NO161175B - Pyrido (1,4) benzodiazepine. - Google Patents

Description

The present invention relates to new pyrido[1,4]-benzodiazepines. The new compounds are intermediates in the analogue process for the production of therapeutically active pyrido[1,4]benzodiazepines according to Norwegian patent document no. 157,700.

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

wherein Ar is selected from the group consisting of phenyl or phenyl substituted with halogen, C₁-C₁ alkyl, C₁-C₁ alkoxy, trifluoromethyl or nitro, and

Z is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

The compounds according to the invention can be prepared by 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 for removal of water and cyclization. The production is also evident from reaction core 1 below. The [2-[(amino-pyridinyl)amino]phenyl]-arylmethanone intermediates (or precursors) of formula II are the subject of Norwegian patent application no. 872271. As mentioned, the new compounds according to the present invention can be used as intermediates in the preparation of therapeutically active end products. The end products that are produced according to Norwegian patent document no. 157,700 are pyrido[1,4]benzodiazepines with the general 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-(C1~C4 alkyl), or R and R together with the adjacent; nitrogen atom form a 1-phthalimido-, 1-pyrrolidinyl-, 4-morpholino- or 1-piperidinyl -

res t,

alk"*" is a straight-chain or branched hydrocarbon chain containing 1-4 carbon atoms,

Ar and Z have the meanings given above,

and acid addition salts thereof.

The use of the new compounds according to the invention is also shown in reaction scheme 1 below.

Alternative methods for the preparation of certain compounds of formula I are indicated by reaction equations in reaction schemes 2 and 3.

Preparation of the new pyrido[1,4]benzodiazepine compounds is more fully exemplified in the following examples. Furthermore, the use of the compounds in the preparation of a therapeutically active compound is exemplified. The structures of the compounds in the examples are illustrated in Table 2.

Example 1

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

A mixture of 19.7 g (0.1 mol) of 2-aminobenzophenone and 15.0 g (0.12 mol) of 3-amino-2-chloropyridine was heated under a nitrogen atmosphere to 190°C for 1.75 hours. The mixture was cooled to room temperature and partitioned between 3N aqueous sodium hydroxide and methylene chloride. The combined methylene chloride extracts were washed with water, dried and magnesium sulfate and evaporated under reduced pressure. The residue, 32.7 g, was dissolved in benzene and chromatographed on a column of florisil packed in benzene, and eluted with benzene and 1-2% acetone-benzene mixtures. After evaporation, the solid material was crystallized from benzene to form 7.3 g of product with a melting point of 106 - 108°C.

Analysis: calculated, for Cl8H13<N>3: C 79.68 H 4.83 N 15.49

Found: C 79.70 H 4.81 N 15.42 Example 2

8-chloro-6-phenyl-IIH-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 at <1.> 200° C. (in a oil bath) for 0.75 hours under a nitrogen atmosphere. The mixture was cooled and methylene chloride was added. The mixture was stirred for 1 hour and then allowed to stand overnight. Brown solid precipitate weighing 8.7 g was separated by filtration. The filtrate was evaporated under reduced pressure. The residue was combined with the brown solid and partitioned between aqueous sodium hydroxide and methylene chloride, and impure product was isolated as described in Example 1, with the exception that the crystallization solvent was ethanol. Recrystallization from ethanol and drying overnight at 82°C/0.1 mmHg gave 3.0 g of product, m.p. 156.5 - 158.5° C.

Analysis: Calculated for C18H12C1N3:C 71.71 H 3.96 N 13.74

Found: C 70.24 H 4.01 N 13.76 Example 3

9- chloro- 6- phenyl- 11H- pyrldo[ 2, 3-b][ 1, 4] benzodiazepine

A suspension of 6.6 g (0.02 mol) [2-[(3-amino-2-pyridyl)amino]-4-chlorophenyl]-(phenyl)methanone (Intermediate 2) in 200 ml toluene was heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was filtered hot and the filtrate reheated to reflux temperature. The precipitate formed on cooling to room temperature was separated by filtration and recrystallized from benzene and dried for 4 hours at 97-98°C/0.1 mmHg and overnight at room temperature/0.1 mmHg to give 3.7 g of sm. p. 250.5 - 252° C. Elemental analysis for carbon was high and the product was dried again at 139° C (xylenes in drying gun) for 8 hours. Although the carbon analysis remained high, the proton nuclear magnetic resonance spectrum and mass spectrum were consistent with the proposed structure. Analysis: Calculated for C^H^Cl^: 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- llH- pyrido[ 2, 3- b]-[ 1, 4] benzodiazepine

Further elution of the florisil column in the preparation of Intermediate 4 with 10-15% acetone in benzene and 5-25% methanol in benzene gave two fractions of the title product according to this example, 6.4 g and 5.7 g, and the other mass was relatively impure. 6.4 g of fraction was recrystallized from benzene-isooctane to give 3.7 g of solid with m.p. 203 - 206°C (decomposition) which was identified by chemical ionization mass spectral analysis, "'"H and "^C NMR

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

Example 5

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

A mixture of 23.2 g (0.10 mol) 2-amino-4'-chloro-benzophenone and 14.7 g (0.11 mol) 3-amino-2-chloropyridine (96%) was heated in 1 1 /2 hours at 180° C under a nitrogen atmosphere. The mixture was cooled to room temperature and methylene chloride added. After stirring for 30 minutes, the solid material was separated by filtration and triturated in hot 95% ethanol. The remainder of the insoluble material was collected by filtration and recrystallized from benzene-isooctane to give 2.7 g of product m.p. 203 - 204.5° C. Drying conditions before the analyzes were: drying overnight at 9 7 - 9 8° C/0.1 mmHg.

