HU187393B - Process for producing phenyl-substitited pyrido-bracket-1,4-bracket closed-benzodiazepines and intermediates and pharmaceutical compositions containing thes as active agents - Google Patents

Abstract

Title cpds. (I)[R=H, alkyl, alk'-NR1R2, alk'-N=CH-OC2Hs; R1, R2=H, alkyl, C(O)O-alkyl, NR1R2=heterocyclic residue; Ar=(un) substd. Ph, pyridinyl, thienyl; alk'=hydrocarbon; Z=H, halogen, alkyl, alkoxy, OH, NO2; Y=H, alkyl, alkoxy, OH; n=0-1 and their salts, useful as antidepressants, were prepd.. Thus, a mixt. of 2-aminobenzophenone and 3-amino-2-chloropyridine was heated under N2 at 190≰C to give (I)[Ar=Ph, Z, R=H, n=0, Y=H).

Description

The present invention relates to novel phenyl substituted pyrido [1,4] benzodiazepines of the general formula ( _w ) and their acid addition salts, and to pharmaceutical compositions containing such compounds as active ingredients.

In the formula

R is hydrogen, (C 1 -C 4) -alkyl, or -alk'-NR'R ^{2 in} which R ¹ and R ^{2 are} hydrogen, (C 1 -C 4) -alkyl, and R ¹ and R ² are taken together with the nitrogen atom to which they are attached. forms a phthalimido, 1-piperidyl or 4-morpholino group, and alk ¹ represents a straight or branched alkylene group containing from 1 to 6 carbon atoms, Ar is unsubstituted or substituted with a halogen atom, a C 1-4 alkyl group, phenyl substituted with C1-C4 alkoxy, trifluoromethyl or nitro, or 2-pyridyl, 2-thienyl or 3-thienyl, Z is hydrogen or halogen, n is zero or 1 and when n is zero dashed line means double bond,

The present invention relates to a process for preparing antidepressant pharmaceutical compositions of compounds of formula I _w as well as their acid addition salts containing as active ingredient as well.

Similar compounds are known in the art. Thus, No. 907,646. Wander, A., in U. S. Patent No. 6,198, discloses dibenzodiazepines which are substituted by a phenyl group attached to a carbon atom and an alkyl or aminoalkyl group attached to a nitrogen atom connecting the phenyl rings.

Greig Μ. E. et al. Describe dibenzodiazepines similar to those described above and find them useful in the treatment of anaphylactic shock [J. Chem. 14, 2, 153 (1971)].

Japanese Patent Publication No. 73/43,520 (C.A. 80: 133,501n) discloses 6-phenyl-2,3,4,4a-tetrahydro-11H-pyrido [2,3-b] - [1,4] benzodiazepines. These compounds have anticonvulsant activity. Their preparation is exemplified starting from 2-aminobenzophenones and omitin.

Part I _w The compounds of the invention are used as active agents in the treatment of depression by antidepressant effects of, while others are used as intermediates in the preparation of other compounds of formula I _w,

Before the formation of the diazepine ring closure reaction of the compounds of formula II, _W [2 - [(amino-pyridyl) amino] phenyl] -aryl-methanone derivatives are formed. In the formula, Ar and Z are as defined above. These intermediates (or precursors) and their pharmaceutically acceptable acid addition salts also possess antidepressant activity and are thus useful in the treatment of depression.

The meaning of each term mentioned in the definition of symbols in the formulas is defined below.

The term "alk ¹ " refers to a straight or branched saturated alkylene group containing from ^{1 to} 6 carbon atoms, such as methylene, ethylene, propylene, 1,2-propylene, or 1,3-butylene.

Gas (C 1 -C 4) -alkyl includes, for example, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine, but in particular chlorine, bromine or fluorine.

Pharmaceutically acceptable acid addition salts include the salts of the pyridobenzodiazepines of the present invention with the physiologically tolerated acids of warm-blooded animals. The salt-forming acids may be strong acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or weak acids such as fumaric acid, maleic acid, succinic acid, oxalic acid and the like.

The antidepressant activity of the compounds of the invention was determined according to the method of Englehardt E. L. et al. Med. Chem. II (2), 325 (1968)]. This method, which has long been used to demonstrate the suitability of human therapy for depression, has been used as follows.

Five adult female mice of the ICR-DUB strain were dosed with the test compound at 20 mg / kg intravenously, and after 30 minutes the ptotic dose (32 mg / kg) of tetrabenazine (as methanesulfonate) was also administered intraperitoneally. After another 30 minutes, the animals were observed to have their eyes completely closed (ptosis) or not. The effect of the agent was evaluated accordingly. For each test compound, the ED ₅₀ dose required to inhibit tetrabenazine-induced depression in mice was determined. Evaluation by the method of Litchfield et al. Pharmacol. Exp. Therap. 96, 99-113 (1949)].

In animal experiments, it has been found that compounds of formula I _w wherein R is -alk'-NR'R ² in which R ¹ and R ² are (C 1 -C 4) -alkyl or hydrogen are the antidepressant effect is accompanied by mild antihistamine, anticholinergic and cardiotoxic side effects.

Pyridobenzodiazepines that are preferred for the treatment of depression are summarized in the following table, with reference to the example illustrating the preparation of the compound.

ma _

11- [3- (N, N-dimethylamino) -propyl] -6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

6- (4-fluorophenyl) -11- [3- (N, N-dimethylamino) • propyl] -1H-pyrido [2,3-b] [1,4] benzodiazepine

6-phenyl-1- (3-aminopropyl) -1H-pyrido (2,3-b] [1,4] benzodiazepine

11- [3- (N-methylamino) -propyl] -6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

34b 6- (2-Chloro-phenyl) -11- [3- (N, Ν-dimethylamino) -propyl] -1H-pyrido [2,3-b] [1,4] -benzodiazepine.

187,393

It is an object of the present invention to provide a process

6-aryl-11H-pyrido [1,4] benzodiazepines and their pharmaceutically acceptable acid addition salts, and processes for the preparation of pharmaceutical compositions containing such compounds as active ingredients.

The invention and its advantages will be described in detail herein.

The preparation of these compounds is illustrated in Scheme A. Further possibilities for the preparation of certain types of compounds of formula I _w are shown in Scheme B.

The intermediate methanone compounds are prepared by heating a haloaminopyridine of formula IV and an aminobenzophenone of formula III. Heating is continued for a shorter period of time than is necessary for conversion to pyridobenzodiazepine, namely ring closure, by chemical ionization mass spectroscopy. For example, for the preparation of [2- (3-amino-2-pyridyl) -amino] -phenylmethanones, the reaction is carried out at about 170-200 ° C for about 1-1.5 hours. If desired, the methanones as the main products can be isolated by cooling the reaction mixture and adding a suitable organic solvent, such as methylene chloride. The solvent dissolves the unreacted starting materials and the cyclized product of formula Ia. The reaction product is then worked up by conventional isolation techniques such as partitioning between solvent and aqueous base or aqueous methanol, followed by washing, drying, evaporating the organic solvent and recrystallizing the product from a solvent.

Unsubstituted pyrido-benzodiazepines of formula Ia and Ia-1, i.e. I _w Compound hydrogen substituent R can be prepared as shown in Scheme, the purified or crude II _W compound is further heated in a aprotic solvent such as is also converted to the compound of formula Ia by ring closure. The water formed during the reaction is removed by any known method, for example by boiling the reaction mixture in a Dean-Stark flask. However, it is not necessary to interrupt the heating when the intermediate compound is formed. Generally, it is satisfactory that the original reaction mixture, i.e. the reaction mixture comprising the compounds of formulas III and IV, is heated for a longer period of time until the ring closure is complete. The relationship between temperature and time of ring closure leading to the formation of the compounds of formula Ia will vary to some extent with the reagents used. The heating should continue until the desired product is formed as determined by chemical ionization mass spectroscopy. The resulting unsubstituted pyridobenzodiazepines are purified by partitioning between a solvent such as methylene chloride and an aqueous base, washing and drying the solvent phase, then evaporation and chromatography on a suitable solvent system such as acetone-betzol. This reduction can be converted to ¹ 'with sodium borohydride in two the corresponding cyanohydrin dihidrodiazepinné productivity • -i.

If la or Ia-1 compounds is reacted with an alkyl halide, it is possible to prepare compounds of formula I _w, wherein R is alkyl. Subsequently, the compounds of formula I _w wherein n is 0 may be reduced, if desired, with sodium tri borohydride as described above.

Substituted pyridylbenzodiazepines of the formulas Ib and Ib-1, i.e. compounds having the af substituent R as the substituent R (wherein Q is N-R ¹ R ² ), are prepared as follows in Scheme A *. The compounds of formula Ia (or Ia-1), which correspond to the compounds of formula Iw containing a hydrogen atom as R, are introduced into an alkylamino group or a group which can be converted into an alkylamino group. These compounds are first reacted with sodium hydride and then with a reagent of the formula halo-afiri-Q. In the latter formula, alk ¹ is as defined above, halo is halogen and Q is -M- (C 1 -C 4 alkyl) 2,1-piperidyl, 4-morpholino, 1-phthalimido, or halo. . The compounds are suspended in a solvent such as dimethylformamide and added, with stirring, to a suspension of sodium hydride in the same solvent. The haloalk'-Q reagent (i.e., the alkylamino or convertible group reagent) is added to the reaction mixture at room temperature and the reaction mixture is stirred until the reaction is complete. The completion of the reaction can be determined, for example, by thin layer chromatography. To quench the unreacted sodium hydride, the reaction mixture is poured into water and the product is extracted with a solvent such as methylene chloride. The product is extracted from the methylene chloride ex trak needle with an aqueous acid and selected by neutralization. The product is re-extracted with methylene chloride, the extract is evaporated and the product precipitated in the form of an acid addition salt such as fumarate, hydrochloride, oxalate or maleate. After recovery and purification of the acid addition salt, the free base can generally be obtained by dividing the salt between an aqueous base and a solvent such as methylene chloride and evaporating the methylene chloride phase. The corresponding dihydrodiazepines can be prepared from this product by reduction with sodium borocyanohydrin. Alternatively, the compounds of formula Ib containing a halogen substituent Q may be reacted with a dialkylamine to convert compounds Q containing a -N- (lower alkyl) ₂ substituent. The latter conversion is illustrated in Scheme B.

