FR2479818A1 - 2-Substd. phenyl 7-nitro 3H 1,4-benzodiazepinyl aminoacid derivs. - are anxiolytics, tranquillisers, sedatives and anticonvulsants, prepd. by reacting aminoacid or peptide with benzodiazepin-2-thione - Google Patents

Abstract

2-R-5-X-substd.-phenyl-7-nitro 3H-1,4-benzodiazepine derivs. of formula (I) and their functional derivs. are new (where X is chloro or fluoro; R is an alpha-amino-carboxylic acid deriv. chosen from Ala, Val, Ival, Leu, Ile, Asp, Asn, Glu, Gln, Ser, Thr, Cys, Met, Lys, Arg, Phe, Tyr, Trp, His, Pro, Nva, Nle, Hyp, Orn(these acids have D, L or DL configuration or are a mixt. of the D and L forms) or Sar or R is a peptide deriv. contg. 2 or 3 alpha-amino- carboxylic acids chosen from the above and also Gly). Specifically claimed is (I) where X is 2-chloro and R is -L-Pro-Gly, -L-Pro-Gly-L-Leu, -L-Pro-L-Leu-Gly, L-Pro or L-Ala as the optical isomers or their mixts. I are used as anxiolytics, tranquillisers, sedatives and anticonvulsants, which show a more or less marked dissociation according to cpd., between their anxiolytic and sedative activities. The cpds. may be administered orally e.g. in daily doses of 1-50 mg. Activity and toxicity tests are described.

Description

 The present invention relates to novel 3H-1,4 benzodiazepines substituted in the 2-position by a peptide radical.

dans laquelle X représente un atome de chlore ou un atome de fluor, et R représente un radical dérivé d'un acide aamino carboxylique choisi dans le groupe constitué par Ala,
Val, nival, Leu, Ile, Asp, Asn, Glu, Gln, Ser, Thr,Cys, Met,
Lys, Arg, Phe, Tyr, Trp, His, et Pro, Nva, Nle, Hyp, Orn, ces acides étant sous la forme D, L, DL, ou sous forme de mélange en quantité quelconque de la forme D et de la forme L et Sar, ou R représente un radical dérivé d'un peptide comprenant 2 ou 3 acides a-amino carboxyliques choisis dans le groupe constitué par les acides ci-dessus et en outre l'aci- de Gly, ainsi que les dérivés fonctionnels desdits produits de formule (I).The subject of the present invention is the products of general formula (I)

wherein X represents a chlorine atom or a fluorine atom, and R represents a radical derived from an amino carboxylic acid selected from the group consisting of Ala,
Val, nival, Leu, Ile, Asp, Asn, Glu, Gln, Ser, Thr, Cys, Met,
Lys, Arg, Phe, Tyr, Trp, His, and Pro, Nva, Nle, Hyp, Orn, these acids being in the form D, L, DL, or as a mixture in any amount of the D-form and the form L and Sar, where R represents a radical derived from a peptide comprising 2 or 3 α-amino carboxylic acids selected from the group consisting of the above acids and furthermore Gly acid, as well as functional derivatives said products of formula (I).

 It will be accepted by convention that the symbols of the α-amino carboxylic acids represent these acids in their D, L or DL configuration and not only in the L configuration (for example, the term Ala means Alanine in D-form, L-form or sub-form). DL form).

 Unless otherwise agreed, the nomenclature used in this application is the IUPAC nomenclature, the rules of which are published in particular in Biochem. J. (1972) 126, 773-780.

Thus the following symbols have been used to denote α-amino carboxylic acids
Alanine Ala
Arginine Arg
Asparagine Asn
Aspartic acid
Cysteine Cys
Sutamic Acid Glu
Glutamine Gln
Glycine Gly
Histidine His
Isoleucine Island
Leucine Leu
Lysine Lys
Methionine Met
Phenylalanine Phe
Proline Pro
Serine Ser
Threonine Thr
Tryptophan Trp
Tyrosine Tyr
Valine Val Isovaline Ival
Norvaline Nva
Norleucine Nle
Hydroxyproline Hyp
Ornitine Orn
Sarcosine Sar
The term "functional derivatives" of peptides of formula (I) may denote - base salts, preferably a base derived from an alkali metal, such as for example sodium hydroxide, sodium carbonate, or carbonate sodium acid, - alkyl esters in which the alkyl radical preferably contains from 1 to 5 carbon atoms, such as methyl, ethyl or propyl radicals, for example, primary amides or alkyl-substituted amides in which the s) alkyl group (s) contains 1 to 5 carbon atoms.

 Among the products which are the subject of the invention, the products as defined by formula (I) above in which R represents a radical derived from an α-amino carboxylic acid chosen from the group consisting of Ala, are more particularly selected. , Val, Ival, Leu, Ile, Glu, Gln, Fis, Pro these acids being in the form D, L or DL, or R represents a radical derived from a peptide comprising 2 to 3 alpha-amino carboxylic acids selected from the group comprising the acids which have just been mentioned and, in addition, the Gly acid as well as the functional derivatives of the said products of formula (I).

Among these products, particular mention may be made of products as defined by formula (T) above in which R represents an Ala, Val, Ival or Leu radical.
Glu, His, Pro, Pro-Gly, Pro-Leu, Glu-His, Gly-Leu, Leu-Pro,
Pro-Val, Pro-Ala, Pro-Gly-Leu, Leu-Gly, Pro-Gly-Val, Pro
Leu-Gly, Glu-His-Pro, Gly-Lau-Pro, Leu-Pro-Gly, Lau-Gly-Pro, and their functional derivatives.

Among the products of the invention, the products as defined by formula (I) above in which R represents a radical derived from an α-amino carboxylic acid or from a peptide comprising 2 or 3 are more particularly selected. α-amino carboxylic acids as defined above and in particular: the products of formula (I) in which - R represents a radical Pro, Ala, Pro-Gly, Pro-Gly-Leu,
Pro-Leu, Pro-Leu-Gly, X represents a chlorine atom and R represents a radical
Pro, Ala, Pro-Gly, Pro-Gly-Leu, Pro-Leu, Pro-Leu-Gly.