Analysis: Calculated for ClgH12ClN3: C 70.71 H 3.96 N 13.74

Found: C 70.76 H 3.92 N 13.95 Example 6

6-(4-methylphenyl)-llH-pyrido[2,3-b][1,4jbenzodiazepine

A solution of 3.6 g (0.012 mol) [2-[(3-amino-2-pyridyl)amino]phenyl](4-methylphenyl)methanone in 100 ml of anhydrous toluene was treated with a catalytic amount of para-toluenesulfonic acid and boiled under reflux overnight while water was separated with a Dean-Stark trap. The reaction mixture was filtered hot. The product precipitated as the filtrate was cooled to room temperature, and was collected by filtration. Weight of the solid material after evaporation of the solvent was 2.5 g, m.p. 203.5 - 205° C (decomposition).

Analysis: Calculated for C19H15<N>3<:> C 79.98 H 5.30 N 14.73

Found: C 79.95 H 5.27 N 14.76 Example 7

6-(4-Methoxyphenyl)-HH-pyrido[2,3-b][1,4]benzodiazepine

A stirred mixture of 20.0 g (0.088 mol) 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mol) 3-amino-2-chloro-pyridine (96%) was heated to 180 °C under nitrogen atmosphere for 2 hours. The reaction mixture was cooled to approx. 70° C. and 100 ml of methylene chloride were added slowly. After the mixture was cooled to room temperature, an additional 50 ml of methylene chloride was added and the mixture was stirred overnight. The suspended solid was collected by filtration, air dried, dissolved in methanol and basified with 3N sodium hydroxide. The suspension was diluted with 500 ml water and extracted with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis by mass spectrum (EI and CI) indicated that the residue was a mixture of [2-[(3-amino-2-pyridyl)amino]phenyl](4-methoxy-phenyDmethanone and the title compound. The residue mixture was dissolved in 250 mL of toluene with a catalytic amount of para-toluenesulfonic acid, and the solution was refluxed overnight under a nitrogen atmosphere while water was separated in a Dean-Stark trap. The reaction mixture was filtered hot. The product precipitated as the filtrate cooled to room temperature and was collected by filtration. After recrystallization from benzene, the product weighed 1.8 g,

and had sm.p. 198.5 - 200.5° C (decomposition).

Analysis: Calculated for C19<H>15<N>30: C 75.73 H 5.02 N 13.94

Found: C 75.65 H 4.98 N 14.03 Example 8

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

A mixture of 14 g (0.0433 mol) of [2-[(3-amino-2-pyridinyl)amino]phenyl](3-chlorophenyl)-methanone and 0.3 g of para-toluenesulfonic acid in 500 ml of toluene was heated to overnight reflux using a Dean-Stark trap to collect water. At the end of the reflux time, some toluene (ca. 250 ml) was distilled off and the hot solution was filtered. Petroleum ether (30 - 60° C) was added to the boiling point. The solution was cooled overnight and filtered to give, after air drying, 10 g (76%) of gold-colored crystals. A portion was recrystallized from isopropyl alcohol-isopropyl ether, m.p. 160 - 160.5° C.

Analysis: Calculated for ClgH12<N>3Cl: C 70.71 H 3.96 N 13.74

Found : C 70.47 H 3.98 N 13.62

Example 9

6-(4-fluorophenyl)-llH-pyrido[2,3-b][1,4]benzodiazepine

A mixture of 11.5 g (0.037 mol) [2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone and 0.6 g of para-toluenesulfonic acid in toluene was refluxed for 24 hours using a Dean-Stark trap to collect water. At the end of the reflux, some of the toluene (300 mL) was distilled off and the hot solution was filtered. Petroleum ether (30 - 60° C) was added to the boiling point. The solution was cooled overnight (0° C.) and filtered to form 10.7 g of crystals. A portion of the material was recrystallized from isopropyl alcohol and dried in vacuo overnight at 65° C., m.p. 203 - 205° C. Analysis: Calculated for C18H12N3F: C 74.73 H 4.18 N 14.52

Found : C 74.61 H 4.17 N 14.54

Use in the preparation of the therapeutically active compound N/N-dimethyl-6-phenyl-IIH-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine-fumarate [1:1]

A suspension of 8.0 g (0.029 mol) 6-phenyl-11H-pyrido[2, 3-b]-[1,4]benzodiazepine in 20 ml of 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 mole) 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 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 311 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/0.1 mmHg.

Analysis: Calculated for C27<H2gH>4<0>4: C 68.63 H 5.97 N 11.86

Found : C 68.37 H 6.05 N 11.73

Claims (1)

Pyrido[1,4]-benzodiazepines, characterized in that they have the general formula wherein Ar is selected from the group consisting of phenyl or phenyl substituted with halogen, C₁-C₁ alkyl, C₁-C₁ alkoxy, trifluoromethyl or nitro, and Z is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.