PL143597B1 - Process for preparing novel phenyl substituted pyrido (1,4) benzodiazepines - Google Patents

Description

The subject of the invention is a method for preparing new phenyl-substituted pyrido[1,4] benzodiazepines. British Patent No. 907,646 discloses a method for preparing certain dibenzodiazepines substituted with phenyl radicals on carbon and alkyl or aminoalkyl radicals on a bridging nitrogen atom between the phenyl rings. Freig M.E. et al., J. Med.Chem. 14, No. 2, pp. 153/1971/ describe dibenzodiazepines similar to those disclosed in the above patent, useful as anti-anaphylactic agents. Japanese patent no. 73/43520/CA 80, 13350in/ discloses 6-phenyl-2,3,4,4a-tetrahydrogen-11H-pyrido[2,3-b][1,4]-benzodiazepines, having anticonvulsant activity, which are, for example, prepared from 2-aminobenzophenones and ornithine. The method of the invention prepares new pyrido[l,4] benzodiazepines of the formula 1, in which R denotes the -alkyl1-NHCH3 group, alkyl1 denotes a straight or branched hydrocarbon chain with 1- 8 carbon atoms, Ar is a 2-, 3- and 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl group substituted with 1-3 radicals such as halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro and may be the same or different, Z represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group or a nitro group, Y represents a hydrogen atom or 1-2 radicals representing a lower alkyl group, a lower alkoxy group or a hydroxyl group and which may be the same or different, n means 0 or 1, where when n means zero, then the dashed line means a double bond, and their acid addition salts. Compounds of formula 1 are used as agents for the treatment of depression. In the further definition of the symbols occurring in the description and claims, the individual terms have the following meanings. The term "alkyl" means a straight or branched hydrocarbon chain containing 1-8 carbon atoms, for example methylene, ethylene, propylene, ethylidene, 1,2-propylene, isopropyl -denium or 1,3-butylene and the like.143 597 2 The term "lower alkyl" means straight- and branched-chain hydrocarbon radicals containing up to eight carbon atoms, for example groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like. The term "halogen" includes chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine. Pharmaceutically acceptable acid addition salts are those formed by pyridobenzodiazepines , prepared according to the invention, with any acid, both strong and weak, which is physiologically tolerated by warm-blooded animals. Examples of strong acids are hydrochloric acid, sulfuric acid and phosphoric acid. Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, cyclohexamine acid and the like. 6-aryl-11H-pyrido [2,3-b] [1,4] benzodiazepines and their 5,6-dihydrogen derivatives covered by formula 1 have formula Iw. 6-aryl-11H-pyrido [3,4-b] [1,4] benzodiazepines and their 5,6-dihydrogen derivatives covered by formula 1 have the formula lx. 10-aryl-5H-pyrido [4,3-b] [1,4] benzodiazepines and their 10,11-dihydrogen derivatives covered by formula 1 have the formula ly. 10-aryl-5H-pyrido [3,2-b] [1,4] benzodiazepines and their 10,11-dihydrogen derivatives covered by formula 1 have the formula Iz. In all these formulas Iw to Iz, the symbols R, Ar, Z and Y have the meanings given above. The method according to the invention consists in carrying out cyclization reactions by heating a mixture of halogen-aminopyridine of formula 4 and (aminophenyl/arylmethanone of formula 3, or the product of their reaction having the formula 2, in which Y, Z and Ar have the meanings given above, and removing the water formed, then the compound of the formula Ia, in which Ar, Y and Z have the meanings given above, is optionally reduced to sodium borocyanohydrin to the compound formula la-1, and then the product of formula la or la-1 is reacted with the reagent of the formula halogen-alkyl Q, in which Q is a phthalimide group and when in the obtained compound of formula Ib n is O, sodium borocyanohydrin is optionally reduced to compound of formula lb-1, then the compound of formula Ib or lb-1 is reacted with an alcoholic solution of hydrazine hydrate and acid, and the obtained compound of formula lc is reacted with ethyl chloroformate and triethylamine and the obtained compound of formula lc-2 is reduced with lithium aluminum hydride to obtain a compound of the formula le-1, which is optionally reacted with an acid. The compound of the formula 4 with the compound of the formula 3 or their reaction product of the formula 2 is preferably heated at a temperature of 170-200°C. The water formed in the reaction is preferably removed at the boiling point under a reflux condenser in an aprotic solvent. The reaction sequence covered by the equation presenting the preparation of compounds according to the invention is illustrated by the diagram shown in the figure, in which the substituents have the meanings given above, and Q denotes the 1-group phthalimide.Methanones of formula 2, in which the substituents have the meanings given above, according to the scheme, are prepared by heating a mixture of haloaminopyridine and aminobenzophenone for a time shorter than that required for cyclization to pyridobenzodiazepine, indicated by the mass spectral analysis method with chemical ionization. Examples of their preparation are given in patent application No. P 234,426. Unsubstituted pyridobenzodiazepines of the formulas la and la-1 / R = H /, in which the substituents have the meanings given above according to the scheme, are prepared by heating further purified or unpurified compounds of formula 2 in an aprotic solvent to cyclize to compounds of formula Ia, removing water from the reaction mixture by conventional methods, for example, by refluxing using a Dean-Stark water removal head. There is no need to interrupt the heating at an intermediate stage, it is usually sufficient to continue heating the original reaction mixture, i.e. the mixture of compounds of formula 3 and 4, for a longer period of time, during which cyclization to the compound of formula Ia will take place. In the cyclization step, no matter which alternative is used, the temperature-time dependence will vary to some extent, depending on the reagents used, it is only necessary to heat for a sufficient time to produce the desired product, as indicated by the spectral method. mass analysis with chemical ionization. Unsubstituted pyridobenzodiazepines are purified by partitioning between a suitable solvent and the aqueous phase, washing and drying the solvent layer, evaporating to dryness and chromatography in a suitable solvent system such as acetone-benzene. The corresponding dihydrodiazepines are obtained by reduction with sodium borocyanohydrin. The substituted pyridobenzodiazepines of the formulas Ib and Ib-1 (R = lower alkyl), according to the scheme, in which the substituents have the meanings given above, are obtained starting from the compounds of the formula Ia or Ia -1/, in which R is a hydrogen atom, which is alkylamated or into which radicals which lead to alkylamation are introduced, by reacting first with sodium hydride and then with an appropriate reagent of the formula