FR2694006A1 - New amide derivs. of benzo-hetero cyclic cpds. - for treating gastrointestinal disorders, including ulcers and gastric hypersecretion - Google Patents

Abstract

Amide derivs. of benzoheterocyclic cpds. of formula (I), their salts, and their diastereomers and enantiomers are new. In the formula X1 = O, S or N-R4; X2 = N or C-R5; X3 = a single bond, 1-6C alkylene or N-R6; X4 = H, alkoxy, cyano or N(R7)R8; R1 = gp. (a) or (b); R2 = H or lower alkyl; R3 = H, methyl, halo, alkoxy, cyano or nitro; R4, R5 = H, 1-6C alkyl, carboxyalkyl, alkyloxycarbonylalkyl or alkoxyalkyl; R6 = H or 1-6C alkyl; R7,R8 = H, 1-6C alkyl, alkyloxycarbonyl, or aralkyloxycarbonyl; R9 = H, 1-6C alkyl, hydroxycarbonylalkyl, alkoxyoxycarbonyl or alkyloxycarbonylalkyl; R10 = H, alkoxy or halo; R11 = 3-indolylmethyl or hydroxycarbonylalkyl; R12 = N(R13)R14 or 8-azaspiro(4,5)decan-8-yl; R13, R14 = H, alkyl pref. n-pentyl or alkyloxyalkyl; Z1-Z2 = C=N or NCO. 15 Cpds. are claimed e.g. 3-(3-(1,2-benzisoxazolyl)methylcarbonylamino)-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4-benzodiazepin-2-one. USE - Use of (I) as inhibitors of gastric acid secretion, as anti-ulcer agents and as cytoprotective agents, to treat gastrointestinal disorders is claimed. They are useful in mammals including man. (I) are also useful as intermediates in the prepn. of other cpds. in this series.

Description

 The present invention relates to new derivatives of amides of benzoheterocycles, the heterocyclic nucleus of which is five knuckles, their process of preparation, as well as their application as medicaments.

 The compounds which are the subject of the present invention can also be used in the pharmaceutical industry as intermediates and for the preparation of medicaments intended for the treatment of gastrointestinal diseases.

 These compounds have in particular as pharmacological activity an antiulcer activity and / or a gastric anti-secretory activity and therefore are useful as antiulcer agents and for the treatment of gastric hypersecretion. In particular, the compounds are suitable for preventing or treating gastrointestinal diseases of mammals, including humans, mainly the secretion of gastric acid and the cytoprotective capacity. The compounds are also useful as intermediates for the preparation of other compounds in these series.

dans laquelle - X1 représente un hétératome choisi parmi l'oxygène ou le soufre ou un
atome d'azote lié à un autre radical R4 (N-R4) ~ X2 représente un atome d'azote ou un atome de carbone lié à un autre
radical R5 (C-R5) - X3 représente une simple liaison, un radical alkylène linéaire ou ramifié
en C1-C6, ou un atome d'azote lié à un autre radical R6 (N-R6) X4 représente un atome d'hydrogène, un radical alcoxy, un radical cyano
ou un atome d'azote lié à deux radicaux R7 et R8 - R 1 représente

R2 représente un atome d'hydrogène ou un radical alkyle linéaire ou
ramifié R3 représente un atome d'hydrogène, un radical méthyle, un atome
d'halogène, un radical alcoxy, un radical cyano, ou un radical nitro R4 et R5 représentent indépendamment un atome d'hydrogène, un radical
alkyle linéaire ou ramifié en Cl-C6, un radical carboxyalkyle, un radical
alkyloxycarbonylalkyle, ou un radical alcoxyalkyle R6 représente un atome d'hydrogène ou un radical alkyle linéaire ou
ramifié en C1-C6;; R7 et R8 représentent indépendamment un atome d'hydrogène, un radical
alkyle linéaire ou ramifié en C1-C6, un radical alkyloxycarbonyle, ou aralkyloxycarbonyle ; Rq représente un atome d'hydrogène, un radical alkyle linéaire ou
ramifié en C1-C6, un radical hydroxycarbonylalkyle, alkyloxycarbonyle ou alkyloxycarbonyl-alkyle ; - R10 représente un atome d'hydrogène, un radical alcoxy, ou un atome
d'halogène - R 11 représente un groupe 3-indolylméthyle ou un radical hydroxy carbonylalkyle ;; - R12 représente un atome d'azote lié à deux autres radicaux R13 et R14
ou un groupe 8-azaspiro[4,5]decan-8-yl - R13 et R14 représentent indépendamment un atome d'hydrogène, un
radical alkyle linéaire ou ramifié, de préférence n-pentyl, ou un radical
alkyloxyalkyl ; ~ Z1 Z2 représente un radical C=N ou un radical