The primary amines of Formula Ic, i.e. the compounds of Formula I 'containing R ¹ and R ^{2 as} hydrogen substituents, are prepared from the omega- (1-phthalimido) -alk ^{1 as} shown in Scheme A by reacting these compounds with hydrazine hydrate. (Org. Syn. Coll. Vol. III, 151-153) 3

187,393 action taken. The reaction is usually heated to reflux for 2-3 hours, after which time aqueous acid is added and the reaction mixture is filtered. The primary alkyl ^1- amines are isolated from a solvent such as isopropanol, preferably in the form of the hydrochloride or hydrochloride hydrate. The corresponding dihydrodiazepines are prepared by reducing these products with sodium borocyanohydrin.

The -alk'-omega monoalkilaminokat described formula, that is, I _w compound of formula in which ^R1 is methyl, ^R2 is hydrogen, as shown in Scheme I can be prepared by Ic or Ic 1 overall The alk'-NH ₂ derivatives of formula Ia are reacted with triethyl ortho-formic acid. The reaction mixture is heated under reflux until the formation of the niethanimide ester of Formula Id takes place. The latter compound is then reacted with sodium borohydride. The unreacted borohydride is quenched with water and the product is extracted with a solvent such as ethyl acetate. The product was purified by column chromatography and partitioning with a basic solvent. The product is preferably isolated in the form of the hydrochloride. This conversion is also illustrated in detail in Example 27. These compounds can be reduced with sodium borocyanohydrin to produce the corresponding dihydrobenzodiazepines.

Intermediates of phenyl-substituted pyrido [1,4] benzodiazepines, the preparation of the new [(aminopyridyl) amino] phenylaryl methanones, are described in the following Examples 1-6. reaction.

Reaction 1 [2 - [(3-Amino-2-pyridyl) -amino] -phenyl] -phenyl-methanone

A mixture of 39.4 g (0.20 mole) of 2-aminobenzisophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180 'C under nitrogen for 1.5 hours. The reaction mixture was allowed to cool slightly, then methylene chloride (200 mL) was added slowly. Stir for 3 hours and then leave to stand at room temperature overnight. 40.1 g of a solid are precipitated which is filtered off and recrystallized from methanol-isopropyl ether. 4.3 g of product are obtained, which is presumably the hydrochloride salt. Melting point: 187-190 ° C. The resulting solid was dissolved in water-methanol, basified with 3N sodium hydroxide, and extracted with methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was recrystallized from isopropyl ether by purification with charcoal. 2.1 g of product are obtained, m.p. 91-93 ° C. This product was dried overnight at room temperature and 0.02 mm Hg before analysis.

Elemental composition of C ₁₈ H ₁₅ N ₃ O: Calcd: C 74.72%, H 5.23%, N 14.52%;

Found: C 74.94%, H 5.23%, N 14.69%.

Reaction 2 [2- (3-amino-2-pyridyl) amino] -4-chlorophenyl] -

phenyl-methanone

23.2 g (0.1 mol) of 2-amino-4'-chlorobenzophenone and

3-Amino-2-chloropyridine (14.2 g, 0.11 mol) was heated with stirring at 180 ° C under nitrogen for 2.5 hours. After cooling to room temperature, the reaction solidifies and is shredded with a spatula. The solid was slurried in 100 mL of methylene chloride and filtered. The filter cake was dissolved in water-methanol, made basic with 3N sodium hydroxide and extracted twice with methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crystallization residue was slurried with isopropyl ether and the solid (16.7 g) was collected by filtration. A 3 g sample of the product was recrystallized from isopropyl ether. 1.6 g of product are obtained, m.p. 153-155 ° C.

Elemental composition of C ₁₈ Hi C1N ₃ O _4: Calcd: C 66.77%, H 4.36%, N 12.98%;

Found: C, 67.06; H, 4.36; N, 13.17.

Reaction 3 [2- (3-amino-2-pyridyl) amino] phenyl] -4-methylphenyl [methanone

20.0 g (0.095 mol) of 2-amino-4'-methylbenzophenone and 13.95 g (0.104 mol) of 96% 3-amino-2-chloropyridine are heated under nitrogen with stirring for two hours. ° C. The reaction mixture cooled to a glassy solid. This was crushed and slurried with methylene chloride and the resulting mixture was stirred overnight. The solid was filtered off and dissolved in warm methanol. The solution was made basic with 3N sodium hydroxide, diluted with 500 ml of water and extracted three times with 250 ml of methylene chloride. The methylene chloride extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue which crystallized on standing was recrystallized twice from benzene isooctane. At

4.2 g of product are obtained, m.p. 126-127.5 ° C.

The elemental composition of C ₁₉ H ₁₇ N ₃ O: Calcd: C 75.23%, H 5.65%, N 13.85%;

Found: C, 75.81; H, 5.69; N, 13.96.

Reaction 4 [2- (3-amino-2-pyridyl) amino] -5-chlorophenyl] - (2-chlorophenyl [methanone)

20.0 g (0.156 mol) of 3-amino-2-chloropyridine and 37.3 g (0.14 mol) of 2-amino-2 ', 5-dichlorobenzophenone

The mixture was heated under nitrogen with stirring at 190 ° C for 5.5 hours. TLC (5% methyl alcohol / benzene on silica gel) showed essentially no reaction. After stirring overnight at 190 ° C, the reaction mixture was cooled slightly and methylene chloride (100 mL) was carefully added. The suspension was stirred for 2 hours. The black solid formed was filtered off. The solid was suspended in methylene chloride (500 mL) and dilute sodium hydroxide solution (300 mL) was added. This gives an emulsion which is filtered off. After filtration, the two phases are separated. The methylene chloride phase was washed with water (2 x 250 mL), dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in benzene and filtered through a column packed with 300 g of Florisil to remove the low-value material _Rf. All fractions were combined and concentrated under reduced pressure. The thin-layer chromatogram of the resulting material shows the presence of two major components, of which the lower R _f is predominant. The residue was dissolved in benzene and chromatographed on a column filled with 600 g of florisil in benzene. The higher R _f material was eluted with 1% acetone in benzene. The resulting solution was evaporated, the residue was slurried with benzene and the product was recrystallized from benzene-isooctane. 2.7 g of product are obtained, m.p. 162-164 ° C.

Elemental: Calculated for C ₁₈ H ₁₃ Cl ₂ N ₃ O: C 60.35%, H 3.66%, N 11.73%;

Found: C, 60.67; H, 3.67; N, 11.77.

Reaction 5 [2- (3-Amino-2-pyridyl) -amino] -phenyl] - (3-chloro-phenyl) -methanone g (0.152 mol) of 2-amino-3'-chloro-benzophenone and 23; 3-Amino-2-chloropyridine (4 g, 0.182 mol) was heated at 180 ° C for 2 hours with stirring. The hot melt was allowed to cool to 110 ° C and 100 ml of hot toluene was added dropwise with vigorous stirring. The reaction mixture was allowed to cool to 30 ° C with stirring, then methylene chloride (50 mL) was added. After stirring for a further 0.5 hours, the solid was filtered off. The solid is suspended in methylene chloride, the suspension is stirred for 0.5 hour and then the methylene chloride is filtered off. The product-containing solid (25.4 g) was partially dissolved in 150 mL of hot methanol. The resulting system was made basic with 50% aqueous sodium hydroxide. Ice water was added and the solution was extracted with methylene chloride. The methylene chloride extract was washed with water and dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in isopropanol and refluxed with charcoal. The solution was filtered and concentrated. This gave 16 g (33%) of crystalline first product. The crystalline material is recrystallized from isopropanol to give a brick red solid, m.p. 119-120 ° C.

Basic composition:

Calculated: C 66.77%, H 4.36%, H 12.98%; Found: C, 66.78; H, 4.42; N, 12.94.

Reaction 6 [2 - [(3-Amino-2-pyridyl) -amino] -phenyl] - (4-fluoro-phenyl) -methanone g (0.163 mol) 2-amino-4'-fluorobenzophenone and 27 g 3-Amino-2-chloropyridine (0.21 mol) was heated with stirring at 175-180 ° C for 2.5 hours. The reaction mixture was cooled to 110 ° C, then hot toluene (100 mL) was added. The mixture was cooled to 50 ° C and methylene chloride (50 ml) was added. The solvent phase was decanted and the residual black solid was dissolved in hot methanol. The resulting solution was reduced to half volume and the concentrated solution was allowed to stand overnight at room temperature. The solid was filtered off and washed twice on the filter, slurried with methylene chloride. 22.5 g of crude solid are obtained. This was dissolved in methanol and basified with 50% aqueous sodium hydroxide. The solution was extracted with methylene chloride, and the extract was dried and concentrated. The resulting residue was recrystallized twice from isopropanol and purified a second time with activated carbon. 14 g (28%) of an orange-red solid are obtained, m.p. 121.5-122.5 ° C. Calculated for C ₁₈ H ₁₄ N ₃ OF: C, 70.35%. H 4.59%, N 13.67%;

Found: C 70.23%, H 4.59%, N 13.64%.

The intermediate compounds prepared by the above reactions are summarized in Table 1 below.

Table 1

Summary of intermediates

Reaction _W of formula II compounds Price Y Z 1 c ₆ h ₅ - H H 2 c ₆ h- H 4- cl 3 4-CH ₃ -C ₆ H ₄ - H H 4 2-Cl-C ₆ H ₄ - H 5 cl 5 3-Cl-C ₆ H ₄ - H H 6 4 — F — C ₆ H ₄ - H H

The following examples illustrate the process for the novel phenyl-substituted pyrido [1,4] benzodiazepine compounds without limiting the scope of the invention. The compounds exemplified are summarized in Table 2 below.