halogen-alkyl1Q, in which the symbols alkyl1 and Q have the meaning given above. The compounds suspended in a suitable solvent, such as dimethylformamide, are added to a stirred suspension of sodium hydride in the same solvent. The halogen-alkyl1Q reagent (alkylamating agent or alkylamating agent) is added at about room temperature and the reaction mixture is stirred for the time required to complete the reaction, as determined, for example, by thin layer chromatography. The unreacted sodium hydride is decomposed by introducing it into water and the product is extracted with a suitable solvent such as methylene chloride, then the solvent layer is extracted with an aqueous acid solution and the product is isolated from this aqueous layer by neutralization and repeated extraction with methylene chloride, followed by evaporation and loss, preferably as an addition salt such as the fumarate, hydrochloride, oxalate, maleate, etc. Generally, after obtaining and purifying the acid addition salt, the free base can be regenerated by partitioning the salt between an aqueous base and a suitable solvent such as methylene chloride and evaporating layers of methylene chloride. The corresponding dihydrodiazepines are obtained by reduction with sodium borocyanohydrin. * Primary amines of the formula lc, i.e. those in which both R1 and R2 are hydrogen, are obtained from -alkyl1-6-(1-phthalimido) derivatives, as shown in Scheme 1, by reacting with hydrazine hydrate, using the method given in Org.Syn.Coll.Vol.III.pp.151-153. Refluxing for 2 to 3 hours is usually sufficient, after which an aqueous acid solution is added and the mixture is filtered. Primary -alkyl-1-amines are isolated from a suitable solvent such as isopropyl alcohol. Preferred salts for the isolation step are the hydrochlorides and hydrochloride hydrates. The corresponding dihydrodiazepines are obtained by reduction of sodium boracyanohydride.-Alkyl1-6)-monoalkylamines are obtained by reaction of a primary amine with ethyl chloroformate as shown in Example XLV and subsequent reduction with lithium aluminum hydride as illustrated in scheme (3). All formulas la, la-1, Ib, lb-1, lb-2, lb-3, lb-4, lc, lc-1, lc-2, le, le-1, are covered by formula 1. To test the operation The compounds obtained according to the invention as antidepressant drugs were used using the method described below, as reported by Englehardt E.L. et al., J. Med.Chem. 11(2), pp. 325 (1968), as proven in the past to demonstrate the usefulness of the compounds in the treatment of depression in humans. The test compound was administered at a dose of 20 mg/kg to five adult female mice (strain ICR—DUB) intraperitoneally 30 minutes before administration of a ptotic dose (32 mg/kg intraperitoneally) of tetrabenzine in the form of a methanesulfonate salt. Thirty minutes later, each animal was assessed for the presence or absence of complete eyelid closure (ptosis). For each test compound, the EDso/50% effective dose for blocking tetrabenazine-induced depression in mice can be determined using the method of Litchfield et al., J. Pharmacol. Exp. Therap. 96, 99-113 /1949/. As a result of animal studies, it was found that compounds of formula 1, in which R is the -alkyl1-NHCH3 group, have a low incidence of side effects in the form of antihistamine, anticholinergic and karyotoxic effects. Effective amounts of the above pharmacologically active compounds of formula 1 can be administered to humans using the usual modes of administration and in the usual forms, that is, orally in solutions, emulsions, suspensions, pills, tablets and capsules, in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions.4 143 597 Examples of solid carriers for oral administration are lactose, magnesium stearate , china clay, sucrose, talc, stearic acid, gelatin, agar, pectin, or acacia. Examples of liquid carriers for oral administration are vegetable oils and water. For intramuscular administration, the carrier or vehicle may be a sterile, parenterally acceptable liquid, e.g. water, or an oil acceptable for parenteral administration, e.g. peanut oil, contained in ampoules. Although in cases of less serious treatment or in cases of administering drugs at a relatively low body weight, very small amounts of the active materials according to the invention are sufficient, the unit doses are usually from 5 mg or above and preferably 10, 25, 50, or 100 mg or even more, preferably administered three or four times daily, of course depending on the severity of the situation, the compound used, and the specific desired result. The optimal unit dose appears to be 25 to 200 mg, with wider unit dose ranges usually ranging from approximately 10 to 500 mg. Typically, daily doses required should be from about 0.3 to about 20 mg/kg/day, preferably 0.3 to 10 mg/kg for the more active compounds. The active ingredients produced by the method of the invention can be combined with other compatible, pharmacologically active agents. It is only necessary that this active ingredient constitutes an effective amount, i.e. such that an effective dose is achieved according to the dosage form used. Of course, a number of unit dose forms can be administered at the same time. The exact amounts of individual doses as well as daily doses are, of course, determined in accordance with accepted medical principles under the supervision of a physician. The course of the reaction for obtaining compounds of formulas 2, laja-l, Ib, lb-1, lc-2, le-i is presented in the diagram. The following examples illustrate the invention in more detail. Example I. Preparation of 6-phenyl-11H-pyrido[2,3-b] [1,4] benzodiazepines. Mixture of 19.7 g/0.1 mol/2-aminobenzophenone and 15.0 g (0.12 mol) of 3-amino-2-chloro-pyridine is heated in a nitrogen atmosphere at 190°C for 1.75 hours. The mixture is cooled to room temperature and partitioned between 3N aqueous sodium hydroxide solution and methylene chloride. The combined methylene chloride extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, is dissolved in benzene and chromatographed on a column with florisil packed in benzene, eluted with benzene and 1-2% acetone-benzene mixtures. After evaporation, the solid substance is crystallized from benzene, obtaining 7.3 g of a product with a melting point of 106-108°C. Elemental analysis for CisHi3N3. calculated values C 79.68 H 4.83 N 15.49 found values C 79.70 H 4.81 N 15.42 Example. Preparation of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. Mixture of 15.0 g/0.0647 mol/2-amino-5-chlorobenzophenone and 9.1 g/0.068 mol/3- amino-2-chloropyridine is heated at 200°C (in an oil bath) for 0.75 hours. in a nitrogen atmosphere. The mixture is cooled and methylene chloride is added. The mixture is stirred for 1 hour. and leaves it alone overnight. The brown precipitate weighing 8.7 g is separated by filtration. The filtrate is evaporated under reduced pressure. The residue was combined with this brown precipitate and partitioned between aqueous sodium hydroxide and methylene chloride to isolate the crude product as in Example 17, except that the solvent used for crystallization was ethanol. Recrystallization from ethanol and drying overnight at 82°C under a pressure of 13.33 Pa