The present invention relates to compounds of general formula (I)

in which - X1 represents a heteratome chosen from oxygen or sulfur or a
nitrogen atom linked to another radical R4 (N-R4) ~ X2 represents a nitrogen atom or a carbon atom linked to another
radical R5 (C-R5) - X3 represents a single bond, a linear or branched alkylene radical
in C1-C6, or a nitrogen atom linked to another radical R6 (N-R6) X4 represents a hydrogen atom, an alkoxy radical, a cyano radical
or a nitrogen atom linked to two radicals R7 and R8 - R 1 represents

R2 represents a hydrogen atom or a linear alkyl radical or
branched R3 represents a hydrogen atom, a methyl radical, an atom
of halogen, an alkoxy radical, a cyano radical, or a nitro radical R4 and R5 independently represent a hydrogen atom, a radical
linear or branched C1-C6 alkyl, a carboxyalkyl radical, a radical
alkyloxycarbonylalkyle, or an alkoxyalkyle radical R6 represents a hydrogen atom or a linear alkyl radical or
branched in C1-C6 ;; R7 and R8 independently represent a hydrogen atom, a radical
linear or branched C1-C6 alkyl, an alkyloxycarbonyl, or aralkyloxycarbonyl radical; Rq represents a hydrogen atom, a linear alkyl radical or
branched at C1-C6, a hydroxycarbonylalkyl, alkyloxycarbonyl or alkyloxycarbonyl-alkyl radical; - R10 represents a hydrogen atom, an alkoxy radical, or an atom
halogen - R 11 represents a 3-indolylmethyl group or a hydroxy carbonylalkyl radical; - R12 represents a nitrogen atom linked to two other radicals R13 and R14
or an 8-azaspiro [4,5] decan-8-yl group - R13 and R14 independently represent a hydrogen atom, a
linear or branched alkyl radical, preferably n-pentyl, or a radical
alkyloxyalkyl; ~ Z1 Z2 represents a radical C = N or a radical

their physiologically acceptable salts, and when they exhibit
minus a center of chirality, their racemates, diastereoisomers or not,
their pure enantiomers and their mixtures.

 In the case where there are two centers of chirality one can have a racemic mixture which can be separated into two pure disemereoisomeric racemates by means of chromatographic processes or by fractional crystallization. The racemates obtained can be separated to obtain their enantiomers using optically active acids so as to form salts which can be separated by difference in solubilities, recrystallization with an optically active solvent or by means of microorganisms.

 In general, the alkyl or alkylene radicals, alone or part of an alkoxy, carboxyalkyl, alkyloxycarbonyl, alkoxyalkyl, alkyloxycarbonyl, aralkyloxycarbonyl, hydroxycarbonylalkyl, or alkyloxyalkyl radical have a linear or branched C1-C6 skeleton.

Preferably, the alkyl radicals, linear or branched in
C1-C6 are chosen from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl radicals.

Likewise, the linear or branched alkylene radicals
C1-C6 are preferably chosen from bivalent derivatives of the alkyl radicals defined above.

 The aryl radicals, alone or part of an aralkyloxycarbonyl radical, are chosen from mono or polycyclic aromatic radicals, each cycle possibly comprising one or more nitrogen atoms.

 The monocyclic aromatic radicals are preferably chosen from the phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl radicals, as well as the pyrrolyl, imidazolyl and pyrazolyl radicals.

 Among the polycyclic aromatic radicals, the naphytyl, benzimidazolyl, indolyl, isoindolyl, quinolyl and naphthiridinyl radicals will preferably be chosen.

 Finally, by halogen is preferably meant the chlorine, fluorine, bromine and iodine atoms.

 The new derivatives of general formula (I) can be prepared in accordance with the invention, according to the methods described below.

dans laquelle Xl, X2, X3, X4 et R3 ont la signification indiqué plus haut, et Y est un atome d'halogène, un groupe azido (-N3), un groupe imidazole-1-yle, un groupe O-CO-Rls, R15 pouvant être, un radical aikyle encombré comportant de trois à six atomes de carbone, ou aryle, de préférence substitué par un ou plusieurs halogènes, ou un groupe de formule générale (fui):

dans laquelle X1, X2, X3, X4 et R3 ont la signification définie plus haut, ou un groupe -OR16, R16 étant un groupe aromatique comportant un ou deux cycles substitué par un ou plusieurs radicaux nitro ou halogènes, ou un groupe N-succinimide::
- avec une amine de formule génerale (W)

dans laquelle R1 et R2 ont la signification indiquée plus haut, pour obtenir un composé de formule (I). By reaction of a carboxylic acid derivative of general formula (II)

in which Xl, X2, X3, X4 and R3 have the meaning indicated above, and Y is a halogen atom, an azido group (-N3), an imidazole-1-yl group, an O-CO-Rls group , R15 possibly being a hindered alkyl radical comprising from three to six carbon atoms, or aryl, preferably substituted by one or more halogens, or a group of general formula (fui):

in which X1, X2, X3, X4 and R3 have the meaning defined above, or a group -OR16, R16 being an aromatic group comprising one or two rings substituted by one or more nitro or halogen radicals, or an N-succinimide group ::
- with an amine of general formula (W)

in which R1 and R2 have the meaning indicated above, to obtain a compound of formula (I).

