MXPA97002637A - Diazepin-indoles, as inhibitors of phosphodysterase - Google Patents

Abstract

Application of the diazepin-indole derivatives of the formula (I): in which: R is hydrogen, lower alkyl or lower alkoxy, A is a mono-to tri-substituted heteroaryl or aryl, their racemic salts, their enantiomers and its pharmaceutically acceptable salts, which comprises novel products, for the preparation of medicaments, which are intended for the treatment of disorders for which the therapy by the phosphodiesterase IV inhibitors is pertinent

Description

PIAZEPIN-INPOI.ES. AS INHIBITORS OF PHOSPHODIESTERASE IV Field of the Invention The present invention relates to the use of [1, 4] diazepin [6,7, l-hi] indoles, some of which are novel, in the preparation of medications that make possible the treatment of disorders for which therapy by a phosphodiesterase IV inhibitor is relevant . These drugs are useful, in particular, as anti-inflammatory agents, antiallergic agents, bronchodilators or antasmáticos, and lack side effects in the digestive system or the heart.

Technical Background of the Invention In contrast to the properties described by the present invention, the prior art proposes [1, 4] diazepin [6,7, l-hi] indoles, for which the antagonistic properties with respect to the colecisto-quinina (CCK) and / or gastrina, and which are proposed for disorders of the digestive tract: stomach, intestine, pancreas and gall bladder and, in particular, for disorders of satiety. Thus, European Patent Application No. 340 064 describes compounds of the formula: wherein R ^ and R2 are hydrogen or halogen, Ar is indolyl or phenyl and n is 2 or 3. These compounds are peripheral antagonists of cholecystokinin (CCKA). European Patent Application No. 360 079 discloses peripheral and / or central CCK antagonist compounds of the formula: wherein R1 is optionally substituted aryl, X is oxygen or methylene, which is optionally substituted by a lower alkyl radical, A is a bond or lower alkylene, which may carry one or more lower alkyl groups and R2 is hydrogen or acyl, in an excessively broad sense. In fact, it appears that the preferred products of this application, EP 360 079, are those in which: R1 is 2-fluorophenyl and / or - R2 is an aryl-propenoyl or heteroaryl-propenoyl group, and / or the configuration about The carbon of diazepine in the position aa its carbonyl function is (S) or (R, S). With respect to the inhibition of phosphodiesterases, it is recalled that the 3 ', 5'-cyclic adenosine monophosphate (cAMP) is a secondary intracellular universal messenger, intermediate between a primary messenger (a hormone, neurotransmitter or autocoid) and functional responses Cellular: the primary messenger stimulates the enzyme, which is responsible for the synthesis of cAMP and this cAMP acts, depending on the cells in question, in a large number of functions: metabolic, contractile or secretory. The effects of the cAMP end, when broken by the cyclic nucleotide phosphodiesterases, which are intracellular enzymes that catalyze their hydrolysis to 5-monophosphate. of inactive adenosine. In mammals, a distinction is made between at least five major classes of cyclic nucleotide phosphodiesterases (PDEs) numbered I to V, according to their structure, their kinetic characteristics, their substrate specificity or their sensitivity to effectors (Beavo JA (1990) Trenas Pharmacol, Sci. 11, 150-155). The PDEs IV are specific to the cAMP. Non-specific phosphodiesterase inhibitor compounds are known, which inhibit various classes of enzymes. This is the case for some methylxanthines, such as theophylline. These compounds have a therapeutic index that results in particular from their action on types of PDEs present in the cells, different in the target cells. In contrast, some classes of PDEs can be selectively inhibited by several pharmacological agents: the hydrolysis of the cyclic nucleotides is reduced and thus their concentration increases only in those cells that contain the type of PDE that is sensitive to the inhibitor. Particular interest is evident for phosphodiesterases IV (PDE IV), which have been identified in numerous tissues including those of the central nervous system, heart, vascular endothelium, vascular and respiratory smooth muscle and myeloid lines and lymphoid An increase in cAMP in the cells involved in inflammation inhibits its activation: the inhibition of the synthesis and release of mediators at the level of the asto-cytos, monocytes, eosinophil and basophil polymorphonuclear leukocytes, inhibition of chemotaxis and degranulation of neutrophil and eosinophil polymorphonuclear leukocytes, and the inhibition of lymphocyte divisions and differentiation. Cytokines, especially TNF and interleukins, produced by different types of leukocytes, for example T lymphocytes and eosinophil polymorphonuclear leukocytes, play an important role in the onset of inflammatory manifestations, especially in response to stimulation by an allergen. at the level of the respiratory tracts. On the other hand, cAMP reduces the tone of the smooth muscle fibers of the respiratory tract; Inhibitors of PDE IV produce bronchial relaxation. Therefore, it is possible to expect selective PDE IV inhibitors to possess therapeutic activity such as anti-inflammatory drugs, antiallergic drugs and bronchodilators and in the treatment of asthma, where the infiltration of the respiratory tract by inflammatory cells and bronchoconstriction are observed. .

Theophylline has been widely used for a long time in the treatment of asthma and, although its mechanism of action is complete, inhibition of PDE contributes to its action, but also to certain undesired effects, such as nausea and headache. . However, the development of potent inhibitors of PDE IV, up to now, has proven difficult, due to the fact that many potential inhibitors of PDE IV do not lack activity in phosphodiesterases from other classes. The lack of selectivity of the PDE IV inhibitors, therefore, represents a problem, given the extension of the functions regulated by the cAMP. Therefore, there is a need for potent PDE IV inhibitors that are selective, ie do not have an action on PDEs that belong to other classes. The rolipram (INN), a derivative of pyrrolidone, first synthesized in 1975, is considered representative of the specific inhibitors of PDE IV. Numerous compounds related to rolipram have been synthesized, with a view to their use as inhibitors of PDE IV. The rolipram, in vitro, inhibits the activity of inflammatory cells in rodents: the inhibition of mediator synthesis by mast cells, eosinophil and basophil polymorphonuclear leukocytes and monocytes; inhibition of chemotaxis and degranulation of polymorphonuclear leukocytes. Rolipram has been proposed as an antidepressant; however, its use is accompanied by unwanted effects of the type that involve nausea and vomiting.

Compendium of the Invention Turning now to the prior art, it has been found that derivatives of [1,4] diazepin [6, 7, 1-hi], some of which are novel, are - surprisingly - potent inhibitors of the PDE IV at concentrations where they have little or no action in the other PDE classes. The invention essentially relates to the use of the diazepin-indoles, some of which are novel, of the formula (I): A (I) in which: R is hydrogen, lower alkyl or lower alkoxy; - A is aryl, heteroaryl containing nitrogen or heteroaryl containing sulfur, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino , t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido.

Detailed Description of the Invention First, the invention relates to the use, for the preparation of drugs that make possible the treatment of disorders for which the therapy by a phosphodiesterase IV inhibitor is relevant, of diazepin-indoles, of the formula ( I): A (i) wherein: R is hydrogen, lower alkyl or lower alkoxy; and A is aryl, nitrogen-containing heteroaryl or sulfur-containing heteroaryl, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino , t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; of its racemic forms, of its isomers, whose configuration is determined by the carbon in the 3-position of the diazepinindole-4-one ring system, and of its pharmacologically acceptable salts. Secondly, the invention relates to the diazepin-indoles of the formula (I1): (I ') wherein: R is hydrogen, lower alkyl or lower alkoxy; and A is aryl, nitrogen-containing heteroaryl or sulfur-containing heteroaryl, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino , t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; to its racemic forms and its isomers whose configuration is determined by the carbon in the 3-position of the diazepinindole-4-one ring system, and also to its pharmacologically acceptable salts, with the proviso that, when R is hydrogen: ) Not to be represented by the 2-indolyl radical or a phenyl radical substituted by one to three alkoxy groups; ii) for racemic forms, or shapes of the configuration (S), A does not represent a phenyl radical substituted with a halogen, a halogen and an amino group, or a haloalkyl group. In the above text and in the following: aryl refers to a phenyl or naphthyl group; "Nitrogen-containing heteroaryl" refers to an unsaturated monocyclic or polycyclic group, which contains at least one nitrogen atom and, preferably, these nitrogen-containing heterocyclic groups can be four to seven membered dheteromonomical groups, containing from 1 to 4 atoms of nitrogen, or condensed, unsaturated heterocyclic groups, containing from 1 to 4 nitrogen atoms; the nitrogen-containing heteroaryl group can be methylated or ethylated in a positively charged nitrogen; halogen refers to fluorine, chlorine, bromine or iodine; "lower alkyl" refers to alkyl groups, linear or branched, containing from one to four carbon atoms; "cycloalkyl" refers to the cyclopropyl, cyclobutyl and cyclopentyl groups; "lower alkoxy" refers to an O-alkyl group, in which the alkyl group is a lower alkyl, as defined above; and haloalkyl refers to a mono-, di- or tri-haloalkyl group, containing from 1 to 4 carbon atoms. A review of the salts that are acceptable in the pharmacy can be found in J. Pharm. Sci. , 1977, 66., 1-19. However, the pharmaceutically acceptable salt range of a compound of the formula (I), which has a basic part, refers to the addition salts of the compounds of the formula (I), which are formed from non-toxic acids , inorganic or organic, for example the salts of hydrobromic, hydrochloric, sulfuric, sulfuric, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, mucic, ascorbic, pamical, maleic, hydroxymalic acid , phenylacetic, glutamic, benzoic, salicylic, sulfanilic, acetoxybenzoic, fumaric, toluenesulfonic, ethanedisulfonic, oxalic, isethionic and other acids. The various quaternary ammonium salts of the derivatives (I) are similarly included in this category of compounds of the invention. Also, the pharmacologically acceptable salt phrase of a compound of the formula (I) having an acid part, refers to the usual salts of compounds of the formula (I) which are formed of non-toxic, inorganic or organic bases, by Examples are alkali metal and alkaline earth metal hydroxides (for example lithium, sodium, potassium, magnesium and calcium), amines (dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, etc.) or alternatively quaternary ammonium hydroxides, such as hydroxide. tetramethylammonium. Among the diazepin-indoles of the formula (I) and (I1), preference is given to those in which R is lower alkyl or lower alkoxy and preferably methyl or methoxy. In a general manner, these diazepin-indoles of the formula (I) and (I1) are preferred when the asymmetric carbon atom in the alpha position, with respect to the carbonyl function of the diazepine ring, has the absolute configuration (R ) (according to the nomenclature of Cahn, Ingold and Prelog); that is, the configuration which is opposite to that of (S), which is said to be favorable for the antagonist type affinity of the CCK receptors. The invention also relates to a process for the preparation of the diazepin-indoles of the formula (I), which comprises reacting a racemic or optically active amine of the formula II): (II) with a carboxylic acid derivative of the formula (III) (III) in which A has the meanings given above and Z is a halogen, an azido group, a 1-imidazolyl group, a -O-CO-Zi group, where Z ^ can be, in addition to A, a radial hindered alkyl, containing from 3 to 6 carbon atoms, or in addition Z can be a group 0-Z2, with Z2 being an aromatic group containing one or two rings substituted by one or more nitro or halogen radicals, to obtain a compound optically active or racemic, of the formula (I). Specifically, the preparation of the diazepin-indoles of the formula (I) can be described according to three methods, A, B and C, in which (III) represents the products of the formula (IHA) (IIIB) and ( IIIQ) / respectively: (I l! A) (Hl8) (Ule) according to the reaction: Method A - C l í i c3 i ~ ' In particular, the following methods are possible: Method A A compound of the formula (II) was dissolved in 5 to 50 volumes of an anhydrous organic solvent, such as, for example, a chlorinated hydrocarbon, such as dichloromethane or chloroform, an ether linear or cyclic, such as 1,2-dimethoxy-ethane, tetrahydrofuran or dioxane, a polar aprotic solvent, such as pyridine, dimethyl sulfoxide or dimethylformamide, or any other solvent that is suitable to carry a condensation reaction, in this case, or in addition an appropriate mixture of two or more of these solvents, and one to two equivalents of an acid halide of the formula A-CO-X, where X is halogen, preferably chlorine, and A has the meanings defined above , they were added. Next, an equal, equimolar amount of an organic and inorganic base, preferably triethylamine, was added and the mixture was stirred at a temperature between -20 ° C and the boiling temperature of the mixture, for a period between thirty minutes. and 24 hours. The reaction medium, optionally diluted with one of the aforementioned solvents, was then treated in succession with a dilute solution of a mineral acid, then with a saturated solution of sodium hydrogen carbonate and then with water. After evaporation of the solvent, the product was generally purified by evaporative chromatography on a silica column, according to a method adapted from Still et al. , (1978), J. Org-Chem. 43: 2923.

Method B: Step 1: A compound of the formula A-COOH, in which A has the meaning defined above, was dissolved in 5 to 50 volumes of an organic solvent, as described for method A. From one to three equivalents of a compound of the formula Z 2 -OH, in which Z 2 has the meanings indicated above, the Z 2 groups being preferably para-nitrophenyl, 2,5-dinitrophenyl and, in particular, pentafluorophenyl, were added in the presence of a dehydration agent, such as a carbodiimide and, optionally, a pyridinium salt. The reaction conditions are similar to those of method A. After the evaporation of the solvent and, depending on its degree of purity, as determined by thin layer chromatography (TLC), the product was purified by evaporative chromatography or was used as such in the reaction of step 2. Step 2: The ester prepared in the preceding step was added to an equivalent of compound (II), dissolved in anhydrous ethyl acetate. The reaction conditions are similar to those of method A. After evaporation of the solvent, the product was purified by evaporative chromatography.

Method C: A slight excess of the acid of the formula A-COOH, in which A has the meanings defined above, was added directly to a compound of the formula (II) in solution, in 5 to 50 volumes of one of the solvents mentioned for method A, in the presence of an equivalent of a condensing agent, such as N, N'-disubstituted carbodiimide, N, N'-carbonyl-diimidazole or preferably 0- [(ethoxycarbonyl) -tetrafluoroborate] cyanomethylamino] -N, N, N ', N * -tetramethyluronium or also bromo-tris-pyrrolidinophosphonium hexafluorophosphate and, in the presence of two equivalents of a tertiary alkylamine. The operating conditions are similar to those of method A. The mixture was extracted, in succession, with a dilute solution of a mineral acid, a saturated solution of NaHCC-3 and water. After evaporation of the solvent, the product was purified by evaporative chromatography.

The general procedure for the preparation of the intermediate amines (II) in their racemic and / or enantiomeric forms is documented in the prior art. For example, it is possible to prepare an amine of the formula (II) by amination, in the alpha position, to the carbonyl function, a diazepin-indole of the formula (V): (V) using a hydroxylamine derivative or a chloroamine; or also, in two steps, by the reaction of a compound of the formula (V) with an oximation reagent, to obtain an oxime of the formula (IV): the second stage consists of the catalytic reduction of the oxime by hydrogen, in the presence of a reduction catalyst or by the reaction with zinc, in the presence of acetic acid or with stannous chloride, in the presence of hydrochloric acid, to obtain the amine derivative (II). The following equation illustrates the process of the synthesis of (II): The indole (IX) is reduced to the corresponding indoline (VIII), which is condensed with benzonitrile (VII) in the presence of a Lewis acid, to give, after hydrolysis, the benzophenone (VI). The preparation of (VI), in the presence of ethyl glycinate in pyridine, of the product of the formula (V), is adapted from the method described (method N) by Hester J.

B. et al. , 1970, J. Med. Chem. 13: 827-835. The possibilities to prepare an optically active compound of the formula (II), include: - the condensation of a racemic compound (II) with a derivative of an alpha-amino acid, which belongs to the D series or the L series and in which the amine function is protected by a highly labile group (unstable), preferably the tert-butoxycarbonyl group; the compound obtained is deprotected by hydrolysis, preferably in an acidic medium, in the presence of trifluoroacetic acid, and the product obtained is separated into its diastereoisomers by chromatography; the two isomers are obtained from the amine condensed with the amino acid. The degradation of Ed an then supplies the two enantiomers with the amine (II); or alternatively the dissolution of a racemic compound (II) in a solution of an optically active acid, for example an enantiomer of mandelic acid, dibenzoyltartaric, di-p-tolyl-tartaric, camphor-sulphonic, p-nitrobenzoylglutamic or tartaric, to form two diastereoisomeric salts, followed, using the difference in solubility, by the selective crystallization of one of them in an appropriate solvent. The intermediates of the formula (IV) and the products of the formula (II) are useful for the preparation of the active products, according to the invention. The invention also relates to a medicament for combating inflammatory and allergic diseases and bronchial constriction, or a medicament which is useful in the treatment of asthma, characterized in that it comprises a diazepin-indole, according to the invention, in a pharmaceutical form which is suitable for the disorder that is going to be treated.