gave 3.0 g of product with a melting point of 156.5-158.5°C. Elemental analysis for C18H12CIN3 calculated values C 70.71 H 3, 96 N 13.74 found values C 70.24 H 4.01 N 13.76 Example III. Preparation of 9-chloro-6-phenyl-11H-pyrido[2,3-b] [1,4]benzodiazepine.Suspension 6.6 g /0.02 mol/[2-[/3-amino-2-pyridyl (amino]-4-chlorophenyl]-phenylmethanone) from Example II in 200 ml of toluene is refluxed overnight under a nitrogen atmosphere. The reaction mixture is filtered off while hot and the filtrate is heated to reflux again. The precipitate formed during cooling to room temperature is separated by filtration, recrystallized from benzene and dried for 4 hours. at a temperature of 97-98°C under a pressure of 13.33 Pa, then overnight at room temperature under a pressure of 13.33 Pa, obtaining 3.7 g of product with a melting point of 250.5 to 252°C. The results of the elemental analysis were overestimated for carbon and the product was dried again at 139°C (xylenes) in a vacuum drying set for 8 hours. Although the results of the carbon content determination remained overestimated, the results of the proton nuclear magnetic resonance spectrum and mass spectrum were consistent with the proposed structure of the compound. Elemental analysis for C16H12CIN3 calculated values C 70.71 H 3.96 N 13.74 found values C 71.46 H 4.06 N 13.46 Example IV. Preparation of 8-chloro-6-(2-chlorophenyl)-5,6-dihydro-11H-pyrido[2,3- b ] [1,4] benzodiazepine. Further elution of the florisil-filled columns using 10-15% acetone in benzene and 5-25% methanol in benzene gave two fractions of the title product of this example, 6.4 g and 5.7 g, the latter being heavily contaminated. The fraction constituting 6.4 g of the product after recrystallization from the benzene-isooctane mixture gave 3.7 g of a solid substance with a melting point of 203-6°C (with decomposition), which was identified as 8-chloro-6V2-chlorophenyl/-5,6-dihydrogen-11H-pyrido [2,3-b] [1,4] benzodiazepine.Example V. Preparation of 6-(4-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine. Mixture of 23.3 g (0.10 mol) 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mol) 3-amino-2-chloropyridine (96%) is heated for 1.5 hours. at 180°C under nitrogen. The mixture is cooled to room temperature and methylene chloride is added. After stirring for 30 minutes, the solids are separated by filtration and triturated in hot 95% ethanol. The remaining insoluble material is separated by filtration and recrystallized from the benzene-isooctane mixture to give 2.7 g of product, melting point 203-204, 5°C. Before starting the analysis, the product is dried overnight at a temperature of 97-98°C under a pressure of 13.33 Pa. Elemental analysis for C18H12CIN3 calculated values C 70.71 H 3.96 N 13.74 found values C 70.78 H 3 .92 N 13.95 Example VI. Preparation of 6-(4-methylphenyl)-11H-pyrido[2,3-b] [1,4]benzodiazepine. Solution 3.6 g (0.012 mol) [2-[/3-amino-2-pyridyl/amino]phenyl ]/4-methylphenyl/methanone in 100 ml of anhydrous toluene is treated with a catalytically effective amount of p-toluenesulfonic acid and refluxed overnight, removing the water using a Dean-Stark distillation device. The reaction mixture is filtered while hot. The product precipitates when the filtrate is cooled to room temperature and is separated by filtration. After evaporating the solvent, 2.5 g of a solid product with a melting point of 203.5-205°C (decomposition) are obtained. Elemental analysis for C19H15N3 calculated values C 79.98 H 5.30 N 14.73 found values C 79.95 H 5.27 N 14.76 Example VII. Preparation of 6-(4-methoxyphenyl)-11H-pyrido [2,3-b] [1,4] benzodiazepine. Mixture of 20.0 g (0.088 mol) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mol) of 3-amino-2-chloropyridine (96%) is heated at 180°C with constant stirring in a nitrogen atmosphere for 2.0 hours. The reaction mixture is cooled to approximately 70°C and 100 ml of methylene chloride are slowly added. After the mixture has cooled to room temperature, an additional 50 ml of methylene chloride is added and the mixture is stirred overnight. The suspended solid is separated by filtration, air-dried, dissolved in methanol and made basic with 3N sodium hydroxide solution. The suspension is diluted with 500 ml of water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. Mass spectral analysis (El and CI) showed that the residue was a mixture of [2-[/3-amino-2-pyridyl/amino]phenyl] (4-methoxyphenyl) methanone and the title compound. The residue mixture is dissolved in 250 ml of toluene with a catalytically active amount of p-toluenesulfonic acid and the solution is refluxed overnight under nitrogen, removing the water using a Dean-Stark distillation device. The reaction mixture is filtered while hot. The product precipitates when the filtrate is cooled to room temperature and is separated by filtration. After recrystallization from benzene, 1.8 g of product with a melting point of 198.5-200.5°C (with decomposition) are obtained. Elemental analysis for C19H15N3O calculated values C 75.73 H 5.02 N 13.94 found values C 75.65 H 4.98 N 14.03 Example VIII. Preparation of 8-chloro-N,N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzenediazepine-11-propanamine oxalate [1:1]. To a stirred suspension of 1.05 g / 0.044 mol/ of sodium hydride / in mineral oil / in 50 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, 6.1 g / 0.02 mol / 8-chloro-6-phenyl-1 is added in portions lH-pyrido [2,3-b] [1,4] benzodiazepines. The reaction mixture is stirred at room temperature for 1.5 hours, during which time hydrogen evolution ceases. 3.5 g (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride are added to the mixture in portions. After stirring overnight at room temperature, the reaction mixture is poured into 1600 ml of water and extracted with three 250 ml portions of methylene. The combined methylene chloride extracts were washed with two 260 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in benzene and the acetone-benzene mixture is chromatographed on a column containing 300 g of florisil packed in benzene. 1.6 g of the starting material was recovered after elution with benzene, and 3.6 g of the free base product was obtained from elution with the acetone-benzene mixture after evaporation of the solvent. Part of the crude free base, 2.5 g, is dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.0064 mol) of oxalic acid dihydrate. The oxalate that precipitated upon cooling was separated by filtration and, after recrystallization from ethanol, 2.2 g of product was obtained, melting point 206-208°C. Before analysis, the product was dried for 5 hours. at a temperature of 97-98°C under a pressure of 2.66 Pa, and then overnight at room temperature under a pressure of 2.66 Pa. Elemental analysis for C25H25CIN4O4 calculated values C 62.43 H 5.24 Nil .65 found values C 62, 52 H 5.23 N 11.76 Example IX. Preparation of N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine fumarate [1:1]. To a stirred suspension of 1.68 g (0.070 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, a suspension of 8.0 g (0.029 mol) of 6-phenyl-11H-pyrido [2 .3-b] [1.4] benzodiazepines in 20 ml of anhydrous dimethylformamide. The mixture is stirred for an additional 30 minutes after the addition is complete, heated to 65°C for 15 minutes and cooled back to room temperature. 