NO157700B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIDO (1,4) BENZODIAZEPINES. - Google Patents

Description

The present invention relates to the production of therapeutically active, new pyrido[1,4]benzodiazepines which can be used in the treatment of depression in humans.

Wander, A., describes in British patent literature

907 646 preparation of certain dibenzodiazepines substituted with phenyl radicals on carbon and with alkyl or aminoalkyl radicals on the nitrogen bridge atom between the phenyl rings.

Greig, M.E., et al., J. Med. Chem. 14 no. 2, page 153 (1971) describes dibenzodiazepines similar to the preceding publication, which are useful against anaphylactic shock.

Japanese patent document 73/43,520 (CA. 80: 1335501n) describes 6-phenyl-2,3,4,4a-tetrahydro-11H-pyrido[2,3-b]-[1,4]benzodiazepines with anticonvulsant activity as illu- stratively is produced from 2-aminobenzophenones and ornithine.

The new pyrido[1,4]benzodiazepines produced according to the invention have the formula

in which

R1 and R2 are selected from the group consisting of hydrogen, C1-C4

1 2

alkyl or -C(O)O-(C1~C4 alkyl), or R and R together with the adjacent nitrogen atom form a 1-phthalimido-, 1-pyrrolidinyl-, 4-morpholino- or 1-piperidinyl-

rest,

alk<1> is a straight-chain or branched hydrocarbon chain containing 1-4 carbon atoms,

Ar is selected from the group consisting of 2-, 3- or 4-pyridinyl,

2- or 3-thienyl, phenyl or phenyl substituted with halo-

gene, C1-C4 alkyl or C1-C4 alkoxy, trifluoromethyl or nitro,

Z is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy,

and acid addition salts thereof.

The compounds of formula I are used as antidepressants in the treatment of depression.

By the further definition of symbols in the formulas

and where these would otherwise appear in this description and requirements, the expressions have the following meaning:

"alk"*"" which is a straight-chain or branched, cross-linking hydrocarbon chain containing 1-4 carbon atoms, can be exemplified by methylene (-CH^-), ethylene (-CH2-CH2-),

The term "C 1 -C 4 alkyl" includes straight or branched chain hydrocarbon radicals of up to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl.

Pharmaceutically acceptable acid addition salts are those salts formed by pyridobenzodiazepines: prepared according to the invention with any acid physiologically compatible in warm-blooded animals, and such salts are formed either by strong or weak acids. 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, cyclohexanoic acid and the like.

To test the antidepressant activity of the new compounds, the method described by Englehardt, E.L., et al., J. Med. Chem. 11(2): 325 (1968) applied, which has been indicative in recent times of the applicability of compounds for the treatment of human depressions:

20 mg/kg of the compound to be tested was administered to five adult female mice (ICR-DUB strain), intra-peritoneally 30 minutes before the administration of a ptotic dose (32 mg/kg IP) of tetrabenazine (as the methanesulfonate salt). 30 minutes later, the presence or absence of complete eyelid closure (ptosis) was determined in each animal. An eD5q (mean effective dose) can be determined for each tested compound in blocking tetrabenazine-induced depression in mice following the procedure described by Litchfield et al., J. Pharmacol. Exp. Therap. 96: 99-113 (1949). 1 2 ' The compounds of formula I wherein R and R are C 1 -C 4 alkyl or hydrogen have shown evidence of low incidence of antihistamine, anticholinergic and cardiotoxic side effects when tested in animals.

The preferred pyridobenzodiazepines for treatment

of depression are the following:

The analogous process for the production of the new pyridobenzodiazepines of formula I is characterized by 1) a mixture of haloaminepyridine of formula and an (aminophenyl)arylmethanone of formula or a reaction product thereof of formula in which Z and Ar are as defined above, is heated under conditions to remove water and cyclize these to a pyrido[1,4]benzodiazepine of formula

in which Ar and Z are as above defined, after which

2) the product from step 1) is sold

with a halo-alk^-Q reagent wherein Q is selected from the group consisting of -N-(C1-C4 alkyl)2, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholino, 1-phthalimido,

0

-N-C-O-(C1~C4 alkyl) or halogen,

(-^i-c4 alkyl1)

while forming a compound of formula

after which

3) when Q is phthalimido, a compound prepared in step 2) is optionally reacted with alcoholic hydrazine hydrate and an acid to form a compound of formula

4) a compound prepared in step 3) is optionally reacted with triethylorthoformate for a period of time sufficient to form the methanimidine acid ester of formula and then the methanimidine ester is reduced with sodium borohydride to a compound of formula 5) a compound prepared in step 2) in which Q is alkyl) optionally hydrolyzed while forming a compound of formula in which Ar, Z and alk<1> are as indicated above, and 6) when Q is halogen in a compound prepared in step 2), that this is reacted with a dialkylamine while forming a compound of formula

after which, if desired, a compound obtained is converted into an acid addition salt thereof.