In particular, we can operate as follows:
A compound of formula (IV) is dissolved in 5 to 50 volumes of an anhydrous or hydrated organic solvent such as for example a chlorinated hydrocarbon such as methylene chloride or chloroform, a linear or cyclic ether oxide such as 1,2 -dimethoxyethane, tetrallydrofuran or dioxane, a polar aprotic solvent such as pyridine, dimethylsulfoxide or dimethylformamide or any other solvent suitable for carrying out a condensation reaction thereon or an appropriate mixture of two or more of these solvents and add one to two equivalents of an acylating agent of formula (II) in which X1, X2, X3, X4 and R3 have the meaning defined above and Y is ::
- a halogen preferably a chlorine atom,
- an azido group (-N3),
- an imidazol-l-yle group,
a group -O-CO-RIs in which R15 has the meaning defined above, the preferred R15 groups being tert-butyl or 2,4,6-trichlorobenzoyl,
a group of formula -O-R16 in which R16 has the meaning indicated above, the preferred R16 groups being para-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl, pentafluorophenyl, benzotriazol-1-yl and N-succinimide.The last two groups can be prepared by reaction of the carboxylic acid of general formula (11) in which X1, X2, X3, X4 and R3 have the meaning defined above and Y represents a hydroxyl group, with l 'hydroxy-l-benzotriazole or
N-hydroxysuccinimide, respectively in the presence of a carbodiimide such as for example dicyclohexylcarbodiimide, diisopropylcarbodiimide or l-ethyl-3- (3-dirnethylamino) propylcarbodiimide. Then the same amount of an inorganic or organic base is added such as an aliphatic amine, preferably triethylamine or N-methylmorpholine and the mixture is stirred at a temperature between -200C and the boiling temperature of the mixture during a period between ten minutes and several hours, a period of thirty minutes to three hours being generally sufficient to ensure the completion of the reaction. The reaction medium, optionally diluted with one of the solvents mentioned above, is then successively treated with a dilute solution of a mineral acid, such as for example sulfuric acid, or a hydrohalic acid, preferably approximately decinormal hydrochloric acid, then with a saturated solution of sodium bicarbonate and then with water. After evaporation of the solvent, the product is generally purified by chromatography on a silica column or by high pressure liquid chromatography (HPLC) then optionally by recrystallization.

When R15 is a group of general formula (III), another possibility consists in using as acylation reagent a mixture of the carboxylic acid of general formula (II) in which X1, X2, X3, X4 and R3 have the meaning defined above and Y represents a hydroxyl group, with a carbodiimide
such as, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide or i -ethyl-3 - (3 -dimethylamino) propylcarbodiimide.

Any other known procedure for the in situ formation of a reagent of general formula (II) used to form an amide function or a urea function is
also suitable and is object of the present invention.

The racemic or optically active carboxylic acids of general formula (II) are commercial or have been prepared according to the methods described in the bibliography, such as for example: J. Heterocycl. Chem., 2,385 (1965); Phytochemistry, 10, 539 (1971);
Ann., 227, 303, (1885).

 The amines of general formula (IV) racemic or optically active were prepared according to the methods described in the bibliography, such as for example: J. Org.

Chem., 52, 955, (1987); Justus Liebigs Ann. Chem., 763, 66, (1972); J. Med. Chem. 34, 3351, (1991).

 EXAMPLE 1: 3- L3- (1,2-Benzisoxazolyl) methylcarbonylaminoj-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 A solution of 3-amino hydrochloride is introduced into a dry flask kept away from moisture by a calcium chloride guard, and protected from oxygen by a stream of nitrogen. 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazein-2-one (1.56 g, 5.2 mmol) in 50 ml of anhydrous methylene chloride. 1.02 g (5.2 mmol) of 1,2-benzysoxazole-3-acetic acid chloride are added and the mixture is stirred at room temperature. Triethylamine (15 mmol) is added dropwise; and the progress of the reaction is monitored by thin layer chromatography.