5.6 g (0.035 mol) of 3-dimethylaminopropylchloride hydrochloride are added to the mixture. After stirring overnight at room temperature, thin layer chromatography showed that the reaction was almost complete. The reaction mixture is poured into 1500 ml of water and extracted with 250 ml of methylene chloride. The methylene chloride extract is washed with three portions of 250 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and extracted with 100 ml and 150 ml of 3N hydrochloric acid solution. The unreacted starting material in the form of 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine is precipitated from the aqueous acidified solution and separated by careful decanting of the supernatant liquid. The aqueous solution is made basic with 3N sodium hydroxide and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to give 7.7 g of a residue which is the free base of the title compound. A solution of 6.6 g of this residue in hot isopropyl alcohol is reacted with 2.15 g of fumaric acid and the mixture is heated until completely dissolved. After standing for 48 hours salt is lost and separated by filtration. After recrystallization from the isopropyl alcohol-isopropyl ether mixture, 5.9 g of product are obtained at a temperature of 171-173°C. Before analysis, the product was dried for 4 hours. at 90°C under a pressure of 13.33 Pa, and then overnight at room temperature under a pressure of 13.33 Pa. Elemental analysis for C27H28N4O4 calculated values C 68.63 H 5.97 Nil.86 found values C 68.37 H 6.05 N 11.73 Example To a stirred suspension of 1.48 g (0.062 mol) of sodium hydride (in mineral oil) in 35 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, 7.0 g (0.026 mol) of 6-phenyl-11H-pyrido [2,3 -b] [1,4] benzodiazepines. After cooling the reaction mixture to room temperature, 4.46 g (0.031 mol) of 3-dimethylaminoethyl chloride hydrochloride are added portionwise and stirring is continued overnight. The reaction mixture is poured into 1500 ml of water and the resulting mixture is extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with three 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure to obtain 8.6 g of oil, which is the free base of the title compound. Part of this oil, 6.9 g, was reacted with an equivalent amount of fumaric acid in isopropyl alcohol. Addition of isopropyl ether gave an oily precipitate. This mixture is evaporated under reduced pressure and the residue crystallizes on standing. These crystals are triturated with acetone and recrystallized from the acetone-isopropyl ether mixture, obtaining 4.3 g of fumarate, melting point 175-177.5°C. Elemental analysis for C26H26N4O4 calculated values C 68.11 H 5.72 N 12 .22 found values C 67.88 H 5.72 N 12.17 Example XI. Preparation of ll-[3-(4-morpholinyl)-propyl]-6-phenyl-11H- pyrido [2,3-b] [1,4] benzodiazepine fumarate [1:1]. To a stirred suspension of 1.10 g / 0.046 mole of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, 5.0 g /0.0184 mole of -6-phenyl-11H-pyrido is added in portions [2,3-b] [1,4] benzodiazepines. The reaction mixture is stirred at room temperature for 15 minutes, warmed to 65-70°C for 10 minutes and allowed to cool to room temperature. 4.1 g (0.02 mol) of 4-(3-chloropropyl)morpholmy hydrochloride are added portionwise to this mixture. The reaction mixture is stirred at room temperature for 16 hours. and then poured into 800 ml of water. This mixture is extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride extracts are extracted with 150 ml and 75 ml of 3N hydrochloric acid solution each, and the combined aqueous extracts are basified with 3N sodium hydroxide solution. The obtained suspension is extracted with two 150 ml portions of methylene chloride and the two extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue, which is the free base of the title compound, is reacted with an equivalent molar amount of fumaric acid in warm isopropyl alcohol and the mixture is treated with isopropyl ether. The fumarate is separated by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g of product, m.p. 154-7°C. Before analysis, the product was dried for 4 hours. at a temperature of 97-98°C under a pressure of 13.33 Pa, and then overnight at room temperature under a pressure of 13.33 Pa.8 143 597 Elemental analysis for C29H30N4O5 calculated values C 67.69 H 5.88 N 10.90 values found C 67.52 H 5.84 N 10.90 Example XII, Preparation of N,N-diethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine oxalate [1 :1 ]. To a stirred suspension of 1.10 g/0.0461 mol/sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, 5.0 g/0.0184 mol/6-phenyl-11H- is added in portions pyrido [2,3-b] [1,4] benzodiazepines. The reaction mixture is stirred at room temperature for 0.5 hour, warmed to 65-70°C and slowly cooled to room temperature. To this mixture, 3.77 g (0.020 mol) of 3-diethylaminopropylchloride hydrochloride are added portionwise and the reaction mixture is stirred at room temperature for 16 hours. The mixture is poured into 750 ml of water and extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extracts are extracted with 150 ml and 75 ml of 3N hydrochloric acid solution. The combined aqueous extracts are made alkaline with 3N sodium hydroxide solution and then extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give 7.5 g of the free base of the title compound. Part 5.6 g is reacted with an equivalent molar amount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalate is separated by filtration, obtaining 5.5 g of the product with a melting point of 196-199°C. Before analysis, the product was dried for 1 hour. at a temperature of 97-98°C at a pressure of 13.33 Pa. Elemental analysis for C27H3oN404 calculated values C 68.34 H 6.37 N 11.81 found values C 68.31 H 6.43 N 11.86 Example XIII. Preparation of 9-chloro-N,N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate [1:1]. To a stirred suspension of 0.98 g (0.041 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, under a nitrogen atmosphere, 5.0 g (0.016 mol) of 9-chloro-6-phenyl-11H-pyrido is added in portions [2,3-b] [1,4] benzodiazepines within 45 minutes. The reaction mixture is stirred at room temperature for 1 hour, warmed to 70° C. and then slowly cooled to room temperature. To this mixture, 2.84-g (0.018 mol) of 3-dimethylaminopropylchloride hydrochloride is added portionwise over 30 minutes and the reaction mixture is stirred at room temperature for 17 hours. The mixture is poured into 750 ml of water and extracted with 150 ml and two 100 ml portions of methylene chloride. The combined extracts in methylene chloride are washed with two portions of 100 ml of water, and then extracted with portions of 100 ml and 75 ml of a 3N hydrochloric acid solution. The acidic extracts are combined and filtered to remove the precipitate formed, and the filtrate is made alkaline with a 3N sodium oxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methylene chloride and filtered through 50-60 g of florisil in a fritted glass funnel. This bed is successively washed with mixtures of 1%, 2%, 3%, and 5% methanol-methylene chloride, and the filtrates are combined and evaporated under reduced pressure to obtain the free base of the title compound. The free base is reacted with an equivalent molar amount of fumaric acid in hot isopropanol to obtain 3.3 g of fumarate with a melting point of 199-202°C. Elemental analysis for C27H27N4O4CI calculated values C 63.96 H5.37 N 11.05 found values C 63.63 H 5.36 NI 1.00 Example XIV. Preparation of 6-phenyl-11-[3-(1-piperidinyl/propyl-11H-pyrido [2,3-b] [1,4] benzodiazepine fumarate [1:1]. To a stirred suspension of 1.10 g / 0.0461 mole of sodium hydride in mineral oil / in 25 ml of anhydrous dimethylformamide, under nitrogen atmosphere, 5.0 g / 0.018 mole / 143 597 9 of 6-phenyl-11H-pyrido is added in portions [2,3-b] [1,4] benzodiazepines. The reaction mixture is stirred for 30 minutes, warmed to 70°C and cooled to room temperature. 