Example 1

6-phenyl-11 H -pyrido [2,3-b] [1,4] benzodiazepine

A mixture of 19.7 g (9.1 mol) of 2-aminobenzophenone and 15.0 g (0.12 mol) of 3-amino-2-chloropyridine is heated at 190 ° C under nitrogen for 1.75 hours. The mixture was then cooled to room temperature and partitioned between 3N aqueous sodium hydroxide and methylene chloride. The methylene chloride extracts Lead was combined, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue (32.7 g) was dissolved in benzene and chromatographed on the column with florisil in benzene. Benzene and benzene containing 1-2% acetone were used for the elution. The solid obtained after evaporation of the eluate is crystallized from benzene. 7.3 g of product are obtained, m.p. 106-108 ° C.

Elemental composition of C ₁₈ H ₁₃ N ₃ O Calculated: C 79.68% H 4.83% NI5,49%;

Found: C, 79.70; H, 4.81; N, 15.42.

Example 2

8-Chloro-6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepine

A mixture of 15.0 g (0.0647 mol) of 2-amino-5-chlorobenzophenone and 9.1 g (0.068 mol) of 3-amino-2-chloropyridine was heated in an oil bath at 200 ° C under a nitrogen atmosphere of 0.75 hours. The reaction mixture was cooled and methylene chloride was added. Stir for one hour and then stand overnight,

8.7 g of a brown solid precipitated, which was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was combined with the former brown solid and partitioned between aqueous sodium hydroxide solution and methylene chloride. The crude product was isolated as in Example 1, except that ethanol was used as the solvent for crystallization, and the product was recrystallized from ethanol and dried overnight at 82 ° C at 0.1 mm Hg. 3.0 g of product are obtained, m.p. 156.5-158.5 ° C.

Elemental composition of C _I8 H _I2 C1N ₃ O Calculated: 'C 70.71%, H 3.96%, N 13.74%;

Found: C, 70.24; H, 4.01; N, 13.76.

Example 3

9-Chloro-6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepine

6.6 g (0.02 mol) of [2 - [(3-amino-2-pyridyl) amino] -4-chlorophenyl] (phenyl) methanone (intermediate prepared in Reaction 2) are suspended in 200 ml of toluene, and refluxing the slurry overnight under a nitrogen atmosphere. The reaction mixture was filtered hot and the filtrate was again heated to reflux. After cooling the reaction mixture to room temperature, the precipitate formed is filtered off and recrystallized from benzene and dried for 4 hours at 97-98 ° C, 0.1 mm Hg, then overnight at room temperature and 0.1 mm Hg. 3.7 g of product are obtained, m.p. 250.5-252 ° C. In elemental analysis. the high carbon product was further dried at 139 ° C for 8 hours with a xylene drying gun. Elemental analysis of the product thus obtained still shows high carbon content, but the proton NMR and mass spectra are consistent with the assumed structure.

Its elemental composition is C | ₆ H ₁₂ C1N ₃ O Calculated: C 70.71%, H 3.96%, N 13.74%;

Found: C, 71.46; H, 4.06; N, 13.46.

Example 4

8-Chloro-6- (2-chlorophenyl) -5,6-dihydro-11 H -pyrido [2,3-b] [1,4] benzodiazepine

The column packed with the florisil mentioned in Reaction 4 was further eluted with benzene containing 10-15% acetone and benzene containing 5-25% methanol. This gives two fractions containing the title compound. One is 6.4 g and the other is 5.7 g. The second fraction is contaminated. The 6.4 g fraction was recrystallized from benzene isooctane to give 3.7 g of product, m.p. 203-206 ° C with decomposition. Chemical ionization mass spectroscopic analysis showed ¹ H and ¹³ C NMR to give 8-chloro-6- (2-chlorophenyl) -5,6-dihydro-11 H -pyrido [2,3-b] [1,4] ] benzodiazepine.

Example 5

- 6- (4-chlorophenyl) -11H-pyridoph-2,3-b] + 1,4-benzodiazepine

23.2 g (0.10 mol) of 2-amino-4'-chlorobenzophenone and

A mixture of 14.7 g (0.11 mol) of 96% 3-amino-2-chloropyridine was heated at 180 ° C for 1.5 hours under nitrogen. The reaction mixture was cooled to room temperature and methylene chloride was added and stirred for 30 minutes. The solid was filtered off and pulverized with ethanol. The insoluble material was isolated by filtration and recrystallized from benzene-isooctane. 2.7 g of product are obtained, m.p. 203-204.5 ° C. The product was dried overnight at 97-98 ° C and 0.1 mm Hg.

Elemental composition of C _I8 H ₂ C1N ₃ O Calculated: C 70.71%, H 3.96%, N 13.74%;

Found: C, 70.76; H, 3.92; N, 13.95.

Example 6

6-14-methylphenyl] -1H-pyrido [2,3-b] [1,4] benzodiazepine

To a solution of 3.6 g (0.012 mol) of [2 - [(3-amino-2-pyridyl) amino] phenyl] - (4-methylphenyl) methanone in 100 ml of anhydrous toluene was added a catalytic amount of p-toluenesulfonic acid, and the reaction mixture was refluxed overnight while separating the water with a Dean-Stark trap. The reaction mixture was filtered hot. The filtrate was cooled to room temperature and the precipitated product was filtered off. After evaporation of the solvent, the solid product weighed 2.5 g. The product melts at 203.5 205 ° C with decomposition.

The elemental composition _of C _15> H ₁₅ N ₃ O Calculated: C 79.98%, H 5.30%, N 14.73%;

Found: C, 79.95; H, 5.27; N, 14.76.

Example 7

6- (4-methoxyphenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine

20.0 g (0.088 mol) of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mol) of 3-amino-2-chloropyridine (96%) are heated under stirring for 2 hours.

187,393 products were dried for 5 hours prior to analysis

97-98 ° C, 0.02 mm Hg, then overnight at room temperature and 0.02 mm Hg,

Elemental composition of C _{2 J} H _2J C1N ₄ O _4: Calcd: C, 62.43%; Η 5.24%, N 11.65%;

Found: C 62.52%, Η 5.23%, N 11.76%.

At 180 ° C under nitrogen. The reaction mixture was then cooled to about 70 ° C and methylene chloride (100 mL) was added slowly. After cooling to room temperature, additional methylene chloride (50 ml) was added and stirred overnight. The suspended solid was filtered off, air dried, dissolved in methanol and basified with 3N sodium hydroxide. The resulting slurry was diluted with 500 mL of water and extracted three times with 250 mL of methylene chloride. The methylene chloride extracts were combined and dried over magnesium sulfate and then concentrated under reduced pressure. Mass spectral analysis (E1 and Cl) showed the residue to be a mixture of [2 - [(3-amino-2-pyridyl) amino] phenyl] - (4-methoxyphenyl) methanone and the title compound. This mixture was dissolved in toluene (250 mL), a catalytic amount of p-toluenesulfonic acid was added, and the solution was refluxed overnight under nitrogen while the water was separated by a Dean-Stark trap. The reaction mixture was filtered hot. The filtrate was then cooled to room temperature and the precipitate was filtered off and recrystallized from benzene. 1.8 g of product are obtained, m.p. 198.5-200.5 ° C with decomposition.

Elemental composition of C ₁₉ H ₁₅ N ₃ O: Calcd: C 75.73%, H 5.02%, N 13.94%;

Found: C, 75.65; H, 4.98; N, 14.03.

Example 8 1- [8-Chloro-6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-propane oxalate [ 1: 1]

Sodium hydride (1.05 g, 0.044 mol) in petroleum oil was suspended in anhydrous dimethylformamide (50 mL), and 8-chloro-6-phenyl-11H-pyrido (6.1 g, 0.02 mol) was added in small portions under nitrogen. [2,3bj [l, 4] benzodiazepine. The reaction mixture was stirred for 1.5 hours at room temperature. During this time, hydrogen evolution ceases. 3.5 g (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride are added in small portions. The reaction mixture was stirred overnight at room temperature, then poured into water (1600 mL) and extracted with methylene chloride (3 x 250 mL). The combined methylene chloride extracts were washed with water (2 x 250 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in benzene and chromatographed on a column filled with 300 g of phosphorus in benzene. The eluent was acetone-benzene. Elution with benzene gave 1.6 g of the starting compound and 3.6 g of product, after eluting with acetone-benzene, namely the free base corresponding to the title compound after evaporation of the solvent. 2.5 g of the latter crude product are dissolved in hot isopropanol and 0.8. g (0.0064 mol) of oxalic acid dihydrate. The oxalate salt precipitated from the reaction mixture for cooling was isolated by filtration and recrystallized from ethanol. 2.2 g of product are obtained, m.p. 206-208 ° C. This

Example 9 1- [6-Phenyl-1H-pyrido [2,3-b] [1,4] -benzodiazepin-11-yl] -3-dimethylamino-propane fumarate [1: 1]

To a suspension of 1.68 g (0.070 mol) of sodium hydride in mineral oil is added 25 ml of anhydrous dimethylformamide and 8.0 g (0.029 mol) of 6-phenyl-11 H -pyrido [2.3] is added portionwise under stirring under nitrogen. -b] [1,4] benzodiazepine in 20 nl of anhydrous dirtiethylformamide. After the addition was complete, the reaction mixture was stirred for 30 minutes, then heated at 65 ° C for 15 minutes, then cooled to room temperature. 5.6 g (0.035 mol) of 3-dimethylaminopropyl chloride hydrochloride are added and the mixture is stirred overnight at room temperature. At this point, TLC showed that the reaction was almost complete. The reaction mixture was poured into water (1500 ml) and extracted with methylene chloride (250 ml). The methylene chloride extract was washed with water (3 x 250 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methylene chloride and extracted with 3N hydrochloric acid (100 mL, then L50 mL). Unreacted 6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepine is precipitated from the aqueous acidic solution. The starting compound is isolated by carefully decanting the liquid from the solid phase. The aqueous solution was made basic with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. 7.7 g of a residue are obtained, which is the free base of the title compound. 6.6 g of this is dissolved in hot isopropanol and treated with 2.15 g of fumaric acid. The reaction mixture is heated until dissolution is complete. The reaction mixture was allowed to stand for 48 hours and the precipitated salt was filtered off. The product is recrystallized from isopropanol / isopropyl ether. 5.9 g of product are obtained, m.p. 171-173 ° C. Prior to analysis, this product was dried for 4 hours at 90 ° C and 0.1 mm Hg and then at room temperature overnight at 0.1 mm HG. Elemental composition of C ₂₇ H ₂₈ N ₄ O _4: Calcd: C 68.63%, H 5.97%, N 11.86%;

Found: C, 68.37; H, 6.05; N, 11.73.