After disappearance of the starting product (approximately three hours of reaction) the reaction medium is diluted with methylene chloride (50 ml) and washed successively with normal hydrochloric acid (50 ml), a saturated solution of sodium bicarbonate ( 50 ml) and water (50 ml). The organic phase is dried and evaporated under reduced pressure and the residue is recrystallized from acetonitrile. 1.45 g (66%) of a microcrystalline solid are obtained. F = 197-199 C
IR (KBr): 3290, 1685, 1645, 1523, 1444 cm ~ l.

1H-NMR (CDCl3-TFA): 9.18 (d, 1H, NH); 8.00-7.42 (m, 13H, Ar); 5.92 (d, 1H,
CH); 4.44 (dd, 2H, CH; 3.62 (s, 3H, NCH3).

 EXAMPLE 2: (3S) -3 [3- (1,2-Benzisoxazolyl) methylcarbonylamino] -2,3-dihyro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 In the same way as in Example 1, starting from (3S) -3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the chloride 1,2-benzisoxazole-3-acetic acid and N-methylmorpholine, a microcrystalline solid is obtained. [aD] = -24.2; c = 1.05 (methanol).

 IR (KBr): 3320, 1670, 1666, 1519 cm "1.

 EXAMPLE 3: (3R) -3- [3- (1,2-Benzisoxazolyl) methylcarbonylamino] -2,3-dihy dro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 In the same way as in Example 1, starting from la- (3R) -3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the 1,2-benzisoxazole-3-acetic acid chloride and N-methylmorpholine, a microcrystalline solid is obtained. [aD] = +23.9; c = 1.0 (methanol).

 EXAMPLE 4 3-t3- (1,2-Benzisoxazolyl) methylcarbonylamino] -1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2,4-dione .

 In the same way as in Example 1, starting from 3-amino-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2,4-dione ( 0.865 g, 3.0 mmol) and 1,2-benzisoxazole-3-acetic acid chloride (0.575 g, 3.0 mmol) are obtained by recrystallization from acetonitrile 0.860 g (65%) of a solid microcrystalline. F = 117-120 C.

 IR (KBr): 3363, 1711, 1663, 1650, 1499, 1401 cm "1.

1H-NMR (DMSO-D6-TFA): 9.11 (d, 1H, NH); 7.94-6.93 (m, 13H, Ar); 5.19 (d, 1H,
CH); 4.20 (s, 2H, CH2); 3.49 (s, 3H, N-CH3).

 EXAMPLE 5: N- [S1,2-Benzisoxazolyl) methylcarbonyl- (R) -tryptophan di-npentylamide.

In the same way as in Example 1 from hydrochloride
(R) -tryptophan di-n-pentylamide (2.0 g, 5.27 mmol), acid chloride
1,2-benzisoxazolyl-3-acetic (1.03 g, 5.27 mmol) and N-methylmorpholine (12 mmol) are obtained, after purification by chromatography on a silica column, the eluent used being a mixture of 1 ethyl acetate and hexane (1: 2), (1.90 g, 72%) of a white solid.

F = 84-87 "C. [D] = -12.7; c = 1.0 (chloroform).

 IR (KBr): 3280, 1667, 1616, 745 cm "1.

 1H-NMR (CDCl3): 7.68-6.92 (m, 9H, Ar); 5.25 (m, 1H); 3.93 (s, 2H); 3.35-2.73 (m, 6H); 1.44-0.70 (m, 18H).

 EXAMPLE 6 N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (S) -tryptophan di-npentylamide.

 In the same way as in Example 5, starting from (S) -tryptophan di-n-pentylamide hydrochloride, a white solid is obtained. [ED] = +13.1; c = 1.12 (chloroform).

 EXAMPLE 7: N - [(1,2-B enz isoxazolyl) methylcarbonyU- (S) -glutamic acid di-n-pentylamide.

 In the same way as in Example 1 from hydrochloride of (S) -glutamic acid-di-n-pentylamide r-benzylester (2.5 g, 6.0 mmol), the chloride of l 1,2-benzisoxazolyl-3-acetic acid (1.17 g, 6.0 mmol) and N-methylmorpholine (15 mmol) are obtained, after purification by chromatography on a silica column, the eluent used being chloroform , N - [(1,2-benzisoxazolyl) methylcarbonyl] - (S) -glutamic-di-npentylamide r-benzyl ester (2.40 g). To a solution of this product in a mixture of iliF and water (1: 1) (50 ml), lithium hydroxide monohydrate (0.207 g, 4.9 mmol) is added.

The mixture is left to stir for 24 hours at room temperature, the THF is removed under reduced pressure, the mixture is washed with diethyl ether and the aqueous phase is acidified with glacial acetic acid. Extraction is carried out with ethyl acetate and this organic phase is washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The solvent is removed under reduced pressure. The oily residue obtained is purified by chromatography on a silica column, the eluent used being ethyl acetate. 1.78 g (66% overall) of oily product are obtained. [aD] = -12.1; c = 1.54 (chloroform)
IR (NaCl): 3500-3100, 1758, 1618, 1245 cm "1.

