEP> ------------------------: ------------------: --------)
<tb><SEP>(<SEP> Example <SEP> 1 <SEP> + <SEP> ... <SEP>: <SEP>: <SEP>
<tb><SEP> -----------------------: -------------------- : ------------------ <SEP>)
<tb><SEP>(<SEP> Example <SEP> 2 <SEP>. <SEP><SEP> + <SEP> 337 <SEP>% <SEP> -: <SEP> + <SEP> 47 <SEP> % <SEP> (Ns) <SEP>)
<tb> -----------------------: --------------------: - -----------------)
<tb><SEP>(<SEP> Example <SEP> 7 <SEP>: <SEP> + <SEP> 480 <SEP>% <SEP> * <SEP> * <SEP>: <SEP>: <SEP><SEP> + <SEP> 58 <SEP>% <SEP> (Ns) <SEP>)
<tb> (----------------------: --------------------: - ------------------- <SEP>)
<tb><SEP>(<SEP> Example <SEP> 12 <SEP>: <SEP> + <SEP> + <SEP> 348 <SEP>% <SEP> * <SEP>: <SEP> + <SEP> 40 <SEP>% <SEP> (NS) <SEP>)
<tb> (----------------------: --------------------: - --------------------)
<tb>(<SEP> Example <SEP> 14 <SEP>: <SEP> + <SEP> 339% <SEP><SEP><SEP> * <SEP> * <SEP> * <SEP>: <SEP> - <SEP> 7 <SEP>% <SEP> (Ns)
<tb>(<SEP>:<SEP>:<SEP>)
<tb> ------------------------------: ---------------- ---------: ------------)
<tb>(<SEP> Example <SEP> 18 <SEP>: <SEP> + <SEP> 1205 <SEP> * <SEP> * <SEP>: <SEP> + <SEP> 94 <SEP> * <SEP >)
<tb>(<SEP>:<SEP>:<SEP>)
<Tb>
The products of the invention are advantageously compared with amiloride (N-amidino-3,5-diamino-6-chloro-pyrazinecarboxamide hydrochloride) known for its natriuretic properties and its potassium-sparing nature. Table II summarizes the comparison of one of the products of the invention with this standard, according to a protocol identical to that described above.

TABLE II

(<SEP>: <SEP>: <SEP>: <SEP>)
<tb><SEP>(<SEP> PRODUCT <SEP>: <SEP> Dose <SEP> (mg / kg) <SEP>: <SEP> Na <SEP> + <SEP>: <SEP> k <SEP> + <SEP>)
<tb><SEP>(<SEP>:<SEP>:<SEP>:<SEP>)
<tb><SEP>(<SEP> AMILORIDE <SEP> 20 <SEP>: <SEP> + <SEP> + <SEP> 497 <SEP>% <SEP>: <SEP> + <SEP> + <SEP> 120 <SEP>%
<tb><SEP> (------------------------------------------- ----------------------)
<tb><SEP>(<SEP> Example <SEP> 1 <SEP> 10 <SEP>: <SEP> + <SEP> 297 <SEP>% <SEP>: <SEP> - <SEP> 50 <SEP> % <SEP>)
<tb><SEP>(<SEP>:<SEP><SEP> 40 <SEP>: <SEP> + <SEP> 592 <SEP>% <SEP>: <SEP> - <SEP> 22 <SEP>% <SEP>)
<tb>(<SEP>:<SEP>:<SEP>:<SEP>)
<tb><SEP>(<SEP>:<SEP> 160 <SEP>: <SEP> + <SEP> 1016% <SEP>: <SEP> + <SEP> 27 <SEP>% <SEP>)
<tb>(<SEP>:<SEP>:<SEP>:<SEP>)
<Tb>
The derivatives of the invention exhibit low toxicity. Lethal doses 50 (LD 50) determined orally on the SWISS mouse, products listed in Table I are given in Table III.