Experimental Section Chemical Section Without limiting the invention, the following examples illustrate the embodiment of the processes and products of the invention. The purity, identity and physicochemical characteristics of the products and the prepared intermediates were determined as follows: - the purity was verified by thin layer chromatography on silica gel (Merck 60 - F254) and the Rf observed was the eluent used, which is most commonly identical with that used for the preparative chromatographic purification of the compounds. These solvents are identified by the following labels: S. A: methylene chloride, S. Al: methylene chloride / acetone, 97: 3 (v (v), S. A2: methylene chloride / acetone, 96: 4 (v (v), S. A3: methylene chloride / acetone, 95: 5 ( v (v), S. A4: methylene chloride / acetone, 90:10 (v (v), S. A5: methylene chloride / acetone, 88:12 (v (v), S. A6: methylene chloride / acetone, 85:15 (v (v), S. A7: methylene chloride / ethyl acetate, 98: 2 (v (v), S. A8: methylene chloride / methanol, 98: 2 (v (v), S. A9: methylene chloride / methanol, 97: 3 (v (v), S. A10: methylene chloride / methanol, 95: 5 ( v (v), SB: ethyl acetate, S.B1: ethyl acetate / cyclohexane, 70/30 (v / v), S.B2: ethyl acetate / cyclohexane, 60:40 (v / v), S.B.sub.3: ethyl acetate / methanol, 97: 3 (v / v), S.B.sub.4: ethyl acetate / methanol, 95: 5 (v / v). the identity of the empirical formula of the compounds obtained with that of the desired structures is verified by the analysis of the main elements. The results are not given as such, but they are indicated as being in agreement with the proposed structure, taking into account any solvate or hydrate, - the identity of the products obtained with the proposed structures was verified by their magnetic-nuclear resonance spectrum. protons, and for its infrared spectrum. The proton nuclear magnetic resonance spectra ^ H NMR were recorded at 400 MHz, in a Brücker instrument, the compounds were dissolved in deuterochloroform with tetramethylsilane as the internal standard. The nature of the signals, their chemical shifts in ppm, the number of protons they represent and their capacity to exchange with D2O, were noted. The infrared spectrum was recorded in the form of a disc of potassium bromide on a Shimadzu IR-435 spectrometer; - the physicochemical characteristics given are the melting point, determined by the capillary tube method and reported as uncorrected values, the optical rotation, determined at room temperature up to 202C in a Polartronic apparatus in a 10 cm long tank, whose Results make it possible, in some cases, to calibrate the optical purity by a calculation of the enantiomeric excess (ee). With the help of standardization, the chemical nomenclature of the products given as examples is that determined with the help of the software (program) "Autonom", version 1.0 (Beilstein Institut - Ed. Springler), which generates the systematic nomenclatures of the compounds , in accordance with the rules of the IUPAC. Also, for simplicity, the nature of the substituent R in the products given as examples is only indicated when it is different from H.

Intermediate Compounds (II) Intermediate Compound 1.a: (3RS) -3-amino-1-phenyl-6,7-dihydro-3H-f 1.41 diazepin f 6.7.1-hi 1 -indol-4-one (II-) R, S). The compound was prepared according to the procedure described in Example 1, steps a) and b) of EP 0 340 064 A1. Intermediate Compound lb: (3S) -3-amino-1-phenyl-6,7-dihydro -3H- [1.4] diazepino T 6, 7, 1-hi] -indol-4-one (II-R). The preparation of the compound is described in Example 5, steps a), b), c), g), h) of the experimental section of EP 0 340 064 Al. However, preference is given to the alternative method, which consists of the resolution of the racemic intermediate compound a. a by the formation and separation of diasateroisomers with N-acetyl-L-phenylalanine. 74.0 g (267 mmol) of (3R, S) -3-amino-1-phenyl-6,7-dihydro-3H- [1,4] diazepino [6,7, 1-hi] indol-4-one (Intermediate Compound 1.a) were dissolved in 210 ml of boiling n-propanol. Separately, 44.1 g (267 mmoles) of the N-acetyl-L-phenylalanine were dissolved in 140 ml of boiling n-propanol. The two solutions were mixed, allowed to cool and planted with a few crystals. After three days, the rest of the crystals were filtered, separated and dried. Weight: 50.0 g (e.e = 77%). The product was recrystallized twice in succession from boiling ethyl acetate. 39.0 g (e.e. = 97%) were obtained. The mother liquors of the first crystallization were evaporated and the residue was taken in boiling ethyl acetate. After crystallization, filtration and drying, 35.0 g of crystals (ee = 50%) were obtained, which, after two successive crystallizations in boiling ethyl acetate, it was possible to obtain 17.0 g (ee = 97%) of the product. When the two batches are combined, they represent 56.0 g (yield = 95%) of the salt of the 3R enantiomer of the amine with the N-acetyl-L-phenylalanine. P.F. = 1712C. [α] D = +1322 (c = 1, methanol); 42.4 g (96 mmol) of the al 3R amine were vigorously stirred in the presence of 500 ml of ethyl acetate and 500 ml of a normal sodium hydroxide solution. After dissolution, the ethyl acetate phase was separated, washed with saturated aqueous sodium chloride and then dehydrated and evaporated. 25.4 g of the intermediate compound lb. of amine were obtained. Yield = 95%. P. F. = 792C. [a] D = +1722 (c = 1, CH2C12). XH NMR d (ppm): 3.05-3.5 (m, 2H), 3.3 (broad s, intercam. 2H); 3.9-4.0 (m, 1H); 4.6-4.7 (m, 1H); 7.05-7.6 (m, 9H). IR: 3350, 1670, 1600, 1560, 1420, 1380, 1340, 1290, 1240, 760, 730, 690 cm "1. Intermediate Compound 2.a: (3R. S) -3-amino-9-methyl-1 phenyl-6,7-dihydro-3H-f 1.41 diazepino \ 6, 7.1-hi] indole-4-one (II-R, S, R = CH3) Step 1: 5-methylindoline 28.74 g (457 mmol) of cyanoborohydride of sodium were added, in small portions, below 202 ° C, to a solution of 20.0 g (152 mmol) of 5-methylindole in 300 ml of glacial acetic acid.The addition, which is slightly exothermic, was done in 3 hours and it was accompanied by a hydrogen evolution.The mixture was stirred for 12 hours, below 202 ° C, and then 300 ml of water was added and the pH of the reaction medium was adjusted between 10 and 12., by the addition of 500 ml of a 30% sodium hydroxide solution. The mixture was extracted twice with dichloromethane and the organic phase was washed with 100 ml of water. Evaporated and the residue was purified by evaporative chromatography on a silica column, the eluent used was a mixture of increasing polarity of methanol in methylene chloride. 15.3 g (yield = 75%) of a colorless oil was obtained, which developed a brown color during storage (under a nitrogen atmosphere, with the exclusion of light). TLC: S.A8; 0.39! H NMR d (ppm): 2.2 (s, 3H); 2.95 (t, 2H); 3.4 (m, 3H, which includes 1 exchange); 6.5 (d, 1H), 6.8 (d, 1H); 6.95 (s, 1H). Step 2: 7-benzoyl-5-methylindoline. 13.70 g (103 mmol) of the 5-methylindoline was dissolved in 360 ml of 1,2-dichloroethane. 13.24 g (113 mmol) of boron trichloride as a molar solution in dichloromethane were added dropwise at T < 5 c, followed by 20.36 g (197 mmoles) of benzonitrile and 13.73 g (103 mmoles) of anhydrous aluminum tricuride. The mixture was refluxed for 16 hours (mass temperature = 82-84SC). After cooling, the hydrolysis was carried out by the addition of 103 ml of 4N hydrochloric acid and heating to 80 ° C for 20 minutes. The mixture was cooled to about 20 ° C and extracted with dichloromethane. The aqueous phase was back-extracted with 100 ml of dichloromethane. The combined organic phases were washed with a solution of sodium hydroxide and then with a concentrated solution of sodium chloride and dried over sodium sulfate. After filtration and evaporation, 22.10 g of a yellow solid was obtained; Yield = 91%. P. F. = 842C. Analysis according to C ^ H ^ NO: TLC: S.A .; 0.46! H NMR d (ppm): 2.2 (s, 3H); 3.05 (t, 2H); 3.75 (t, 2H); 6.9 (broad S, Intercam. 1H); 7.05 (broad s, 2H); 7.5 (m, 3H), 7.65 (m, 2H). Step 3: 9-methyl-1-phenyl-6,7-dihydro-3H- [1,4] -diazepin [6,7,1-hi] indol-4-one. 21.0 g (88 mmol) of the 7-benzoyl-5-methylindoline were introduced into 140 ml of pyridine, followed by 43.2 g (31 mmol) of the ethyl glycinate hydrochloride. The mixture was heated to 110-1152C, with stirring, while the light fractions that formed were distilled. After 12 hours, the mixture was cooled and 150 ml of a 2.5% aqueous solution of sodium carbonate and 150 ml of dichloromethane were added. The aqueous phase was separated and extracted with 150 ml of dichloromethane. The organic phases were combined and washed with water. The solvent was evaporated and then the residue was purified by evaporative chromatography on a column of silica gel, the eluent used was ethyl acetate. 22.0 g of the purified product were obtained in the form of a light brown solid. Performance = 80%. P. M. = 1322c. TLC: S. B; 0.70. H NMR d (ppm): 2.3 (s, 3H); 3.15 (t, 2H); 4.25 (t, 2H); 4.3 (t, 2H); 7.0 (s, 1H); 7.25 (s, 1H); 7.45 (m, 3H); 7.55 (, 2H). Step 4: 3-hydroxyimino-9-methyl-1-phenyl-6,7-dihydro-3H- [1,4] -diazepino [6,7-1-hi] indol-4-one 21.0 g (76 mmol) of the above product were dissolved in a mixture of 84 ml of tetrahydrofuran and 168 ml of toluene. The mixture was cooled and 21.3 g (190 mmol) of tere were added. - potassium butylate at a temperature below 02C. The addition is exothermic and the solution took on a black color. After stirring for 20 minutes, 9.35 g (80 mmoles) of isoamyl nitrite was added in the course of about 10 minutes. Stirring was continued for 10 minutes, below 02c, and then 31.2 ml of glacial acetic acid and 300 ml of water were added. An insoluble compound was filtered off and 200 ml of dichloromethane were added. The phases were separated by sedimentation and the aqueous phase was washed with 200 ml of dichloromethane. The organic phases were combined and washed with 200 ml of water. After evaporation of the solvent, the residue was taken up in 40 ml of methanol. The crystallized product was filtered, washed with 20 ml of cold methanol and then dried. 15.06 g of a yellow solid were obtained. Performance = 65%. P. F. = 2472c. TLC: S.B2; 0.38. H NMR d (ppm): 2.3 (s, 3H); 3.2 (t, 2H); 4.4 (t, 2H); 7.3 (m, 3H); 7.4-7.6 (m, 3H); 7.9 (broad s, 1H) Step 5: (3R, S) -3-amino-9-methyl-1-phenyl-6,7-dihydro-3H- [1,4] -diazepine [6, 7-1- hi] indole-4-one. 1.32 g of 5% ruthenium on carbon were added to a solution of 4.4 g (24.4 mmoles) of the product obtained in the previous step, in 150 ml of methanol. The mixture was hydrogenated at 802C and a pressure of 8 bar, for 6 hours, and then filtered and the catalyst rinsed. After evaporation, the residue was purified by evaporative chromatography on a silica column, the eluent used was a mixture of ethyl acetate, which was progressively enriched with methanol. 2.87 g of the purified amine was obtained in the form of a yellow-brown solid. Yield = 68%. P. F. = 1162C. TLC: S.B4; 0.14 1 H NMR d (ppm): 2.3 (s, 3H); 2.4 (broad s, Intercam 2H); 3.1 (m, 1H); 3.3 (m, 1H); 3.95 (m, 1H); 4.65 (, 1H); 7-7.6 (m, 8H). Intermediate Compound 2. b: (3R) -3-amino-9-methyl-1-phenyl-6,7-dihydro-3H- [1,4] -diazepinof 6,7-1-hi] indol-4-one. (II-R, R = CH3). 19. 95 g (68 mmol) of (R, S) amine 2.a were dissolved in 200 ml of refluxing acetonitrile. Separately, 26.45 g (68 mmoles) of the di-para-tolyltartaric acid were dissolved, at reflux, in 260 ml of acetonitrile. The hot solutions were mixed and allowed to stand for 24 hours at laboratory temperature. The white crystals were separated by filtration and washed with 100 ml of cold acetonitrile, and then dried. The optical purity was determined by the reaction of 5 mg of amine with 3-phenyl methylisocyanate and examining the product obtained on a column of chromatography of the Pirkle type, eluting with a mixture of 50:50 (v (v) isopropanol / cyclohexane The filtered crystals, weighing 20.6 g (ee = 45%), were recrystallized three times in succession from acetonitrile, in order to obtain the purified product (ee = 98%), 12.0 g of the product were obtained. PF = 2332C. [A] D = + 1772C (c = 1, methanol) The above salt was suspended in 100 ml of ethyl acetate.Saturated sodium bicarbonate solution was added, with vigorous stirring. minutes, the aqueous phase was separated The organic phase was washed with water, dried and the solvent was cooled by evaporation under a nitrogen atmosphere The purified base was obtained PF = 682C. [a] D = +2072 (c = 1, CH2C12) • Intermediate 3.a: (3R. S) -3-amino-9-methoxy-l-phenyl-6,7-dihydro -3H- \ 1.4] -diazepine r 6.7.1-hi] indol-4-one. (II - R, S; R = CH30). The compound was prepared from 5-methoxy-indole in 5 steps, according to the procedure described for the preparation of intermediate compound 2.a. Stage 1: 5-methoxyindoline Yield = 83% - light yellow liquid, which becomes colored in light. TLC: S.B2; 0.38. H NMR d (ppm): 3.0 (t, 2H); 3.41 (s, 1H, Intercam.1H); 3.5 (t, 2H); 3.7 (S, 3H); 6.6 (s, 2H); 6.8 (s, 1H). Step 2: 7-benzoyl-5-methoxyinodoline Yield = 38% - orange solid - P.F. = 1232c. TLC: S.A7; 0.81 iH NMR d (ppm): 3.05 (t, 2H); 3.65 (s, 3H); 3.75 (t, 2H); 6. 75 (s, width, 2H including Intercam. 1H); 6.95 (s wide, 1 HOUR); 7.4-7.55 (m, 3H); 7.65 (, 2H). Step 3: 9-methoxy-l-phenyl-6,7-dihydro-3H- [1,4] -diazepin [6,7-1-hi] indol-4-one. Yield: 82% - brown resin. TLC: S.A6; 0.73. iH NMR d (ppm): 3.a (t, 2H); 3.7 (s, 3H); 4.3 (t, 2H); 3.9 (s, 2H); 6.6 (s, 1H); 7.0 (s, 1H); 7.3-7.5 (m, 3H); 7.6 (d, 2H).