 1H-NMR (CDCl3): 7.79-7.27 (m, 4H, Ar); 5.04 (m, 1H); 4.01 (s, 2H); 3.29-3.01 (m, 6H); 2.37 (m, 2H); 1-57-0.84 (m, 18H).

 EXAMPLE 8 N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (R) -glutamic acid di-n-pentylamide.

 In the same way as in Example 7, starting from (R) -glutamic acid di-n-pentylamide v-benzylester hydrochloride, an oily product is obtained. [aD] = +11.9; c = 1.27 (chloroform).

 EXAMPLE 9 3- [3- (Benzothiophenyl) methylcarbonylamino] -2,3-dihydro-1methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 In the same way as in Example 1 from 3-amino 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride (0.754 g, 2 , 5 mmol) and benzothiopene-3-acetic acid chloride (0.526 g, 2.5 mmol), obtained by recrystallization from ethyl acetate 0.752 g (69%) of a microcrystalline solid. F = 220-222 C.

 IR (KBr): 3290, 1692, 1643, 1530, 1326, 1108 cm-.

1H-NMR (CDCl3, TFA): 8.65 (m, 1H, NH); 8.01-7.35 (m, 14H, Ar); 5.79 (d, 1H,
CH); 4.21 (dd, 2H, CH; 3.57 (s, 3H, NCH3).

 EXAMPLE 10: 2,3-Dihydro-3- (3-indazolylmethylcarbonylamino) -1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 A mixture consisting of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (1 is stirred at room temperature for 18 hours. , 20 g, 4.0 mmol), indazole-3-acetic acid (0.70 g, 4.0 mmol), 1-ethyl-3- (3-dimethylamino) propyl carbodiimide hydrochloride ( 1.15 g, 6.0 mmol), l-hydroxybenzotriazole (1.10 g), triethylamine (20 mmol) and methylene chloride (50 ml). The reaction medium is diluted with methylene chloride (50 ml) and washed successively with normal hydrochloric acid (50 ml), a saturated solution of sodium bicarbonate (50 ml) and water (50 ml). The organic phase is dried and evaporated under reduced pressure, the residue is purified by chromatography on a silica column, the eluent used being a mixture of methylene chloride and ethyl acetate (8: 2). After recrystallization from ethyl acetate, 0.885 g (52%) of a white solid is obtained. F = 187-189 C.

 IR (KBr): 3351, 1669, 1654, 1500, 743 cm "1.

1H-NMR (CDCl3, TFA): 9.07 (m, 1H, NH); 8.04-7.46 (m, 13H, Ar); 5.87 (d, 1H,
CH); 4.61 (dd, 2H, CH; 3.61 (s, 3H, NCH3).

EXAMPLE 11: 2,3-Dihydro-3- (3-indolylmethylcarbonylamino) -1-methyl-5-
phenyl-1H-1,4-benzodiazepin-2-one.

 In the same way as in Example 10, starting from 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride (1.0 g, 3.3 mmol), indole-3-acetic acid (0.58 g, 3.3 mmol), 3-ethyl-3 - (3-dimethylamino) propylcarbodiimide hydrochloride (0.915 g, 5.0 mmol ), 1-hydroxy-benzotriazole (0.90 g) and tryethylamine, after recrystallization from diethyl ether, 0.725 g (52%) of a microcrystalline solid is obtained. F = 137-1410C.

 IR (KBr): 3295, 1673, 1655, 742, 680 cm "i.

 1H-NMR (CDCl3): 8.64 (m, 1H, NH); 7.83-6.95 (m, 14H, Ar); 5.54 (d, 1H, CH); 3.84 (s, 2H, CH; 3.39 (s, 3H, NCH3).

 EXAMPLE 12 3- [3- (1,2-Benzisothiazol) methylcarbonylamino] -2,3-dihydro-1 methyl-5-phenyl-1H-1,4-benzodiazépln-2-one.

 In the same way as in Example 10, starting from 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride (1.25 g, 4.15 mmol), 1,2-benzisothiazole-3-acetic acid (0.80 g, 4.15 mmol), 1-ethyl-3- (3-dimethylamino) propylcarbodiimide hydrochloride (1 , 25 g, 5.8 mmol), 1-hydroxybenzotriazole (1.20 g) and tryethylamine, 1.26 g (69%) of a microcrystalline solid are obtained after recrystallization from acetonitrile. F = 201-205 "C.