TABLE III

<tb>(<SEP>:<SEP>)
<tb>(<SEP> PRODUCT <SEP>: <SEP> DL <SEP> 50 <SEP> po <SEP> (mg / kg) <SEP>)
<tb>(<SEP>:<SEP>)
<tb> (----------------------------: ----------------- ---------)
<tb>(<SEP>:<SEP> 1 <SEP> 400 <SEP>)
<tb> (Example <SEP> 1 <SEP>: <SEP>)
<tb> (---------------------------------------------- ---------)
<tb>(<SEP>)
<tb> Example <SEP> 2 <SEP> 1 <SEP> 500 <SEP>)
<tb> c <SEP>)
<tb>(<SEP>)
<tb> (Example <SEP> 7 <SEP>: <SEP> 1 <SEP> 000 <SEP>)
<tb><SEP>(<SEP>:
<tb> (---------------------------------------------- ---------)
<tb>(<SEP>:<SEP>)
<tb>(<SEP> Example <SEP> 12 <SEP>: <SEP> 2 <SEP> 240 <SEP>)
<tb>(<SEP>)
<tb> (---------------------------------------------- --------- <SEP>)
<tb>(<SEP>)
<tb> Example <SEP> 14 <SEP>. <SEP> 2 <SEP> 400
<tb> (-----------------------: ---------------------- -------
<tb> Example <SEP> 18 <SEP>. <SEP> 540 <SEP>)
<tb>(<SEP>:<SEP>)
<Tb>
The present invention also relates to the application of compounds I as medicaments, particularly diuretic and natriuretic drugs. These drugs can be administered orally in the form of tablets, coated tablets or capsules. The active ingredient is associated with various pharmaceutically compatible excipients. Daily dosages depend on the severity of the condition being treated and may range from 10 to 500 mg but preferably from 30 to 300 mg / day.

Some pharmaceutical formulations are given below by way of nonlimiting example. Composition of a 200 mg tablet
active ingredient 30 mg
lactose 70 mg
wheat starch 64 mg
gelatin 5 mg
. alginic acid 20 mg
talcum 10 mg
magnesium stearate 1 mg - Composition of one capsule
active ingredient 30 mg
lactose 50 mg
wheat starch 40 mg
talcum 9 mg
magnesium stearate 1 mg
The following preparative examples illustrate the invention but are in no way limiting. In the nuclear magnetic resonance (NMR) data the following abbreviations have been used. e = singlet, m = multiplet.

EXAMPLE 1 7-Ghloro-2,6-dimethylanilino-5-henyl-4,5-dihydro-3H-benzodiazepine-1,3, hydrochloride.

 A mixture of 24 g (0.088 mole) of 7-chloro-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one-2 and 26 cm3 (0.28 mole) of phosphorus oxychloride is carried 1 hour at reflux. After cooling, the reaction medium is diluted with 50 cm3 of ethyl acetate and the resulting solution is poured with stirring into 500 cm3 of diisopropyl ether. He separates a brown oil. After decantation of the solvent and trituration of this oil in diisopropyl ether, there is obtained 2,5-dichloro-phenyl-5-dihydro-4,5-benzodiazepide-1,3 hydrochloride as a solid product which is filtered, washed extensively with diisopropyl ether and dried under vacuum. It is used in the next step without further purification.

 The solid obtained above is added portionwise to 110 cm3 of 2,6-dimethylaniline. The reaction is exothermic. The mixture is then heated progressively, under nitrogen, at 1400C and maintained for 1 hour at this temperature. After cooling, the solution is poured into 500 cm3 of potassium hydroxide 20%. The mixture is extracted with ether. The ether solution is washed with water and dried over sodium sulphates. The ether is evaporated and then the excess of 2,6-dimethylaniline is distilled under reduced pressure. The residue is purified by recrystallization from heptane. 7-chloro-2,6-dimethyl-2-anilino-5-phenyl-4,5-dihydro-1,3-benzodiazepine melts at 167 ° -168 ° C (yield 61%).