 Among these products, mention may be made especially of: N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl / L-prolyl-glycine, its optical antipode, and their mixture, N- [N- [N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycyl-L-leucine.

N- [N- [N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-L-leucyl-glycine, N- [5- ( 2-chloro-phenyl) 7-nitro-3H-1,4-benzodiazepin-2-yl / -L proline, its optical antipode, and their mixture, - N- [5- (2-chloro-phenyl)] -7-nitro-3H 1,4-benzodiazepin-2-yl / -L alanine, its optical antipode, and their mixture, - N- / N- / 5- (2-chloro-phenyl) 7-nitro-3H-1,4-benzodiazepin-2-yl Methyl prolylyl glycinate, N / N- / N- / 3 (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl / L prolyl / L-glycyl / L-ethyl leucinate, methyl N- [N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L prolyl / L-leucinate, - N- / N- / 5- (2- chlorophenyl) 7 nitro 3H 1,4-benzodiazepin-2-yl / L-prolyl / L leucine, N- / N- / N- / 5- (2-chloro-phenyl) -7-nitro-3H-1,4-diazepine -2yl / L prolyl / L leucyl / glycinate methyl, - N - / - 5- (2-chloro-phenyl) 7-nitro 3H 1,4-benzodiazepin-2yl / L valine.

N - / - 5- (2-chloro-phenyl) -7-nitro-1,4-benzodiazpin-2-yl / L-isovaline, N- [5- (2-chlorophenyl)] -7-nitro-3H-1 4-benzodiazepin-2-yl / L leucine, N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl] -Lprolyl / glycyl / leucine N- [N- [N- [(2-chlorophenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-glutamyl / L-histidyl / L-praline, - N- / N- 5- (2-chloro-phenyl) 7-nitro-3H-1,4-benzodiazepin-2-yl / L-laucyl / Glycyl / L proline, N- / N- / 5- (2-chlorophenyl) 7-nitro-3H 1,4-benzodiazepin-2-yl / L leucyl / L prolyl / glycine, LaNN &num; Methyl N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-banzodiazepin-2-yl] -L-prolyl-glycyl-L-leucinate, - N- / N- / N- / 5- (2-chloro-phenyl) 7-nitro-3H-1,4-benzodiazepin-2-yl / L prolyl / glycyl / L valine, N- / N- / N- / 5 <2-chloro-phenyl) 7 -Nitro-3H 1,4-benzodiazepin-2-yl / glycyl / L leucyl / L proline, N- / N- / 5- (2-fluorophenyl) 7-nitro-3H 1,4-benzodiazepin-2-yl Prolyl glycine, N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl / L prolyl / L valine, - N- / 5- (2-chloro-phenyl) -N 3-chloro-phenyl) 7-nitro-3H-1,4-benzod-azepin-2-yl / L methyl prolinate, N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H] 4-benzodiazepin-2-yl / DL-prolyl / glycine, N-methyl-N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] glycine, N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] DL proline.

dans laquelle X représente un atome de chlore ou un atome de fluor, avec l'acide a-amino carboxylique ou le peptide choisi, ou successivement avec les différents acides aamino carboxyliques ou peptidesdans l'ordre convenable, les acides a-amino carboxyliques ou peptides étant sous la forme stéréochimique désirée étant si nécessaire protégés, et que l'on élimine, si désiré, le ou les groupes protecteurs s'ils sont présents, et que l'on transforme, si désiré, le produit de formule (I) obtenu en un dérivé fonctionnel.The invention also relates to a process for preparing the products as defined by the formula (I) above and their functional derivatives, characterized in that a product of formula (II) is reacted.

in which X represents a chlorine atom or a fluorine atom, with the α-amino carboxylic acid or the peptide chosen, or successively with the different amino carboxylic acids or peptides in the appropriate order, α-amino carboxylic acids or peptides being in the desired stereochemical form, if necessary protected, and if desired, the protecting group (s) are removed if they are present, and if the product of formula (I) obtained is converted, if desired. in a functional derivative.

 Under preferred conditions of implementation of the invention, the process described above is carried out as follows: the reaction of a product of formula (II) with an α-amino carboxylic acid or a peptide is carried out at in an organic solvent which may be for example an alcohol such as methanol, ethanol, propanol, - the reaction of a product of formula (I) in which R represents a radical derived from an acid; amino carboxylic acid or derivative of a peptide with an α-amino carboxylic acid or a peptide is carried out in the presence of a condensing agent. The condensing agent may for example be a carbodiimide such as dicyclohexylcarbodiimide. These condensation methods are well known, and described for example in "The Peptides Volume I, 1965 (Academic Press).

 It is possible to carry out the spread by activating the COOH function of the reaction product beforehand, according to methods known to those skilled in the art.

 Temporary protection of functional groups is achieved by traditional methods: protection of protective groups which are subsequently removed by hydrolysis or by reaction. A carboxyl group may be protected, for example, by esterification with methanol, ethanol, tertiary butanol, benzyl alcohol, p-nitrobenzyl alcohol. Examples of this type of protection are given below in the experimental section.

 The amino function may be protected for example by an acidic residue of an aliphatic carboxylic acid, aromatic acid (acetic acid, benzoic acid), or an acidic residue derived from a carbonic acid (ethoxy-carbonyl residue, benzyloxycarbonyl), or a acid residue derived from a sulphonic acid (benzene sulphonic acid, p-toluenesulphonic acid).

 The conversion of the products of formula (I) into functional derivatives may comprise the formation of salts formed by reaction of the product of formula (I) with a base such as sodium hydroxide, sodium hydrogen carbonate, hydroxyl potassium, - esters, formed by reaction of the product of formula (I) with an alcohol such as for example methanol, ethanol, propanol, isopropanol, butanol, amides, or substituted alkyl amides in which the (s) alkyl group (s) contains (s) 1 to 5 carbon atoms according to known methods (see, for example, HOUBEN-WEYL, Methoden der organischen Chemie, '40 edition, volume XVI, 1, page 315 and following) .