The reaction order for the preparation of the compounds is indicated in reaction core 1. Alternative procedures for the preparation of certain compounds of formula I are indicated by reaction equations in reaction cores 2 and 3.

Compounds of formula Ia in which R is hydrogen are alkylaminated, or radicals are introduced which will lead to alkylamination by first reacting with sodium hydride and then with a suitable reagent represented by halo-alk^Q in which "alk<1>" has the above meaning and Q is as defined in the reaction core. 1. The compounds suspended in a suitable solvent such as dimethylformamide are added to a stirred suspension of sodium hydride in the same solvent. The halo-alk^Q reagent (alkyl-aminating agent or agent leading to alkylamination) is added at room temperature and the reaction mixture is stirred for a period of time until the reaction is complete, for example as determined by thin layer chromatography. The unreacted sodium hydride is split by addition of water and the product is extracted with a suitable solvent such as methylene chloride followed by aqueous acid extraction of the solvent layer and isolation of the product from the aqueous layer by neutralization and re-extraction with methylene chloride, followed by evaporation and precipitation, preferably as an addition salt such as fumarate, hydrochloride, oxalate, maleate and the like. Once an acid addition salt has been obtained and purified, the free base can generally be regenerated by partitioning the salt between an aqueous base and a suitable solvent such as methylene chloride, and evaporating the methylene chloride layer. Alternatively, compounds of formula Ib in which Q is halogen can be converted into compounds in which Q is -N-(C 1 -C 4 alkyl) 2 by reaction with a suitable dialkylamine as indicated in the reaction series in reaction scheme 2.

The primary amines of formula Ic; i.e. R<1> and R<2> are both hydrogen, are prepared from the -alk1-!!)-(1-f thalimido)-derivatives as shown in reaction core 1, by reaction with hydrazine hydrate, using the method which is described by Org. Sight. Coll. Vol. III, pp. 151 - 153. In general, 2 to 3 hours of refluxing is sufficient, after which aqueous acid is added and the mixture is filtered. The primary -alk<1->amines are isolated from suitable solvents such as isopropyl alcohol. Hydrochlorides and hydrochloride hydrates are preferred salts in the isolation step.

Alk 1 -C 1 -monoalkylamines (formula le), e.g. R<1> = methyl, R 2= hydrogen, can be prepared as shown in reaction scheme 1 by reacting the primary -alk^-N^-deri-

hydrate Ic with refluxing triethyl orthoformate for a time sufficient to form the methanimidine acid ester (I-d) which is then reacted with sodium borohydride. The unreacted borohydride is split with water and the product is extracted with a suitable solvent, such as ethyl acetate, and can

purified by column chromatography and partitioning with a basic solvent. Hydrochlorides are preferred salts in the isolation step. The method is fully exemplified in example 16.

A further more generalized alternative for introducing -alk1-&>-mono (C1-C4 alkyl) amine radicals is via the radical:

See reaction nucleus 3.

<*> Q is selected from the group consisting of -N-(C-^-C^ alkyl) 2, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholino, 1-phthalimido, or halogen.

Preparation of the new phenyl-substituted pyrido[1,4]-benzodiazepine compounds is exemplified in the following examples. The structures for the compounds in the examples are illustrated in table 1.

Example 1

8- chloro- N, N- d±methyl- 6- phenyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- ll- propanamine- oxalate [ 1:1]

6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H-pyrido[ 2,3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 1 1/2 hours, during which time evolution of hydrogen ceased. 3.5 g (0.022 mol) of 3-dimethylaminopropyl chloride hydrochloride was added portionwise to the mixture. After stirring overnight at room temperature, the reaction mixture was poured into 1600 ml of water and the combination extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extract was washed with two 250 mL portions of water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in benzene and chromatographed with acetone-benzene on a 300 g column of florisil packed in benzene. The starting material, 1.6 g, was recovered

in the benzene elution and 3.6 g containing the product as free base was obtained from the acetone-benzene elution by evaporation of the solvent. A portion of the impure free base, 2.5 g, was dissolved in hot isopropyl alcohol and reacted with 0.8 g (0.0064 mol) of oxalic acid dihydrate. The oxalate salt that precipitates on cooling was collected by filtration and recrystallized from ethanol to form 2.2 g of product with m.p. 206 - 208° C. The drying conditions for the analyzes were: 5 hours at 97 - 98° C/0.02 mnHg; overnight at room temperature/ 0.02 mmHg.