Example 10

1- [6-Phenyl-1H-pyrido [2,3-b] [1,4-benzodiazepin-11-yl] -2-dimethylamino-ethane fumarate [1: 1]

1.48 g (0.062 mol) of sodium hydride suspended in mineral oil in 35 ml of anhydrous dimethylformamide 7

To a suspension of 187,393 songs under nitrogen, is added in small portions 7.0 g (0.026 mol) of 6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepine. The reaction mixture was cooled to room temperature and 4.46 g (0.031 mol) of 2-dimethylaminoethyl chloride hydrochloride were added in small portions. After stirring overnight, the reaction mixture was poured into 1500 ml of water and extracted with 250 ml of methylene chloride. The methylene chloride extract was washed three times with 500 ml of water, dried over magnesium sulfate and concentrated under reduced pressure. 8.6 g of an oily product are obtained, which is the free base corresponding to the title compound. 6.9 g of this are reacted with an equivalent molar amount of fumaric acid in isopropanol. Isopropyl ether is added to the reaction mixture, whereupon an oily solid precipitates. The reaction mixture was concentrated under reduced pressure and the residue crystallized on standing. The crystalline material is slurried with acetone and recrystallized from acetone-isopropyl ether. 4.3 g of fumarate are obtained, m.p. 175-177.5 ° C.

Elemental composition of C ₂₆ H ₂₆ N ₄ O _4: Calcd: C 68.11%, H 5.72%, N 12.22%;

Found: C, 67.88; H, 5.72; N, 12.17.

Example 11

1- [3- (4-Morpholinyl) propyl] -6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine fumarate [1: 1]

To a suspension of 1.10 g (0.046 mol) of sodium hydride in mineral oil in 25 ml of anhydrous dimethylformamide was added 5.0 g (0.0184 mol) of 6-phenyl-1H-pyrido [2.3] in portions with stirring. b] [l, 4] benzodiazepine. The reaction mixture was stirred at room temperature for 15 minutes, then heated at 65-70 ° C for 10 minutes, then allowed to cool to room temperature. At this time, 4- (3-chloropropyl) morpholine hydrochloride (4.1 g, 0.02 mol) was added in portions. After stirring for 16 hours at room temperature, the reaction mixture was poured into 800 ml of water and extracted twice with 200 ml of methylene chloride. The combined methylene chloride extract was extracted with 150 ml, then 75 ml of 3N hydrochloric acid, and the combined aqueous extract was made basic with 3N sodium hydroxide. This gives a suspension which is extracted twice with 150 ml of methylene chloride. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue is obtained as the free base corresponding to the title compound. This is reacted with an equivalent molar amount of fumaric acid in warm isopropanol. Isopropyl ether was added to the reaction mixture. The fumarate salt was filtered off and recrystallized from ethanol-ethyl acetate. 5.6 g of product are obtained, m.p. 154-157 ° C. The product was dried for 4 hours before analysis at 97-98 ° C, 0.1 mm Hg and overnight at room temperature and 0.1 mm Hg.

Found: C, 67.69; H, 10.88; N, 5.88; C ₂₉ H ₃₀ N ₄ O ₅ requires C, 67.69;

Found: C, 67.52; H, 10.90; N, 5.84.

Example 12 1- [6-Phenyl-1H-pyrido [2,3-b] [1,4] -benzodiazepin-11-yl] -3-diethylamino-oxalate [1: 1]

To a suspension of 1.10 g (0.0461 mole) of sodium hydride in petroleum oil in 25 ml of anhydrous dimethylformamide was added 5.0 g (0.0184 mole) of 6-phenyl-1H-pyrido [2] under stirring. , 3-b] [l, 4] benzodiazepine. The reaction mixture was stirred for 0.5 hour at room temperature, then heated to 65-70 ° C and then slowly cooled to room temperature. 3-Diethylaminopropyl chloride hydrochloride (3.77 g, 0.020 mol) was added portionwise and stirred at room temperature for 16 hours. The reaction mixture was poured into water (750 ml) and extracted with methylene chloride (3 x 150 ml). The methylene chloride extract was combined and extracted with 150 ml and then 75 ml 3N hydrochloric acid. The combined aqueous extracts were made basic with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. 7.5 g of product are obtained, which is the free base corresponding to the title compound. 5.6 g of this are reacted with an equivalent molar amount of oxalic acid dihydrate in hot isopropanol. The oxalate salt was isolated by filtration. 5.5 g of product are obtained, m.p. 196-199 ° C. The product was dried for one hour before analysis at 97-98 ° C at 0.1 mm Hg.

Elemental composition of C ₂₇ H ₃₀ N ₄ O _4: Calcd: C 68.34%, H 6.37%, N 11.81%;

Found: C, 68.31; H, 6.43; N, 11.86.

Example 13

- [9-Chloro-6-phenyl-11H-pyridine [2,3-b] [1,4 [benzodiazepin-11-yl] -3- (dimethylamino) propane fumarate [1: 1]

To a suspension of 0.98 g (0.041 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added 5.0 g (0.016 mol) of 9-chloro-6-phenyl-1H-pyrido [2 , 3-b] [l, 4] benzodiazepine. The reaction mixture was stirred for 1 hour at room temperature, then warmed to 70 ° C, then slowly cooled to room temperature. At this time, 2.84 g (0.018 mol) of 3-dimethylaminopropyl chloride hydrochloride were added over 30 minutes, and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into water (750 ml) and extracted with methylene chloride (150 ml, then 100 ml twice). The combined methylene chloride extracts were washed with water (2 x 100 mL) and extracted with 3N hydrochloric acid (100 mL, then 75 mL). The hydrochloric acid extracts were combined and the precipitate formed was filtered off. The filtrate was made basic with 3N sodium hydroxide and extracted with methylene chloride (3 x 100 mL). The combined methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methylene chloride and filtered through a glass filter through a 50-60 g florisil filter bed

187,393 filtered. The filter bed was washed with methylene chloride containing 1%, then 2%, then 3% and finally 5% methanol. The filtrates were combined and concentrated under reduced pressure. This gives the free base corresponding to the title compound. This is reacted with an equivalent molar amount of fumaric acid in hot isopropanol. 3.3 g of fumarate are obtained, m.p. 199-202 ° C.

Elemental composition of C ₂₇ H ₂₇ N ₄ O ₄ C1: Calcd: C 63.96%, H 5.37%, N 11.05%;

Found: C 63.63%, H 5.36%, N 11.00%.

Example 14

6-Phenyl-11- [3- (1-pyridyl) propyl] -11H-pyrido [2,3-b] [1,4] benzodiazepine fumarate [1: 1]

To a suspension of sodium hydride (1.10 g, 0.0461 mole) in petroleum oil (25 ml) was added 5.0 g (0.018 mole) of 6-phenyl-11H-pyrido [2,3-b] under nitrogen with stirring. ] [l, 4] benzodiazepine. The reaction mixture was stirred for 30 minutes, then warmed to 70 ° C, then cooled again to room temperature. It is then added in portions

4.14 g (0.0203 mol) of N- (3-chloropropyl) piperidine hydrochloride are added and the reaction mixture is stirred for 16 hours at room temperature and then poured into 750 ml of water and stirred for 15 minutes with 150 ml of methylene chloride. The aqueous phase is then extracted twice more with 100 ml of methylene chloride, the combined methylene chloride extract is extracted with 150 ml and then 75 ml of 3N hydrochloric acid, the combined acidic extracts are made basic with 3N sodium hydroxide and extracted three times with 100 ml of methylene chloride each time. The residue was dissolved in a small amount of methylene chloride and the solution was filtered through a glass filter through a 100 g florisil filter bed, washed with methylene chloride containing 1%, then 2%, then 3% and finally 5% methanol. The filtrates were combined and evaporated under reduced pressure to give 1.3 g of fumaric acid. k in hot isopropanol, and isopropyl ether was added to the reaction mixture to form an amorphous precipitate. The whole reaction mixture was evaporated to dryness and the resulting residue was dissolved in ethanol (200 mL). The solution is heated to boiling, filtered and isopropyl ether is added to the filtrate. The crystals precipitated overnight are filtered off. 4.1 g of the fumarate salt are obtained, m.p. 153-156 ° C. Prior to analysis, the product was dried at 97-98 ° C and 0.1 mm Hg for 4 hours.

Elemental composition ₃₀ H ₃₂ N ₄ O ₄ Calcd C: calculated: C 70.29%, H 6.29%, N 10.93%;

Found: C, 70.38; H, 6.32; N, 10.92.

Example 15 1- [6- (4-Chloro-phenyl) -1H-pyrido [2,3-b] [1,4] -benzodiazepin-II-yl] -3- (dimethylamino-propane fumarate) f: 1 ]

To a suspension of sodium hydride (1.57 g, 0.065 mol) in petroleum oil (25 ml) was added 6- (4-chlorophenyl) -1H-pyrido (8.0 g, 0.026 mol) under nitrogen with stirring. 2,3-b] [l, 4] benzodiaze-. pint. The reaction mixture was stirred at room temperature for 1 hour, then heated at 80 ° C for 15 minutes, then re-cooled to room temperature. At this time, 4.55 g (0.029 mol) of 3-dimethylaminopropyl chloride hydrochloride were added portionwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water (750 ml), methylene chloride (150 ml) was added and the mixture was stirred for 30 minutes. The aqueous phase is then extracted three more times with 100 ml of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. This gives the free base corresponding to the title compound. This is reacted with an equivalent molar amount of fumaric acid in hot isopropanol. The fumarate salt precipitates to cool the reaction mixture. 3.6 g of product are obtained

200.5-202.5 'C are present. The product was further air-dried before analysis.