 Of course, the products of formula (I) containing one or more α-amino carboxylic acids in the DL form can be obtained by recombination of their antipodes.

 The diastereoisomeric racemates of formula (I) can be obtained separately, for example, by selective crystallization, by counter-current distribution or by column chromatography.

 The racemic products of formula (I) can be further split into their optical antipodes according to the usual methods in the field, for example by salt formation using optically active bases and separation of salts by functional crystallization.

 The products of formula (I) above, and the functional derivatives of said products of formula (I), possessing interesting pharmacological properties they are endowed notably with a remarkable anxiolytic, tranquillizing, and anticonvulsant activity.

 The products of the invention show a dissociation, more or less marked according to the products, between their anxiolytic effects on the one hand, and their sedative effects on the other hand.

 These properties justify their application in therapeutics, and the object of the invention is also, as medicaments, the products as defined by formula (I) above, as well. that their functional derivatives are pharmaceutically acceptable.

The invention more particularly relates to medicinal products, as defined above, characterized in that in formula (I) R represents a radical derived from an α-amino-carboxylic acid selected from the group consisting of in Ala,
Val, Ival, Leu, Ile, Glu, Gln, His, Pro, these acids being in the form D, L or DL, or R represents a radical derived from a peptide comprising 2 or 3 α-amino carboxylic acids selected from group comprising the above acids and furthermore Gly, - R represents a radical Ala, Val, ival, Leu, Glu, His, Pro,
Pro-Gly, Pro-Leu, Glu-His, Leu-Pro, Gly-Leu, Pro-Val, Pro
Ala, Leu Gly, Pro-Gly-Leu, Pro-Gly-Val, Pro-Leu-Gly, Glu-Hi s-
Pro, Gly-Leu-Pro, Leu-Pro-Gly, Leu-Gly-Pro, -R represents a radical Pro, Ala, Pro-Gly, Pra-Gly-Lau, Pro Lau, Pro-Leu-Gly, -X represents a chlorine atom and R represents a radical
Pro, Ala, Pro-Gly, Pro-Gly-Leu, Pro-Leu, Pro-Leu-Gly, as well as the pharmaceutically acceptable functional derivatives of said translated formula (I).

 The subject of the invention is especially for the purpose of medicaments; N- [N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] prolyl-glycine, optically antipode, and their mixture, - N- / N- / N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycyl-L-leucine, - N- / N- / N- / 5 - chloro-rhenyl) 7-nitro-3H 1,4-benzodiazepin-2-yl / L prolyl / L leucyl / glycine, N- [5- (2-chloro-phenyl)] -7-nitro-3H 1 , 4-oenzodiazepin-2-yl / L proline its optical antipode, and their mixture, - N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodia-2-yl / L alanine, its optical antipode and their mixture.

 The products according to the invention find, for example, their use in the treatment of states of anxiety, irritability, aggressiveness, sleep disorder, certain psychosomatic manifestations, certain personality disorders, certain behavioral disorders. , spasms, muscle contractions, convulsions.

 The usual dose is variable depending on the condition, the product used, the subject treated and the route of administration. It may be, for example, from 1 to 50 mg per day, orally in the adult.

 The invention extends to pharmaceutical compositions containing, as active principle, at least one of the abovementioned medicaments.

 These compositions are made so that they can be administered by the digestive or parenteral route. They can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, single or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.

 The active ingredient (s) can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or no, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 The examples given below illustrate the invention without limiting it.

Example 1: N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L proline.

 6.63 g of 5- (2-chlorophenyl) -7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-thione, 9.2 g of Proline L, 8 g of sodium are mixed under nitrogen with stirring. sodium bicarbonate, 150 cm3 of ethanol and 70 cm3 of dcc, refluxed for 5 hours, cooled, poured into 500 cm3 of water, extracted the neutral fraction with methylene chloride.

 The aqueous phase is carefully acidified with N hydrochloric acid to pH 3.5, this aqueous phase is extracted with methylene chloride, dried, evaporated under reduced pressure and 5.8 g of crude expected product is obtained.

15 g of product are purified as obtained by operating as indicated above as follows
15 g of crude product are dissolved in 1 liter of ether under reflux for half an hour, filtered, concentrated to a volume of 500 cm.sup.3, then added at 20.degree. C., 2.8 cm.sup.3 of diethylamine, stirred strongly, drained and dried. The mixture is washed with ether and then the product obtained is dissolved in 500 cm 3 of water, washed with ethyl acetate, the aqueous phase is acidified with 30 cm 3 of N hydrochloric acid and 60 g of monosodium phosphate, extracted with water. ether, dried, concentrated under reduced pressure, and after drying obtained 4.775 g purified expected product / a / D = + 9 + 1 (c = 1%, methanol).

 The product of Example 1 was repreceded by varying the operating conditions somewhat, and observed that the rotatory power of the product obtained was modified. This suggests that during the preparation, racemization occurs at the proline level. The product obtained above presumably comprises a small amount of corresponding D-proline derivative (hence corresponding DL-proline derivative).

NMR spectrum (Deuterochloroform, 90 Mhz)
160 to 244 Hz the CH2 in ss of N 331 - 341 Hz 433 - 444 Hz

717 - 719,5 Hz - H aromatiques en ortho de N02 couplé
méta 739,5 - 742 Hz 748,5-751 Hz

CH2-N of the condensed cycle 340 to 356 Hz the other CH2N 418 - 426

717 - 719.5 Hz - aromatic H in ortho coupled N02
meta 739.5 - 742 Hz 748.5-751 Hz

Ortho ortho-meta coupled ortho-meta from 646 to 680 Hz the other aromatic H.

 Example II: N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzo diazepin-2-methyl / methyl prolyl / glycinate.