Step 4: 3-hydroxyimino-9-methoxy-1-phenyl-6,7-dihydro-3H- [1,4] -diazepino [6,7, 1-hi] indol-4-one. Yield = 53% - an orange-orange solid - P.F. = 2052C. TLC: S.A5; 0.17. iH NMR d (ppm): 3.2 (t, 2H); 3.7 (s, 3H); 4.4 (t, 2H); 6.7 (t 2H); 7.1 (s, 1H); 7.4-7.6 (, 3H); 7.8 (d, 2H); 8.6 (s, 1 HOUR) . Step 5: (3R, s) -3-amino-9-methoxy-l-phenyl-6,7-dihydro-3H- [1,4] -diazepin [6,7,1-hi] indol-4-one . Yield = 67% - chestnut yellow solid - P.F. = 842C TLC: S.B3; 0.24. iH NMR d (ppm): 3.2 (t, 2H), 3.8 (s, 3H); 4.4 (t, 2H); 5.3 (s, 1H); 6.7 (s, 1H); 7.1 (s, 3H); 7.4 - 7.8 (, 5H); 2.1 and 8.5 (s wide, exchange 2H). Intermediate 3.b: (3R) -3-amino-9-methoxy-l-phenyl-6,7-dihydro-3H-1,4] -diazepin [6.7, 1-hi] indol-4-one. (II-R; R = CH30) 10.0 g (32.3 mmoles) of the (R, S) amine 3.a were dissolved in 100 ml of acetonitrile, at reflux.

Separately, 12.47 g (32.3 mmoles) of the di-para-tolyltartaric acid were dissolved, under reflux, in 100 ml of acetonitrile.

The hot solutions were mixed and then allowed to crystallize by cooling to laboratory temperature.

After standing overnight, the white crystals were filtered off and washed with 100 ml of cold acetonitrile and then dried. These crystals (e.e. = 37%) were recrystallized twice in succession from acetonitrile, to give the purified product (e.e. = 99.5%). This purification is followed by chromatography on a C ^ s optically active column, of Pirckle type, eluting with a 50:50 mixture of isopropanol / n-hexane. 9.9 g of the product were obtained. Performance = 44%. P. F. = 1682C. The 9.9 g of the preceding salt were suspended in 100 ml of ethyl acetate. A saturated solution of sodium bicarbonate was added, with vigorous stirring and after several minutes, the aqueous phase was separated. The organic phase was washed with 50 ml of water, dried and then the solvent was evaporated and cooled under a nitrogen atmosphere. 4.1 g of the purified base was obtained. Yield = 95%. P.F. = 842C. [a] = +232 (c = 1.1, CH2C12). Examples of the Invention (I) As described above, the preparation of the compounds (I) of the invention employ the reaction of the intermediates (II), 3-amino-1-phenyl-6,7-dihydro-3H- [1, 4] diazepin [6,7-l-hi] indol-4-one, with halides (IIIA), according to method A, with esters, especially the pentafluorophenyl esters (IIIB), according to method B, or with carboxylic acids (IIIC), according to method C. The general procedures for these methods are presented below. Method A: 10.0 mmoles of an intermediate amine (II) were dissolved, with stirring, in 60 ml of anhydrous methylene chloride in a reactor, which was protected against moisture. 10.0 mmole of acid halide (IIIA), then added at a temperature in the 202C region, followed by the addition, in drops, of 10.0 mmole of triethylamine. The reaction was continued with stirring at room temperature, between 15 and 25 ° C, and its progress was monitored by thin layer chromatography. When the reaction was considered to be at the end, 120 ml of methylene chloride were added to the reaction medium and the mixture was extracted in succession with 60 ml of an IN HCl solution, 60 ml of a saturated solution of sodium bicarbonate and finally 60 ml of water. After drying, the methylene chloride was evaporated under reduced pressure and the residue was purified by evaporative chromatography on a silica column, the eluent, a mixture of increasing polarity, consisting, for example, of acetone in methylene chloride. The eluted fractions, which were found to contain the pure compound, were combined and then evaporated under reduced pressure. The remaining purified product was subjected to the structural determinations and purity analyzes described above.

Method B: Step 1: 10.0 mmoles of an intermediate acid (IIIC), of the formula A-COOH and 3.55 g (19.3 mmoles) of the pentafluorophenol, were dissolved in 25 ml of dichloromethane. Then 0.81 g (2.6 mmol) of the para-dimethylaminopyridinium para-toluene sulphonate was added, in addition to: either 22.4 mmoles of the dicyclohexyl-carbodiimide in the "Ba" method, or 22.4 mmoles of the N- (3- dimethylaminopropyl). N'-ethylcarbodiimide in the "Bb" method. The mixture was stirred for 16 hours at laboratory temperature, which is in the 202C region, and then the insoluble components were filtered off. The solvent was removed by distillation and the residue was purified by the evaporative chromatography technique on a silica column, the eluent used is more commonly a gradient of acetone in methylene chloride. The fractions found to be pure by TLC chromatography were combined, the solvent was evaporated and, after analysis, the residual intermediate ester (Illß) in the form of an amorphous foam was used as such in the next step. Step 2: 10.0 mmoles of the pentafluorophenyl ester (IIIB), prepared in the previous step, were added to 10.0 mmoles of the intermediate amine (II), dissolved in anhydrous ethyl acetate. After stirring for 16 hours at room temperature, which is in the 202c region, the insoluble components were separated by filtration, the ethyl acetate was evaporated under vacuum and then the residue was purified by the evaporative chromatography technique on a column of silica, the eluent used being more commonly a gradient of methanol in methylene chloride. The fractions that were found were pure, by TLC chromatography, were combined, the solvent was evaporated and the purified residue was identified and analyzed.

Method C: 10.0 mmoles of an intermediate amine (II) were dissolved, with stirring, in 50.0 ml of anhydrous methylene chloride in a reactor protected from moisture. At the laboratory temperature, which is in the 202C region, 11.0 mmoles of an intermediate acid (Ule) of the formula A-COOH were added, followed by 10.0 mmoles (3.28 g) of "TOTU" (abbreviation for the tetrafluoroborate of O- [(ethoxycarbonyl) cyanomethylamino] -N, N, N ', N' -tetramethyluronium-supplied by Fluka, Ref. 02580). The mixture was cooled to 02c, then 20.0 mmole (2.55 g) of N, N-diisopropylethylamine was added, after which the mixture was stirred for 12 hours at room temperature and then extracted in succession with 50 ml of a IN HCl solution, 50 ml of a saturated solution of sodium bicarbonate and finally 50 ml of water.

The solvent was evaporated under vacuum and the residue was purified by the evaporative chromatography technique on a silica column, the eluent used is more commonly a gradient of methanol in methylene chloride. The fractions that were found were pure by TLC, were combined, the solvent was evaporated and the purified residue was identified and analyzed.

Example 1A: (3R.S) -2-Chloro-4-trifluoromethylpyrimidin- (4-oxo-l-phenyl-3.4.6.7-tetrahydro-1,41-diazepin- [6,7,1-hi] indol-3-amide) 5-carboxylic. [(I); A = 5- (2-chloro-4-trifluoromethylpyrimidyl)] The compound was prepared according to method A from intermediate 1.a and 5- (2-chloro) chloride -4-trifluoromethyl) pyrimidylcarboxylic Yield = 72% - white solid - Melting Point (PF) = 2822C (decomposition). Analysis according to C23H15CIF3N5O2: TLC: S.A4; 0.70. iH NMR (DMSO) d (ppm): 2.9-3.6 (m, 2H); 3.7-4.2 (m, 1H); 4.4- 4.75 (m, 1H); 5.45 (d, 1H, arrives at s by exchange.); 7.1-7.8 (m, 8H); 9.25 (s, 1H); 10.2 (d, 1H exchange.). IR: 3200, 1670, 1560, 1540, 1520, 1430, 1345, 1210, 1140, 800, 735, 700 cm "1.

Example 1B: N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro-f1.4") diazepin [6, 7.1-hi] indol-3-yl) (3R.S) -imidazori acid amide. 2-alpyridine-2-carboxylic acid [(I): A = 2-imidazo [1,2-a] pyridyl] The compound was prepared from intermediate 1.a and imidazo [1,2-a] pyridine- 2-carboxylic acid, according to a method derived from method C, which consists in carrying out the condensation in tetrahydrofuran (THF), in the presence of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate ("PyBrop") and triethylamine 4.50 g (16.23 mmoles) of intermediate amine 1.a were dissolved in 150 ml of anhydrous THF, 3.20 g (16.3 mmoles) of imidazo [1,2-a] pyridine-2-carboxylic acid and 4.95 g (6.82 ml). 49 mmol) of triethylamine were added.The mixture was cooled in an ice bath and 9.13 g (18.6 mmol) of "PyBrop" in 50 ml of THF were added.After stirring for 16 hours at laboratory temperature, the Insoluble components were separated by filtration and the solvents were They were removed by distillation, under vacuum. The residue (12.2 g) was purified by chromatography on a silica column, eluting with ethyl acetate containing 5% acetone. The fractions, which were found by TLC, contained the purified product were combined and the solvent was evaporated. 5.1 g of the pure product was obtained in an amorphous form. Yield = 71% - P.F .: 2602C.

Analysis according to C25H19FN5O2"^ O: TLC: S.A6; 0.27 * H NMR (DMSO) d (ppm): 2.80-3.55 (m, 2H); 3.70-4.10 (m, 1H); 4.30-4.75 (m , 1H), 5.50-5.68 (d, 1Hs per exchange.), 6.65-7.70 (m, 11H), 8.00-8.15 (m, 2H), 8.85-8.95 (d, 1H exchange.). IR: 3100, 1725, 1640, 1520, 1390, 1275, 1020, 820, 800, 750 cm "1.

Example 2.A: (3R) -2-fluoro-N- (4-oxo-l-phenyl-3.4.6.7-tetra-hydro T 1.4] diazepin r 6.7.1-hi1 indol-3-yl) benzamide [( I); A = 2-fluorophenyl] The compound was prepared according to method A from intermediate l.b and 2-fluorobenzoyl chloride yield = 50.5% - amorphous solid - P.F. = 192 c [a] D = +512 (c = l, CH2C12). Analysis according to C24H? GFN3 ° 2: TLC: S.A3; 0.43. H NMR (DMSO) d (ppm): 3.10-3.20 (m, 1H); 3.30-3.45 (m, 1H); 3. 95-4.05 (m, 1H); 4.65-4.75 (m, 1H); 5.65 (d, 1H); 7.10-7.60 (m, 11H, including exchange, 1H); 8.15 (m, 1H), 8.50-8.65 (m, 1H). IR: 3300, 1640, 1490, 1430, 1380, 1340, 1230, 1160, 725, 690 cm "1.

Example 2.B: (3R) -3-fluoro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.41 diazepinf 6.7.1-hyl indol-3-yl) benzamide [(I); A = 3-fluorophenyl] The compound was prepared according to method A from intermediate l.b and 3-fluorobenzoyl chloride yield = 78% - amorphous solid - P.F. = 244 c [a] D = +482 (C = 1, CH2C12). Analysis according to C24H18FN3? 2: TLC: S.A3; 0.43. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1 HOUR); 4.65 (m, 1H); 5.60 (d, 1H); 7.10-7.60 (m, 10H); 7.65-7.80 (m, 2H); 8.00 (d, exchange 1H). IR: 3250, 1670, 1620, 1560, 1520, 1430, 1380, 1340, 1280, 1240, 1220, 1140, 790, 670 cm "1.

Example 2.C: (3R) -4-fluoro-N- (4-oxo-l-phenyl-3.4, 6.7-tetrahydro T 1.41 diazepin [6.7, 1-hi] indol-3-yl) benzamide [(I); A = 4-fluorophenyl] The compound was prepared according to method A from intermediate l.b and 4-fluorobenzoyl chloride yield = 50.4% - amorphous solid - P.F. = 2282C [a] D = +482 (C = 1, CH2C12). Analysis according to C24H? ßFN3 ° 2 '0.25H2O TLC: S.A3; 0.52. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 3.95 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 7.10-7.60 (m, 10H, including 1H exchange); 8.00 (m, 1H). IR: 3400, 1640, 1590, 1490, 1440, 1420, 1380, 1340, 1230, 1160, 1050, 800, 760, 690, 660 cm "1.

Example 2.D: (3R) -2-chloro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1,4] diazepin [6, 7.1-hi] indol-3-yl) benzamide [ (I); A = 2-chlorophenyl] The compound was prepared according to method A from intermediate l.b and 2-chlorobenzoyl chloride yield = 66% - amorphous solid - P.F. = 1212C [a] D = +822 (c = 1, CH2C12). Analysis according to C24Hi8 lN302 • 0.1CH2C12 TLC: S.A3; 0.57. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 7.10 (m, 1H); 7.20-7.60 (m, 10H); 7.80 (m, 1H); 8.00 (d, exchange 1H). IR: 3300, 1650, 1590, 1490, 1430, 1380, 1220, 1160, 1040, 750, 730, 690 cm "1.

Example 2.E: (3R) -3-chloro-N- (4-oxo-l-phenyl-3.4.6, 7-tetra-hydror 1.4] diazepin [6,7, 1-hi] indol-3-yl ) benzamide [(I); A = 2-chlorophenyl] The compound was prepared according to method A from intermediate l.b and 3-chlorobenzoyl chloride Yield = 85% - white solid - P.F. = 2302C (decomposition.). [a] D = +342 (c = 1, CH2C12). Analysis according to Ci4H? GClN3? 2: TLC: S.A3; 0.49. lH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.0 (m, 1H); 4.67 (m, 1H); 5.65 (d, 1H, s per exchange); 7.15 (m, 1 HOUR); 7.25 (m, 1H), 7.3-7.6 (m, 8H); 7.85 (, 1H); 8.0 (m, 1H); 8. 15 (d, exchange 1H). IR: 3250 (wide), 3050, 1680, 1650, 1505, 1440, 1275, 1240, 725, 690 cm "1.

Example 2.F: (3R) -2-Iodo-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepinr 6.7.1-hi] indol-3-yl) benzamide [(I); A = 2-iodophenyl] The compound was prepared according to method A from intermediate l.b and 2-iodobenzoyl chloride Yield = 69% - amorphous solid - P.F. = 1232C [a] D = +812 (C = 1, CH2C12). Analysis according to Ci4Hi8IN3 ° 2: TLC: S.A3; 0.55.

H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.40 (m, 1H); 4.0 (m, 1H); 4.67 (m, 1H); 5.65 (d, 1H, s per exchange); 7.12 (m, 2H); 7.25 (m, 1H), 7.3-7.5 (m, 5H); 7.58 (m, 2H); 7.70 (, 2H, including 1 exchange); 7.92 (d, 1H). IR: 3400, 3260, 1650, 1490, 1440, 1385, 1160, 725, 690 cm "1.

Example 2.G: (3R) -3-chloro-4-fluoro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7, 1-hi] indole-3- il) benzamide [(I); A = 3-chloro-4-fluorophenyl] The compound was prepared according to method C from intermediate l.b and 3-chloro-4-fluorobenzoic acid. Yield = 97% - amorphous solid - P.F. = 1482C [a] D = +432 (C = 1, CH2C12). Analysis according to C24H17CIFN3O2 'TLC: S.A3; 0.70. H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1 HOUR); 4.65 (, 1H); 5.60 (d, 1H); 7.10-7.60 (m, 9H, including 1H exchange); 7.85 (m, 1H), 8.05 (m, 2H). IR: 3300, 3050, 1650, 1480, 1380, 1250, 1170, 1050, 750, 730, 690 cm "1.

Example 2.H: (3R) -3,4-dichloro- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi] indol-3-yl) benzamide [(I ); A = 3,4-dichlorophenyl] The compound was prepared according to method A from intermediate l.b and 3,4-dichlorobenzoyl chloride. Yield = 84.4% - amorphous solid - P.F. = 1632c [a] D = +422 (c = 1, CH2C12). Analysis according to C 24 H 17 Cl 2 N 3 O 2: TLC: S.A3; 0.76. H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 7.10-7.60 (m, 9H, including 1H exchange); 7.85 (m, 1H), 8.05 (m, 2H). IR: 3300, 3050, 1640, 1500, 1380, 1280, 1230, 1130, 1020, 750, 730, 690 cm "1.