Elemental composition of C ₂₇ H ₂₇ C1N ₄ O _4: Calcd: C 63.96%, H 5.37%, N 11.05%;

Found: C, 64.18; H, 5.33; N, 11.07.

Example 16 1- [8-Chloro-6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-ethane oxalate [1 : 1]

To a suspension of 1.05 g (0.044 mol) of sodium hydride in 5 ml of anhydrous dimethylformamide was added portionwise (6.1 g / 0.02 mol) of 8-chloro-6-phenyl-11 H -pyrido [2,3 b] [l, 4] benzodiazepine. The reaction mixture was stirred for 1.5 hours at room temperature. During this time hydrogen evolution ceases. The reaction mixture was cooled to 5 'C and 3.2 g (0.022 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise and the reaction mixture was stirred at room temperature for about 60 hours. It was then poured into water (1600 mL) and extracted with methylene chloride (3 x 500 mL). The combined extracts were washed with water (2 x 500 mL), dried over magnesium sulfate and evaporated under reduced pressure. TLC on silica gel with 20% methanol in benzene showed the product to be a starting material in addition to the free base corresponding to the title compound. The residue was dissolved in benzene and chromatographed on a column filled with 200 g of florisil in benzene. The starting compound was eluted with benzene from the column to give 1.3 g of 8-chloro-6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine. The free base corresponding to the title compound was eluted with acetone-benzene. The free base is reacted with an equivalent molar amount of oxalic acid dihydrate in hot isopropanol. The product was recrystallized from isopropanol. 1.6 g of product are obtained

228.5-232 'C-are. Prior to analysis, the product was dried for 6 hours at 82 ° C and 0.1 mm Hg and then overnight at room temperature.

187,393

Elemental composition of C ₂₄ H ₂₃ C1N ₄ O _4: Calcd: C 61.74%, H 4.96%, N 12.00%;

Found: C, 61.62; H, 4.95; N, 11.98.

Found: C, 69.12; H, 6.22; N, 11.52; C ₂₈ H ₃₀ N ₄ O ₄ requires C, 69.12;

Found: C, 68.86; H, 6.32; N, 11.36.

Example 17

8-chloro-ll-methyl-6-phenyl-llH-pyrido [2,3-b] [l, 4] benzodiaz'epin

To a suspension of sodium hydride (0.25 g, 0.01 mol) in mineral oil in 15 ml of anhydrous dimethylformamide was added in portions 3.05 g (0.01 mol) of 8-chloro-6-phenyl-1H-pyrido [2 3-b] [l, 4] benzodiazepine. The reaction mixture was heated at 60 ° C for 1 hour and a solution of 1.42 g (0.01 mol) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over 0.5 hour. After stirring overnight at room temperature, the reaction mixture was poured into 400 ml of water and stirred for 2 hours. The solid thus precipitated was recrystallized twice from isopropyl alcohol to give 2.0 g of product. 153-156 ° C. Prior to analysis, the product was dried for one hour at 82 ° C and 0.1 mm Hg.

Elemental composition of C ₁₉ H ₁₄ C1N ₃ O Calculated: C 71.36%, H 4.41%, N 13.14%;

Found: C, 71.64; H, 4.43; N, 13.32.

Example 18 1- [6- (4-Methylphenyl) -1H-pyrido [2,3-b] [1,4] -benzodiazepin-11-yl] -3-NN-dimethylamino-propane fumarate [1: 1]

To a suspension of 0.51 g (0.022 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added 4.2 g (0.0147 mol) in portions under nitrogen with stirring for 45 minutes.

6- (4-methylphenyl) -l IH-pyrido [2,3-b] [l, 4] benzodiazepine. The reaction mixture was stirred at room temperature for 1 hour, then heated at 75-80 ° C for 1 hour, then cooled to room temperature and a solution of 3-dimethylaminopropyl chloride (0.0184 mol) in dry dimethylformamide (10 ml) was added dropwise. After stirring overnight at room temperature, the reaction mixture was poured into 1000 ml of water and the suspension was extracted with three 150 ml portions of methylene chloride. The combined methylene chloride extract was extracted twice with 150 ml of 3N hydrochloric acid. The precipitate from the acidic solution was removed by filtration. The filtrate was made basic with 3N sodium hydroxide and extracted with methylene chloride (3 x 100 mL). The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. This gives an oily product which is the free base corresponding to the title compound. This is dissolved in hot isopropanol and reacted with an equivalent molar amount of fumaric acid. The reaction mixture was cooled to room temperature, whereupon the fumarate salt crystallized. This was recrystallized twice from isopropanol / isopropyl ether to give 1.7 g of product, m.p. 187-189 ° C.

Example 19 1- [6- (4-Methoxyphenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propane fumarate [1: 1]

To a suspension of 0.45 g (0.0187 mole) of sodium hydride in 25 ml of anhydrous dimethylformamide was added 4.5 g (0.015 'mole) of 6- (4-methoxyphenyl) -1H-pyrido [2,3-b] [l, 4] benzodiazepine. After stirring for 30 minutes at room temperature, the reaction mixture was heated at 80-90 ° C for 1 hour, then cooled to room temperature and a solution of 0.019 mol of 3-dimethylaminopropyl chloride in 5 ml of anhydrous dimethylformamide was added dropwise. The reaction mixture was stirred overnight at room temperature and then poured into 800 ml of water. The suspension was extracted with methylene chloride (2 x 150 mL). The combined extracts were washed with 500 mL of water and extracted twice with 100 mL of 3N hydrochloric acid. The precipitated solid was filtered off from the combined acidic extracts. The filtrate was made basic with 3N sodium hydroxide and extracted with methylene chloride (3 x 100 mL). The combined methylene chloride extract was dried over magnesium sulfate and concentrated under reduced pressure. The partially crystallized oily residue is slurried with methylene chloride and filtered. 0.32 g of a residue is obtained. The filtrate was concentrated under reduced pressure and the residual oil was slurried with hot benzene and filtered. 0.8 g of a residue is obtained. The benzene filtrate was concentrated under reduced pressure and the resulting oily residue was treated with 1.02 g of fumaric acid in hot isopropanol. On cooling, an oil precipitates from the reaction mixture. The supernatant was separated by decantation and the oil was inoculated with a crystal germ. The mixture obtained after partial crystallization was filtered. This gives 2.5 g of a solid, m.p. 157-160 ° C. Recrystallization with isopropanol-isopropyl ether again yields a mixture of an oily solid. Isopropyl alcohol was added to the mixture, heated, dissolved, filtered, seeded with crystal seed and cooled. The fumarate salt precipitated was filtered off. 2.0 g of product are obtained, m.p. 159-161 ° C. Elemental composition C _2g H ₃₀ N ₄ O _5: Calcd: C 66.92%, H 6.02%, N 11.15%;

Found: C, 66.90; H, 6.08; N, 11.08.

Example 20

6- (3-chlorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine g (0.0433 mol) [2 - [(3-amino-2-pyridyl) - A solution of amino] phenyl] - (3-chlorophenyl) methanone and 0.3 g of p-toluenesulfonic acid in 500 mL of toluene is refluxed overnight while the water is separated by a Dean-Stark trap. Before

-10187 393, about 250 ml of toluene were distilled off and the hot solution was filtered. Then petroleum ether, boiling at 30-60 ° C, is added to the reaction mixture until it becomes cloudy. The solution is then placed in the refrigerator overnight and the precipitated solid is filtered off. 10 g (76%) of a gold crystalline product are obtained after air drying. A portion of the product was recrystallized from isopropanol / isopropyl ether. 160-160.5 ° C.

Elemental composition of C ₁₈ Hi C1 ₂ N _3: Calcd: C 70.71%, H 3.96%, N 13.74%;

Found: C, 70.47; H, 3.98; N, 13.62.

Example 21

1- (6- (3-Chloro-yenyl) -1H-pyrido [2,3-b] [1,4-benzodiazepin-11-yl] -3-dimethylamino-propane fumarate [ 1: 1]

To a suspension of sodium hydride (3.4 g, 0.07 mol) in petroleum oil (250 ml) was added 6- (3-chlorophenyl) -11H- (8.5 g, 0.028 mol) under nitrogen with stirring. pyrido [2,3-b] [l, 4] benzodiazepine. The reaction mixture was stirred for 30 minutes at room temperature, then heated at 80 ° C for 3 hours, then cooled to room temperature. A solution of 4.9 g (0.031 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide is added dropwise over 20 minutes. The reaction mixture was stirred overnight at room temperature under nitrogen. Thereafter, TLC showed that the reaction mixture still contained the starting material. At this time, 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 were added and stirring was continued for 4 minutes. Continue for 5 hours. Water (20 mL) was added dropwise to the reaction mixture, filtered and concentrated on a rotary evaporator. The resulting residue was partitioned between diethyl ether and dilute sodium hydroxide solution. The ether layer was washed three times with water and extracted with dilute aqueous hydrochloric acid. The aqueous phase was made basic with granular sodium hydroxide and extracted with methylene chloride. The methylene chloride phase was dried and evaporated. 7.5 g of product are obtained. The resulting free base is reacted with fumaric acid and the fumarate salt is recrystallized from ethyl acetate-ethanol. Melting point: 167.5-168.5 ° C.

Elemental composition of C ₂₃ H ₂₃ N ₄ C1: Calcd: C 63.96%, H 5.47%, N 11.05%;

Found: C, 63.95; H, 5.39; N, 11.00.

Example 22

6- (4-Fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine

A mixture of 11.5 g (0.037 mol) of [2 - [(3-amino-2-pyridyl) amino] phenyl] - (4-fluorophenyl) methanone and 0.6 g of p-toluenesulfonic acid in toluene is heated at reflux for 24 hours. while separating the water with a Dean-Stark trap, 300 ml of toluene were distilled off and the solution was hot filtered before heating was complete, then petroleum ether boiling at 30-60 ° C was added until the reaction mixture was stirred at 0 ° C. After cooling and allowing to stand overnight at this temperature, the precipitated solid is filtered off to give 10.7 g of crystalline material, part of which is recrystallized from isopropanol and dried overnight in vacuo at 65 ° C. They are C's.