 1.030 g of N- [5- (2-chlorophenyl) -7-nitro-3H-1,4-benzodiazepin-3-yl] -L proline are mixed under nitrogen while stirring, as obtained in Example I, 10 cm 3 of dimethylformamide. 0.5 cc of N-ethyl morpholine, 315 mg of methyl glycinate hydrochloride and 337.5 mg of hydroxy benzotriazole, are brought to the temperature of 00C-50C and 600 mg of dicyclohexylcarbodiimide redistille are added. It is left for half an hour at 00C-50C in an ice bath, then 20 hours at room temperature with stirring. Dimethylformamide is removed under reduced pressure at 400C, the residue is taken up in 20 cm3 of methylene chloride, filtered and the filtrate is collected. washed with sodium bicarbonate, and with water, then evaporated at 400C under vacuum, and 1.13 g of crude product which is purified by chromatography on silica eluting with a chloroform-methanol (97: 3 ). 0.713 g of purified expected product is collected.

NMR spectrum (CDCl, base frequency 60 Hz).

225 Hz = COOCH3
240 - 245 Hz = CH2 - NH
CH2 - 295 Hz = CH2 - N - tricycle
477 - 479.5 Hz = aromatic H in ortho of NO2 and coupled
meta, 490 - 492.5 Hz 499 - 501.5 Hz

Aromatic H in ortho
N02 and coupled ortho and meta
440 to 465 Hz = other aromatics
As indicated previously for the product obtained in Example I, the product obtained in Example II probably contains a small amount of Pro-gly-OMe derivative D (or DL Pro-Gly-OMe derivative).

Example III: N- / N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycine.

242 mg of the product obtained in Example II above, 5 cm3 of methanol, 1 cm3 of sodium hydroxide N are stirred under nitrogen and stirred for 3 hours at room temperature, then 1 hour at 500 ° C. the solvent is evaporated off at 500 ° C. under reduced pressure, the residue is taken up in water, the neutral fraction is extracted with ethyl acetate, the aqueous phase is carefully acidified to pH # 3 with acetic acid, extracted with ethyl acetate, dried eva pore at 40 ° C. under reduced pressure, and obtains 205 mg of expected product dg, / β-α = 19 # 2 (DMF)
RMM spectrum (CDCl3, basic frequency 60 Hz)

les CH2N et N-CH-CO
120 à 180 Hz les autres CH2
Le produit obtenu à l'exemple 3 pourraitcontenir une certaine quantité de dérivé D Pro-gly (ou DL Pro-gly).Aromatic ortho of NO2 and coupled aromatic artho - meta 474 - 476 Hz aromatic ortho of NO2 448 Hz other aromatic

CH2N and N-CH-CO
120 to 180 Hz the other CH2
The product obtained in Example 3 could contain a certain amount of D Pro-gly derivative (or DL Pro-gly).

Example IV: N- [N- [N] -5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycyl-L-ethyl leucinate.

 1.41 g of N- [N- [5- (2-chlorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycine, obtained in Example III above, are mixed under nitrogen, 0.705 g of ethyl leucinate hydrochloride, 20 cm3 of anhydrous dimethylformamide, 0.426 g of N-ethyl morpholine, 0.406 g of hydroxybenzo triazole, cooled to 0.degree. C. with an ice bath and a solution of 0.618 g of dicycloalkylcarbodiimide in 10 cm3 of anhydrous dimethylformamide. The mixture is allowed to return to ambient temperature, thus stirring for 20 hours, the dimethylformamide is evaporated and the residue is taken up in 100 cm3 of ethyl acetate, filtered, the filtrate is collected, the organic phase is washed with an aqueous solution of hydroxide sodium hydroxide N and then with water. The organic phase is dried and then the solvent is evaporated off at 50 ° C. under reduced pressure to give 2.5 g of crude product which is purified by chromatography on silica eluting with a chloroform-methanol mixture (95.degree. : 5). 1.450 g of purified expected product are obtained.

NMR Spectrum (CDCL3, basic frequency = 60 H2) - 54 - 59 Hz

478 - 480 Hz H aromatique en ortho de NO2 et
couple méta 491 - 493 499 - 501

l'autre H en ortho de NO2
220 - 295 Hz et les CH2N et = CH -N
Exemple V : N-/N-/N-/5-(2-chloro-phénvl) 7-nitro 3H 14- benzodiazépin-2-yl/ L prolyl/ glycly/ L leucine.

478 - 480 Hz aromatic H in ortho of NO2 and
meta couple 491 - 493 499 - 501

the other H in ortho of NO2
220 - 295 Hz and the CH2N and = CH -N
Example V: N- / N- / N- / 5- (2-chloro-phenyl) -7-nitro-3H-14-benzodiazepin-2-yl / L prolyl / glycly / L leucine.

 1 g of N- [N- [N] -5- (2-chlorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl / prolyl / glycyl / ethylbuccinate are mixed under nitrogen while stirring. in Example IV, 3 cm3 of sodium hydroxide N, 20 ml of methanol, heated to 500C with stirring for one hour, the methanol evaporated and taken up in 50 ml of ethyl acetate. The product is then extracted with an aqueous solution of sodium hydroxide N, the alkaline phase is acidified with acetic acid to pH # 3.5, extracted with ethyl acetate and dried to obtain 870 mg of crude product which is purified by chromatography on silica eluting with chloroform-methanol-acetic acid (90 × 0.5) and gives 405 mg of purified product expected.

mal résolu
476 - 478 Hz H aromatique en ortho de N02 et
couplé méta
492 - 5Q1 Hz l'autre H en ortho de N02
440 à 455 Hz les autres H aromatiques
#200 à 300 Hz les CH2 -N et CH
# 65 à 145 Hz les autres CH2 et CH /&alpha;/D = = - 550 (c = 0,2%, diméthylformamide)
Exemple VI : N-/N-/5-(2-chloro-phényl) 7-nitro 3H 1,4-benzodiazépin-2-yl/ L prolyl/ L leucinate de méthyle et N/N/5 (2-chloro phényl) 7-nitro 3H 1t4-benzodiazepin-2-yl/L prolyl
D leucinate de méthyle.NMR spectrum (Deuterochloroform 60 Mhz) - 52 Hz (massive)

badly solved
476 - 478 Hz aromatic H in ortho of NO2 and
coupled meta
492 - 5Q1 Hz the other H in ortho of N02
440 to 455 Hz the other aromatic H
# 200 to 300 Hz CH2-N and CH
# 65 at 145 Hz the others CH2 and CH / &alpha; / D = = - 550 (c = 0.2%, dimethylformamide)
Example VI: N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl / L-prolyl / methyl leucinate and N / N / 5 (2-chlorophenyl) ) 7-nitro 3H-1,4-benzodiazepin-2-yl / L prolyl
Methyl leucinate.