Example 2.1: (3R) -2-methyl-N- (4-oxo-l-phenyl-3.4.6, 7-tetra-hydro r 1, 4] diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 2-methylphenyl] The compound was prepared according to method C from intermediate l.b and 2-methylbenzoyl chloride. Yield = 33% - white solid - P.F. = 1542C [a] D = +782 (C = 1, CH2C12). Analysis according to C25H21N3O2: TLC: S.A3; 0.34. iH NMR (DMSO) d (ppm): 2.6 (s, 3H); 3.15 (m, 1H); 3.38 (m, 1H); 3.48 (m, 1H); 4.68 (m, 1H); 5.66 (d, 1H, s per exchange); 7. 12 (m, 1H); 7.25 (m, 3H); 7.3-7.5 (m, 5H); 7.56 (m, 2H); 7. 68 (m, 2H, 1H exchange). IR: 3300, 3000, 1650, 1470, 1380, 1250, 1160, 725, 690 cm "1.

Example 2. J: (3R) -2-methoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetra-hydroT 1.4] diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 2-methoxyphenyl] The compound was prepared according to method A from intermediate l.b and 2-methoxybenzoyl chloride. Yield = 72% - white solid - P.F. = 2282C [a] D = +342 (c = 1, CH2C12). Analysis according to C25H21 303 • (0.25H2O): TLC: S.A3; 0.53. lH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.37 (m, 1H); 4.00 (m, 1H); 4.08 (s, 3H); 4.67 (m, 1H); 5.70 (d, 1H s per exchange); 7.0-7.15 (m, 3H); 7.25 (m, 1H), 7.38 (m, 2H); 7.45 (m, 3H); 7.55 (m, 2H); 8.25 (m, 1H); 9.85 (, exchange 1H); IR: 3350, 2900, 1670, 1640, 1590, 1500, 1470, 1380, 1280, 1240, 1170, 1010, 750, 730, 690 cm "1.

Example 2.K: (3R) -3-methoxy-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1.4] diazepin [6.7, 1-hi] indol-3-yl) benzamide [(I); A = 3-methoxyphenyl] The compound was prepared according to method A from intermediate l.b and 3-methoxybenzoyl chloride. Yield = 74% - white solid - P.F. = 1812C [a] D = +482 (c = 1, CH2C12). Analysis according to C25H21N3O3: TLC: S.A3; 0.51. H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 3.85 (s, 3H); 4.00 (m, 1H); 4.65 (m, 1H); 5.65 (d, 1H s by interchange); 7.10 (m, 3H); 7.25 (m, 1H), 7.35 7.6 (m, 9H); 7.97 (m, 1H exchange); IR: 3400, 2900, 1650, 1600, 1480, 1500, 1475, 1440, 1380, 1275, 1240, 1030, 790, 750, 720, 695 cm "1.

Example 2.L: (3R) -4-methoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi 1 -indol-3-yl] ) benzamide [(I); A = 4-methoxyphenyl] The compound was prepared according to method A from intermediate l.b and 4-methoxybenzoyl chloride. Yield = 67% - white solid - P.F. = 2212C [a] D = +512 (c = 1, CH2C12). Analysis according to C25H21N3O3. TLC: S.A3; 0.49. * H NMR (DMSO) d (ppm): 3.13 (m, 1H); 3.35 (m, 1H); 3.85 (s, 3H), 4.00 (m, 1H); 4.65 (m, 1H); 5.65 (d, 1H s by interchange); 6.95 (d, 2H); 7.10 (t, 1H); 7.25 (t, 1H), 7.38 (m, 2H); 7.45 (m, 2H); 7.55 (m, 2H); 7.95 (m, 3H) including the exchange). IR: 3350, 1680, 1650, 1600, 1480, 1390, 1250, 1200, 1030, 840, 760, 725, 695 cm "1.

Example 2.M: (3R) -3.4.5-trimethoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro r 1.41diazepin [6,7, 1-hi] indol-3-yl) benzamide [(I); A = 3,4,5-trimethoxyphenyl] The compound was prepared according to method C from intermediate l.b and 3,4,5-trimethoxy-benzoic acid. Yield = 81.4% - amorphous solid - P.F. = 2212C (decomposition.) [a] D = +542 (C = 1, CH2C12). Analysis according to ^ 7 ^ 5 ^ 05: TLC: S.A4; 0.76. 1 H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 3.90 (d, 9H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 7.10 (m, 1H); 7.15-7.30 (m, 3H); 7.30-7.60 (m, 6H); 7.90 (d, 1H). IR: 3300, 2900, 1640, 1520, 1470, 1300, 1230, 1170, 1120, 1000, 750, 730, 690 cm "1.

Example 2.N: (3R) -2-methoxy-5-chloro-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1 r 4] diazepin [6.7, 1-hi] indol-3-yl) benzamide [(I); A = 2-methoxyphenyl] The compound was prepared according to method C from intermediate l.b and 2-methoxy-5-chlorobenzoic acid. Yield = 90.1% - amorphous solid - P.F. = 2342C Ca] D = ° (zero) (c = 1, CH2C12). Analysis according to C 5Hi7ClN3? 5: TLC: S.A3; 0.64. H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1H); 4.10 (s, 3H); 4.70 (m, 1H); 5.6 (d, 1H); 7.00 (d, 1H); 7.10 (t, 1H), 7.20-7.50 (m, 6H); 7.55 (d, 2H); 8.2 (m, 1H); 9.75 (d, exchange 1H). IR: 3350, 1650, 1590, 1470, 1380, 1260, 1240, 1180, 1010, 730, 690, 640 cm "1.

Example 2.0: (3R) -4-acetamido-N- (4-oxo-l-phenyl-3, 4.6,7-tetrahydro [1,4] diazepin [6.7.1-hi] indol-3-yl) benzamide [ (I); A = 4-acetamidophenyl] The compound was prepared according to the method B.a from intermediate l.b and the intermediate product pentafluorophenyl ester, obtained with acetamidobenzoic acid. Yield = 32% - amorphous product - P.F. = 2662c [a] D = +432 (c = 1, CH2C12). Analysis according to C? GH22N4? 3: TLC: S.B; 0.20 1 H NMR (DMSO) d (ppm): 2.10 (s, 3H); 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 7.10-7.60 (m, 8H); 7.65 (d, 2H); 7.85 (d, 2H); 7.95 (d, exchange 1H); 8.35 (broad s, exchange 1H). IR: 3300, 1690, 1740, 1600, 1510, 1440, 1390, 1310, 1260, 1180, 1120, 1020, 860, 760, 730, 700 cm "1.

Example 2.P: (3-Oxo-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) amide of (3R) -pyridine-2-carboxylic acid [2-carboxylic acid] (I); A = 2-pyridyl] The compound was prepared according to method C from intermediate l.b and 2-pyridinecarboxylic acid. Yield = 86% - amorphous solid - P.F. = 208 C [a] D = +572 (c = 1, CH2C12). Analysis according to C23H? GN4 ° 2 • 0.2CH2C12 • 0.1H20: TLC: S.A3; 0.67. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.00 (m, 1H); 4.65 (m, 1H); 5.65 (d, 1H); 7.10 (m, 1H); 7.20-7.60 (m, 8H); 7.85 (m, 1H); 8.20 (d, 1H); 8.65 (d, 1H); 9.70 (d, exchange 1H). IR: 3300, 1660, 1490, 1440, 1380, 1240, 1160, 750, 690 cm "1.

Example 2.Q: (3R) -N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepin [6.7, 1-hi] indol-3-yl) isonicotinamide [(I); A = 4-pyridyl] The compound was prepared according to the method B.a from the intermediate product l.b and the intermediate product of pentafluorophenyl ester, obtained with the isonicotinic acid. Yield = 83% - amorphous product - P.F. = 2342c [a] D = +232 (c = i, CH2C12). Analysis according to Ci5H2oN3 ° 3: TLC: S.A10; 0.60. * H NMR (DMSO) d (ppm): 3.10 (m, 1H); 3.30 (m, 1H), 3.90 (m, 1 HOUR); 4.60 (m, 1H); 5.60 (d, 1H); 7.05-7.50 (m, 8H including 1H exchange); 7.75 (m, 2H); 8.50 (m, 1H); 8.70 (m, 2H); IR: 3300, 1640, 1470, 1430, 1380, 1270, 1160, 1110, 1040, 750, 720, 690 cm "1.

Example 2.R: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) (3R) -lH-indole-2-aide carboxylic [(I); A = 2-lH-indolyl] The compound was prepared according to method A from intermediate l.b and lH-indole-2-carboxylic chloride. Yield = 81% - white solid - P.F. = 1962C [a] D = +742 (c = 1, CH2C12). Analysis according to C26H? 9N402 -0.5C4HgO2: TLC: S.A3; 0.62. iH NMR (DMSO) d (ppm): 2.8-3.6 (m, 2H); 3.7-4.25 (m, 1H); 4.4-4.7 (1H); 5.55-5.65 (d, 1H s per exchange); 6.9-7.7 (m, 13H); 7.9-7.7 (m, 13H); 7.9-8.1 (d, exchange 1H); 10.05 (s, exchange 1H). IR: 3250, 1685, 1630, 1530, 1440, 1385, 1340, 1235, 740, 690 cm "1, Example 2.S: (3R) -quinolin-3-carboxylic acid (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin- [6, 7,1-hylindol-3-yl] amide [(I)] ); A = 4-quinolyl] The compound was prepared according to method A from intermediate l.b and 3-quinoline-carboxylic chloride. Yield = 65% - white solid - P.F. = 1522c [a] D = +432 (C = 1, CH2C12). Analysis according to C 7H2? N4? 2 • 0.4H O: TLC: S.A4; 0.22. iH NMR (DMSO) d (ppm): 2.70-3.6 (m, 2H); 3.6-4.15 (m, 1H); 4.3-4.8 (1H); 5.5-5.7 (d, 1H s per exchange); 6.8-8.3 (m, 13H); 8.60-8.8 (m, 1H); 9.2-9.4 (m, 1H). IR: 3300, 1680, 1660. 1510, 1445, 1285, 840, 785, 695 cm "1.

Example 2.T: (3-Oxo-l-phenyl-3 f-4,6,7-tetrahydro [1,4] diazepin- [6,7,1-hi] indol-3-yl) (3R) -quinoline acid 6-carboxylic [(I); A = 6-quinolyl] The compound was prepared according to method A from intermediate l.b and 6-quinoline-carboxylic chloride. Yield = 57% - white solid - P.F. = 1822C [a] D = +592 (c = 1, CH2C12). Analysis according to C27H2oN402 '° - 75H20: TLC: S.A4; 0.40. iH NMR (DMSO) d (ppm): 2.80-3.6 (m, 2H); 3.7-4.30 (m, 1H); 4.5-4.9 (m, 1H); 5.75 (d, 1H s per exchange); 6.9-7.70 (, 10H); 8.00-8.40 (m, 4H including 1H exchange);; 8.55 (m, 1H); 9.00 (, 1H). IR: 3300, 1680, 1650. 1510, 1490, 1440, 1280, 780, 730, 695 cm -1 Example 2.U: (3R) -2- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1.4] diazepin- [6,7,1-hi] indol-3-yl) -amide of the acid (3R) -2- methoxyquinoline-4-carboxylic [(I); A = 4- (2-methylquinolyl)] The compound was prepared according to the method Ba from intermediate l.b and the intermediate product of the pentafluorophenyl ester, obtained with 2-methylquinoline-carboxylic acid. Yield = 94% - amorphous product - P.F. = 2802C (decomposition.) Analysis according to C2gH22N4 ° 2 '0 > 1CH2cl2: TLC: S.A3; 0.58. JH NMR (DMSO) d (ppm): 2.70 (s, 3H); 3.2 (m, 1H); 3.45 (m, 1H); 4.00 (m, 1H); 4.70 (m, 1H); 5.80 (d, 1H); 7.10-7.75 (m, 11H); 8.15 (d, 1H); 8.20 (d, exchange 1H); 8.85 (s, 1H). IR: 3300, 1650, 1600. 1520, 1450, 1390, 1340, 1240, 1160, 760, 700 cm "1.

Example 2.V: (3-Oxo-l-phenyl-3,4,6,7-tetrahydro [1.4] diazepin- [6,7,1-hi] indol-3-yl) (3R) -isoquinolin-3-aide carboxylic [(I); A = 3-isoquinolyl] The compound was prepared according to method A from intermediate lb and the intermediate product of pentafluorophenyl ester, obtained with 3-methylquinoline-4-carboxylic acid, in the presence of the N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide. Yield = 84% - amorphous product - P.F. = 2502C [a] D = +102 (c = 1, CH2C12). Analysis according to C27H20N4? 2 • 0.3H20- 0.15CH2C12: TLC: S.Al; 0.25. * H NMR (DMSO) d (ppm): 3.12 (m, 1H); 3.38 (m, 1H); 3.75 (s, 3H); 4.0 (m, 1H); 4.63 (m, 1H); 5.72 (d, 1H s per exchange); 7.12 (m, 1H); 7.28 (m, 1H); 7.35 (m, 2H); 7.47 (, 2H); 7.59 (m, 2H); 7.72 (m, 2H); 8.0 (d, 1H); 8.1 (d, 1H); 8.65 (s, 1H); 9.28 (s, 1H); 9.86 (d, exchange 1H).

IR: 3400, 1670, 1600, 1485, 1450, 1260, 900, 970, 785, 755, 730, 700, 670 cm "1. The hydrochloride was prepared from the base in hydrochloric acid containing propanol. rinsed with ether and dried in vacuo PF = 2252C. [a] D = -4162 (c = 1, CH2C12) TLC: S.A3; 0.35 Example 2. Fluorosulfonate of (3-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi] indol-3-yl) amide of (3R) -N-methylisoquinoline-3 -carboxylic [(I); A = N-methyl-3-isoquinolinium] 1.0 g (2.31 mmol) of the product of Example 2.V, dissolved in 12 ml of dichloromethane, the solution was cooled to 02c and 0.184 g (2.31 mmol) of fluorosulfonate were added. methyl. After one hour at 02c, the temperature was allowed to return to ambient, and then the mixture was evaporated under reduced pressure. The residue was purified by evaporative chromatography on a silica column, the eluent being a mixture of increasing polarity of acetone in methylene chloride. 1.1 g of the compound were obtained in the form of a white solid. Melting point of 2282c. Yield = 87% - [a] D = - 408 C (c = 1, CH2CL2). Analysis, according to C2 H23FN4? 5S-O.5H2O: TLC: S.A10; 0.10.

H NMR (DMSO) d (ppm): 3.35 (m, 1H), 3.45 (m, 1H); 3.52 (s, 3H); 4.5 (m, 1H); 4.78 (m, 1H); 5.75 (d, 1H, s per exchange); 7.0 (m, 1H); 7.25 (m, 1H); 7.45 (m, 1H), 7.65 (m, 2H); 7.7-7.9 (m, 5H); 8.02 (m, 1H); 8.12 (s, 1H); 8.65 (s, 1H); 9.25 (s, 1H); 10.5 (d, exchange 1H). IR: 3450, 3350, 1680, 1600, 1560, 1480, 1430, 1270, 1070, 770, 700, 580 cm "1.

Example 2.X: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin- [6,7, l-hi] indol-3-yl) imidazo [lf 2-a] pyrimidine amide - 2-carboxylic [(I); A = imidazo [1,2-a] pyrimidinyl] The compound was prepared according to the method B.a from the intermediate product l.b and the intermediate product of pentafluorophenyl ester, obtained with the imidazo [1,2-a] pyrimidine-2-carboxylic acid. Yield = 57% - amorphous product - P.F. = 2702C (decomposition.) [a] D = -212 (c = 1, CH2C12). Analysis according to C H18N60 • 0.5C3H6 • 0.2CH2C1: TLC: S.A9; 0.13. * H NMR (DMSO) d (ppm): 2.90-3.5 (2H); 3.5-4.20 (m, 1H); 4.2- 4.7 (m, 1H); 5.40-5.6 (d, 1H per exchange); 7.0-7.7 (m, 9H); 7.6-7.8 (m, 1H); 8.0 (s, 1H); 8.6-8.75 (m, 1H); 8.75-8.95 (d, 1H exchange).

IR: 3400 (wide), 3200, 1685, 1645, 1530, 1440, 1260, 1220, 1155, 730, 700 cm "1.