Elemental composition of C ₁₈ Hi ₂ N ₃ F: Calc: C 74.73%, H 4.18%, N 14.52%;

Found: C 74.61%, H 4.17%, N 14.54%.

Example 23

1- (6- (4-Fluorophenyl) -1H-pyridopho-2,3-b] [1,4 J benzodiazepin-11-yl] -3- (dimethylamino) propane hydrochloride hemihydrate

To a suspension of sodium hydride (3.6 g, 0.075 mol) in petroleum oil (250 ml) was added 6- (4-fluorophenyl) -1H (8.7 g, 0.03 mol) under nitrogen with stirring. pyrido [2,3-b] [l, 4] benzodiazepine. The reaction mixture was stirred for 30 minutes at room temperature, then heated at 80 'C for 3.5 hours, then allowed to cool to 45' C. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride hydrochloride in 30 ml of dimethylformamide is added dropwise. The reaction mixture was stirred overnight at room temperature and then examined by thin layer chromatography. The reaction showed that the reaction mixture still contained starting material. To the reaction mixture was added additional sodium hydride (3.6 g, 0.075 mol), and stirring was continued for 45 minutes, followed by heating at 50-60 ° C for 0.5 hour. The reaction mixture will then turn green and gas will develop. After stirring for 3 hours at room temperature, a solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide was added dropwise. (During the addition of the reagent, about half of the reagent is added, the reaction mixture turns green, and the addition of the reagent is suspended for about one hour.) The reaction mixture is stirred overnight at room temperature and 30 ml of water are added while cooling. After the evolution of gas ceased, the reaction mixture was filtered and concentrated in a rotary evaporator. The residue was partitioned between diethyl ether and water and the ethyl ether layer was extracted with dilute aqueous hydrochloric acid. The aqueous phase was filtered after 1.5 hours to remove the solid. The filtrate was made basic by the addition of sodium hydroxide particles and extracted with methylene chloride. The extract was dried and concentrated. The resulting residue was divided into two equal portions and purified by chromatography on a dry silica gel column over two 51 cm long and 3.8 cm diameter columns. The column loaded silica gel was pre-deactivated with a chromatographic solvent mixture containing 10% methanol, 1% concentrated ammonium hydroxide and 89% methylene chloride. The middle section of the column was cut out and chromatographed

-111

Extracted with 187,393 refining solvents. The combined extracts were concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol and the solution was acidified with concentrated hydrochloric acid. The hydrochloride salt thus obtained was recrystallized from ethanol-ethyl acetate. The resulting solid was filtered and dried at 99 ° C for 48 hours. This gives the title compound as the monohydrochloride hemihydrate. Melting point: 120-123 ° C. · Elementary analysis of the formula C _{4 <5} N ₈ F H _{SO 2} C1 ₂ 0: C 65.78%, H 6.00%, N 13.34%;

Found: C, 65.58; H, 5.77; N, 13.47.

Example 24, 3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -propyl] -6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

To a suspension of 0.56 g (0.023 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added 5.0 g (0.0184 mol) of 6-phenyl-1H-pyrido [2,3-b] [l] with stirring. , 4] benzodiazepine. The reaction mixture was heated at 80 ± 2 ° C for one hour, then cooled to room temperature. A solution of 5.55 g (0.020 mol) of N- (3-bromopyropyl) phthalimide in 10 ml of anhydrous dimethylformamide is added dropwise and the reaction mixture is stirred for 16 hours. It is then poured into 650 ml of water and stirred for 30 minutes. A yellow solid precipitates, which is filtered off and recrystallized three times from isopropanol. 3.7 g of product are obtained, m.p. 170-172 ° C.

Elemental composition of C ₂₉ H ₂₂ N ₄ O _2: Calcd: 'C 75.97%, H 4.84%, N 12.22%;

Found: C, 76.25; H, 4.87; N, 12.34.

Example 25 [6-Phenyl-11H-pyrido [2,3-b] [1,4] -benzodiazepin-11-yl] -3-aminopropane dihydrochloride hemihydrate

16.2 g (0.035 mole) of 6-phenyl-11- [3-phthalimidopropyl] 11H-pyrido [2,3-b] [1,4] benzodiolisepine and 2.29 g (0.0387 mole) % hydrazine hydrate in 175 mL of ethyl alcohol was refluxed for 2.5 hours and the reaction was allowed to stand for 72 hours. A mixture of concentrated hydrochloric acid (10 ml) in water (50 ml) was added and the reaction mixture was stirred overnight. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The still slightly wet residue was suspended in 200 ml of water, the suspension was stirred for 2 hours and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was suspended in 100 ml of ethyl alcohol and concentrated under reduced pressure. The latter operations are repeated. 42.1 g of a crude wet residue are obtained, which is recrystallized from isopropanol with about 15 hours of rest. The resulting solid was filtered and dried at 82 ° C, 0.1 mm Hg for 3 hours, over phosphoric anhydride. The product is melted at 210-220'C during decomposition.

Elemental composition of the formula C ₄₂ H ₄₆ N ₈ Cl ₄ 0: C 61.47%, H 5.65%, N 13.65%;

Found: C, 61.36%; H, 5.72%; * N, 13.90%.

.

Example 26

- [6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-aminopropane

A portion of the 1- [6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-aminopropane dihydrochloride hemihydrate prepared in Example 25 was dissolved in water. The solution was made basic with dilute sodium hydroxide solution and extracted three times with methylene chloride. The combined methylene chloride extract was filtered through a glass filter through a 50-60 g florisil filter bed. The filter bed was washed with methylene chloride containing 1%, then 2%, then 3%, and finally 5% methanol. The filtrates were combined and concentrated under reduced pressure. This gives the title compound as the free base.

Example 27 1- [6-Phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine

-11-yl] -3-methylamino-propane dihydrochloride Preparation of the imidate ester

The imidate ester was prepared according to the methods of Crochet T.A. and Blanton C.D., Jr. (Synthesis 1974 (1) 55-56) as follows.

1- [6-Phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-aminopropane dihydrochloride hemihydrate prepared in Example 25 (0.06) mole) to the free base by partitioning between dilute sodium hydroxide solution and methylene chloride, the methylene chloride phase was dried and evaporated to dryness, and to the residue was added anhydrous benzene and the solution was evaporated to dryness. The resulting free base was dissolved in freshly distilled ortho-formic acid triethyl ester (300 mL, 267 g, 1.8 mol) and the solution was heated under reflux for 9 hours. The reaction mixture was concentrated in vacuo, ethanol was added to the residue and the solution was evaporated again.

Conversion of amidate to amine

Dissolve 23.4 g (0.061 mol) of the above amidate in 200 ml of ethanol and add sodium borohydride at 15-20 ° C with stirring until the reaction is substantially complete by TLC. It takes place. In other words, the TLC shows no significant amount of starting material; At this time, 50 ml of water was slowly added with stirring, and cooling was continued for 15 minutes after the addition of water. The reaction mixture was poured into water (2 L) and extracted with ethyl acetate. The ethyl acetate layer was washed with water until a neutral wash was obtained and then saturated with methylene chloride. The ethyl acetate layer was then dried and evaporated. To the residue was added diethyl ether and cooled. The resulting solid was removed by filtration and the ether layer was evaporated. The product obtained is chromatographed on a neutral column packed with activity 1 alumina. Elution with ethyl 121

187,393 recrystallized from pis-alcohol-isopropyl ether. M.p. 160-162 ° C;

C ₂₈ H ₂₇ N ₄ O ₄ F ₃ .

acetate-methanol-triethylamine mixture containing only traces of the latter. The fractions containing the product were selected by thin layer chromatography and partitioned between ethyl acetate and aqueous sodium hydroxide. Hydrochloric acid ether was added to the ethyl acetate phase, and the crystalline product thus precipitated was recrystallized from acetonitrile / water. M.p. 139-141 ° C.

Elemental composition of C ₂₂ H ₂₄ N ₄ Cl 2: Calcd: C 63.62%, H 5.82%, N 13.49%;

Found: C, 63.81; H, 6.15; N, 13.60.

Example 28 1- [5,6-Dihydro-6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-propane , dihydrochloride hemihydrate

A solution of 3.0 g (0.0064 mol) of 1- [6-phenyl-11 H -pyrido [2,3b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propane in anhydrous methanol is adjusted to 5.6 with methanolic hydrochloric acid. Sodium borocyanohydrin (0.7 g, 0.011 mol) was added all at once and the reaction mixture was heated under reflux for 20 minutes. The ethanol is then distilled off in vacuo. The residue was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride phase was dried over magnesium sulfate and evaporated. The residue was crystallized twice from isopropanol and isopropyl ether. 1.6 g (57%) of a yellow solid are obtained which loses its crystalline structure by heating at 156-160 ° C and decomposes at 180-195 ° C.

Elemental composition of C ₄₆ H ₅₈ N ₈ OC1 _4: Calc: C 62.73%, H 6.64%, N 12.72%;

Found: C, 62.40; H, 6.90; N, 12.61.

Example 29

The procedure of Example 15 was followed except that equivalent molar amounts of 6- (4-ethylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine were used as starting material. The following 6-phenyl-substituted-pyridobenzodiazepine is obtained as the product:

- [6- (4-ethylphenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-propane.

This compound was converted to the monohydrochloride salt and recrystallized from isopropyl alcohol. This gave a yellow solid, m.p. 239-240 ° C;

C ₂₃ H ₂₄ N ₅ O ₂ Cl.

Example 30

- [N, N-dimethyl-6- [4- (trifluoromethyl) phenyl] -1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) - Propane was prepared using a procedure analogous to Example 15, but using 6- (3-trifluoromethylphenyl) -1H-pyrido [2,3-b] [1,4] diazepine as starting material. The monofumarate salt of this compound is prepared, the product is isopropyl. Example 1- 1- [6- (2-Thienyl) -1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propane monohydrochloride hemihydrate

6- (2-Thienyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine was treated with sodium hydride as described in Example 23 and treated with 3-dimethylaminopropyl chloride. The title compound is obtained, the monohydrochloride hemihydrate salt of which is prepared with ethereal hydrogen chloride in a mixture of isopropyl alcohol and isopropyl ether. After recrystallization from isopropyl alcohol-ethyl acetate, yellow granules are obtained; 176-178 ° C;

Molecular formula; C ₂ iH ₂₄ O ₀₅ S.