Example 2 N,N-dimethy1-6-phenyl-llH-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 and under a nitrogen atmosphere a suspension of 8.0 g (0.029 mol) of 6-phenyl-11H-pyrido[2,3-b]-[1,4]benzodiazepine was added portionwise in 20 ml anhydrous dimethylformamide. The mixture was stirred for 30 minutes after the addition was complete, heated to 65°C for 15 minutes and cooled again to room temperature. To the mixture was added 5.8 g (0.035 mol) of 3-dimethylaminopropyl chloride hydrochloride. After stirring overnight at room temperature, thin layer chromatography indicated that the reaction was almost complete. The reaction mixture was poured over 1500 ml of water and extracted with 250 ml of methylene chloride. The methylene chloride extract was washed with three 250 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methylene chloride and extracted with 100 ml and 150 ml portions of 3N hydrochloric acid. Unreacted 6-phenyl-11H-pyrido-[2,3-b][1,4]benzodiazepine starting material was precipitated from the aqueous acid solution and was separated by careful decantation of the liquid from the solid. The aqueous solution was basified with 3N sodium hydroxide and extracted with three 150 mL portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give 7.7 g of residue, the free base of the title compound. A solution of 6.6 g of the residue in hot isopropyl alcohol was reacted with 2.15 g of fumaric acid, and the mixture was heated until dissolution was complete. After standing for 48 hours, the salt that had settled was collected by filtration. After recrystallization from isopropyl alcohol-isopropyl ether, 15.9 g of product with m.p. 171 - 173° C. Drying conditions before the analyzes from: 4 hours at 90° C/0.1 mmHg; overnight at room temperature/O .1 mmHg.

Example . 3

N,N- dimethyl- 6-f ertyl- llH- pyrido [ 2 , 3- b] [ 1, 4] benzodiazepine-11- ethamine- fumarate [ 1:1]

7.0 g (0.026 mol) of 6-phenyl-11H-pyrido[2,3-b ][1,4]benzodiazepine. After cooling the reaction mixture to room temperature, 4.46 g (0.031 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise and stirring was continued overnight. The reaction mixture was poured into 1500 ml of water, and the resulting mixture was extracted with 250 ml of methylene chloride. The ethylene chloride extract was washed with three 500 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure to give 8.6 g of an oil, the free base of the title compound. A portion of the oil, 6.9 g, was reacted with an equal molar amount of fumaric acid in isopropyl alcohol. Addition of isopropyl ether gave an oily solid. The mixture was evaporated under reduced pressure and the residue recrystallized on standing. The crystals were triturated with acetone and crystallized from acetone-isopropyl ether to give 4.3 g of the fumarate salt with m.p. 175 - 177.5° C.

Example 4.

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

5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido[2,3- b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 15 minutes, was heated to 65-70°C for 10 minutes and allowed to cool to room temperature. 4.1 g (0.02 mol) of 4-(3-chloropropyl)morpholine hydrochloride was added portionwise to the mixture. The reaction mixture was stirred at room temperature for 16 hours and then poured into 800 ml of water. This mixture was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 mL and 75 mL portions of 3N hydrochloric acid, and the combined aqueous extracts were basified with 3N sodium hydroxide. The resulting suspension was extracted with two 150 ml<1>s portions of methylene chloride,

and these two latter extracts were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue, the free base of the title compound, was reacted with an equal molar amount of fumaric acid in hot isopropyl alcohol, and the mixture was treated with isopropyl ether. The fumarate salt was collected by filtration and recrystallized from ethanol-ethyl acetate to give 5.6 g of m.p. 154 - 157° C. The drying conditions before the analysis were: 4 hours at 97 - 98° C/ 0.1 mmHg; overnight at room temperature/0.1 mm Hg.

Example 5

N, N- diethy1- 6- phenyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine-11- propanamine- oxalate [ 1:1]

To a stirred suspension of 1.10 g (0.0461 mol) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under a nitrogen atmosphere was added portionwise 5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido[2, 3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 1/2 hour, was heated to 65 - 70° C. and cooled slowly to room temperature. 3.77 g (0.020 mol) of 3-diethylaminopropyl chloride hydrochloride was added portionwise to the mixture, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into 750 ml of water and added

three 150 ml portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 mL and 75 mL portions of 3N hydrochloric acid. The combined aqueous extracts were basified with 3N sodium hydroxide and then extracted with 300 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. One portion, 5.6 g, was

reacted with an equal molar amount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalate salt was collected by filtration to form 5.5 g of product with m.p. 196 - 199° C. Drying conditions before the analyzes were: 1 hour at 97 - 98° C/ 0.11 mit Hg.