Example 2. Y: (3R) -4.7-dimethyl- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1.4] diazepin- [6,7,1-hi] indol-3-yl) -amide) pyrazolo [5.1-cl [1.2.4] triazine-3-carboxylic [(I); A = 3- (4,7-dimethyl-pyrazolo [5, 1-c] - [1, 2, 4] -triazinyl)] The compound was prepared according to the method B.a from intermediate l.b and the intermediate product pentafluorophenyl ester, obtained with 4,7-dimethyl-pyrazolo [5,1-c] - [1,2,4] -triazine-3-carboxylic acid. Yield = 46% - white product - P.F. = 2602C [a] D = +212 (c = 1, CH2C12). Analysis according to C25H21N702 - 0.75H2O: TLC: S.A3; 0.20 i H NMR (DMSO) d (ppm): 2.65 (s, 3 H), 3.15 (m, 1 H); 3.30 (s, 3H); 3.40 (m, 1H); 4.00 (m, 1H); 4.70 (m, 1H); 5.70 (d, 1H); 7. 10-7.60 (m, 9H); 9.90 (d, 1H exchange). IR: 3350, 1660, 1600, 1560, 1470, 1380, 1370, 1300, 1230, 1170, 800, 730, 690, 640 cm "1.

Example 3: (3R.S) (9-Methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) -amide of the acid (3R.S. ) -auinoline-3-carboxylic acid [(I); A = 3-quinolyl, R = CH3] The compound was prepared according to method A from intermediate 2.a: (3R, S) -3-amino-9-methyl-1-phenyl-6, 7-dihydro [1,4] diazepin [6,7-1, hi] indol-4-one and 3-quinolinecarboxylic chloride. Yield = 56% - white solid - P.F. = 2382C Analysis according to C H22N4? 2 '0.2H2O: TLC: S.A4; 0.18. H NMR (DMSO) d (ppm): 2.45 (s, 3H); 3.1 (m, 1H); 3.45 (m, 1H); 3.95 (m, 1H); 4.65 (m, 1H); 5.71 (d, 1H, s by interchange); 7.25-7.65 (m, 8H); 7.85 (, 1H); 7.95 (d, 1H); 8.2 (d, exchange 1H); 8.25 (d, 1H); 8.8 (s, 1H); 9.45 (s, 1H). IR: 3450 (width), 3200, 3005, 1690, 1660, 1530, 1430, 1375, 1280, 1245, 1160, 920, 780, 695 cm "1.

Example 4: (3R) -isoquinolin-3- (9-methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1.4] -diazepin [6,7,1-hi] indol-3-yl) -amide) carboxylic [(I); A = 3-isoquinolyl, R = CH3] The compound was prepared according to method B.b, by a procedure, which is identical to Example 2. V, with intermediate 2.b: (3R) -3-amino-9-methyl-1-phenyl-6,7-dihydro [1,4] diazepin [6,7-1, hi] indole-4 -one Yield = 93% - white solid - P.F. = 1302C [a] D = +82 (c = 1, CH2C12). Analysis according to C27H2oN402 • 0.4H 0- 0.15CH2C12: TLC: S.A4; 0.17. * H NMR (DMSO) d (ppm): 2.35 (s, 3H); 3.1 (m, 1H); 3.35 (m, 1 HOUR); 4.0 (m, 1H); 4.65 (m, 1H); 5.7 (d, 1H, s per exchange); 7.25-7.5 (m, 5H); 7.6 (m, 2H); 7.75 (m, 2H); 8 (d, 1H); 8.1 (d, 1H); 8.65 (s, 1H); 8.8 (s, 1H); 9.9 (d, exchange 1H). IR: 3380, 1660, 1490, 1350, 1235, 1160, 740, 695 cm "1.

Example 5: (3R.S) -isoquinolin- (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) -amide) 3-carboxylic [(I); A = 3-isoquinolyl, R = CH30] The compound was prepared according to method A from intermediate 3.a: (3R, S) -3-amino-methyl-9-methoxy-1-phenyl- 6,7-dihydro [1,4] diazepin [6, 7, 1, hi] -indol-4-one and 3-quinolinecarboxylic chloride. Yield = 40% - white solid - P.F. = 2042C Analysis according to C28H22N403 • 0.33H20- 0.33CH2C12: TLC: S.B1; 0.25. * H NMR (DMSO) d (ppm): 3.1 (m, 1H); 3.35 (m, 1H); 3.75 (s, 3H); 4.0 (, 1H); 4.7 (m, 1H); 5.7 (d, 1H, s per exchange); 6.7 (broad s, 1H), 7.1 (broad s, 1H); 7.25-7.85 (m, 7H); 7.95 (d, 1H); 8.2 (d, 1H); 8.25 (d, exchange 1H); 8.75 (m, 1H); 9.75 (m, 1H). IR: 3300 (wide), 1660, 1520, 1480, 1390, 1290, 1230, 1120, 780, 700 cm "1.

Example 6A: (3R) -3-chloro-N- (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin r 6.7.1-hi] indole-3-yl) benzamide [(I); A = 3-chlorophenyl, R = CH30] The compound was prepared according to method C from intermediate 3.b: (3R) -3-amino-9-methoxy-1-phenyl-6, 7- dihydro [1,4] diazepin [6, 7-1, hi] indol-4-one and chlorobenzoic acid. Yield = 75% - amorphous solid - P.F. = 119 C [a] D = +292 (c = 1, CH2C12). Analysis according to C25H QC1N303: TLC: S.A2; 0.59. H NMR (DMSO) d (ppm): 3.10 (m, 1H); 3.35 (m, 1H); 3.70 (s, 3H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H), 6.70 (s, 1H); 7.10 (s, 1H); 7.35-7.65 (m, 7H); 7.85 (d, 1H); 8.00 (s, 1H); 8. 05 (d, exchange 1H) .. IR: 3300, 1660, 1570, 1510, 1460, 1370, 1340, 1260, 1230, 1170, 1140, 1040, 760, 740, 700 cm "1.

Example 6B (3R) -4-chloro-N- (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi] indole-3-yl ) benzamide [(I); A = 4-chlorophenyl, R = CH30] The compound was prepared according to method A from intermediate 3.b and 4-chlorobenzoyl chloride. Yield = 83% - white solid - P.F. = 1752C [a] D = +3.262 (c = 1, CH2C12). Analysis according to C25H20 IN3O3. O.25H2O: TLC: S.A3; 0.49. H NMR (DMSO) d (ppm): 3.1 (m, 1H); 3.35 (m, 1H); 3.75 (s, 3H); 4.00 (m, 1H); 4.65 (m, 1H); 5.6 (d, 1H, s per exchange), 6.7 (s, 1H); 7.1 (s, 1H); 7.35-7.6 (m, 7H); 7.9 (d, 2H); 8.00 (s, exchange 1H). IR: 3300, 2900, 1650, 1470, 1365, 1340, 1265, 1230, 1140, 1085, 840, 750, 700 cm "1.

Example 6.C (3R) -N- (9-methoxy-4-oxo-l-phenyl-3.4.6.7-tetra-hydro T 1.4] diazepin [6.7.1-hi1 indol-3-yl) isonixotinamide [(I ); A = 4-pyridyl, R = CH30] The compound was prepared according to method B from intermediate 3.b and the intermediate product, the pentafluorophenyl ester, obtained with isonicotinic acid. Yield = 55% - amorphous yellow product - P.F. = 220-2242C [a] D = +2.42 (c = 1, CH2C12). Analysis according to C 4H2oN4 ° 3 • ° «15CH2C12: TLC: S.A3; 0.42. X H NMR (DMSO) d (ppm): 3.15 (m, 1 H); 3.35 (m, 1H); 3.75 (s, 3H); 4.00 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H, s per exchange), 6.70 (s, 1H); 7.10 (s, 1H); 7.25-7.6 (m, 5H); 7.80 (d, 2H); 8.10 (d, exchange 1H); 8.80 (d, 2H).

IR: 3350, 1685, 1650, 1525, 1570, 1460, 1230, 695 cm "1.

Example 6D (9-methoxy-4-oxo-l-phenyl-3.4.6.7-tetrahydro T 1.4] (3R) -quinolin-3-diazepin [6,7,1-hi] indol-3-yl) amide carboxylic [(I); A = 3-quinolyl, R = CH30] The compound was prepared according to the Bb method by a procedure, which is identical to Example 2.V, with intermediate 3.b and the intermediate pentafluorophenyl ester product of the acid 3-quinolinecarboxylic. Yield = 77% - white solid - P.F. = 1122C [] D = +4.62 (c = 1, CH2C12). Analysis according to C2gH22N4 © 3.0.66 H20: TLC: S.B1; 0.30. * H NMR (DMSO) d (ppm): 3.1 (m, 1H); 3.35 (m, 1H); 3.75 (s, 3H); 4.00 (m, 1H); 4.7 (m, 1H); 5.7 (d, 1H s per exchange); 6.7 (broad s, 1H); 7.10 (broad s, 1H); 7.25-7.85 (, 7H); 7.95 (d, 1H); 8.2 (d, 1H); 8.25 (d, exchange 1H); 8.75 (m, 1H); 9.75 (m, 1H). IR: 3300, 1660, 1520, 1480, 1389, 1290, 1230, 1120, 780, 700 cm "1.

Example 6E (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro r 1.4] (3R) -quinolin-6-carboxylic acid [6,7,1-hi] indol-3-yl) -diazepin [6,7,1-hi] indol-3-yl) amide [(I); A = 6-quinolyl, R = CH30] The compound was prepared according to the Bb method by a procedure, which is identical to Example 2.V, with the intermediate 3.b and the pentafluorophenyl ester intermediate of the acid 6-quinolinecarboxylic. Yield = 80% - white solid - P.F. = 2062C [a] D = +2.952 (c = 1, CH2C12). Analysis according to C2gH22N4? 3H20: TLC: S.A10; 0.43. H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.4 (m, 1H); 3.75 (s, 3H); 4.00 (m, 1H); 4.7 (m, 1H); 5.65 (d, 1H s per exchange); 6.7 (s, 1H); 7.10 (s, 1H); 7.35-7.65 (m, 7H); 8.2-8.35 (m, 4H, 1H exchange); 8.5 (s, 1H); 9 (m, 1H). IR: 3400 (width), 1650, 1470, 1370, 1345, 1270, 1230, 1190, 1140, 840, 780, 700 cm "1. Example 6F (9-methoxy-4-oxo-l-phenyl-3.4.6.7 -tetrahydro- [1.41 diazepin [6.7.1-hi] indol-3-yl) (3R) -isosuinoline-3-carboxylic acid [(I); A = 3-isoquinolyl, R = CH3O] The compound was prepared according to the method Bb by a process, which is identical to Example 2.V, with intermediate 3.b and the intermediate product of pentafluorophenyl ester of 3-isoquinolinecarboxylic acid Yield = 87% - white solid - PF = 2112C [a] D = +0.302 (C = 1, CH2C12).

Analysis according to C2 H22N4? 3.0.1 H2O * 0.1 CH2C1: TLC: S.Al; 0.18. H NMR (DMSO) d (ppm): 3.1 (m, 1H); 3.35 (m, 1H); 3.75 (s, 3H); 4.00 (m, 1H); 4.7 (m, 1H); 5.7 (d, 1H s per exchange); 6.7 (broad s, 1H); 7.10 (broad s, 1H); 7.2-7.8 (m, 7H); 8.00 (m, 1H); 8.1 (m, 1H); 8.65 (s, 1H); 9.3 (s, 1H); 9.9 (d, exchange 1H). IR: 3360, 1665, 1500, 1490, 1470, 1345, 1265, 1225, 1145, 700 cm "1.

Example 6G (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro- [1,4] diazepin [6,7,1-hi] indol-3-yl) amide of (3R) -4,7-dimethylpyrazolo [5.1] -cl r 1, 2.41 -triazine-3-carboxylic acid [(I); A = 3- (4,7-dimethylpyrazolo [5, lc] [1, 2, 4] triazinyl), R = CH30] The compound was prepared according to method C with intermediate 3.b and acid 4, 7-Dimethyl-pyrazolo [5, 1-c] [1,2, 4] -triazine-3-carboxylic acid. Yield = 60.9% - amorphous solid - P.F. = 95se [a] D = +19.62 (C = 1, CH2C12). Analysis according to C26H23N7 ° 4: TLC: S.A9; 0.82. iH NMR (DMSO) d (ppm): 2.60 (s, 3H); 3.05 (m, 1H); 3.25 (s, 3H); 3.30 (m, 1H); 3.65 (s, 3H); 3.90 (m, 1H); 4.60 (m, 1H); 5.6 (d, 1H); 6.60 (s, 1H); 7.00 (s, 2H); 7.25-7.45 (m, 3H); 7.55 (m, 2H); 9.80 (d, exchange 1H); IR: 3350, 1670, 1570, 1530, 1490, 1440, 1370, 1350, 1300, 1260, 1230, 1140, 1040, 800, 780, 740, 700 cm "1.

Example 7A (3R) -2,4-difluoro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepin [6.7.1-hi1 indol-3-yl) benzamide [(I); A = 2,4-difluorophenyl] The compound was prepared according to method A from intermediate l.b and 2,4-difluorobenzoyl chloride. Yield = 88% - white solid - P.F. = 1722C [a] D = +422 (C = l, CH2C12). Analysis according to C24Hi7N3? 2F: TLC: S.A3; 0.83. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.0 (m, 1H); 4.65 (m, 1H); 5.55 (d, 1H); 6.95 (m, 1H); 7.0 (m, 1H); 7. 12 (m, 1H); 7.25 (m, 1H); 7.35 (m, 2H); 7.45 (m 2H); 7.53 (m, 2H); 8.15 (m, 1H); 8.50 (m, 1H exchange).

Example 7.B (3R) -2.5-difluoro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 2,4-difluorophenyl] The compound was prepared according to method A from intermediate l.b and 2,5-difluorobenzoyl chloride. Yield = 92% - white solid - P.F. = 1872C [a] D = +422 (c = i, CH2C12).

Analysis according to C24H17N3O2F2: TLC: S.A3; 0.80. iH NMR (DMSO) d (ppm): 3.14 (m, 1H); 3.35 (, 1H); 3.95 (m, 1H); 4.65 (m, 1H); 5.13 (d, 1H); 7.15 (m, 3H); 7.25 (m, 1H); 7.35 (m, 2H); 7.45 (m 2H); 7.55 (m, 2H); 7.80 (, 1H); 8.6 (m, exchange 1H).

Example 7.C (3R) -3,4-difluoro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi] indol-3-yl) benzamide [(I); A = 3,4-difluorophenyl] The compound was prepared according to method A from intermediate l.b and 3,4-difluorobenzoyl chloride. Yield = 77% - white solid - P.F. = 2362C [a] D = +462 (C = 1, CH2C12). Analysis according to C24Hi7N3? F2 TLC: S.A3; 0.70. * H NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.0 (q, 1 HOUR); 4.65 (m, 1H); 5.58 (d, 1H); 7.12 (m, 1H); 7.25 (m, 2H); 7.35 (m, 2H); 7.45 (m 2H); 7.55 (m, 2H); 7.72 (m, 1H); 7.82 (m, 1H); 7.95 (d, exchange 1H). IR: 3300, 1680, 1630, 1600, 1540, 1500, 1280, 1250, 780, 690 cm "1.

Example 7.D (3R) -3,5-difluoro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro 11.41 diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 3,5-difluorophenyl] The compound was prepared according to method A from intermediate l.b and 3,5-difluorobenzoyl chloride. Yield = 90% - pale yellow solid - P.F. = 2792C [a] D = +442 (c = 1, CH2C12). Analysis according to C24H17N3? 2F2: TLC: S.A3; 0.70. lH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.35 (m, 1H); 4.0 (m, 1H); 4.65 (m, 1H); 5.60 (d, 1H); 6.95 (m, 1H); 7.10 (m, 1H); 7.48 (m, 2H); 7.45 (m 6H); 8.0 (d, exchange 1H) IR: 3200, 1680, 1640, 1590, 1540, 1440, 1380, 1300, 1120, 990, 840, 690 cm "1.