 IR (KBr): 3246, 3061, 1681, 1640, 1528, 1509, 697 cm "1.

 1H-NMR (CDCl3): 8.24 (d, 1H, NH); 8.09-7.53 (m, 13H, Ar); 5.92 (d, 1H, CH); 4.67 (s, 2H, CH; 3.63 (s, 3H, NCH3).

 EXAMPLE 13 2,3-Dihydro-3- (3-indolylethylcarbonylamino) -1-methyl-5 phenyl-1H-1,4-benzodiazepin-2-one.

To a solution of indole-3-propionic acid (3 g, 15.87 mmol) and the
N-hydroxysuccinimide (1.83 g, 15.87 mmol) in ethyl acetate at 0 ° C., dicyclohexylcarbodiimide (3.27 g, 15.87 mmol) is added and the mixture is left stirring at 0 ° C. for 24 hours. The solid formed is removed by filtration and added to the solution of hexane.

The solid formed is filtered and after recrystallization from a mixture of ethyl acetate and hexane (1: 1), 3.14 g of ester are obtained. Then, in the same way as in Example 1, from 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride ( 3.30 g, 11.0 mmol) and the ester derived from N-hydroxisuccinimide and indole-3-propionic acid (3.14 g), which is obtained by recrystallization from acetonitrile 3.57 g ( 53% overall) of a solid microcrystalline. F = 130-133 C.

 IR (KBr): 3260, 1693, 1670, 1590, 786, 747 cm ~ l.

 1H-NMR (CDCl3): 7.67-7.08 (m, 14H, Ar); 5.56 (d, 1H, CH); 3.19 (t, 2H, CH2); 2.80 (t, 2H, CH.

 EXAMPLE 14: N- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) N '- [3- (1,2-benzisoxazolyl) methyl ]urea.

To a solution of 2,3-dihydro- 1-methyl-3 - (p-nitrophenyloxycarbonyl) amino - 5-phenyl-1H-1,4-benzodiazepin-2-one (0.90 g, 1.91 mmol) and 3-aminomethyl-1,2-benzysoxazole hydrochloride (0.53 g, 2.87 mmol) in acetonitrile, tiethylamine (3 ml) is added and the mixture is heated to boiling point for 18 hours. It is cooled in an ice bath, the solid is filtered and after recrystallization from acetonitrile a microcrystalline solid is obtained (0.657 g, 79%). F = 158-160 "C
IR (KBr): 3310, 1683, 1677, 1628, 1556 cm ~ l.

 1H-NMR (CDCl3): 8.52-7.33 (m, 13H, Ar); 6.79 (d, 1H, NH); 5.85 (t, 1H, N'H); 5.49 (d, 1H, CH); 4.79 (d, 2H, CH; 3.39 (s, 3H NCH3).

 EXAMPLE 15: 3- [3- (1,2-Benzisoxazolyl) ethylcarbonylamino] -2,3-dihydro-1- methyl-5-phenyl-1H-1,4-benzodiazepin-2-one.

 In the same manner as in Example 1, starting from 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one hydrochloride (0.873 g, 2.9 mmol), 1,2-henzisoxazole-3-propionic acid chloride (0.565 g, 2.7 mmol), and tryethylamine (1.2 ml), which are obtained after recrystallization from acetonitrile, a microcrystalline solid (0.74 g, 63%). F = 228-230 C.

 IR (KBr): 3280, 1681, 1645, 1522, 1446 cm ~ l.

1H-NMR (CDCl3TFA): 8.64 (m, 1H, NH); 8.01-7.34 (m, 13H, Ar); 5.81 (d, 1H,
CH); 3.58 (s, 3H, NCH3); 3.49-3.41 (m, 2H, CH; 3.17 (t, 2H, CH.

Gastric antisecretory activity
The gastric antisecretory activity of the products object of the invention is demonstrated by using the isolated and perfused stomach test of mice [Black et al., Br. J. Pharmac., 86, 571 (1985); Lotti et al., Digestion, 35, 170, (1986)].

 The method used was as follows: the stomach isolated from male Swiss mice weighing 18 to 25 g was used. Once the stomach is isolated, we cannulate at the level of the fundus and the pylorum with polyethylene cannulas and wash carefully with a mucous solution at 37 "C. The stomach is placed in an organ bath of 100 ml at 37 C. The mucous solution, perfused at 1 ml / min is gasified with oxygen and serosed with carbogen. The composition of these solutions is described by Lotti et al. The pyloric effluent is raised 7 cm above the cannula of the cardias, which causes gastric distension.