20.6 g of N- [5- (2-chlorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L proline are mixed with stirring as obtained in Example I, 200 cm3 of anhydrous dimethylformamide. 9 μg of methyl leucyl chloride hydrochloride, then added at 0 ° C. 6.75 g of 1-hydroxy benzotriazole, 6.5 cm 3 of
N-ethyl morpholine and then again to OOC, 12 g of redistilled dicyclohexylcarbodiimide. Stirring is carried out for 8 hours between +2 and +5 ° C., then poured into one liter of water and extracted with ethyl ether. The organic phase is washed with a saturated solution of sodium hydrogen carbonate, dried and concentrated under reduced pressure. 23 g of crude expected product are obtained, which is chromatographed on silica eluting with a chloroform / acetone mixture (90-10) and 10 g of N- / N- / 5- (2-chlorophenyl) are obtained. nitro 3H 1,4-benzodiazepin-2-yl / L methyl prolyl / L leucinate, // D = -1360 + (c = 1 96, methanol).

337,5 Hz 320 à 360 Hz 410 à 440 Hz

715,5 - 717,5 Hz H en ortho de N02 couplé méta 736 - 738 Hz 745 - 747 Hz

NMR spectrum (deuterochloroform, base frequency: 90 Mhz) 80 - 85.5 Hz

337.5 Hz 320 to 360 Hz 410 to 440 Hz

715.5 - 717.5 Hz in ortho of coupled N02 meta 736 - 738 Hz 745 - 747 Hz

H in ortho of coupled NOx meta-ortho from 654 to 685 Hz the other aromatic H.

Analysis (C 27 H 30 Cl N 0.55)
C% H9Ó N% Cl%
Calculated 60.05 5.6 12.97 6.56
Found 59.9 5.6 12.6 7.5 = - 136 # 2 (c = 1%, methanol) - 2 g of N / N5- (2-chloro-phenyl) 7-nitro 3H 1,4-benzodiazepine 2-yl / L proly-D methyl leucinate.

334 Hz C02CH3 405 à 435 Hz (3H) 310 à 365 Hz (3H)

736 - 738 Hz 745 - 747 Hz

/ alD = + 22605 + 305 (C = 1%, methanol)
NMR Spectrum (Deuterochloroform, base frequency 90Mhz) 84.5 - 90 Hz

334 Hz C02CH3 405 to 435 Hz (3H) 310 to 365 Hz (3H)

736 - 738 Hz 745 - 747 Hz

Ortho ortho-meta coupled ortho
716 - 718 Hz H in ortho of coupled N02 meta of 654 to 687 Hz the other aromatic H
Analysis: (C27H30 (ClN5 05)
CX6 H% Cl96 N%
Calculated 60.05 5.60 6.56 12.97
Found 60.2 5.6 7.3 12.5
Example VII: N / N / 5- (2-chlorophenyl) 7-nitro 3H 1,4-benzo diazepin-2-yl / Lolol / L leucine
10 g of N- [N- [5- (2-chlorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl / methyl leucinate are obtained as obtained in Example VI, 80 cm3 of methanol, 10 cm3 of water, and 20 cm3 of 2N sodium hydroxide, stirred 18 hours at room temperature, then 150 cm3 of water and the methanol is removed under reduced pressure, again added 100 cm3 of water and washed with ether. The aqueous phase is saturated with sodium chloride, 2N hydrochloric acid (20 cc) is added, the mixture is extracted with ethyl acetate, dried, concentrated under reduced pressure and 9.8 g of expected product are obtained. .

- 474 - 476 Hz H en ortho de N02 couple meta - 486 - 488 Hz
494 - 496 Hz

NMR spectrum (deuterochloroform, 60 MHz base frequency) - 52 - 55 Hz - 200 to 300 Hz

- 474 - 476 Hz in ortho of N02 meta torque - 486 - 488 Hz
494 - 496 Hz

Ortho ortho N02 coupled ortho meta
- 430 to 470 Hz the other aromatic H
Example VIII: N- [N- [N] -5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzo diazepin-2-yl / L-prolyl / L-leucyl / methyl glycinate.

 11 g of the product obtained in Example VII, 100 cm 3 of anhydrous dimethylformamide, 2.92 g of methyl glycinate hydrochloride, 2.9 g of hydroxy 1-benzotriazole and 2.65 cm 3 of N-ethylmozpholine are mixed. The mixture is cooled to 50 ° C. and 4.75 g of redistilled dicyclohexylcarbodiimide are added. The mixture is stirred for half an hour at 50.degree. C. and then 18 hours at room temperature, and then 2.92 g of methyl glycinate hydrochloride, 2.9 g of hydroxypropine, are added again. benzotriazole, 2.65 cc of N-ethylmorpholine and then 4.75 g of dicyclohexylcarbodiimide and stirred for 8 hours at room temperature. The dimethylformamide is concentrated under reduced pressure and taken up in 300 cm3 of ethyl acetate, the suspension is filtered off The organic phase is washed with water and then with saturated sodium bicarbonate solution and finally dried and evaporated under reduced pressure. 15 g of crude expected product is obtained which is chromatographed on silica eluting with acetone-chloroform (3-7) and gives 9.55 g of purified product.

## EQU1 ## (D = 1.1%, methanol)
NMR Spectrum (Deutero Chloroform, Basic Frequency = 60 MHz) - 52 - 56 Hz

- 237 - 242 Hz N-CH2-CO2
- 475 - 477 Hz H in ortho of NO2 meta couple
- 489 - 487 Hz H in ortho of N02
- 496 - 498 Hz) coupled ortho meta
- 430 to 450 Hz the other aromatic H.

Analysis: (C29 H33ClN6O6)
C% H% Cl% N%
Calculated 58.14 5.55 5.92 14.03
Found 58.3 5.6 6.0 13.9
Example IX: N- / N- / N- / 5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl / L-prolyl / L-leucyl / glycine.