Example 7.E (3R) -2,4-dichloro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro T 1.4] diazepin [6,7,1-hi] indol-3-yl) benzamide [( I); A = 2,4-dichlorophenyl] The compound was prepared according to method A from intermediate l.b and 2,4-dichlorobenzoyl chloride. Yield = 77% - yellowish solid - P.F. = 1862C [a] D = +782 (C = 1, CH2C12). Analysis according to C24Hi7N302Cl2: TLC: S.A3; 0.64. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.38 (m, 1H); 4.0 (m, 1 HOUR); 4.20 (m, 1H); 5.63 (d, 1H); 7.15 (t, 1H); 7.25 (m, 1H); 7. 36 (m, 3H); 7.45 (m 3H); 7.55 (m, 2H); 7.80 (d, 1H); 8.10 (d, exchange 1H).

Example 7.F (3R) -3.5-dichloro-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 3,5-dichlorophenyl] The compound was prepared according to method A from intermediate l.b and 3,5-dichlorobenzoyl chloride. Yield = 65% - yellow solid - P.F. = 211C [a] D = +462 (C = 1, CH2C12). Analysis according to C24Hi7N3? 2Cl2: TLC: S.A3; 0.85. iH NMR (DMSO) d (ppm): 3.12 (m, 1H); 3.35 (m, 1H); 3.95 (, 1H); 4.65 (m, 1H); 5.56 (d, 1H); 7.10 (m, 1H); 7.20 (m, 1H); 7. 35 (m, 1H); 7.45 (m, 6H); 7.8 (s, 2H); 8.12 (d, exchange 1 HOUR); IR: 3300, 1680, 1650, 1560, 1530, 1440, 1400, 1280, 1240, 1120, 800, 700 cm "1.

Example 7.G (3R) -3,5-bis (trifluoromethyl) -N- (4-oxo-l-phenyl-3.4.6, 7-tetrahydro [1,4] diazepin 6, 7,1-hi] indol-3-yl) benzamide [(I); A = 3,5-bis (trifluoromethyl) phenyl] The compound was prepared according to method A from intermediate l.b and 3,5-bis (trifluoromethyl) benzoyl chloride.

Yield = 92% - yellowish solid - P.F. = 2082C [a] D = +462 (c = 1, CH2C12). Analysis according to C26Hi7N3? 2Fg. TLC: S.A3; 0.88. * H NMR (DMSO) d (ppm): 3.5 (m, 1H); 3.35 (m, 1H); 3.98 (q, 1 HOUR); 4.65 (m, 1H); 5.60 (d, 1H); 7.12 (m, 1H); 7.25 (m, 2H); 7.35 (m, 2H); 7.45 (, 2H); 7.52 (m, 2H); 7.22 (m, 1H); 7.82 (m, 1H); 7.95 (d, exchange 1H). IR: 3250, 1650, 1520, 1440, 1380, 1280, 1170, 1130, 910, 700 cm "1.

Example 7.H (3R) -3,4-dimethoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1 f 4] diazepin [6,7,1-hi 1 indol-3-yl) benzamide [(I ); A = 3,4-dimethoxyphenyl] The compound was prepared according to method A from intermediate l.b and 3,4-dimethoxybenzoyl chloride. Yield = 91% - white solid - P.F. = 1442c [a] D = +542 (c = 1, CH2C12). Analysis according to C26H23N3O4: TLC: S.A3; 0.33. * H NMR (DMSO) d (ppm): 3.15 (, 1H); 3.35 (, 1H); 3.95 (d, 6H); 3.95 (m, 1H), 4.65 (t, 1H); 5.65 (d, 1H); 6.90 (d, 1H); 7. 10 (t, 1H); 7.25 (t, 1H); 7.35 (t, 2H); 7.45 (m 2H); 7.55 (m, 4H); 7.95 (d, exchange 1H).

IR: 3300, 1680, 1650, 1600, 1490, 1440, 1260, 1220, 1020, 760, 700 cm1.

Example 7.1: (3R) -3-chloro-4-methoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6.7.1-hi] indol-3-yl) benzamide [ (I); A = 3-chloro-4-methoxyphenyl] The compound was prepared according to method C from intermediate l.b and 3-chloro-4-methoxybenzoic acid. Yield = 82% - pink solid - P.F. = 1582c [a] D = +502 (c = 1, CH2C12). Analysis according to C 5H2? N3? 3Cl. TLC: S.A3; 0.60. iH NMR (DMSO) d (ppm): 3.12 (, 1H); 3.35 (m, 1H); 3.95 (s, 3H); 5.10 (d, 1H); 6.95 (d, 1H); 7.10 (t, 1H); 7.25 (m, 1H); 7. 35 (m, 2H); 7.43 (m, 2H); 7.50 (m, 2H); 7.85 (m, 1H); 7.95 (m exchange 1H); 8.15 (d, 1H). IR: 3300, 1650, 1600, 1480, 1440, 1390, 1260, 1060, 760, 700 cm -1 Example 7.J (3R) -4-amino-3,5-dichloro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6.7, 1-hyl indol-3-yl] benzamide [(I); A = 4-amino-3,5-dichlorophenyl] The compound was prepared according to method C from intermediate l.b and 4-amino-3,5-dichlorobenzoic acid.

Yield = 90% - salmon-pink solid - P.F. = 1682C [a] D = +542 (c = 1, CH2C12). Analysis according to C 4H ^ gN? 2Cl2. TLC: S.A3; 0.62. lH NMR (DMSO) d (ppm): 7.9 (s, 1H), 7.3 (m 8H); 5.6 (d, 1H), 4.9 (s, 2H), 4.7 (t, 1H); 4 (q, 1H); 3.4 (m, 1H); 3.1 (m, 1H). IR: 3300, 1600, 1520, 1470, 1390, 1350, 1280, 1120, 780, 700 cm "1.

Example 7.K: (3R) -2-acetamido-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro r 1.41diazepin [6.7.1-hi] indol-3-yl) benzamide [(I); A = 2-acetamidophenyl] The compound was prepared according to method A from intermediate l.b and N-acetyl anthranilic acid. Yield = 27% - white solid - P.F. = 2102C [a] D = +462 (c = 1, CH2C12). Analysis according to C2gH2N4? 3 TLC: S.A9; 0.26. 1 H NMR (DMSO) d (ppm): 1.75 (broad s, exchange), 2.85 (s, 3H); 3.15 (m, 1H); 3.4 (m, 1H); 4.0 (m, 1H); 4.22 (m, 1H); 7. 12 (m, 1H); 7.20 (s, 1H); 7.25 (m, 1H); 7.45 (5H); 7.55 (d, 2H); 7.75 (m, 2H); 8.2 (d, 1H).

Example 7.L (3R) -2-acetoxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7, 1-hi] indol-3-yl ) benzamide [(I); A = 2-acetoxyphenyl] The compound was prepared according to method C from intermediate l.b and N-acetylsalicylic acid. Yield = 14% - P.F. = 1472c [a] D = +572 (C = 1, CH2C12). Analysis according to C26 ^^ 403: TLC: S.A3; 0.50. * H NMR (DMSO) d (ppm): 2.5 (s, 3H), 3.12 (m, 1H); 3.36 (m, 1H), 3.95 (q, 1H), 4.5 (t, 1H); 5.63 (d, 1H); 7.1 (t, 1H); 7. 7 (d, 1H); 7.25 (m, 1H); 7.35 (m, 3H); 7.45 (m, 2H); 7.62 (m, 3H); 8.18 (d, 1H), 8.48 (d, 1H exchange). IR: 3400, 1760, 1660, 1500, 1180, 1090, 1910, 730, 700 cm "1.

Example 7.M Potassium salt of (3R) -2-hydroxy-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro \ 1.41 diazepin [6,7,1-hi] indol-3-yl) benzamide [(I); A = 2-potassium phenate] The ester functional group of the product of the Example 7.L was hydrolyzed with potassium hydroxide in methanol, at reflux, for 2 hours, and then the solvent was evaporated.

Yield = 89% - yellow solid - P.F. = 2432c [a] D = +42 (c = 1, CH2C12). Analysis according to C24H? N3? 3K-2.5 H20 TLC: S.A3; 0.67. H NMR (DMSO) d (ppm): 3.16 (m, 1H); 3.35 (m, 1H); 3.5 (H20), 3.92 (q, 1H), 4.98 (t, 1H), 5.1 (s, 1H); 5.3 (t, 1H); 6.75 (d, 1H); 7.02 (m, 1H); 7.2 (m, 2H); 12.7 (1H, width, exchange); 7.48 (m, 5H); 7.6 (m, 1H), 7.7 (m, 1H).

Example 7.N (3R) -5,6-dichloro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7,1-hi] indol-3-yl. ) nicotinamide [(I); A = 3- (5,6-dichloropyridyl)] The compound was prepared according to method C from intermediate l.b and 5,6-dichloro-nicotinic acid. Yield = 49% - white solid - P.F. = 138-1402C [a] D = +43.72 (c = 1, CH2C12). Analysis according to C23Hi6Cl2N4? 2: TLC: S.A3; 0.30. H NMR (DMSO) d (ppm): 3.1-3.25 (m, 1H); 3.3-3.5 (m, 1H); 3.95-4.1 (q, 1H); 4.6-4.75 (t, 1H), 5.5-5.6 (d, 1H), 7.1- 7.6 (m, 8H); 8.1-8.25 (d, 1H); 8.25-8.35 (s, 1H); 8.75-8.9 (s, 1H). IR: 3250, 1650, 1520, 1360, 1290, 1240, 1150, 1040, 760, 690 cm "1.

Example 7.0 (3R) -3,5-dichloro-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6, 7.1-hi1 indol-3-yl) isonicotinamide [(I); A = 3,5-dichloro-4-pyridyl] The compound was prepared according to method C from intermediate l.b and 3,5-dichloro-isonicotinic acid Yield = 18% - white solid - P.F. = 1822C [] D = +136.52 (c = 1, CH2C12). Analysis according to C23H? GCl2N4? 2: TLC: S.A10; 0.45. H NMR (DMSO) d (ppm): 3.1-3.25 (m, 1H), 3.35-3.5 (m, 1H); 3.9-4.1 (m, 1H), 4.64.75 (m, 1H), 5.6-5.7 (d, 1H); 7.1-7.6 (m, 8H); 7.7-7.85 (d, 1H); 8.5-8.6 (d, 2H). IR: 3300, 1670, 1600, 1520, 1390, 1280, 1200, 880, 820, 700 cm "1.

Example 7.P: (3R) -3-t-Butyloxycarbonylamino-N- (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1.4] diazepin [6.7.1-hi] indole-3- il) isonicotinamide [(I); A = 3-t-butyloxycarbonylamino-4-pyridyl] The compound was prepared in dimethylformamide, according to method C described in Example IB, ie in the presence of PyBrop and triethylamine, from intermediate lb and N-Boc derivative of 3-aminoisonicotinic acid. Yield = 67% - yellow solid TLC: S.A10; 0.40. iH NMR (DMSO) d (ppm): 1.45 (s, 9H), 3.15 (, 1H); 3.4 (m, 1H); 3.95 (q, 1H); 4.5 (t, 1H); 5.45 (d, 1H); 7.5 (m, 9H); 8.4 (d, 1H), 9.35 (s, 1H); 9.9 (s, 1H); 10.2 (d, 1H).

Example 7.Q: (3R) -3-amino-N- (4-oxo-l-phenyl-3.4.6.7-tetra-hydro T 1.4] diazepin [6.7, 1-hi] indol-3-yl) isonicotinamide [ (I); A = 3-amino-4-pyridyl] The condensation product obtained in Example 7. Previous P was N-deprotected using trifluoroacetic acid in methylene chloride. After stirring for 30 minutes at room temperature, the solvent was removed, the residue was taken up in ethyl acetate and the mixture was extracted with a saturated solution of NaHC 3. The extract was dried, the solvent was evaporated and the residue was purified by chromatography on a silica column, eluting with the mixture of CH212 / MeOH, 98/2 (v / v). Yield = 68% - beige solid - P.F. = 1752C TLC: S.B; 0.15. iH NMR (DMSO) d (ppm): 3.15 (m, 1H); 3.4 (, 1H); 3.95 (q, 1H); 4.5 (t, 1H); 5.5 (d, 1H); 5.75 (s, 1H); 6.54 (s, 1H); 7.5 (m, 9H); 8.2 (s, 1H); 9.7 (d, 1H). IR: 3300, 2900, 1680, 1640, 1600, 1580, 1500, 1230, 1040, 700 cm "1.

Example 7. R: (3R) -3-acetamido-N- (4-oxo-l-phenyl-3.4.6.7-tetrahydro [1.4] diazepin [6.7.1-hi] indol-3-yl) isonicotinamide [(I ); A = 3-acetamido-4-pyridyl] 0.2 g (0.5 mmol) of the product of Example 7.Q were dissolved in 2 ml of pyridine; 1 ml of acetic anhydride was added and the mixture was stirred for 12 hours at room temperature, before adding 10 ml of water. After stirring for 4 hours at room temperature, it was extracted with ethyl acetate; The organic phase was washed with a saturated solution of NaHC 3 and then dried. After evaporation, the residue was purified by chromatography on a silica column, eluting with a mixture of increasing polarity, of acetone in methylene chloride. Yield = 45% - white solid - P.F. = 1902C TLC: S.B; 0.17. H NMR d (ppm): 2.2 (s, 3H), 3.2 (m, 1H); 3.4 (m, 1H), 4 (q, 1H), 4.7 (t, 1H); 5.6 (d, 1H); 7.3 (m, 9H); 8.3 (d, 1H), 8.45 (d, 1H); 9.9 (s, 1H); 10.5 (s, 1H). IR: 3300, 1680, 1650, 1560, 1500, 1410, 1280, 1240, 700 cm "1.

Example 7.S: (3R) -3-Cyclopropylcarbonylamido-N- (4-oxo-l-phenyl-3, 4.6.7-tetrahydro [1.4] diazepin [6.7.1-hi] indol-3-yl) isonicotinamide [ (I); A = 3-cyclopropylcarbonylamido-4-pyridyl] 0.15 g (0.38 mmol) of the product of Example 7.Q were dissolved in 2 ml of methylene chloride; of pyridine; 1 ml of acetic anhydride was added and the mixture and one equivalent of triethylamine was added. The mixture was cooled and 40 mg (0.38 mmoles) of cyclopropanecarbonyl chloride was added at a temperature of less than 5 c. The mixture was then stirred for 16 hours at room temperature, before adding 20 ml of methylene chloride. After washing with a ln solution of sodium hydroxide, drying and evaporating the solvent, the residue was purified by chromatography on a silica column, eluting with a mixture of S.A8. Yield = 20% TLC: S.A10; 0.17. * H NMR d (ppm): 0.85 (m 2 H), 1.1 (m, 2H); 1.6 (m, 1H), 3.15 (m, 1H), 3.4 (m, 1H); 4 (q, 1H); 4.7 (t, 1H); 5.6 (d, 1H); 7.3 (m, 9H); 8.3 (d, 1H); 8.4 (d, 1H); 9.9 (s, 1H); 10.35 (s, 1H).

Example 7.T: (3-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin-6,7,1-hi] indol-3-yl) (3R) -pyrazine-2-carboxylic acid amide [(I ); A = 2-pyrazinyl] Compound prepared according to method C, from intermediate l.b and 2-pyrazine carboxylic acid. Performance = 45% - bright orange solid -P. F .: 213-2142C - [a] D = +562 (c = 1, CH2C12) Analysis according to C22Hi7N5? 2: TLC: S.A10; 0.75. H NMR d (ppm): 3.1-3.25 (m, 1H); 3.3-3.5 (m, 1H), 3.9-4.1 (m, H), 4.6-4.75 (m, 1H), 5.55-5.7 (d, 1H); 7.7 (, 8H); 8.6-8.7 (d, 1H); 8.7-8.85 (d, 1H); 9.35-9.6 (m, 2H). IR: 3370, 1670, 1600, 1510, 1450, 1390, 1020, 800, 690 cm "1.