4.14 g (0.0203 mol) of N-(3-chloro-propyl)piperidine hydrochloride are added portionwise to this mixture and the reaction mixture is stirred at room temperature for 16 hours. The mixture is poured into 750 ml of water, extracted with 150 ml of methylene chloride, stirring for 15 minutes. The aqueous layer is extracted with two additional 100 ml portions of methylene chloride. The combined extracts in methylene chloride are extracted with 150 ml and 75 ml of 3N hydrochloric acid solution and the combined acid extracts are made alkaline with 3N sodium hydroxide solution and then extracted with three 100 ml portions of methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in a minimum amount of methylene chloride and filtered through a bed of 100 g of florisil in a fritted glass funnel. This bed is successively washed with mixtures of 1%, 2%, 3%, and 5% methanol-methylene chloride. All the filtrates were combined and evaporated under reduced pressure. The residue was reacted with 1.3 g of fumaric acid in hot isopropanol and isopropyl ether was added. An amorphous precipitate was then formed. The entire mixture is evaporated to dryness and the residue is dissolved in 200 ml of ethanol. The solution is heated to reflux temperature, filtered and isopropyl ether is added to the filtrate. The crystals formed after standing overnight are filtered to obtain 4.1 g of fumarate, melting point 153-6°C. Before analysis, the product was dried for 4 hours. at a temperature of 97-98°C and a pressure of 13.33 Pa. Elemental analysis for C30H32N4O4 calculated values C 70.29 H 6.29 N 10.93 found values C 70.38 H 6.32 N 10.92 Example XV. Preparation of 6-(4-chlorophenyl)-N,N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate [1:1]. To a stirred suspension of 1.57 g (0.065 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide, 8.0 g (0.026 mol) of 6-/- chlorophenylAHH-pyrido/ [2,3-b] are added under nitrogen. ] [1,4] benzodiazepines. The reaction mixture is stirred at room temperature for 1 hour, warmed to 80°C for 15 minutes and cooled to room temperature. 4.55 g (0.029 mol) of 3-dimethylaminopropylchloride hydrochloride are added portionwise to this mixture and the mixture is stirred overnight at room temperature. The mixture is poured into 750 ml of water and stirred for 30 minutes with 150 ml of methylene chloride. Aqueous layer is then extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure to give the free base of the title compound. The free base is reacted with an equivalent molar amount of fumaric acid in hot isopropanol. Upon cooling, 3.6 g of fumarate with a melting point of 200.5-202.5°C are precipitated. This product is dried in air before analysis. Elemental analysis for C27H27CIN4O4 calculated values C 63.96 H 5.37 N 11.05 found values C 64.18 H 5.33 N 11.07 Example XVI. Preparation of 8-chloro-N,N-dimethyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-ethanamine oxalate [1:1]. To a stirred suspension of 1.05 g (0.044 mol) of sodium hydride (in mineral oil) in 5 ml of anhydrous dimethylformamide, 6.1 g (0.02 mol) of 8-chloro-6-phenyl-1 1H-pyrido [ 2 .3-b] [1.4] benzodiazepines. The reaction mixture is stirred at room temperature for 1.5 hours. and during this time the evolution of hydrogen stops. The reaction mixture is cooled to 5°C and 3.2 g (0.022 mol) of 2-dimethyl-aminoethyl chloride hydrochloride are added portionwise, and then it is stirred at room temperature for about 60 hours. The reaction mixture is poured into 1600 ml of water and the mixture is extracted three times with 500 ml of methylene chloride each time. The combined extracts were washed with two 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. Thin layer chromatography (20% methanol/benzene mixture on silica gel) showed the presence of the free base of the title compound and the starting material. The residue is dissolved in benzene and chromatographed on a column packed with 200 g of florisil packed in benzene. The starting material, 1,3g8-chloro-6-phenyl-HH-pyrido[2,3-b]+[1,4]benzodiazepines, was eluted with benzene, while the free base of the title compound was eluted with mixtures of acetone in benzene. The free base is reacted with a molar equivalent amount of oxalic acid dihydrate in isopropyl alcohol heated to reflux and after recrystallization from isopropyl alcohol, 1.6 g of product is obtained, melting point 228-232°C. Before analysis, the product was dried for 6 hours. at a temperature of 82°C under a pressure of 13.33 Pa, and then overnight at room temperature. Elemental analysis for C24H23CIN4O4 calculated values C 61.74 H 4.96 N 12.00 found values C 61.62 H 4.95 N 11 .98 Example XVII. Preparation of 8-chloro-1-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. For a stirred suspension of 0.25 g (0.01 mol) of sodium hydride (in mineral oil). in 15 ml of anhydrous dimethylformamide, 3.05 g (0.01 mol) of 8-chloro-6-phenyl-1 1H-pyrido [2,3-b] [1,4] benzodiazepine are added in portions. The mixture is heated at 60°C for 1 hour. Then for 0.5 hour. a solution of 1.42 g/0.01 mol/methyl iodide in 10 ml of anhydrous dimethylformamide is added dropwise and the reaction mixture is stirred overnight at room temperature, then poured into 400 ml of water and stirred for 2 hours. The precipitate was recrystallized twice from isopropyl alcohol to obtain 2.0 g of product with a melting point of 153-6°C. Before analysis, the product was dried for 1 hour. at a temperature of 82°C and a pressure of 13.33 Pa. Elemental analysis for C19H14CIN3 calculated values C 71.36 H 4.41 N 13.14 found values C 71.64 H 4.43 N 13.32 Example XVIII. Preparation of N,N-dimethyl-6-(4-methylphenyl)-11H-pyrid- to [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate [1:1]. To a stirred suspension of 0.51 g (0.022 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide, 4.2 g (0.0147 mol) of 6-(4-methylphenylAl11H-) are added portionwise over a period of 45 minutes, under a nitrogen atmosphere. pyrido [2,3-b] [1,4] benzodiazepines. This mixture is stirred for 1 hour. at room temperature, heated for 1 hour. to a temperature of 75-80°C, cooled to room temperature and a solution of 0.0184 mol of 3-dimethylaminopropyl chloride in 10 ml of anhydrous dimethylformamide is added dropwise. This mixture is stirred overnight at room temperature and poured into 1000 ml of water. The