Example 6

9- chloro- N, N- diarethy. l- 6- phenyl- llH- pyrido[ 2, 3-b] [ l, 4] benzodiazepine- ll- 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[2, 3-b][l,4]benzodiazepine over a 45 minute period. The reaction mixture was stirred at room temperature for 1 hour, was heated to 70° C., and then slowly cooled to room temperature. To the mixture was added portionwise over a 30 minute period, 2.84 g (0.018 mol) of 3-dimethylaminopropyl chloride hydrochloride, and the reaction mixture was stirred at room temperature for 17 hours. The mixture was poured into 750 ml of water and extracted with 150 ml and two 100 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 200 ml portions of water, followed by extraction with 100 ml and 75 ml portions of 3N hydrochloric acid. The acid extracts were combined and filtered to remove any precipitate that had formed, and the filtrate was basified with 3N sodium hydroxide and extracted with 300 mL portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methylene chloride and filtered through

a 50 - 60 g layer of florisil in a sintered glass funnel. The layer was washed successively with 1%, 2%, 3% and 5% methanol-methylene chloride mixtures, the filtrates were combined and evaporated under reduced pressure to give the free base of the title compound. The free base was reacted with an equal molar amount of fumaric acid in hot isopropanol below

formation of 3.3 g of fumarate, m.p. 199 - 202° C.

Example 7.

6- f eny 1- 11- [ 3- ( 1- plperldlnyl) propyl] - HH- pyrido [ 2 , 3- b] -

[ 1, 4] benzodiazepine fumarate [ 1:1]

5.0 g (0.018 mol) of 6-phenyl-11H-pyrido[2,3- b][1,4]benzodiazepine. The reaction mixture was stirred for 30 minutes, was heated to 70°C and cooled to room temperature. To the mixture was added portionwise 4.14 g (0.0203 mol) of N-(3-chloropropyl)-piperidine hydrochloride, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into 750 ml of water, extracted with 150 ml of methylene chloride and stirred for 15 minutes. The aqueous layer was extracted with two additional 100 mL portions of methylene chloride. The combined methylene chloride extracts were extracted with 150 ml and 75 ml<1>s portions of 3N hydrochloric acid and the combined acid extracts were basified with 3N sodium hydroxide 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 was dissolved in a minimum of methylene chloride and filtered through a 100 g layer of florisil in a sintered glass funnel. The layer was washed successively with methylene chloride, 1%, 2%, 3% and 5% methanol-methylene chloride mixtures. 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 formed. The entire mixture was evaporated to dryness and the residue dissolved in 200 ml of ethanol. The solution was heated to reflux, filtered and isopropyl ether added to the filtrate. Crystals that formed overnight were filtered off to give 4.1 g of fumarate salt, m.p. 153 - 156° C. drying conditions before analysis were: 4 hours at 97 - 98° q/ 0.1 mm Hg.

Example 8.

6-( 4- Chlorophenyl)- N, N- dimethyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- ll- 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 was added under a nitrogen atmosphere, 8.2 g (0.0 26 mol) of 6-(4-chlorophenyl)-11H-pyrido [2,3-b][1,4]benzodiazepine. The reaction mixture was stirred for 1 hour at room temperature, was heated to 80° C. for 15 minutes and cooled to room temperature. 4.55 g (0.029 mol) of 3-dimethylaminopropyl chloride-hydrochloride was added portionwise to the mixture, and the mixture was stirred overnight at room temperature. The mixture was poured into 750 ml of water and stirred for 30 minutes with 150 ml of methylene chloride. The aqueous layer was further extracted with 300 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the free base of the title compound. The free base was reacted with an equal molar amount of fumaric acid in hot isopropanol. On cooling, 3.6 g of the fumar salt with a melting point of 200.5 - 202.5° C. was precipitated. The product was air-dried before the analysis. Analysis: Calculated for C27H2?C1N4O4: C 63.96 H 5.37 N 11.05

Found : C 64.18 H 5.33 N 11.07 Example - 9

8- chloro- N, N- dimethyl- 6- phenyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- ll- ethanamine- oxalate [ 1:1]