Centesimal analysis: C23H22ClN3 (M = 375.89)
C% H% Cl% N%
Calculated 73.49 5.90 9.43 11.18
Found 73.41 6.07 9.25 11.11
The hydrochloride is prepared by dissolving the base in ethanol, adding 10 N hydrochloric acid and then evaporating to dryness. It is purified by recrystallization in acetone. Chloro-7 (2,6-dimethyl-2-anilino) -5-phenyl-4,5-dihydro-1,3-benzodiazepine hydrochloride melts at mp 188 ° -189 ° C.

Centesimal analysis: C23H23Cl2N3 (M = 412.34)
C% H% Cl% N%
Calculated 67.00 5.62 17.20 10.19
Found 67.16 5.60 17.15 10.20
BMN (DMSO d6 + D2O) # = 1.8 (3H, s); 2.3 (3H, e); 3.7 - 4.0 (2H, m); 4.6 -4.9
(1H, m); 6.9 - 7.6 (11H, m).

By operating as in Example 1, the following compounds are obtained (Examples 2 to 22)
EXAMPLE 2 (2,6-Dimethylanilino) -2,5-phenyl-4,5-dihydro-1,3-benzodiazepine, chlorphydrate
Obtained from 5-phenyl-1,3,4,5-tetrahydro-2H.

Benzodiazerine-1,3-one-2 and 2,6-dimethyl-aniline. F = 236-2380C
Centesimal analysis: C23H24ClN3 (M = 377.90)
C% H% Cl% N%
Calculated 73.10 6.40 9.38 11.12
Found 73.08 6.60 9.43 10.99
EXAMPLE 3 (2,6-Dichloro-anilino) -5-phenyl-4,5-dihydro-1,3-benzodiazepine hydrochloride
Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one-2 and 2,6-dichloroaniline. F-253-2550C (ethanol).

Analytical analysis: C21H18Cl3N3 (M = 418.74)
C% H% Cl% N%
Calculated 60.24 4.33 25.40 10.04
Found 60.10 4.65 25.41 -9.90
EXAMPLE 4 (2,3-Dichloroanilino) -2,5-phenyl-4,5-dihydro-1,3-benzodiazepine
Obtained from 5-phenyl-1,3,415-tetrahydro-1,3-benzodiazepine-1,3-one-2 and 2,3-dichloroaniline.F = 151-153 ° C (ethanol).

Centesimal analysis: C21H17Cl2N3 (M = 382.28)
C% H% Cl% N%
Calculated 65.98 4.48 18.55 10.99
Found 65.96 4.48 18.57 10.96
EXAMPLE 5
Anilino-2-phenyl-5-dihydro-4,5-3H-benzodiazepine-1,3
Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and aniline.F = 151-1530C (ethanol).

Centesimal analysis: C21H19N3 (M = 313.38)
C% H% N%
Calculated 80.48 6.11 13.41
Found 80.53 6.13 13.41
EXAMPLE 6 (2,3-Dimethylanilino) -2,5-phenyl-4,5-dihydro-1,3-benzodiazepine, maleate.

 Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and 2,3-dimethyl-aniline. The maleate is obtained by treatment of the base with n equivalent of maleic acid in acetone, evaporation to dryness and recrystallization of the residue in isopropanol. F = 154-1560C.

Centesimal analysis; C17H27N3O4 (M = 457.51)
C 'o H% N%
Calculated 70.88 5.95 9.19
Found 70.89 5.89 9.15
EXAMPLE 7 (2-Methylanilino) -2-phenyl-5,5-dihydro-3H-benzodiazepine-1,3.

hydrochloride
Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one and orthotoluidine. M.p. 193-195C (ethanol).

Centesimal analysis: C22H22ClN3 (M = 363.88)
% H% Cl% N%
Calculated 72.61 6.10 9.74 11.55
Found 72.47 6.13 9.63 11.51
EXAMPLE 8
Phenyl-5 (2,4,6-trimethylanilino) -2,5-dihydro-4,53-3H-benzodiazepine1,3, hydrochloride.