At the end of this cannula there is a 0.2 ml chamber provided with a combined pH electrode, Metrohm 6.0204. The continuous reading of the pH of the defluent is measured with a Metrohm 605 or 654 pH meter and is recorded by an IBM-286-AT computer. Under these conditions, isobutylmethylxanthine (IBMX) is added to the bath to obtain a concentration of 4 M and the preparation is left to stabilize for 2.5 hours. The presence of the agonist in the stabilized preparation (pentagastrin 104 M) causes a decrease in the pH of the infusion solution by 0.5 pH units. The products to be studied are added to the bath 45 minutes before the agonist. For each concentration of the product tested, the percentage inhibition of the agonist response is calculated. With these results, the inhibitory concentration 50% (CI-50) is calculated.

EXAMPLE CI-50 EMl
Cimetidine 3x10-6
Proglumide lx10-3
1 1x10-7
4 3x10-7
9 2xi04
10 3x10-6
There 5x10-6
12 3x10-7
14 7x10-7
The products of the invention are administered in the form of compositions appropriate to the nature and extent of the condition to be treated. The daily dosage in humans is usually between 100 milligrams and 2 grams of product which can be administered in one or more doses. The compositions are prepared in forms compatible with the intended route of administration, such as, for example, tablets, dragees, capsules, suppositories or suspensions. These compositions are prepared by methods common to a person skilled in the art and comprise from 1 to 60% by weight of active principle (compound of formula I) and 40 to 99% by weight of suitable pharmaceutical vehicle compatible with the principle active ingredient and the physical form of the composition envisaged. By way of example, the formula of a tablet containing a compound of the invention is presented below.

TABLETS
Example 1: 50 to 200 mg
Polyvinylpyrrolidone: 4 mg
Carboxymethyl starch: 16 mg
Magnesium stearate: 6 mg
Lactose: 264 to 137 mg
Monocrystalline cellulose: 160 to 137 mg for a 500 mg tablet.

Claims (10)

1. Compounds of general formula (I)

 in which X1 represents a heteratome chosen from oxygen or sulfur or a  nitrogen atom linked to another radical R4 (N-R4), X2 represents a nitrogen atom or a carbon atom linked to another  radical R5 (C-R5) X3 represents a single bond, a linear or branched alkylene radical  in C1-C6, or a nitrogen atom linked to another radical R6 (N-R6) -X4 represents a hydrogen atom, an alkoxy radical, a cyano radical  or a nitrogen atom linked to two radicals R7 and R8 R R1 represents

 their physiologically acceptable salts, and when they have at least one center of chirality, their racemates, diastereoisomers or not, their pure enantiomers and their mixtures.

 alkyloxyalkyl ;; ~ Zle Z2 represents a radical # = N or a radical  linear or branched alkyl radical, preferably n-pentyl, or a radical  or an ss-azaspiro [4,5] decan-8-yl group; Rl3 and R14 independently represent a hydrogen atom, a R12 represents a nitrogen atom linked to two other radicals R13 and R14  carbonylakyle R R11 represents a 3-indolylmethyl group or a hydroxy radical  halogen  or alkyloxycarbonyl-alkyl -R10 represents a hydrogen atom, an alkoxy radical, or an atom  branched in Cl-C6, a hydroxycarbonylalkyl, alkyloxycarbonyl radical  linear or branched C1-C6 alkyl, an alkyloxycarbonyl or aralkyloxycarbonyl radical; - R9 represents a hydrogen atom, a linear alkyl radical or  branched in C1-C6 R7 and R8 independently represent a hydrogen atom, a radical  alkyloxycarbonylalkyle, or an alkoxyalkyle radical R6 represents a hydrogen atom or a linear alkyl radical or  linear or branched C1-C6 alkyl, a carboxyalkyl radical, a radical  of halogen, an alkoxy radical, a cyano radical, or a nitro radical R4 and R5 independently represent a hydrogen atom, a radical  branched R3 represents a hydrogen atom, a methyl radical, an atom R2 represents a hydrogen atom or a linear alkyl radical or  1H-1,4-Benzodiazepin-2-one.  - 3- [3- (1,2-Benzi soxazolyl) methylcarbonylamino] -2,3-dihydro-1-methyl-5-phenyl-  2 - The compounds corresponding to the general formula (I) according to claim 1, selected from the following group:  phenyl-1H-1,4-benzodiazepin-2-one.  - (3S) -3- [3- (1,2-Benzisoxazolyl) methylcarbonylamino] -2,3-dihydro-1-methyl-5  phenyl-1H-1,4-benzodiazepin-2-one.  - (3R) -3- [3- (1,2-Benzisoxazolyl) methylcarbonylamino] -2,3-dihydro-1-methyl-5  tetrahydro-1H-1,5-benzodiazepin-2,4-dione.  - 3 - [3- (1, 2-B enzsoxazolyl) methylcarbonylamino] -1 -methyl-5-phenyl-2,3, 4,5-  -N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (R) -trytophane di-n-pentylamide.  -N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (S) -trytophane di-n-pentylamide.  N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (S) -glutamic acid di-n-pentylamide.  - N - [(1,2-Benzisoxazolyl) methylcarbonyl] - (R) -glutamic acid di-n-pentylamide.  -3 [3- (1-Benzothiophenyl) methylcarbonylamino] -2,3-dihydro-1-methyl-5-phenyl 1 H-, 4-henzodiazepin-2-one.  -2,3-Dihydro-3- (3-indazolylmethylcarbonylamino) -1-methyl-5-phenyl-1H-1,4 benzodiazepin-2-one.  benzodiazepin-2-one.  -2,3-Dihydro-3- (3-indazolylmethylcarbonylamino) -1-methyl-5-phenyl-1H-1,4  1H-1, 4-benzodiazepin-2-one.  - 3 - [3- (1, 2-Benzi sothiazol) methylcarbonylaminoj-2,3 -dihydro- 1 -methyl-5-phenyl-  diazepin-2-one.  -2,3-Dihydro-3- (3-indazolylmethylcarbonylamino) -1-methyl-5-phenyl-1H-1,4-benzo  -N- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl) N '- [3- (1,2 benzisoxazolyl) methyl] urea.  phenyl-1H-1,4-benzodiazepin-2-one.  -3 [3- (1,2-Benzisoxazolyl) ethylcarbonylamino] -2,3-dihydro-1-methyl-5   in which R1 and R2 have the meaning indicated above.