6.1 g (0.02 mol) of 8-chloro-6-phenyl-11H-pyrido[2, 3-b][1,4]benzodiazepine. The reaction mixture was stirred at room temperature for 1 1/2 hours, during which time evolution of hydrogen had ceased. The reaction mixture was cooled to 5°C, and 3.2 g (0.022 mol) of 2-dimethylaminoethyl chloride hydrochloride was added portionwise, followed by stirring at room temperature for approx. 60 hours. The reaction mixture was poured into 1600 ml of water and the mixture was extracted three times with 500 ml portions of methylene chloride. 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 on silica gel) indicated the presence of free base of the title compound and of the starting material. The residue was dissolved in benzene and chromatographed on a 200 g column of florisil packed in benzene. The starting material, 1.3 g of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, was eluted with benzene, and the free base of the title compound was eluted with mixtures of acetone in benzene . The free base was reacted with an equal molar amount of oxalic acid dihydrate in refluxing isopropyl alcohol, and the product recrystallized from iso-pronyl alcohol weighed 1.6 g and had a melting point of 228.5 - 232° C. Drying conditions before analysis were 6 hours at 82° C/ 0.1 mmHg; overnight at room temperature.

Example 10

N,N- dimethyl- 6-( 4- methylphenyl)- llH- pyrido[ 2, 3-b][ 1, 4]-benzodiazepine- ll- propanamine- fumarate [ 1:1]

To a stirred suspension of 0.51 g (0.022 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide under a nitrogen atmosphere, 4.2 g (0.0147 mol) of 6-(4-methylphenyl)-11H-pyrido[2,3- b][1,4]benzodiazepine within 45 minutes. The mixture was stirred for 1 hour at room temperature, was heated to 75-80°C for 1 hour, was cooled to room temperature, and a solution of 0.0184 mol of 3-dimethylaminopropyl chloride in 10 ml of anhydrous dimethylformamide was added dropwise. The mixture was stirred overnight at room temperature and poured into 1000 ml of water. The suspension was extracted with three 150 ml portions of methylene chloride, and the combined methylene chloride extracts were extracted with two 150 ml portions of 3N hydrochloric acid. A precipitate formed in the acidic solution was removed by filtration and discarded. The filtrate was basified with 3N NaOH 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, the free base of the title compound. This residual oil was dissolved in hot isopropyl alcohol and reacted with an equal molar amount of fumaric acid. The fumarate salt crystallized as the solution was cooled to room temperature, and was recrystallized twice from isopropyl alcohol-isopropyl ether to give 1.7 g of product, mp 187-189°C (dec).

Example 11

6-(4-Methoxypheny1)-N,N-dimethy1-1lH-pyrido[2,3-b] [1,4]-benzodiazepine-ll-propanamine- fumarate [1:1]

4.5 g (0.015 mol) of 6-(4-methoxy-phenyl)-HH-pyrido [2 , 3 -b] [1, 4] benzodiazepine within 30 minutes. The mixture was stirred for 30 minutes at room temperature followed by heating to 80-90°C for 1 hour,

and was cooled to room temperature whereupon 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 poured into 800 ml of water. The suspension was extracted with two 150 ml portions of methylene chloride. The combined extracts were washed with 500 ml of water and then extracted with two 100 ml portions of 3N hydrochloric acid. The solid material that precipitated from the combined acid extracts was filtered off and discarded. The filtrate was basified with 3N sodium hydroxide 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. The residual oil had partially crystallized and was triturated in methylene chloride and filtered, forming a residue of 0.32 g. The filtrate was evaporated under reduced pressure and the residual oil triturated in hot benzene and filtered, forming a residue of 0.8 g. The benzene filtrate was evaporated during

reduced pressure and the residual oil was reacted with 1.02 g of fumaric acid in hot isopropyl alcohol. On cooling, the oil separates from the solution. The supernatant liquid was decanted and the oil seeded. After partial crystallization, the mixture was filtered to give 2.5 g of solid material with m.p. 157 -

160° C. An attempt at recrystallization from isopropyl alcohol-isopropyl ether again gave an oil-solid mixture. The mixture was heated with additional isopropyl alcohol, dissolved, filtered, seeded and cooled. The precipitated fumarate salt was collected by filtration to give 2.0 g of m.p. 159 - 161° C.