Obtained from 5-phenyl-tetrahydro-3,4,5-2H-benzodiazepine-1,3-one-2 and trimethyl-244,6-aniline. F = 154156 C (methanol-diisopropyl ether)
Centesimal analysis: C24H26ClN3 (M = 391.93)
C% H% Cl% N%
Calculated 73.54 6.69 9.05 10.72
Found 73.38 6.70 8.84 10.47 EXAMPLE 9 (2,6-Dimethylanilino) -2 (4-methyl-phenyl) -5,5-dihydro-3H-benzodiazepine-1,3 hydrochloride
Obtained from (methyl-4-phenyl) -5-tetrahydro-1,3,4,5-H-benzodiazepine-1,3-one-2 and 2,6-dimethyl-aniline
Mp 209 - 2110C (acetone)
Centesimal analysis :: C24H26ClN3 (M = 391.93)
C% z% Cl% N%
Calculated 73.54 6.69 9.05 10972
Found $ 73.63 $ 6.80 $ 8.99 10.64
EXAMPLE 10 (2,3-Dimethylanilino) -2 (4-methylphenyl) -5,5-dihydro-3H-benzodiazepine-1,3, hydrochloride.

Obtained from (4-methyl-5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and 2-dimethyl-2,3-aniline
F = 186 - 1880C (acetone)
Centesimal analysis; C24H26ClN3 (M = 391.93)
C% H% Cl% N%
Calculated 73.54 6.69 9.05 10.72
Found 73.63 6.74 9.11 10.57
EXAMPLE 11 (2,6-Diethyl-anilino) -2,5-phenyl-4,5-dihydro-1,3-benzodiazepine hydrochloride
Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and 2,6-dimethyl-aniline. M.p. 184 184 C (isopropanol-diisopropyl ether)
Centesimal analysis: C25H28ClN3 (M = 405.95)
C% H% Cl%
Calculated 73.96 6.95 8.73 10.35
Found 73.89 6.93 8.88 10.37
EXAMPLE 12 (2,6-Dimethylanilino) -2 (2-methoxyphenyl) -5,5-dihydro-3H-benzodiazepine-1,3 hydrochloride.

 Obtained from (2-methoxy-phenyl) -5,3,5-tetrahydro-1,3-benzodiazepine-1,3-one-2-one and 2,6-dimethyl-aniline.

Mp 202-2040C (diisopropyl ether acetone)
Centesimal analysis: C24H26ClN3O (M = 407.93)
These% Cl% N%
Calculated 70.66 6.43 8.69 10.30
Found 70.50 6.45 8.88 10.16
EXAMPLE 13 (2-Chloro-6-methyl-anilino) -2-phenyl-5,5-dihydro-3H-benaodiaepin -1,3, hydrochloride.

Obtained from 5-phenyl-1,3,4,5-tetrahydro-2-benzodiazepine-1,3-one and 2-chloro-2-methyl-6-aniline. M.p. 244-245 ° C (ethanol-dimethylformamide)
Centesimal analysis: C22H21Cl2N3 (M = 398.33)
C% H% Cl% N%
Calculated 66.34 5.31 17.80 10.55
Found 66.16 5.30 17.54 10.44 EXAMPLE 14 (4-Chloro-phenyl) -5 (2,6-dimethyl-anilino) -2,5-dihydro-1,3-benzodiazepine-1,3-hydrochloride
Obtained from (4-chlorophenyl) -5,3,3,4-tetrahydro-1,3-benzodiazepine-1-one and 2,6-dimethyl-aniline.

M.p. 193-195C ethanol-ether).

Centesimal analysis: C23H23Cl2N3 (M = 412.34)
C% H% Cl% N%
Calculated 67.00 5.62 17.20 10.19
Found 67.12 5.71 17.15 10.18
EXAMPLE 15 (2-Trifluoromethylanilino) -2-phenyl-5,5-dihydro-3H-benzodiazepine-1,3 hydrochloride.

 Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one and 2-trifluoromethylaniline.