9 g of the product obtained in Example VIII, 80 cm3 of methanol, 10 cm3 of water and 20 cm3 of 2N sodium hydroxide are stirred, the mixture is stirred for 3 hours at room temperature and then 200 cm3 of water are added and the methanol is removed. under reduced pressure, the aqueous phase is washed with ether, neutralized with 20 cm 3 of 2 N hydrochloric acid and extracted with ethyl acetate, the organic phase is dried, filtered and concentrated under reduced pressure for 24 hours at 20 ° C. C, and obtained 5.1 g of expected product
/ &alpha;; / D = - 206 # 3 (c = 1.2%, methanol)
NMR Spectrum (Deutero Chloroform, Basic Frequency = 60 Mhz) - 53 Hz

- 205 to 300 Hz CH-N and CH2-N
- 474, 476 Hz in ortho of N02 coupled meta
- 489 - 497 Hz H ortho ortho coupled ortho
meta
# 445 Hz the other aromatic H
Analysis: C28 H31ClN6 06
C% H% N% Cl%
Calculated 57.68 5.36 14.42 6.08
Found 57.9 5.5 13.9 5.9
Example X: N- [5- (2-chloro-n-phenyl) -7-nitro-3H-1,4-benzodiazin-2-yl] -Lalanine.

13.2 g of 5- (2-chloro-phenyl) -7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-thione, 150 cm3 of water and 320 cm3 of ethanol are mixed with stirring. 14 g of L alanine, 16 g of sodium carbonate, is refluxed for 2 hours 30 minutes,
At room temperature, 1 liter of water is added, the aqueous phase is washed with methylene chloride, slowly added 150 cm 3 of 2N hydrochloric acid, extracted with methylene chloride, the organic phase is dried, filtered and concentrated to obtain 15.7 g g of expected crude product. The crude product obtained is dissolved in 500 cm 3 of ether, filtered, and a mixture of 7 cm 3 of dicyclohexyl amene in 300 cm 3 of ether is added with vigorous stirring. The crystals obtained are filtered off, washed several times with ether and dried. under vacuum, suspended in 1 liter of water, added 35 cm3 of 2N hydrochloric acid and 500 cm3 of ether, and 15 g of monosodium phosphate, stirred for one hour at room temperature, decanted and then extracted the aqueous phase at room temperature. the ether, dried the ether phase, filtered, concentrated under reduced pressure at room temperature, dried under vacuum and 10.1 g of pure expected product.

= = -201 + 30 (c = 1%, methanol)
By reprocessing the product a variation in the rotatory power has been observed, which suggests that the product obtained above is stereochemically impure, and contains a certain amount of corresponding D-Ala derivative (or DL Ala).

- H aromatiques 651 - 660 Hz (en méta de N02) 713 - 715,5 Hz (en ortho de NO2) 736,5-739 Hz en ortho de N02 745,5-748 Hz couplé ortho méta

413 - 420 - 427 - 434 Hz

116 - 122 Hz
- 4 mobile 626 à 810 Hz.NMR spectrum (deuterochloroform, 90 Mhz) - CH2 cyclic system AB

Aromatic H 651 - 660 Hz (in meta of NO 2) 713 - 715.5 Hz (in ortho of NO2) 736.5-739 Hz in ortho of N02 745.5-748 Hz coupled ortho meta

413 - 420 - 427 - 434 Hz

116 - 122 Hz
- 4 mobile 626 at 810 Hz.

Example XI: N- [5- (2-fluorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] proline.

 15.76Eg of 5- (2-fluoro-phenyl) -7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-thione, 23.02g of proline, 400 cm3 of ethyl alcohol, 200 cm3 water, 21.2 g of sodium carbonate, stirred, and refluxed for 4 hours 30 minutes, cooled, poured into 1 liter of water, washed with methylene chloride, acidified mother liquors to pHN3 by 2N hydrochloric acid and then extracted with methylene chloride, the organic phase washed with water, dried, evaporated to dryness under reduced pressure and 19.3 g of expected product.

NMR spectrum (Deuterochloroform, 60Mhz)
276 to 298 Hz CH2-N of the bicycle (complex)
210 to 245 Hz CH2-N and C: H-N
105 to 160 Hz the CH2 in ss of N
N 490 - 499 Hz aromatic H in ortho NO2 and in
ortho meta
# 486 and # 479 Hz aromatic H in ortho of NO2 and in meta
415 to 460 Hz the other aromatics.

 The product obtained above could contain a certain amount of derivative D-Pro (thus DL Pro) corresponding.

Example XII: N / N- [5- (2-Fluoro-n-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] propyl methyl glycinate.

 18.5 g of the product as in Example XI, 185 cm3 of dimethylformamide, 5.775 g of methyl glycinate hydrochloride, 6.22 g of hydroxybenzotriazole, and 8.8 cm3 of N-ethyl morpholine, were cooled. the solution with stirring at # 5 C then 10.4 g of dicyclohexylcarbodiimide is added, the mixture is stirred for 20 minutes at 50 ° C., then 10.4 g of dicyclohexylcarbodiimide are added, the mixture is stirred for 20 minutes at 50 ° C. and then the temperature is allowed to rise to room temperature. ; dimethylformamide is evaporated at 500C under reduced pressure, then 500 cm3 of methylene chloride, washed with a saturated solution of sodium bicarbonate, then with water and dried the organic phase, and treated with activated charcoal, filtered, leads to Dry the filtrate and obtain 19.3 g of crude expected product.

NMR spectrum (Deuterochloroform, 60 Mhz)
- COOCH3 at 223 Hz
- N - CH-2 - COO at 240 - 245 Hz
- aromatic H in ortho of N02 and coupled ortho-meta
at 489 - 492 Hz and 498 - 501 Hz
- other aromatics from 410 to 486 Hz
The product obtained in Example XII could contain a certain amount of derivative D Pro-Gly-OMe (thus DL Pro-Gly
) corresponding.

Example XIII: N / N- [5- (2-fluorphenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] prolyl-glycine.