Example 12

6-( 3- Chlorophenyl)- N, N- dimethyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- ll- 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 was added under a nitrogen atmosphere and portionwise 8.5 g (0.028 mol) of 5-(3-chlorophenyl)-11H-pyrido [2,3-b][1,4]-benzodiazepine. The mixture was stirred for 30 minutes at room temperature. The temperature was raised to 80° C. for 3 hours and then allowed to cool to room temperature. A solution of 4.9 g was added dropwise to the reaction mixture

(0.031 mol) of 3-dimethylaminopropyl chloride-hydrochloride in 30 ml of dimethylformamide over 20 minutes. The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The thin layer chromatography indicated some starting material was present. Additional sodium hydride, 1.4 g (0.03 mol), was added and after 15 minutes, 4.7 g (0.03 mol) of 3-dimethylaminopropyl chloride hydrochloride was added followed by stirring for 4 1/2 hours. 20 ml of water was added dropwise and the reaction mixture was filtered and concentrated on a rotary evaporator. The residue was partitioned between diethyl ether and dilute sodium hydroxide. The ether layer was washed with water three times and extracted with dilute

aqueous hydrochloric acid. The aqueous layer was basified with sodium hydroxide pellets and extracted with methylene chloride. The methylene chloride layer was dried and concentrated to give a residue of 7.5 g of product. The free base was reacted with fumaric acid and the fumarate salt was recrystallized from ethyl acetate-ethanol, m.p. 167.5 - 168.5° C.

Example 13

6-( 4- fluorophenyl)- N, N- dimethyl- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11- propanamine- hydrochloride- hemihydrate

To a stirred suspension of 3.6 g (0.075 mol) of sodium hydride (in mineral oil) in 250 ml of anhydrous dimethylformamide was added under a nitrogen atmosphere and in portions, 8.7 g (0.03 mol) of 6-(4-fluorophenyl )-11H-pyrido[2,3-b] [1, 4]-benzodiazepine. The mixture was stirred for 30 minutes at room temperature. The temperature was raised to 80° C. for 3 1/2 hours, and then allowed to cool to 45° C. A solution of 5.2 g (0.033 mol) 3-dimethylaminopropyl chloride hydrochloride in 30 ml dimethylformamide was added dropwise to the reaction mixture. . After stirring overnight at room temperature, thin layer chromatography indicated the presence of starting material. Additional sodium hydride, 3.6 g (0.075 mol), was added and after 45 minutes of stirring, the reaction mixture was heated to 50-60°C for 1/2 hour. A green color was developed during the formation of gas. The mixture was stirred at room temperature for 3 hours. A solution of 5.2 g (0.033 mol) of 3-dimethylaminopropyl chloride in 30 ml of dimethylformamide was added dropwise. (About halfway through the addition, a green color developed and the addition was stopped temporarily for about 1 hour). The reaction mixture was stirred overnight at room temperature. 30 ml of water was added to the mixture while cooling. After gas evolution had stopped, the mixture was filtered and concentrated in a rotary evaporator. The residue was partitioned between diethyl ether and water, and the ether layer was extracted with dilute aqueous hydrochloric acid solution. The aqueous layer was filtered off

1 - 1/2 hour to remove solid material. The filtrate was basified with sodium hydroxide pellets and extracted with methylene chloride. The extract was dried and concentrated. The residue was divided into two equal portions and purified by dry column chromatography on two 50.8 x 3.8 cm columns of silica gel that had been deactivated by the developing solvent (10% methanol, 1% conc. ammonium hydroxide, 89% methylene chloride). . The center of the column was cut out and extracted with the developing solvent. The combined extracts were concentrated under reduced pressure and the residue dissolved in ethyl acetate-ethanol mixture and acidified with concentrated hydrochloric acid. The hydrochloride salt was recrystallized from the ethanol-ethyl acetate mixture. The solid material obtained by filtration was dried at 99° C. for 48 hours to give the title compound as monohydrochloride hemihydrate of m.p. 120 - 123° C.

Example 14

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

To a stirred suspension of 0.56 g (0.023 mol) of sodium hydride in 25 ml of anhydrous dimethylformamide was added portionwise, 5.0 g (0.0184 mol) of 6-phenyl-11H-pyrido[2,3]-[1,4 ]benzodiazepine. The reaction mixture was heated to 80°C - 2°C for 1 hour and was cooled to room temperature.

A solution of 5.55 g (0.020 mol) N-(3-bromopropyl)-phthalimide in 10 ml of anhydrous dimethylformamide was added dropwise, and after stirring for 16 hours, the reaction mixture was poured into 650 ml of water and stirred for 30 minutes.

The yellow solid was collected by filtration and recrystallized three times from isopropyl alcohol to give 3.7 g of product, m.p. 170 - 172° C.