Mp 137 ° -1400 ° C (ethanol-ether)
Centesimal analysis: C22H19ClF3N3 (M = 415.85)
C% H% F% Cl% N%
Calculated 63.23 4.58 13.64 8.49 10.06
Found 62.92 4.68 13.47 8.51 10.02
EXAMPLE 16 (2,6-Dimethyl-anilino) -2 (4-methoxy-phenyl) -5,5-dihydro-1,3-benzodiazepia, hydrochloride
Obtained from (4-methoxyphenyl) -5,4,5,5-tetrahydro-2H-benzodiazepine-1,3-one-2 and 2,6-dimethyl-aniline
Mp: 227-222 ° C (ethanol-ether)
Centesimal analysis: C24H26ClN3O $ (M = 407.93)
C% H% Cl% N%
Calculated 70.66 6.43 8.69 10.30
Found 70.50 6.43 8.66 10.21
EXAMPLE 17

(2,6-Dimethylanilino) -2-methyl-5-phenyl-4,5-dihydro-4,5-benzodiazepine-1,3-hydrochloride
Obtained from 7-methyl-5-phenyl-1,3,3,4-tetrahydro-1,3-benzodiazepine-1,3-one and 2,6-dimethyl-aniline
Mp = 198-200 ° C (isopropanol-diisopropyl ether)
Centesimal analysis; C24H26ClN3 (M = 391.93)
C% H% Cl% N%
Calculated 73.54 6.69 9905 10.72
Found 73s45 6.72 8.94 10.71
EXAMPLE 18 (2-Methoxy-anilino) -2-phenyl-5-dihydro-4,5-H-benzodiazepine-1,3 hydrochloride.

 Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and orthoanisidine. F = 156-1580C (ethanol-ether).

Centesimal analysis: C22H22ClN3O (M = 343.41)
C% H% Cl% N%
Calculated 69.55 5.84 9.33 11.06
Found 69.38 5.78 9.11 10.91
EXAMPLE 19 (2,6-Dimethylanilino) -2-fluoro-7-phenyl-4,5-dihydro-1,3-benzodiazepine-1,3-hydrochloride.

 Obtained from 7-fluoro-5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one and 2,6-dimethyl aniline.

M.p. 245 - 2470C (ethanol)
Centesimal analysis: C23H23Cl FN3 (M = 395.89)
C% H% F% Cl% N%
Calculated 69.77 5.86 4.80 8.96 10.61
Found 69.54 5.88 4.84 8.86 10.41
EXAMPLE 20 (N-methyl-2,6-dimethyl anilino) -5-phenyl-4,5-dihydro-1,3-benzodiazepine, oxalate
Obtained from 5-phenyl-1,3,4,5-tetrahydro-benzodiazepine-1, 3-one-2 and N-methyl-2,6-dimethyl aniline.

The oxalate is obtained by treatment of the base with one equivalent of oxalic acid in acetone, evaporation to dryness and recrystallization of the residue in an ethanol-ether mixture. Mp = 180 - 182C.

Centesimal analysis: C26H27N3O4 (M = 445.50)
C% H% N%
Calculated 70.09 6.11 9.43
Found 70.01 6.14 9.40
EXAMPLE 21
Methyl-3-phenyl-5-dihydro-4,5-3H-benzodiazepinyl-2-amino-4-methyl benzoate
Obtained from 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1,3-one and methyl-4-methyl-3-benzoate. Mp: 213-2140C (ethanol-dimethylformamide)
Centesimal analysis: C24H23N302 (M = 385.44)
CXH% N%
Calculated 74.78 6.01 10.90 Found 74.89 5.91 10.85
EXAMPLE 22
Methoxy-7-methyl-2-anilino-2-phenyl-5-dihydro-4,5-3H-benzodiazepine-1,3, ethyl monooxalate
Obtained from 5-methoxy-5-phenyl-4,5-dihydro-3H.

benzodiazepine-1,3-one-2 and orthotoluidine. M.p. 150-152 ° C (hexane-ethyl acetate).