2.37 g of the product are mixed as obtained in the example
XII, 10.15 cm3 of sodium hydroxide N, 47 cm3 of methanol, stirred at ambient temperature for 2 hours, the methanol is evaporated off under reduced pressure at 35 ° C., diluted with water, washed with sodium acetate. ethyl, abut sodium chloride, acidifies the aqueous phase with 5.05 cm3 of 2N hydrochloric acid, extracted with methylene chloride, dried, brought to dryness, and obtains 1.61 g of expected product.

de ~280 à r 460 Hz,

Massive NMR spectrum (Deuterochloroform, 90 Mhz) of CH2 in ss of N (v200 Hz following small CH2-N massifs and

from ~ 280 to r 460 Hz,

H in ortho of N02 and coupled ortho meta 721,5 - 724Hz H in ortho of N02 coupled meta
other aromatics from 625 to 705 Hz.

 The product obtained in Example XIII could contain a certain amount of derivative D-Pro-Gly, (therefore DL-Pro-Gly) corresponding.

Example XIV: N- [N- [N] -5- (2-fluorophenyl) -7-nitro-3H-benzodiazepin-2-yl] -L-prolyl-glycyl-L-methyl-leucinate.

 2.8 g of the product as obtained in Example XIII, 1.45 g of ethyl L-leucinate hydrochloride, 30 cm 3 of dimethylformamide, 0.78 cm 3 of N-ethylmorpholine, 1 g are mixed under nitrogen. of 1-hydroxybenzotriazole, cooled in an ice bath, 1.527 g of dicyclohexylcarbodiimide is added, then stirred at room temperature for 20 hours, then 603 mg of ethyl leucinate hydrochloride, 0.39 cm3 of N-ethylmorpholine, 416 mg are added. of hydroxybenzotriazole, 634 mg of dicyclohexylcarbodiimide and 5 cm3 of dimethylformamide, stirred at room temperature for 3 hours, filtered with dimethylformamide, evaporated under reduced pressure at a temperature below 400C, diluted in ethyl acetate, washed with with sodium bicarbonate and then with water, brought to dryness under reduced pressure, chromatography on silica eluting with a mixture of chloroform - acetone (8/2) and 2.64 g of expected product.

C02 Et 306 à 450 Hz les CH2-N et

727 - 728,5 Hz H aromatiques en ortho de N02
couplé méta

l'autre H en ortho de NO2 629 à 690 Hz les autres aromatiques 582 - 590 Hz

NMR spectrum (Deuterochloroform, 90 Mhz)
82.9 - 88 Hz CH3 106.5 -114 - 121.5 Hz 363 - 370.5 - 378 - 385.5Hz

C02 and 306 at 450 Hz the CH2-N and

727 - 728.5 Hz aromatic H in ortho of N02
coupled meta

the other H in ortho NO2 629 at 690 Hz the other aromatics 582 - 590 Hz

Example XV: N- [N-] - N - [5- (2-fluorophenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] prolyl-glycyl-L-leucine.

 2.39 g of the product as obtained in Example XIV, 48 cm 3 of methanol, cooled in an ice bath, were slowly mixed in order to slowly add 8 cm 3 of sodium hydroxide N, stirred at ambient temperature for 5 hours, evaporated at 300 ° C. under reduced pressure, the residue is redissolved in water, washed with ethyl acetate, the aqueous phase is neutralized with 4 cm 3 of 2N hydrochloric acid, extracted with methylene chloride, dried, brought to dryness, and 2 is obtained, 04 g of expected product.

ev48 à 60 Hz

NMR spectrum (Deuterochloroform, 60 Mhz)
484 - 486 Hz $ aromatic H in ortho of NO2 and
coupled meta
490 to 502 Hz the other aromatic H in ortho of
NO2 (complete)
405 to 4b0 Hz the other aromatic 180 to 310 Hz the CH2-N and

ev48 at 60 Hz

Example XVI: Nharmaceutical forms.

a) Tablets having the formula
next - N- / N- / N- / 5- (2-chloro-phenyt) 7-nitro 3H 1,4benzodiazepin-2-yl / L prolyli glycyl / L leucine ....... 10 mg - Excipient qs for a tablet finished at .......... 100 mg (Detail of 11 excipient, talc, magnesium stearate, aerosil) b) Capsules having the following formula were prepared: - N- / 5- (2-chloro-phenyl) 7-nitro 3H 1,4 benzodiazepin-2-yl / L proline .......................... ..... 10 mg - Excipient for one capsule completed at .................. 100 mg (Detail of the excipient, talc, magnesium stearate, aerosil)
PHARMACOLOGICAL STUDY 1) Antagonism of convulsions caused by pentetrazol in mice.

 The tests are carried out on batches of 10 mice. The test compound is administered orally one hour before the subcutaneous injection of 160 mg / kg of pentetrazol. Convulsions and mortality are noted during the half-hour following pentetrazol administration.

DESO, the dose that opposes in 50% of animals to clonic convulsions is calculated.

<Tb>

Product <SEP> of <SEP> DE <SEP> 50
<tb> the example <SEP> mg <SEP> / <SEP> kg
<tb><SEP> 1 <SEP> 5
<tb><SEP> 3 <SEP> 10
<tb><SEP> 5 <SEP> I <SEP> 8.5
<tb><SEP> 9 <SEP> 6
<tb> 2) Actimetry.

 The experimental conditions and the equipment used have been described by BOISSIER and SIMON (Arch Int Pharmacodyn.

1965, 158, 212-221; Psychopharmacology (bers.) 1966, 8, 428-436).

 The experiment is carried out on batches of 10 naive mice. Each animal is individually deposited in one of the boxes of the device one hour after the oral administration of the compound. The meters are read after 10 minutes.

 In order to eliminate the diurnal influences that can lead to significant differences between the morning and afternoon tests, the values obtained after treatment are compared with those obtained at the same time in control animals.