Example 7.U: (3R) -thiophene-2-carboxylic acid (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4-diazepin [6,7,1-hi] indol-3-yl) amide [( I); A = 2-thienyl] Compound prepared according to method C, from intermediate l.b and 2-thiophene carboxylic acid. Yield = 57% - white solid - P.F .: 217-2182C - [a] D = +562 (c = 1, CH2C12) Analysis according to C22Hi7N3? 2S: TLC: S.A8; 0.50. iH NMR d (ppm): 3.1-3.25 (, 1H); 3.25-3.5 (m, 1H), 3.9-4.1 (m, H), 4.6-4.75 (m, 1H), 5.55-5.7 (d, 1H); 7.0-7.6 (m, 10H); 7.65-7.75 (d, 1H); 7.75-7.9 (d, 1H). IR: 3250, 1690, 1630, 1540, 1440, 1380, 1270, 1160, 710, 520 cm "1.

Example 8.: (3R) -4-chlorosuinoline-3-carboxylic acid (4-oxo-l-phenyl-3 f 4 f 6.7-tetrahydrof 1.41-diazepin [6.7.1-hi] indol-3-yl) amide [(I); A = 3- (4-chloroquinolyl)] Compound prepared according to method C, described in Example IB, from intermediate l.b and 4-chloroquinoline-3-carboxylic acid. Yield = 27% - orange solid - P.F .: 1922C Analysis according to C27H? GClN4? 2: TLC: S.B .; 0.48. H NMR d (ppm): 3.1 (m, 1H); 3.5 (m, 1H), 3.9 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 8H); 7.6 (t, 1H); 7.7 (t, 1H); 8.1 (d, 1H); 8.25 (d, 1H); 8.35 (d, 1H), 9.15 (s, 1H). IR: 3200, 1650, 1600, 1500, 1440, 1340, 1240, 840, 760, 700 cm "1.

EXAMPLE 8B: (3-Oxo-1-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7] -hy1indol-3-yl) (3R) -4-chloro-6-fluorosuinoline- 3-carboxylic [(I); A = 3- (4-chloro-6-fluoroquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4-chloro-6-fluoroquinoline-3-carboxylic acid. Yield = 29% - orange solid - P. F .: 1912C - [a] D = +932 (c = 1, CH2C12) Analysis according to C27H? GClFN4? 2: TLC: S.B; 0.60. iH NMR d ppm): 3.1 (m, 1H); 3.4 (m, 1H), 3.9 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 9H); 7.9 (d, 1H); 8.1 (d, 1H); 8.2 (d, 1H); 9.1 (s, 1H). IR: 3250, 1660, 1600, 1580, 1490, 1440, 1340, 1295, 830, 700 cm "1.

Example 8.C: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7], 1-hi] indol-3-yl) (3R) -4,6-dichloroquinolin-3- (3R) acid amide carboxylic [(I); A = 3- (4,6-dichloroquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4,6-dichloro-3-carboxylic acid. Yield = 31% - yellow solid -P. F .: 2002C - [a] D = +892 (c = 1, CH2C12) Analysis according to C27H? GCl2FN4? 2: TLC: S.B; 0.55. iH NMR d (ppm): 3.2 (m, 1H); 3.4 (m, 1H), 4.0 (q, 1H), 4.7 (t, 1H), 5.7 (d, 1H); 7.3 (m, 8H); 7.7 (d, 1H); 8.1 (d, 1H); 8.2 (d, 1H); 9.1 (s, 1H). IR: 3500, 1660, 1600, 1580, 1480, 1440, 1330, 1240, 820, 700 cm "1.

EXAMPLE 8D: (3R) -4.8- (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) -amide). dichloroquinoline-3-carboxylic acid [(I); A = 3- (4,8-dichloroquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4,8-dichloro-3-carboxylic acid. Yield = 33% - yellow solid -P. F .: 2252C - [a] D = +812 (c = 1, CH2Cl2) Analysis according to C 7H? GCl N4? 2: TLC: S.B; 0.90. H NMR d (ppm): 3.1 (m, 1H); 3.4 (m, 1H), 3.95 (q, 1H), 4.2 (t, 1H), 5.7 (d, 1H); 7.4 (m, 9H); 7.95 (d, 1H); 8.3 (d, 1H); 8.4 (d, 1H); 9.3 (s, 1H). IR: 3200, 1660, 1600, 1510, 1465, 1440, 1390, 1340, 750, 700 cm "1.

Example 8.E: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) (3R) -4-chloro-6-amide bromoquinoline-3-carboxylic acid [(I); A = 3- (4-chloro-6-bromoquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4-chloro-6-bromoquinoline-3-carboxylic acid. Yield = 33% - yellow solid - P. F .: 1912C - [a] D = +862 (c = 1, CH2C12) Analysis according to C27H? BrClN4? 2 • 0.5H O: TLC: S.B; 0.70. iH NMR d / ppm): 3.15 (m, 1H); 3.45 (, 1H), 4.0 (q, 1H), 4.7 (t, 1H), 5.7 (d, 1H); 7.3 (m, 8H); 7.9 (d, 1H); 8 (d, 1H); 8.4 (d, 1H); 8.55 (s, 1H); 9.2 (s, 1H). IR: 3250, 1660, 1600, 1580, 1500, 1470, 1330, 1220, 820, 700 cm "1.

EXAMPLE 8.F: (3-Oxo-l-phenyl-3,4,6,7-tetrahydro r 1.4) -diazepin [6,7,1-hylindol-3-yl] -amide of (3R) -4-chloro-6-methylquinoline- 3-carboxylic [(I); A = 3- (4-chloro-6-methylquinolyl)] Compound prepared according to method C, in the presence of TOTU and diisopropylethylamine, from intermediate lb and 4-chloro-6-methylquinoline-3-acid carboxylic Yield = 29% - yellow solid - P. F .: 1962C - [a] D = +892 (c = 1, CH2C12) Analysis according to C28H21C1N402.0.33 H20: TLC: S.B; 0.55. H NMR d (ppm): 2.6 (s, 1H); 3.2 (m, 1H); 3.4 (m, 1H), 4.0 (q, 1H), 4.7 (t, 1H), 5.7 (d, 1H); 7.4 (m, 9H); 8.05 (d, 1H); 8.1 (s, 1H); 8.4 (d, 1H); 9.1 (s, 1H). IR: 3250, 1650, 1600, 1580, 1490, 1440, 1340, 1240, 820, 700 cm "1.

Example 8.G: (3R) -4-chloro-8 (4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4-diazepin [6,7,1-hi] indol-3-yl) -amide) -methylsuinoline-3-carboxylic [(I); A = 3- (4-chloro-8-methylquinolyl)] Compound prepared according to method C, described in Example IB, from intermediate l.b and 4-chloro-8-methylquinoline-3-carboxylic acid. Yield = 30% - yellow solid - P.F .: 2402C (decomposition) - [a] ß = +822 (c = 1, CH2C12) Analysis according to C gH2? ClN4? 2 •: TLC: S.B; 0.76. H NMR d (ppm): 3.1 (m, 1H); 3.4 (m, 1H), 3.9 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 10H); 8.15 (d, 1H); 8.3 (d, 1H); 9. 1 (s, 1H). IR: 3200, 1660, 1600, 1520, 1440, 1350, 1240, 830, 760, 700 c "1.

Example 8.H: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7, l-hi] indol-3-yl) (3R) -4-chloro-6-amide methoxyquinoline-3-carboxylic [(I); A = 3- (4-chloro-6-methoxyquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4-chloro-6-methoxyquinoline-3-carboxylic acid. Yield = 35% - beige solid -P. F .: 2252C - [a] D = +942 (c = 1, CH2C12) Analysis according to C2gH? ClN4? 3: TLC: S.B; 0.55. iH NMR d (ppm): 3.1 (m, 1H); 3.4 (m, 1H), 4.0 (m, 4H), 4.7 (t, 1H), 5.7 (d, 1H); 7.3 (m, 10H); 8.1 (d, 1H); 8.3 (d, 1H); 9.5 (s, 1H). IR: 3250, 1640, 1580, 1530, 1490, 1440, 1400, 1230, 820, 700 cm "1.

Example 8.1: (4-oxo-l-phenyl-3 r 4.6.7-tetrahydro r 1.4] (3R) -4-chloro-8- (3R) -4-chloro-8-diazepin [6.7.1-hi] indol-3-yl) amide methoxyquinoline-3-carboxylic [(I); A = 3- (4-chloro-8-methoxyquinolyl)] Compound prepared according to method C, described in Example l.B, from intermediate l.b and 4-chloro-8-methoxyquinoline-3-carboxylic acid. Yield = 30% - yellow solid - P. F .: 2652C - [a] D = +912 (c = 1, CH2C12) Analysis according to C gH2? ClN4? 3: TLC: S.B; 0.20 ! H NMR d (ppitl): 3.05 (m, 1H); 3.3 (m, 1H), 3.95 (q, 1H), 4.05 (s, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 10H); 7.8 (d, 1H); 8. 2 (d, 1H); 9.1 (s, 1H) IR: 3200, 1655, 1600, 1520, 1360, 1270, 1180, 800, 700 cm "1.

Example 8.J: (4-Oxo-l-phenyl-3.4.6.7-tetrahydro r 1.4) -diazepin [6,7,1-hi] indol-3-yl) amide of (3R) -4-chloro- 5.7- dimethylsuinoline-3-carboxylic [(I); A = 3- (4-chloro-5,7-dimethylquinolyl)] Compound prepared according to method C, described in Example lB, from intermediate lb and 4-chloro-5,7-dimethylquinoline- 3-carboxylic acid.

Yield = 26% - yellow solid - P. F .: 2662C - [a] D = +1182 (c = 1, CH2C12) Analysis according to C29H23ClN4? 2: TLC: S.B; 0.55. iH NMR d (ppm): 2.4 (s, 3 H), 2.9 (s, 3 H), 3.05 (m, 1 H); 3.3 (m, 1H), 3.9 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 9H); 7. 7 (s, 1H); 8 (d, 1H); 8.4 (s, 1H) IR: 3250, 1680, 1660, 1600, 1580, 1520, 1440, 1220, 700 cm "1.

EXAMPLE 8K: (3-Oxo-1-phenyl-3,4,6,7-tetrahydrof 1.4) -diazepin [6,7,1-hi] indol-3-yl) (3R) -4-chloro-5-f8-amide acid -dimethylquinoline-3-carboxylic acid [(I); A = 3- (4-chloro-5,8-dimethylquinolyl)] Compound prepared according to method C, described in Example lB, from intermediate lb and 4-chloro-5,8-dimethylquinoline- 3-carboxylic acid.

Yield = 30% - beige solid -P. F.: 2402C (decomposition) - [a] ß = +762 (c = 1, CH2C12) Analysis according to C2gH23ClN4? 2: TLC: S.B; 0.80. ^ NMR dipppm): 3.05 (m, 1H); 3.3 (m, 1H), 3.8 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 1H); 8.1 (d, 1H); 8.9 (s, 1H) IR: 3250, 1660, 1600, 1520, 1440, 1390, 1220, 830, 730, 700 cm "1.

Example 8.L: (4-Oxo-l-phenyl-3,4,6,7-tetrahydro [1.4] -diazepin [6,7,1-hi] indol-3-yl) (3R) -4-chloro- 6.8- dimethylquinoline-3-carboxylic acid [(I); A = 3- (4-chloro-6,8-dimethylquinolyl)] Compound prepared according to method C, described in Example lB, from intermediate lb and 4-chloro-6,8-dimethylquinoline- 3-carboxylic acid.

Performance = 25% - white solid -P. F .: 2802C - [a] D = +872 (c = 1, CH2C12) Analysis according to C gH23ClN4? -0.33 H20: TLC: S.B; 0.85. H NMR d (ppm): 2.6 (s, 3 H), 2.8 (s, 3 H), 3.1 (m, 1 H); 3.4 (m, 1H), 3.9 (q, 1H), 4.65 (t, 1H), 5.7 (d, 1H); 7.3 (m, 9H); 7.95 (S, 1H); 8.4 (d, 1H); 9.1 (s, 1H) IR: 3250, 1660, 1600, 1520, 1490, 1440, 1360, 1220, 840, 700 cm "1.

Example 8.M: (4-oxo-l-phenyl-3,4,6,7-tetrahydro r 1.4] -diazepin [6.7.1-hi] indol-3-yl) (3R) -4-chloro-7.8- dimethylquinoline-3-carboxylic acid [(I); A = 3- (4-chloro-7,8-dimethylquinolyl)] Compound prepared according to method C, described in Example lB, from intermediate lb and 4-chloro-7,8-dimethylquinoline- 3-carboxylic acid. Yield = 35% - yellow solid -P. F .: 2032C - [a] D = +882 (c = 1, CH2C12) Analysis according to C29H23CIN4O2: TLC: S.B; 0.90. iH NMR d (ppm): 3.1 (m, 1H); 3.3 (m, 1H), 3.9 (q, 1H), 4.6 (t, 1H), 5.6 (d, 1H); 7.3 (m, 9H); 8 (d, 1H); 8.3 (d, 1H), 9.1 (s, 1H). IR: 3250, 1660, 1600, 1515, 1440, 1395, 1360, 1230, 780, 700 cm "1.

Example 9.A: (3R) -2-methoxy-N- (9-methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6,7, 1-hi] indole-3- il) benzamide [(I); A = 2-methoxyphenyl, R = CH3] Compound prepared according to method A, from intermediate 2.b and 2-methoxybenzoyl chloride. Yield = 80% - pale yellow solid - P.F .: 123-1252C (decomposition) - [a] ß = +1342 (C = 1, CH2C12) Analysis according to C26H23CIN3O3: TLC: S.A9; 0.66.

* H NMR d (ppm): 2.35 (s, 3H), 3.1 (m, 1H); 3.35 (m, 1H), 4 (m, 1H), 4.1 (s, 3H), 4.65 (m, 1H), 5.7 (d, 1H); 7-7.5 (m, 10H); 8.25 (d, 1H); 9.8 (interchange 1H). IR: 3350, 1680, 1650, 1600, 1510, 1490, 1290, 1240, 1160, 1020, 750, 700 cm-1.

Example 9.B: f 3R) N- f 9 -methi 1-4-oxo-l-pheny1 -3.4.6.7-tetrahldrop. 4] diazepin? 6.7.1-hi] indole -3-i .1) isoni cn inami a [(I); A = 4-pyridyl, R = CH 3] Compound prepared according to method A, from intermediate 2.b and isonicotinoyl chloride. Yield = 88% - white solid - P.F .: 238-240sC - [a] D = + 54s (c = 1. CH C12) Analysis according to C24H2oN4 ° 2: TLC: S.A10; 0.57. lH NMR d (ppm): 2.35 (s, 3H), 3.05 (m, 1H); 3.25 (m, 1H), 3.9 (m, 1H), 4.6 (m, 1H), 5 (d, 1H); 7 (m, 1H); 7.2-7.5 (m 6H); 7. 7 (d, 2H); 8.1 (d, exchange 1H); 8.7 (d, 2H). IR: 3700, 1680, 1650, 1520, 1350, 1280, 1230, 1170, 690, 650 cm-1.

Example 9.C: c 3R -4, 7-d, imethylPirazolo [5, 1-c] [1, 2, 4] t Is it, a-3-acid? carboxylic acid 9-methyl 1-4-oxo-l-pheni 1-3.4.6.7-tetrahydrop.4] diaz? pine [6.7.1-hi. ] indo] -3-yl lamida [(I); A = 3- (4,7-dimethylpyrazolo [5, lc] - [1, 2,4] -triazinyl), R = CH3] Compound prepared according to method C, from intermediate 2.b and acid 4,7-dimethylpyrazolo [5, 1-c] - [1, 2, 4] -triazine-3-carboxylic acid. Yield = 72% - yellow solid -P. F .: 1302C - [a] D = +202 (c = 1, CH2C12) Analysis according to C2gH23N7? 2: TLC: S.A4; 0.37. H NMR d (ppm): 2.3 (s, 3 H), 2.5 (s, 3 H), 3.2 (S, 3 H); 5.6 (d, 1H); 9.8 (d, 1H). IR: 3100, 2950, 1665 cm "1.