suspension is extracted with three 150 ml portions of methylene chloride and the combined methylene chloride extracts are extracted with two 150 ml portions of 3N hydrochloric acid solution. A precipitate forms in the acidic solution, which is removed by filtration and discarded. The filtrate is made alkaline with 3N sodium hydroxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give an oil of the free base of the title compound. The remaining oil is dissolved in hot isopropyl alcohol and reacted with an equivalent molar amount of fumaric acid. Fumaran crystallises while cooling the solution to room temperature and after two recrystallization from the mixture of isopropyl alcohol and isopropyl ether, 1.7 g of product is obtained, melting point 187-189°C (with decomposition). Elemental analysis for C28H30N4O4 calculated values C 69.12 H 6.22 N 11.52 found values C 68.86 H 6.32 N 11.36 Example XIX. Preparation of 6-(4-methoxyphenyl)-N,N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate [1:1].143 597 11 For mixed suspension 0 45 g (0.0187 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide are added within 30 minutes. 4.5 g (0.015 mol) of 6-(4-methoxyphenyl)-11H-pyrido[2,3-b ] [1,4] benzodiazepines. The mixture is stirred for 30 minutes at room temperature, then heated at 80-90°C for 1 hour, cooled to room temperature and dropwise, and a solution of 0.019 mol of 3-dimethylaminopropyl chloride in 5 ml of anhydrous dimethylformamide is added. . The reaction mixture is stirred overnight at room temperature and poured into 800 ml of water. The suspension is extracted with two 150 ml portions of methylene chloride. The combined extracts are washed with 500 ml of water and then extracted with two 100 ml portions of a 3N hydrochloric acid solution. The precipitate from the combined acid extracts is filtered off and discarded. The filtrate is made alkaline with 3N sodium hydroxide solution and extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and evaporated under reduced pressure. The remaining, partially crystallized oil is triturated in methylene chloride and filtered to obtain a residue of 0.32 g. The filtrate is evaporated under reduced pressure and the remaining oil is triturated in hot benzene and filtered to obtain a residue of 0.8 g. The benzene filtrate is evaporated under reduced pressure and the remaining oil is reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. On cooling, oil is released from the solution. The clarified liquid above the oil is decanted and the oil is seeded with crystallization nuclei. After partial crystallization, the mixture is filtered to obtain 2.5 g of a solid, melting point 157-60°C. When an attempt is made to recrystallize from isopropyl alcohol-isopropyl ether mixture, an oil-solid mixture is obtained again. The mixture is heated again with the addition of isopropyl alcohol, dissolved, filtered and cooled. Fumarate is lost, which after filtration gives 2.0 g of product with a melting point of 159-161°C. Elemental analysis for C28H30N4O5 calculated values C 66.92 H 6.02 N 11.15 found values C 66.90 H 6 .08 N 11.08 Example XX. Preparation of 6-(3-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine. Mixture 14 g (0.0433 mol) [2-[/3-amino-2-pyridinyl]-amino] Phenyl]/3-chlorophenylmethanone and 0.3 g of p-toluenesulfonic acid in 500 ml of toluene are heated to reflux overnight, using a Dean-Stark still to collect the water. At the end of the heating time, part of the toluene (about 250 ml) is distilled off under the reflux condenser and the hot solution is filtered. Petroleum ether (30-60°C) is then added until the clouding point is reached. The solution is cooled overnight and filtered to give 10 g (76%) of golden crystals after air drying. Some of them were recrystallized from the isopropyl alcohol-isopropyl ether mixture, obtaining a product with a melting point of 160-160.5°C. Elemental analysis for C18H12N3Cl calculated values C 70.71 H 3.96 N 13.74 found values C 70.47 H 3.98 N 13.62 Example XXI. Preparation of 6-(3-chlorophenyl)-N,N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine fumarate [1:1]. To a stirred suspension of 3.4 g (0.07 mol) of sodium hydride in mineral oil (in 250 ml of anhydrous dimethylformamide) 8.5 g (0.028 mol) of 6-(3-chlorophenyl)-11H-pyrido are added portionwise under nitrogen. [2,3-b] [1,4] benzodiazepines. This mixture is stirred for 30 minutes at room temperature. The temperature increases to 80°C for 3 hours. and then set aside to cool to room temperature. A solution of 4.9 g (0.031 mol) of 3-dimethylaminopropylchloride hydrochloride in 30 ml of dimethylformamide is added dropwise to the reaction mixture over a period of 20 minutes. The reaction mixture is stirred overnight at room temperature under nitrogen. Thin layer chromatography showed that the starting material was present. 12 143 597 An additional 1.4 g (0.03 mol) of sodium hydride was added and after 15 minutes 4.7 g (0.03 mol) of 3-dimethylaminopropyl chloride hydrochloride, and stirring was continued for 4 1/2 hours Then 20 ml of water were added dropwise and the reaction mixture was filtered and concentrated on a rotary evaporator. The residue was partitioned between ethyl ether and dilute sodium hydroxide. The ether layer was washed three times with water and extracted with a dilute aqueous solution of hydrochloric acid. The aqueous layer is basified with sodium hydroxide pellets and extracted with methylene chloride. The methylene chloride layer was dried and concentrated to leave 7.5 g of product. The free base is reacted with fumaric acid and after recrystallization from the ethyl acetate-ethanol mixture, fumarate is obtained with a melting point of 167.5-168.5°C. Elemental analysis for C23H23N4CI calculated values C 63.96 H 5.47 N 11.05 found values C 63.95 H 5.39 N 11.00 Example XXII. Preparation of 6-(fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine. Mixture 11.5 g (0.037 mol) [2-[/3-amino-2-pyridinyl]-amino]phenyl] (4-fluorophenyl) methanone and 0.6 g of p-toluenesulfonic acid in toluene are heated for 24 hours, using a Dean-Stark still to collect the water. At the end of the heating time, part of the toluene (300 ml) is distilled off under the reflux condenser and the hot solution is filtered. Petroleum ether is then added (30-60°C) until the clouding point is reached. The solution is cooled overnight (0°C) and filtered, yielding 10.7 g of crystals. Part of this material is recrystallized from isopropyl alcohol and dried overnight under reduced pressure at 65°C, obtaining a product with a melting point of 203-205°C. Elemental analysis for C18H12N3F calculated values C 74.73 H 4.18 N 14 .52 found values C 74.61 H 4.17 N 14.54 Example XXIII. Preparation of 6-(4-fluorophenyl)-N,N-dimethyl-HH-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine hydrochloride hemihydrate. For a stirred suspension 3.6 g (0.075 mol) of hydride sodium (in mineral oil) in 250 ml of anhydrous dimethylformamide, 8.7 g (0.03 mol) of 6-(4-fluorophenyl)-1 1H-pyrido [2,3-b] [1,4] are added in portions under a nitrogen atmosphere ] benzodiazepines. The mixture is stirred for 30 minutes at room temperature. The temperature rises to 80°C for 3.5 hours. and then the mixture is allowed to cool to 45°C. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropylchloride hydrochloride in 30 ml of dimethylformamide is added dropwise to the reaction mixture. After stirring overnight at room temperature, thin layer chromatography showed the presence of starting material. An additional 3.6 g (0.075 mol) of sodium hydride was added and after 45 minutes of stirring the reaction mixture was heated to 50-60°C for 1/2 hour. The mixture turned green with the evolution of gas. The mixture was stirred at room temperature for 3 hours. Then a solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide is added dropwise. /Approximately halfway through the addition, a green color appears and the addition is stopped for about an hour/. The reaction mixture is stirred overnight at room temperature. While cooling, 30 ml of water is added to the mixture. After gas evolution stops, the mixture is filtered and concentrated in a rotary evaporator. The residue is partitioned between ethyl ether and water and the ether layer is extracted with a dilute aqueous solution of hydrochloric acid. After 1-1/2 hours, the aqueous layer is filtered to remove sediment. The filtrate is made alkaline with sodium hydroxide pellets and extracted with methylene chloride. The extract is dried and concentrated. The residue is divided into two equal parts and purified by dry column chromatography on two 500 x 37.6 mm columns filled with silica gel, which has been deactivated with a developing solvent / 10% methanol, 1% concentrated ammonium hydroxide, 89 % methylene chloride/. The middle part of the column is cut out and extracted with a developing solvent. The combined extracts are concentrated under reduced pressure and the residue is dissolved in an ethyl acetate-ethanol mixture and acidified with concentrated hydrochloric acid. The hydrochloric acid salt 143597 13 is recrystallized from an ethanol-ethyl acetate mixture. The solid substance obtained by filtration is dried at 99°C for 48 hours. obtaining the title compound as hydrochloride hemihydrate with a melting point of 120-123°C. Elemental analysis for C46H50N8F2Cl2O calculated values C 65.78 H6.00 N 13.34 found values C 65.58 H 5.77 N 13.47 Example XXIV. Preparation of ll-[S-Zl^hydrogen-l^iox^^-isoindcrfflo-l/iM-opyl]-6-phenyl-HH-pyrido-[2,3-b] [1,4] benzodiazepines. For 5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido [2,3-b] [1, 4] benzodiazepines. The reaction mixture is heated to a temperature of 80 ± 2°C for 1 hour. and cools to room temperature. Then, a solution of 5.55 g (0.020 mol) of N-(3-bromopropyl phthalimide) in 10 ml of anhydrous dimethylformamide is added dropwise and after stirring for 16 hours. the reaction mixture is poured into 650 ml of water and stirred for 30 minutes. The yellow precipitate is separated by filtration and recrystallized three times from isopropyl alcohol, obtaining 3.7 g of the product with a melting point of 170-172°C. Elemental analysis for CaoHas^Oa calculated values C 75.97 H4.84 N 12.22 found values C 76.25 H4.87 N 12.34 Example XXV. Preparation of 6-phenyl-11H-pyrido[2,3-'b] [M] benzodiazepine-11-propanamine dihydrochloride hemihydrate. Mixture 16.2g/0.035 moles/6-phenyl-ll-[3-/f^ 1.4 l benzodiazepines and 2.29 g (0.0387 moles) of hydrazine, 85% in 175 ml of 95% ethyl alcohol are heated at reflux temperature for 2.5 hours and left for 72 hours. A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water is then added to this mixture. The mixture is stirred overnight. The solid precipitate is separated by filtration and discarded. The filtrate is evaporated under reduced pressure. The wet residue is suspended in 200 ml of water and the mixture is stirred for 2 hours. and filtered through celite. The filtrate is evaporated under reduced pressure, and the residue is suspended in 100 ml of 100% ethyl alcohol and evaporated under reduced pressure. These operations are repeated. The crude, wet residue (42.1 g) is recrystallized from isopropanol and left to stand for about 15 hours. The precipitate separated by filtration is dried at 82°C for 3 hours. under a pressure of 13.3 Pa over phosphoric anhydride, obtaining a product with a melting point of 210-220°C (with decomposition). Elemental analysis for C42H46CI4N8O calculated values C 61.47 H 5.65 N 13.65 found values C 61.36 H 5.72 N 13.90 Example XXVI. Preparation of N-methyl-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine dihydrochloride. The synthesis begins with the preparation of the imide ester, according to the method described by Crochst.T.A. and Blanton C.D. Jr., Synthesis 1974/l/, pp. 55-56.25 g /0.06 mol/6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine dihydrochloride hemihydrate is converted into into the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and evaporating the methylene chloride layer to dryness, adding dry benzene and concentrating again to drive off the benzene. The obtained free base is dissolved in 300 ml/267 g; 1.8 mol/freshly distilled ethyl orthoformate and heated at reflux for 9 hours. The mixture is concentrated under reduced pressure, ethanol is added and the mixture is concentrated again. 23.4 g (0.061 mol) of the amide prepared in this way are dissolved in 200 ml of ethanol and sodium borohydride is added with constant stirring at a temperature of 15-20°C until, when examined by thin layer chromatography, the reaction is completed. which indicates a lack of starting material. With constant stirring, 50 ml of water are then added and cooling is continued for 15 minutes after the addition of water. The mixture is then poured with 2 liters of water and extracted with ethyl acetate. The ethyl acetate layer is washed with water until the water is neutral and then saturated with sodium chloride. The resulting ethyl acetate layer is dried and concentrated, then ethyl ether is added and the mixture is cooled. The insoluble material is filtered and discarded. The ether layer is concentrated and the product is chromatographed on a column filled with aluminum oxide (neutral, activity-1), eluting with a mixture of ethyl acetate + methanol + traces of triethylamine. The fractions containing mainly the product (thin layer chromatography) were partitioned between ethyl acetate and aqueous sodium hydroxide solution. Ether saturated with hydrogen chloride gas is added to the ethyl acetate layer and the crystalline product is recrystallized from the acetonitrile-water mixture, obtaining a product with a melting point of 139-141°C. Elemental analysis for C22H24N4Cl2 calculated values C 63.62 H 5.82 N 13.49 found values C 63.81 H 6.15 N 13.60 Example XXVII. Preparation of 5,6-dihydro-N,N-dimethyl-6-phenyl-HH-pyrido [2,3-b] [1,4] benzodiazepine-ll-propanamine dihydrochloride hemihydrate. Solution 3.0 g (0.0064 mol ) N,N-dimethyl-6-phenyl-11H-pyrido [2,3-b][1,4]benzodiazepine-11-propanamine in absolute methanol is adjusted to pH 5.6 with a methanol solution of hydrogen chloride . 