The ED 50 dose which reduces by 50% the motor activity observed in the control animals is calculated:

<tb><SEP> Product <SEP> of <SEP> DE <SEP> 50
<tb> the example <SEP> mg <SEP> / <SEP> kg
<tb><SEP> 1 <SEP> 100
<tb><SEP> 3 <SEP> 120
<tb><SEP> 5 <SEP> 120
<tb> 9 <SEP>. <SEP><SEP> 300
<Tb>
The tested products cause a decrease in motor activity only at high doses.

3) Test of the stairs.

The device and protocol used were described by
THIEBOT et al. (Psychopharmacologia, 1973, 31, 77).

 The experiment is carried out on batches of 10 born rats. Each animal is individually deposited in the chamber one hour after oral administration of the test compound. The number of adjustments made and the number of steps mounted are counted for 3 minutes.

 The straightening is the manifestation of the anxiety of the animals and the mounted steps reflect their locomotive activity.

The values obtained in the treated animals are compared, by the DUNNETT test, with those obtained in control animals.

<Tb>

Doses <SEP> Product <SEP> of <SEP> Example
<tb> mg / kg <SEP> 3 <SEP> 5
<tb><SEP>%<SEP> of the <SEP><SEP> variations of
<tb><SEP> straightening <SEP> steps <SEP>, straightening <SEP> @ <SEP> steps
<tb><SEP> mounted <SEP> mounted
<tb><SEP> 10 <SEP> - <SEP> 9.5 <SEP> + <SEP> 24
<tb><SEP> 20 <SEP> -59 <SEP> * <SEP> + <SEP> 7 <SEP> - <SEP> 2 <SEP> + <SEP> 2
<tb><SEP> 50 <SEP> -38 * <SEP> -14
<tb> 100 <SEP> - <SEP> 52 * <SEP> - <SEP> 37
<tb> * significant result.

The products tested significantly reduce the number of restorations reflecting the anxiety of animals to non-sedating doses.

4) Acute toxicity study.

 The experiment is carried out on batches of 5 mouse mules weighing about 20 grams.

 The products were administered orally and the mortality was overall counted after 7 days.

 The products of Examples 1,3,5 and 9 did not cause any mortality at a dose of 1 g / kg.

Claims (19)

1) - The products of general formula (I)

 wherein X represents a chlorine atom or a fluorine atom, and R represents a radical derived from an α-amino carboxylic acid selected from the group consisting of Ala, Val, Ival, Leu, Ile, Asp, Asn, Glu, Gln, Ser, Thr, Cys, and, Lys, Arg, Phe, Tyr, Trp, His, and Pro, Nva, Nle, Hyp, Orn, these acids being in the form D, L, DL, or as a mixture in any amount of the D-form and the L-form and Sar, where R represents a radical derived from a peptide comprising 2 or 3 α-amino carboxylic acids selected from the group consisting of the above acids and furthermore Gly acid, as well as functional derivatives thereof. products of formula (I). 2) - The products as defined by the formula (I) of claim 1, wherein R represents a radical derived from an α-amino carboxylic acid selected from the group consisting of Ala, Val, Ival, Leu, island, Glu, Gin, His, Pro, these acids being in the form D, L or DL, or R represents a radical derived from a peptide comprising 2 or 3 amino carboxylic acids selected from the group comprising the above acids and furthermore Gly acid as well as the functional derivatives of said products of formula (I).  3j - The products as defined by formula (I) of claim 1, wherein R represents an Ala radical, Val, Ival, Leu, Glu, His, Pro, Pro-Gly, Pro-Leu, Gbu-His, Gly-Leu, Leu-Pro, Pro-Val, Pro-Ala, Leu-Gly, Pro-Gly-Leu, Pro-Gly-Val, Pro-Leu-Gly, Pro-Gly-Leu, Gly-Leu-Pro, Leu-Pro Gly, Leu-Gly-Pro and their functional derivatives. 4) - The products as defined by formula (I) of claim 1 wherein R represents a radical derived from an α-amino carboxylic acid or a peptide comprising 2 or 3 α-amino carboxylic acids according to any of claims 1 to 3. 5) - The products as defined by the formula (I) of claim 1, wherein R represents a radical Pro, Ala, Pro-Gly, Pro-Gly-Leu, Pro-Leu, Pro-Leu-Gly. 6) - The products as defined by formula (I) of claim 1, wherein X represents a chlorine atom and R represents a radical Pro, Ala, Pro-GlyJ Pro-Gly Leu, Pro-Leu, Pro-Leu-Gly. 7) - N- [N- [5- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl / prolyl-glycine, its optical antipode, and their mixture. 8) N- [N- [N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L-prolyl-glycyl-L-leucine. 9) - N- [N-] - [N- (2-chloro-phenyl)] -7-nitro-3H-1,4-benzodiazepin-2-yl] prolyl leucyl / glycine. 10) - N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -L proline its optical antipode, and their mixture. 11) - N- [5- (2-chloro-phenyl) -7-nitro-3H-1,4-benzodiazepin-2-yl] -Lalanine, its optical antipode, and their mixture. 12) - Process for the preparation of the products as defined by the formula (I) of claim 1, and their functional derivatives, characterized in that a product of formula (II) is reacted:

 in which X represents a chlorine atom or a fluorine atom, with the α-amino carboxylic acid or the chosen peptide, or successively with the different α-amino carboxylic acids or peptidg in the appropriate order, the α-amino acids carboxylic acids or peptides being in the desired stereochemical form and being so necessary. protected, and if removed, if desired, the protective group (s) are present, and that is converted, if desired, the product of formula (I) obtained into a functional derivative. 13) - As medicaments, the products as defined by formula (I) of claim 1, as well as their pharmaceutically acceptable functional derivatives. 14) - Drug according to claim 13, characterized in that in the formula (I), X and R have the values indicated in any one of claims 2 to 6, as well as the pharmaceutically acceptable functional derivatives of said products of formula ( I). 15) - As a medicament, the product defined in claim 7. 16) - As a medicament, the product defined in claim 8. 17) - As a medicament, the product defined in claim 9. 18) - As a medicament, the product defined in claim 10. 19) - As a medicament, the product defined in claim 11. 20) - The pharmaceutical compositions containing as active principle, at least one of the medicaments as defined in any one of claims 13 to 19.