Biological Section Phosphodiesterase - inhibitory activity The ability of the compounds of the formula (I) of the invention to inhibit cyclic nucleotide phosphodiesterases by measuring their IC 50 (concentration required to inhibit enzymatic activity by 50%) was evaluated. In the case of PDE IV, this value was compared with the IC50 of rolipram, a specific inhibitor of PDE IV, by the ratio of the IC50 of rolipram to the IC50 of the product to be tested, with respect to the same enzyme preparation.

The different classes of phosphodiesterases were obtained in partially purified form from a DEAE-cellulose column of the trachea of guinea pigs and aortas of dogs, according to a method adapted from WJ Thompson et al., 1979, in Advances in Cyclic Nucleotide Research , Vol. 10: 69-92, Ed. G. Brooker et al. , Raven Press, New York, and of P. J. Silver et al. , 1988, Eur. J. Pharmacol. 150: 85-94. Subsequently, the measurement of the enzymatic activity of the different classes of the PDEs and, in particular, of the PDEs IV was carried out, according to a method that was similarly adopted from that of W. J. Thompson, ibidem. For the determination of the IC 50, the enzymatic activity was measured in the presence of the inhibitor, in the range of concentrations of 0.1 to 100 μM. The following table illustrates the inhibitory activity of PDE IV compared to that of rolipram, for an enzyme preparation obtained from guinea pig trachea.

Table l; Inhibitory effect of PDE IV, compared to rolipram An examination of the results of the above table shows that the products of the invention, tested in the study, generally inhibit the PDE IV enzyme from the guinea pig trachea more efficiently than the rolipram, and in a number of cases is from two to three times more active than the rolipram. Likewise, the studies carried out in the PDEs of different classes, purified from the tracheae of guinea pigs or dog aortas, showed that the IC 50 values obtained with the products of the invention, in relation to the PDEs of the class III and of class I and V, are much larger than the measures for PEDs of class IV.

These results are strong evidence of a potent and selective inhibitory activity of the products of the invention, in relation to the PDE IV.

Anti-inflammatory and antiallergic activity in vivo The effects of the products of the invention on guinea pigs were studied in a model of eosinophilic infiltration induced by antigenic stimulation or by exposure to a PAF aerosol, according to the methodology described by Lagente V et al. al , (1994) Br. J. Pharmacol. 112, 83P. The administration of the products of the examples (1-30 mg / kg, p.o.) significantly reduces the number of eosinophils in the bronchoalveolar lavage fluid. The administration of the products of the invention also reduces the inflammatory responses induced by the intratracheal instillation of IL-5 in the guinea pig.

Inhibition of cytokine secretion The activity of the products of the invention in the secretion of cytokines by human mononuclear leukocytes was measured, in vitro, according to the method described by Konno S. et al. , (1994) Eur. J. Pharamacol. 264: 265-268 and Endo H et al. , (1993) Int. Arch. Allergy Immunol. , 101: 425-430 for the interleukins. and by Semmler J et al. , (1993) Int. J. Immunopharmac. 15: 409-413 and Vergese M.. et al. , (1995) J. Pharmacol. Exp. Ther. 272_1313-1320 for TNFa, was carried out by an immunoenzyme method. The IC 50 concentration was calculated, which inhibits cytokine production by 50%, as stimulated by concanavalin A, phytohemagglutinin or lipopolysaccharides. Under these conditions, the products (I) of the invention that were tested, showed a marked inhibitory activity, with the IC 50 values, which are generally less than or equal to 10 ~ 5 mol. I "1.

Toxicoloqia Subacute oral toxicity was studied in Example 2. V in the rat. When administered for two weeks, as a 1% aqueous suspension in methylcellulose, at a dose of 100 mg / kg / day, the product showed no activity that could be linked with a toxic effect. In particular, the absence of emetic effects was confirmed in the dog. The products of Examples 4 and 9.B, at an intravenous dose of 3 mg / kg, showed no emetic effects. These results demonstrate the anti-inflammatory and / or immunosuppressive activity of the products of the invention. Therefore, the products of the invention will be particularly useful for the treatment or prevention: of allergic pathologies and especially asthma and atopic dermatitis; of inflammatory pathologies, especially of the bronchial region, but also rheumatoid arthritis and inflammatory bowel disorders (hemorrhagic rectocolitis and Crohn's disease); which include cases where there is an autoimmune component.

Pharmaceutical Section The Products of the invention were administered in the form of compositions that are appropriate to the nature and severity of the disorder to be treated. The daily dose for humans is commonly between 2 mg and 1 g of the product, which can be taken in one or more individual doses. The compositions are prepared in forms that are compatible with the intended route of administration, for example, tablets, coated tablets, capsules, mouthwashes, aerosols, powders for inhalation, suppositories, gels or suspensions. These compositions are prepared by methods that are familiar to the person skilled in the art and comprise from 0.5 to 60% by weight of the active principle (composed of formula I) and from 40 to 99.5% by weight of a pharmaceutical vehicle, which is appropriate and compatible with the active principle and with the physical form of the composition intended. By way of example, the composition and preparation of the tablets containing a compound of the invention is shown. Active substance of the formula (I) 1 to 75 mg Lactose 124 to 74 mg Microcrystalline cellulose 36 to 60 mg Polyvinyl pyrrolidone 6 mg Carboxymethyl-sodium starch 8 mg Magnesium stearate 1 mg The active substance, lactose, microcrystalline cellulose and carboxymethyl starch is mixed. It is milled and granulated with the aid of an aqueous or alcoholic polyvinylpyrrolidone solution of appropriate concentration. Be the granules and adjust to their size distribution. It is homogeneously mixed in magnesium stearate. The tabletting process is carried out, to give 200 mg per tablet.

Claims (18)

1. CLAIMS 1. Use of a diazepin-indole, to prepare a medication that makes possible the treatment of disorders, for which therapy by an inhibitor of foasphodiesterase IV is appropriate.
2. 2. Use, according to claim 1, of the diazepin-indoles of the formula: wherein: R is hydrogen, lower alkyl or lower alkoxy; and A is aryl, nitrogen-containing heteroaryl or sulfur-containing heteroaryl, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino , t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; of its racemic forms, of its isomers, whose configuration is determined by the carbon in the 3-position of the diazepinindole-4-one ring system, and of its pharmacologically acceptable salts.
3. 3. Use of a diazepin-indole, of the formula: wherein: R is hydrogen, lower alkyl or lower alkoxy; and - A is aryl, heteroaryl containing nitrogen or heteroaryl containing sulfur, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; of its racemic forms and its isomers whose configuration is determined by the carbon in the 3-position of the ring system of diazepinindole-4-one, and also of its pharmacologically acceptable salts, with the proviso that, when R is hydrogen: i) A not represented by the 2-indolyl radical; ii) for the racemic forms, A does not represent a phenyl radical substituted by: a halogen, a halogen and an amino group, a haloalkyl group or from one to three alkoxy groups.
4. 4. Use according to one of claims 1 to 3, characterized in that the medicament makes possible the prevention or treatment of inflammatory pathologies, such as asthma or rheumatoid arthritis.
5. 5. Diazepin-indoles, of the formula: wherein: R is hydrogen, lower alkyl or lower alkoxy; and A is aryl, nitrogen-containing heteroaryl or sulfur-containing heteroaryl, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino , t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; of its racemic forms and its isomers whose configuration is determined by the carbon in the 3-position of the ring system of diazepinindole-4-one, and also of its pharmacologically acceptable salts, with the proviso that, when R is hydrogen: i) A not represented by the 2-indolyl radical; ii) for the racemic forms, A does not represent a phenyl radical substituted by: a halogen, a halogen and an amino group, a haloalkyl group or from one to three alkoxy groups.
6. 6. Diazepin-indoles, according to claim 5, characterized in that the absolute configuration of the carbon in the alpha position relative to the carbonyl function of the diazepine ring is (R).
7. 7. Diazepin-indoles, according to claims 5 or 6, characterized in that A is phenyl, naphthyl, pyridyl, thienyl, pyrazinyl, pyrimidyl, indolyl, quinolyl, isoquinolyl, pyrazolo-triazinyl, imidazo-pyridyl or imidazo-pyrimidyl, each of which is optionally substituted by one to three groups, which are independently selected from halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonyl-amino and acetamido.
8. 8. Diazepin-indoles according to one of claims 5 to 7, characterized in that R is lower alkyl or lower alkoxy.
9. 9. Diazepin-indoles, according to one of claims 5 to 8, characterized in that R is methyl or methoxy.
10. 10. Diazepin-indoles, according to claim 5, which are: a) (3R) -N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin- [6,7] , l-hi] indol-3-yl) isonicotinamide, b) (3R) -N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin- [6, 7, 1-hi] indol-3-yl) isoquinoline-3-carboxamide, c) (3R) -N- (4-oxo-l-nyl-3, 4,6,7-tetrahydro [1,4] -diazepin - [6,7, l-hi] indol-3-yl) -4,7-dimethylpyrazolo [5, 1-c] - [1,2,4] -triazine-3-carboxamide, d) (3R) - N- (9-methoxy-4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [6,7, l-hi] indol-3-yl) -isoquinoline-3 -carboxamide, e) (3R) -N-4-chloro-N- (9-methoxy-4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [6,7] , 1-hi] indol-3-yl) -benzamide, f) (3R) -N- (9-methoxy-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] - diazepin [6,7, 1-hi] indol-3-yl) -quinolin-3-carboxamide, g) (3R) -N- (9-methoxy-4-oxo-l-phenyl-3, 4,6, 7-tetrahydro [1,4] -diazepin [6,7, l-hi] indol-3-yl) -quinolin-6-carboxamide, h) (3R) -3-chloro-4-methoxy-N- (4) -oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indole -3-yl) -benzamide, i) (3R) -4-amino-3,5-dichloro-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] - diazepin [6, 7, 1-hi] indol-3-yl) -benzamide, j) (3R) -5,6-dichloro-N- (4-oxo-l-phenyl-3, 4,6,7- tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -nicotinamide, k) (3R) -2-methoxy-N- (9-methyl-4-oxo-l-phenyl) -3, 4,6,7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -benzamide, 1) (3R) -N- (9-methyl-4-) oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] diazepin [6, 7, 1-hi] indol-3-yl) -isonicotinamide, m) (3R) -N- (9 -methyl-4-oxo-l-phenyl-3,4,6,7-tetrahydro [1,4] -diazepin [6,7,1-hi] indol-3-yl) -4,7-dimethylpyrazolo [5] , 1-c] [1,2,4] -triazine-3-carboxamide.
11. 11. Diazepin-indoles, of the formula: wherein R is methyl or methoxy.
12. 12. Pharmaceutical composition, characterized in that it comprises, as an active ingredient, at least one diazepin-indole, as defined in claim 5 in combination, if appropriate, with a pharmaceutically acceptable carrier.
13. 13. Pharmaceutical composition according to claim 12, characterized in that the absolute configuration of the carbon in the alpha position, relative to the carbonyl function of the diazepine ring of diazepin-indole is (R).
14. 14. Pharmaceutical composition, according to claim 12 or 13, characterized in that in the diazepin-indole, the group R is methyl or methoxy.
15. 15. Pharmaceutical composition, according to one of claims 12 or 14, characterized in that the diazepin-indole is: a) (3R) -N- (4-oxo-l-phenyl-3, 4,6, 7-tetrahydro [1 , 4] -diazepin- [6,7, 1-hi] indol-3-yl) isonicotinamide, b) (3R) -N- (4-oxo-l-phenyl-3, 4,6, 7-tetrahydro [ 1,4] -diazepin- [6,7, 1-hi] indol-3-yl) isoquinoline-3-carboxamide, c) (3R) -N- (4-oxo-l-phenyl-3, 4,6 , 7-tetrahydro [1,4] -diazepin- [6,7, 1-hi] indol-3-yl) -4, 7-dimethylpyrazolo [5, 1-c] - [1,2,4] -triazin -3-carboxamide, d) (3R) -N- (9-methoxy-4-oxo-l-phenyl-3, 4,6, 7-tetrahydro [1,4] -diazepin [6, 7, 1-hi] ] indol-3-yl) -isoquinoline-3-carboxamide, e) (3R) -N-4-chloro-N- (9-methoxy-4-oxo-l-phenyl-3, 4,6,7-tetrahydro) [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -benzamide, f) (3R) -N- (9-methoxy-4-oxo-l-phenyl-3,4, 6,7-tetrahydro [1,4] diazepin [6,7, l-hi] indol-3-yl) -quinolin-3-carboxamide, g) (3R) -N- (9-methoxy-4-oxo) -l-phenyl-3, 4,6, 7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -quinolin-6-carboxamide, h) (3R) -3 -cloro-4-meto xi-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [6, 7, 1-hi] indol-3-yl) -benzamide, i) ( 3R) -4-amino-3, 5-dichloro-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indole -3-yl) -benzamide, j) (3R) -5,6-d-chloro-N- (4-oxo-l-phenyl-3, 4,6,7-tetrahydro [1,4] -diazepin [ 6,7, 1-hi] indol-3-yl) - nicotinamide, k) (3R) -2-methoxy-N- (9-methyl-4-oxo-l-phenyl-3, 4,6,7- tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -benzamide, 1) (3R) -N- (9-methyl-4-oxo-l-phenyl-3, 4 , 6,7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -isonicotinamide, m) (3R) -N- (9-methyl-4-oxo-l- phenyl-3, 4,6, 7-tetrahydro [1,4] -diazepin [6,7, 1-hi] indol-3-yl) -4,7-dimethylpyrazolo [5, 1-c] - [1, 2,4] triazine-3-ca oxamide.
16. 16. Process for the preparation of diazepin-indoles, according to claim 5, characterized in that it consists of reacting an racemic or optically active amine of the formula: wherein R is hydrogen, lower alkyl or lower alkoxy, with a carboxylic acid derivative, of the formula: wherein: - A is aryl, nitrogen-containing heteroaryl or sulfur-containing heteroaryl, each of which is optionally substituted by one to three groups which are independently selected from: halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl , acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonylamino and acetamido; with the proviso that, when R is hydrogen: i) A does not represent the 2-indolyl radical; ii) for the racemic forms, A does not represent a phenyl radical substituted by: a halogen, a halogen and an amino group, a haloalkyl group or from one to three alkoxy groups. Z is a halogen, a hydroxyl group, an azido group, an imidazol-1-yl group, a -0-C-Zlf group where - ^ can be, in addition to A, an hindered alkyl radical, containing from 3 to 6 carbon atoms or can be a 0-Z group, Z2 is an aromatic group comprising one or two rings, which are substituted by one or more nitro or halogen radicals, to obtain a diazino-indole of the formula: in which R and A have the above definitions.
17. 17. Process according to claim 16, characterized in that R is methyl or methoxy.
18. 18. Process for the preparation of diazepin-indoles, according to claim 11, characterized in that it consists of: a) in order to prepare a diazepin-indole, according to claim 11, in racemic form: 1) reduce a Indole derivative, of the formula: wherein R is methyl or methoxy, a} .a corresponding indololine of the formula: 2) condensing this indoline with the benzonitrile, in the presence of a Lewis acid, in order to supply, after hydrolysis, the benzophenone of the formula: 3) cyclize this benzophenone with ethyl glycinate, in order to supply a diazepin-indole, of the formula: 4) aminating the alpha position of the carbonyl function of diazepin-indole, obtained in step 3) above, in order to obtain a diazepin-indole of the formula (II): wherein R is methyl or methoxy; for the purpose of preparing an optically active diazepin-indole according to claim 11: - condensing a racemic compound (II) with an alpha-amino acid derivative, which belongs to the series D or the L series, and in which the amine function is protected by a highly labile group, preferably the tert-butyloxycarbonyl group; the compound obtained is deprotected by hydrolysis, preferably in an acidic medium, in the presence of trifluoroacetic acid, and the product obtained is separated into its diasteroisomers by chromatography; the two isomers are obtained from the amine condensed with the amino acid; the Edman degradation then supplies the two enantiomers of the amine (II); or alternatively - dissolving a racemic compound in a solution of an optically active acid, for example an enantiomer of mandelic acid, dibenzoyltartaric, di-p-tolyltartaric, camphor-sulphonic, p-nitrobenzoylglutamic or tartaric, to form two diastereomeric salts, followed, using the solubility difference, by a selective crystallization of one of them in a suitable solvent.