0.7 g (0.011 mol) of NaBHaCN is added to this solution at one time and the reaction mixture is heated at reflux temperature for 20 minutes. The ethanol is removed under reduced pressure and the residue is partitioned between dilute sodium hydroxide solution and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated to give a residue which was crystallized twice from 2-propanol and isopropyl ether. A yellow solid is obtained in the amount of 1.6 g /57%/, which loses its crystalline structure upon heating starting from 156-160°C, with decomposition at a temperature of 180-195°C. Elemental analysis for C46H58N8OCI4 calculated values C 62.73 H 6.64 N 12.72 found values C 62.40 H 6.90 N 12.61 Examples XXVIIIa-XXVIIIc. Using the method described in Example XXIII, only introducing instead of 6-(4-fluorophenyl/11H-pyrido[2,3-b] [1,4] benzodiazepines the following pyrido[1,4] benzodiazepines: 6-/2-fluorophenyl/- llH-pyrido [ 2,3-b ] [ 1,4 ] benzodiazepine, 6-/2-chlorophenyl/- llH-pyrido [ 2,3-b ] [ 1,4 ] benzodiazepine and 6-/2-bromophenyl/- llH-pyrido [2,3-b] [1,4] benzodiazepine, obtained: a/ 6-/2-fluorophenyl/-N,N-dimethyl-llH-pyrido [2,3-b] [1,4 ] benzodiazepine-11-propanamine, melting point 92-94°C, a mixture of isopropyl alcohol - isopropyl ether was used as a recrystallization solvent; b/ 6-(2-chlorophenyl)-N,N-dimethyl-11H-pyrido [2,3-b] [1,4] benzodiazepine-11-propanamine, melting point 104-105°C; Isopropyl ether was used for recrystallization; and c/ 6-(2-bromophenyl)-N,N-dimethyl-11H-pyrido-[2,3-b] [1,4] benzodiazepine-11-propanamine, melting point 96-98°C; Isopropyl ether was used for recrystallization. Patent claims 1. Method for preparing new phenyl-substituted pyrido[1,4] benzodiazepines of formula 1, in which R is the -alkyl1-NHCH3 group, alkyl1 is a straight or branched hydrocarbon chain with 1-8 carbon atoms, Ar is a 2-, 3- or 4 group -pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted with 1-3 radicals such as halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro and may be the same or different, Z is hydrogen, halogen , a lower alkyl group, a lower alkoxy group, a hydroxyl or nitro group, Y is hydrogen or 1-2 radicals representing a lower alkyl group, a lower alkoxy or hydroxyl group and which may be the same or different, n is 0 or 1, wherein when n is zero, then the dashed line indicates a double bond, and acid addition salts thereof, characterized in that the cyclization reaction is carried out by heating a mixture of haloaminopyridine of the formula 4i/aminophenyl/arylmethanone of the formula 3 or their product reaction of the formula 2, in which Y, Z and Ar have the above-mentioned meanings, and removing the water formed, the compound of the formula Ia is then produced, in which Ar, Y and Z have the above-described meanings, optionally reducing sodium borocyanohydrin to the compound of the formula la-1, then the product of formula la or la-1 is reacted with the reagent of the formula halogen-alkyl1 Q, in which Q is a phthalimide group and when in the obtained compound of formula Ib n is O, sodium borocyanohydrin is optionally reduced to compound of formula lb-1, then the compound of formula Ib or lb-1 is reacted with an alcoholic solution of hydrazine hydrate and acid, and the obtained compound of formula lc is reacted with ethyl chloroformate and triethylamine and the obtained compound of formula lc-2 is reduced lithium aluminum hydride, obtaining a compound of the formula le-1, which is optionally reacted with an acid. 2. The method according to claim 1, characterized in that the compound of formula 4 with the compound of formula 3 or their reaction product of formula 2 is heated at a temperature of 170-200°C. 3. The method according to claim 1, characterized in that the water is removed at reflux temperature in an aprotic solvent. -Ar N I H Y FORMULA 2d O.V C-Ar NH2 FORMULA 3 O NH2 halo heating NU short period V Z FORMULA k C-Ar H2N nA^-y N H FORMULA 2 Ar ^ H FORMULA la-1 M heating long period Hf NaBH3CN Ar N 'additional heating-H2O Y acid Z-^^ N -^^^Y FORMULA la SCHEME !( i) 1 I NaH+halosolvent-alk^C143 597 A,r Mn FORMULA Iz Ar (H)n ' I R FORMULA Ip H FORMULA 2 H FORMULA 2a H FORMULA 2b143 597 formula :ÓR 1a-1 A, l alk^Cj FORMULA 1b-1 when n=0 Y NaBH3CN, acid alk'-Q FORMULA Ib when 0=(1-ttalimido) ) alcoholic solution of Ar (H)n Hydrazine ihydrate, acid alk1-NH2 FORMULA 1c SCHEME -(2) solvent + N ^Hc^ EtOC(0)CL Ar (H)r alk^NH-CfCO-OC^ FORMULA lc-2 H JJAIH Ar ¦iik1- PATTERN te-1 N-CH3 SCHEME'1(3) Pracownia PoUgraficzna UP PRL. Edition: 100 copies. Price: PLN 220 PL PL PL PL

Claims (3)

Patent claims 1. Method for preparing new phenyl-substituted pyrido [1,4] benzodiazepines of formula 1, where R is the group -alkyl1 -NHCH3, alkyl1 is a straight or branched hydrocarbon chain with 1-8 carbon atoms, Ar is the group 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted with 1-3 radicals such as halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro and may be the same or different, Z is hydrogen, halogen, lower alkyl, lower alkoxy-143 597 15 Iowa, hydroxyl or nitro, Y is hydrogen or 1-2 radicals representing lower alkyl, lower alkoxy or hydroxyl and which may be the same or different, n means 0 or 1, wherein when n means zero, then the dashed line means a double bond, and acid addition salts thereof, characterized in that the cyclization reaction is carried out by heating a mixture of haloaminopyridine of the formula 4 and aminophenyl/arylmethanone of the formula 3 or the product of their reaction of formula 2, in which Y, Z and Ar have the meanings given above, and removing the water formed, then the compound of formula Ia, in which Ar, Y and Z have the meanings given above, is optionally reduced to sodium borocyanohydrin to the compound of formula la-1, and then the product of formula la or la-1 is reacted with the reagent of the formula halogen-alkyl1 Q, in which Q is a phthalimide group and when in the obtained compound of formula Ib n is O, borocyanohydrin is optionally reduced sodium to the compound of formula lb-1, then the compound of formula Ib or lb-1 is reacted with an alcoholic solution of hydrazine hydrate and acid, and the obtained compound of formula lc is reacted with ethyl chloroformate and triethylamine and the compound of formula lc-2 is obtained is reduced with lithium aluminum hydride to obtain a compound of the formula le-1, which is optionally reacted with an acid. 2. The method according to claim 1, characterized in that the compound of formula 4 with the compound of formula 3 or their reaction product of formula 2 is heated at a temperature of 170-200°C. 3. The method according to claim 1, characterized in that the water is removed at reflux in an aprotic solvent. (H)f Ar lf"n FORMULA 1 Ar (H)n FORMULA Iw FORMULA lx143 597 O % C-Ar H2N N I H N Y FORMULA 2c O C-Ar N I H Y FORMULA 2d O. V C-Ar NH2 FORMULA 3 O NH2 halo heating NU short period of time ^Y FORMULA la SCHEME !(i) 1 I NaH+halo-alk dissolver^C143 597 A,r Mn FORMULA Iz Ar (H)n ' I R FORMULA Ip H FORMULA 2 H FORMULA 2a H FORMULA 2b143 597 formula :ÓR 1a- 1 A, l alk^Cj FORMULA 1b-1 when n=0 •Y NaBH3CN, acid alk'-Q FORMULA Ib when 0=(1-ttalimido) ) alcohol solution of Ar (H)n Hydrazine ihydrate, acid alk1-NH2 FORMULA 1c SCHEME -(2) solvent + N ^Hc^ EtOC(0)CL Ar (H)r alk^NH-CfCO-OC^ FORMULA lc-2 H JJAIH Ar ¦iik1- FORMULA te-1 N-CH3 SCHEME'1 (3) Printing Studio of the UP PRL. Circulation: 100 copies. Price: PLN 220