Example 15

6- phenyl- llH- pyrido[ 2, 3-b][ 1, 4] benzodiazepine- ll-propanamine— dihydrochloride- hemihydrate

A mixture of 16.2 g (0.035 mol) of 6-phenyl-11-[3-(phthalimido)propyl]-11H-pyrido[2,3-b][1,4]benzodiazepine and 2.29 g (0, 0387 mol) hydrazine hydrate, 85% in 175 ml of 95% ethyl alcohol was boiled under reflux for 2 1/2 hours and allowed to stand for 72 hours. A solution of 10 ml of concentrated hydrochloric acid in 50 ml of water was added to the mixture. The mixture was stirred overnight. The solid precipitate was collected by filtration and removed. The filtrate was evaporated under reduced pressure. The residue which was considerably wet was suspended in 200 ml of water, the mixture was stirred for 2 hours and filtered through celite. The filtrate was evaporated under reduced pressure and the residue suspended in 100 ml of 100% ethyl alcohol and evaporated under reduced pressure. The latter procedure was repeated. The impure, moist residue (42.1 g) was recrystallized from isopropanol under standing for approx. 15 hours. The solid material, collected by filtration, was dried at 82°C over phosphoric anhydride at 0.1 mm HG for 3 hours; sm.p. 210 - 220° C (decomposition).

Example 16

N- methyl- 6- phenyl- llH- pyrido[ 2, 3-b][ 1, 4] benzodiazepine- ll-propanamine- dihydrochloride

Preparation of imide tests

[Procedure described by Crochet, T.A. & Blanton, C.D., Jr. Synthesis 1974 (1) 55-56]

25 g (0.06 mol) 6-phenyl-11H-pyrido[2,3-b][1,4]-benzodiazepine-11-propanamine dihydrochloride hemihydrate from

Example 15 was converted to the free base by partitioning between dilute sodium hydroxide and methylene chloride, drying and concentrating the methylene chloride layer to dryness, adding dry benzene, and again concentrating to drive off the benzene. The resulting free base was dissolved in 300 mL (267 g, 1.8 mol) of freshly distilled triethyl orthoformate under reflux for 9 hours. The mixture was concentrated in

vacuum, ethanol was added and the mixture was concentrated again.

Conversion of amidate to amine

23.4 g (0.061 mol) of the amidate prepared in the previous section was dissolved in 200 ml of ethanol and sodium borohydrate was added with stirring at 15 - 20° C until thin layer chromatography indicated that the reaction was substantially complete as indicated by the absence of starting material. 50 ml of water was slowly added with stirring and cooling was continued for 15 minutes after the water addition. The mixture was then poured with 2 liters of water and extracted with ethyl acetate. The ethyl acetate layer was washed with water until

neutral wash water was obtained, and was then saturated with sodium chloride. The resulting ethyl acetate layer was dried and concentrated. Diethyl ether was added and the mixture cooled. Some insoluble material was filtered off and discarded. The ether layer was concentrated and the product chromatographed on an aluminum oxide column (neutral, activity-1) and eluted with ethyl acetate + methanol + traces of triethylamine. The fractions containing mainly product (TLC) were partitioned between ethyl acetate and aqueous sodium hydroxide. Etheric hydrogen chloride was added to the ethyl acetate layer and the crystalline product was recrystallized from acetonitrile-water mixture. The melting point of the product was 139 - 141° C.

Example 17

5, 6- dihydro- N, N- dimethyl- 6- phenyl- llH- pyrido[ 2, 3- b][ 1, 4]-benzodiazepine- ll- propanamine- dihydrochloride- hemihydrate

A solution of 3.0 g (0.0064 mol) of N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine in absolute methanol was adjusted to pH 5.6 with methanolic hydrogen chloride solution. To this solution was added at once 0.7 g (0.011 mol) of NaBH 2 CN and the reaction mixture was refluxed for 20 minutes. The ethanol was removed in vacuo and the residue partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated to form a residue which was crystallized twice from 2-propanol and isopropyl ether. A yellow solid, 1.6 g (57%) was obtained, which lost its crystalline structure on heating starting at 156-160°C with decomposition at 180-195°C.

Examples 18a - 18b

Using the procedure described in Example 8, but using equal molar amounts of each of 6-(4-ethylphenyl)-11H-pyrido[2,3-b][1,4Jbenzodiazepine and 6-(3-trifluoromethyl- phenyl)-llH-pyrido[2,3-b][1,4]benzodiazepine, the following 6-phenyl-substituted-pyridobenzodiazepines were prepared: a) 6-(4-ethylphenyl)-N,N-dimethyl-llH-pyrido [2,3-b][1,4]-benzodiazepine-11-propanamine.

The monohydrochloride salt of the compound prepared above was prepared and recrystallized from isopropyl alcohol to give a yellow solid, mp 239-240°C. Formula: C23H24N502C1. b) N,N-dimethyl-6-[4-(trifluoromethyl)phenyl]-HH-pyrido[2,3-b]-[1,4]benzodiazepine-11-propanamine.