Example 32

3-Thienyl) -11H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-propane monooxalate

The procedure of Example 23 was repeated except that 6- (3-thienyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine was treated with sodium hydride and the product was then treated with 3-dimethyl aminopropyl chloride. This gives the title compound, which is prepared as its monooxalate salt. Recrystallized from isopropyl alcohol-water mixture was dark yellow. a fluffy substance is obtained, m.p. 203-204 ° C; C ₂₃ H ₂₄ N ₄ S.

Example 33 1- [6- (2-Pyridyl) -H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propane monooxalate

The procedure of Example 23 was followed except that 6- (2-pyridyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine was reacted with sodium hydride to give 3- (2-pyridyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine. dimethylaminopropyl chloride. This gives the title compound, which is converted to the monooxalate, the salt is separated from the reaction mixture, recrystallized from isopropyl alcohol / ethyl acetate and dried at 98 ° C for 36 hours under vacuum. The product is a yellow solid, m.p. 176.5-178 ° C (dec);

c ₂₄ h ₂₅ n ₅ o ₄ .

Examples 34a-34c

In the same manner as in Example 23, the following pyrido [2,3-b] [6- (4-fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine is used as starting material. 1,4] benzodiazepines are used: 6- (2-fluorophenyl) -1H-pyrido [2,3-b] [1,4] behzodiazepine,

6- (2-chlorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepine and

-13187393

6- (2-Bromophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine.

The following compounds were obtained as a product:

a) 1- [6- (2-Fluorophenyl-11H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl) -3- (dimethylamino) propane, which is isopropanol; recrystallized from a mixture of isopropyl ether, m.p. 92-94 ° C,

b) 1- (6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propanoic acid, which is isopropyl recrystallized from ether, m.p. 104-105 ° C and

c) 1- [6- (2-Bromophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3-dimethylamino-propane which is isopropyl; Recrystallization from ether 96 98 ° C ¹⁵ wild-ol.

Examples 35a-35c

8-chloro-6- (2-nitrophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine,

8-chloro-6- (2-chlorophenyl) -11H-pyrido [2,3-b] [1,4] benzodiazepine and ⁵ 8-chloro-6- (2-bromophenyl) 11 H -pyrido [2,3-b] [1,4] benzodiazepine.

The following compounds are obtained as a product:

a) 8-chloro-l-methyl-6- (2-nitrophenyl) -l H-pyrido [2,3 · ¹⁰ b] [l, 4] benzodiazepine, which is recrystallized from ethanol 165-166 ° C melted

b) 8-Chloro-6- (2-chlorophenyl) -11-methyl-11H-pyrido [2,3b] [1,4] benzodiazepine, which is recrystallized from isopropanol / isopropyl ether at 150-152 ° C. melt and

c) 6- (2-Bromophenyl) -8-chloro-11-methyl-11H-pyrido [2,3b] [1,4] benzodiazepine, m.p. 121-123 ° C by recrystallization from isopropyl ether.

The procedure of Example 17 is repeated, but the following compounds are used instead of 8-chloro-6-phenyl-11H-pyrido [2,3-b] (1,4) benzodiazepine:

Table 2

Summary of the Examples

Compounds of formula I _w

Example R Price Y Z n Salt 1 H c ₆ h _s - H H 0 - 2 H c ₆ h ₅ - H 8-C1 0 - 3 H C ₆ H _s - H 9-C1 0 - 4 H 2-Cl-C ₆ H ₄ - H 8-C1 1 - 5 H 4-C 1 -C ₆ H ₄ - H H 0 - 6 H ' 4-CH ₃ -C ₆ H ₄ - · H H 0 - 7 H 4-OCH ₃ -C ₆ H ₄ - H H 0 - 8 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ c ₆ h ₅ - H 8-C1 0 oxalate 9 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ C ₆ Hj- H H 0 fumarate 10 - (CH ₂ ) ₂ -N (CH ₃ ) ₂ c ₆ h ₅ - H H 0 fumarate 11 - (CH ₂ ) ₃ -4-morpholinyl c ₆ h ₅ - ' H H 0 fumarate 12 - (CH ₂ ) ₃ -N (C ₂ H ₅ ) ₂ C ₆ H ₅ - H H 0 oxalate 13 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ C ₆ H _s - ' H 9-C1 0 fumarate 14 - (CH ₂ ) ₃ -1-piperidyl c ₆ h ₅ - H H 0 fumarate 15 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 4-C 1 -C ₆ H ₄ - H H 0 fumarate 16 -CH ₂ -N (CH ₃ ) ₂ c ₆ h ₅ - H 8-C1 0 oxalate 17 -ch ₃ c ₆ h ₅ - H 8-C1 0 - 18 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 4-CH ₃ -C _e H ₄ - H H 0 fumarate 19 - (CH ₂ ) j -N (CH ₃ ) ₂ 4-OCH ₃ -C ₆ H ₄ - H H 0 fumarate 20 H 3-C 1 -C ₆ H ₄ - H H 0 - 21 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 3-C 1 -C _e H ₄ - H H 0 fumarate 22 H 4-F-C ₆ H ₄ - H H 0 - 23 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 4-F-C ₆ H ₄ - H H 0 HCl, V ₂ H ₂ O 24 - (CH ₂ ) ₃ -1-phthalimide c ₆ h ₅ - H H 0 - 25 - (CH ₂ ) ₃ -NH ₂ c ₆ h ₅ - Ή H 0 ; 2 HCl »2 H ₂ O 26 - (CH ₂ ) ₃ -nh ₂ c _he h ₃ - H H 0 27 - (CH ₂ ) ₃ -nhch ₃ CJ1 ₅ - H H 0 2 HCl 28 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ c ₆ h ₅ - H H 1 2 HCl, ^l / i H ₂ O 29 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 4-C ₂ H _s —C ₈ H ₄ - H H 0 monohidroklo- anhydride 30 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 3-CF ₃ -C ₆ H ₄ - H H 0 monofumarate 31 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 2-thienyl H H 0 monohydrochloride hemihydrate 32 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 3-thienyl H H 0 monooxalate 33 - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 2-pyridyl H H 0 monooxalate * 34 a) - (CH ₂ ) ₃ -N (CH ₃ ) ₂ , 2-FC ₆ H ₄ - H H 0 - 34 b) - (CH ₃ ) ₃ -N (CH ₃ ) ₂ 2-Cl-C ₆ H ₄ - H H 0

-141

187,393

Table 2 (continued)

Example R Price Y Z n Salt 34 c) - (CH ₂ ) ₃ -N (CH ₃ ) ₂ 2-Br-C ₆ H ₄ ~ H H 0 - 35 a) —CH ₃ 2-NO ₂ -C ₆ H ₄ - H 8-C1 0 - 35 b) —CH ₃ 2-C 1 -C ₆ -H ₄ - H 8-C1 0 35 c) —CH ₃ 2-Br-C ₈ H ₄ - H 8-C1 0 -

Example 36 1- [6-Phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepinyl-11-yl] -2-methyl-3- (dimethylamino) propane

Following the procedure of Example 9 but substituting 3-dimethylaminopropyl chloride with 3-dimethylamino-2-methylpropyl chloride, the title compound is obtained as a yellow powder, m.p. 141-143 ° C. C ₂₄ H ₂₆ N ₄ .

Example 37

1- [6- (2-Fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzo [25] diazepin-11-yl] -2-methyl-3- (dimethylamino) propane

Following the procedure of Example 9, but using 6-phenyl-11H-pyrido [2,3-b] [1,4] benzodiazepine, 6- (2-fluorophenyl) -1H-pyrido [2,3-b] [ 4] benzodiazepine and substituting 3-dimethylaminopropyl chloride with 3-dimethylamino-2-methylpropyl chloride to give the title compound; Recrystallization from isopropyl alcohol gave a yellow solid, m.p. 121-123 ° C.

C ₂₄ H ₂₅ N ₄ F.

Example 38 1- [6- (3-Fluorophenyl) -1H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] -3- (dimethylamino) propane , hydrochloride

The procedure of Example 9 was followed, however, by replacing 6-phenyl-1H-pyrido [2,3-b] [1,4] benzodiazepine with 6- (3-45-fluorophenyl) -11H-pyrido [2,3-b] ] [1,4] benzodiazepine is used as starting material. The title compound was converted to its hydrochloride salt with ethereal hydrogen chloride in a mixture of isopropyl alcohol and isopropyl ether. to give a yellow solid _'0 g, melting point 214-215 ° C, öszszegképlete is C ₂₃ H ₂₄ N ₄ FC1.

In human therapy, the compounds of formula I _w or II _W may be administered in the amounts necessary to exert their therapeutic effect in a conventional manner such as oral, solution, emulsion, suspension, pill, tablet or capsule form with the appropriate pharmaceutical carriers. for parenteral administration in the form of a sterile solution. θθ

For oral administration, solid carriers such as lactose, magnesium stearate, magnesium, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia are prepared from the active ingredients. ₆₅

Vegetable oils or water may be used as a liquid carrier for oral administration.

For intramuscular administration, the vehicle is formulated into a vial with a sterile, parenteral-acceptable liquid such as water or an oil for parenteral use, such as peanut oil.

The active compounds are already effective in small quantities, for example in the case of lesser intervention (minor therapy) or in the treatment of patients with light weight, but their unit dosage is generally at least 5 mg, preferably 10, 25, 50 or 100 mg, but may be higher. The formulation is administered three or four times daily. The dose and frequency of administration will depend on the severity of the case, the nature of the active ingredient, and the therapeutic result to be achieved. Unit doses may contain from 10 to 500 mg of active ingredient, but preferably from 25 to 200 mg. Generally, the required daily dose will be from about 0.3 mg to about 20 mg, preferably from 0.3 mg to 10 mg per kilogram body weight. The active ingredient of the present invention may also be combined with other pharmaceutically active ingredients. Of course, the active ingredient must always be administered in the amount necessary to produce the desired effect, so that a unit dosage form of a particular form is effective. Various unit dosage formulations may be used simultaneously. The exact individual dose or daily dose will, of course, be determined by the physician on the basis of medical considerations.