 - with an amine of general formula (IV)  in which X1, X2, X3, X4 and R3 have the meaning defined above, or a group -OR16, R16 being an aromatic group comprising one or two rings substituted by one or more nitro or halogen radicals, or an N-succimmide group

 in which X1, X2, X3, X4 and R3 have the meaning indicated above, and Y is a halogen atom, an azido group (-N3), an imidazole-1-yl group, an O-CO-R15 group , R15 possibly being a hindered aryl radical containing from three to six carbon atoms, or aryl, preferably substituted by one or more halogens, or a group of general formula (II):

 - a carboxylic acid derivative of general formula (II):  3 - Process for the preparation of compounds of general formula (I) according to one of claims l or 2, characterized in that it consists in reacting  4. Method according to claim 3, characterized in that the reaction is carried out in an anhydrous or hydrated organic solvent, preferably chosen from chlorinated hydrocarbons such as methylene chloride or chloroform, linear or cyclic ether-oxide such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, polar apratic solvents such as pyridine, dimethylsulfoxide or dimethylformamide and their mixtures.  5. Method according to one of claims 3 or 4, characterized in that Y is - a halogen, preferably a chlorine atom, - an azido group (-N3), - an imidazol-l-yl group, - a group -O-CO-R15 in which R15 has the defined meaning more  high, preferably tert-butyl or 2,4,6-trichlorobenzoyl, - a group of formula -O-R16 in which R16 has the meaning  indicated above, preferably para-nitrophenyl, 2,4  dinitrophenyl, pentachlorophenyl, pentafluorophenyl, benzo  triazol-l-yle and N-succinimide.  6. Method according to claim 5, characterized in that the groups -O-CO-R15 and -O-R16 are prepared by reacting a compound of general formula II in which Y is a hydroxyl group with hydroxy-l- benzotriazole or N-hydroxysuccinimide, respectively in the presence of a carbodiimide, preferably chosen from dicyclohexylcarbodiimide, diisopropylcarbodiimide or l-ethyl-3- (3-dimethylamino) propylcarbodiimide.  7. Method according to claim 5, characterized in that the group O-CO-R15 for which R15 is a group of general formula III is prepared by reacting a compound of general formula II with a carbodiimide, preferably chosen from dicyclohexylcarbodiimide , diisopropylcarbodiimide or 1-ethyl-3- (3-dimethylamino) propylcarbodiimide.  8. As medicaments, the compounds of general formula (I) and their physiologically acceptable salts according to one of claims 1 or 2, in particular as medicaments intended for the treatment of gastrointestinal diseases mainly indicated as inhibitors of secretion of gastric acid, as antiulcer agents and as cytoprotective agents.  9. Pharmaceutical compositions, characterized in that they contain, in addition to a pharmaceutically acceptable carrier, at least one compound of general formula (I) or one of its physiologically acceptable salts, according to claim 1 or 2.  10. Use of the compounds of general formula (I) and their physiologically acceptable salts according to one of claims 1 or 2, for the manufacture of medicaments intended for the treatment of gastrointestinal diseases, in particular for the manufacture of agents inhibiting the secretion of gastric acid, antiulcer agents and cytoprotective agents.