The monofumarate salt of the compound prepared above

was prepared and recrystallized from isopropyl alcohol/isopropyl ether, whereby 1.48 g of yellow solid was obtained, melting point 160 - 162°C. Formula: C28H27N4°4F3*

Example 19

N, N- dimethyl1- 6-( 2- thienyl)- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11- propanamine •

Following the procedure described in Example 13, 6-(2-thienyl)-11H-pyrido[2,3-b][1,4]-benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to form of the title compound.

The monohydrochloride hemihydrate salt of the compound prepared above was prepared from ethereal hydrogen chloride in isopropyl alcohol/isopropyl ether mixture and recrystallized from isopropyl alcohol/ethyl acetate to give yellow small grains.

melting point 176 - 178°C. Formula: c2iH24N4°o 5S'

Example 20

N, N- dimethyl- 6-( 3- thlenyl)- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11- propanamine

Following the procedure described in Example 13, 6-(3-thienyl)-11H-pyrido[2,3-b][1,4]-benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to form of the title compound.

The monooxalate salt of the compound prepared above was prepared and recrystallized from isopropyl alcohol/water, whereby dark yellow flakes were obtained, melting point 203-204°C. Formula: C0-,H„ .N .0.S.

23 24 4 4

Example 21

N, N- dimethy1- 6-( 2- pyridiny1)- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11- propanamine

Following the procedure described in Example 13, 6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]-benzodiazepine was reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to form of the title compound.

The monooxalate salt of the compound prepared above was prepared from ethereal hydrogen chloride in isopropyl alcohol/isopropyl ether mixture, separated and recrystallized from isopropyl alcohol/ethyl acetate and dried at 98°C under vacuum for 36 hours. The product is a yellow solid, melting point 176.5 - 178°C (with decomposition). Formula: C24H25N5°4"

Example 22a - 22c

By following the procedure described in Example 13, but using the following pyrido[1,4]benzodiazepines instead of 6-(4-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine: 6-(2-fluorophenyl)-llH-pyrido[2,3-b][1,4]benzodiazepine, 6-(2-chlorophenyl)-llH-pyrido[2,3-b][1,4]benzodiazepine, 6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine,

was obtained:

a) 6-(2-fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]-benzodiazepine-11-propanamine, m.p. 92 - 94°C; recrystallization solvent: isopropyl alcohol-isopropyl ether, b) 6-(2-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]-benzodiazepine-11-propanamine, m.p. . 104 - 105 C; recrystallization solvent: isopropyl ether, and c) 6-(2-bromophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]-benzodiazepine-11-propanamine, sm. p. 96 - 98°C; recrystallization solvent: isopropyl ether.

Comparative data

Claims (1)

Analogy method for the preparation of therapeutic active pyrido[1,4]benzodiazepines of formula in which R 1 and R 2 are selected from the group consisting of hydrogen, C1-C. 1 2 14 alkyl or -C(0)0-(C^-C4 alkyl), or R and R together with the adjacent nitrogen atom form a 1-phthalimido-, 1-pyrrolidinyl-, 4-morpholino- or 1-piperidinyl- rest, alk1 is a straight or branched hydrocarbon chain containing 1-4 carbon atoms, Ar is selected from the group consisting of 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted with halogen, C-^-C 4 alkyl or C-^-C 4 alkoxy, trifluoromethyl or nitro, Z is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and acid addition salts thereof, characterized in that (1) a mixture of haloaminepyridine of formula and an (aminophenyl)arylmethanone of formula or a reaction product thereof of formula in which Z and Ar are as defined above, heated under conditions to remove water and cyclize these to a pyridote1,4]benzodiazepine of formula in which Ar and Z are defined as above, after which 2) the product from step 1) is reacted with a halo-alk^-Q reagent wherein Q is selected from the group consisting of -N-(C1-C4 alkyl)2, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholino, 1-phthalimido, or halogen, forming a compound of formula after which 3) when Q is phthalimido, a compound prepared in step 2) is optionally reacted with alcoholic hydrazine hydrate and an acid while forming a compound of formula 4) a compound prepared in step 3) is optionally reacted with triethylorthoformate for a period of time sufficient to form the methanimidine ester of formula and then the methanimidine ester is reduced with sodium borohydride to a compound of formula 5) a compound prepared in step 2) wherein Q is possibly hydrolyzed during formation of a compound of formula in which Ar, Z and alk<1> are as indicated above, and 6) when Q is halogen in a compound prepared in step 2), that this is reacted with a dialkylamine to form a compound of formula after which, if desired, a compound obtained is converted into an acid addition salt thereof.