Centesimal analysis: C27H29N3O5 (M = 447.47)
C% H% N%
Calculated 68.19 6.15 8.84
Found 68.14 6.14 9.03
EXAMPLE 23
Acid (5-phenyl-4,5-dihydro-3-benzodiazepinyl-2-amino) benzoic acid, hydrochloride
Firstly, 2- (5-phenyl-4,5-dihydrom-2-benzodiazepinyl-2-amino) ethyl benzoate is prepared by condensing 5-phenyl-1,3-tetahydro-1, according to the procedure of Example 1. , 4,5-2H-benzodiazepine-1,3-one-2 and ethyl-4-benzoate
A mixture of 24.4 g of this ester, 390 cm3 of diglyme and 15.2 g of sodium hydroxide is heated at 100 C for 3 hours.
After cooling, the precipitate is filtered and then dissolved in one liter of water. The solution is acidified with 3N hydrochloric acid. The hydrochloride of the acid (5-phenyl-4,5-dihydro-4,5-H-benzodiazepinyl-2-amino) benzoic acid separates It is filtered and recrystallized in ethanol. Mp = 263-265 C.

Centesimal analysis: C22H20ClN3O2 (M = 393.86)
C% H% Cl% N%
Calculated 67.09 5.12 9900 10.67
Found 66.90 5.20 8.82 10.53

Claims (11)

 1. 2-Anilino-5-phenyl-1,3-benzodiazepines, characterized by formula I

 wherein R1 and R2 are hydrogen, halogen, alkyl or lower alkoxy; R3, R4, R5 may be the same or different and are hydrogen, a halogen, an alkolyl or lower alkoxy, trifluoromethyl, carboxy, alkoxycarbonyl, the substituents R3, R4, R5 may occupy any of the available positions on the anilino nucleus; R6 is hydrogen or a lower alkyl radical, and their pharmaceutically acceptable mineral or organic acid salts.  2. Anilino-2-phenyl-5-benzodiazepine-1,3 according to claim 1, characterized in that R6 is hydrogen.  3. Anilino-2-phenyl-5-benzodiazepine-1,3 according to claim 2, characterized in that R1 is hydrogen or chlorine.  4. Anilino-2-phenyl-5 benzodiazepine 3-1,3 according to claim 3, characterized in that R3 is chloro-2, R4 is methyl-6 and R5 is hydrogen.  5. Anilino-2-phenyl-5-benzodiazepine-1,3 according to claim 3, characterized in that R3 is methyl-2, R4 is methyl-6 and R5 is hydrogen.  6. Anilino-2-phenyl-5-benzodiazepine-1,3 according to claim 3, characterized in that R3 is methoxy-2, R4 and R5 are hydrogen.  7. Anilino-2-phenyl-5-benzodiazepine (1) as claimed in claim 3, wherein R3 is methyl-2, R4 and is hydrogen.  8. 2- (2-Methoxy-anilino) -5-phenyl-4,5-dihydro-1,3-benzodiazepine and 2- (2-methyl-anilino) -5-phenyl-4,5-dihydro-3-benzodiazepine 1,3 and their pharmaceutically acceptable mineral or organic acid salts.  9. Process for the preparation of the compounds according to any one of Claims 1 to 8, characterized in that a 5-phenyl-1,3,4,5-tetrahydro-1,3-benzodiazepine-1-one-2 is treated. Formula

 by phosphorus oxychloride to give intermediate III

 which is condensed with an aniline of the general formula V

 the substituents R1, R2, R3, R4 and Pi R6 having the meanings given above.  10. Drug containing as active ingredient a 2-anilino-5-phenyl-1,3-benzodiazepine represented by the formula

 wherein R1 and R2 are hydrogen, halogen, alkyl or lower alkoxy; R3, R4, R5 may be the same or different and are hydrogen, halogen, alkyl or lower alkoxy, trifluoromethyl, carboxy, alkoxycarbonyl, substituents R3, R4 'Rg may occupy any of the positions available on the anilino nucleus; R6 is hydrogen or a lower alkyl radical, and their pharmaceutically acceptable mineral or organic acid salts.  11. Drug constitné by the combination of an active ingredient according to claim 10, with a diuretic of the class thiazidiques.