The following are some examples of pharmaceutical compositions containing the compounds of the present invention as active ingredients.

I. Capsule Preparation Capsules containing mg or 50 mg of active ingredient are prepared according to the table below. The higher active ingredient formulation contains less lactose according to the excess active ingredient.

Blend ingredients 10 mg capsules 50 mg capsules Active ingredient in salt form 10 mg ^: 50 mg Lactose 259 mg 219 mg Starch 126 mg 126 mg Magnesium stearate 4 mg 4 mg 399 mg 399 mg

-15187 393

Other, higher dose capsule compositions may be formulated, for example, with the following composition.

Blend Component-100 mg 250 mg 500 mg section capsule capsule capsule Active ingredient, salt 100 mg 250 mg 500 mg the form Lactose 214 mg 163 mg 95 mg Starch 87 mg 81 mg 47 mg Magnesium- 4 mg 6 mg 8 mg stearate 399 mg 500 mg 650 mg

For each formulation, the active ingredient selected is mixed with lactose, starch and magnesium stearate, homogenized and filled into a capsule. 20

II. Preparation of tablets

A tablet composition of 5.0 to 25 mg of active ingredient is prepared in the following table. Similarly, a composition with a higher active ingredient content can be prepared except that the amount of dicalcium phosphate is reduced proportionately.

Active ingredient 10 mg

Corn starch 15.0 mg

Corn starch (paste) 12.0 mg

Lactose 35.0 mg

Dicalcium phosphate 132.0 mg

Calcium stearate 2.0 mg

The active ingredient, corn starch, lactose and dicalcium phosphate are mixed and homogenized. A 10% solution of the corn starch paste is prepared with water. The former mixture is granulated with starch paste and the wet mass is then passed through a 2.38 mm mesh sieve. The wet granulate was dried and passed through a 1.41 mm mesh screen. The dried granulate is then mixed with calcium stearate and compressed into tablets.

III. Preparation of injection solution

A sterile solution for injection containing 2% of the active ingredient is prepared with the following composition:

active substance 20 mg chlorobutanol preservative 0.5 w / v. % sterile viz q. s.

A solution of the above ingredients is prepared, then purified by filtration, filled into an ampoule, sealed and autoclaved.

Many other variations and embodiments of the invention will be apparent to one of ordinary skill in the art, both with respect to the compounds, compositions, and methods of the process. However, this is within the scope of the claims.

I _w according to the invention offers comparable results regarding the effect of compounds of the formula I _x A compound of formula ³⁰ general investigations are summarized in the following Table 3:

202.0 mg

Table 3

Example number: Z Price alk ¹ .. r ₂ r ₂ TTBZ ⁸ ED ₅₀ 10 H c ₆ h ₅ - (CH ₂ ) ₂ - CH ₃ ; CH ₃ 0.3 9 H c ₆ h ₅ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.2 to 0.07 27 H c ₆ h ₅ - (CH ₂ ) ₃ - CH ₃ ; H 0.07 12 H c ₆ h ₅ - (ch ₂ ) ₃ - C ₂ H ₅ ; C ₂ H _s 6.4 11 H c ₆ h ₅ - (ch ₂ ) ₃ - 4-methylmorpholine > 10.0 14 H c ₆ h ₅ - (ch ₂ ) ₃ - 1-piperidinyl > 10.0 16 8-C1 c ₆ h ₅ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 1.9 8 8-C1 c ₆ h ₅ - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 0.7 13 9-C1 c ₆ h ₅ - (CH ₂ ) ₃ - ch ₃ ; ch ₃ 7.1 15 H 4-H C1c _{ö 4} - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 4.8 23 H 4-FC ₆ H ₄ - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 0.2 18 H 4-CH ₃ C ₆ H ₄ - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 9.8 19 H 4-CH ₃ OC ₆ H ₄ - (CH ₂ ) j - ' CH ₃ ; CH ₃ > 20.0 21 H 3-H _{4 ö} C1c - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 0.7 34c H 2-BrC ₆ H ₄ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.9 34b H 2-ClC ₆ H ₄ - (ch ₂ ) ₃ - CH ₃ ; CH ₃ 0.1 34a H 2-FC ₆ H ₄ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.01-0.03 29 H 2-NO ₂ C ₆ H ₄ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.6 33 H 2-C ₅ H ₄ N - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.7 25 H c ₆ h ₅ - (CH ₂ ) ₃ - CH ₃ H; H 0.3-0.4 36 H c ₆ h, CH CH ₃ ; CH ₃ 3.3

(CH, -CHCH,)

-161

187,393

Table J (continued)

Example number: Z Price alk ¹ r, r ₂ TTBZ ⁱⁿ ED ₅₀ 37 H 2-FC _e H ₄ ch ₃ 1 (CH ₂ —CH — CH,) CH ₃ ; CH ₃ 1.4 38 H 3-FC _e H ₄ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 0.18 31 H 2-thienyl - <ch ₂ ) ₃ - CH ₃ ; CH ₃ 0.94 32 H 3-thienyl ~ (CH ₂ ) ₃ - CH ₃ ; CH ₃ 1.85 30 H 2-CF 3 - C ₆ H ₄ - (CH ₂ ) ₃ - CH ₃ ; CH ₃ 10.0 imipramine clomipramine desipramine amitriptyline 0.2-0.4 0.4 0.2 0.9

³ Tetrabenazine-Induced Ptosis Protection, ip. dosage based on the free base of the active ingredient.

Claims (7)

1. A process for the I _w pyrido [l, 4] benzodiazepines and pharmaceutically acceptable salts thereof, wherein R is hydrogen, (C 1 -C 4) -alkyl or -alk'-NR'R ^{2 in} which R * and R ^{2 are} hydrogen, (C 1 -C 4) -alkyl or R * and R ² together with the nitrogen atom enclosed are 1-phthalimido- . Forms a 1-piperidyl or 4-morpholino group, and alk ¹ represents a straight or branched alkylene group containing from ¹ to 6 carbon atoms, Ar represents unsubstituted or substituted by a halogen atom, a C 1-4 alkyl group, a 1-4 sulfur alkoxy group. , phenyl substituted by trifluoromethyl or nitro, or 2-pyridyl, 2-thienyl or 3-thienyl, Z is hydrogen or halogen, n is zero or 1, and if n is zero then the dashed 40 line represents a double bond, characterized in that 1 is a IV Formula halogen-aminopyridine, and a III aminophenyl arilmetanont wherein Ar and Z are as defined above, or the two compounds 45 II, _{W is} the reaction product of the formula wherein Z and Ar are as defined above, to ring closure and the water formed during the reaction is removed 2. reducing the resulting pyridof1,4] benzodiazepine of formula Ia, wherein Ar and Z are as defined above, optionally with sodium borocyanohydrin, to a compound of formula Ia-1 wherein Ar and Z are as defined above, and 3. the product of Steps 1 or 2, optionally 55, with a haloalk'-Q compound, wherein Q is lower dialkylamino, 1-piperidyl, 4-morpholino or 1-phthalimido; or The group of formula (2) or halogen and halo is halogen are reacted and, if n in the resulting compound of formula Ib is zero, the resulting compound is optionally reduced with sodium borocyanohydrin and 4. reacting the resulting compound of formula Ib, when 65 is phthalimido with Q, with an alcoholic hydrazine hydrate and an acid, and if n is present in the resulting compound of formula Ic, the resulting product may optionally be treated with sodium borohydride reduced, (5) optionally reacting the compound of formula Ic obtained in step 4 with triethyl ortho-formic acid to form the methanimide ester of formula Id, followed by reduction of the methanimide ester with sodium borohydride, where n is reduced to zero, optionally with sodium borohydride, 6. converting the compound of formula Ib obtained in Step 3, when Q is chlorine, into a compound of formula Ib-3 with a dialkylamine wherein Ar, Z, alk * and n are as defined above, 7. The product of step 1 or 2 with an alkyl halide, if desired, to give compounds of formula (I _w is obtained, wherein R is C1-4 alkyl, followed, the compounds (compounds of Formula I _w for which n = 0, optionally reduced with sodium borohydride cyanohydrin, and, if desired, the resulting I _w compound of formula into a pharmaceutically acceptable salt thereof. A process for the preparation of pyrido [1,4] benzodiazepines of formula I _A, which is a narrower class of compounds of formula I _w , wherein: Ar is unsubstituted or substituted by one substituent, namely, halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro, Z is hydrogen or halogen, characterized in that a haloaminopyridine of formula IV and a aminophenyl-aryl-methanone in which Ar and Z are as defined above, or a compound of formula II, _W reaction desired; where Z and Ar are as described above, are cyclized, the water formed during the reaction is removed and the resulting pyrido17 -171 187,393 [1,4] benzodiazepine, wherein Ar and Z are as defined above, optionally with sodium borocyanohydrin, to form a compound of formula Ia-1, wherein Ar and Z are as defined above. The process according to claim 2, wherein the ring closure is carried out at 170-200 ° C. The process according to claim 2, wherein the water is removed by heating in a non-proton solvent under reflux. ¹ 5. A process for the preparation of antidepressant pharmaceutical composition wherein I _w is a compound wherein _one R is hydrogen, (C 1 -C 4) -alkyl or -alk'-NR'R ² in which R ¹ and R ^{2 are} hydrogen or (C 1 -C 4) -alkyl or R ¹ and R ² together with the nitrogen atom to which they are attached are 1-phthalimido, 1 piperidyl, or 4-morfolino group, alk ¹ is is C 1 -C 6 agreement ^b linear or branched alkylene, Ar is unsubstituted or substituted with a substituent selected from halo, C 14 alkyl, C 1-4 alkoxy or nitro phenyl, or 2 pyridyl, 2-thienyl or 3-thienyl, Z is hydrogen or halogen, n is zero or 1, and when n is zero, the dashed line represents a double bond or is pharmaceutically acceptable. acid addition salts with conventional excipients, diluents and, if desired, e. mixed with other excipients to form a medicament.